Protein biomarkers and alternatively methylated cell-free DNA detect early stage pancreatic cancer.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is commonly diagnosed at an advanced stage. Liquid biopsy approaches may facilitate detection of early stage PDAC when curative treatments can be employed. DESIGN: To assess circulating marker discrimination in training, testing and validation patient cohorts (total n=426 patients), plasma markers were measured among PDAC cases and patients with chronic pancreatitis, colorectal cancer (CRC), and healthy controls. Using CA19-9 as an anchor marker, measurements were made of two protein markers (TIMP1, LRG1) and cell-free DNA (cfDNA) pancreas-specific methylation at 9 loci encompassing 61 CpG sites. RESULTS: Comparative methylome analysis identified nine loci that were differentially methylated in exocrine pancreas DNA. In the training set (n=124 patients), cfDNA methylation markers distinguished PDAC from healthy and CRC controls. In the testing set of 86 early stage PDAC and 86 matched healthy controls, CA19-9 had an area under the receiver operating characteristic curve (AUC) of 0.88 (95% CI 0.83 to 0.94), which was increased by adding TIMP1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.06), LRG1 (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02) or exocrine pancreas-specific cfDNA methylation markers at nine loci (AUC 0.92; 95% CI 0.88 to 0.96; p=0.02). In the validation set of 40 early stage PDAC and 40 matched healthy controls, a combined panel including CA19-9, TIMP1 and a 9-loci cfDNA methylation panel had greater discrimination (AUC 0.86, 95% CI 0.77 to 0.95) than CA19-9 alone (AUC 0.82; 95% CI 0.72 to 0.92). CONCLUSION: A combined panel of circulating markers including proteins and methylated cfDNA increased discrimination compared with CA19-9 alone for early stage PDAC.

Genomic signatures of past and present chromosomal instability in Barrett's esophagus and early esophageal adenocarcinoma.

The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations but how these alterations arise is poorly understood. Here we perform haplotype-specific analysis of chromosomal copy-number evolution in the progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) on multiregional whole-genome sequencing data of BE with dysplasia and microscopic EAC foci. We identify distinct patterns of copy-number evolution indicating multigenerational chromosomal instability that is initiated by cell division errors but propagated only after p53 loss. While abnormal mitosis, including whole-genome duplication, underlies chromosomal copy-number changes, segmental alterations display signatures of successive breakage-fusion-bridge cycles and chromothripsis of unstable dicentric chromosomes. Our analysis elucidates how multigenerational chromosomal instability generates copy-number variation in BE cells, precipitates complex alterations including DNA amplifications, and promotes their independent clonal expansion and transformation. In particular, we suggest sloping copy-number variation as a signature of ongoing chromosomal instability that precedes copy-number complexity. These findings suggest copy-number heterogeneity in advanced cancers originates from chromosomal instability in precancerous cells and such instability may be identified from the presence of sloping copy-number variation in bulk sequencing data.

A blood-based metabolomic signature predictive of risk for pancreatic cancer.

Emerging evidence implicates microbiome involvement in the development of pancreatic cancer (PaCa). Here, we investigate whether increases in circulating microbial-related metabolites associate with PaCa risk by applying metabolomics profiling to 172 sera collected within 5 years prior to PaCa diagnosis and 863 matched non-subject sera from participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cohort. We develop a three-marker microbial-related metabolite panel to assess 5-year risk of PaCa. The addition of five non-microbial metabolites further improves 5-year risk prediction of PaCa. The combined metabolite panel complements CA19-9, and individuals with a combined metabolite panel + CA19-9 score in the top 2.5th percentile have absolute 5-year risk estimates of >13%. The risk prediction model based on circulating microbial and non-microbial metabolites provides a potential tool to identify individuals at high risk of PaCa that would benefit from surveillance and/or from potential cancer interception strategies.

What Can We Learn About Pancreatic Adenocarcinoma from Imaging?

Imaging and endoscopy play several important roles in the diagnosis and management of pancreatic ductal adenocarcinoma (PDAC). Computed tomography (CT) and endoscopic ultrasound play complimentary roles in the initial diagnosis and pathologic confirmation of PDAC. Endoscopy can also be used to manage biliary obstruction and gastrointestinal complications. MRI and fluorodeoxyglucose-PET-CT are typically used as problem-solving tools for complex cases. Neoadjuvant chemotherapy and surgery are often selected based on imaging findings related to vascular involvement by tumors and invasion of adjacent structures. Posttreatment surveillance imaging is used to monitor for complications, local recurrence, and systemic metastasis.

