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Genetic instability is known to drive colorectal carcinogenesis. Generally, a distinction is made between two types of genetic instability: chromosomal instability (CIN) and microsatellite instability (MIN or MSI). Most CIN tumours are aneuploid, whereas MSI tumours are considered near-diploid. However, for MUTYH-associated polyposis (MAP) the genetic instability involved in the carcinogenesis remains unclear, as near-diploid adenomas, aneuploid adenomas and near-diploid carcinomas have been reported. Remarkably, our analysis of 26 MAP carcinomas, using SNP arrays and flow sorting, showed that these tumours are often near-diploid (52%) and mainly contain chromosomal regions of copy-neutral loss of heterozygosity (LOH) (71%). This is in contrast to sporadic colon cancer, where physical loss is the main characteristic. The percentage of chromosomal gains (24%) is comparable to sporadic colorectal cancers with CIN. Furthermore, we verified our scoring of copy-neutral LOH versus physical loss in MAP carcinomas by two methods: fluorescence in situ hybridization, and LOH analysis using polymorphic markers on carcinoma fractions purified by flow sorting. The results presented in this study suggest that copy-neutral LOH is an important mechanism in the tumorigenesis of MAP. Copyright © 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Small-bowel cancer is part of the tumour spectrum of Lynch syndrome. Lynch syndrome, or hereditary non-polyposis colorectal cancer, is caused by germline mutations in one of the mismatch repair genes. Mutation carriers have an estimated lifetime risk for the development of small-bowel cancer of around 4%, corresponding to a relative risk of more than 100 compared with the general population. Patients with Lynch syndrome generally present with small-bowel cancer 10-20 years earlier than the general population, and small-bowel cancer might be the first clinical manifestation of Lynch syndrome. Tumours in patients with Lynch syndrome are evenly distributed within the small bowel. No specific risk factors, such as type of gene mutation, have been identified thus far. Screening for small-bowel cancer in Lynch syndrome has, until now, not been included in guidelines for surveillance, which might partly be due to the fact that, until recently, the possibilities for visualisation of the small bowel were limited. In view of the improved accessibility of the small bowel with the introduction of capsule endoscopy and double balloon enteroscopy, the question of whether patients should be screened for small-bowel neoplasia has regained attention. In this paper, we discuss the rationale for surveillance of small-bowel cancer in Lynch syndrome and highlight issues that need to be addressed in future studies before recommendations can be made. [ABSTRACT FROM AUTHOR]

Background & Aims: The authors assessed whether familial colorectal cancer (FCRC) surveillance in individuals without hereditary CRC can be optimized METHODS: The Adenoma and Serrated Pathway to Colorectal Cancer-FCRC model simulates CRC development in individuals with a family history of CRC at 2-fold and 4-fold increased CRC risk compared with the general population. The authors simulated a strategy without surveillance, the current Dutch guideline (5-yearly colonoscopy between ages 45 and 75 years), and the following 3 sets of alternative strategies: colonoscopy surveillance, surveillance combining colonoscopy and fecal immunochemical test (FIT), and FIT-based surveillance. Each set included a range of strategies differing in age range and test interval. The optimal strategy was defined as the strategy with highest quality-adjusted life-years (QALYs) satisfying all of the following criteria: in the (near-)efficiency area of the cost-effectiveness frontier and compared with current surveillance; noninferior effectiveness; no substantial increase in colonoscopy burden; and not more expensive., Results: The optimal strategy was 10-yearly colonoscopy with 2-yearly FIT between colonoscopies from ages 40 to 80 years for both 2-fold and 4-fold increased CRC risk. At 2-fold risk, this strategy prevented 0.8 more CRC deaths, gained 15.8 more QALYs at 731 fewer colonoscopies, and saved €98,000 over the lifetime of 1000 individuals compared with current surveillance. At 4-fold risk, figures were 2.1 more CRC deaths prevented, 37.0 more QALYs gained at 567 fewer colonoscopies, and €127,000 lower costs. Current surveillance was not (near-)efficient., Conclusions: FIT could play an important role in FCRC surveillance. Surveillance with 10-yearly colonoscopy and 2-yearly FIT between colonoscopies from ages 40 to 80 years increased QALYs and reduced colonoscopy burden and costs compared with current FCRC surveillance., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The study aimed to investigate the added value of blood glucose monitoring in high-risk individuals (HRIs) participating in pancreatic cancer surveillance., Materials and Methods: High-risk individuals with a CDKN2A/p16 germline pathogenic variant participating in pancreatic cancer surveillance were included in this study. Multivariable logistic regression was performed to assess the relationship between new-onset diabetes (NOD) and pancreatic ductal adenocarcinoma (PDAC). To quantify the diagnostic performance of NOD as a marker for PDAC, receiver operating characteristic curve with area under the curve was computed., Results: In total, 220 HRIs were included between 2000 and 2019. Median age was 61 (interquartile range. 