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Background and Aims Identification and resection of successful targets, i.e., T1 N0M0 pancreatic ductal adenocarcinoma (PDAC) and high-grade precursors during surveillance of high-risk individuals (HRIs) confers improved survival. Late-stage PDACs refer to T2-4 N0M0 and nodal or distant metastatic PDAC stages diagnosed during the follow-up phase of HRI surveillance. This study aimed to quantify late-stage PDACs during HRI surveillance and identify associated clinicoradiologic factors. Methods A systematic search (PROSPERO:CRD42018117189) from Cochrane Library, Embase, Google Scholar, Medline, PubMed, Scopus, and Web of Science was last performed on April 18, 2021. Only original HRI surveillance manuscripts which specified follow-up strategies were included, while studies with only baseline information were excluded. Cumulative incidences of advanced neoplasia: high-grade precursors and all PDACs, and surveillance-detected/interval late-stage PDACs were calculated through random-effects model. Incidence of late-stage PDACs underwent metaregression to identify association with HRI clinicoradiologic features. Publication bias was assessed through the Funnel plot and Egger’s Regression line. Results Thirteen original surveillance studies included 2169 HRIs followed over 7302.72 patient-years. Cumulative incidence of advanced neoplasia and late-stage PDACs was 3.3 [95% CI:0.6-7.4] and 1.7 [95% CI:0.2-4.0] per 1000 patient-years, respectively. Late-stage PDACs lacked significant association with surveillance imaging, baseline pancreatic morphology, study location, genetic background, gender, or age. Limited information on diagnostic error, symptoms, timing of presentation, lesion site, and surveillance adherence precluded formal meta-analysis. Conclusion A sizable proportion of late-stage PDACs were detected during follow-up. Their incidence lacked association with baseline clinicoradiologic features. Further causal investigation of stage-based outcomes is warranted for overall improvement in HRI surveillance.

Supplementary Table 1 shows number of TAP cases per site

Prior small reports have postulated a link between gastrointestinal polyposis and childhood and young adulthood cancer (CYAC) treatment (therapy-associated polyposis; TAP), but this remains a poorly understood phenomenon. The aim of this study was to describe the phenotypic spectrum of TAP in a multi-institutional cohort. TAP cases were identified from eight high-risk cancer centers. Cases were defined as patients with ≥10 gastrointestinal polyps without known causative germline alteration or hereditary colorectal cancer predisposition syndrome who had a history of prior treatment with chemotherapy and/or radiotherapy for CYAC. A total of 34 TAP cases were included (original CYAC: 27 Hodgkin lymphoma, three neuroblastoma, one acute myeloid leukemia, one medulloblastoma, one nephroblastoma, and one non-Hodgkin lymphoma). Gastrointestinal polyposis was first detected at a median of 27 years (interquartile range, 20–33) after CYAC treatment. A total of 12 of 34 (35%) TAP cases had ≥50 colorectal polyps. A total of 32 of 34 (94%) had >1 histologic polyp type. A total of 25 of 34 (74%) had clinical features suggestive of ≥1 colorectal cancer predisposition syndrome [e.g., attenuated familial adenomatous polyposis (FAP), serrated polyposis syndrome, extracolonic manifestations of FAP, mismatch repair–deficient colorectal cancer, or hamartomatous polyposis] including 8 of 34 (24%) with features of multiple such syndromes. TAP is an apparently acquired phenomenon that should be considered in patients who develop significant polyposis without known causative germline alteration but who have had prior treatment for a CYAC. Patients with TAP have features that may mimic various hereditary colorectal cancer syndromes, suggesting multiple concurrent biologic mechanisms, and recognition of this diagnosis may have implications for cancer risk and screening.

Supplementary Table 3 shows types of surgical resection

Supplementary Table 2 shows individual case-level data (clinical history, genetic testing, secondary cancers)

BACKGROUND: COVID-19 pandemic-related disruptions to EUS-based pancreatic cancer surveillance in high-risk individuals remain uncertain. METHODS: Analysis of enrolled participants in the CAPS5 Study, a prospective multicenter study of pancreatic cancer surveillance in high-risk individuals. RESULTS: Amongst 693 enrolled high-risk individuals under active surveillance, 108 (16%) had an EUS scheduled during the COVID-19 pandemic-related shutdown (median length of 78 days) in the spring of 2020, with 97% of these procedures being canceled. Of these canceled surveillance EUSs, 83% were rescheduled in a median of 4.1 months, however 17% were not rescheduled after 6 months follow-up. Prior history of cancer was associated with increased likelihood of rescheduling. To date no pancreatic cancer has been diagnosed among those whose surveillance was delayed. CONCLUSIONS: COVID-19 delayed pancreatic cancer surveillance with no adverse outcomes in efficiently rescheduled individuals. However, 1 in 6 high-risk individuals had not rescheduled surveillance, indicating the need for vigilance to ensure timely surveillance rescheduling.

