West Jerusalem, Israel
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PubMed | Hebrew University of Jerusalem, Institute of Oncology, Champions Oncology, Teva Pharmaceutical Industries and 4 more.
Type: | Journal: Clinical lung cancer | Year: 2017

RET (rearranged during transfection) fusions have been reported in 1% to 2% of lung adenocarcinoma (LADC) cases. In contrast, KIF5B-RET and CCDC6-RET fusion genes have been identified in 70% to 90% and 10% to 25% of tumors, respectively. The natural history and management of RET-rearranged LADC are still being delineated.We present a series of 14 patients with RET-rearranged LADC. The response to therapy was assessed by the clinical response and an avatar model in 2 cases. Patients underwent chemotherapy, targeted therapy, and immunotherapy.A total of 14 patients (8 women; 10 never smokers; 4 light smokers; mean age, 57 years) were included. KIF5B-RET and CCDC6-RET variants were diagnosed in 10 and 4 cases, respectively. Eight patients had an early disseminated manifestation, seven with KIF5B-RET rearranged tumor. The features of this subset included bilateral miliary lung metastases, bone metastases, and unusual early visceral abdominal involvement. One such patient demonstrated an early and durable complete response to cabozantinib for 7 months. Another 2 patients treated with cabozantinib experienced a partial response, with rapid significant clinical improvement. Four patients with tumors harboring CCDC6-RET and KIF5B-RET fusions showed pronounced and durable responses to platinum-based chemotherapy that lasted for 8 to 15 months. Two patients tumors showed programmed cell death ligand 1-positive staining but did not respond to pembrolizumab. The median overall survival was 22.8 months.RET-rearranged LADC in our series tended to occur as bilateral disease with early visceral involvement, especially with KIF5B fusion. Treatment with cabozantinib achieved responses, including 1 complete response. However, further studies are required in this group of patients.


Domchek S.M.,Basser Research Center and Abramson Cancer Center | Aghajanian C.,Sloan Kettering Cancer Center | Shapira-Frommer R.,Sheba Medical Center | Schmutzler R.K.,Center for Familial Breast and Ovarian Cancer | And 14 more authors.
Gynecologic Oncology | Year: 2016

Objective The efficacy and safety of olaparib, an oral poly(ADP-ribose) polymerase (PARP) inhibitor, was investigated in a subgroup of patients with germline BRCA1/2 mutated (gBRCA1/2m) advanced ovarian cancer who had received ≥ 3 prior lines of chemotherapy. Primary data from this Phase II study (Study 42, ClinicalTrials.gov NCT01078662) have been reported previously. Methods Eligible patients were treated with oral olaparib 400 mg bid capsule monotherapy until disease progression according to RECIST v1.1. Objective response rate (ORR) and duration of response (DoR) were assessed for patients with measurable disease at baseline. Safety and tolerability were assessed for all patients by adverse event (AE) incidence and changes in laboratory parameters. Platinum resistance status was obtained retrospectively, and responses to olaparib evaluated. Results In patients with gBRCA1/2m ovarian cancer, 154/193 (80%) had received ≥ 3 prior lines of chemotherapy, of whom 137/154 (89%) had measurable disease at baseline. ORR was 34% (46/137; 95% confidence interval [CI] 26-42) and median DoR was 7.9 (95% CI 5.6-9.6) months. ORR in platinum-resistant tumors was 30%. Median DoR for platinum-sensitive and platinum-resistant disease was similar: 8.2 months (95% CI 5.6-13.5) compared with 8.0 months (4.8-14.8), respectively. Six of the 193 (3%) patients had an AE with an outcome of death. None of these AEs at time of occurrence was considered causally related to olaparib. Conclusion Following ≥ 3 prior lines of chemotherapy, olaparib 400 mg bid (capsule form) monotherapy demonstrated notable antitumor activity in patients with gBRCA1/2m advanced ovarian cancer. No new safety signals were identified. © 2016 Elsevier Inc.


Sivan S.,Ella Institute for Treatment and Research of Melanoma and Skin Cancer | Suzan F.,Sharett Institute of Oncology | Rona O.,Ella Institute for Treatment and Research of Melanoma and Skin Cancer | Tamar H.,Sharett Institute of Oncology | And 7 more authors.
Clinical and Developmental Immunology | Year: 2012

The search for melanoma biomarkers is crucial, as the incidence of melanoma continues to rise. We have previously demonstrated that serum CEACAM1 (sCEACAM1) is secreted from melanoma cells and correlates with disease progression in metastatic melanoma patients. Here, we have used a different cohort of melanoma patients with regional or metastatic disease (N = 49), treated with autologous vaccination. By monitoring sCEACAM1 in serum samples obtained prior to and after vaccination, we show that sCEACAM1 correlates with disease state, overall survival, and S100B. The trend of change in sCEACAM1 following vaccination (increase/decrease) inversely correlates with overall survival. DTH skin test is used to evaluate patients' anti-melanoma immune response and to predict response to vaccination. Importantly, sCEACAM1 had a stronger prognostic value than that of DTH, and when sCEACAM1 decreased following treatment, this was the dominant predictor of increased survival. Collectively, our results point out the relevance of sCEACAM1 in monitoring melanoma patients. Copyright © 2012 Sapoznik Sivan et al.