53-71) years and 62.7% of participants were female. During the study period, 26 (11.8%) HRIs developed NOD, of whom 5 (19.2%) later developed PDAC. The other 23 (82.1%) PDAC cases remained NOD-free. Multivariable analysis showed no statistically significant relationship between NOD and PDAC (odds ratio, 1.21; 95% confidence interval, 0.39-3.78) and 4 of 5 PDAC cases seemed to have NOD within 3 months before diagnosis. Furthermore, NOD did not differentiate between HRIs with and without PDAC (area under the curve, 0.54; 95% confidence interval, 0.46-0.61)., Conclusions: In this study, we found no added value for longitudinal glucose monitoring in CDKN2A pathogenic variant carriers participating in an imaging-based pancreatic cancer surveillance program., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Constitutional mismatch repair deficiency (CMMRD) is a rare autosomal recessively inherited syndrome that is caused by biallelic pathogenic variants of the mismatch repair genes. It is characterised by the development of multiple tumours in the first and second decade of life including brain, gastrointestinal and haematological tumours often resulting in early death. In order to improve the prognosis of these patients, the European collaborative group 'care for CMMRD' developed a surveillance programme in 2014 and established a registry of patients with CMMRD in Paris. The aim of the study was to evaluate the outcome of this programme., Methods: Twenty-two patients with a definitive diagnosis of CMMRD and with at least one follow-up study were selected from the registry. Medical data on the outcome of surveillance were collected from these patients., Results: During a mean follow-up of 4 years, the programme detected eight malignant tumours including three brain tumours, three upper gastrointestinal cancers and two colorectal cancers. Most tumours could successfully be treated. In addition, many adenomas were detected in the duodenum, and colorectum and subsequently removed. Seven patients developed a symptomatic malignancy, including two brain tumours, one small bowel cancer and four haematological malignancies. At the end of the follow-up, 16 out of 22 patients (73%) who participated in the surveillance programme were still alive., Conclusion: The study suggests a beneficial effect of surveillance of the digestive tract and brains., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background & Aims: Recent pancreatic cancer surveillance programs of high-risk individuals have reported improved outcomes. This study assessed to what extent outcomes of pancreatic ductal adenocarcinoma (PDAC) in patients with a CDKN2A/p16 pathogenic variant diagnosed under surveillance are better as compared with patients with PDAC diagnosed outside surveillance., Methods: In a propensity score matched cohort using data from the Netherlands Cancer Registry, we compared resectability, stage, and survival between patients diagnosed under surveillance with non-surveillance patients with PDAC. Survival analyses were adjusted for potential effects of lead time., Results: Between January 2000 and December 2020, 43,762 patients with PDAC were identified from the Netherlands Cancer Registry. Thirty-one patients with PDAC under surveillance were matched in a 1:5 ratio with 155 non-surveillance patients based on age at diagnosis, sex, year of diagnosis, and tumor location. Outside surveillance, 5.8% of the patients had stage I cancer, as compared with 38.7% of surveillance patients with PDAC (odds ratio [OR], 0.09; 95% confidence interval [CI], 0.04-0.19). In total, 18.7% of non-surveillance patients vs 71.0% of surveillance patients underwent a surgical resection (OR, 10.62; 95% CI, 4.56-26.63). Patients in surveillance had a better prognosis, reflected by a 5-year survival of 32.4% and a median overall survival of 26.8 months vs 4.3% 5-year survival and 5.2 months median overall survival in non-surveillance patients (hazard ratio, 0.31; 95% CI 0.19-0.50). For all adjusted lead times, survival remained significantly longer in surveillance patients than in non-surveillance patients., Conclusion: Surveillance for PDAC in carriers of a CDKN2A/p16 pathogenic variant results in earlier detection, increased resectability, and improved survival as compared with non-surveillance patients with PDAC., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: CDKN2A-p16-Leiden mutation carriers have a high lifetime risk of developing pancreatic ductal adenocarcinoma (PDAC), with very poor survival. Surveillance may improve prognosis., Objective: To assess the cost-effectiveness of surveillance, as compared to no surveillance., Methods: In 2000, a surveillance program was initiated at Leiden University Medical Center with annual MRI and optional endoscopic ultrasound. Data