Screening for Colorectal Cancer.

Colorectal cancer (CRC) is the second leading cause of cancer death. Screening has been proven to reduce both cancer incidence and cancer-related mortality. Various screening tests are available, each with their own advantages and disadvantages and varying levels of evidence to support their use. Clinicians should offer CRC screening to average-risk persons aged 50 to 75 years; starting screening at age 45 years remains controversial. Screening may be beneficial in select persons aged 76 to 85 years, based on their overall health and screening history. Offering a choice of screening tests or sequentially offering an alternate test for those who do not complete screening can significantly increase participation.

Artificial Intelligence for Real-Time Prediction of the Histology of Colorectal Polyps by General Endoscopists.

BACKGROUND: Real-time prediction of histologic features of small colorectal polyps may prevent resection and/or pathologic evaluation and therefore decrease colonoscopy costs. Previous studies showed that computer-aided diagnosis (CADx) was highly accurate, though it did not outperform expert endoscopists. OBJECTIVE: To assess the diagnostic performance of histologic predictions by general endoscopists before and after assistance from CADx in a real-life setting. DESIGN: Prospective, multicenter, single-group study. (ClinicalTrials.gov: NCT04437615). SETTING: 6 centers across the United States. PARTICIPANTS: 1252 consecutive patients undergoing colonoscopy and 49 general endoscopists with variable experience in real-time prediction of polyp histologic features. INTERVENTION: Real-time use of CADx during routine colonoscopy. MEASUREMENTS: The primary end points were the sensitivity and specificity of CADx-unassisted and CADx-assisted histologic predictions for adenomas measuring 5 mm or less. For clinical purposes, additional estimates according to location and confidence level were provided. RESULTS: The CADx device made a diagnosis for 2695 polyps measuring 5 mm or less (96%) in 1252 patients. There was no difference in sensitivity between the unassisted and assisted groups (90.7% vs. 90.8%; P = 0.52). Specificity was higher in the CADx-assisted group (59.5% vs. 64.7%; P < 0.001). Among all 2695 polyps measuring 5 mm or less, 88.2% and 86.1% (P < 0.001) in the CADx-assisted and unassisted groups, respectively, could be resected and discarded without pathologic evaluation. Among 743 rectosigmoid polyps measuring 5 mm or less, 49.5% and 47.9% (P < 0.001) in the CADx-assisted and unassisted groups, respectively, could be left in situ without resection. LIMITATION: Decision making based on CADx might differ outside a clinical trial. CONCLUSION: CADx assistance did not result in increased sensitivity of optical diagnosis. Despite a slight increase, the specificity of CADx-assisted diagnosis remained suboptimal. PRIMARY FUNDING SOURCE: Olympus America Corporation served as the clinical study sponsor.

Effect of an online educational module incorporating real-time feedback on accuracy of polyp sizing in trainees: a randomized controlled trial.

BACKGROUND: Although polyp size dictates surveillance intervals, endoscopists often estimate polyp size inaccurately. We hypothesized that an intervention providing didactic instruction and real-time feedback could significantly improve polyp size classification. METHODS: We conducted a multicenter randomized controlled trial to evaluate the impact of different components of an online educational module on polyp sizing. Participants were randomized to control (no video, no feedback), video only, feedback only, or video + feedback. The primary outcome was accuracy of polyp size classification into clinically relevant categories (diminutive [1-5mm], small [6-9mm], large [≥10mm]). Secondary outcomes included accuracy of exact polyp size (inmm), learning curves, and directionality of inaccuracy (over- vs. underestimation). RESULTS: 36 trainees from five training programs provided 1360 polyp size assessments. The feedback only (80.1%, P=0.01) and video + feedback (78.9%, P=0.02) groups had higher accuracy of polyp size classification compared with controls (71.6%). There was no significant difference in accuracy between the video only group (74.4%) and controls (P=0.42). Groups receiving feedback had higher accuracy of exact polyp size (inmm) and higher peak learning curves. Polyps were more likely to be overestimated than underestimated, and 29.3% of size inaccuracies impacted recommended surveillance intervals. CONCLUSIONS: Our online educational module significantly improved polyp size classification. Real-time feedback appeared to be a critical component in improving accuracy. This scalable and no-cost educational module could significantly decrease under- and overutilization of colonoscopy, improving patient outcomes while increasing colonoscopy access.

