Subfertility, use of fertility treatments and BRCA mutation status and the risk of ovarian cancer.

PURPOSE: The objective of the study is to evaluate the possible association between history of subfertility, fertility treatments, BRCA mutations and the risk of ovarian cancer. METHODS: This Israeli National Case-Control study included 1269 consecutive ovarian cancer cases and 2111 individually matched healthy controls. All participants were interviewed and molecular analysis of BRCA mutations were performed to 896 cases. The main outcome measure was reported history of subfertility and exposure to fertility treatments. RESULTS: The rate of reported subfertility was 15.1% and 14.3% in ovarian cancer cases and controls, respectively. However, subfertility was more prevalent in cases with borderline ovarian cancer (but not for invasive ovarian cancer cases) than controls. Multivariate conditional logistic regression revealed that the risk of borderline ovarian cancer was elevated in both women treated for subfertility and those that were not treated for subfertility, (OR = 1.74; 95% CI 0.9-3.36 and OR = 1.79; 95% CI 0.98-3.26, respectively). In non-carriers of BRCA1/2 mutations, fertility treatments were associated with a decreased risk of invasive ovarian cancer while a significant increased risk of borderline ovarian cancer was observed (OR = 2.92, 95%CI 1.67-5.10). CONCLUSIONS: Reported subfertility and exposure to fertility treatments were associated with borderline but not with invasive ovarian tumors. This association was more prominent in women who are non-carriers of a BRCA mutation.

Sex and ethnic-origin specific BMI cut points improve prediction of 40-year mortality: the Israel GOH study.

BACKGROUND: Although obesity has been associated with a higher risk for premature death, the sex and ethnic-origin specific body mass index (BMI) levels that are associated with increased mortality are controversial. We investigated the 40-year cumulative all-cause mortality, in relation to the BMI in adult life, among men and women originating from Yemen, Europe/America, Middle East and North Africa, using sex and ethnic-origin specific BMI cut points. METHODS: A random stratified cohort (n = 5710) was sampled from the central population registry and followed since 1969 for vital status. Weight, height and blood pressure were measured, and smoking status was recorded at baseline. BMI was analysed according to conventional categories and according to sex and ethnic-origin specific quintiles. RESULTS: Elevated and significant mortality hazard ratios (HRs) of 1.21 [95% confidence interval (CI) 1.00-1.45] for women and 1.22 (95%CI 1.03-1.44) for men were found for the highest origin-specific BMI quintile. In men, the lowest ethnic-origin specific quintile was also significantly associated with increased mortality (HR of 1.22 95% CI 1.03-1.45), adjusting for age, smoking and blood pressure. Obesity was associated with mortality in non-smokers (HR = 1.29, 95% CI 1.04-1.61 in men and HR = 1.46, 95% CI 1.19-1.79 in women), whereas leanness was associated with mortality only among smoking men (HR = 1.39, 95% CI 1.09-1.77). CONCLUSION: Refinement of BMI categories using country of origin specific quintiles demonstrated significantly increased mortality in the upper quintile in both sexes, while according to the conventional values this association did not prevail in men. We propose the establishment of sex and origin-specific BMI categories when setting goals for disease prevention.

Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer.

CONTEXT: Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear. OBJECTIVE: To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. DESIGN, SETTING, AND PARTICIPANTS: A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n = 909) or BRCA2 (n = 304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998). MAIN OUTCOME MEASURE: Five-year overall mortality. RESULTS: The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P < .001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P < .001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P < .001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P < .001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity = .003). CONCLUSION: Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis.

An international case-control study of maternal diet during pregnancy and childhood brain tumor risk: a histology-specific analysis by food group.

