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Naama Halpern,1,2 Albert Grinshpun,3 Ben Boursi,1,2 Talia Golan,1,2 Ofer Margalit,1,2 Dan Aderka,1,2 Eitan Friedman,2,4 Yael Laitman,2,3 Ayala Hubert,3 Luna Kadouri,3 Tamar Hamburger,3 Inbal Barnes-Kedar,2,5 Zohar Levi,2,6 Irit Ben-Aharon,2,7 Baruch Brenner,2,7 Yael Goldberg,2,5 Tamar Peretz,3 Einat Shacham-Shmueli1,2 1Department of Oncology, Sheba Medical Center, Tel-Hashomer, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; 4The Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Human Genetics, Chaim Sheba Medical Center, Tel-Hashomer, Israel; 5Recanati Genetics Institute, Rabin Medical Center, Beilinson Hospital, Petach Tikva, Israel; 6Division of Gastroenterology, Rabin Medical Center, Early Detection and High Risk Unit, Petach Tikva, Israel; 7Institute of Oncology, Davidoff Center, Rabin Medical Center, Petach Tikva, IsraelCorrespondence: Naama HalpernDepartment of Oncology, Sheba Medical Center, Tel-Hashomer, Rmat Gan, IsraelTel +972-3-530-2668Fax +972-3-5304958Email naama.halpern@sheba.gov.ilBackground: 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 BRCA1 or BRCA2 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.Keywords: gastric cancer, BRCA1, BRCA2, DNA-damaging agents, PARP inhibitors

Tamar Zahavi,1,2,* Amir Sonnenblick,1,3,* Yael Shimshon,2 Luna Kadouri,1 Tamar Peretz,1 Asher Y Salmon,1,* Mali Salmon-Divon,2,* 1Sharett Institute of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel; 2Genomic Bioinformatics Laboratory, Department of Molecular Biology, Ariel University, Ariel, Israel; 3Sackler Faculty of Medicine, Sourasky Medical Center, Institute of Oncology, Tel Aviv University, Tel Aviv, Israel *These authors contributed equally to this work Background: About 5%–10% of breast cancer and 10%–15% of ovarian cancer are hereditary. BRCA1 and BRCA2 are the most common germline mutations found in both inherited breast and ovarian cancers. Once these mutations are identified and classified, a course of action to reduce the risk of developing either ovarian or breast cancer – including surveillance and surgery – is carried out. Purpose: The purpose of the current research is to characterize the gene expression differences between healthy cells harboring a mutation in BRCA1/2 genes and normal cells. This will allow detection of candidate genes and help identify women who carry functional BRCA1/2 mutations, which cannot always be detected by the available sequencing methods, for example, carriers of mutations found in regulatory sequences of the genes. Materials and methods: Our cohort consisted of 50 healthy women, of whom 24 were individuals with BRCA1 or BRCA2 heterozygous mutations and 26 were non-carrier controls. RNA purified from non-irradiated lymphocytes of nine BRCA1/2 mutation carriers versus four control mutation-negative individuals was utilized for RNA-Seq analysis. The selected RNA-Seq transcripts were validated, and the levels of spleen tyrosine kinase (SYK) mRNA were measured by using real-time quantitative polymerase chain reaction. Results: Differences in gene expression were found when comparing untreated lymphocytes of BRCA1/2 mutation carriers and controls. Among others, the SYK gene was identified as being differently expressed for BRCA1/2 mutation carriers. The expression level of SYK was significantly higher in untreated healthy lymphocytes of BRCA1 heterozygote carriers compared with controls, regardless of irradiation. In contrast to normal tissues, in cancerous breast tissues, the expression levels of the BRCA1 and SYK genes were not intercorrelated. Conclusion: Collectively, our observations demonstrate that SYK may prove to be a good candidate for better diagnosis, treatment, and prevention of BRCA1 mutation-associated breast cancer. Keywords: RNA-Seq, breast cancer susceptibility, peripheral blood

Introduction: The majority of patients with gastric cancer relapse after definitive surgery and 5-year survival after surgery is very poor. The Intergroup 0116 study showed a modest survival benefit for postoperative bolus 5-fluorouracil-based chemoradiation with a high rate of toxicity. We hypothesised that treatment outcome could be further improved with feasible toxicity using a combination of bolus 5-fluorouracil, continuous 5-fluorouracil, and cisplatin followed by chemoradiation after 3 months of chemotherapy. Materials and Methods: Thirty-six patients with stages Ib through IV adenocarcinoma of the stomach or gastrooesophageal junction who had undergone gastric resection and negative margins were assigned to postoperative chemoradiation. The treatment consisted of 6 cycles of continuous 5-fluorouracil (600 mg/m2) for 24 hours, push 5-fluorouracil (400 mg/m2) and leucoverin (LCV) (200 mg/m2) on day 1 to 2 every 2 weeks, cisplatin (60 mg/m2) every 4 weeks followed by combined modality therapy using 45 Gy at 1.8 Gy per day concomitant with weekly bolus 5-fluorouracil (600 mg/m2) and LCV (50 mg). Results: The median age was 59 years (range, 29 to 75) and 25 patients were male. Thirty-five per cent had proximal tumour, T3 or T4 were diagnosed in 92% of the patients and lymph nodes metastases were confirmed in 83%. Grade 3 or 4 neutropaenia was documented in 25%, and gastrointestinal toxicity in 16%. There was no toxic death, but 1 patient had long-term complications. The median disease-free survival was 37.4 months and the overall survival was 40.3 months. Conclusions: Postoperative chemoradiation with combination of bolus 5-fluorouracil, continuous 5-fluorouracil and cisplatin is a feasible and well-tolerated approach. Larger clinical trials should be conducted to further evaluate the toxicity and the efficacy of this regimen. Key words: Adjuvant, Combined modality therapy, Gastric neoplasms

Background. There is not yet an agreed adjuvant treatment for melanoma patients with American Joint Committee on Cancer stages III B and C. We report administration of an autologous melanoma vaccine to prevent disease recurrence. Patients and Methods. 126 patients received eight doses of irradiated autologous melanoma cells conjugated to dinitrophenyl and mixed with BCG. Delayed type hypersensitivity (DTH) response to unmodified melanoma cells was determined on the vaccine days 5 and 8. Gene expression analysis was performed on 35 tumors from patients with good or poor survival. Results. Median overall survival was 88 months with a 5-year survival of 54%. Patients attaining a strong DTH response had a significantly better (p = 0.0001) 5-year overall survival of 75% compared with 44% in patients without a strong response. Gene expression array linked a 50-gene signature to prognosis, including a cluster of four cancer testis antigens: CTAG2 (NY-ESO-2), MAGEA1, SSX1, and SSX4. Thirty-five patients, who received an autologous vaccine, followed by ipilimumab for progressive disease, had a significantly improved 3-year survival of 46% compared with 19% in nonvaccinated patients treated with ipilimumab alone (p = 0.007). Conclusion. Improved survival in patients attaining a strong DTH and increased response rate with subsequent ipilimumab suggests that the autologous vaccine confers protective immunity.