Spectrum of Advanced Colorectal Neoplasia and Anticipated Yield of Average-Risk Screening in Veterans Under Age 50.

The incidence of early onset colorectal cancer, or colorectal cancer (CRC) diagnosed before age 50, is increasing.1 In response, multiple societal guidelines in the United States now recommend initiating CRC screening at age 45 in average-risk individuals (ie, those without high-risk clinical characteristics, such as bleeding, or iron deficiency anemia), inflammatory bowel disease, or family history of colorectal neoplasia.2 The Veterans Health Administration (VHA) is the largest integrated health system in the United States and is contending with how best to expand CRC screening access to this younger population in the setting of limited colonoscopy resources. Understanding the rate and anatomic location of colorectal neoplasia in Veterans younger than age 50 can inform the expected yield of different screening modalities. Prior work has shown that individuals undergoing colonoscopy for low-risk diagnostic indications have equivalent risk of colorectal neoplasia as those undergoing average-risk screening.3 This study and a recent meta-analysis4 reported that 3.6% (95% confidence interval, 1.9%-6.7%) to 3.7% (95% confidence interval, 3.0%-4.7%) of average-risk individuals age 45-49 have advanced colorectal neoplasia (ACN), defined as an advanced polyp or carcinoma; however, data specific to the VHA population are lacking.

Updates on Age to Start and Stop Colorectal Cancer Screening: Recommendations From the U.S. Multi-Society Task Force on Colorectal Cancer.

This document is a focused update to the 2017 colorectal cancer (CRC) screening recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer, which represents the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy. This update is restricted to addressing the age to start and stop CRC screening in average-risk individuals and the recommended screening modalities. Although there is no literature demonstrating that CRC screening in individuals under age 50 improves health outcomes such as CRC incidence or CRC-related mortality, sufficient data support the U.S. Multi-Society Task Force to suggest average-risk CRC screening begin at age 45. This recommendation is based on the increasing disease burden among individuals under age 50, emerging data that the prevalence of advanced colorectal neoplasia in individuals ages 45 to 49 approaches rates in individuals 50 to 59, and modeling studies that demonstrate the benefits of screening outweigh the potential harms and costs. For individuals ages 76 to 85, the decision to start or continue screening should be individualized and based on prior screening history, life expectancy, CRC risk, and personal preference. Screening is not recommended after age 85.

Diagnosis and Management of Cancer Risk in the Gastrointestinal Hamartomatous Polyposis Syndromes: Recommendations From the US Multi-Society Task Force on Colorectal Cancer.

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This U.S Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.

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.

Varied Trainee Competence in Cold Snare Polypectomy: Results of the COMPLETE Randomized Controlled Trial.

INTRODUCTION: Cold snare polypectomy (CSP) is strongly recommended as the optimal technique for the complete removal of small polyps. Though significant variability in polypectomy technique and quality has been established, the learning curve and impact of targeted training on CSP are unknown. Video feedback has shown promise as an effective pedagogy to improve performance among surgical trainees. We aimed to compare CSP performance between trainees who received video-based feedback and those who received conventional apprentice-based concurrent feedback. We hypothesized that video-based feedback would accelerate competence. METHODS: We conducted a single-blinded, randomized controlled trial on competence for CSP of polyps <1 cm, comparing video-based feedback with conventional feedback. We randomly assigned deidentified consecutively recorded CSP videos to blinded raters to assess using the CSP Assessment Tool. We shared cumulative sum learning curves every 25 CSP with each trainee. The video feedback trainees also received biweekly individualized terminal feedback. Control trainees received conventional feedback during colonoscopy. The primary outcome was CSP competence. We also assessed competence across domains and change over polypectomy volume. RESULTS: We enrolled and randomized 22 trainees, 12 to video-based feedback and 10 to conventional feedback, and evaluated 2,339 CSP. The learning curve was long; 2 trainees (16.7%) in the video feedback achieved competence, after a mean of 135 polyps, and no one in the control ( P = 0.481) achieved competence. Overall and in all steps of CSP, a higher percentage of the video feedback group met competence, increasing 3% every 20 CSP ( P = 0.0004). DISCUSSION: Video feedback aided trainees to competence in CSP. However, the learning curve was long. Our findings strongly suggest that current training methods are not sufficient to support trainees to competency by the completion of their fellowship programs. The impact of new training methods, such as simulation-based mastery learning, should be assessed to determine whether such methods can result in achievement of competence at a faster rate; ClinicalTrials.gov : NCT03115008.