PURPOSE: Maternal dietary data from an international collaborative case-control study on childhood brain tumors were used to evaluate associations between histology-specific risk and consumption of specific food groups during pregnancy. METHODS: Nine study centers from seven countries contributed 1218 cases and 2223 controls. Most cases were diagnosed between 1982 and 1992 and ranged in age from 0 to 19 years. Dietary consumption was measured as average grams per day. RESULTS: Foods generally associated with increased risk were cured meats, eggs/dairy, and oil products; foods generally associated with decreased risk were yellow-orange vegetables, fresh fish, and grains. The cured meat association was specific to astrocytomas (odds ratio [OR] range=1.8-2.5 across astrocytoma subtypes for 4th vs. 1st quartile of consumption, p trends

An international case-control study of adult diet and brain tumor risk: a histology-specific analysis by food group.

PURPOSE: Existing studies of diet and adult brain tumors have been limited by small numbers in histology-specific subgroups. Dietary data from an international collaborative case-control study on adult brain tumors were used to evaluate associations between histology-specific risk and consumption of specific food groups. METHODS: The study included 1548 cases diagnosed between 1984 and 1991 and 2486 control subjects from 8 study centers in 6 countries. Of the 1548 cases, 1185 were gliomas, 332 were meningiomas, and 31 were other tumor types. Dietary consumption was measured as average grams per day. RESULTS: We found inverse associations between some vegetable groups and glioma risk, the strongest for yellow-orange vegetables (odds ratio [OR], 0.7, 95% confidence interval [CI], 0.5-0.9 for the 4th vs. 1st quartile of consumption, p for trend<0.001), and the association was limited to specific glioma subtypes. There was no association with cured meat. Non-cured meat was associated with a modest increase in glioma risk (OR, 1.3; 95% CI, 1.0-1.7 for 4th quartile vs. 1st quartile, p for trend=0.01). We also found positive associations between egg, grain, and citrus fruit consumption and glioma but not meningioma risk. CONCLUSIONS: Our study suggests that selected dietary food groups may be associated with adult gliomas and its subtypes but not meningiomas.

Family cancer history and risk of brain tumors in children: results of the SEARCH international brain tumor study.

OBJECTIVE: To examine whether childhood brain tumors (CBTs) are associated with a family history of brain tumors or other cancers in an international case-control study. METHODS: Cancers in children's first- and second-degree relatives were ascertained by interview with parents of 620 children with astroglial tumors, 255 with primitive neuroectodermal tumors, 324 with other CBTs, and 2,218 controls from Australia, Canada, France, Israel, Italy, Spain, and the US. These were used with histories of neurofibromatosis or tuberous sclerosis to exclude in subanalyses children with Li-Fraumeni or other hereditary syndromes predisposing to brain tumors. RESULTS: A first- or second-degree relative of 4% of children with astroglial tumors, 6% with PNET, 5% with other CBTs, and 5% of controls had had a brain tumor. Any potential differences were statistically non-significant, including when focusing on relatives diagnosed in childhood. In the US, where anatomical sites of relatives' other cancers were known, CBT occurrence was not associated with any other specific site. Results were not markedly altered by exclusion of children with hereditary syndromes. CONCLUSION: Consistent with most prior studies using these methods, we observed no strong relationship between CBT occurrence and cancers in family members.

Effect of BRCA1/2 mutations on long-term survival of patients with invasive ovarian cancer: the national Israeli study of ovarian cancer.