Approximately 10% of patients with gastric cancer show familial aggregation and up to 3% are related to an inherited cancer syndrome. There are multiple germline pathogenic variants and cancer syndromes associated with an increased risk of gastric cancer. Appropriate assessment of familial and genetic risk may allow a personalized approach to gastric cancer prevention through screening and risk-reducing surgeries. The ability to better identify carriers with pathogenic genetic variants associated with gastric cancer before a diagnosis of cancer requires effective genetic risk assessment and testing, followed by optimal screening and surveillance recommendations to further reduce the morbidity and mortality.

Objectives Data from the International Cancer of the Pancreas Screening Consortium studies have demonstrated that screening for pancreatic ductal adenocarcinoma can be effective and that surveillance improves survival in high-risk individuals. Endoscopic ultrasound (EUS) and cross-sectional imaging are both used, although there is some suggestion that EUS is superior. Demonstration of the cost-effectiveness of screening is important to implement screening in high-risk groups. Methods Results from centers with EUS-predominant screening were pooled to evaluate efficacy of index EUS in screening. A decision analysis model simulated the outcome of high-risk patients who undergo screening and evaluated the parameters that would make screening cost-effective at a US $100,000 per quality-adjusted life-year willingness to pay. Results One-time index EUS has a sensitivity of 71.25% and specificity of 99.82% to detection to detect high-risk lesions. Screening with index EUS was cost-effective, particularly at lifetime pancreatic cancer probabilities of greater than 10.8%, or at lower probabilities if life expectancy after resection of a lesion that was at least 16 years, and if missed, lesion rates on index EUS are 5% or less. Conclusions Pancreatic cancer screening can be cost-effective through index EUS, particularly for those individuals at high-lifetime risk of cancer.

Germline mutation of CDH1 is rare and leads to hereditary diffuse gastric cancer (DGC).Patients (pts) with CDH1 mutation who underwent multidisciplinary counseling followed by open prophylactic total gastrectomy (PTG) by a single surgeon were reviewed.Fifty-four pts with a median age of 41 years (16-70 years) underwent PTG between 2006 and 2021. Median operative time was 161 min, and median hospital stay was 7 days (range 6-12). There were 5 complications (9.2%) within 30 days, and two complications (pulmonary embolism and pancreatitis) required readmission. There were no anastomotic leaks. The pathologic analysis of the first 10 pts included the entire gastric mucosa, revealing a median of 15 foci of DGC (range 5-136). The subsequent 44 pts with more limited analysis had a median of 2 foci (range 0-5), and two pts (3.7%) had no foci identified. Median maximum weight loss was 19%. In long-term follow-up (median 4.6 years) of 20 pts, median global QOL was 2.0 (very good), the majority had persistent difficulty with certain foods or liquids, and all stated they would again elect PTG over surveillance endoscopy.PTG can be performed safely at high-volume referral centers with very good QOL but nutritional sequelae persist.

PURPOSE To report pancreas surveillance outcomes of high-risk individuals within the multicenter Cancer of Pancreas Screening-5 (CAPS5) study and to update outcomes of patients enrolled in prior CAPS studies. METHODS Individuals recommended for pancreas surveillance were prospectively enrolled into one of eight CAPS5 study centers between 2014 and 2021. The primary end point was the stage distribution of pancreatic ductal adenocarcinoma (PDAC) detected (stage I v higher-stage). Overall survival was determined using the Kaplan-Meier method. RESULTS Of 1,461 high-risk individuals enrolled into CAPS5, 48.5% had a pathogenic variant in a PDAC-susceptibility gene. Ten patients were diagnosed with PDAC, one of whom was diagnosed with metastatic PDAC 4 years after dropping out of surveillance. Of the remaining nine, seven (77.8%) had a stage I PDAC (by surgical pathology) detected during surveillance; one had stage II, and one had stage III disease. Seven of these nine patients with PDAC were alive after a median follow-up of 2.6 years. Eight additional patients underwent surgical resection for worrisome lesions; three had high-grade and five had low-grade dysplasia in their resected specimens. In the entire CAPS cohort (CAPS1-5 studies, 1,731 patients), 26 PDAC cases have been diagnosed, 19 within surveillance, 57.9% of whom had stage I and 5.2% had stage IV disease. By contrast, six of the seven PDACs (85.7%) detected outside surveillance were stage IV. Five-year survival to date of the patients with a screen-detected PDAC is 73.3%, and median overall survival is 9.8 years, compared with 1.5 years for patients diagnosed with PDAC outside surveillance (hazard ratio [95% CI]; 0.13 [0.03 to 0.50], P = .003). CONCLUSION Most pancreatic cancers diagnosed within the CAPS high-risk cohort in the recent years have had stage I disease with long-term survival.

