The Pancreatic Cancer Early Detection (PRECEDE) Study is a Global Effort to Drive Early Detection: Baseline Imaging Findings in High-Risk Individuals.

BACKGROUND: Pancreatic adenocarcinoma (PC) is a highly lethal malignancy with a survival rate of only 12%. Surveillance is recommended for high-risk individuals (HRIs), but it is not widely adopted. To address this unmet clinical need and drive early diagnosis research, we established the Pancreatic Cancer Early Detection (PRECEDE) Consortium. METHODS: PRECEDE is a multi-institutional international collaboration that has undertaken an observational prospective cohort study. Individuals (aged 18-90 years) are enrolled into 1 of 7 cohorts based on family history and pathogenic germline variant (PGV) status. From April 1, 2020, to November 21, 2022, a total of 3,402 participants were enrolled in 1 of 7 study cohorts, with 1,759 (51.7%) meeting criteria for the highest-risk cohort (Cohort 1). Cohort 1 HRIs underwent germline testing and pancreas imaging by MRI/MR-cholangiopancreatography or endoscopic ultrasound. RESULTS: A total of 1,400 participants in Cohort 1 (79.6%) had completed baseline imaging and were subclassified into 3 groups based on familial PC (FPC; n=670), a PGV and FPC (PGV+/FPC+; n=115), and a PGV with a pedigree that does not meet FPC criteria (PGV+/FPC-; n=615). One HRI was diagnosed with stage IIB PC on study entry, and 35.1% of HRIs harbored pancreatic cysts. Increasing age (odds ratio, 1.05; P<.001) and FPC group assignment (odds ratio, 1.57; P<.001; relative to PGV+/FPC-) were independent predictors of harboring a pancreatic cyst. CONCLUSIONS: PRECEDE provides infrastructure support to increase access to clinical surveillance for HRIs worldwide, while aiming to drive early PC detection advancements through longitudinal standardized clinical data, imaging, and biospecimen captures. Increased cyst prevalence in HRIs with FPC suggests that FPC may infer distinct biological processes. To enable the development of PC surveillance approaches better tailored to risk category, we recommend adoption of subclassification of HRIs into FPC, PGV+/FPC+, and PGV+/FPC- risk groups by surveillance protocols.

Pancreatic Cysts Greater Than 1 cm Are Associated With an Increased Risk for Developing Pancreatic Cancer in Individuals From Pancreatic-Cancer Prone Kindreds Undergoing Surveillance.

BACKGROUND: The International Cancer of the Pancreas Screening Consortium recommended annual imaging for individuals at increased risk for developing a pancreatic ductal adenocarcinoma (PDAC) who did not have concerning pancreatic findings or a cyst <3 cm without worrisome features. We aimed to determine if 3-cm cyst size accurately predicted advanced precursor lesions in high-risk individuals undergoing surveillance. METHODS: Imaging for high-risk individuals (HRIs) undergoing PDAC surveillance from 2007 to 2021 was reviewed and pancreatic abnormalities were recorded including dominant cyst size and number of cysts. Subjects were excluded if they had the following: (1) no follow-up imaging after baseline, (2) solid lesion at baseline, or (3) development of solid lesion without having cyst on prior imaging. RESULTS: Five of the 77 HRIs found to have a cystic lesion on surveillance developed a PDAC: 3 with cystic lesion >1 cm as compared with only 2 of 67 HRIs with cystic lesions <1 cm (P < 0.05). None of these cysts developed worrisome findings and 4/5 PDACs did not arise from visualized cystic precursor lesion. CONCLUSIONS: Patients with a cyst ≥1 cm were at increased risk for developing PDAC compared with patients with cyst <1 cm. Pancreatic ductal adenocarcinoma usually did not arise from a recognized cystic lesion.

Tryptophan intake and pancreatic cancer: findings from a case-control study.