PURPOSE: To evaluate the long-term survival of ovarian cancer (OvC) patients in total and by BRCA1/2 mutation status. PATIENTS AND METHODS: In a nationwide case-control study on OvC conducted in Israel between 1994 and 1999, 779 Jewish women with epithelial invasive OvC were tested for the three Ashkenazi Jewish founder mutations in BRCA1 (185delAG; 5382insC) and BRCA2 (6174delT) genes and followed for survival up to 2003. Of the 605 women of Ashkenazi origin, 213 (35.2%) carried a mutation in the BRCA1/2 genes. Clinical characteristics were abstracted from the patients' medical records. The Kaplan-Meier method, log-rank tests, and stepwise Cox regression model were used for survival analyses. RESULTS: The 5-year survival rate for the entire group was 39%. Median survival for carriers was significantly longer than for noncarriers (53.7 v 37.9 months, respectively; P = .002). This differential survival was pronounced among women diagnosed at stages III to IV (5-year survival rates of 38.1% and 24.5% for carriers and noncarriers, respectively; P < .001) and for women with poor grade (45.4% v 31.5%, for carriers and noncarriers, respectively; P < .001). These results remained significant after controlling for age at diagnosis, grade, and morphology. This benefit in prognosis was seen for both BRCA1 and BRCA2 carriers compared with noncarriers. During the study period (median follow-up, 6.2 years), being a BRCA1/2 mutation carrier decreased the mortality rate by 28%. CONCLUSION: This study confirms that, among Ashkenazi OvC patients, BRCA1/2 mutations are associated with improved long-term survival. This may be due to distinct clinical behavior and/or to a better response to chemotherapy.

Obesity among Arabs and Jews in Israel: a population-based study.

BACKGROUND: Arabs in Israel have high morbidity and mortality from diabetes and cardiovascular disease. Obesity is a risk factor for both conditions. OBJECTIVES: To investigate the prevalence of obesity (body mass index >30 kg/m2), subjects' knowledge and behaviors, and their reports on practices of health-care professionals regarding body weight among Arabs and Jews. METHODS: The study participants (n=880) were randomly sampled from the urban population of the Hadera district in Israel. Data on demographic, socioeconomic and lifestyle characteristics; reports on height, current body weight and body weight at the age of 18 years; knowledge and behavior; and health-care professionals' practices with regard to body weight were obtained by interview. Anthropometric measurements were performed subsequently. RESULTS: Information on BMI was available on 868 participants (49% Arabs, 49% women, median age 46 years). Although the median BMI did not differ significantly between Arabs and Jews at age 18, the prevalence of current obesity was 52% in Arab women compared to 31% in Jewish women (P < 0.001), and 25% in Arab men compared to 23% in Jewish men (P = 0.6). On multivariate analysis, obesity was significantly associated with age, BMI at the age of 18 years, leisure time physical activity and cigarette smoking, but not with ethnicity. Fewer Arabs reported measuring their body weight and Arab women were less frequently advised to maintain an active lifestyle. CONCLUSIONS: The high prevalence of obesity among Arab women may be explained by lifestyle characteristics. Prevention of obesity in Arabs should be directed at women and should start preferably before adulthood.

Dietary intake changes and their association with ovarian cancer risk.

There are reasons to suspect that dietary changes through adult life may modify risk for some cancers. We examined the association of recent and past dietary habits and changes in dietary intake over time with ovarian cancer risk. Long-term nutritional assessment was performed retrospectively in 631 incident cases of invasive epithelial ovarian cancer and in 1174 matched controls (matched by age +/- 2 y, country of origin, and period of immigration) as part of a nationwide case-control study of ovarian cancer conducted between the years of 1994 and 1996 in Israel. Using a 2-step quantified Food Frequency Questionnaire, participants were first asked about their consumption of food items 1 y prior to the interview, and then whether their consumption had changed over time. The time of the change and consumption level before the change were recorded, allowing reconstruction of daily intakes for several time points. The reported mean percentage of animal fat intake decreased by 1.3% in cases but by 1.9% in controls (P for difference = 0.003). Conditional multivariate logistic regression was used to estimate odds ratios adjusted for total energy, parity, and oral contraceptive use. Substituting nonanimal fat in preference to animal fat over a relatively short term (between 2 and 7 y prior to interview) decreased the risk of ovarian cancer [OR = 0.65/100 kcal (418.4 kJ), 95% CI = 0.50 - 0.85]. Our results suggest that substitution of nonanimal for animal fat during adult life might reduce the risk of ovarian cancer, but this requires confirmation in prospective studies.