Digital Point Solutions for Extending Contact Tracing Capacity.

BACKGROUND: Initial COVID-19 surges in the United States created a need for technology to supplement human resources to increase efficiency and efficacy. METHODS: Resolve to Save Lives worked with jurisdictions to co-design four technology solutions-Epi Viaduct data pipeline, Epi Contacts contact elicitation webform, Epi Locator contact information search plugin, and Epi Viewpoint case management system (CMS)-to expand the capacity of case investigation and contact tracing (CI/CT) teams. We assessed impact on reducing CI/CT time intervals for COVID-19 using product data and user feedback. RESULTS: Epi Viaduct accelerated the transfer of approximately 7,400,000 records from an electronic laboratory reporting system in a single jurisdiction to the respective CMS from more than 2.5 hours to less than 1 minute and reduced time to remove duplicate laboratory results from multiple days to less than 6 hours. Epi Contacts focused on increasing the efficacy of contact elicitation, and during a single period, 10% of index cases (9,440 of 96,319) completed Epi Contacts for a total of approximately 18,700 contacts elicited. User interviews indicated the tool increased speed of CI/CT workflows. In total, 134,410 searches were run in Epi Locator by 7320 distinct users-75% of which returned 1 or more person matches. A simple CMS, Epi Viewpoint, was developed and completed, but not deployed. CONCLUSIONS: Systems to mount large-scale population-based contact tracing programs were developed and implemented during the COVID-19 pandemic and can be adapted for CI/CT programs aiming to control the spread of other communicable diseases such as sexually transmitted diseases.

Optimizing Endoscopy Procedure Documentation Improves Guideline-Adherent Care in Upper Gastrointestinal Bleeding.

BACKGROUND AND AIMS: Upper GI bleeding (UGIB) is a common indication for inpatient esophagogastroduodenoscopy (EGD). Guideline adherence improves post-EGD care, including appropriate medication dosing/duration and follow-up procedures that reduce UGIB-related morbidity. We aimed to optimize and standardize post-EGD documentation to improve process and clinical outcomes in UGIB-related care. METHODS: We performed a prospective quality improvement study of inpatient UGIB endoscopies at an academic tertiary referral center during 6/2019-7/2021. Guidelines were used to develop etiology/severity-specific electronic health record note templates. Participants (39 faculty/15 trainees) completed 10-min training in template content/use. We collected pre/post-intervention process data on "Minimal Standard Report" (MSR) documentation including patient disposition, diet, and medications. We also recorded documentation of re-bleed precautions and follow-up procedures. Study outcomes included guideline-based medication prescriptions, ordering of follow-up EGD, and post-discharge re-bleeding. Pre/post-intervention analysis was performed using chi-square tests. RESULTS: From a pre-intervention baseline of 199 patients to 459 patients post-intervention, compliance improved with inpatient PPI (53.4-77.9%, p < 0.001) and discharge PPI (31.3-61.0%, p < 0.001) prescriptions. There was improvement in MSR completion (28.6-42.5%, p < 0.001). Compliance improved with octreotide prescriptions (75.0-93.6%, p = 0.002) and follow-up EGD order (61.3-87.1%, p < 0.001). There was no change in post-discharge re-bleeding. 82.6% of cases used templates. CONCLUSIONS: Our project leveraged endoscopy software to standardize documentation, resulting in improved clinical care behavior and efficiency. Our intervention required low burden of maintenance, and sustainability with high utilization over 9 months. Similar endoscopy templates can be applied to other health systems and procedures to improve care.

Adoption of Optimal Small (6-9 mm) Colorectal Polyp Resection Technique Over Time.

