Laboratory for Applied Cancer Research

Tel Aviv, Israel

Laboratory for Applied Cancer Research

Tel Aviv, Israel
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Ebrahimi A.,Royal Prince Alfred Hospital | Ebrahimi A.,Macquarie University | Ebrahimi A.,University of New South Wales | Gil Z.,Laboratory for Applied Cancer Research | And 20 more authors.
Cancer | Year: 2014

BACKGROUND A study was conducted to assess for prognostic heterogeneity within the N2b and N2c classifications for oral cancer based on the number of metastatic lymph nodes and to determine whether laterality of neck disease provides additional prognostic information. METHODS An international multicenter study of 3704 patients with oral cancer undergoing surgery with curative intent was performed. The endpoints of interest were disease-specific survival and overall survival. Model fit was assessed by the Akaike Information Criterion and comparison of models with and without the covariate of interest using a likelihood ratio test. RESULTS The median number of metastatic lymph nodes was significantly higher in patients with N2c disease compared to those with N2b disease (P<.001). In multivariable analyses stratified by study center, the addition of the number of metastatic lymph nodes improved model fit beyond existing N classification. Next, the authors confirmed significant heterogeneity in prognosis based on the number of metastatic lymph nodes (≤ 2, 3-4, and≥5) in patients with both N2b and N2c disease (P<.001). A proposed reclassification combining N2b and N2c disease based on the number of metastatic lymph nodes demonstrated significant improvement in prognostic accuracy compared with the American Joint Committee on Cancer staging system, and no improvement was noted with the addition of a covariate for contralateral or bilateral neck disease (P=.472). CONCLUSIONS The prognosis of patients with oral cancer with N2b and N2c disease appears to be similar after adequate adjustment for the burden of lymph node metastases, irrespective of laterality. Based on this finding, the authors propose a modified lymph node staging system that requires external validation before implementation in clinical practice. Cancer 2014;120:1968-1974. © 2014 American Cancer Society.

Amit M.,Laboratory for Applied Cancer Research | Amit M.,Technion - Israel Institute of Technology | Yen T.C.,Chang Gung Memorial Hospital | Liao C.T.,Chang Gung Memorial Hospital | And 21 more authors.
Annals of Surgical Oncology | Year: 2013

Background: We aimed to study the importance of clinical N classification (cN) in a subgroup of patients with oral cavity squamous cell carcinoma (OSCC) and pathologically negative neck nodes (pN-). Methods: A total of 2,258 patients from 11 cancer centers who underwent neck dissection for OSCC (1990-2011) had pN- disease. The median follow-up was 44 months. 5-year overall survival (OS), disease-specific survival (DSS), disease free survival, local control, locoregional control, and distant metastasis rates were calculated by the Kaplan-Meier method. cN classification and tumor, node, metastasis classification system staging variables were subjected to multivariate analysis. Results: A total of 345 patients were preoperatively classified as cN+ and 1,913 were classified as cN-. The 5-year OS and DSS of cN- patients were 73.6 and 82.2 %, respectively. The 5-year OS and DSS of cN+ patients were 64.9 and 76.9 %, respectively (p < 0.0001 each). A cN+ classification was a significant predictor of worse OS (p = 0.03) and DSS (p = 0.016), regardless of treatment, depth of invasion, or extent of neck dissection. cN classification was associated with recurrence-free survival (p = 0.01) and locoregional (neck and primary tumor) control (p = 0.004), but not with local (p = 0.19) and distant (p = 0.06) recurrence rates. Conclusions: Clinical evidence of neck metastases is an independent predictor of outcome, even in patients with pN- nodes. © 2013 Society of Surgical Oncology.

Ebrahimi A.,Royal Prince Alfred Hospital | Ebrahimi A.,Liverpool Hospital | Ebrahimi A.,Macquarie University | Ebrahimi A.,University of New South Wales | And 21 more authors.
JAMA Otolaryngology - Head and Neck Surgery | Year: 2014