BACKGROUND: Pancreatic cancer is a leading cause of cancer-related death worldwide. Tryptophan plays a vital role in cell growth and maintenance as a building block of protein and coordination of organismal responses to environmental and dietary cues. Animal model study showed that dietary tryptophan improved treatment response in those who received chemotherapy or immune checkpoint inhibitors. Limited data are available assessing the association between tryptophan intake and risk of pancreatic cancer. We aimed to evaluate this association in a case-control study in Vietnam. METHODS: We analyzed data from a case-control study, including 3759 cancer cases and 2995 control subjects of whom 37 with pancreatic cancer cases. Tryptophan intake was derived from food frequency questionnaire. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for different levels of tryptophan intake with pancreatic cancer risk. RESULTS: Overall, tryptophan intake was inversely associated with pancreatic cancer risk in a dose-dependent manner. The ORs and 95% CIs of pancreatic cancer were 0.51 (0.29-0.92) for continuous scale, 0.27 (0.10-0.73) for tertile 2 and 0.34 (0.11-1.06) for tertile 3, compared with tertile 1 (the lowest intake) (Ptrend = 0.02). In stratified analysis, this inverse association pattern was present among those with BMI < 23 kg/m2 and ever drinkers. CONCLUSION: A diet with a higher intake of tryptophan was significantly associated with a lower incidence of pancreatic cancer among Vietnamese population. These suggest that dietary modification may be an effective strategy for primary prevention of pancreatic cancer development.

UNSEG: unsupervised segmentation of cells and their nuclei in complex tissue samples.

Multiplexed imaging technologies have made it possible to interrogate complex tumor microenvironments at sub-cellular resolution within their native spatial context. However, proper quantification of this complexity requires the ability to easily and accurately segment cells into their sub-cellular compartments. Within the supervised learning paradigm, deep learning based segmentation methods demonstrating human level performance have emerged. Here we present an unsupervised segmentation (UNSEG) method that achieves deep learning level performance without requiring any training data. UNSEG leverages a Bayesian-like framework and the specificity of nucleus and cell membrane markers to construct an a posteriori probability estimate of each pixel belonging to the nucleus, cell membrane, or background. It uses this estimate to segment each cell into its nuclear and cell-membrane compartments. We show that UNSEG is more internally consistent and better at generalizing to the complexity of tissue samples than current deep learning methods. This allows UNSEG to unambiguously identify the cytoplasmic compartment of a cell, which we employ to demonstrate its use in an example biological scenario. Within the UNSEG framework, we also introduce a new perturbed watershed algorithm capable of stably and accurately segmenting a cell nuclei cluster into individual cell nuclei. Perturbed watershed can also be used as a standalone algorithm that researchers can incorporate within their supervised or unsupervised learning approaches to replace classical watershed. Finally, as part of developing UNSEG, we have generated a high-quality annotated gastrointestinal tissue dataset, which we anticipate will be useful for the broader research community. Segmentation, despite its long antecedents, remains a challenging problem, particularly in the context of tissue samples. UNSEG, an easy-to-use algorithm, provides an unsupervised approach to overcome this bottleneck, and as we discuss, can help improve deep learning based segmentation methods by providing a bridge between unsupervised and supervised learning paradigms.

Outcomes of the IMMray PanCan-d Test in High-Risk Individuals Undergoing Pancreatic Surveillance: Pragmatic Data and Lessons Learned.

PURPOSE: An effective blood-based test for pancreatic cancer (PC) screening has remained elusive. The IMMray PanCan-d is the first commercially available blood-based test specifically designed for early detection of PC; however, outcomes from its use in clinical practice have not been reported. METHODS: We performed a blinded spike-in study of 100 individuals who had an IMMray PanCan-d test, including 94 high-risk individuals (HRIs) undergoing PC surveillance and six individuals with known PC. Specimens were processed blindly following the commercial laboratory's standardized operating procedure. Positive predictive value (PPV) and negative predictive value (NPV) were calculated. RESULTS: Cohort characteristics included a median age of 63 (IQR, 55-70) years, 57% female, 96% non-Hispanic White, 57% with a pathogenic variant in a PC risk gene (BRCA2 most commonly-18%), and 83% with a family history of PC. Among IMMray PanCan-d results from 94 HRIs undergoing PC surveillance, there was one positive (1%), seven borderlines (7%), 73 negatives (78%), and 13 tests not performed because of low CA19-9 expression (14%). No PC was diagnosed among these HRIs; however, there were two sub-cm pancreatic neuroendocrine tumors, seven clinically diagnosed side branch intraductal papillary mucinous neoplasms ≥1 cm, and a sub-cm solid mass with indeterminate cytology requiring close follow-up; all these individuals had negative IMMray PanCan-d tests. Of the six spiked-in PCs, four (67%) yielded a positive and two (33%) yielded a negative. With an estimated disease prevalence of 2%, the PPV and NPV are 52% and 99%, respectively, if borderline results are considered negative and 12% and 99%, respectively, if borderline tests are considered positive. CONCLUSION: In clinical practice, IMMray PanCan-d has a robust NPV; however, PPV is dramatically influenced by whether borderline results are characterized as a positive or negative result.

