Publications by authors named "Irit Ben-Aharon"

66 Publications

Long-term ovarian reserve and fertility outcomes in female survivors of childhood acute lymphoblastic leukemia.

Leuk Lymphoma 2021 Mar 22:1-10. Epub 2021 Mar 22.

Division of Oncology, Rambam Health Care Center, Haifa, Israel.

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, yet data regarding long-term ovarian reserve of female survivors are limited. The aim of this study was to investigate whether there is a differential pattern of anti-Mullerian hormone (AMH) levels in female childhood ALL survivors compared with the normal age-matched population. In a cohort of 56 female childhood ALL survivors (median age 29 years; median follow-up 20.6 years), a negative correlation was found between age at leukemia diagnosis and age-adjusted anti-Mullerian hormone (AMH) levels ( = -0.334,  = .031). Despite alkylating agent therapy, AMH levels did not differ significantly from age-related nomograms (age < 30,  = .17; age ≥ 30,  = .94). The mean number of children per fertile woman adjusted for maternal age was similar to the national average (2.76 versus 3.11,  = .19). Our results imply that reproductive outcomes are not significantly hampered in female pediatric ALL survivors. Long-term surveillance of ovarian reserve may enable personalized survivorship counseling.
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http://dx.doi.org/10.1080/10428194.2021.1901093DOI Listing
March 2021

Chemotherapy-induced acute vascular injury involves intracellular generation of ROS via activation of the acid sphingomyelinase pathway.

Cell Signal 2021 Jun 26;82:109969. Epub 2021 Feb 26.

Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Electronic address:

Several categories of chemotherapy confer substantial risk for late-term vascular morbidity and mortality. In the present study, we aimed to investigate the mechanism of acute chemotherapy-induced vascular injury in normal tissues. Specifically, we looked at activation of the acid sphingomyelinase (ASMase)/ceramide pathway, which leads to generation of reactive oxygen species (ROS) and induction of oxidative stress that may result in vascular injury. In particular, we focused on two distinct drugs, doxorubicin (DOX) and cisplatin (CIS) and their effects on normal endothelial cells. In vitro, DOX resulted in increased ASMase activity, intra-cellular ROS production and induction of apoptosis. CIS treatment generated significantly reduced effects in endothelial cells. In-vivo, murine femoral arterial blood flow was measured in real-time, during and after DOX or CIS administration, using fluorescence optical imaging system. While DOX caused constriction of small vessels and disintegration of large vessels' wall, CIS induced minor vascular changes in arterial blood flow, correlating with the in vitro findings. These results demonstrate that DOX induces acute vascular injury by increased ROS production, via activation of ASMase/ceramide pathway, while CIS increases ROS production and its immediate extracellular translocation, without causing detectable acute vascular injury. Our findings may potentially lead to the development of new strategies to prevent long-term cardiovascular morbidity in cancer survivors.
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http://dx.doi.org/10.1016/j.cellsig.2021.109969DOI Listing
June 2021

Cancer-associated fibroblasts promote aggressive gastric cancer phenotypes via heat shock factor 1-mediated secretion of extracellular vesicles.

Cancer Res 2021 Feb 5. Epub 2021 Feb 5.

Dept. of Biomolecular Sciences, Weizmann Institute of Science

Gastric cancer is the 3rd most lethal cancer worldwide, and evaluation of the genomic status of gastric cancer cells has not translated into effective prognostic or therapeutic strategies. We therefore hypothesize that outcomes may depend on the tumor microenvironment (TME), in particular, cancer-associated fibroblasts (CAF). However, very little is known about the role of CAFs in gastric cancer. To address this, we mapped the transcriptional landscape of human gastric cancer stroma by microdissection and RNA sequencing of CAFs from gastric cancer patients. A stromal gene signature was associated with poor disease outcome, and the transcription factor heat shock factor 1 (HSF1) regulated the signature. HSF1 upregulated inhibin subunit beta A (INHBA) and thrombospondin 2 (THBS2), which were secreted in CAF-derived extracellular vesicles (EV) to the TME to promote cancer. Together, our work provides the first transcriptional map of human gastric cancer stroma and highlights HSF1 and its transcriptional targets as potential diagnostic and therapeutic targets in the genomically stable tumor microenvironment.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-2756DOI Listing
February 2021

Prophylactic Topical Treatment for EGFR Inhibitor-Induced Papulopustular Rash: A Randomized Clinical Trial.

Dermatology 2020 Dec 30:1-7. Epub 2020 Dec 30.

Institute of Oncology, Davidoff Cancer Center, Petah Tikva, Israel.

Background: The incidence of epidermal growth factor receptor inhibitor (EGFRI)-induced papulopustular rash is 60-85%.

Objective: To investigate prophylactic topical treatment for EGFRI-induced rash.

Methods: A single-center, randomized, double-blind, placebo-controlled trial. Adult cancer patients initiating treatment with EGFRIs were randomized to receive facial topical treatment with chloramphenicol 3% + prednisolone 0.5% (CHL-PRED) ointment, chloramphenicol 3% (CHL) ointment, or aqua cream (AQUA). The primary end points were the incidence of ≥grade 3 rash using the Common Terminology Criteria for Adverse Events (CTCAE), on days 14 and 30. A subanalysis was conducted for incidence of a protocol-specified significant rash, defined as ≥10 facial papulopustular lesions.

Results: The per-protocol analysis on day 14 included 69 patients, who received CHL-PRED (21), CHL (23), or AQUA (25). The incidence of CTCAE ≥grade 3 rash was not statistically significant between arms; however, the incidence of the protocol-specified significant rash was: CHL-PRED 14%, CHL 39%, and AQUA 48% (p = 0.03, CHL-PRED vs. AQUA). At 30 days, the CTCAE ≥grade 3 incidence was similar, but the incidences of protocol-specified significant rash were 6%, 16%, and 43% (p = 0.03, CHL-PRED vs. AQUA). No significant differences were found between CHL and CHL-PRED and between CHL and AQUA.

Conclusions: Prophylactic topical CHL-PRED was efficacious when compared to AQUA, in the treatment of EGFRI-induced facial papulopustular rash.
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http://dx.doi.org/10.1159/000511869DOI Listing
December 2020

Anti-HER2/neu Antibody Reduces Chemotherapy-Induced Ovarian Toxicity-From Bench to Bedside.

