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Genetic analyses of BRCA1 mutant cell lines and PDX models.

Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q protein was capable of promoting partial PARPi and cisplatin resistance relative to full-length BRCA1, both in vitro and in vivo. Furthermore, spliceosome inhibitors reduced BRCA1-Δ11q levels and sensitized cells carrying exon 11 mutations to PARPi treatment. Taken together, our results provided evidence that cancer cells employ a strategy to remove deleterious germline BRCA1 mutations through alternative mRNA splicing, giving rise to isoforms that retain residual activity and contribute to therapeutic resistance. Cancer Res; 76(9); 2778–90. ©2016 AACR.

Legend for Supplementary Figures S1-S6.

age at allergy onset

RNA-seq analyses of global exon splicing events (S1); Cell line therapy sensitivities (S2); Hazard ratios for survival of patients with serous ovarian carcinomas associated with BRCA1 mutation, age at diagnosis and stage (S3); Characteristics of studies included in survival analysis from Fig. 5A (S4).

PDF file, 102K, Linkage locations suggested by Loki on chromosome 17 by batches of 100K iterations and over all 500K iterations.

Background: Several previous studies have found inverse associations between glioma susceptibility and a history of allergies or other atopic conditions. Some evidence indicates that respiratory allergies are likely to be particularly relevant with regard to glioma risk. Using data from the Glioma International Case-Control Study (GICC), we examined the effects of respiratory allergies and other atopic conditions on glioma risk.Methods: The GICC contains detailed information on history of atopic conditions for 4,533 cases and 4,171 controls, recruited from 14 study sites across five countries. Using two-stage random-effects restricted maximum likelihood modeling to calculate meta-analysis ORs, we examined the associations between glioma and allergy status, respiratory allergy status, asthma, and eczema.Results: Having a history of respiratory allergies was associated with an approximately 30% lower glioma risk, compared with not having respiratory allergies (mOR, 0.72; 95% confidence interval, 0.58–0.90). This association was similar when restricting to high-grade glioma cases. Asthma and eczema were also significantly protective against glioma.Conclusion: A substantial amount of data on the inverse association between atopic conditions and glioma has accumulated, and findings from the GICC study further strengthen the existing evidence that the relationship between atopy and glioma is unlikely to be coincidental.Impact: As the literature approaches a consensus on the impact of allergies in glioma risk, future research can begin to shift focus to what the underlying biologic mechanism behind this association may be, which could, in turn, yield new opportunities for immunotherapy or cancer prevention. Cancer Epidemiol Biomarkers Prev; 25(2); 282–90. ©2016 AACR.

PDF file, 212K, Genome-wide multipoint model-based linkage under the three trait locus segregation models. Multipoint LOD scores have been truncated at -3. Some scores are below -3, such as for the whole of chromosome 15.

Supplementary Tables S1-S6, Supplementary References. Supplementary Table S1. Characteristics of included studies; S2. Complete-case analysis of ten years estimated hazard ratios (HR) for all cause death in patients with ovarian cancer. S3. Complete-case analysis of ten years estimated subhazard ratios (SHR) for ovarian cancer death in patients with ovarian cancer. S4. Ten years estimated subhazard ratios (SHR) for ovarian cancer death in patients with ovarian cancer (with multiple imputation for missing grade and stage). S5. Complete-case analysis of ten years estimated hazard ratios (HR) for all cause death in patients with high grade serous ovarian cancer. S6. Ten years estimated hazard ratios (HR) for all cause death in patients with high grade serous ovarian cancer (with multiple imputation for missing stage).

PDF file, 302K, Scatter plot of the visits at possible linked QTL locations on chromosome 17 vs. iteration.

PDF file, 133K, Additional methods describing the segregation-linkage analysis approach with variable age at onset.

PDF file, 89K, L-scores for three prior settings, after discarding the beginning 5K iterations

PDF file, 34K, Typical assumptions in model-based vs. model-free multipoint linkage analysis.

Description of additional methods and procedures used in the study. Also includes Supplementary References.