Immune microenvironment profiling of normal appearing colorectal mucosa biopsied over repeat patient visits reproducibly separates lynch syndrome patients based on their history of colon cancer.

Introduction: Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC), increasing lifetime risk of CRC by up to 70%. Despite this higher lifetime risk, disease penetrance in LS patients is highly variable and most LS patients undergoing CRC surveillance will not develop CRC. Therefore, biomarkers that can correctly and consistently predict CRC risk in LS patients are needed to both optimize LS patient surveillance and help identify better prevention strategies that reduce risk of CRC development in the subset of high-risk LS patients. Methods: Normal-appearing colorectal tissue biopsies were obtained during repeat surveillance colonoscopies of LS patients with and without a history of CRC, healthy controls (HC), and patients with a history of sporadic CRC. Biopsies were cultured in an ex-vivo explant system and their supernatants were assayed via multiplexed ELISA to profile the local immune signaling microenvironment. High quality cytokines were identified using the rxCOV fidelity metric. These cytokines were used to perform elastic-net penalized logistic regression-based biomarker selection by computing a new measure - overall selection probability - that quantifies the ability of each marker to discriminate between patient cohorts being compared. Results: Our study demonstrated that cytokine based local immune microenvironment profiling was reproducible over repeat visits and sensitive to patient LS-status and CRC history. Furthermore, we identified sets of cytokines whose differential expression was predictive of LS-status in patients when compared to sporadic CRC patients and in identifying those LS patients with or without a history of CRC. Enrichment analysis based on these biomarkers revealed an LS and CRC status dependent constitutive inflammatory state of the normal appearing colonic mucosa. Discussion: This prospective pilot study demonstrated that immune profiling of normal appearing colonic mucosa discriminates LS patients with a prior history of CRC from those without it, as well as patients with a history of sporadic CRC from HC. Importantly, it suggests the existence of immune signatures specific to LS-status and CRC history. We anticipate that our findings have the potential to assess CRC risk in individuals with LS and help in preemptively mitigating it by optimizing surveillance and identifying candidate prevention targets. Further studies are required to validate our findings in an independent cohort of LS patients over multiple visits.

Mirroring UC care pathways in refractory immune checkpoint inhibitor (ICI)-mediated colitis: distinct features and common pathways.

Immune checkpoint inhibitors (ICI) have transformed the management of cancer, producing durable responses in a subset of treated patients across multiple malignancies. Immune-mediated diarrhea and colitis (imDC) occurs in up to 20% of ICI-treated patients. The risk of ICI imDC is dependent upon the agent and is commoner with anti-CTLA-4 compared to anti-PD-1 ICIs. Generally, imDC is treated with steroids and agents targeting TNFα or α4ß7 integrin. However, the management of steroids and/or biologic refractory imDC is unclear. We present a case of imDC in a 68-year-old female who failed to respond clinically, biochemically and immunohistochemically to corticosteroids, infliximab and vedolizumab. A trial of tofacitinib, a pan-JAK inhibitor, led to rapid clinical, biochemical and immunohistochemical control of imDC. ICIs result in a striking accumulation of cytotoxic and proliferative CD8 + T cells within tumor. However, the cellular and molecular mechanisms underlying imDC remain unclear. Herein, we observed significant T cell enrichment; and the successful treatment with tofacitinib highlights the potential of multiple convergent inflammatory pathways in imDC and inflammatory colitis.

Somatic loss of ATM is a late event in pancreatic tumorigenesis.

