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Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time.Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender.Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers.Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.

While constitutional pathogenic variants in theAPCgene cause familial adenomatous polyposis,APCc.3920T>A; p.Ile1307Lys (I1307K) has been associated with a moderate increased risk of colorectal cancer (CRC), particularly in individuals of Ashkenazi Jewish descent. However, published data include relatively small sample sizes, generating inconclusive results regarding cancer risk, particularly in non-Ashkenazi populations. This has led to different country/continental-specific guidelines regarding genetic testing, clinical management and surveillance recommendations for I1307K. A multidisciplinary international expert group endorsed by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT), has generated a position statement on theAPCI1307K allele and its association with cancer predisposition. Based on a systematic review and meta-analysis of the evidence published, the aim of this document is to summarise the prevalence of theAPCI1307K allele and analysed the evidence of the associated cancer risk in different populations. Here we provide recommendations on the laboratory classification of the variant, define the role of predictive testing for I1307K, suggest recommendations for cancer screening in I1307K heterozygous and homozygous individuals and identify knowledge gaps to be addressed in future research studies. Briefly, I1307K, classified as pathogenic, low penetrance, is a risk factor for CRC in individuals of Ashkenazi Jewish origin and should be tested in this population, offering carriers specific clinical surveillance. There is not enough evidence to support an increased risk of cancer in other populations/subpopulations. Therefore, until/unless future evidence indicates otherwise, individuals of non-Ashkenazi Jewish descent harbouring I1307K should be enrolled in national CRC screening programmes for average-risk individuals.

Hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS), the most common inherited cancer syndromes, are attributed to a single heterozygous pathogenic variant (PV) in BRCA1/2 or in a DNA MMR gene, respectively. Little is known about the phenotype in double heterozygotes who carry PVs in both genes. Carriers of double-PVs in any DNA MMR gene and BRCA1/2 attending one of three tertiary oncogenetic clinics between 1/2005 and 1/2020 were identified by database search, and their relevant data were retrieved and analyzed. Eleven double carriers from four seemingly unrelated Ashkenazi Jewish families were evaluated. All carried an Ashkenazi Jewish founder BRCA PV, BRCA2 c.5946delT/c.6174delT (n = 10) or BRCA1 c.185delAG (n = 1). Four carried the MSH2 c.1906G > C founder PV, and 3, the MSH6 c.3984_3987dupGTCA founder PV; 3 patients had the MSH6 c.3956_3957dup PV. Eight double carriers (73%) had cancer: breast cancer (5 cases, 2 bilateral), melanoma (2 cases), urothelial cancer (2 cases), and colon, endometrial, prostate, cutaneous squamous cell cancer, glioblastoma, gastric stromal tumor, and lymphoma (1 case each). Six carriers had 1–2 tumors, one had 3 tumors, and one had 5 primary tumors. Age at diagnosis of the first tumor was 36–76 years. All carriers met NCCN BRCA1/2 testing criteria, and 3 met the revised Bethesda guidelines. This case series, supported by the literature, suggests that the phenotype of double MSH2/6 and BRCA1/2 carriers is not associated with early disease onset or a more severe phenotype. The findings have implications for improved genetic testing guidelines and treatment strategies.

Background Recently, three updated guidelines for post‐polypectomy colonoscopy surveillance (PPCS) have been published. These guidelines are based on a comprehensive summary of the literature, while some recommendations are similar, different surveillance intervals are recommended after detection of specific types of polyps. Aim In this review, we aimed to compare and contrast these recommendations. Methods The updated guidelines for PPCS were reviewed and the recommendations were compared. Results For patients with 1–4 adenomas

Lynch syndrome is an inherited cancer predisposition syndrome caused by germline defects in any of the mismatch repair (MMR) genes. Diagnosis of carriers makes precision prevention, early detection, and tailored treatment possible. Herein we report a novel founder deletion of 18,758 bp, mediated by Alu repeats on both sides, detected in Ethiopian Jews. The deletion, which encompasses exon 9–10 of the MSH2 coding sequence, is associated mainly with early-onset MSH2/MSH6-deficient colorectal cancer (CRC) and liposarcoma. Testing of 35 members of 5 seemingly unrelated families of Ethiopian origin yielded 10/21 (48%) carriers, of whom 9 had CRC. Age at first tumor diagnosis ranged from 16 to 89 years. Carriers from the oldest generations were diagnosed after age 45 years (mean 57), and carriers from the younger generation were diagnosed before age 45 years (mean 30). Awareness of this founder deletion is important to improve patient diagnosis, institute surveillance from an early age, and refer patients for genetic counseling addressing the risk of bi-allelic constitutional MMR deficiency syndrome.

New fecal microbiota for cancer patients The composition of the gut microbiome influences the response of cancer patients to immunotherapies. Baruch et al. and Davar et al. report first-in-human clinical trials to test whether fecal microbiota transplantation (FMT) can affect how metastatic melanoma patients respond to anti–PD-1 immunotherapy (see the Perspective by Woelk and Snyder). Both studies observed evidence of clinical benefit in a subset of treated patients. This included increased abundance of taxa previously shown to be associated with response to anti–PD-1, increased CD8 + T cell activation, and decreased frequency of interleukin-8–expressing myeloid cells, which are involved in immunosuppression. These studies provide proof-of-concept evidence for the ability of FMT to affect immunotherapy response in cancer patients. Science , this issue p. 602 , p. 595 ; see also p. 573

