Position statement of the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) on APC I1307K and cancer risk.

While constitutional pathogenic variants in the APC gene cause familial adenomatous polyposis, APC c.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 the APC I1307K 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 the APC I1307K 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.

Diagnostic yield of multigene panel testing in an Israeli cohort: enrichment of low-penetrance variants.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

PURPOSE: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. METHODS: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. RESULTS: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. CONCLUSION: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

Correction: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Comorbidities in adolescents with inflammatory bowel disease: findings from a population-based cohort study.

BACKGROUND: 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. METHODS: Jewish Israeli adolescents who underwent a general health evaluation prior to enlistment to the Israeli Defense Forces from 2002 to 2016 were included. RESULTS: 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. CONCLUSIONS: At adolescence, both Crohn's disease and ulcerative colitis are associated with multiple comorbidities, not limited to autoimmune disorders.

Lack of association between screening interval and cancer stage in Lynch syndrome may be accounted for by over-diagnosis; a prospective Lynch syndrome database report.

BACKGROUND: Recent epidemiological evidence shows that colorectal cancer (CRC) continues to occur in carriers of pathogenic mismatch repair (path_MMR) variants despite frequent colonoscopy surveillance in expert centres. This observation conflicts with the paradigm that removal of all visible polyps should prevent the vast majority of CRC in path_MMR carriers, provided the screening interval is sufficiently short and colonoscopic practice is optimal. METHODS: To inform the debate, we examined, in the Prospective Lynch Syndrome Database (PLSD), whether the time since last colonoscopy was associated with the pathological stage at which CRC was diagnosed during prospective surveillance. Path_MMR carriers were recruited for prospective surveillance by colonoscopy. Only variants scored by the InSiGHT Variant Interpretation Committee as class 4 and 5 (clinically actionable) were included. CRCs detected at the first planned colonoscopy, or within one year of this, were excluded as prevalent cancers. RESULTS: Stage at diagnosis and interval between last prospective surveillance colonoscopy and diagnosis were available for 209 patients with 218 CRCs, including 162 path_MLH1, 45 path_MSH2, 10 path_MSH6 and 1 path_PMS2 carriers. The numbers of cancers detected within < 1.5, 1.5-2.5, 2.5-3.5 and at > 3.5 years since last colonoscopy were 36, 93, 56 and 33, respectively. Among these, 16.7, 19.4, 9.9 and 15.1% were stage III-IV, respectively (p = 0.34). The cancers detected more than 2.5 years after the last colonoscopy were not more advanced than those diagnosed earlier (p = 0.14). CONCLUSIONS: The CRC stage and interval since last colonoscopy were not correlated, which is in conflict with the accelerated adenoma-carcinoma paradigm. We have previously reported that more frequent colonoscopy is not associated with lower incidence of CRC in path_MMR carriers as was expected. In contrast, point estimates showed a higher incidence with shorter intervals between examinations, a situation that may parallel to over-diagnosis in breast cancer screening. Our findings raise the possibility that some CRCs in path_MMR carriers may spontaneously disappear: the host immune response may not only remove CRC precursor lesions in path_MMR carriers, but may remove infiltrating cancers as well. If confirmed, our suggested interpretation will have a bearing on surveillance policy for path_MMR carriers.

Risk factors associated with gastroenteropancreatic neuroendocrine tumors in a cohort of 2.3 million Israeli adolescents.

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.

Loss of the transforming growth factor-ß effector ß2-Spectrin promotes genomic instability.

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 transforming growth factor ß/mothers against decapentaplegic homolog 3 adaptor ß2-Spectrin (ß2SP, gene Sptbn1) in maintaining genomic stability following alcohol-induced DNA damage. ß2SP supports DNA repair through ß2SP-dependent activation of Fanconi anemia complementation group D2 (Fancd2), a core component of the Fanconi anemia complex. Loss of ß2SP leads to decreased Fancd2 levels and sensitizes ß2SP mutants to DNA damage by ethanol treatment, leading to phenotypes that closely resemble those observed in animals lacking both aldehyde dehydrogenase 2 and Fancd2 and resemble human fetal alcohol syndrome. Sptbn1-deficient cells are hypersensitive to DNA crosslinking agents and have defective DNA double-strand break repair that is rescued by ectopic Fancd2 expression. Moreover, Fancd2 transcription in response to DNA damage/transforming growth factor ß stimulation is regulated by the ß2SP/mothers against decapentaplegic homolog 3 complex. CONCLUSION: Dysfunctional transforming growth factor ß/ß2SP signaling impacts the processing of genotoxic metabolites by altering the Fanconi anemia DNA repair pathway. (Hepatology 2017;65:678-693).