Supplementary Table S1. Description of ELF levels in the most frequent jobs in low (

Background . A major, prolonged measles outbreak occurred in Israel during 2018-19, despite vaccination coverage rates of 97% and 96% for the first and second doses, respectively, of measles containing vaccine (MCV). Aim . To study the causes and patterns of the outbreak through analysis of the epidemiological data, review the control measures taken, and identify lessons learned and efforts needed to prevent recurrences. Methods . All reported cases of measles in Israel from 1 March 2018 through 30 September 2019 were analysed using the epidemiological, clinical, laboratory, and demographic data that are systematically reported to the Division of Epidemiology of the Ministry of Health. Results . A total of 4,311 measles cases were reported. 75% of case patients were children and 25% were adults. Pockets of undervaccination and delayed vaccination were identified: 72.6% of measles patients whose vaccination histories were known had not received any doses of MCV. Case importation was also a key factor, with a majority being adults coming from European countries and over half from Ukraine, a major locus of measles cases during the recent measles resurgence in Europe. Control measures were implemented at the local, district, and national levels. Conclusions . Similarities were noted between the 2018-19 outbreak and the prior one in 2007-08, principally pockets of undervaccination in the Jewish ultra-orthodox community, and case importation. Efforts to improve timeliness and coverage in pockets of undervaccination, and compliance with travel immunization guidelines, will be continued.

Background Exposure to high doses of ionizing radiation is among the few well-established brain tumour risk factors. We used data from the Interphone study to evaluate the effects of exposure to low-dose radiation from diagnostic radiological examinations on glioma, meningioma and acoustic neuroma risk. Methods Brain tumour cases (2644 gliomas, 2236 meningiomas, 1083 neuromas) diagnosed in 2000–02 were identified through hospitals in 13 countries, and 6068 controls (population-based controls in most centres) were included in the analysis. Participation across all centres was 64% for glioma cases, 78% for meningioma cases, 82% for acoustic neuroma cases and 53% for controls. Information on previous diagnostic radiological examinations was obtained by interviews, including the frequency, timing and indication for the examinations. Typical brain doses per type of examination were estimated based on the literature. Examinations within the 5 years before the index date were excluded from the dose estimation. Adjusted odds ratios were estimated using conditional logistic regression. Results No materially or consistently increased odds ratios for glioma, meningioma or acoustic neuroma were found for any specific type of examination, including computed tomography of the head and cerebral angiography. The only indication of an elevated risk was an increasing trend in risk of meningioma with the number of isotope scans, but no such trends for other examinations were observed. No gradient was found in risk with estimated brain dose. Age at exposure did not substantially modify the findings. Sensitivity analyses gave results consistent with the main analysis. Conclusions There was no consistent evidence for increased risks of brain tumours with X-ray examinations, although error from selection and recall bias cannot be completely excluded. A cautious interpretation is warranted for the observed association between isotope scans and meningioma.

The first local spread of COVID-19 in Israel was detected in March 2020. Due to the diversity in clinical presentations of COVID-19, diagnosis by RT-PCR alone might miss patients with mild or no symptoms. Serology testing may better evaluate the actual magnitude of the spread of infection in the population. This is the first nationwide seroprevalence study conducted in Israel. It is one of the most widespread to be conducted thus far, and the largest per-country population size. The survey was conducted between June 28 and September 14, 2020 and included 54,357 patients who arrived at the Health Maintenance Organizations to undergo a blood test for any reason. A patient was considered seropositive after two consecutive positive results with two different kits (Abbott and DiaSorin).The overall seroprevalence was 3.8% (95%CI 3.7–4.0), males higher than females [4.9% (95%CI 4.6–5.2) vs. 3.1% (95%CI 2.9–3.3) respectively]. Adolescents had the highest prevalence [7.8% (95%CI 7.0–8.6)] compared to other age groups. Participants who had undergone RT-PCR testing had a tenfold higher risk to be seropositive. The prevalence-to-incidence ratio was 4.5–15.7. Serology testing is an important complimentary tool for assessing the actual magnitude of infection and thus essential for implementing policy measures to control the pandemic. A positive serology test result was recently accepted in Israel as being sufficient to define recovery, with possible far-reaching consequences, such as the deploying of employees to ensure the maintenance of a functional economy. Supplementary Information The online version contains supplementary material available at 10.1007/s10654-021-00749-1.

