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BackgroundMost patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival.Objective and designThis observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age.Results3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer.ConclusionCarriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient’s age, gender and path_MMR variant. We have updated our open-access website www.lscarisk.org to facilitate this.

ObjectiveLynch syndrome is a hereditary cancer syndrome caused by mismatch repair gene mutations, and female carriers are at an increased risk of endometrial and ovarian cancer. The best approach to screening is not yet clear and practice varies across countries and centers. We aimed to provide evidence to inform the best approach to screening and risk reduction.MethodsA systematic search of the literature was conducted (Medline, Embase, PubMed). Studies evaluating the following were included: women with Lynch syndrome (by mismatch repair mutation or Amsterdam II criteria), screening methods for endometrial and/or ovarian cancer, intervention included endometrial biopsy, transvaginal ultrasound, or serum cancer antigen 125 (CA-125), outcomes evaluated were number of cancers and/or endometrial hyperplasia.ResultsA total of 18 studies of Lynch syndrome carriers which screened for endometrial cancer using transvaginal ultrasound and/or hysteroscopy/endometrial biopsy revealed an incidence of 3.9% at the time of screening. Most (64.1%) endometrial cancers detected were from screening, with the balance detected in symptomatic women at the first screening visits, regular review, or between screening intervals. In mismatch repair carriers, the overall sensitivity of endometrial screening was 66.7%, and the number needed to screen ranged between 4 and 38 (median 7). The sensitivity of endometrial biopsy was 57.1% and the number needed to screen was 23–380 (median 78). The sensitivity of transvaginal ultrasound was 34.4% and the number needed to screen was 35–973 (median 170). Fourteen studies which screened for ovarian cancer using transvaginal ultrasound and/or CA-125 revealed an incidence of 1.3% at the time of screening and 42.9% of ovarian cancers were detected at asymptomatic screening. The sensitivity of ovarian screening was 54.6%, and the number needed to screen was 9–191 (median 23) in mismatch repair carriers. Thirteen studies reported 5.8% incident endometrial cancers and 0.5% ovarian cancers at time of risk reducing surgery.ConclusionsThere is limited evidence to support screening for endometrial and ovarian cancer in Lynch syndrome and data on mortality reduction are not available. Further prospective, randomized trials comparing targeted screening methods are needed. Risk reducing surgery remains the most reliable way to reduce endometrial and ovarian cancer risk in Lynch syndrome.

Most patients with Crohn's disease need an intestinal resection, but a majority will subsequently experience disease recurrence and require further surgery. This study aimed to identify the optimal strategy to prevent postoperative disease recurrence. In this randomised trial, consecutive patients from 17 centres in Australia and New Zealand undergoing intestinal resection of all macroscopic Crohn's disease, with an endoscopically accessible anastomosis, received 3 months of metronidazole therapy. Patients at high risk of recurrence also received a thiopurine, or adalimumab if they were intolerant to thiopurines. Patients were randomly assigned to parallel groups: colonoscopy at 6 months (active care) or no colonoscopy (standard care). We used computer-generated block randomisation to allocate patients in each centre to active or standard care in a 2:1 ratio. For endoscopic recurrence (Rutgeerts score ≥i2) at 6 months, patients stepped-up to thiopurine, fortnightly adalimumab with thiopurine, or weekly adalimumab. The primary endpoint was endoscopic recurrence at 18 months. Patients and treating physicians were aware of the patient's study group and treatment, but central reading of the endoscopic findings was undertaken blind to the study group and treatment. Analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00989560. Between Oct 13, 2009, and Sept 28, 2011, 174 (83% high risk across both active and standard care groups) patients were enrolled and received at least one dose of study drug. Of 122 patients in the active care group, 47 (39%) stepped-up treatment. At 18 months, endoscopic recurrence occurred in 60 (49%) patients in the active care group and 35 (67%) patients in the standard care group (p=0·03). Complete mucosal normality was maintained in 27 (22%) of 122 patients in the active care group versus four (8%) in the standard care group (p=0·03). In the active care arm, of those with 6 months recurrence who stepped up treatment, 18 (38%) of 47 patients were in remission 12 months later; conversely, of those in remission at 6 months who did not change therapy recurrence occurred in 31 (41%) of 75 patients 12 months later. Smoking (odds ratio [OR] 2·4, 95% CI 1·2–4·8, p=0·02) and the presence of two or more clinical risk factors including smoking (OR 2·8, 95% CI 1·01–7·7, p=0·05) increased the risk of endoscopic recurrence. The incidence and type of adverse and severe adverse events did not differ significantly between patients in the active care and standard care groups (100 [82%] of 122 vs 45 [87%] of 52; p=0·51) and (33 [27%] of 122 vs 18 [35%] of 52; p=0·36), respectively. Treatment according to clinical risk of recurrence, with early colonoscopy and treatment step-up for recurrence, is better than conventional drug therapy alone for prevention of postoperative Crohn's disease recurrence. Selective immune suppression, adjusted for early recurrence, rather than routine use, leads to disease control in most patients. Clinical risk factors predict recurrence, but patients at low risk also need monitoring. Early remission does not preclude the need for ongoing monitoring. AbbVie, Gutsy Group, Gandel Philanthropy, Angior Foundation, Crohn's Colitis Australia, and the National Health and Medical Research Council.

