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Facet Joint Disease

StatPearls-/- 2019; ():

Facet joints form from the superior and inferior articular processes of two adjacent vertebrae. They are synovial joints as a fibrous capsule encompasses the bone and articulating cartilage and is continuous with the periosteum. The joint also contains synovial fluid which is kept in place by an inner membrane. The function of these joints is to allow for flexion and extension of the spine while limiting rotation and preventing the vertebrae from slipping over each other. The sensory nerve of these joints is the medial branch of the dorsal spinal ramus. Facet joint disease, also known as facet syndrome, is a condition in which these joints become a source of pain. Facet joint mediated pain is a common source of disability amongst our population with significant economic impact. Chronic low back pain often results from facet joint disease, with a prevalence of 15 to 41%.[1]

*31082093*
 31082093

Cancer, T Cell Prolymphocytic Leukemia

StatPearls-/- 2019; ():

T-PLL (T Prolymphocytic leukemia) is mature and aggressive T-cell leukemias characterized by the proliferation of small to medium-sized prolymphocytes that show mature or post-thymic T cell phenotype. T-PLL involve peripheral blood (PB), bone marrow (BM), lymph nodes, liver, spleen, and skin. The name "prolymphocyte" is not accurate, as the tumor cells in this disease are of post-thymic T cell in origin.[1]

*31082044*
 31082044

Essential Thrombocytosis (Essential Thrombocythemia, ET)

StatPearls-/- 2019; ():

Essential thrombocytosis is also known as essential thrombocythemia (ET). It was first recognized in 1934; however, at that time, it was described as hemorrhagic thrombocythemia. Essential thrombocytosis is one of the myeloproliferative neoplasms. It was classified as a myeloproliferative neoplasm in 1951 by Damesheck.[1] Myeloproliferative neoplasm includes polycythemia vera, primary myelofibrosis, and essential polycythemia.[2] The three types of myeloproliferative neoplasm are similar as they share the same mutations. Approximately 55% of patients with essential thrombocytosis have the JAK2 mutation.[3] Essential thrombocytosis is characterized by thrombocytosis with the presence of megakaryocytic hyperplasia in the bone marrow. Due to thrombocytosis, there are risks of vascular events such as thrombosis and hemorrhage and sometimes the conversion to a blast phase of myelofibrosis.[4] According to the World Health Organization, essential thrombocytosis is a disease that occurs when the platelet count is more than 450000 with the presence of Janus kinase 2 (JAK2), Calreticulin (CALR) or myeloproliferative leukemia virus oncogene (MPL) mutation, lacking clonal or reactive causes.[5] This review article will focus on reviewing the etiology, epidemiology, pathophysiology, evaluation, and treatment of this disease.

*30969531*
 30969531

Cancer, Chondrosarcoma

StatPearls-/- 2019; ():

Chondrosarcomas are malignant cartilaginous neoplasms with diverse morphological features and clinical behavior. They account for about 20% of all primary malignant tumors of the bone [1]. They usually arise in the pelvis or long bones [2]. Primary or conventional chondrosarcoma arises in preexisting normal bone and is distinguished from the rarer secondary tumors, which occur in a preexisting enchondroma or osteochondroma [1]. Conventional chondrosarcoma which accounts for 85-90% of chondrosarcomas is subdivided into the central, periosteal and peripheral subgroups [3]. Non-conventional chondrosarcoma variants include clear cell chondrosarcoma, mesenchymal chondrosarcoma and dedifferentiated chondrosarcoma [3]. The radiographic features of chondrosarcoma are often very characteristic, and a definitive diagnosis can usually be made by imaging examination alone.

*30844159*
 30844159

Cancer, Telangiectatic Osteosarcoma

StatPearls-/- 2019; ():

Telangiectatic osteosarcoma is a rare high-grade malignant neoplasm, accounting for less than 4% of all cases of osteosarcoma.[1] It is a rare variant of osteosarcoma characterized by distinctive radiographic, gross, and microscopic features. It is a bone-forming tumor which mimics radiologically and microscopically aneurysmal bone cyst.

*30725994*
 30725994

Renal Oncocytoma

StatPearls-/- 2019; ():

Renal oncocytomas are common benign kidney neoplasms that account for 3% to 7% of all renal neoplasms.[1] They usually occur in adults, most frequently in the seventh decade of life. Renal oncocytomas may be discovered incidentally or may be diagnosed on biopsy or excision. Oncocytomas have a classic gross appearance of a well-circumscribed tan or mahogany colored mass with a stellate central scar. Histologically they classically appear as well-circumscribed lesions with nested architecture, bland cytology, regular nuclei with prominent central nucleoli, and eosinophilic cytoplasm.[2] Despite the classic appearance, there are several entities that mimic oncocytoma so diagnosis remains a challenge. Diagnosis is primarily made based on histologic appearance and, in challenging cases, with immunohistochemistry. Rarely cytogenetic studies may be useful.[2] Renal oncocytomas usually have an excellent prognosis and are not associated with an aggressive clinical course; however, there can occasionally be metastasis to liver and bone and fatalities have occurred. Surgical excision is curative if there have not been metastases.[3]

*30725948*
 30725948

Cancer, Lymphoblastic Lymphoma

StatPearls-/- 2019; ():

Acute leukemia accounts for up to 30% of all childhood malignancies. Acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) is a clonal hematopoietic stem cell disorder of B or T cell origin. The World Health Organization (WHO) 2017 classification system categorizes these disease entities under precursor lymphoid neoplasm. The WHO 2017 classification of precursor lymphoid neoplasm includes 4 distinct entities: B-ALL/LBL not otherwise specified (NOS); B-ALL/LBL with recurrent genetic abnormalities; T-ALL/LBL; and NK-ALL/LBL. Lymphoblasts are the characteristic cells of this disease entity. The lymphoblasts are usually small to medium-sized with scant cytoplasm, moderately condensed to dispersed chromatin and inconspicuous nucleoli. The lymphoblasts traditionally involve the bone marrow (BM) and/or blood in ALL and involve the lymph nodes in LBL. The diagnosis is of ALL is rendered when the blast count exceeds 20%. Occasionally, patients present with primary lymph node involvement of nodal or extranodal sites (LBL). Sometimes, there is an overlap between ALL and LBL, and it has been widely accepted to render a combined diagnosis. NK-ALL/LBL is a currently a provisional entity in the WHO 2017 classification. It is a rare entity, and diagnosis often overlaps with T-ALL/LBL. ALL is one of the earliest neoplasms where chemotherapeutic treatment showed a favorable outcome. It has also been one of the earliest neoplastic disease entities where the understanding of biology has led to direct changes in the management of patients.[1][2]

*30725922*
 30725922

Cancer, Osteoblastoma

StatPearls-/- 2019; ():

Osteoblastoma is an uncommon benign bone-forming neoplasm which accounts for about 1% of all primary bone tumors. It commonly arises in the posterior elements of the spine and the sacrum. Accurate diagnosis of osteoblastoma is critical in determining the appropriate treatment modality and prognosis. In most cases, the basis for diagnosis is from clinical, radiological and mainly histopathological examination. Osteoblastomas have a variable radiologic appearance ranging from indolent to very aggressive.[1] In general, osteoblastoma has a good prognosis, and patients are often cancer free after surgical treatments of intralesional curettage or marginal en bloc resection.[2]

*30725639*
 30725639

Hematopoietic Stem Cell Transplantation

StatPearls-/- 2019; ():

Bone marrow transplant (hematopoietic stem cell transplant) (HPSCT) involves the administration of healthy hematopoietic stem cells in patients with dysfunctional or depleted bone marrow. This helps to augment bone marrow function and allows, depending on the disease being treated, to either destroy tumor cells with malignancy or to generate functional cells that can replace the dysfunctional ones in cases like immune deficiency syndromes, hemoglobinopathies, and other diseases. History and Evolution Hematopoietic stem cell transplantation (HSCT) was first explored in humans in the 1950s and was based on observational studies in mice models which showed that infusion of healthy bone marrow components into a myelosuppressed bone marrow could induce recovery of its function in the recipient.[1] These animal-based studies soon found their clinical application into humans when the first successful bone marrow transplant was performed in monozygotic twins in New York in 1957 (syngeneic transplant) in a patient with acute leukemia.[2] As a result, the physician Dr. Thomas who performed the procedure continued his research on the development of bone marrow transplantation and later received the Nobel Prize of physiology and medicine in appreciation of his work. The first successful allogeneic bone marrow transplant was reported in Minnesota in 1968 for a pediatric patient with severe, combined immunodeficiency syndrome.[3] Since then, allogeneic and autologous stem cell transplant has increased in the United States and worldwide. The Center for International Blood and Marrow Transplant Research (CIBMTR) reported over 8000 allogenic transplants performed in the United States in 2016 with a higher number of autologous transplants with a steady and higher increase of autologous compared to allogenic.[4] Definitions Major Histocompatibility Complex (MHC) The group of genes on the short arm of chromosome 6 (p6) that encodes human leukocyte antigens (HLA) which are considered being highly polymorphic leading to a large difference in the resultant expressed proteins on human cells. They are divided into MHC I and MHC II Human Leukocyte Antigens (HLA) These are the proteins expressed on the cellular surface and play an important role in alloimmunity. HLA can be divided into (HLA-A, B, and C) which are encoded by class I MHC and are expressed on all cell types and present peptides derived from the cytoplasm and are recognized by CD8+ T cells. The other HLA type is classified as (HLA- DP, DQ, and DR) which are encoded by MHC II and can be found on antigen-presenting cells (APCs) and this class is recognized by CD4+ T cells. Syngeneic Bone Marrow Transplantation The donor and the recipient are identical twins. The advantages include no graft versus host disease (GVHD) and no graft failure. However, only a tiny number of transplant patients will have the ability to have an identical twin for transplantation. Autologous Bone Marrow Transplantation The bone marrow products are collected from the patient and are reinfused after purification methods. The advantages include no GVHD. The disadvantage is that the bone marrow products may contain abnormal cells that can cause relapse in the case of malignancy hence; theoretically, this method cannot be used in all cases of abnormal bone marrow diseases. Allogenic Transplantation The donor is an HLA matched family member, unrelated matched donor or mismatched family donors (haploidentical). Engraftment The process of which infused transplanted hematopoietic stem cells produce mature progeny in the peripheral circulation Preparative Regimen This is a regimen that comprises high-dose chemotherapy and/or total body irradiation (TBI) which are administered to the recipient prior to stem cell infusion to eliminate the largest number of malignant cells and to allow for immunosuppression in the recipient so that engraftment can occur.

*30725636*
 30725636

Cancer, Chondroblastoma

StatPearls-/- 2019; ():

Chondroblastoma is a benign, chondroid-producing neoplasm composed of chondroblasts. It accounts for less than 1% of all bone tumors and usually arises in the epiphyses or apophysis of skeletally immature patients.[1] The treatment of choice of chondroblastoma is surgical. In general, chondroblastoma has a good prognosis, and patients often experience full resolution after surgical treatment.

*30725632*
 30725632

Peutz-Jeghers Syndrome

StatPearls-/- 2019; ():

Peutz-Jeghers syndrome (PJS) is a hereditary cancer syndrome characterized by gastrointestinal (GI) polyposis, mucocutaneous pigmented macules, and cancer predisposition. Patients with Peutz-Jeghers syndrome are at an increased risk for developing GI cancers of the colorectal, pancreatic, and gastric organs in addition to a wide variety of non-GI epithelial malignancies such as breast, uterine, and cervical cancers, lung cancer, and tumors of the ovaries and testicles. Among the various malignancies, colorectal is most common with a lifetime risk of 39%. Followed by breast cancer in females with a lifetime risk of 32% to 54%. Females with Peutz-Jeghers syndrome are also at risk for gynecological cancers such as benign ovarian sex cord tumors with annular tubules (SCTATs) and mucinous tumors of the ovaries and fallopian tubes. Males with Peutz-Jeghers syndrome are at risk of Sertoli cell tumors of the testes, which are often hormonally active, secreting estrogen. Males present with gynecomastia, advanced bone age, and rapid growth with short stature. Due to the increased risk for various malignancies, diligent surveillance is recommended.[1]

*30570978*
 30570978

Myelodysplastic Syndrome

StatPearls-/- 2019; ():

Myelodysplastic syndrome (MDS) is a heterogeneous group of hematologic neoplasms classically described as a clonal disorder of hematopoietic stem cells leading to dysplasia and ineffective hematopoiesis in the bone marrow. Some patients with MDS may have a transformation into acute myeloid leukemia (AML). MDS is usually diagnosed in older patients over the age of 65. Clinical manifestations include a decrease in the number of red blood cells (RBC), platelets, and white blood cells (WBC). The disease course is variable. Not all patients require treatment initially, as there is no survival benefit with the treatment of asymptomatic, low-risk patients. Treatment is reserved for symptomatic patients, such as those requiring frequent blood transfusions. Prognosis and overall survival depend upon multiple factors such as the severity of cytopenias, the percentage of blasts in the peripheral blood and bone marrow, and karyotype.

*30480932*
 30480932

Vitamin D Deficiency

StatPearls-/- 2019; ():

Vitamin D is a fat-soluble vitamin used by the body for normal bone development and maintenance by increasing the absorption of calcium, magnesium, and phosphate. A circulating level of 25-hydroxyvitamin D greater than 30 ng/mL is required to maintain a healthy level of vitamin D. About 1 billion people worldwide have vitamin D deficiency.[1] Vitamin D deficiency can lead to an array of problems, most notably rickets in children and osteoporosis in adults. The fortification of milk with vitamin D in the 1930s was effective in eradicating rickets in the world. However, vitamin D deficiency is now more prevalent than ever and should be screened in high-risk populations. Many conflicting studies are now showing an association between vitamin D deficiency and cancer, cardiovascular disease, diabetes, autoimmune diseases, and depression.[2]

*30335299*
 30335299

Cancer, Myeloproliferative Neoplasms

StatPearls-/- 2019; ():

Hematopoietic pluripotent stem cells have self-renewal capability and give rise to either myeloid or the lymphoid lineage which further differentiates into various mature blood cells such as red blood cells (RBC), lymphocytes, granulocytes, megakaryocytes, and macrophages. The hematopoietic process is determined by the bone marrow environment, growth factors, and transcription factors. The abnormal proliferation of one or more terminal myeloid cell lines in the peripheral blood gives rise to a heterogeneous group of disorders called myeloproliferative neoplasms. In 1951, William Dameshek coined the term myeloproliferative disorders which are now reformed to myeloproliferative neoplasms (MPNs) by the World Health Organization (WHO). Chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are four classic types of myeloproliferative neoplasms. WHO classification also included chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia (CEL), and MPN, unclassifiable.[1] Out of the classic types of MPNs, CML is BCR-ABL1 positive, but PV, ET, and PMF are BCR-ABL1 negative. Besides, the fourth edition of WHO classification for myeloid and acute leukemia was revised in 2016 due to recent advances in hematology with the identification of molecular markers and prognostic markers, giving a better understanding of the molecular pathogenesis and genetics of the hematological malignancies.[2]

*30285359*
 30285359

Cancer, Chronic Myelogenous Leukemia (CML, Chronic Granulocytic Leukemia)

StatPearls-/- 2019; ():

Chronic myeloid leukemia (CML), BCR-ABL1-positive is classified as a myeloproliferative neoplasm predominantly composed of proliferating granulocytes and determined to have the Philadelphia chromosome/translocation t(9;22)(q34;q11.2). CML affects both the peripheral blood and the bone marrow.

*30285354*
 30285354

Cancer, Lymphoplasmacytic Lymphoma (Waldenstrom Macroglobulinemia)

StatPearls-/- 2019; ():

Lymphoplasmacytic lymphoma, or Waldenstrom macroglobulinemia, is a low-grade B cell lymphoproliferative neoplasm characterized by small lymphocytes and monoclonal IgM monoclonal gammopathy. The disorder presents with symptoms related to bone marrow infiltration and IgM monoclonal gammopathy. Lymphoplasmacytic lymphoma is a diagnosis of exclusion; a diagnosis should only be rendered after the exclusion of all other small B cell lymphomas. Waldenstrom macroglobulinemia was described in 1944 by Jan G. Waldenstrom, who reported an unusual presentation of lymphadenopathy bleeding, anemia, elevated sedimentation rate, hyperviscosity, and hypergammaglobulinemia in two patients [1][2][3].

*30020728*
 30020728

Monoclonal Gammopathy Of Undetermined Significance (MGUS)

StatPearls-/- 2019; ():

Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant plasma cell disorder that is characterized by the presence of serum M-protein less than 30 g/L, bone marrow (BM) clonal plasma cells less than 10%, absence of plasma cell myeloma (PCM) related end-organ damage (CRAB symptoms: hypercalcemia, renal insufficiency, anemia and, bone lesions) and absence of B-cell lymphoma or other disease known to produce an M-protein. MGUS is generally considered a preneoplastic disorder that does not always progress to overt malignancy [1]There are 2 distinct types of MGUS [2]: 1. Non-IgM MGUS. 2. IgM MGUS: Non-IgM MGUS (IgG, IgA, IgD or light chain (LC) MGUS) accounts for the majority of MGUS cases and is characterized by a monoclonal plasma cell. Non-IgM MGUS may progress to a malignant plasma cell neoplasm. IgM MGUS is considered a separate entity by the 2017 WHO classification. IgM MGUS may progress to Waldenstrom macroglobulinemia, immunoglobulin light chain (AL) amyloidosis, or lymphoma. Light chain MGUS is characterized by a monoclonal protein that lacks the immunoglobulin heavy chain component. LC-MGUS may show progression to idiopathic Bence Jones proteinuria, light chain PCM, AL amyloidosis, or light chain deposition disease [3]

*29939657*
 29939657

Cancer, Acute Myeloid Leukemia (AML, Erythroid Leukemia, Myelodysplasia-Related Leukemia, BCR-ABL Chronic Leukemia)

StatPearls-/- 2019; ():

Acute myeloid leukemia (AML) is the most common leukemia among the adult population and accounts for about 80% of all cases. It is characterized by clonal expansion of immature "blast cells" in the peripheral blood and bone marrow resulting in ineffective erythropoiesis and bone marrow failure. With recent advancements in the management guidelines, the cure rates have increased up to 15% in patients older than 60 years and about 40% in patients below 60 years of age. Despite advancements in therapeutic regimens, the prognosis remains very poor in the elderly population.[1][2][3]

*29939652*
 29939652

Cancer, Hairy Cell Leukemia

StatPearls-/- 2019; ():

Hairy cell leukemia (HCL) is a relatively rare chronic B-cell malignancy that involves the bone marrow, spleen, and peripheral blood. The complete blood count may reveal pancytopenia including monocytopenia. Median age at diagnosis is approximately 55. Poor prognostic features, while somewhat variable in the literature, may include age, hemoglobin less than 10, platelets less than 100, ANC less than 1000, the presence of lymphadenopathy, and massive splenomegaly. Differential diagnosis includes other B-cell lymphoproliferative disorders, including splenic marginal zone lymphoma. A distinct entity is known as hairy cell leukemia variant (HCL-V), which is biologically unique from HCL also exists. Response to typical HCL in this disease is poor. The variant can be identified by immunophenotypic differences, lack of BRAF mutation, and lack of monocytopenia.[1][2] HCL accounts for 2% of all leukemias with approximately 1000 new cases being reported in the United States each year.

*29763020*
 29763020

Cancer, Prostate

StatPearls-/- 2019; ():

Worldwide, prostate cancer is the most commonly diagnosed malignancy and the sixth leading cause of cancer death in men.[1] In 2012, this amounted to 1,100,000 newly diagnosed cases and 307,000 deaths around the world from this disease.[2] Fortunately, the majority of prostate cancers tend to grow slowly and are low-grade with relatively low risk and limited aggressiveness.[3] There are no initial or early symptoms in most cases, but late symptoms may include fatigue due to anemia, bone pain and paralysis from spinal metastases, and renal failure from bilateral ureteral obstruction. Diagnosis is primarily based on prostate-specific antigen (PSA) testing, and transrectal ultrasound-guided (TRUS) prostate tissue biopsies, although PSA testing for screening remains controversial.[4][5] Newer diagnostic modalities include free and total PSA levels, PCA3 urine testing, Prostate Health Index scoring (PHI), the"4K" test, genomic analysis, MRI imaging, PIRADS scoring, and MRI-TRUS fusion guided biopsies.[6] When the cancer is limited to the prostate, it is considered localized and potentially curable.[7] If the disease has spread to the bones or elsewhere outside the prostate, pain medications, bisphosphonates, rank ligand inhibitors, hormonal treatment, chemotherapy, radiopharmaceuticals, immunotherapy, focused radiation, and other targeted therapies can be used. Outcomes depend on age, associated health problems, tumor histology and the extent of cancer.[8]

*29261872*
 29261872

Cancer, Acute Promyelocytic Leukemia (APL, APML)

StatPearls-/- 2019; ():

Acute promyelocytic leukemia is a distinguished subset of acute myeloid leukemia which is characterized by fusion gene transcript PML-RAR-alpha and high cure rates with treatment. This entity was first described in 1957 in patients with severe bleeding tendencies with fibrinolysis, rapid deterioration of the clinical condition, and the presence of promyelocytes in peripheral blood and bone marrow.[1][2][3]

*29083825*
 29083825

Doxorubicin

StatPearls-/- 2019; ():

Doxorubicin is an antibiotic derived from the Streptomyces peucetius bacterium. It has wide use as a chemotherapeutic agent since the 1960s. Doxorubicin is part of the anthracycline group of chemotherapeutic agents; other anthracyclines include daunorubicin, idarubicin, and epirubicin. Commonly, doxorubicin is used in the treatment of solid tumors in adult and pediatric patients. Doxorubicin may be used to treat soft tissue and bone sarcomas as well as cancers of the breast, ovary, bladder, and thyroid. It is also used in the treatment of acute lymphoblastic leukemia, acute myeloblastic leukemia, Hodgkin lymphoma, and small cell lung cancer. The liposomal formulation of doxorubicin is FDA-approved for the treatment of ovarian cancer in patients who have failed platinum-based chemotherapy, AIDS-related Kaposi sarcoma, and multiple myeloma.[1][2][3][4]

*29083582*
 29083582

Cancer, Acute Lymphocytic Leukemia (ALL)

StatPearls-/- 2019; ():

Acute Lymphocytic Leukemia (ALL) is a malignancy of B or T lymphoblasts characterized by uncontrolled proliferation of abnormal, immature lymphocytes and their progenitors which ultimately leads to the replacement of bone marrow elements and other lymphoid organs resulting in a typical disease pattern characteristic of Acute Lymphocytic Leukemia. ALL accounts for approximately 2 percent of the lymphoid neoplasms diagnosed in the United States. Acute Lymphocytic Leukemia occurs slightly more frequently in males than females, and three times as frequently in Whites as in Blacks. Patients with Acute Lymphocytic Leukemia typically present with symptoms related to anemia, thrombocytopenia, and neutropenia due to the replacement of the bone marrow with tumor. Symptoms can include fatigue, easy or spontaneous bruising/bleeding, and infections. B-symptoms, such as fever, night sweats, and unintentional weight loss are often present, but may be mild. Hepatomegaly, splenomegaly, and lymphadenopathy can be seen in up to half of adults on presentation. Central nervous system (CNS) involvement is common and can be accompanied by cranial neuropathies or symptoms, predominantly meningeal, related to increased intracranial pressure.[1][2][3]

*29083572*
 29083572

Cancer, Spinal Metastasis

StatPearls-/- 2019; ():

Spinal metastases are the most common tumors of the spine, compromising approximately 90% of masses encountered with spinal imaging. Spinal metastases are more commonly found as bone metastasis, although they are not limited to bone metastasis, and approximately 20% present with symptoms of spinal canal invasion and cord compression. Within the spinal column, metastasis is more commonly found in the thoracic region, followed by the lumbar region, while the cervical region is the least likely place professionals find metastasis [1]. When evaluating spinal metastasis on MRI imaging, a defining feature of these lesions is the sparing of intervertebral disc space. This disc space is almost always involved during an infection. Metastatic diseases to the spine spread through several different routes which include venous hematogenous spread versus the arterial spread, direct tumor extension, and lastly lymphatic spread. Among the routes mentioned above, hematogenous spread through Batson's plexus system is the most common pathway for tumor embolization and spinal invasion. The following summary emphasizes the essential knowledge necessary to have while treating patients with spinal metastasis [2][3].

*28722979*
 28722979

WHO Guidelines for the Pharmacological and Radiotherapeutic Management of Cancer Pain in Adults and Adolescents

WHO Guidelines for the Pharmacological and Radiotherapeutic Management of Cancer Pain in Adults and Adolescents-/-WHO Guidelines Approved by the Guidelines Review Committee 2018; ():

Cancers are among the leading causes of morbidity and mortality worldwide, responsible for 18.1 million new cases and 9.6 million deaths in 2018. Pain is experienced by 55% of patients undergoing anti-cancer treatment and by 66% of patients who have advanced, metastatic, or terminal disease. This can be relieved in most cases through medicines and other treatments. The World Health Organization (WHO) has developed Guidelines for the pharmacologic and radiotherapeutic management of cancer pain in adults and adolescents to provide evidence-based guidance to initiating and managing cancer pain. The aims of these guidelines are to provide guidance to health-care providers (i.e. the end-users of these guidelines: physicians, nurses, pharmacists and caregivers) on the adequate relief of pain associated with cancer. They also assist policy-makers, programme managers and public health personnel to create and facilitate appropriately balanced policies on opioids and prescribing regulations for effective and safe cancer pain management. Proper and effective stewardship of opioid analgesics in the cancer treatment setting is essential to ensure the safety of patients and to reduce the risk of diversion of medicine into society. The goal of cancer pain management is to relieve pain to a level that allows for an acceptable quality of life. The last set of WHO guidelines focused on cancer pain management were issued in 1996. The clinical guidelines and recommendations in this document are organized into three focal areas: Analgesia of cancer pain: This addresses the choice of analgesic medicine when initiating pain relief and the choice of opioid for maintenance of pain relief, including optimization of rescue medication, route of administration, and opioid rotation and cessation. Adjuvant medicines for cancer pain: This includes the use of steroids, antidepressants and anticonvulsants as adjuvant medicines. Management of pain related to bone metastases: This incorporates the use of bisphosphonates and radiotherapy to manage bone metastases.

*30776210*
 30776210

Determining the Crystal Structure of TRPV6

Calcium Entry Channels in Non-Excitable Cells-/- 2018; (): 275-292

Calcium ions play important roles in many physiological processes, including neurotransmitter release, excitation-contraction coupling, cell motility, and gene expression [1]. Cellular calcium levels are precisely tuned by various channels and transporters. Transient receptor potential (TRP) channels, which are generally nonselective cation channels, conduct Ca(2+) in response to disparate activators, including sensory stimuli such as temperature, touch, and pungent chemicals [2]. Members 5 and 6 of vanilloid subfamily (TRPV5 and TRPV6, previously named ECaC1 and ECaC2/CaT1, respectively) are uniquely Ca(2+)-selective (PCa/PNa > 100) [3,4] TRP channels, both of which were identified in 1999 by expression cloning strategies utilizing cDNA libraries from rabbit kidney [5] and rat duodenum [6], respectively. While TRPV5 expression is mainly restricted to the kidney, TRPV6 is expressed in various tissues including the stomach, small intestine, prostate, esophagus, colon, and placenta. Genetic knockout of TRPV5 or TRPV6 in mice suggests the importance of these channels for Ca(2+) homeostasis. TRPV5 knockout mice showed defects in renal Ca(2+) reabsorption and reduced bone thickness [7], and the knockout of TRPV6 resulted in defective intestinal calcium absorption, decreased bone mineral density, reduced fertility, and hypocalcemia when challenged with a low Ca(2+) diet [8]. Further support for the role of these channels in Ca(2+) absorption and homeostasis stems from the robust regulation of their expression by the calciotropic hormone vitamin D [9-12] (see Chapter 13). TRPV6 has been shown to be aberrantly expressed in numerous cancer types, including carcinomas of the colon, prostate, breast, and thyroid [13-18]. The correlation between TRPV6 expression and tumor malignancy and its potential contribution to cancer cell survival has highlighted TRPV6 as a target for cancer diagnosis and treatment [15,17,19,20]. Indeed, a selective inhibitor of TRPV6 activity derived from northern short-tailed shrew venom [21] has entered phase I clinical trials in patients with advanced solid tumors of tissues known to express TRPV6, including the pancreas and ovary [22]. Structurally, TRPV5 and TRPV6 share approximately 75% sequence identity with each other and are approximately 25% identical to the founding member of the TRPV subfamily TRPV1. The transmembrane (TM) domain has the same topology as tetrameric K(+) channels [23], with six TM helices (S1-S6) and a pore-forming re-entrant loop between the S5 and S6. Importantly, this loop contains a conserved aspartate residue that is critical for the calcium permeability of TRPV5 and TRPV6 [24,25], suggesting that this residue at least in part comprises the selectivity filter. Flanking the TM domain are relatively large intracellular N- and C-termini. The N-terminus, which includes six ankyrin repeats [26], is critical for proper channel assembly and function [27,28], while the C-terminus contains domains involved in Ca(2+)/calmodulin-dependent inactivation [29-31] (see Chapter 13). To help understand the functional mechanisms of TRPV5/6 and potentially inform rational drug design, we sought to obtain a high-resolution structure of an intact channel. Until several years ago, the only viable method of obtaining such a structure was x-ray crystallography. However, producing well-diffracting crystals can be a notoriously difficult and resource-consuming process because membrane proteins typically have low expression and purification yields, poor stability in detergent, and inherent flexibility [32]. However, structural biologists are now able to circumvent this major bottleneck, owing to recent advances in single-particle cryo-electron microscopy (cryo-EM), which have facilitated the determination of membrane protein structures at near-atomic resolutions without prior crystallization [33]. These advances have had a particularly profound effect on the TRP channel field, as atomic-level cryo-EM structures have been determined for TRPV1 [34-36]; TRPV2 [37,38]; and ankyrin subfamily member [39]. The ability to computationally select specific conformational states from a heterogeneous cryo-EM sample can be especially powerful when studying mechanisms of gating, as exemplified by studies of TRPV1 in various ligand-induced conformations [34-36]. Cryo-EM will surely continue to be exploited with great effect to elucidate structures of TRP channels and other membrane proteins. As yet, there are several benefits that may make obtaining an x-ray structure desirable over cryo-EM. First, crystallographers can use true statistical approaches such as the Free R value [40] to evaluate the accuracy of atomic models against experimental data, while analogous methods in cryo-EM [41-43] are still relatively nascent. Second, the resolution of a cryo-EM map usually varies widely across a single reconstruction, with more flexible regions, typically in the periphery, being less resolved or completely absent. For example, in TRPV1, while the TM domain is well resolved, the first two ankyrin repeats at the distal N-terminus are missing from the electron density maps [34-36], presumably due to their flexibility (Figure 14.1a). In x-ray structures, the resolution obtained from the diffraction data is more representative of the structure as a whole, and peripheral or flexible regions may be stabilized by crystal contacts and thus adequately resolved (Figure 14.1b). Third and perhaps most importantly, the position of anomalous scatterers, such as selenium atoms in selenomethionine-labeled protein, sulfur atoms in native cysteine or methionine side chains, or heavy atoms bound to the protein, can be accurately identified with little ambiguity. Anomalous scattering can therefore be utilized to robustly aid or validate sequence registry (Figure 14.1c), which is especially important for low-resolution structures and/or regions with poor electron density. Using anomalous scattering to identify bound ions is particularly useful for studying ion channel structures, as ion binding at specific locations is vital for understanding permeation and ion channel block. For TRPV6, we used these techniques to identify binding sites for the permeant cations Ca(2+) and Ba(2+), as well as the channel blocker Gd(3+) (Figure 14.1d through g). Methods to unambiguously identify specific atoms or small labels in cryo-EM electron density maps have yet to be developed. We were motivated by each of these factors as we attempted to crystallize TRPV5/6 in the midst of the cryo-EM "resolution revolution." In 2016, we reported the crystal structure of intact rat TRPV6 at 3.25 A resolution [44]. To our knowledge, this represented the first crystal structure of a TRP channel and the second crystal structure of a naturally occurring Ca(2+)-selective channel, after the structure of the calcium release-activated calcium (CRAC) channel Orai reported in 2012 [45]. A detailed description of the TRPV6 structure can be found elsewhere [44]. In this chapter we will focus on the multiyear journey taken to determine the structure, in which >150 constructs were purified and subjected to crystallization screening, and thousands of crystals were tested for diffraction. We will summarize the methods used to screen constructs and precrystallization conditions, express and purify protein, grow and optimize crystals, and collect and analyze diffraction data. Finally, we will briefly compare the structural bases of Ca(2+)-selective permeation in TRPV6 and Orai.

*30299652*
 30299652

Some Industrial Chemicals

Some Industrial Chemicals-/-IARC Monographs on the Evaluation of Carcinogenic Risks to Humans 2018; ():

This volume of the IARC Monographs provides evaluations of: N,N-dimethylformamide, a solvent produced in high volumes and commonly used in many industrial processes; 2-mercaptobenzothiazole, a rubber accelerant and preservative; the rocket fuel hydrazine; the widely used fire retardant tetrabromobisphenol A; 1-bromopropane, a solvent used in dry cleaning, degreasing and adhesive resins; the seed fumigant 3-chloro-2-methylpropene; and N,N-dimethyl-p-toluidine, a hardening agent in dental and bone adhesives. Exposure to all seven agents considered may occur in the general population as well as in different occupational settings. An IARC Monographs Working Group reviewed epidemiological evidence, animal bioassays, and mechanistic and other relevant data to reach conclusions as to the carcinogenic hazard to humans of environmental or occupational exposure to these agents.

*29863829*
 29863829

Radium-223 for Patients with Castration Resistant Prostate Cancer with Bone Metastases: A Review of Clinical Effectiveness, Cost-effectiveness and Guidelines

Radium-223 for Patients with Castration Resistant Prostate Cancer with Bone Metastases: A Review of Clinical Effectiveness, Cost-effectiveness and Guidelines-/-CADTH Rapid Response Reports 2016; ():

The aim of this report is to review the clinical effectiveness, cost-effectiveness, and evidence-based guidelines of radium-223 (Ra-223) in patients with bone metastatic castration-resistant prostate cancer (mCRPC).

*27929625*
 27929625

Denosumab versus Zoledronic Acid for Men with Osteoporosis: A Review of Clinical Effectiveness and Guidelines

Denosumab versus Zoledronic Acid for Men with Osteoporosis: A Review of Clinical Effectiveness and Guidelines-/-CADTH Rapid Response Reports 2016; ():

There is a need to determine if there is a preferred non-oral agent to increase bone mineral density (BMD) in men with osteoporosis, particularly for cases when patients have failed on or cannot tolerate oral bisphosphonates, for patients with comorbidities that may affect choice of therapy, or for men with early prostate cancer undergoing androgen-deprivation therapy (ADT). In 2015, denosumab (Prolia) was evaluated by the CADTH Common Drug Review (CDR) for the treatment of osteoporosis in men, but zoledronic acid has not been reviewed by CDR for this indication. The Canadian Drug Expert Committee (CDEC) noted that at the time of the CDR review, there were no direct comparisons of denosumab with other therapeutic agents approved for the treatment of men with osteoporosis. The purpose of this report is to evaluate the comparative clinical effectiveness of denosumab and zoledronic acid for the treatment of men with osteoporosis, including men with non-metastatic prostate cancer who are receiving ADT, and to identify evidence-based guidelines for the use of these agents for these indications.

*28121108*
 28121108

Denosumab (Xgeva)

Denosumab (Xgeva)-/-CADTH Common Drug Reviews 2016; ():

Bone is a common site of metastasis for many cancers including breast, prostate, thyroid, lung, renal, and melanoma. Skeletal metastatic disease is the cause of considerable morbidity in patients with advanced cancer and has been associated with an increase in cancer-related pain, hypercalcemia, fractures, spinal instability, and compression of the spinal cord. Denosumab is a human monoclonal antibody binding to human receptor activator of nuclear factor kappa-B ligand (RANKL). Denosumab has a Health Canada indication for reducing the risk of developing skeletal-related events (SREs) in patients with bone metastases from breast cancer, prostate cancer, non-small cell lung cancer, and other solid tumours. Denosumab is not indicated for reducing the risk of developing SREs in patients with multiple myeloma. The drug plans that participate in the CADTH Common Drug Review (CDR) process have requested that denosumab be evaluated for reimbursement for reducing the risk of developing SREs in patients with bone metastases from solid tumours (except breast and prostate cancer). The objective of this report was to perform a systematic review of the beneficial and harmful effects of denosumab for reducing the risk of developing SREs in patients with bone metastases from solid tumours (except from breast cancer or prostate cancer).

*28121111*
 28121111

Imaging for the Pretreatment Staging of Small Cell Lung Cancer

Imaging for the Pretreatment Staging of Small Cell Lung Cancer-/-AHRQ Comparative Effectiveness Reviews 2016; ():

OBJECTIVES: For small cell lung cancer (SCLC), several imaging modalities can be used to determine cancer staging, which is important to ensure optimal management. Our aim was to synthesize the literature on whether some imaging modalities are better than others for the pretreatment staging of small cell lung cancer. We searched for evidence on comparative accuracy (sensitivity, specificity) as well as subsequent clinical outcomes (choice of treatment, survival, and quality of life). DATA SOURCES: We searched EMBASE, MEDLINE, PubMed, and the Cochrane Library from 2000 through June 15, 2015, for full-length articles on the use of multidetector computed tomography (MDCT), positron emission tomography/computed tomography (PET/CT), magnetic resonance imaging (MRI), combined PET/MRI, endobronchial ultrasound (EBUS), endoscopic ultrasound with fine-needle aspiration (EUS-FNA), and bone scintigraphy in the pretreatment staging of small cell lung cancer. REVIEW METHODS: We included studies of pertinent imaging tests on SCLC patients before treatment that reported one or more of the outcomes of interest (studies did not have to directly compare two or more imaging modalities). We extracted data from the included studies and constructed evidence tables. Comparative outcomes of interest included test concordance, staging accuracy (sensitivity and specificity), choice of treatment, timeliness of treatment, tumor response, harms due to overtreatment or undertreatment, survival, and quality of life. For each pair of tests and each assessed aspect (e.g., determination of metastases), we determined whether the evidence was sufficient to permit a conclusion of a difference, a conclusion of similar accuracy, or neither (i.e., insufficient). We rated the risk of bias of individual studies using an internal validity instrument and graded the overall strength of evidence of conclusions using Evidence-Based Practice Center guidance. RESULTS: The searches identified 2,880 citations; after screening against the inclusion criteria, we included seven primary studies that enrolled a total of 408 patients. Six of the seven studies were deemed moderate risk of bias (principally due to failure to report on patient selection, reader blinding to results of comparator tests, and possible spectrum bias), and one was deemed high risk of bias (due to failure to blind readers to results of comparator tests and presence of spectrum bias). One of the studies reported test concordance, three studies reported the comparative accuracy of two or more testing strategies (one of which had also reported test concordance), and four studies reported the accuracy of a single imaging modality. Staging determinations included limited versus extensive disease, osseous (bone or bone marrow) metastases, lymph node involvement, liver metastases, spleen metastases, adrenal metastases, brain metastases, and any distant metastases. The most frequently reported imaging tests were MDCT, [(18)F]-fluorodeoxyglucose (FDG) PET/CT, and bone scintigraphy. No studies were included for any other outcomes or for associations with patient comorbidity, body habitus, or tumor characteristics. CONCLUSIONS: Evidence is sparse on imaging modalities in the pretreatment staging of small cell lung cancer. Nevertheless, we drew three conclusions about comparative accuracy: (1) FDG PET/CT is more sensitive than MDCT for detecting osseous metastases; (2) FDG PET/CT is more sensitive than bone scintigraphy for detecting osseous metastases; (3) Standard staging plus FDG PET/CT is more sensitive than standard staging alone for detecting any distant metastases. We assigned a grade of low to the strength of evidence for these conclusions, mostly due to risk of bias and a small number of studies. Research gaps include the dearth of evidence on several tests of interest (particularly MRI, EBUS, EUS, and PET/MRI), a lack of study designs to compare tests on patient-oriented outcomes such as survival, and a lack of data on whether comparative accuracy or effectiveness are associated with patient factors.

*27195349*
 27195349

Wilms' tumour antigen 1 Immunity via DNA fusion gene vaccination in haematological malignancies by intramuscular injection followed by intramuscular electroporation: a Phase II non-randomised clinical trial (WIN)

Wilms' tumour antigen 1 Immunity via DNA fusion gene vaccination in haematological malignancies by intramuscular injection followed by intramuscular electroporation: a Phase II non-randomised clinical trial (WIN)-/-Efficacy and Mechanism Evaluation 2016; ():

BACKGROUND: In the UK almost 7000 people are diagnosed with leukaemia each year, but despite continuing advances in diagnosis and treatment with new drugs, such as the tyrosine kinase inhibitors, the majority of these patients will eventually die from their disease. Until quite recently, the only treatment to offer the possibility of long-term disease-free survival was allogeneic stem cell transplantation. However, this carries a substantial risk of mortality and is available to only a minority of patients. OBJECTIVES: The aim of the study was to test the hypothesis that molecular and clinical responses, induced by T lymphocytes (T cells), can be predicted by increases in the number of CD8+ (cluster of differentiation 8-positive) T cells specific for the vaccine-encoded T-cell epitopes. This project also aimed to build on the established programme of deoxyribonucleic acid (DNA) fusion-gene vaccination delivered by intramuscular injection, exploiting a unique experience with electroporation, to induce durable immune responses with the aim of controlling disease by precision attack of the tumour by CD8+ T cells. METHOD: A non-randomised, open-label, single-dose-level Phase II clinical trial in two patient groups [chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML)] on stable doses of imatinib. Human leucocyte antigen A2-positive (HLA A2+) patients were vaccinated with two DNA vaccines: (1) p.DOM-WT1-37 (epitope sequence: VLDFAPPGA); and (2) p.DOM-WT1-126 (epitope sequence: RMFPNAPYL). The HLA A2-negative patients formed an unvaccinated control group. The sample size for the HLA A2+ group was originally determined following Simon's optimal Phase II trial design (Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1-10). This was changed to A'Hern's single-stage design during the course of the trial (A'Hern RP. Sample size tables for single-stage phase II designs. Stat Med 2001;20:859-66), which was endorsed by the trial's independent oversight committees. RESULTS: The study included 12 patients with CML who were vaccinated and nine patients with CML who were unvaccinated as the control group. Both the vaccines and the electroporation were safe, with no new or unexpected toxicities. The evaluation adverse events of special interest (heart, bone marrow, renal) did not reveal safety concerns. Two BCR-ABL (breakpoint cluster region-Abelson murine leukaemia viral oncogene homolog 1) responses were observed, both of which were defined as a major response, with one in each group. Two Wilms' tumour antigen 1 (WT1) molecular responses were observed in the vaccinated group and one was observed in the control group. At an immunological level, the vaccine performed as expected. CONCLUSIONS: The study met its primary decision-making target with one major molecular response in BCR-ABL transcript levels. Overall, the data showed, in this clinical setting, the immunogenicity and safety of the vaccine. LIMITATIONS: The study did not complete recruitment and there were multiple hurdles that contributed to this failure. This is disappointing given the robust induction immune responses against WT1 T-cell responses in 7 out of 10 evaluable patients. FUTURE WORK: Evaluation of the p.DOM-WT1 vaccines in AML remains attractive clinically, but it is unlikely to be feasible at this time. Combination of the DNA vaccine approach with strategies to expand T-cell responses with immunomodulatory antibodies is in development. FUNDING DETAILS: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership, and Bloodwise.

*27099895*
 27099895

Immediate Osseointegrated Implants for Cancer Patients: A Review of Clinical and Cost-Effectiveness

Immediate Osseointegrated Implants for Cancer Patients: A Review of Clinical and Cost-Effectiveness-/-CADTH Rapid Response Reports 2015; ():

Oral cancers can develop in any part of the mouth, but most oral cancers start within the tongue or the floor of the mouth. They can also spread or originate from the bony structures of the mandibles. Oral cancers are commonly treated with ablative surgery alone or in combination with radiation and/or chemotherapy. Ablative surgeries may range from minor soft tissue trimming to a major resection of the tongue and jaw and face bones. Ablative surgeries of the face and mouth can introduce significant defects in the orofacial region. If not restored, these defects can compromise essential functions such as mastication, speech, and even breathing. Therefore, prosthetic rehabilitation is planned along with the ablative surgery. Oral prosthetics are usually constructed for edentulous patients, and they are stabilized and retained over the jaw bones. However, their stability and retention can be compromised due to the ablative surgery conducted on oral soft tissues and bone. The use of osseointegrated implants is suggested to improve the stability and retention of oral prosthetics in oral cancer patients. Osseointegrated implants are metallic, or even ceramic, structures which can be fixed within the jaw bones. They are connected to external structures which can be used to anchor oral prostheses. Classically, oral prostheses are put directly on the defective area and rely on the remaining oral structure for retention and stability. The purpose of this report is to review the evidence of the clinical effectiveness and cost-effectiveness of immediate osseointegrated implants for cancer patients.

*25632497*
 25632497

Imaging Techniques for Treatment Evaluation for Metastatic Breast Cancer

Imaging Techniques for Treatment Evaluation for Metastatic Breast Cancer-/-AHRQ Comparative Effectiveness Technical Briefs 2014; ():

BACKGROUND: Although multiple imaging modalities to evaluate treatment response in patients with metastatic breast cancer are used clinically, their comparative effectiveness has not been determined. PURPOSE: The purpose of this technical brief is to understand current utilization of metastatic breast imaging modalities for treatment evaluation in the United States, both in order to summarize the current state of the science and to inform future research on this topic. METHODS: We worked with Key Informants, including clinicians, patient advocates, representatives from the device manufacturing industry, and a product purchaser. Additionally, we searched gray and published literature from 2003 to 2013. We qualitatively synthesized the information from the Key Informant interviews and the gray literature. From the published literature, we abstracted data on the types of imaging used to evaluate treatment of metastatic breast cancer. FINDINGS: We identified bone scan (scintigraphy), magnetic resonance imaging (MRI), computed tomography (CT), and fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT as the major modalities used for treatment evaluation of metastatic breast cancer in the United States. We also identified four types of imaging not commonly used currently that might become important within the next decade: F-fluoromisonidazole-(F-FMISO) PET/CT, fluorothymidine-(FLT) PET/CT, fluoroestradiol-(FES) PET/CT, and PET/MRI. All published reports pertaining to imaging evaluation of treatment response among metastatic breast cancer patients were limited to small observational studies. A review of the published literature found that, in general, uptake of tracers such as FDG in PET/CT scans is associated with tumor response as determined by bone scans, MRI, or CT. CONCLUSIONS: Literature pertaining to imaging evaluation of treatment response among metastatic breast cancer patients was limited. An important potential advantage of FDG-PET/CT over conventional imaging for assessing tumor response among metastatic breast cancer patients is that it provides functional information regarding tumor metabolism in addition to information on gross morphologic changes. While some early evidence suggests that the metabolic response assessed by FDG-PET/CT after initial cycles of chemotherapy may be predictive of response to treatment among metastatic breast cancer patients, more rigorous research is needed before definitive conclusions can be reached. Future research efforts should focus on identifying novel radiotracers and biomarkers that may clarify breast tumor biology, addressing the lack of information on patient-centered outcomes (e.g., patient preferences) related to imaging, better delineating clinical outcomes associated with treatment response identified by imaging (e.g., progression-free and overall survival), and determining the costs associated with frequent imaging for treatment response.

*25375016*
 25375016

Radium-223 Dichloride -- Benefit Assessment According to section sign35a Social Code Book V

Radium-223 Dichloride -- Benefit Assessment According to section sign35a Social Code Book V-/-IQWiG Dossier Assessment Extracts 2014; ():

The aim of this report is to assess the added benefit of radium-223 dichloride (hereinafter referred to as "radium-223") in comparison with the appropriate comparator therapy (ACT) in patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastases. The Federal Joint Committee (G-BA) specified an ACT for each different patient group:for patients with the primary treatment goal of prolongation of life: docetaxel in combination with prednisone or prednisolone; for patients with the primary treatment goal of symptom control and prevention of late complications and for patients for whom docetaxel treatment is not an option: best supportive care (BSC) (particularly adequate pain therapy, treatment with bisphosphonates and/or radionuclides). In this benefit assessment, the group of patients with the primary treatment goal of symptom control and prevention of late complications and the group of patients for whom docetaxel treatment is not an option were primarily considered jointly, also because of the identical ACT, and are hereinafter referred to as "BSC population". The group of patients with the primary treatment goal of prolongation of life is hereinafter referred to as "docetaxel population". Studies that investigated a comparison of radium-223 with or without BSC versus BSC could be considered for the benefit assessment of radium-223 compared with the ACT BSC. The assessment was based on patient-relevant outcomes. One direct comparative randomized controlled trial (RCT) was included in the assessment.

*27905769*
 27905769

Pathogenesis and Models of Enterococcal Infection

Enterococci: From Commensals to Leading Causes of Drug Resistant Infection-/- 2014; ():

The vast majority of enterococci, including species that are major agents of nosocomial infection, are peaceful inhabitants of the gastrointestinal (GI) tracts of animals that range from insects to humans. However, situations arise in which enterococci can cause serious disease. The era of modern medicine has created circumstances that facilitate the pathogenic behavior of these microbes in the following ways. First, the use, and arguable overuse, of antibiotics has selected for bacteria that are resistant to these medicines. Even though enterococci may not be as inherently virulent as some other bacterial pathogens, they are facile at collecting and exchanging antibiotic resistance determinants, in addition to being naturally resistant to many antibitoics. Such properties give enterococci a selective advantage in environments with heavy antibiotic usage, such as the hospital, and may allow them to out-compete other species that would normally keep them in check. Another factor is the increasing susceptible population of immunocompromised individuals, which includes the elderly, solid organ and bone marrow transplant patients, and cancer patients. The action of the immune system likely contributes to the commensal balance, and a severely weakened defense system may be unable to keep these species in check. Finally, there are genetic factors that contribute to the ability of enterococci to survive and cause infection in a host environment, which are defined as virulence determinants for the purpose of this discussion. Some of these factors are part of the core genome, while others are traits that can be acquired and shared. Much work has been done over the last 20 years to identify these virulence determinants, and to characterize their mechanisms of action, which is is the main focus of this chapter. Animal models have made critical contributions to our understanding of the pathogenesis of enterococcal infection. A number of advances recently have been made that allow for new and more facile models to be employed in these studies. However, since the motivation behind a given study usually relates to some aspect of human infection, it is important to understand the parallels and limitations of each model, in order to know the extent to which the results can be extrapolated to humans.

*24649512*
 24649512

Capecitabine Therapy and DPYD Genotype

Medical Genetics Summaries-/- 2012; ():

Capecitabine is a chemotherapy agent that belongs to the drug class of fluoropyrimidines. It is widely used in the treatment of colon cancer, metastatic colorectal cancer, and metastatic breast cancer. Capecitabine is a prodrug that is enzymatically converted to its active form, fluorouracil, which acts as an antimetabolite to slow tumor growth. The DPYD gene encodes dihydropyrimidine dehydrogenase (DPD), an enzyme that catalyzes the rate-limiting step in fluorouracil metabolism. Individuals who are carriers of non-functional DPYD variants, such as DPYD2A, may not be able to metabolize capecitabine at normal rates, and are at risk of potentially life-threatening capecitabine toxicity, such as bone marrow suppression and neurotoxicity. The prevalence of DPD deficiency in Caucasians is approximately 3%-5%. The FDA-approved drug label for capecitabine states that no capecitabine dose has been proven safe in patients with absent DPD activity, and that there is insufficient data to recommend a specific dose in patients with partial DPD activity as measured by any specific test (1). The Clinical Pharmacogenetics Implementation Consortium (CPIC) has published dosing recommendations for fluoropyrimidines (capecitabine, fluorouracil, and tegafur) based on DPYD genotype (2) (Table 1). CPIC recommends using an alternative drug for patients who are "poor metabolizers". These individuals carry two copies of non-functional DPYD variants and typically have complete DPD deficiency. CPIC also recommends considering a 50% reduction in starting dose for "intermediate metabolizers". These individuals carry a combination of a normal-function and a non-functional variant and typically have reduced DPD activity (approximately 50% reduced) (2, 3).

*28520372*
 28520372

Mercaptopurine Therapy and TPMT Genotype

Medical Genetics Summaries-/- 2012; ():

Mercaptopurine is an immunosuppressant and antineoplastic agent that belongs to the drug class of thiopurines. It is used in combination with other drugs to treat acute lymphoblastic leukemia, which is the most common form of cancer in children (1). In addition, off-label uses include the treatment of inflammatory bowel disease (IBD). Mercaptopurine is a prodrug that must first be activated to form thioguanine nucleotides (TGNs), the major active metabolites. Thiopurine S-methyltransferase (TPMT) inactivates mercaptopurine, leaving less parent drug available to form TGNs. An adverse effect of mercaptopurine therapy is bone marrow suppression, which can occur in any patient, is dose-dependent, and may be reversed by reducing the dose of mercaptopurine. However, patients who carry two nonfunctional TPMT alleles universally experience life-threatening myelosuppression when treated with mercaptopurine, due to high levels of TGNs. Patients who carry one nonfunctional TPMT allele may also be unable to tolerate conventional doses of mercaptopurine (2, 3). The FDA-approved drug label for mercaptopurine states that heterozygous patients with low or intermediate TPMT activity accumulate higher concentrations of active TGNs than people with normal TPMT activity and are more likely to experience mercaptopurine toxicity; and that TPMT genotyping or phenotyping (red blood cell TPMT activity) can identify patients who are homozygous deficient or have low or intermediate TPMT activity (1). The Clinical Pharmacogenetics Implementation Consortium (CPIC) has published dosing recommendations for TPMT genotype-based mercaptopurine dosing. These recommendations include: Start with reduced doses of mercaptopurine for patients with one nonfunctional TPMT allele, or drastically reduced doses for patients with malignancy and two nonfunctional alleles; adjust dose based on degree of myelosuppression and disease-specific guidelines. Consider alternative nonthiopurine immunosuppressant therapy for patients with nonmalignant conditions and two nonfunctional alleles (see Table 1) (2-4).

*28520348*
 28520348

Pancreatic cancer stem cell and mesenchymal stem cell

Pancreatic Cancer and Tumor Microenvironment-/- 2012; ():

Pancreatic cancer is one of the most life-threatening cancers and its prognosis has not been improved despite advances in diagnostic and therapeutic strategies. The reasons for resistance against conventional therapy and re-growth of untreatable tumor are now attributed to the existence of cancer stem cells (CSC), which occupy only a small part of the entire cancer tissue. CSC has characteristic features such as chemoresistance, establishment of metastasis and reconstruction of a hierarchical population of tumor cells. Specific surface markers have been identified, enabling the purification of CSC fractions from cell lines or clinical samples, serving to dissect the nature of CSCs. In addition, tumor stromal cells also contribute to the malignant behavior of cancer cells by promoting an invasive phenotype and the development of metastasis. Among those stromal cells, a mesenchymal stem cell (MSC) has unique contributions to the cancer tissue since this type of cell could accumulate in the tumor from distant organs such as bone marrow. MSC also acts as a defender of cancer cells by infiltrating into the tumor. This unique feature is now applied to generating cancer-specific delivery systems by utilizing MSC as a vehicle of therapeutic agents. The tumor microenvironment, which is created by the complex interaction between cancer cells and stromal cells, yields cancer promoting effects, especially induction of a hypoxic environment. Hypoxia- induced signals activate cellular adaptation machinery such as increased cell survival or enhanced stemness in pancreatic cancer cells. Tumor stromal cells also support engraftment of metastatic nodules which provide a partial CSC niche. Targeting the tumor stroma, CSCs, and MSCs will possibly lead to the development of novel therapeutic methods against pancreatic cancer.

*22876386*
 22876386

Effectiveness of Recombinant Human Growth Hormone (rhGH) in the Treatment of Patients With Cystic Fibrosis

Effectiveness of Recombinant Human Growth Hormone (rhGH) in the Treatment of Patients With Cystic Fibrosis-/-AHRQ Comparative Effectiveness Reviews 2010; ():

OBJECTIVES: This is an evidence report prepared by the University of Connecticut/Hartford Hospital Evidence-based Practice Center (EPC) examining the benefits and harms associated with using recombinant human growth hormone (rhGH) in patients with cystic fibrosis (CF). DATA SOURCES: MEDLINE (starting from 1950), Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews from the earliest possible date through April 2010. REVIEW METHODS: The methods used to answer questions of rhGH usage in CF patients specifically are given. Randomized controlled trials, observational studies, systematic reviews/meta-analyses, or case reports were included if they: administered rhGH therapy to patients with CF and reported data on pre-specified harms, intermediate outcomes or final health outcomes. Using a standardized protocol with predefined criteria, data on study design, interventions, quality criteria, study population, baseline characteristics, and outcomes was extracted. Some of the data allowed for statistical pooling. When pooling continuous endpoints, weighted mean differences (WMD) with 95 percent confidence intervals (CIs) were calculated using a DerSimonian and Laird random effects model. I(2) was used to detect statistical heterogeneity. Visual inspection of funnel plots and Egger's weighted regression statistics were used to assess for publication bias. The overall body of evidence was graded for each outcome as insufficient, low, moderate, or high. RESULTS: Ten articles based on unique trials, eight articles based on trials reported in previous articles, and eight articles based on observational studies met our inclusion criteria. Controlled trials were limited to patients with CF and impaired baseline growth indices. Upon quantitative synthesis of controlled trials, several markers of pulmonary function [forced vital capacity (FVC) (WMD 0.67 L, 95 percent CI 0.24 to 1.09 L), percent predicted FVC (WMD 9.34 percent, 95 percent CI 3.41 to 15.27 percent), and forced expiratory volume in one second (FEV1) (WMD 0.23 L, 95 percent CI 0.01 to 0.46 L)], anthrometrics [change in height (WMD 3.13 cm, 95 percent CI 0.88 to 5.38 cm), height velocity (WMD 3.27 cm/year, 95 percent CI 2.33 to 4.21 cm/year), and height Z-score (WMD 0.51, 95 percent CI 0.35 to 0.66), weight (WMD 1.48 kg, 95 percent CI 0.62 to 2.33 kg), weight velocity (WMD 2.15 kg/year, 95 percent CI 1.52 to 2.78 kg/year), body mass index (BMI) (WMD 2.08 kg/m(2), 95 percent CI 1.20 to 2.96 kg/m(2)), percent ideal body weight (IBW) (WMD 12.57, 95 percent CI 7.01 to 18.12), lean body mass (LBM) (WMD 1.92 kg, 95 percent CI 1.47 to 2.37 kg)] and bone strength (bone mineral content (WMD 192 g, 95 percent CI 110 to 273 g)] were significantly improved versus control. A moderate to high degree of statistical heterogeneity was seen for many of these intermediate outcomes, but the directions of effect for individual studies were almost always consistent. Single-arm observational studies for the aforementioned outcomes were generally supportive of findings in clinical trials. Patients receiving rhGH therapy in controlled trials had no significant changes in percent predicted FEV1 (WMD 2.43 percent, 95 percent CI -3.99 to 8.85 percent ), weight Z-score (WMD 0.49, 95 percent CI -0.02 to 1.00), exercise work rate (WMD 11.80 W, 95 percent CI -0.44 to 24.04 W), FEV1 Z-score (WMD -0.005, 95 percent CI -0.22 to 0.21) or BMI Z-score (WMD -0.05, 95 percent CI -0.30 to 0.20) versus control therapy. Despite promising findings on intermediate outcomes, there is insufficient evidence to determine the effect of rhGH on IV antibiotic use during therapy, pulmonary exacerbations, health-related quality-of-life (HRQoL), bone consequences, or total mortality. There is moderate evidence to suggest that rhGH therapy reduces the rate of hospitalization (WMD -1.62 hospitalizations per year, 95 percent CI -1.98 to -1.26 hospitalizations per year) versus control although one trial not amenable for quantitative synthesis reported that there were no statistically significant differences in hospitalization days between groups. In qualitative assessment, rhGH therapy does not seem to improve sexual maturation in males and the impact in females cannot be determined at this time. In quantitative synthesis of controlled trials, rhGH therapy significantly increases fasting blood glucose (WMD 5.68 mg/dl, 95 percent CI 0.43 to 10.93 mg/dl) and nonsignificantly increases stimulated glucose concentrations (WMD 4.93 mg/dl (95, percent CI -15.13 to 24.98 mg/dl) but long term glucose control, as assessed by hemoglobin A1c, is not impacted (WMD -0.10 percent, 95 percent CI -0.40 to 0.20 percent) versus control. In qualitative analysis, insulin-like growth factor-I (IGF-I) concentrations in rhGH treated patients are more than 100 ng/mL higher than control. While IGF-I is a marker for malignancy, insufficient evidence exists to determine the impact of rhGH on cancer incidence. In patients with CF not receiving rhGH, the associations between the aforementioned intermediate outcomes and final health outcomes were generally weak. CONCLUSIONS: rhGH improved almost all intermediate measures of pulmonary function, height, and weight in patients with CF. Improvements in bone mineral content are also promising. However, with the exception of hospitalizations, the benefits on final health outcomes cannot be directly determined at this time. In the relatively low doses used in CF patients for a time period of 6 to 12 months, rhGH therapy may worsen short term markers of glucose control but may not impact long terms glucose control. The increase in IGF-I with rhGH therapy is above a threshold thought to increase the risk of malignancy but the strength of this marker in determining malignancy is not firmly established.

*21938797*
 21938797

Screening for Osteoporosis: Systematic Review to Update the 2002 U.S. Preventive Services Task Force Recommendation

Screening for Osteoporosis: Systematic Review to Update the 2002 U.S. Preventive Services Task Force Recommendation-/-U.S. Preventive Services Task Force Evidence Syntheses, formerly Systematic Evidence Reviews 2010; ():

BACKGROUND: Osteoporosis and related fractures are common in older individuals and lead to premature mortality, loss of function and independence, reduced quality of life, and high costs. Despite its importance, osteoporosis is under detected in the United States. This review updates evidence since the 2002 U.S. Preventive Services Task Force recommendation on osteoporosis screening. PURPOSE: To determine the effectiveness and harms of osteoporosis screening in reducing fractures for men and postmenopausal women without known previous fractures; the performance of risk-assessment instruments and bone measurement tests in identifying persons with osteoporosis; optimal screening intervals; and efficacy and harms of medications to reduce primary fractures. DATA SOURCES: Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (through the 4th Quarter of 2009), MEDLINE (January 2001 to December 2009), reference lists, and Web of Science searches. STUDY SELECTION: Randomized, controlled trials of screening or medications with fracture outcomes published in English; performance studies of validated risk-assessment instruments; and systematic reviews and population-based studies of bone measurement tests or medication harms. DATA EXTRACTION: Data on patient populations, study design, analysis, follow-up, and results were abstracted; study quality was rated by using criteria developed by the USPSTF. DATA SYNTHESIS: Risk-assessment instruments are modest predictors of low bone density (area under the curve, 0.13 to 0.87; 14 instruments) and fractures (area under the curve, 0.48 to 0.89; 11 instruments); simple and complex instruments perform similarly. Dual-energy x-ray absorptiometry predicts fractures similarly for men and women; calcaneal quantitative ultrasonography also predicts fractures, but correlation with dual-energy x-ray absorptiometry is low. Repeating a bone density measurement up to 8 years after an initial measurement does not significantly improve predictive performance for fracture outcomes. For postmenopausal women, bisphosphonates, parathyroid hormone, raloxifene, and estrogen reduce primary vertebral fractures; bisphosphonates reduce primary nonvertebral fractures in sensitivity analysis. Medications are effective for bone density T-scores of -2.5 or less for women without previous known fractures. Primary prevention trials are lacking for men. Bisphosphonates are not consistently associated with serious adverse events; raloxifene and estrogen increase thromboembolic events; estrogen increases stroke; and estrogen with progestin increases coronary heart disease and breast cancer. LIMITATIONS: Trials of screening with fracture outcomes, screening intervals, and medications to reduce primary fractures, particularly enrolling men, are lacking. CONCLUSIONS: Although methods to identify risk for osteoporotic fractures are available and mediations to reduce fractures are effective, no trials directly evaluate screening effectiveness, harms, and intervals.