Improvements in diagnosis and treatment of Breast Cancer (BC) have resulted in an increase in the life expectancy of survivors and in the importance of quality of life in BC survivorship care. The current study aimed to assess the Health-Related Quality Of Life (HRQOL) of BC survivors and to investigate the association of comorbidities with HRQOL compared to a group of women with no history of cancer. Women were residents of the central district in Israel, the case group included 250 women diagnosed with BC between 1999 and 2003, with no prior cancer history and no evidence of disease after 8–12 years. The comparison group included 250 women with no cancer history, individually matched to cases by age and area of residence. Data were collected through in-person interviews, and HRQOL was assessed using the Short Form-36 (SF-36) questionnaire. Regression analyses were performed evaluating the influence of demographic, socioeconomic, lifestyle characteristics and comorbidities on physical and mental HRQOL. The physical and mental summary scores means, were 48.5 ± 11.1 and 49.2 ± 10.8 compared to 51.5 ± 10.2 and 50.9 ± 10.6, in BC survivors and the comparison group, respectively (p = 0.002 and p = 0.097). BC survivors and controls did not differ in number and type of comorbidities and for both groups a negative association was seen with HRQOL. Controlling for age, income, number of comorbidities, BMI and physical activity, BC survivor had decreased physical (b = −2.49, p = 0.001) and mental summary scores (b = −1.27, p = 0.18). HRQOL of BC survivors should gain more attention in the area of cancer care, especially when comorbidities are present.

Introduction: We used data from MOBI-Kids, a 14-country international collaborative case-control study of brain tumors (BTs), to study clinical characteristics of the tumors in older children (10 years or older), adolescents and young adults (up to the age of 24). Methods: Information from clinical records was obtained for 899 BT cases, including signs and symptoms, symptom onset, diagnosis date, tumor type and location. Results: Overall, 64% of all tumors were low-grade, 76% were neuroepithelial tumors and 62% gliomas. There were more males than females among neuroepithelial and embryonal tumor cases, but more females with meningeal tumors. The most frequent locations were cerebellum (22%) and frontal (16%) lobe. The most frequent symptom was headaches (60%), overall, as well as for gliomas, embryonal and 'non-neuroepithelial' tumors; it was convulsions/seizures for neuroepithelial tumors other than glioma, and visual signs and symptoms for meningiomas. A cluster analysis showed that headaches and nausea/vomiting was the only combination of symptoms that exceeded a cutoff of 50%, with a joint occurrence of 67%. Overall, the median time from first symptom to diagnosis was 1.42 months (IQR 0.53-4.80); it exceeded 1 year in 12% of cases, though no particular symptom was associated with exceptionally long or short delays.Conclusions: This is the largest clinical epidemiology study of BT in young people conducted so far. Many signs and symptoms were identified, dominated by headaches and nausea/vomiting. Diagnosis was generally rapid but in 12% diagnostic delay exceeded 1 year with none of the symptoms been associated with a distinctly long time until diagnosis. This work was supported by the MOBI-Kids study and the work in this study was obtained from the European Community's Seventh Framework Programme under Grant Agreements Number 226873—the MOBI-Kids Project—and 603794—the GERoNiMO project. Additional funds for the coordination of MOBI-Kids were obtained from the Spanish Ministry of Science and Innovation (MINECO), while complementary funds for the conduct of MOBI-Kids in Spain were obtained from the Spanish Health Research Fund (FIS) of the National Institute for Health Carlos III. Italian participation is partially supported by a Ministry of Health grant (RF-2009-1546284). In Canada, funding was provided by a grant from the Canadian Institutes for Health Research under a peer-reviewed university-industry partnership program that involved the Canadian Wireless Telecommunications Association, who provided technical data on wireless telecommunications practices in Canada. The German study centre received additional support by the Federal Office for Radiation Protection (BfS). Japanese participation in MOBI-Kids was supported by the Ministry of Internal Affairs and Communications. New Zealand participation was supported by Health Research Council and Cure Kids. In France, this study received funds from the French National Agency for Sanitary Safety of Food, Environment and Labour (ANSES, contract FSRF2008-3), French National Cancer Institute (INCa), Pfizer Foundation and League against cancer. India received funding from Board of Research in Nuclear Sciences (BRNS). The funding sources had no role in: the study design; the collection, analysis, and interpretation of data; the writing of the report; and the decision to submit the article for publication.