were collected on the resection rate of screen-detected tumors and on survival. The Kaplan-Meier method and a parametric cure model were used to analyze and compare survival. Based on the surveillance and survival data from the screening program, a state-transition model was constructed to estimate lifelong outcomes., Results: A total of 347 mutation carriers participated in the surveillance program. PDAC was detected in 31 patients (8.9%) and the tumor could be resected in 22 patients (71.0%). Long-term cure among patients with resected PDAC was estimated at 47.1% (p < 0.001). The surveillance program was estimated to reduce mortality from PDAC by 12.1% and increase average life expectancy by 2.10 years. Lifelong costs increased by €13,900 per patient, with a cost-utility ratio of €14,000 per quality-adjusted life year gained. For annual surveillance to have an acceptable cost-effectiveness in other settings, lifetime PDAC risk needs to be 10% or higher., Conclusion: The tumor could be resected in most patients with a screen-detected PDAC. These patients had considerably better survival and as a result annual surveillance was found to be cost-effective., (© 2023 The Authors. United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

Purpose: Pancreatic cancer surveillance in high-risk individuals may lead to detection of pancreatic ductal adenocarcinoma (PDAC) at an earlier stage and with improved survival. This study evaluated the yield and outcomes of 20 years of prospective surveillance in a large cohort of individuals with germline pathogenic variants (PVs) in CDKN2A ., Methods: Prospectively collected data were analyzed from individuals participating in pancreatic cancer surveillance. Surveillance consisted of annual magnetic resonance imaging with magnetic resonance cholangiopancreatography and optional endoscopic ultrasound., Results: Three hundred forty-seven germline PV carriers participated in surveillance and were followed for a median of 5.6 (interquartile range 2.3-9.9) years. A total of 36 cases of PDAC were diagnosed in 31 (8.9%) patients at a median age of 60.4 (interquartile range 51.3-64.1) years. The cumulative incidence of primary PDAC was 20.7% by age 70 years. Five carriers (5 of 31; 16.1%) were diagnosed with a second primary PDAC. Thirty (83.3%) of 36 PDACs were considered resectable at the time of imaging. Twelve cases (12 of 36; 33.3%) presented with stage I disease. The median survival after diagnosis of primary PDAC was 26.8 months, and the 5-year survival rate was 32.4% (95% CI, 19.1 to 54.8). Individuals with primary PDAC who underwent resection (22 of 31; 71.0%) had an overall 5-year survival rate of 44.1% (95% CI, 27.2 to 71.3). Nine (2.6%; 9 of 347) individuals underwent surgery for a suspected malignant lesion, which proved to not be PDAC, and this included five lesions with low-grade dysplasia., Conclusion: This long-term surveillance study demonstrates a high incidence of PDAC in carriers of a PV in CDKN2A . This provides evidence that surveillance in such a high-risk population leads to detection of early-stage PDAC with improved resectability and survival.

Objective: The aim of this study was to evaluate the safety and efficacy of a modified CAL-WR., Summary Background Data: The use of segmental colectomy in patients with endoscopically unresectable colonic lesions results in significant morbidity and mortality. CAL-WR is an alternative procedure that may reduce morbidity., Methods: This prospective multicenter study was performed in 13 Dutch hospitals between January 2017 and December 2019. Inclusion criteria were (1) colonic lesions inaccessible using current endoscopic resection techniques (judged by an expert panel), (2) non-lifting residual/recurrent adenomatous tissue after previous polypectomy or (3) an undetermined resection margin after endoscopic removal of a low-risk pathological T1 (pT1) colon carcinoma. Thirty-day morbidity, technical success rate and radicality were evaluated., Results: Of the 118 patients included (56% male, mean age 66 years, standard deviation ± 8 years), 66 (56%) had complex lesions unsuitable for endoscopic removal, 34 (29%) had non-lifting residual/recurrent adenoma after previous polypectomy and 18 (15%) had uncertain resection margins after polypectomy of a pT1 colon carcinoma. CAL-WR was technically successful in 93% and R0 resection was achieved in 91% of patients. Minor complications (Clavien-Dindo i-ii) were noted in 7 patients (6%) and an additional oncologic segmental resection was performed in 12 cases (11%). Residual tissue at the scar was observed in 5% of patients during endoscopic follow-up., Conclusions: CAL-WR is an effective, organ-preserving approach that results in minor complications and circumvents the need for major surgery. CAL-WR, therefore, deserves consideration when endoscopic excision of circumscribed lesions is impossible or incomplete., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Surveillance of individuals at risk of developing pancreatic ductal adenocarcinoma (PDAC) has the potential to improve survival, yet early detection based on solely imaging modalities is challenging. We aimed to identify