Multicancer Early Detection Technologies: A Review Informed by Past Cancer Screening Studies.

More than 75% of cancer-related deaths occur from cancers for which we do not screen. New screening liquid biopsies may help fill these clinical gaps, although evidence of benefit still needs to be assessed. Which lessons can we learn from previous efforts to guide those of the future? Screening trials for ovarian, prostate, pancreatic, and esophageal cancers are revisited to assess the evidence, which has been limited by small effect sizes, short duration of early-stage disease relative to screening frequency, study design, and confounding factors. Randomized controlled trials (RCT) to show mortality reduction have required millions of screening-years, two-decade durations, and been susceptible to external confounding. Future RCTs with late-stage incidence as a surrogate endpoint could substantially reduce these challenges, and clinical studies demonstrating safety and effectiveness of screening in high-risk populations may enable extrapolation to broader average-risk populations. Multicancer early detection tests provide an opportunity to advance these practical study designs. Conditional approvals based on RCTs with surrogate endpoints, contingent upon real world evidence generation and continuation of trials to definitive endpoints, may lower practical barriers to innovation in cancer screening and enable greater progress.

A Quality Improvement Intervention Leveraging a Safety Net Model for Surveillance Colonoscopy Completion.

Systems to address follow-up testing of clinically positive surveillance colonoscopy results are lacking. The impact of an ambulatory safety net (ASN) intervention on rates of colonoscopy completion was assessed. The ASN team identified patients using an electronic registry, conducted patient outreach, coordinated care, and tracked colonoscopy completion. In all, 701 patients were captured in the ASN program: 58.1% (407/701) had possible barriers to follow-up colonoscopy completion, with rates of 80.1% (236/294) if no barrier, and 40.9% (287/701) overall. Colonoscopy completion likelihood increased with prior polypectomy (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.1-2.3), and decreased with White race (OR, 0.5; 95% CI, 0.3-0.9), increased inpatient visits (OR, 0.6; 95% CI, 0.4-0.9), more outreach attempts (OR, 0.6; 95% CI, 0.5-0.7), and fair/poor/inadequate preparation (OR, 0.4; 95% CI, 0.2-0.7) in logistic regression models. An ASN model for quality improvement promotes colonoscopy completion rates and identifies patient barriers.

Endoscopic band ligation in the treatment of gastric antral vascular ectasia: a systematic review and meta-analysis.

Background and study aims While argon plasma coagulation (APC) is the first-line treatment for gastric antral vascular ectasia (GAVE), endoscopic band ligation (EBL) has shown promising results. The aim of this study was to perform a systematic review and meta-analysis to evaluate the effectiveness of EBL for the treatment of GAVE. Methods Individualized search strategies were developed in accordance with PRISMA and MOOSE guidelines through September 1, 2020. Measured outcomes included endoscopic success (defined as GAVE eradication/improvement), change in hemoglobin, transfusion dependency, number of treatment sessions, adverse events, rebleeding, and bleeding-associated mortality. Outcomes were compared among studies evaluating EBL versus APC. Results Eleven studies (n = 393; 59.39 % female; mean age 58.65 ±â€Š8.85 years) were included. Endoscopic success was achieved in 87.84 % [(95 % CI, 80.25 to 92.78); I 2  = 11.96 %] with a mean number of 2.50 ±â€Š0.49 treatment sessions and average of 12.40 ±â€Š3.82 bands applied. For 8 studies comparing EBL (n = 143) versus APC (n = 174), there was no difference in baseline patient characteristics. However, endoscopic success was significantly higher for EBL [OR 6.04 (95 % CI 1.97 to 18.56; P  = 0.002], requiring fewer treatment sessions (2.56 ±â€Š0.81 versus 3.78 ±â€Š1.17; P  < 0.001). EBL was also associated with a greater increase in post-procedure hemoglobin [mean difference 0.35 (95 % CI 0.07 to 0.62; P  = 0.0140], greater reduction in transfusions required [mean difference -1.46 (95 % CI -2.80 to -0.12; P  = 0.033], and fewer rebleeding events [OR 0.11 (95 % CI, 0.04 to 0.36); P  < 0.001]. There was no difference in adverse events or bleeding-associated mortality ( P  > 0.050). Conclusions EBL appears to be safe and effective for treatment of GAVE, with improved outcomes when compared to APC.

