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Background:The impact of cancer therapies on cardiac disease in the general adult cancer survivor population is largely unknown. Our objective was to evaluate which tyrosine kinase-targeting drugs are associated with greater risk for new-onset heart failure (HF).Methods:A nested case-control analysis was conducted within a cohort of 27 992 patients of Clalit Health Services, newly treated with a tyrosine kinase-targeting, and/or chemotherapeutic drug, for a malignant disease, between 1 January 2005 and 31 December 2012. Each new case of HF was matched to up to 30 controls from the cohort on calendar year of cohort entry, age, gender, and duration of follow-up. Main outcome measure was odds ratio (OR) with 95% confidence interval (CI) of new-onset HF.Results:There were 936 incident cases of HF during 71 742 person-years of follow-up. Trastuzumab (OR 1.90, 95% CI 1.46-2.49), cetuximab (OR 1.72, 1.10-2.69), panitumumab (OR 3.01, 1.02-8.85), and sunitinib (OR 3.39, 1.78-6.47) were associated with increased HF risk. Comorbidity independently associated with higher risk in a multivariable conditional regression model was diabetes mellitus, hypertension, chronic renal failure, ischaemic heart disease, valvular heart disease, arrhythmia, and smoking.Conclusions:Trastuzumab, cetuximab, panitumumab, and sunitinib are associated with increased risk for new-onset HF. [ABSTRACT FROM AUTHOR]

Familial-genetic counselling for breast/ovarian cancers is a process initiated by a proband, and designed for all her/his blood relatives. This study focused on family members' uptake of an invitation to participate in counselling as a function of proband and family determinants. Of 163 breast/ovarian syndrome families tested, 67 carrying one of the three known Jewish mutations were included. For both the proband and family members, demographic variables, cancer status, position in the family and type of referral (proband only) were examined. Eligible family members' uptake rate was 34%. Lower family uptake was associated with the proband having cancer, and/or being doctor-referred (vs self-referred). Individuals of either the proband's or older generations had lower uptake rates compared with family members of younger generations. Being a cancer patient or a first degree relative of either a cancer patient or the proband was related to higher uptake. The study results indicate that baseline information routinely gathered by counselling services can be useful in predicting uptake. Providing insight into complex barriers to genetic counselling, these results also suggest potential directions for interventions to improve uptake, thereby enhancing individuals' abilities to make informed decisions regarding issues such as genetic testing. [ABSTRACT FROM AUTHOR]

Background Diabetes is associated with an increased risk of stroke in patients with atrial fibrillation. Whether glycemic control, evaluated by glycated hemoglobin, affects the risk of stroke in diabetic patients with atrial fibrillation remains unknown. Objective To examine the association between glycated hemoglobin and risk of first episode stroke in diabetic patients with atrial fibrillation. Methods By using the computerized database of the largest health maintenance organization in Israel, we identified a cohort of adults (age ≥20 years) in whom atrial fibrillation was diagnosed before January 1, 2012. Eligible subjects had no previous stroke or transient ischemic attack and were not on anticoagulants at baseline. The cohort (37,358 subjects) was followed for the first episode stroke or transient ischemic attack up to December 31, 2012. Results A total of 1052 subjects had stroke during 35,278 person-years of follow-up (stroke rate 2.98 per 100 person-years). Cox proportional hazards regression analysis adjusting for CHA 2 DS 2 -VASc score risk factors revealed that compared with subjects without diabetes, the hazard ratio for stroke was 1.04 (95% confidence interval [CI] 0.83–1.30) for the lowest glycated hemoglobin quartile (<6.35%), 1.14 (95% CI 0.92–1.42) for the second quartile (6.35%–6.90%), 1.46 (95% CI 1.19–1.79) for the third quartile (>6.90%–7.70%), and 1.63 (95% CI 1.33–2.00) for the highest quartile(>7.70%) (for trend, P < .001). In diabetic patients (n = 11,176), the hazard ratio for stroke was 1.17 (95% CI 1.09–1.26) for every 1% increment in glycated hemoglobin level. The area under the receiver operating characteristic curve was 0.585 for the CHA 2 DS 2 -VASc score, which increased to 0.604 when glycated hemoglobin was included in the model ( P = .038). Conclusion Glycated hemoglobin is directly associated with stroke risk, and it improves the predictive accuracy for stroke in diabetic patients with atrial fibrillation. [ABSTRACT FROM AUTHOR]