BACKGROUND Although the association of attention deficit hyperactivity disorder (ADHD) with psychiatric disorders is well known, its association with somatic diseases is unclear. Only few studies have investigated the gastrointestinal (GI) morbidity in adult patients with ADHD. AIM To measure gastrointestinal comorbidity and its burden on healthcare in young adults with ADHD. METHODS The cohort included subjects aged 17-35 years recruited to the Israel Defense Forces in 2007-2013, 33380 with ADHD and 355652 without (controls). The groups were compared for functional and inflammatory conditions of the gastrointestinal tract and clinic and specialist visits for gastrointestinal symptoms/disease during service (to 2016). Findings were analyzed by generalized linear models adjusted for background variables. RESULTS Compared to controls, the ADHD group had more diagnoses of functional gastrointestinal disorders (referred to as FGID), namely, dyspepsia [odds ratio (OR): 1.48, 95% confidence interval (CI): 1.40-1.57, P < 0.001], chronic constipation (OR: 1.64, 95%CI: 1.48-1.81, P < 0.001), and irritable bowel syndrome (OR: 1.67, 95%CI: 1.56-1.80, P < 0.001) but not of organic disorders (inflammatory bowel disease, celiac disease). They had more frequent primary care visits for gastrointestinal symptoms [rate ratio (RR): 1.25, 95%CI: 1.24-1.26, P < 0.001] and referrals to gastrointestinal specialists (RR: 1.96, 95%CI: 1.88-2.03, P < 0.001) and more episodes of recurrent gastrointestinal symptoms (RR: 1.29, 95%CI: 1.21-1.38, P < 0.001). Methylphenidate use increased the risk of dyspepsia (OR: 1.49, 95%CI: 1.28-1.73, P < 0.001) and constipation (OR: 1.42, 95%CI: 1.09-1.84, P = 0.009). CONCLUSION ADHD in young adults is associated with an excess of FGID and increased use of related health services. Research is needed to determine if an integrative approach treating both conditions will benefit these patients and cut costs.

Concomitant common bile duct (CBD) stone in the setting of acute calculous cholecystitis (ACC) should be suspected once abnormal liver indices are noticed. We aimed to identify predictors of CBD stone in patients hospitalized with ACC. We performed a retrospective multi-center, case-controlled, study from 1st of January 2016 until the 31th of December 2018. Inclusion criteria included patients with an established diagnosis of ACC based on clinical, laboratory and radiological criteria and who had an endoscopic ultrasound (EUS) for suspected CBD stone. One-hundred and twelve patients were included, of these fifty-three patients (47.3%) were diagnosed with CBD stone by EUS. In univariate analysis, Age (OR 1.038, P = 0.001), total bilirubin (mg/dl) (OR 1.429, P = 0.02) and CBD width (mm) by US (OR 1.314, P = 0.01) were statistically significant in predicting CBD stone and remained significant in multivariate regression analysis. We developed a diagnostic score that included these three parameters, with assignment of weights for each variable according to the coefficient estimate. A low cut-off score of 0 was associated with sensitivity of 100% for CBD stone, whereas a high cut-off score of 3 was associated with sensitivity of 10% and specificity of 96.6% with a positive predictive value of 67% (ROC of 0.7558). We validated this score with an independent cohort (ROC of 0.7416) with a sensitivity of 46.6%, a specificity of 91.5% and a PPV of 87.1%. We recommend incorporating this score as an aid for stratifying patients with ACC into low or high probability for concomitant CBD stone.

Background Meningiomas are the most common primary central nervous system tumors. Potential risk factors include obesity, height, history of allergy/atopy, and autoimmune diseases, but findings are conflicting. This study sought to assess the role of the different risk factors in the development of meningioma in adolescents/young adults. Methods The cohort included 2,035,915 Jewish men and women who had undergone compulsory physical examination between 1967 and 2011, at age 16 to 19 years, prior to and independent of actual military enlistment. To determine the incidence of meningioma, the military database was matched with the Israel National Cancer Registry. Cox proportional hazard models were used to estimate the hazard ratios for meningioma according to sex, body mass index (BMI), height, and history of allergic or autoimmune disease. Results A total of 480 subjects (328 females) were diagnosed with meningioma during a follow-up of 40,304,078 person-years. Median age at diagnosis was 42.1 ± 9.4 years (range 17.4–62.6). On univariate analysis, female sex (p Conclusions This large population study showed that sex and adolescent height in males (> 1.85 m) were associated with an increased risk of meningioma in adulthood.

Inflammatory bowel diseases are associated with various immune- and non-immune-mediated conditions. We aimed to assess the association of inflammatory bowel diseases with comorbidities at late adolescence. Jewish Israeli adolescents who underwent a general health evaluation prior to enlistment to the Israeli Defense Forces from 2002 to 2016 were included. Overall, 891 subjects (595 Crohn’s disease, 296 ulcerative colitis, median age 17.1 years) and 1,141,841 controls were analyzed. Crohn’s disease was associated with arthritis (odds ratio (OR) 4.7, 95% confidence interval (CI) 2.4–9.1), thyroid disease (OR 2.6, 95% CI 1.2–5.5), atopic dermatitis (OR 2, 95% CI 1.1–3.6), autoimmune hepatitis (OR 4.4, 95% CI 2.3–8.6), nephrolithiasis (OR 3.6, 95% CI 1.2–11.4), and pancreatitis (OR 41.8, 95% CI 17.2–101.9). Ulcerative colitis was associated with arthritis (OR 3.6, 95% CI 1.0–9.8), thyroid disease (OR 4.8, 95% CI 1.2–19.4), autoimmune hepatitis (OR 8, 95% CI 4–16.2), and pancreatitis (OR 51, 95% CI 16.1–158.9). Primary sclerosing cholangitis was associated with both diseases. Asthma, celiac, type 1 diabetes, psoriasis, and bone fractures were not more common in both diseases. Male predominance was noted for most associations. At adolescence, both Crohn’s disease and ulcerative colitis are associated with multiple comorbidities, not limited to autoimmune disorders.

