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Dynkevich Y.,Queens Long Island Medical Group | Rother K.I.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Whitford I.,Feinstein Institute for Medical Research | Qureshi S.,Feinstein Institute for Medical Research | And 14 more authors.
Endocrine Reviews

Tumors of mesenchymal and epithelial origin produce IGF-2, which activates pathways in the tumors. In a minority of patients, the tumors (hepatomas, fibromas, and fibrosarcomas are the most common among many) release into the circulation enough IGF-2-related peptides to mimic the fasting hypoglycemia characteristic of patients with insulin-producing islet-cell tumors. Rarely, markedly elevated IGF-2 levels produce somatic changes suggestive of acromegaly. Typically, the elevated IGF-2 levels are associated with suppressed plasma levels of insulin, IGF-1, and GH. Complicating the pathophysiology are the IGF binding proteins (IGFBPs) that can bind IGF-2 and IGF-1, modifying hormone metabolism and action. IGFBP concentrations are often altered in the presence of these tumors. At the cellular level, the 3 hormone-related ligands, IGF-2, IGF-1, and insulin, all bind to 4 (or more) types of IGF-1 receptor (IGF-1R) and insulin receptor (IR). Each receptor has its own characteristic affinity for each ligand, a tyrosine kinase, and overlapping profiles of action in the target cells. The IGF-2R, in addition to binding mannose-6-phosphate-containing proteins, provides an IGF-2 degradation pathway. Recent evidence suggests IGF-2R involvement also in signal transduction. Surgery, the treatment of choice, can produce a cure. For patients not cured by surgery, multiple therapies exist, for the tumor and for hypoglycemia. Potential future therapeutic approaches are sketched. From 1910 to 1930, hypoglycemia, insulin, insulinomas, and non-islet-cell tumors were recognized. The latter third of the century witnessed the emergence of the immunoassay for insulin; the IGFs, their binding proteins, and assays to measure them; and receptors for the insulin-related peptides as well as the intracellular pathways beyond the receptor. In closing, we replace non- islet-cell tumor hypoglycemia, an outdated and misleading label, with IGF-2-oma, self-explanatory and consistent with names of other hormone-secreting tumors. © 2013 by The Endocrine Society. Source

Perets R.,Clinical Research Institute at Rambam | Drapkin R.,University of Pennsylvania
Cancer Research

Hereditary breast and ovarian cancer syndrome carries significant mortality for young women if effective preventive and screening measures are not taken. Preventive salpingo-oophorectomy is currently the only method known to reduce the risk of ovarian cancer-related death. Histopathological analyses of these surgical specimens indicate that a high proportion of ovarian cancers in women at high risk and in the general population arise from the fallopian tube. This paradigm shift concerning the cell of origin for the most common subtype of ovarian cancer, high-grade serous carcinoma, has sparked a major effort within the research community to develop new and robust model systems to study the fallopian tube epithelium as the cell of origin of "ovarian" cancer. In this review, evidence supporting the fallopian tube as the origin of ovarian cancer is presented as are novel experimental model systems for studying the fallopian tube epithelium in high-risk women as well as in the general population. This review also addresses the clinical implications of the newly proposed cell of origin, the clinical questions that arise, and novel strategies for ovarian cancer prevention. © 2015 American Association for Cancer Research. Source

Amit M.,Head and Neck Cancer Center | Amit M.,Clinical Research Institute at Rambam | Na'Ara S.,Head and Neck Cancer Center | Na'Ara S.,Clinical Research Institute at Rambam | And 8 more authors.
Head and Neck

Background A positive margin is among the most significant factors that affects the outcome in head and neck squamous cell carcinoma (SCC). The purpose of this study was to compare the negative margin rates between 2 methods of intraoperative margin assessment in patients with oral cavity SCC. Methods A prospective, randomized controlled trial comparing 2 methods of intraoperative margin assessment: specimen-driven margins and patient-driven margins. Results The final analysis included 71 patients, 20 (29%) in the patient-driven margin arm. Frozen section analysis revealed positive/close surgical margins that led to an extension of the surgical resection in 22 of 51 patients (43%) in the specimen-driven margin arm, and 2 of 20 patients (10%) in the patient-driven margin arm (p =.01). After final pathological analysis, the wide negative margin rate was 84% in the specimen-driven margin arm, compared to 55% in the patient-driven margin arm (p =.02). Extension of the surgical resection prevented escalation of adjuvant treatment in 19 patients (38%) in the specimen-driven margin arm and 10% in the patient-driven margin arm. Conclusion Specimen derived margin assessment led to significant improvement in the rate of negative margins. © 2015 Wiley Periodicals, Inc.. Source