*20722176*
 20722176

Probing the CXCR6/CXCL16 Axis: Targeting Prevention of Prostate Cancer Metastasis

Probe Reports from the NIH Molecular Libraries Program-/- 2010; ():

Prostate cancer (PCa) has been cited as the second leading cause of cancer-related death in American men and its morbidity/mortality has increased globally in recent years. The high mortality rate is closely associated with the spread of malignant cells to various tissues especially to bone. Nearly 10% of patients whose conditions are diagnosed as PCa clinically present with bone metastasis and almost all patients who die of prostate cancer have skeletal involvement. Identifying new mechanisms that control bone metastasis is of great consequence to facilitate the design of therapeutics aimed at decreasing metastatic risk and/or resulting secondary complications. We completed an interrogation of the Molecular Libraries Small Molecule Repository (MLSMR) for antagonists of the CXCR6 receptor in cell-based functional assay. Here, we report for the first time a novel potent (140 nM IC50) small molecule CXCR6 antagonist that is selective (>79 muM IC50) against CXCR5, CXCR4, CCR6 and APJ receptors. It is non-promiscuous against 23 other G protein-coupled receptors (GPCRs), showing only moderate activity against 5-HT2B and DAT at 10 muM in competitive binding assays. This probe will assist in addressing a key hypothesis that the CXCR6/CXCL16 axis significantly contributes to PCa cell metastasis, proliferation and subsequent bone invasion. A small molecule antagonist would block cancer cell trafficking; hence mediate a metastatic event and disease progression. Access to pharmacologically available small molecule antagonists will ultimately enable our targeted studies in disease relevant models and allow for a more seamless translational advancement toward clinical applications.

*24049849*
 24049849

Potent Anti-Diabetic Actions of a Novel Non-Agonist PPARgamma Ligand that Blocks Cdk5-Mediated Phosphorylation

Probe Reports from the NIH Molecular Libraries Program-/- 2010; ():

The incidence of diabetes is increasing rapidly as the percentage of the population ages and becomes more obese. According to the National Center for Health Statistics diabetes is now the sixth leading cause of death in the US. The biguanide metformin is typically the first-line medication used for treatment of type 2 diabetes mellitus (T2DM) as safety concerns over the use of the thiazolidinedione class [(TZD); rosiglitazone (Avandia) and pioglitazone (Actos) [1]] of insulin sensitizers has grown. This is unfortunate as TZDs have consistently shown robust efficacy for treatment of T2DM. TZDs target the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) and are classified as full agonists. While weight gain is associated with use of TZDs, the major safety concerns include edema, plasma volume expansion (PVE or hemodilution) which is likely linked to cardiomegaly and increased risk of congestive heart failure, and an increased risk of bone fractures. The latter risk is most troublesome as detection is typically only made when a patient suffers a fracture. Studies in animal models and in clinical trials have shown that indicators of weight gain and PVE, while not eliminated, can be minimized without loss of insulin sensitization by the use of modulators that are weak or partial agonists of PPARgamma (e.g., minimal agonism of the receptor as compared to TZDs). Partial agonists have been referred to as selective PPARgamma modulators or SPPARgammaMs and this class of ligand has been shown to have a different binding mode in the PPARgamma ligand binding pocket (LBP) as compared to the full agonists [2]. Selective recruitment of transcriptional coactivators by partial agonists has also been demonstrated. A combination of different ligand binding mode and distinct coactivator recruitment profile may explain the change in gene expression patterns compared to that of full agonists [3]. While it is unclear if the bone fracture risk has been minimized with use of such agents, these studies clearly demonstrate that the anti-diabetic efficacy of partial agonists is uncoupled from their transcriptional activity but does correlate well with binding potency. Recently we have shown that many PPARgamma-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARgamma by Cdk5. Due to their improved adverse event profile of partial agonists and the observation of separate biochemical activities of PPARgamma ligands, we sought to develop compounds with high affinity binding to PPARgamma but that lacked classical agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Here we describe one such compound, ML244, which has a unique mode of binding to PPARgamma, has potent anti-diabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPARgamma drugs. Unlike TZDs, ML244 does not interfere with bone formation in culture. These data illustrate that new classes of anti-diabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPARgamma.

*23762958*
 23762958

Cancer Pain: From the Development of Mouse Models to Human Clinical Trials

Translational Pain Research: From Mouse to Man-/-Frontiers in Neuroscience 2010; ():

Cancer-associated pain can be present at any time during the course of the disease, but the frequency and intensity of cancer pain tends to increase with advancing stages of cancer. In patients with advanced cancer, 62%-86% experience significant pain, which is described as moderate to severe in approximately 40%-50% and as very severe in 25%-30% (van den Beuken-van Everdingen et al. 2007). Bone cancer pain is the most common pain in patients with advanced cancer; two-thirds of patients with metastatic bone disease experience severe pain (Coleman 2006; Mercadante and Fulfaro 2007). Although bone is not a vital organ, many of the most common tumors (breast, prostate, thyroid, kidney, and lung) have a strong predilection for bone metastasis (Figure 4.1). Tumor metastases to the skeleton are major contributors to morbidity and mortality in metastatic cancer. Tumor growth in bone results in pain, hypercalcemia, anemia, increased susceptibility to infection, skeletal fractures, compression of the spinal cord, spinal instability, and decreased mobility-all of which compromise the patient's survival and quality of life (Coleman 2006, 2008). Once tumor cells have metastasized to the skeleton, tumor-induced bone pain is usually described as dull in character, constant in presentation, and gradually increasing in intensity with time (Dy et al. 2008). As tumor-induced bone remodeling progresses, severe incident pain frequently occurs (Mercadante 1997), and given that the onset of this pain is both acute and unpredictable, this component of bone cancer pain can be highly debilitating to the patient's functional status and quality of life (Coleman 1997; Mercadante 1997). Incident or breakthrough pain, which is defined as an intermittent episode of extreme pain, can occur spontaneously, or more commonly is induced by either movement of or weight-bearing on the tumor-bearing bone(s) (Mercadante et al. 2004). Currently, the treatment of pain from bone metastases involves the use of multiple complementary approaches, including radiotherapy applied to the painful area, surgery, chemotherapy, bisphosphonates, calcitonin, and analgesics (Mercadante 1997; Mercadante and Fulfaro 2007). However, bone cancer pain is one of the most difficult of all persistent pains to fully control (Mercadante 1997) because the metastases are generally not limited to a single site and the analgesics that are most commonly used to treat bone cancer pain-nonsteroidal anti-inflammatory drugs (NSAIDs) (Mercadante 1997) and opioids (Mercadante 1997; Cherny 2000; Lussier et al. 2004; Reid et al. 2008)-are limited by significant adverse side effects (Weber and Huber 1999; Harris 2008). Over the last decade a major focus of our lab has been to investigate the mechanisms that drive cancer pain (mostly due to bone cancer) and to develop mechanism-based therapies to attenuate the pain and reduce disease progression (Honore et al. 2000; Halvorson et al. 2005; Sevcik et al. 2006). These efforts have provided a new understanding of the factors that drive bone cancer pain and disease progression and have provided the preclinical data that has resulted in several clinical trials of these mechanism-based therapies.

*21882467*
 21882467

Translational Pain Research: From Mouse to Man

Translational Pain Research: From Mouse to Man-/-Frontiers in Neuroscience 2010; ():

One of the Most Rapidly Advancing Fields in Modern Neuroscience The success of molecular biology and the new tools derived from molecular genetics have revolutionized pain research and its translation to therapeutic effectiveness. Bringing together recent advances in modern neuroscience regarding genetic and genomic studies in mice and humans and the practicality of clinical trials, Translational Pain Research: From Mouse to Man effectively bridges the gap between basic research and patient care by humanely examining rodent models for pain associated with bone cancer, osteoarthritis, and cardiac episodes. Distinguished Team of International Contributors In addition to addressing the groundbreaking technical advances in tract tracing, endocannabinoids, cannabis, gene therapy, siRNA gene studies, and the role of glia, cytokines, P2X receptors, and ATP, this book also presents cutting-edge information on: Nociceptor sensitization. Visceral afferents in disease. Innovative rodent model for bone cancer pain. Highly specific receptor cloning. Modular molecular mechanisms relevant to painful neuropathies. This sharply focused work also discusses unexpected discoveries derived from brain imaging studies related to thalamic pain. Translational Pain Research covers the progress made toward bringing laboratory science (much of it at the molecular level) to our understanding of pain phenomena in humans, with the ultimate goal of reducing the suffering that often accompanies pain and its indirect consequences.

*21882466*
 21882466

Neurotrophic Factors and Nociceptor Sensitization

Translational Pain Research: From Mouse to Man-/-Frontiers in Neuroscience 2010; ():

NGF is the most commonly studied growth factor in relation to nociceptor sensitization and serves to promote the survival of DRG neurons during development that express its receptor, trkA (Averill et al. 1995; Huang et al. 2001; Patapoutian and Reichardt 2001). These neurons are generally part of the small and medium diameter DRG population, but some larger cells also express trkA (Wright and Snider 1995; Patapoutian and Reichardt 2001). In addition to its role in development and neuronal survival, it promotes sprouting and regulates innervation density of NGF-responsive neurons in peripheral targets in early post-natal and adult life. For example, it has been shown that ligation of a peripheral nerve induces NGF expression in its target area and these elevated levels are associated with sprouting of adjacent, non-injured afferents into the denervated region (Pertens et al. 1999). Other studies analyzing constitutive overexpression of NGF in the skin (NGF-OEs) report enhanced innervation of the epidermis by both sensory and sympathetic neurons (Albers et al. 1994; Davis et al. 1994, 1996; Goodness et al. 1997). Although NGF appears to be necessary and beneficial for development and maintenance of the peripheral sensory neuron system (Diamond et al. 1992), it has also been shown to participate in the development of thermal and mechanical hyperalgesia (i.e., increased pain in response to normally painful stimuli; Malin et al. 2006; Pertens et al. 1999; Andreev et al. 1995; Lewin et al. 1993) and pain in disorders such as bone cancer and interstitial cystitis (Lowe et al. 1997; Sevcik et al. 2005). Rats chronically treated with NGF are hypersensitive to both mechanical and radiant heat stimulation (Lewin et al. 1993; Andreev et al. 1995; Pertens et al. 1999) in a dose-dependent fashion, and injection of NGF directly into the paw of mice induces a decrease in the paw withdrawal latency to radiant heat (Malin et al. 2006). This NGF sensitization is partially dependent on sympathetic neurons, as sympathectomy partly reduces the effect of NGF in causing hyperalgesia (Andreev et al. 1995). NGF also acts indirectly by activating mast cells and neutrophils, which in turn release additional inflammatory mediators causing hypersensitivity (Lewin et al. 1994; Andreev et al. 1995; Amann et al. 1996; Woolf et al. 1996; Bennett et al. 1998; Bennett 2001). Regardless, it is clear that NGF levels in the target tissue participate in sensitization of nociceptors. For example, NGF-OEs display increases in afferent responses to thermal and mechanical stimulation in a skin-nerve preparation. Stucky and Lewin (1999) found that large diameter Abeta non-nociceptive afferents (typically trkA negative) were unaffected by NGF overexpression, but thermal responsiveness was significantly increased in nociceptive afferents as a result of enhanced cutaneous NGF levels. NGF-sensitive, trkA positive neurons co-label with a variety of other molecules thought to be involved in pain processing. trkA overlaps with neurons containing peptides CGRP and SP (Averill et al. 1995; Molliver and Snider 1997), known mediators of pain behaviors (Koltzenburg et al. 1999; Reeh and Kress 2001; Li et al. 2008) shown to induce hyperalgesia (Oku et al. 1987; Nakamura-Craig and Gill 1991; McMahon, 1996; Sann and Pierau 1998). This population also co-labels with TRPV1, crucial for the development of heat hyperalgesia (Caterina et al. 2000). NGF-induced hyperalgesia may also be mediated by sodium channel, Nav1.8. In mice lacking this channel, NGF does not induce heat hyperalgesia (Kerr et al. 2001), although Nav1.8 knockout mice display indistinguishable thermal thresholds under normal conditions compared to wildtypes (WTs). Since many NGF-responsive neurons contain TRPV1, this channel is suspected of a role in NGF-mediated hypersensitivity (Caterina et al. 1997; Tominaga et al. 1998; Michael and Priestley 1999). Cultured DRG neurons treated with NGF display enhanced inward current in response to application of the TRPV1 agonist capsaicin (Shu and Mendell 1999; Caterina et al. 2000; Zhu et al. 2004). NGF can increase TRPV1 expression (Donnerer et al. 2005; Xue et al. 2007) and promote TRPV1 insertion into the plasma membrane (Zhang et al. 2005). Furthermore, anti-NGF antibodies injected into the hindpaw after peripheral inflammation decrease levels of TRPV1 in DRGs and reduce inflammation-induced hyperalgesia (Ji et al. 2002; Cheng and Ji 2008). Given a clear role for NGF in sensory neuron sensitization and hyperalgesia, anti-NGF treatments may constitute an effective means of treating pain in humans (Anand et al. 1997; Lowe et al. 1997; Saldanha et al. 1999; Sena et al. 2006; Jimenez-Andrade et al. 2007). These hypotheses, however, have not been extensively studied (Abdiche et al. 2008) or verified. Perhaps NGF may only affect a small proportion of nociceptors in the DRG, and other molecules and neurotrophic factors most certainly are involved in hyperalgesia and overall sensory neuron sensitization.

*21882462*
 21882462

Report on the Relative Efficacy of Oral Cancer Therapy for Medicare Beneficiaries Versus Currently Covered Therapy: Part 4 Thalidomide for Multiple Myeloma

Report on the Relative Efficacy of Oral Cancer Therapy for Medicare Beneficiaries Versus Currently Covered Therapy: Part 4 Thalidomide for Multiple Myeloma-/-AHRQ Technology Assessments 2005; ():

Multiple myeloma is a progressive, debilitating malignancy characterized by the proliferation and accumulation of cancerous plasma cells and the overabundance of monoclonal paraprotein. It is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. Extensive skeletal destruction with osteolytic lesions, osteopenia, and/or pathologic fractures is common, as well as anemia, hypercalcemia, and kidney dysfunction. Although treatable, multiple myeloma is considered incurable and accounts for approximately 2 percent of all cancer deaths.1 Historically, intermittent oral melphalan and prednisone (MP) was standard therapy for untreated symptomatic multiple myeloma. In more recent years, newer combination chemotherapy regimens have been used both as initial first-line chemotherapy and as salvage chemotherapy, with better response rates but little effect on overall survival. Example combination chemotherapy programs include VBCMP (vincristine, carmustine, cyclophosphamide, melphalan, and prednisone) and VAD (vincristine, doxorubicin, and dexamethasone). There is a survival benefit when patients responding to chemotherapy such as VAD are treated with high dose chemotherapy plus single or double autologous stem cell transplantation. Nonetheless, over 80 percent of patients still relapse within 7 years. Treatment programs that include transplantation have limited applicability due to toxicity and associated age, performance status, and organ function requirements. Nearly all patients with multiple myeloma will eventually relapse and become resistant to further treatment. Median survival remains approximately 4 years. Thalidomide, a glutamic acid derivative, was used as sedative in the late 1950s until it was withdrawn from the market because it caused severe birth defects. Thalidomide's anti-angiogenic properties were appreciated in the 1990s and because bone marrow angiogenesis plays a substantial role in the development of multiple myeloma, thalidomide has been tried in multiple myeloma. Since the first publication documenting objective responses with thalidomide in patients with refractory myeloma was published in 1999, there has been a rapid proliferation of published and abstract reports on the use of thalidomide in multiple myeloma. In 1998, the Food and Drug Administration (FDA) approved thalidomide for use in treating leprosy (Hansen's disease); it is not currently FDA-approved for multiple myeloma. Thalidomide can only be prescribed under the System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) program, patented by Celgene Corporation. The key questions for this review were developed with experts in the field of oncology, health economics, and health policy. The key questions are as follows: 1. For patients with relapsed or refractory multiple myeloma, what is the effect of thalidomide compared to standard chemotherapy regimens (e.g., VBMCP (vincristine, carmustine, melphalan, cyclophosphamide, and prednisone) and VAD (vincristine, doxorubicin, and dexamethasone)) on 2-year survival, disease-free survival, CR, PR (m-protein), and quality of life? 2. For patients with relapsed or refractory multiple myeloma, what is the effect of thalidomide compared to standard chemotherapy regimens (e.g., VBMCP (vincristine, carmustine, melphalan, cyclophosphamide, and prednisone) and VAD (vincristine, doxorubicin, dexamethasone)) on adverse effects, tolerability, and compliance? 3. What patient or tumor characteristics distinguish treatment responders from non-responders and have potential to be used to target therapy? As there was emerging information regarding the role of thalidomide for newly diagnosed and smoldering multiple myeloma, these groups were also considered as part of this review.

*25950076*
 25950076

Report on the Relative Efficacy of Oral Cancer Therapy for Medicare Beneficiaries Versus Currently Covered Therapy: Part 3, Imatinib for Chronic Myeloid Leukemia (CML)

Report on the Relative Efficacy of Oral Cancer Therapy for Medicare Beneficiaries Versus Currently Covered Therapy: Part 3, Imatinib for Chronic Myeloid Leukemia (CML)-/-AHRQ Technology Assessments 2005; ():

Chronic myeloid leukemia (CML) is a malignant clonal disorder of blood cells resulting from the cancerous transformation of a very primitive hematopoietic stem cell. CML's hallmark is the chromosome 9;22 translocation that produces the BCR-ABL gene, which is present in more than 95 percent of all cases of CML. Imatinib (Gleevec(R)) is an orally administered drug that competitively inhibits the BCR-ABL tyrosine kinase, a cellular enzyme that is encoded in the BCR-ABL gene. Imatinib works by blocking, or turning off, the signal from the tyrosine kinase protein, so that cancerous cells stop growing. Imatinib is approved by the Food and Drug Administration (FDA) for patients in the first-line and relapsed settings of all phases of CML. There are three clinical phases of CML-chronic phase (CP), accelerated phase (AP), and blastic phase/blast crisis (BP)-distinguished by their prognoses and clinical presentation. Therapeutic options include imatinib, interferon-alpha with or without cytarabine, hydroxyurea, busulfan, other conventional chemotherapies, and stem cell transplantation (bone marrow transplantation, SCT). Allogeneic SCT is the only curative treatment for CML, however it is only available for 20-25 percent of patients predominantly due to lack of a suitable donor; 15-30 percent treatment-related mortality can be expected with SCT. This assessment of imatinib for treatment of CML was performed at the request of the Centers for Medicare and Medicaid Services (CMS) and is designed to inform the likely health outcomes associated with a current demonstration project which provides for payment for certain oral medications, including imatinib for CML, that are prescribed as replacements for other drugs currently covered under Medicare Part B.

*25927124*
 25927124

Referral Guidelines for Suspected Cancer in Adults and Children

Referral Guidelines for Suspected Cancer in Adults and Children-/-National Institute for Health and Clinical Excellence: Guidance 2005; ():

The guideline is divided into sections which cover in detail specific topics relating to twelve groups of cancers: lung, upper gastrointestinal cancers, lower gastrointestinal cancers, breast cancer, gynaecological cancers, urological cancers, haematological cancers, skin cancers, head and neck including oral cancers, brain/central nervous system cancers, bone and sarcoma, and children's and young people's cancers. In each section, the symptoms, signs and risk factors relevant to initial assessment in primary health care are considered. The role of investigations in primary care is then addressed, and the sections conclude with consideration of factors related to delay and difficulties in diagnosis. Two additional sections are included at the beginning of the guideline. The first deals with the needs of patients with suspected cancer at the time of referral. The second considers the process followed by healthcare professionals in reaching an initial diagnosis, and interventions to help healthcare professionals improve their ability to identify patients who should be suspected of having cancer. Important general methodological issues are flagged up as appropriate. Where appropriate, full details of the papers reviewed are presented in the evidence tables

*21473024*
 21473024

Palliative Treatment of Cancer-Related Pain

Palliative Treatment of Cancer-Related Pain-/-NIPH Systematic Reviews: Executive Summaries 2005; ():

BACKGROUND: The majority of cancer patients with advanced disease have pain. Pain severely impairs health-related quality of life and is the most feared symptom in cancer patients. The quality of palliative treatment of cancer-related pain depends both on knowledge and competence of the health care workers involved, as well as on organisational aspects including a well-developed health services and well-functioning collaboration among health personnel at the different treatment levels. International research as well as national reports emphasize the potential for improving pain therapy for cancer patients in the palliative phase by means of improving all three factors: knowledge, competence and health services organisation. OBJECTIVE: The main objective was to conduct a systematic review to evaluate the best available evidence on the analgesic efficacy of medication and radiotherapy in the palliative cancer patient. In addition, economical, organisational, ethical and juridical aspects of these treatment methods, with particular reference to the Norwegian healthcare system, were evaluated. The report focused on pain caused by the cancer disease itself, i.e. pain due to tumour growth.The main outcome of the systematic review was pain relief, whereas treatment-related side effects were secondary outcomes. METHODS: An interdisciplinary review team performed a health technology assessment according to internationally approved principles by doing a systematic review of the published literature. This systematic review was based on two evidence reports from Agency for Healthcare Results and Quality (AHRQ, USA) focusing on the management of cancer pain published in 2001 and 2002, ten Cochrane reviews covering the topic, and an additional 47 Medline recorded studies reporting on cancer pain treatment published between 2001 and 2003 (not included in AHRQ). We selected randomized controlled trials (RCTs) and meta-analyses reporting on cancer pain treatment, however comparative case series were included for treatments where studies of higher evidence level were lacking (switch the opioid and/or switch the route, pain palliation of children, invasive procedures). Two reviewers assessed 172 each publication according to criteria defined by protocol for evaluating relevance, quality, and validity. The two AHRQ reports and the 10 Cochrane reviews include a total of 258 relevant RCTs (of which 253 RCTs were published no later than 2000, the year before our own literature search and assessment). The references to these studies are shown in Appendix 3. The literature identified in the time period 2001-2003 was assessed stepwise. Among 1326 abstracts identified, 85 were read as full text articles, and 47 studies were critically assessed as relevant publications (one meta-analysis, 37 RCTs and 9 case series). The relevant studies were systematised in three subgroups according to the quality of the study design in question and the validity of the results: high, moderate and low. In order to be rated as acceptable (high or moderate quality), studies had to: i) report effect estimates of pain relief assessed with a validated and widely acknowledged pain assessment tool (defined as a method able to convert a subjective pain experience to a unit of measure on a scale, for example VAS/NRS scale), ii) systematically report pain relief in the whole patient group (independent of whether pain is a primary or secondary outcome in the study), and iii) simultaneously report the consumption or change in consumption of analgesic (as pain relief is the sum of pain intensity and analgesic consumption). Of the 47 included studies, 30 studies (one meta-analysis, 24 RCTs and 5 case series) were rated as high and moderate (acceptable) quality, the remaining 17 studies as low quality. Evidence tables of studies of high and moderate quality and characteristics of studies of low quality are shown in Appendix 5 (in English). The collected documentation (from AHRQ reports, Cochrane reviews and our own literature assessment) was a total of 300 studies, which were synthesized using qualitative methodology. MAIN RESULTS: The results were summarized according to the following ten treatment categories: OPIOID ANALGESICS: Opioids are effective in relieving moderate to severe cancer pain. No specific opioid drug has been shown to have greater analgesic efficacy, and the side effects profile of the different drugs have not been shown to be different. Morphine is generally the accepted drug of choice; however, its position is being challenged by the introduction of other opioids such as oxycodone and hydromorphone. There are data indicating that the combination oxycodonemorphine is more effective than morphine alone. No differences in analgesic efficacy of different formulations (e.g. immediate-release versus sustained-release) and routes of administration (e.g. oral versus rectal) have been demonstrated. Still, some formulations and routes of administration have advantages in certain patient groups. There are data indicating that oral-transmucosal fentanyl is more effective for breakthrough pain than immediate release morphine. Switching opioids and/or administration route is an adequate clinical manoeuvre for improving pain palliation or reducing side effects both in adults and children. NON-OPIOID ANALGESICS: Non-steroidal anti-inflammatory drugs (NSAIDs) are effective in relieving moderate cancer pain. There has not been shown any difference in analgesic efficacy or side effects of different drugs. The analgesic efficiency of the combination NSAIDs and weak opioids is not different from NSAIDs alone. The coadministration of NSAIDs to strong opioids has an opioid dosesparing effect, but there is no evidence that this combination reduces side effects due to opioid use. The documentation of the analgesic efficacy of paracetamol on cancer-related pain is sparse. Most studies have analysed paracetamol in combination with other analgesics. Available data do not give any information of the analgesic effect that paracetamol provides on its own. Paracetamol s pain relieving effect has, however, been documented in other pain conditions than cancer and is as effective as NSAIDs. ADJUVANT ANALGESICS: It is not possible from the available documentation to conclude whether adjuvant analgesics give an additive pain relief gain beyond the treatment effect obtained with standard analgesics. No adjuvant drug has been shown to have greater analgesic efficacy than others. Based on the existing data it is not possible to conclude whether analgesic efficacy is different among specific drug groups (e.g. antidepressive agents, anticonvulsants, corticosteroids or NMDA-antagonists). Pain relieving effect of adjuvant analgesics has, however, been documented in other pain conditions than cancer. CHEMOTHERAPY: It is unclear whether palliative chemotherapy causes pain relief beyond the analgesic effect obtained with standard analgesics. There has not been shown any difference in analgesic efficacy between various chemotherapeutic agents or chemotherapeutic regimens. Combination regimens with chemotherapeutic agents and corticosteroids or external radiation therapy seem to have better analgesic efficiency on certain cancer diseases than regimens without chemotherapeutic agents. HORMONES: It is unclear whether hormonal therapy causes pain relief beyond the analgesic effect obtained with standard analgesics. There has not been shown any difference in analgesic efficacy between different hormones/hormonal regimens or between hormonal regimens versus other medications. BISPHOSPHONATES: There is evidence to support that bisphosphonates provide an additive analgesic effect beyond the treatment effect obtained with standard analgesics. Current data indicate that bisphosphonates have a weak or moderate effect on bone pain after 4-12 weeks of medication. Whether certain bisphosphonates are more effective in reducing bone pain than others is not clarified. INTRASPINAL AND EPIDURAL ANALGESICS: Intraspinal and epidural analgesics are both effective in relieving cancer pain in selected patients. Available documentation does not clarify whether this route of administration is more effective in relieving pain than other administration routes. There is no evidence of any difference in analgesic efficacy between various intraspinal / epidural analgesics or combinations and various categories of administration route (intraspinal versus epidural, continuous infusion versus bolus doses, catheter versus implantable pump). Pain relief by intraspinal and epidural administration of analgesics is feasible for most cancer patients. NEUROLYTIC BLOCKADES: Treatment with neurolytic blockades is effective in relieving pain due to cancer in the area of the pancreatic gland. Available documentation does not clarify whether neurolytic blockades are more effective in relieving pain than conventional pain treatment with opioids and 175 NSAIDs. Also, current data are inconclusive regarding possible effect differences between various blockade techniques or between various medications (volume and concentration). EXTERNAL RADIATION THERAPY: External radiotherapy is effective in relieving cancer pain due to bone metastases. Available documentation, however, does not clarify whether this treatment effect is obtained without any change in the consumption of analgesics. Current data is too restricted for making conclusions about possible effect differences between external radiation therapy and radionuclides or medications. Data indicate that single dose (unfractionated) radiation is as effective as fractionated radiation on bone pain. That is, short courses of palliative radiotherapy with higher doses yield results that are similar to those of longer courses that provide a lower dose per treatment. The re-treatment rate and pathological fractures seem to be more frequent in patients receiving unfractionated radiation. The minimal total dose of radiation that relieves pain has not yet been determined. RADIONUCLIDES: Radionuclide therapy is effective in relieving cancer pain due to bone metastases. Evidence is, however, too sparse to conclude whether pain reduction after radionuclide therapy is a result also of simultaneous changes in consumption of analgesics. Radionuclide therapy is as effective as external radiation therapy. Available data are inconclusive regarding possible effect differences between radionuclide therapy and bisphosphonates, as well as between different radionuclides. COMMENTS: RCTs of cancer pain control often enroll few subjects, have low methodological quality and involve heterogeneous interventions and outcome measures assessed by different pain assessment tools. This review demonstrates that a significant body of research has failed to produce a clear answer to key questions in the management of cancer pain. The heterogeneity of existing trials precludes meta-analyses for most sub questions. Future trials of cancer pain relief would benefit from common criteria for the reporting of pain response, thus improving the comparability and thereby allowing for meta-analyses.

*29320015*
 29320015

Bone Marrow or Blood Stem Cell Transplants in Children With Severe Forms of Autoimmune Disorders or Certain Types of Cancer: A Review of the Research for Parents and Caregivers

Comparative Effectiveness Review Summary Guides for Consumers-/-AHRQ Comparative Effectiveness Reviews 2005; ():

This summary will cover: Information about each autoimmune disorder and type of cancer. Possible benefits of an HSCT. What researchers have found about children with a very severe form of one of these diseases who received an HSCT that used their own stem cells. What an HSCT is and how it is done. Possible risks of an HSCT.

*24199268*
 24199268

(99m)Tc-Labeled (1S,3S)-3-acetyl-1,2,3,4,6,11-hexahydro-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1 -naphthacenyl 3-amino-2,3,6-trideoxy-alpha-l-lyxo-hexopyranoside

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Daunorubicin, a member of the anthracycline family of antibiotics, is approved by the United States Food and Drug Administration (FDA) for the remission induction of acute nonlymphocytic leukemia in adults and for the remission induction of acute lymphocytic leukemia in children and adults. Anthracyclines are known to inhibit cancer cell proliferation by several mechanisms, but it is well established that these antibiotics intercalate between the nucleotides of DNA and RNA and interfere with the replication of these nucleic acids. In addition, anthracyclines inhibit the topoisomerase II group of enzymes that have an important role in DNA replication (2). Doxorubicin, another anthracycline antibiotic with a structure and mechanism of action similar to that of daunorubicin, has been approved by the FDA for the treatment of several types of cancers, such as acute lymphoblastic leukemia, acute myeloblastic leukemia, Wilms' tumor, neuroblastoma, soft tissue and bone sarcomas, breast carcinoma, ovarian carcinoma, transitional cell bladder carcinoma, thyroid carcinoma, gastric carcinoma, Hodgkin's disease, malignant lymphoma, and bronchogenic carcinoma. Several radiochemicals, such as [(99m)Tc]-methoxyisobutyl-isonitrile ([(99m)Tc]-MIBI), [(99m)]Tc-tetrofosmin, and [(18)F]-fluorodeoxyglucose ([(18)F]-FDG), are often used in the clinic with single-photon emission computed tomography (SPECT; for noninvasive imaging with [(99m)Tc]-MIBI and [(99m)]Tc-tetrofosmin) and positron emission tomography (for imaging with [(18)F]-FDG) to detect and monitor cancerous tumors. However, these tracers are of limited use for the detection and monitoring of neoplastic lesions because they often generate false-positive results, as detailed elsewhere (3). Transformed cells have a characteristically high proliferation rate and consequently exhibit a higher rate of DNA synthesis compared with the normal cells. Therefore, cells with an elevated rate of DNA synthesis would be expected to intercalate high levels of anthracycline antibiotics within the nucleic acid structure. Based on this assumption, Kumar et al. evaluated the use of (99m)Tc-labeled doxorubicin for the noninvasive detection of tumors in mice, and the investigators showed that the tracer was probably suitable for visualization of the lesions with scintigraphy in the rodents (3). Faheem et al. investigated the biodistribution of (99m)Tc-labeled daunorubicin ([(99m)Tc]-daunorubicin) in normal rats, and scintigraphy was used to study the biodistribution of this radiolabeled compound in a rabbit (1). Results obtained from studies performed with [(99m)Tc]-daunorubicin are presented in this chapter.

*23469379*
 23469379

Gadolinium-Hexyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid-progesterone

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Estrogens and progesterones are endogenous hormones that produce many physiological effects (1). Estrogens act primarily by regulating gene expression. Estrogen receptors (ERs) are found in the cytoplasm and nucleus of cells in the female reproductive tract, breast, pituitary gland, hypothalamus, bone, liver, and other tissues, as well as in various tissues in men. Estrogens are lipophilic in that they enter the cell passively by diffusion through the cellular membrane. They bind to ERs in the cytoplasm and are transported to the nucleus. Breast cancer is the most common malignancy in women. Approximately 33% of women who have this disease will die of disseminated breast cancer. The growth of breast epithelial cells is dependent on estrogen stimulation to induce progesterone receptor (PR) expression. Two-thirds of breast carcinomas express ERs. It has also been established that the ER status of the tumor is an important prognostic indicator in breast cancer (2). Women with ER-positive and PR-positive breast tumors have a better prognosis than women with ER-negative and PR-negative tumors in terms of responsiveness to anti-estrogen treatment. ER content in breast cancer has been assessed in vitro with receptor binding assays, which suffer from inter-assay variability and are also limited by intrinsic receptor heterogeneity of the primary and metastatic tumors. 16alpha-[(18)F]Fluoro-17beta-estradiol ([(18)F]FES) has been proven to be a valuable tracer for studies of the ER status of primary and metastatic breast cancer (3). However, [(18)F]FES is cleared from the blood and metabolized in 20 min with only 20% of [(18)F]FES intact in a study with 15 breast cancer patients (4). Similarly, a [(18)F]-labeled progestin is also metabolized rapidly in humans (5). For magnetic resonance imaging (MRI), Sukerkar et al. (6) found that coupling of gadolinium-hexyl-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (Gd-hexyl-DO3A) to the C21 hydroxyl group of 21-hydroxylprogesterone renders the MRI probe (ProGlo) inaccessible for metabolism but still able to bind specifically to PR(+) breast cancer cells. ProGlo was shown to accumulate in PR-rich uterus and PR(+) tumors in vivo in mice.

*22896862*
 22896862

Recombinant human erythropoietin coupled to near-infrared fluorescence dye Cy5.5

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Erythropoietin (Epo) is a heavily glycosylated chemokine that is expressed primarily in the adult kidney (during the fetal stage of development, Epo is produced mainly in the liver and not the kidneys), mediates its effects through the erythropoietin receptor (Epo-R), and is known to regulate the process of erythropoiesis (red blood cell formation from hematopoietic cells in the bone marrow) in the hematopoietic system (1). Epo-R is also found in other tissues and is believed to protect cells in the cardiac and neuronal tissues from hypoxic injury and apoptosis. The expression of Epo and Epo-R and the cell signaling pathways involved in bringing about the biological effects of this receptor-ligand complex have been described by Chateauvieux et al. (1). The use of recombinant human Epo (rhuEpo) has been approved by the United States Food and Drug Administration for the treatment of anemia in certain HIV patients and individuals undergoing chemotherapy for non-myeloid cancer or those who are experiencing chronic kidney failure. Meta-analysis of data obtained from clinical trials has shown that the use of rhuEpo in the clinic is associated with increased adverse thrombo-vascular events or neoplastic tumor progression that results in the mortality of individuals with certain types of cancer (2). In a mouse model of breast cancer it has been shown that, when rhuEpo was used in combination with chemotherapy, there was an increased incidence of cancer metastasis in the animals (3). The co-expression of Epo and Epo-R has been observed in certain neoplasms, including non-small cell lung cancer (NSCLC), and a clinical investigation has shown that expression of these genes in the NSCLC tumors correlated with a negative outcome for the patient (4). However, other studies could not establish a clear link between the expression of Epo and Epo-R and the development of cancer because the Epo-R status of a tumor cannot be determined accurately with currently used immunohistochemical methods, due to the lack of antibodies that can specifically and selectively bind to the Epo-R (5). Therefore, the development of alternative probes that specifically target the Epo-R and can be used with noninvasive imaging techniques to detect and quantify the receptor in vivo is necessary (5). Doleschel et al. coupled Cy5.5, a near-infrared dye, to rhuEpo (Epo-Cy5.5) and evaluated the fluorescent conjugate to visualize the expression of EpoR with fluorescence-mediated tomography (FMT) in human lung cancer xenografts in mice (5). The biodistribution of the probe in these animals was also investigated.

*22379640*
 22379640

Cy5.5-Gly-Pro-Leu-Gly-Val-Arg-Gly-(TDOPA)3-flower-like gold-Fe3O4 optical nanoparticles

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Extracellular matrix (ECM) adhesion molecules consist of a complex network of fibronectins, collagens, chondroitins, laminins, glycoproteins, heparin sulfate, tenascins, and proteoglycans that surround connective tissue cells, and they are mainly secreted by fibroblasts, chondroblasts, and osteoblasts (1). Cell substrate adhesion molecules are considered essential regulators of cell migration, differentiation, and tissue integrity and remodeling. These molecules play a role in inflammation and atherogenesis, but they also participate in the process of invasion and metastasis of malignant cells in the host tissue (2). Tumor cells adhere to the ECM, which provides a matrix environment for permeation of tumor cells through the basal lamina and underlying interstitial stroma of the connective tissue. Overexpression of matrix metalloproteinases (MMPs) and other proteases by tumor cells allows intravasation of tumor cells into the circulatory system after degrading the basement membrane and ECM (3). Gold has not been used as an X-ray contrast agent in vivo. Gold has a higher atomic number and a higher absorption coefficient than iodine, providing 2.7-fold greater contrast/weight than iodine (4). Furthermore, imaging gold at 80-100 keV reduces interference from bone absorption and provides lower soft tissue absorption, which would reduce radiation to patients. Hainfeld et al. (4) used gold nanoparticles (AuNPs; 1.9 nm in diameter, ~50 kDa) as a computed tomography (CT) contrast agent in mice; these experiments showed enhanced CT contrast of the vasculature, kidneys, and tumors in mice. However, plasma proteins in blood adsorb onto the surface of bare AuNPs, which produces large aggregates (5) that may result in altered pharmacokinetics and biodistribution of AuNPs (6). Polyethylene glycol (PEG) is found to minimize nonspecific adsorption of proteins onto NPs and to reduce their uptake by the liver (6). PEG-AuNPs have been being studied as cancer CT imaging and photothermal agents (7). Several families of MMPs are involved in atherogenesis, myocardial infarction, angiogenesis, and tumor invasion and metastases (8-11). MMP expression is highly regulated in normal cells, such as trophoblasts, osteoclasts, neutrophils, and macrophages. Elevated levels of MMPs have been found in tumors associated with a poor prognosis for cancer patients (12). The peptide Gly-Pro-Leu-Gly-Val-Arg-Gly-Cys-NH2 was found to be a MMP substrate and is cleaved between the Leu and Gly residues. Lee et al. (13) used this sequence with a Cy5.5 NIR dye molecule to attach to AuNPs to form fluorescence-quenched nanoparticles (Cy5.5-Gly-Pro-Leu-Gly-Val-Arg-Gly-Cys-AuNPs (Cy5.5-MMP-AuNPs or GANPs). The Cy5.5 molecules are in close proximity, resulting in fluorescence quenching because of efficient fluorescence resonance energy transfer to Au. NIR fluorescence signal will increase when the Leu-Gly bond is cleaved by MMPs, releasing Cy5.5-containing fragments. Cy5.5 is a NIR fluorescent dye with an absorbance maximum at 675 nm, an emission maximum at 694 nm, and a high extinction coefficient of 250,000 M-(1)cm-(1). Cy5.5-MMP-AuNPs are being developed for NIR fluorescence imaging of MMPs expressed in tumors, atherosclerosis, myocardial infarction, and other diseases. Xie et al. (14) replaced the AuNP with Au-Fe3O4, a composite NP shaped like a flower, to induce a fluorescently quenched state to the overall nanostructure. There were three iron oxide "petals" on each AuNP. The MMP peptide was covalently linked to an anchoring unit, Lys-tridihydrophenylalanine (Lys-TDOPA) on the surface of the iron oxide NP. The gold surface was passivated with a thiolated PEG (SH-PEG5000). Cy5.5-Gly-Pro-Leu-Gly-Val-Arg-Gly-(Lys-TDOPA)3-flower-like gold-Fe3O4 optical NPs (FANPs) have been evaluated for imaging protease expression in vivo.

*22238802*
 22238802

Pamidronate-IRDye78

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Optical fluorescence imaging is increasingly used to obtain biological functions of specific targets in vitro and in small animals (1, 2). However, the intrinsic fluorescence of biomolecules poses a problem when visible light (350-700 nm) absorbing fluorophores are used because of high tissue absorption and scatter. Near-infrared (NIR) fluorescence (700-900 nm) detection avoids the background fluorescence interference of natural biomolecules, providing a high contrast between target and background tissues. NIR fluorophores have wider dynamic range and minimal background as a result of reduced scattering compared to visible fluorescence detection. They also have high sensitivity resulting from low infrared background, and high extinction coefficients, which provide high quantum yields. The NIR region was also compatible with solid-state optical components such as diode lasers and silicon detectors. NIR fluorescence imaging is becoming a non-invasive alterative to radionuclide imaging in vitro and in small animals. IRDye78 is a heptamethine indocyanine-type NIR fluorophore with peak absorption at 771 nm, and peak excitation emission at 806 nm. It provides a quantum yield of 14.2%. It has a molecular weight of 1083 Da. IRDye78 is a highly charged IR-786 derivative, which localized to mitochondria at low concentrations and endoplasmic reticulum (ER) at high concentrations in vitro (3). IRDye78 was shown to be a useful perfusion agent in myocardium. IRDye78 N-hydroxysuccinimide (NHS) ester can be conjugated to antibodies and low-molecular weight ligands with one or more free primary amines. Osteoblasts (mineralization) and osteoclasts (demineralization) are two importance cell types in development and integrity of vertebral skeleton (4, 5). Osteoblast-like cells are present in vascular tissues and play a role in arteriosclerosis (6). Microcalcifications are found in breast tissue (7, 8). Hydroxyapatite (HA) is a mineral product deposited in the bone and vascular tissue by the osteoblast. HA binds pyrophosphates and phosphonates with high affinity. Nitrogen-containing synthetic diphosphonates are inhibitors of farnesyl diphosphate synthase (FDPS) of osteoclast and are used for treatment of osteoporosis (bone resorption) (9). Inhibition of FDPS inhibits osteoclast bone-resorption activity and induces osteoclast apoptosis (10, 11). Diphosphonates bind to bone mineral with high affinity for their long duration of action. For example, [(99m)Tc]Methylene diphosphonate (MDP) was developed for bone scanning (12) and it is believed that it binds to HA. Pamidronate (Pam) is a diphosphonate derivative with a single primary amine for conjugation with IRDye78-NHS ester to form Pam78. Pam78 exhibits rapid and specific binding to HA in vitro and in vivo. Zaheer et al. (13) demonstrated NIR fluorescence detection of bone with Pam78 in nude mice. A simple and rapid rat model of focal calcification in breast cancer tumors was validated by Pam78 NIR imaging (14).

*20641269*
 20641269

Methyl-[(11)C]-4'-thiothymidine

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Most anti-cancer drugs are aimed at curbing the processes of rapid cell proliferation and an increased rate of DNA synthesis, which are both necessary for the progression of all cancers and the development of neoplastic tumors. Usually invasive procedures such as biopsies are used to confirm the presence of malignant tumors, but it can be difficult to take multiple biopsies from a patient if the cancer has metastasized to several different areas of the body (1). Therefore, non-invasive imaging methods that use radiolabeled thymidine analogs (a nucleoside present only in the DNA) in conjunction with positron emission tomography (PET) have been developed to detect tumors and to evaluate the efficacy of anti-cancer treatments in animals and humans (1). Initially, (11)C-labeled thymidine was developed to visualize cancerous tumors, but this radiolabeled compound is quickly metabolized in the cell and has been determined to have limited application in the clinic (2). Subsequently, (18)F-labeled PET agents with a thymidine base, such as 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]-FLT) and 1-(2'-deoxy-2'-[(18)F]fluoro-beta-D-arabinofuranosyl) thymine ([(18)F]-FMAU), were generated and evaluated for the visualization of neoplastic tumors. Among these, FLT is phosphorylated by thymidine kinase 1 (a cytosolic isozyme of thymidine kinase), but the phosphorylated molecule is not incorporated into the cellular DNA and is trapped within the cell (2). Hence, [(18)F]-FLT is considered to be a surrogate marker for the visualization of cell proliferation under in vivo conditions. In addition, this cell proliferation tracer has several limitations that have been discussed elsewhere (3). The second tracer, [(18)F]-FMAU, has to be phosphorylated by thymidine kinase 2 (TK2), a mitochondrial enzyme, before it is incorporated into the DNA (2). However, [(18)F]-FMAU is considered suitable only for the detection of neoplasia in the pelvic region or for visualization of tumors that have metastasized to the bone, because with this radiolabeled compound there is a high retention of label in the liver, kidneys, and the myocardium (2). It has also been reported that there is no correlation between the uptake of a TK2-selective arabinothymidine substrate and the proliferation of cells in a malignant tumor (3). With the information described above, in an effort to produce an alternative tracer that can be used to visualize tumor proliferation, Toyohara et al. synthesized 4'-thiothymidine (in this molecule, the 4'-oxo of thymidine is substituted with a 4'-sulfur) and showed that its methylated and (14)C-labeled derivative, 4'-methyl-[(14)C]-thiothymidine ([(14)C]-4DST), accumulated mainly in rapidly proliferating tissues in mice (spleen, duodenum, and thymus), including the xenograft tumors (4). It has also been shown that the label from [(14)C]-4DST is present mainly in the DNA fraction of these tissues. On the basis of these observations, (11)C-labeled 4'-methyl-thiothymidine ([(11)C]-4DST) was synthesized and evaluated for the visualization of cell proliferation with PET in mice bearing xenograft tumors generated from several different cell lines (3). The biodistribution and use of [(11)C]-4DST for the imaging of brain tumors in humans with PET was investigated in a recent pilot study (5).

*21919248*
 21919248

N-(4-[(18)F]Fluoro-benzoyl)-N'-{2-[5-(4-fluoro-benzyl)-1-(4-methoxy-benzyl)-4,6-d ioxo-1,4,5,6-tetrahydro-[1,3,5]triazin-2-ylamino]-ethyl}-guanidine

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Bv8 is a small protein secreted by frog skin (1). The prokineticins PK1 and PK2, which are mammalian homologs of Bv8, and their G-protein-coupled receptors prokineticin receptor 1 (PKR1) and prokineticin receptor 2 (PKR2) have been identified and linked to several biological functions such as gut motility, neurogenesis, angiogenesis, circadian rhythms, hematopoiesis, and nociception (2-4). Prokineticins are also associated with pathologies of the reproductive and nervous systems, myocardial infarction, and tumorigenesis. PKR1 shares 33% identity with human neuropeptide Y receptor-2, and PKR1 is expressed in the brain, spleen, prostate, testis, leukocytes, pancreas, adrenal gland, thyroid, salivary gland, pituitary, stomach, small intestine, colon, and rectum. On the other hand, PKR2 is expressed mainly in the ileocecum and discrete nuclei of the central nervous system. PK1 is secreted by endocrine glands, whereas PK2 is highly expressed in the bone marrow, lymphoid organs, and leukocytes, which suggests a role for PK2 in inflammation, immunomodulation, and hematopoiesis. Binding of PK2 to PKR1 has been shown to reduce the pain threshold in sensory neurons and can contribute to inflammatory pain. PK2 is highly expressed by neutrophils and other inflammatory cells as a pronociceptive mediator in inflamed tissues. Several nonpeptidic PK antagonists have been developed for pain reduction and cancer therapy (5). However, noninvasive quantification of PKR1 levels in vivo is not available for drug development. A nonpeptidic PKR1 antagonist, N-{2-[5-(4-fluoro-benzyl)-1-(4-methoxy-benzyl)-4,6-dioxo-1,4,5,6-tetrahydro-[1,3, 5]triazin-2-ylamino]-ethyl}-guanidine (PC-7), which contains a free guanidine group, was labeled with (18)F by reacting the guanidine moiety with N-succinimidyl-4-[(18)F]fluorobenzoate ([(18)F]FBA) to form N-(4-[(18)F]fluoro-benzoyl)-N'-{2-[5-(4-fluoro-benzyl)-1-(4-methoxy-benzyl)-4,6-d ioxo-1,4,5,6-tetrahydro-[1,3,5]triazin-2-ylamino]-ethyl}-guanidine ([(18)F]PC-10). Jacobson et al. (6) evaluated [(18)F]PC-10 binding in mice injected with complete Freund adjuvant (CFA) to induce inflammatory pain by upregulation of PK2 and PKR1.

*21882405*
 21882405

(111)In/(125/131)I-Labeled anti-mucin-1 murine, chimeric or humanized antibody hPAM4

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Mucins (MUC) are a distinct class of transmembrane glycoproteins (designated as MUC1, MUC3A, MUC3B, MUC4, etc.) that are expressed primarily by the glandular and ductal cells of the epithelium in the human body and are known to modulate the tumorigenicity, progression, and pathogenesis of different cancers (1). The structure, physiological function, and process of promoting the development of malignancies by MUCs, particularly MUC1 and MUC4, are discussed in detail by Bafna et al. (1). MUC1 has been shown to be characteristically overexpressed by pancreatic adenocarcinoma (PAC) cells and is not detectable in normal pancreatic ducts or other normal tissues, or during an incident of pancreatitis (2). Because it is detectable only in the serum of patients suffering from PAC, it was suggested recently that the MUC1 antigen can be used as a biomarker for the early detection this malignancy (3, 4). The majority of individuals suffering from PAC do not survive for more than 1 year after diagnosis, and <1% of these patients live beyond 5 years (5). Although surgical resection of the cancer is a possible treatment for this disease, only 10%-25% of the patients are considered suitable for this treatment because, by the time that the neoplasm is detected, the malignancy has metastasized and the tumor load in the patient is too high to warrant surgery (5). Patients with nonresectable PAC are treated either with gemcitabine or radiotherapy; however, these treatments are not curative and only prolong survival and improve the quality of life of the patient (5). The detection of this invasive cancer at an early stage would facilitate proper staging of the disease, which could be followed either by surgical resection of the tumor or the initiation of a vigorous treatment regimen that could possibly improve patient prognosis (6). More than a decade ago, a (131)I-labeled murine monoclonal antibody, PAM4 ([(131)I]-mPAM4), directed against a mucin (later identified to be MUC1 (5)) was reported to detect human xenograft PAC tumors in mice with high specificity and, compared to controls, significantly extended the survival time of the animals when used for radiotherapy of the cancer (7-9). In a preliminary study, [(131)I]-PAM4 was demonstrated to detect the primary and the metastasized pancreatic carcinoma tumors in humans, and there was a low nonspecific uptake of the tracer in the liver, spleen, and bone marrow of the patients (10). In another study, a chimeric form of PAM4 (cPAM4) was labeled with (125)I and (111)In to obtain [(125)I]-cPAM4 and [(111)In]-cPAM4, respectively, and the biodistribution of these labeled mAbs was investigated in mice bearing human xenograft PAC tumors (11). Recently, Gulec et al. studied the biodistribution of (111)In-labeled humanized PAM4 ( [(111)In]-hPAM4) in a phase I clinical trial (2).

*21834178*
 21834178

(177)Lu-Labeled methylene diphosphonate

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Most patients with malignancies of the breast, prostate, lungs, thyroid, or kidneys suffer from severe bone pain due to metastases of the cancer in the skeletal tissue (1, 2). Although several interventions such as analgesics, bisphosphonates, hormone therapy, and systemic radionuclide therapy are available to manage bone pain, these treatments are known to have many undesirable secondary effects on the patient (2). Radiopharmaceuticals containing nuclides such as strontium-89 (as (89)SrCl2) and samarium-153 (administered as (153)Sm-labeled ethylenediamine tetramethylene phosphonic acid (EDTMP)), which have been approved by the United States Food and Drug Administration (FDA) for the treatment of bone pain due to metastases, are commonly used for the palliative care of bone pain in cancer patients (2). However, these are not ideal agents to treat bone pain because the radionuclide either has a long half-life and generates high-energy beta(-) particles ((89)Sr has a half-life of ~50 days; Ebeta(max) = 1.49 MeV) or is short-lived and has to be produced in close vicinity to the treatment center ((153)Sm has a half-life of ~47 h; Ebeta(max) = 0.81 MeV; Egamma = 103 keV (28%)) (1). A major limitation of using these bone pain palliative agents is that they produce myelotoxicity in some patients (3). Between the two labeled compounds, (89)SrCl2 appears to be the agent of choice for clinical applications because its longer half-life allows some flexibility to develop a suitable treatment regimen for the patient. There is great interest in the development of alternative radiolabeled compounds that can be used to treat pain resulting from osseous metastases (2). An important characteristic of a new labeled compound is that it must have the ability to be targeted specifically to the cancerous lesions on the skeleton and should be minimally toxic to the bone marrow as discussed elsewhere (3-5). In a study with healthy rats, it was reported that EDTMP labeled with lutetium-177 ([(177)Lu]-EDTMP) was cleared rapidly from blood circulation, showed little uptake in the soft tissues, and accumulated primarily in the bones of these animals (6). Chakraborty et al. made similar observations when they investigated the biodistribution of [(177)Lu]-EDTMP in rats (7), and a freeze-dried kit for the preparation of this radiopharmaceutical has also been developed (8). On the basis of these observations, there is a renewed interest to use (177)Lu (half-life, ~7 days; Ebeta(max) = 497 keV; Egamma = 113 keV (6.4%); 208 keV (11%)) as an alternative nuclide to those currently in use ((89)Sr and (153)Sm) in the development of a palliative care agent for pain due to the metastases of cancer to the skeletal tissue (4, 5). The main advantages of using (177)Lu are that it can be easily transported to places where it is not available, and the low-energy gamma photons emitted by the nuclide allow detection of the bone lesions with scintigraphy. The International Atomic Energy Agency has initiated projects to develop (177)Lu-labeled compounds as palliative care agents for bone pain (5). Methylene diphosphonate (MDP; also known as methylene diphosphate) labeled with technetium-99m is a commonly used bone-imaging agent approved by the FDA to investigate osteogenesis, and it is commercially available in the form of a kit (9). Because of its easy availability, and on the basis of the information mentioned above, Abbasi developed (177)Lu-labeled MDP ([(177)Lu]-MDP) as a possible alternate radiopharmaceutical for the palliative care of bone pain (10). The biodistribution of this tracer was studied in Sprague-Dawley rats and confirmed with gamma planar imaging.

*21735586*
 21735586

(177)Lu-Labeled ethylenediamine tetramethylene phosphonic acid

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Most patients with malignancies of the breast, prostate, lungs, thyroid, or kidneys suffer from severe bone pain due to metastases of the cancer to the skeletal tissue (2, 3). Although several interventions such as analgesics, bisphosphonates, hormone therapy, and systemic radionuclide therapy are available to manage the pain, these treatments are known to have many undesirable secondary effects on the patient (3). Radiopharmaceuticals containing nuclides such as strontium-89 (as (89)SrCl2) and samarium-153 (administered as (153)Sm-labeled ethylenediamine tetramethylene phosphonic acid (EDTMP)), which have been approved by the United States Food and Drug Administration for the treatment of bone pain due to metastases, are commonly used for palliative care of pain in the bones of cancer patients (3). However, these are not ideal agents to treat bone pain because the radionuclide either has a long half-life and generates high-energy beta(-) particles ((89)Sr has a half-life of ~50 days; Ebeta(max) = 1.49 MeV) or is short-lived and has to be produced in close vicinity to the treatment center ((153)Sm has a half-life of ~47 h; Ebeta(max) = 0.81 MeV; Egamma = 103 keV (28%)) (2). A major limitation of using these bone pain palliative agents is that they produce myelotoxicity in some patients (4). Between the two labeled compounds, (89)SrCl2 appears to be the agent of choice for clinical applications because its longer half-life allows some flexibility to develop a suitable treatment regimen for the patient. There is great interest in the development of alternative radiolabeled compounds that can be used to treat pain resulting from osseous metastases (3). An important characteristic of this labeled compound is that it must have the ability to be targeted specifically to the cancerous lesions on the skeleton and should be minimally toxic to the bone marrow as discussed elsewhere (4-6). In an earlier study with healthy rats, it was reported that EDTMP labeled with lutetium-177 ([(177)Lu]-EDTMP) was cleared rapidly from blood circulation, showed little uptake in the soft tissues, and accumulated primarily in the bones of these animals (7). Chakraborty et al. made similar observations when they investigated the biodistribution of [(177)Lu]-EDTMP in rats (8). A freeze-dried kit for the preparation of [(177)Lu]-EDTMP was developed subsequently by Garnuszek et al. (9). On the basis of these observations, there is a renewed interest to use (177)Lu (half-life, ~7 days; Ebeta(max) = 497 keV; Egamma = 113 keV (6.4%); 208 keV (11%)) as an alternative nuclide to those currently in use ((89)Sr and (153)Sm) in the development of a palliative care agent for pain due to the metastases of cancer to the skeletal tissue (5, 6). The main advantages of using (177)Lu are that it can be easily transported to places where it is not available and the low-energy gamma photons emitted by the nuclide allow detection of the bone lesions with scintigraphy. The biodistribution of [(177)Lu]-EDTMP was studied recently in mice, rats, and rabbits, and scintigraphic imaging was performed on rodents, rabbits, and dogs (5, 6). In addition, the International Atomic Energy Agency has initiated projects to develop (177)Lu-labeled compounds as palliative care agents for bone pain (6).

*21656987*
 21656987

[(170)Tm]-Labeled ethylenediamine tetramethylene phosphonic acid

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Due to the metastases of cancer in the skeletal tissue, severe bone pain affects the quality of life of most patients suffering from malignancies of the breast, prostate, lungs, thyroid, or kidneys (2, 3). Although several interventions such as analgesics, bisphosphonates, hormone therapy, and systemic radionuclide therapy are available to manage the pain, these treatments are known to have many undesirable secondary effects (3). Radiopharmaceuticals that contain nuclides, such as strontium-89 (as (89)SrCl2) and samarium-153 (administered as (153)Sm-ethylenediamine tetramethylene phosphonic acid (EDTMP)), which are commonly used for palliative care of pain in the bones of these cancer patients, have been approved by the United States Food and Drug Administration (FDA) for the treatment of this condition (3). However, these are not the most ideal agents to treat pain due to bone metastases because the radionuclide either has a long half-life and generates high-energy beta(-) particles ((89)Sr has a half-life of ~50 days and Ebeta(max) = 1.49 MeV) or is short-lived and has to be produced in close vicinity to the treatment center ((153)Sm has a half-life of ~47 h, Ebeta(max) = 0.81 MeV, and Egamma = 103 keV (28%)) (2). In addition, both of these bone pain palliative agents are known to produce myelotoxicity in some patients (4). Between the two labeled compounds, (89)SrCl2 appears to be the agent of choice for clinical applications because of its longer half-life, which provides the flexibility to develop a suitable treatment regimen for the patient. There is much interest to develop alternative radiolabeled compounds that do not suppress the bone marrow but are suitable to treat pain resulting from osseous metastases as discussed by Jansen et al. (4). Recently, Das et al. evaluated the use of thulium-170 ((170)Tm has a half-life of ~128 days, Ebeta(max) = 968 keV, and Egamma = 84 keV (3.26%)) as an alternative to (89)SrCl2 for the development of a bone pain palliative (2). According to these investigators, (170)Tm would probably exhibit low myelosupression because it emits beta(-) particles of lower energy than those emitted by (89)Sr, and the gamma-photons generated by the nuclide can be used for scintigraphy to detect the accumulation and location of the radiolabel in the organs of an animal. This chapter describes the biodistribution of (170)Tm-labeled EDTMP ((170)Tm-EDTMP) in normal Wistar rats (2).

*21656985*
 21656985

[(18)F]Fluoropropyl-Tanaproget

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Estrogens and progesterones are endogenous hormones that produce many physiological effects (1). Estrogens act primarily by regulating gene expression. Estrogen receptors (ERs) are found in the cytoplasm and nucleus of cells in the female reproductive tract, breast, pituitary, hypothalamus, bone, liver, and other tissues, as well as in various tissues in men. Estrogens are lipophilic in that they enter the cell passively by diffusion through the cellular membrane. They bind to ERs in the cytoplasm and are transported to the nucleus. Breast cancer is the most common malignancy in women. Approximately 33% of women who have this disease will die of disseminated breast cancer. The growth of breast epithelial cells is dependent on estrogen stimulation to induce progesterone receptor (PR) expression. Two-thirds of breast carcinomas express ERs. It has also been established that the ER status of the tumor is an important prognostic indicator in breast cancer (2). Women with ER-positive breast tumors have a better prognosis than women with ER-negative tumors in terms of responsiveness to anti-estrogen treatment. ER content in breast cancer was assessed in vitro with receptor binding assays, which suffer from inter-assay variability and are also limited by intrinsic receptor heterogeneity of the primary and metastatic tumors. 16alpha-[(18)F]Fluoro-17beta-estradiol ([(18)F]FES) has been proven to be a valuable tracer for studies of the ER status of primary and metastatic breast cancer (3). However, [(18)F]FES is cleared from the blood and metabolized in 20 min with only 20% of [(18)F]FES intact in a study with 15 breast cancer patients (4). A newly developed nonsteroidal progestin analog, Tanaproget, exhibits a potent agonist activity for PR with a high binding affinity (Kd = 0.2 nM) (5). Lee et al. (6) reported the synthesis of [(18)F]fluoropropyl-Tanaproget ([(18)F]FPTP) and its tissue distribution in immature, estrogen-primed, female rats with a high uterus/blood ratio.

*21204318*
 21204318

(89)Zr-Labeled N-suc-desferrioxamine-conjugated anti-carbonic anhydrase IX chimeric monoclonal antibody cG250-F(ab')2 fragments

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Hypoxic tumors are often resistant to radio- and chemotherapy, have a high metastatic potential, and predict a poor outcome for the cancer patient (1). Although several methods (invasive and noninvasive) are available for the detection of hypoxia in tumors, including the use of radiolabeled small molecules, but these methods are not completely reliable because they either yield variable diagnoses, have functional limitations, show incomplete penetration of tumors, do not detect hypoxia in all tumor types, etc (1, 2). A common feature of most solid cancerous tumor types is the presence of hypoxic conditions (3) and the overexpression of carbonic anhydrase IX (CA IX), a transmembrane cell surface enzyme that is known to regulate the pH and adhesion of tumor cells (4). Therefore, as an alternative to the currently available agents used to detect hypoxic tumors, targeting the CA IX as a hypoxia biomarker is of great interest to investigators (1-3, 5). As an alternative to small molecules, the chimeric monoclonal antibody (cMab) cG250, directed against the CA IX, was developed, labeled with (131)I, and evaluated as an immunotherapeutic agent for the detection and treatment of renal cell carcinoma (RCC) (6). This cMab was subsequently labeled with other nuclides (such as (89)Zr, (177)Lu, (90)Y, etc.) and used in preclinical studies in rats (7) and in clinical trials for the radioimmunotherapy of RCC (6). However, only minor responses were observed in the clinical investigations and dose escalation studies are ongoing (6). The ability of radiolabeled antibodies (Abs) used to detect or treat cancer is limited because these agents show only a peripheral penetration of solid tumors (due to large size, ~150 kDa) and leave many malignant cells untreated (8). In addition, Abs have a long blood circulation time and present a high radiation-absorbed dose to the bone marrow (9). It has been shown that, compared to intact Abs, the smaller monovalent Fab (~50kDa) or the divalent F(ab')2 (~100 kDa) fragments derived from the parent Ab have a better tumor penetration and a shorter circulating half-life and are therefore likely to yield better results if used to detect or treat solid malignant tumors (8). With these observations in mind, a divalent F(ab')2 fragment of cG250 was developed, labeled with (131)I, and compared with the intact (131)I-cG250 Ab for its pharmacokinetic behavior and tumor-targeting ability in mice and RCC patients (9). However, the investigators concluded that the intact Ab was superior to the divalent fragment for targeting the RCC tumors. Recently, the cG250-F(ab')2 fragments were labeled with (89)Zr (to produce [(89)Zr]-cG250-F(ab')2) and evaluated for the visualization of tumor hypoxia in mice bearing SCCNij3 cell xenograft tumors (of human head and neck squamous cell carcinoma origin) with positron emission tomography (PET) (5).