This protocol for a Cochrane Review is out of date. The authors have abandoned it.

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene-and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syn-drome to improve outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd.

Background Inflammatory bowel disease (IBD) is a set of chronic inflammatory diseases associated with significant morbidity and high hospitalization rate. IBD patients are particularly prone to re-hospitalization resulting in high medical cost and morbidity. The aim of this study is to assess laboratory and clinical predictors of re-admission in patients who were hospitalized with IBD flare. Methods a multicenter, retrospective, cross-sectional analysis included IBD patients who were admitted with disease exacerbation from January 1st 2019 to January 1st 2020 in three Israeli university hospitals (Nazareth hospital, Galilee Medical Center and Hadassah Medical Organization). Results Overall, a total of 176 hospitalizations for IBD flares were included. Seventeen patients were re-admitted within 30 days after discharge (group A), as compared to 159 patients who were not (group B). The average age was 35.3 ± 19.2 years in group A vs. 38.6 ± 16 years in group B. Eight (47.1%) and 9 (52.9%) patients had Crohn's disease (CD) and ulcerative colitis (UC) in group A as compared to 102 (64.2%) and 57 (35.9%) in group B, respectively. On univariate analysis, only the attendance to gastroenterology clinic follow-up after discharge from hospitalization due to IBD flare was significantly protective factor to with 30-days readmission (OR 0.37, 95% CI 0.13-1, P=0.05). There were no associations with the other assessed clinical and laboratory parameters and importantly IBD type (OR 1.99, 95% CI 0.74-5.34, P=0.17). Notably, there was no effect of the day of discharge white blood counts, albumin and C reactive protein (CRP) values on re-admission rates (odds ratio [OR] 1.07, 95% CI 0.96-1.20, P=0.19, OR 0.86, 95% CI 0.39-1.91, P=0.71 and OR 0.99, 95% CI 0.97-1.01, P=0.59), respectively. Conclusions attendance to out-patient gastroenterologist follow-up is the only significant protective parameter to 30-days readmission in patients with IBD. This finding highlights the vital need of adequate gastroenterological follow up of these patients after hospital discharge. Further studies are warranted to precisely define timing and role of outpatient follow-up in reducing IBD readmissions.

Purpose To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR ( path_MMR ) variants. Methods The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages. Results Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1 , path_MSH2 , path_MSH6 , and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively. Conclusion Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.

BACKGROUND The incidence and prevalence trends of inflammatory bowel disease (IBD) vary between developed and developing countries. AIM To investigate the prevalence and associated sociodemographic factors of IBD in Israeli Jewish adolescents METHODS: The files of the army medical corps were reviewed for adolescents recruited in 2002-2016 with confirmed IBD. Covariate data included birth date, patient and parental country of birth, number of children in the household, age at diagnosis, and socioeconomic status. Findings were compared with the remaining recruits without IBD. RESULTS Of the 1,144,213 adolescents recruited, 2372 (0.2%) had IBD (Crohn's disease, 68%). Median age of the cohort was 17.1 years (interquartile range, 16.9-17.3). Over the study period, the annual point prevalence per 100,000 examinees significantly increased: total IBD, 58 to 373; Crohn's disease, 42 to 425; ulcerative colitis, 16 to 128. Mean age at IBD diagnosis decreased from 15.0 ± 2.8 years in 2002-2008 to 14.3 ± 3.1 years in 2009-2016 (P

BACKGROUND There is growing concern regarding the impact of adolescent obesity on adult health. The objective of this study was to evaluate the association between body mass index (BMI) in late adolescence and the incidence of pancreatic cancer during adulthood. METHODS The authors analyzed a cohort of 1087,358 Israeli Jewish men and 707,212 Jewish women who underwent a compulsory physical examination between ages 16 and 19 years from 1967 to 2002. Pancreatic cancer incidence through December 31, 2012 was identified by linkage to the national cancer registry. Multivariable-adjusted Cox regression was used to estimate hazard ratios (HRs) for pancreatic cancer according to the US Centers for Disease Control and Prevention (CDC) BMI percentiles at baseline. RESULTS Over a median 23 year follow-up, 551 incident cases of pancreatic cancer cases occurred (423 men; 128 women). Compared with normal weight (5th to

Background Routine screening for establishing Lynch syndrome (LS) in young individuals diagnosed with adenomas is not recommended due to its low yield, and limited sensitivity of the employment of immunohistochemistry for DNA mismatch-repair proteins on polyps. Hence we aimed to evaluate the yield of germline mutational analysis in diagnosis of LS in a young Israeli cohort with colorectal adenomatous polyps. Methods Data were retrospectively collected on consecutive patients, age ≤ 45 years, who underwent colonoscopy with removal of at least one adenoma during 2015–2020, and subsequently genetic testing by multigene panel or LS-Jewish founder mutation panel. Results Overall, 92 patients were included (median age 35 years, range 23–45 years), of whom 79 (85.8%) underwent multigene panel genotyping, and 13 (14.2%) analysis for Jewish founder LS gene mutations. Altogether, 18 patients were identified with pathogenic mutations in actionable genes, including LS-associated genes in 6 (6.5%), BRCA2 in 2 (2.5%), GREM1 in 1(1.2%), and low-penetrance genes- APC I1307K and CHEK2- in 9 (11.4%) patients. Compared with non-LS patients, LS-carriers had a significantly higher median PREMM5 score (2.6 vs. 1.3; P = 0.04). Conclusions Young individuals diagnosed with adenomatous polyps should be offered genetic testing when fulfilling clinical guidelines for LS, but weight should also be given to adenoma characteristics in the PREMM5 score.