Biomedicines 2020 Dec 7;8(12). Epub 2020 Dec 7.

Division of Oncology, Rambam Health Care Campus, Haifa 3109601, Israel.

Background: Trastuzumab, a humanized anti-human epidermal growth factor receptor 2 (HER2/neu) antibody, is considered a standard treatment in addition to chemotherapy in the adjuvant setting for HER2/neu-positive breast cancer, yet its impact on fertility and ovarian reserve remains obscure. We aimed to study the effect of anti-HER2/neu on chemotherapy-induced ovarian toxicity in both clinical and preclinical settings.

Methods: We prospectively enrolled breast cancer patients below the age of 42 years who were treated with chemotherapy with or without trastuzumab into the study. Anti-Müllerian hormone (AMH) was measured 6 and 12 months post-chemotherapy as an ovarian reserve indicator. In the animal model, pubertal mice were injected with cyclophosphamide or paclitaxel with or without anti-HER2/neu, or saline, and sacrificed 1 week or 3 months later. Ovarian apoptosis, proliferation and vascularity were measured by immunohistochemistry and ovarian reserve was measured by morphometric analysis and serum-AMH.

Results: Thirty-three patients with early breast cancer were enrolled into the study. Nineteen patients had HER2/neu negative cancer and were treated with chemotherapy and 14 had HER2/neu positive cancer and were treated with chemotherapy and trastuzumab. In all patients, AMH levels declined to undetectable values immediately post-treatment, but regained for 57.1% of the HER2/neu positive cohort and 36.8% of the negative cohort ( < 0.05). In the preclinical setting, anti-HER2/neu antibody, in combination with chemotherapy, displayed lessened ovarian and vascular damage.

Conclusions: Our results indicate that trastuzumab may alleviate chemotherapy-induced ovarian toxicity that may be mediated via its effect on ovarian vasculature.
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http://dx.doi.org/10.3390/biomedicines8120577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762209PMC
December 2020

ERBB2 Pathway in Biliary Tract Carcinoma: Clinical Implications of a Targetable Pathway.

Oncol Res Treat 2021 4;44(1-2):20-27. Epub 2020 Dec 4.

Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petah Tiqwa, Israel.

Background/aims: Current chemotherapy regimens for cholangiocarcinoma (CCA) yield poor outcomes, with a median overall survival of <12 months. Recent data on the genomic landscape of CCAs have created opportunities for targeted therapy. Yet, data regarding its efficacy are scarce. We aimed to describe the genomic landscape of a CCA patient cohort using next-generation sequencing (NGS), focusing on the ERBB/EFGR pathway and assessing response to anti-HER2 agents.

Methods: Tissue samples of intrahepatic CCA (IHCC) and extrahepatic CCA (EHCC) underwent NGS for somatic aberrations. The clinical outcomes for patients treated with anti-HER2 agents were evaluated.

Results: A total of 1,863 CCA cases (1,615 IHCCs and 248 EHCCs) underwent NGS, and they revealed a high prevalence of ERBB alterations (IHCC, 4.2%; EHCC, 9.7%). Among these, 23.8% of the IHCCs and 53.6% of the EHCCs had a point mutation in ERBB2, and 66.6% of the IHCCs and 41.2% of the EHCCs had ERBB copy number amplification. Three EHCC patients were diagnosed at our institute with ERBB/EGFR aberrations; 2 patients were treated with neratinib and 1 patient with a chemotherapy-trastuzumab combination. All 3 achieved disease stabilization and a clinical benefit. One patient underwent a liquid biopsy before and after 3 months of treatment, demonstrating disappearance of the ERBB2 clone and emergence of a Myc-mutated clone after treatment.

Conclusions: The genomic landscape of CCAs may harbor targetable alterations, especially in the ERBB/EGFR pathway. These alterations may have clinical significance in everyday practice.
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http://dx.doi.org/10.1159/000511919DOI Listing
December 2020

Clinical Characteristics and Prognosis of Gastric Cancer Patients with Germline Mutations: Report of Ten Cases and a Literature Review.

Onco Targets Ther 2020 13;13:11637-11644. Epub 2020 Nov 13.

Department of Oncology, Sheba Medical Center, Tel-Hashomer, Israel.

Background: The prognosis of gastric cancer (GC) is poor with a median overall survival (OS) of less than 12 months in advanced-stage disease. The search for distinct genetic subgroups of GC patients and predictive biomarkers is ongoing. While or germline mutations (gBRCAm) have potential therapeutic implications in ovarian, breast and pancreatic cancers, their significance in GC patients has not been established.

Patients And Methods: A retrospective multi-center data analysis of GC patients with gBRCAm was conducted, detailing the clinical characteristics and disease course in this unique subset of patients.

Results: Ten GC patients with gBRCAm were identified, six of them with metastatic disease. The median OS of all ten GC patients was 47.5 (13-192) months. Median OS for patients diagnosed with operable disease was 55.5 (13-192) months and of the patients with metastatic disease (calculated from metastatic disease diagnosis) 32 (15-52) months with an exceptional 1-, 2- and 3-year survival rate of 100%, 83.3% and 50%, respectively.

Conclusion: These preliminary data suggest that gBRCAm in GC patients are associated with a favorable prognosis. Furthermore, gBRCAm might be a predictive biomarker to DNA-damaging agents response in GC patients, similarly to its established role in other malignancies. Further research is needed to confirm our findings.
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http://dx.doi.org/10.2147/OTT.S276814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677647PMC
November 2020

The Potential Role of Immune Alteration in the Cancer-COVID19 Equation-A Prospective Longitudinal Study.

Cancers (Basel) 2020 Aug 26;12(9). Epub 2020 Aug 26.

Division of Oncology, Rambam Health Care Campus, Haifa 31096, Israel.