changes in serum glycosylation levels over time to earlier detect PDAC in high-risk individuals., Methods: Individuals with a hereditary predisposition to develop PDAC were followed in two surveillance programs. Those, of which at least two consecutive serum samples were available, were included. Mass spectrometry analysis was performed to determine the total N-glycome for each consecutive sample. Potentially discriminating N-glycans were selected based on our previous cross-sectional analysis and relative abundances were calculated for each glycosylation feature., Results: 165 individuals ("FPC-cohort" N = 119; Leiden cohort N = 46) were included. In total, 97 (59%) individuals had a genetic predisposition (77 CDKN2A, 15 BRCA1/2, 5 STK11) and 68 (41%) a family history of PDAC without a known genetic predisposition (>10-fold increased risk of developing PDAC). From each individual, a median number of 3 serum samples (IQR 3) was collected. Ten individuals (6%) developed PDAC during 35 months of follow-up; nine (90%) of these patients carried a CDKN2A germline mutation. In PDAC cases, compared to all controls, glycosylation characteristics were increased (fucosylation, tri- and tetra-antennary structures, specific sialic linkage types), others decreased (complex-type diantennary and bisected glycans). The largest change over time was observed for tri-antennary fucosylated glycans, which were able to differentiate cases from controls with a specificity of 92%, sensitivity of 49% and accuracy of 90%., Conclusion: Serum N-glycan monitoring may support early detection in a pancreas surveillance program., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Lynch syndrome is the most frequent hereditary colorectal cancer (CRC) syndrome, affecting approximately 1 in 300 in the Western population. It is caused by pathogenic variants in the mismatch repair (MMR) genes including MLH1, MSH2 (EPCAM), MSH6 and PMS2, and is associated with high risks of CRC, endometrial cancer and other cancers. In view of these risks, carriers of such variants are encouraged to participate in colonoscopic surveillance programs that are known to substantially improve their prognosis. In the last decade several important studies have been published that provide detailed cancer risk estimates and prognoses based on large numbers of patients. These studies also provided new insights regarding the pathways of carcinogenesis in CRC, which appear to differ depending on the specific MMR gene defect. In this report, we will discuss the implications of these new findings for the development of new surveillance protocols., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V. part of Springer Nature.)

Background: Lynch syndrome (LS), the most common inherited form of colorectal cancer (CRC), is responsible for 3% of all cases of CRC. LS is caused by a mismatch repair gene defect and is characterized by a high risk for CRC, endometrial cancer and several other cancers. Identification of LS is of utmost importance because colonoscopic surveillance substantially improves a patient's prognosis. Recently, a network of physicians in Middle Eastern and North African (ME/NA) countries was established to improve the identification and management of LS families. The aim of the present survey was to evaluate current healthcare for families with LS in this region., Methods: A questionnaire was developed that addressed the following issues: availability of clinical management guidelines for LS; attention paid to family history of cancer; availability of genetic services for identification and diagnosis of LS; and assessment of knowledge of LS surveillance. Members of the network and authors of recent papers on LS from ME/NA and neighbouring countries were invited to participate in the survey and complete the online questionnaire., Results: A total of 55 individuals were invited and 19 respondents from twelve countries including Algeria, Azerbaijan, Cyprus, Egypt, Iran, Jordan, Kuwait, Lebanon, Morocco, Palestine, Tunisia, and Turkey completed the questionnaire. The results showed that family history of CRC is considered in less than half of the surveyed countries. Guidelines for the management of LS are available in three out of twelve countries. The identification and selection of families for genetic testing were based on clinical criteria (Amsterdam criteria II or Revised Bethesda criteria) in most countries, and only one country performed universal screening. In most of the surveyed countries genetic services were available in few hospitals or only in a research setting. However, surveillance of LS families was offered in the majority of countries and most frequently consisted of regular colonoscopy., Conclusion: The identification and management of LS in ME/NA countries are suboptimal and as a result most LS families in the region remain undetected. Future efforts should focus on increasing awareness of LS amongst both the general population and doctors, and on the improvement of the infrastructure in these countries.

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&#95;MLH1 ) and MSH2 ( path&#95;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&#95;MSH2 .