Adolescent body mass index and risk of colon and rectal cancer in a cohort of 1.79 million Israeli men and women: A population-based study.

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 <95th percentile; obesity, ≥95th percentile). RESULTS: Over a median follow-up of 23 years, 2967 incidence cases of colorectal cancer, including 1977 among men (1403 in the colon and 574 in the rectum) and 990 among women (764 in the colon and 226 in the rectum), were identified. Overweight and obesity were associated with the risk for colon cancer among both men (HR for overweight, 1.53; 95% confidence interval [CI], 1.28-1.84; HR for obesity, 1.54; 95% CI, 1.15-2.06; statistically significant from a BMI of 23.4 kg/m2 [spline analysis]) and women (HR for overweight, 1.54; 95% CI, 1.22-1.93; HR for obesity, 1.51; 95% CI, 0.89-2.57; significant from a BMI of 23.6 kg/m2 ). Obesity, but not overweight, was associated with a risk for rectal cancer among men (HR, 1.71; 95% CI, 1.11-2.65; significant from a BMI of 29.6 kg/m2 ) and women (HR, 2.03; 95% CI, 0.90-4.58; significant from a BMI of 30.6 kg/m2 ). CONCLUSIONS: Being overweight or obese in adolescence was associated with an increased risk of subsequent colon cancers in men and women, whereas obesity was associated with rectal cancer. Cancer 2017;123:4022-30. © 2017 American Cancer Society.

Incidence and Determinants of Hepatocellular Carcinoma in Autoimmune Hepatitis: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: The risk of hepatocellular carcinoma (HCC) in patients with autoimmune hepatitis (AIH) is unclear. We conducted a systematic review and meta-analysis of the incidence of HCC and associated risk factors among patients with AIH. METHODS: We searched PubMed, Embase, and reference lists from relevant articles through June 2016 to identify cohort studies that examined the incidence of HCC in patients with AIH. We used random effects models to estimate pooled incidence rates overall and in subgroup of patients with cirrhosis. The between-study heterogeneity was assessed using I2 statistic. RESULTS: A total of 25 studies (20 papers and 5 abstracts), including 6528 patients, met the eligibility criteria. The median cohort size was 170 patients with AIH (range, 25-1721 patients), followed for a median of 8.0 years (range, 3.3-16.0 years). The pooled incidence rate for HCC in patients with AIH was 3.06 per 1000 patient-years (95% confidence interval, 2.22-4.23; I2 = 51.5%; P = .002). The pooled incidence of HCC in patients with cirrhosis at AIH diagnosis was 10.07 per 1000 patient-years (95% confidence interval, 6.89-14.70; I2 = 48.8%; P = .015). In addition, 92 of 93 patients who had HCC had evidence of cirrhosis before or at the time of their HCC diagnosis. The risk of HCC seems to be lower in patients with AIH and cirrhosis than that reported for patients with cirrhosis from hepatitis B, hepatitis C, or primary biliary cholangitis. CONCLUSIONS: Based on the increased risked of HCC shown in this meta-analysis, there may be a role for HCC surveillance in patients with AIH and cirrhosis.

Cardiovascular Risk Factors in Adolescents With Celiac Disease: A Cross-sectional Population-Based Study.

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 ±â€Š8.5, P < 0.0001; women: 70.0 ±â€Š8.3 vs 69.0 ±â€Š8.2, P < 0.0001), whereas systolic BP did not differ between groups. Resting heart rate was higher in CD cases (an absolute difference of 0.4 beats per minute, P < 0.0001). The proportions of overweight and obese subjects were significantly lower in CD cases. Noninsulin-dependent diabetes mellitus (relative risk [RR], 4.1; 95% confidence interval [CI] 2.8-5.7), hypercoagulability (RR, 2.6; 95% CI 1.5-4.5), and hyperlipidemia (RR, 1.9; 95% CI 1.2-3) were significantly more common in subjects with CD. CONCLUSIONS: At the age of 17 years, the prevalence of risk factors for CVD is higher in subjects with CD compared with the general population. There is, however, neither increase in BP nor increase in overweight and obesity rates.