We investigated the association of allergic diseases and epilepsy with risk of brain tumours, in Interphone, a 13-country case–control study. Data were obtained from 2693 glioma cases, 2396 meningioma cases, and 1102 acoustic neuroma cases and their 6321 controls. Conditional logistic regression models were used to estimate pooled odds ratios (ORs) and their respective 95% confidence intervals (CIs), adjusted for education and time at interview. Reduced ORs were observed for glioma in relation to physician-diagnosed asthma (OR = 0.73; CI 0.58–0.92), hay fever (OR 0.72; CI 0.61–0.86), and eczema (OR 0.78, CI 0.64–0.94), but not for meningioma or acoustic neuroma. Previous diagnosis of epilepsy was associated with an increased OR for glioma (2.94; CI 1.87–4.63) and for meningioma (2.12; CI 1.27–3.56), but not for acoustic neuroma. This large-scale case–control study adds to the growing evidence that people with allergies have a lower risk of developing glioma, but not meningioma or acoustic neuroma. It also supports clinical observations of epilepsy prior to the diagnosis of glioma and meningioma. acceptedVersion

Glioma incidence is highest in non-Hispanic Whites, and to date, glioma genome-wide association studies (GWAS) to date have only included European ancestry (EA) populations. African Americans and Hispanics in the US have varying proportions of EA, African (AA) and Native American ancestries (NAA). It is unknown if identified GWAS loci or increased EA is associated with increased glioma risk. We assessed whether EA was associated with glioma in African Americans and Hispanics. Data were obtained for 832 cases and 675 controls from the Glioma International Case-Control Study and GliomaSE Case-Control Study previously estimated to have

Concern has been raised regarding the possible effects of mobile phone use on health, especially by children and adolescents. Thus, it is important to evaluate factors affecting their patterns of use. This study aimed to identify determinants of heavy mobile phone use among Israeli adolescents. Data were collected using a self-report questionnaire regarding mobile phone usage, leisure activity, sociodemographics, and opinion regarding mobile phone use. "Heavy use" was defined as >1 hour of daily duration of voice calls, or >50 daily text messages. The survey included 1,688 seventh and ninth graders in eight middle schools. The vast majority (96.1 percent) used the mobile phone for voice calls daily. Girls were heavier users than boys, and ninth graders were heavier users than seventh graders. Among students attending religious schools, the rate of heavy users was lower than among those attending secular schools. About half of the students did not use hands-free devices at least half of the time. Leisure activities were significantly associated with mobile phone use. This study demonstrates that several variables, including sociodemographics and leisure activities, may predict heavy mobile phone use among teenagers. This information can be useful for exposure assessment and for designing intervention programs for reducing radio frequency (RF) radiation exposure.

There is limited evidence that non-leukaemic lymphoid malignancies are radiogenic. As radiation-related cancer risks are generally higher after childhood exposure, we analysed pooled lymphoid neoplasm data in nine cohorts first exposed to external radiation aged 0.4). In six cohorts with estimates of lymphatic tissue dose, borderline significant increased risks (p-trend = 0.02-0.07) were observed for NHL + CLL, NHL, andCLL. Further pooled epidemiological studies are needed with longer follow-up, central outcome review by expert hematopathologists, and assessment of radiation doses to lymphoid tissues.

Improvements in diagnosis and treatment of Breast Cancer (BC) have resulted in an increase in the life expectancy of survivors and in the importance of quality of life in BC survivorship care. The current study aimed to assess the Health-Related Quality Of Life (HRQOL) of BC survivors and to investigate the association of comorbidities with HRQOL compared to a group of women with no history of cancer.Women were residents of the central district in Israel, the case group included 250 women diagnosed with BC between 1999 and 2003, with no prior cancer history and no evidence of disease after 8-12 years. The comparison group included 250 women with no cancer history, individually matched to cases by age and area of residence. Data were collected through in-person interviews, and HRQOL was assessed using the Short Form-36 (SF-36) questionnaire. Regression analyses were performed evaluating the influence of demographic, socioeconomic, lifestyle characteristics and comorbidities on physical and mental HRQOL.The physical and mental summary scores means, were 48.5 ± 11.1 and 49.2 ± 10.8 compared to 51.5 ± 10.2 and 50.9 ± 10.6, in BC survivors and the comparison group, respectively (p = 0.002 and p = 0.097). BC survivors and controls did not differ in number and type of comorbidities and for both groups a negative association was seen with HRQOL. Controlling for age, income, number of comorbidities, BMI and physical activity, BC survivor had decreased physical (b = -2.49, p = 0.001) and mental summary scores (b = -1.27, p = 0.18).HRQOL of BC survivors should gain more attention in the area of cancer care, especially when comorbidities are present.

The COVID-19 pandemic substantially impacted countries' democratic election. On March 2020 Israel held a general parliamentary elections. The participation rate was 71.5%, compared with a 70% rate on the previous elections held in September 2019. We review Israel's actions which lead to a safe elections process and enhanced participation rate.