The risk of cancer patients to develop COVID19 infection is unclear. We aimed to prospectively study cancer patients and oncology healthcare workers for COVID19 serology. In IgG+ cases, immune profile was determined to portray the pattern of immune response to SARS-CoV2. Cancer patients on active treatment and healthcare workers were enrolled. During the study period (3/2020-6/2020), demographic data and blood were collected at three time points. Expression of IgG, IgM, and IgA were assessed. In SARS-CoV-2 IgG+ cases and matched negative cases, we performed mass cytometry time of flight (CyTOF) analysis on the basis of the expression of surface markers. The study included 164 cancer patients on active intravenous treatment and 107 healthcare workers at the cancer center. No symptomatic cases were reported during the study period. Serology analysis revealed four IgG+ patients (2.4%) and two IgG+ healthcare workers (1.9%)-all were asymptomatic. CyTOF analysis demonstrated substantial reduction in myeloid cells in healthcare workers who were SARS-CoV-2 IgG+ compared to those who were SARS-CoV-2 IgG-, whereas in cancer patients, the reduction was relatively milder (≈50% reduction in SARS-CoV-2 IgG+ cancer patients compared with ≈90% reduction in SARS-CoV-2 IgG+ workers). Our results indicate a similar rate of asymptomatic COVID19 infection in cancer patients and healthcare workers in a longitudinal study throughout the pandemic time. Due to differential immune cell profiles of cancer patients who are treated with immunomodulatory agents, the host response to the SARS-COV2 may play a role in COVID19 course and representation. The immunological perspective of cancer treatments on the risk for COVID19 infection should be further explored.
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http://dx.doi.org/10.3390/cancers12092421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563644PMC
August 2020

Cancer During Pregnancy: The Role of Vascular Toxicity in Chemotherapy-Induced Placental Toxicity.

Cancers (Basel) 2020 May 18;12(5). Epub 2020 May 18.

Oncology, Rambam Health Care Center, Haifa 3109601, Israel.

Breast cancer is diagnosed in ~0.3% of pregnant women. Studies that have addressed gestational and neonatal outcomes of chemotherapy during pregnancy have demonstrated increased gestational complications including preeclampsia and intrauterine growth retardation. We hypothesized that anthracycline-induced gestational complications could be derived from direct toxicity on the placenta vasculature. Pregnant ICR mice (day E12.5) were treated with doxorubicin (DXR; 8 mg/kg) or saline, while their umbilical cord blood flow was imaged by pulse-wave (PW) Doppler. Mice were euthanized on day E18.5, and their embryos and placentae were collected for further analysis. Unlike control mice, the DXR-treated mice presented an acute change in the umbilical cord's blood flow parameters (velocity time integral and heart rate interval), reduced embryos' weight, reduced placenta efficiency, and modulation in vascular-related pathways of treated placenta proteomics. Apoptosis and proliferation were also enhanced, as demonstrated by TUNEL and proliferating cell nuclear antigen (PCNA) analysis. We further examined the placentae of patients treated with epirubicin (EPI), who had been diagnosed with breast cancer during pregnancy (weeks 27-35). The immunohistochemistry of the EPI-treated human placentae showed enhanced proliferation and apoptosis as compared with matched chemo-naïve placentae, as well as reduced neovascularization (CD34). Our findings suggest that anthracycline-induced vascular insult promotes placental toxicity, and could point to potential agents designated to offset the damage and to reduce gestational complications in pregnant cancer patients.
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http://dx.doi.org/10.3390/cancers12051277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7281110PMC
May 2020

Young patients with cancer and a digital social network: the voice beyond the clinic.

ESMO Open 2020 05;5(3):e000651

Gastrointestinal Tract Cancer Group, EORTC, Brussels, Belgium; Hematology, Cell Therapy, Medical Oncology, Hemostaseology, University of Leipzig Faculty of Medicine, Leipzig, Sachsen, Germany.

Introduction: Digital social networks have become a key player in the ecosystem of young patients with cancer, with regard to their unique perspectives and unmet needs. This study aims to investigate the web-based social community tools and to characterise the user profile, unmet needs and goals of young patients with cancer.

Methods: A web-based survey was distributed via large-scale social network designated for young patients with cancer (age 18-45 years) Stop Cancer. The survey collected demographic data and oncological status. Primary outcome was potential goals of accessing the network; secondary outcomes were emotional impact, effect of disease status, education, marital status and employment, on user satisfaction rate.

Results: The survey was available for 5 days (10/2018) and was filled by 523 participants. Breast cancer, haematological malignancies and colorectal cancer were the most common diagnoses. The majority had non-metastatic disease at diagnosis, 79% had no evidence of disease at time of the survey. Forty-five per cent considered the network as a reliable source for medical information. Academic education was associated with higher satisfaction from the platform. There were no differences between cancer survivors and patients with active disease in patterns of platform usage. The social network had an allocated section for 'patient mentoring' of newly diagnosed members by survivors.

Discussion: Our study portrayed the user prototype of a social digital network among young adult patients with cancer, indicating challenging trends. Whereas social media may prove a powerful tool for patients and physicians alike, it may also serve as a research tool to appraise wide practices within a heterogeneous population. Nevertheless, it acts as a double-edged sword in the setting of uncontrolled medical information. It is our role as healthcare providers to join this race and play an active role in shaping its medical perspectives.
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http://dx.doi.org/10.1136/esmoopen-2019-000651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228558PMC
May 2020

miR-125a Induces HER2 Expression and Sensitivity to Trastuzumab in Triple-Negative Breast Cancer Lines.

Front Oncol 2020 28;10:191. Epub 2020 Feb 28.

Division of Oncology, Rambam Health Care, Haifa, Israel.

The EGFR/HER2 signaling network is an effective therapeutic target for HER2-positive cancers, which are known for their aggressive biological course. Evidence indicates that the EGFR/HER2 network plays a role in the aggressive basal-like subtype as well. Here, we studied the potential role of miR-125a-3p as a modulator of the EGFR/HER2 pathway in basal-like breast cancer. Over-expression of miR-125a-3p reduced the migratory capability of MDA-MB-231 cells and led to an increase in the expression of ErbB2 transcript and protein. The induced ErbB2 responded to trastuzumab and underwent internalization and subsequent intra-lysosomal degradation. Trastuzumab treatment further reduced the migratory capability and induced the apoptosis of the cells. An mouse model, which supported the findings, showed a synergistic effect for miR-125a-3p and trastuzumab. Trastuzumab-treated miR-125a-3p-induced tumors were significantly smaller than control induced tumors. Our findings indicate that, in the basal-like subtype of breast cancer, miR-125a-3p may act as a tumor suppressor. miR-125a-3p induces an increase in the expression of ErbB2 that may render the cells suitable for treatment with anti-HER2 therapies.
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http://dx.doi.org/10.3389/fonc.2020.00191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7058585PMC
February 2020

Young-onset gastric cancer and Epstein-Barr Virus (EBV) - a major player in the pathogenesis?