Background Colorectal cancer screening reduces colorectal cancer morbidity and mortality. Identifying the factors associated with screening participation is needed to overcome barriers to screening. While several of those factors have been identified, the impact of mental and physical health on screening behaviour is not well understood. Methods This retrospective cohort study compared the self-reported mental and physical health of those who did screen for colorectal cancer and those who did not. Participants of the Australasian Colorectal Cancer Family Registry Cohort that were aged 45-75 years and had never been diagnosed with colorectal cancer were asked to complete a questionnaire detailing their colorectal cancer screening participation in the preceding 5 years, and a validated questionnaire of mental and physical health. Multivariable logistic regression was used to adjust for measured potential confounders. Results Of the 1130 eligible participants, 781 had a family history of colorectal cancer (69.5%), and 819 reported colorectal cancer screening in the past 5 years (72%). After adjusting for potential confounders, there was no evidence that overall mental or physical health was associated with colorectal cancer screening. However, those reporting higher levels of general health were more likely to participate in colorectal cancer screening (OR = 1.02 (100 point scale), 95% CI 1.004, 1.037, P = .014). Conclusion We found limited evidence that mental and physical health were associated with colorectal cancer screening. The high proportion of participants with a family history of colorectal cancer limits the generaliseability of the findings to the general population, although we observed no differences in findings by strength of family history.

Background This study aimed to investigate clinicopathological and molecular tumour features associated with intratumoral pks + Escherichia coli ( pks + E.coli + ), pks + E.coli - (non- E.coli bacteria harbouring the pks island), Enterotoxigenic Bacteroides fragilis (ETBF) and Fusobacterium nucleatum ( F. nucleatum ). Methods We screened 1697 tumour-derived DNA samples from the Australasian Colorectal Cancer Family Registry, Melbourne Collaborative Cohort Study and the ANGELS study using targeted PCR. Results Pks + E.coli + was associated with male sex ( P  < 0.01) and APC :c.835-8 A > G somatic mutation ( P  = 0.03). The association between pks + E.coli + and APC :c.835-8 A > G was specific to early-onset CRCs (diagnosed<45years, P  = 0.02). The APC :c.835-A > G was not associated with pks + E.coli - ( P  = 0.36). F. nucleatum was associated with DNA mismatch repair deficiency (MMRd), BRAF: c.1799T>A p.V600E mutation, CpG island methylator phenotype, proximal tumour location, and high levels of tumour infiltrating lymphocytes ( P s < 0.01). In the stratified analysis by MMRd subgroups, F. nucleatum was associated with Lynch syndrome, MLH1 methylated and double MMR somatic mutated MMRd subgroups ( Ps  < 0.01). Conclusion Intratumoral pks + E.coli + but not pks + E.coli - are associated with CRCs harbouring the APC :c.835-8 A > G somatic mutation, suggesting that this mutation is specifically related to DNA damage from colibactin-producing E.coli exposures . F. nucleatum was associated with both hereditary and sporadic MMRd subtypes, suggesting the MMRd tumour microenvironment is important for F. nucleatum colonisation irrespective of its cause.