Background 16–25% of colorectal cancers (CRCs) diagnosed under age 50 are associated with hereditary cancer syndromes. Advanced adenomas are considered precursors to CRC. Although polyp removal prevents cancer, polypectomy does not change underlying genetic risk. Patients with isolated advanced polyps do not currently qualify for genetic testing unless they have a personal or family history of cancer. Aim Describe the prevalence of hereditary cancer syndromes among patients with advanced colorectal polyps. Methods We performed a single center retrospective review from 2015 to 2019 of patients who underwent germline genetic testing with indication for testing listed as colorectal polyp. We excluded patients with a personal history of CRC and those with ≥10 cumulative polyps. We collected patient demographics, polyp characteristics, family history data and genetic testing results from the medical record. Discrete variables were reported as frequency and percentages and continuous variables reported as mean with range. Results A total of 42 patients underwent genetic testing due to a personal history of advanced adenoma. 17% of patients met current genetic testing criteria. All patients underwent multi-gene panel testing. Two patients (4.8%) had a germline pathogenic mutation (one in MLH1 and one in CHEK2). The patient with an MLH1 mutation met current criteria for genetic testing (PREMM5 score 5.8), however the patient with the CHEK2 mutation did not. Both mutation carriers had a personal history of synchronous or metachronous advanced adenomas. 38% had a variant of uncertain significance. Conclusions 5% of patients with advanced adenomas in our retrospective series had a pathogenic germline mutation in a cancer predisposition gene. Though the patient with a pathogenic mutation in MLH1 met current clinical criteria for genetic testing, this was not recognized prior to referral; he was referred based on a personal history of advanced adenoma. Advanced polyps may be a red flag to identify patients who are at risk for hereditary cancer syndromes.

BACKGROUND The incidence and mortality of colorectal cancer (CRC) are increasing in adults under 50 years. Risk factors associated with early-onset colorectal neoplasia (CRN) are uncertain. We aimed to identify clinical predictors associated with the presence of CRN detected by diagnostic colonoscopy in symptomatic individuals under 50 years of age. METHODS We used a single-center endoscopy database to identify symptomatic patients 18-49 years of age who underwent ambulatory colonoscopy between 2007 and 2017. Pathology reports identified CRN as adenomas, advanced adenomas (based on size or histology), or adenocarcinomas. Multivariable analysis was used to determine factors associated with CRN. RESULTS We identified 4333 eligible patients of whom 363 (8.4%) had any CRN and 48 (1.1%) had advanced neoplasia (advanced adenoma or adenocarcinoma). Factors associated with any CRN on multivariable analysis included male sex [odds ratio (OR) 1.50 (1.19-1.88)], older age group [compared to 18-29 years, OR for 30-39: 3.12 (1.93-5.04); OR for 40-49: 4.68 (2.97-7.36)], obesity [OR for BMI 30-34.9 compared to 18-24.9: 1.44 (1.04-2.01)], and any tobacco use [OR 1.63 (1.18-2.23)]. Anemia was associated with advanced neoplasia [OR 3.11 (1.32-7.34)]. Of the advanced neoplastic lesions, 38 of 48 (79.2%) were located in the distal colon. CONCLUSIONS In the largest study to date of symptomatic individuals under 50 years of age undergoing colonoscopy in the USA, advanced CRN was most often detected in the distal colon and was associated with anemia, but not with abnormal bowel habits or abdominal pain. We also found that patients with CRN under 50 years of age were more likely to be male, smokers, and obese. These findings should prompt further investigation of these risk factors alone and in combination.

Pancreatic cancer (PC) is a highly lethal cancer and projected to be the second leading cause of cancer death by 2030. Multigene panel testing has facilitated the identification of germline variants associated with an increased risk of PC. Precision treatment has led to improved outcomes for patients with these findings. Because of these improved outcomes as well as the implications for at-risk family members who may benefit from additional cancer screening, the NCCN recommends universal genetic testing for newly diagnosed PC patients. This review describes the most common heritable conditions associated with PC and those who may benefit from screening.

Purpose: Emerging evidence implicates the microbiome in the development of pancreatic cancer. We investigated whether increased levels of microbial-related metabolites in circulation are associated with pancreatic cancer risk. Methods: We applied metabolomics profiling to sera from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cohort to quantify and build a model based on 14 microbial-related metabolites. The study involved samples collected from 172 subjects within five years prior to diagnosis and 863 matched controls. Data from five PLCO centers were used for training and from two centers for validation and model selection. The model was subsequently tested using samples from three independent centers. The contributions of non-microbial-associated metabolites as well as CA19-9 was also assessed. Results: A 3-marker microbial-related metabolite panel yielded in the PLCO testing set an AUC of 0.64 (95% CI: 0.53-0.76) for 5-year probability of pancreatic cancer. Five additional non-microbial metabolites were identified that when combined with the microbiome panel yielded an AUC of 0.79 (95% CI: 0.71-0.88) for 5-year probability of pancreatic cancer in the PLCO testing set. The combined metabolite panel and CA19-9 yielded an AUC of 0.86 (95% CI: 0.77-0.95) for 2-year probability of pancreatic cancer in the PLCO testing set, which was improved compared to CA19-9 alone (AUC: 0.70 (95% CI: 0.57-0.82), p< 0.001). Conclusion: We developed a metabolite panel derived in part from the microbiome for risk assessment of pancreatic cancer, which has relevance to prevention and early detection. Citation Format: Johannes F. Fahrmann, Ehsan Irajizad, Ana Kenney, Tiffany Tang, Jody Vykoukal, Ranran Wu, Jennifer B. Dennison, Marta Sans Escofet, James P. Long, Maureen Loftus, John A. Chabot, Michael D. Kluger, Fay Kastrinos, Lauren Brais, Ana Babic, Kunal Jajoo, Linda S. Lee, Thomas E. Clancy, Kimmie Ng, Andrea Bullock, Jeanine M. Genkinger, Anirban Maitra, Kim-Anh Do, Bin Yu, Brian M. Wolpin, Samir Hanash. Contribution of the microbiome to a metabolomic signature predictive of risk for pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P076.