BMC Cancer 2020 Jan 14;20(1):34. Epub 2020 Jan 14.

Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Ze'ev Jabotinsky Rd 39, 4941492, Petah Tikva, Israel.

Objective: Gastric cancer (GC) is a leading cause of cancer death, occurs predominantly in older age, with increasing incidence in young patients. The Cancer Genome Atlas indicates four subtypes for GC among which Epstein-Barr virus (EBV) subtype is estimated at 8.7%. We aim to determine the prevalence of EBV subtype in young GC patients (≤45 years) compared with an average-onset cohort (≥55 years) and characterize the clinicopathologic pattern of young-onset GC.

Methods: Gastric cancer samples of patients of both cohorts were screened for EBV by qPCR. Additional staining was done for Human epidermal growth factor receptor 2 (HER2), microsatellite instability (MSI) status and Programmed death-ligand 1 (PD-L1). Demographics and clinical data were retrieved from the medical records.

Results: Thirty-nine young-onset and 35 average-onset GC patients were reviewed. There was no apparent difference in tumor location, family history, histology and HER2 status between the cohorts. More young-onset patients were diagnosed with metastatic disease (27% vs 9%, p = 0.0498). EBV was significantly more prevalent in the young-onset cohort (33% vs 11%, p = 0.025). 15/17 EBV positive patients were under the median age of diagnosis for GC in the US (68 years). MSI-H was found only in the average-onset cohort [0% vs 27%, p = 0.001). PD-L1 positivity was higher in the young-onset cohort (31% vs 3%, p = 0.002).

Conclusion: Our study indicates that EBV subtype is more prevalent in young-onset GC and may play a key role in the pathogenesis. Higher rate of PD-L1 positivity in young-onset GC could change treatment strategies. We are currently evaluating these findings in a prospective trial.
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http://dx.doi.org/10.1186/s12885-020-6517-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6961297PMC
January 2020

Breast Cancer during Pregnancy-Current Paradigms, Paths to Explore.

Cancers (Basel) 2019 Oct 28;11(11). Epub 2019 Oct 28.

Division of Oncology, Rambam Health Care Center, Haifa 3109601, Israel.

Breast cancer is the most common form of malignancy in pregnant women. The prevalence of pregnancy-associated breast cancer (PABC) is up to 0.04% of pregnancies and is expected to rise in developed countries. PABC represents a unique clinical scenario which requires a delicate balance of risks and benefits for both maternal and fetal well-being. Currently, there is paucity of data regarding the short- and long-term outcomes of in-utero exposure to anti-neoplastic agents. In general, when possible, treatment for PABC should follow the same guidelines as in non-pregnant patients. Surgery, including sentinel lymph node biopsy, is possible during all trimesters of pregnancy. Radiotherapy is contraindicated during pregnancy, although it might be considered in highly selected patients based on risk-benefit assessment. Evidence supports that administration of chemotherapy may be safe during the second and third trimesters, with cessation of treatment three weeks prior to expected delivery. Currently, hormonal therapy and anti-HER2 agents are contraindicated during pregnancy and should be postponed until after delivery. Prematurity is associated with worse neonatal and long-term outcomes, and thus should be avoided. While current data on the long-term effects of anti-neoplastic treatments are reassuring, grade of evidence is lacking, hence additional large prospective studies with long-term follow-up are essential to rule out any treatment-induced adverse effects.
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http://dx.doi.org/10.3390/cancers11111669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896197PMC
October 2019

Social networks for young patients with cancer: the time for system agility.

Lancet Oncol 2019 Jun;20(6):765

European Organisation for Treatment and Research of Cancer, Gastrointestinal Tract Cancer Group, Brussels, Belgium; University Cancer Center Leipzig and University Medicine Leipzig, Leipzig, Germany.

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http://dx.doi.org/10.1016/S1470-2045(19)30346-8DOI Listing
June 2019

Sidedness Matters: Surrogate Biomarkers Prognosticate Colorectal Cancer upon Anatomic Location.

Oncologist 2019 08 12;24(8):e696-e701. Epub 2019 Feb 12.

Institute of Oncology, Davidoff Cancer Center, Beilinson Hospital, Petah Tikva, Israel.

Background: Anatomic location of primary tumors across the colon correlate with survival in the metastatic setting, whereas left-sided tumors may exhibit superior survival compared with right-sided tumors. The Oncotype Recurrence Score (RS) assay is a clinically validated predictor of recurrence risk in patients with stage II colorectal cancer (CRC). Previous studies had indicated that without adjuvant chemotherapy, CDX2-negative stage II CRC tumors are associated with a lower rate of disease-free survival than CDX2-positive stage II CRC tumors. We aimed to evaluate whether these two validated prognostic biomarkers may correlate with primary tumor location, and whether tumor location may reflect differential prognosis in stage II CRC.

Materials And Methods: We retrospectively analyzed patients with T3 mismatch repair-proficient (MMR-P) stage II CRC for whom RS assay was performed. Pathological report was reviewed for exact primary tumor location and CDX2 immunostaining. RS and CDX2 expression were correlated with primary tumor location.

Results: The analysis included 1,147 patients with MMR-P stage II CRC (median age 69 years [range 29-93]). Tumor distribution across the colon was as follows: 46% ( = 551) were right-sided and 54% ( = 596) were left-sided. RS was higher in right-sided tumors ( = .01). The RS results gradually decreased across the colon (cecum, highest score; sigmoid, lowest score; = .04). Right-sided tumors exhibited more CDX2-negative tumors ( = .07).

Conclusion: Our study indicates that right-sided colorectal tumors may display worse prognosis compared with left-sided tumors in MMR-P stage II CRC. Primary tumor location may serve as a prognostic factor that should be taken into account for recurrence risk assessment and consideration of adjuvant treatment.

Implications For Practice: Sidedness matters, even in stage II colorectal cancer (CRC). Using two previously established prognostic tools, the Oncotype DX assay and CDX2 expression, this study found that right-sided tumors may display worse prognosis compared with left-sided tumors in mismatch repair-proficient stage II CRC. Therefore, primary tumor location should be taken into account for recurrence risk assessment and consideration of adjuvant treatment.
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http://dx.doi.org/10.1634/theoncologist.2018-0351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693694PMC
August 2019

Genomic Landscape of Pancreatic Adenocarcinoma in Younger versus Older Patients: Does Age Matter?