Large population study shows that adolescents with celiac disease have an increased risk of multiple autoimmune and nonautoimmune comorbidities.

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.

Colorectal and Endometrial Cancer Risk and Age at Diagnosis in BLMAsh Mutation Carriers.

BACKGROUND: Biallelic BLM gene mutation carriers are at an increased risk for cancer, including colorectal cancer (CRC). Whether heterozygous BLM gene mutations confer an increased cancer risk remains controversial. OBJECTIVES: To evaluate CRC and endometrial cancer risk in BLM heterozygous mutation carriers. METHODS: Jewish Ashkenazim at high risk for colon or endometrial cancer and endometrial cancer cases unselected for family history were genotyped for the BLMAsh predominant mutation. RESULTS: Overall, 243 high-risk individuals were included: 97 men CRC patients (55.12 ± 12.3 years at diagnosis), 109 women with CRC (56.5 ± 13.7 years), 32 women with endometrial cancer (58.25 ± 13.4 years) and 5 women with both CRC and endometrial cancer. In addition, 120 unselected Ashkenazi women with endometrial cancer (64.2 ± 11.58 years) were genotyped. The BLMAsh mutation was present in 4/243 (1.65%) high-risk patients; 2 CRC (0.97%) 2 endometrial cancer (5.4%), and 1/120 unselected endometrial cancer patients (0.84%). Notably, in high-risk cases, BLMAsh mutation carriers were diagnosed at a younger age (for CRC 47.5 ± 7.8 years; P = 0.32 ; endometrial cancer 49.5 ± 7.7 years; P = 0.36) compared with non-carriers. CONCLUSIONS: Ashkenazi high risk CRC/endometrial cancer, and women with endometrial cancer have a higher rate of BLMAsh heterozygous mutation compared with the general population. BLMAsh heterozygous mutation carriers are diagnosed with CRC and endometrial cancer at a younger age compared with non-carriers. These observations should be validated and the possible clinical implications assessed.

Interventions for the management of fatigue in adults with a primary brain tumour.

BACKGROUND: Fatigue is a common and disabling symptom in people with a primary brain tumour (PBT). The effectiveness of interventions for treating clinically significant levels of fatigue in this population is unclear. OBJECTIVES: To assess the effectiveness and safety of pharmacological and non-pharmacological interventions for adults with PBT and high levels of fatigue. SEARCH METHODS: In March 2016, we searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO and CINAHL and checked the reference lists of included studies. We also searched relevant conference proceedings, searched for ongoing trials via ClinicalTrials.gov and contacted major co-operative groups with trials in this area. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that investigated any pharmacological or non-pharmacological intervention in adults with PBT and fatigue, where fatigue was the primary outcome measure. We restricted inclusion specifically to studies that enrolled only participants with clinically significant levels of fatigue. DATA COLLECTION AND ANALYSIS: Three review authors (JD, SYK, DC) independently evaluated search results, extracted data from selected studies and carried out a bias risk assessment. We extracted data on fatigue, cognition, mood, quality of life and adverse events outcomes. MAIN RESULTS: We identified nine studies. We excluded eight of these as they did not restrict participation to people with high fatigue. The single eligible trial investigated the use of modafinil compared to placebo. Although this study found a significant improvement over time in the primary outcome of fatigue, the improvement occurred after both modafinil and placebo with no significant difference in response between the two groups. The included trial did not reach its planned recruitment target and therefore may not, in practice, have been adequately powered to detect a difference. The trial was at a low risk of bias across most areas. There was an unclear risk of bias related to the use of mean imputation because the investigators did not analyse the impact of imputation on the results. AUTHORS' CONCLUSIONS: There was insufficient evidence to draw reliable and generalisable conclusions regarding potential effectiveness or harm of any pharmacological or non-pharmacological treatments for fatigue in people with PBT. More research is needed on how best to treat people with brain tumours with high fatigue.

Low ALT Is Associated with IBD and Disease Activity: Results from a Nationwide Study.