Individuals with Lynch syndrome (LS), have an increased risk of developing cancer. Common genetic variants of telomerase reverse transcriptase (TERT) have been associated with a wide range of cancers, including colorectal cancer (CRC) in LS. We combined genotype data from 1881 LS patients, carrying pathogenic variants in MLH1, MSH2 or MSH6, for rs2075786 (G>A, intronic variant), 1207 LS patients for rs2736108 (C>T, upstream variant) and 1201 LS patients for rs7705526 (C>A, intronic variant). The risk of cancer was estimated by heterozygous/homozygous odds ratio (OR) with mixed-effects logistic regression to adjust for gene/gender/country of sample origin considering family identity. The AA genotype of SNP rs2075786 is associated with 85% higher odds at developing cancer compared to GG genotype in MSH2 pathogenic variant carriers (p = 0.0160). Kaplan-Meier analysis also shows an association for rs2075786; the AA allele for MSH2 variant carriers confers risk for earlier diagnosis of LS cancer (log-rank p = 0.0011). We report a polymorphism in TERT to be a possible modifier of disease risk in MSH2 pathogenic variant carriers. The rs2075786 SNP in TERT is associated with a differential risk of developing cancer for MSH2 pathogenic variant carriers. Use of this information has the potential to personalise screening protocols for LS patients.

Background: Pathogenic variants in the CDKN2A gene are generally associated with the development of melanoma and pancreatic ductal adenocarcinoma (PDAC), but specific genotype-phenotype correlations might exist and the extent of PDAC risk is not well established for many variants., Methods: Using the Dutch national familial melanoma database, we identified all families with a pathogenic CDKN2A variant and investigated the occurrence of PDAC within these families. We also estimated the standardised incidence ratio and lifetime PDAC risk for carriers of a highly prevalent variant in these families., Results: We identified 172 families in which 649 individuals carried 15 different pathogenic variants. The most prevalent variant was the founder mutation c.225&#95;243del (p16- Leiden , 484 proven carriers). Second most prevalent was c.67G>C (55 proven carriers). PDAC developed in 95 of 163 families (58%, including 373 of 629 proven carriers) harbouring a variant with an effect on the p16INK4a protein, whereas PDAC did not occur in the 9 families (20 proven carriers) with a variant affecting only p14ARF. In the c.67G>C families, PDAC occurred in 12 of the 251 (5%) persons at risk. The standardised incidence ratio was 19.1 (95% CI 8.3 to 33.6) and the cumulative PDAC incidence at age 75 years (lifetime risk) was 19% (95% CI 7.5% to 30.1%)., Conclusions: Our results support the notion that pathogenic CDKN2A variants affecting the p16INK4a protein, including c.67G>C, are associated with increased PDAC risk and carriers of such variants should be offered pancreatic cancer surveillance. There is no clinical evidence that impairment of only the p14ARF protein leads to an increased PDAC risk., Competing Interests: Competing interests: DLC is a consultant to Tramedico. MJB received research funding from Boston Scientific, Cook Medical, and Pentax Medical. He is a consultant to Boston Scientific, Cook Medical, Pentax Medical and Mylan. The other authors have no potential competing interests to disclose., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

A cancer diagnosis is suggested to be associated with changes in dietary and lifestyle habits. Whether this applies to persons with familial cancer, such as Lynch syndrome (LS) is unknown. We investigated whether a colorectal neoplasm (CRN) diagnosis in persons with LS is associated with changes in dietary and lifestyle habits over time. We used data of confirmed LS mutation carriers from the GEOLynch study, a prospective cohort study. Information on dietary intake and lifestyle habits was collected with a validated semi-quantitative food frequency questionnaire and a general questionnaire administered at baseline (2006-2008) and follow-up (2012-2017). Participants' medical records were used to identify CRN diagnoses. Changes in dietary and lifestyle habits in the CRN and the no-CRN group were compared using multivariable linear regression models for continuous variables and cross-tables with percentage change at follow-up compared with baseline for categorical variables. Of the 324 included participants, 146 developed a CRN (CRN group) between baseline and follow-up, while 178 did not (no-CRN group). Smoking cessation was more often reported in the CRN than in the no-CRN group (41.4% vs. 35.0%). There were no differences in changes of energy intake, alcohol, red meat, processed meat, dairy, fruit, vegetables and dietary fiber consumption, BMI, physical activity and NSAID use. Apart from a potentially higher likelihood of smoking cessation, we found little evidence that a CRN diagnosis is associated with changes in lifestyle habits in persons with LS.