Clin Cancer Res 2019 04 7;25(7):2185-2193. Epub 2019 Jan 7.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: State-of-the-art genomic analyses of pancreatic adenocarcinoma (PDAC) have yielded insight into signaling pathways underlying carcinogenesis. PDAC is characterized by substantial genomic heterogeneity. We aimed to determine whether early-onset PDAC (EOPC; ≤55 years) displays a distinctive molecular landscape from average-age onset PDAC (AOPC; ≥70 years).

Experimental Design: Three distinct datasets for PDAC were analyzed. In the first, patients undergoing treatment at Memorial Sloan Kettering (MSK) were consented for MSK-IMPACT next-generation sequencing. The second cohort analyzed was The Cancer Genome Atlas (TCGA) dataset for differences in somatic mutations, gene expression, and protein expression. The third dataset was an Australian cohort of PDAC. Clinical data were correlated with genomic analyses.

Results: A total of 293 samples were analyzed, yielding 90 patients aged ≤55 years and 203 patients aged ≥70 years. Among the genes known to be associated with carcinogenesis, displayed higher mutation rates in younger patients. Comprehensive transcriptomic analysis of cellular pathways indicated that the TGFβ pathway has increased activation, and the expression levels of phospho-GSK3 were higher in EOPC. Survival outcomes revealed no differences between age groups.

Conclusions: These exploratory analyses suggest that there may be somatic gene alterations within the population of patients with early-onset PDAC that involve unique cellular pathways compared with average-onset PDAC. Former studies imply these cellular pathways may play a role in smoking-related PDAC carcinogenesis. Larger genomic datasets are warranted for future evaluation to extend these observations.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786265PMC
April 2019

Early PET-CT in patients with pathological stage III colon cancer may improve their outcome: Results from a large retrospective study.

Cancer Med 2018 11 22;7(11):5470-5477. Epub 2018 Oct 22.

Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Petach Tiqva, Israel.

Background: Current staging of pathological stage III colon cancer (CC) is suboptimal; many patients recur despite unremarkable preoperative staging. We previously reported that early postoperative PET-CT can alter the stage and management of up to 15% of patients with high-risk stage III CC. This study aimed to determine the role of the test in the general stage III CC population.

Methods: A retrospective study of all consecutive patients with stage III CC who underwent early postoperative PET-CT between 2005 and 2017.

Results: A total of 342 patients, 166 (48.5%) males, median age 66 years (range, 29-90), were included. Pathological stage was IIIA, IIIB, and IIIC in 18 (5.3%), 257 (75.1%), and 67 (19.6%) patients, respectively. Median number of positive lymph nodes was 2 (range, 0-32). PET-CT results modified the management of 46 patients (13.4%): 37 (10.8%) with overt metastatic disease and 9 (2.6%) with a second primary. The 5-year disease-free survival for true stage III patients was 81%. The median overall survival for the entire cohort and for true stage III patients was not reached and was 57.2 months for true stage IV. Of the 37 patients found to be metastatic, 14 (37.8%) underwent curative treatments and 9/14 (64.3%) remain disease-free, with a median follow-up of 83.8 months. Predictive factors for upstaging following PET-CT were identified.

Conclusion: Early postoperative PET-CT changed the staging and treatment of 13.4% of stage III CC patients and has the potential for early detection of curable metastatic disease. Outcome results are encouraging. Prospective validation is ongoing.
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http://dx.doi.org/10.1002/cam4.1818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6246942PMC
November 2018

Treosulfan induces distinctive gonadal toxicity compared with busulfan.

Oncotarget 2018 Apr 10;9(27):19317-19327. Epub 2018 Apr 10.

Institute of Oncology, Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah-Tiqva, Israel.

Treosulfan (L-treitol-1,4-bis-methanesulfonate) has been increasingly incorporated as a main conditioning protocol for hematopoietic stem cell transplantation in pediatric malignant and non-malignant diseases. Treosulfan presents lower toxicity profile than other conventional alkylating agents containing myeloablative and immunosuppressive traits such as busulfan. Yet, whereas busulfan is considered highly gonadotoxic, the gonadal toxicity profile of treosulfan remains to be elucidated. To study the gonadotoxicity of treosulfan, pubertal and prepubertal male and female mice were injected with treosulfan or busulfan and sacrificed one week, one month or six months later. Testicular function was assessed by measurements of sperm properties, testes and epididymides weights as well as markers for testicular reserve, proliferation and apoptosis. Ovarian function was assessed by measurements of ovary weight and markers for ovarian reserve, proliferation and apoptosis. Treosulfan testicular toxicity was milder than that of busulfan toxicity; possibly by sparing the stem spermatogonia in the testicular sanctuary. By contrast, ovarian toxicity of both treosulfan and busulfan was severe and permanent and displayed irreversible reduction of reserve primordial follicles in the ovaries. Our data indicate that treosulfan exerts a different gonadal toxicity profile from busulfan, manifested by mild testicular toxicity and severe ovarian toxicity.
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http://dx.doi.org/10.18632/oncotarget.25029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5922399PMC
April 2018

Premature ovarian aging in carriers: a prototype of systemic precocious aging?

Oncotarget 2018 Mar 23;9(22):15931-15941. Epub 2018 Mar 23.

Institute of Oncology, Davidoff Center, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel.

Purpose: Though former evidence implies a correlation of breast cancer susceptibility gene () mutation with reduced ovarian reserve, the data is yet inconsistent. Our aim was to investigate biomarkers of ovarian aging in a cohort of young healthy carriers of the mutation. We hypothesized that the role played by genes in aging pathways is not exclusive to the ovary.

Experimental Design: Healthy female carriers, 40 years or younger and healthy male carriers, 50 years or younger, were enrolled in the study. Serum anti-mullerian Hormone (AMH), fibroblast growth factor-23 (FGF-23), Klotho and IL-1 were measured by enzyme-linked immunosorbent assay (ELISA). Ovarian AMH and protein kinase B (AKT) mRNA from carriers who underwent prophylactic oophorectomy and from age-matched, healthy, non-carriers who underwent partial oophorectomy due to benign conditions were analyzed by qPCR.