Understanding the timing and spectrum of genetic alterations that contribute to the development of pancreatic cancer is essential for effective interventions and treatments. The aim of this study was to characterize somatic ATM alterations in noninvasive pancreatic precursor lesions and invasive pancreatic adenocarcinomas from patients with and without pathogenic germline ATM variants. DNA was isolated and sequenced from the invasive pancreatic ductal adenocarcinomas and precursor lesions of patients with a pathogenic germline ATM variant. Tumor and precursor lesions from these patients as well as colloid carcinoma from patients without a germline ATM variant were immunolabeled to assess ATM expression. Among patients with a pathogenic germline ATM variant, somatic ATM alterations, either mutations and/or loss of protein expression, were identified in 75.0% of invasive pancreatic adenocarcinomas but only 7.1% of pancreatic precursor lesions. Loss of ATM expression was also detected in 31.0% of colloid carcinomas from patients unselected for germline ATM status, significantly higher than in pancreatic precursor lesions [pancreatic intraepithelial neoplasms (p = 0.0013); intraductal papillary mucinous neoplasms, p = 0.0040] and pancreatic ductal adenocarcinoma (p = 0.0076) unselected for germline ATM status. These data are consistent with the second hit to ATM being a late event in pancreatic tumorigenesis. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Racial, Ethnic, and Sex-based Disparities among High-risk Individuals Undergoing Pancreatic Cancer Surveillance.

Since its inception two years ago, the international, multicenter Pancreatic Cancer Early Detection (PRECEDE) Consortium has enrolled high-risk individuals (HRI) undergoing pancreatic ductal adenocarcinoma (PDAC) surveillance. Herein we aim to evaluate enrollment disparities in PRECEDE. Data on HRIs enrolled between May 2020 and March 2022 were collected, with HRIs defined as participants enrolled in PRECEDE meeting guideline-based criteria for PDAC surveillance. Of 1,273 HRIs enrolled, 1,113 were eligible for inclusion, with 47.2% meeting familial pancreatic cancer criteria without a known pathogenic variant (PV) and the remainder having a pathogenic variant in a PDAC-risk gene (CDKN2A, STK11, PRSS1, BRCA1, BRCA2, PALB2, ATM, MLH1, MSH2, MSH6, PMS2, or EPCAM). Study participants were predominantly from the United States (82.7%), the most common age range at enrollment was 60-69 years (37.4%), and a non-PDAC cancer was present in 32.4%. There were racial/ethnic- and sex-based disparities among enrolled subjects, as the majority of participants were female (65.9%) and self-reported white (87.7%), with only 2.9% having Hispanic ethnicity. While more than 97% of participants consented to utilize imaging data and biosamples for research, there was no difference in rate of consent based on race/ethnicity, sex, or age, thereby demonstrating uniform participation in research activities among all subgroups after enrollment. Ensuring that diversity of HRIs in PDAC surveillance programs mirrors the communities served by participating centers is important. Substantial racial/ethnic- and sex-based disparities persist among recently enrolled HRIs undergoing PDAC surveillance, and therefore reducing these disparities will be a major focus of the PRECEDE Consortium moving forward. PREVENTION RELEVANCE: Pancreatic cancer surveillance is critical to decreasing pancreatic cancer mortality; therefore, it is important that pancreatic cancer surveillance studies enroll diverse patients. We demonstrate that substantial racial/ethnic- and sex-based disparities exist amongst enrollment in the international PRECEDE consortium, highlighting the dire need for future efforts to reduce these disparities. See related Spotlight, p. 305.

A Combined DNA/RNA-based Next-Generation Sequencing Platform to Improve the Classification of Pancreatic Cysts and Early Detection of Pancreatic Cancer Arising From Pancreatic Cysts.