BACKGROUND: Cold snare polypectomy (CSP) is the preferred resection technique for small (6-9 mm) polyps due to lower rate of incomplete resection compared to cold forceps polypectomy (CFP) and improved safety profile over hot snare polypectomy (HSP). AIMS: To describe resection techniques for small (6-9 mm) polyps and determine factors associated with sub-optimal technique. METHODS: This was retrospective cohort study of colonoscopies performed by gastroenterological and surgical endoscopists from 2012 to 2019 where at least one 6-9 mm polyp was removed. Patient, provider, and procedure characteristics were collected. Univariate and multivariate regression analyses were performed to determine factors associated with sub-optimal technique. RESULTS: In total, 773 colonoscopies where 1,360 6-9 mm polyps removed by 21 endoscopists were included. CSP was used for 1,122 (82.5%), CFP for 61 (4.5%), and HSP for 177 (13.0%). Surgeon specialty was associated with CFP use (aOR 7.81; 95% CI 3.02-20.16). Polyp location in left colon (aOR 1.65; 95% CI 1.17-2.33) and pedunculated morphology (aOR 12.76; 95% CI 7.24-22.50) were associated with HSP. There was a significant increase in overall CSP use from 30.4% in 2012 to 96.8% in 2019. CONCLUSIONS: 82.5% of all 6-9 mm polyps removed from 2012 to 2019 were removed using a cold snare with significant increase in CSP from 2012 to 2019. Differences in how optimal technique was adopted over time based on specialty highlight the need for standardized practice guidelines and quality monitoring.

Early-Age Onset Colorectal Neoplasia in Average-Risk Individuals Undergoing Screening Colonoscopy: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Incidence and mortality associated with early-age onset colorectal cancer (EAO-CRC) is increasing, prompting professional society recommendations to lower the screening age in average-risk individuals. The yield of screening individuals younger than 50 years is not known. METHODS: A systematic review of 3 databases from inception through July 2020 was performed in all languages that reported colonoscopy findings in average-risk individuals younger than 50 years. The primary outcomes were EAO colorectal neoplasia (CRN) and advanced colorectal neoplasia (aCRN) prevalence. Subgroup analyses were performed based on sex, geographic location, time period, and age, including comparison with those aged 50-59 years. Generalized linear mixed model with random intercept logistic regression and fixed subgroup effects were performed. RESULTS: Of 10,123 unique articles, 17 studies published between 2002 and 2020, including 51,811 average-risk individuals from 4 continents, were included. The pooled rate of EAO-CRN was 13.7% (95% confidence interval [CI], 0.112%-0.168%) and EAO-aCRN was 2.2% (95% CI, 0.016%-0.031%). Prevalence of CRC was 0.05% (95% CI, 0.00029%-0.0008%). Rates of EAO-CRN were higher in men compared with women (relative risk, 1.71%; 95% CI, 1.49%-1.98%), and highest in the United States (15.6%; 95% CI, 12.2%-19.7%) compared with Europe (14.9%; 95% CI, 6.9%-29.3%), East Asia (13.4%; 95% CI, 10.3%-17.2%), and the Middle East (9.8%; 95% CI, 7.8%-12.2%) (P = .04) The rate of EAO-CRN in age groups 45-49 years and 50-59 years was 17.8% (95% CI, 14.5%-21.6%) and 24.8% (95% CI, 19.5%-30.8%), respectively (P = .04). The rate of EAO-aCRN in age group 45-49 years was 3.6% (95% CI, 1.9%-6.7%) and 4.2% (95% CI, 3.2%-5.7%), respectively (P = .69). CONCLUSIONS: The rate of aCRN in individuals aged 45-49 years was similar to the rate observed in individual aged 50-59 years, suggesting that expanding screening to this population could yield a similar impact on colorectal cancer risk reduction.

Updates on Age to Start and Stop Colorectal Cancer Screening: Recommendations From the U.S. Multi-Society Task Force on Colorectal Cancer.