Background: The success of Helicobacter pylori (H. pylori) eradication depends on several host and treatment factors. Serum vitamin D levels may be associated with H. pylori infection and eradication rates. We investigated the association between vitamin D and H. pylori infection and eradication, using a large electronic database based on medical records from a population-based health maintenance organization. Methods: Data regarding adults who underwent H. pylori testing and had vitamin D measurements within one month of H. pylori testing were collected. H. pylori infection was ascertained using urea breath or stool antigen tests. A negative H. pylori test following a positive result implied eradication. Multivariate regression models were constructed to assess associations between H. pylori infection, eradication, and vitamin D. Results: Among 150,483 members who underwent H. pylori testing from 2009 to 2018, 27,077 (18%) had vitamin D measurements. Vitamin D levels were inversely associated with H. pylori infection, p &lt, 0.001. The odds of a positive H. pylori test were 31% higher among patients with vitamin D levels &lt, 20 ng/mL, compared with those with levels &ge, 20 ng/mL (OR 1.31, 99% CI 1.22&ndash, 1.4, p &lt, 0.001). Purchase of vitamin D supplements was associated with a negative subsequent H. pylori test (p &lt, 0.001). Mean vitamin D levels were moderately higher in those with successful vs. failed H. pylori eradication (19.34 &plusmn, 9.55 vs. 18.64 &plusmn, 9.61, p &lt, 0.001). Conclusions: Vitamin D levels are associated with H. pylori infection. Increased vitamin D levels are associated with successful H. pylori eradication. Vitamin D may have a role in H. pylori eradication.

Background: The success of Helicobacter pylori (H. pylori) eradication depends on several host and treatment factors. Serum vitamin D levels may be associated with H. pylori infection and eradication rates. We investigated the association between vitamin D and H. pylori infection and eradication, using a large electronic database based on medical records from a population-based health maintenance organization. Methods: Data regarding adults who underwent H. pylori testing and had vitamin D measurements within one month of H. pylori testing were collected. H. pylori infection was ascertained using urea breath or stool antigen tests. A negative H. pylori test following a positive result implied eradication. Multivariate regression models were constructed to assess associations between H. pylori infection, eradication, and vitamin D. Results: Among 150,483 members who underwent H. pylori testing from 2009 to 2018, 27,077 (18%) had vitamin D measurements. Vitamin D levels were inversely associated with H. pylori infection, p < 0.001. The odds of a positive H. pylori test were 31% higher among patients with vitamin D levels

In the colon, long-term exposure to chronic inflammation drives colitis-associated colon cancer (CAC) in patients with inflammatory bowel disease. While the causal and clinical links are well established, molecular understanding of how chronic inflammation leads to the development of colon cancer is lacking. Here we deconstruct the evolving microenvironment of CAC by measuring proteomic changes and extracellular matrix (ECM) organization over time in a mouse model of CAC. We detect early changes in ECM structure and composition, and report a crucial role for the transcriptional regulator heat shock factor 1 (HSF1) in orchestrating these events. Loss of HSF1 abrogates ECM assembly by colon fibroblasts in cell-culture, prevents inflammation-induced ECM remodeling in mice and inhibits progression to CAC. Establishing relevance to human disease, we find high activation of stromal HSF1 in CAC patients, and detect the HSF1-dependent proteomic ECM signature in human colorectal cancer. Thus, HSF1-dependent ECM remodeling plays a crucial role in mediating inflammation-driven colon cancer., Expression and activation of Heat shock factor 1 (HSF1) in cancer associated fibroblasts have been associated with protumorigenic functions. Here the authors show that, in a model of colitis-induced colorectal cancer, HSF1 is activated in stromal fibroblasts in the early stages of inflammation, leading to extracellular matrix remodelling that sustains tumor initiation and progression.

Lynch syndrome (LS) results from pathogenic variants in the mismatch repair (MMR) genes and is the most common hereditary cancer syndrome, affecting an estimated 1 in 300 individuals. Pathogenic variants in each of the MMR genes path_MLH1, path_MSH2, path_MSH6, and path_PMS2 result in different risks for cancers in organs including the colorectum, endometrium, ovaries, stomach, small bowel, bile duct, pancreas, and upper urinary tract. Accurate estimates of these risks are essential for planning appropriate approaches to the prevention or early diagnosis of cancers but the robustness of previous studies has been limited by factors including retrospective design,1,2 lack of validation in independent cohorts,3-5 and inconsistent classification of genetic variants. Unexpected findings from previous studies have included path_MLH1 and path_MSH2 carriers appearing to have a lifetime risk of colorectal cancer (CRC) of approximately 50%, despite surveillance colonoscopy,6-8 and that shorter intervals between colonoscopies do not seem to reduce the incidence of CRC in LS.9,10 These findings challenge the assumptions that CRC in LS usually develops from a noninfiltrative adenoma precursor and that CRC can be prevented by colonoscopic detection and removal of adenomas in the colon and rectum. Additionally, previous studies in the Prospective Lynch Syndrome Database (PLSD) have shown no increase in cancer risk in path_PMS2 carriers before 40 years of age and, although observation years were limited in older path_PMS2 carriers, LS-associated cancers other than endometrial and prostate were not observed.6-8 In this study we collected prospective data from a new large cohort of path_MMR carriers to validate previous findings from PLSD. We also updated information on the original cohort to ensure consistent classification of pathogenicity of MMR gene variants. We then combined both data sets, providing larger numbers that allowed us to derive more precise risk estimates for cancers in LS categorized by gene and gender.