*20963940*
 20963940

[(111)In]-Labeled divalent Fab fragment of chimeric monoclonal antibody cG250 directed against carbonic anhydrase IX

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

A common feature of most solid cancerous tumor types is the presence of hypoxic conditions (1) and the overexpression of carbonic anhydrase IX (CA IX), a transmembrane cell-surface enzyme that is known to regulate the pH and adhesion of tumor cells (2). Hypoxic tumors are often resistant to radio- and chemotherapy, have a high metastatic potential, and usually predict a poor outcome for the cancer patient (3). Although several methods (invasive and noninvasive) are available for the detection of hypoxia in tumors, including the use of radiolabeled small molecules, these methods are not completely reliable because they either yield variable diagnoses or have functional limitations due to incomplete penetration of tumors and fail to detect hypoxia in all tumor types (3, 4). Because CA IX is overexpressed in most solid tumors, it is considered to be a hypoxia biomarker, and targeting the CA IX for the detection of hypoxic tumors is of great interest to investigators (1, 3-5). A (131)I-labeled murine monoclonal antibody (mAb) that targets the CA IX, designated G250, was developed and evaluated for the radiotherapy of metastatic renal cell carcinoma (RCC) patients, but no major responses were observed because the individuals developed immunity to the mAb (6). Subsequently, a (131)I-labeled chimeric form of G250, [(131)I]-cG250, was developed and evaluated as an immunotherapeutic agent for the treatment of RCC (7). cG250 has been labeled with other nuclides (such as (89)Zr, (177)Lu, (90)Y, etc.) and has been used in preclinical studies in rats (8) and for the treatment of RCC (7). However, only minor responses were observed in the clinical investigations, and dose escalation studies are ongoing (7). Radiolabeled antibodies (Abs) have a limited ability to detect or treat cancer because these agents show only a peripheral penetration of solid tumors (due to a large size, ~150 kDa) and leave many neoplastic cells in the lesion untreated (9). In addition, Abs have prolonged blood circulation and present a high radiation dose risk to the bone marrow (10). In comparison, the smaller monovalent Fab (~50 kDa) and the divalent F(ab')2 (~100 kDa) fragments derived from the parent Ab exhibit better tumor penetration and a shorter circulating half-life and are likely to yield better results if used to detect or treat solid malignant tumors (9). Between the two fragment types, the divalent F(ab')2 fragments may be more useful for the detection or treatment of malignant tumors because they have a higher affinity for the antigen (11). With these observations in mind, a divalent F(ab')2 fragment of cG250 was developed, labeled with (131)I, and compared with the intact [(131)I]-cG250 Ab for its pharmacokinetic behavior and its ability to target tumors in mice and RCC patients (10). However, from this study the investigators concluded that the intact Ab was superior to the divalent fragment for targeting the RCC tumors. A clinical trial to investigate the safety of a (124)I-labeled version of cG250 in patients with renal masses has been reported (12). In addition, cG250 is also under evaluation in several other clinical trials. Recently, (89)Zr-labeled F(ab')2 fragments of cG250 were shown to be suitable for the visualization of hypoxic head and neck cancer xenograft tumors in mice (5). Brouwers et al. compared the use of [(111)In]-isothiocynate-diethylenetriamine pentaacetic acid-cG250 and [(131)I]-cG250 for the detection of RCC metastases in five patients and concluded that the former tracer was superior to the latter for visualization of the tumors (13). In another study involving three patients, it was shown that neither (131)I- labeled cG250 nor (111)In-labeled cG250 were suitable for the radioimmunotherapy of biliary cancer (14). In a recent study using 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) as a nuclide conjugating agent, (111)In-labeled cG250 Ab ([(111)In]-DOTA-cG250) and its Fab ([(111)In]-DOTA-Fab-cG250) and F(ab')2 ([(111)In]-DOTA-F(ab')2-cG250) fragments were generated and compared for their biodistribution and detection of hypoxic HT-29 cell (of human colorectal adenocarcinoma origin) xenograft tumors in mice (1). This chapter details the studies performed with [(111)In]-DOTA-F(ab')2-cG250. Studies performed with [(111)In]-DOTA-cG250 (15) and [(111)In]-DOTA-Fab-cG250 (16) are discussed in separate chapters of MICAD (www.micad.nih.gov).

*20827820*
 20827820

[(111)In]-Labeled monovalent Fab fragment of chimeric monoclonal antibody cG250 directed against carbonic anhydrase IX

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

A common feature of most solid cancerous tumor types is the presence of hypoxic conditions (1) and the overexpression of carbonic anhydrase IX (CA IX), a transmembrane cell-surface enzyme that is known to regulate the pH and adhesion of tumor cells (2). Hypoxic tumors are often resistant to radio- and chemotherapy, have a high metastatic potential, and usually predict a poor outcome for the cancer patient (3). Although several methods (invasive and noninvasive) are available for the detection of hypoxia in tumors, including the use of radiolabeled small molecules, these methods are not completely reliable because they either yield variable diagnoses or have functional limitations due to incomplete penetration of tumors and fail to detect hypoxia in all tumor types (3, 4). Because CA IX is overexpressed in most solid tumors, it is considered to be a hypoxia biomarker, and targeting the CA IX for the detection of hypoxic tumors is of great interest to investigators (1, 3-5). A (131)I-labeled murine monoclonal antibody (mAb) that targets the CA IX, designated G250, was developed and evaluated for the radiotherapy of metastatic renal cell carcinoma (RCC) patients, but no major responses were observed because the individuals developed immunity to the mAb (6). Subsequently, a (131)I-labeled chimeric form of G250, [(131)I]-cG250, was developed and evaluated as an immunotherapeutic agent for the treatment of RCC (7). cG250 has been labeled with other nuclides (such as (89)Zr, (177)Lu, (90)Y, etc.) and has been used in preclinical studies in rats (8) and for the treatment of RCC (7). However, only minor responses were observed in the clinical investigations, and dose escalation studies are ongoing (7). Radiolabeled antibodies (Abs) have a limited ability to detect or treat cancer because these agents show only a peripheral penetration of solid tumors (due to a large size, ~150 kDa) and leave many neoplastic cells in the lesion untreated (9). In addition, Abs have prolonged blood circulation and present a high radiation dose risk to the bone marrow (10). In comparison, the smaller monovalent Fab (~50 kDa) and the divalent F(ab')2 (~100 kDa) fragments derived from the parent Ab exhibit better tumor penetration and a shorter circulating half-life and are likely to yield better results if used to detect or treat solid malignant tumors (9). Between the two fragment types, the divalent F(ab')2 fragments may be more useful for the detection or treatment of malignant tumors because they have a higher affinity for the antigen (11). With these observations in mind, a divalent F(ab')2 fragment of cG250 was developed, labeled with (131)I, and compared with the intact [(131)I]-cG250 Ab for its pharmacokinetic behavior and its ability to target tumors in mice and RCC patients (10). However, from this study the investigators concluded that the intact Ab was superior to the divalent fragment for targeting the RCC tumors. A clinical trial to investigate the safety of a (124)I-labeled version of cG250 in patients with renal masses has been reported (12). In addition, cG250 is also under evaluation in several other clinical trials. Recently, (89)Zr-labeled F(ab')2 fragments of cG250 were shown to be suitable for the visualization of hypoxic head and neck cancer xenograft tumors in mice (5). Brouwers et al. compared the use of [(111)In]-isothiocynate-diethylenetriamine pentaacetic acid-cG250 and [(131)I]-cG250 for the detection of RCC metastases in five patients and concluded that the former tracer was superior to the latter for visualization of the tumors (13). In another study involving three patients, it was shown that neither (131)I-labeled cG250 nor (111)In-labeled cG250 were suitable for the radioimmunotherapy of biliary cancer (14). In a recent study using 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) as a nuclide conjugating agent, (111)In-labeled cG250 Ab ([(111)In]-DOTA-cG250) and its Fab ([(111)In]-DOTA-Fab-cG250) and F(ab')2 ([(111)In]-DOTA-F(ab')2-cG250) fragments were generated and compared for their biodistribution and detection of hypoxic HT-29 cell (of human colorectal adenocarcinoma origin) xenograft tumors in mice (1). This chapter details the studies performed with [(111)In]-DOTA-Fab-cG250. Studies performed with [(111)In]-DOTA-cG250 (15) and [(111)In]-DOTA-F(ab')2-cG250 (16) are discussed in separate chapters of MICAD (www.micad.nih.gov).

*20827819*
 20827819

[(111)In]-Labeled chimeric monoclonal antibody cG250 directed against carbonic anhydrase IX

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

A common feature of most solid cancerous tumor types is the presence of hypoxic conditions (1) and the overexpression of carbonic anhydrase IX (CA IX), a transmembrane cell-surface enzyme that is known to regulate the pH and adhesion of tumor cells (2). Hypoxic tumors are often resistant to radio- and chemotherapy, have a high metastatic potential, and usually predict a poor outcome for the cancer patient (3). Although several methods (invasive and noninvasive) are available for the detection of hypoxia in tumors, including the use of radiolabeled small molecules, these methods are not completely reliable because they either yield variable diagnoses or have functional limitations due to incomplete penetration of tumors and fail to detect hypoxia in all tumor types (3, 4). Because CA IX is overexpressed in most solid tumors, it is considered to be a hypoxia biomarker, and targeting the CA IX for the detection of hypoxic tumors is of great interest to investigators (1, 3-5). A (131)I-labeled murine monoclonal antibody (mAb) that targets the CA IX, designated G250, was developed and evaluated for the radiotherapy of metastatic renal cell carcinoma (RCC) patients, but no major responses were observed because the individuals developed immunity to the mAb (6). Subsequently, a (131)I-labeled chimeric form of G250, [(131)I]-cG250, was developed and evaluated as an immunotherapeutic agent for the treatment of RCC (7). cG250 has been labeled with other nuclides (such as (89)Zr, (177)Lu, (90)Y, etc.) and has been used in preclinical studies in rats (8) and for the treatment of RCC (7). However, only minor responses were observed in the clinical investigations, and dose escalation studies are ongoing (7). Radiolabeled antibodies (Abs) have a limited ability to detect or treat cancer because these agents show only a peripheral penetration of solid tumors (due to a large size, ~150 kDa) and leave many neoplastic cells in the lesion untreated (9). In addition, Abs have prolonged blood circulation and present a high radiation dose risk to the bone marrow (10). In comparison, the smaller monovalent Fab (~50 kDa) and the divalent F(ab')2 (~100 kDa) fragments derived from the parent Ab exhibit better tumor penetration and a shorter circulating half-life and are likely to yield better results if used to detect or treat solid malignant tumors (9). Between the two fragment types, the divalent F(ab')2 fragments may more useful for the detection or treatment of malignant tumors because they have a higher affinity for the antigen (11). With these observations in mind, a divalent F(ab')2 fragment of cG250 was developed, labeled with (131)I, and compared with the intact [(131)I]-cG250 Ab for its pharmacokinetic behavior and its ability to target tumors in mice and RCC patients (10). However, from this study the investigators concluded that the intact Ab was superior to the divalent fragment for targeting the RCC tumors. A clinical trial to investigate the safety of a (124)I-labeled version of cG250 in patients with renal masses has been reported (12). In addition cG250 is also under evaluation in several other clinical trials. Recently, (89)Zr-labeled F(ab')2 fragments of cG250 were shown to be suitable for the visualization of hypoxic head and neck cancer xenograft tumors in mice (5). Brouwers et al. compared the use of [(111)In]-isothiocynate-diethylenetriamine pentaacetic acid-cG250 and [(131)I]-cG250 for the detection of RCC metastases in five patients and concluded that the former tracer was superior to the latter for visualization of the tumors (13). In another study involving three patients, it was shown that neither (131)I-labeled cG250 nor (111)In-labeled cG250 were suitable for the radioimmunotherapy of biliary cancer (14). In a recent study using 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) as a nuclide conjugating agent, (111)In-labeled cG250 Ab ([(111)In]-DOTA-cG250) and its Fab ([(111)In]-DOTA-Fab-cG250) and F(ab')2 ([(111)In]-DOTA-F(ab')2-cG250) fragments were generated and compared for their biodistribution and detection of hypoxic HT-29 cell (of human colorectal adenocarcinoma origin) xenograft tumors in mice (1). This chapter details the studies performed with [(111)In]-DOTA-cG250. Studies performed with [(111)In]-DOTA-Fab-cG250 (15) and [(111)In]-DOTA-F(ab')2-cG250 (16) are discussed in separate chapters of MICAD (www.micad.nih.gov).

*20827818*
 20827818

(124)I-Anti-prostate stem-cell antigen back-mutated 2B3 diabody

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Prostate stem-cell antigen (PSCA) is a cell-surface protein (123 amino acids) that is expressed in normal prostate tissue and overexpressed in prostate cancer tissues (1). PSCA expression is detected in >80% of patients with local disease, including high expression in bone metastases (2). Elevated levels of PSCA are correlated with increased tumor stage, grade, and androgen independence (3). PSCA overexpression is also observed in bladder and pancreatic cancers (4). The anti-PSCA murine monoclonal antibody (mAb) 1G8 has been shown to have anti-tumor activity (5). A humanized version of the 1G8 mAb (hu1G8) has been radiolabeled as (124)I-hu1G8 for tumor imaging in mice (6). However, it took ~1 week to observe an enhanced target/background ratio with positron emission tomography (PET) because of the slow kinetics of the mAb. A hu1G8 minibody fragment (2B3), a dimer of scFvs-CH3 with a linker composed of 18 amino acids (molecular weight, ~80 kDa), has been developed and labeled as (124)I-2B3 minibody for tumor-targeting studies (7). To create a stable, rapidly clearing antibody fragment, the parental 2B3 diabody (p2B3-Db) (molecular weight, 55 kDa) was mutated back to the original mouse residues to produce a high-affinity, back-mutated diabody with a linker of 8 amino acids (bm2B3-Db8) (8). (124)I-p2B3-Db8 and (124)I-bm2B3-Db8 were evaluated for tumor imaging.

*20681082*
 20681082

(99m)Tc-(3Z)-4-{4-[2-(Dimethylamino)ethoxy]phenyl}-3,4-diphenylbut-3-en-1-ylN,N-b is[2-(2,6-dioxomorpholin-4-yl)ethyl]glycinate

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Estrogens and progestins are endogenous hormones that produce many physiological effects (1). Estrogens act primarily by regulating gene expression. Estrogen receptors (ERs) are found in the cytoplasm and nucleus of cells of the female reproductive tract, breast, pituitary, hypothalamus, bone, liver, and other tissues, and also in various tissues in men. Estrogens are lipophilic in that they enter the cell passively by diffusion through the cellular membrane. Estrogens bind to ERs that are present in the cytoplasm and the complexes are transported into the nucleus. Breast cancer is the most common malignancy in women. Approximately 33% of women who have this disease will die of disseminated breast cancer. The growth of breast epithelial cells is dependent on estrogen stimulation, which induces progestin receptor expression. Two thirds of breast carcinomas express ERs. It has also been established that the ER status of the tumor is an important prognostic indicator in breast cancer (2). Women with ER-positive breast tumors have a better prognosis than women with ER-negative tumors in terms of responsiveness to anti-estrogen treatment. ER content in breast cancer is assessed in vitro with receptor binding assays, which suffer from interassay variability, are limited by intrinsic receptor heterogeneity of the tumor, and do not yield information on the ER density in metastases. 16alpha-[(18)F]Fluoro-17beta-estradiol ([(18)F]FES) has been proven to be a valuable tracer for studies of the ER status of primary and metastatic breast cancer (3). However, [(18)F]FES was cleared from the blood and was metabolized in 20 min with only 20% of [(18)F]FES intact in a study of 15 breast cancer patients (4). Toremifene (TOR) is a chlorinated analog of tamoxifen (5, 6), which was first approved by the United States Food and Drug Administration in the 1970s for use in breast cancer treatment. TOR is primarily used in the treatment of patients with metastatic breast cancer (7). Yurt et al. (8) coupled diethylenetriamine pentaacetic acid (DTPA) to TOR to form (3Z)-4-{4-[2-(dimethylamino)ethoxy]phenyl}-3,4-diphenylbut-3-en-1-ylN,N-bis[2-(2, 6-dioxomorpholin-4-yl)ethyl]glycinate (DTPA-TOR) and radiolabeled the DTPA-TOR with (99m)Tc. (99m)Tc-DTPA-TOR exhibited high breast tissue/background ratio in female rats.

*20642020*
 20642020

(186)Re-Labeled [N-[2[[3-(3,3-diphosphonopropylcarbamoyl)propyl]-2-thioethylamino]acetyl]-2-amino ethylenethiolate] oxorhenium (V)

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Bisphosphonates (BPs) or nitrogen-containing bisphosphonates (NBPs) are often used for the management of pain palliation and disorders related to skeletal tissue, including those arising from cancer metastases, because these compounds have a very high affinity for hydroxyapatite (HA), a component of the bone matrix. These phosphonates or their derivatives tend to accumulate in osteoclasts located at areas of increased bone metabolism by inhibiting the enzyme farnesyl diphosphate (or pyrophosphate) synthase, an important regulatory enzyme of the cellular mevalonate pathway, which is involved in protein prenylation (1). The molecular mechanism of action of BPs and the NBPs has been described by Drake et. al. (2). Several BPs and NBPs are commercially available for clinical use to treat different bone disorders, and there are ongoing clinical trials approved by the United States Food and Drug Administration to evaluate these compounds for the treatment of various bone ailments. In addition, BPs are often labeled with (99m)Tc or (186/188)Re and used for the imaging and treatment of pain as a result of bone metastases from cancer such as that of the breast or the prostate (3). However, these compounds have limited efficacy primarily because they exist either as a mixture of anionic compounds with varying properties (e.g., (99m)Tc- labeled methyl diphosphonate (MDP)) or are unstable (e.g., (86)Re-labeled 1-hydroxyethylidene-1,1-diphosphonate) under in vivo conditions, resulting in a reduced uptake at targeted bone areas and an increased accumulation in non-target soft tissue such as the gastric lining of the stomach (4). The limited clinical utility of radiolabeled BPs was suggested to be caused by the dual activities exhibited by the compounds: one phosphonate group acts as a radionuclide chelator, and the other phosphonate group binds to the target(s).Therefore, due to the close proximity of the two groups, one activity may be interfering with the other (4). In an effort to solve the stability problems observed with the (186)Re-labeled NBPs, Ogawa et al. developed two new NBPs, (186)Re-[N-[2-[[3-(3,3-diphosphonopropylcarbamoyl)propyl]-2-thioethylamino]acetyl ]-2-aminoethylenethiolate] oxorhenium (V) ([(186)Re]MAMA-BP) and its hydroxylated derivative, (186)Re-[N-[2-[[4-[(4-hydroxy-4,4-diphosphonobutyl)amino]-4-oxobutyl]-2-thioethyl amino]acetyl]-2-aminoethanethiolate] oxorhenium (V) ([(186)Re]MAMA-HBP) (3). The investigators then compared the two compounds for their affinity to HA under in vitro conditions and studied the biodistribution of the radiochemicals in normal mice. This chapter presents the results obtained with [(186)Re]MAMA-BP. Results obtained with [(186)Re]MAMA-HBP are presented in a separate chapter of MICAD (5).

*20642012*
 20642012

(186)Re-Labeled [N-[2-[[4-[(4-hydroxy-4,4-diphosphonobutyl)amino]-4-oxobutyl]-2-thioethylamino]ac etyl]-2-aminoethanethiolate] oxorhenium (V)

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Bisphosphonates (BPs) or nitrogen-containing bisphosphonates (NBPs) are often used for the management of pain palliation and disorders related to skeletal tissue, including those arising from cancer metastases, because these compounds have a very high affinity for hydroxyapatite (HA), a component of the bone matrix. These phosphonates or their derivatives tend to accumulate in osteoclasts located at areas of increased bone metabolism by inhibiting the enzyme farnesyl diphosphate (or pyrophosphate) synthase, an important enzyme of the cellular mevalonate pathway, which is involved in protein prenylation (1). The mechanism of action of BPs and the NBPs has been described in detail by Drake et. al. (2). Several BPs and NBPs are commercially available for clinical use to treat different bone disorders, and there are ongoing clinical trials approved by the United States Food and Drug Administration to evaluate these compounds for the treatment of various bone ailments. In addition, BPs are often labeled with (99m)Tc or (186/188)Re and used for the imaging and treatment of pain as a result of bone metastases from cancer such as that of the breast or the prostate (3). However, these compounds have limited efficacy primarily because they exist either as a mixture of anionic compounds with varying properties (e.g., (99m)Tc-labeled methyl diphosphonate (MDP)) or are unstable (e.g., (86)Re-labeled 1-hydroxyethylidene-1,1-diphosphonate) under in vivo conditions, resulting in a reduced uptake at targeted bone areas and an increased accumulation in non-target soft tissue such as the gastric lining of the stomach (4). The limited clinical utility of radiolabeled BPs was suggested to be caused by the dual activities exhibited by the compounds: one phosphonate group acts as a radionuclide chelator, and the other phosphonate group binds to the target(s). Therefore, due to the close proximity of the two groups, one activity may be interfering with the other (4). In an effort to solve the stability problems observed with the (186)Re-labeled NBPs, Ogawa et al. developed two new NBPs, (186)Re-[N-[2-[[3-(3,3-diphosphonopropylcarbamoyl)propyl]-2-thioethylamino]acetyl ]-2-aminoethylenethiolate] oxorhenium (V) ([(186)Re]MAMA-BP) and its hydroxylated derivative, (186)Re-[N-[2-[[4-[(4-hydroxy-4,4-diphosphonobutyl)amino]-4-oxobutyl]-2-thioethyl amino]acetyl]-2-aminoethanethiolate] oxorhenium (V) ([(186)Re]MAMA-HBP) (3). The two compounds were then compared for their affinity to HA under in vitro conditions and the biodistribution of the radiochemicals was investigated in normal mice. This chapter presents the results obtained with [(186)Re]MAMA-HBP. Results obtained with [(186)Re]MAMA-BP are presented in a separate chapter of MICAD (5).

*20642011*
 20642011

(99m)Tc-Labeled 6-hydrazinopyridine-3-carboxylic acid conjugated to hydroxy-bisphosphonate

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Bisphosphonates (BPs) or nitrogen-containing bisphosphonates (NBPs) are often used for the management of pain palliation and disorders related to skeletal tissue, including those arising from cancer metastases, because these compounds exhibit a very high affinity for hydroxyapatite (HA), a component of the bone matrix (1). The NBPs tend to accumulate in osteoclasts at areas of increased bone metabolism by inhibiting the farnesyl diphosphate synthase, an important enzyme of the mevalonate pathway in the cell (2). Several BPs and NBPs are available commercially for clinical use to treat different bone disorders, and there are ongoing clinical trials approved by the United States Food and Drug Administration to evaluate these compounds for the treatment of various bone ailments. In addition, BPs are often labeled with (99m)Tc or (186/188)Re and used for the imaging and treatment of bone metastases. However, these compounds have limitations primarily because they either exist as a mixture of anionic compounds with varying properties (e.g., [(99m)Tc]-labeled methylene-diphosphonate (MDP) or [(99m)Tc]-labeled hydroxymethylene-diphosphonate (HMDP)) or are rapidly degraded (e.g., [(186/188)Re]MDP) under in vivo conditions, resulting in a reduced uptake at targeted bone areas and an increased accumulation in non-target soft tissue (3). The (99m)Tc- or (186/188)Re-labeled BPs were suggested to have these limitations because the compounds possess dual activities: one phosphonate group of the BP molecule acts as a radionuclide chelator, and the other phosphonate group binds to the target(s). Therefore, due to close proximity of the two groups, one activity may be interfering with the other (3). To circumvent problems associated with the radiolabeled BPs, investigators developed NBPs with two independent activities such that the nitrogen-containing part would only chelate the radiotracer and the BP part would target the bone (4). Ogawa et al. synthesized and labeled two NBPs, 6-hydrazinopyridine-3-carboxylic acid-hydroxy-bisphosphonate (HYNIC-HBP) and mercaptoacetylglycylglycylglycine-hydroxy-bisphosphonate (MAG3-HBP), with (99m)Tc to obtain [(99m)Tc]HYNIC-HBP and [(99m)Tc]MAG3-HBP (4). The two imaging agents were valuated for binding to hydroxyapatite (HA) under in vitro conditions and for bone scintigraphy in normal rats (4). This chapter presents the studies performed and the results obtained with [(99m)Tc]HYNIC-HBP. The in vitro and in vivo studies and the results obtained with [(99m)Tc]MAG3-HBP are presented in a separate chapter in MICAD (www.micad.nih.gov) (5).

*20642004*
 20642004

(99m)Tc-Labeled mercaptoacetylglycylglycylglycine conjugated to hydroxy-bisphosphonate

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Bisphosphonates (BPs) or nitrogen-containing bisphosphonates (NBPs) are often used for the management of pain palliation and disorders related to skeletal tissue, including those arising from cancer metastases, because these compounds exhibit a very high affinity for hydroxyapatite (HA), a component of the bone matrix (1). The NBPs tend to accumulate in osteoclasts at areas of increased bone metabolism by inhibiting the farnesyl diphosphate synthase, an important enzyme of the mevalonate pathway in the cell (2). Several BPs and NBPs are available commercially for clinical use to treat different bone disorders, and there are ongoing clinical trials approved by the United States Food and Drug Administration to evaluate these compounds for the treatment of various bone ailments. In addition, BPs are often labeled with (99m)Tc or (186/188)Re and used for the imaging and treatment of bone metastases. However, these compounds have limitations primarily because they either exist as a mixture of anionic compounds with varying properties (e.g., [(99m)Tc]-labeled methylene-diphosphonate (MDP) or [(99m)Tc]-labeled hydroxymethylene-diphosphonate (HMDP)) or are rapidly degraded (e.g., [(186/188)Re]MDP) under in vivo conditions, resulting in a reduced uptake at targeted bone areas and an increased accumulation in non-target soft tissue (3). The (99m)Tc- or (186/188)Re-labeled BPs were suggested to have these limitations because the compounds possess dual activities: one phosphonate group of the BP molecule acts as a radionuclide chelator, and the other phosphonate group binds to the target(s). Therefore, due to close proximity of the two groups, one activity may be interfering with the other (3). To circumvent problems associated with the radiolabeled BPs, investigators developed NBPs with two independent activities such that the nitrogen-containing part would only chelate the radiotracer and the BP part would target the bone (4). Ogawa et al. synthesized and labeled two NBPs, mercaptoacetylglycylglycylglycine-hydroxy-bisphosphonate (MAG3-HBP) and 6-hydrazinopyridine-3-carboxylic acid-hydroxy-bisphosphonate (HYNIC-HBP), with (99m)Tc to obtain [(99m)Tc]MAG3-HBP and [(99m)Tc]HYNIC-HBP (4). The two imaging agents were valuated for binding to hydroxyapatite (HA) under in vitro conditions and for biodistribution in normal rats (4). This chapter presents the studies performed and the results obtained with [(99m)Tc]MAG3-HBP. The studies and the results obtained with [(99m)Tc]HYNIC-HBP are presented in a separate chapter in MICAD (www.micad.nih.gov) (5).

*20642002*
 20642002

Carbobenzoxy-capped Phe-Lys(BODIPY TMR-X-acyloxymethyl ketone(QSY7)

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

The human cysteine cathepsins have 11 members (cathepsins B, C, H, F, K, L, O, S, V, W, and X/Z) and share a conserved active site that is formed by cysteine, histidine, and asparagine residues (1-5). Cathepsins B, L, H, F, O, X/Z, and C are expressed ubiquitously, whereas the expression of cathepsins S, K, W, and V are relatively organ-limited. Cysteine cathepsins interact with other proteases (aspartic, metallo, serine, and threonine) in a cascade-like manner, involving various physiological processes, including protein degradation, precursor protein activation, MHC-II-mediated antigen presentation, bone remodeling, keratinocytes differentiation, hair follicle cycle, reproduction, and apoptosis (6, 7). Increased expression and activity, and relocalization to the plasma membrane of cysteine cathepsins are associated with the pathogenesis of a number of human diseases such as cancer, atherosclerosis, and neurodegenerative diseases, and changes related to cysteine cathepsins have been shown to be of diagnostic and prognostic value for the diseases (2, 8-11). Significant efforts have been made in developing optical molecular probes of protease activity (4, 7, 12, 13). These probes are either substrate-based or activity-based, providing a readout of the enzyme activity rather than simple protein abundance. Substrate-based probes (SBPs) are designed using fluorescent peptide sequences tethered to a large polymer or dendramer backbone, and these SBPs are internally quenched by the high density of fluorophores loaded onto the backbone structure. Similar to conventional enzymatic tests, SBPs appear to be less reliable because of overlapping substrate specificities, enzymatic activity instability, and interactions with endogenous inhibitors. Activity-based probes (ABPs) label target proteases through the formation of a covalent bond with the active site cysteine. The selectivity of an ABP is controlled by both its peptide selectivity sequence and reactive functional group. The fluorescent reporter allows probe-labeled cathepsins to be directly visualized. Because ABPs tend to be small molecules, the in vivo half-lives of ABPs are relatively short, which results in the production of high-contrast images. A drawback of using a covalent probe is the lack of signal amplification because the target proteases are inactivated upon binding the probe. However, sufficient levels of the active proteases have been found to exist in tumor tissues, which allows the generation of reasonable contrast images using noninvasive methods (4, 7, 12). Blum et al. synthesized a group of near-infrared fluorescent activity-based probes (NIRF-ABPs) for noninvasive optical imaging of cysteine protease activity (4, 7, 12, 14). These probes can be subgrouped into quenched ABPs (qABPs) (e.g., GB117, GB119, GB135, and GB137) and nonquenched ABPs (e.g., GB111, GB123, and GB138). In short, the probes consist of a reactive group of peptide acyloxymethyl ketone (AOMK) that targets diverse members of cysteine cathepsins. The ketone in AOMK reacts with the cysteine in the enzyme active site and produces a stable thiomethyl ketone adduct. The covalent binding involves the loss of the acyloxy group of AOMK. Thus, a probe carrying a fluorescent reporter group on its peptide scaffold and a highly efficient quenching molecule attached to the acyloxy-losing group should result in a quenched probe that only becomes fluorescent upon covalent binding with an enzyme. In addition, a spacer is designed to reduce the steric congestion between the reporter and the fluorescence quencher. Blum et al. have shown that the NIRF-ABPs are nontoxic to cells, reasonably water soluble, potentially valuable as imaging agents for disease diagnosis, and powerful tools for in vivo preclinical and clinical testing of small-molecule therapeutic agents. Although NIRF-ABPs present different features regarding stability, specificity, and kinetics, the quenched probes can be used to image specific protease activity at considerably earlier time points than can be used for substrate-based methods or nonquenched ABPs. However, high levels of signal in large organs with high cathepsin activity such as liver, kidney, and spleen make activity-based imaging of specific locations within the central body cavity difficult. In this chapter, the synthesis and analytic results of quenched GB117 were introduced, which were compared with that of GB111. The quenched GB117 and its corresponding nonquenched control GB111 are the first generation of this group of NIRF-ABPs.

*20641999*
 20641999

Carbobenzoxy-capped Phe-Lys(Cy5)-acyloxymethyl ketone

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

The human cysteine cathepsins have 11 members (cathepsins B, C, H, F, K, L, O, S, V, W, and X/Z) and share a conserved active site that is formed by cysteine, histidine, and asparagine residues (1-5). Cathepsins B, L, H, F, O, X/Z, and C are expressed ubiquitously, whereas the expression of cathepsins S, K, W, and V are relatively organ-limited. Cysteine cathepsins interact with other proteases (aspartic, metallo, serine, and threonine) in a cascade-like manner, involving various physiological processes, including protein degradation, precursor protein activation, MHC-II-mediated antigen presentation, bone remodeling, keratinocytes differentiation, hair follicle cycle, reproduction, and apoptosis (6, 7). Increased expression and activity, and relocalization to the plasma membrane of cysteine cathepsins are associated with the pathogenesis of a number of human diseases such as cancer, atherosclerosis, and neurodegenerative diseases, and changes related to cysteine cathepsins have been shown to be of diagnostic and prognostic value for the diseases (2, 8-11). Significant efforts have been made in developing optical molecular probes of protease activity (4, 7, 12, 13). These probes are either substrate-based or activity-based, providing a readout of the enzyme activity rather than simple protein abundance. Substrate-based probes (SBPs) are designed using fluorescent peptide sequences tethered to a large polymer or dendramer backbone, and these SBPs are internally quenched by the high density of fluorophores loaded onto the backbone structure. Similar to conventional enzymatic tests, SBPs appear to be less reliable because of overlapping substrate specificities, enzymatic activity instability, and interactions with endogenous inhibitors. Activity-based probes (ABPs) label target proteases through the formation of a covalent bond with the active site cysteine. The selectivity of an ABP is controlled by both its peptide selectivity sequence and reactive functional group. The fluorescent reporter allows probe-labeled cathepsins to be directly visualized. Because ABPs tend to be small molecules, the in vivo half-lives of ABPs are relatively short, which results in the production of high-contrast images. A drawback of using a covalent probe is the lack of signal amplification because the target proteases are inactivated upon binding the probe. However, sufficient levels of the active proteases have been found to exist in tumor tissues, which allows the generation of reasonable contrast images using noninvasive methods (4, 7, 12). Blum et al. synthesized a group of near-infrared fluorescent activity-based probes (NIRF-ABPs) for noninvasive optical imaging of cysteine protease activity (4, 7, 12, 14). These probes can be subgrouped into quenched ABPs (qABPs) (e.g., GB117, GB119, GB135, and GB137) and nonquenched ABPs (e.g., GB111, GB123, and GB138). In short, the probes consist of a reactive group of peptide acyloxymethyl ketone (AOMK) that targets diverse members of cysteine cathepsins. The ketone in AOMK reacts with the cysteine in the enzyme active site and produces a stable thiomethyl ketone adduct. The covalent binding involves the loss of the acyloxy group of AOMK. Thus, a probe carrying a fluorescent reporter group on its peptide scaffold and a highly efficient quenching molecule attached to the acyloxy-losing group should result in a quenched probe that only becomes fluorescent upon covalent binding with an enzyme. In addition, a spacer is designed to reduce the steric congestion between the reporter and the fluorescence quencher. Blum et al. have shown that the NIRF-ABPs are nontoxic to cells, reasonably water soluble, potentially valuable as imaging agents for disease diagnosis, and powerful tools for in vivo preclinical and clinical testing of small-molecule therapeutic agents. Although NIRF-ABPs present different features regarding stability, specificity, and kinetics, the quenched probes can be used to image specific protease activity at considerably earlier time points than can be used for substrate-based methods or nonquenched ABPs. However, high levels of signal in large organs with high cathepsin activity such as liver, kidney, and spleen make activity-based imaging of specific locations within the central body cavity difficult. In this chapter, the synthesis and analytic results of nonquenched ABP GB123 were introduced. GB123 is the Cy5 version of the first generation of nonquenched ABP GB111.

*20641998*
 20641998

(99m)Tc/(188)Re-Labeled dipicolylamine-alendronate

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Bisphosphonates (BPs) or nitrogen-containing bisphosphonates (NBP) are often used for the management of pain palliation and disorders related to skeletal tissue, including those arising from cancer metastases, because these compounds exhibit a very high affinity for hydroxyapatite (HA), a component of the bone matrix. These phosphonates tend to accumulate in osteoclasts at areas of increased bone metabolism by inhibiting the farnesyl diphosphate synthase, an important enzyme of the mevalonate pathway in the cell (1), as described by Drake et. al. (2). Several BPs and NBPs are available commercially for clinical use to treat different bone disorders, and there are ongoing clinical trials approved by the United States Food and Drug Administration to evaluate these compounds for the treatment of various bone ailments. In addition, BPs are often labeled with (99m)Tc or (186/188)Re and used for the imaging and treatment of bone metastases. However, these compounds have limitations primarily because they exist either as a mixture of anionic compounds with varying properties (e.g., (99m)Tc-labeled methyl diphosphonate (MDP)) or are rapidly degraded (e.g., [(186/188)Re]MDP) under in vivo conditions, resulting in a reduced uptake at targeted bone areas and an increased accumulation in non-target soft tissue (3). The (99m)Tc- or (186/188)Re-labeled BPs were suggested to have these limitations because the compounds possess dual activities: one phosphonate group of the BP molecule acts as a radionuclide chelator, and the other phosphonate group binds to the target(s). Therefore, due to the close proximity of the two groups, one activity may be interfering with the other (3). To circumvent problems associated with the radiolabeled BPs, investigators developed NBPs with two independent activities such that the nitrogen-containing part would only chelate the radiotracer and the BP part would target the bone (4, 5). These NBPs are produced by complex synthetic procedures, are usually obtained as enantomeric mixtures, and bind to plasma proteins (3). In an effort to produce a NBP that does not have these limitations, Torres Martin de Rosales et al. synthesized an easy-to-produce dipicolylamine-alendronate (DPA-alendronate), which has the radionuclide binding part separated from the BP by a spacer. After labeling the agent with (99m)Tc ([(99m)Tc]DPA-alendronate), the investigators compared its biodistribution and use as an imaging agent against [(99m)Tc]MDP in normal Balb/c mice (3). In another study the investigators compared the ex vivo biodistribution and imaging characteristics of (188)Re(CO)3-labeled DPA-alendronate ([(188)Re(CO)3]-alendronate) to those of clinically approved (188)Re-hydroxyethylidene-1,1-diphosphonate ([(188)Re]-HEDP) (6).

*20641992*
 20641992

Polyethylene glycol-gold nanoparticles

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

X-Ray imaging, or computed tomography (CT), visualizes tissue density differences that provide the image contrast produced by X-ray attenuation between soft tissues and electron-dense bone (1). Radiopaque X-ray contrast agents are needed to enhance the degree of contrast between diseased tissues and normal tissues. Water-soluble X-ray contrast agents are generally based on small tri-iodobenzene compounds such as monomers or dimers (2), which can be ionic (high osmolality) or nonionic (low osmolality). When injected intravenously, commonly via intra-arterial catheterization, these agents exhibit highly nonspecific vascular permeation and rapid renal excretion, which limits their targeting performance. Gold has not been used as an X-ray contrast agent in vivo. Gold has a higher atomic number and a higher absorption coefficient than iodine, providing 2.7-fold greater contrast/weight than iodine (3). Furthermore, imaging gold at 80-100 keV reduces interference from bone absorption and provides lower soft tissue absorption, which would reduce radiation to patients. Hainfeld et al. (3) used gold nanoparticles (AuNPs; 1.9 nm in diameter, ~50 kDa) as a CT contrast agent in mice; these experiments showed enhanced CT contrast of the vasculature, kidneys, and tumor in mice. However, plasma proteins in blood adsorb onto the surface of bare AuNPs, which produces large aggregates (4) that may result in altered pharmacokinetics and biodistribution of AuNPs (5). Polyethylene glycol (PEG) is found to minimize nonspecific adsorption of proteins onto NPs and to reduce their uptake by the liver (5). PEG-AuNPs are being studied as cancer CT imaging and photothermal agents (6).

*20641962*
 20641962

(123)I-Labeled (S)-2-(3-((S)-1-carboxy-5-(4-iodobenzylamino)pentyl)ureido)pentanedoic acid

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

The prostate-specific membrane antigen (PSMA), a membrane-bound glycoprotein that possesses different peptidase activities (see Table above), is expressed mainly in the prostate epithelium. Because of its overexpression in primary, metastatic or hormone-refractory prostate and other cancers, including the neovasculature of solid tumors, this antigen is considered to be a cancer marker and a good target for imaging agents and therapy (1). Hence, PSMA has been targeted in several clinical trials that have been approved by the United States Food and Drug Administration (FDA) for the treatment of prostate cancer. In addition, capromab pendetide, a commercially available monoclonal antibody (MAb) that binds to the intracellular domain of the PSMA and was approved by the FDA for the diagnostic imaging of prostate cancer, has limited use because the MAb binds primarily to necrotic parts of the tumor and may not detect any viable malignant tumor cells (2). Investigators have also developed and evaluated MAbs directed against the extracellular domains of PSMA, and after preclinical studies they reported that these MAbs could be of potential use in the detection and treatment of PSMA-positive cancers (3-5). However, results obtained from a phase I clinical trial to evaluate the use of (111)In-labeled/unlabeled J591 MAb mixture to detect and target the PSMA-positive vasculature of progressive solid tumors in patients with breast, colon, liver, or kidney cancers showed that, although the antibody was well tolerated, selectively targeted a variety of solid tumors, but it did not yield any positive therapeutic response(s) (6). The investigators concluded that this was probably because the large molecular size of the MAb was a hindrance to its complete penetration into the tumors. In addition, therapeutic MAbs have poor pharmacokinetic profiles in normal tissues because they have an extended circulation period compared with the small molecule drugs. Radiolabeled small molecule drugs have an advantage over MAbs because they are inexpensive to produce, can easily penetrate solid tumors, and, due to their pharmacokinetic properties, are superior for use in the detection (by imaging techniques) and therapy of cancerous tumors. On the basis of the facts presented above, a series of small-molecule inhibitors of PSMA were recently synthesized for possible use in conjunction with single-photon emission computed tomography/computed tomography (SPECT/CT) for the detection and staging of prostate cancer (7). Two of these compounds, (S)-2-(3-((S)-1-carboxy-5-(3-(4-iodobenzylamino)pentyl)ureido)pentanedoic acid (MIP-1072) and (S)-2-(3-((S)-1-carboxy-5-(3-(4-iodophenyl)ureido)pentyl)ureido)pentanedoic acid (MIP-1095), were labeled with (123)I by Hillier et al. for evaluation as molecular imaging agents to detect prostate cancer in a mouse model (8). This chapter describes the studies performed with [(123)I]MIP-1072 under in vitro conditions and its biodistribution in mice bearing LNCaP (derived from human metastatic prostate carcinoma; expresses PSMA) and PC (developed from the bone marrow of a patient with secondary myelodisplastic syndrome; does not express PSMA; for further details regarding this cell line see (9)) cell xenograft tumors. Studies performed with [(123)I]MIP-1095 are presented in a separate chapter in MICAD (www.micad.nih.gov) (10).

*20641935*
 20641935

(99m)Tc-Labeled trans-1,2-cyclohexyldinitrilo tetramethylene phosphonic acid

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Cancers such as those of the breast, prostate, kidney, and thyroid have a high incidence of metastases, particularly in the bone, which results in bone resorption, pain, hypercalcemia, spinal compression, decreased mobility, and even fractures (1). In addition, osteoporosis (bone resorption), a common condition experienced most frequently by menopausal women as well as aging women and men, often leads to bone fractures in these individuals (2). Although chemo- and radiotherapy are often used to treat bone metastases, none of these treatments control the progression of this disease or result in a better prognosis for the patient. Because of their attraction to hydroxyapatite, a major component of bone, bisphosponates (BPs) or their nitrogen-containing derivatives (N-BPs) are the most commonly used compounds for the selective targeting and treatment of bone-related ailments observed during cancer metastases or osteoporosis (3, 4). The chemical structure, characteristics, and pharmacological behavior of BPs and their derivatives have been described by Hirabayashi and Fujisaki (3). Briefly, the parent BP compound contains a characteristic phosphate-carbon-phosphate (P-C-P) bond that is resistant to enzymatic digestion and has no substitution at the central carbon (5); N-BPs, however, have a nitrogen-containing moiety substituted on the carbon atom (6). BPs and N-BPs have been shown to inhibit bone-related events by different mechanisms (7), and N-BPs were reported to be 100- to 10,000-fold more potent than BPs (8). Both BPs and N-BPs are approved by the United States Food and Drug Administration for the treatment of bone diseases such as osteoporosis, Paget's disease of the bone, hypercalcemia, and bone metastases. In addition, these drugs are being evaluated in clinical trials for the treatment and imaging of different bone-related disorders. Accurate and early noninvasive detection of osteoporosis or bone metastases can assist in the development of a suitable treatment strategy and possibly improve the prognosis for a patient. Radiolabeled BPs, such as methyl diphosphonate (MDP) (9), hydroxymethylene diphosphonate, 1-hydroxyethylene diphosphonate, etc., are often used as imaging agents for the detection of bone remodeling (e.g., during cancer metastases) or repair (e.g., after a fracture) because these compounds tend to accumulate in osteoclasts at active bone sites (10). Although radiolabeled N-BPs have been used for the therapy of bone cancer in animals (11) and humans (12), no N-BPs have been evaluated or used for bone imaging. Panwar et al. (13) synthesized a (99m)Tc-labeled multidentated N-BP, trans-1,2-cyclohexyldinitrilo tetramethylene phosphonic acid ((99m)Tc-CDTMP) and investigated its biodistribution in mice. The investigators also compared the whole-body scintigraphic images of rabbits treated with (99m)Tc-CDTMP with those obtained after treatment with (99m)Tc-MDP. In addition, imaging with (99m)Tc-CDTMP was performed on cancer patients with bone metastases, and the ratios of radioactivity accumulated in the bone lesion to soft tissue and the normal bone were determined.

*20641928*
 20641928

(99m)Tc-Methyl diphosphonate

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Invasive procedures are often necessary to treat internal bone injuries or disorders. Therefore it is important for individuals providing treatment to accurately diagnose the disorder to provide the most suitable therapy before subjecting the patient to any invasive procedures. Bone injuries are often investigated either by magnetic resonance imaging (MRI) or single-photon emission computed tomography (SPECT) scans using radionuclides (1). The SPECT technique is based on imaging of radionuclides and the fact that certain elements or compounds concentrate selectively in specific tissue. Compared to other imaging techniques, e.g., planar scintigraphy, SPECT provides detailed information about the anatomy and physiological state of the bone (1, 2). Bone SPECT has been used to detect early osteonecrosis of the femoral head in renal transplant patients (3), to investigate internal derangement and stress fractures of the knee (4, 5) and also to monitor bone metastasis in breast (6), gastric (7), and prostate (8) cancers. Imaging with (99m)Tc-methylene diphosphonate ((99m)Tc-MDP) is the initial method of choice to detect skeletal metastases in cancer patients (9). For SPECT of the bone, metastable technetium ((99m)Tc) is tagged onto a phosphonate compound such as MDP to generate (99m)Tc-MDP, which selectively concentrates in the bone. Although accumulation of (99m)Tc-MDP in the bone is caused by its chemical adsorption onto, and into, the crystalline structure of hydroxyapatite (10), but the enzyme aminoacyl-tRNA synthetase is believed to convert it into ATP analogues that inhibit any ATP-dependent enzymes and result in cellular apoptosis (11). For scintigraphy the labeled compound is administered intravenously to the patient and SPECT is subsequently performed after suitable time periods. (99m)Tc-MDP has been approved by the US Food and Drug Administration as an imaging agent to investigate osteogenesis and is commercially available in kit form (12).Results obtained with any new radiolabeled compound being evaluated for bone imaging in clinical trials are compared to those obtained with (99m)Tc-MDP.

*20641923*
 20641923

(64)Cu-4,11-Bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-cyclic-a rginine-glycine-aspartic acid peptide

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

(64)Cu-4,11-Bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-cyclic arginine-glycine-aspartic acid peptide [(64)Cu-CD-TE2A-c(RGDyK)] is an integrin-targeted molecular imaging agent developed for positron emission tomography (PET) of tumor vasculature, tumor angiogenesis, and osteoclasts (1). Cellular survival, invasion, and migration control embryonic development, angiogenesis, tumor metastasis, and other physiologic processes (2, 3). Among the molecules that regulate angiogenesis are integrins, which comprise a superfamily of cell adhesion proteins that form heterodimeric receptors for extracellular matrix (ECM) molecules (4, 5). These transmembrane glycoproteins consist of two noncovalently associated subunits, alpha and beta (18 alpha- and 8 beta-subunits in mammals), which are assembled into at least 24 alpha/beta pairs. Several integrins, such as integrin alphavbeta3, have affinity for the arginine-glycine-aspartic acid (RGD) tripeptide motif, which is found in many ECM proteins. Expression of integrin alphavbeta3 receptors on endothelial cells is stimulated by angiogenic factors and environments. The integrin alphavbeta3 receptor is generally not found in normal tissue, but it is strongly expressed in vessels with increased angiogenesis, such as tumor vasculature. It is significantly upregulated in certain types of tumor cells and in almost all tumor vasculature. Molecular imaging probes carrying the RGD motif that binds to the integrin alphavbeta3 can be used to image tumor vasculature and evaluate angiogenic response to tumor therapy (6, 7). Various RGD peptides in both linear and cyclic forms have been developed for in vivo binding to integrin alphavbeta3 (8). Chen et al. (9) evaluated a cyclic RGD peptide [c(RGDyK)] labeled with (64)Cu or (18)F in nude mice bearing breast tumor. They used 1,4,7,10-tetrazadodecane-N,N',N'',N'''-tetraacetic acid (DOTA) for c(RGDyK) conjugation with (64)Cu. (64)Cu-DOTA-c(RGDyK) showed prolonged tumor radioactivity retention but persistent liver radioactivity. Osteoclasts express high levels of alphavbeta3 (1, 10), and alphavbeta3 ligands have also been shown to inhibit osteoclastic bone resorption (11). The skeleton is one of the most common organs of cancer metastasis. Osteolytic bone lesions are difficult to detect, and molecular imaging agents that target osteoclasts in vivo can be useful for imaging osteolytic bone metastases and monitoring their responses to therapy. Boswell et al. (12) showed that the (64)Cu complex of the cross-bridged macrocyclic chelator 4,11-bis(carboxymethyl)-1,4,8,11-tetraazabicyclo[6.6.2]hexadecane (CB-TE2A) had less in vivo transchelation and improved liver clearance in normal rats than other cyclen derivatives. Sprague et al. (1) prepared (64)Cu-CB-TE2A-c(RGDyK)] and showed that this radioligand selectively bound to osteoclasts in mice with induced osteoclastogenesis.

*20641878*
 20641878

(99m)Tc-Labeled 5-amino-1,3-bis(ethylamine-(N,N-dimethyl diphosphonic acid)acetamido)benzene

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Cancers such as those of the breast, prostate, kidney, and thyroid have a high incidence of metastases, particularly in the bone, which results in bone resorption, pain, hypercalcemia, spinal compression, decreased mobility, and even fractures (1). In addition, osteoporosis (bone resorption), a common condition experienced most frequently by menopausal women as well as aging women and men, often leads to bone fractures in these individuals (2). Although chemo- and radiotherapy are often used to treat bone metastases, none of these treatments control the progression of this disease or result in a better prognosis for the patient. Bisphosponates (BPs) or their nitrogen-containing derivatives (N-BPs) are the most commonly used compounds for the selective targeting and treatment of bone-related ailments observed during cancer metastases or osteoporosis (3, 4) because of their attraction to hydroxyapatite, a major component of bone, and because they alleviate, to some extent, the symptoms and complications arising from these conditions. The chemical structure, characteristics, and pharmacological behavior of BPs has been described by Hirabayashi and Fujisaki (3). Briefly, the parent BP compound contains a characteristic phosphate-carbon-phosphate (P-C-P) bond that is resistant to enzymatic digestion and has no substitution at the central carbon (5); N-BPs, however, have a nitrogen-containing moiety substituted on the carbon atom (6). BPs and N-BPs were shown to inhibit bone-related events by different mechanisms (7), and N-BPs were reported to be 100- to 10,000-fold more potent than BPs (8). BPs and N-BPs are approved by the United States Food and Drug Administration for the treatment of bone diseases such as osteoporosis, Paget's disease of the bone, hypercalcemia, and bone metastases. In addition, these drugs also being evaluated in clinical trials for the treatment and imaging of different bone-related disorders. Accurate and early noninvasive detection of osteoporosis or bone metastases can assist in the development of a suitable treatment strategy and possibly improve the prognosis for a patient. Radiolabeled BPs, such as methyl diphosphonate (MDP) (9), hydroxymethylene diphosphonate, 1-hydroxyethylene diphosphonate, etc., are often used as imaging agents for the detection of bone remodeling (e.g., during cancer metastases) or repair (e.g., after a fracture) because these compounds tend to accumulate in osteoclasts at active bone sites (10). Although radiolabeled N-BPs have been used for the therapy of bone cancer in animal models (11) and humans (12), no N-BPs have been used for bone imaging. Panwar et al. (13) synthesized a (99m)Tc-labeled multidentated N-BP, 5-amino-1,3-bis(ethylamine-(N,N-dimethyl phosphonic acid)acetamido)benzene (or 5-aminoisophthalate tetramethylene phosphonic acid ((99m)Tc-IPTMP)) and investigated its biodistribution in mice. The accumulation of (99m)Tc-IPTMP in select organs of the animals was compared to that of the same organs obtained from animals treated with (99m)Tc-MDP. Whole-body scintigraphic imaging of rabbits treated with the radiolabeled compound was also performed by the investigators.

*20641869*
 20641869

(123)I-Labeled (S)-2-(3-((S)-1-carboxy-5-(3-(4-iodophenyl) ureido)pentyl)ureido)pentanedoic acid

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

The prostate-specific membrane antigen (PSMA), a membrane-bound glycoprotein that possesses different peptidase activities (see Table above), is expressed mainly in the prostate epithelium. Because of its overexpression in primary, metastatic or hormone-refractory prostate and other cancers, including the neovasculature of solid tumors, this antigen is considered to be a cancer marker and a good target for imaging agents and therapy (1). Hence, PSMA has been targeted in several clinical trials that have been approved by the United States Food and Drug Administration (FDA) for the treatment of prostate cancer. In addition, capromab pendetide, a commercially available monoclonal antibody (MAb) that binds to the intracellular domain of the PSMA and was approved by the FDA for the diagnostic imaging of prostate cancer, has limited use because the MAb binds primarily to necrotic parts of the tumor and may not detect any viable malignant tumor cells (2). Investigators have also developed and evaluated MAbs directed against the extracellular domains of PSMA, and after preclinical studies they reported that these MAbs could be of potential use in the detection and treatment of PSMA-positive cancers (3-5). However, results obtained from a phase I clinical trial to evaluate the use of (111)In-labeled/unlabeled J591 MAb mixture to detect and target the PSMA-positive vasculature of progressive solid tumors in patients with breast, colon, liver, or kidney cancers showed that, although the antibody was well tolerated, selectively targeted a variety of solid tumors, but it did not yield any positive therapeutic response(s) (6). The investigators concluded that this was probably because the large molecular size of the MAb was a hindrance to its complete penetration into the tumors. In addition, therapeutic MAbs have poor pharmacokinetic profiles in normal tissues because they have an extended circulation period compared with the small molecule drugs. Radiolabeled small molecule drugs have an advantage over MAbs because they are inexpensive to produce, can easily penetrate solid tumors, and, due to their pharmacokinetic properties, are superior for use in the detection (by imaging techniques) and therapy of cancerous tumors. On the basis of the facts presented above, a series of small-molecule inhibitors of PSMA were recently synthesized for possible use in conjunction with single-photon emission computed tomography/computed tomography (SPECT/CT) for the detection and staging of prostate cancer (7). Two of these compounds, (S)-2-(3-((S)-1-carboxy-5-(3-(4-iodophenyl)ureido)pentyl)ureido)pentanedoic acid (MIP-1095) and (S)-2-(3-((S)-1-carboxy-5-(3-(4-iodobenzylamino)pentyl)ureido)pentanedoic acid (MIP-1072), were labeled with (123)I by Hillier et al. for evaluation as molecular imaging agents to detect prostate cancer in a mouse model (8). This chapter describes the studies performed with [(123)I]MIP-1095 under in vitro conditions and its biodistribution in mice bearing LNCaP (derived from human metastatic prostate carcinoma; expresses PSMA) and PC (developed from the bone marrow of a patient with secondary myelodisplastic syndrome; does not express PSMA; for further details regarding this cell line please see (9)) cell xenograft tumors. Studies performed with [(123)I]MIP-1072 are presented in a separate chapter in MICAD (www.micad.nih.gov) (10).

*20641856*
 20641856

2'-Fluoro-5-([(11)C]-methyl)-1-beta-D-arabinofuranosyluracil

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Thymidine radiolabeled with radioactive C-14 or H-3 (TdR) is routinely used in vitro to measure cell proliferation and cell growth in various biological systems because it is a necessary and exclusive precursor for the synthesis of DNA (1). However, TdR can be easily catabolized by enzymes after in vivo administration and has resulted in the development of TdR derivatives that are not degraded and can be used to follow DNA synthesis to measure cell proliferation and growth (2, 3). Initially, a C- or H-labeled TdR was produced for imaging studies with positron emission tomography (PET); however, because this compound was catabolized and produced recirculating labeled products that reduced the tumor/normal tissue contrast, it was difficult to interpret results after its incorporation into DNA (4). As a consequence, to circumvent the catabolite issue observed with TdR, some investigators developed TdR analogs that could be used for tumor imaging but were not catabolized (3, 5). Among the various TdR derivatives, those labeled with radioactive fluorine ((18)F) or (11)C were developed to image and monitor tumors because, compared to normal tissue, rapid cell proliferation is a characteristic feature of these cancer lesions (6). Although [(18)F]-3'-deoxy-3'-fluorothymidine ([(18)F]FLT) has been used in the clinic to study different cancers, it has a limitation in that, within the cell, it is only converted into a triphosphate nucleoside, is not incorporated into the growing strand of DNA, and leads to DNA chain termination (7). The phosphorylation of FLT is taken to be an indicator of cytosolic thymidine kinase (TK1) activity rather than DNA synthesis, and the use of TK1 activity as a measure of DNA synthesis is not well established (8). Also, [(18)F]FLT is not a suitable agent to detect malignancies in the liver and bone marrow because it produces a high background in these tissue (9). In addition, because [(18)F]FLT is excreted through the urinary system, pelvic lesions may not be detected with this radiochemical (1). Another analog of TdR, 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)thymidine (FMAU) has been labeled with either (18)F or (11)C and used to study cell proliferation or image tumors in vivo (2, 10, 11). The only difference between FMAU and TdR is the substitution of a hydrogen atom with fluorine at the 2'-position of the deoxyarabinose sugar moiety in the molecule (2). FMAU was shown to possess the same biological properties as TdR, including transport across the cell membrane, enzymatic phosphorylation, and incorporation into cellular DNA (12). Compared to TdR, clearance of (11)C-labeled FMAU ([(11)C]FMAU) from the blood was observed to be slower and showed a higher incorporation in tumors (12). After conversion to a triphosphate, FMAU was shown to have an inhibitory effect on the hepatitis B virus polymerase and is approved by the United States Food and Drug Administration for evaluation in clinical trials to treat this infection (13). This chapter details the preclinical studies performed with [(11)C]FMAU. Studies performed with [(18)F]FMAU are presented in a separate chapter in MICAD (www.micad.nih.gov).

*20641855*
 20641855

(64)Cu-1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid-quantum dot-vascular endothelial growth factor

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Vascular endothelial growth factor (VEGF), also known as vascular permeability factor, is a homodimeric glycoprotein weighing ~45 kDa (1). The VEGF family consists of six groups: VEGF-A, -B, -C, -D, -E, and the placental growth factor (PIGF) (2). Structurally, VEGFs are related to the platelet-derived growth factors (PDGF), and they all contain the characteristic eight-cysteine residues known as the cysteine knot motif (3). Intrachain and interchain disulfide bonds are formed between these cysteine residues in conserved positions (2). VEGFs bind specifically to three cell-surface receptor tyrosine kinases, including fms-like tyrosine kinase-1 (Flt-1) or VEGF receptor-1 (VEGFR-1), kinase insert domain-containing receptor (KDR) or VEGRF-2, and Flt-4 or VEGFR-3. Each VEGFR contains a 750-amino acid-residue extracellular domain that is organized into seven immunoglobulin-like folds. VEGF and VEGFRs have been implicated in angiogenesis in many solid tumors, including breast cancer, colon cancer, hepatoma, bladder cancer, gastric cancer, and prostate cancer (3). VEGFR-2 (~220 kDa) is expressed exclusively in endothelial cells in cell differentiation, tumor vascularization, and metastasis. VEGF-A (the original VEGF) binds to the second and third extracellular immunoglobulin G loop of VEGFR-2 with a dissociation constant of ~100 pM (4). Hypoxia appears to be an important stimulus for producing VEGF in malignant and normal endothelial cells (3). Upon binding to its receptor VEGFR-2, VEGF-A elicits a pronounced angiogenic response, so it is considered as a predominant stimulator of angiogenesis. Human VEGF-A has five different isoforms generated by alternative slicing of a single pre-mRNA species, VEGF-A121, VEGF-A145, VEGF-A165, VEGF-A189, and VEGF-A206, which comprises 121,145,165, 189, and 206 amino acids, respectively (2). These isoforms differ in their ability to bind to heparin sulfate and extracellular matrix (ECM). Quantum dots (QDs) are semiconductor nanocrystals of 2 to 10 nm in diameter (200-10,000 atoms) that possess a quantum confinement effect (hence the name "quantum dots") caused by the restriction of electrons and holes in all three dimensions (5, 6). Like classic semiconductors that are composed of two types of atoms from the II/VI or III/V group elements in the periodic table, the nanocrystals have a valence band and a conduction band separated by an energy gap (band gap). Upon excitation, an electron is promoted from the filled valence band to the largely empty conduction band, which creates a positive vacancy "hole" in the valence band. The spatial separation (Bohr radius) of this electron-hole pair ("exciton") is typically 1 to 10 nm for most semiconductors (6). The quantum confinement arises when one of the dimensions in the nanocrystals becomes comparable to its Bohr radius, these valence/conduction bands are quantized with an energy value that is directly related to the nanocrystal size. Thus, the excitons are confined in a manner similar to a particle-in-the-box problem, leading to a finite band gap and discretization of energy levels. When the electron fills the vacancy in the valence band, light of a certain wavelength is emitted, which corresponds to the respective band gap energy that is a function of nanocrystal size. For instance, the emission wavelength is 550 nm for 3-nm CdSe QDs and 650 nm for 7-nm CdSe QDs (7). The wavelength is also a function of semiconductor compositions, i.e., 5-nm CdTe has an emission wavelength of 700 nm, which is much higher than the 620 nm for 5-nm CdSe (8). QDs are 100 to 1,000 times more stable against photobleaching and are 10 to 100 times brighter than organic dyes. QDs have relatively long fluorescence lifetime (20-50 ns), which allows for time-resolved detection of their emitted fluorescence. For biological applications, QDs are generally encapsulated with biocompatible polymers that can increase their hydrodynamic diameter as much as two-fold (9). When their size is <5 nm, QDs are quickly cleared by renal filtration, whereas larger particles are more likely to be taken up by the reticuloendothelial system before reaching the targeted disease sites. Thus, after systematic administration, non-targeted QDs and some targeted QDs accumulate in substantial quantities in reticuloendothelial system, including the phagocytic cells in the liver, spleen, lymph nodes, and bone marrow (5). QDs can also accumulate in solid tumor tissue through the enhanced permeability and retention (EPR) effect regardless of whether they are conjugated with targeting ligands. As a whole, QDs have been widely used in cell trafficking, vasculature imaging, sentinel lymph node mapping, neural imaging, and targeting imaging (5). (64)Cu-1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid-QD-VEGF factor ((64)Cu-DOTA-QD-VEGF) is a multimodal agent used for imaging VEGFRs with positron emission tomography (PET) and near-infrared (NIFR) optical imaging (10). (64)Cu-DOTA-QD-VEGF consists of three components. An amine-functionalized QD (QD705) is used as a NIFR sensor and as a platform for carrying target-specific ligands. VEGF proteins are attached to the surface of QDs for recognition of VEGFRs. Complexes of the macrocyclic chelating agent DOTA with (64)Cu(II) ((64)Cu-DOTA) are also covalently attached to the surface of QDs. (64)Cu is a positron-emitting radionuclide with an intermediate half-life (12.7 h) that decays by positron (beta(+)) with a branching factor of 17.4% and a maximum beta(+) energy of 0.653 MeV (11). (64)Cu has been used as a radiotracer in PET imaging and as a radiotherapy agent in cancer treatment. QD705, which is commercially available, comprises a CdTe core shell with a thin layer of ZnS and polyethylene glycol (PEG2000)-attached amine groups (12). The emission wavelength of QD705 (705 nm) is located in the NIRF region (700-900 nm) where the absorbance of all biomolecules reaches a minimum (10). The use of a ZnS shell can increase the quantum yield of CdTe up to 30% to 50% (5). The PEG is used to decrease surface charge, increase colloidal stability of QDs, and reduce non-specific binding of QDs (13). Although QDs are used to examine cellular alteration, their in vivo detection is limited by the penetration depth of light. Thus, PET as a highly sensitive and quantitative modality can provide complementary information about tissues in depth. This PET/NIRF dual-modality probe may combine the advantages of QD optical imaging and PET imaging to assess the pharmacokinetics and targeting efficacy of QDs.