The 2020 National Comprehensive Cancer Network guidelines recommend neoadjuvant FOLFIRINOX or neoadjuvant gemcitabine plus nab-paclitaxel (G-nP) for borderline resectable/locally advanced pancreatic ductal adenocarcinoma (BR/LA PDAC).The purpose of our study was to compare treatment outcomes, toxicity profiles, costs, and quality-of-life measures between these two treatments to further inform clinical decision-making.We developed a decision-analytic mathematical model to compare the total cost and health outcomes of neoadjuvant FOLFIRINOX against G-nP over 12 years. The model inputs were estimated using clinical trial data and published literature. The primary endpoint was incremental cost-effectiveness ratios (ICERs) with a willingness-to-pay threshold of $100 000 per quality-adjusted-life-year (QALY). Secondary endpoints included overall (OS) and progression-free survival (PFS), total cost of care, QALYs, PDAC resection rate, and monthly treatment-related adverse events (TRAE) costs (USD). FOLFIRINOX was the cost-effective strategy, with an ICER of $60856.47 per QALY when compared to G-nP. G-nP had an ICER of $44639.71 per QALY when compared to natural history. For clinical outcomes, more patients underwent an "R0" resection with FOLFIRINOX compared to G-nP (84.9 vs. 81.0%), but FOLFIRINOX had higher TRAE costs than G-nP ($10905.19 vs. $4894.11). A one-way sensitivity analysis found that the ICER of FOLFIRINOX exceeded the threshold when TRAE costs were higher or PDAC recurrence rates were lower.Our modeling analysis suggests that FOLFIRNOX is the cost-effective treatment compared to G-nP for BR/LA PDAC despite having a higher cost of total care due to TRAE costs. Trial data with sufficient follow-up are needed to confirm our findings.

Approximately 35% of patients with colorectal cancer (CRC) have a family history of the disease attributed to genetic factors, common exposures, or both. Some families with a history of CRC carry genetic variants that cause CRC with high or moderate penetrance, but these account for only 5% to 10% of CRC cases. Most families with a history of CRC and/or adenomas do not carry genetic variants associated with cancer syndromes; this is called common familial CRC. Our understanding of familial predisposition to CRC and cancer syndromes has increased rapidly due to advances in next-generation sequencing technologies. As a result, there has been a shift from genetic testing for specific inherited cancer syndromes based on clinical criteria alone, to simultaneous testing of multiple genes for cancer-associated variants. We summarize current knowledge of common familial CRC, provide an update on syndromes associated with CRC (including the nonpolyposis and polyposis types), and review current recommendations for CRC screening and surveillance. We also provide an approach to genetic evaluation and testing in clinical practice. Determination of CRC risk based on family cancer history and results of genetic testing can provide a personalized approach to cancer screening and prevention, with optimal use of colonoscopy to effectively decrease CRC incidence and mortality.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive gastrointestinal malignancy with a poor 5-year survival rate. Its high mortality rate is attributed to its aggressive biology and frequently late presentation. While surgical resection remains the only potentially curative treatment, only 10-20% of patients will present with surgically resectable disease. Over the past several years, development of vascular bypass graft techniques and introduction of neoadjuvant treatment regimens have increased the number of patients who can undergo resection with a curative intent. While the role of conventional imaging in the detection, characterization, and staging of patients with PDAC is well established, its role in monitoring treatment response, particularly following neoadjuvant therapy remains challenging because of the complex anatomic and histological nature of PDAC. Novel morphologic and functional imaging techniques (such as DECT, DW-MRI, and PET/MRI) are being investigated to improve the diagnostic accuracy and the ability to measure response to therapy. There is also a growing interest to detect PDAC and its precursor lesions at an early stage in asymptomatic patients to increase the likelihood of achieving cure. This has led to the development of pancreatic cancer screening programs. This article will review recent updates in imaging techniques and the current status of screening and surveillance of individuals at a high risk of developing PDAC.

Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (p 0 center dot 0001 for each of the three three continents). These familial risk factors resulted in a wide within-gene variation in the risk of colorectal cancer for men and women from each continent who all carried pathogenic variants in the same gene or the MSH2 c.942+3A T variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and onlyBackground Existing clinical practice guidelines for carriers of pathogenic variants of DNA mismatch repair genes (Lynch syndrome) are based on the mean age-specific cumulative risk (penetrance) of colorectal cancer for all carriers of pathogenic variants in the same gene. We aimed to estimate the variation in the penetrance of colorectal cancer between carriers of pathogenic variants in the same gene by sex and continent of residence. Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero. Findings 5585 families with Lynch syndrome from 22 countries were eligible for the analysis. Of these, there were insufficient numbers to estimate penetrance for Asia and South America, and for those with EPCAM variants. Therefore, we used data (collected between July 11, 2014, and Dec 31, 2018) from 5255 families (1829 MLH1, 2179 MSH2, 798 MSH6, and 449 PMS2), comprising 79 809 relatives, recruited in 15 countries in North America, Europe, and Australasia. There was strong evidence of the existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers (pT variant. The variation was especially prominent for MLH1 and MSH2 variant carriers, depending on gene, sex and continent, with 7-56% of carriers having a colorectal cancer penetrance of less than 20%, 9-44% having a penetrance of more than 80%, and only 10-19% having a penetrance of 40-60%. Interpretation Our study findings highlight the important role of risk modifiers, which could lead to personalised risk assessments for precision prevention and early detection of colorectal cancer for people with Lynch syndrome. Funding National Health and Medical Research Council, Australia. Copyright (c) 2021 Elsevier Ltd. All rights reserved.Methods In this retrospective cohort study, we sourced data from the International Mismatch Repair Consortium, which comprises 273 members from 122 research centres or clinics in 32 countries from six continents who are involved in Lynch syndrome research. Families with at least three members and at least one confirmed carrier of a pathogenic or likely pathogenic variant in a DNA mismatch repair gene (MLH1, MSH2, MSH6, or PMS2) were included. The families of probands with known de-novo pathogenic variants were excluded. Data were collected on the method of ascertainment of the family, sex, carrier status, cancer diagnoses, and ages at the time of pedigree collection and at last contact or death. We used a segregation analysis conditioned on ascertainment to estimate the mean penetrance of colorectal cancer and modelled unmeasured polygenic factors to estimate the variation in penetrance. The existence of unknown familial risk factors modifying colorectal cancer risk for Lynch syndrome carriers was tested by use of a Wald p value for the null hypothesis that the polygenic SD is zero.

Background and Aims Pancreatic ductal adenocarcinoma is an aggressive disease most often diagnosed after local progression or metastatic dissemination, precluding resection and resulting in a high mortality rate. For individuals with elevated personal risk of the development of pancreatic cancer, EUS is a frequently used advanced imaging and diagnostic modality. However, there is variability in the expertise and definition of EUS findings among gastroenterologists, as well as lack of standardized reporting of relevant findings at the time of examination. Adoption of standardized EUS reporting, using a universally accepted and agreed upon terminology, is needed. Methods A consensus statement designed to create a standardized reporting template was authored by a multidisciplinary group of experts in pancreatic diseases that includes gastroenterologists, radiologists, surgeons, oncologists, and geneticists. This statement was developed using a modified Delphi process as part of the Pancreatic Cancer Early Detection Consortium (PRECEDE) and >75% agreement was required to reach consensus. Results We identified reporting elements and present standardized reporting templates for EUS indications, procedural data, EUS image capture, and descriptors of findings, tissue sampling, and for postprocedural assessment of adequacy. Conclusions Adoption of this standardized EUS reporting template should improve consistency in clinical decision making for individuals with elevated risk of pancreatic cancer by providing complete and accurate reporting of pancreatic abnormalities. Standardization will also help to facilitate research and clinical trial design by using clearly defined and consistent imaging descriptions, thus allowing for comparison of results across different centers.

Caldwell and colleagues ([1][1]) highlight several challenges associated with employing a pancreatic cancer screening test. Several questionable assumptions in their study, especially regarding individuals at high risk of pancreatic cancer, limit their conclusions. First, patients with a positive

Background & Aims There is substantial interest in liquid biopsy approaches for cancer early detection among subjects at risk, using multi-marker panels. CA19-9 is an established circulating biomarker for pancreatic cancer; however, its relevance for pancreatic cancer early detection or for monitoring subjects at risk has not been established. Methods CA19-9 levels were assessed in blinded sera from 175 subjects collected up to 5 years before diagnosis of pancreatic cancer and from 875 matched controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. For comparison of performance, CA19-9 was assayed in blinded independent sets of samples collected at diagnosis from 129 subjects with resectable pancreatic cancer and 275 controls (100 healthy subjects; 50 with chronic pancreatitis; and 125 with noncancerous pancreatic cysts). The complementary value of 2 additional protein markers, TIMP1 and LRG1, was determined. Results In the PLCO cohort, levels of CA19-9 increased exponentially starting at 2 years before diagnosis with sensitivities reaching 60% at 99% specificity within 0 to 6 months before diagnosis for all cases and 50% at 99% specificity for cases diagnosed with early-stage disease. Performance was comparable for distinguishing newly diagnosed cases with resectable pancreatic cancer from healthy controls (64% sensitivity at 99% specificity). Comparison of resectable pancreatic cancer cases to subjects with chronic pancreatitis yielded 46% sensitivity at 99% specificity and for subjects with noncancerous cysts, 30% sensitivity at 99% specificity. For prediagnostic cases below cutoff value for CA19-9, the combination with LRG1 and TIMP1 yielded an increment of 13.2% in sensitivity at 99% specificity (P = .031) in identifying cases diagnosed within 1 year of blood collection. Conclusion CA19-9 can serve as an anchor marker for pancreatic cancer early detection applications.