Binenbaum Y.,Clinical Research Institute at Rambam | Na'Ara S.,Clinical Research Institute at Rambam | Gil Z.,Clinical Research Institute at Rambam | Gil Z.,Technion - Israel Institute of Technology
Drug Resistance Updates

Pancreatic ductal adenocarcinoma (PDA) ranks fourth among cancer related deaths. The disappointing 5-year survival rate of below 5% stems from drug resistance to all known therapies, as well as from disease presentation at a late stage when PDA is already metastatic. Gemcitabine has been the cornerstone of PDA treatment in all stages of the disease for the last two decades, but gemcitabine resistance develops within weeks of chemotherapy initiation. From a mechanistic perspective, gemcitabine resistance may result from alterations in drug metabolism until the point that the cytidine analog is incorporated into the DNA, or from mitigation of gemcitabine-induced apoptosis. Both of these drug resistance modalities can be either intrinsic to the cancer cell, or influenced by the cancer microenvironment. Mechanisms of intrinsic gemcitabine resistance are difficult to tackle, as many of the genes that drive the carcinogenic process itself also interfere with gemcitabine-induced apoptosis. In this regard, recent understanding of the involvement of microRNAs in gemcitabine resistance may offer new opportunities to overcome intrinsic gemcitabine resistance. The characteristically fibrotic and immune infiltrated stroma of PDA that accompanies tumor inception and expansion is a lush ground for treatments aimed at targeting tumor microenvironment-mediated drug resistance. In the last couple of years, drugs interfering with tumor microenvironment have matured to clinical trials. Although drugs inducing 'stromal depletion' have yet failed to improve survival, they have greatly increased our understanding of tumor microenvironment-mediated drug resistance. In this review we summarize the current knowledge on intrinsic and environment-mediated gemcitabine resistance, and discuss the impact of these pathways on patient screening, and on future treatments aimed to potentiate gemcitabine activity. © 2015 Elsevier Ltd. All rights reserved. Source

Amit M.,Clinical Research Institute at Rambam | Amit M.,Technion - Israel Institute of Technology | Yen T.C.,Chang Gung Memorial Hospital | Liao C.T.,Chang Gung Memorial Hospital | And 24 more authors.
Annals of Surgical Oncology

Background: The American Joint Committee on Cancer (AJCC) stage III classification of oral cavity squamous cell carcinoma (OCSCC) represents a heterogeneous group of patients with early local disease with regional metastases (T1N1 and T2N1) and advanced local disease with or without regional metastasis (T3N0 and T3N1). Objective: The aim of this study was to evaluate prognostic heterogeneity in the stage III category. Methods and Patients: An international retrospective multicenter study of 1815 patients who were treated for OCSCC from 2003 to 2011. Results: Kaplan–Meier survival analysis and multivariate models of stage III patients revealed better overall survival (OS; HR 2.12, 95 % CI 1.03–4.15; p = 0.01) and disease-specific survival (DSS; HR 1.7, 95 % CI 1.16–4.12; p = 0.04) rates for patients with T1–2N1/T3N0 disease than for patients with T3N1 disease. The outcomes of patients with T3N1 and stage IVa disease were similar (p = 0.89 and p = 0.78 for OS and DSS, respectively). Modifying stage classification by transferring the T3N1 category to the stage VIa group resulted in a better prognostic performance [Harrell’s concordance index, C index 0.76; Akaike’s Information Criterion (AIC) 4131.6] compared with the AJCC 7th edition staging system (C index 0.65; AIC 4144.9) for OS. When DSS was assessed, the suggested staging system remained the best performing model (C index 0.71; AIC 1061.3) compared with the current AJCC 7th edition staging (C index 0.64; AIC 1066.2). Conclusions: The prognosis of T3N1 and stage IVa disease are similar in OCSCC, suggesting that these categories could be combined in future revisions of the nodal staging system to enhance prognostic accuracy. © 2015, Society of Surgical Oncology. Source

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