*20641777*
 20641777

(124)I-Anti-PSCA 2B3 minibody

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Prostate stem-cell antigen (PSCA) is a cell-surface protein (123 amino acids) that is expressed in normal prostate tissue and overexpressed in prostate cancer tissues (1). PSCA expression is detected in >80% of patients with local disease including high expression in bone metastases (2). Elevated levels of PSCA are correlated with increased tumor stage, grade, and androgen independence (3). PSCA overexpression is also observed in bladder and pancreatic cancers (4). The anti-PSCA murine monoclonal antibody (mAb) 1G8 has been shown to have anti-tumor activity (5). A humanized version of the 1G8 mAb (hu1G8) has been radiolabeled as (124)I-hu1G8 for tumor imaging in mice (6). However, it took ~1 week to observe an enhanced target/background ratio with positron emission tomography because of the slow kinetics of the mAb. A hu1G8 minibody fragment (2B3) (a dimer of scFvs-CH3 with a linker composed of 18 amino acids; molecular weight,~80 kDa) has been developed and labeled as (124)I-2B3 minibody for tumor targeting studies (7).

*20641706*
 20641706

4,16alpha-[16alpha-(18)F]Difluoro-11beta-methoxyestradiol

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Estrogens and progestins are endogenous hormones that produce many physiological effects (1). Estrogens act primarily by regulating gene expression. Estrogen receptors (ERs) are found in the nucleus of cells of the female reproductive tract, breast, pituitary, hypothalamus, bone, liver, and other tissues, and also in various tissues in men. Estrogens are lipophilic in that they enter the cell passively by diffusion through the cellular membrane. They bind to ERs that are present in the nucleus. Breast cancer is the most common malignancy in women. Approximately 33% of women who have this disease will die of disseminated breast cancer. The growth of breast epithelial cells is dependent on estrogen stimulation to induce progestin receptor expression. Two-thirds of breast carcinomas express ERs. It has also been established that the ER status of the tumor is an important prognostic indicator in breast cancer (2). Women with ER-positive breast tumors have a better prognosis than women with ER-negative tumors in terms of responsiveness to anti-estrogen treatment. ER content in breast cancer was assessed in vitro with receptor binding assays, which suffer from interassay variability and are also limited by intrinsic receptor heterogeneity of the tumor. 16alpha-[(18)F]Fluoro-17beta-estradiol ([(18)F]FES) has been proven to be a valuable tracer for studies of the ER status of primary and metastatic breast cancer (3). However, [(18)F]FES is cleared from the blood and metabolized in 20 min with only 20% of [(18)F]FES intact in a study with 15 breast cancer patients (4). A newly developed estradiol analog, 4,16alpha-[16alpha-(18)F]difluoro-11beta-methoxyestradiol (4F-M[(18)F]FES), exhibited favorable biodistribution in small animals and high uterus/background ratios in rodents (5) and humans (6).

*20641704*
 20641704

(131)I-Labeled [Z]-2-[4-(1,2-diphenyl-1-di-butenyl)-phenoxy]-N,N-dimethylethanamine

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Tamoxifen ([Z]-2-[4-(1,2-diphenyl-1-di-butenyl)-phenoxy]-N,N-dimethylethanamine (TAM)) is the first selective estrogen receptor (ER) modulator with extensive investigation for its anticancer properties (1, 2). The (131)I-labeled form of TAM ((131)I-TAM) was developed to study the tumor response to antiestrogenic treatment and the ER expression in tumors and critical normal tissues (3). TAM as first approved by the United States Food and Drug Administration in the 1970s for use in breast cancer treatment. Currently, it is widely used for the treatment of both early and advanced ER-positive breast cancer, as well as for the prevention of breast cancer in high-risk women (1, 4, 5). TAM itself is a prodrug, having relatively little affinity to ER. It is metabolized in the liver, mainly by the CYP2D6 and CYP3A4 enzymes (5, 6). Active metabolites such as 4-hydroxytamoxifen and N-desmethyl-4-hydroxytamoxifen have 30-100 times more affinity with the ER than TAM itself. These metabolites compete with estrogen for binding to ER and form a nuclear complex that inhibits DNA synthesis and blocks estrogen effects (5, 6). As a result, tumor cells stop proliferating and remain in the G0 and G1 phases of the cell cycle. In combination with other therapeutic agents or alone, TAM has also been shown to be antiangiogenic, which is, at least in part, independent of its ER-antagonist properties (7). TAM also has a number of other beneficial properties. For example, TAM lowers low-density lipoprotein cholesterol levels, increases bone density in postmenopausal women, and is effective against infertility in women with anovulatory disorders. In men, TAM is used to treat breast cancer, and it is also used to treat gynecomastia that arises from anti-androgen treatment in patients with prostate cancer. TAM has some side effects. It blocks the estrogen effects on mammary epithelial cells, but it mimics the estrogen actions in other tissues (2). The result of such selective effects on the uterus is stimulated proliferation of the endometrium (8). Each year, the risk of developing endometrial cancer is ~2 per thousand in women taking TAM compared with ~1 per thousand in women taking placebo (9). TAM also slightly increases the risk of developing uterine sarcoma. The other side effects include blood clots, strokes, cataracts, and symptoms of menopause. To maintain the beneficial properties without sharing the potentially harmful effects of TAM, a number of derivatives have been developed (2). However, these derivatives demonstrate differing amounts of success. Their ability to inhibit cancer ranges widely. Studies of tissue-based pharmacokinetics of TAM and its derivatives provide direct concentration-effect relationships in tumors and critical normal tissues, thus providing a more rational basis for the evaluation of new compounds and tumor response to treatment (10, 11). Generally speaking, the study results are controversial. Imaging studies have shown that [(18)F]fluorotamoxifen is useful in predicting the effect of TAM therapy in patients with ER-positive breast cancer (12, 13). The (123)I-trans-Z-iodomethyl-N,N-diethyltamoxifen has also been shown to be preferentially taken up by ER-positive tumors in patients with untreated primary breast cancer (14, 15). On the contrary, studies have failed to show the suitability for tumor localization of some derivatives, such as (131)I- and (99m)Tc-labeled geometrical isomers (E and Z) of the aminotamoxifen, (125)I-idoxifene and (11)C-toremifene (16-19). Recently, Muftuler et al. produced (131)I-TAM and investigated its biodistribution in rats. Their study demonstrated that the biodistribution of (131)I-TAM is ER-specific (3).

*20641702*
 20641702

[(99m)Tc]-1,4,7,10-Tetraazacyclododecane tetramethylenephosphonic acid

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Pathological conditions such as neoplastic diseases, metabolic disorders, infections, and cancers often result in metastases of the disease to the skeletal system. During the past 50 years, a variety of bone-seeking radiopharmaceuticals have been developed and evaluated to detect skeletal metastases by imaging (1-3) or as pain palliative agents in patients (4). The diagnostic radiochemicals, usually phosphate and phosphonate derivatives of compounds, are particularly useful to detect the metastasis because they localize avidly in the bone (5, 6). Most bone lesions have an elevated concentration of minerals (mostly calcium salts) that form a major part of the matrix surface area, and these lesions have a high affinity for and facilitate the adsorption of the bone imaging agents (1, 7). Compared to phosphates, the phosphonate compounds are more stable under in vivo conditions because the phosphate bond with oxygen in pyrophosphate (P-O-P) is easily cleaved by chemical or enzymatic action, whereas the phosphonate bond in the diphosphonate (P-C-P) is insensitive to enzymatic or chemical action (8). Because of its stability and long retention in the bone, radionuclide-labeled methylene diphosphonate and its derivatives are routinely used for bone imaging to detect fractures or to detect and treat osteomyelitis and cancer metastasis (9-11). Radioactive samarium ((153)Sm) coupled to a tetraphosphonate (ethylenediamine-tetramethylenephosphonic acid ((153)Sm-lexidronam)) is approved by the United States Food and Drug Administration for pain palliation as a result of cancer that has metastasized to the bone. Similarly, another tetraphosphonate, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetramethylene phosphonic acid (DOTMP), was conjugated with radioactive bismuth ((212)Bi, a gamma emitter) and has been shown to be promising for the treatment of bone cancer under preclinical conditions (12). In an effort to develop an imaging agent, Datta et al. (13) envisioned that DOTMP conjugated with radioactive technetium ((99m)Tc-DOTMP) could possibly be used for the early detection of bone cancer or metastasis with single-photon emission computed tomography (SPECT). In a preliminary study the radiolabeled compound was evaluated for bone scintigraphy in normal rabbits, and its biodistribution was investigated in normal BALB/c mice.

*20641623*
 20641623

Thermally cross-linked superparamagnetic iron oxide nanoparticle-A10 RNA aptamer-doxorubicin conjugate

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Prostate-specific membrane antigen (PSMA) is a type II membrane glycoprotein with a molecular weight of ~100 kDa (1). PSMA is composed of several domains, including a potential phosphorylation site in the cytoplasmic tail (amino acids 1-18), a highly hydrophobic alpha-helix in the transmembrane region (amino acids 19-43), and catalytic sites in the extensive extracellular domain (amino acids 44-750). Two unique enzymatic functions are found in PSMA: N-acetylated, alpha-linked, dipeptidase (NAALADase) activity and folate hydrolase activity. As a prostate cancer cell (PCa) marker, PSMA expression is primarily prostate-specific (~100% in androgen-independent PCa cells), with very low levels (~1,000-fold less) in the brain, salivary glands, and small intestine. Thus, PSMA has become an excellent target for imaging and therapy. Aptamers (from the Latin aptus, to fit, and the Greek meros, part or region) are single-stranded or double-stranded oligonucleotides (RNA or DNA, respectively) that are modified to bind a variety of targets with high binding affinity and specificity (2). Aptamers range in size from 20 to 80 base pairs (~6-26 kDa) with dissociation constants in the range of 10 pM to 10 nM (3). Unlike linear oligonucleotides, which contain genetic information or antisense oligonucleotides that interrupt the transcription of genetic information, aptamers are globular molecules with a shape similar to tRNA and bind to target proteins specifically (4). A10 RNA aptamer (Apt) is a nuclease-stabilized 2'-fluoropyrimidine RNA molecule of 57 base pairs with a molecular weight of 18.5 kDa (5). Its 2'-fluoro-modified ribose on all pyrimidines and 3'-inverted deoxythymidine cap provide significant resistance to nuclease in blood (6). Apt has a single 5'-CG-3' sequence in its predicted double-stranded stem region, which is a preferred binding site for the anthracycline class of anticancer drugs such as doxorubicin (Dox) (7). Dox intercalates within the GC pair in Apt to form physical conjugate Apt(Dox) at molar ratio of 1.11:1 (dissociation constant = 600 nM) and emit fluorescence simultaneously. Because Dox possesses high efficacy against a range of neoplasms, including acute lymphoblastic and myeloblastic leukemias, malignant lymphomas, soft tissue and bone sarcomas, and breast, ovarian, prostate bladder, gastric, and bronchogenic carcinomas (8), this complex can be used as a PSMA-specific drug carrier to deliver Dox to PCa. Superparamagnetic iron oxide nanoparticles (SPION) consist of magnetite (Fe3O4), which has a high magnetic susceptibility to induce a significant magnetization inside a magnetic field. The resulting microscopic field gradients diphase nearby protons and cause a reduction of T2 relaxation times (9). SPION readily forms aggregates as a result of nonspecific adsorption of plasma protein in blood, and SPION is cleared rapidly from the body by functions of the reticular endothelial system (RES) such as via macrophages (10). Coating the surface of SPION with a protein-repelling polymer layer such as poly(ethyleneglycol) (PEG) can prevent the absorption of plasma proteins or cells onto the surface of SPION (11). The coating can be conducted via surface trialkoxysilane as an anchor part (12). For example, poly(3-trimethoxysilyl)propyl methacrylate-r-PEG methyl ether methacrylate) (poly(TMSMA-r-PEGMA)) is a PEG-silane copolymer consisting of surface-reactive Si(OMe)3 groups and protein-repelling PEG chains (11). This coating becomes highly stabilized by simple heat treatment through condensation of hydrolyzed silane group (Si(OH)3) to form a thermally cross-linked (TCL) polymer. TCL-SPION-A10 RNA aptamer-doxorubicin conjugate (TCL-SPION-Apt(Dox)) is a PSMA-specific agent used for magnetic resonance imaging the delivery of the anticancer drug Dox (13). TCL-SPION-Apt(Dox) contains three components: a PSMA-specific RNA aptamer A10 (Apt) covalently attached to the core surface as a targeting molecule and drug carrier, an anthracycline class of anticancer drug Dox as chemotherapeutic agent and optical sensor, and a TCL-SPION coated with a TCL carboxylic acid-PEG-silane copolymer as a magnetic resonance contrast agent and as a carrier for Apt(Dox). The PEGylated surface prevents protein and cell adsorption, while the carboxyl groups allow for conjugation of targeting moieties such as Apt. TCL-SPION-Apt(Dox) can be used to image the drug delivery to PCas.

*20641568*
 20641568

FluidMAG iron nanoparticle-labeled mesenchymal stem cells for tracking cell homing to tumors

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Personalized diagnosis and treatment with allogenic or autologous cells are becoming a reality in the field of medicine (1, 2). Cytotoxic or engineered T-cells are under clinical trial for the treatment of hematopoietic or other malignant diseases (3). Contrast agent-tagged macrophages are used as cellular probes to image the early inflammatory processes in macrophage-rich conditions such as inflammation, atherosclerosis, and acute cardiac graft rejection (4). The roles of stem cells are under intensive investigation in therapeutic and regenerative medicine, such as regenerating cardiomyocytes, neurons, bone, and cartilage (1). Genetically modified cells are used to treat genetic disorders (5). With promising results from these studies, a critical issue is how to monitor the temporal and spatial migration and the homing of these cells, as well as the engraftment efficiency and functional capability of the transplanted cells in vivo (6, 7). Histopathological techniques have only been used to obtain information on the fate of implanted cells at the time of animal euthanization or via biopsy or surgery. To track the real-time changes of cell location, viability, and functional status, cell imaging techniques have been introduced during the last few years. Cells of interest are labeled with reporter genes, fluorescent dyes, or other contrast agents that transform the tagged cells into cellular probes or imaging agents (2, 6, 7). The ability to monitor superparamagnetic iron oxide particles (SPIO) with magnetic resonance imaging (MRI) has been utilized in animal models as well as in a few clinical settings to investigate the fate of labeled cells (6-10). The advantages of using MRI for cell tracking include the high spatial resolution with high anatomic background contrast, the lack of exposure to ionizing radiation, and the ability to follow the cells for months, although it is difficult to measure the rate of cell division and to determine whether each progeny shares the SPIO in vivo. In addition, cell labeling with SPIO nanoparticles is generally nontoxic and does not affect the cell proliferation and differentiation capacity, although a few studies have reported that the stem cells labeled with SPIO lose part of their differentiation capacity in a SPIO concentration-dependent manner. An important limitation of MRI is the fact that MRI signals cannot indicate whether cells are dead or alive. It is also unknown whether the MRI signal comes from targeted or labeled cells or from macrophages. Basically, SPIO particles are used to label the target cells by systemic application or by injection into the tissue area of interest to monitor target cell migration after phagocytosis. SPIO are more frequently used to label the cells in vitro by incorporating into the cells directly. Furthermore, SPIO are usually encapsulated by organic polymers to increase their stability and biocompatibility and to allow the chemical modification of their surfaces. The fact is that the uptake of different particles varies largely between different cell types and between particle coatings (6, 7). Msenchymal stem cells (MSCs) represent a heterogeneous subset of pluripotent stromal cells that can be isolated from different adult tissues including adipose tissue, liver, muscle, amniotic fluid, placenta, umbilical cord blood, and dental pulp, although the bone marrow remains the principal source for most preclinical and clinical studies (1, 11, 12). Although MSCs account for only 0.001-0.01% of the total nucleated cells within isolated bone marrow aspirates, they can easily be isolated and expanded in vitro through as many as 40 population doublings after 8-10 weeks of culture (1, 13). These cells exhibit the potential to differentiate into cells of diverse lineages such as adipocytes, chondrocytes, osteocytes, myoblasts, cardiomyocytes, neurons, and astrocytes. In addition, MSCs show tropism or homing to tumors and thus have been used as vehicles for directed cancer delivery (14, 15). The mechanism responsible for the homing of MSCs to tumors is thought to involve chemokine ligands and receptors, as with the recruitment of leukocytes to areas of inflammation. However, unlike with leukocytes, the specific chemokines responsible for MSC migration are poorly characterized (14, 15). Nevertheless, homing to tumors has been confirmed with traditional immunohistochemistry and other methods in many studies. Loebinger et al. labeled MSCs with fluidMAG iron nanoparticles and imaged homing of the labeled MSCs to tumors with MRI (16). FluidMAG nanoparticles are commercially available ferrofluids consisting of an aqueous dispersion of magnetic iron oxides with a hydrodynamic diameter of 200 nm and a starch coating. The investigators showed that as few as 1,000 labeled MSCs were detected 1 month after their co-injection with breast cancer cells that formed subcutaneous tumors. The investigators further demonstrated that intravenously injected labeled cells could be tracked in vivo to home to multiple lung metastases (16).

*20641467*
 20641467

16alpha-[(18)F]Fluoro-17beta-estradiol

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Estrogens and progestins are endogenous hormones that produce many physiological effects. Estrogens act primarily by regulating gene expression. Estrogen receptors are found in the cell nucleus of the female reproductive tract, breast, pituitary, hypothalamus, bone, liver, and other tissues, and also in various tissues in men. Estrogens are lipophilic that they enter the cell passively by diffusion through the cellular membrane. They bind to estrogen receptors that are present in the nucleus. Breast cancer is the most common malignancy in women. About 33% of women who have this disease will die of disseminated breast cancer. The growth of breast epithelial cells is dependent on estrogen stimulation to induce progestin receptor expression. Two-thirds of breast carcinomas express ERs. It has also been established that the ER status of the tumor is an important prognostic indicator in breast cancer (1). Women with ER-positive breast tumors have a better prognosis than women with ER-negative tumors in terms of responsiveness to anti-estrogen treatment. ER content in breast cancer was assessed by receptor binding assays, which suffer from inter-assay variability and are also limited by intrinsic receptor heterogeneity of the tumor. 16alpha-[(18)F]Fluoro-17beta-estradiol ([(18)F]FES) was proven to be a valuable tracer for the studies of the ER status of primary and metastatic breast cancer (2).

*20641441*
 20641441

(S)-6-[(4-Chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-1-[(11)C]methyl-1H-benzotri azole

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Aromatase is an enzyme complex of the cytochrome P450 superfamily (1). It is composed of P450 and a flavoprotein called NADPH-P450 reductase. Its main function is to aromatize androgens to estrogens. Aromatase is present in many tissues, including granulosa cells of the ovary, brain, fat, placenta, blood vessels, skin, bone, and endometrium. Aromatase is overexpressed in tissue of endometriosis, uterine fibroids, breast cancer, and endometrial cancer (2-6). (S)-6-[(4-Chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole (vorozole) is an aromatase inhibitor with a inhibition constant (Ki) value of 1 nM. Lidstrom et al. (7) prepared [(11)C]vorozole by N-methylation of (S)-6-[(4-chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-1H-benzotriazole (nor-vorozole) to use as a positron emission tomography (PET) radioligand to study aromatase activity.

*20641399*
 20641399

Quantum dot-A10 RNA aptamer-doxorubicin conjugate

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Prostate-specific membrane antigen (PSMA) is a type II membrane glycoprotein with a molecular weight of ~100 kDa (1). PSMA is composed of several domains, including a potential phosphorylation site in the cytoplasmic tail (amino acids 1-18), a highly hydrophobic alpha-helix in the transmembrane region (amino acids 19-43), and catalytic sites in the extensive extracellular domain (amino acids 44-750). Two unique enzymatic functions are found in PSMA: N-acetylated, alpha-linked, dipeptidase (NAALADase) activity and folate hydrolase activity. As a prostate cancer cell marker, PSMA expression is primarily prostate-specific, with very low levels (~1,000-fold less) in the brain, salivary glands, and small intestine. PSMA has become an excellent target for imaging and therapy prostate cancer. Aptamers (from the Latin aptus, to fit, and the Greek meros, part or region) are single-stranded or double-stranded oligonucleotides (RNA or DNA, respectively) that are modified to bind a variety of targets with high binding affinity and specificity (2). Aptamers range in size from 20 to 80 base pairs (~6-26 kDa) with dissociation constants in the range of 10 pM to 10 nM (3). Unlike linear oligonucleotides, which contain genetic information or antisense oligonucleotides that interrupt the transcription of genetic information, aptamers are globular molecules with a shape similar to tRNA and bind to target proteins specifically (4). A10 RNA aptamer (Apt) is a nuclease-stabilized 2'-fluoropyrimidine RNA molecule of 57 base pairs with a molecular weight of 18.5 kDa (5). Its 2'-fluoro-modified ribose on all pyrimidines and 3'-inverted deoxythymidine cap provide significant resistance to nuclease in blood (6). Apt has a single 5'-CG-3' sequence in its predicted double-stranded stem region, which is a preferred binding site for the anthracycline class of anticancer drugs such as doxorubicin (Dox) (7). Dox intercalates within the GC pair in Apt to form physical conjugate Apt(Dox) at molar ratio of 1.11:1 (dissociation constant = 600 nM) and emit fluorescence simultaneously. Because Dox possesses high efficacy against a range of neoplasms, including acute lymphoblastic and myeloblastic leukemias, malignant lymphomas, soft tissue and bone sarcomas, and breast, ovarian, prostate bladder, gastric, and bronchogenic carcinomas (8), this complex can be used as a PSMA-specific drug carrier to deliver Dox to prostate cancer cells. Quantum dots (QDs) are semiconductor nanocrystals 2 to 10 nm in diameter (200-10,000 atoms) that possess a quantum confinement effect (hence the name "quantum dots") caused by the restriction of electrons and holes in all three dimensions (9, 10). Like classic semiconductors that are composed of two types of atoms from the II/VI or III/V group elements in the periodic table, these nanocrystals have a valence band and a conduction band separated by an energy gap (band gap). Upon excitation, an electron is promoted from the filled valence band to the largely empty conduction band, which creates a positive vacancy "hole" in the valence band. The spatial separation (Bohr radius) of this electron-hole pair ("exciton") is typically 1-10 nm for most semiconductors (10). The quantum confinement arises when one of the dimensions in the nanocrystals becomes comparable to its Bohr radius, at which time these valence/conduction bands are quantized with an energy value that is directly related to the nanocrystal size. Thus, the excitons are confined in a manner similar to a particle-in-the-box problem, leading to a finite band gap and discretization of energy levels. When the electron fills the vacancy in the valence band, light of a certain wavelength is emitted, which corresponds to the respective band gap energy that is a function of nanocrystal size. For instance, the emission wavelength is 550 nm for 3-nm CdSe QDs and 650 nm for 7-nm CdSe QDs (11, 12). For biological applications, QDs are generally encapsulated with biocompatible polymers, functionalized for various bioconjugations, and widely used to label molecules for optical imaging. The QD-Apt(Dox) conjugate is an PSMA-specific agent used for optical imaging of the delivery of the anticancer drug Dox (13). QD-Apt(Dox) consists of three components: PSMA-specific Apt covalently attached to the core surface as targeting molecule and drug carrier, an anthracycline class of anticancer drug Dox as a therapeutic agent and optical sensor, and a carboxyl core-CdSe/ZnS shell QD (QD490) as a carrier of A10 and Dox and as the second optical sensor. The two sensors (Dox and QD) generate an optical signal via formation of bi-molecular fluorescence resonance energy transfer (Bi-FRET) complex. FRET is a near-field dipole-dipole interaction that involves energy transfer between two molecules in close proximity (3-6 nm). In QD-Apt(Dox), there is a donor-acceptor relationship between QDs and Dox. The fluorescence of both QD and Dox is quenched ("OFF") when QD-Apt is loaded with Dox, and fluorescence is restored upon the release of Dox ("ON") after the uptake of QD-Apt(Dox) by prostate cancer cells. Thus, QD-Apt(Dox) can be used to image drug delivery to prostate cancer cells.

*20641322*
 20641322

Cy5.5-Gly-Pro-Leu-Gly-Val-Arg-Gly-Cys-gold nanoparticles

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Extracellular matrix (ECM) adhesion molecules consist of a complex network of fibronectins, collagens, chondroitins, laminins, glycoproteins, heparin sulfate, tenascins, and proteoglycans that surround connective tissue cells, and they are mainly secreted by fibroblasts, chondroblasts, and osteoblasts (1). Cell substrate adhesion molecules are considered essential regulators of cell migration, differentiation, and tissue integrity and remodeling. These molecules play a role in inflammation and atherogenesis, but they also participate in the process of invasion and metastasis of malignant cells in the host tissue (2). Invasive tumor cells adhere to the ECM, which provides a matrix environment for permeation of tumor cells through the basal lamina and underlying interstitial stroma of the connective tissue. Overexpression of matrix metalloproteinases (MMPs) and other proteases by tumor cells allows intravasation of tumor cells into the circulatory system after degrading the basement membrane and ECM (3). Gold has not been used as an X-ray contrast agent in vivo. Gold has a higher atomic number and a higher absorption coefficient than iodine, providing 2.7-fold greater contrast/weight than iodine (4). Furthermore, imaging gold at 80-100 keV reduces interference from bone absorption and provides lower soft tissue absorption, which would reduce radiation to patients. Hainfeld et al. (4) used gold nanoparticles (AuNPs; 1.9 nm in diameter, ~50 kDa) as a computed tomography (CT) contrast agent in mice; these experiments showed enhanced CT contrast of the vasculature, kidneys, and tumor in mice. However, plasma proteins in blood adsorb onto the surface of bare AuNPs, which produces large aggregates (5) that may result in altered pharmacokinetics and biodistribution of AuNPs (6). Polyethylene glycol (PEG) has been found to minimize nonspecific adsorption of proteins onto NPs and to reduce their uptake by the liver (6). PEG-AuNPs have been being studied as cancer CT imaging and photothermal agents (7). Several families of MMPs are involved in atherogenesis, myocardial infarction, angiogenesis and tumor invasion and metastases (8-11). MMP expression in normal cells, such as trophoblasts, osteoclasts, neutrophils, and macrophages, is highly regulated. Elevated levels of MMPs have been found in tumors associated with a poor prognosis for cancer patients (12). The peptide Gly-Pro-Leu-Gly-Val-Arg-Gly-Cys-NH2 was found to be a MMP substrate and is cleaved between Leu and Gly residues. Lee et al. (13) used this sequence with a Cy5.5 NIR dye molecule to attach to AuNPs to form fluorescence-quenched nanoparticles (Cy5.5-Gly-Pro-Leu-Gly-Val-Arg-Gly-Cys-AuNPs (Cy5.5-MMP-AuNPs)). The Cy5.5 molecules are in close proximity, which results in fluorescence quenching because of efficient fluorescence resonance energy transfer to Au. The NIR fluorescence signal increases when the Leu-Gly bond is cleaved by MMPs, releasing Cy5.5-containing fragments. Cy5.5 is a NIR fluorescent dye with absorbance maximum at 675 nm and emission maximum at 694 nm with a high extinction coefficient of 250,000 M(-1)cm(-1). Cy5.5-MMP-AuNPs are being developed for NIR fluorescence imaging of MMPs expressed in tumors, atherosclerosis, myocardial infarction, and other diseases.

*20641223*
 20641223

(111)In-Diethylenetriamine pentaacetic acid-human epidermal growth factor

Molecular Imaging and Contrast Agent Database (MICAD)-/- 2004; ():

Radioimmunotherapy is an attractive choice for the treatment of lymphomas because antibodies directed against specific tumor cell targets can be linked to radionuclides such as iodine ((131)I), yttrium ((90)Y), etc., for the lethal irradiation of cancer cells (1). The main advantage of these agents is the ability of the emitted beta-particles, because of their long path lengths, to provide therapeutic doses that are evenly distributed to cells in the tumor and affect even the surrounding cancerous cells that do not bind the radiolabeled antibody (2). Radioimmunotherapy with beta-emitters has shown some success in the treatment of lymphomas, but the long circulation time and high dose of the labeled antibodies resulted in the development of dose-limiting, nonspecific myelotoxicity in some patients (3). In contrast, the short-range, Auger electron-emitting radionuclides such as iodine ((125)I) and indium ((111)In) are radiotoxic to cells only after internalization because they cause cellular DNA fragmentation that leads to cell death (4). Reilly et al. envisioned that Auger electron emitters could be used to target cancerous cells after conjugation to internalized antibodies, and the radiopharmaceutical would potentially show little or no toxicity to the bone marrow cells (5). The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein that mediates biological activity through an intracellular tyrosine kinase-signaling pathway. It is known to be overexpressed in a variety of human malignancies, and the degree of EGFR expression often indicates the clinical prognosis for the patient because individuals with higher levels of EGFR were shown to have a poor survival rate (6). Blocking EGFR activity appears to be an effective approach for the treatment of cancers, and a variety of agents, including monoclonal antibodies (MAb), have been developed for this purpose (7). The EGFR is particularly a target for the treatment of breast cancer because it is present in most estrogen receptor-negative and hormone-resistant forms of the neoplastic condition (8). In an effort to develop an alternate treatment, a radiopharmaceutical was developed by derivatizing human epidermal growth factor (hEGF) with diethylenetriamine pentaacetic acid (DTPA) and conjugating it with (111)In to obtain (111)In-DTPA-hEGF (9-16). The labeled hEGF was then evaluated in vitro and in vivo for imaging and possible treatment of hormone-resistant breast cancer in a mouse model (9-16).

*20641206*
 20641206

Counseling to Promote a Healthy Diet

Counseling to Promote a Healthy Diet-/-U.S. Preventive Services Task Force Evidence Syntheses, formerly Systematic Evidence Reviews 2002; ():

CONTEXT: Diseases associated with overeating, undereating, and dietary or nutritional imbalance rank among the leading causes of illness and death in the United States. The relationships between specific dietary elements and specific health outcomes have been widely researched and are reasonably well understood; similarly, the role of primary care providers in providing or arranging for dietary counseling has been extensively investigated, but controversy exists about the magnitude of change than can be achieved and the effectiveness of different counseling strategies. OBJECTIVE: To update the chapter from the 1996 Guide to Clinical Preventive Services examining the effectiveness of counseling to promote a healthy diet and to assist the US Preventive Services Task Force in making recommendations on this topic. DESIGN AND DATA SOURCES: To produce this systematic evidence review, we developed an analytic framework and 7 key questions that represent the logical chain between dietary counseling (especially about intake of total and saturated fat, fruits and vegetables, and fiber) and health practices and outcomes, together with linkages between diet and nutritional constituents and health outcomes for a wide array of disorders (e.g., cardiovascular disease, cancer). To supplement citations from the 1996 Guide, we sought studies examining the effectiveness of dietary assessment and counseling using searches of MEDLINE for publications appearing from 1966 to 2000, by combining Medical Subject Headings related to diet and nutrition, primary care settings and practices, and counseling. We supplemented these searches with searches of the Cochrane Collaboration database and various bibliographies for recent systematic reviews and meta-analyses on the link between dietary patterns and health outcomes or between counseling and dietary behaviors. STUDY SELECTION: To examine the relationship with diet and health outcomes, we selected systematic reviews, observational studies, and randomized trials relating specific dietary patterns and health outcomes. For studies of dietary assessment, we selected studies that examined test accuracy compared with a criterion standard. For studies linking counseling interventions with dietary change, we selected randomized controlled trials with pre- and post-test measures. DATA EXTRACTION: Trained reviewers and the authors abstracted data from the eligible articles onto evidence tables; the first authors checked all abstractions. DATA SYNTHESIS: The relationships between dietary patterns and health outcomes have been examined in a wide range of observational studies. Few randomized trials have examined the effect of dietary interventions on health outcomes. The majority of studies show that persons consuming diets high in fruits, vegetables, fish, and whole grains or fiber and low in saturated and trans-unsaturated fats have lower rates of coronary heart disease and some forms of cancer. Similarly strong evidence supports the relationship between dietary intake of calcium and the risk of low bone mineral density. High intake of dietary sodium and low intake of dietary potassium are associated with higher blood pressure levels and increased incidence of hypertension. Efforts to reduce sodium intake and increase potassium have shown moderate effects on blood pressure, with greater effects seen in African-Americans and persons with hypertension. Several brief, valid dietary assessment instruments are feasible for the primary care setting. Although these instruments have not been evaluated as to their impact on health outcomes, they serve an important role of identifying dietary counseling needs and monitoring change over time. Many of these instruments are designed for specific patient populations or nutrients. We identified 33 articles examining the effect of nutritional counseling in primary care patients. Among primary care patients, nutrition counseling can produce modest improvements in saturated and total fat consumption, as well as fruit and vegetable consumption. The evidence is insufficient to determine the effectiveness of counseling in changing consumption of whole grains or fiber, calcium, sodium, or fish. Intensive interventions are more likely to produce large changes, but typical strategies pursued in primary care settings tend to be of lower intensity and produce smaller changes. Interventions using mailed or computer-generated materials appeared moderately effective, particularly in increasing fruit and vegetable consumption. Isolating the effect of a single counseling approach as more or less effective is made difficult by the tendency for counseling interventions to test multiple approaches simultaneously. Studies employing 3 or more well-proven counseling elements were more effective than those employing fewer elements. CONCLUSIONS: Diets low in saturated and trans-unsaturated fat and high in fruits, vegetables, fish, and whole grains are associated with better health outcomes. Counseling patients can improve dietary behaviors, including reduction in dietary total and saturated fat and increases in fruit and vegetable intake. More intensive counseling and counseling directed to higher-risk patients have generally produced larger changes than less intensive interventions delivered to low-risk populations.

*20722113*
 20722113

Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment (PDQ(R)): Health Professional Version

PDQ Cancer Information Summaries-/- 2002; ():

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of osteosarcoma and malignant fibrous histiocytoma of bone. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

*26389179*
 26389179

Oral Complications of Chemotherapy and Head/Neck Radiation (PDQ(R)): Patient Version

PDQ Cancer Information Summaries-/- 2002; ():

This PDQ cancer information summary has current information about the causes and treatment of oral complications of chemotherapy and head/neck radiation. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care. Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary ("Date Last Modified") is the date of the most recent change. The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Supportive and Palliative Care Editorial Board.

*26389169*
 26389169

Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment (PDQ(R)): Patient Version

PDQ Cancer Information Summaries-/- 2002; ():

This PDQ cancer information summary has current information about the treatment of osteosarcoma and malignant fibrous histiocytoma of bone. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care. Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary ("Date Last Modified") is the date of the most recent change. The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Pediatric Treatment Editorial Board.

*26389380*
 26389380

Oral Complications of Chemotherapy and Head/Neck Radiation (PDQ(R)): Health Professional Version

PDQ Cancer Information Summaries-/- 2002; ():

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of oral complications of chemotherapy and head/neck radiation. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions. This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

*26389320*
 26389320

Pathology And Pathogenesis Of Pituitary Adenomas And Other Sellar Lesions

Endotext-/- 2000; ():

The pituitary gland, or hypophysis, and adjacent structures of the sellar region can be affected by a wide range of pathologies leading to endocrine and neurological disorders. These include neoplasms arising from the adenohypophysis, such as pituitary adenomas associated with distinctive endocrine disorders such as acromegaly or Cushing's disease; cysts or neoplasms derived from remnants of Rathke's pouch (Rathke's cleft cyst, craniopharyngioma); tumours of the neurohypophysis and pituitary stalk (pituicytoma, granular cell tumour) and neoplasms of the parasellar bone (chordoma). Further, conditions like lymphocytic or granulomatous hypophysitis may mimic pituitary neoplasms. Here, we provide an overview of the molecular pathogenesis and neuropathological features of these common lesions. For complete coverage of this and related areas of Endocrinology, please visit our free web -book, www.endotext.org.

*28402620*
 28402620

Growth Hormone in Aging

Endotext-/- 2000; ():

Growth hormone (GH) serves important roles in adult life, including maintenance of lean body mass and bone mass, promoting lipolysis, thereby limiting visceral adiposity, and regulating carbohydrate metabolism, cardiovascular system function, aerobic exercise capacity and cognitive function. Younger adults with growth hormone deficiency (AGHD) exhibit abnormalities in body composition, physical and cognitive function and quality of life which are reversed by GH replacement therapy. With advancing age GH production declines, paralleled by physical and functional alterations similar to those of AGHD, however the degree to which the decrease in GH contributes to these age-related changes is unknown. Seemingly in opposition to the theory that the diminished GH secretion of older age is a net detriment are observations that animal models of congenital GH deficiency have remarkably increased life span and humans with congenital GH deficiency may have decreased rates of age-related diseases such as diabetes and cancer. Several short-term studies aiming to increase GH in older adults by a variety of interventions including exercise, administration of GH or treatment with GH secretagogues have demonstrated consistent effects to improve body composition, yet inconsistent effects on physical and cognitive function. While side effects of GH administration in older adults include edema, arthralgias and elevated blood glucose, data regarding the possible long-term effects on "hard end points" such as risk of fractures, cancer, cardiovascular disease, life expectancy, and mortality are lacking. For extensive review of all related areas of Endocrinology, visit WWW.ENDOTEXT.ORG.

*25905386*
 25905386

Paget's Disease of Bone

Endotext-/- 2000; ():

Sir James Paget described a skeletal disorder affecting one or more areas of the skeleton in 1876. It is most common in England and in countries to which the English migrated. In recent years the prevalence in most countries has decreased. A common feature is skeletal deformity which evolves over many years and is most visible in the skull and lower extremities. Pathological fractures are most likely to occur in the femurs. Pain is a common feature in patients with Paget's disease and may be of skeletal, joint, neurologic or muscle origin. The radiologic features begin with a localized area of osteolysis which advances very slowly in the absence of therapy. Over time the lesion becomes osteosclerotic and once an entire bone is affected the entire lesion is sclerotic with areas of osteolysis remaining. Bone scans utilizing technetium99m-labeled bisphosphonates exhibit markedly increased uptake in the untreated state. Histologic evaluation of early lesions reveals an increased number of osteoclasts advancing at the interface of normal bone. They are often larger than normal and contain many more nuclei than normal osteoclasts. Subsequently numerous osteoblasts are found to be producing a large amount of disorganized bone. Associated with the increase in osteoclasts and osteoblasts there is a highly vascular fibrocellular marrow replacing the hematopoietic marrow. The osteoclasts have an abnormal ultrastructure featuring nuclear inclusions, and sometimes, cytoplasmic inclusions resembling nucleocapsid-like structures of the Paramyxoviridae family. Measurement of serum or urine N- or C-telopeptides documents the degree of bone resorption and serum total alkaline phosphatase activity, serum bone specific alkaline phosphatase and serum procollagen type 1 amino-propeptide document bone formation. Serum total alkaline phosphatase activity is the least expensive and most widely used test. Patients may develop sarcomas or giant cell tumors in affected bone but this is rare. Metabolic complications include hypercalcemia associated with immobilization and hyperuricemia and gout in patients with more extensive disease. Increased cardiac output may occur in patients with extensive disease due to the vascularity of the lesions. The earliest effective treatment was calcitonin but with the increased efficacy of the more potent bisphosphonates calcitonin is seldom prescribed. The treatment of choice is presently an intravenous infusion of 5 mg zoledronate. This normalizes bone resorption and formation markers for up to six and a half years in most patients. Indications for treatment include bone pain, hypercalcemia, neurologic deficits with vertebral disease, congestive heart failure, preparation for orthopaedic surgery and prevention of complications such as hearing loss and deformity. Surgery most commonly is needed for lower extremity joint replacement and correction of deformities of the lower extremity. The etiology remains somewhat controversial with some studies indicating a role for measles virus. The observation that the prevalence of the disease has decreased could be explained by the introduction of measles vaccine in 1963. Clearly genetic factors also play a role. Mutations in the sequestosome 1 gene produce susceptibility to develop Paget's disease but not all family members with the mutation develop Paget's disease. Other gene abnormalities may also increase disease susceptibility. For complete coverage of this and all related ares of Endocrinology, please see our FREE web-book www.endotext.org.

*25905262*
 25905262

Metabolic Syndrome

Endotext-/- 2000; ():

Significant interest exists in understanding the shared metabolic dysregulation leading to obesity, diabetes, and cardiovascular disease (CVD). Hence came the concept of the "metabolic syndrome" (MetS). Reaven first described MetS in his 1988 Banting lecture as "Syndrome X". Reaven suggested that the syndrome hinged on the existence of insulin resistance and resulted in glucose intolerance, hypertension and dyslipidemia. The World Health Organization (WHO) produced the first formalized definition of the MetS in 1998. Since then multiple definitions of the syndrome have been proposed, the most recent being the Harmonized Definition where 3 of the 5 risk factors are present: enlarged waist circumference with population-specific and country-specific criteria; triglycerides >/= 150 mg/dL, HDL-C < 40 mg/dL in men and < 50 mg/dL in women, systolic blood pressure >/= 130 mm Hg or diastolic blood pressure >/= 85 mm Hg and fasting glucose > 100 mg/dL, with the inclusion of patients taking medication to manage hypertriglyceridemia, low HDL-C, hypertension, and hyperglycemia. The National Health and Nutrition Examination Survey (NHANES) estimated the overall prevalence of MetS in adults (aged >/= 20 years) in the United States as 33% from 2003 to 2012. The high prevalence is particularly alarming given that MetS also predisposes to a number of serious conditions beyond diabetes and CVD including non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), polycystic ovarian syndrome (PCOS), obstructive sleep apnea (OSA), cancer, and many other serious disease states. Hence, early identification and intervention are warranted. Lifestyle modification is the foundational intervention in treatment of MetS. Specifically, a healthy low-calorie, low fat diet and moderate physical activity of at least 150 minutes/week, resulting in a weight reduction of 7%. Obesity, hypertension and dyslipidemia may also be treated pharmacologically to meet individualized patient goals. Beyond the clinic imperative around MetS are its pathophysiologic underpinnings. This review will focus on the investigative work into the proximal origins of the MetS. Defects in insulin signaling occur in a shared environment of pro-inflammation, untoward adipokines coming from dysregulated fatty acid metabolism, as well as novel pathways involving the gut microbiota. Collectively, MetS continues to exist as a fertile area of research yielding significant insights into early events leading to the most prevalent cause of human morbidity and mortality. For in depth review of all related aspects of endocrinology, visit www.endotext.org.

*25905173*
 25905173

Possible Health Effects of Exposure to Residential Electric And Magnetic Fields

Possible Health Effects of Exposure to Residential Electric And Magnetic Fields-/- 1997; ():

Can the electric and magnetic fields (EMF) to which people are routinely exposed cause health effects? This volume assesses the data and draws conclusions about the consequences of human exposure to EMF. The committee examines what is known about three kinds of health effects associated with EMF: cancer, primarily childhood leukemia; reproduction and development; and neurobiological effects. This book provides a detailed discussion of hazard identification, dose-response assessment, exposure assessment, and risk characterization for each. Possible Health Effects of Exposure to Residential Electric and Magnetic Fields also discusses the tools available to measure exposure, common types of exposures, and what is known about the effects of exposure. The committee looks at correlations between EMF exposure and carcinogenesis, mutagenesis, neurobehavioral effects, reproductive and developmental effects, effects on melatonin and other neurochemicals, and effects on bone healing and stimulated cell growth.

*25121270*
 25121270

Sotos Syndrome

GeneReviews((R))-/- 1993; ():

CLINICAL CHARACTERISTICS: Sotos syndrome is characterized by a distinctive facial appearance (broad and prominent forehead with a dolichocephalic head shape, sparse frontotemporal hair, downslanting palpebral fissures, malar flushing, long and narrow face, long chin); learning disability (early developmental delay, mild-to-severe intellectual impairment); and overgrowth (height and/or head circumference >/=2 SD above the mean). These three clinical features are considered the cardinal features of Sotos syndrome. Major features of Sotos syndrome include behavioral problems (most notably autistic spectrum disorder), advanced bone age, cardiac anomalies, cranial MRI/CT abnormalities, joint hyperlaxity with or without pes planus, maternal preeclampsia, neonatal complications, renal anomalies, scoliosis, and seizures. DIAGNOSIS/TESTING: The diagnosis of Sotos syndrome is established in a proband by identification of a heterozygous NSD1 pathogenic variant or a deletion encompassing NSD1 on molecular genetic testing. MANAGEMENT: Treatment of manifestations: Referral to appropriate specialists for management of learning disability / speech delays, behavior problems, cardiac abnormalities, renal anomalies, scoliosis, seizures; intervention is not recommended if the brain MRI shows ventricular dilatation without raised intracranial pressure. Surveillance: Regular review by a general pediatrician for younger children, individuals with many medical complications, and families requiring more support than average; less frequent review of older children / teenagers and those individuals without many medical complications. GENETIC COUNSELING: Sotos syndrome is inherited in an autosomal dominant manner. More than 95% of individuals have a de novo pathogenic variant. If neither parent of a proband has Sotos syndrome, the risk to sibs of the proband is low (<1%). The risk to offspring of affected individuals is 50%. Prenatal testing for pregnancies at risk and preimplantation genetic diagnosis are possible if the NSD1 pathogenic variant has been identified in an affected family member.

*20301652*
 20301652

Fibrous Dysplasia/McCune-Albright Syndrome

GeneReviews((R))-/- 1993; ():

CLINICAL CHARACTERISTICS: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS), the result of an early embryonic postzygotic somatic activating pathogenic variant in GNAS (encoding the cAMP pathway-associated G-protein, Gsalpha), is characterized by involvement of the skin, skeleton, and certain endocrine organs. However, because Gsalpha signaling is ubiquitous, additional tissues may be affected. Cafe au lait skin macules are common and are usually the first manifestation of the disease, apparent at or shortly after birth. Fibrous dysplasia (FD), which can involve any part and combination of the craniofacial, axial, and/or appendicular skeleton, can range from an isolated, asymptomatic monostotic lesion discovered incidentally to severe disabling polyostotic disease involving practically the entire skeleton and leading to progressive scoliosis, facial deformity, and loss of mobility, vision, and/or hearing. Endocrinopathies include: Gonadotropin-independent precocious puberty resulting from recurrent ovarian cysts in girls and autonomous testosterone production in boys; Testicular lesions with or without associated gonadotropin-independent precocious puberty; Thyroid lesions with or without non-autoimmune hyperthyroidism; Growth hormone excess; FGF23-mediated phosphate wasting with or without hypophosphatemia in association with fibrous dysplasia; and Neonatal hypercortisolism. The prognosis for individuals with FD/MAS is based on disease location and severity. DIAGNOSIS/TESTING: In most individuals, the diagnosis of FD/MAS is based on the finding of two or more typical clinical features. In individuals whose only clinical finding is monostotic fibrous dysplasia, identification of a somatic activating pathogenic variant in GNAS by molecular genetic testing is required to establish the diagnosis. Variant detection depends on the level of mosaicism in the tissue and the sensitivity of the technique. MANAGEMENT: Treatment of manifestations: Management is most effectively accomplished by a multidisciplinary team of specialists. FD. Management focuses on optimizing function and minimizing morbidity related to fractures and deformity (including scoliosis). Precocious puberty. Treatment prevents bone age advancement and compromise of adult height. For girls, the aromatase inhibitor letrozole is used; for boys, treatment options are less well established. Thyroid disease. Methimazole effectively manages hyperthyroidism; however, because hyperthyroidism is persistent, thyroidectomy is common. Growth hormone excess. Medical therapy is the preferred first-line treatment; options include (alone or in combination) octreotide and the growth hormone receptor antagonist pegvisomant. Hypercortisolism. Treatment varies by the presentation of neonatal Cushing syndrome. Surveillance: FD/MAS. Monitor for the following: Infants: clinical signs of hypercortisolism. All children: growth acceleration and other clinical signs of precocious puberty and/or growth hormone excess. Children: Age <5 years: thyroid function abnormalities. With thyroid abnormalities on ultrasound examination but normal thyroid function: periodic monitoring of thyroid function. Males: testicular lesions (physical examination and testicular ultrasound). Individuals on: Pegvisomant: hepatotoxicity. Somatostatin analogs: signs and symptoms of gallbladder disease. Females: breast cancer (earlier than is recommended for the general population). FD: Periodic radiographs to monitor existing FD and development of new lesions. Periodic serum phosphorus (for development of hypophosphatemia) and 25-hydroxyvitamin D levels. Craniofacial FD: yearly vision and hearing evaluations; periodic skull CT; routine serum IGF-1 levels through young adulthood. Spine FD: close monitoring for progressive scoliosis. Agents/circumstances to avoid: Contact sports and other high-risk activities (when skeletal involvement is significant); prophylactic optic nerve decompression (in individuals with craniofacial FD); surgical removal of ovarian cysts; radiation therapy for treatment of FD; risk factors for malignancy (e.g., radiation exposure). GENETIC COUNSELING: FD/MAS is not inherited. No parent of a child with FD/MAS has been demonstrated to have any significant, distinctive manifestations of the disorder. The risk to sibs is expected to be the same as in the general population. There are no verified instances of vertical transmission of FD/MAS.

*25719192*
 25719192

Diamond-Blackfan Anemia

GeneReviews((R))-/- 1993; ():

CLINICAL CHARACTERISTICS: Diamond-Blackfan anemia (DBA) in its classic form is characterized by a profound normochromic and usually macrocytic anemia with normal leukocytes and platelets, congenital malformations in up to 50% of affected individuals, and growth retardation in 30% of affected individuals. The hematologic complications occur in 90% of affected individuals during the first year of life. The phenotypic spectrum ranges from a mild form (e.g., mild anemia, no anemia with only subtle erythroid abnormalities, physical malformations without anemia) to a severe form of fetal anemia resulting in nonimmune hydrops fetalis. DBA is associated with an increased risk for acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), and solid tumors including osteogenic sarcoma. DIAGNOSIS/TESTING: The diagnosis is established in a proband when all four of the following diagnostic criteria are present: Age younger than one year. Macrocytic anemia with no other significant cytopenias. Reticulocytopenia. Normal marrow cellularity with a paucity of erythroid precursors. Other causes of bone marrow failure (e.g., Fanconi anemia, Pearson syndrome, dyskeratosis congenita, human immunodeficiency virus infection) need to be considered and ruled out as appropriate. DBA has been associated with pathogenic variants in 19 genes that encode ribosomal proteins and in GATA1 and TSR2. A pathogenic variant in one of these 21 genes is identified in approximately 65% of individuals with DBA. MANAGEMENT: Treatment of manifestations: Corticosteroid treatment, recommended in children older than age 12 months, initially improves the red blood cell count in approximately 80% of affected individuals. Chronic transfusion with packed red blood cells is initially necessary while the diagnosis is made and in those not responsive to corticosteroids. Hematopoietic stem cell transplantation (HSCT), the only curative therapy for the hematologic manifestations of DBA, is often recommended for those who are transfusion dependent or develop other cytopenias. Treatment of malignancies should be coordinated by an oncologist. Chemotherapy must be given cautiously as it may lead to prolonged cytopenia and subsequent toxicities. Prevention of secondary complications: Transfusion-related iron overload is the most common complication in transfusion-dependent individuals. Iron chelation therapy with deferasirox orally or desferrioxamine subcutaneously is recommended after ten to 12 transfusions. Corticosteroid-related side effects must also be closely monitored, especially as related to risk for infection, growth retardation, and loss of bone density in growing children. Often individuals will be placed on transfusion therapy if these side effects are intolerable. Surveillance: Complete blood counts several times a year; bone marrow aspirate/biopsy periodically to evaluate morphology and cellularity in the event of another cytopenia or a change in response to treatment. In steroid-dependent individuals: monitor blood pressure and (in children) growth. Agents/circumstances to avoid: Deferiprone for the treatment of iron overload, which has led to severe neutropenia in a few individuals with DBA; infection (especially those on corticosteroids). Evaluation of relatives at risk: Molecular genetic testing of at-risk relatives of a proband with a known pathogenic variant allows for early diagnosis and appropriate monitoring for bone marrow failure, physical abnormalities, and related cancers. GENETIC COUNSELING: DBA is most often inherited in an autosomal dominant manner; GATA1-related and TSR2-related DBA are inherited in an X-linked manner. Approximately 40% to 45% of individuals with autosomal dominant DBA have inherited the pathogenic variant from a parent; approximately 55% to 60% have a de novo pathogenic variant. Each child of an individual with autosomal dominant DBA has a 50% chance of inheriting the pathogenic variant. Males with GATA1- or TSR2-related DBA pass the pathogenic variant to all of their daughters and none of their sons. Women heterozygous for a GATA1 or TSR2 pathogenic variant have a 50% chance of transmitting the pathogenic variant in each pregnancy: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be affected. Carrier testing of at-risk female relatives is possible if the GATA1 or TSR2 pathogenic variant has been identified in the family. Prenatal testing for pregnancies at increased risk is possible if the familial pathogenic variant has been identified.

*20301769*
 20301769

Retinoblastoma

GeneReviews((R))-/- 1993; ():

CLINICAL CHARACTERISTICS: Retinoblastoma is a malignant tumor of the developing retina that occurs in children, usually before age five years. Retinoblastoma develops from cells that have cancer-predisposing variants in both copies of RB1. Retinoblastoma may be unifocal or multifocal. About 60% of affected individuals have unilateral retinoblastoma with a mean age of diagnosis of 24 months; about 40% have bilateral retinoblastoma with a mean age of diagnosis of 15 months. Heritable retinoblastoma is an autosomal dominant susceptibility for retinoblastoma. Individuals with heritable retinoblastoma are also at increased risk of developing non-ocular tumors. DIAGNOSIS/TESTING: The diagnosis of retinoblastoma is usually established by examination of the fundus of the eye using indirect ophthalmoscopy. Imaging studies can be used to support the diagnosis and stage the tumor. The diagnosis of heritable retinoblastoma is established in a proband with retinoblastoma or retinoma and a family history of retinoblastoma or by identification of a heterozygous germline pathogenic variant in RB1. The following staging has been recommended for individuals with retinoblastoma and/or risk of heritable retinoblastoma to include "H" to describe the genetic risk for an individual to have a germline pathogenic variant in RB1: HX. Unknown or insufficient evidence of a constitutional (germline) RB1 pathogenic variant. H0. Normal RB1 alleles in blood tested with demonstrated high-sensitivity assays. [H0. Normal RB1 in blood with <1% residual risk for mosaicism]. H1. Bilateral retinoblastoma, trilateral retinoblastoma (retinoblastoma with intracranial CNS midline embryonic tumor), family history of retinoblastoma, or RB1 pathogenic variant identified in blood. MANAGEMENT: Treatment of manifestations: Early diagnosis and treatment of retinoblastoma and non-ocular tumors can reduce morbidity and increase longevity; care is best provided by multidisciplinary teams of specialists including ophthalmology, pediatric oncology, pathology, and radiation oncology. Treatment options depend on tumor stage, number of tumor foci (unifocal, unilateral multifocal, or bilateral), localization and size of the tumor(s) within the eye(s), presence of vitreous seeding, the potential for useful vision, the extent and kind of extraocular extension, and the resources available. Treatment options include enucleation; cryotherapy; laser, systemic, or local ocular chemotherapy including intra-arterial chemotherapy, combined with or followed by laser or cryotherapy; radiation therapy using episcleral plaques; and, as a last resort, external beam radiotherapy. Prevention of secondary manifestations: If possible, radiation (including x-ray, CT scan, and external beam radiation) should be avoided in H1 individuals with heritable retinoblastoma to minimize the lifetime risk of developing late-onset second cancers. Surveillance: Children known to have an RB1 germline pathogenic variant (H1) have eye examination under anesthesia every three to four weeks until age six months, then less frequently until age three years, in order to identify retinoblastoma tumors as early and small as possible. Clinical examinations with cooperative children are performed every three to six months until age seven years, then annually and eventually biennially for life. Individuals who have unilateral retinoblastoma without an identified heterozygous germline RB1 pathogenic variant (H0) are still at risk for low-level mosaicism and should have regular clinical examination of the eyes, including clinical ultrasound. Individuals with retinomas are followed with retinal examinations and imaging every one to two years. To detect second non-ocular tumors in H1 individuals with retinoblastoma, physicians and parents should promptly evaluate complaints of bone pain or lumps because of the high risk for sarcomas and other cancers; however, effective screening protocols have not yet been developed. Agents/circumstances to avoid: Limiting exposure to DNA-damaging agents (radiation, tobacco, and UV light) may reduce the excess cancer risks in H1 survivors of heritable retinoblastoma. Evaluation of relatives at risk: Molecular genetic testing for early identification of asymptomatic at-risk children in a family reduces the need for costly screening procedures in those family members who have not inherited the pathogenic variant (i.e., H0). GENETIC COUNSELING: Heritable retinoblastoma is inherited in an autosomal dominant manner. Individuals with heritable retinoblastoma (H1) have a heterozygous de novo or inherited germline RB1 pathogenic variant. Offspring of H1 individuals have a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the RB1 pathogenic variant has been identified in an affected family member.

*20301625*
 20301625

Shwachman-Diamond Syndrome

GeneReviews((R))-/- 1993; ():

CLINICAL CHARACTERISTICS: Shwachman-Diamond syndrome (SDS) is characterized by: exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure; hematologic abnormalities with single- or multilineage cytopenias and susceptibility to myelodysplasia syndrome (MDS) and acute myelogeneous leukemia (AML); and bone abnormalities. In almost all affected children, persistent or intermittent neutropenia is a common presenting finding, often before the diagnosis of SDS is made. Short stature and recurrent infections are common. DIAGNOSIS/TESTING: The diagnosis of SDS is established in a proband with the classic clinical findings of exocrine pancreatic dysfunction and bone marrow dysfunction and/or by identification of biallelic pathogenic variants in DNAJC21, EFL1, or SBDS, or a heterozygous pathogenic variant in SRP54. MANAGEMENT: Treatment of manifestations: Care by a multidisciplinary team is recommended. Exocrine pancreatic insufficiency is treated with oral pancreatic enzymes and fat-soluble vitamin supplementation. Blood and/or platelet transfusions may be considered for anemia and/or thrombocytopenia associated with bi- or trilineage cytopenia. If recurrent infections are severe and absolute neutrophil counts are persistently

*20301722*
 20301722

EZH2-Related Overgrowth

GeneReviews((R))-/- 1993; ():

CLINICAL CHARACTERISTICS: EZH2-related overgrowth includes EZH2-related Weaver syndrome at one end of the spectrum and tall stature at the other. Although most individuals diagnosed with a heterozygous EZH2 pathogenic variant have been identified because of a clinical suspicion of Weaver syndrome, a minority have been identified through molecular genetic testing of family members of probands or individuals with overgrowth who did not have a clinical diagnosis of Weaver syndrome. Thus, the extent of the phenotypic spectrum associated with a heterozygous EZH2 pathogenic variant is not yet known. Weaver syndrome is characterized by tall stature, variable intellect (ranging from normal intellect to severe intellectual disability), characteristic facial appearance, and a range of associated clinical features including advanced bone age, poor coordination, soft doughy skin, camptodactyly of the fingers and/or toes, umbilical hernia, abnormal tone, and hoarse low cry in infancy. Brain MRI has identified abnormalities in a few individuals with EZH2-related overgrowth. Neuroblastoma occurs at a slightly increased frequency in individuals with a heterozygous EZH2 pathogenic variant but data are insufficient to determine absolute risk. There is currently no evidence that additional malignancies (including hematologic malignancies) occur with increased frequency. DIAGNOSIS/TESTING: The diagnosis of EZH2-related overgrowth is based on detection of a heterozygous germline EZH2 pathogenic variant on molecular genetic testing. MANAGEMENT: Treatment of manifestations: For individuals with developmental delay and/or learning disability, referral for learning/behavior/speech assessment and support may be indicated. Occasionally, toe camptodactyly may require surgical release. Physiotherapy may be of benefit to those experiencing joint pain secondary to ligamentous laxity or joint contractures. Treatment of scoliosis is routine. The appropriate specialist referral(s) should be made for other clinical issues. Surveillance: Regular medical follow up of young children with EZH2-related Weaver syndrome to monitor developmental progress, camptodactyly (for resolution/improvement), and/or hypotonia; medical follow up of older children/teenagers who do not have medical complications may be less frequent. If scoliosis is present, monitoring as per the recommendations of an orthopedist. Although current data do not support specific tumor surveillance programs, clinicians should have a low threshold for investigating any findings that may be tumor (particularly neuroblastoma) related. Pregnancy management: Families and their health care providers should be aware that an affected baby may be large so that appropriate delivery plans can be made. GENETIC COUNSELING: EZH2-related overgrowth is inherited in an autosomal dominant manner; however, many germline pathogenic EZH2 variants arise de novo. Each child of an individual with an EZH2 pathogenic variant has a 50% chance of inheriting the pathogenic variant; the severity of the phenotype in an individual inheriting the EZH2 pathogenic variant cannot be predicted. If the pathogenic variant has been identified in an affected family member, prenatal diagnosis for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

*23865096*
 23865096

ANKRD26-Related Thrombocytopenia

GeneReviews((R))-/- 1993; ():

CLINICAL CHARACTERISTICS: ANKRD26-related thrombocytopenia is characterized by lifelong mild-to-moderate thrombocytopenia with a normal platelet size and no syndromic associations. Most individuals have normal hemostasis or a mild bleeding phenotype and do not develop severe spontaneous bleeding. Some individuals may have concomitant erythrocytosis and leukocytosis. The risk for myeloid malignancies (including myelodysplastic syndrome, acute myelogenous leukemia, and chronic myelogenous leukemia) is increased in individuals with ANKRD26 pathogenic variants. DIAGNOSIS/TESTING: The diagnosis of ANKRD26-related thrombocytopenia is established in a proband by the presence of lifelong thrombocytopenia and identification of a heterozygous pathogenic variant in ANKRD26 on molecular genetic testing. MANAGEMENT: Treatment of manifestations: Adjunct hemostatic agents (e.g., antifibrinolytics, desmopressin) for bleeding or a major surgical procedure; platelet transfusions are reserved for severe bleeding or procedures with a high bleeding risk. Prevention of secondary complications: For individuals with a myeloid neoplasm, careful consideration of stem cell transplant eligibility and pre-transplant therapies undertaken through a large academic institution with experience in the management of individuals with germline predisposition syndromes. Surveillance: Surveillance for early detection of myeloid neoplasms should include an annual complete blood count with bone marrow examination if abnormalities are noted. Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by evaluation of the platelet count and molecular genetic testing of the ANKRD26 pathogenic variant in the family in order to identify as early as possible those who may benefit from surveillance. GENETIC COUNSELING: ANKRD26-related thrombocytopenia is inherited in an autosomal dominant manner. All individuals reported to date have an affected parent. Each child of an individual with ANKRD26-related thrombocytopenia has a 50% chance of inheriting the ANKRD26 pathogenic variant. Once the ANKRD26 pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible; however, phenotypic variability (due to variable expressivity) within families is observed.