Endoscopic gallbladder drainage for symptomatic gallbladder disease: a cumulative systematic review meta-analysis.

BACKGROUND: Endoscopic ultrasound (EUS)-guided transmural or endoscopic retrograde cholangiography (ERC)-based transpapillary drainage may provide alternative treatment strategies for high-risk surgical candidates with symptomatic gallbladder (GB) disease. The primary aim of this study was to perform a systematic review and meta-analysis to investigate the efficacy and safety of endoscopic GB drainage for patients with symptomatic GB disease. METHODS: Searches of PubMed, EMBASE, Web of Science, and Cochrane Library databases were performed in accordance with PRISMA and MOOSE guidelines. Pooled proportions were calculated for measured outcomes including technical success, clinical success, adverse event rate, recurrence rate, and rate of reintervention. Subgroup analyses were performed for transmural versus transpapillary, transmural lumen apposing stent (LAMS), and comparison to percutaneous transhepatic drainage. Heterogeneity was assessed with I2 statistics. Publication bias was ascertained by funnel plot and Egger regression testing. RESULTS: Thirty-six studies (n = 1538) were included. Overall, endoscopic GB drainage achieved a technical and clinical success of 87.33% [(95% CI 84.42-89.77); I2 = 39.55] and 84.16% [(95% CI 80.30-87.38); I2 = 52.61], with an adverse event rate of 11.00% [(95% CI 9.25-13.03); I2 = 7.08]. On subgroup analyses, EUS-guided transmural compared to ERC-assisted transpapillary drainage resulted in higher technical and clinical success rates [OR 3.91 (95% CI 1.52-10.09); P = 0.005 and OR 4.59 (95% CI 1.84-11.46); P = 0.001] and lower recurrence rate [OR 0.17 (95% CI 0.06-0.52); P = 0.002]. Among EUS-guided LAMS studies, technical success was 94.65% [(95% CI 91.54-96.67); I2 = 0.00], clinical success was 92.06% [(95% CI 88.65-94.51); I2 = 0.00], and adverse event rate was 11.71% [(95% CI 8.92-15.23); I2 = 0.00]. Compared to percutaneous drainage, EUS-guided drainage possessed a similar efficacy and safety with significantly lower rate of reintervention [OR 0.05 (95% CI 0.02-0.13); P < 0.001]. DISCUSSION: Endoscopic GB drainage is a safe and effective treatment for high-risk surgical candidates with symptomatic GB disease. EUS-guided transmural drainage is superior to transpapillary drainage and associated with a lower rate of reintervention compared to percutaneous transhepatic drainage.

Hybrid Stomach-Intestinal Chromatin States Underlie Human Barrett's Metaplasia.

BACKGROUND & AIMS: Tissue metaplasia is uncommon in adults because established cis-element programs resist rewiring. In Barrett's esophagus, the distal esophageal mucosa acquires a predominantly intestinal character, with notable gastric features, and is predisposed to developing invasive cancers. We sought to understand the chromatin underpinnings of Barrett's metaplasia and why it commonly displays simultaneous gastric and intestinal properties. METHODS: We profiled cis-regulatory elements with active histone modifications in primary human biopsy materials using chromatin immunoprecipitation followed by DNA sequencing. Mutations in Barrett's esophagus were examined in relation to tissue-specific enhancer landscapes using a random forest machine-learning algorithm. We also profiled open chromatin at single-cell resolution in primary Barrett's biopsy specimens using the assay for transposase-accessible chromatin. We used 1- and 2-color immunohistochemistry to examine protein expression of tissue-restricted genes. RESULTS: Barrett's esophagus bears epigenome fingerprints of human stomach and intestinal columnar, but not esophageal squamous, epithelia. Mutational patterns were best explained as arising on the epigenome background of active gastric cis-elements, supporting the view that adjoining stomach epithelium is a likely tissue source. Individual cells in Barrett's metaplasia coexpress gastric and intestinal genes, reflecting concomitant chromatin access at enhancers ordinarily restricted to one or the other epithelium. Protein expression of stomach-specific mucins; CLDN18; and a novel gastric marker, ANXA10, showed extensive tissue and subclonal heterogeneity of dual stomach-intestinal cell states. CONCLUSIONS: These findings reveal mixed and dynamic tissue-restricted chromatin states and phenotypic heterogeneity in Barrett's esophagus. Pervasive intragland variation argues against stem-cell governance of this phenotype.