Lynch syndrome is characterised by heterozygous germline mutations in the MisMatch Repair (MMR) genes and an increased risk of cancer. Previous population estimates based on cohorts with colorectal cancer suggest one in 300 people have a disease-causing variant. This study calculated the population frequency of Lynch syndrome from Predicted pathogenic variants in MMR genes in the general population. MLH1, MSH2, MSH6 and PMS2 variants were downloaded from gnomAD v.2.1, and annotated in ANNOVAR. Our population frequencies of heterozygous Predicted pathogenic variants were calculated from the sum of structural, null, rare computationally-damaging missense changes, and founder variants. Population frequencies were also derived from the proposed ClinGen variant specifications, and from pathogenic variants in the ClinVar, LOVD or InSiGHT websites. Predicted pathogenic variants were found in one in 94 people in gnomAD v.2.1.1 using our strategy, and one in 122, 203, 199 or 594 using the proposed ClinGen specifications, and the ClinVar, LOVD or InSiGHT databases, respectively. The frequencies derived from ClinVar (one in 203) and LOVD (one in 199) were based on accurate assessments of penetrant variants since they were largely derived from patient testing, but were underestimates because not all gnomAD variants had been assessed. Our strategy and that of the proposed ClinGen specifications examined each variant in gnomAD and resulted in more common population frequencies but some assessments may have been inaccurate, and variants incompletely penetrant. The number of Predicted pathogenic MMR gene variants in the general population suggests that Lynch syndrome is more common than reported previously.

Abstract Background Patients with Crohn’s disease (CD) undergo frequent endoscopic procedures, with visualization of the gastrointestinal mucosa central to treatment decision-making. Subsequently, a noninvasive alternative to optical colonoscopy (OC) would be welcomed. One such technology is capsule endoscopy, including the PillCam COLON 2 (PCC2), though research validating its use in ileocolonic CD is limited. This study aims to compare PCC2 with ileocolonoscopy (OC) in assessing mucosal CD through use of a standardized scoring system. Methods At an Australian tertiary hospital, same-day PCC2 and ileocolonoscopy results of 47 CD patients, with known nonstricturing disease, were prospectively collected and analyzed for correlation and agreement. Deidentified recordings were reported by a single expert gastroenterologist. Mucosal disease was quantified using the Simple Endoscopic Score for Crohn’s Disease (SES-CD). The SES-CD results of paired endoscopic modalities were compared in total per bowel segment and per SES-CD variable. Results Of 47 PCC2 recordings, 68% were complete, fully assessing terminal ileum to rectum, and OC was complete in 89%. Correlation (r) between total SES-CD scores was strongest in the terminal ileum (r = 0.77, P < .001), with the SES-CD variable of “ulcer detection” showing the strongest agreement. The PCC2 (vs OC) identified additional ulcers in the terminal ileum; ascending, transverse, and descending colon; and rectum; scores were 5 (1), 5 (3), 1 (1), 2 (1), and 2 (2), respectively. Conclusions The PCC2 shows promise in assessing ileocolonic mucosa, especially in proximal bowel segments, with greater reach of visualization in the small bowel. Given the resource and safety considerations raised by the Coronavirus disease 2019 pandemic, capsule endoscopy has particular significance. This article aims to contribute to the limited body of research surrounding the validity of capsule endoscopy technology in assessing ileocolonic mucosa in Crohn’s Disease patients. In doing so, an alternative option for patients enduring frequent endoscopies is given potential.