OBJECTIVE: We report the development and validation of a combined DNA/RNA next-generation sequencing (NGS) platform to improve the evaluation of pancreatic cysts. BACKGROUND AND AIMS: Despite a multidisciplinary approach, pancreatic cyst classification, such as a cystic precursor neoplasm, and the detection of high-grade dysplasia and early adenocarcinoma (advanced neoplasia) can be challenging. NGS of preoperative pancreatic cyst fluid improves the clinical evaluation of pancreatic cysts, but the recent identification of novel genomic alterations necessitates the creation of a comprehensive panel and the development of a genomic classifier to integrate the complex molecular results. METHODS: An updated and unique 74-gene DNA/RNA-targeted NGS panel (PancreaSeq Genomic Classifier) was created to evaluate 5 classes of genomic alterations to include gene mutations (e.g., KRAS, GNAS, etc.), gene fusions and gene expression. Further, CEA mRNA ( CEACAM5 ) was integrated into the assay using RT-qPCR. Separate multi-institutional cohorts for training (n=108) and validation (n=77) were tested, and diagnostic performance was compared to clinical, imaging, cytopathologic, and guideline data. RESULTS: Upon creation of a genomic classifier system, PancreaSeq GC yielded a 95% sensitivity and 100% specificity for a cystic precursor neoplasm, and the sensitivity and specificity for advanced neoplasia were 82% and 100%, respectively. Associated symptoms, cyst size, duct dilatation, a mural nodule, increasing cyst size, and malignant cytopathology had lower sensitivities (41-59%) and lower specificities (56-96%) for advanced neoplasia. This test also increased the sensitivity of current pancreatic cyst guidelines (IAP/Fukuoka and AGA) by >10% and maintained their inherent specificity. CONCLUSIONS: PancreaSeq GC was not only accurate in predicting pancreatic cyst type and advanced neoplasia but also improved the sensitivity of current pancreatic cyst guidelines.

Mutation-specific Mismatch Repair-deficient Benign Endometrial Glands in Endometrial Biopsies and Curettings Are a Biomarker of Lynch Syndrome and Associate With Endometrial Carcinoma Development.

Endometrial carcinoma is the most common extraintestinal cancer in Lynch syndrome (LS). Recent studies have demonstrated mismatch repair (MMR) deficiency can be detected in benign endometrial glands in LS. We performed MMR immunohistochemistry in benign endometrium from endometrial biopsies and curettings (EMCs) from a study group of 34 confirmed LS patients and a control group of 38 patients without LS who subsequently developed sporadic MLH1-deficient or MMR-proficient endometrial carcinoma. MMR-deficient benign glands were only identified in patients with LS (19/34, 56%) and were not identified in any control group patient (0/38, 0%) ( P < 0.001). MMR-deficient benign glands were identified as large, contiguous groups in 18 of 19 cases (95%). MMR-deficient benign glands were identified in patients with germline pathogenic variants in MLH1 (6/8, 75%), MSH6 (7/10, 70%), and MSH2 (6/11, 55%) but not in patients with variants in PMS2 (0/4). MMR-deficient benign glands were seen in all EMC samples (100%) but in only 46% of endometrial biopsy samples ( P =0.02). Patients with MMR-deficient benign glands were significantly more likely to have endometrial carcinoma (53%) compared with LS patients with only MMR-proficient glands (13%) ( P =0.03). In conclusion, we demonstrated that MMR-deficient benign endometrial glands are frequently identified in EMB/EMC in women with LS and are a specific marker for LS. Women with LS with MMR-deficient benign glands were more likely to have endometrial carcinoma suggesting that MMR-deficient benign glands may be a biomarker of increased risk of endometrial carcinoma development in LS.

Immune Microenvironment Profiling of Normal Appearing Colorectal Mucosa Biopsied Over Repeat Patient Visits Reproduciably Separates Lynch Syndrome Patients Based on Their History of Colon Cancer.