Background: As many countries consider and employ various lockdown exit strategies, health authorities seek tools to provide differential targeted advice for social distancing based on personal risk for severe COVID-19. However, striking a balance between a scientifically precise multivariable risk prediction model, and a model which can easily be used by the general public, remains a challenge. A list of risk criteria, as defined by the CDC for example, provides a simple solution, but may be too inclusive by classifying a substantial portion of the population at high risk. Score-based risk classification tools may provide a good compromise between accuracy and simplicity. Objective: To create a score-based risk classification tool for severe COVID-19. Methods: The outcome was defined as a composite of being labeled severe during hospitalization or dying due to COVID-19. The risk classification tool was developed using retrospective data from all COVID-19 patients that were diagnosed until April 1st, 2020 in a large healthcare organization ("training set"). The developed tool combines 10 risk factors using simple summation, and defines three risk levels according to the patient's age and number of accumulated risk points - basic risk, high risk and very-high risk (the last two levels are also considered together as the elevated risk group). The tool's performance in accurately identifying individuals at risk was evaluated using a "temporal test set" of COVID-19 patients diagnosed between April 2nd and April 22nd, 2020, later than those used for model development. The tool's performance was also compared to that of the CDC's criteria. The healthcare organization's general population was used to evaluate the proportion of patients that would be classified to each of the model's risk levels and as elevated risk by the CDC criteria. Results: A total of 2,421, 2,624 and 4,631,168 individuals were included in the training, test, and general population cohorts, respectively. The outcome rate in the training and test sets was 5%. Overall, 18% of the general population would be classified at elevated risk by the model, with a resulting sensitivity of 92%, compared to 35% that would be defined as elevated risk by the CDC criteria, with a resulting sensitivity of 96%. Within the model's elevated risk groups, the high and very-high risk groups comprised 15% and 3% of the general population, with an incidence rate (PPV) of 15% and 33%, respectively. Discussion: A simple to communicate score-based risk classification tool classifies at elevated risk about half of the population that is considered to have an elevated risk by the CDC risk criteria, with only a 4% reduction in sensitivity. The model's ability to further divide the elevated risk population into two markedly different subgroups allows providing more refined recommendations to the general public and limiting the restrictions of social distancing to a smaller and more manageable subset of the population. This model was adopted by the Israeli ministry of health as its risk classification tool for COVID-19 lab tests prioritization and for targeting its instructions on risk management during the lockdown exit strategy.

Glioblastoma (GBM) is the most common malignant brain tumor in the United States. Incidence of GBM increases with age, and younger age-at-diagnosis is significantly associated with improved prognosis. While the relationship between candidate GBM risk SNPs and age-at-diagnosis has been explored, genome-wide association studies (GWAS) have not previously been stratified by age. Potential age-specific genetic effects were assessed in autosomal SNPs for GBM patients using data from four previous GWAS. Using age distribution tertiles (18–53, 54–64, 65+) datasets were analyzed using age-stratified logistic regression to generate p values, odds ratios (OR), and 95% confidence intervals (95%CI), and then combined using meta-analysis. There were 4,512 total GBM cases, and 10,582 controls used for analysis. Significant associations were detected at two previously identified SNPs in 7p11.2 (rs723527 [p(54–63)=1.50×10(−9), OR(54–63)=1.28, 95%CI(54–63)=1.18–1.39; p(64+)=2.14×10(−11), OR(64+)=1.32, 95%CI(64+)=1.21–1.43] and rs11979158 [p(54–63)=6.13×10(−8), OR(54–63)=1.35, 95%CI(54–63)=1.21–1.50; p(64+)=2.18×10(−10), OR(64+)=1.42, 95%CI(64+)=1.27–1.58]) but only in persons >54. There was also a significant association at the previously identified lower grade glioma (LGG) risk locus at 8q24.21 (rs55705857) in persons ages 18–53 (p(18–53)=9.30×10(−11), OR(18–53)=1.76, 95%CI(18–53)=1.49–2.10). Within The Cancer Genome Atlas (TCGA) there was higher prevalence of ‘LGG’-like tumor characteristics in GBM samples in those 18–53, with IDH1/2 mutation frequency of 15%, as compared to 2.1% [54–63] and 0.8% [64+] (p=0.0005). Age-specific differences in cancer susceptibility can provide important clues to etiology. The association of a SNP known to confer risk for IDH1/2 mutant glioma and higher prevalence of IDH1/2 mutation within younger individuals 18–53 suggests that more younger individuals may present initially with ‘secondary glioblastoma.’

