Cancer risk among Holocaust survivors in Israel-A nationwide study.

BACKGROUND: Holocaust survivors during World War II were exposed to various factors that are associated with cancer risk. The objective of this study was to determine whether Holocaust survivors had an increased risk for developing cancer. METHODS: The study population included 152,622 survivors. The main analysis was based on a comparison between individuals who were entitled to compensation for suffering persecution during the war and individuals who were denied such compensation. A complementary analysis compared survivors who were born in countries governed by Nazi Germany with survivors born in nonoccupied countries. A Cox proportional hazards model was used, with the time at risk of cancer development starting on either January 1, 1960, or the date of immigration to the date of cancer diagnosis or death or the date of last follow-up (December 31, 2006). RESULTS: Cancer was diagnosed in 22.2% of those who were granted compensation versus 16% of those who were denied compensation (P < .0001). Adjusting for birth cohort, sex, country of origin, and period of immigration, both analyses revealed significant increased risks of developing cancer in those who were exposed. For those who were granted versus denied compensation, the hazard ratios were 1.06 (P < .001) for all sites, 1.12 (P = .07) for colorectal cancer, and 1.37 (P = .008) for lung cancer. For those born in occupied countries versus nonoccupied countries, the hazard ratios were 1.08 (P < .001), 1.08 (P = .003), and 1.12 (P = .02), respectively. CONCLUSIONS: The current results, based on a large cohort of Holocaust survivors who were exposed to a variety of severe deprivations, add to the conflicting and sparse knowledge on this issue and support the notion that this group has a small but consistent increase in cancer development. Cancer 2017;123:3335-45. © 2017 American Cancer Society.

Dexrazoxane added to doxorubicin-based adjuvant chemotherapy of breast cancer: a retrospective cohort study with a comparative analysis of toxicity and survival.

Dexrazoxane is indicated as a cardioprotective agent for patients receiving doxorubicin who are at increased risk for cardiotoxicity. Concerns have been raised on the use of dexrazoxane, particularly in adjuvant therapy, because of the risk of interference with the antitumor effect of doxorubicin. Two meta-analyses in metastatic breast cancer have rejected this hypothesis, but have shown an apparent increase in the severity of myelosuppression when dexrazoxane is used. Here, we analyzed retrospectively a cohort of our institute database to assess whether the addition of dexrazoxane causes more bone marrow suppression in breast cancer patients receiving doxorubicin-based adjuvant therapy. The secondary objectives were assessment of the incidence of febrile neutropenia, dose-schedule modifications, recorded cardiac events or cardiac test abnormalities, and overall survival. Eight hundred and twenty-two female patients who received adjuvant (or neoadjuvant) doxorubicin and cyclophosphamide for breast cancer between 2001 and 2013 were included. One hundred and four of these patients also received dexrazoxane concurrently with the adjuvant treatment. Hospital records and, when accessible, community clinic records were reviewed. The median follow-up duration was 7 years for patients receiving dexrazoxane and 7.5 years for patients not receiving dexrazoxane. 85.6% of patients were alive at data lock. Compared with the nondexrazoxane group, patients who received dexrazoxane were older (median age at diagnosis 59 vs. 52 years) and more likely to receive dose-dense AC therapy (73 vs. 59%) and adjuvant trastuzumab treatment (29 vs. 15%). Compared with the nondexrazoxane group, dexrazoxane treatment was associated with a higher rate of hematological side effects: leukopenia (48 vs. 39%), neutropenia (45 vs. 31%, P=0.003), anemia (86 vs. 73%, P=0.005), and thrombocytopenia (37 vs. 22%, P=0.001). There were more febrile neutropenia hospitalizations (20 vs. 10%, P=0.001) and dose reductions (22 vs. 8%, P<0.001) in the dexrazoxane group, but no significant difference in the incidence of treatment delays or cancellations. The incidence of cardiac events was the same in both treatment groups with and without dexrazoxane. There was a nonsignificantly lower mortality rate in the dexrazoxane group (9.6%) compared with the nondexrazoxane group (15.0%) at data lock. Adding dexrazoxane to doxorubicin in adjuvant therapy patients leads to higher rates of bone marrow suppression in all blood components, as well as more febrile neutropenia events, and dose reductions. No differences in events defined as cardiac toxicities were detected. Dexrazoxane had no detrimental effect on survival, despite the higher hematological toxicity, the older median age, and the higher prevalence of HER2-positive disease in the dexrazoxane group.

Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2.

In the Ashkenazi Jewish (AJ) population of Israel, 11% of breast cancer and 40% of ovarian cancer are due to three inherited founder mutations in the cancer predisposition genes BRCA1 and BRCA2. For carriers of these mutations, risk-reducing salpingo-oophorectomy significantly reduces morbidity and mortality. Population screening for these mutations among AJ women may be justifiable if accurate estimates of cancer risk for mutation carriers can be obtained. We therefore undertook to determine risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained irrespective of personal or family history of cancer. Families harboring mutations in BRCA1 or BRCA2 were ascertained by identifying mutation carriers among healthy AJ males recruited from health screening centers and outpatient clinics. Female relatives of the carriers were then enrolled and genotyped. Among the female relatives with BRCA1 or BRCA2 mutations, cumulative risk of developing either breast or ovarian cancer by age 60 and 80, respectively, were 0.60 (± 0.07) and 0.83 (± 0.07) for BRCA1 carriers and 0.33 (± 0.09) and 0.76 (± 0.13) for BRCA2 carriers. Risks were higher in recent vs. earlier birth cohorts (P = 0.006). High cancer risks in BRCA1 or BRCA2 mutation carriers identified through healthy males provide an evidence base for initiating a general screening program in the AJ population. General screening would identify many carriers who are not evaluated by genetic testing based on family history criteria. Such a program could serve as a model to investigate implementation and outcomes of population screening for genetic predisposition to cancer in other populations.

Neo-adjuvant doxorubicin and cyclophosphamide followed by paclitaxel in triple-negative breast cancer among BRCA1 mutation carriers and non-carriers.

The purpose of this study was to assess pathological complete response and whether it serves a surrogate for survival among patients receiving neo-adjuvant doxorubicin-cyclophosphamide followed by paclitaxel for triple-negative breast cancer with respect to BRCA1 mutation status. From a neo-adjuvant systemic therapy database of 588 breast cancer cases, 80 triple-negative cases who had undergone BRCA genotyping were identified. Logistic regression model was fitted to examine the association between BRCA1 status and pathological complete response. Survival outcomes were evaluated using Kaplan-Meier method, differences between study groups calculated by log-rank test. Thirty-four BRCA1 carriers and 43 non-carriers were identified. The BRCA1 carriers had pathological complete response rate of 68 % compared with 37 % among non-carriers, p = 0.01. Yet this did not translate into superior survival for BRCA1 carriers compared with non-carriers. No difference in relapse-free survival were noted among those with or without pathological complete response in BRCA1 carriers regardless of pathological complete response status (Log-rank p = 0.25), whereas in the non-carrier cohort, relapse-free survival was superior for those achieving pathological complete response (Log-rank p < 0.0001). Response to neo-adjuvant systemic therapy differed in BRCA1-associated triple-negative breast cancer compared with triple-negative non-carriers, with a higher rate of pathological complete response. However, compared with non-carrier triple-negative breast cancer, pathological complete response was not a surrogate for superior relapse-free survival in BRCA1 patients. Future studies using specific chemotherapy regimens may provide further improvements in outcomes.

Immunosuppressive treatments reduce long-term immunity to smallpox among patients with breast cancer.

BACKGROUND: Mass vaccination is the principal preventive measure against a smallpox outbreak after an act of bioterrorism. Vaccination of subjects who received immunosuppressive therapies is problematic because of smallpox vaccine reactogenicity. Moreover, long-term immunity to vaccinia might be affected. OBJECTIVE: The objective of the study was to examine the effect of cytotoxic chemotherapy on long-term immunity to vaccinia. METHODS: In a case-control study, 67 patients with breast cancer who received cytotoxic chemotherapy and who were disease free for at least 1 year were matched with healthy controls according to age, sex, and the number of smallpox vaccinations received. Markers of immunity to smallpox were examined. Forty-one patients with breast cancer who did not receive chemotherapy were used to assess the affect of cancer and radiotherapy on immunity to smallpox. RESULTS: Patients with breast cancer who received chemotherapy had lower levels of vaccinia total immunoglobulin G and immunoglobulin G1 (expressed as enzyme-linked immunosorbent assay units per milliliter), neutralizing antibodies, vaccinia:memory B cell ratio (expressed as a percentage), and interferon-gamma level (expressed as picograms per milliliter), compared with healthy control individuals. CONCLUSIONS: Immunity to smallpox is reduced after receipt of chemotherapy for breast cancer. This finding should be considered when planning smallpox vaccination campaigns. The effect of immunosuppressive treatments on persistence of immunity should be tested with respect to additional vaccines or natural infections.