Guez J.,Soroka University Medical Center | Guez J.,P.A. College | Cohen J.,Sharett Institute of Oncology | Naveh-Benjamin M.,University of Missouri | And 4 more authors.
Psychiatry Research | Year: 2013

Stress and episodic memory impairment have previously been associated. Acute stress disorder (ASD) is a maladaptive stress response, which develops in some individuals following traumatic life events. Recently, the authors demonstrated a specific deficit in associative memory for emotionally neutral stimuli in ASD and posttraumatic stress disorder (PTSD). This study further tested the relationship between this memory impairment and the course of ASD. We assessed new learning and memory for item and associative information in patients diagnosed with ASD (n=14) and matched trauma naïve controls (n=14). Memory performance and posttraumatic symptoms were examined for approximately 1 and 10 week periods following the traumatic experience. In the two experiments, participants studied a list of stimuli pairs (verbal or visual) and were then tested for their memory of the items (item recognition test), or for the association between items in each pair (associative recognition test). In both experiments, ASD patients showed a marked associative memory deficit compared to the control group. After 10 weeks, ASD symptoms were resolved in most patients. Interestingly, their performance on associative recognition for verbal stimuli improved, while the associative deficit for visual stimuli remained unchanged. Potential mechanisms underlying such an associative memory deficit in post-trauma patients are discussed. © 2012 Elsevier Ireland Ltd.


Basheer M.,Sharett Institute of Oncology | Schwalb H.,Hebrew University of Jerusalem | Nesher M.,Hebrew University of Jerusalem | Gilon D.,Hebrew University of Jerusalem | And 4 more authors.
Journal of Allergy and Clinical Immunology | Year: 2010

Background: Haptides are a family of short peptides homologous to C-termini sequences of fibrinogen chains β and γ (haptides Cβ and preCγ, respectively) which were previously shown to penetrate and bind cells. Objectives: This work investigates the systemic effect of the haptides with possible clinical implications. Methods: Intra-arterial monitoring in rats recorded the haptides' effects on systemic blood pressure. In parallel, their effect was also tested in vitro on isolated rat peritoneal mast cells and on human mast cells. Results: Intra-arterial monitoring in rats showed that intravenous administration of low haptides concentrations (35-560 μg/kg rat) caused a shocklike behavior with transient decrease in the systolic and diastolic blood pressure by up to 55% (P < .05) in a dose-dependent manner and a minor increase in their heart rate. Randomly scrambled sequences of the haptides had no such effect, suggesting a specific interaction with receptors. Intravenous administration of blockers to histamine receptors H1 and H2 before haptides administration attenuated this effect. Furthermore, in vitro incubation of human LAD2 mast cell line or isolated rat peritoneal mast cells with the haptides caused degranulation of the mast cells. We found that the haptides Cβ and preCγ activated mast cells causing histamine release, resulting in a steep decrease in blood pressure, comparable to anaphylactic shock. Conclusion: In treating vascular occlusive diseases, massive fibrinolysis is induced, and haptide-containing sequences are released. We suggest that treatment with histamine receptor blockers or with mast cell stabilizing agents in such pathological conditions may overcome this effect. © 2010 American Academy of Allergy, Asthma & Immunology.


Saar-Ashkenazy R.,Ben - Gurion University of the Negev | Saar-Ashkenazy R.,Ashkelon Academic College | Saar-Ashkenazy R.,Achva Academic College | Shalev H.,Soroka University Medical Center | And 5 more authors.
Psychiatry Research - Neuroimaging | Year: 2015

Patients with posttraumatic stress disorder (PTSD) display abnormal emotional processing and bias towards emotional content. Most neurophysiological studies in PTSD found higher amplitudes of event-related potentials (ERPs) in response to trauma-related visual content. Here we aimed to characterize brain electrical activity in PTSD subjects in response to non-trauma-related emotion-laden pictures (positive, neutral and negative). A combined behavioral-ERP study was conducted in 14 severe PTSD patients and 14 controls. Response time in PTSD patients was slower compared with that in controls, irrespective to emotional valence. In both PTSD and controls, response time to negative pictures was slower compared with that to neutral or positive pictures. Upon ranking, both control and PTSD subjects similarly discriminated between pictures with different emotional valences. ERP analysis revealed three distinctive components (at ~300, ~600 and ~1000. ms post-stimulus onset) for emotional valence in control subjects. In contrast, PTSD patients displayed a similar brain response across all emotional categories, resembling the response of controls to negative stimuli. We interpret these findings as a brain-circuit response tendency towards negative overgeneralization in PTSD. © 2015 Elsevier Ireland Ltd.