Summary Background Substantial evidence links exposure to moderate or high doses of ionising radiation, particularly in childhood, with increased risk of leukaemia. The association of leukaemia with exposure to low-dose (

In the Tinea Capitis Study (Israel, 1966–2011), we assessed the association between childhood exposure to low to moderate doses of ionizing radiation (IR) to the head and neck and the development of vascular diseases (ischemic heart disease, carotid artery stenosis, and stroke) in adulthood. The study included 17,734 individuals from the Tinea Capitis cohort (7,408 irradiated in childhood and 10,326 nonirradiated), insured by Israel’s largest health provider. Individual dosimetry was estimated based on measurements made on a head phantom and original treatment records. The mean doses were 1.5, 0.09, 0.78, and 0.017 Gy to brain, thyroid, salivary gland, and breast, respectively. Data on vascular diseases was abstracted from computerized medical records. Using Poisson regressions, we examined the association of radiation with morbidity. Any vascular disease was reported for 2,221 individuals. Adjusted for age, sex, socioeconomic status, smoking, hypertension, and diabetes, exposure to IR increased the risk of developing any vascular diseases (relative risk (RR) = 1.19, 95% confidence interval (CI): 1.09, 1.29), stroke (RR = 1.35, 1.20, 1.53), carotid artery stenosis (RR = 1.32, 1.06, 1.64), and ischemic heart disease (RR = 1.12, 1.01, 1.26). The risk of developing vascular diseases was positively associated with dose and inversely associated with age at exposure. In conclusion, the results indicate that early exposure to low to moderate doses of IR increases the risk of cerebro- and cardiovascular impairments.

Background: The purpose of this study was to evaluate the distribution of glioma-related seizures and seizure control at the time of tumor diagnosis with respect to tumor histologic subtypes, tumor treatment and patient characteristics, and to compare seizure history preceding tumor diagnosis (or study enrollment) between glioma patients and healthy controls. Methods: The Glioma International Case Control study (GICC) risk factor questionnaire collected information on demographics, past medical/medication history, and occupational history. Cases from eight centers were also asked detailed questions on seizures in relation to glioma diagnosis; cases (n = 4533) and controls (n = 4171) were also asked about seizures less than 2 years from diagnosis and previous seizure history more than 2 years prior to tumor diagnosis, including childhood seizures. Results: Low-grade gliomas (LGGs), particularly oligodendrogliomas/oligoastrocytomas, had the highest proportion of glioma-related seizures. Patients with low-grade astrocytoma demonstrated the most medically refractory seizures. A total of 83% of patients were using only one antiepileptic drug (AED), which was levetiracetam in 71% of cases. Gross total resection was strongly associated with reduced seizure frequency (p < 0.009). No significant difference was found between glioma cases and controls in terms of seizure occurring more than 2 years before diagnosis or during childhood. Conclusions: Our study showed that glioma-related seizures were most common in low-grade gliomas. Gross total resection was associated with lower seizure frequency. Additionally, having a history of childhood seizures is not a risk factor for developing glioma-related seizures or glioma.

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.

The increased use of diagnostic and therapeutic procedures that involve radiation raises concerns about radiation effects, particularly in children and the radiosensitive thyroid gland.Evaluation of relative risk (RR) trends for thyroid radiation doses0.2 gray (Gy); evidence of a threshold dose; and possible modifiers of the dose-response, e.g., sex, age at exposure, time since exposure.Pooled data from nine cohort studies of childhood external radiation exposure and thyroid cancer with individualized dose estimates, ≥1000 irradiated subjects or ≥10 thyroid cancer cases, with data limited to individuals receiving doses0.2 Gy.Cohorts included the following: childhood cancer survivors (n = 2); children treated for benign diseases (n = 6); and children who survived the atomic bombings in Japan (n = 1). There were 252 cases and 2,588,559 person-years in irradiated individuals and 142 cases and 1,865,957 person-years in nonirradiated individuals.There were no interventions.Incident thyroid cancers.For both0.2 and0.1 Gy, RRs increased with thyroid dose (P0.01), without significant departure from linearity (P = 0.77 and P = 0.66, respectively). Estimates of threshold dose ranged from 0.0 to 0.03 Gy, with an upper 95% confidence bound of 0.04 Gy. The increasing dose-response trend persisted45 years after exposure, was greater at younger age at exposure and younger attained age, and was similar by sex and number of treatments.Our analyses reaffirmed linearity of the dose response as the most plausible relationship for "as low as reasonably achievable" assessments for pediatric low-dose radiation-associated thyroid cancer risk.