BACKGROUND: Germline variants in the APC and MUTYH genes contribute to colorectal cancer (CRC) and adenoma risk, though may occur with varying frequencies in individuals of different ancestries. The aim of this study was to evaluate the prevalence of APC, monoallelic MUTYH and biallelic MUTYH germline variants in Ashkenazi Jewish (AJ) and Other Ancestry (OA) individuals with colorectal adenomas. METHODS: We studied 7,225 individuals with colorectal adenomas who had germline APC and MUTYH testing at a commercial laboratory. Cross-sectional medical history data were extracted from provider-completed test requisition forms. We performed bivariate analysis to compare the frequency of APC and MUTYH variants between AJ and OA, and examined APC p.I1307K and monoallelic MUTYH carrier phenotypes using logistic regression. RESULTS: Pathogenic APC variants occurred in 38/285 AJ (13%) and 1342/6940 OA (19%; P=0.09); biallelic MUTYH variants in 2/285 (1%) AJ and 399/6940 (6%) OA (P

Background and Aims Lynch syndrome is associated with pathogenic variants in 4 mismatch repair (MMR) genes that increase lifetime risk of colorectal cancer. Guidelines recommend intensive colorectal cancer surveillance with colonoscopy every 1–2 years starting at age 25 years for all carriers of Lynch syndrome–associated variants, regardless of gene product. We constructed a simulation model to analyze the effects of different ages of colonoscopy initiation and surveillance intervals for each MMR gene (MLH1, MSH2, MSH6, and PMS2) on colorectal cancer incidence and mortality, quality-adjusted life-years, and cost. Methods Using published literature, we developed a Markov simulation model of Lynch syndrome progression for patients with each MMR variant. The model simulated clinical trials of Lynch syndrome carriers, varying age of colonoscopy initiation (5-year increments from 25–40 years), and surveillance intervals (1–5 years). We assessed the optimal strategy for each gene, defined as the strategy with the highest quality-adjusted life-years and incremental cost-effectiveness ratio below a $100,000 willingness-to-pay threshold. Results Optimal surveillance for patients with pathogenic variants in the MLH1 and MSH2 genes was colonoscopy starting at age 25 years, with 1- to 2-year surveillance intervals. Initiating colonoscopy at age 35 and 40 years, with 3-year intervals, was cost-effective for patients with pathogenic variants in MSH6 or PMS2, respectively. Conclusions We developed a simulation model to select optimal surveillance starting ages and intervals for patients with Lynch syndrome based on MMR variant. The model supports recommendations for intensive surveillance of patients with Lynch syndrome–associated variants in MLH1 or MSH2. However, for patients with Lynch syndrome–associated variants of MSH6 or PMS2, later initiation of surveillance at 35 and 40 years, respectively, and at 3-year intervals, can be considered.

Individuals with acute recurrent and chronic pancreatitis may have an inherited predisposition to the development of the disease. Pancreatitis in the setting of a significant family history of the disease can be classified as hereditary or familial pancreatitis. In this article, the authors closely examine the specific genes implicated in pancreatitis, investigate the role of genetic testing for diagnosis, and describe the impact of genetic testing results on clinical management.

Importance With the expansion of multigene testing for cancer susceptibility, Lynch syndrome (LS) has become more readily identified among women. The condition is caused by germline pathogenic variants in DNA mismatch repair genes (ie, MLH1, MSH2, MSH6, and PMS2) and is associated with high but variable risks of endometrial and ovarian cancers based on genotype. However, current guidelines on preventive strategies are not specific to genotypes. Objective To assess the cost-effectiveness of genotype-specific surveillance and preventive strategies for LS-associated gynecologic cancers, including a novel, risk-reducing surgical approach associated with decreased early surgically induced menopause. Design, Setting, and Participants This economic evaluation developed a cohort-level Markov simulation model of the natural history of LS-associated gynecologic cancer for each gene, among women from ages 25 to 75 years or until death from a health care perspective. Age was varied at hysterectomy and bilateral salpingo-oophorectomy (hyst-BSO) and at surveillance initiation, and a 2-stage surgical approach (ie, hysterectomy and salpingectomy at age 40 years and delayed oophorectomy at age 50 years [hyst-BS]) was included. Extensive 1-way and probabilistic sensitivity analyses were performed. Interventions Hyst-BSO at ages 35 years, 40 years, or 50 years with or without annual surveillance beginning at age 30 years or 35 years or hyst-BS at age 40 years with oophorectomy delayed until age 50 years. Main Outcomes and Measures Incremental cost-effectiveness ratio (ICER) between management strategies within an efficiency frontier. Results For women with MLH1 and MSH6 variants, the optimal strategy was the 2-stage approach, with respective ICERs of $33 269 and $20 008 compared with hyst-BSO at age 40 years. Despite being cost-effective, the 2-stage approach was associated with increased cancer incidence and mortality compared with hyst-BSO at age 40 years for individuals with MLH1 variants (incidence: 7.76% vs 3.84%; mortality: 5.74% vs 2.55%) and those with MSH6 variants (incidence: 7.24% vs 4.52%; mortality: 5.22% vs 2.97%). Hyst-BSO at age 40 years was optimal for individuals with MSH2 variants, with an ICER of $5180 compared with hyst-BSO at age 35 years, and was associated with 4.42% cancer incidence and 2.97% cancer mortality. For individuals with PMS2 variants, hyst-BSO at age 50 years was optimal and all other strategies were dominated; hyst-BSO at age 50 years was associated with an estimated cancer incidence of 0.68% and cancer mortality of 0.29%. Conclusions and Relevance These findings suggest that gene-specific preventive strategies for gynecologic cancers in LS may be warranted and support hyst-BSO at age 40 years for individuals with MSH2 variants. For individuals with MLH1 and MSH6 variants, these findings suggest that a novel 2-stage surgical approach with delayed oophorectomy may be an alternative to hyst-BSO at age 40 years to avoid early menopause, and for individuals with PMS2 variants, the findings suggest that hyst-BSO may be delayed until age 50 years.