Introduction: Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC), increasing lifetime risk of CRC by up to 70%. Despite this higher lifetime risk, disease penetrance in LS patients is highly variable and most LS patients undergoing CRC surveillance will not develop CRC. Therefore, biomarkers that can correctly and consistently predict CRC risk in LS patients are needed to both optimize LS patient surveillance and help identify better prevention strategies that reduce risk of CRC development in the subset of high-risk LS patients. Methods: Normal-appearing colorectal tissue biopsies were obtained during repeat surveillance colonoscopies of LS patients with and without a history of CRC, healthy controls (HC), and patients with a history of sporadic CRC. Biopsies were cultured in an ex-vivo explant system and their supernatants were assayed via multiplexed ELISA to profile the local immune signaling microenvironment. High quality cytokine signatures were identified using rx COV fidelity metric. These signatures were used to perform biomarker selection by computing their selection probability based on penalized logistic regression. Results: Our study demonstrated that cytokine based local immune microenvironment profiling was reproducible over repeat visits and sensitive to patient LS-status and CRC history. Furthermore, we identified sets of biomarkers whose differential expression was predictive of LS-status in patients when compared to sporadic CRC patients and in identifying those LS patients with or without a history of CRC. Enrichment analysis based on these biomarkers revealed an LS and CRC status dependent constitutive inflammatory state of the normal appearing colonic mucosa. Discussion: This prospective pilot study demonstrated that immune profiling of normal appearing colonic mucosa discriminates LS patients with a prior history of CRC from those without it, as well as patients with a history of sporadic CRC from HC. Importantly, it suggests existence of immune signatures specific to LS-status and CRC history. We anticipate that our findings have the potential to assess CRC risk in individuals with LS and help in preemptively mitigating it by optimizing surveillance and identifying candidate prevention targets. Further studies are required to validate our findings in an independent cohort of LS patients over multiple visits.

Pancreatic Cancer: Changing Epidemiology and New Approaches to Risk Assessment, Early Detection, and Prevention.

Pancreatic cancer usually results in poor survival with limited options for treatment, as most affected individuals present with advanced disease. Early detection of preinvasive pancreatic neoplasia and identifying molecular therapeutic targets provide opportunities for extending survival. Although screening for pancreatic cancer is currently not recommended for the general population, emerging evidence indicates that pancreatic surveillance can improve outcomes for individuals in certain high-risk groups. Changes in the epidemiology of pancreatic cancer, experience from pancreatic surveillance, and discovery of novel biomarkers provide a roadmap for new strategies for pancreatic cancer risk assessment, early detection, and prevention.

Single-strand mismatch and damage patterns revealed by single-molecule DNA sequencing.

Mutations accumulate in the genome of every cell of the body throughout life, causing cancer and other genetic diseases1-4. Almost all of these mosaic mutations begin as nucleotide mismatches or damage in only one of the two strands of the DNA prior to becoming double-strand mutations if unrepaired or misrepaired5. However, current DNA sequencing technologies cannot resolve these initial single-strand events. Here, we developed a single-molecule, long-read sequencing method that achieves single-molecule fidelity for single-base substitutions when present in either one or both strands of the DNA. It also detects single-strand cytosine deamination events, a common type of DNA damage. We profiled 110 samples from diverse tissues, including from individuals with cancer-predisposition syndromes, and define the first single-strand mismatch and damage signatures. We find correspondences between these single-strand signatures and known double-strand mutational signatures, which resolves the identity of the initiating lesions. Tumors deficient in both mismatch repair and replicative polymerase proofreading show distinct single-strand mismatch patterns compared to samples deficient in only polymerase proofreading. In the mitochondrial genome, our findings support a mutagenic mechanism occurring primarily during replication. Since the double-strand DNA mutations interrogated by prior studies are only the endpoint of the mutation process, our approach to detect the initiating single-strand events at single-molecule resolution will enable new studies of how mutations arise in a variety of contexts, especially in cancer and aging.

rxCOV is a quantitative metric for assessing immunoassay analyte fidelity.

Immunoassay based bioanalytical measurements are widely used in a variety of biomedical research and clinical settings. In these settings they are assumed to faithfully represent the experimental conditions being tested and the sample groups being compared. Although significant technical advances have been made in improving sensitivity and quality of the measurements, currently no metrics exist that objectively quantify the fidelity of the measured analytes with respect to noise associated with the specific assay. Here we introduce ratio of cross-coefficient-of-variation (rxCOV), a fidelity metric for objectively assessing immunoassay analyte measurement quality when comparing its differential expression between different sample groups or experimental conditions. We derive the metric from first principles and establish its feasibility and applicability using simulated and experimental data. We show that rxCOV assesses fidelity independent of statistical significance, and importantly, identifies when latter is meaningful. We also discuss its importance in the context of averaging experimental replicates for increasing signal to noise ratio. Finally, we demonstrate its application in a Lynch Syndrome case study. We conclude by discussing its applicability to multiplexed immunoassays, other biosensing assays, and to paired and unpaired data. We anticipate rxCOV to be adopted as a simple and easy-to-use fidelity metric for performing robust and reproducible biomedical research.