Background: Sarcopenia is underdiagnosed in patients with inflammatory bowel disease (IBD). Low alanine transaminase (ALT) is associated with sarcopenia. We evaluated the association between low ALT and the presence of IBD and disease activity. Methods: Data were collected from a national Israeli health insurer cohort comprising 976,615 patients. Patients with a diagnosis of IBD were compared to healthy controls. After exclusion of patients with liver disease, ALT > 40 IU/L and age < 18, a total of 233,451 patients were included in the analysis. Low ALT was defined as <10 IU/L. Results: Low ALT was more common amongst patients with IBD than in healthy controls (7.76% vs. 5.7% p < 0.001). Low ALT was found in 148 (7.9%) of the patients with CD and 69 (6.9%) of the patients with UC. For CD, low ALT was associated with increased fecal calprotectin (FC) and CRP (223.00 µg/mg [63.45-631.50] vs. 98.50 [31.98-324.00], p < 0.001, 9.10 mg/L [3.22-19.32] vs. 3.20 [1.30-8.30], p < 0.001) and decreased albumin and hemoglobin (3.90 g/dL [3.60-4.20] vs. 4.30 [4.00-4.50], p < 0.001,12.20 g/dL [11.47-13.00] vs. 13.60 [12.60-14.70], p < 0.001). For UC, low ALT was associated with higher FC and CRP (226.50 µg/mg [143.00-537.00] vs. 107.00 [40.85-499.50], p = 0.057, 4.50 mg/L [1.90-11.62] vs. 2.30 [1.00-6.20], p < 0.001) and with lower albumin and hemoglobin (4.00 g/dL [3.62-4.18] vs. 4.30 [4.10-4.40], p < 0.001, 12.40 g/dL [11.60-13.20] vs. 13.60 [12.60-14.60], p < 0.001). These findings remained consistent following multivariate regression and in a propensity score-matched cohort. Conclusions: Low ALT is more common in patients with IBD and is associated with biochemical disease activity indices.

A computer-aided polyp detection system in screening and surveillance colonoscopy: an international, multicentre, randomised, tandem trial.

BACKGROUND: Studies on the effect of computer-aided detection (CAD) in a daily clinical screening and surveillance colonoscopy population practice are scarce. The aim of this study was to evaluate a novel CAD system in a screening and surveillance colonoscopy population. METHODS: This multicentre, randomised, controlled trial was done in ten hospitals in Europe, the USA, and Israel by 31 endoscopists. Patients referred for non-immunochemical faecal occult blood test (iFOBT) screening or surveillance colonoscopy were included. Patients were randomomly assigned to CAD-assisted colonoscopy or conventional colonoscopy; a subset was further randomly assigned to undergo tandem colonoscopy: CAD followed by conventional colonoscopy or conventional colonoscopy followed by CAD. Primary objectives included adenoma per colonoscopy (APC) and adenoma per extraction (APE). Secondary objectives included adenoma miss rate (AMR) in the tandem colonoscopies. The study was registered at ClinicalTrials.gov, NCT04640792. FINDINGS: A total of 916 patients were included in the modified intention-to-treat analysis: 449 in the CAD group and 467 in the conventional colonoscopy group. APC was higher with CAD compared with conventional colonoscopy (0·70 vs 0·51, p=0·015; 314 adenomas per 449 colonoscopies vs 238 adenomas per 467 colonoscopies; poisson effect ratio 1·372 [95% CI 1·068-1·769]), while showing non-inferiority of APE compared with conventional colonoscopy (0·59 vs 0·66; p<0·001 for non-inferiority; 314 of 536 extractions vs 238 of 360 extractions). AMR in the 127 (61 with CAD first, 66 with conventional colonoscopy first) patients completing tandem colonoscopy was 19% (11 of 59 detected during the second pass) in the CAD first group and 36% (16 of 45 detected during the second pass) in the conventional colonoscopy first group (p=0·024). INTERPRETATION: CAD increased adenoma detection in non-iFOBT screening and surveillance colonoscopies and reduced adenoma miss rates compared with conventional colonoscopy, without an increase in the resection of non-adenomatous lesions. FUNDING: Magentiq Eye.

Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma restrict CD8+ T cell activation and limit responsiveness to immunotherapy in mice.

Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions. However, the identities and traits of these cells, and the potential for improving cancer therapy through their targeting, remain poorly characterized. Here, we identify a senescent subset within previously-defined cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs isolated from mouse and humans expressed elevated levels of immune-regulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8+ T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8+ T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.

Diverticulitis in the young is not more aggressive than in the elderly, but it tends to recur more often: systematic review and meta-analysis.