Pancreatic ductal adenocarcinoma (PDAC) is known as a highly aggressive malignant disease. Prognosis for patients is notoriously poor, despite improvements in surgical techniques and new (neo)adjuvant chemotherapy regimens. Early detection of PDAC may increase the overall survival. It is furthermore foreseen that precision medicine will provide improved prognostic stratification and prediction of therapeutic response. In this review, omics-based discovery efforts are presented that aim for novel diagnostic and prognostic biomarkers of PDAC. For this purpose, we systematically evaluated the literature published between 1999 and 2020 with a focus on protein- and protein-glycosylation biomarkers in pancreatic cancer patients. Besides genomic and transcriptomic approaches, mass spectrometry (MS)-based proteomics and glycomics of blood- and tissue-derived samples from PDAC patients have yielded new candidates with biomarker potential. However, for reasons discussed in this review, the validation and clinical translation of these candidate markers has not been successful. Consequently, there has been a change of mindset from initial efforts to identify new unimarkers into the current hypothesis that a combination of biomarkers better suits a diagnostic or prognostic panel. With continuing development of current research methods and available techniques combined with careful study designs, new biomarkers could contribute to improved detection, prognosis, and prediction of pancreatic cancer.

People with Lynch syndrome (LS), who carry a pathogenic mutation in a DNA mismatch repair gene, have increased risks of colorectal cancer (CRC) and endometrial cancer (EC). A high reported variability in cancer risk suggests the existence of factors that modify cancer risk for persons with LS. We aimed to investigate the associations between height and CRC and EC risk for persons with LS using data from 2 large studies. Information on 1,115 men and 1,553 women with LS from the Colon Cancer Family Registry (1998-2007) and the GEOLynch Cohort Study (2006-2017) was harmonized. We used weighted Cox proportional hazards regression models with age on the time axis to estimate adjusted hazard ratios and 95% confidence intervals for each 5-cm increment in self-reported height. CRC was diagnosed in 947 persons during 65,369 person-years of observation, and 171 women were diagnosed with EC during 39,227 person-years. Height was not associated with CRC for either men (per 5-cm increment, hazard ratio (HR) = 1.00, 95% confidence interval (CI): 0.91, 1.11) or women (per 5-cm increment, HR = 1.01, 95% CI: 0.92, 1.11), nor was height associated with EC (per 5-cm increment, HR = 1.08, 95% CI: 0.94, 1.24). Hence, we observed no evidence for an association of height with either CRC or EC among persons with LS., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Persons with Lynch syndrome (LS) have an increased risk of developing colorectal tumors (CRTs). Adherence to diet quality indices associated with colorectal cancer (CRC) risk in the general population has not been studied before in LS., Methods: Dietary habits of 490 participants with LS from a prospective cohort study was collected using a food frequency questionnaire. The Dutch Healthy Diet index 2015 (DHD15-index) and Dietary Approaches to Stop Hypertension (DASH) were used to score food-based diet quality. Diet quality scores were divided into tertiles where a higher tertile reflects a higher diet quality. Multivariable Cox proportional hazard regression models were used to estimate the association between the DHD15-index, DASH score and CRT risk., Results: During a median follow-up time of 53.4 months, 210 participants (42.9%) developed CRTs. The DHD-index and DASH score were not associated with CRT risk; hazard ratios for highest vs. lowest tertile were 1.00 (95% Confidence Interval (CI): 0.67-1.48) and 1.11 (95% CI: 0.74-1.69), respectively. No linear trends across the DHD-index and DASH score tertiles were observed (P-trend = 0.97 and 0.83 respectively)., Conclusion: In contrast to observations in the general population, no evidence for an association between the food-based DHD15-index or DASH score and CRT risk was observed in persons with LS. Further studies are needed investigating the association between diet quality and mechanisms leading to the development of LS-associated tumors., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In the recent years two innovative approaches have become available for minimally invasive en bloc resections of large non-pedunculated rectal lesions (polyps and early cancers). One is Transanal Minimally Invasive Surgery (TAMIS), the other is Endoscopic Submucosal Dissection (ESD). Both techniques are standard of care, but a direct randomised comparison is lacking. The choice between either of these procedures is dependent on local expertise