*29927566*
 29927566

CDC73-Related Disorders

GeneReviews((R))-/- 1993; ():

CLINICAL CHARACTERISTICS: The spectrum of CDC73-related disorders includes the following phenotypes: Hyperparathyroidism-jaw tumor (HPT-JT) syndrome. Primary hyperparathyroidism, the main finding of HPT-JT syndrome, occurs in up to 95% of affected individuals; onset is typically in late adolescence or early adulthood. HPT-JT-associated primary hyperparathyroidism is usually caused by a single parathyroid adenoma. In approximately 10%-15% of individuals, primary hyperparathyroidism is caused by parathyroid carcinoma. Ossifying fibromas of the mandible or maxilla, also known as cementifying fibromas and cemento-ossifying fibromas, occur in 30%-40% of individuals with HPT-JT syndrome. Although benign, these tumors can be locally aggressive and may continue to enlarge if not treated. Approximately 20% of individuals with HPT-JT syndrome have kidney lesions, most commonly cysts; renal hamartomas and (more rarely) Wilms tumor have also been reported. Benign and malignant uterine tumors appear to be common in women with HPT-JT syndrome. Parathyroid carcinoma. Most parathyroid carcinomas are functional, resulting in hyperparathyroidism and a high serum calcium level; however, non-functioning parathyroid carcinomas are also rarely described in individuals with a CDC73-related disorder. A germline CDC73 pathogenic variant has been identified in 20%-29% of individuals with apparently sporadic parathyroid carcinoma. Familial isolated hyperparathyroidism (FIHP). FIHP is characterized by primary hyperparathyroidism without other associated syndromic features. Individuals with CDC73-related FIHP tend to have a more severe clinical presentation and younger age of onset than individuals with FIHP in whom a CDC73 pathogenic variant has not been identified. DIAGNOSIS/TESTING: The diagnosis is established in a proband by identification of a germline heterozygous CDC73 pathogenic variant on molecular genetic testing. MANAGEMENT: Treatment of manifestations: The optimal surgical approach to primary hyperparathyroidism in HPT-JT syndrome has not yet been established; however, because many individuals with HPT-JT syndrome present with a single benign parathyroid tumor, a minimally invasive approach to remove the abnormal parathyroid gland followed by close monitoring for recurrent primary hyperparathyroidism has been suggested. If parathyroid carcinoma is clinically suspected (large tumor on imaging, palpable neck mass, severe presentation of primary hyperparathyroidism), an en bloc resection of the parathyroid gland with surrounding, adherent tissue and the ipsilateral thyroid lobe should be considered. Cinacalcet hydrochloride has been approved for the treatment of severe hypercalcemia secondary to primary hyperparathyroidism in individuals who are unable to undergo parathyroidectomy and for the treatment of parathyroid carcinoma-related hypercalcemia. Jaw tumors should be treated surgically as indicated by size, location, and symptoms; the treatment of choice is complete resection, which may not be possible in all individuals. Renal and uterine manifestations are managed on a case-by-case basis. Prevention of secondary complications: Decrease the risk of postoperative hypoparathyroidism: ensure normal preoperative 25-(OH) vitamin D concentration; recognize risk factors for hungry bone syndrome, such as an elevated alkaline phosphatase level; postoperative monitoring with replacement of calcium and vitamin D. Minimize postoperative nausea and vomiting to prevent devascularization of the remaining in situ parathyroid glands. Avoid biopsy of extrathyroidal tissue to reduce the risk of seeding of a parathyroid carcinoma. Consider en bloc resection in those with suspected parathyroid carcinoma to optimize a surgical cure and prevent positive surgical margins or seeding of parathyroid tissue (parathyromatosis) during removal. Surveillance: Starting at age five years, serum calcium, intact parathyroid hormone (iPTH), and 25-(OH) vitamin D levels annually, and dental panoramic x-ray with neck shielding at least every five years starting at age ten. Renal ultrasound examination at least every five years, starting at the age of diagnosis. For women, starting at reproductive age, lifelong monitoring for uterine tumors with routine gynecologic care and pelvic ultrasound examination as clinically indicated. Agents/circumstances to avoid: Dehydration; radiation exposure; biopsy of extrathyroidal tissue in the neck, which increases the risk of seeding of parathyroid tissue. Evaluation of relatives at risk: If the family-specific CDC73 pathogenic variant is known, molecular genetic testing of at-risk relatives should be offered starting around age five years in order to identify as early as possible those who would benefit from initiation of surveillance, treatment, and/or preventive measures. GENETIC COUNSELING: CDC73-related disorders are inherited in an autosomal dominant manner. An individual with a CDC73-related disorder may have inherited the disorder from an affected parent or developed it as the result of a de novo pathogenic variant of CDC73. The proportion of individuals with a de novo pathogenic variant is unknown. Each child of an individual with a CDC73-related disorder has a 50% chance of inheriting the pathogenic variant. Prenatal diagnosis for pregnancies at increased risk is possible if the CDC73 pathogenic variant in the family is known.

*20301744*
 20301744

Baller-Gerold Syndrome

GeneReviews((R))-/- 1993; ():

CLINICAL CHARACTERISTICS: Baller-Gerold syndrome (BGS) can be suspected at birth in an infant with craniosynostosis and upper limb abnormality. The coronal suture is most commonly affected; the metopic, lambdoid, and sagittal sutures may also be involved alone or in combination. Upper limb abnormality can include a combination of thumb hypo- or aplasia and radial hypo- or aplasia and may be asymmetric. Malformation or absence of carpal or metacarpal bones has also been described. Skin lesions may appear anytime within the first few years after birth, typically beginning with erythema of the face and extremities and evolving into poikiloderma. Slow growth is apparent in infancy with eventual height and length typically at 4 SD below the mean. DIAGNOSIS/TESTING: The diagnosis of BGS is established in a proband with typical clinical findings and/or the identification of biallelic pathogenic variants in RECQL4 by molecular genetic testing. MANAGEMENT: Treatment of manifestations: Surgery before age six months to repair bilateral craniosynostosis; pollicization of the index finger as needed to create a functional grasp; sunscreen use with poikiloderma to protect against skin cancer. Surveillance: Because individuals with allelic RECQL4 disorders are at increased risk for osteosarcoma and lymphoma, attention to clinical findings (e.g., bone pain, swelling, and/or limp) for osteosarcoma and lymph node enlargement or generalized symptoms (e.g., fever or unexplained weight loss) for lymphoma is recommended for those with BGS. Agents/circumstances to avoid: Sun exposure because of risk for skin cancer. GENETIC COUNSELING: Baller-Gerold syndrome is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and therefore carry one pathogenic variant. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members, prenatal diagnosis for pregnancies at increased risk, and preimplantation genetic diagnosis are possible if both pathogenic variants in the family have been identified.

*20301383*
 20301383

Fanconi Anemia

GeneReviews((R))-/- 1993; ():

CLINICAL CHARACTERISTICS: Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors - particularly of the head and neck, skin, gastrointestinal tract, and genitourinary tract - are more common in individuals with FA. DIAGNOSIS/TESTING: The diagnosis of FA is established in a proband with increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes with diepoxybutane (DEB) and mitomycin C (MMC). The diagnosis is confirmed by identification of one of the following: Biallelic pathogenic variants in one of the 19 genes known to cause autosomal recessive FA. A heterozygous pathogenic variant in RAD51, known to cause autosomal dominant FA. A hemizygous pathogenic variant in FANCB, known to cause X-linked FA. MANAGEMENT: Treatment of manifestations: Administration of oral androgens (e.g., oxymetholone) improves blood counts (red cell and platelets) in approximately 50% of individuals with FA; administration of G-CSF improves the neutrophil count in some; hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the hematologic manifestations of FA, but the high risk for solid tumors remains and may even be increased in those undergoing HSCT. All these treatments have potential significant toxicity. Early detection and surgical removal remains the mainstay of therapy for solid tumors. Prevention of primary manifestations: Human papilloma virus (HPV) vaccination to reduce the risk of gynecologic cancer in females, and possibly reduce the risk of oral cancer in all individuals. Prevention of secondary complications: T-cell depletion of the donor graft to minimize the risk of graft vs host disease; conditioning regimen without radiation prior to HSCT to reduce the risk of subsequent solid tumors. Surveillance: Annual evaluation with a multidisciplinary team including an endocrinologist; monitoring for evidence of bone marrow failure (regular blood counts; at least annual bone marrow aspirate/biopsy to evaluate morphology, cellularity, and cytogenetics); for those receiving androgen therapy, monitoring liver function tests and regular ultrasound examination of the liver; monitoring for solid tumors (oropharyngeal and gynecologic examinations). Agents/circumstances to avoid: Transfusions of red cells or platelets for persons who are candidates for HSCT; family members as blood donors if HSCT is being considered; blood products that are not filtered (leukodepleted) or irradiated; toxic agents that have been implicated in tumorigenesis; unsafe sex practices, which increase the risk of HPV-associated malignancy; radiographic studies solely for the purpose of surveillance (i.e., in the absence of clinical indications). Evaluation of relatives at risk: DEB/MMC testing or molecular genetic testing (if the family-specific pathogenic variants are known) of all sibs of a proband for early diagnosis, treatment, and monitoring for physical abnormalities, bone marrow failure, and related cancers. GENETIC COUNSELING: Fanconi anemia (FA) can be inherited in an autosomal recessive manner, an autosomal dominant manner (RAD51-related FA), or an X-linked manner (FANCB-related FA). Autosomal recessive FA: Each sib of an affected individual has a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being a carrier, and a 25% chance of inheriting both normal alleles and not being a carrier. Carriers (heterozygotes) for autosomal recessive FA are asymptomatic. Autosomal dominant FA: Given that all affected individuals with RAD51-related FA reported to date have the disorder as a result of a de novo RAD51 pathogenic variant, the risk to other family members is presumed to be low. X-linked FA: For carrier females the chance of transmitting the pathogenic variant in each pregnancy is 50%; males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be affected. Carrier testing for at-risk relatives (for autosomal recessive and X-linked FA) and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant(s) in the family are known.

*20301575*
 20301575

Juvenile Polyposis Syndrome

GeneReviews((R))-/- 1993; ():

CLINICAL CHARACTERISTICS: Juvenile polyposis syndrome (JPS) is characterized by predisposition to hamartomatous polyps in the gastrointestinal (GI) tract, specifically in the stomach, small intestine, colon, and rectum. The term "juvenile" refers to the type of polyp rather than to the age of onset of polyps. Most individuals with JPS have some polyps by age 20 years; some may have only four or five polyps over their lifetime, whereas others in the same family may have more than 100. If the polyps are left untreated, they may cause bleeding and anemia. Most juvenile polyps are benign; however, malignant transformation can occur. Risk for GI cancers in families with JPS ranges from 9% to 50%. Most of this increased risk is attributed to colon cancer, but cancers of the stomach, upper GI tract, and pancreas have also been reported. A combined syndrome of JPS and hereditary hemorrhagic telangiectasia (JPS/HHT) is present in most individuals with an SMAD4 pathogenic variant. DIAGNOSIS/TESTING: The diagnosis of JPS is established in a proband with any of the following: more than five juvenile polyps of the colorectum; multiple juvenile polyps throughout the GI tract; any number of juvenile polyps and a family history of juvenile polyposis. Identification of a heterozygous pathogenic variant in SMAD4 or BMPR1A confirms the diagnosis if clinical features are inconclusive. MANAGEMENT: Treatment of manifestations: Routine colonoscopy with endoscopic polypectomy to reduce the risk of cancer, bleeding, and intestinal obstruction. When a large number of polyps are present, removal of all or part of the colon or stomach may be necessary. Treatment as needed for manifestations of HHT. Prevention of primary manifestations: Cancer prevention/risk reduction through cancer screening. Prevention of secondary complications: Anemia may be improved by polypectomy or surgery. Surveillance: For individuals following surgical resection: endoscopic evaluation of the rectum and pouch is required. For individuals at risk: monitoring for rectal bleeding and/or anemia, abdominal pain, constipation, and diarrhea; screening by complete blood count (CBC), colonoscopy, and upper endoscopy starting in the mid-teens (age 15 years) or earlier if symptoms occur. In families with JPS/HHT syndrome and/or a known SMAD4 pathogenic variant: it may be appropriate to follow the HHT surveillance guidelines. Evaluation of relatives at risk: When the family-specific pathogenic variant is known, it is appropriate to perform molecular genetic testing on at-risk family members in the first to second decade of life to identify those who will benefit from early surveillance and intervention. GENETIC COUNSELING: JPS is inherited in an autosomal dominant manner. Approximately 33% of individuals with JPS have an affected parent; approximately 67% of probands with JPS have no previous history of polyps in the family and may have the disorder as the result of a de novo pathogenic variant. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant and developing JPS. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant in the family is known.

*20301642*
 20301642

Dyskeratosis Congenita

GeneReviews((R))-/- 1993; ():

CLINICAL CHARACTERISTICS: Dyskeratosis congenita (DC), a telomere biology disorder, is characterized by a classic triad of dysplastic nails, lacy reticular pigmentation of the upper chest and/or neck, and oral leukoplakia. The classic triad may not be present in all individuals. People with DC are at increased risk for progressive bone marrow failure (BMF), myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), solid tumors (usually squamous cell carcinoma of the head/neck or anogenital cancer), and pulmonary fibrosis. Other findings can include: abnormal pigmentation changes not restricted to the upper chest and neck, eye abnormalities (epiphora, blepharitis, sparse eyelashes, ectropion, entropion, trichiasis), and dental abnormalities (caries, periodontal disease, taurodauntism). Although most persons with DC have normal psychomotor development and normal neurologic function, significant developmental delay is present in the two variants in which additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome). Onset and progression of manifestations of DC vary: at the mild end of the spectrum are those who have only minimal physical findings with normal bone marrow function, and at the severe end are those who have the diagnostic triad and early-onset BMF. DIAGNOSIS/TESTING: All individuals with DC have abnormally short telomeres for their age, as determined by multicolor flow cytometry fluorescence in situ hybridization (flow-FISH) on white blood cell (WBC) subsets. To date, ACD, CTC1, DKC1, NHP2, NOP10, PARN, RTEL1, TERC, TERT, TINF2, and WRAP53 are the genes in which pathogenic variants are known to cause DC and result in very short telomeres. Pathogenic variants in one of these 11 genes have been identified in approximately 70% of individuals who meet clinical diagnostic criteria for DC. MANAGEMENT: Treatment of manifestations: Treatment is tailored to the individual. Hematopoietic cell transplantation (HCT) is the only curative treatment for BMF and leukemia but historically has had poor long-term efficacy; if a suitable donor is not available, androgen therapy may be considered for BMF. Treatment of other cancers is tailored to the type of cancer. Of note, cancer therapy may pose an increased risk for prolonged cytopenias as well as pulmonary and hepatic toxicity. Treatment of pulmonary fibrosis is primarily supportive, although lung transplantation may be considered. Surveillance: For BMF: complete blood count (CBC) annually if normal and more often if abnormal; consider annual bone marrow aspirate and biopsy. For those on androgen therapy: routine monitoring of liver function. For cancer risk: monthly self-examination for oral, head, and neck cancer; annual cancer screening by an otolaryngologist and dermatologist; annual gynecologic examination. For pulmonary fibrosis: annual pulmonary function tests starting either at diagnosis or when the individual can perform the test (often around age eight years). Routine dental screening every six months and good oral hygiene are recommended. Agents/circumstances to avoid: Blood donation by family members if HCT is being considered; non-leukodepleted and non-irradiated blood products; the combination of androgens and G-CSF in treatment of BMF (has been associated with splenic rupture); toxic agents implicated in tumorigenesis (e.g., smoking). Evaluation of relatives at risk: If a relative has signs or symptoms suggestive of DC or is being evaluated as a potential HCT donor, telomere length testing is warranted or molecular genetic testing if the pathogenic variant(s) in the family are known. GENETIC COUNSELING: The mode of inheritance of DC varies by gene: X-linked: DKC1. Autosomal dominant: TERC and TINF2. Autosomal dominant or autosomal recessive: ACD, RTEL1, and TERT. Autosomal recessive: CTC1, NHP2, NOP10, PARN, and WRAP53. Genetic counseling regarding risk to family members depends on accurate diagnosis, determination of the mode of inheritance in each family, and results of molecular genetic testing. Once the DC-related pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk for DC is possible.

*20301779*
 20301779

X-Linked Severe Combined Immunodeficiency

GeneReviews((R))-/- 1993; ():

CLINICAL CHARACTERISTICS: X-linked severe combined immunodeficiency (X-SCID) is a combined cellular and humoral immunodeficiency caused by a hemizygous pathogenic variant in IL2RG. In typical X-SCID lack of IL2RG function results in near-complete absence of T and natural killer (NK) lymphocytes and nonfunctional B lymphocytes. X-SCID is almost universally fatal in the first two years of life unless reconstitution of the immune system is achieved through bone marrow transplant or gene therapy. In the absence of family history of X-SCID and prior to newborn screening for X-SCID, most males with typical X-SCID come to medical attention between ages three and six months with failure to thrive, oral/diaper candidiasis, absent tonsils and lymph nodes, recurrent infections, infections with opportunistic organisms such as Pneumocystis, and persistence of infections despite conventional treatment. Additional common features include rashes, diarrhea, cough and congestion, fevers, pneumonia, sepsis, and other severe bacterial infections. Males with atypical X-SCID may have immune dysregulation and autoimmunity associated with rashes, gastrointestinal malabsorption, and short stature. DIAGNOSIS/TESTING: In many states, testing for X-SCID is now frequently part of newborn screening. Follow-up confirmatory testing includes lymphocyte counts, lymphocyte subset enumeration by flow cytometry, and molecular testing of IL2RG, the only gene in which pathogenic variants are known to cause X-SCID. Absolute lymphocyte count compared to age-matched normal infants is usually low. The number of T cells is usually very low; B cells are generally present but nonfunctional; NK cells are low or absent. Sequence analysis of the IL2RG coding region detects a pathogenic variant in more than 99% of affected males. MANAGEMENT: Treatment of manifestations: Immune reconstitution by bone marrow transplantation (BMT) or gene replacement therapy is required for survival; thus, diagnosis at as young an age as possible enables early immune reconstitution and prevents difficult-to-treat infections that may compromise vital organs. In the interval between diagnosis and immune reconstitution, management includes treatment of infections, immunoglobulin infusions and prophylactic antibiotics (particularly against Pneumocystis jirovecii), and isolation from cytomegalovirus (CMV) exposures. Prevention of primary manifestations: BMT using HLA-matched bone marrow from a relative is presently the preferred option. Haploidentical parental bone marrow depleted of mature T cells or matched, unrelated bone marrow or cord blood stem cells can be used for transplantation as well, but each has particular conditioning and graft-versus-host disease risks to consider along with infection status. The best timing for BMT is immediately after birth. Infants undergoing transplantation in the first 3.5 months of life have a much higher rate of survival than those undergoing transplantation later. Long-term periodic administration of immunoglobulin may be required in those who fail to develop allogeneic, functional B lymphocytes. Gene therapy using retroviral transduction of autologous bone marrow stem/progenitor cells with a therapeutic gene has been successful for T-cell immune reconstitution for some individuals, but is presently only considered for those who are not candidates for BMT or have failed BMT. Prevention of secondary complications: Pneumocystis jirovecii, viral and encapsulated organism prophylaxis should be applied per transplantation protocols; IVIG prophylaxis should be considered to maintain serum IgG levels above 400mg/dL; prompt evaluation of illness should occur until the individual is immunologically competent; avoid immunizations until after restoration of immunocompetence; only use CMV-negative, irradiated blood products; avoid breast feeding and exposure to young children to prevent CMV transmission to babies with X-SCID. Surveillance: Monitor growth, immune and lung function, and gastrointestinal and dermatologic findings every 6-12 months after successful BMT. Agents/circumstances to avoid: Live vaccines; transfusion of non-irradiated blood products; breast-feeding and breast milk; exposure to young children, sick contacts, or individuals with cold sores. Evaluation of relatives at risk: When the pathogenic variant in the family is known, prenatal diagnosis of at-risk males allows preparation for bone marrow transplantation to be initiated before birth. Therapies under investigation: A variety of second-generation therapeutic gene transfer vectors for X-SCID are presently under evaluation in clinical trials that have removed the likely cancer-causing elements from the vectors. GENETIC COUNSELING: X-SCID is inherited in an X-linked manner. More than half of affected males have no family history of early deaths in maternal male relatives. If the mother of a proband is a heterozygote (carrier), the chance of transmitting the pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes (carriers) and will not be affected. Males with X-SCID will pass the pathogenic variant to all of their daughters and none of their sons. Carrier testing of at-risk female relatives is most informative if the IL2RG pathogenic variant has been identified in an affected family member. Prenatal testing is possible for pregnancies at increased risk if the familial pathogenic variant is known.

*20301584*
 20301584

Schimke Immunoosseous Dysplasia

GeneReviews((R))-/- 1993; ():

CLINICAL CHARACTERISTICS: Schimke immunoosseous dysplasia (SIOD) is an autosomal recessive multisystem disorder characterized by spondyloepiphyseal dysplasia (SED) resulting in short stature, nephropathy, and T-cell deficiency. Radiographic manifestations of SED include ovoid and mildly flattened vertebral bodies, small deformed capital femoral epiphyses, and shallow dysplastic acetabular fossae. Adult height is 136-157 cm for men and 98.5-143 cm for women. Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease (ESRD). The majority of tested individuals have T-cell deficiency and an associated risk for opportunistic infection, a common cause of death. SIOD involves a spectrum that ranges from an infantile or severe early-onset form with death early in life to a juvenile or milder later-onset form with survival into adulthood if renal disease is appropriately treated. DIAGNOSIS/TESTING: The diagnosis of SIOD is established in a proband with the characteristic clinical and radiographic features. Identification of biallelic pathogenic variants in SMARCAL1 on molecular genetic testing establishes the diagnosis if clinical features are inconclusive. MANAGEMENT: Treatment of manifestations: Renal transplantation as indicated using mild immunosuppressive therapy; hip replacement as needed in older individuals; granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor for neutropenia; bone marrow transplantation as indicated; immunosuppressive therapy for those with autoimmune manifestations; acyclovir for recurrent herpetic infections; imiquimod and cidofovir for severe disseminated cutaneous papilloma virus infections; agents that improve blood flow or decrease coagulability to treat transient ischemic attacks or strokes; standard treatment for hypothyroidism. Prevention of secondary complications: Vaccinations according to the protocol for other T-cell immunodeficiencies (i.e., an avoidance of live attenuated vaccines) in individuals with severe early-onset disease; prophylaxis against Pneumocystis jirovecii pneumonia; prophylactic acyclovir or valacylovir if recurrent oral herpetic infections or shingles occur. Surveillance: Regular monitoring of the hips; annual monitoring of renal, immune, and hematologic status. Agents/circumstances to avoid: Hypertension; heat, stress, and lack of sleep; live attenuated immunizations in those who are T-cell deficient; DNA damaging anti-cancer therapies. GENETIC COUNSELING: SIOD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing and prenatal testing are possible if both pathogenic variants in the family are known.

*20301550*
 20301550

Familial Monosomy 7 Syndrome

GeneReviews((R))-/- 1993; ():

CLINICAL CHARACTERISTICS: Familial monosomy 7 is characterized by early-childhood onset of bone marrow insufficiency/failure associated with increased risk for myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). In all reported individuals, the monosomy 7 is believed to be an acquired cytogenetic abnormality within hematopoietic cells due to as-yet poorly defined inherited genetic predisposition. Identification of peripheral blood leukocytes with monosomy 7 usually precedes bone marrow failure/MDS/AML by a few months to years. Nearly all individuals reported with familial monosomy 7 have died of their disease. Note: Only a minority of individuals with bone marrow failure/MDS/AML with monosomy 7 have familial monosomy 7. DIAGNOSIS/TESTING: Detection of cells with monosomy 7 during evaluation of a hematologic abnormality or malignancy or in the context of chromosomal studies in the diagnosis of unrelated conditions needs to be confirmed with bone marrow cytogenetic and interphase FISH studies. A bone marrow karyotype of 45,XX,-7 in females or 45,XY,-7 in males, often mosaic with normal cells (i.e., 46,XX in females and 46,XY in males), confirms the presence of monosomy 7. Of note, individuals with a family history of monosomy 7 (e.g., an affected sib) may initially have a normal karyotype in peripheral blood and/or bone marrow and later transition to mosaic monosomy 7 in peripheral blood and/or bone marrow. MANAGEMENT: Treatment of manifestations: Urgent referral to an oncologist should be considered for individuals with monosomy 7 (mosaic or non-mosaic). Definitive therapy is bone marrow transplantation (BMT) prior to the emergence of a leukemic clone. The suitability of sibs who are potential bone marrow donors may be evaluated with appropriate hematologic and cytogenetic studies to rule out bone marrow disease associated with familial monosomy 7. However, given that the underlying germline pathogenic variant may not be known, a matched sib donor may not be an ideal candidate (unless much older than the affected individual and with no evidence of hematologic disorders). An unrelated donor may be more suitable. Prevention of secondary complications: It is unknown if the standard protocols for ablative therapy prior to BMT should be modified. Surveillance: Annual monitoring of peripheral blood karyotype, hematologic status, and hemoglobin F levels helps identify emerging bone marrow abnormalities (cytopenias and bone marrow dysplasia) prior to the development of overt AML or MDS. Evaluation of relatives at risk: In both children and adults with a family history of monosomy 7, otherwise unexplained signs and symptoms should be evaluated by a physician as possible early indications of the disorder. GENETIC COUNSELING: The mode of inheritance of familial monosomy 7 is unknown.

*20614583*
 20614583

Nonsyndromic 46,XX Testicular Disorders of Sex Development

GeneReviews((R))-/- 1993; ():

CLINICAL CHARACTERISTICS: Nonsyndromic 46,XX testicular disorders of sex development (46,XX testicular DSD) are characterized by the presence of a 46,XX karyotype; male external genitalia ranging from normal to ambiguous; two testicles; azoospermia; and absence of mullerian structures. Approximately 85% of individuals with nonsyndromic 46,XX testicular DSD present after puberty with normal pubic hair and normal penile size but small testes, gynecomastia, and sterility resulting from azoospermia. Approximately 15% of individuals with nonsyndromic 46,XX testicular DSD present at birth with ambiguous genitalia. Gender role and gender identity are reported as male. If untreated, males with 46,XX testicular DSD experience the consequences of testosterone deficiency. DIAGNOSIS/TESTING: Diagnosis of nonsyndromic 46,XX testicular DSD is based on the combination of clinical findings, endocrine testing, and cytogenetic testing. Endocrine studies usually show hypergonadotropic hypogonadism secondary to testicular failure. Cytogenetic studies at the 550-band level demonstrate a 46,XX karyotype. SRY, the gene that encodes the sex-determining region Y protein, is the principal gene known to be associated with 46,XX testicular DSD. Approximately 80% of individuals with nonsyndromic 46,XX testicular DSD are SRY positive as shown by use of FISH or chromosomal microarray (CMA). Rearrangements in or around SOX9 and SOX3 detected by CMA, or rarely karyotype, have recently been reported in a few cases; at least one more as-yet-unknown gene at another locus is implicated. MANAGEMENT: Treatment of manifestations: Similar to that for other causes of testosterone deficiency. After age 14 years, low-dose testosterone therapy is initiated and gradually increased to reach adult levels. In affected individuals with short stature who are eligible for growth hormone therapy, testosterone therapy is either delayed or given at lower doses initially in order to maximize the growth potential. Reduction mammoplasty may need to be considered if gynecomastia remains an issue following testosterone replacement therapy. Treatment for osteopenia is by standard protocols. Providers are encouraged to anticipate the need for further psychological support. Surveillance: Monitor for testosterone effects during testosterone replacement therapy, including prostate size and prostate-specific antigen (PSA) in adults; routine monitoring of hematocrit, lipid profile, and liver function tests; bone mineral density determination by bone densitometry (DEXA) annually, if osteopenia has been diagnosed. Agents/circumstances to avoid: Contraindications to testosterone replacement therapy include prostate cancer (known or suspected) and breast cancer; oral androgens such as methyltestosterone and fluoxymesterone should not be given because of liver toxicity. GENETIC COUNSELING: SRY-positive 46,XX testicular DSD is generally not inherited because it results from de novo abnormal interchange between the Y chromosome and the X chromosome, resulting in the presence of SRY on the X chromosome and infertility. When SRY is translocated to another chromosome or when fertility is preserved, sex-limited autosomal dominant inheritance is observed. Autosomal dominant inheritance has been documented for familial cases thought to be caused by CNV in or around SOX9. The mode of inheritance of other SRY-negative 46,XX testicular DSD is not known, but autosomal recessive inheritance has been postulated. Prenatal diagnosis for pregnancies at risk for SRY-positive 46,XX testicular DSD is possible.

*20301589*
 20301589

Molecular and functional characterization of myxobacteria isolated from soil in India.

3 Biotech 2017; 7 (2): 112 rkaur.biotech@gmail.com.;

This study reports the isolation of myxobacteria from soil collected from plains in north India. Based on the morphology and 16S rDNA sequence, the isolated myxobacteria were identified as Corallococcus sp., Pyxidicoccus sp., Myxococcus sp., Cystobacter sp. and Archangium sp. The myxobacteria were functionally characterized to assess their ability to produce antibacterial and anticancer metabolites. The isolates were found to be functionally versatile as they produced extracellular bioactive molecules that exhibited high frequency of activities against Bacillus cereus, Mycobacterium smegmatis, Enterobacter cloacae and Pseudomonas syringae. The strains also showed cytotoxic activity against the human cancer cell lines of liver, pancreas, prostrate, bone and cervix. These results indicate the importance of isolating diverse strains of myxobacteria from unexplored habitats to find novel bioactive compounds. Moreover, the bioactive molecules explored in this study are predominantly hydrophilic compounds, obviating the limitations of solubility-related aspect of drug discovery.

*28567623*
 28567623

Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents.

AAPS J 2016; 18 (3): 737-45 phelps.32@osu.edu.;

AR-42, a new orally bioavailable, potent, hydroxamate-tethered phenylbutyrate class I/IIB histone deacetylase inhibitor currently is under evaluation in phase 1 and 2 clinical trials and has demonstrated activity in both hematologic and solid tumor malignancies. This report focuses on the preclinical characterization of the pharmacokinetics of AR-42 in mice and rats. A high-performance liquid chromatography-tandem mass spectrometry assay has been developed and applied to the pharmacokinetic study of the more active stereoisomer, S-AR-42, when administered via intravenous and oral routes in rodents, including plasma, bone marrow, and spleen pharmacokinetics (PK) in CD2F1 mice and plasma PK in F344 rats. Oral bioavailability was estimated to be 26 and 100% in mice and rats, respectively. R-AR-42 was also evaluated intravenously in rats and was shown to display different pharmacokinetics with a much shorter terminal half-life compared to that of S-AR-42. Renal clearance was a minor elimination pathway for parental S-AR-42. Oral administration of S-AR-42 to tumor-bearing mice demonstrated high uptake and exposure of the parent drug in the lymphoid tissues, spleen, and bone marrow. This is the first report of the pharmacokinetics of this novel agent, which is now in early phase clinical trials.

*26943915*
 26943915

Properties of thalidomide and its analogues: implications for anticancer therapy.

AAPS J 2005; 7 (1): E14-9 steo@celgene.com

Thalidomide and its immunomodulatory (IMiDs) analogs (lenalidomide, Revlimid, CC-5013; CC-4047, ACTIMID) are a novel class of compounds with numerous effects on the body's immune system, some of which are thought to mediate the anticancer and anti-inflammatory results observed in humans. Thalidomide is currently being used experimentally to treat various cancers and inflammatory diseases. It is approved for the treatment of dermal reaction from leprosy and is currently in phase III trials for multiple myeloma. Thalidomide and IMiDs inhibit the cytokines tumor necrosis factor-alpha (TNF-alpha), interleukins (IL) 1beta, 6, 12, and granulocyte macrophage-colony stimulating factor (GM-CSF). They also costimulate primary human T lymphocytes inducing their proliferation, cytokine production, and cytotoxic activity thereby increasing the T cells' anticancer activity. They induce an IL-2-mediated primary T cell proliferation with a concomitant increase in IFN-gamma production and decrease the density of TNF-alpha-induced cell surface adhesion molecules ICAM-1, VCAM-1, and E-selectin on human umbilical vein endothelial cells. Thalidomide stimulates the Th-1 response increasing IFN-gamma levels while CC-4047 increased IL-2 as well. Some of the above immunomodulatory activities along with anti-angiogenic, anti-proliferative, and pro-apoptotic properties are thought to mediate the IMiDs' antitumor responses observed in relapsed and refractory multiple myeloma and some solid tumor cancers. This has led to their use in various oncology clinical trials. The second generation IMiD, lenalidomide, has shown potential in treating the bone marrow disorders myelodysplastic syndrome and multiple myeloma. It is currently in phase II and III trials for these diseases respectively with numerous phase II trials in other hematologic and solid tumors.

  • Thalidomide
  • *16146335*
     16146335

    Prostate cancer bone metastases on staging prostate MRI: prevalence and clinical features associated with their diagnosis.

    Abdom Radiol (NY) 2017; 42 (1): 271-277 vargasah@mskcc.org.;

    PURPOSE: Bone lesions on prostate MRI often raise concern about metastases. This study aimed to evaluate the prevalence of bone metastases on staging prostate MRI and evaluate associations between their MRI features and clinical/pathologic characteristics. METHODS: Retrospective, IRB-approved study of 3765 patients undergoing prostate MRI for newly diagnosed PCa between 2000 and 2014. The reference standard to calculate the prevalence of bone metastases was bone biopsy and/or >/=1-year follow-up after MRI. In a subsample of 228 patients, the MRI characteristics of bone lesions were recorded by two radiologists independently. Associations between MRI and clinical/pathologic findings, including National Comprehensive Cancer Network (NCCN) risk categories, were calculated. RESULTS: 57/3765 patients (1.5%, 95% CI 1.2-2.0%) had bone metastases. No patient with NCCN low-risk PCa (Gleason < 7, PSA < 10 ng/mL, cT1-2a) had bone metastases. In the subsample, >/=1 bone lesion was present on MRI in 74% (95% CI 0.67-0.79) and 72% (95% CI 0.66-0.78) of patients (R1 and R2). Larger lesion diameter (OR 1.33/1.19; p < 0.001 for both readers) and the absence of intralesional fat (OR 0.07/0.11; p = 0.004/0.002 for R1/R2) were significantly associated with bone metastases. CONCLUSION: Bone lesions are common in prostate MRI, but only rarely represent metastases. MRI should be interpreted in the context of clinical features that influence the likelihood of metastatic disease.

    *27480976*
     27480976

    Clinicopathological conference: a 29-year-old man with vomiting and chest pain.

    Acad Emerg Med 2005; 12 (3): 237-44 rmerchant@lifespan.org

    *15741587*
     15741587

    Multiparametric Whole-body MRI with Diffusion-weighted Imaging and ADC Mapping for the Identification of Visceral and Osseous Metastases From Solid Tumors.

    Acad Radiol 2018; 25 (11): 1405-1414 mikej@mri.jhu.edu.;

    RATIONALE AND OBJECTIVES: The purpose of this study was to investigate the use of multiparametric, whole-body, diffusion-weighted imaging (WB-DWI) and apparent diffusion coefficient (ADC) maps with T2-weighted magnetic resonance imaging (MRI) at 3T for the detection and monitoring of metastatic disease in patients. MATERIALS AND METHODS: Fifty-four participants (32 healthy subjects and 22 patients) were scanned with WB-DWI methods using a 3T MRI scanner. Axial, sagittal, or coronal fat-suppressed T2-weighted (T2WI), T1-weighted (T1WI), and DWI images were acquired. Total MRI acquisition and set-up time was approximately 45 minutes. Metastatic disease on MRI was confirmed based on T2WI characteristics. The number of lesions was established on computed tomography (CT) or positron emission tomography (PET-CT). Whole-body ADC maps and T2WI were constructed, and region-of-interests were drawn in normal and abnormal-appearing tissue for quantitative analysis. Statistical analysis was performed using a paired t tests and P < .05 was considered statistically significant. RESULTS: There were 91 metastatic lesions detected from the CT or PET-CT with a missed recurrent lesion in the prostate. Multiparametric WB-MRI had excellent sensitivity (96%) for detection of metastatic lesions compared to CT. ADC map values and the ADC ratio in metastatic bone lesions were significantly increased (P < .05) compared to normal bone. In soft tissue, ADC map values and ratios in metastatic lesions were decreased compared to normal soft tissue. CONCLUSION: We have demonstrated that multiparametric WB-MRI is feasible for oncologic staging to identify bony and visceral metastasis in breast, prostate, pancreatic, and colorectal cancers. WB-MRI can be tailored to fit the patient, such that an "individualized patient sequence" can be developed for a comprehensive evaluation for staging and response during treatment.

    *29627288*
     29627288

    Diagnosis of Spinal Lesions Using Heuristic and Pharmacokinetic Parameters Measured by Dynamic Contrast-Enhanced MRI.

    Acad Radiol 2017; 24 (7): 867-875 huishuy@bjmu.edu.cn.;

    RATIONALE AND OBJECTIVES: This study aimed to evaluate the diagnostic performance of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in differentiation of four spinal lesions by using heuristic and pharmacokinetic parameters analyzed from DCE signal intensity time course. MATERIALS AND METHODS: DCE-MRI of 62 subjects with confirmed myeloma (n = 9), metastatic cancer (n = 22), lymphoma (n = 7), and inflammatory tuberculosis (TB) (n = 24) in the spine were analyzed retrospectively. The region of interest was placed on strongly enhanced tissues. The DCE time course was categorized as the "wash-out," "plateau," or "persistent enhancement" pattern. The maximum enhancement, steepest wash-in enhancement, and wash-out slope using the signal intensity at 67 seconds after contrast injection as reference were measured. The Tofts 2-compartmental pharmacokinetic model was applied to obtain K(trans) and kep. Pearson correlation between heuristic and pharmacokinetic parameters was evaluated, and receiver operating characteristic curve analysis was performed for pairwise group differentiation. RESULTS: The mean wash-out slope was -22% +/- 10% for myeloma, 1% +/- 0.4% for metastatic cancer, 3% +/- 3% for lymphoma, and 7% +/- 10% for TB, and it could significantly distinguish myeloma from metastasis (area under the curve [AUC] = 0.884), lymphoma (AUC = 1.0), and TB (AUC = 1.0) with P = .001, and distinguish metastasis from TB (AUC = 0.741) with P = .005. The kep and wash-out slope were highly correlated (r = 0.92), and they showed a similar diagnostic performance. The K(trans) was significantly correlated with the maximum enhancement (r = 0.71) and the steepest wash-in enhancement (r = 0.85), but they had inferior diagnostic performance compared to the wash-out slope. CONCLUSIONS: DCE-MRI may provide additional diagnostic information, and a simple wash-out slope had the best diagnostic performance. The heuristic and pharmacokinetic parameters were highly correlated.

    *28162875*
     28162875

    Development of a high-performance dual-energy chest imaging system: initial investigation of diagnostic performance.

    Acad Radiol 2009; 16 (4): 464-76

    RATIONALE AND OBJECTIVES: The aim of this study was to assess the performance of a newly developed dual-energy (DE) chest radiographic system in comparison to digital radiographic (DR) imaging in the detection and characterization of lung nodules. MATERIALS AND METHODS: An experimental prototype was developed for high-performance DE chest imaging, with total dose equivalent to a single posterior-anterior DR image. Projections at low and high peak kilovoltage were used to decompose DE soft tissue and bone images. A cohort of 55 patients (31 men, 24 women; mean age, 65.6 years) was drawn from an ongoing trial involving patients referred for percutaneous computed tomography-guided biopsy of suspicious lung nodules. DE and DR images were acquired of each patient prior to biopsy. Image quality was assessed by means of human observer tests involving five radiologists independently rating the detection and characterization of lung nodules on a nine-point scale. Results were analyzed in terms of the fraction of cases at or above a given rating, and statistical significance was evaluated using Wilcoxon's signed-rank test. Performance was analyzed for all cases pooled as well as by stratification of nodule size, density, lung region, and chest thickness. RESULTS: The studies demonstrated a significant performance advantage for DE imaging compared to DR imaging (P < .001) in the detection and characterization of lung nodules. DE imaging improved the detection of both small and large nodules and exhibited the most significant improvement in regions of the upper lobes, where overlying anatomic noise (ribs and clavicles) are believed to reduce nodule conspicuity on DR imaging. CONCLUSIONS: DE imaging outperformed DR imaging overall, particularly in the detection of small, solid nodules. DE imaging also performed better in regions dominated by anatomic noise, such as the lung apices. The potential for improved nodule detection and characterization at radiation doses equivalent to DR imaging is encouraging and could augment the broader use of DE imaging. Future studies will extend the initial cohort and rating scale tests to a larger cohort evaluated by receiver-operating characteristic analysis and will evaluate DE imaging in comparison and as an adjuvant to low-dose computed tomography.

    *19268859*
     19268859

    Phage as a Genetically Modifiable Supramacromolecule in Chemistry, Materials and Medicine.

    Acc Chem Res 2016; 49 (6): 1111-20

    Filamentous bacteriophage (phage) is a genetically modifiable supramacromolecule. It can be pictured as a semiflexible nanofiber ( approximately 900 nm long and approximately 8 nm wide) made of a DNA core and a protein shell with the former genetically encoding the latter. Although phage bioengineering and phage display techniques were developed before the 1990s, these techniques have not been widely used for chemistry, materials, and biomedical research from the perspective of supramolecular chemistry until recently. Powered by our expertise in displaying a foreign peptide on its surface through engineering phage DNA, we have employed phage to identify target-specific peptides, construct novel organic-inorganic nanohybrids, develop biomaterials for disease treatment, and generate bioanalytical methods for disease diagnosis. Compared with conventional biomimetic chemistry, phage-based supramolecular chemistry represents a new frontier in chemistry, materials science, and medicine. In this Account, we introduce our recent successful efforts in phage-based supramolecular chemistry, by integrating the unique nanofiber-like phage structure and powerful peptide display techniques into the fields of chemistry, materials science, and medicine: (1) successfully synthesized and assembled silica, hydroxyapatite, and gold nanoparticles using phage templates to form novel functional materials; (2) chemically introduced azo units onto the phage to form photoresponsive functional azo-phage nanofibers via a diazotization reaction between aromatic amino groups and the tyrosine residues genetically displayed on phage surfaces; (3) assembled phage into 2D films for studying the effects of both biochemical (the peptide sequences displayed on the phages) and biophysical (the topographies of the phage films) cues on the proliferation and differentiation of mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) and identified peptides and topographies that can induce their osteogenic differentiation; (4) discovered that phage could induce angiogenesis and osteogenesis for MSC-based vascularized bone regeneration; (5) identified novel breast cancer cell-targeting and MSC-targeting peptides and used them to significantly improve the efficiency of targeted cancer therapy and MSC-based gene delivery, respectively; (6) employed engineered phage as a probe to achieve ultrasensitive detection of biomarkers from serum of human patients for disease diagnosis; and (7) constructed centimeter-scale 3D multilayered phage assemblies with the potential application as scaffolds for bone regeneration and functional device fabrication. Our findings demonstrated that phage is indeed a very powerful supramacromolecule suitable for not only developing novel nanostructures and biomaterials but also advancing important fields in biomedicine, including molecular targeting, cancer diagnosis and treatment, drug and gene delivery, stem cell fate direction, and tissue regeneration. Our successes in exploiting phage in chemistry, materials, and medicine suggest that phage itself is nontoxic at the cell level and can be safely used for detecting biomarkers in vitro. Moreover, although we have demonstrated successful in vivo tissue regeneration induced by phage, we believe future studies are needed to evaluate the in vivo biodistribution and potential risks of the phage-based biomaterials.

    *27153341*
     27153341

    Rare Metastasis of Primary Pancreatic Adenocarcinoma to the Bladder.

    ACG Case Rep J 2018; 5 (): e27

    Pancreatic cancer commonly metastasizes to the liver, lungs, stomach, bone, and bowel, but rarely does it spread to the bladder. We describe a case of a 66-year-old woman with diabetes mellitus who presented with abnormal liver function laboratory tests, abdominal discomfort, unintentional weight loss, and no urinary symptoms. Abdominal CT revealed a pancreatic and bladder mass. Pathology of the bladder mass confirmed metastatic adenocarcinoma of pancreaticobiliary origin. To our knowledge, this is only the third case of metastatic pancreatic cancer spreading to the bladder since 1953.

    *29619402*
     29619402

    Rapid Bioorthogonal Chemistry Enables in Situ Modulation of the Stem Cell Behavior in 3D without External Triggers.

    ACS Appl Mater Interfaces 2018; 10 (31): 26016-26027

    Chemical modification of engineered microenvironments surrounding living cells represents a means for directing cellular behaviors through cell-matrix interactions. Presented here is a temporally controlled method for modulating the properties of biomimetic, synthetic extracellular matrices (ECM) during live cell culture employing the rapid, bioorthogonal tetrazine ligation with trans-cyclooctene (TCO) dienophiles. This approach is diffusion-controlled, cytocompatible, and does not rely on light, catalysts, or other external triggers. Human bone-marrow-derived mesenchymal stem cells (hMSCs) were initially entrapped in a hydrogel prepared using hyaluronic acid carrying sulfhydryl groups (HA-SH) and a hydrophilic polymer bearing both acrylate and tetrazine groups (POM-AT). Inclusion of a matrix metalloprotease (MMP)-degradable peptidic cross-linker enabled hMSC-mediated remodeling of the synthetic environment. The resultant network displayed dangling tetrazine groups for subsequent conjugation with TCO derivatives. Two days later, the stiffness of the matrix was increased by adding chemically modified HA carrying multiple copies of TCO (HA-TCO) to the hMSC growth media surrounding the cell-laden gel construct. In response, cells developed small processes radially around the cell body without a significant alteration of the overall shape. By contrast, modification of the 3D matrix with a TCO-tagged cell-adhesive motif caused the resident cells to undergo significant actin polymerization, changing from a rounded shape to spindle morphology with long cellular processes. After additional 7 days of culture in the growth media, quantitative analysis showed that, at the mRNA level, RGD tagging upregulated cellular expression of MMP1, but downregulated the expression of collagen I/III and tenascin C. RGD tagging, however, was not sufficient to induce the classic osteoblastic, chondrogenic, adipogenic, or fibroblastic/myofibroblastic differentiation. The modular approach allows facile manipulation of synthetic ECM to modulate cell behavior, thus potentially applicable to the engineering of functional tissues or tissue models.

    *30015482*
     30015482

    Bisphosphonate-Functionalized Hydroxyapatite Nanoparticles for the Delivery of the Bromodomain Inhibitor JQ1 in the Treatment of Osteosarcoma.

    ACS Appl Mater Interfaces 2017; 9 (31): 25887-25904

    Osteosarcoma (OS) is one of the most common neoplasia among children, and its survival statistics have been stagnating since the combinatorial anticancer therapy triad was first introduced. Here, we report on the assessment of the effect of hydroxyapatite (HAp) nanoparticles loaded with medronate, the simplest bisphosphonate, as a bone-targeting agent and JQ1, a small-molecule bromodomain inhibitor, as a chemotherapeutic in different 2D and 3D K7M2 OS in vitro models. Both additives decreased the crystallinity of HAp, but the effect was more intense for medronate because of its higher affinity for HAp. As the result of PO4(3-)-NH(+) binding, JQ1 shielded the surface phosphates of HAp and pushed its surface charge to more positive values, exhibiting the opposite effect from calcium-blocking medronate. In contrast to the faster and more exponential release of JQ1 from monetite, its release from HAp nanoparticles followed a zero-order kinetics, but 98% of the payload was released after 48 h. The apoptotic effect of HAp nanoparticles loaded with JQ1, with medronate and with both JQ1 and medronate, was selective in 2D culture: pronounced against the OS cells and nonexistent against the healthy fibroblasts. While OS cell invasion was significantly inhibited by all of the JQ1-containing HAp formulations, that is, with and without medronate, all of the combinations of the targeting compound, medronate, and the chemotherapeutic, JQ1, delivered using HAp, but not HAp alone, inhibited OS cell migration from the tumor spheroids. JQ1 delivered using HAp had an effect on tumor migration, invasion, and apoptosis even at extremely low, subnanomolar concentrations, at which no effect of JQ1 per se was observed, meaning that this form of delivery could help achieve a multifold increase of this drug's efficacy. More than 80% of OS cells internalized JQ1-loaded HAp nanoparticles after 24 h of coincubation, suggesting that this augmentation of the activity of JQ1 may be due to the intracellular delivery and sustained release of the drug enabled by HAp. In addition to the reduction of the OS cell viability, the reduction of the migration and invasion radii was observed in OS tumor spheroids challenged with even JQ1-free medronate-functionalized HAp nanoparticles, demonstrating a definite anticancer activity of medronate alone when combined with HAp. The effect of medronate-functionalized JQ1-loaded HAp nanoparticles was most noticeable against OS cells differentiated into an osteoblastic lineage, in which case they surpassed in effect pure JQ1 and medronate-free compositions. The activity of JQ1 was mediated through increased Ezrin expression and decreased RUNX2 expression and was MYC and FOSL1 independent, but these patterns of gene expression changed in cells challenged with the nanoparticulate form of delivery, having been accompanied by the upregulation of RUNX2 and downregulation of Ezrin in OS cells treated with medronate-functionalized JQ1-loaded HAp nanoparticles.

    *28731328*
     28731328

    Temporary Single-Cell Coating for Bioprocessing with a Cationic Polymer.

    ACS Appl Mater Interfaces 2017; 9 (15): 12967-12974

    Temporary single-cell coating is a useful tool for cell processing, allowing manipulation of cells to prevent cell attachment and agglomeration, before re-establishing normal cell function. In this work, a speckled coating method using a known polycation [poly(l-lysine), PLL] is described to induce cell surface electrostatic charges on three different cell types, namely, two bone cancer cell lines and fibroblasts. The morphology of the PLL speckled coating on the cell surface, internalization and metabolization of the polymer, and prevention of cellular aggregations are reported. Polymer concentration was found to be the key parameter controlling both capsule morphology and cell health. This approach allows a temporary cell coating over the course of 1-2 h, with cells exhibiting phenotypically normal behavior after ingesting and metabolizing the polymer. The process offers a fast and efficient alternative to aid single-cell manipulation for bioprocessing applications. Preliminary work on the application of PLL speckled cell coating in enabling reliable bioprinting is also presented.

    *28323412*
     28323412

    3d Tissue Engineered In Vitro Models Of Cancer In Bone.

    ACS Biomater Sci Eng 2018; 4 (2): 324-336

    Biological models are necessary tools for gaining insight into underlying mechanisms governing complex pathologies such as cancer in the bone. Models range from in vitro tissue culture systems to in vivo models and can be used with corresponding epidemiological and clinical data to understand disease etiology, progression, driver mutations, and signaling pathways. In bone cancer, as with many other cancers, in vivo models are often too complex to study specific cell-cell interactions or protein roles, and 2D models are often too simple to accurately represent disease processes. Consequently, researchers have increasingly turned to 3D in vitro tissue engineered models as a useful compromise. In this review, tissue engineered 3D models of bone and cancer are described in depth and compared to 2D models. Biomaterials and cell types used are described, and future directions in the field of tissue engineered bone cancer models are proposed.

    *29756030*
     29756030

    Combinatorial Discovery of Defined Substrates That Promote a Stem Cell State in Malignant Melanoma.

    ACS Cent Sci 2017; 3 (5): 381-393

    The tumor microenvironment is implicated in orchestrating cancer cell transformation and metastasis. However, specific cell-ligand interactions between cancer cells and the extracellular matrix are difficult to decipher due to a dynamic and multivariate presentation of many signaling molecules. Here we report a versatile peptide microarray platform that is capable of screening for cancer cell phenotypic changes in response to ligand-receptor interactions. Using a screen of 78 peptide combinations derived from proteins present in the melanoma microenvironment, we identify a proteoglycan binding and bone morphogenic protein 7 (BMP7) derived sequence that selectively promotes the expression of several putative melanoma initiating cell markers. We characterize signaling associated with each of these peptides in the activation of melanoma pro-tumorigenic signaling and reveal a role for proteoglycan mediated adhesion and signaling through Smad 2/3. A defined substratum that controls the state of malignant melanoma may prove useful in spatially normalizing a heterogeneous population of tumor cells for discovery of therapeutics that target a specific state and for identifying new drug targets and reagents for intervention.

    *28573199*
     28573199

    Selective Inhibition of the Myeloid Src-Family Kinase Fgr Potently Suppresses AML Cell Growth in Vitro and in Vivo.

    ACS Chem Biol 2018; 13 (6): 1551-1559

    Acute myelogenous leukemia (AML) is the most common hematologic malignancy in adults and is often associated with constitutive tyrosine kinase signaling. These pathways involve the nonreceptor tyrosine kinases Fes, Syk, and the three Src-family kinases expressed in myeloid cells (Fgr, Hck, and Lyn). In this study, we report remarkable anti-AML efficacy of an N-phenylbenzamide kinase inhibitor, TL02-59. This compound potently suppressed the proliferation of bone marrow samples from 20 of 26 AML patients, with a striking correlation between inhibitor sensitivity and expression levels of the myeloid Src family kinases Fgr, Hck, and Lyn. No correlation was observed with Flt3 expression or mutational status, with the four most sensitive patient samples being wild-type for Flt3. Kinome-wide target specificity profiling coupled with in vitro kinase assays demonstrated a narrow overall target specificity profile for TL02-59, with picomolar potency against the myeloid Src-family member Fgr. In a mouse xenograft model of AML, oral administration of TL02-59 for 3 weeks at 10 mg/kg completely eliminated leukemic cells from the spleen and peripheral blood while significantly reducing bone marrow engraftment. These results identify Fgr as a previously unrecognized kinase inhibitor target in AML and TL02-59 as a possible lead compound for clinical development in AML cases that overexpress this kinase independent of Flt3 mutations.

    *29763550*
     29763550

    Selective Targeting of Bromodomains of the Bromodomain-PHD Fingers Family Impairs Osteoclast Differentiation.

    ACS Chem Biol 2017; 12 (10): 2619-2630

    Histone acetyltransferases of the MYST family are recruited to chromatin by BRPF scaffolding proteins. We explored functional consequences and the therapeutic potential of inhibitors targeting acetyl-lysine dependent protein interaction domains (bromodomains) present in BRPF1-3 in bone maintenance. We report three potent and selective inhibitors: one (PFI-4) with high selectivity for the BRPF1B isoform and two pan-BRPF bromodomain inhibitors (OF-1, NI-57). The developed inhibitors displaced BRPF bromodomains from chromatin and did not inhibit cell growth and proliferation. Intriguingly, the inhibitors impaired RANKL-induced differentiation of primary murine bone marrow cells and human primary monocytes into bone resorbing osteoclasts by specifically repressing transcriptional programs required for osteoclastogenesis. The data suggest a key role of BRPF in regulating gene expression during osteoclastogenesis, and the excellent druggability of these bromodomains may lead to new treatment strategies for patients suffering from bone loss or osteolytic malignant bone lesions.

    *28849908*
     28849908

    Ligand-independent and tissue-selective androgen receptor inhibition by pyrvinium.

    ACS Chem Biol 2014; 9 (3): 692-702

    Pyrvinium pamoate (PP) is a potent noncompetitive inhibitor of the androgen receptor (AR). Using a novel method of target identification, we demonstrate that AR is a direct target of PP in prostate cancer cells. We demonstrate that PP inhibits AR activity via the highly conserved DNA binding domain (DBD), the only AR inhibitor that functions via this domain. Furthermore, computational modeling predicts that pyrvinium binds at the interface of the DBD dimer and the minor groove of the AR response element. Because PP acts through the DBD, PP is able to inhibit the constitutive activity of AR splice variants, which are thought to contribute to the growth of castration resistant prostate cancer (CRPC). PP also inhibits androgen-independent AR activation by HER2 kinase. The antiandrogen activity of pyrvinium manifests in the ability to inhibit the in vivo growth of CRPC xenografts that express AR splice variants. Interestingly, PP was most potent in cells with endogenous AR expression derived from prostate or bone. PP was able to inhibit several other hormone nuclear receptors (NRs) but not structurally unrelated transcription factors. PP inhibition of other NRs was similarly cell-type selective. Using dual-energy X-ray absorptiometry, we demonstrate that the cell-type specificity of PP manifests in tissue-selective inhibition of AR activity in mice, as PP decreases prostate weight and bone mineral density but does not affect lean body mass. Our results suggest that the noncompetitive AR inhibitor pyrvinium has significant potential to treat CRPC, including cancers driven by ligand-independent AR signaling.

    *24354286*
     24354286

    Discovery of small-molecule enhancers of reactive oxygen species that are nontoxic or cause genotype-selective cell death.

    ACS Chem Biol 2013; 8 (5): 923-9 dadams@broadinstitute.org

    Elevation of reactive oxygen species (ROS) levels has been observed in many cancer cells relative to nontransformed cells, and recent reports have suggested that small-molecule enhancers of ROS may selectively kill cancer cells in various in vitro and in vivo models. We used a high-throughput screening approach to identify several hundred small-molecule enhancers of ROS in a human osteosarcoma cell line. A minority of these compounds diminished the viability of cancer cell lines, indicating that ROS elevation by small molecules is insufficient to induce death of cancer cell lines. Three chemical probes (BRD5459, BRD56491, BRD9092) are highlighted that most strongly elevate markers of oxidative stress without causing cell death and may be of use in a variety of cellular settings. For example, combining nontoxic ROS-enhancing probes with nontoxic doses of L-buthionine sulfoximine, an inhibitor of glutathione synthesis previously studied in cancer patients, led to potent cell death in more than 20 cases, suggesting that even nontoxic ROS-enhancing treatments may warrant exploration in combination strategies. Additionally, a few ROS-enhancing compounds that contain sites of electrophilicity, including piperlongumine, show selective toxicity for transformed cells over nontransformed cells in an engineered cell-line model of tumorigenesis. These studies suggest that cancer cell lines are more resilient to chemically induced increases in ROS levels than previously thought and highlight electrophilicity as a property that may be more closely associated with cancer-selective cell death than ROS elevation.

    *23477340*
     23477340

    Glycosylation Changes in Brain Cancer.

    ACS Chem Neurosci 2018; 9 (1): 51-72

    Protein glycosylation is a posttranslational modification that affects more than half of all known proteins. Glycans covalently bound to biomolecules modulate their functions by both direct interactions, such as the recognition of glycan structures by binding partners, and indirect mechanisms that contribute to the control of protein conformation, stability, and turnover. The focus of this Review is the discussion of aberrant glycosylation related to brain cancer. Altered sialylation and fucosylation of N- and O-glycans play a role in the development and progression of brain cancer. Additionally, aberrant O-glycan expression has been implicated in brain cancer. This Review also addresses the clinical potential and applications of aberrant glycosylation for the detection and treatment of brain cancer. The viable roles glycans may play in the development of brain cancer therapeutics are addressed as well as cancer-glycoproteomics and personalized medicine. Glycoprotein alterations are considered as a hallmark of cancer while high expression in body fluids represents an opportunity for cancer assessment.

    *28982002*
     28982002

    Ca(2+) Selective Host Rotaxane Is Highly Toxic Against Prostate Cancer Cells.

    ACS Med Chem Lett 2017; 8 (2): 163-167

    New therapies are needed to eradicate androgen resistant, prostate cancer. Prostate cancer usually metastasizes to bone where the concentration of calcium is high, making Ca(2+) a promising toxin. Ionophores can deliver metal cations into cells, but are currently too toxic for human use. We synthesized a new rotaxane (CEHR2) that contains a benzyl 15-crown-5 ether as a blocking group to efficiently bind Ca(2+). CEHR2 transfers Ca(2+) from an aqueous solution into CHCl3 to greater extent than alkali metal cations and Mg(2+). It also transfers Ca(2+) to a greater extent than CEHR1, which is a rotaxane with an 18-crown-6 ether as a blocking group. CEHR2 was more toxic against the prostate cancer cell lines PC-3, 22Rv1, and C4-2 than CEHR1. This project demonstrates that crown ether rotaxanes can be designed to bind a targeted metal cation, and this selective cation association can result in enhanced toxicity.

    *28197305*
     28197305

    Development of ML390: A Human DHODH Inhibitor That Induces Differentiation in Acute Myeloid Leukemia.

    ACS Med Chem Lett 2016; 7 (12): 1112-1117

    Homeobox transcription factor A9 (HoxA9) is overexpressed in 70% of patients diagnosed with acute myeloid leukemia (AML), whereas only a small subset of AML patients respond to current differentiation therapies. A cell line overexpressing HoxA9 was derived from the bone marrow of a lysozyme-GFP mouse. In this fashion, GFP served as an endogenous reporter of differentiation, permitting a high-throughput phenotypic screen against the MLPCN library. Two chemical scaffolds were optimized for activity yielding compound ML390, and genetic resistance and sequencing efforts identified dihydroorotate dehydrogenase (DHODH) as the target enzyme. The DHODH inhibitor brequinar works against these leukemic cells as well. The X-ray crystal structure of ML390 bound to DHODH elucidates ML390s binding interactions.

    *27994748*
     27994748

    Farnesyl diphosphate synthase inhibitors with unique ligand-binding geometries.

    ACS Med Chem Lett 2015; 6 (3): 349-54

    Farnesyl diphosphate synthase (FPPS) is an important drug target for bone resorption, cancer, and some infectious diseases. Here, we report five new structures including two having unique bound ligand geometries. The diamidine inhibitor 7 binds to human FPPS close to the homoallylic (S2) and allosteric (S3) sites and extends into a new site, here called S4. With the bisphosphonate inhibitor 8, two molecules bind to Trypanosoma brucei FPPS, one molecule in the allylic site (S1) and the other close to S2, the first observation of two bisphosphonate molecules bound to FPPS. We also report the structures of apo-FPPS from T. brucei, together with two more bisphosphonate-bound structures (2,9), for purposes of comparison. The diamidine structure is of particular interest because 7 could represent a new lead for lipophilic FPPS inhibitors, while 8 has low micromolar activity against T. brucei, the causative agent of human African trypanosomiasis.

    *25815158*
     25815158

    Design, synthesis, and osteogenic activity of daidzein analogs on human mesenchymal stem cells.

    ACS Med Chem Lett 2014; 5 (2): 143-8

    Osteoporosis is caused by an overstimulation of osteoclast activity and the destruction of the bone extracellular matrix. Without the normal architecture, osteoblast cells are unable to rebuild phenotypically normal bone. Hormone replacement therapy with estrogen has been effective in increasing osteoblast activity but also has resulted in the increased incidence of breast and uterine cancer. In this study we designed and synthesized a series of daidzein analogs to investigate their osteogenic induction potentials. Human bone marrow derived mesenchymal stem cells (MSCs) from three different donors were treated with daidzein analogs and demonstrated enhanced osteogenesis when compared to daidzein treatment. The enhanced osteogenic potential of these daidzein analogs resulted in increased osterix (Sp7), alkaline phosphatase (ALP), osteopontin (OPN), and insulin-like growth factor 1 (IGF-1), which are osteogenic transcription factors that regulate the maturation of osteogenic progenitor cells into mature osteoblast cells.

    *24900787*
     24900787

    Discovery of AC710, a Globally Selective Inhibitor of Platelet-Derived Growth Factor Receptor-Family Kinases.