Results: Thirty-three female (median age 35y) and 20 male (44y) carriers were enrolled into the study and matched to control non-carriers (34y and 43y, respectively). Serum AMH level was significantly lower in female carriers than in both non-carrier controls and age-matched nomograms. The levels of ovarian AMH and AKT mRNA were significantly lower in carriers than in controls. The systemic aging cytokines FGF-23, klotho and IL-1 displayed a differential expression in carriers of both genders. FGF-23 level was higher in carriers (P=0.06).

Conclusions: Our results suggest a link between mutation, accelerated ovarian aging and systemic aging-related pathophysiology.
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http://dx.doi.org/10.18632/oncotarget.24638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882308PMC
March 2018

Use of Aromatase Inhibitors in IVF for Fertility Preservation of Non-Breast Cancer Patients: A Case Series.

Isr Med Assoc J 2018 Mar;20(3):145-146

Department of Obstetrics and Gynecology, Davidoff Center, Rabin Medical Center (Beilinson Campus), Petah Tikva, associated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: Controlled ovarian hyperstimulation (COH) followed by oocyte retrieval is a leading option for fertility preservation before chemotherapy, yet this procedure causes excessive serum levels of estradiol (E2), which are often detrimental for cancer patients. Aromatase inhibitors are often used in breast cancer patients during COH to prevent elevated levels of E2.

Objectives: To describe our experience with COH for oocyte cryopreservation in non-breast cancer patients using aromatase inhibitors.

Methods: Of the five patients treated, two had an aggressive abdominal desmoid tumor, one had endometrial carcinoma, one had uterine sarcoma, and one patient had a brain oligodendroglioma. In all cases the treating oncologist suggested an association between estrogen and possible tumor progression. All patients were treated with a standard in vitro fertilization antagonist protocol combined with aromatase inhibitors, similar to the protocol used for breast cancer patients.

Results: The average duration of treatment was 10.5 days, mean peak E2 was 2348 pmol/L, mean number of oocytes aspirated was 17.3, and a mean of 14.6 embryos/oocytes were cryopreserved.

Conclusions: COH with aromatase inhibitors is apparently effective in non-breast cancer patients and spares exposure to high E2 levels.
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March 2018

Brain metastasis in gastroesophageal adenocarcinoma and HER2 status.

J Neurooncol 2018 Jun 10;138(2):315-320. Epub 2018 Feb 10.

Neuro-Oncology Center, Davidoff Center, Rabin Medical Center, Beilinson Hospital, 4941492, Petach Tikva, Israel.

The increased survival of patients with gastroesophageal adenocarcinoma (GAD) following improvements in treatment has been accompanied by a rising incidence of secondary brain metastasis. HER2 amplification/overexpression, which has been associated with an increased risk of brain metastasis in breast cancer, is found in about 20% of patients with GAD. The aim of this study was to evaluate the effect of HER2 status on brain metastasis in GAD. The database of a tertiary cancer center was searched for patients with GAD diagnosed in 2011-2015, and data were collected on clinical characteristics, brain metastasis, HER2 status, and outcome. We identified 404 patients with a confirmed diagnosis of GAD. HER2 results were available for 298: 69 (23.2%) positive and 227 negative. Brain metastasis developed in 15 patients with GAD (3.7%); HER2 results, available in 13, were positive in 6, negative in 6, and equivocal in 1. The brain metastasis rate was significantly higher in HER2-positive than HER2-negative patients with GAD (6/69, 8.7% vs. 6/227, 2.6%; RR = 3.3, 95% CI 1.1-9.9, p = 0.034). Median overall survival from diagnosis of brain metastasis was 2.3 months, with no significant difference by HER2 status. HER2 positive GAD patients may be at increased risk to develop BM. Clinicians should maintain a lower threshold for performing brain imaging in patients with HER2-positive GAD given their increased risk of brain metastasis. The role of anti-HER2 agents in the development and treatment of brain metastasis in GAD warrants further study.
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http://dx.doi.org/10.1007/s11060-018-2798-4DOI Listing
June 2018

Can molecular profiling enhance radiotherapy? Impact of personalized targeted gold nanoparticles on radiosensitivity and imaging of adenoid cystic carcinoma.

Theranostics 2017 14;7(16):3962-3971. Epub 2017 Sep 14.

Sackler Faculty of Medicine, Tel-Aviv University, Ramat Aviv, Israel.

Personalized molecular profiling has an established role in selection of treatment for metastatic disease; however, its role in improving radiosensitivity and functional imaging has not been evaluated. In the current study, we examined molecular profiling as a tool for designing personalized targeted gold nanoparticles (GNP) to serve as dual-modal tumor radiosensitizers and functional imaging enhancers. To this end, molecular profiling of a patient's salivary gland adenoid cystic carcinoma (ACC) was performed, and anaplastic lymphoma kinase (ALK) mutation was detected. The extracted tumor was subcutaneously injected into mice, which were then treated either with radiation, the specific ALK inhibitor crizotinib, or a combination of therapies. One of these combinations, namely, ALK-targeted GNP (via crizotinib coating), was found to enhance radiation treatment, as demonstrated by a significant decrease in tumor volume over 24 days. In parallel, ALK-targeted GNP substantially augmented tumor visualization via computed tomography. The mechanism of radiosensitivity enhancement was mostly related to a diminished cell repair mechanism in tumors, as demonstrated by proliferating cell nuclear antigen staining. These findings indicate that personalized molecular profiling is an effective technique for enhancing cancer theranostics.
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http://dx.doi.org/10.7150/thno.19615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667418PMC
June 2018

Esophageal Cancer in Israel has Unique Clinico-Pathological Features: A Retrospective Study.

J Cancer 2017 22;8(13):2417-2423. Epub 2017 Jul 22.

Institute of Oncology, Davidoff Center, Rabin Medical Center, Petach Tikva, Israel.