Background:The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity.Methods:To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively.Results:There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10-2.04 and HR 2.16, 95%CI 1.24-3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele.Conclusion:The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers. [ABSTRACT FROM AUTHOR]

Levothyroxine is a synthetic T(4) hormone commonly used to treat thyroid disease. Increased incidence of mostly autoimmune thyroid disease has been associated with breast and other malignancies, and thyroid hormone levels might also be associated with risk of colorectal cancer (CRC). In this population-based matched case-control study (2566 pairs) of CRC in northern Israel, use of levothyroxine for at least 5 years was assessed using structured interviews and validated by prescription records. The analysis included use of statins, aspirin, and hormone replacement therapy; CRC family history; physical activity; vegetable consumption; ethnicity; age; and sex. All statistical tests were two-sided. The use of levothyroxine was associated with a statistically significantly reduced relative risk of CRC (odds ratio = 0.59, 95% confidence interval = 0.43 to 0.82, P = .001). This association remained statistically significant after adjustment for age, sex, use of aspirin and statins, sports activity, family history of CRC, ethnic group, and level of vegetable consumption (odds ratio = 0.60, 95% confidence interval = 0.44 to 0.81, P = .001). No statistically significant interactions were seen between use of levothyroxine and aspirin, statins, or hormone replacement therapy. [ABSTRACT FROM AUTHOR]

Background: The TP53 pathway, in which TP53 and its negative regulator MDM2 are the central elements, has an important role in carcinogenesis, particularly in BRCA1- and BRCA2-mediated carcinogenesis. A single nucleotide polymorphism (SNP) in the promoter region of MDM2 (309T>G, rs2279744) and a coding SNP of TP53 (Arg72Pro, rs1042522) have been shown to be of functional significance.Methods: To investigate whether these SNPs modify breast cancer risk for BRCA1 and BRCA2 mutation carriers, we pooled genotype data on the TP53 Arg72Pro SNP in 7011 mutation carriers and on the MDM2 309T>G SNP in 2222 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analysed using a Cox proportional hazards model within a retrospective likelihood framework.Results: No association was found between these SNPs and breast cancer risk for BRCA1 (TP53: per-allele hazard ratio (HR)=1.01, 95% confidence interval (CI): 0.93-1.10, P(trend)=0.77; MDM2: HR=0.96, 95%CI: 0.84-1.09, P(trend)=0.54) or for BRCA2 mutation carriers (TP53: HR=0.99, 95%CI: 0.87-1.12, P(trend)=0.83; MDM2: HR=0.98, 95%CI: 0.80-1.21, P(trend)=0.88). We also evaluated the potential combined effects of both SNPs on breast cancer risk, however, none of their combined genotypes showed any evidence of association.Conclusion: There was no evidence that TP53 Arg72Pro or MDM2 309T>G, either singly or in combination, influence breast cancer risk in BRCA1 or BRCA2 mutation carriers. [ABSTRACT FROM AUTHOR]

Exposure to low levels of ionizing radiation after the Chernobyl accident in the Ukraine could potentially have influenced the neurobehavioral and cognitive performances of exposed children. A cohort study of adolescents who were children at the time of the accident and who subsequently emigrated to Israel was conducted in 1998-2001. A total of 1,629 children (59% of all 2,769 invited) were included in the study (41% from higher contamination areas, 25% from lower contamination areas, 34% from noncontaminated areas). Mean scores of the Raven Standard Progressive Matrices Test were highest in children in all exposure groups whose parents had a high level of education. No overall relation was found between the cognitive function scores of the child and his/her putative radiation exposure level. Conners' test T scores did not differ significantly by level of exposure. Mothers of all exposure groups who were pregnant at the time of the accident gave their children significantly higher Conners' test scores than did those who were not pregnant. Scores for hyperactivity and attention-deficit/hyperactivity disorder were significantly higher among those who were in utero at the time of the accident. These results do not show differences of neurobehavioral or cognitive performance in exposed versus nonexposed children. There is a possible behavioral effect among offspring of pregnant mothers or mothers of very young children in all exposure levels. [ABSTRACT FROM AUTHOR]