BACKGROUND Inflammatory bowel disease (IBD) is a set of chronic inflammatory diseases associated with significant morbidity. Generally, IBD patients have twice the risk of venous thromboembolism (VTE) compared to healthy controls. VTE can occur both, during hospital stay or after discharge. We aimed to assess the incidence among IBD patients who were hospitalized for disease exacerbation. METHODS In a retrospective cross-sectional analysis all IBD patients who were admitted with disease exacerbation at Galilee Medical Center and Hadassah Medical Organization were included in the study. Excluding criteria was IBD with already known hypercoagulable state. RESULTS One-hundred and sixteen patients with 176 admissions due to IBD flare were included in the study. The average age was 38.3±16.3 years. Sixty-six admissions (37.5%) occurred in patients with ulcerative colitis exacerbation and 110 in patients with Crohn's disease exacerbation (62.5%). Thirty-nine patients (22.1%) were smokers. Fifty-four patients (30.7%) and 68 patients (38.6%) were on previous (within 3 months) biological and steroid treatment, respectively. Twelve patients (6.8%) were on prophylactic subcutaneous anticoagulation (enoxaparin) throughout their hospital stay and only 3 patient (1.7%) developed in-hospital clinical VTE episode. The mean hospitalization length was 6.8±7.9 days and among patients who developed VTE episode, the length of stay was significantly higher as compared to patients without VTE episodes (36.7 vs. 6.3 days, P

BACKGROUND To characterize variables that may predict the need for endoscopic intervention in inpatients admitted for several causes who during the hospitalization developed acute non-variceal upper gastrointestinal bleeding (NVUGIB). METHODS A retrospective analysis of inpatients who underwent upper gastro-intestinal endoscopy for acute NVUGIB while hospitalized for other causes from 1 January 2016 to 1 December 2017, was performed. In the primary outcome analysis, patients (N.=14) who underwent endoscopic intervention (group A) were compared to those (N.=87) who did not need for endoscopic intervention (group B). Secondary outcome analysis included patients who had significant endoscopic findings compared to those who did not have them. RESULTS Multivariate regression analysis showed that in the primary outcome analysis, two parameters were significant: the number of packed red blood cells (PRBC) units transfused (odds ratio [OR]: 1.5, P=0.01) and Rockall Score (RS) (OR: 1.4, P=0.06) with receiver operator characteristic (ROC) curve of 0.7844. In the secondary outcome analysis, only the use of proton pump inhibitor drugs at admission was associated with protective effect for the development of significant endoscopic findings (odds ratio [OR]: 0.42, P=0.05) with ROC curve of 0.7342. CONCLUSIONS In hospitalized patients, in case of de novo NVUGIB, the number of PRBC units transfused and RS are predictive of significant endoscopic findings.

Carriers of pathogenic variants (PVs) in moderate–high-penetrance cancer susceptibility genes are offered tailored surveillance schemes for early cancer diagnosis. The clinical implications of low-penetrance variant carriers are less clear. Clinical and demographic data were retrieved for a cohort of Israeli individuals who underwent oncogenetic testing by the 30-gene cancer panel at Color Genomics laboratory, between 04/2013 and 12/2018. Of 758 genotyped individuals, 504 had been diagnosed with cancer prior to testing: 283 (56%) had breast cancer and 106 (21%) colorectal cancer. Pathogenic or likely pathogenic (P/LP) variants were detected in 123 (16%) individuals. Overall, 44 different P/LP variants were detected in 18/30 cancer susceptibility genes; 20 of them were founder/recurrent mutations. Of the carriers, 39 (32%), 10 (8%), and 74 (60%) carried high-, moderate-, or low-penetrance variants, respectively. After excluding low-penetrance variants, 7% (33/504) of all cancer patients, 6% of breast or ovarian cancer patients were found to be carriers, as well as 7% (14/203) of individuals with colonic polyps, and 4% (11/254) of cancer-free individuals. The diagnostic yield of moderate- and high-penetrance PVs using multigene panel testing was 6%, with 3.7% carriers of non-recurrent PVs. This yield should be discussed during pre-test counseling, and emphasizes the need for harmonized recommendations regarding clinical implications of low-penetrance variants.