Understanding Physicians' Perceptions of Overuse of Health Services in Oncology.

Overuse rates in oncology are high, but areas of possible improvement exist for reducing it and improving quality of care. This study explores perceptions and experiences of oncologists in Israel regarding overuse of health services within oncology. In-depth, semistructured interviews were conducted focusing on causes of overuse, facilitators for reduction, and suggestions for improvement. Interviews were audio recorded, transcribed, coded, and thematically analyzed. Physicians reported patient-level causes including "well-informed" and "demanding" patients; physician-level causes including desire to satisfy patients, lack of confidence, time, and skills; and system-level causes like ease of access, and lack of alignment and coordination. Physicians can reduce overuse through patient dialogue, building trust and solidifying patient-physician relationships, and further reduce overuse with better teamwork. Improvements can be made through educational initiatives, and bottom-up solutions. Policy makers and decision makers should develop appropriate interventions addressing health service overuse, including improving patient education and instilling confidence and knowledge in physicians.

Pain palliation in patients with bone metastases using MR-guided focused ultrasound surgery: a multicenter study.

BACKGROUND: Noninvasive thermal ablation using magnetic resonance (MR)-guided focused ultrasound (MRgFUS) has been shown to be clinically effective in uterine fibroids, and is being evaluated for ablation of breast, liver, and brain lesions. Recently MRgFUS has been evaluated for palliation of pain caused by bone metastases. We present the clinical results of a multicenter study using MRgFUS for palliation of bone metastases pain. METHODS: A multicenter study to evaluate the safety and efficacy of MRgFUS palliative treatment of bone metastases was conducted in patients suffering from painful metastatic bone lesions for which other treatments were either ineffective or not feasible. Thirty-one patients with painful bone metastases underwent the MRgFUS procedure in three medical centers. Treatment safety was evaluated by assessing the device-related complications. Effectiveness of pain palliation was evaluated using the visual analog pain score (VAS), and measurable changes in the intake of opioid analgesics. RESULTS: Thirty-six procedures were performed on 31 patients. Mean follow-up time was 4 months. 25 patients underwent the planned treatment and were available for 3 months post-treatment follow-up. 72% of the patients (18/25) reported significant pain improvement. Average VAS score was reduced from 5.9 prior to treatment to 1.8 at 3 months post treatment. 67% of patients with recorded medication data reported a reduction in their opioid usage. No device-related severe adverse events were recorded. CONCLUSION: The results suggest that MRgFUS has the ability to provide an accurate, effective, and safe noninvasive palliative treatment for patients with bone metastases.

The association between adherence with oral bisphosphonates and the risk of breast cancer in post-menopausal women.

BACKGROUND: Several observational studies have suggested a protective effect of oral bisphosphonates (BP) on the risk of breast cancer, but no such association has been seen in randomized control trials. The role of oral BP in breast cancer prevention remains unclear. AIM: To investigate the association between different levels of BP exposure and breast cancer incidence in a cohort of osteoporotic post-menopausal women. SUBJECTS AND METHODS: This historical prospective study was conducted using the computerized databases of Maccabi Healthcare Services (MHS) in Israel. Included in the study were osteopenic and osteoporotic women aged 55-75 years who started BP therapy between 1998 and 2012. The subjects were enrolled in MHS for at least 3 years before therapy initiation, and had a minimum follow-up of 5 years in MHS. Women with a previous cancer, and women treated with selective estrogen receptor modulators (SERMs) were excluded. BP exposure was expressed in quintiles of proportion of days covered (PDC) with BP during follow-up period and cancer incidence was ascertained by the Israel National Tumor Registry. Person-years of follow-up began on January 1st, 1998 and ended at the date of cancer diagnosis, death, or December 31st, 2012, whichever occurred first. RESULTS: A total of 11,717 patients (mean age = 66.87 ±â€¯4.38) were eligible for the analysis. During a total of 130,252 person-years of follow-up, (mean 7.2 years) 173 incident cases of breast cancer were diagnosed. Compared to women with a PDC with BP of 20% or lower, the adjusted hazard ratio for breast cancer were HR = 0.81 (95%CI: 0.48-1.39), HR = 0.82 (95%CI: 0.50-1.33), HR = 0.72 (95%CI:0.45-1.15) and HR = 1.14 (95%CI:0.76-1.70) among women with 20-40%, 40-60%, 60%-80%, and 80% or higher, PDC, respectively. CONCLUSION: In this study, we did not find a significant association between oral BP therapy for osteoporosis and the risk of breast cancer in postmenopausal women. The discrepancy between our results and the reports of such an association in observational studies might originate from an indication bias.