Lead-Time Trajectory of CA19-9 as an Anchor Marker for Pancreatic Cancer Early Detection.

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.

Gastrointestinal Hemorrhage: A Manifestation of the Telomere Biology Disorders.

OBJECTIVE: To describe the clinical features, therapeutic interventions, and patient outcomes of gastrointestinal (GI) hemorrhage in individuals with a telomere biology disorder, including dyskeratosis congenita, Hoyeraal-Hreidarsson syndrome, Revesz syndrome, and Coats plus. STUDY DESIGN: Clinical Care Consortium for Telomere Associated Ailments members were invited to contribute data on individuals with telomere biology disorders at their institutions who experienced GI bleeding. Patient demographic, laboratory, imaging, procedural, and treatment information and outcomes were extracted from the medical record. RESULTS: Sixteen patients who experienced GI hemorrhage were identified at 11 centers. Among 14 patients who underwent genetic testing, 8 had mutations in TINF2, 4 had mutations in CTC1 or STN1, and 1 patient each had a mutation in TERC and RTEL1. Ten patients had a history of hematopoietic cell transplantation. The patients with Coats plus and those without Coats plus had similar clinical features and courses. Angiodysplasia of the stomach and/or small bowel was described in 8 of the 12 patients who underwent endoscopy; only 4 had esophageal varices. Various medical interventions were trialed. No single intervention was uniformly associated with cessation of bleeding, although 1 patient had a sustained response to treatment with bevacizumab. Recurrence was common, and the overall long-term outcome for affected patients was poor. CONCLUSIONS: GI bleeding in patients with telomere biology disorders is associated with significant morbidity and with vascular ectasias rather than varices.

Clinical decision support system, using expert consensus-derived logic and natural language processing, decreased sedation-type order errors for patients undergoing endoscopy.

OBJECTIVE: Determination of appropriate endoscopy sedation strategy is an important preprocedural consideration. To address manual workflow gaps that lead to sedation-type order errors at our institution, we designed and implemented a clinical decision support system (CDSS) to review orders for patients undergoing outpatient endoscopy. MATERIALS AND METHODS: The CDSS was developed and implemented by an expert panel using an agile approach. The CDSS queried patient-specific historical endoscopy records and applied expert consensus-derived logic and natural language processing to identify possible sedation order errors for human review. A retrospective analysis was conducted to evaluate impact, comparing 4-month pre-pilot and 12-month pilot periods. RESULTS: 22 755 endoscopy cases were included (pre-pilot 6434 cases, pilot 16 321 cases). The CDSS decreased the sedation-type order error rate on day of endoscopy (pre-pilot 0.39%, pilot 0.037%, Odds Ratio = 0.094, P-value < 1e-8). There was no difference in background prevalence of erroneous orders (pre-pilot 0.39%, pilot 0.34%, P = .54). DISCUSSION: At our institution, low prevalence and high volume of cases prevented routine manual review to verify sedation order appropriateness. Using a cohort-enrichment strategy, a CDSS was able to reduce number of chart reviews needed per sedation-order error from 296.7 to 3.5, allowing for integration into the existing workflow to intercept rare but important ordering errors. CONCLUSION: A workflow-integrated CDSS with expert consensus-derived logic rules and natural language processing significantly reduced endoscopy sedation-type order errors on day of endoscopy at our institution.

The SAFE-T upper endoscopy tool: a web-based application for the point-of-care evaluation of gastroenterology fellow performance in upper endoscopy.