Maternal medication use and the risk of brain tumors in the offspring: the SEARCH international case-control study.

N-nitroso compounds (NOC) have been associated with carcinogenesis in a wide range of species, including humans. There is strong experimental data showing that nitrosamides (R(1)NNO.COR(2)), a type of NOC, are potent neuro-carcinogens when administered transplacentally. Some medications are a concentrated source of amides or amines, which in the presence of nitrites under normal acidic conditions of the stomach can form NOC. Therefore, these compounds, when ingested by women during pregnancy, may be important risk factors for tumors of the central nervous system in the offspring. The aim of the present study was to test the association between maternal use of medications that contain nitrosatable amines or amides and risk of primary childhood brain tumors (CBT). A case-control study was conducted, which included 1,218 cases and 2,223 population controls, recruited from 9 centers across North America, Europe and Australia. Analysis was conducted for all participants combined, by tumor type (astroglial, primitive neuroectodermal tumors and other glioma), and by age at diagnosis (< or =5 years; >5 years). There were no significant associations between maternal intake of medication containing nitrosatable amines or amides and CBT, for all participants combined and after stratification by age at diagnosis and histological subtype. This is the largest case-control study of CBT and maternal medications to date. Our data provide little support for an association between maternal use of medications that may form NOC and subsequent development of CBT in the offspring.

Primary peritoneal carcinoma--Uterine involvement and hysterectomy.

OBJECTIVE: To assess the frequency of uterine involvement in primary peritoneal carcinoma (PPC) and to describe selected clinical characteristics in patients with and without hysterectomy. METHODS: All incident cases of histologically confirmed cancer of the ovary or peritoneum, diagnosed in Israeli Jewish women between March 1 1994 and June 30, 1999, were identified within the framework of a nationwide epidemiological study of these neoplasms. The study population was accrued through an active search of all newly diagnosed patients in all the departments of gynecology in Israel. The data of 81 PPC patients included in the present study were abstracted from medical records. RESULTS: Hysterectomy was performed in 48 patients. These patients had a lower mean age (62.4 +/- 9.4 vs. 66.9 +/- 10.4; P = 0.05) at diagnosis and a higher rate of < or =2 cm residual disease (54.2% vs.24.2%; P = 0.02). Of those with hysterectomy, microscopic involvement was verified in all those with macroscopic involvement. Overall microscopic involvement was present in 28 (58.3%) of the patients who underwent hysterectomy. In the majority of them, only the serosa was involved. Macroscopic uterine involvement was present in 27 (33.3%) patients but in only 12% it was >2 cm. The median survival in patients with hysterectomy was 36 months and in those without hysterectomy 29 months, this difference was statistically not significant (P = 0.2). CONCLUSIONS: Our study indicates that in an unselected group of PPC patients 33% have any macroscopic uterine involvement. The therapeutic value of routine hysterectomy at the initial operation for PPC should be further investigated.

Demographic and genetic characteristics of patients with borderline ovarian tumors as compared to early stage invasive ovarian cancer.

OBJECTIVE: Evaluation whether Jewish founder mutations in BRCA predispose to borderline tumors as they do to early invasive ovarian cancers. METHODS: All Jewish women with borderline or invasive ovarian tumors, diagnosed over a 5-year period (1994-1999), were identified in the frame of a nationwide epidemiological study on ovarian cancer in Israel. Out of a total of 1489 patients, 1269 were interviewed; of them 256 (20.2%) patients were identified with stage I and II invasive epithelial ovarian tumors, and 233 (18.3%) patients were identified with borderline tumors. All patients underwent interviews, and blood or tissue samples from 117 borderline tumors and 161 early stage invasive tumors were analyzed for the presence of the 185delAG and 5382insC BRCA1, and the 6174delT BRCA2 Jewish founder mutations. RESULTS: Patients with borderline tumors were younger at diagnosis, and more frequently of the serous type (P < 0.001) as compared to patients with early stage ovarian cancer. Prevalence of Jewish founder mutations in BRCA1 and BRCA2 was only 4.3% of patients with borderline tumors as compared to 24.2% of patients with early stage ovarian cancer (P = 0.001). CONCLUSIONS: This nationwide study comparing patients with early stage borderline and invasive epithelial tumors of the ovary confirms our previous pilot study that showed a lower incidence of BRCA mutations in patients with borderline tumors. Our results suggest that the genetic predisposition and the molecular mechanisms underlying tumor initiation differ between invasive and borderline tumors of the ovary.