Concurrent chemobiotherapy with cisplatin, dacarbazine, decrescendo interleukin-2 and interferon alpha2b in patients with metastatic melanoma.

We aimed to evaluate a concurrent chemobiotherapy (CBT) regimen consisting of cisplatin (CDDP), dacarbazine (DTIC), decrescendo interleukin-2 (IL-2), and interferon alpha2b (INF-alpha2b), in metastatic melanoma patients. A total of 60 patients with biopsy proven, metastatic melanoma were treated between October 2000 and November 2005 at the Oncology Institutes of RMC and CSMC. Patients received concurrent CBT for 5 days, consisting of CDDP, DTIC, decrescendo IL-2, and subcutaneous INF-alpha2b. GM-CSF was given subcutaneously on days 8 to 12 of each cycle, to the first 26 patients. Treatment was administered q21d for a total of six cycles or until severe toxicity or progression; 57 patients who received at least two cycles, followed for at least 24 months, were included in response analysis. The overall response rate (RR) reached 44% (28/57 patients); 14 patients had a complete response (CR, 25%); 11 (19%) reached a partial response. The median progression-free survival was 7 months. Median overall survival (OS) was 11.7 months. At a median follow-up of 29 months, 8 of 14 complete responders remain alive for more than two years, with no clinical evidence of disease. Median OS of patients with CR has not been reached; 17% of the courses were modified due to toxicity, and 20% of the patients were removed from the protocol due to toxicity or refusal to continue. The data from this study indicate that this protocol of concomitant CBT is feasible with a fraction of the patients achieving a durable CR.

High efficacy of pre-operative trastuzumab combined with paclitaxel following doxorubicin & cyclophosphamide in operable breast cancer.

BACKGROUND: Trastuzumab in combination with adjuvant chemotherapy improves disease free survival and overall survival in HER2 over-expressing breast cancer patients. Data concerning the use of trastuzumab in the neo-adjuvant setting is limited. We aimed to compare outcome of HER2 over-expressing breast cancer patients treated with either standard chemotherapy, consisting of doxorubicin, cyclophosphamide and a taxane to outcome of patients treated with the same chemotherapy regimen with the addition of trastuzumab in concurrence with paclitaxel. METHODS: We conducted a retrospective review of all consecutive HER2 over-expressing breast cancer patients treated at the participating institutions during the study period and received neo-adjuvant therapy. Allocation to trastuzumab was not based on clinical parameters and was approved only by part of the insurers. Clinical and pathological characteristics, as well as response rate and type of surgery were analyzed. RESULTS: Thirty seven patients received chemotherapy alone and 24 patients received chemotherapy and trastuzumab. A similar distribution of age, clinical stage and histology was noted in both groups. The rate of pathological complete response (pCR) was significantly higher among the trastuzumab-treated group compared to chemotherapy-alone group (75 vs. 24% respectively, p=0.0002). pCR in the breast was noted in 18 of 24 (75%) compared to 10 of 36 (28%, p=0.0005) and pCR in the axillary lymph nodes was noted in 19 of 20 (95%) compared to 8 of 28 (29%, p=0.0001), in the trastuzumab group compared to the chemotherapy-alone group respectively. The safety profile was similar between both groups and no clinical cardiotoxicity were noted. CONCLUSIONS: The addition of trastuzumab to standard chemotherapy in the neo-adjuvant setting improves pathological complete response rates in HER2 over-expressing breast cancer patients.

Adjuvant chemotherapy and whole abdominal irradiation for gastric carcinoma.