Background Germ-line mutations in the exonuclease domains of the POLE and POLD1 genes are associated with an increased, but yet unquantified, risk of colorectal cancer (CRC). Methods We identified families with POLE or POLD1 variants by searching PubMed for relevant studies prior to October 2016 and by genotyping 669 population-based CRC cases diagnosed in patients under 60 years of age, from the Australasian Colorectal Cancer Family Registry. We estimated the age-specific cumulative risks (penetrance) using a modified segregation analysis. Results We observed 67 CRCs (mean age at diagnosis = 50.2 (SD = 13.8) years) among 364 first- and second- degree relatives from 41 POLE families, and 6 CRCs (mean age at diagnosis = 39.7 (SD = 6.83) years) among 69 relatives from 9 POLD1 families. We estimated risks of CRC up to the age of 70 years (95% confidence interval) for males and females, respectively, to be 40% (26–57%) and 32% (20–47%) for POLE mutation carriers and 63% (15–99%) and 52% (11–99%) for POLD1 mutation carriers. Conclusion CRC risks for POLE mutation carriers are sufficiently high to warrant consideration of annual colonoscopy screening and implementation of management guidelines comparable to those applied in cases of Lynch syndrome. Refinement of estimates of CRC risk for POLD1 carriers is needed; however, clinical management recommendations could follow those made for POLE carriers.

Background. Vaccination is an effective public health measure to combat the SARS-CoV-2 pandemic. However, vaccine “hesitancy” has limited uptake in some, including inflammatory bowel disease (IBD) patients who may have unique concerns influencing uptake. Aim. The aim of the study is to explore attitudes, concerns, and the influence of different sources of information on COVID-19 vaccine uptake in IBD patients. Methods. Patients from a specialist IBD clinic at a tertiary hospital in Australia and a national IBD patient society were invited to complete an anonymous online survey regarding COVID-19 vaccination. Demographic characteristics, attitudes towards vaccination, and trust in sources of information were explored. Logistic regression was used to identify variables associated with vaccine uptake. Results. Of 441 respondents, 93% of respondents had received at least 1 dose of COVID-19 vaccination. Self-perceived risk of being more unwell with COVID-19 infection due to IBD (AOR 5.25, 95% CI 1.96–14.04, p<0.001) was positively associated with vaccine uptake. Concerns regarding the safety of vaccination in pregnancy (OR 0.22, 95% CI 0.08–0.65, p=0.006) and of causing an IBD flare (OR 0.28, 95% CI 0.10–0.77, p=0.01) were negatively associated with vaccine uptake. In total, 282 (73.7%) responders ranked healthcare workers the most trusted source to obtain information surrounding vaccination. Conclusion. Vaccine hesitancy in IBD patients is low. Concerns about the safety of vaccination in pregnancy and in causing an IBD flare are both associated with vaccine hesitancy. Healthcare providers play a key role in proactively addressing these misconceptions particularly in the context of emerging virus variants and the availability of boosters.

ObjectiveGermline pathogenic variants (PVs) in the DNA mismatch repair (MMR) genes and in the base excision repair gene MUTYH underlie hereditary colorectal cancer (CRC) and polyposis syndromes. We evaluated the robustness and discriminatory potential of tumour mutational signatures in CRCs for identifying germline PV carriers.DesignWhole-exome sequencing of formalin-fixed paraffin-embedded (FFPE) CRC tissue was performed on 33 MMR germline PV carriers, 12 biallelic MUTYH germline PV carriers, 25 sporadic MLH1 methylated MMR-deficient CRCs (MMRd controls) and 160 sporadic MMR-proficient CRCs (MMRp controls) and included 498 TCGA CRC tumours. COSMIC V3 single base substitution (SBS) and indel (ID) mutational signatures were assessed for their ability to differentiate CRCs that developed in carriers from non-carriers.ResultsThe combination of mutational signatures SBS18 and SBS36 contributing >30% of a CRC’s signature profile was able to discriminate biallelic MUTYH carriers from all other non-carrier control CRCs with 100% accuracy (area under the curve (AUC) 1.0). SBS18 and SBS36 were associated with specific MUTYH variants p.Gly396Asp (p=0.025) and p.Tyr179Cys (p=5×10-5), respectively. The combination of ID2 and ID7 could discriminate the 33 MMR PV carrier CRCs from the MMRp control CRCs (AUC 0.99); however, SBS and ID signatures, alone or in combination, could not provide complete discrimination (AUC 0.79) between CRCs from MMR PV carriers and sporadic MMRd controls.ConclusionAssessment of SBS and ID signatures can discriminate CRCs from biallelic MUTYH carriers and MMR PV carriers from non-carriers with high accuracy, demonstrating utility as a potential diagnostic and variant classification tool.