Delphi Initiative for Early-Onset Colorectal Cancer (DIRECt) International Management Guidelines.

BACKGROUND & AIMS: Patients with early-onset colorectal cancer (eoCRC) are managed according to guidelines that are not age-specific. A multidisciplinary international group (DIRECt), composed of 69 experts, was convened to develop the first evidence-based consensus recommendations for eoCRC. METHODS: After reviewing the published literature, a Delphi methodology was used to draft and respond to clinically relevant questions. Each statement underwent 3 rounds of voting and reached a consensus level of agreement of ≥80%. RESULTS: The DIRECt group produced 31 statements in 7 areas of interest: diagnosis, risk factors, genetics, pathology-oncology, endoscopy, therapy, and supportive care. There was strong consensus that all individuals younger than 50 should undergo CRC risk stratification and prompt symptom assessment. All newly diagnosed eoCRC patients should receive germline genetic testing, ideally before surgery. On the basis of current evidence, endoscopic, surgical, and oncologic treatment of eoCRC should not differ from later-onset CRC, except for individuals with pathogenic or likely pathogenic germline variants. The evidence on chemotherapy is not sufficient to recommend changes to established therapeutic protocols. Fertility preservation and sexual health are important to address in eoCRC survivors. The DIRECt group highlighted areas with knowledge gaps that should be prioritized in future research efforts, including age at first screening for the general population, use of fecal immunochemical tests, chemotherapy, endoscopic therapy, and post-treatment surveillance for eoCRC patients. CONCLUSIONS: The DIRECt group produced the first consensus recommendations on eoCRC. All statements should be considered together with the accompanying comments and literature reviews. We highlighted areas where research should be prioritized. These guidelines represent a useful tool for clinicians caring for patients with eoCRC.

A Reduced Pancreatic Polypeptide Response is Associated With New-onset Pancreatogenic Diabetes Versus Type 2 Diabetes.

PURPOSE: Pancreatogenic diabetes refers to diabetes mellitus (DM) that develops in the setting of a disease of the exocrine pancreas, including pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). We sought to evaluate whether a blunted nutrient response of pancreatic polypeptide (PP) can differentiate these DM subtypes from type 2 DM (T2DM). METHODS: Subjects with new-onset DM (<3 years' duration) in the setting of PDAC (PDAC-DM, n = 28), CP (CP-DM, n = 38), or T2DM (n = 99) completed a standardized mixed meal tolerance test, then serum PP concentrations were subsequently measured at a central laboratory. Two-way comparisons of PP concentrations between groups were performed using Wilcoxon rank-sum test and analysis of covariance while adjusting for age, sex, and body mass index. RESULTS: The fasting PP concentration was lower in both the PDAC-DM and CP-DM groups than in the T2DM group (P = 0.03 and <0.01, respectively). The fold change in PP at 15 minutes following meal stimulation was significantly lower in the PDAC-DM (median, 1.869) and CP-DM (1.813) groups compared with T2DM (3.283; P < 0.01 for both comparisons). The area under the curve of PP concentration was significantly lower in both the PDAC-DM and CP-DM groups than in T2DM regardless of the interval used for calculation and remained significant after adjustments. CONCLUSIONS: Fasting PP concentrations and the response to meal stimulation are reduced in new-onset DM associated with PDAC or CP compared with T2DM. These findings support further investigations into the use of PP concentrations to characterize pancreatogenic DM and to understand the pathophysiological role in exocrine pancreatic diseases (NCT03460769).

Prospective, Multi-Institutional, Real-Time Next-Generation Sequencing of Pancreatic Cyst Fluid Reveals Diverse Genomic Alterations That Improve the Clinical Management of Pancreatic Cysts.