IMPORTANCE: The current American Joint Committee on Cancer (AJCC) staging system for oral cancer demonstrates wide prognostic variability within each primary tumor stage and provides suboptimal staging and prognostic information for some patients. OBJECTIVE To determine if a modified staging system for oral cancer that integrates depth of invasion (DOI) into the T categories improves prognostic performance compared with the current AJCC T staging. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analysis of 3149 patients with oral squamous cell carcinoma treated with curative intent at 11 comprehensive cancer centers worldwide between 1990 and 2011 with surgery ± adjuvant therapy, with a median follow-up of 40 months. MAIN OUTCOMES AND MEASURES: We assessed the impact of DOI on disease-specific and overall survival in multivariable Cox proportional hazard models and investigated for institutional heterogeneity using 2-stage random effects meta-analyses. Candidate staging systems were developed after identification of optimal DOI cutpoints within each AJCC T category using the Akaike information criterion (AIC) and likelihood ratio tests. Staging systems were evaluated using the Harrel concordance index (C-index), AIC, and visual inspection for stratification into distinct prognostic categories, with internal validation using bootstrapping techniques. RESULTS: The mean and median DOI were 12.9mmand 10.0 mm, respectively. On multivariable analysis, DOI was a significantly associated with disease-specific survival (P < .001), demonstrated no institutional prognostic heterogeneity (I2 = 6.3%; P = .38), and resulted in improved model fit compared with T category alone (lower AIC, P < .001). Optimal cutpoints of 5mmin T1 and 10mmin T2-4 category disease were used to develop a modified T staging system that was preferred to the AJCC system on the basis of lower AIC, visual inspection of Kaplan-Meier curves, and significant improvement in bootstrapped C-index. CONCLUSIONS AND RELEVANCE: We propose an improved oral cancer T staging system based on incorporation of DOI that should be considered in future versions of the AJCC staging system after external validation. Copyright 2014 American Medical Association. All rights reserved.

Semo J.,Tel Aviv Sourasky Medical Center | Semo J.,Tel Aviv University | Sharir R.,Tel Aviv Sourasky Medical Center | Sharir R.,Tel Aviv University | And 11 more authors.
European Heart Journal | Year: 2014

Aims MicroRNAs (miRNAs, miR) are endogenous short RNA sequences that regulate a wide range of physiological and pathophysiological processes. Several miRNAs control the formation of new blood vessels either by increasing or by inhibiting angiogenesis. Here, we investigated the possible role of the miR-106b∼25 cluster in postnatal neovascularization and in regulation of the angiogenic properties of adult bone marrow-derived stromal cells. Methods and results To study the effect of miR-106b∼25 deletion on neovascularization, we used a miR-106b∼25 knockout (KO) mouse model. After inducing hindlimb ischaemia, we showed that vascularization in ischaemic mice devoid of miR-106b∼25 is impaired, as evident from the reduced blood flow on laser Doppler perfusion imaging. The miR-106b∼25 cluster was also shown here to be an essential player in the proper functioning of bone marrow-derived stromal cells through its regulation of apoptosis, matrigel tube formation capacity, cytokine secretion, and expression of the stem-cell marker Sca-1. In addition, we showed that capillary sprouting from miR-106b∼25 KO aortic rings is diminished. Conclusion These results show that the miR-106b∼25 cluster regulates post-ischaemic neovascularization in mice, and that it does so in part by regulating the function of angiogenic bone marrow-derived stromal cells and of endothelial cells. © 2013 Published on behalf of the European Society of Cardiology.

Shabtay-Orbach A.,Laboratory for Applied Cancer Research | Amit M.,Laboratory for Applied Cancer Research | Amit M.,Technion - Israel Institute of Technology | Binenbaum Y.,Laboratory for Applied Cancer Research | And 4 more authors.
International Journal of Cancer | Year: 2015

It was suggested that the brain microenvironment plays a role in glioma progression. Here we investigate the mechanism by which astrocytes which are abundant in glioma tumors, promote cancer cell invasion. In this study, we evaluated the effects of astrocytes on glioma biology both in vitro and in vivo and determined the downstream paracrine effect of glial-derived neurotrophic factor (GDNF) on tumor invasion. Astrocytes-conditioned media (ACM) significantly increased human and murine glioma cells migration compared to controls. This effect was inhibited when the activity of GDNF on glioma cells was blocked by RET-Fc chimera or anti-GDNF Ab and by small interfering RNA directed against GDNF expression by astrocytes. Glioma cells incubated with ACM led to time dependent phosphorylation of the GDNF receptor, RET and downstream activation of AKT. Tumor migration and GDNF-RET-AKT activation was inhibited by the RET small-molecule inhibitor pyrazolopyrimidine-1 (PP1) and by the AKT inhibitor LY294002. Finally, blocking of RET by PP1 or knockout of the RET coreceptor GFRα1 in glioma cells reduced the size of brain tumors in immunocompetent mice. We suggest a mechanism by which astrocytes attracted to the glioma tumors facilitate brain invasion by secretion of GDNF and activation of RET/GFRα1 receptors expressed by the cancer cells. What's new? Glioblastomas arise in astrocytes, the cells that support the brain, but reproduce quickly and spread to the brain itself. How do astrocytes promote this invasiveness? These authors tested the role of the signaling molecule GDNF in spurring cancer growth. They found that in an astrocyte-rich environment, cultured glioma cells migrated more than usual - but this mobility boost vanished when they prevented GDNF from binding to its receptor, RET. In mice with gliomas, blocking RET slowed the growth of the tumors considerably. This demonstrates for the first time that astrocytes promote tumor invasion via GDNF and RET, and could suggest new treatment avenues. © 2014 UICC.

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