Data regarding esophageal cancer (EC) in Israel are limited. The aim of this study was hence to characterize this entity in the Israeli population and to compare it to the literature. This is a retrospective study of all consecutive EC patients treated at our institution between 1997-2013. Data were retrieved from patients' medical files. Two hundred patients were included. The median age at diagnosis was 70.5 years; 63.5% were males; 63% were Ashkenazi Jews, 29% were Sephardic Jews, and 0.5% were Arabs. Squamous cell carcinoma (SCC) was predominant: 52% versus 45.5% with adenocarcinoma (ADC). SCC was common even in the distal esophagus (45%). The overall 5-year survival rate was 25.5%. A temporal trend (2006-2013 vs 1997-2005) shows a decline in the proportion of SCC (47% vs 63%, p=0.061) and a rise in ADC (50% vs 33%, p=0.041), with a parallel decrease in patients' age (median: 68.5 vs 73 years, p=0.014). In the later period, patients received more treatment for localized and metastatic disease, with a trend for improved median survival (20.1 vs 14.9 months, p=0.658). Ashkenazi Jews were diagnosed at an older age than Sephardic Jews (median: 73 vs. 65 years, p=0.001), had a higher rate of family history of GI cancer (34% vs. 17%, p=0.026) and a higher rate of cardiovascular co-morbidity (41% vs. 24%, p=0.041). EC in Israel represents an intermediate entity between the Western and the endemic subtypes, showing some unique features. These included delayed reversal of the SCC/ADC ratio, commonness of SCC in the distal esophagus, prevalence of other malignancies and predominance of Ashkenazi ethnicity. The reason for these findings is unclear and its further evaluation is warranted.
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http://dx.doi.org/10.7150/jca.19210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595070PMC
July 2017

[FERTILITY PRESERVATION IN YOUNG CANCER PATIENTS - CAN WE OPTIMIZE THE PATH?]

Harefuah 2017 May;156(5):326-329

Department of Pediatric Oncology, Schneider Children's Hospital, Petah Tikvah.

Introduction: Advances in cancer therapy have improved the long-term survival of cancer patients. Concerns about fertility represent a major issue for young cancer patients. The emergent discipline of oncofertility, an intersection between oncology and fertility, is a new concept that describes an integrated network of clinical resources that focus on fertility preservation from both clinical and research perspectives. Patients and methods: In this article we describe our designated multidisciplinary program for fertility preservation in pediatric and young adult populations. The program is also designed to serve as a prospective platform for the evaluation of reproductive outcomes in this patient cohort.

Results: We have observed considerably higher referral rates following launching the program and earlier referral of chemonaïve patients that concedes maximal fertility preservation. Two hundred and thirty five patients were referred to the program over a period of 3 years.

Conclusions: Our program demonstrates that multidisciplinary programs that encompass relevant specialists, skilled laboratory resources and a facilitated path that drives the process in the shortest time, maximizes the yield.
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May 2017

Role of Induction Chemotherapy Prior to Chemoradiation in Head and Neck Squamous Cell Cancer-Systematic Review and Meta-analysis.

Cancer J 2017 Mar/Apr;23(2):79-83

From the *Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petah Tikva; †Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and ‡Division of Hematology/Oncology, Department of Medicine, and Translational Science, UC San Diego Moores Cancer Center, La Jolla, CA.

The objective of this study was to review and assess the impact of additional induction chemotherapy to concomitant chemoradiation in head and neck squamous cell cancer. We performed a comparative systematic review and meta-analysis of clinical trials of induction chemotherapy + chemoradiation and chemoradiation alone in this setting. We identified trials randomizing 1314 patients (published 2004-2015). A non-statistically significant trend was observed in favor of induction chemotherapy + chemoradiation on overall survival (hazard ratio, 0.88; 95% confidence interval, 0.75-1.04). Disease control was superior in the induction chemotherapy + chemoradiation group (hazard ratio, 0.69; 95% confidence interval, 0.57-0.83). The rate of complete response improved with induction chemotherapy compared with concomitant chemoradiation (relative risk, 1.52; 95% confidence interval, 1.20-1.92). This study showed no benefit of induction chemotherapy + chemoradiation on overall survival. However, improved complete response rate and death certificate-only registrations may imply that selected patients may benefit from induction chemotherapy.
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http://dx.doi.org/10.1097/PPO.0000000000000253DOI Listing
May 2017

Octogenarian patients with colorectal cancer: Characterizing an emerging clinical entity.

World J Gastroenterol 2017 Feb;23(8):1387-1396

Hadar Goldvaser, Irit Ben-Aharon, Ofer Purim, Yulia Kundel, Aaron Sulkes, Baruch Brenner, Institute of Oncology, Davidoff Cancer Center, Beilinson Hospital, Rabin Medical Center, Petach Tikva 4941492, Israel.

Aim: To characterize colorectal cancer (CRC) in octogenarians as compared with younger patients.

Methods: A single-center, retrospective cohort study which included patients diagnosed with CRC at the age of 80 years or older between 2008-2013. A control group included consecutive patients younger than 80 years diagnosed with CRC during the same period. Clinicopathological characteristics, treatment and outcome were compared between the groups. Fisher's exact test was used for dichotomous variables and was used for variables with more than two categories. Overall survival was assessed by Kaplan-Meier survival analysis, with the log-rank test. Cancer specific survival (CSS) and disease-free survival were assessed by the Cox proportional hazards model, with the Fine and Gray correction for non-cancer death as a competing risk.

Results: The study included 350 patients, 175 patients in each group. Median follow-up was 40.2 mo (range 1.8-97.5). Several significant differences were noted. Octogenarians had a higher proportion of Ashkenazi ethnicity (64.8% 47.9%, < 0.001), a higher rate of personal history of other malignancies (22.4% 13.7%, = 0.035) and lower rates of family history of any cancer (36.6% 64.6%, < 0.001) and family history of CRC (14.4% 27.3%, = 0.006). CRC diagnosis by screening was less frequent in octogenarians (5.7% 20%, < 0.001) and presentation with performance status (PS) of 0-1 was less common in octogenarians (71% 93.9%, < 0.001). Octogenarians were more likely to have tumors located in the right colon (45.7% 34.3%, = 0.029) and had a lower prevalence of well differentiated histology (10.4% 19.3%, = 0.025). They received less treatment and treatment was less aggressive, both in patients with metastatic and non-metastatic disease, regardless of PS. Their 5-year CSS was worse (63.4% 77.6%, = 0.009), both for metastatic (21% 43%, = 0.03) and for non-metastatic disease (76% 88%, = 0.028).

Conclusion: Octogenarians presented with several distinct characteristics and had worse outcome. Further research is warranted to better define this growing population.
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http://dx.doi.org/10.3748/wjg.v23.i8.1387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330823PMC
February 2017

Optimizing the process of fertility preservation in pediatric female cancer patients - a multidisciplinary program.

BMC Cancer 2016 08 9;16:620. Epub 2016 Aug 9.