Life-style habits and homocysteine levels in an elderly population.

BACKGROUND AND AIMS: Increased plasma total homocysteine (Hcy) is a known cardiovascular disease (CVD) risk factor, related to several components of the established CVD risk profile. Observational studies support the role of modifying life-style related risk factors such as diet, physical activity and alcohol consumption in CVD prevention. Regular physical activity protects against coronary artery disease, possibly through its role in controlling risk factors such as hypertension, diabetes mellitus and obesity, but also independently. The aim of our study was to test the hypothesis that there is an association between physical activity, life-style habits and plasma Hcy levels in an elderly population. METHODS: In this cross-sectional study, 423 males and females aged 69.0 +/- 6.7 years completed an interview and laboratory examinations. Our main outcome measure was plasma levels of Hcy. RESULTS: Mean Hcy values were 10.5 +/- 5.5 micromol/L (11.4 +/- 6.1 for males and 9.3 +/- 4.5 for females; p < 0.001). Smoking and BMI were not found to be associated with Hcy levels. Physically active subjects, as well as B vitamin supplement users, had significantly lower Hcy levels (p = 0.002 and p = 0.004, respectively). In a multiple linear regression model, the Hcy level was 10% higher amongst participants with a sedentary life-style, 17% higher amongst males, 1% higher for each one-year increment in age, and 10% higher amongst participants who used no B vitamin supplements. CONCLUSIONS: Any level of physical activity was found to be an independent life-style habit associated with a lower Hcy level in an elderly population. This study supports existing recommendations for elderly persons to maintain a physically active life-style.

Gynecologic surgeries and risk of ovarian cancer in women with BRCA1 and BRCA2 Ashkenazi founder mutations: an Israeli population-based case-control study.

BACKGROUND: In the general population, the risk of developing ovarian cancer is reduced in women who have undergone tubal ligation, hysterectomy, or oophorectomy, although peritoneal cancer can arise after bilateral oophorectomy. In studies from genetic screening clinics, women with mutations in the breast and ovarian susceptibility genes BRCA1 and BRCA2 have been found to have a low risk of peritoneal carcinoma in the first years after bilateral oophorectomy. We assessed the level and persistence of reduction of ovarian (including peritoneal) cancer risk after gynecologic surgeries for women who carry BRCA1/2 mutations but were not selected from high-risk clinics. METHODS: We identified 1124 Israeli women with incident ovarian cancer or primary peritoneal cancer and tested 847 of them for the three Ashkenazi founder mutations. We compared gynecologic surgery history among all case patients, BRCA1 (n = 187) and BRCA2 (n = 64) carrier case patients, and the non-carrier case patients (n = 598) with that in control subjects drawn from a population registry (n = 2396). We estimated ovarian cancer risk (odds ratios [ORs] with 95% confidence intervals [CIs]) after gynecologic surgery in mutation carriers and non-carriers with logistic regression models. RESULTS: Eight women with primary peritoneal cancer and 128 control subjects reported a previous bilateral oophorectomy (OR = 0.12, 95% CI = 0.06 to 0.24). Other gynecologic surgeries were associated with a 30%-50% reduced risk of ovarian cancer, depending on the type of surgery, with surgery to remove some ovarian tissue associated with the most risk reduction (OR = 0.34, 95% CI = 0.16 to 0.74). Reduced risks were seen in BRCA1/2 carriers and non-carriers. Age at surgery and years since surgery did not affect risk reductions. CONCLUSION: Both BRCA1/2 mutation carriers and non-carriers have reduced risk of ovarian or peritoneal cancer after gynecologic surgery. The magnitude of the reduction depends upon the type and extent of surgery.