BACKGROUND: High calcium intakes during adolescence may increase bone acquisition. The magnitude of the effect of dietary calcium supplementation and the timing of its administration to achieve significant effects on bone health are still incompletely defined. OBJECTIVE: The objective of this study was to assess the effect of calcium supplementation on bone mass accretion in postmenarcheal adolescent girls with low calcium intakes. DESIGN: A double-blind, placebo-controlled calcium supplementation study was implemented. One hundred girls with a mean (+/- SD) age of 14 +/- 0.5 y with habitual calcium intakes < 800 mg/d completed a 12-mo protocol. The treatment group received a daily supplement containing 1000 mg elemental calcium. Bone mineral density (BMD) and bone mineral content (BMC) of the total body, lumbar spine, and femoral neck were determined at inclusion, 6 mo, and 12 mo. Also measured were serum concentrations of biochemical markers of bone turnover (osteocalcin and deoxypyridinoline), parathyroid hormone, and vitamin D. RESULTS: The calcium-supplemented group had greater accretion of total-body BMD and lumbar spine BMD but not BMC than did the control group. Calcium supplementation appeared selectively beneficial for girls who were 2 y postmenarcheal. Calcium supplementation significantly decreased bone turnover and decreased serum parathyroid hormone concentrations. CONCLUSION: Calcium supplementation of postmenarcheal girls with low calcium intakes enhances bone mineral acquisition, especially in girls > 2 y past the onset of menarche. Copyright © 2003 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

Background: Oral contraceptive use has been associated with an increase in the risk of breast cancer in young women. We examined whether this association is seen in women at high risk of breast cancer because they carry a mutation in one of two breast cancer susceptibility genes, BRCA1 and BRCA2.Methods: We performed a matched case-control study on 1311 pairs of women with known deleterious BRCA1 and/or BRCA2 mutations recruited from 52 centers in 11 countries. Women who had been diagnosed with breast cancer were matched to control subjects by year of birth, country of residence, mutation (BRCA1 or BRCA2), and history of ovarian cancer. All study subjects completed a questionnaire about oral contraceptive use. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived by conditional logistic regression. All statistical tests were two-sided.Results: Among BRCA2 mutation carriers, ever use of oral contraceptives was not associated with an increased risk of breast cancer (OR = 0.94, 95% CI = 0.72 to 1.24). For BRCA1 mutation carriers, ever use of oral contraceptives was associated with a modestly increased risk of breast cancer (OR = 1.20, 95% CI = 1.02 to 1.40). However, compared with BRCA1 mutation carriers who never used oral contraceptives, those who used oral contraceptives for at least 5 years had an increased risk of breast cancer (OR = 1.33, 95% CI = 1.11 to 1.60), as did those who used oral contraceptives before age 30 (OR = 1.29, 95% CI = 1.09 to 1.52), those who were diagnosed with breast cancer before age 40 (OR = 1.38, 95% CI = 1.11 to 1.72), and those who first used oral contraceptives before 1975 (OR = 1.42, 95% CI = 1.17 to 1.75).Conclusions: Among BRCA1 mutation carriers, women who first used oral contraceptives before 1975, who used them before age 30, or who used them for 5 or more years may have an increased risk of early-onset breast cancer. Oral contraceptives do not appear to be associated with risk of breast cancer in BRCA2 carriers, but data for BRCA2 carriers are limited. [ABSTRACT FROM AUTHOR]

BackgroundText message (short message service, SMS) interrogative reminders were adopted in population screening for the early detection of colorectal cancer (CRC). ObjectiveThis study aims to examine responses to text message (SMS) reminders and associate responses with senders’ characteristics, message type (interrogative/declarative), and subsequent screening uptake. MethodsWe conducted a prospective cohort intervention. Text message (SMS) reminders to undergo CRC screening, randomized into interrogative and declarative phrasing, were sent to nonadherent 40,000 women and men (age 50-74 years) at CRC average risk. We analyzed recipient responses by message phrasing, recipient characteristics, and for content, the latter predicting subsequent CRC screening per program database. ResultsWhile interrogative text message (SMS) reminders elicited 7.67% (1475/19,227) responses, declarative ones elicited 0.76% (146/19,262) responses. Text message (SMS) responses were content analyzed and grouped into attitudes toward CRC screening (1237/1512, 81.8% positive) and intention to screen (1004/1512, 62.6%). Text message (SMS) respondents screened significantly more than nonrespondents after 6 months (415/1621, 25.6% vs 3322/36,868, 9.0%; χ12=487.5, P