Objective Compare 5, 10 and 15 year survival in invasive epithelial ovarian cancer, between patients with and without BRCA1/2 germ line mutation in a nonselective group of patients diagnosed during 1994–99. Methods The analysis was based on 779 Jewish patients: 229 carriers to the Ashkenazi Jewish founder mutations in BRCA1 (185delAG; 5382insC) and BRCA2 (6174delT); and 550 non-carriers. Clinical characteristics were abstracted from the patients' medical records and vital status was updated through the National Population Registry up to 11/2015. The Kaplan-Meier method, log-rank tests, and Cox-regression model were used for survival analyses. Results By the end of the follow-up period, (range 1–20 years), 629 (80.7%) deaths occurred. While considerably higher survival was observed during the first 5 years from diagnosis among carriers compared to non-carriers (46.7% vs. 36.2%, p = 0.0004), the survival rates at 15 years were 22.3% vs. 21.8% respectively (p = 0.04). The age-adjusted hazard ratio for all-cause mortality of carriers versus non-carriers was 0.74 (95%CI 0.60–0.91) in the first 5 years. For women who survived 5 and 10 years, the age-adjusted hazard ratios for mortality during 5 additional years, of carriers compared to non-carriers, were 1.38 (95%CI 0.93–2.04) and 1.08 (95%CI 0.61–1.92), respectively. Conclusion The results of this study, with up to 20 years follow-up, support studies with shorter follow-up that suggested that the advantage in survival observed among BRCA1/2 carriers during the first 5 years decreases over time. Clinically, this may have implications for follow-up and therapy, especially of new agents that are particularly effective in BRCA carriers.

International audience; The aim of the study was to examine associations between occupational exposure to metals and meningioma risk in the international INTEROCC study. INTEROCC is a seven-country population-based case-control study including 1906 adult meningioma cases and 5565 population controls. Incident cases were recruited between 2000 and 2004. A detailed occupational history was completed and job titles were coded into standard international occupational classifications. Estimates of mean workday exposure to individual metals and to welding fumes were assigned based on a job-exposure-matrix. Adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated using conditional logistic regression. Although more controls than cases were ever exposed to metals (14 vs. 11 %, respectively), cases had higher median cumulative exposure levels. The ORs for ever vs. never exposure to any metal and to individual metals were mostly greater than 1.0, with the strongest association for exposure to iron (OR 1.26, 95 % CI 1.0-1.58). In women, an increased OR of 1.70 (95 % CI 1.0-2.89) was seen for ever vs never exposure to iron (OR in men 1.19, 95 % CI 0.91-1.54), with positive trends in relation with both cumulative and duration of exposure. These results remained after consideration of other occupational metal or chemical co-exposures. In conclusion, an apparent positive association between occupational exposure to iron and meningioma risk was observed, particularly among women. Considering the fact that meningioma is a hormone dependent tumor, the hypothesis that an interaction between iron and estrogen metabolism may be a potential mechanism for a carcinogenic effect of iron should be further investigated.

Background: There have been few studies of sufficient size to address the relationship between glioma risk and the use of aspirin or NSAIDs, and results have been conflicting. The purpose of this study was to examine the associations between glioma and aspirin/NSAID use, and to aggregate these findings with prior published studies using meta-analysis. Methods: The Glioma International Case-Control Study (GICC) consists of 4,533 glioma cases and 4,171 controls recruited from 2010 to 2013. Interviews were conducted using a standardized questionnaire to obtain information on aspirin/NSAID use. We examined history of regular use for ≥6 months and duration-response. Restricted maximum likelihood meta-regression models were used to aggregate site-specific estimates, and to combine GICC estimates with previously published studies. Results: A history of daily aspirin use for ≥6 months was associated with a 38% lower glioma risk, compared with not having a history of daily use [adjusted meta-OR = 0.62; 95% confidence interval (CI), 0.54–0.70]. There was a significant duration-response trend (P = 1.67 × 10−17), with lower ORs for increasing duration of aspirin use. Duration-response trends were not observed for NSAID use. In the meta-analysis aggregating GICC data with five previous studies, there was a marginally significant association between use of aspirin and glioma (mOR = 0.84; 95% CI, 0.70–1.02), but no association for NSAID use. Conclusions: Our study suggests that aspirin may be associated with a reduced risk of glioma. Impact: These results imply that aspirin use may be associated with decreased glioma risk. Further research examining the association between aspirin use and glioma risk is warranted.