Lifestyle and ethnicity play a role in all-cause mortality.

The Israeli population is characterized by its marked ethnic diversity. These ethnic groups (originating mainly from Yemen/Aden, the Middle East, North Africa and Europe/America) have kept traditional distinct lifestyle habits and exhibit different morbidity and mortality trends. The aim of the present study was to evaluate the associations among ethnic background, lifestyle patterns and 18-y all-cause mortality. A subgroup of 632 individuals aged 41-70 y, drawn from a larger stratified cohort from the Israel Glucose Intolerance, Obesity and Hypertension study, were personally interviewed, using a quantified food-frequency questionnaire, including most food items consumed by the different subpopulations in Israel. Physical activity was also evaluated, as well as smoking status. Weight, height and blood pressure (BP) measurements were taken. Predictors of mortality were assessed using Cox proportional hazards models. Over the 18-y follow-up period, 151 deaths occurred (24%). In comparison with Yemenites, the adjusted hazard ratios (HR) for all cause mortality were HR = 1.77 [95% confidence interval (CI): 1.01-3.09] for Europeans/Americans; HR = 1.63 (95% CI: 0.89-2.99) for those from a Middle Eastern background; and HR = 1.56 (95% CI: 0.82-2.97) for North Africans. Mortality risk was 43% lower among those consuming > or =25 g of dietary fiber daily [HR = 0.57 (95% CI: 0.41-0.72)], and 42% lower for those consuming <300 mg/d of cholesterol [HR = 0.58 (95% CI: 0.34-0.96)]. Accumulating an average of 0.5 h/d of moderate physical activity reduced mortality by 47% [HR = 0.53 (95% CI: 0.29-0.97)]. Smoking, increased systolic BP, older age and male sex increased mortality risk. We conclude that in our study, although ethnic origin and lifestyle habits are interrelated, each affects mortality independently.

Farm-related exposures and childhood brain tumours in seven countries: results from the SEARCH International Brain Tumour Study.

A total of 1218 cases of childhood brain tumours (CBT) and 2223 control subjects from the general population were included in a population-based case-control study conducted in nine centres in seven countries. Mothers were asked about farm- or agriculture-related exposures. Significantly elevated odds ratios (OR) for CBT were associated with children's personal and maternal prenatal exposure while living on a farm with pigs (child OR = 1.7, mother OR = 2.3), horses (child OR = 1.6, mother OR = 1.8), dogs (child OR = 1.5, mother OR = 1.5) and cats (child OR = 1.5, mother OR = 1.7). Children who were exposed to pigs, horses and cats combined, while living on a farm, had a threefold elevated OR for CBT. Increased ORs for primitive neuroectodermal tumours (PNET) were associated with children's farm exposure to dogs (OR = 1.9) and cats (OR = 2.2), and maternal farm exposure to pigs (OR = 4.2). The OR for CBT was elevated (OR = 2.3) for children of mothers who had preconception/prenatal farm- or agriculture-related employment involving potential contact with animals, relative to no farm- or agriculture-related employment. In particular, increased ORs for CBT were observed for children of mothers who were employed as general farmers (OR = 4.1) or general farm workers (OR = 3.8). During the 5 years preceding the index child's birth, maternal exposures were related to CBT, relative to no maternal exposure to agricultural chemicals or animal products: fertilisers (OR = 1.8), pesticides (OR = 2.0), animal manure (OR = 2.0) and unprocessed wool (OR = 3.0). Our findings suggest that various farm-related exposures are positively associated with CBT and warrant further investigation into the public health importance of these associations.