AIMS AND BACKGROUND: To analyze the efficacy and toxicity of adjuvant chemotherapy followed by whole abdominal irradiation in the treatment of resectable gastric cancer with positive lymph nodes. METHODS AND STUDY DESIGN: Between 1996 and 1999, 10 patients with node-positive gastric cancer underwent complete gross resection and were treated by postoperative chemoradiotherapy. The chemotherapy regimen consisted of 5-fluorouracil, 1000 mg/m2/day as a 96-hr continuous infusion on day 1, and cisplatin, 100 mg/m2 on day 2, every 21 days. Six courses were planned. Radiotherapy was administered 3 weeks after completion of the chemotherapy protocol as a single-fraction dose of 600 cGy in a two-field (anterior and posterior) configuration. RESULTS: Treatment was generally well tolerated, with no treatment-related deaths. However, 9 of the 10 patients died of recurrent disease, with a median survival of 20 months (range, 7-84). CONCLUSIONS: Adjuvant chemotherapy with whole abdominal irradiation for gastric cancer is safe and tolerable but has no apparent effect on patient outcome. Studies in larger series are needed to evaluate the role of the approach in this disease.

[Three-dimensional conformal radiation therapy concurrent with full dose Gemcitabine for locally advanced inoperable pancreatic cancer].

BACKGROUND: Gemcitabine is a potent radiosensitizer of pancreatic cancer cells. Concomitant full dose Gemcitabine and three dimensional conformal radiation to a small field is a novel approach to unresectable locally advanced pancreatic cancer. The aim of this study is to report the outcome, tolerability and toxicity of this combined therapy. METHODS: A retrospective chart review, with survival data confirmed by the population registry and statistic analysis was performed with SPSS. Radiotherapy was planned using computerized tomography, treated only the gross tumor without regional lymph nodes and was delivered in 15 fractions of 2.4 Gy to a dose of 36 Gy. Gemcitabine was administered weekly during radiation at a dose of 1000 mg/m2. Gastrointestinal toxicity was scored according to the NCI Common Toxicity Criteria. Local control was assessed by RECIST criteria, a partial response defined as a decrease of at least 30% in the longest diameter of the tumor. RESULTS: Eighteen of the 19 patients completed treatment as planned without the need for treatment break. Four patients subsequently developed severe grade III-IV gastrointestinal toxicity; 37% of patients achieved a partial response and 52% experienced significant clinical benefit. The median survival was 11.7 months. DISCUSSION: Full dose gemcitabine with conformal 3-D radiotherapy to a small field was well tolerated and was associated with a low incidence of severe gastrointestinal toxicity compared with previous studies of combination therapy using standard large radiation portals which encompass both the tumor and the regional lymph nodes. A partial response was observed in over one third of patients, non-progression of the irradiated tumor in the rest with pain relief and clinical benefit in more than half the patients. CONCLUSION: This treatment approach was well tolerated with little morbidity and achieves outcomes equal to or better than other contemporary combination modality approaches.

Exposure to alendronate is associated with a lower risk of bone metastases in osteoporotic women with early breast cancer.

BACKGROUND: Bisphosphonate (BP) treatment to prevent bone loss in breast cancer patients is already well established. However, data on the association between oral BP exposure before cancer diagnosis and disease outcomes in patients with early breast cancer are still scarce. Limited information is available on alendronate, the most common oral agent for the treatment of post-menopausal osteoporosis, regarding the association with bone metastases. AIM: To examine the association between oral bisphosphonate exposure before cancer diagnosis and the risk of bone metastases in osteoporotic women diagnosed with early breast cancer. SUBJECTS AND METHODS: This historical cohort study was conducted at the oncology division at Tel Aviv Medical Center. The study population included post-menopausal women with early breast cancer, diagnosed between 2002 and 2012. Data on cancer characteristics, diagnosis of osteoporosis, prior bisphosphonate exposure and outcome were collected from medical files. RESULTS: Among 297 osteoporotic women identified, 145 (49%) were treated with bisphosphonates (alendronate in 90% of the cases) before cancer diagnosis. BP-treated women were significantly older than the BP-naïve ones (67.9 years vs 64.6 years, p = 0.01), but comparable in risk factors and disease characteristics. Over a mean follow up of 5.6 years, nine cases of bone metastases were identified, eight of them among BP-naïve patient (cumulative incidence of 9.9%) and one among BP-treated patients (0.7%). In a multivariable Cox's proportional hazards survival model the use of BP prior to cancer diagnosis was associated with a hazard ratio of 0.04 (95%CI:0.004-0.403, p = 0.006) for bone metastasis. The HR remained similar after further adjustment for tumor stage and cancer therapy. CONCLUSIONS: History of alendronate use is associated with a lower likelihood of bone metastases in postmenopausal women with early breast cancer. Oral bisphosphonate treatment could be sufficient for reducing the risk of bone metastases.