Department of Pediatric Oncology, Schneider Children's Hospital, Petah Tikvah and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background: Current evidence indicates sub-optimal incidence of fertility preservation (FP) in eligible patients. We present herein our designated multidisciplinary program for FP in pediatric and adolescent population and present our data on FP in female patients.

Methods: Pediatric patients (age 0-18) who were candidate for highly gonadotoxic treatments were referred to FP program for a multidisciplinary discussion and gonadal risk-assessment followed by either oocyte cryopreservation or ovarian cryopreservation (OCP) for female patients, and sperm banking for male patients. The OCP protocol consists of aspiration of oocytes from small antral follicles and in-vitro maturation followed by cryopreservation, as well as ovarian tissue cryopreservation.

Results: The establishment of a designated FP program resulted in a significant increase in referral and subsequent FP procedures of all eligible patients. Sixty-two female patients were referred for FP discussion during a period of 36 months; 41 underwent OCP; 11 underwent oocyte cryopreservation and six were declined due to parental decision. The median age was 13.2y (range 18 months-18y). Thirty-two (51.6 %) were chemotherapy-naïve. Seventeen patients (27 %) had sarcoma, 16 patients (26 %) had acute leukemia. The mean number of mature oocytes that were eventually vitrified was significantly higher in chemotherapy-naïve patients compared with chemotherapy-exposed patients (mean 12 oocytes (1-42) versus 2 (0-7)).

Conclusion: Multidisciplinary programs that encompass experts of all relevant fields, skilled laboratory resources and a facilitated path appear to maximize the yield. We observed a considerable higher referral rates following launching a designated program and earlier OCP in chemo-naïve patients that culminated in a better fertility preservation procedure.
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http://dx.doi.org/10.1186/s12885-016-2584-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979150PMC
August 2016

Cetuximab intensifies cisplatin-induced testicular toxicity.

Reprod Biomed Online 2016 Jul 20;33(1):102-10. Epub 2016 Apr 20.

Institute of Oncology, Davidoff Center, Rabin Medical Center, Beilinson Campus, Petah-Tiqva, and Sackler Faculty of Medicine, Tel-Aviv University, Israel. Electronic address:

Epidermal growth factor receptor (EGFR) has proliferative properties in the testis. Cetuximab, an anti-EGFR, is administered together with chemotherapy to patients with various types of cancer. This studies aim was to investigate the effect of cetuximab on testicular function. Adult male mice were injected with cetuximab (10 mg/kg), cisplatin (8 mg/kg) or a combination of both, and killed one week or one month later. The doses were chosen by human equivalent dose calculation. Testicular function was evaluated by epididymal-spermatozoa total motile count and sperm motility, weights of testes and epididymides, and the level of anti-Müllerian hormone (AMH) in the serum. Immunohistochemistry was performed to examine germ cell proliferation (Ki-67), apoptosis (Terminal transferase-mediated deoxyuridine 5-triphosphate nick-end labelling), reserve (DAZL-Deleted in azoospermia-like, Promyelocytic leukaemia zinc-finger), blood vessels (CD34) and Sertoli cells (GATA-4). Administration of cetuximab alone increased testicular apoptosis and decreased epididymal-spermatozoa total motile count over time. When added to cisplatin, cetuximab exacerbated most of the recorded testicular parameters, compared with the effect of cisplatin alone, including testis and epididymis weights, epididymal-spermatozoa total motile count, AMH concentration, meiosis and apoptosis. In conclusion, cetuximab has only a mild effect on testicular reserve, but when added to cisplatin, it exacerbates cisplatin-induced testicular toxicity.
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http://dx.doi.org/10.1016/j.rbmo.2016.04.004DOI Listing
July 2016

Actively targeted gold nanoparticles as novel radiosensitizer agents: an in vivo head and neck cancer model.

Nanoscale 2016 Feb;8(5):2678-85

Faculty of Engineering & The Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan 5290002, Israel.

A major problem in the treatment of head and neck cancer today is the resistance of tumors to traditional radiation therapy, which results in 40% local failure, despite aggressive treatment. The main objective of this study was to develop a technique which will overcome tumor radioresistance by increasing the radiation absorbed in the tumor using cetuximab targeted gold nanoparticles (GNPs), in clinically relevant energies and radiation dosage. In addition, we have investigated the biological mechanisms underlying tumor shrinkage and the in vivo toxicity of GNP. The results showed that targeted GNP enhanced the radiation effect and had a significant impact on tumor growth (P < 0.001). The mechanism of radiation enhancement was found to be related to earlier and greater apoptosis (TUNEL assay), angiogenesis inhibition (by CD34 level) and diminished repair mechanism (PCNA staining). Additionally, GNPs have been proven to be safe as no evidence of toxicity has been observed.
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http://dx.doi.org/10.1039/c5nr07496gDOI Listing
February 2016

BRCA1/2 mutations perturb telomere biology: characterization of structural and functional abnormalities in vitro and in vivo.

Oncotarget 2016 Jan;7(3):2433-54

The Felsenstein Medical Research Center, Beilinson Medical Center, Tel-Aviv University, Tel-Aviv, Israel.

BRCA1 mutation is associated with carcinogenesis, especially of breast tissue. Telomere maintenance is crucial for malignant transformation. Being a part of the DNA repair machinery, BRCA1 may be implicated in telomere biology. We explored the role of BRCA1 in telomere maintenance in lymphocytes of BRCA1/2 mutation carriers and in in vitro system by knocking down its expression in non-malignant breast epithelial cells.The results in both systems were similar. BRCA1/2 mutation caused perturbation of telomere homeostasis, shortening of the single stranded telomere overhang and increased the intercellular telomere length variability as well as the number of telomere free chromosomal ends and telomeric circles. These changes resulted in an increased DNA damage status. Telomerase activity, inducibility and expression remained unchanged. BRCA1 mutation resulted also in changes in the binding of shelterin proteins to telomeres. DNMT-1 levels were markedly reduced both in the carriers and in in vitro system. The methylation pattern of the sub-telomeric regions in carriers suggested hypomethylation in chromosome 10. The expression of a distinct set of genes was also changed, some of which may relate to pre-disposition to malignancy.These results show that BRCA gene products have a role in telomere length homeostasis. It is plausible that these perturbations contribute to malignant transformation in BRCA mutants.
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http://dx.doi.org/10.18632/oncotarget.5693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823046PMC
January 2016