We investigated whether obesity and sociodemographic factors at adolescence are associated with incident gastroenteropancreatic neuroendocrine tumors (GEP-NET).Our cohort included 2.3 million Israeli adolescents examined at ages 16 to 19 years between 1967 and 2010. The baseline database included sex, country of birth, residential socioeconomic status (SES), body-mass index (BMI) and height. Participants were followed through linkage with the National Cancer Registry up to 2012. We identified 221 cases of GEP-NET (66 pancreatic, 52 gastric, 39 rectal, 27 appendiceal, 23 small bowel and 14 colonic). Immigration from the Former Soviet Union (FSU) was associated with the risk of small bowel and rectal NET's, [Hazard Ratio (HR) 4.79, 95% Confidence Interval (CI) 1.37-16.76 and 3.43, 95% CI 1.20-9.83, respectively].Height >75th percentile and BMI ≥ 85th percentile were associated with increased risk of gastric NET (HR 2.25 95% CI 1.14-4.42 and HR 2.38, 95% CI 1.19-4.75, respectively). Female sex was associated with appendiceal NET (HR 2.30, 95% CI 1.06-4.96) while male gender was associated with an increased risk for NET of the small bowel [HR 4.72 (95% CI 1.10-20.41)].In conclusion, our findings suggest different risk factor associations with the various GEP-NETS: immigrants from the FSU were at increased risk for small bowel and rectal NET; increased height and weight were associated with the risk of gastric NET and females were at increased risk for appendiceal NET. Further focus on the FSU population is indicated in addition to studies verifying the association of BMI and height with gastric NET.

Background We previously reported that in pathogenic mismatch repair (path_MMR) variant carriers, the incidence of colorectal cancer (CRC) was not reduced when colonoscopy was undertaken more frequently than once every 3 years, and that CRC stage and interval since last colonoscopy were not correlated. Methods The Prospective Lynch Syndrome Database (PLSD) that records outcomes of surveillance was examined to determine survival after colon cancer in relation to the time since previous colonoscopy and pathological stage. Only path_MMR variants scored by the InSiGHT variant database as class 4 or 5 (clinically actionable) were included in the analysis. Results Ninety-nine path_MMR carriers had no cancer prior to or at first colonoscopy, but subsequently developed colon cancer. Among these, 96 were 65 years of age or younger at diagnosis, and included 77 path_MLH1, 17 path_MSH2, and 2 path_MSH6 carriers. The number of cancers detected within 3.5 years after previous colonoscopy were 9, 43, 31 and 13, respectively. Of these, 2, 8, 4 and 3 were stage III, respectively, and only one stage IV (interval 2.5–3.5 years) disease. Ten-year crude survival after colon cancer were 93, 94 and 82% for stage I, II and III disease, respectively (p 3.5 years before diagnosis, was 89, 90, 90 and 92%, respectively (p = 0.91). Conclusions In path_MLH1 and path_MSH2 carriers, more advanced colon cancer stage was associated with poorer survival, whereas time since previous colonoscopy was not. Although the numbers are limited, together with our previously reported findings, these results may be in conflict with the view that follow-up of path_MMR variant carriers with colonoscopy intervals of less than 3 years provides significant benefit.

BACKGROUND This study assessed adolescent predictors of noncardia gastric cancer (NCGC) with a focus on the body mass index (BMI) in late adolescence. METHODS This study analyzed a cohort of 1,087,358 Israeli Jewish males and 707,212 Israeli Jewish females who underwent a compulsory physical examination between the ages of 16 and 19 years from 1967 to 2002. By linkage to the national cancer registry, participants were followed for NCGC through December 31, 2012. With a median follow-up of 23 years, 515 NCGC cases occurred (379 men and 136 women), and the median age was 47.0 years (interquartile range, 39.3-53.4 years). Multivariate-adjusted Cox regression was used to estimate hazard ratios (HRs) for NCGC according to the US Centers for Disease Control and Prevention BMI percentiles at the baseline (normal weight, 5th to

HSF1 promotes inflammation induced tumor development through ECM remodelingAbstractIn the colon, long-term exposure to chronic inflammation drives colitis associated colon cancer (CAC) in patients with inflammatory bowel disease (IBD). Chronic inflammation underlies tumor initiation, promotion, invasion, and metastasis. While the causal and clinical link between chronic inflammation and CAC is well established, we lack a molecular understanding of what is the way in which chronic inflammation leads to develop colon cancer. Within the tumor, cancer cells are surrounded by a variety of non-malignant cells, such as macrophages, endothelial cells, neutrophils, cancer-associated fibroblasts (CAFs), and together with the extracellular matrix (ECM) they compose the tumor microenvironment (TME), also termed the stroma. Even the most aggressive cancers depend and interact with their environment mostly through secreted factors. Unlike cancer cells, stromal cells are genomically stable, and do not harbor oncogenic mutations that could drive their co-evolution and functional reprogramming. Rather, stromal reprogramming is thought to be achieved by transcriptional rewiring. Previous work by us and others has shown that the master regulator heat shock factor 1 (HSF1) plays a crucial role in this process, by mediating a transcriptional program in fibroblasts that enables their reprogramming into cancer-associated fibroblasts (CAFs) to promote malignancy. We hypothesizde that HSF1 plays a crucial role in inflammation-driven cancer by initiation of a transcriptional program that leads to changes in the extracellular matrix (ECM). We found that, in cell culture, cancer-induced ECM assembly by fibroblasts requires HSF1. Using an inflammation-driven cancer model in mice, we measured the changes in proteomic and ECM organization over time. We found that HSF1 drives a transcriptional program that leads to ECM remodeling in early stages and results in development of colon cancer. Loss of HSF1 prevents inflammation-induced ECM remodeling. Further to that, in CAC patients, we found high activation of stromal HSF1 and similarity to our HSF1 proteomic ECM signature in human colorectal cancer driven by HSF1. Thus, HSF1-dependent ECM remodeling mediates the transition from chronic inflammation to colon cancer. Citation Format: Oshrat Levi Galibov, Hagar Lavon, Rina Wassermann-Dozorets, Meirav Pevsner-Fischer, Shimrit Mayer, Esther Wershof, Yaniv Stein, Lauren E. Brown, Wenhan Zhang, Gil Friedman, Reinat Nevo, Ofra Golani, Lior H. Katz, Rona Yaeger, Ido Laish, John A. Porco, Erik Sahai, Dror S Shouval, David Kelsen, Ruth Scherz-Shouval. HSF1 promotes inflammation induced tumor development through ECM remodeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB204.