BACKGROUND AND AIM: For years, the natural course of diverticulitis in the young has been debatable in terms of its severity and recurrence rate, and no consensus has been reached regarding its treatment and timing of surgery. Thus, the study aims to evaluate by meta-analysis the natural course of acute diverticulitis in the young. METHODS: Data were obtained from electronic databases and manual search of studies comparing the course of diverticulitis in young versus elderly patients. The age cut-off was selected to be 40-50 years, and only studies using computed tomography as the sole modality for diagnosis were included. Primary outcomes were surgery during hospitalization and disease recurrence. Relative risks (RRs) with 95% confidence intervals (CIs) are reported. RESULTS: One thousand eighty publications were found, 12 of which were included. The total number of patients was 4982. Most young patients were males (RR 1.70, 95% CI 1.31-2.21), without tendency toward a more complicated disease at admission (RR 0.95, 95% CI 0.46-1.97). While there was no significant difference in the rate of surgery during hospitalization (RR 0.69, 95% CI 0.46-1.06), young patients underwent more elective surgeries (RR 2.39, 95% CI 1.82-3.15). No mortality was recorded among young patients. The disease recurrence rate was significantly higher than that of elderly patients (RR 1.70, 95% CI 1.31-2.21); however, no study specified the mean follow-up period for each group. CONCLUSIONS: The course of diverticulitis in the young is not more severe than that in elderly patients; however, the disease tends to recur more often. Therefore, while choosing a therapeutic regimen, factors other than age should also be considered.

Efficacy of urine alkalinization by oral administration of sodium bicarbonate: a prospective open-label trial.

BACKGROUND: Urine alkalinization is indicated for various medical conditions. Alkalinization is usually achieved by intravenous administration of alkali substances titrated by repeated urinalyses. Some situations such as mass casualty events might require urine alkalinization by the oral route. We evaluated the efficacy of oral sodium bicarbonate administration for urine alkalinization. METHODS: In a prospective open-label trial, 4 g of sodium bicarbonate was administered orally 3 times daily to 9 healthy volunteers for 24 hours. Serial blood and urine samples were collected, and urine pH was evaluated. Plasma electrolytes and pH were also measured for safety purposes. RESULTS: All participants had a urine pH of at least 7 after 10 hours. At 20 hours, all participants had a urine pH of at least 8. No adverse effects or abnormal blood results were documented during the 24-hour follow-up. CONCLUSIONS: Oral administration of a standard dose of sodium bicarbonate tablets resulted in effective urine alkalinization. Further research is needed to investigate the natural course of urine pH after cessation of our protocol and the efficacy of longer periods of treatment.

Patients with low ALT levels are at increased risk for severe COVID-19.

Introduction: Frailty is a known risk factor for many diseases, including COVID-19. However, many frail patients are undiagnosed as the diagnosis can be cumbersome. Alanine transaminase (ALT) is found not only in the liver but also in the muscle tissue, and multiple studies show that frail sarcopenic patients have lower ALT. Frail patients are at increased risk for severe COVID-19. We evaluated the association between pre-infection low ALT and the risk for severe COVID-19. Methods: We collected data regarding all subjects tested for SARS-CoV-2 between 1 March 2020 and 31 December 2021 from a national state-mandatory HMO in Israel, serving more than 1.3 million patients. Clinical and laboratory data were collected, including ALT from the year prior to infection. Severe COVID-19 was defined either as death, ICU admission, or ≥10 hospitalization days. Patients with low ALT (ALT ≤ 10 IU/l) were compared with patients with normal ALT (11-40 IU/l). Patients younger than 18 years with a diagnosis of liver disease and with ALT > 40 IU/l were excluded. Results: During the study period, 58,961 patients tested positive for SARS-CoV-2. The patients in the low ALT group were younger (40.53 vs. 42.73, p < 0.001), less likely to be males (12.3 vs. 38.7%, p < 0.001), and had lower BMI (25.97 vs. 27.15, p < 0.001). The patients in the low ALT group had higher mortality (2.36 vs. 0.57%, p < 0.001), more ICU hospitalizations (0.49 vs. 0.41%, p = 0.47), and more prolonged hospitalizations [2.63% (95% CI 2-3.2%) vs. 0.98% (95% CI 0.86-1.1%) p < 0.001]. In multivariate logistic regression analyses, low ALT was associated with an increased risk of severe COVID-19, with increased mortality (OR 1.88, 95% CI 1.37-2.56) and prolonged hospitalization (OR 1.78, 95% CI 1.33-2.35). Conclusion: Low ALT level prior to infection is a significant risk factor for morbidity and mortality from COVID-19 infection. Further studies are warranted to address treatment options for this population.