BACKGROUND: Attending assessment is a critical part of endoscopic education for gastroenterology fellows. The aim of this study was to develop and validate a concise, web-based assessment tool to evaluate real-time fellow performance in upper endoscopy. METHODS: We developed the Skill Assessment in Fellow Endoscopy Training (SAFE-T) upper endoscopy tool to capture both summative and formative feedback in a concise, five-part questionnaire. The tool mirrors the previously validated SAFE-T colonoscopy tool and is administered electronically via a web-based application. We evaluated the tool in a prospective study of 15 gastroenterology fellows (5 fellows each from Years 1-3 of training) over the 2018-2019 academic year. An independent reviewer evaluated a subset of these procedures and completed both the SAFE-T and Assessment of Competency in Endoscopy (ACE) upper endoscopy forms for reliability testing. RESULTS: Twenty faculty completed 413 SAFE-T evaluations of the 15 fellows in the study. The mean SAFE-T overall score differentiated each sequential fellow year of training, with first-year cases having lower performance than second-year cases (3.31 vs 4.25, P < 0.001) and second-year cases having lower performance than third-year cases (4.25 vs 4.56, P < 0.001). The mean SAFE-T overall score decreased with increasing case-complexity score, with straightforward compared with average cases (3.98 vs 3.39, P < 0.001) and average compared with challenging cases (3.39 vs 2.84, P = 0.042). In dual-observed procedures, the SAFE-T tool showed excellent inter-rater reliability with a Kappa agreement statistic of 0.815 (P = 0.001). The SAFE-T overall score also highly correlated with the ACE upper endoscopy overall hands-on score (r = 0.76, P = 0.011). CONCLUSIONS: We developed and validated the SAFE-T upper endoscopy tool-a concise and web-based means of assessing real-time gastroenterology fellow performance in upper endoscopy.

Endoscopically Injectable Shear-Thinning Hydrogels Facilitating Polyp Removal.

Submucosal elevation, the process of instilling material in the submucosal space for separation of the surface mucosa and deeper muscularis layer, is a significant aspect of the endoscopic mucosal resection of large lesions performed to facilitate lesion removal and maximize safety. Submucosal injection, when applied, has historically been performed with normal saline, though this is limited by its rapid dissipation; solutions ideally need to be easily injectable, biocompatible, and provide a long-lasting submucosal cushion with a desirable height. Here, reported is a new set of materials, endoscopically injectable shear-thinning hydrogels, meeting these requirements because of their biocompatible components and ability to form a solid hydrogel upon injection. These findings are supported by evaluation in a large animal model and ultimately demonstrate the potential of these shear-thinning hydrogels to serve as efficient submucosal injection fluids for cushion development. Given these unique characteristics, their broad application in mucosal resection techniques is anticipated.

Ambulatory Safety Nets to Reduce Missed and Delayed Diagnoses of Cancer.

BACKGROUND: An ambulatory safety net (ASN) is an innovative organizational intervention for addressing patient safety related to missed and delayed diagnoses of abnormal test results. ASNs consist of a set of tools, reports and registries, and associated work flows to create a high-reliability system for abnormal test result management. METHODS: Two ASNs implemented at an academic medical center are described, one focusing on colon cancer and the other on lung cancer. Data from electronic registries and chart reviews were used to evaluate the effectiveness of the ASNs, which were defined as follows: colon cancer-the proportion of patients who were scheduled for or completed a colonoscopy following safety net team outreach to the patient; lung cancer-the proportion of patients for whom the safety net was able to identify and implement appropriate follow-up, as defined by scheduled or completed chest CT. RESULTS: The effectiveness of the colon cancer ASN was 44.0%, and the effectiveness of the lung cancer ASN was 56.9%. The ASNs led to the development of registries to address patient safety, fostered collaboration among interdisciplinary teams of clinicians and administrative staff, and created new work flows for patient outreach and tracking. CONCLUSION: Two ASNs were successfully implemented at an academic medical center to address missed and delayed recognition of abnormal test results related to colon cancer and lung cancer. The ASNs are providing a framework for development of additional safety nets in the organization.

Understanding the evolving phenotype of vascular complications in telomere biology disorders.

Vascular complications such as bleeding due to gastrointestinal telangiectatic anomalies, pulmonary arteriovenous malformations, hepatopulmonary syndrome, and retinal vessel abnormalities are being reported in patients with telomere biology disorders (TBDs) more frequently than previously described. The international clinical care consortium of telomere-associated ailments and family support group Dyskeratosis Congenita Outreach, Inc. held a workshop on vascular abnormalities in the TBDs at the National Cancer Institute in October 2017. Clinicians and basic scientists reviewed current data on vascular complications, hypotheses for the underlying biology and developed new collaborations to address the etiology and clinical management of vascular complications in TBDs.