Studies have confirmed an increased risk of colorectal cancer in patients with ulcerative colitis; hence, surveillance is recommended. Optional modalities include white light endoscopy (WLE) or dye-spray chromoendoscopy. However, narrow-band imaging (NBI) is still not considered comparable to chromoendoscopy. The aim of this study was to compare the diagnostic yield (DY) of WLE, chromoendoscopy, NBI for detection of neoplasia in patients with inflammatory bowel disease (IBD) by performing a meta-analysis of the existing literature. We searched databases for prospective studies. For each modality, we performed comparative per-lesion analysis (any neoplasia detection) and per-patient analysis (patient with neoplastic lesions). Meta-analysis was performed using fixed-effect model unless heterogeneity was high. Odds ratios (ORs) with 95% CIs were calculated and pooled. Five studies compared chromoendoscopy to WLE. Chromoendoscopy (n = 361) was superior to WLE (n = 358) with per-patient analysis OR 2.05 (95% CI 1.26, 3.35) and per-lesion analysis OR 2.79 (95% CI 2.08, 3.73). High-definition (HD) chromoendoscopy was superior to HD-WLE with per-lesion analysis OR 2.48 (95% CI 1.55, 3.97). In four studies comparing NBI to WLE (n = 305), no difference was found in per-patient analysis OR 0.97 (95% CI 0.62, 1.53) and per-lesion analysis OR 0.94 (95% CI 0.63, 1.4). In two studies comparing CE to NBI (n = 104), no difference was found in per-patient analysis OR 1.0 (95% CI 0.51, 1.95) and per-lesion analysis OR 1.29 (95% CI 0.69, 2.41). Chromoendoscopy is superior to WLE for detection of dysplasia in IBD, even with HD endoscopy. No difference in DY could be demonstrated for NBI in comparison with other modalities.

BACKGROUND Recent data have shown that adults with celiac disease (CD) may have a higher prevalence of risk factors for cardiovascular disease (CVD) compared with the general population. Thus, we aimed to investigate the association of CD with CVD risk factors at late adolescence in a cross-sectional population-based study. METHODS A total of 2,001,353 Jewish Israeli adolescents who underwent a general health examination at median age of 17.1 years from 1988 to 2015 were included. Covariate data included demographic measures, blood pressure (BP), resting heart rate, and risk factors associated with CVD. RESULTS Overall, 10,566 cases of CD were identified (0.53%). Multivariate analysis showed that mean diastolic BP was significantly lower in subjects with CD (men: 72.0±8.7 vs 70.4 ± 8.5, P

BACKGROUND This study examined the association between the body mass index (BMI) in late adolescence and the risk of colon and rectal cancer. METHODS This study analyzed a cohort of 1,087,358 Jewish men and 707,212 Jewish women who underwent health examinations at the ages of 16 to 19 years between 1967 and 2002 and were followed by linkage to the national cancer registry up to 2012. Cox regression was used to estimate hazard ratios (HRs) for cancer according to age- and sex-adjusted BMI percentiles from the US Centers for Disease Control and Prevention (overweight, 85th percentile to

Aim Celiac disease (CD) is a systemic disorder that is associated with various autoimmune disorders and a higher prevalence of other diagnoses and complications. This large, cross-sectional, population-based study investigated the associations between CD and various medical conditions during late adolescence. Methods We included 2 001 353 Jewish Israeli adolescents who underwent a general health examination at a median age of 17.1 (16.9–17.4) years from 1988 to 2015. Comprehensive data regarding medical status were available for 1 588 041 (79%) subjects. A definite diagnosis of CD was based on accepted criteria. Covariate data included demographic measures and data on associated medical conditions. Results Overall, data on 7145 subjects with CD and 1 580 896 controls were analysed. Multivariate analyses showed that autoimmune diseases were significantly more common in subjects with CD, including insulin dependent diabetes, with an odds ratio (OR) of 5.5, inflammatory bowel diseases (OR = 3.8), arthritis (OR = 2.4), thyroid diseases (OR = 1.8) and psoriatic skin disorders (OR = 1.6). Further associations included asthma (OR = 1.5), bile stones (OR = 3.6), migraine (OR = 2.3), anaemia (OR = 1.7) and menstrual abnormalities (OR = 1.5). Long bone fractures and axial fractures were no more common in adolescents with CD than controls. Conclusion CD was already associated with multiple comorbidities by adolescence, and these were not limited to autoimmune disorders.