or availability rather than evidence-based. The European Society for Endoscopy has recommended that a comparison between ESD and local surgical resection is needed to guide decision making for the optimal approach for the removal of large rectal lesions in Western countries. The aim of this study is to directly compare both procedures in a randomised setting with regard to effectiveness, safety and perceived patient burden., Methods: Multicenter randomised trial in 15 hospitals in the Netherlands. Patients with non-pedunculated lesions > 2 cm, where the bulk of the lesion is below 15 cm from the anal verge, will be randomised between either a TAMIS or an ESD procedure. Lesions judged to be deeply invasive by an expert panel will be excluded. The primary endpoint is the cumulative local recurrence rate at follow-up rectoscopy at 12 months. Secondary endpoints are: 1) Radical (R0-) resection rate; 2) Perceived burden and quality of life; 3) Cost effectiveness at 12 months; 4) Surgical referral rate at 12 months; 5) Complication rate; 6) Local recurrence rate at 6 months. For this non-inferiority trial, the total sample size of 198 is based on an expected local recurrence rate of 3% in the ESD group, 6% in the TAMIS group and considering a difference of less than 6% to be non-inferior., Discussion: This is the first European randomised controlled trial comparing the effectiveness and safety of TAMIS and ESD for the en bloc resection of large non-pedunculated rectal lesions. This is important as the detection rate of these adenomas is expected to further increase with the introduction of colorectal screening programs throughout Europe. This study will therefore support an optimal use of healthcare resources in the future., Trial Registration: Netherlands Trial Register, NL7083 , 06 July 2018.

Objective: This study aimed to assess psychological functioning, quality of life, and regret about screening after a positive fecal immunochemical test (FIT) and subsequent colonoscopy, and to evaluate changes over time., Methods: This is a prospective cohort study. Individuals aged 55 to 75 with a positive FIT that were referred for colonoscopy between July 2017 and November 2018, were invited to complete questionnaires related to psychological distress and health-related quality of life at three predefined time points: before colonoscopy, after histopathology result notification, and after 6 months. Four questionnaires were used: the Psychological Consequences Questionnaire (PCQ), the six-item Cancer Worry Scale (CWS), the Decision Regret Scale (DRS), and the 36-item Short-Form (SF-36)., Results: A total of 1066 participants out of 2151 eligible individuals were included. Patients with cancer showed a significant increase in psychological dysfunction (P = .01) and cancer worry (P = .008) after colonoscopy result notification, and a decline to pre-colonoscopy measurements after 6 months. In the no-cancer groups, psychological dysfunction and cancer worry significantly decreased over time (P < .05) but there was no ongoing decline. After 6 months, 17% of participants with no cancer experienced high level of cancer worry (CWS ≥ 10). Yet, only 5% reported high level of regret about screening participation (DRS > 25). A good global quality of life was reported in participants with no cancer., Conclusion: Some psychological distress remains up to 6 months after colonoscopy in participants who tested false-positive in the Dutch bowel cancer screening program., (© 2020 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd.)

Barrett's oesophagus (BE) has been associated with an increased risk of both colorectal adenomas and colorectal cancer. A recent investigation reported a high frequency of BE in patients with adenomatous polyposis coli (APC)-associated polyposis (FAP). The aim of the present study is to evaluate the prevalence of BE in a large cohort of patients with MUTYH-associated polyposis (MAP) and APC-associated adenomatous polyposis. Patients with a genetically confirmed diagnosis of familial adenomatous polyposis (FAP) or MAP were selected and upper gastrointestinal (GI) endoscopy reports, pathology reports of upper GI biopsies were reviewed to determine the prevalence of BE in these patients. Histologically confirmed BE was found in 7 (9.7%) of 72 patients with MAP. The mean age of diagnosis was 60.2 years (range 54.1-72.4 years). Two patients initially diagnosed with low grade dysplasia showed fast progression into high grade dysplasia and esophageal cancer, respectively. Only 4 (1.4%) of 365 patients with FAP were found to have pathologically confirmed BE. The prevalence of BE in patients with MAP is much higher than reported in the general population. We recommend that upper GI surveillance of patients with MAP should not only focus on the detection of gastric and duodenal adenomas but also on the presence of BE.