This document is a focused update to the 2017 colorectal cancer (CRC) screening recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer, which represents the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy. This update is restricted to addressing the age to start and stop CRC screening in average-risk individuals and the recommended screening modalities. Although there is no literature demonstrating that CRC screening in individuals under age 50 improves health outcomes such as CRC incidence or CRC-related mortality, sufficient data support the U.S. Multi-Society Task Force to suggest average-risk CRC screening begin at age 45. This recommendation is based on the increasing disease burden among individuals under age 50, emerging data that the prevalence of advanced colorectal neoplasia in individuals ages 45 to 49 approaches rates in individuals 50 to 59, and modeling studies that demonstrate the benefits of screening outweigh the potential harms and costs. For individuals ages 76 to 85, the decision to start or continue screening should be individualized and based on prior screening history, life expectancy, CRC risk, and personal preference. Screening is not recommended after age 85.

Diagnosis and Management of Cancer Risk in the Gastrointestinal Hamartomatous Polyposis Syndromes: Recommendations From the US Multi-Society Task Force on Colorectal Cancer.

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This US Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.

Potency of the novel PolC DNA polymerase inhibitor CRS0540 in a disseminated Listeria monocytogenes intracellular hollow-fibre model.

BACKGROUND: Listeriosis is an orphan disease, which is nevertheless fatal in immunocompromised people. CRS0540 is a novel PolC DNA polymerase inhibitor that has demonstrated good in vitro and in vivo activity against Listeria monocytogenes. METHODS: Rodent-to-human allometry projection-based human population pharmacokinetics of CRS0540 were used for all studies. CRS0540 pharmacokinetics/pharmacodynamics studies in an intracellular hollow-fibre system model of disseminated listeriosis (HFS-Lister) examined the effect of eight treatment doses, administered daily over 7 days, in duplicate units. Total bacterial burden versus AUC/MIC exposures on each day were modelled using the inhibitory sigmoid Emax model, while CRS0540-resistant bacterial burden was modelled using a quadratic function. Ten thousand-subject Monte Carlo simulations were used to predict an optimal clinical dose for treatment. RESULTS: The mean CRS0540 intracellular/extracellular AUC0-24 ratio was 34.07 (standard error: 15.70) as measured in the HFS-Lister. CRS0540 demonstrated exposure-dependent bactericidal activity in the HFS-Lister, with the highest exposure killing approximately 5.0 log10 cfu/mL. The free drug AUC0-24/MIC associated with 80% of maximal kill (EC80) was 36.4. Resistance emergence versus AUC/MIC was described by a quadratic function, with resistance amplification at an AUC/MIC of 54.8 and resistance suppression at an AUC/MIC of 119. Monte Carlo simulations demonstrated that for the EC80 target, IV CRS0540 doses of 100 mg/kg achieved PTAs of >90% at MICs up to 1.0 mg/L. CONCLUSIONS: CRS0540 is a promising orphan drug candidate for listeriosis. Future PK/PD studies comparing it with penicillin, the standard of care, could lead to this drug as a new treatment in immunocompromised patients.

Evaluation of a fit-for-purpose assay to monitor antigen-specific functional CD4+ T-cell subpopulations in rheumatoid arthritis using flow cytometry-based peptide-MHC class-II tetramer staining.

Antigen-specific T cells can serve as a response biomarker in non-clinical or clinical immunotherapy studies in autoimmune disease. There are protocols with optimized multimer staining methods to detect peptide (p)MHCII+ CD4+ T cells, and some qualified and validated protocols for pMHCI+ CD8+ T cells. However, no protocol is fully or partially qualified to enumerate and characterize antigen-specific pMHCII+ CD4+ T cells from patient samples. Implementing such an assay requires a desired level of specificity and precision, in terms of assay repeatability and reproducibility. In transgenic type II collagen (CII)-immunized HLA-DR1/DR4 humanized mouse models of collagen-induced arthritis (CIA), CII259-273-specific T cells dominantly expand. Therefore antigen-specific T cells recognizing this epitope presented by rheumatoid arthritis (RA)-associated risk HLA-DR allomorphs are of interest to understand disease progression and responses to immunotherapy in RA patients. Using HLA-DRB1∗04:01 or ∗01:01-collagen type II (CII)259-273 tetramers, we evaluated parameters influencing precision and reproducibility of an optimized flow cytometry-based method for antigen-specific CD4+ T cells and eight specific subpopulations with and without tetramer positivity. We evaluated specificity, precision, and reproducibility for research environments and non-regulated laboratories. The assay has excellent overall precision with %CV<25% for intra-assay repeatability, inter-analyst precision, and inter-assay reproducibility. The precision of the assay correlated negatively with the cell viability after thawing, indicating that post-thaw viability is a critical parameter for reproducibility. This assay is suitable for longitudinal analysis of treatment response and disease activity outcome in RA patients, and adaptable for translational or immunotherapy clinical trial settings.