Purpose Current Lynch syndrome (LS) prediction models quantify the risk to an individual of carrying a pathogenic germline mutation in three mismatch repair (MMR) genes: MLH1, MSH2, and MSH6. We developed a new prediction model, PREMM5, that incorporates the genes PMS2 and EPCAM to provide comprehensive LS risk assessment. Patients and Methods PREMM5 was developed to predict the likelihood of a mutation in any of the LS genes by using polytomous logistic regression analysis of clinical and germline data from 18,734 individuals who were tested for all five genes. Predictors of mutation status included sex, age at genetic testing, and proband and family cancer histories. Discrimination was evaluated by the area under the receiver operating characteristic curve (AUC), and clinical impact was determined by decision curve analysis; comparisons were made to the existing PREMM1,2,6 model. External validation of PREMM5 was performed in a clinic-based cohort of 1,058 patients with colorectal cancer. Results Pathogenic mutations were detected in 1,000 (5%) of 18,734 patients in the development cohort; mutations included MLH1 (n = 306), MSH2 (n = 354), MSH6 (n = 177), PMS2 (n = 141), and EPCAM (n = 22). PREMM5 distinguished carriers from noncarriers with an AUC of 0.81 (95% CI, 0.79 to 0.82), and performance was similar in the validation cohort (AUC, 0.83; 95% CI, 0.75 to 0.92). Prediction was more difficult for PMS2 mutations (AUC, 0.64; 95% CI, 0.60 to 0.68) than for other genes. Performance characteristics of PREMM5 exceeded those of PREMM1,2,6. Decision curve analysis supported germline LS testing for PREMM5 scores ≥ 2.5%. Conclusion PREMM5 provides comprehensive risk estimation of all five LS genes and supports LS genetic testing for individuals with scores ≥ 2.5%. At this threshold, PREMM5 provides performance that is superior to the existing PREMM1,2,6 model in the identification of carriers of LS, including those with weaker phenotypes and individuals unaffected by cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive gastrointestinal malignancy with a poor 5-year survival rate. Its high mortality rate is attributed to its aggressive biology and frequently late presentation. While surgical resection remains the only potentially curative treatment, only 10-20% of patients will present with surgically resectable disease. Over the past several years, development of vascular bypass graft techniques and introduction of neoadjuvant treatment regimens have increased the number of patients who can undergo resection with a curative intent. While the role of conventional imaging in the detection, characterization, and staging of patients with PDAC is well established, its role in monitoring treatment response, particularly following neoadjuvant therapy remains challenging because of the complex anatomic and histological nature of PDAC. Novel morphologic and functional imaging techniques (such as DECT, DW-MRI, and PET/MRI) are being investigated to improve the diagnostic accuracy and the ability to measure response to therapy. There is also a growing interest to detect PDAC and its precursor lesions at an early stage in asymptomatic patients to increase the likelihood of achieving cure. This has led to the development of pancreatic cancer screening programs. This article will review recent updates in imaging techniques and the current status of screening and surveillance of individuals at a high risk of developing PDAC.

Background: Lynch syndrome confers markedly increased risks of various malignancies, including urinary tract cancers (UTC; renal pelvis, ureter, bladder, and possibly kidney cancers). It is unknown how to determine which Lynch syndrome carriers are at highest UTC risk. Our aim was to identify clinical factors associated with UTC among Lynch syndrome carriers. Methods: The study population was a cohort of 52,758 consecutively ascertained individuals undergoing Lynch syndrome testing at a commercial laboratory. Clinical data were obtained from test request forms completed by the ordering provider. Univariate analysis and multivariate logistic regression were performed to identify factors associated with UTC among Lynch syndrome carriers. Results: Compared with noncarriers, Lynch syndrome carriers were significantly more likely to have had UTC (4.1% vs. 1.2%; P < 0.0001). Lynch syndrome–associated UTC was independently associated with male sex [OR 1.95; 95% confidence interval (CI), 1.38–2.76], increased age (OR 2.44 per 10 years; 95% CI, 2.11–2.82), familial burden of UTC (OR 2.69 per first-/second-degree relative with UTC; 95% CI, 1.99–3.63), and pathogenic EPCAM/MSH2 variants (OR 4.01; 95% CI, 2.39–6.72) but not MLH1 variants (OR 1.17; 95% CI, 0.63–2.17), race, or history of other Lynch syndrome–associated malignancy. A total of 143 of 158 (90.5%) Lynch syndrome carriers with UTC had ≥1 of the following characteristics: male sex, EPCAM/MSH2 variants, or family history of UTC; 1,236 of 1,251 (98.8%) Lynch syndrome carriers lacking all of these characteristics had no history of UTC. Conclusions: Specific clinical factors can reliably identify Lynch syndrome carriers most likely to be at risk for UTC. Impact: A predictable subset of Lynch syndrome carriers may be most likely to benefit from UTC surveillance/prevention.