A phase II study of Imatinib for advanced adenoid cystic carcinoma of head and neck salivary glands.

Adenoid cystic carcinoma of the salivary glands is characterized by a poor response to chemotherapy. Most cases of adenoid cystic carcinoma express the c-kit protein. Imatinib mesylate (Gleevec) inhibits several protein-tyrosine kinases, including c-kit. We therefore hypothesized that Imatinib may be an effective drug in patients with locally advanced or metastatic adenoid cystic carcinoma and conducted a phase 2 trial in order to study this. Patients with locally advanced or metastatic adenoid cystic carcinoma and c-kit positive tumours were eligible. Fourteen patients were screened and 10 patients (71%) with c-kit positive tumours entered the study. Treatment was begun at a dose of Imatinib of 400mg/day. Dose escalation was allowed in the absence of toxicity. The dose was increased to 600mg/d in three patients and 800mg/d in one patient. Three patients required dose reduction to 300mg/d, due to grade 3 toxicity. No grade 4 toxicity was seen. No objective responses were seen. Two patients (20%) exhibited stable disease for 11 and 14 months, respectively. All other patients stopped treatment after 2-14 (median 6) months due to progressive disease. Imatinib has no major effect on advanced adenoid cystic carcinoma of the head and neck.

A phase II study of oral UFT and leucovorin concurrently with pelvic irradiation as neoadjuvant chemoradiation for rectal cancer.

BACKGROUND: Neoadjuvant chemoradiation with continuous infusion (CI) of 5-fluorouracil (5FU) is widely used in rectal cancer. The aim of this study was to evaluate the use of oral tegafur-uracil (UFT) and leucovorin (LV) instead of CI 5FU. PATIENTS AND METHODS: Patients had resectable T3-4 or low T2 rectal adenocarcinoma. Chemoradiation consisted of pelvic irradiation (45 Gy in fractions of 1.8 Gy) and oral UFT (240 mg/m2/day) and LV (30 mg/day) given during the first 28 days of radiotherapy. RESULTS: Thirty-two patients were treated; 81% had T3-4 tumors and 25% had N+ disease. Toxicity, predominantly gastrointestinal, was generally mild. Grade 3 toxicity occurred in only one patient. Pathological down-staging was noted in 13 patients (42%) and pathological complete response in 3 (10%). Sphincter preservation was possible in 71% of patients undergoing surgery. CONCLUSION: Neoadjuvant chemoradiation with oral UFT/LV is well-tolerated and active against rectal cancer. Formal comparison with the current standard treatment is warranted.

[Imatinib mesylate (glivec) as a treatment for gastrointestinal stromal tumor (GIST)--long term follow-up].

BACKGROUND: Gastrointestinal stromal tumor (GIST) is a rare gastrointestinal tumor. It is known to be resistant to radiotherapy and chemotherapy. The administration of imatinib mesylate, a tyrosine kinase inhibitor, resulted in a dramatic response and improved survival in patients with GIST. This study examined the long term response and side effects of imatinib treatment in Israeli patients with GIST. PATIENTS AND METHODS: The study followed-up on 25 patients from various hospitals in Israel treated between the years 2001 and 2006. The mean follow-up time was 36.3 months (17-63 months). RESULTS: One patient achieved complete response, 13 patients (52%) achieved partial response, 9 patients (35%) achieved stable disease, and 2 patients did not have measurable disease. The median survival was not yet reached. Twelve patients (48%) had a decrease in the attenuation of the tumor into a cystic appearance. Eleven patients (44%) developed late resistance to the treatment (after 7-54 months). The median time to progression was not yet reached. The adverse events were mostly mild. Severe adverse events (grade 3-4 Common Toxicity Criteria (CTC)) occurred in 24% of the patients. There was no advantage regarding survival or time to progression for the patients who had partial response compared to those patients who had stable disease (P=0.39 and P=0.71 respectively). CONCLUSIONS: Imatinib results in a dramatic response in patients with GIST, and is well tolerated. The introduction of new drugs such as sunitinib which is now in an advanced phase of clinical study, may provide additional solutions in the treatment of GIST.