BackgroundLittle is known about occupational risk factors for meningioma.ObjectivesTo study whether risk of meningioma is associated with several occupational exposures, including selected combustion products, dusts and other chemical agents.MethodsThe INTEROCC study was an international case-control study of brain cancer conducted in seven countries. Data collection by interview included lifetime occupational histories. A job exposure matrix was used to derive estimates of exposure for the 12 agents. ORs for ever versus never exposed and for exposure-response using duration of exposure and cumulative exposure were derived using conditional logistic regression stratified by sex, age group, country/region, adjusted for education.ResultsThese analyses included 1906 cases and 5565 controls. For 11 of the 12 agents, no excess risk was found for ever exposed. For ever exposure to oil mists, an elevated OR of 1.57 (95% CI 1.10 to 2.22, 51 exposed cases) was found. Statistically significant exposure-response relationships were observed with cumulative exposure (p=0.01) and duration of exposure (p=0.04). Among women, there were also significant trends for cumulative and duration of exposure to asbestos and excesses in the highest exposure categories for formaldehyde.ConclusionsMost agents examined did not provoke excess risks of meningioma. The main finding from this study is that it is the first study to identify a statistical association between exposure to oil mists and meningioma. This may be a chance finding or could be due to confounding with iron exposure and further research is required to understand whether the relationship is causal.

BackgroundGenome-wide association studies (GWAS) have identified 25 risk variants for glioma, which explain ~30% of heritable risk. Most glioma histologies occur with significantly higher incidence in males. A sex-stratified analysis ide7ntified sex-specific glioma risk variants, and further analyses using gene- and pathway-based approaches may further elucidate risk variation by sex.MethodsResults from the Glioma International Case-Control Study were used as a testing set, and results from three GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for autosomal SNPs found to be nominally significant (p−6in ⅔ algorithms.Results25 genes within five regions and 19 genes within six regions reached the set significance threshold in at least 2/3 algorithms in males and females, respectively.EGFRandRTEL1-TNFRSF6Bwere significantly associated with all glioma and glioblastoma in males only, and a female-specific association inTERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the Telomeres, Telomerase, Cellular Aging, and Immortality pathway in both males and females.ConclusionsThese results suggest that there may be biologically relevant significant differences by sex in genetic risk for glioma. Additional gene- and pathway-based analyses may further elucidate the biological processes through which this risk is conferred.

International audience; In absence of clear evidence regarding possible effects of occupational chemical exposures on brain tumour aetiology, it is worthwhile to explore the hypothesis that such exposures might act on brain tumour risk in interaction with occupational exposure to extremely low frequency magnetic fields (ELF).INTEROCC is a seven-country (Australia, Canada, France, Germany, Israel, New Zealand and UK), population-based, case-control study, based on the larger INTERPHONE study. Incident cases of primary glioma and meningioma were ascertained from 2000 to 2004. Job titles were coded into standard international occupational classifications and estimates of ELF and chemical exposures were assigned based on job-exposure matrices. Dichotomous indicators of cumulative ELF (≥50th vs

Genome-wide association studies (GWAS) have identified 26 risk variants for glioma, and these explain ~27% and ~34% of heritability for glioblastoma and lower grade glioma, respectively. Genetic risk for these tumors is likely polygenic; gene- and pathway-based analyses may increase power to detect new sources of genetic risk. Most glioma histologies occur with significantly higher incidence in males. A sex-stratified analysis has identified glioma risk variants that differ by sex, and further analyses using gene- and pathway-based approaches may further elucidate risk variation by sex. Sex-specific summary statistics from the Glioma International Case-Control Study were used as a discovery set. Data from three prior glioma GWAS were used for validation. For both the discovery and validation datasets, summary statistics where generated using sex-stratified logistic regression models to estimate betas, standard errors, and p values for the autosomal chromosomes. Pascal was used to estimate gene- and pathway-based scores corrected for linkage disequilibrium structure, and empirical p values were calculated for glioma overall in both datasets. 12,711 genes contained ≥10 SNPs, and results were considered significant at 1.9x10-6 (Bonferroni correction 0.05/(12,711 genes * 2 for each sex)). 14 genes were significantly associated with all glioma in males, and 8 genes in females. EGFR was significantly associated with glioma in males only (Males: pdiscovery=5.31x10-9 pvalidation=0.0025; Females: pdiscovery=0.01, pvalidation=0.1299). Statistics were calculated for 217 pathways (defined by Biocarta), and considered significant at p