Background & Aims Lynch syndrome is the most common inherited cause of gastrointestinal cancer and increases risk for a variety of malignancies, including gastric cancer. We aimed to identify clinical factors associated with gastric cancer in carriers of germline variants causing Lynch syndrome. Methods We collected data from 52,758 consecutive individuals tested for genetic variants associated with Lynch syndrome from June 2006 through July 2013 at a commercial laboratory. We obtained clinical and demographic data, as well as information on personal and family histories of cancer (first- and second-degree relatives) from forms completed by ordering providers. We performed multivariate logistic regression to identify clinical factors associated with gastric cancer in carriers of mutations that cause Lynch syndrome (pathogenic mutations). Results After we excluded individuals with missing clinical data (n=1664) or with multiple pathogenic mutations (n=8), we analyzed data from 51,086 individuals. Of these, 3828 persons carried pathogenic mutations (1346 with mutations in MLH1 , 1639 with mutations in MSH2 , 670 with mutations in MSH6 , 145 with mutations in PMS2 , and 28 with mutations in EPCAM ). Of the 3828 carriers of pathogenic mutations, 41 (1.1%) had a previous gastric cancer and 350 (9.1%) had 1 or more first- or second-degree relatives with gastric cancer. In multivariate analysis, male sex (odds ratio [OR], 2.82; 95% CI, 1.48–5.38), older age (OR, 2.07 per 10 years; 95% CI, 1.64–2.61), mutations in MLH1 (OR, 6.53; 95% CI, 1.50–28.42) or MSH2 (OR, 5.23 compared to mutations in MSH6 , PMS2 , or EPCAM ; 95% CI, 1.21–22.71), and first-degree relative with gastric cancer (OR, 2.52; 95% CI, 1.42–4.45), but not second-degree relatives (OR, 1.12; 95% CI, 0.40–3.18) were independently associated with gastric among carriers of pathogenic mutations. Conclusions In an analysis of data from almost 4000 carriers of Lynch syndrome-associated mutations, we found history of gastric cancer to be independently associated with male sex, older age, mutations in MLH1 or MSH2 , and with having a first-degree relative with gastric cancer. These findings suggest that personalized, risk-stratified approaches to gastric cancer surveillance may be appropriate for individuals with Lynch syndrome-associated mutations.

Quality performance measures for screening colonoscopy vary among endoscopists. The impact of practice setting is unknown. We aimed to (1) compare screening colonoscopy performance measures among three different US practice settings; (2) evaluate factors associated with adenoma detection; and (3) assess a scorecard intervention on performance metrics. This multi-center prospective study compared patient, endoscopist, and colonoscopy characteristics performed at a tertiary care hospital (TCH), community-based hospital (CBH), and private practice group (PPG). Withdrawal times (WT), cecal intubation, and adenoma detection rates (ADR) were compared by site at baseline and 12 weeks following scorecard distribution. Generalized linear mixed models identified factors associated with adenoma detection. Twenty-eight endoscopists performed colonoscopies on 1987 asymptomatic, average-risk individuals ≥50 years. Endoscopist and patient characteristics were similar across sites. The PPG screened more men (TCH: 42.8%, CBH: 45.0%, PPG: 54.2%; p

Objective To evaluate limitations of common statistical modeling approaches in deriving clinical prediction models and explore alternative strategies. Study Design and Setting A previously published model predicted the likelihood of having a mutation in germline DNA mismatch repair genes at the time of diagnosis of colorectal cancer. This model was based on a cohort where 38 mutations were found among 870 participants, with validation in an independent cohort with 35 mutations. The modeling strategy included stepwise selection of predictors from a pool of over 37 candidate predictors and dichotomization of continuous predictors. We simulated this strategy in small subsets of a large contemporary cohort (2,051 mutations among 19,866 participants) and made comparisons to other modeling approaches. All models were evaluated according to bias and discriminative ability (concordance index, c) in independent data. Results We found over 50% bias for five of six originally selected predictors, unstable model specification, and poor performance at validation (median c = 0.74). A small validation sample hampered stable assessment of performance. Model prespecification based on external knowledge and using continuous predictors led to better performance (c = 0.836 and c = 0.852 with 38 and 2,051 events respectively). Conclusion Prediction models perform poorly if based on small numbers of events and developed with common but suboptimal statistical approaches. Alternative modeling strategies to best exploit available predictive information need wider implementation, with collaborative research to increase sample sizes.