Saar-Ashkenazy R.,Ben - Gurion University of the Negev | Saar-Ashkenazy R.,Achva Academic College | Cohen J.E.,Sharett Institute of Oncology | Guez J.,Achva Academic College | And 5 more authors.
Journal of Traumatic Stress | Year: 2014

Memory deficits are a common complaint of patients with posttraumatic stress disorder (PTSD). Despite vivid trauma-related memory, previous studies report memory impairment for nontrauma-related stimuli when compared to controls, specifically in associative memory (Guez et al., 2011). Healthy individuals show hemispheric memory asymmetry with left-prefrontal lateralization of encoding and right-prefrontal lateralization of episodic retrieval, suggesting a role for interhemispheric communication in memory-related tasks (Gazzaniga, ; Ringo, Doty, Demeter, & Simard, ). Because brain magnetic resonance imaging (bMRI) studies in PTSD patients report volume changes in various regions, including white matter and corpus callosum (CC), we aimed to test the relationship between memory deficits and CC volume in PTSD patients. We probed for specific alterations in associative memory in PTSD and measured the volume of subportions within the CC employing bMRI. Our main finding was a reduction in CC white-matter volume in PTSD patients, as compared to controls, t(35) = -2.7, p = .010, that was correlated with lower associative performance (r = .76, p = .003). We propose that CC volume reduction is a substrate for the associative memory deficits found in PTSD. Copyright © 2014 International Society for Traumatic Stress Studies.


PubMed | Hebrew University of Jerusalem, Sharett Institute of Oncology and ImProDia Ltd.
Type: Journal Article | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

High levels of circulating myeloid-derived suppressor cells (MDSCs) in various cancer types, including melanoma, were shown to correlate with poor survival. We investigated whether frequencies of circulating CD33Peripheral blood samples from 56 patients and 50 healthy donors (HDs) were analyzed for CD33Patients with melanoma had significantly higher levels of circulating CD33Our study suggests the use of CD33


PubMed | Sharett Institute of Oncology and Hebrew University of Jerusalem
Type: Journal Article | Journal: PloS one | Year: 2015

Trogocytosis is a contact-dependent unidirectional transfer of membrane fragments between immune effector cells and their targets, initially detected in T cells following interaction with professional antigen presenting cells (APC). Previously, we have demonstrated that trogocytosis also takes place between melanoma-specific cytotoxic T lymphocytes (CTLs) and their cognate tumors. In the present study, we took this finding a step further, focusing on the ability of melanoma membrane-imprinted CD8+ T cells to act as APCs (CD8+ T-APCs). We demonstrate that, following trogocytosis, CD8+ T-APCs directly present a variety of melanoma derived peptides to fraternal T cells with the same TCR specificity or to T cells with different TCRs. The resulting T cell-T cell immune synapse leads to (1) Activation of effector CTLs, as determined by proliferation, cytokine secretion and degranulation; (2) Fratricide (killing) of CD8+ T-APCs by the activated CTLs. Thus, trogocytosis enables cross-reactivity among CD8+ T cells with interchanging roles of effectors and APCs. This dual function of tumor-reactive CTLs may hint at their ability to amplify or restrict reactivity against the tumor and participate in modulation of the anti-cancer immune response.


PubMed | Goldyne Savad Institute of Gene Therapy, University of Kiel and Sharett Institute of Oncology
Type: | Journal: Hepatology (Baltimore, Md.) | Year: 2016

Liver cancer, which typically develops on a background of chronic liver inflammation, is now the second leading cause of cancer mortality worldwide. For these patients surgical resection is a principal treatment modality that offers a chance of prolonged survival. However, tumor recurrence after resection, the mechanisms of which remain obscure, markedly limits the long-term survival of these patients. We have previously shown that partial hepatectomy (PH) in Mdr2 knockout (Mdr2Our findings indicate that genomic instability derived during the IL6-mediated liver regenerative response within a milieu of chronic inflammation links PH to accelerated hepatocarcinogenesis. This suggests a new therapeutic approach through the usage of an anti-IL6 treatment to extend the tumor-free survival of patients undergoing surgical resection. This article is protected by copyright. All rights reserved.

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