    ACS Med Chem Lett 2012; 3 (12): 997-1002

    A series of potent, selective platelet-derived growth factor receptor-family kinase inhibitors was optimized starting from a globally selective lead molecule 4 through structural modifications aimed at improving the physiochemical and pharmacokinetic properties, as exemplified by 18b. Further clearance reduction via per-methylation of the alpha-carbons of a solubilizing piperidine nitrogen resulted in advanced leads 22a and 22b. Results from a mouse tumor xenograft, a collagen-induced arthritis model, and a 7 day rat in vivo tolerability study culminated in the selection of compound 22b (AC710) as a preclinical development candidate.

    *24900421*
     24900421

    Nanoparticle Biokinetics in Mice and Nonhuman Primates.

    ACS Nano 2017; 11 (9): 9514-9524

    Despite the preponderance of iron oxide nanoparticles (NPs) designed for theranostic applications, widespread clinical translation of these NPs lags behind. A better understanding of how NP pharmacokinetics vary between small and large animal models is needed to rapidly customize NPs for optimal performance in humans. Here we use noninvasive magnetic resonance imaging (MRI) to track iron oxide NPs through a large number of organ systems in vivo to investigate NP biokinetics in both mice and nonhuman primates. We demonstrate that pharmacokinetics are similar between mice and macaques in the blood, liver, spleen, and muscle, but differ in the kidneys, brain, and bone marrow. Our study also demonstrates that full-body MRI is practical, rapid, and cost-effective for tracking NPs noninvasively with high spatiotemporal resolution. Our techniques using a nonhuman primate model may provide a platform for testing a range of NP formulations.

    *28885825*
     28885825

    In Situ Imaging of Tissue Remodeling with Collagen Hybridizing Peptides.

    ACS Nano 2017; 11 (10): 9825-9835

    Collagen, the major structural component of nearly all mammalian tissues, undergoes extensive proteolytic remodeling during developmental states and a variety of life-threatening diseases such as cancer, myocardial infarction, and fibrosis. While degraded collagen could be an important marker of tissue damage, it is difficult to detect and target using conventional tools. Here, we show that a designed peptide (collagen hybridizing peptide: CHP), which specifically hybridizes to the degraded, unfolded collagen chains, can be used to image degraded collagen and inform tissue remodeling activity in various tissues: labeled with 5-carboxyfluorescein and biotin, CHPs enabled direct localization and quantification of collagen degradation in isolated tissues within pathologic states ranging from osteoarthritis and myocardial infarction to glomerulonephritis and pulmonary fibrosis, as well as in normal tissues during developmental programs associated with embryonic bone formation and skin aging. The results indicate the general correlation between the level of collagen remodeling and the amount of denatured collagen in tissue and show that the CHP probes can be used across species and collagen types, providing a versatile tool for not only pathology and developmental biology research but also histology-based disease diagnosis, staging, and therapeutic screening. This study lays the foundation for further testing CHP as a targeting moiety for theranostic delivery in various animal models.

    *28877431*
     28877431

    A Carbon Nanotube Optical Reporter Maps Endolysosomal Lipid Flux.

    ACS Nano 2017; 11 (11): 10689-10703

    Lipid accumulation within the lumen of endolysosomal vesicles is observed in various pathologies including atherosclerosis, liver disease, neurological disorders, lysosomal storage disorders, and cancer. Current methods cannot measure lipid flux specifically within the lysosomal lumen of live cells. We developed an optical reporter, composed of a photoluminescent carbon nanotube of a single chirality, that responds to lipid accumulation via modulation of the nanotube's optical band gap. The engineered nanomaterial, composed of short, single-stranded DNA and a single nanotube chirality, localizes exclusively to the lumen of endolysosomal organelles without adversely affecting cell viability or proliferation or organelle morphology, integrity, or function. The emission wavelength of the reporter can be spatially resolved from within the endolysosomal lumen to generate quantitative maps of lipid content in live cells. Endolysosomal lipid accumulation in cell lines, an example of drug-induced phospholipidosis, was observed for multiple drugs in macrophages, and measurements of patient-derived Niemann-Pick type C fibroblasts identified lipid accumulation and phenotypic reversal of this lysosomal storage disease. Single-cell measurements using the reporter discerned subcellular differences in equilibrium lipid content, illuminating significant intracellular heterogeneity among endolysosomal organelles of differentiating bone-marrow-derived monocytes. Single-cell kinetics of lipoprotein-derived cholesterol accumulation within macrophages revealed rates that differed among cells by an order of magnitude. This carbon nanotube optical reporter of endolysosomal lipid content in live cells confers additional capabilities for drug development processes and the investigation of lipid-linked diseases.

    *28898055*
     28898055

    Beyond PubMed : called unfree



    Unanticipated Compression of the Trachea in a 5-Month-Old Undergoing an MRI for Evaluation of Neurofibromatosis.

    A A Case Rep 2017; 8 (1): 1-3

    Neurofibromatosis type 1 is an autosomal-dominant disorder with the tendency toward the formation of tumors. Plexiform neurofibromas are the most common type of tumors seen in neurofibromatosis type 1. Approximately 50% occur in the head and neck region with a 5% incidence of airway involvement. We describe the case of a 5 month old with a plexiform neurofibroma of the neck who developed complete airway obstruction on induction of anesthesia. Magnetic resonance imaging revealed a skull base neurofibroma extending to the hypopharynx and resulting in deviation of the airway. Because of the possibility of airway involvement, a careful preanesthetic evaluation as well as a slow induction with the maintenance of spontaneous ventilation should be considered in patients presenting with facial neurofibromas.

    *28036318*
     28036318

    Hemophagocytic Lymphohistiocytosis.

    AACN Adv Crit Care 2019; 30 (2): 151-164 (jskinne2@jhmi.edu).

    Hemophagocytic lymphohistiocytosis is a life-threatening condition associated with hyperinflammation and multiple organ dysfunction. It has many causes, symptoms, and outcomes. Early recognition is critical for treatment. Fever, cytopenias, coagulopathy, and hepatosplenomegaly are hallmark findings. Identifying the trigger event is crucial but challenging because of the varied presentations and infrequent provider experience. Diagnostic features include anemia, thrombocytopenia, neutropenia, elevated ferritin, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis (in bone marrow, spleen, or lymph nodes), low or absent natural killer cells, and elevated soluble interleukin 2 receptor assay. Primary treatment goals are eliminating the underlying trigger and suppressing hyperinflammation with steroids, immunoglobulins, or immunomodulators. Specific treatment includes corticosteroids, etoposide, and antithymocyte globulin followed by hematopoietic stem cell transplantation in patients with refractory or relapsing disease. Prompt immunochemical therapy is essential but often complicated by a high risk of treatment-related morbidity and disease recurrence. Despite these challenges, improvements in diagnostic technology and treatment have enhanced survival.

    *31151946*
     31151946

    Gastrointestinal manifestations of graft-versus-host disease: diagnosis and management.

    AACN Clin Issues 1999; 10 (4): 500-6

    The number of bone marrow transplantations performed to treat diseases such as leukemia, lymphoma, and aplastic anemia has been increasing during the past 2 decades. Improvements in histocompatibility testing, transfusion support, conditioning regimens, and antibiotics have dramatically improved survival after transplantation. As more patients survive the acute phase of bone marrow transplantation and leave major medical centers for their homes, healthcare providers across the country are caring for these patients and their transplantation-associated complications. Graft-versus-host disease (GVHD) of the skin, liver, and gastrointestinal tract are complications that patients may experience months after transplantation. As clinicians, advanced practice nurses encounter these patients in clinics, hospitals, and intensive care units, whether it be for specific GVHD-associated problems or other health conditions. This article reviews the current standards of care for the prevention, diagnosis, and treatment of GVHD of the gastrointestinal tract.

    *10865534*
     10865534

    Bone marrow transplantation: issues for critical care nurses.

    AACN Clin Issues 1996; 7 (1): 95-108; quiz 179-80

    Bone marrow transplantation (BMT) is becoming a wide used therapeutic modality in the field of cancer care. Offering long-term disease-free survival in more than half of some patients with previously fatal diseases, this therapy has challenged clinicians to reevaluate critical care management strategies for such patients. Critical illness occurs in approximately one third of allogeneic transplants, necessitating that critical care nurses be familiar with this therapy and its reported complications. Critical care nurses are an integral part of producing the reported cure and remission rates, despite significant complications. In this article, the authors outline the common critical care problems of this patient population. The chronologic format enables the practitioner to correlate and differentiate key characteristics of potential complications. A case study, with clinical symptoms representing several potential etiologies, demonstrates the application of these concepts. Through the use of nursing knowledge of the unique needs of these patients, there is the potential to continue to improve patient outcomes.

    *8697119*
     8697119

    Issues and trends in critical care of patients with cancer.

    AACN Clin Issues 1996; 7 (1): 9-25

    The specialty of critical care oncology has emerged as a result of changes in treatment of malignancies and technologic critical care developments. In this article, the author provides the experienced critical care nurse with an overview of the practice of critical care oncology and the unique needs of these patients. Methods for predicting critical illnesses in specialized cancer populations are provided. Also included is a summary of universal cancer care issues such as bone marrow suppression, venous access, chronic pain, and nutrition disorders that cross all specialty areas. This article serves as a basis and resource for practicing critical care nurses and includes background information for the other articles included in this journal issue.

    *8697118*
     8697118

    Cancer: new therapies and new approaches to recurring problems.

    AANA J 2003; 71 (1): 55-62

    Caring for patients with cancer presents unique challenges to anesthetists. Chemotherapeutic regimens can cause cardiac, pulmonary, and other complications that will influence the anesthesia provider's care. New surgical techniques, including vertebroplasty, vertebrectomy, radiofrequency ablation of the liver, and sentinel node biopsy, present issues related to the surgical techniques and drugs administered. Recurring problems, including tumors of the airway and cardiac tamponade, continue to present challenges for anesthesia providers. Many patients with cancer who undergo surgery not only have acute pain related to the surgical procedure but also have chronic pain that will influence anesthetic and postoperative pain management. This Journal course discusses new therapies and procedures and approaches to recurring problems in cancer care.

    *12776652*
     12776652

    A case study: the use of trans-tracheal guide for a patient with a large protruding oral myxoma.

    AANA J 1987; 55 (1): 81-2

    *3645952*
     3645952

    CAR T Cell Immunotherapy in Human and Veterinary Oncology: Changing the Odds Against Hematological Malignancies.

    AAPS J 2019; 21 (3): 50 jmochel@iastate.edu.;

    The advent of the genome editing era brings forth the promise of adoptive cell transfer using engineered chimeric antigen receptor (CAR) T cells for targeted cancer therapy. CAR T cell immunotherapy is probably one of the most encouraging developments for the treatment of hematological malignancies. In 2017, two CAR T cell therapies were approved by the US Food and Drug Administration: one for the treatment of pediatric acute lymphoblastic leukemia (ALL) and the other for adult patients with advanced lymphomas. However, despite significant progress in the area, CAR T cell therapy is still in its early days and faces significant challenges, including the complexity and costs associated with the technology. B cell lymphoma is the most common hematopoietic cancer in dogs, with an incidence approaching 0.1% and a total of 20-100 cases per 100,000 individuals. It is a widely accepted naturally occurring model for human non-Hodgkin's lymphoma. Current treatment is with combination chemotherapy protocols, which prolong life for less than a year in canines and are associated with severe dose-limiting side effects, such as gastrointestinal and bone marrow toxicity. To date, one canine study generated CAR T cells by transfection of mRNA for CAR domain expression. While this was shown to provide a transient anti-tumor activity, results were modest, indicating that stable, genomic integration of CAR modules is required in order to achieve lasting therapeutic benefit. This commentary summarizes the current state of knowledge on CAR T cell immunotherapy in human medicine and its potential applications in animal health, while discussing the potential of the canine model as a translational system for immuno-oncology research.

    *30963322*
     30963322

    Predicting the Effects of Different Triazole Antifungal Agents on the Pharmacokinetics of Tamoxifen.

    AAPS PharmSciTech 2019; 20 (1): 24 zlq0713@aliyun.com.;

    Tamoxifen is an antiestrogen drug that is widely used in the adjuvant chemotherapy of estrogen receptor-alpha (ERalpha)-positive breast cancer. Chemotherapy could suppress immune function in breast cancer patients, which may cause invasive fungal infections (IFIs). Triazoles (voriconazole, fluconazole, and itraconazole) were commonly used for IFI. The physiologically based pharmacokinetic (PBPK) models were developed to investigate the influence of different triazoles on tamoxifen pharmacokinetics in this paper. To investigate the influence of different triazoles (voriconazole, fluconazole, itraconazole) on tamoxifen pharmacokinetics. Adjusted physicochemical data and pharmacokinetic parameters of voriconazole, fluconazole, itraconazole, and tamoxifen were obtained from published literatures. PBPK models were built and verified in healthy subjects using GastroPlus. Voriconazole, itraconazole, and tamoxifen were administered orally. Fluconazole was administered intravenously. Simulated plasma concentration-time curves of the voriconazole, fluconazole, itraconazole, and tamoxifen showed good agreement with the observed profiles, respectively. The DDI simulations showed that the pharmacokinetic parameters of tamoxifen were increased by various degrees when coadministered with different triazoles. In healthy subjects, the area under the plasma concentration-time curve from 0 to t h (AUC0-t) of tamoxifen was increased by 41%, 5%, and1% when coadministrated with voriconazole, fluconazole, and itraconazole, respectively. The PBPK models adequately characterized the pharmacokinetics of tamoxifen and triazoles. Among the three triazoles, voriconazole exhibited the greatest effect on tamoxifen pharmacokinetics. In clinical practice, an effective dosage adjustment of tamoxifen may need to be considered and TDM for tamoxifen is advisable to guide dosing and optimize therapy when coadministered with voriconazole.

    *30604153*
     30604153

    Colloidally Stable Small Unilamellar Stearyl Amine Lipoplexes for Effective BMP-9 Gene Delivery to Stem Cells for Osteogenic Differentiation.

    AAPS PharmSciTech 2018; 19 (8): 3550-3560 misraan@hotmail.com.

    The biocompatibility of cationic liposomes has led to their clinical translation in gene delivery and their application apart from cancer to cardiovascular diseases, osteoporosis, metabolic diseases, and more. We have prepared PEGylated stearyl amine (pegSA) lipoplexes meticulously considering the physicochemical properties and formulation parameters to prepare single unilamellar vesicles (SUV) of < 100 nm size which retain their SUV nature upon complexation with pDNA rather than the conventional lipoplexes which show multilamellar nature. The developed PEGylated SA lipoplexes (pegSA lipoplexes) showed a lower N/P ratio (1.5) for BMP-9 gene complexation while maintaining the SUV character with a unique shape (square and triangular lipoplexes). Colloidal and pDNA complexation stability in the presence of electrolytes and serum indicates the suitability for intravenous administration for delivery of lipoplexes to bone marrow mesenchymal stem cells through sinusoidal vessels in bone marrow. Moreover, lower charge density of lipoplexes and low oxidative stress led to lower toxicity of lipoplexes to the C2C12 cells, NIH 3T3 cells, and erythrocytes. Transfection studies showed efficient gene delivery to C2C12 cells inducing osteogenic differentiation through BMP-9 expression as shown by enhanced calcium deposition in vitro, proving the potential of lipoplexes for bone regeneration. In vivo acute toxicity studies further demonstrated safety of the developed lipoplexes. Developed pegSA lipoplexes show potential for further in vivo preclinical evaluation to establish the proof of concept.

    *30187446*
     30187446

    Facile Synthesis of Chitosan Capped Mesoporous Silica Nanoparticles: A pH Responsive Smart Delivery Platform for Raloxifene Hydrochloride.

    AAPS PharmSciTech 2018; 19 (3): 1344-1357 sjrajput@gmail.com.

    An encapsulation of model drug raloxifene hydrochloride (RAL) inside the chitosan decorated pH responsive mesoporous system has a greater potential for accumulating in the tumor cells. The present study involves synthesis of surface modified mesoporous silica nanoparticles (MSN) with the aim of achieving pH sensitive drug delivery system. A silanol skeleton of MSN has been productively modified to amine intermediate which served as a firm platform to adapt chitosan grafted assembly and systematically evaluated. RAL incorporation inside the featured mesopores was performed employing novel immersion solvent evaporation methodology and evaluated further. The pH responsive behavior of formulated nano framework was studied at three different pH of a phosphate buffer saline individually. The in vitro cell viability assay on MCF-7 breast carcinoma cells was performed in time and concentration dependent manner. Finally, the hemolysis assay of designed nanoparticle was accomplished to envisage the hemocompatibility. The outcome of characterization details unveiled a perfect 2D hexagonal spherical structure gifted with higher surface area and optimum pore size for designed nanoparticles. The higher percentage grafting of amine and chitosan residue, i.e., 4.01 and 28.51% respectively along with 31.89 and 33.57% RAL loading efficiency made MSNs more attractive and applicable. Eventually, in vitro release study exhibited higher RAL release in acidic media for extended time periods confirming successful formation of pH responsive nanoparticle having controlled release property. Conclusively potential of designed nanosystem to serve efficient anti-cancer remedy was confirmed by superior behaviour of chitosan grafted MSN towards MCF-7 cells with supreme hemocompatibility.

    *29340980*
     29340980

    Formulation and In Vitro Characterization of Bioactive Mesoporous Silica with Doxorubicin and Metronidazole Intended for Bone Treatment and Regeneration.

    AAPS PharmSciTech 2017; 18 (8): 3163-3171 kczar@gumed.edu.pl.;

    The purpose of this study was to evaluate the surface mineralization activity and in vitro drug behavior potential of two forms of mesoporous silica: powder and granulate. Ordered mesoporous SiO2 powder was synthesized by surfactant-assisted sol-gel process using tetraethoxysilane as a silica precursor and hexadecyltrimethylammonium bromide as the structure-directing agent. The granulate was prepared using silica powder and ethyl cellulose as a binding agent. Metronidazole (MT)-an anti-inflammatory substance and doxorubicin hydrochloride (ChD)-an anti-cancer drug were chosen as drug models for delivery studies. The results of structural characteristic studies, utilizing transmission electron microscope (TEM) and scanning electron microscope (SEM) images, powder X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and nitrogen adsorption-desorption (BET) measurements, show that obtained materials have two-dimensional hexagonal p6mm symmetry, high specific surface area, narrow pore size, and a satisfactory mineralization behavior in the simulated body solution (SBF, pH = 7.4). The release rate of drugs depends upon the structural features of the drug molecules and the form of the carrier material. Of both the drugs analyzed, faster release was observed for small MT molecules characterized by weaker interactions with the carrier. In addition, the slower drug release was observed with granulate form due to increased diffusion barrier for drugs. Obtained results prove that the MT/ChD-loaded silica formulations could be attractive materials for filling bone defects and for local delivery systems.

    *28534298*
     28534298

    Bioactive/Natural Polymeric Scaffolds Loaded with Ciprofloxacin for Treatment of Osteomyelitis.

    AAPS PharmSciTech 2017; 18 (4): 1056-1069 aa.monem@nrc.sci.eg.;

    Local delivery of antibiotic into injured bone is a demand. In this work, different scaffolds of chitosan (C) with or without bioactive glass (G) were prepared using the freeze-drying technique in 2:1, 1:1, and 1:2 weight ratios. Chitosan scaffolds and selected formulas of chitosan to bioglass were loaded with ciprofloxacin in 5%, 10%, and 20% w/w. Scaffold morphology showed an interconnected porous structure, where the glass particles were homogeneously dispersed in the chitosan matrix. The kinetic study confirmed that the scaffold containing 1:2 weight ratio of chitosan to glass (CG12) showed optimal bioactivity with good compromise between Ca and P uptake capacities and Si release rate. Chitosan/bioactive glass scaffolds showed larger t 50 values indicating less burst drug release followed by a sustained drug release profile compared to that of chitosan scaffolds. The cell growth, migration, adhesion, and invasion were enhanced onto CG12 scaffold surfaces. Samples of CG12 scaffolds with or without 5% drug induced vascular endothelial growth factor (VEGF), while those containing 10% drug diminished VEGF level. Only CG12 induced the cell differentiation (alkaline phosphatase activity). In conclusion, CG12 containing 5% drug can be considered a biocompatible carrier which would help in the localized osteomyelitis treatment.

    *27520562*
     27520562

    Correlation of CT patterns of primary intrahepatic cholangiocarcinoma at the time of presentation with the metastatic spread and clinical outcomes: retrospective study of 92 patients.

    Abdom Imaging 2014; 39 (6): 1193-201

    OBJECTIVE: To study the CT appearance and histopathology of mass-forming intrahepatic cholangiocarcinoma (IHCC) at presentation and correlate these features with metastatic disease and patient survival. MATERIALS AND METHODS: In this IRB-approved, HIPAA compliant retrospective study, we reviewed pathology database of 459 patients with cholangiocarcinoma seen from 2004 through 2013 to identify 92 patients with IHCC (48 women, 44 men, mean age 61 years) who had CT scans of primary tumor available for review. All baseline and follow-up CT's were reviewed by two radiologists in consensus to record imaging characteristics and metastatic patterns. Clinical and histopathology data were obtained from electronic medical records. Imaging patterns and histopathology were analyzed for associations with metastatic spread and survival. RESULTS: Three distinct CT patterns of IHCC at presentation were identified: solitary dominant mass (type I IHCC, n = 34), dominant mass with satellite nodules in same segment (type II IHCC, n = 19), and multiple scattered hepatic lesions (type III IHCC, n = 39). Distant metastases developed in 49/92 patients (53%); 39 (42%) of which were present at diagnosis. Lungs (22/92; 24%), peritoneum (17/92; 18%), and bones (13/92; 14%) were most common metastatic sites. Type I IHCC had smaller size, lowest incidence of metastases at presentation, and best overall survival, while type III IHCC had shortest survival (p < 0.017). Poorly differentiated IHCC had higher proportion of osseous metastases (p = 0.042) and worse survival (p = 0.027). CONCLUSION: IHCC has three distinct CT patterns at presentation with different prognoses. Knowledge of these patterns can help radiologists to detect the extrahepatic disease and predict prognosis.

    *24869789*
     24869789

    MR imaging of the pelvis: a guide to incidental musculoskeletal findings for abdominal radiologists.

    Abdom Imaging 2014; 39 (4): 776-96

    Occasionally patients who undergo magnetic resonance imaging for presumed pelvic disease demonstrate unexpected musculoskeletal imaging findings in the imaged field. Such incidental findings can be challenging to the abdominal radiologist, who may not be familiar with their appearance or know the appropriate diagnostic considerations. Findings can include both normal and abnormal bone marrow, osseous abnormalities such as Paget's disease, avascular necrosis, osteomyelitis, stress and insufficiency fractures, and athletic pubalgia, benign neoplasms such as enchondroma and bone island, malignant processes such as metastasis and chondrosarcoma, soft tissue processes such as abscess, nerve-related tumors, and chordoma, joint- and bursal-related processes such as sacroiliitis, iliopsoas bursitis, greater trochanteric pain syndrome, and labral tears, and iatrogenic processes such as bone graft or bone biopsy. Though not all-encompassing, this essay will help abdominal radiologists to identify and describe this variety of pelvic musculoskeletal conditions, understand key radiologic findings, and synthesize a differential diagnosis when appropriate.

    *24682526*
     24682526

    Oncology imaging in the abdomen and pelvis: where cancer hides.

    Abdom Imaging 2013; 38 (4): 647-71 seberhardt@salud.unm.edu

    As the incidence of cancer continues to increase, imaging will play an ever more important role in the detection, diagnosis, staging, surveillance, and therapeutic monitoring of cancer. Diagnostic errors in the initial discovery of cancer or at follow-up assessments can lead to missed opportunities for curative treatments or altering or reinitiating therapies, as well as adversely impact clinical trials. Radiologists must have an understanding of cancer biology, treatments, and imaging appearance of therapeutic effects and be mindful that metastatic disease can involve virtually any organ system. Knowledge of patient history and tumor biology allows for optimizing imaging protocols. The majority of cancer imaging utilizes computed tomography, where contrast enhancement characteristics of lesions can be exploited and detection of subtle lesions can involve manipulation of window width and level settings, multiplanar reconstruction, and maximum intensity projections. For magnetic resonance imaging, diffusion-weighted imaging can render lesions more conspicuous, improve characterization, and help assess therapeutic response. Positron emission tomography with (18)F-labeled fluorodeoxyglucose and sodium fluoride are invaluable in detecting occult existing and new cancerous lesions, characterizing indeterminate lesions, and assessing treatment effects. The most common anatomic "hiding places" for cancer include metastases to solid organs, such as the kidneys and pancreas, gastrointestinal tract, peritoneum and retroperitoneum, neural axis, muscular body wall, and bones. Consistent work habits, employment of appropriate technologies, and particular attention to the above anatomic areas can enhance detection, staging, and reassessments of these complex and often stealthy diseases, ensuring the radiologists' integral role in the cancer care team.

    *22875476*
     22875476

    Staging of colon cancer: whole-body MRI vs. whole-body PET-CT--initial clinical experience.

    Abdom Imaging 2008; 33 (6): 676-88 ettoresquillaci@tiscali.it

    BACKGROUND: To assess the accuracy of whole-body MR imaging (WB-MRI) in comparison with whole-body [18(F)]-2-fluoro-2-deoxy-D-glucose (FDG) PET-CT in staging patients with diagnosed colorectal carcinoma (CRC). METHODS: Twenty consecutive patients with previously diagnosed CRC underwent WB-MRI (3T) and PET-CT for staging of lymph node (N) and distant metastases (M). Evaluation was done according to the American Joint Committee on Cancer Staging Criteria. MR images were evaluated by two radiologists while PET-CT images by one radiologist and one nuclear medicine physician. Histology and/or a clinical follow-up of 3-6 months served as standard of reference. RESULTS: Lymph node involvement was determined in 10/20 cases as N-positive in WB-MRI and in 15/20 in PET-CT. M-stage was evaluated for liver metastases (27 lesions in 15 patients with WB-MRI, 23/15 patients with PET-CT), lung (19/5 patients with WB-MRI, 25/7 patients with PET-CT), and bone (9/3 patients with WB-MRI, 9/3 patients with PET-CT). Two patients showed peritoneal implants and three patients demonstrated local recurrence at the surgery site on both modalities. No brain metastases were found. CONCLUSIONS: WB-MRI is a feasible method for examining colon cancer patients but cannot displace the present role of PET-CT.

    *18373114*
     18373114

    Pediatric Burkitt's lymphoma: CT findings.

    Abdom Imaging 2007; 32 (3): 381-6

    PURPOSE: To review and analyze all CT scans of the cases of Burkitt's lymphoma (BL) in children diagnosed in our institution. MATERIALS AND METHODS: A retrospective analysis of 33 children with BL between the years 2003 and 2005 seen in our institution was undertaken. Twenty-nine male and four female patients from age 3 to 16 years (with a mean age 5.9 years) were reviewed. RESULTS: The gastrointestinal tract was involved in 19 patients (57.5%), kidneys in 9 (27.2%), peritoneum in 8 (24.2%), liver in 4 (12.1%), spleen in 3 (9%), adrenals in 3 (9%), and pancreas in 1 patient (3%). Extra-nodal head and neck involvement was seen in eight patients (24.2%). Bone involvement in four (12.1%), lung in three (9%), heart in two (6%), skin in two (6%), and testis in one (3%) of these patients. Abdominal lymph nodes were enlarged in 21 children (63.6%), while cervical lymph nodes were enlarged in 8 (24.2%). CONCLUSION: CT proved to be an invaluable tool in the characterization of the disease processes in these children. In addition, it provided us with useful information about the anatomical distribution, patterns of involvement, as well as complications of BL.

    *16933114*
     16933114

    Recurrent ovarian malignancy: patterns and spectrum of imaging findings.

    Abdom Imaging 2003; 28 (3): 404-15

    Ovarian carcinoma is the most common cause of death from a gynecologic malignancy. The most important prognostic factors are the presence and magnitude of residual or recurrent disease after therapy. Recurrent ovarian malignancy usually manifests as pelvic masses in the surgical bed, peritoneal seeding, nodal recurrence and pleuropulmonary lesions, and liver metastasis. Pelvic recurrence involves the vaginal stump, parametria, urinary bladder, and/or bowel adjacent to the surgical bed. Peritoneal seeding presents as nodules on the peritoneal surface, most commonly around the liver or cul-de-sac, and mesenteric infiltration. Pseudomyxoma peritonei is the other form of peritoneal seeding. Nodal recurrence appears as enlarged paraaortic nodes, especially at the renal hilar level. Unusual manifestations include metastasis in the extrahepatic abdominal solid organs, bone metastasis, and abdominal wall lesion involving subcutaneous fat or muscle. Familiarity with the patterns and spectrum of imaging findings of recurrent ovarian malignancy will facilitate accurate diagnosis and prompt treatment.

    *12719914*
     12719914

    Peripheral bone metastasis from hepatocellular carcinoma: sonographic findings.

    Abdom Imaging 2001; 26 (5): 524-8

    BACKGROUND AND METHODS: We reviewed medical and radiologic records of five patients with bone metastasis from hepatocellular carcinoma (HCC) to evaluate the role of sonography (US) in the diagnosis of this bone metastasis. RESULTS: The metastatic lesions were clearly visualized by US as expansive, homogeneous, soft tissue masses with bony destruction, and color Doppler US showed fine vessels within the lesions. After treatment, US showed a decrease in tumor size with an increase in echogenicity and a decrease in blood flow. Hepatic US at the time of bone metastasis showed a portal tumor thrombus in all cases. CONCLUSION: When US detects a portal venous tumor thrombus in HCC patients, attention should be directed not only to the liver but also to bone to improve patient care. US is useful not only in detecting the metastatic lesion but also in evaluating the treatment effect.

    *11503093*
     11503093

    Preoperative assessment of local tumor extent in advanced rectal cancer: CT or high-resolution MRI?

    Abdom Imaging 2000; 25 (5): 533-41

    BACKGROUND: We compared high-resolution magnetic resonance imaging (MRI) with computed tomography (CT) in the assessment of tumor infiltration in surrounding structures for locally advanced primary and recurrent rectal cancer. METHODS: Twenty-six patients with operable, locally advanced rectal cancer (15 recurrent and 11 primary) were evaluated with conventional pelvic CT and 1.5-T high-resolution MRI with a quadrature phased-array coil. The images were scored for invasion of nine neighboring pelvic structures, and the results were compared with surgical and histologic findings. RESULTS: A total of 234 structures in 26 patients was evaluated for tumor invasion. For MRI the, sensitivity was 97% and the specificity 98%; for CT, the sensitivity was 70% and the specificity was 85%. The difference in performance was statistically significant (p<0.001). The failure most frequently made on CT was the false-positive prediction of pelvic floor and piriform muscle invasion (14), whereas MRI showed only four false-positive predictions. MRI correctly predicted all four cases of sacral bone invasion, three of which were missed by CT. MRI was accurate in 20 patients (80%) and CT in only five patients (19%). CONCLUSION: High-resolution MRI using a quadrature phased-array coil is highly accurate and superior to CT in predicting tumor infiltration in surrounding structures for locally advanced primary or recurrent rectal cancer and is recommended in the preoperative work-up of these tumors.

    *10931993*
     10931993

    Intact PTH-producing hepatocellular carcinoma treated by transcatheter arterial embolization.

    Abdom Imaging 1999; 24 (2): 144-6

    We report a case of hepatocellular carcinoma with hypercalcemia. There was no evidence of bone metastasis or increase in parathyroid hormone-related protein. The serum level of intact parathyroid hormone (intact PTH) was very high, and the results of the hepatic venous sampling suggested that the tumor produced intact PTH. Transcatheter arterial chemoembolization effectively controlled the humoral hypercalcemia.

    *10024399*
     10024399

    Primary non-Hodgkin's lymphoma of the esophagus.

    Abdom Imaging 1997; 22 (1): 8-10

    The esophagus is the least commonly involved gastrointestinal organ, accounting for fewer than 1% of patients with lymphoma. Such involvement is mostly secondary, from mediastinal lymph nodes or gastric lymphoma. The primary form arises from the esophageal wall itself and occurs much less frequently. Primary esophageal lymphoma is mostly seen in male patients with Hodgkin's disease. A primary non-Hodgkin's lymphoma of the esophagus with concomitant involvement of the bone marrow is presented, and imaging features of esophageal lymphoma are reviewed.

    *9000346*
     9000346

    MR appearances of urinary bladder in amyloidosis associated with multiple myeloma.

    Abdom Imaging 1996; 21 (5): 468-9

    Amyloidosis led to thickening of the urinary bladder wall, with hypointensity in T2-weighted images, which was distinguished from multiple myeloma involvement.

    *8832874*
     8832874

    Serum prostate-specific antigen as a predictor of staging abdominal/pelvic computed tomography in newly diagnosed prostate cancer.

    Abdom Imaging 1996; 21 (4): 364-7

    BACKGROUND: The standard staging evaluation for prostate cancer includes digital rectal examination, measurement of serum tumor markers, and radionuclide bone scan. In many institutions, abdominal/pelvic computed tomography (CT) scan or nuclear magnetic resonance imaging (MRI) is performed. We retrospectively reviewed 425 cases of newly diagnosed, untreated adenocarcinoma of the prostate to evaluate the ability of serum prostate-specific antigen (PSA) to predict results of staging abdominal pelvic CT. METHODS: The medical records of 425 newly diagnosed, untreated prostate cancer patients were reviewed. The following information was collected on a standard data form: age, clinical stage based on digital rectal exam, method of diagnosis, histological grade, serum PSA level, and results of abdominal pelvic CT including adenopathy and abnormalities of the upper urinary tract. The results of this review were tabulated and analyzed with regard to the ability of serum PSA level to predict positive results of abdominal pelvic CT. RESULTS: The mean PSA level of the study group was 22.1 ng/ml. Fourteen patients (3.6%) presented with a positive abdominal/pelvic CT (12 with adenopathy, one with a renal cell tumor, and one with an adrenal metastasis). Eleven of these (79%) had serum PSA levels of 30.0 ng/ml or greater, ranging from 30.0 to 234 ng/ml. No patient with a positive study presented with a normal serum PSA level. Two patients with a positive study had a serum PSA level between 4.1 and 10.0 ng/ml (0.6%), and one had a PSA level between 10.1 and 20 ng/ml (0.3%). CONCLUSION: We conclude that in asymptomatic patients with newly diagnosed, untreated prostate cancer and serum PSA levels of less than 20 ng/ml the likelihood of positive findings on abdominal/pelvic CT is extremely low (<1.0%). Abdominal/pelvic CT does not appear necessary in this setting. With 200,000 cases of newly diagnosed prostate cancer each year in the United States, elimination of staging abdominal/pelvic CT in these patients could reduce medical expenditures for prostate cancer management by $20-50 million per year.

    *8661585*
     8661585

    Imaging of prostate cancer.

    Abdom Imaging 1995; 20 (6): 505-15

    Prostate cancer diagnosis and treatment is fast emerging as a major health care issue in the United States. However, there are great uncertainties about the value of specific tests and therapies. Imaging modalities play a major role in the current management of patients with prostate cancer and this role is likely to expand in the future. Transrectal ultrasound is used to identify nonpalpable lesions, direct systematic biopsies, determine gland volume and stage prostate cancers. For staging skeletal metastases, the bone scan is acknowledged as the best method, however controversy surrounds its routine use in patients with low prostate specific antigen (PSA) values. Computed tomography (CT) and transrectal ultrasound have limited value in detecting extracapsular disease but CT can be used in conjunction with percutaneous biopsy to identify nodal metastases. The role of Endorectal coil MRI is currently evolving in the wake of a disappointing multi-institutional trial but MRI still holds the most promise for accurately detecting local extent of prostate cancer. New radiolabeled techniques with monoclonal antibodies and peptide imaging are also having early but promising results. The role of imaging in prostate cancer is continuing to evolve as technology and knowledge about prostate cancer biology improves and health care economics force a more judicious use of imaging resources.

    *8580742*
     8580742

    Baseline perfusion CT parameters as potential biomarkers in predicting long-term prognosis of localized clear cell renal cell carcinoma.

    Abdom Radiol (NY) 2019; (): drxinmingzh@163.com.;

    PURPOSE: We aimed to explore the relationship among baseline perfusion CT parameters, clinical, and pathological factors with post-nephrectomy long-term progression-free survival in localized clear cell renal cell carcinoma. MATERIALS AND METHODS: This study retrospectively collected 127 patients from March 2005 to May 2007 who undertook perfusion CT. 61 patients were confirmed of pT1N0M0 or pT2N0M0 ccRCC. The mean follow-up time is 118.8 months (+/- 13.1 m, range 72-135 m). We compared clinical, pathological factors (gender, T stage, age, Fuhrmann grade, VEGF level, and MVD), and perfusion parameters before treatment [blood flow (BF), blood volume, mean transition time, and permeability surface-area product] between groups with post-nephrectomy metastasis and without metastasis. Association between covariates and progression-free survival (PFS) were analyzed using Cox proportional regression. RESULTS: Among 61 patients, 11 developed distant metastasis (10 in the lung, one in the bone). BF in metastatic group [429.1 (233.8, 570.1) ml/min/100 g] was significantly higher than non-metastatic group [214.3 (153.3, 376.5) ml/min/100 g] (p = 0.011). Metastatic group also had more patients with higher Fuhrmann grade. Multi-covariant Cox regression demonstrated T staging, Fuhrmann grade, and BF were significantly associated with PFS [hazard ratio (HR) 3.35, 3.08, and 1.006]. In another model, BF > 230 ml/min/100 g was associated with PFS (HR 12.90), along with T staging and Fuhrmann grade (HR 4.73, 3.69). CONCLUSION: Baseline tumor BF is a potential biomarker in prediction long-term metastasis of localized ccRCC and may help screening for higher risk localized ccRCC patients who need personalized surveillance strategy after nephrectomy.

    *31399787*
     31399787

    Magnetic resonance imaging features of pubic symphysis urinary fistula with pubic bone osteomyelitis in the treated prostate cancer patient.

    Abdom Radiol (NY) 2019; 44 (4): 1453-1460 rajan.gupta@duke.edu.;

    INTRODUCTION: Pubic bone osteomyelitis with pubic symphysis urinary fistula represents a debilitating complication of radiation and ablative treatments for prostate cancer. The definitive radiographic diagnosis of this clinical entity is not described. In this study, we characterize the plain film and magnetic resonance imaging findings of pubic osteomyelitis. MATERIALS AND METHODS: We reviewed a database of prostate cancer survivors with diagnosed pubic osteomyelitis from 2011 to 2015. These patients underwent pelvic plain radiographs and magnetic resonance imaging with T1-weighted and fat-suppressed T2-weighted fast spin echo sequences. Intravenous gadolinium was utilized. The diagnosis was verified with extirpative surgery. 16 patients with diagnosed pubic osteomyelitis from 2011 to 2015 underwent imaging at our institution. RESULTS: All patients demonstrated increased signal on T2- weighted sequences and decreased signal on T1-weighted sequences along the pubic symphysis and the marrow of the involved pubic rami. Inflammatory myositis with diastasis of the pubic symphysis and cortical bone erosion were identified in the majority of patients. Fluid collections were identified in 75% of patients. 63% of conventional radiographs demonstrated no radiographic evidence of pubic osteomyelitis. CONCLUSION: Magnetic resonance imaging of pubic symphysis osteomyelitis in the prostate cancer survivor is characterized by high signal on T2-weighted images and low signal on T1-weighted images of the involved pubic rami, with the majority of patients demonstrating regional myositis. Imaging data combined with clinical assessment should prompt diagnosis and management of pubic osteomyelitis. Conventional radiography is generally insensitive to these findings. We consider magnetic resonance imaging to be the definitive diagnostic modality for this clinical entity.

    *30460532*
     30460532

    The incidental bone lesion on computed tomography: management tips for abdominal radiologists.

    Abdom Radiol (NY) 2017; 42 (5): 1586-1605 lshin@stanford.edu.

    Incidental bone lesions are commonly seen on abdominal and pelvic computed tomography (CT) examinations. These incidental bone lesions can be diagnostically challenging to the abdominal radiologist who may not be familiar with their appearance or their appropriate management. The characterization of such bone lesions as non-aggressive or aggressive based on their CT appearance involves similar principles to their morphologic evaluation on radiographs. Knowledge of the age of the patient and the presence of symptoms, mainly bone pain, can improve analysis. Examples of bone lesions that may be encountered include solitary or multifocal bone lesions, osteochondromatous and chondroid tumors, Paget's disease, avascular necrosis/bone infarctions, iatrogenic lesions, and periarticular lesions. This pictorial essay aims to provide a framework for the analysis of incidental bone lesions on CT and when further imaging and clinical work-up should be recommended.

    *28132074*
     28132074

    Current clinical status of (18)F-FLT PET or PET/CT in digestive and abdominal organ oncology.

    Abdom Radiol (NY) 2017; 42 (3): 951-961 toyo.nakajo@dolphin.ocn.ne.jp.;

    Positron emission tomography (PET) or PET/computed tomography (CT) using (18)F-3'-fluoro-3'-deoxythymidine ((18)F-FLT) offers noninvasive assessment of cell proliferation in human cancers in vivo. The present review discusses the current status on clinical applications of (18)F-FLT-PET (or PET/CT) in digestive and abdominal oncology by comparing with (18)F-fluorodeoxyglucose ((18)F-FDG)-PET (or PET/CT). The results of this review show that although (18)F-FLT uptake is lower in most cases of digestive and abdominal malignancies compared with (18)F-FDG uptake, (18)F-FLT-PET can be used to detect primary tumors. (18)F-FLT-PET has shown greater specificity for N staging than (18)F-FDG-PET which can show false-positive uptake in areas of inflammation. However, because of the high background uptake in the liver and bone marrow, it has a limited role of assessing liver and bone metastases. Instead, (18)F-FLT-PET will be a powerful tool for monitoring response to treatment and provide prognostic information in digestive and abdominal oncology.

    *27770160*
     27770160

    The "polka-dot" sign.

    Abdom Radiol (NY) 2017; 42 (8): 2194-2196 edshim1214@gmail.com.;

    *28337520*
     28337520

    The "winking owl" sign.

    Abdom Radiol (NY) 2016; 41 (3): 582-3 brandon.l.roller@gmail.com.;

    *27039328*
     27039328

    Impact of histologic subtype and sarcomatoid transformation on metastasis in renal cell carcinoma: a single institute experience in 149 patients.

    Abdom Radiol (NY) 2016; 41 (2): 295-302 Sreeharsha_Tirumani@DFCI.HARVARD.EDU.;

    PURPOSE: To compare the metastatic pattern and outcome of clear cell RCC (ccRCC) and papillary RCC (pRCC), and to assess the impact of sarcomatoid transformation on the disease spread and prognosis. MATERIALS AND METHODS: This IRB-approved, HIPAA-compliant retrospective study included 149 consecutive patients (108 men; mean age 58 years; range 25-86) with metastatic RCC (ccRCC = 116, pRCC = 33), identified from imaging database. All available imaging studies and electronic records of these patients were reviewed to document pathological features, distribution and timing of metastasis, and survival. The metastatic pattern and survival was first compared between the ccRCC and pRCC groups, and then between those with and without sarcomatoid transformation; all 27 cases of sarcomatoid transformation occurred in the ccRCC group. RESULTS: Metastases were noted at presentation in 62 (42%) and after median 13 months in the remaining 87 (58%) patients. Lymph nodes (134/149), lung (125/149), and bone (60/149) were the most common metastatic sites, which did not differ between the RCC subtypes. Pancreatic (p = 0.0014) and renal (p = 0.046) metastases were more common in ccRCC, lymphangitic spread (p = 0.0003) and peritoneal metastasis (p = 0.039) more common in pRCC. In ccRCC, sarcomatoid transformation was associated with high-grade tumors (p < 0.0001), more frequently demonstrated lymphangitic (p = 0.016), pleural (p = 0.0018), and peritoneal metastases (p = 0.0002), and had shorter metastasis-free survival and overall survival (log-rank test, p < 0.0001). In the absence of sarcomatoid transformation, ccRCC had longer metastasis-free interval (median 22 months compared to 6 months) (p = 0.0238) and overall survival (median survival 48 months vs. 25 months) (p = 0.0193) compared to pRCC. CONCLUSION: Histologic subtype, as well as the presence of sarcomatoid transformation, affects the metastatic pattern and metastasis-free survival of RCC. In the absence of sarcomatoid transformation, ccRCC has a better outcome than pRCC.

    *26867911*
     26867911

    Doctors and divination.

    Acad Med 2008; 83 (7): 652

    *18580081*
     18580081

    Internal Derangement of the Shoulder Joint in Asymptomatic Professional Baseball Players.

    Acad Radiol 2019; (): suboying0831@gmail.com.;

    RATIONALE AND OBJECTIVES: To evaluate the influence of throwing activity on shoulder morphology and the difference in shoulder morphology on MRI between asymptomatic professional baseball players and volunteers who play baseball as a recreational activity. MATERIALS AND METHODS: This retrospective case-control study included 68 asymptomatic professional baseball players (32 pitchers, 36 batters) and 30 male volunteers. Morphologic changes in the following shoulder structures were assessed on MRI: rotator cuff, glenoid labrum, humeral head, subacromial-subdeltoid bursa, subcoracoid bursa, long head of the biceps tendon, deltoid muscle, acromion, and clavicle. RESULTS: Partially torn supraspinatus, posterior glenoid or labral lesions, bone marrow edema, intraosseous cysts of the humeral head, and edematous subacromial-subdeltoid bursa were significantly more commonly observed in players (p = 0.01, p < 0.001, p = 0.03, p< 0.001, and p < 0.001). Players with more than 10 years of experience had a significantly higher incidence of patchy intermediate signal abnormality (odds ratio: 3.73, p = 0.03), partial tear in the supraspinatus tendon (odds ratio: 6.20, p = 0.03), and edematous change in the subacromial-subdeltoid bursa (odds ratio: 2.96, p = 0.03). CONCLUSION: The results from our study showed that repetitive throwing activities cause macroscopic structural lesions of the shoulder joints in asymptomatic baseball players. Significance of these lesions is to be determined.

    *31300356*
     31300356

    Accuracy of Opposed-phase Magnetic Resonance Imaging for the Evaluation of Treated and Untreated Spinal Metastases.

    Acad Radiol 2018; 25 (7): 877-882 Ronnie.sebro@uphs.upenn.edu.

    RATIONALE AND OBJECTIVES: To assess whether the accuracy of opposed-phase magnetic resonance (MR) imaging to differentiate spinal metastases from benign lesions is influenced by treatment. MATERIALS AND METHODS: We retrospectively evaluated 25 benign lesions, 25 untreated spinal metastases, and 89 treated spinal metastases in 101 patients who underwent opposed-phase MR spine imaging at our institution. The largest possible region of interest was placed over the lesion in question on out-of-phase and in-phase MR sequences, and the signal intensity ratio (SIR) of the lesions was calculated. The SIRs were compared between benign, untreated, and treated lesions. Receiver operator characteristic (ROC) curves were used to identify the optimal threshold to differentiate benign lesions from untreated spinal metastases, and the accuracy of this threshold was assessed for treated spinal metastases, chemotherapy-treated spinal metastases, and radiated spinal metastases. RESULTS: Benign lesions had lower mean SIR than untreated (P = 2.4 x 10(-8), 95% confidence interval [0.29, 0.51]) and treated spinal metastases (P = .51; 95% confidence interval [-0.13, 0.06]). A cutoff SIR of 0.856 had an accuracy of 88.00% for untreated lesions, 77.48% for previously treated lesions, and 70.45% for previously radiated lesions. The ROC curve to differentiate benign lesions from radiated spinal metastases was significantly different from the ROC curve to differentiate benign lesions from untreated spinal metastases (P = .0180). The ROC curve to differentiate benign lesions from lesions treated with chemotherapy only was significantly different from the ROC curve to differentiate between benign lesions and radiated spinal metastases (P = .041). CONCLUSIONS: Opposed-phase imaging is less accurate for treated spinal metastases, in particular after radiation.

    *29398437*
     29398437

    Characterization of Metastatic Sternal Lesions on Dynamic Contrast-Enhanced Breast MRI in Women with Invasive Breast Cancer.

    Acad Radiol 2018; (): amie.lee2@ucsf.edu.;

    RATIONALE AND OBJECTIVES: Detecting sternal lesions is not the purpose of breast MRI, but diagnosing metastasis has major clinical implications. Our purpose was to determine the breast MRI features of sternal metastases detected on PET-CT and bone-scan. MATERIALS AND METHODS: Between 01/2010-09/2018, 379 patients with breast cancer had sternal findings on PET-CT or bone-scan, 21 of which underwent breast MRI within 100 days. Sternal lesions were considered metastatic if (1) biopsy demonstrated metastasis, (2) the lesion had similar appearance to synchronous sites of biopsy-proven osseous metastases, or (3) there were numerous suspicious lesions in which widespread osseous metastasis was presumed. Four radiologists reviewed the MR images to determine if metastases were retrospectively detectable. MRI reports were reviewed to determine if lesions were prospectively described. MRI features of metastatic sternal lesions were compared to benign controls. RESULTS: Fourteen sternal metastases met inclusion criteria. Lesions were retrospectively detectable on breast MRI by all radiologists in 86% (12/14) of cases, but prospectively reported in 57%. Of the 12 MRI-detectable metastases, mean maximum dimension was 33 mm, 7 had >1 lesion, all were T1-hypointense, 11 were T2-hyperintense, 11 were noncircumscribed, 6 extended beyond cortex, 11 enhanced heterogeneously, and 11 demonstrated washout. Heterogeneous enhancement (p=0.002), noncircumscribed margins (p < 0.001), multiplicity (p=0.005), and size >1 cm (p < 0.001) were more frequent with metastatic compared to benign sternal lesions. CONCLUSION: Most sternal metastases (86%) were retrospectively detectable on breast MRI, but only 57% were prospectively reported, emphasizing the importance evaluating the sternum on breast MRI. Certain MRI features may raise suspicion for metastasis.

    *30527457*
     30527457

    Automated "Bone Subtraction" Image Analysis Software Package for Improved and Faster CT Monitoring of Longitudinal Spine Involvement in Patients with Multiple Myeloma.

    Acad Radiol 2017; 24 (5): 623-632 christopher.kloth@med.uni-tuebingen.de.

    RATIONALE AND OBJECTIVES: The study aimed to assess the diagnostic benefit of a novel computed tomography (CT) post-processing software generating subtraction maps of longitudinal non-enhanced CT examinations for monitoring the course of myeloma bone disease in the spine. MATERIALS AND METHODS: The local institutional review board approved the retrospective data evaluation. Included were 82 consecutive myeloma patients (46 male; mean age, 65.08 +/- 9.76) who underwent 188 repeated whole-body reduced-dose Multislice Detector Computed Tomography (MDCT) at our institution between December 2013 and January 2016. Lytic bone lesions were categorized as new or enlarging versus stable. Bone subtraction maps were read in combination with corresponding 1-mm source images comparing results to those of standard image reading of 5-mm axial and 2-mm multiplanar reformat reconstructions (MPR) scans and hematologic markers, and classified as either progressive disease (PD) or stable disease (SD or remission). The standard of reference was 1-mm axial CT image reading + hematologic response both confirmed at follow-up. For statistical purposes, we subgrouped the hematologic response categories similarly to those applied for CT imaging (progression vs stable/response). RESULTS: According to the standard of reference, 16 patients experienced PD and 66 SD at follow-up. Th sensitivity, specificity, and accuracy for axial 5 mm + 2 mm MPR image versus bone subtraction maps in a "lesion-by-lesion" reading were 97.6%, 92.3%, and 97.2% versus 97.8%, 96.7%, and 97.7%, respectively. The use of bone subtraction maps resulted in a change of response classification in 9.7% of the patients (n = 8) versus 5 mm + 2 mm MPR image reading from SD to PD. Bone sclerosis lesions were detected in 52 out of 82 patients (63.4%). The reading time was significantly lower with the software bone subtraction compared to standard reading (P < 0.01) and 1-mm image reading (P < 0.001). CONCLUSION: Accuracy of bone subtraction maps reading for monitoring multiple myeloma is slightly increased over that of conventional axial + MPR image reading and significantly speeds up the reading time.

    *28256439*
     28256439

    Orbital Indeterminate Lesions in Adults: Combined Magnetic Resonance Morphometry and Histogram Analysis of Apparent Diffusion Coefficient Maps for Predicting Malignancy.

    Acad Radiol 2016; 23 (2): 200-8 wfy_njmu@163.com.

    RATIONALE AND OBJECTIVES: The aim of this study was to evaluate the added value of histogram analysis of apparent diffusion coefficient (ADC) maps in differentiating indeterminate orbital malignant tumors from benign tumors, compared to using magnetic resonance (MR) morphological features alone. MATERIALS AND METHODS: We retrospectively evaluated 54 patients with orbital tumors from March 2013 to February 2015. All the patients were assessed by both routine MR and diffusion-weighted imaging, and divided into benign group and malignant group. Routine MR imaging features and histogram parameters derived from ADC maps, including mean ADC (ADCmean), median ADC (ADCmedian), standard deviation, skewness, kurtosis, and 10th and 90th percentiles of ADC (ADC10 and ADC90), were compared between two groups. Univariate and multivariate logistic regression analyses were used to identify the most valuable variables in predicting malignancy. Receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic value of significant variables. RESULTS: Multivariate logistic regression analysis indicated that two or more quadrants involved, iso-intense on T2-weighted imaging (T2WI), and ADC10 were significant predictors for orbital malignancy. By using model 2 (iso-intense on T2WI + two or more quadrants involved + ADC10 < 0.990) as the criterion, higher AUC and specificity could be achieved than by using model 1 (iso-intense on T2WI + two or more quadrants involved) alone, (model 2 vs model 1; area under curve (AUC), 0.827 vs 0.793; sensitivity, 65.4% vs 69.2%; specificity, 100% vs 89.3%). CONCLUSIONS: Iso-intense on T2WI, two or more quadrants involved, and ADC10 are risk factors for orbital malignancy. Histogram analysis of ADC map might provide added value in predicting orbital malignancy.

    *26625705*
     26625705

    Imaging for the Pretreatment Staging of Small cell Lung Cancer: A Systematic Review.

    Acad Radiol 2016; 23 (8): 1047-56 mdmitchell@uphs.upenn.edu.;

    BACKGROUND: Small cell lung cancer (SCLC) is an aggressive form of lung cancer. Accurate staging is essential to select the optimal treatment plan to maximize survival. No consensus exists on standard imaging modalities for pretreatment staging of SCLC. MATERIALS AND METHODS: We conducted a systematic review of the literature on imaging modalities in the pretreatment staging of SCLC. A systematic search of multiple databases identified relevant studies published from 2000 through June 2015. Outcomes of interest included test concordance, staging accuracy (sensitivity and specificity), choice of treatment, timeliness of treatment, and patient outcomes. RESULTS: The search identified 2880 citations; 7 studies met inclusion criteria, n = 408 patients. Six of the seven studies were deemed to have moderate risk of bias, and one was deemed to have high risk of bias. One of the studies reported test concordance, three studies reported comparative accuracy of testing strategies, and four studies reported the accuracy of a single imaging modality. Analysis from these studies revealed that fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is more sensitive than multidetector CT for detecting osseous metastases, more sensitive than bone scintigraphy for detecting osseous metastases, and more sensitive for detecting any distant metastases. CONCLUSIONS: Evidence is sparse on the use of imaging in the pretreatment staging of SCLC. There is a lack of evidence on patient-oriented outcomes and a lack of evidence on whether comparative accuracy or effectiveness is associated with patient factors. We found low-strength evidence suggesting that FDG-PET/CT is more sensitive than CT and bone scintigraphy for detecting osseous metastases.

    *27259379*
     27259379

    The application of dynamic contrast-enhanced MRI and diffusion-weighted MRI in patients with maxillofacial tumors.

    Acad Radiol 2015; 22 (2): 210-6 kitamoto@rad.dent.kyushu-u.ac.jp.;

    RATIONALE AND OBJECTIVES: To elucidate the characteristics of four types of tumors, including squamous cell carcinoma (SCC), malignant lymphoma (ML), malignant salivary gland tumors (MSGTs), and pleomorphic adenoma (Pleo), in the maxillofacial region using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted MRI (DW-MRIdata. MATERIALS AND METHODS: A total of 59 tumors were included in this research. DCE-MRI and DW-MRI were performed. We applied the Tofts and Kermode model (TK model) for the DCE-MRI data and obtained three dependent parameters: the influx forward volume transfer constant into the extravascular extracellular space from the plasma (K(trans)), the fractional volume of extravascular extracellular space per unit volume of tissue (ve), and the fractional volume of plasma (vp). RESULTS: Among the K(trans) values, there were no significant differences between the three types of malignant tumors; however, there was a significant difference between the SCC and Pleo (P = .0099). The ve values of the Pleo were highest, with significant differences compared to the other categories (SCC, P = .0012; ML, P = .0017; and MSGT, P = .041). The ML had the lowest ve values, and there were significant differences between ML and the other two types of malignant tumors (SCC, P = .0278 and MSGT, P = .0062). In 14 (24%) cases, apparent diffusion coefficient (ADC) could not be measured because of poor image quality. The ADC values of the ML were lowest, whereas those of Pleo were highest, similar to that observed for ve. CONCLUSIONS: The Pleo tumors had lower K(trans) values and higher ve values, which are useful for differentiating them from the malignant tumors. Moreover, the ve was also useful for establishing a diagnosis of ML.

    *25442795*
     25442795

    Computer-aided nodule detection system: results in an unselected series of consecutive chest radiographs.

    Acad Radiol 2015; 22 (4): 475-80 feng@uchicago.edu.;

    RATIONALE AND OBJECTIVES: To evaluate the performance of a computer-aided detection (CAD) system with bone suppression imaging when applied to unselected consecutive chest radiographs (CXRs) with computed tomography (CT) correlation. MATERIALS AND METHODS: This study included 586 consecutive patients with standard or portable CXRs who had a chest CT scan on the same day. Among the 586 CXRs, 438 had various abnormalities, including 46 CXRs with 66 lung nodules, and 148 CXRs had no significant abnormalities. A commercially available CAD system was applied to all 586 CXRs. True nodules and false positives (FPs) marked on CXRs by the CAD system were evaluated based on the corresponding chest CT findings. RESULTS: The CAD system marked 47 of 66 (71%) lung nodules in this consecutive series of CXRs. The mean FP rate per image was 1.3 across all 586 CXRs, with 1.5 FPs per image on the 438 abnormal CXRs and 0.8 FPs per image on the 148 normal CXRs. A total of 41% of the 752 FP marks were related to non-nodule pathologic findings. CONCLUSIONS: A currently available CAD system marked 71% of radiologist-identified lung nodules in a large consecutive series of CXRs, and 41% of "false" marks were caused by pathologic findings.

    *25592026*
     25592026

    Improved detection of bone metastases from lung cancer in the thoracic cage using 5- and 1-mm axial images versus a new CT software generating rib unfolding images: comparison with standard (1)(8)F-FDG-PET/CT.

    Acad Radiol 2015; 22 (4): 505-12 georg.homann@med.uni-tuebingen.de.;

    RATIONALE AND OBJECTIVES: To evaluate the performance of a dedicated computed tomography (CT) software called "bone reading" generating rib unfolded images for improved detection of rib metastases in patients with lung cancer in comparison to readings of 5- and 1-mm axial CT images and (18)F-Fluordeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). MATERIALS AND METHODS: Ninety consecutive patients who underwent (18)F-FDG-PET/CT and chest CT scanning between 2012 and 2014 at our institution were analyzed retrospectively. Chest CT scans with 5- and 1-mm slice thickness were interpreted blindly and separately focused on the detection of rib metastases (location, number, cortical vs. medullary, and osteoblastic vs. sclerotic). Subsequent image analysis of unfolded 1 mm-based CT rib images was performed. For all three data sets the reading time was registered. Finally, results were compared to those of FDG-PET. Validation was based on FDG-PET positivity for osteolytic and mixed osteolytic/osteoblastic focal rib lesions and follow-up for sclerotic PET-negative lesions. RESULTS: A total of 47 metastatic rib lesions were found on FDG-PET/CT plus another 30 detected by CT bone reading and confirmed by follow-up CT. Twenty-nine lesions were osteolytic, 14 were mixed osteolytic/osteoblastic, and 34 were sclerotic. On a patient-based analysis, CT (5 mm), CT (1 mm), and CT (1-mm bone reading) yielded a sensitivity, specificity, and accuracy of 76.5/97.3/93, 81.3/97.3/94, and 88.2/95.9/92, respectively. On segment-based (unfolded rib) analysis, the sensitivity, specificity, and accuracy of the three evaluations were 47.7/95.7/67, 59.5/95.8/77, and 94.8/88.2/92, respectively. Reading time for 5 mm/1 mm axial images and unfolded images was 40.5/50.7/21.56 seconds, respectively. CONCLUSIONS: The use of unfolded rib images in patients with lung cancer improves sensitivity and specificity of rib metastasis detection in comparison to 5- and 1-mm CT slice reading. Moreover, it may reduce the reading time.

    *25586709*
     25586709

    Assessing treatment response of osteolytic lesions by manual volumetry, automatic segmentation, and RECIST in experimental bone metastases.

    Acad Radiol 2014; 21 (9): 1177-84 tobias.baeuerle@uk-erlangen.de.

    RATIONALE AND OBJECTIVES: Aim of the study was to compare between volumetric and unidimensional approaches for treatment response monitoring in a nude rat model of experimental bone metastases. For the volumetric approach, an automated segmentation algorithm of osteolytic lesions was introduced and compared to manual volumetry. MATERIAL AND METHODS: Nude rats bearing osteolytic metastases were treated with zoledronate and sunitinib and compared to controls. Treatment response was assessed longitudinally in vivo using flat-panel volumetric computed tomography at days 30, 35, 45, and 55 after tumor cell inoculation. The mean sizes and volumes of osteolytic lesions were determined according to response evaluation criteria in solid tumors (RECIST) and by automated and manual volumetry (software: MITK [The Medical Imaging Interaction Toolkit, Heidelberg, Germany] and VIRTUOS, Heidelberg, Germany). RESULTS: In contrary to RECIST, the manual volumetric approach indicated a significant decrease in osteolytic lesion volume in response to treatment. The presented automatic segmentation algorithm for treatment monitoring identified bone metastases adequately and assessed changes in the osteolytic lesion volume over time according to manual volumetry. CONCLUSIONS: In an animal model, volumetric treatment response assessment of osteolytic bone metastases is superior to unidimensional measurements, and automated volumetric segmentation may be a valuable alternative to manual volume determination.

    *24998693*
     24998693

    Use of diffusion-weighted, intravoxel incoherent motion, and dynamic contrast-enhanced MR imaging in the assessment of response to radiotherapy of lytic bone metastases from breast cancer.

    Acad Radiol 2014; 21 (10): 1286-93 cate.benedetto@gmail.com.;

    RATIONALE AND OBJECTIVES: To investigate the value of diffusion-weighted (DW), perfusion-sensitive, and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) techniques in assessing the response of bone metastases from breast cancer to radiotherapy, with particular emphasis on the role of intravoxel incoherent motion (IVIM)-DW parameters as a potential valuable imaging marker of tumor response. MATERIALS AND METHODS: Fifteen women having breast cancer and bone metastases underwent MRI before and after radiotherapy (3 weeks [time 1], 2 months [time 2], and 4 months [time 3]), consisting of DW, perfusion-sensitive (IVIM), and DCE acquisitions. MR-based DW and perfusion parameters, including water diffusivity (D), perfusion fraction (f), pseudodiffusion (D), total apparent diffusion coefficient (ADC-total), fractionated ADCs (ADC-high and ADC-low), and initial area under the gadolinium concentration curve after the first 60 seconds (IAUGC60), were determined. The morphologic MRI findings were also recorded. A one-way repeated measures analysis of variance was used to compare the value of MR-based parameters at the different time points. RESULTS: A significant variation between pretreatment (time 0) and post-treatment (times 1, 2, and 3) was found for ADC-total and D parameters (P < .001). A statistically significant reduction was also found for IAUGC60 values between times 0 and 3 (P < .001). A significant change across the different time points was observed for D and IAUGC60 parameters (P < .001). On the contrary, there was no statistically significant change over time for parameters ADC-total, D, f, and IAUGC60 comparing response between each metastasis, that is, the response to therapy was similar for each metastasis. CONCLUSIONS: DW, IVIM, and DCE-MRI techniques show effectiveness in assessing the response to radiotherapy in bone metastases from breast cancer.