Background: Many immigrants from the former USSR arrived in Israel during the period 1989 to 1992 and now comprise 10% of the Israeli population. They are expected to cause a change in the health profile of the country due to their different patterns of disease and an analysis was undertaken to predict these expected changes.Method: Official mortality statistics from Israel and the USSR were compared for differences in major causes of death. Russian mortality rates were then incorporated into a calculation taking into account the total size of the Israeli population and the relative size of the immigrant population to give the expected overall age-adjusted mortality in Israel following the wave of immigration.Results: Reported mortality rates in the European republics of the former USSR were found to be higher, by about 40%, than mortality rates in Israel. Cardiovascular diseases (40%) and cancer (20%) were found to contribute equally to male mortality in Israel and the USSR, but cardiovascular diseases were more important in females in the USSR (65% versus 44% in Israel). Cerebrovascular disease was three times more common as a cause of death in the USSR than in Israel, in both sexes. Cancer, though similar in overall rate, was differently distributed in the two countries with lung and stomach cancer predominating and causing much higher mortality in the former USSR. Projections from these observations showed an expected immediate increase in mortality of 6% in males and 4.4% in females, assuming the mortality patterns reported are valid for Russian immigrants to Israel.Conclusion: Massive immigration to a country has the potential to significantly affect the overall health picture of the host country. Therefore, an evaluation of the health status and health-related habits of the immigrant population is warranted to target areas requiring intervention in order to both protect the host country and to facilitate assimilation. [ABSTRACT FROM AUTHOR]

Background: Genes of the adiponectin pathway are interesting candidates for colorectal cancer risk based on the potential association between colorectal cancer and obesity. However, variants of the adiponectin gene (ADIPOQ) have been demonstrated to be inconsistently associated with risk of colorectal cancer.Methods: The current study attempted to evaluate these findings by examining several single nucleotide polymorphisms (SNPs) that were previously genotyped as part of a genome-wide association study in the ADIPOQ gene. Genotyping was also performed for a previously reported risk variant, rs266729, in 1062 individuals with a diagnosis of colorectal cancer and 1062 controls matched on age, gender and ethnicity (Jewish or not Jewish) as part of a population-based case-control study in Israel.Results: No evidence was found for an association between ADIPOQ and risk of colorectal cancer. The single nucleotide variant previously associated with decreased risk of colorectal cancer, rs266729, revealed an adjusted odds ratio of 1.04; 95% confidence interval, 0.88-1.23.Conclusion: The SNP, rs266729, was not strongly associated with colorectal cancer in patients of Ashkenazi Jewish descent or other ethnic groups in Israel. [ABSTRACT FROM AUTHOR]

Background: Combined oral contraceptives are a common method of contraception, but they carry a risk of venous and arterial thrombosis. We assessed whether use of drospirenone was associated with an increase in thrombotic risk relative to third-generation combined oral contraceptives.Methods: Using computerized records of the largest health care provider in Israel, we identified all women aged 12 to 50 years for whom combined oral contraceptives had been dispensed between Jan. 1, 2002, and Dec. 31, 2008. We followed the cohort until 2009. We used Poisson regression models to estimate the crude and adjusted rate ratios for risk factors for venous thrombotic events (specifically deep vein thrombosis and pulmonary embolism) and arterial thromboic events (specifically transient ischemic attack and cerebrovascular accident). We performed multivariable analyses to compare types of contraceptives, with adjustment for the various risk factors.Results: We identified a total of 1017 (0.24%) venous and arterial thrombotic events among 431,223 use episodes during 819 749 woman-years of follow-up (6.33 venous events and 6.10 arterial events per 10,000 woman-years). In a multivariable model, use of drospirenone carried an increased risk of venous thrombotic events, relative to both third-generation combined oral contraceptives (rate ratio [RR] 1.43, 95% confidence interval [CI] 1.15-1.78) and second-generation combined oral contraceptives (RR 1.65, 95% CI 1.02-2.65). There was no increase in the risk of arterial thrombosis with drospirenone.Interpretation: Use of drospirenone-containing oral contraceptives was associated with an increased risk of deep vein thrombosis and pulmonary embolism, but not transient ischemic attack or cerebrovascular attack, relative to second- and third-generation combined oral contraceptives. [ABSTRACT FROM AUTHOR]