BACKGROUND & AIMS: Next-generation sequencing (NGS) of pancreatic cyst fluid is a useful adjunct in the assessment of patients with pancreatic cyst. However, previous studies have been retrospective or single institutional experiences. The aim of this study was to prospectively evaluate NGS on a multi-institutional cohort of patients with pancreatic cyst in real time. METHODS: The performance of a 22-gene NGS panel (PancreaSeq) was first retrospectively confirmed and then within a 2-year timeframe, PancreaSeq testing was prospectively used to evaluate endoscopic ultrasound-guided fine-needle aspiration pancreatic cyst fluid from 31 institutions. PancreaSeq results were correlated with endoscopic ultrasound findings, ancillary studies, current pancreatic cyst guidelines, follow-up, and expanded testing (Oncomine) of postoperative specimens. RESULTS: Among 1933 PCs prospectively tested, 1887 (98%) specimens from 1832 patients were satisfactory for PancreaSeq testing. Follow-up was available for 1216 (66%) patients (median, 23 months). Based on 251 (21%) patients with surgical pathology, mitogen-activated protein kinase/GNAS mutations had 90% sensitivity and 100% specificity for a mucinous cyst (positive predictive value [PPV], 100%; negative predictive value [NPV], 77%). On exclusion of low-level variants, the combination of mitogen-activated protein kinase/GNAS and TP53/SMAD4/CTNNB1/mammalian target of rapamycin alterations had 88% sensitivity and 98% specificity for advanced neoplasia (PPV, 97%; NPV, 93%). Inclusion of cytopathologic evaluation to PancreaSeq testing improved the sensitivity to 93% and maintained a high specificity of 95% (PPV, 92%; NPV, 95%). In comparison, other modalities and current pancreatic cyst guidelines, such as the American Gastroenterology Association and International Association of Pancreatology/Fukuoka guidelines, show inferior diagnostic performance. The sensitivities and specificities of VHL and MEN1/loss of heterozygosity alterations were 71% and 100% for serous cystadenomas (PPV, 100%; NPV, 98%), and 68% and 98% for pancreatic neuroendocrine tumors (PPV, 85%; NPV, 95%), respectively. On follow-up, serous cystadenomas with TP53/TERT mutations exhibited interval growth, whereas pancreatic neuroendocrine tumors with loss of heterozygosity of ≥3 genes tended to have distant metastasis. None of the 965 patients who did not undergo surgery developed malignancy. Postoperative Oncomine testing identified mucinous cysts with BRAF fusions and ERBB2 amplification, and advanced neoplasia with CDKN2A alterations. CONCLUSIONS: PancreaSeq was not only sensitive and specific for various pancreatic cyst types and advanced neoplasia arising from mucinous cysts, but also reveals the diversity of genomic alterations seen in pancreatic cysts and their clinical significance.

Acute pancreatitis precedes chronic pancreatitis in the majority of patients: Results from the NAPS2 consortium.

INTRODUCTION: The mechanistic definition of chronic pancreatitis (CP) identifies acute pancreatitis (AP) as a precursor stage. We hypothesized that clinical AP frequently precedes the diagnosis of CP and is associated with patient- and disease-related factors. We describe the prevalence, temporal relationship and associations of AP in a well-defined North American cohort. METHODS: We evaluated data from 883 patients with CP prospectively enrolled in the North American Pancreatitis Studies across 27 US centers between 2000 and 2014. We determined how often patients had one or more episodes of AP and its occurrence in relationship to the diagnosis of CP. We used multivariable logistic regression to determine associations for prior AP. RESULTS: There were 624/883 (70.7%) patients with prior AP, among whom 161 (25.8%) had AP within 2 years, 115 (18.4%) within 3-5 years, and 348 (55.8%) >5 years prior to CP diagnosis. Among 504 AP patients with available information, 436 (86.5%) had >1 episode. On multivariable analyses, factors associated with increased odds of having prior AP were a younger age at CP diagnosis, white race, abdominal pain, pseudocyst(s) and pancreatic duct dilatation/stricture, while factors associated with a lower odds of having prior AP were exocrine insufficiency and pancreatic atrophy. When compared with patients with 1 episode, those with >1 AP episode were diagnosed with CP an average of 5 years earlier. CONCLUSIONS: Nearly three-quarters of patients were diagnosed with AP prior to CP diagnosis. Identifying which AP patients are at-risk for future progression to CP may provide opportunities for primary and secondary prevention.