Background Inflammatory bowel disease (IBD) patients have twice the risk of venous thromboembolism (VTE) compared with healthy controls. VTE can occur at both hospitalisation and after discharge. We aimed to assess the prevalence of VTE among IBD patients who were hospitalised with disease flare at three Israeli Hospitals. Methods A retrospective cross-sectional analysis including all IBD patients who were admitted with disease flare at Galilee Medical Center, EMMS Nazareth Hospital and Hadassah Medical Center. Exclusion criteria were patients with confirmed diagnosis of hypercoagulable state or patients on drugs with pro-coagulable potential. Results Eighty-one patients with overall 114 admissions were included in the study. The average age was 42.2 ± 18.5 years. Sixty-six patients (57.9%) were males. Forty-five admissions (39.5%) were due to ulcerative colitis (UC) flare and 69 admissions (60.5%) were secondary to Crohn’s disease (CD) flare. Twenty-eight patients (24.6%) were smokers. Twenty-five patients (21.9%) and 39 patients (34.2%) were on recent biological and steroid treatment (within 3 months). The mean C-reactive protein and albumin levels at the day of discharge were 4.2 ± 4.6 mg/dl (normal range 0–0.5) and 3.5 ± 0.7 g/dl (normal values above 3.2), respectively. During hospitalisation, 57 (50%), 55 (48.2%), 29 (25.4%), 19 (16.7%) and 8 (7%) patients were treated with intravenous steroids, antibiotics, amino-salicylates, surgery and immunomodulators, respectively. Only four patients (3.5 %) were on prophylactic subcutaneous anticoagulation (enoxaparin) throughout their hospital stay and only 1 patient (0.9%) who have not been on anticoagulation developed in-hospital symptomatic VTE episode. Notably, this patient suffering from CD with ileo-colonic involvement developed subclavian vein thrombosis two day after PICC line insertion for total parenteral nutrition to optimise his nutritional state before performing surgery. The mean hospitalisation length was 6.5 ± 6.6 days. Conclusion In-hospital VTE was rare among our IBD patients admitted with disease flare. In fact, the only one VTE event reported in our cohort is probably related to the PICC line insertion and not related to IBD flare. Notably undergoing surgery in our cohort was not correlated with VTE episodes. Further studies are warranted to characterise IBD patients at risk for VTE, to assess the risk factors for in-hospital VTE development and to address further the role of prophylactic anticoagulation among hospitalised IBD patients, mainly those with bloody diarrhoea.

Exposure to genotoxins such as ethanol-derived acetaldehyde leads to DNA damage and liver injury, and promotes the development of cancer. We report here a major role for the TGF-β/Smad3 adaptor β2-Spectrin (β2SP, gene Sptbn1) in maintaining genomic stability following alcohol-induced DNA damage. β2SP supports DNA repair through β2SP-dependent activation of Fancd2, a core component of the Fanconi anemia complex. Loss of β2SP leads to decreased Fancd2 levels and sensitizes β2SP mutants to DNA damage by ethanol treatment, leading to phenotypes that closely resemble those observed in animals lacking both Aldh2 and Fancd2, and resemble human fetal alcohol syndrome. Sptbn1-deficient cells are hypersensitive to DNA cross-linking agents, and have defective DNA double-strand break repair that is rescued by ectopic Fancd2 expression. Moreover, Fancd2 transcription in response to DNA damage/TGF-β stimulation is regulated by the β2SP/Smad3 complex. Thus, dysfunctional TGF-β/β2SP signaling impacts the processing of genotoxic metabolites by altering the Fanconi anemia DNA repair pathway. This article is protected by copyright. All rights reserved.

Communication gaps in families with unexplained mismatch repair (MMR) deficiency (UMMRD) could negatively impact the screening behaviors of relatives of individual with UMMRD. We evaluated cancer risk perception, screening behaviors, and family communication among relatives of colorectal cancer (CRC) patients with UMMRD. Fifty-one family members of 17 probands with UMMRD completed a questionnaire about cancer risk perception, adherence to Lynch syndrome (LS) screening recommendations, and communication with relatives. Clinical data about the probands were obtained from medical records. Thirty-eight participants (78%) were worried from having cancer and twenty-one participants (42%) had undergone colonoscopy in the past 2 years, as recommended for LS families. In terms of screening for extracolonic cancers, only two eligible participants (3.9%) were screened for gastric, endometrial (10.0%), and ovarian (9.5%) cancers. Additionally, 5 participants (10%) underwent genetic counseling. Most participants were not told by anyone to be screened for extracolonic cancers (84, 85, and 95% for gastric, ovarian, and endometrial cancers, respectively). A minority of family members of CRC patients with UMMRD follow cancer screening as recommended for LS families. Health care providers should encourage patients with UMMRD to share information on LS-related cancers screening, especially extracolonic cancers, with their relatives.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To evaluate the beneficial and harmful effects of lamivudine in preventing reactivation of HBV during or following immunosuppressive therapy in HBsAg‐positive patients. To estimate the optimal time of initiating lamivudine prophylactic therapy in HBsAg‐positive patients receiving immunosuppressive therapy.

Background cranial X radiation therapy was the standard of care for treating dermatological conditions until the 1960s, when its association to cancer and particularly high rates of brain tumors was discovered. This study examines associations found between incidence of brain tumor and ethnicity. Methods This study analyzed two cohorts who underwent examination at age 17 and were followed by linkage to the national cancer registry. The first cohort included 376,336 participants born in 1948–1959 (when treatment with cranial X radiation was standard care for treating tinea capitis), and the second 474,923 participants born in 1960–1971. Results In the first cohort, ethnicity was strongly associated with the incidence of brain tumor (BT), with higher incidence observed among patients with origins in North Africa or the Middle East. This effect was ablated in the second cohort, and a significant decrease in the rate of meningiomas was noted. Conclusion The association of brain tumor with ethnicity was present only during the period when treatment with cranial X radiation was the standard of care for TC in Israel, therefore it is most likely that radiation exposure was a confounding factor, and that ethnic susceptibility for brain cancer was not causative in these cohorts.