Association between diabetes mellitus and adverse characteristics of breast cancer at presentation.

Type 2 diabetes mellitus is associated with increased incidence and inferior outcome of various malignancies. The aim of this study was to explore the impact of type 2 diabetes on breast cancer characteristics at presentation. The study population included 79 diabetic and 158 age-matched non-diabetic patients. Parity, country of birth, co-morbidity other than diabetes, and mode of diagnosis were similar in both groups. Mean body mass index (BMI) was higher among diabetic patients. Tumour stage and size were higher among diabetic patients and the differences remained significant after adjustment for BMI. Moreover, after adjustment for BMI, breast cancer among diabetic patients was more often hormone receptor negative. Our results show that diabetes mellitus is associated with negative prognostic factors at breast cancer presentation.

Adoptive cell therapy for metastatic melanoma patients: pre-clinical development at the Sheba Medical Center.

BACKGROUND: Metastatic melanoma is an aggressive and highly malignant cancer. The 5 year survival rate of patients with metastatic disease is less than 5% with a median survival of only 6-10 months. Drugs like dacarbazin (DTIC) as a single agent or in combination with other chemotherapy agents have a response rate of 15-30%, but the duration of response is usually short with no impact on survival. Interleukin-2-based immunotherapy has shown more promising results. The National Institutes of Health recently reported that lymphodepleting chemotherapy, followed by an adoptive transfer of large numbers of anti-tumor specific tumor-infiltrating lymphocytes, resulted in an objective regression in 51% of patients. OBJECTIVES: To introduce the TIL technology to advanced metastatic melanoma patients in Israel. METHODS: We generated TIL cultures from tumor tissue, choosing those with specific activity against melanoma and expanding them to large numbers. RESULTS: TIL cultures from nine patients were established and examined for their specific activity against the patients' autologous tumor cells. Twelve TIL cultures derived from 5 different patients showed the desired anti-tumor activity, making those 5 patients potential candidates for the therapy. CONCLUSIONS: Pre-clinical studies of the TIL technology in a clinical laboratory set-up were performed successfully and this modality is ready for treating metastatic melanoma patients at the Sheba Medical Center's Ella Institute.

[Body weight, nutritional factors and physical activity--their influence on prognosis after breast cancer diagnosis].

Numerous studies have examined the association between body weight, nutritional factors, physical activity and the risk for primary breast cancer. Relatively few studies, however, have examined the associations between these issues and the recurrence of the disease and cure of the primary tumor. Today, three areas of focus are actively being researched for breast cancer survivors: body weight, diet composition and physical activity with specific emphasis on the risk for recurrence, survival and quality of life. Increased body weight or BMI (Body Mass Index) at diagnosis was found to be a significant risk factor for recurrent disease, decreased survival, or both. Overall obesity has been shown to adversely affect prognosis. Appropriate weight control may be particularly beneficial for breast cancer survivors. Breast cancer survivors should be encouraged to achieve and maintain a healthy weight. Limiting fat intake can reduce the risk of breast cancer recurrence. Increasing consumption of vegetables and fruits seems to have possible beneficial effects during and after treatments. To date physical activity after breast cancer diagnosis has been found to reduce the risk of death. The greatest benefit occurred in women who performed the equivalent of walking 3-5 hours per week at an average pace. Safe weight loss via increased physical activity and healthful food choices should be encouraged for normal, overweight or obese breast cancer survivors in order to improve survival and life quality.

[Update on the treatment of common gastrointestinal malignancies].

Common gastrointestinal malignancies, including esophageal, gastric, pancreatic and colorectal cancer are among the leading causes of cancer morbidity and mortality worldwide. Modern surgical techniques, increasing use of endoscopic procedures, the use of new chemotherapy regimens and the development of novel biological therapies are among the major advances in the treatment of these malignancies that were achieved during the last years. In this review we provide an update of the current treatment of common gastrointestinal malignancies and focus on these recent advances.