    *25088834*
     25088834

    Comparison of chest dual-energy subtraction digital tomosynthesis and dual-energy subtraction radiography for detection of pulmonary nodules: initial evaluations in human clinical cases.

    Acad Radiol 2013; 20 (11): 1357-63 gomi@kitasato-u.ac.jp.

    RATIONALE AND OBJECTIVES: To compare initial evaluations of chest dual-energy subtraction digital tomosynthesis (DES-DT) and dual-energy subtraction radiography (DES-R) for detection of pulmonary nodules. MATERIALS AND METHODS: DES-DT and DES-R systems with pulsed x-rays and rapid kV switching were used to evaluate pulmonary nodules (>4-6 mm, 2 nodules; >6-8 mm, 2 nodules; >8 mm, 32 nodules). Multidetector computed tomography was used as a reference. A filtered back-projection algorithm was used to reconstruct low-voltage (60 kVp), high-voltage (120 kVp), and soft-tissue or bone-subtracted tomograms of the desired layer thicknesses from the image data acquired during a single tomographic scan. DES-R images were processed from the low- and high-voltage images. To detect the pulmonary nodules, we used both systems to examine 36 patients with and 36 patients without pulmonary nodules. Two radiologists and three doctors of pulmonary medicine (average experience, 18 years) performed receiver operating characteristic (ROC) curve analysis to evaluate the results. RESULTS: The ROC analysis results suggested that the detection ability was significantly better for DES-DT than for DES-R (P < .0001; 95% confidence interval: DES-DT, 0.94 [0.83-0.99]; DES-R, 0.76 [0.68-0.85]; sensitivity: DES-DT, 87.7 +/- 2.9%; DES-R, 53.8 +/- 3.5%; specificity: DES-DT, 78.3 +/- 5.6%; DES-R, 78.4 +/- 3.4%; accuracy: DES-DT, 83.1 +/- 3.8%, DES-R, 66.1 +/- 2.0%). When the nodules were no longer superimposed over the normal structures, their characteristics and distribution could be observed much more clearly. CONCLUSION: Compared with DES-R, DES-DT provided greater sensitivity for detection of pulmonary nodules, particularly for the larger ones.

    *24119347*
     24119347

    Meta-analysis: comparison of F-18 fluorodeoxyglucose-positron emission tomography and bone scintigraphy in the detection of bone metastasis in patients with lung cancer.

    Acad Radiol 2012; 19 (3): 349-57

    RATIONALE AND OBJECTIVES: The aim of this review was to evaluate the diagnostic properties of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) or PET/computed tomography (CT) and bone scintigraphy in the detection of osseous metastases in patients with lung cancer. MATERIALS AND METHODS: MEDLINE was searched for relevant original articles published between January 1995 and August 2010. Inclusion criteria were as follows: FDG-PET or PET/CT and bone scintigraphy was carried out to detect bone metastases in patients with lung cancer, sufficient data were presented to construct a 2 x 2 contingency table, and histopathologic analysis and/or close clinical and imaging follow-up and/or radiographic confirmation by multiple imaging modalities was used as the reference standard. Two reviewers independently extracted data related to research design, sample size, imaging techniques, technical characteristics, reference standards, methods of imaging interpretation, and totals of true-positives, false-positives, true-negatives, and false-negatives. Stata was used to obtain per patient and per lesion pooled estimates of sensitivity, specificity, and positive and negative likelihood ratios, and areas under summary receiver-operating characteristic curves (AUCs) were calculated. RESULTS: The pooled patient-based sensitivity of FDG-PET or PET/CT was 0.93 (95% confidence interval [CI], 0.88-0.96), specificity was 0.95 (95% CI, 0.91-0.98), and the AUC was 0.94. The pooled sensitivity of bone scans was 0.87 (95% CI, 0.79-0.93), specificity was 0.82 (95% CI, 0.62-0.92), and the AUC was 0.91. The pooled lesion-based sensitivity of FDG-PET or PET/CT was 0.93 (95% CI, 0.84-0.97), specificity was 0.91 (95% CI, 0.80-0.96), and the AUC was 0.97. The pooled sensitivity of bone scans was 0.92 (95% CI, 0.87-0.95), specificity was 0.57 (95% CI, 0.09-0.95), and the AUC was 0.92. CONCLUSIONS: Although FDG-PET or PET/CT has higher sensitivity and specificity than bone scintigraphy, further research with a less biased design is needed to determine the most efficacious imaging modality for the detection of metastatic lung cancer.

    *22173321*
     22173321

    Clinicopathologic significance of high signal intensity on diffusion-weighted MR imaging in the ureter, urethra, prostate and bone of patients with bladder cancer.

    Acad Radiol 2012; 19 (7): 827-33 m2rbimn@gmail.com

    RATIONALE AND OBJECTIVES: The aim of this study was to determine the clinicopathologic significance of high-intensity areas in the ureter, urethra, prostate, and bone incidentally found on diffusion-weighted magnetic resonance imaging (DWI) for the staging of bladder cancer. MATERIALS AND METHODS: Axial and sagittal DWI and T2-weighted imaging of the pelvis were evaluated in 157 patients with bladder cancer. Two observers assessed T2-weighted imaging with DWI independently. The observers pointed out 67 areas showing abnormal high signal intensity on DWI in the ureter (n = 17), urethra (n = 8), prostate (n = 20), and bone (n = 22). Of the 67 high-intensity areas, 33 lesions were confirmed histopathologically (ureter, n = 10; urethra, n = 7; prostate, n = 16), and 22 bone lesions were diagnosed using T1-weighted imaging and follow-up computed tomography. Thus, 55 lesions were evaluable for correlation with DWI findings. RESULTS: Of the 55 high-intensity areas, 28 (53%) were synchronous or metastatic urothelial cancer or invasion of urothelial cancer. The remaining 27 (47%) were a ureteral clot in one, a ureteral stone granuloma in one, prostatic cancer in six, granulomatous prostatitis in three, and normal red bone marrow in 16. CONCLUSIONS: DWI is useful to comprehend the extent of bladder cancer and to detect incidentally coexisting diseases. Other imaging, endoscopic, and clinical findings would be useful to reduce false positivity.

    *22341371*
     22341371

    Can whole-body low-dose multidetector CT exclude the presence of myeloma bone disease in patients with monoclonal gammopathy of undetermined significance (MGUS)?

    Acad Radiol 2012; 19 (1): 89-94 daniel.spira@med.uni-tuebingen.de

    RATIONALE AND OBJECTIVES: To determine the benefit of using whole-body low-dose computed tomography (WBLD-CT) in patients with monoclonal gammopathy of undetermined significance (MGUS) for exclusion of multiple myeloma (MM) bone disease. MATERIALS AND METHODS: Seventy-one consecutive patients with confirmed MGUS (as defined by the latest criteria of the International Myeloma Working Group) who underwent WBLD-CT for diagnosis were identified retrospectively by a search of our institution's electronic medical record database (2002-2009). Patients were classified as low-risk or intermediate/high-risk and followed over a >/=2-year period with additional CT imaging and/or laboratory parameters. Presence of osteolysis, medullary, or extramedullary abnormalities compatible with involvement by MM was recorded. A diffuse or focal increase in medullary density to Hounsfield unit (HU) values >20 HU/>0 HU was considered suspicious for bone marrow infiltration if no other causes identifiable. RESULTS: The presence of osteolysis was excluded in all 71 patients with MGUS at initial diagnosis and patients were surveilled for >/=2 years. Lytic changes were observed at follow-up in 1/71 patients that progressed to MM and were detectable via WBLD-CT at an early stage (even before a significant rise in M-protein was recorded). In 3/71 patients with MGUS (4%) suspicious bone marrow attenuation values were measured, disclosing disease progression to smoldering myeloma in another patient and false-positive results in 2/71 patients. Bone marrow attenuation assessment resulted in a specificity and negative predictive value of 97%, respectively. No significant difference with respect to bone marrow attenuation was observed in patients with low-risk MGUS versus intermediate- to high-risk MGUS. One of 71 patients showed serologic disease progression to active MM without bone abnormalities detectable. CONCLUSION: WBLD-CT reliably excludes findings compatible with myeloma in MGUS and thereby complements hematologic laboratory analysis.

    *22142681*
     22142681

    Low-grade bone lesions in survivors of childhood medulloblastoma/primitive neuroectodermal tumor.

    Acad Radiol 2012; 19 (1): 35-9 korgun.koral@utsouthwestern.edu

    OBJECTIVES AND RATIONALE: Medulloblastoma/primitive neuroectodermal tumor (MB/PNET) is the most common malignant tumor of the central nervous system (CNS) in children. MB/PNET survivors are at an increased risk for developing second malignancies. Little has been reported on development of low-grade lesions of the calvarium in the radiation field in MB/PNET survivors. The purpose of this study was to assess the frequency of the low-grade bone lesion development in the radiotherapy field in pediatric MB/PNET survivors and describe the imaging characteristics of these lesions. MATERIALS AND METHODS: Institutional review board approval was obtained for this retrospective review which was compliant with Health Insurance Portability and Accountability Act. Forty-one MB/PNET patients (29 male) who survived for at least 2 years after initiation of radiation therapy were included. The medical records were reviewed. The most recent available brain magnetic resonance imaging studies were evaluated. RESULTS: Three patients (7.3%) developed low-grade calvarial lesions and underwent resection and/or biopsy of the lesions. There were one Langerhans cell histiocytosis, one benign spindle cell lesion with myxoid change, and one fibrous dysplasia. CONCLUSION: Development of low-grade bone lesions of calvarium is not very rare in pediatric PNET/MB survivors. Bones in the radiation therapy field need to be carefully examined for assessment of secondary lesions.

    *22054800*
     22054800

    Measuring the "unmeasurable": assessment of bone marrow response to therapy using FDG-PET in patients with lymphoma.

    Acad Radiol 2010; 17 (9): 1175-85

    RATIONALE AND OBJECTIVES: To determine if anatomically "nonmeasurable" disease in bone marrow (BM) is assessable for response to therapy by [(18)F]-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT). MATERIALS AND METHODS: FDG PET/CT images of 27 patients with lymphoma, FDG-avid bone marrow (BM) lesions, and >or=1 FDG-avid, tumor-involved lymph node (LN) at baseline were retrospectively reviewed. FDG uptake in target LNs and BM foci was determined pre- and posttherapy using the standardized uptake value corrected for lean body mass (SUL(mean)). Size of the same target LNs was measured pre- and posttherapy on CT. Percentage decreases of LN size and LN and BM SUL were calculated. Response was classified according to revised International Workshop Criteria (IWC) with and without modification for metabolic evaluation of BM and correlated to overall survival. Statistical analyses were performed using paired t-tests, Pearson correlation coefficients, and z-tests. RESULTS: LN size, LN SUL(mean), and BM SUL(mean) were significantly higher pre- versus posttherapy (2337 mm(2) +/- 1810 vs. 309 mm(2) +/- 323; 6.94 +/- 4.96 vs. 1.02 +/- 1.00; and 6.81 +/- 4.58 to 1.84 +/- 1.58, all P < .001, respectively). After therapy, significant correlation was found between percentage declines of LN size and SUL(mean) of LNs (r = 0.84, P < .001) or BM (r = 0.56, P = .002) and SUL(mean) of LN and BM (r = 0.76, P < .001). Including a metabolic assessment of BM correctly altered overall response assessment in 5/27 (19%) patients and better predicted overall survival than revised IWC. CONCLUSION: Anatomically "unmeasurable" BM infiltration with lymphoma behaves similarly to LN disease after therapy and is "measurable" by FDG PET/CT. FDG PET/CT is valuable for monitoring tumor response in "measurable" disease and BM, which was previously considered "unmeasurable" by anatomical imaging.

    *20634105*
     20634105

    Impact of abdominopelvic CT on Ewing sarcoma management.

    Acad Radiol 2010; 17 (10): 1288-91 matthew.dobbs@vanderbilt.edu

    RATIONALE AND OBJECTIVES: Abdominopelvic computed tomography (APCT) is often performed in patients with skeletal Ewing sarcoma family of tumors during initial staging and for subsequent clinical indications, such as metastasis surveillance; however, its clinical impact is unknown. The purpose of this study was to evaluate whether these computed tomographic examinations alter oncologic management and therefore patient outcomes. MATERIALS AND METHODS: One hundred eight consecutive patients with skeletal Ewing sarcoma family of tumors seen from 1985 to 2008 were retrospectively reviewed to identify imaging workup, pathology, primary site, evidence of metastatic disease, and patient outcomes. Data were analyzed using Wilcoxon's rank sum tests. RESULTS: Sixty-five of the 108 patients (60%) underwent 342 abdominopelvic computed tomographic examinations during a mean follow-up period of 8.9 years. During this time period, only one of the 65 patients (1.5%) who underwent APCT was discovered to have abdominal metastatic disease. There was no significant difference in the incidence of metastatic disease to the skeleton or chest between the groups without and with APCT (P = .10). There were 26 pelvic and lumbosacral primaries (24%) and 82 limb primaries (76%). Subgroup analysis performed on the 82 patients with limb primaries without (n = 36) and with (n = 46) APCT showed no significant differences in metastatic incidence to the skeleton or chest (P = .14). CONCLUSIONS: This study indicates that APCT, associated with increased radiation exposure and health expenditure, has a limited role in initial staging and follow-up in patients with skeletal Ewing sarcoma, particularly in patients with limb primaries.

    *20634109*
     20634109

    Diagnostic performance of a prototype dual-energy chest imaging system ROC analysis.

    Acad Radiol 2010; 17 (3): 298-308

    RATIONALE AND OBJECTIVES: To assess the performance of an experimental prototype dual-energy (DE) chest imaging system in comparison to digital radiography (DR) in detection and characterization of lung lesions using receiver-operating characteristic (ROC) tests. MATERIALS AND METHODS: A cohort of 129 patients (80 M, 49 F; mean age, 64.8 years) was drawn from a trial of patients referred for percutaneous biopsy of a lung lesion. DR and DE images were acquired of each patient (posteroanterior view) before biopsy using a prototype system developed in our laboratory. The system incorporated a flat-panel detector and previously reported imaging techniques optimized such that the total dose for the DE image was equivalent to that of a DR acquisition. Each DE image was decomposed to three components (soft-tissue, bone, and composite "equivalent radiograph") by log subtraction with optimized noise reduction techniques. ROC tests were performed to evaluate the diagnostic performance of DR imaging in comparison to DE for nodule detection, with 258 left/right "half-chest" images derived from the 129 cases to give a roughly equal number of disease and normal cases. Five chest radiologists scored 258 half-chest DE and 258 half-chest DR (516 in total) images on a 5-point scale, and results (including ROC and area under the curve [AUC]) were analyzed using the ROCkit toolkit. Statistical significance in the observed differences was evaluated in terms of P values determined by a z test. Performance was analyzed for all cases pooled (258 DE vs. 258 DR images) and by retrospective stratification of the data according to nodule size, density, gender, lung region, and chest thickness. RESULTS: For results pooled over the entire cohort, there was no significant difference in ROC performance between DE and DR (AUC(DE) = 0.795 AUC(DR) = 0.789; P = .696). This finding is believed to be due to a large portion of lesions that were fairly conspicuous in either modality. In retrospective analysis of subgroups, a significant advantage was measured for DE imaging of small nodules (<1 cm diameter; AUC(DE) = 0.778; AUC(DR) = 0.706; P = .056), for nodules located in the right upper lobe (AUC(DE) = 0.836; AUC(DR) = 0.779; P = .003), and nodules located in right lower lobe (AUC(DE) = 0.804; AUC(DR) = 0.752; P = .054). DE imaging provided a clinically significant differential diagnosis in approximately one third of patients (49/158) (ie, disease cases in which the lesion was correctly identified in DE [(ROC rating > or =3], but missed in DR [ROC rating < or =2]). DE imaging also appeared to provide more definitive diagnosis (ie, a greater proportion of ROC ratings = 5 and 1 for identification of disease and normal cases, respectively), which presumably translates to increased confidence and a steeper ROC curve (even if the AUC are the same). CONCLUSIONS: DE imaging at dose equivalent to DR exhibited similar overall ROC performance to DR, although the radiologists noted qualitatively improved visualization (eg, improved characterization of lesion margins, visibility of calcifications and rib fractures). DE imaging demonstrated significant improvement in diagnostic performance for specific subgroups, including subcentimeter lung lesions and lesions in the right upper lobe, each of which is a potentially important factor in detecting early-stage malignancy.

    *20042351*
     20042351

    Body diffusion-weighted MR imaging using high b-value for malignant tumor screening: usefulness and necessity of referring to T2-weighted images and creating fusion images.

    Acad Radiol 2007; 14 (6): 643-50 yoshito@xa2.so-net.ne.jp

    RATIONALE AND OBJECTIVES: To evaluate the potential usefulness of high b-value body diffusion-weighted images (DWIs) as a screening tool in the depiction of abdominal malignant tumors. MATERIALS AND METHODS: We selected 110 abdominal magnetic resonance examinations (1.5 T; 60 men; age range, 25-90 years) with and without malignant tumors (n = 37 and n = 73, respectively). Axial DWIs were obtained by single-shot spin-echo (SE) type echo planar imaging (EPI) sequence with inversion pulse (repetition time, 6,800 msec; echo time, 100 msec; T1, 150 msec; b value, 1,000 sec/mm(2)) without breath-holding. Two radiologists independently interpreted the DWIs, T2-weighted images (T2-WI), all three types of images including DWIs, T2-WIs, and fusion images at the same time (DWIs + T2-WIs + fusion) with 7-14 days' interval, and the diagnostic confidence for each patient was scored. RESULTS: The area under the curve (AUC) of the composite receiver operating characteristic (ROC) curve of DWIs + T2-WIs + fusion (0.904) was significantly higher than those of DWIs (0.720; P < .001) and T2-WIs (0.822; P < .05). Both sensitivity and specificity were higher in DWIs + T2-WIs + fusion (89.5% and 81.9%, respectively) compared with those of DWIs (72.4% and 59.0%; P < .01 and P < .001, respectively). CONCLUSIONS: Abdominal high b-value DWIs have a high sensitivity and specificity for malignant tumors when T2-WIs are referred and image fusion technique is employed, suggesting that it may potentially be a new screening tool.

    *17502253*
     17502253

    Usefulness of 18F-FDG PET-directed skeletal biopsy for metastatic neoplasm.

    Acad Radiol 2006; 13 (8): 1011-5

    RATIONALE AND OBJECTIVES: Technium-99m methylene diphosphonate (99mTc-MDP) bone scintigraphy and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) are useful imaging modalities to detect skeletal metastases. Several other conditions such as infection, fractures, and arthritis can cause false-positive results with either modality. However, PET is felt to be more specific than bone scintigraphy for malignancy. Our objective was to investigate the value of PET scan compared with bone scintigraphy for directing biopsies in patients with suspected metastatic bone lesions. MATERIALS AND METHODS: Retrospective case series of subjects with undergoing skeletal biopsy of suspected metastases detected by 99mTc-MDP scintigraphy or 18F-FDG PET scan. Reference standards were pathologic reports and follow-up for 6 months. The diagnostic test performance measures of true positive (TP), false positive (FP), and positive predictive value (PPV) were calculated for each group. The PPV with 95% confidence intervals (CI) was compared using the Fisher exact test. RESULTS: There were a total of 68 subjects. PET-directed skeletal biopsies (n = 39) showed 35 TP, 4 FP, and an 89.7% PPV (95% CI: 75.7-97.1%). Bone scintigraphy directed biopsies (n = 29) had 21 TP, 8 FP, and 72.4 % PPV (95% CI: 52.7-82.7%). The PPV was not significantly different between the groups (P = .10). CONCLUSION: This study supports that PET can be used to effectively direct bone biopsies to confirm metastatic neoplasm and suggests that PET may provide incremental improvement to diagnostic yield over bone scintigraphy. The role of PET compared with bone scintigraphy for directing skeletal biopsies warrants further verification.

    *16843854*
     16843854

    Arterial spin labeling blood flow magnetic resonance imaging for the characterization of metastatic renal cell carcinoma(1).

    Acad Radiol 2005; 12 (3): 347-57

    RATIONALE AND OBJECTIVE: This study sought to assess the feasibility of arterial spin labeling (ASL) blood flow (BF) magnetic resonance imaging (MRI) for the study of metastatic renal cell carcinoma (RCC) in the body, where the respiratory, cardiac, and peristaltic motions present challenges when applying ASL. MATERIALS AND METHODS: ASL was performed using a background-suppressed single-section flow-alternating inversion recovery (FAIR) preparation and a single-shot fast spin-echo imaging sequence on a 3.0-T whole body imager. Tumor BF was evaluated for 26 patients with RCC metastatic to the liver, bone, lung, or lymph nodes before VEGF receptor inhibitor therapy. Two cases with tumor size change after treatment were also scanned 1 month after therapy. For validation, kidney cortex BF in five normal volunteers was measured with the same technique and compared with literature values. RESULTS: ASL was successfully performed in all normal volunteers and in 20 of 26 patients. The six failures resulted from a systematic error, which can be avoided in future studies. For normal volunteers, measured kidney cortex BF was 275 +/- 14 mL/min/100 g, a value consistent with the literature. ASL determined tumor BF averaged across tumor volume and subjects was 194 mL/min/100 g (intersubject SD = 100), resulting in high perfusion signal and conspicuity of lesions. Bright signal was also seen in large vessels and occasionally in bowel. In the two cases studied 1 month after therapy, ASL perfusion changes were consistent with tumor size changes. CONCLUSION: With background suppression, ASL MRI is a feasible method for quantifying BF in patients with renal cell carcinoma. This technique may be useful for evaluating tumor response to antiangiogenic agents.

    *15766695*
     15766695

    Qualitative diagnosis of calvarial metastasis by neural network and logistic regression.

    Acad Radiol 2004; 11 (1): 45-52

    RATIONALE AND OBJECTIVES: To simplify the diagnostic features used by an artificial neural network compared with logistic regression (LR) in the diagnosis of calvarial metastasis with computed tomography and analyze their accuracy. MATERIALS AND METHODS: Twenty-one of 167 patients with calvarial lesions were found to have metastasis. Clinical and computed tomography data were used for LR and neural network models. Both models were tested with the leave-one-out method. The final results of each model were compared using the area under receiver operating characteristic curve (Az). RESULTS: The neural network identified metastasis significantly more successfully than LR with an Az of 0.9324 +/- 0.0386 versus 0.9192 +/- 0.0373, P = .01. The most important features selected by the LR and neural network were age and edge definition. CONCLUSION: Neural networks offer wide possibilities over statistics for the study of calvarial metastases other than their minimum clinical and radiologic features for diagnosis.

    *14746401*
     14746401

    Automatic registration of MR and SPECT images for treatment planning in prostate cancer.

    Acad Radiol 2003; 10 (6): 673-84

    RATIONALE AND OBJECTIVES: To aid in surgical and radiation therapy planning for prostate adenocarcinoma, a general-purpose automatic registration method that is based on mutual information was used to align magnetic resonance (MR) images and single photon emission computed tomographic (SPECT) images of the pelvis and prostate. MATERIALS AND METHODS: The authors assessed the effects of various factors on alignment between pairs of MR and SPECT images, including the use of particular pulse sequences in MR imaging, image voxel intensity scaling, the use of different regions on the MR-SPECT histogram, spatial masking of nonoverlapping visual data between images, and multiresolution optimization. A mutual information algorithm was used as the cost function for automatic registration. Automatic registration was deemed acceptable when it resulted in a transformation with less than 2 voxel units (6 mm) difference in translation and less than 2 degree difference in rotation from that obtained with manual registration performed independently by nuclear medicine radiologists. RESULTS: Paired sets of MR and SPECT image volumes from four of five patients were successfully registered. For successful registration, MR images must be optimal and registration must be performed at full spatial resolution and at the full intensity range. Masking, cropping, and the normalization of mutual information, used to register partially overlapping MR-SPECT volumes, were not successful. Multiresolution optimization had little effect on the accuracy and speed of the registration. CONCLUSION: Automatic registration between MR and SPECT images of the pelvis can be achieved when data acquisition and image processing are performed properly. It should prove useful for prostate cancer diagnosis, staging, and treatment planning.

    *12809423*
     12809423

    CT and radionuclide study of BMP-2 gene therapy-induced bone formation.

    Acad Radiol 2002; 9 (6): 632-7

    RATIONALE AND OBJECTIVES: Gene therapy techniques have the potential to treat numerous diseases, from cancer to diabetes. One promising application is the use of bone morphogenetic protein (BMP) gene transfer to induce bone formation. Previous studies have demonstrated that both direct and ex vivo BMP gene therapy have the capacity to initiate the normal endochondral pathway, leading to rapid mature bone formation. In the present study, computed tomography (CT) and radionuclide imaging was used to assess bone formation induced by BMP gene therapy accurately and noninvasively. MATERIALS AND METHODS: Athymic nude rodents were treated with 1.25 x 10(10) particles of adenovirus-BMP-2 (Ad-BMP-2) (treatment group) or adenovirus-beta-gal (control group). At various intervals after treatment, the animals underwent CT, planar digital radiography, and planar radionuclide scintigraphic imaging. RESULTS: Radionuclide scintigraphy clearly demonstrated active bone deposition that began as early as 15 days after treatment and peaked at approximately 36 days, only at the Ad-BMP-2 injection sites. CT clearly demonstrated ectopic bone induction over time at the Ad-BMP-2 treatment sites, in perfect correlation with the scintigraphic findings. CONCLUSION: This study clearly illustrates that gene therapy-induced osteogenesis can be studied with multimodality imaging and supports the use of these approaches in future preclinical and clinical studies.

    *12061736*
     12061736

    Use of serial FDG PET to measure the response of bone-dominant breast cancer to therapy.

    Acad Radiol 2002; 9 (8): 913-21

    RATIONALE AND OBJECTIVES: The authors performed this study to determine the feasibility of using quantitative 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) to monitor the response of breast cancer bone metastases to therapy. MATERIALS AND METHODS: Twenty-four women with stage IV bone-dominant breast carcinoma were included in this study. Whole-body FDG PET imaging was performed at serial time points during the course of therapy. FDG PET scans were interpreted quantitatively by using the maximum standard uptake value (SUV) of the most conspicuous bone lesion at baseline FDG PET. PET results were compared to the overall assessment of response (response, stable disease, progressive disease) with a combination of conventional imaging, change in tumor marker values, and subjective symptom changes by experienced medical oncologists blinded to the findings at FDG PET. Changes in FDG SUV were also correlated quantitatively to the changes in a particular tumor marker (CA 27.29). RESULTS: The changes in FDG SUV with therapy showed correlation with the overall clinical assessment of response (P < .01). The percentage change in FDG uptake with therapy showed strong correlation with the percentage change in tumor marker value (P < .01). CONCLUSION: Preliminary results indicate that serial whole-body FDG PET can help quantitatively assess the response of breast cancer bone metastases to therapy. Prospective trials are needed to further investigate its accuracy.

    *12186440*
     12186440

    Image-guided percutaneous thermal ablation of bone tumors.

    Acad Radiol 2002; 9 (4): 467-77

    *11942662*
     11942662

    Accuracy and precision of spiral CT in the assessment of neoplastic lesions associated with the mandible.

    Acad Radiol 2000; 7 (2): 94-9

    RATIONALE AND OBJECTIVES: The purpose of this study was to determine the accuracy (validity) and precision (reliability) of spiral computed tomographic (CT) images by using film- and computer graphics-based measurements of simulated neoplastic lesions associated with the mandible. MATERIALS AND METHODS: Four cadaver heads, each with two simulated tumors containing contrast medium positioned medial to the mandibles, were examined by using a subsecond spiral CT scanner. Data were transferred to film and to a computer workstation. With computer graphics, data were analyzed by using multiplanar reconstructed images. Linear measurements of the length, width, and depth of simulated tumors were made by two observers, twice each, on the film scans by using manual calipers and on the multiplanar reconstructed images by using computerized measurements. The soft tissues were then removed from the cadavers and the same measurements made by using the same calipers. RESULTS: No statistically significant differences between computer graphics- or film-based measurements and physical measurements (P > .05) or between inter- and intraobserver measurements (P > .05) were found. CONCLUSION: The authors found high reproducibility of measurements for all dimensions. Spiral CT allows accurate computer graphics- and film-based measurements of neoplastic lesions associated with the mandible.

    *10730164*
     10730164

    Imaging of the cranium: pictorial essay.

    Acad Radiol 1999; 6 (2): 132-40

    *12680436*
     12680436

    Non-small-cell lung cancer: practice patterns of extrathoracic imaging.

    Acad Radiol 1999; 6 (4): 211-5

    RATIONALE AND OBJECTIVES: The purpose of this study was to identify practice patterns of extrathoracic imaging in patients newly diagnosed with non-small-cell lung, cancer. MATERIALS AND METHODS: The authors retrospectively reviewed the charts of 125 patients (71 men, 54 women; mean age, 67 years) from five hospitals (25 patients each) with newly diagnosed non-small-cell lung cancer. Charts were reviewed for cancer cell type, evidence of metastatic disease, and performance and results of extrathoracic imaging, including computed tomography (CT) and magnetic resonance (MR) imaging of the brain, bone scanning, and abdominal CT. RESULTS: Of 125 patients, 77 (62%) underwent extrathoracic imaging. These patients included 64 (64%) of 100 patients with clinical symptoms or laboratory signs of metastatic disease and 13 (52%) of 25 patients with no such indications. Extrathoracic imaging did not differ according to cancer cell type: It was performed for 30 (60%) of 50 patients with squamous cell carcinoma, 26 (60%) of 43 patients with adenocarcinoma, and 16 (73%) of 22 patients with non-small-cell lung cancer that was not further characterized. Brain CT or MR imaging bone scanning, or abdominal CT were performed in only 48%, 39%, and 30% of patients, respectively. Brain CT or MR images or bone scans revealed metastatic disease in seven of 20 and nine of 22 patients with clinical symptoms or laboratory signs of disease, respectively. These examinations revealed disease in four of 40 and two of 27 patients without such symptoms or signs, respectively (P < .05). No significant differences emerged among the practice patterns at the five participating hospitals. CONCLUSION: No consensus was found on performance of extrathoracic imaging in patients with newly diagnosed non-small-cell lung cancer.

    *10894078*
     10894078

    Role of magnetization transfer imaging in bone tumors.

    Acad Radiol 1998; 5 (9): 634-41

    RATIONALE AND OBJECTIVES: The authors evaluated the role of magnetization transfer imaging in differentiation of bone tumors, with special emphasis on cartilaginous tumors. MATERIALS AND METHODS: Fifty-one patients with skeletal tumors or tumor-like lesions who had undergone magnetic resonance (MR) imaging were included. The tumors were divided into three groups according to their gross appearance and the origin of tissue: cyst, cartilaginous tumor, and noncartilaginous solid tumor. A gradient-recalled acquisition in the steady state sequence was used for MR imaging, and examinations were performed both with and without off-resonance magnetization transfer pulses. Magnetization transfer ratios were obtained as an indicator of magnetization transfer effect of the lesions and were compared. Then, the magnetization transfer ratios of all tumors in the cartilaginous tumor group were compared. The magnetization transfer ratios of benign and malignant solid tumors were also compared. RESULTS: The mean magnetization transfer ratio for cartilaginous tumors was 0.31 +/- 0.08 (standard deviation), and that of cysts and noncartilaginous solid tumors was 0.07 +/- 0.03 and 0.40 +/- 0.14, respectively. Comparisons between the three groups showed statistically significant intergroup differences in magnetization transfer ratio (P < .05). In the cartilaginous tumor category, enchondroma and low-grade chondrosarcoma had a lower magnetization transfer effect than chondroblastoma and mesenchymal chondrosarcoma. The mean magnetization transfer ratios of benign (n = 28) and malignant (n = 18) tumors were 0.35 +/- 0.11 and 0.39 +/- 0.15, respectively; there was no statistically significant intergroup difference (P = .14). CONCLUSION: Magnetization transfer imaging could be useful for categorizing bone tumors as cysts, cartilaginous tumors, or noncartilaginous solid tumors.

    *9750894*
     9750894

    The pediatric skull: appearance in health and disease.

    Acad Radiol 1998; 5 (6): 448-55

    *9615156*
     9615156

    Investigation of MR contrast media utility with the VX-2 tumor model.

    Acad Radiol 1998; 5 Suppl 1 (): S34-6; discussion S45-6

    *9561038*
     9561038

    Thoracic spine mass in a 34-year-old man.

    Acad Radiol 1997; 4 (2): 157-8

    *9061090*
     9061090

    Quantitative analysis of signal intensities and contrast after fat suppression in contrast-enhanced magnetic resonance imaging of the spine.

    Acad Radiol 1996; 3 (9): 731-4

    RATIONALE AND OBJECTIVES: We studied the effect of fat suppression on signal intensity and contrast on contrast-enhanced magnetic resonance (MR) images of the spine. METHODS: Contrast-enhanced T1-weighted MR images were obtained at identical levels with and without fat suppression. Signal intensity and contrast were measured in regions of interest in fat, muscle, spinal bone marrow, and enhancing lesions. The differences in the mean values of these signal intensities and the mean values of contrast between enhanced tissues and bone marrow, fat, and muscle were subjected to statistical validation. RESULTS: Mean signal intensity of the extraspinal fat and bone marrow was lower after fat suppression (70% and 46% reduction, p < .001 and p < .05, respectively), whereas the signal intensity of muscle showed no significant change (p < .9). Enhancing spinal lesions showed a difference in mean signal intensity after fat suppression (22% increase, p < .2). Contrast between enhanced lesions and bone marrow and fat was higher after fat suppression (78% increase, p < .01 for bone marrow; 8% increase, p < .001 for fat). CONCLUSION: In contrast-enhanced MR examinations of the spine, the use of fat suppression may increase the signal intensity of the enhancing lesion by expanding the dynamic gray scale of the image and increases the contrast between the lesion and adjacent bone marrow and suppressed fat.

    *8883513*
     8883513

    Physical and clinical evaluation of a 2,048 x 2,048-matrix image intensifier TV digital imaging system in bone radiography.

    Acad Radiol 1996; 3 (10): 842-8

    RATIONALE AND OBJECTIVES: To evaluate the potential utility of a 2,048 x 2,048-matrix image intensifier television digital radiography (DR) system versus a conventional screen-film (S-F) system for bone radiography. METHODS: Basic imaging properties were evaluated including resolution properties, Wiener spectra, and detectabilities of low-contrast signals. DR images were obtained with the same exposure (iso-dose) or one-third the exposure (low-dose) used with the S-F system. The visibility of pathologic details of metastatic disease on bone radiographs of 27 patients was evaluated subjectively by six radiologists. RESULTS: Resolution properties of the DR system were slightly superior to those of the S-F system at low-frequency range, but the S-F system showed considerably higher resolution properties at the high-frequency range. The noise levels for iso-dose DR were slightly greater than those for S-F imaging at low spatial frequency; however, low-dose digital radiographs showed higher noise levels. Visibility of details of diagnostic features on bone radiographs was similar with both systems, but the low-dose digital radiographs were slightly inferior. CONCLUSION: High-resolution image intensifier television DR systems may be clinically useful for bone radiography.

    *8923903*
     8923903

    Costs and benefits of radiology: musculoskeletal system.

    Acad Radiol 1996; 3 Suppl 1 (): S47-8

    *8796510*
     8796510

    Lytic bone lesion in a 12-year-old.

    Acad Radiol 1995; 2 (6): 541-3

    *9419603*
     9419603

    Bioinspired and Biomimetic Nanomedicines.

    Acc Chem Res 2019; 52 (5): 1255-1264

    Nanomedicine development aims to enhance the efficacy, accuracy, safety, and/or compliance of diagnosis and treatment of diseases by leveraging the unique properties of engineered nanomaterials. To this end, a multitude of organic and inorganic nanoparticles have been designed to facilitate drug delivery, sensing, and imaging, some of which are currently in clinical trials or have been approved by the Food and Drug Administration (FDA). In the process, the increasing knowledge in understanding how natural particulates, including cells, pathogens, and organelles, interact with body and cellular systems has spurred efforts to mimic their morphology and functions for developing new generations of nanomedicine formulations. In addition, the advances in bioengineering tools, bioconjugation chemistries, and bio-nanotechnologies have further enabled researchers to exploit these natural particulates for theranostic purposes. In this Account, we will discuss the recent progress in our lab on engineering bioinspired and biomimetic synthetic and cellular systems toward rational design of nanomedicine platforms for treating diabetes and cancer. Inspired by the structure and response mechanism of pancreatic beta-cells, we synthesized a series of insulin granule-like vesicles that can respond to high blood or intestinal glucose levels for aiding in transdermal or oral insulin delivery, respectively. Then, to more closely mimic the multicompartmental architecture of beta-cells, we further developed synthetic artificial cells with vesicle-in-vesicle superstructures which can sense blood glucose levels and dynamically release insulin via a membrane fusion process. Meanwhile, clues drawn from the traits of anaerobic bacteria that selectively invade and proliferate in solid tumors inspired the synthesis of a light-tuned hypoxia-responsive nanovesicle for implementing synergistic cancer therapy. In parallel, we also studied how autologous particulates could be recruited for developing advanced drug delivery systems. Through combination of genetic engineering and top-down cell engineering technologies, biomimetic nanomedicines derived from cytoplasmic membrane with programmed death 1 (PD-1) receptors expressed on surfaces were generated and employed for cancer immunotherapy. Based on our earlier study where aPD-L1 (antibodies against PD ligand 1)-conjugated platelets could release aPD-L1-bearing particles in situ and inhibit postsurgical tumor recurrence, we further genetically engineered megakaryocytes, the precursor cells of platelets, to express PD-1 receptors. In this way, platelets born with checkpoint blocking activity could be produced directly in vitro, avoiding post chemical modification processes while exerting similar therapeutic impact. As a further extension, by virtue of the bone marrow-homing ability of hematopoietic stem cells (HSCs), we recently conceived a cell-combination strategy by conjugating HSCs with platelets decorated with antibodies against PD1 (aPD-1) to suppress the growth and recurrence of leukemia. While we are still on the way of digging deep to understand and optimize bioinspired and biomimetic drug carriers, we expect that the strategies summarized in this Account would contribute to the development of advanced nanomedicines.

    *30977635*
     30977635

    Quantum dot cytotoxicity and ways to reduce it.

    Acc Chem Res 2013; 46 (3): 672-80 francoise.winnik@umontreal.ca

    The dramatic increase in the use of nanoparticles (NP) in industry and research has raised questions about the potential toxicity of such materials. Unfortunately, not enough is known about how the novel, technologically-attractive properties of NPs correlate with the interactions that may take place at the nano/bio interface. The academic, industrial, and regulatory communities are actively seeking answers to the growing concerns on the impact of nanotechnology on humans. In this Account we adopt quantum dots (QDs) as an illustrative example of the difficulties associated with the development of a rational science-based approach to nanotoxicology. The optical properties of QDs are far superior to those of organic dyes in terms of emission and absorption bandwidths, quantum yield, and resistance to photobleaching. Moreover, QDs may be decorated with targeting moieties or drugs and, therefore, are candidates for site-specific medical imaging and for drug delivery, for example in cancer treatment. Earlier this year researchers demonstrated that QD-based imaging using monkeys caused no adverse effects although QDs accumulated in lymph nodes, bone marrow, liver, and spleen for up to 3 months after injection. Such persistence of QDs in live animals does, however, raise concerns about the safety of using QDs both in the laboratory and in the clinic. Researchers anticipate that QDs will be increasingly used not only in clinical applications but also in various manufactured products. For example, QD-solar cells have emerged as viable contenders to complement or replace dye-sensitized solar cells; CdTe/CdS thin film cells have already captured approximately 10 percent of the global market, and in addition, QDs can serve as components of sensors and as emitting materials in LEDs. Given the clear indications that QDs will inevitably become components of a wide range of manufactured and consumer products, researchers and policy makers need to understand the possible health risks associated with exposure to QDs. In this Account, we initially review the known mechanisms by which QDs can damage cells, including oxidative stress elicited by reactive oxygen species (ROS). We discuss lesser-known impairments induced in cells by nanomolar to picomolar concentrations of QDs, which imply that cadmium-containing QDs can exert genotoxic, epigenetic, and metalloestrogenic effects. These observations strongly suggest that minute concentrations of QDs could be sufficient to cause long lasting, even transgenerational, effects. We also consider various modes by which humans could be exposed to QDs in their work or through the environment. Although considerable advances have been made in enhancing the stability and overall quality of QDs, over time they can partially degrade in the environment or in biological systems, and eventually cause small, but cumulative undesirable effects. A combination of toxicological, genetic, epigenetic and imaging approaches is required to create comprehensive guidelines for evaluating the nanotoxicity of nanomaterials, including QDs. Prior to biological investigations with these materials, an indispensible step must be the full characterization of NPs by complementary techniques. Specifically, the concentration, size, charge, and ligand stability of NPs in biological media must be known if we are to understand fully how the properties of nanoparticles and of their biological environment contribute to cytotoxicity.

    *22775328*
     22775328

    Emangioma dell'osso frontale.

    Accad Medica 1953; 68 (6): 170-1

    *13103996*
     13103996

    Aneurisma dell'osso o aneurisma per l'osso?

    Accad Medica 1951; 66 (3): 88-9

    *14877421*
     14877421

    A little too much of the Buchenwald touch? Military radiation research at the University of Cincinnati, 1960-1972.

    Account Res 1998; 6 (1-2): 63-102

    *11660591*
     11660591

    Review: bisphosphonates prevent or delay skeletal events in women with advanced breast cancer and bone metastases.

    ACP J Club 2006; 144 (2): 39

    *16539354*
     16539354

    Review: bisphosphonates are modestly better than placebo for relieving painful bone metastases.

    ACP J Club 2005; 143 (1): 13

    *15989301*
     15989301

    Les reactions immunologiques et les cancers. Les essais d'immunotherapie.

    Acquis Med Recent 1965; (): 113-20

    *5320416*
     5320416

    Liposome-Encapsulated Curcumin-Loaded 3D Printed Scaffold for Bone Tissue Engineering.

    ACS Appl Mater Interfaces 2019; 11 (19): 17184-17192

    Curcumin, the active constituent for turmeric, is known for its antioxidant, anti-inflammatory, anticancer, and osteogenic activities. However, it shows extremely poor bioavailability, rapid metabolism, and rapid systemic elimination. In this study, we have increased the bioavailability of curcumin by encapsulating it in a liposome, followed by the incorporation onto 3D printed (3DP) calcium phosphate (CaP) scaffolds with designed porosity. 3DP scaffolds with a designed shape and interconnected porosity allow for the fabrication of patient-specific implants, providing new tissue ingrowth by mechanical interlocking between the surrounding host tissue and the scaffold. Upon successful encapsulation of curcumin into the liposomes, we have investigated the effect of liposomal curcumin released from the 3DP scaffolds on both human fetal osteoblast cells (hFOB) and human osteosarcoma (MG-63) cells. Interestingly, liposomal curcumin released from the 3DP scaffold showed significant cytotoxicity toward in vitro osteosarcoma (bone cancer) cells, whereas it promoted osteoblast (healthy bone cell) cell viability and proliferation. These results reveal a novel approach toward the fabrication of tissue engineering scaffolds, which couples the advanced additive manufacturing technology with the wisdom of alternative medicine. These bifunctional scaffolds eradicate the osteosarcoma cells and also promote osteoblast proliferation, offering new opportunities to treat bone defects after tumor resection.

    *30924639*
     30924639

    Exfoliated Black Phosphorus Promotes in Vitro Bone Regeneration and Suppresses Osteosarcoma Progression through Cancer-Related Inflammation Inhibition.

    ACS Appl Mater Interfaces 2019; 11 (9): 9333-9342

    Nowadays chemotherapy is the main treatment for osteosarcoma disease, even if limited by the lack of selectivity between healthy and cancer cells during the inhibition of cell division. Herein, we propose the use of few-layer two-dimensional black phosphorous (2D bP) as an alternative tool for osteosarcoma treatment and report how 2D bP can stimulate newly forming bone tissue generation after osteosarcoma resection. In our study, we have developed an in vitro model to evaluate the efficacy of 2D bP material with and without near-infrared light irradiation treatment, and we have demonstrated that the presence of 2D bP without treatment inhibits the metabolic activity of osteosarcoma cells (SAOS-2) while inducing both the proliferation and the osteogenic differentiation of human preosteoblast cells (HOb) and mesenchymal stem cells. Furthermore, we also propose an in vitro coculture model (SAOS-2 and HOb cell lines) in order to study the effect of 2D bP on inflammatory response related to cancer. On this coculture model, 2D bP may increase anti-inflammatory cytokine generation (i.e., interleukin-10) and inhibit proinflammatory mediators synthesis (i.e., interleukin-6), thus suggesting the opportunity to prevent cancer-related inflammation. Finally, we have demonstrated that 2D bP represents a promising candidate for future regenerative medicine and anticancer applications.

    *30758933*
     30758933

    Conjugation of a Small-Molecule TLR7 Agonist to Silica Nanoshells Enhances Adjuvant Activity.

    ACS Appl Mater Interfaces 2019; 11 (30): 26637-26647

    Stimulation of Toll-like receptors (TLRs) and/or NOD-like receptors on immune cells initiates and directs immune responses that are essential for vaccine adjuvants. The small-molecule TLR7 agonist, imiquimod, has been approved by the FDA as an immune response modifier but is limited to topical application due to its poor pharmacokinetics that causes undesired adverse effects. Nanoparticles are increasingly used with innate immune stimulators to mitigate side effects and enhance adjuvant efficacy. In this study, a potent small-molecule TLR7 agonist, 2-methoxyethoxy-8-oxo-9-(4-carboxybenzyl)adenine (1V209), was conjugated to hollow silica nanoshells (NS). Proinflammatory cytokine (IL-6, IL-12) release by mouse bone-marrow-derived dendritic cells and human peripheral blood mononuclear cells revealed that the potency of silica nanoshells-TLR7 conjugates (NS-TLR) depends on nanoshell size and ligand coating density. Silica nanoshells of 100 nm diameter coated with a minimum of approximately 6000 1V209 ligands/particle displayed 3-fold higher potency with no observed cytotoxicity when compared to an unconjugated TLR7 agonist. NS-TLR activated the TLR7-signaling pathway, triggered caspase activity, and stimulated IL-1beta release, while neither unconjugated TLR7 ligands nor silica shells alone produced IL-1beta. An in vivo murine immunization study, using the model antigen ovalbumin, demonstrated that NS-TLR increased antigen-specific IgG antibody induction by 1000x with a Th1-biased immune response, compared to unconjugated TLR7 agonists. The results show that the TLR7 ligand conjugated to silica nanoshells is capable of activating an inflammasome pathway to enhance both innate immune-stimulatory and adjuvant potencies of the TLR7 agonist, thereby broadening applications of innate immune stimulators.

    *31276378*
     31276378

    Understanding the Stiff-to-Compliant Transition of the Meniscal Attachments by Spatial Correlation of Composition, Structure, and Mechanics.

    ACS Appl Mater Interfaces 2019; 11 (30): 26559-26570

    Recently, the scientific community has shown considerable interest in engineering tissues with organized compositional and structural gradients to mimic hard-to-soft tissue interfaces. This effort is hindered by an incomplete understanding of the construction of native tissue interfaces. In this work, we combined Raman microscopy and confocal elastography to map compositional, structural, and mechanical features across the stiff-to-compliant interface of the attachments of the meniscus in the knee. This study provides new insight into the methods by which biology mediates multiple orders of magnitude changes in stiffness over tens of microns. We identified how the nano- to mesoscale architecture mediates complex microscale transitional regions across the interface: two regions defined by chemical composition, five distinguished by structural features, and three mechanically distinct regions. We identified three major components that lead to a robust interface between a soft tissue and bone: mobile collagen fiber units, a continuous interfacial region, and a local stiffness gradient. This tissue architecture allows for large displacements of collagen fibers in the attachments, enabling meniscal movement without localizing strains to the soft tissue-to-bone interface. The interplay of these regions reveals a method relying on hierarchical structuring across multiple length scales to minimize stress concentrators between highly dissimilar materials. These insights inspire new design strategies for synthetic soft tissue-to-bone attachments and biomimetic material interfaces.

    *31267742*
     31267742

    Nanoscale Hybrid Coating Enables Multifunctional Tissue Scaffold for Potential Multimodal Therapeutic Applications.

    ACS Appl Mater Interfaces 2019; 11 (30): 27269-27278

    Through a nature-inspired layer-by-layer assembly process, we developed a unique multifunctional tissue scaffold that consists of porous polyurethane substrate and nanoscale chitosan/graphene oxide hybrid coating. Alternative layers of drug-laden chitosan and graphene oxide nanosheets were held together through strong electrostatic interaction, giving rise to a robust multilayer architecture with control over structural element orientation and chemical composition at nanoscale. Combined pH-controlled co-delivery of multiple therapeutic agents and photothermal therapy has been achieved by our scaffold system. The new platform technology can be generalized to produce other tissue scaffold systems and may enable potential multimodal therapeutic applications such as bone cancer managements.

    *31260238*
     31260238

    A Carboxyl-Terminated Dendrimer Enables Osteolytic Lesion Targeting and Photothermal Ablation of Malignant Bone Tumors.

    ACS Appl Mater Interfaces 2019; 11 (1): 160-168

    Malignant bone tumor accompanied by tumor-associated osteolysis remains a challenging task in clinical practice. Nanomedicines engineered with bone-targeting ligands, such as alendronate and pamidronate, are developed for targeted delivery of therapeutic agents to bone tumors. However, these targeting strategies usually show relatively poor selectivity toward the healthy skeletons and the osteolytic lesions because of the high binding affinity of bisphosphonates with all the bone tissues. Here, we reported a carboxyl-terminated dendrimer as the candidate to preferentially deliver therapeutic nanoparticles to the osteolytic lesions in a malignant bone tumor model. The high density of carboxyl groups on dendrimer surface endow the polymer with natural bone-binding capability. The dendrimer encapsulated with platinum nanoparticle predominantly accumulates at the osteolytic lesions around bone tumors rather than at healthy bone tissues in vivo. The therapeutic experiments reveal that the dendrimer-mediated photothermal therapy efficiently suppresses bone tumors and osteolysis, and the anionic polymer exhibits minimal cytotoxicity and hematologic toxicity. The results suggest that the carboxyl-terminated dendrimer is a promising candidate for selective delivery of therapeutics to the osteolytic lesions and photothermal treatment of malignant bone tumors.

    *30525391*
     30525391

    Zoledronic Acid-containing Nanoparticles With Minimum Premature Release Show Enhanced Activity Against Extraskeletal Tumor.

    ACS Appl Mater Interfaces 2019; 11 (7): 7311-7319

    Bisphosphonates are generally used to treat bone diseases, such as bone metastasis from cancer. There is evidence that, through the modification of the pharmacokinetics and biodistribution of bisphosphonates by formulating them into nanoparticles, they may be able to treat extraskeletal tumors. However, many previously reported bisphosphonate nanoparticle formulations show extensive premature release of bisphosphonates. Herein, using zoledronate (Zol), a third-generation bisphosphonate, we developed a new Zol nanoparticle formulation (denoted as Zol-NPs) by encapsulating anionic lipid-coated Zol-calcium nanocomplexes into poly(lactic- co-glycolic) acid nanoparticles emulsified with octadecanoic acid-hydrazone-polyethylene glycol (2000), an acid-sensitive cleavable emulsifying agent. The resultant Zol-NPs, about 180 nm in hydrodynamic diameter, show very limited premature release of Zol (i.e., <5% in 48 h in a simulated physiological condition) and enhanced cytotoxicity to both murine cancer cells and macrophages. In a mouse model with orthotopically transplanted mammary tumors, Zol-NPs significantly reduced the distribution of Zol in bones, but increased its distribution in tumors. Importantly, Zol-NPs also significantly inhibited tumor growth, whereas the equivalent dose of free Zol did not. This platform technology may be exploited to treat extraskeletal tumors with bisphosphonates.

    *30689348*
     30689348

    Engineering of Bone- and CD44-Dual-Targeting Redox-Sensitive Liposomes for the Treatment of Orthotopic Osteosarcoma.

    ACS Appl Mater Interfaces 2019; 11 (7): 7357-7368

    This study aimed to develop an efficient step-by-step osteosarcoma (OS)-targeting liposome system functionalized with a redox-cleavable, bone- and cluster of differentiation 44 (CD44)-dual-targeting polymer. Furthermore, the effect of coadministration of a tumor-penetrating peptide, internalizing RGD (iRGD), was investigated. First, a bone-targeting moiety, alendronate (ALN), was conjugated with hyaluronic acid (HA), a ligand for CD44. This ALN-HA conjugate was coupled with DSPE-PEG2000-COOH through a bioreducible disulfide linker (-SS-) to obtain a functionalized lipid, ALN-HA-SS-L, to be postinserted into preformed liposomes loaded with doxorubicin (DOX). The roles of ALN, HA, and the redox sensitivity of the ALN-HA-SS-L liposomes (ALN-HA-SS-L-L) in the anti-OS effect were critically evaluated against various reference liposomal formulations (with only ALN, HA, or redox sensitivity). ALN-HA-SS-L-L displayed a zeta potential of -26.07 +/- 0.32 mV and selectively disassembled in the presence of a reducing agent, 10 mM glutathione, which can be found in cancer cells. Compared to various reference liposomes, ALN-HA-SS-L-L/DOX had significantly higher cytotoxicity to human OS MG-63 cells alongside high and rapid cellular uptake. In the orthotopic OS nude mouse models, ALN-HA-SS-L-L/DOX showed remarkable tumor growth suppression and prolonged survival time. This result was further improved by the coadministration of iRGD. The antitumor effects of various liposomes were ranked in the same order as the degree of tumor biodistribution shown by in vivo/ex vivo imaging: ALN-HA-SS-L-L coadministered with iRGD > ALN-HA-SS-L-L > HA-SS-L-L > HA-L-L > PEG-L> free drug. ALN-HA-SS-L-L/DOX also reduced the cardiotoxicity of DOX and lung metastases. Overall, this study demonstrated that ALN-HA-SS-L-L/DOX, equipped with bone- and CD44-dual-targeting abilities and redox sensitivity, could be a promising OS-targeted therapy. The efficacy could also be augmented by coadministration of iRGD.

    *30682240*
     30682240

    Mechanical Property of Hydrogels and the Presence of Adipose Stem Cells in Tumor Stroma Affect Spheroid Formation in the 3D Osteosarcoma Model.

    ACS Appl Mater Interfaces 2019; 11 (16): 14548-14559

    Osteosarcoma is one of the most common metastatic bone cancers, which results in significant morbidity and mortality. Unfolding of effectual therapeutic strategies against osteosarcoma is impeded because of the absence of adequate animal models, which can truly recapitulate disease biology of humans. Tissue engineering provides an opportunity to develop physiologically relevant, reproducible, and tunable in vitro platforms to investigate the interactions of osteosarcoma cells with its microenvironment. Adipose-derived stem cells (ASCs) are detected adjacent to osteosarcoma masses and are considered to have protumor effects. Hence, the present study focuses on investigating the role of reactive ASCs in formation of spheroids of osteosarcoma cells (Saos 2) within a three-dimensional (3D) niche, which is created using gellan gum (GG)-silk fibroin. By modifying the blending ratio of GG-silk, the optimum stiffness of the resultant hydrogels such as GG and GG75: S25 is obtained for cancer spheroid formation. This work indicates that the co-existence of cancer and stem cells can form a spheroid, the hallmark of cancer, only in particular microenvironment stiffness. The incorporation of fibrillar silk fibroin within the hydrophilic network of GG in GG75: S25 spongy-like hydrogels closely mimics the stiffness of commercially established cancer biomaterials (e.g., Matrigel, HyStem). The GG75: S25 hydrogel maintains the metabolically active construct for a longer time with elevated expression of osteopontin, osteocalcin, RUNX 2, and bone sialoprotein genes, the biomarkers of osteosarcoma, compared to GG. The GG75: S25 construct also exhibits intense alkaline phosphatase expression in immunohistochemistry compared to GG, indicating itspotentiality to serve as biomimetic niche to model osteosarcoma. Taken together, the GG-silk fibroin-blended spongy-like hydrogel is envisioned as an alternative low-cost platform for 3D cancer modeling.

    *30943004*
     30943004

    Nanovaccine Incorporated with Hydroxychloroquine Enhances Antigen Cross-Presentation and Promotes Antitumor Immune Responses.

    ACS Appl Mater Interfaces 2018; 10 (37): 30983-30993

    Induction of effective antigen-specific CD8(+) T-cell responses is critical for cancer immunotherapy success. Hydroxychloroquine (HCQ) is a widely used classical antimalarial and antirheumatic drug. HCQ is also an endosomal membrane disrupting agent that can lead to vesicular swelling and membrane permeabilization, which likely facilitates the release of therapeutic agents from lysosomes into the cytoplasm. Here, we develop a minimalistic nanovaccine, which is composed of poly(lactide- co-glycolide)acid (PLGA) nanoparticles (NPs) encapsulating a physical mixture of ovalbumin (OVA, a model antigen) and HCQ (HCQ-OVA-PLGA NPs). We tested whether HCQ could spatiotemporally control the cytosolic delivery of antigens, enhance antigen processing and presentation via the major histocompatibility complex (MHC)-I pathway, and thus generate a sufficient antitumor cytotoxic T-cell response. The results of in vitro experiments showed that HCQ-OVA-PLGA NPs significantly enhanced OVA escape from lysosomes into the cytoplasm within bone-marrow-derived dendritic cells. We also observed that HCQ-OVA-PLGA NPs enhanced the expression level of MHC-I on dendritic cells and improved cross-presentation of antigen, compared to free OVA or OVA-PLGA NPs. Results of in vivo experiments confirmed that HCQ initiated Th1-type responses and strong CD8(+) T-cell responses that induced tumor cell apoptosis. Moreover, vaccination of mice with HCQ-OVA-PLGA NPs effectively generated memory immune responses in vivo and prevented tumor progression. We conclude that co-encapsulation of HCQ with antigens in nanovaccines can boost antigen-specific antitumor immune responses, particularly through CD8(+) T-cells, serving as a simple and effective platform for the treatment of tumors and infectious diseases.

    *30136844*
     30136844

    Cascade Cytosol Delivery of Dual-Sensitive Micelle-Tailored Vaccine for Enhancing Cancer Immunotherapy.

    ACS Appl Mater Interfaces 2018; 10 (44): 37797-37811

    Enhancing cytosol delivery of exogenous antigens in antigen presenting cells can improve cross-presentation and CD8+ T cell-mediated immune response. The antigen cytosol delivery speed, which has great importance on the rate of MHC class I molecules (MHC I) antigen presentation pathway and cytotoxic T lymphocytes (CTLs) induction, has not been well studied. We hypothesized that micelle-tailored vaccine with multiple cascaded lysosomal responsive capabilities could accelerate lysosomal escape and enhance cancer immunotherapy. To test our hypothesis, we created a novel micellar cancer vaccine (ovalbumin-loaded pH/redox dual-sensitive micellar vaccine, OLM-D) by cleavable conjugation of an antigen with house-made amphiphilic poly(l-histidine)-poly(ethylene glycol) (PLH-PEG) in current study. OLM-D was supposed to achieve cascade cytosol delivery of ovalbumin through three steps in terms of (i) initial redox triggered ovalbumin release, (ii) promoted proton inflow and micelle disassembly, and (iii) speeded proton sponge effect and lysosome bulging/broke. Redox-sensitive antigen release and consequently accelerative OLM-D disassembly were confirmed by sodium dodecylsulphate polyacrylamide gel electrophoresis (SDS-PAGE), transmission electronic microscopy (TEM), particle sizes, zeta potentials, and in vitro Ova release evaluation. The speeded cytosol delivery of ovalbumin was visualized under a confocal laser scanning microscope (CLSM). The ability of OLM-D to increase the MHC I molecule combination rate and antigen cross-presentation efficiency was identified by antigen presentation assay and maturation assay in bone marrow-derived dendritic cells (BMDCs). In vivo, the capability of OLM-D to accumulate in draining lymph nodes (LNs) after injection was visualized by real-time near infrared fluorescence imaging (NIRF) and the distribution order in different LNs was first observed (a, d, c, b). Enhanced cancer immunity of OLM-D was confirmed by increased CD3+CD8+ T cell quantity, CD3+CD8+25D11.6+ T cells quantity, and IFN-gamma, IL-2 secretion post subcutaneous or intraperitoneal injection ( p < 0.05). Taken together, our results indicated that OLM-D provided a promising cascade cytosol delivery strategy, which held great potential to guide further design of nano-particulate cancer vaccines for efficient cancer immunotherapy.

    *30360105*
     30360105

    Folic Acid-Functionalized Hybrid Photonic Barcodes for Capture and Release of Circulating Tumor Cells.

    ACS Appl Mater Interfaces 2018; 10 (25): 21206-21212

    Recovery of circulating tumor cells (CTCs) from cancer patients by an efficient CTCs capture and release method can greatly increase their application in diagnostics and treatment of cancers. In this paper, we presented a folic acid (FA)-functionalized hybrid photonic barcode for capture and release of CTCs. The hybrid photonic barcodes were formed by two nano-ordered parts, poly(ethylene glycol) diacrylate (PEGDA) inverse opal structure for sustaining integrity and methacrylated gelatin (GelMA) gel filler for conjugating FA molecules to mediate cell capture. The nano-ordered structures of the hybrid photonic barcodes not only increased contact area, but also decreased steric hindrance among FA molecules. Thus, the topographic interaction between the barcodes and CTCs was greatly enhanced. In addition, GelMA gel was soft and extracellular matrix (ECM) alike, which was beneficial to decrease impairment to CTCs during the CTCs-barcode interaction as well as preserving their viability. Demonstrated by four CTCs types, Hela (epithelial tissue, folate receptor positive, FR+), A02 (bone marrow, FR+), Raji (lymphoid tissue, FR+), and A549 (epithelial tissue, folate receptor negative, FR-), FR+ CTCs could be captured efficiently with reliability and specificity. The captured cells could be controllably released with high viability just by quick trypsinization. The whole processes were simple and efficient. These features indicated that the FA-functionalized hybrid photonic barcodes were promising for full recovery of CTCs from cancer patients, which was important for diagnosis and treatment of cancer.

    *29882648*
     29882648

    A Targeted and pH-Responsive Bortezomib Nanomedicine in the Treatment of Metastatic Bone Tumors.

    ACS Appl Mater Interfaces 2018; 10 (48): 41003-41011

    Bortezomib is a boronate proteasome inhibitor widely used as an efficient anticancer drug; however, the clinical use of bortezomib is hampered by its adverse effects such as hematotoxicity and peripheral neuropathy, and low efficacy on solid tumors due to unfavorable pharmacokinetics and poor penetration in the solid tumors. In this study, we developed a tripeptide Arg-Gly-Asp (RGD)-targeted dendrimer conjugated with catechol and poly(ethylene glycol) groups for the targeted delivery of bortezomib to metastatic bone tumors. Bortezomib was loaded on the dendrimer via a boronate-catechol linkage with pH-responsive property, which plays an essential role in the control of bortezomib loading and release. The nontargeted bortezomib nanomedicine showed minimal cytotoxicity at pH 7.4, but significantly increased anticancer activity when cyclic RGD (cRGD) moieties were anchored on the dendrimer surface. The ligand cRGD enabled efficient internalization of the bortezomib complex by breast cancer cells such as MDA-MB-231 cells. The targeted nanomedicine efficiently depressed the progression of metastatic bone tumors and significantly inhibited the tumor-associated osteolysis in a model of bone tumors. This study provided an insight into the development of nanomedicine for metastatic bone tumors.

