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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 16 more authors.
Endocrine Reviews | Year: 2013

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 In closing, we replace non- islet-cell tumor hypoglycemia, an outdated and misleading label, with IGF-2-oma, self-explanatory and consistent with names of other hormone-secreting tumors.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.


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 | Year: 2016

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..


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 22 more authors.
JAMA Otolaryngology - Head and Neck Surgery | Year: 2014

IMPORTANCE: Squamous cell carcinoma of the oral cavity (OSCC) is a common malignant tumor worldwide. OBJECTIVE To determine if regional failure in patients with OSCC and pathologically negative neck nodes (pN-) is due to an incomplete sampling procedure during surgery. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively reviewed the medical records of 2258 patients from 11 cancer centers worldwide who underwent neck dissection for OSCC (1990-2011) and who were pN-. Of those, 345 had clinical evidence of nodal metastases (cN+) on radiologic workup. The neck specimens were available for reanalysis in 193 patients. Survival rates were calculated using the Kaplan-Meier graphs and analyzed by multivariable analysis. MAIN OUTCOMES AND MEASURES: Five-year overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). RESULTS: Resectioning and analysis of the neck dissection specimens in the cN+/pN-subgroup revealed false-negative results in 29 (15%) of 193 patients. The negative predictive value of the initial pathologic examination was 85%. The 5-year OS and DSS in the cN-/pN-group were 77.6%and 87.2%, respectively. The 5-year OS and DSS of the cN+/pN- group were 62.6%and 78.5%, respectively (P < .001). In multivariable analysis, cN+ classification was significantly associated with poor OS (hazard ratio [HR], 1.7; 95%CI, 1.1-3.8; P = .03) and poor DSS (HR, 1.46; 95%CI, 1.1-4.1; P = .04). A cN+ classification was associated with lower DFS (66.3%vs 76.2%; P = .05) and lower regional recurrence-free survival (68.6%vs 78.8%; P = .02) but not with local (P = .20) or distant recurrence (P = .80). CONCLUSIONS AND RELEVANCE: Pathologic staging underestimates the incidence of nodal metastases in cN+ disease. After correction for pathologically missed nodal metastases, radiologic evidence of neck nodes is an independent predictor of outcome, suggesting that traditional sampling during surgery might miss metastases, and this fact might explain the origin of treatment failure in these patients. Copyright 2014 American Medical Association. All rights reserved.


PubMed | University of Cologne, Chang Gung Memorial Hospital, Royal Prince Alfred Hospital, University of Illinois at Springfield and 10 more.
Type: | Journal: Annals of surgical oncology | Year: 2015

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).The aim of this study was to evaluate prognostic heterogeneity in the stage III category.An international retrospective multicenter study of 1815 patients who were treated for OCSCC from 2003 to 2011.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 [Harrells concordance index, C index 0.76; Akaikes 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).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.


Perets R.,Clinical Research Institute at Rambam | Drapkin R.,University of Pennsylvania
Cancer Research | Year: 2016

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.


PubMed | University of Pennsylvania and Clinical Research Institute at Rambam
Type: Journal Article | Journal: Cancer research | Year: 2016

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.


Na'ara S.,Rambam Health Care Campus | Na'ara S.,Clinical Research Institute at Rambam | Amit M.,Rambam Health Care Campus | Amit M.,Clinical Research Institute at Rambam | And 5 more authors.
Annals of Surgical Oncology | Year: 2014

Background. The common treatment of primary patients with nasopharyngeal carcinoma is chemotherapy and radiotherapy. Surgery is reserved as salvage procedure for recurrent or persistent disease. Nevertheless, information on the outcome of these patients and the role of adjuvant reirradiation treatment is scarce. Methods. We conducted a meta-analysis to identify prognostic factors associated with outcomes of patients with recurrent nasopharyngeal carcinoma treated by salvage surgery. Results. The study group consisted of 779 patients from 17 published studies who met the inclusion criteria. The primary tumor classification at recurrence was T1-2 in 83 % of patients and T3-4 in 16.6 %. Regional lymph node metastases were present in 88 patients. The 5-year overall survival and local recurrence-free survival rates of the entire cohort were 51.2 and 63.4 %, respectively, with a distant metastases rate of 11.3 %. The 5-year overall survival was 63 % in patients receiving surgery and adjuvant radiotherapy compared to 39 % in patients receiving surgery alone (P = 0.05). Independent predictors of outcome on multivariate analysis were sex, N classification, surgical approach (endoscopic vs. open), adjuvant treatment, and margin status. Both endoscopic surgery and reirradiation were independent predictors of improved survival. Conclusions. More than half of the patients with recurrent disease can be salvaged by surgery. Margins status, and N and T classification are significant predictors of outcome. Multivariate analysis revealed that endoscopic surgery offers better outcome than open surgery for T3/4 disease in selected patients, and adjuvant reirradiation offers an additional survival advantage over surgery alone. © 2014 Society of Surgical Oncology.


Binenbaum Y.,Clinical Research Institute at Rambam | Na'Ara S.,Clinical Research Institute at Rambam | Na'Ara S.,Rambam Healthcare Campus | Gil Z.,Clinical Research Institute at Rambam | And 2 more authors.
Drug Resistance Updates | Year: 2015

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.


Binenbaum Y.,Technion - Israel Institute of Technology | Amit M.,Technion - Israel Institute of Technology | Amit M.,Clinical Research Institute at Rambam | Billan S.,Technion - Israel Institute of Technology | And 3 more authors.
Annals of Surgical Oncology | Year: 2014

Background. The minimal clinically important difference (MCID) is defined as the smallest difference in quality of life (QOL) that patients perceive as beneficial and that mandates a change in management. We aimed to determine the MCID among patients with oral cavity and oropharyngeal cancer and to identify domains that are significantly affected during treatment. Methods. The cohort consisted of 1,011 patients analyzed by a metaanalysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. MCID values for the University of Washington Quality of Life Questionnaire (UW-QOLQ) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC C-30) and Head and Neck-35 questionnaires were calculated by using the distribution-based method. Results. The mean MCID for Global QOL was 13.07 points for the UW-QOLQ and 9.43 in the EORTC C-30 questionnaire. High consistency in the MCID values was found between the two questionnaires examined. Heat map analysis indicated a clinically significant improvement in head and neck-associated domains and in domains associated with general cancer treatment 1 year or more after treatment relative to 3 months after treatment (p < 0.001 and p = 0.016, respectively). In contrast, improvement in general and functional domains was not evident 1 year or more after treatment (p = 0.69). Conclusions. This study suggests benchmark values for MCID and variation in QOL scores of oral and oropharyngeal cancer patients after treatment. Improvement in head and neck- and general cancer-associated domains may not be translated into a general and functional improvement during the first year of recovery. © 2014 Society of Surgical Oncology.


PubMed | Technion - Israel Institute of Technology and Clinical Research Institute at Rambam
Type: | Journal: Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy | Year: 2015

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.

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