This study aimed to determine the prevalence of APC-associated familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) in a large cohort, taking into account factors as adenoma count and year of diagnosis. All application forms used to send patients in for APC and MUTYH variant analysis between 1992 and 2017 were collected (n = 2082). Using the data provided on the application form, the APC and biallelic MUTYH prevalence was determined and possible predictive factors were examined using multivariate multinomial logistic regression analysis in SPSS. The prevalence of disease causing variants in the APC gene significantly increases with adenoma count while MAP shows a peak prevalence in individuals with 50-99 adenomas. Logistic regression analysis shows significant odds ratios for adenoma count, age at diagnosis, and, interestingly, a decline in the chance of finding a variant in either gene over time. Moreover, in 22% (43/200) of patients with FAP-related extracolonic manifestations a variant was identified. The overall detection rates are above 10% for patients with >10 adenomas aged <60 and >20 adenomas aged <70. Patients with variants outside these criteria had FAP-related extracolonic manifestations, colorectal cancer aged <40, somatic KRAS c.34G > T variant in the tumor or a first-degree relative with >10 adenomas. Therefore, APC and MUTYH testing in patients with >10 adenomas aged <60 and with >20 adenomas aged <70 is advised. Almost all FAP and MAP patients not meeting these criteria showed other characteristics that can be used as an indication to prompt genetic testing.

Background and Aim: The International Cancer of the Pancreas Screening Consortium met in 2018 to update its consensus recommendations for the management of individuals with increased risk of pancreatic cancer based on family history or germline mutation status (high-risk individuals)., Methods: A modified Delphi approach was employed to reach consensus among a multidisciplinary group of experts who voted on consensus statements. Consensus was considered reached if ≥75% agreed or disagreed., Results: Consensus was reached on 55 statements. The main goals of surveillance (to identify high-grade dysplastic precursor lesions and T1N0M0 pancreatic cancer) remained unchanged. Experts agreed that for those with familial risk, surveillance should start no earlier than age 50 or 10 years earlier than the youngest relative with pancreatic cancer, but were split on whether to start at age 50 or 55. Germline ATM mutation carriers with one affected first-degree relative are now considered eligible for surveillance. Experts agreed that preferred surveillance tests are endoscopic ultrasound and MRI/magnetic retrograde cholangiopancreatography, but no consensus was reached on how to alternate these modalities. Annual surveillance is recommended in the absence of concerning lesions. Main areas of disagreement included if and how surveillance should be performed for hereditary pancreatitis, and the management of indeterminate lesions., Conclusions: Pancreatic surveillance is recommended for selected high-risk individuals to detect early pancreatic cancer and its high-grade precursors, but should be performed in a research setting by multidisciplinary teams in centres with appropriate expertise. Until more evidence supporting these recommendations is available, the benefits, risks and costs of surveillance of pancreatic surveillance need additional evaluation., Competing Interests: Competing interests: The authors disclose the following: JEvH received research funding from Abbott and Cook Medical; she is a consultant to Boston Scientific, Cook Medical, and Medtronics. DLC is a consultant to Tramedico. MB received research funding from Boston Scientific, Cook Medical, Pentax Medical, 3M; he is a consultant to Boston Scientific, Cook Medical, Pentax Medical, Mylan, MediRisk, and Medicom. PF is a consultant to Olympus, Cook Medical, Ethicon Endosurgery and received research funding from Boston Scientific. RB has received research funding from Immunovia and Freenome. MIC received research funding from Pentax C2 Cryoballoon and Endogastric Solutions. DS received research funding from Immunovia, Sanofi and Tempus; she is on the Scientific Advisory Board for Nybo Therapeutics, Interpace and Tyme., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: MRI surveillance in a cohort of CDKN2A-p16-Leiden mutation carriers with a 20% lifetime risk of PDAC led to increased resection rates and improved survival. Patients with screen-detected PDAC were evaluated for main pancreatic duct (MPD) abnormalities in this retrospective review., Methods: Since 2000 annual MRI and optional EUS was performed in mutation carriers. Data of patients with screen-detected PDAC was collected on gender, age at diagnosis, site of tumor, size, outcome of surgery, pathology findings and survival. All MRIs were re-evaluated for MPD abnormalities., Results: 23 PDAC were detected in 22 (10%) of 217 mutation carriers, 10 (45%) males and 12 (55%) females. The mean age at diagnosis was 59.8 years (range 39.2-74.3 years). Revision of the MRI/MRCP revealed a lesion and dilatation of the MPD in 8 of the 22 patients. In 5 of 7 patients with PDAC detected during follow-up, the previous MRI showed MPD dilatation without evidence of tumor. The mean size of PDAC was 12.3 mm (range 5-19 mm). All tumors were resectable., Conclusion: MPD dilation is common in patients with screen-detected PDAC. Abnormalities on MRI during surveillance of high-risk individuals requires intense follow-up or prompt treatment, as early treatment results in a better prognosis., (Copyright © 2019 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)