    *30403331*
     30403331

    Engineering of Micro- to Nanostructured 3D-Printed Drug-Releasing Titanium Implants for Enhanced Osseointegration and Localized Delivery of Anticancer Drugs.

    ACS Appl Mater Interfaces 2017; 9 (35): 29562-29570

    Primary and secondary bone cancers are major causes of pathological bone fractures which are usually treated through implant fixation and chemotherapy. However, both approaches face many limitations. On one hand, implants may suffer from poor osseointegration, and their rejection results in repeated surgery, patient's suffering, and extensive expenses. On the other hand, there are severe systemic adverse effects of toxic chemotherapeutics which are administrated systemically. In this paper, in order to address these two problems, we present a new type of localized drug-releasing titanium implants with enhanced implants' biointegration and drug release capabilities that could provide a high concentration of anticancer drugs locally to treat bone cancers. The implants are fabricated by 3D printing of Ti alloy followed by an anodization process featuring unique micro- (particles) and nanosurface (tubular arrays) topography. We successfully demonstrate their enhanced bone osseointegration and drug loading capabilities using two types of anticancer drugs, doxorubicin (DOX) and apoptosis-inducing ligand (Apo2L/TRAIL). In vitro study showed strong anticancer efficacy against cancer cells (MDA-MB-231-TXSA), confirming that these drug-releasing implants can be used for localized chemotherapy for treatment of primary and secondary bone cancers together with fracture support.

    *28820570*
     28820570

    Nano-Hydroxyapatite Stimulation of Gene Expression Requires Fgf Receptor, Phosphate Transporter, and Erk1/2 Signaling.

    ACS Appl Mater Interfaces 2017; 9 (45): 39185-39196

    Hydroxyapatite (HAp) is critical to health both as the main structural material of the skeleton and storage material of calcium and phosphate. Nanosized HAp (nHAp) is naturally produced by mineralizing cells during bone formation and remodeling and is the main constituent of the skeleton. As such, HAp is currently being investigated as a therapeutic biomaterial for orthopedic and dental purposes. Recent studies have suggested that extracellular nHAp can influence osteoblast lineage commitment and cell function through changes in gene expression; however, the mechanisms remain to be elucidated. Here, the cellular and molecular mechanism by which rod-shaped nHAp (10 x 100 nm) stimulates gene expression in preosteoblast bone marrow stromal cells was investigated. Electron microscopy detected a rapid and stable interaction of nHAp with the cell membrane, which correlated with a strong stimulation of the Erk1/2 signaling pathway. Results also identified the requirement of the Fgf receptor signaling and phosphate-transporters for nHAp regulated gene expression whereas a calcium-sensing receptor inhibitor had no effect. Collectively, the study uncovers novel signaling pathways and cellular events specifically stimulated by and required for the cellular response to free extracellular HAp. The results provide insight into the osteoblastic response to HAp relevant to functional mineralization and pathological calcification and could be used in the development of biomaterials for orthopedic purposes.

    *29045789*
     29045789

    Mussel-Inspired Thermoresponsive Polypeptide-Pluronic Copolymers for Versatile Surgical Adhesives and Hemostasis.

    ACS Appl Mater Interfaces 2017; 9 (20): 16756-16766

    Inspired by marine mussel adhesive proteins, polymers with catechol side groups have been extensively explored in industrial and academic research. Here, Pluronic L-31 alcoholate ions were used as the initiator to prepare a series of polypeptide-Pluronic-polypeptide triblock copolymers via ring-opening polymerization of l-DOPA-N-carboxyanhydride (DOPA-NCA), l-arginine-NCA (Arg-NCA), l-cysteine-NCA (Cys-NCA), and epsilon-N-acryloyl lysine-NCA (Ac-Lys-NCA). These copolymers demonstrated good biodegradability, biocompatibility, and thermoresponsive properties. Adhesion tests using porcine skin and bone as adherends demonstrated lap-shear adhesion strengths up to 106 kPa and tensile adhesion strengths up to 675 kPa. The antibleeding activity and tissue adhesive ability were evaluated using a rat model. These polypeptide-Pluronic copolymer glues showed superior hemostatic properties and superior effects in wound healing and osteotomy gaps. Complete healing of skin incisions and remodeling of osteotomy gaps were observed in all rats after 14 and 60 days, respectively. These copolymers have potential uses as tissue adhesives, antibleeding, and tissue engineering materials.

    *28472883*
     28472883

    Black Phosphorus Quantum Dot Induced Oxidative Stress and Toxicity in Living Cells and Mice.

    ACS Appl Mater Interfaces 2017; 9 (24): 20399-20409

    Black phosphorus (BP), as an emerging successor to layered two-dimensional materials, has attracted extensive interest in cancer therapy. Toxicological studies on BP are of great importance for potential biomedical applications, yet not systemically explored. Herein, toxicity and oxidative stress of BP quantum dots (BPQDs) at cellular, tissue, and whole-body levels are evaluated by performing the systemic in vivo and in vitro experiments. In vitro investigations show that BPQDs at high concentration (200 mug/mL) exhibit significant apoptotic effects on HeLa cells. In vivo investigations indicate that oxidative stress, including lipid peroxidation, reduction of catalase activity, DNA breaks, and bone marrow nucleated cells (BMNC) damage, can be induced by BPQDs transiently but recovered gradually to healthy levels. No apparent pathological damages are observed in all organs, especially in the spleen and kidneys, during the 30-day period. This work clearly shows that BPQDs can cause acute toxicities by oxidative stress responses, but the inflammatory reactions can be recovered gradually with time for up to 30 days. Thus, BPQDs do not give rise to long-term appreciable toxicological responses.

    *28553710*
     28553710

    Design and Construction of a Multi-Organ Microfluidic Chip Mimicking the in vivo Microenvironment of Lung Cancer Metastasis.

    ACS Appl Mater Interfaces 2016; 8 (39): 25840-25847

    Metastasis is a complex pathophysiological process. As the main cause of cancer mortality in humans it represents a serious challenge to both basic researchers and clinicians. Here we report the design and construction of a multi-organ microfluidic chip that closely mimics the in vivo microenvironment of lung cancer metastasis. This multi-organs-on-a-chip includes an upstream "lung" and three downstream "distant organs", with three polydimethylsiloxane (PDMS) layers and two thin PDMS microporous membranes bonded to form three parallel microchannels. Bronchial epithelial, lung cancer, microvascular endothelial, mononuclear, and fibroblast cells were grown separated by the biomembrane in upstream "lung", while astrocytes, osteocytes, and hepatocytes were grown in distant chambers, to mimic lung cancer cell metastasis to the brain, bone, and liver. After culture in this system, lung cancer cells formed a "tumor mass", showed epithelial-mesenchymal transition (with altered expression of E-cadherin, N-cadherin, Snail1, and Snail2) and invasive capacity. A549 cells co-cultured with astrocytes overexpressed CXCR4 protein, indicating damage of astrocytes after cancer cell metastasis to the brain. Osteocytes overexpressed RANKL protein indicates damage of osteocytes after cancer cell metastasis to the bone, and hepatocytes overexpressed AFP protein indicates damage to hepatocytes after cancer cell metastasis to the liver. Finally, in vivo imaging of cancer growth and metastasis in a nude mice model validated the performance of metastasis in the organs-on-chip system. This system provides a useful tool to mimic the in vivo microenvironment of cancer metastasis and to investigate cell-cell interactions during metastasis.

    *27606718*
     27606718

    3D Bioprinting a Cell-Laden Bone Matrix for Breast Cancer Metastasis Study.

    ACS Appl Mater Interfaces 2016; 8 (44): 30017-30026

    Metastasis is one of the deadliest consequences of breast cancer, with bone being one of the primary sites of occurrence. Insufficient 3D biomimetic models currently exist to replicate this process in vitro. In this study, we developed a biomimetic bone matrix using 3D bioprinting technology to investigate the interaction between breast cancer (BrCa) cells and bone stromal cells (fetal osteoblasts and human bone marrow mesenchymal stem cells (MSCs)). A tabletop stereolithography 3D bioprinter was employed to fabricate a series of bone matrices consisting of osteoblasts or MSCs encapsulated in gelatin methacrylate (GelMA) hydrogel with nanocrystalline hydroxyapatite (nHA). When BrCa cells were introduced into the stromal cell-laden bioprinted matrices, we found that the growth of BrCa cells was enhanced by the presence of osteoblasts or MSCs, whereas the proliferation of the osteoblasts or MSCs was inhibited by the BrCa cells. The BrCa cells co-cultured with MSCs or osteoblasts presented increased vascular endothelial growth factor (VEGF) secretion in comparison to that of monocultured BrCa cells. Additionally, the alkaline phosphatase activity of MSCs or osteoblasts was reduced after BrCa cell co-culture. These results demonstrate that the 3D bioprinted matrix, with BrCa cells and bone stromal cells, provides a suitable model with which to study the interactive effects of cells in the context of an artificial bone microenvironment and thus may serve as a valuable tool for the investigation of postmetastatic breast cancer progression in bone.

    *27766838*
     27766838

    Hybrid Collagenase Nanocapsules for Enhanced Nanocarrier Penetration in Tumoral Tissues.

    ACS Appl Mater Interfaces 2015; 7 (43): 24075-81

    Poor penetration of drug delivery nanocarriers within dense extracellular matrices constitutes one of the main liabilities of current nanomedicines. The conjugation of proteolytic enzymes on the nanoparticle surface constitutes an attractive alternative. However, the scarce resistance of these enzymes against the action of proteases or other aggressive agents present in the bloodstream strongly limits their application. Herein, a novel nanodevice able to transport proteolytic enzymes coated with an engineered pH-responsive polymeric is presented. This degradable coat protects the housed enzymes against proteolytic attack at the same time that it triggers their release under mild acidic conditions, usually present in many tumoral tissues. These enzyme nanocapsules have been attached on the surface of mesoporous silica nanoparticles, as nanocarrier model, showing a significatively higher penetration of the nanoparticles within 3D collagen matrices which housed human osteosarcoma cells (HOS). This strategy can improve the therapeutic efficacy of the current nanomedicines, allowing a more homogeneous and deeper distribution of the therapeutic nanosystems in cancerous tissues.

    *26461206*
     26461206

    Target specific delivery of anticancer drug in silk fibroin based 3D distribution model of bone-breast cancer cells.

    ACS Appl Mater Interfaces 2015; 7 (4): 2269-79

    To avoid the indiscriminating action of anticancer drugs, the cancer cell specific targeting of drug molecule becomes a preferred choice for the treatment. The successful screening of the drug molecules in 2D culture system requires further validation. The failure of target specific drug in animal model raises the issue of creating a platform in between the in vitro (2D) and in vivo animal testing. The metastatic breast cancer cells migrate and settle at different sites such as bone tissue. This work evaluates the in vitro 3D model of the breast cancer and bone cells to understand the cellular interactions in the presence of a targeted anticancer drug delivery system. The silk fibroin based cytocompatible 3D scaffold is used as in vitro 3D distribution model. Human breast adenocarcinoma and osteoblast like cells are cocultured to evaluate the efficiency of doxorubicin loaded folic acid conjugated silk fibroin nanoparticle as drug delivery system. Decreasing population of the cancer cells, which lower the levels of vascular endothelial growth factors, glucose consumption, and lactate production are observed in the drug treated coculture constructs. The drug treated constructs do not show any major impact on bone mineralization. The diminished expression of osteogenic markers such as osteocalcein and alkaline phosphatase are recorded. The result indicates that this type of silk based 3D in vitro coculture model may be utilized as a bridge between the traditional 2D and animal model system to evaluate the new drug molecule (s) or to reassay the known drug molecules or to develop target specific drug in cancer research.

    *25557227*
     25557227

    Top-down Fabrication of Spatially Controlled Mineral-Gradient Scaffolds for Interfacial Tissue Engineering.

    ACS Biomater Sci Eng 2019; 5 (6): 2988-2997

    Materials engineering can generally be divided into "bottom-up" and "top-down" approaches, where current state-of-the-art methodologies are bottom-up, relying on the advent of atomic-scale technologies. Applying bottom-up approaches to biological tissues is challenging due to the inherent complexity of these systems. Top-down methodologies provide many advantages over bottom-up approaches for biological tissues, given that some of the complexity is already built into the system. Here, we generate interfacial scaffolds by the spatially controlled removal of mineral content from trabecular bone using a chelating solution. We controlled the degree and location of the mineral interface, producing scaffolds that support cell growth, while maintaining the hierarchical structure of these tissues. We characterized the structural and compositional gradients across the scaffold using X-ray diffraction, microcomputed tomography (muCT), and Raman microscopy, revealing the presence of mineral gradients on the scale of 20 - 40 mum. Using these data, we generated a model showing the dependence of mineral removal as function of time in the chelating solution and initial bone morphology, specifically trabecular density. These scaffolds will be useful for interfacial tissue engineering, with application in the fields of orthopedics, developmental biology, and cancer metastasis to bone.

    *31211246*
     31211246

    Novel Triazole-Piperazine Hybrid Molecules Induce Apoptosis via Activation of the Mitochondrial Pathway and Exhibit Antitumor Efficacy in Osteosarcoma Xenograft Nude Mice Model.

    ACS Chem Biol 2017; 12 (3): 753-768

    Mitochondria impart a crucial role in the regulation of programmed cell death and reactive oxygen species (ROS) generation, besides serving as a primary energy source. Mitochondria appeared as an important target for the therapy of cancer due to their significant contribution to cell survival and death. Here, we report the design and synthesis of a novel series of triazole-piperazine hybrids as potent anticancer agents. MCS-5 emerged as an excellent anticancer agent which showed better anticancer activity than the standard drug doxorubicin in in vitro and in vivo studies. MCS-5 displayed an IC50 value of 1.92 muM and induced apoptosis in Cal72 (human osteosarcoma cell line) cells by targeting the mitochondrial pathway. This compound arrested the G2/M phase of the cell cycle and induced ROS production and mitochondrial potential collapse in Cal72 cells. MCS-5 displayed excellent anticancer activity in the Cal72 xenograft nude mice model, where it significantly reduced tumor progression, leading to enhanced life span in treated animals compared to control and doxorubicin treated animals without exerting noticeable toxicity. In addition, a 2DG optical probe guided study clearly evoked that MCS-5 remarkably reduced tumor metastasis in the Cal72 xenograft nude mice model. These results indicate that MCS-5 appeared as a novel chemical entity which is endowed with excellent in vitro as well as in vivo anticancer activity and may contribute significantly to the management of cancer in the future.

    *28084722*
     28084722

    Bone-Targeted Nanoplatform Combining Zoledronate and Photothermal Therapy To Treat Breast Cancer Bone Metastasis.

    ACS Nano 2019; 13 (7): 7556-7567

    Bone metastasis, a clinical complication of patients with advanced breast cancer, seriously reduces the quality of life. To avoid destruction of the bone matrix, current treatments focus on inhibiting the cancer cell growth and the osteoclast activity through combination therapy. Therefore, it could be beneficial to develop a bone-targeted drug delivery system to treat bone metastasis. Here, a bone-targeted nanoplatform was developed using gold nanorods enclosed inside mesoporous silica nanoparticles (Au@MSNs) which were then conjugated with zoledronic acid (ZOL). The nanoparticles (Au@MSNs-ZOL) not only showed bone-targeting ability in vivo but also inhibited the formation of osteoclast-like cells and promoted osteoblast differentiation in vitro. The combination of Au@MSNs-ZOL and photothermal therapy (PTT), triggered by near-infrared irradiation, inhibited tumor growth both in vitro and in vivo and relieved pain and bone resorption in vivo by inducing apoptosis in cancer cells and improving the bone microenvironment. This single nanoplatform combines ZOL and PTT to provide an exciting strategy for treating breast cancer bone metastasis.

    *31259530*
     31259530

    In Situ Nanoadjuvant-Assembled Tumor Vaccine for Preventing Long-Term Recurrence.

    ACS Nano 2019; 13 (7): 7442-7462

    Although immune checkpoint inhibitors have emerged as a breakthrough in cancer therapy, a monotherapy approach is not sufficient. Here, we report an immune checkpoint inhibitor-modified nanoparticle for an in situ-assembled tumor vaccine that can activate immune systems in the tumor microenvironment and prevent the long-term recurrence of tumors. Adjuvant-loaded nanoparticles were prepared by entrapping imiquimod (IQ) in photoresponsive polydopamine nanoparticles (IQ/PNs). The surfaces of IQ/PNs were then modified with anti-PDL1 antibody (PDL1Ab-IQ/PNs) for in situ assembly with inactivated tumor cells and immune checkpoint blocking of PDL1 (programmed cell death 1 ligand 1). The presence of anti-PDL1 antibodies on IQ/PNs increased the binding of nanoparticles to CT26 cancer cells overexpressing PDL1. Subsequent near-infrared (NIR) irradiation induced a greater photothermal anticancer effect against cells treated with PDL1Ab-IQ/PNs than cells treated with plain PNs or unmodified IQ/PNs. To mimic the tumor microenvironment, we cocultured bone marrow-derived dendritic cells with CT26 cells treated with various nanoparticle formulations and NIR irradiated. This coculture study revealed that NIR-inactivated, PDL1Ab-IQ/PN-bound CT26 cells induced maturation of dendritic cells to the greatest extent. Following a single intravenous administration of different nanoparticle formulations in CT26 tumor-bearing mice, PDL1Ab-IQ/PNs showed greater tumor tissue accumulation than unmodified nanoparticles. Subsequent NIR irradiation of mice treated with PDL1Ab-IQ/PNs resulted in tumor ablation. In addition to primary tumor ablation, PDL1Ab-IQ/PNs completely prevented the growth of a secondarily challenged CT26 tumor at a distant site, producing 100% survival for up to 150 days. A long-term protection study revealed that treatment with PDL1Ab-IQ/PNs followed by NIR irradiation inhibited the growth of distant, secondarily challenged CT26 tumors 150 days after the first tumor inoculation. Moreover, increased infiltration of T cells was observed in tumor tissues treated with PDL1Ab-IQ/PNs and NIR-irradiated, and T cells isolated from splenocytes of mice in which tumor recurrence was prevented showed active killing of CT26 cells. These results suggest that PDL1Ab-IQ/PNs in conjunction with NIR irradiation induce a potent, in situ-assembled, all-in-one tumor vaccine with adjuvant-containing nanoparticle-bound, inactivated tumor cells. Such in situ nanoadjuvant-assembled tumor vaccines can be further developed for long-term prevention of tumor recurrence without the need for chemotherapy.

    *31180642*
     31180642

    Improved Efficacy and Reduced Toxicity Using a Custom-Designed Irinotecan-Delivering Silicasome for Orthotopic Colon Cancer.

    ACS Nano 2019; 13 (1): 38-53

    Irinotecan is a key chemotherapeutic agent for the treatment of colorectal (CRC) and pancreatic (PDAC) cancer. Because of a high incidence of bone marrow and gastrointestinal (GI) toxicity, Onivyde (a liposome) was introduced to provide encapsulated irinotecan (Ir) delivery in PDAC patients. While there is an ongoing clinical trial (NCT02551991) to investigate the use of Onivyde as a first-line option to replace irinotecan in FOLFIRINOX, the liposomal formulation is currently prescribed as a second-line treatment option (in combination with 5-fluorouracil and leucovorin) for patients with metastatic PDAC who failed gemcitabine therapy. However, the toxicity of Onivyde remains a concern that needs to be addressed for use in CRC as well. Our goal was to custom design a mesoporous silica nanoparticle (MSNP) carrier for encapsulated irinotecan delivery in a robust CRC model. This was achieved by developing an orthotopic tumor chunk model in immunocompetent mice. With a view to increase the production volume and to expand the disease applications, the carrier design was improved by using an ethanol exchange method for coating of a supported lipid bilayer (LB) that entraps a protonating agent. The encapsulated protonating agent was subsequently used for remote loading of irinotecan. The excellent irinotecan loading capacity and stability of the LB-coated MSNP carrier, also known as a "silicasome", previously showed improved efficacy and reduced toxicity when compared to an in-house liposomal carrier in a PDAC model. Intravenous injection of the silicasomes in a well-developed orthotopic colon cancer model in mice demonstrated improved pharmacokinetics and tumor drug content over free drug and Onivyde. Moreover, improved drug delivery was accompanied by substantially improved efficacy, increased survival, and reduced bone marrow and GI toxicity compared to the free drug and Onivyde. We also confirmed that the custom-designed irinotecan silicasomes outperform Onivyde in an orthotopic PDAC model. In summary, the Ir-silicasome appears to be promising as a treatment option for CRC in humans based on improved efficacy and the carrier's favorable safety profile.

    *30525443*
     30525443

    Hierarchically Porous Hydroxyapatite Hybrid Scaffold Incorporated with Reduced Graphene Oxide for Rapid Bone Ingrowth and Repair.

    ACS Nano 2019; ():

    Hydroxyapatite (HA), the traditional bone tissue replacement material was widely used in the clinical treatment of bone defects because of its excellent biocompatibility. However, the processing difficulty and poor osteoinductive ability greatly limit the application of HA. Although many strategies have been reported to improve the machinability and osteointegration ability, the performance including mechanical strength, porosity, cell adhesion, etc. of material still can not meet the requirements. In this work, a soft template method was developed and a porous scaffold with hierarchical pore structure, nano surface morphology, suitable porosity and pore size, and good biomechanical strength was successfully prepared. The hierarchical pore structure is beneficial for cell adhesion, fluid transfer, and cell ingrowth. Moreover, the loaded reduced graphene oxide (rGO) can improve the adhesion and promote the proliferation and spontaneous osteogenic differentiation bone marrow mesenchymal stem cells. The scaffold is then crushed, degraded and wrapped by the newly formed bone and the newly formed bone gradually replaces the scaffold. The degradation rate of the scaffold well matches the rate of the new bone formation. The hierarchical porous HA/rGO composite scaffolds can greatly accelerate the bone ingrowth in the scaffold and bone repair in critical bone defects, thus providing a clinical potential candidate for large segment bone tissue engineering.

    *31381856*
     31381856

    Correction to Targeting Osteocytes to Attenuate Early Breast Cancer Bone Metastasis by Theranostic Upconversion Nanoparticles with Responsive Plumbagin Release.

    ACS Nano 2019; 13 (4): 4857

    *30938978*
     30938978

    Soft Conducting Polymer Hydrogels Cross-Linked and Doped by Tannic Acid for Spinal Cord Injury Repair.

    ACS Nano 2018; 12 (11): 10957-10967

    Mimicking soft tissue mechanical properties and the high conductivity required for electrical transmission in the native spinal cord is critical in nerve tissue regeneration scaffold designs. However, fabricating scaffolds of high conductivity, tissue-like mechanical properties, and excellent biocompatibility simultaneously remains a great challenge. Here, a soft, highly conductive, biocompatible conducting polymer hydrogel (CPH) based on a plant-derived polyphenol, tannic acid (TA), cross-linking and doping conducting polypyrrole (PPy) chains is developed to explore its therapeutic efficacy after a spinal cord injury (SCI). The developed hydrogels exhibit an excellent electronic conductivity (0.05-0.18 S/cm) and appropriate mechanical properties (0.3-2.2 kPa), which can be achieved by controlling TA concentration. In vitro, a CPH with a higher conductivity accelerated the differentiation of neural stem cells (NSCs) into neurons while suppressing the development of astrocytes. In vivo, with relatively high conductivity, the CPH can activate endogenous NSC neurogenesis in the lesion area, resulting in significant recovery of locomotor function. Overall, our findings evidence that the CPHs without being combined with any other therapeutic agents have stimulated tissue repair following an SCI and thus have important implications for future biomaterial designs for SCI therapy.

    *30285411*
     30285411

    Targeting Osteocytes to Attenuate Early Breast Cancer Bone Metastasis by Theranostic Upconversion Nanoparticles with Responsive Plumbagin Release.

    ACS Nano 2017; 11 (7): 7259-7273

    The early detection and thus treatment of breast cancer bone metastasis remain a big challenge clinically. As the most abundant cells within bone tissue, osteocytes have been found to manipulate the activity of early cancer bone metastasis by its crosstalk with cancer cells and osteoclasts. However, conventional bone-targeting nanomedicine has limited bone-lesion specificity and ignores the vital role of osteocytes during breast cancer bone metastasis. Also, it lacks detailed insight into the therapeutic mechanisms, which hinders the following translational practice. Previously, we have shown that a combination of zoledronic acid (ZA) and plumbagin (PL) synergistically alleviates cancer-induced bone destruction. Herein, we further develop a pH-responsive bone-targeting drug delivery system, i.e., the ZA-anchored bimodal mesoporous slica covered gadolinium(III) upconversion nanoparticles loaded with PL, to detect and treat bone metastasis sensitively and specifically at an early stage. This multifunctional nanosystem can target osteocytes to release PL as controlled by pH, decreasing osteocytic RANKL expression synergistically through the structural simulation of adenosine phosphate, which competitively inhibits the phosphorylation of osteocytic protein kinase-a, cAMP-response element binding protein, extracellular regulated protein kinase, and c-Jun N-terminal kinase. More importantly, by establishing a breast cancer bone metastasis mice model via intracardiac injection, we show that tumoriogenesis and osteoclastogenesis can both be attenuated significantly. We thereby realize the effective theranostics of tiny bone metastasis in breast cancer bone metastasis. Our work highlights the significance of theranostic nanomedicine and osteocyte-targeting therapy in the treatment of early bone metastasis, which could be applied in achieving efficient theranostic effects for other bone diseases.

    *28692257*
     28692257

    Differential Depth Sensing Reduces Cancer Cell Proliferation via Rho-Rac-Regulated Invadopodia.

    ACS Nano 2017; 11 (7): 7336-7348

    Bone, which is composed of a porous matrix, is one of the principal secondary locations for cancer. However, little is known about the effect of this porous microenvironment in regulating cancer cell proliferation. Here, we examine how the depth of the pores can transduce a mechanical signal and reduce the proliferation of noncancer breast epithelial cells (MCF-10A) and malignant breast cancer cells (MDA-MB-231 and MCF-7) using micrometer-scale topographic features. Interestingly, cells extend actin-rich protrusions, such as invadopodia, to sense the depth of the matrix pore and activate actomyosin contractility to decrease MCF-10A proliferation. However, in MDA-MB-231, depth sensing inactivates Rho-Rac-regulated actomyosin contractility and phospho-ERK signaling. Inhibiting contractility on this porous matrix using blebbistatin further reduces MDA-MB-231 proliferation. Our findings support the notion of mechanically induced dormancy through depth sensing, where invadopodia-mediated depth sensing can inhibit the proliferation of noncancer and malignant breast cancer cells through differential regulation of actomyosin contractility.

    *28654281*
     28654281

    Mesoporous Silica Nanoparticle-Supported Lipid Bilayers (Protocells) for Active Targeting and Delivery to Individual Leukemia Cells.

    ACS Nano 2016; 10 (9): 8325-45

    Many nanocarrier cancer therapeutics currently under development, as well as those used in the clinical setting, rely upon the enhanced permeability and retention (EPR) effect to passively accumulate in the tumor microenvironment and kill cancer cells. In leukemia, where leukemogenic stem cells and their progeny circulate within the peripheral blood or bone marrow, the EPR effect may not be operative. Thus, for leukemia therapeutics, it is essential to target and bind individual circulating cells. Here, we investigate mesoporous silica nanoparticle (MSN)-supported lipid bilayers (protocells), an emerging class of nanocarriers, and establish the synthesis conditions and lipid bilayer composition needed to achieve highly monodisperse protocells that remain stable in complex media as assessed in vitro by dynamic light scattering and cryo-electron microscopy and ex ovo by direct imaging within a chick chorioallantoic membrane (CAM) model. We show that for vesicle fusion conditions where the lipid surface area exceeds the external surface area of the MSN and the ionic strength exceeds 20 mM, we form monosized protocells (polydispersity index <0.1) on MSN cores with varying size, shape, and pore size, whose conformal zwitterionic supported lipid bilayer confers excellent stability as judged by circulation in the CAM and minimal opsonization in vivo in a mouse model. Having established protocell formulations that are stable colloids, we further modified them with anti-EGFR antibodies as targeting agents and reverified their monodispersity and stability. Then, using intravital imaging in the CAM, we directly observed in real time the progression of selective targeting of individual leukemia cells (using the established REH leukemia cell line transduced with EGFR) and delivery of a model cargo. Overall, we have established the effectiveness of the protocell platform for individual cell targeting and delivery needed for leukemia and other disseminated disease.

    *27419663*
     27419663

    Identification of Dormancy-Associated MicroRNAs for the Design of Osteosarcoma-Targeted Dendritic Polyglycerol Nanopolyplexes.

    ACS Nano 2016; 10 (2): 2028-45

    The presence of dormant, microscopic cancerous lesions poses a major obstacle for the treatment of metastatic and recurrent cancers. While it is well-established that microRNAs play a major role in tumorigenesis, their involvement in tumor dormancy has yet to be fully elucidated. We established and comprehensively characterized pairs of dormant and fast-growing human osteosarcoma models. Using these pairs of mouse tumor models, we identified three novel regulators of osteosarcoma dormancy: miR-34a, miR-93, and miR-200c. This report shows that loss of these microRNAs occurs during the switch from dormant avascular into fast-growing angiogenic phenotype. We validated their downregulation in patients' tumor samples compared to normal bone, making them attractive candidates for osteosarcoma therapy. Successful delivery of miRNAs is a challenge; hence, we synthesized an aminated polyglycerol dendritic nanocarrier, dPG-NH2, and designed dPG-NH2-microRNA polyplexes to target cancer. Reconstitution of these microRNAs using dPG-NH2 polyplexes into Saos-2 and MG-63 cells, which generate fast-growing osteosarcomas, reduced the levels of their target genes, MET proto-oncogene, hypoxia-inducible factor 1alpha, and moesin, critical to cancer angiogenesis and cancer cells' migration. We further demonstrate that these microRNAs attenuate the angiogenic capabilities of fast-growing osteosarcomas in vitro and in vivo. Treatment with each of these microRNAs using dPG-NH2 significantly prolonged the dormancy period of fast-growing osteosarcomas in vivo. Taken together, these findings suggest that nanocarrier-mediated delivery of microRNAs involved in osteosarcoma tumor-host interactions can induce a dormant-like state.

    *26815014*
     26815014

    Systemic Gene Silencing in Primary T Lymphocytes Using Targeted Lipid Nanoparticles.

    ACS Nano 2015; 9 (7): 6706-16

    Modulating T cell function by down-regulating specific genes using RNA interference (RNAi) holds tremendous potential in advancing targeted therapies in many immune-related disorders including cancer, inflammation, autoimmunity, and viral infections. Hematopoietic cells, in general, and primary T lymphocytes, in particular, are notoriously hard to transfect with small interfering RNAs (siRNAs). Herein, we describe a novel strategy to specifically deliver siRNAs to murine CD4(+) T cells using targeted lipid nanoparticles (tLNPs). To increase the efficacy of siRNA delivery, these tLNPs have been formulated with several lipids designed to improve the stability and efficacy of siRNA delivery. The tLNPs were surface-functionalized with anti-CD4 monoclonal antibody to permit delivery of the siRNAs specifically to CD4(+) T lymphocytes. Ex vivo, tLNPs demonstrated specificity by targeting only primary CD4(+) T lymphocytes and no other cell types. Systemic intravenous administration of these particles led to efficient binding and uptake into CD4(+) T lymphocytes in several anatomical sites including the spleen, inguinal lymph nodes, blood, and the bone marrow. Silencing by tLNPs occurs in a subset of circulating and resting CD4(+) T lymphocytes. Interestingly, we show that tLNP internalization and not endosome escape is a fundamental event that takes place as early as 1 h after systemic administration and determines tLNPs' efficacy. Taken together, these results suggest that tLNPs may open new avenues for the manipulation of T cell functionality and may help to establish RNAi as a therapeutic modality in leukocyte-associated diseases.

    *26042619*
     26042619

    Suppression of human bone morphogenetic protein signaling by carboxylated single-walled carbon nanotubes.

    ACS Nano 2009; 3 (5): 1139-44

    Effects of carbon nanotubes (CNTs) on living systems such as cells are crucial for the safe development of biosensors, drug carriers, or tumor imaging agents. We report here that SWCNT-COOH inhibited cell proliferation via a nonapoptotic mechanism, which is different from effects caused by pristine CNTs. On the basis of SWCNT-COOH's perturbations on cells, expression of genes and protein, and protein phosphorylations, we conclude that SWCNT-COOH suppresses Smad-dependent bone morphogenetic protein (BMP) signaling pathway and down-regulates Id proteins. These molecular events cause cell cycle arrest at G(1)/S transition and inhibit cell proliferation. The specific suppression of BMP signaling and Id proteins by SWCNT-COOH demonstrates nonapoptotic effects of functionalized CNTs on human cells. This finding may have potential therapeutic applications to treat human diseases related to Id proteins or BMP signaling such as breast cancer and bone diseases.

    *19402638*
     19402638

    Chemodectoma of the orbit: report of a case.

    Acta Acad Med Wuhan 1982; 2 (1): 60-2

    *6302613*
     6302613

    Immunopathological studies of parabiosis in adult mice.

    Acta Allergol 1971; 26 (3): 213-42

    *4935082*
     4935082

    GRAVI COMPLICANZE CARDIO-CIRCOLATORIE IN CORSO DI ANESTESIA IN PAZIENTI CON SOFFERENZA MIDOLLARE.

    Acta Anaesthesiol 1963; 14 (): 179-95

    *14073420*
     14073420

    Anesthetic management in patient with neurofibromatosis: a case report and literature review.

    Acta Anaesthesiol Belg 2016; 67 (1): 48-52

    OBJECTIVE: We report the anesthesia management of a 15 years-old patient with neurofibromatosis type 1, scheduled for resection of a tumor located in the occipitocervical region. In addition, we review the pertaining literature, emphasizing the anesthetic implications of neurofibromatosis manipulation. CASE : A 15-years-old female patient, with Neurofibromatosis type 1 was diagnosed with a large tumor in occipitocervical region suggestive of a plexiform neurofibroma. She presented with cervical instability, difficulty in positioning due to the large cervical mass and other predictors of airway difficulty. Awake intubation was carried out with fiberoptic bronchoscopy after anesthetic block of the airway and remifentanil infusion at low doses (0.05 mcg/kg/min). An inadvertent lesion in the left vertebral artery during the surgical procedure was well controlled by fluid replacement, red blood cell and plasma infusion and norepinephrine. The histopathological report revealed a malignant peripheral nerve sheath tumor originated from a neurofibroma in the craniocervical region. Two months after surgery the patient presented a right crural deficit due to tumor recurrence. CONCLUSION: This case report demonstrates the importance of knowing the anesthetic peculiarities of patients affected by Neurofibromatosis type 1 submitted to surgery. Neurofibromatosis is a rare pathology in surgical centers, which requires special attention from the anesthesiologist.

    *27363215*
     27363215

    The use of potent inhalational agents for the ex- utero intrapartum treatment (exit) procedures: what concentrations?

    Acta Anaesthesiol Belg 2007; 58 (2): 97-9 toshiyukiokutomi@hotmail.com

    The anesthetic management of a parturient undergoing ex-utero intrapartum treatment (EXIT) procedures for airway control of a newborn with a potentially life-threatening difficult airway is complex and often challenging. We herein report on the successful anesthetic management of the EXIT procedure in a 30-year-old primigravida carrying a fetus with large cervical lymphangioma. General anesthesia was maintained with sevoflurane 2%, combined with continuous infusion of nitroglycerine (TNG). Although the use of high concentrations of potent inhalational agents (to keep the uterus fully relaxed) is currently recommended we believe that the use of low concentrations of potent inhalational anesthetics with continuous infusion of TNG may be a safer anesthetic strategy for these operations.

    *17710896*
     17710896

    Intranasal fentanyl in the treatment of acute pain--a systematic review.

    Acta Anaesthesiol Scand 2012; 56 (4): 407-19 morten_sejer@yahoo.dk

    Due to its non-invasive mode of administration, intranasal (IN) application of drugs may be a valuable alternative to non-invasive pain management. With characteristics that appear to be ideal for IN application, IN fentanyl may have a place in the out-of-hospital treatment and the paediatric population. The objective of this systematic review was to evaluate the current evidence of IN fentanyl in the treatment of acute pain. Reports of randomized controlled trials (RCTs) of IN fentanyl in treatment of pain were systematically sought using the PubMed database, Embase, Google scholar, Cochrane database, and Cumulative Index to Nursing and Allied Health Literature. Reports were considered for inclusion if they were double-blinded randomized controlled trials (RCTs) of IN fentanyl in the treatment of acute pain. Thirty-two RCTs were identified, and 16 were included in the final analysis. No significant analgesic differences between IN fentanyl and intravenous (IV) fentanyl were demonstrated in treatment of acute and post-operative pain. Significant analgesic effect of IN fentanyl was demonstrated in the treatment of breakthrough pain in cancer patients. In the paediatric population, results demonstrated some analgesic effect of IN fentanyl following myringotomy, no analgesic effect following voiding cystourethrography, and finally, no significant analgesic difference after long bone fractures, in burns patients, and in post-operative pain relief when compared to IV morphine, oral morphine, or IV fentanyl, respectively. Significant analgesic effect of IN fentanyl was demonstrated in the treatment of breakthrough pain in cancer patients. However, the significant deficiencies in trials investigating acute and post-operative pain, and the paediatric population makes firm recommendations impossible.

    *22260169*
     22260169

    Procedure-related pain among adult patients with hematologic malignancies.

    Acta Anaesthesiol Scand 2009; 53 (3): 354-63 ylva.liden@karolinska.se

    BACKGROUND: Cancer patients undergo numerous invasive diagnostic procedures. However, there are only sparse data on the characteristics and determinants for procedure-related pain among adult cancer patients. METHODS: In this prospective study, we evaluated the characteristics and determinants of procedure-related pain in 235 consecutive hematologic patients (M/F:126/109; median age 62 years, range 20-89 years) undergoing a bone marrow aspiration/biopsy (BMA) under local anesthesia. Questionnaires were used to assess patients before-, 10 min and 1-7 days post BMA. Using logistic regression models, we calculated odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: 165/235 (70%) patients reported pain during BMA; 92 (56%), 53 (32%) and 5 (3%) of these indicated moderate [visual analogue scale (VAS)>or=30 mm], severe (VAS>54 mm) and worst possible pain (VAS=100 mm), respectively. On multivariate analyses, pre-existing pain (OR=2.60 95% CI 1.26-5.36), anxiety about the diagnostic outcome of BMA (OR=3.17 95% CI 1.54-6.52), anxiety about needle-insertion (OR=2.49 95% CI 1.22-5.10) and low employment status (sick-leave/unemployed) (OR=3.14 95% CI 1.31-7.55) were independently associated with an increased risk of pain during BMA. At follow-up 10 min after BMA, 40/235 (17%) patients reported pain. At 1, 3, 6 and 7 days post BMA, pain was present in 137 (64%), 90 (42%), 43 (20%) and 25 (12%) patients, respectively. CONCLUSIONS: We found that 3/4 of hematologic patients who underwent BMA reported procedural pain; one third of these patients indicated severe pain. Pre-existing pain, anxiety about the diagnostic outcome of BMA or needle-insertion, and low employment status were independent risk factors.

    *19243321*
     19243321

    What to do if the endotracheal tube will not pass through the nasal passage during fiberoptic nasotracheal intubation.

    Acta Anaesthesiol Scand 2007; 51 (6): 777-8

    *17567274*
     17567274

    Self-limiting epidural haematoma imitating an incorrectly placed epidural catheter.

    Acta Anaesthesiol Scand 2007; 51 (4): 516

    *17378796*
     17378796

    Intrathecal betamethasone pain relief in cancer patients with vertebral metastasis: a pilot study.

    Acta Anaesthesiol Scand 2007; 51 (4): 490-4 takefumi@wd5.so-net.ne.jp

    BACKGROUND: We have reported previously the usefulness of intrathecal betamethasone for pain relief in cancer patients who suffer from intractable pain caused by vertebral metastasis. The mechanism by which betamethasone relieves pain may be related to alterations in cerebrospinal fluid (CSF) concentrations of pro-inflammatory cytokines and prostanoids. METHODS: Thirteen cancer patients with intractable pain caused by vertebral metastasis received 2-3 mg betamethasone in the lumbar subarachnoid space. CSF concentrations of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, IL-8 and prostaglandin E(2) (PGE(2)) were measured with an enzyme-linked immunosorbent assay (ELISA) and a chemiluminescence enzyme immunoassay. Pain was measured using a numerical pain score (range, 0-10; 0, no pain; 10, worst pain imaginable). RESULTS: Intrathecal betamethasone was associated with a significant decrease in the pain score in six patients. In these cases, the pain score decreased from 6.7 +/- 0.5 (mean +/- standard error of the mean) to 3.3 +/- 0.3 (P < 0.05), and the CSF concentrations of IL-8 and PGE(2) decreased significantly compared with pre-treatment levels (IL-8, 183.3 +/- 21.2 to 116.5 +/- 10.6 pg/ml; PGE(2), 43.8 +/- 10.3 to 14.7 +/- 3.0 pg/ml). There were no significant changes in the CSF concentrations of cytokines and PGE(2) in the remaining seven patients. CONCLUSION: Pain relief with intrathecal betamethasone is related to decreases in the CSF concentration of IL-8 and PGE(2).

    *17378789*
     17378789

    Jaw thrust can deteriorate upper airway patency.

    Acta Anaesthesiol Scand 2005; 49 (4): 583-5 bvonungern@uhbs.ch

    Upper airway obstruction is a frequent problem in spontaneously breathing children undergoing anesthesia or sedation procedures. Failure to maintain a patent airway can rapidly result in severe hypoxemia, bradycardia, or asystole, as the oxygen demand of children is high and oxygen reserve is low. We present two children with cervical masses in whom upper airway obstruction exaggerated while the jaw thrust maneuver was applied during induction of anesthesia. This deterioration in airway patency was probably caused by medial displacement of the lateral tumorous tissues which narrowed the pharyngeal airway.

    *15777312*
     15777312

    The use of gabapentin in a 12-year-old boy with cancer pain.

    Acta Anaesthesiol Scand 2004; 48 (5): 663-4

    *15101869*
     15101869

    Paraplegia in association with spinal/epidural anaesthesia caused by unrecognised vertebral metastasis.

    Acta Anaesthesiol Scand 2003; 47 (6): 781; author reply 782

    *12803603*
     12803603

    Paraplegia associated with combined spinal-epidural anaesthesia caused by preoperatively unrecognized spinal vertebral metastasis.

    Acta Anaesthesiol Scand 2002; 46 (9): 1165-7 alper@dicle.edu.tr

    We describe a case of paraplegia following combined spinal-epidural anaesthesia. It was postoperatively determined that a tumour of the vertebrae which was compressing the spinal cord was responsible for this complication. We suggest that the pre-existing pathology of the spine must be borne in mind as a differential diagnosis of acute postoperative paraplegia.

    *12366516*
     12366516

    Fatigue. Measures and relation to pain.

    Acta Anaesthesiol Scand 1999; 43 (9): 939-47

    Fatigue describes reduced capacity to sustain force or power output, reduced capacity to perform multiple tasks over time and simply a subjective experience of feeling exhausted, tired, weak or having lack of energy. Pain and fatigue have several components in common, such as being subjective, prevalent in most patients with cancer and caused by multiple factors of both a physical and psychological nature. In order to explore the relationship between fatigue and pain, data from five studies were used: two random samples from the Norwegian population (n=2323 and n=1965), Hodgkin's disease survivors (n=459), palliative care patients (n=434) and patients with bone metastases (n=94). All patients had completed one or more of the following instruments: EORTC QLQ-C30, SF-36 and/or Fatigue Questionnaire. The level of fatigue was much higher in the two palliative care populations (54.4 and 63.2) as compared to the normal population samples (25.0). Patients with bone metastases had significantly more pain (72.0) than the patients in the palliative care trial (47.4) and norms (20.5). In the two palliative care and bone metastases populations fatigue was almost unchanged over time, while pain was reduced. In the palliative care population a high level of fatigue (80.3) and pain (57.8) was reported 0-1 month before death. The relationship between pain, fatigue and the health-related quality of life domains should be explored in more detail, especially in follow-up studies in order to assess possible changes over time. In addition, the validity of the existing instruments measuring fatigue should be investigated for use in patients with advanced disease and short life expectancy.

    *10522741*
     10522741

    Improved perioperative care in major orthopaedic surgery: preoperative, intraoperative and postoperative contributions.

    Acta Anaesthesiol Scand Suppl 1997; 111 (): 202-5

    *9421013*
     9421013

    Fatal hyperkalemia during rapid and massive blood transfusion in a child undergoing hip surgery--a case report.

    Acta Anaesthesiol Sin 1999; 37 (3): 163-6

    We report a girl who developed severe and fatal hyperkalemia following rapid and massive blood transfusion during surgery. She was 7-year-old, 20-kg in weight, and received wide resection of the femoral bone with custom prosthesis implant because of malignant femoral osteosarcoma. During the procedure, bleeding was active and profuse and amounted to about 3,000 mL in 4 h, eventuating in shock. Despite rapid transfusion with 15 units of packed red blood cells (RBC) still she remained hypotensive and hypovolemic. When we switched to give her whole blood, actually 100 mL having been given, widening of QRS complex followed immediately by cardiac arrest developed. Cardiopulmonary resuscitation although started at once was unsuccessful. At this juncture, arterial blood gas analysis showed acidosis and severe hyperkalemia (10.3 mmol/L), possibly resulting from transfusion of blood of older storage. The case reminded us once again the importance and necessity of the use of potassium-low blood component (fresh, saline-washed RBCs) in case of massive and rapid blood transfusion especially in pediatric patients with hypovolemia and low cardiac output.

    *10609352*
     10609352

    Postoperative pulmonary edema after lower thoracic spinal tumor surgery--a case report.

    Acta Anaesthesiol Taiwan 2007; 45 (2): 127-30

    Cardiovascular instability is a common manifestation of spinal cord injury, especially if the upper thoracic or cervical spine is involved. Here we report a case of lower thoracic spinal tumor who developed acute pulmonary edema postoperatively at post-anesthesia room following surgery. This might be caused by injudicious fluid administration after trying to correct intraoperative hypotension due to neurogenic shock. Therefore, meticulous calculation in fluid resuscitation together with vasopressors or inotropics support is important in dealing with neurogenic shock. Comprehensive monitoring of hemodynamic parameters, such as with central venous catheter or pulmonary catheter in this sort of surgery should be established for drastic fluid management.

    *17694690*
     17694690

    Effects of conjugated estrogens with or without medroxyprogesterone acetate on mammary carcinogenesis, uterine adenomyosis and femur in mice.

    Acta Anat (Basel) 1997; 159 (4): 204-8

    Although combined hormone replacement therapy using estrogens and progestins reduces the risk of endometrial cancer in postmenopausal women, it has been unclear whether the combined therapy is associated with an alteration of the risk of mammary cancer. Virgin mice of the SHN strain, which has a high potential for the development of mammary cancer and uterine adenomyosis, were given diets containing conjugated estrogens with or without medroxyprogesterone acetate for 230 days. The combined administration of conjugated estrogens and medroxyprogesterone acetate completely suppressed the development of uterine adenomyosis with a decrease in uterine thymidylate synthetase activity, significantly enhanced the bone mineral density in the femur and slightly shortened the latent period of mammary carcinogenesis.

    *9605604*
     9605604

    Bone remodelling in the presence of chondrosarcoma: histomorphometry.

    Acta Anat (Basel) 1993; 148 (1): 1-7

    Accurate knowledge of tissue changes near bone tumors can contribute to a better understanding of tumor behavior. We have used tumor ultrastructure and quantitative bone histomorphometry to evaluate local bone/tumor features associated with a low grade chondrosarcoma in a 39-year-old male. Three noninvolved sites and two sites near the tumor in the proximal femur were studied with bone morphometry. Bone near the tumor showed increased percent osteoid surface, percent osteoid volume and fraction of osteoid surface lined by osteoblasts compared to distant noninvolved sites. Both the number of osteoblasts and mean individual osteoblast size were significantly increased compared to noninvolved sites. Osteoclast number and percent osteoclast surface were also increased near the tumor. Ultrastructural studies of tumor tissue revealed two types of tissue: synthetic mesenchymal cells and cartilage tissue. Results indicate increased bone formation and resorption near the tumor. These local bone changes may possibly reflect responses to local tumor factors and depend on the extent of the tumor.

    *8273441*
     8273441

    Effects of hypercalcemia-producing tumor extract and parathyroid hormone on osteoclast ultrastructure.

    Acta Anat (Basel) 1990; 137 (2): 160-4

    Hypercalcemia is a frequent complication of cancer. Recently, parathyroid hormone-related protein has been isolated from tumors associated with this syndrome. In the present study, the effects of tumor-derived hypercalcemic factor and bovine parathyroid hormone (PTH) on bone were compared in an organ culture system using calvarial bones from newborn mice. Mouse calvaria were incubated for 72 h with control medium or media containing 0.15 mg/m tumor extract (TE) or 2 x 10(-9) M PTH. Bone resorption, as assessed by the amount of calcium released into the medium and the number of osteoclasts counted on light microscopy, was increased by both PTH and TE. On electron microscopy, areas for cytoplasm, ruffled border and clear zone were statistically increased in PTH- and TE-treated calvaria as compared to control. These values were not significantly different between PTH- and TE-treated calvaria. The study therefore demonstrates that the ultrastructural changes in osteoclasts induced by the hypercalcemia-producing TE are similar to those induced by PTH.

    *2316331*
     2316331

    LA GOUTTI'ERE ET LES ANNEAUX OSSEUX DE L'ART'ERE VERT'EBRALE DE L'ATLAS (ETUDE ANATOMIQUE ET RADIOLOGIQUE)

    Acta Anat (Basel) 1963; 55 (): 186-94

    *14101381*
     14101381

    Genetic epidemiology of neoplasia in man: a review.

    Acta Anthropogenet 1983; 7 (3): 153-96

    *6394030*
     6394030

    Deux cas de tumeurs osseuses a cellules geantes.

    Acta Belg Arte Med Pharm Mil 1958; 111 (1): 51-66

    *13582467*
     13582467

    Proliferation inhibition and apoptosis promotion by dual silencing of VEGF and Survivin in human osteosarcoma.

    Acta Biochim Biophys Sin (Shanghai) 2019; 51 (1): 59-67

    Simultaneous silencing of multiple upregulated genes is an attractive and viable treatment strategy for many incurable diseases including cancer. Herein we used a dual gene-targeted siRNA conjugate composed of VEGF and Survivin siRNA sequences in the same backbone to inhibit proliferation and angiogenesis in two human osteosarcoma cell lines. We synthesized siRNA sequences targeting the VEGF and Survivin genes individually (VEGF siRNA and Survivin siRNA) or simultaneously (one-chain-double-target siRNA: dual siRNA). VEGF and Survivin mRNA and protein expression levels in human osteosarcoma MG-63 and Saos-2 cells were detected by qRT-PCR and western blot analysis. VEGF and Survivin protein location and expression were evaluated by immunohistochemistry and immunofluorescence staining. MG-63 and Saos-2 cell migration, proliferation, apoptosis, and angiogenesis were detected by scratch test, MTT assay, flow cytometry, and capillary tube assay respectively. The dual siRNA induced similar downregulation of VEGF and Survivin mRNA and protein levels, compared with VEGF siRNA or Survivin siRNA alone. The dual siRNA caused greater suppression of MG-63 and Saos-2 cell migration, proliferation and angiogenesis, and promoted more cell apoptosis than VEGF siRNA or Survivin siRNA alone, suggesting that the effects of the dual siRNA on inhibiting cell proliferation, migration, and angiogenesis and promoting apoptosis were superior to those of the single-target siRNAs. Simultaneous silencing of VEGF and Survivin using the dual siRNA may be an advantageous alternative for the development of therapeutic strategies against human osteosarcoma.

    *30566604*
     30566604

    Identification of two potential glycogen synthase kinase 3beta inhibitors for the treatment of osteosarcoma.

    Acta Biochim Biophys Sin (Shanghai) 2018; 50 (5): 456-464

    Osteosarcoma is the most common primary malignant bone tumor among adolescents worldwide with high mortality rate. Glycogen synthase kinase 3beta (GSK3beta) is a serine/threonine kinase and is considered as a validated target in osteosarcoma therapy. Therefore, the study of GSK3beta inhibitors is one of the most popular fields in anti-osteosarcoma drug development. Here, the tools of bioinformatics were used to screen novel effective inhibitors of GSK3beta from ZINC Drug Database. The molecular docking, molecular dynamic simulations, MM/GBSA, and energy decomposition analysis were performed to identify the inhibitors. Finally, ZINC08383479 and ZINC08441251 were selected as potential GSK3beta inhibitors. These two inhibitors were evaluated by GSK3beta kinase inhibition assay in vitro. The inhibition of cell proliferation was tested in osteosarcoma cell lines U2OS and MG63 in vitro. The result showed that ZINC08383479 and ZINC08441251 had high inhibition activity against GSK3beta. We found that CHIR99021 (a known GSK3beta inhibitor), ZINC08383479, and ZINC08441251 had significant inhibition activity in U2OS cells and MG63 cells. These findings may provide new ideas for the design of more potent GSK3beta inhibitors and therapeutic targets for osteosarcoma.

    *29546355*
     29546355

    TGF-beta family co-receptor function and signaling.

    Acta Biochim Biophys Sin (Shanghai) 2018; 50 (1): 12-36

    Transforming growth factor-beta (TGF-beta) family members, which include TGF-betas, activins and bone morphogenetic proteins, are pleiotropic cytokines that elicit cell type-specific effects in a highly context-dependent manner in many different tissues. These secreted protein ligands signal via single-transmembrane Type I and Type II serine/threonine kinase receptors and intracellular SMAD transcription factors. Deregulation in signaling has been implicated in a broad array of diseases, and implicate the need for intricate fine tuning in cellular signaling responses. One important emerging mechanism by which TGF-beta family receptor signaling intensity, duration, specificity and diversity are regulated and/or mediated is through cell surface co-receptors. Here, we provide an overview of the co-receptors that have been identified for TGF-beta family members. While some appear to be specific to TGF-beta family members, others are shared with other pathways and provide possible ways for signal integration. This review focuses on novel functions of TGF-beta family co-receptors, which continue to be discovered.

    *29293886*
     29293886

    Hyaluronan arrests human breast cancer cell growth by prolonging the G0/G1 phase of the cell cycle.

    Acta Biochim Biophys Sin (Shanghai) 2018; 50 (12): 1181-1189

    In clinical breast cancer patients, quiescent disseminated tumor cells (DTCs) can persist for a long time in the bone marrow (BM) under the influence of microenvironmental cues. As a high molecular weight polysaccharide, hyaluronan (HA) not only has been shown to regulate cancer processes including cell invasion, metastasis, migration, and proliferation, but also is a major component of the BM extracellular matrix. Here, we tested whether HA promotes breast cancer cell quiescence through detecting cell proliferation, cell cycle phase distribution, and the expression of cell cycle-related regulator proteins. In our results, HA slowed the growth and prolonged the G0/G1 phase of the highly metastatic, bone-seeking human breast cancer MDA-MB-231BO cell line, which is consistent with results that HA activated p38alpha/beta, inhibited phospho-ERK1/2 levels and reduced the ERK/p38 signaling ratio. Additionally, we examined the crucial cell cycle factors p21cip1 and Cyclin D1, both of which influence the transition from G1 to S phase. The results revealed that p21cip1 expression was up-regulated by HA, which was consequently accompanied by a decrease in Cyclin D1 level. Further research with a 3D culture model indicated that HA maintained low Ki-67 and high p21cip1 expression levels in MDA-MB-231BO cells. In summary, our work revealed that HA might contribute to DTC quiescence.

    *30371731*
     30371731

    Resveratrol attenuates bone cancer pain through regulating the expression levels of ASIC3 and activating cell autophagy.

    Acta Biochim Biophys Sin (Shanghai) 2017; 49 (11): 1008-1014

    Bone cancer pain (BCP) is one of the most common pains in patients with malignant cancers. The mechanism underlying BCP is largely unknown. Our previous studies and the increasing evidence both have shown that acid-sensing ion channels 3 (ASIC3) is an important protein in the pathological pain state in some pain models. We hypothesized that the expression change of ASIC3 might be one of the factors related to BCP. In this study, we established the BCP model through intrathecally injecting rat mammary gland carcinoma cells (MRMT-1) into the left tibia of Sprague-Dawley female rats, and found that the BCP rats showed bone destruction, increased mechanical pain sensitivities and up-regulated ASIC3 protein expression levels in L4-L6 dorsal root ganglion. Then, resveratrol, which was intraperitoneally injected into the BCP rats on post-operative Day 21, dose-dependently increased the paw withdrawal threshold of BCP rats, reversed the pain behavior, and had an antinociceptive effect on BCP rats. In ASIC3-transfected SH-SY5Y cells, the ASIC3 protein expression levels were regulated by resveratrol in a dose- and time-dependent manner. Meanwhile, resveratrol also had an antinociceptive effect in ASIC3-mediated pain rat model. Furthermore, resveratrol also enhanced the phosphorylation of AMPK, SIRT1, and LC3-II levels in ASIC3-transfected SH-SY5Y cells, indicating that resveratrol could activate the AMPK-SIRT1-autophagy signal pathway in ASIC3-transfected SH-SY5Y cells. In BCP rats, SIRT1 and LC3-II were also down-regulated. These findings provide new evidence for the use of resveratrol as a therapeutic treatment during BCP states.

    *29036449*
     29036449

    Long non-coding RNA CCAT1/miR-148a axis promotes osteosarcoma proliferation and migration through regulating PIK3IP1.

    Acta Biochim Biophys Sin (Shanghai) 2017; 49 (6): 503-512

    Osteosarcoma is the most frequent type of malignant primary bone tumor. Although many efforts have been made, the survival rate of osteosarcoma still remains unsatisfied. Long non-coding RNAs (lncRNAs) have been demonstrated to be associated with many diseases including tumors, and involved in the regulation of a wide array of pathophysiological processes. Colon-cancer-associated transcript-1 (CCAT1) was first identified in colon cancer and has subsequently been reported to perform many functions in tumor progression. The present study aimed to comprehensively explore the biological functions of CCAT1 and its underlying mechanism in osteosarcoma cells. Our findings revealed that CCAT1 was upregulated in osteosarcoma tissues and cells, and was involved in the proliferation and migration of osteosarcoma via regulating miR-148a/phosphatidyl inositol 3-kinase interacting protein 1 (PIK3IP1) signal pathway.

    *28549102*
     28549102

    Role of the Akt/mTOR signaling pathway in human papillomavirus-associated nasal and sinonasal inverted papilloma.

    Acta Biochim Biophys Sin (Shanghai) 2017; 49 (12): 1067-1074

    Nasal and sinonasal inverted papilloma (NSIP) is a benign tumor in which surface epithelial cells grow downward into the underlying supportive tissue with varying degrees of metaplasia. Human papillomavirus (HPV) has been proposed as the causal agent in the pathogenesis of this disease. Many studies have shown that HPV can activate the Akt/mechanistic target of rapamycin (mTOR) signaling pathway, but the role of this pathway in HPV-associated NSIP is largely unknown. In this study, we enrolled 40 control tissue samples and 80 NSIP tissue samples. HPV genotyping showed that 47 of the 80 examined cases of NSIP were HPV-positive (58.8%), and the most common subtype was HPV11 (20/53, 37.7%). The immunohistochemistry showed statistically significant differences in phosphorylated Akt and phosphorylated S6 ribosomal protein staining among control samples, HPV-positive NSIP and HPV-negative NSIP. The HPV11 L1-L2 plasmid increased the proliferation of normal human nasopharyngeal epithelial NP69-SV40T cells and human nasopharyngeal cancer CNE1 cells. Meanwhile, rapamycin, an mTOR inhibitor, reversed the increased cell proliferation induced by the HPV11 L1-L2 plasmid. Western blot analysis showed that Akt/mTOR/S6 were overexpressed in NP69-SV40T cells and CNE1 cells infected with the HPV11 L1-L2 plasmid. These data demonstrate that HPV promotes cell proliferation through the Akt/mTOR signaling pathway in NSIP.

    *29040365*
     29040365

    Differential expression of bone morphogenetic protein 5 in human lung squamous cell carcinoma and adenocarcinoma.

    Acta Biochim Biophys Sin (Shanghai) 2015; 47 (7): 557-63 fuxn2006@aliyun.com

    Bone morphogenetic proteins (BMPs) play important roles in tumor cell proliferation, metastasis, and invasion. However, the expression patterns of BMPs in patients with non-small-cell lung cancer (NSCLC) and their correlations with NSCLC pathogenesis have not been examined yet. In this study, the mRNA levels of BMP family members in NSCLC tissues were analyzed and results showed that the mRNA levels of BMP5 and BMP7 were significantly down-regulated and up-regulated, respectively, in tumor tissues compared with those in the corresponding noncancerous tissues. Interestingly, the mRNA level of BMP5 was significantly higher in lung adenocarcinoma tissues than that in lung squamous cell carcinoma tissues. Furthermore, results from immunohistochemistry analysis confirmed stronger expression of BMP5 protein in lung adenocarcinoma than in lung squamous cell carcinoma. Our findings suggested that BMP5 might be a potential prognostic biomarker or therapeutic target for patients with NSCLC.

    *25994008*
     25994008

    Everolimus and zoledronic acid--a potential synergistic treatment for lung adenocarcinoma bone metastasis.

    Acta Biochim Biophys Sin (Shanghai) 2014; 46 (9): 792-801 lushun1964@126.com.

    Non-small-cell lung cancer (NSCLC) frequently metastasizes to bone. It is known that zoledronic acid is cytostatic to tumors, and everolimus, the inhibitor for mammalian target of the rapamycin, could inhibit many types of cancer. Herein, we evaluated the effect of zoledronic acid alone and in combination with everolimus on treating lung adenocarcinoma bone metastasis in vitro and in vivo. Mice treated with zoledronic acid in combination with everolimus had more apoptotic lung cancer cells and more cells were arrested in the G1/G0 phase. The phosphorylation of p70S6K was inhibited in the combination treatment group. Lung cancer cell invasion was also significantly inhibited in the group with combination treatment in vitro. Bone nuclear scans revealed more metastatic lesions in controls compared with those in the combination treatment group. Bone scans and radiographic images indicated that combination therapy significantly reduced bone metastasis. The moderate survival rate suggested that the drug combination was synergistic, which can delay NSCLC bone metastasis and prolong survival in vivo.

    *25098623*
     25098623

    Clinical significance of up-regulated miR-181a in prognosis and progression of esophageal cancer.

    Acta Biochim Biophys Sin (Shanghai) 2014; 46 (11): 1007-10 baoguoy718@163.com.

    *25230784*
     25230784

    Nrf2 is associated with the regulation of basal transcription activity of the BRCA1 gene.

    Acta Biochim Biophys Sin (Shanghai) 2013; 45 (3): 179-87

    BRCA1 is closely related to the pathogenesis of breast cancer. The activity of BRCA1 promoter is regulated by transcriptional factors. The transcription factor Nrf2 (Nuclear factor-erythroid-2p45-related factor 2) is a potent transcriptional activator and plays a central role in inducible expression of many cytoprotective genes. In this report, we found that over-expression of Nrf2 stimulated BRCA1 expression, knockdown of Nrf2 attenuated BRCA1 expression. Nrf2 also interacted with CBP and p300 to form an active transcription complex, which could bind to the ARE (antioxidant response element) site on the BRCA1 promoter and activate its transcription by inducing histone acetylation. Our finding could lead to a better understanding of the development of breast cancer.

    *23353771*
     23353771


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