Updates on age to start and stop colorectal cancer screening: recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer.

This document is a focused update to the 2017 colorectal cancer (CRC) screening recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer, which represents the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy. This update is restricted to addressing the age to start and stop CRC screening in average-risk individuals and the recommended screening modalities. Although there is no literature demonstrating that CRC screening in individuals under age 50 improves health outcomes such as CRC incidence or CRC-related mortality, sufficient data support the U.S. Multi-Society Task Force to suggest average-risk CRC screening begin at age 45. This recommendation is based on the increasing disease burden among individuals under age 50, emerging data that the prevalence of advanced colorectal neoplasia in individuals ages 45 to 49 approaches rates in individuals 50 to 59, and modeling studies that demonstrate the benefits of screening outweigh the potential harms and costs. For individuals ages 76 to 85, the decision to start or continue screening should be individualized and based on prior screening history, life expectancy, CRC risk, and personal preference. Screening is not recommended after age 85.

Diagnosis and management of cancer risk in the gastrointestinal hamartomatous polyposis syndromes: recommendations from the U.S. Multi-Society Task Force on Colorectal Cancer.

The gastrointestinal hamartomatous polyposis syndromes are rare, autosomal dominant disorders associated with an increased risk of benign and malignant intestinal and extraintestinal tumors. They include Peutz-Jeghers syndrome, juvenile polyposis syndrome, the PTEN hamartoma tumor syndrome (including Cowden's syndrome and Bannayan-Riley-Ruvalcaba syndrome), and hereditary mixed polyposis syndrome. Diagnoses are based on clinical criteria and, in some cases, confirmed by demonstrating the presence of a germline pathogenic variant. The best understood hamartomatous polyposis syndrome is Peutz-Jeghers syndrome, caused by germline pathogenic variants in the STK11 gene. The management is focused on prevention of bleeding and mechanical obstruction of the small bowel by polyps and surveillance of organs at increased risk for cancer. Juvenile polyposis syndrome is caused by a germline pathogenic variant in either the SMAD4 or BMPR1A genes, with differing clinical courses. Patients with SMAD4 pathogenic variants may have massive gastric polyposis, which can result in gastrointestinal bleeding and/or protein-losing gastropathy. Patients with SMAD4 mutations usually have the simultaneous occurrence of hereditary hemorrhagic telangiectasia (juvenile polyposis syndrome-hereditary hemorrhagic telangiectasia overlap syndrome) that can result in epistaxis, gastrointestinal bleeding from mucocutaneous telangiectasias, and arteriovenous malformations. Germline pathogenic variants in the PTEN gene cause overlapping clinical phenotypes (known as the PTEN hamartoma tumor syndromes), including Cowden's syndrome and related disorders that are associated with an increased risk of gastrointestinal and colonic polyposis, colon cancer, and other extraintestinal manifestations and cancers. Due to the relative rarity of the hamartomatous polyposis syndromes, recommendations for management are based on few studies. This U.S. Multi-Society Task Force on Colorectal Cancer consensus statement summarizes the clinical features, assesses the current literature, and provides guidance for diagnosis, assessment, and management of patients with the hamartomatous polyposis syndromes, with a focus on endoscopic management.

Virtual Gastroenterology Fellowship Recruitment During COVID-19 and Its Implications for the Future.

BACKGROUND AND AIMS: Amid the COVID-19 pandemic, medical education organizations endorsed a virtual recruitment format, representing a stark change from traditional in-person interviews. We aimed to identify the attitudes and perceptions of Gastroenterology Fellowship Program Directors (PDs) and applicants regarding the virtual interview experience and the role of virtual interviews (VI) in the future. METHODS: We designed separate surveys targeting PDs and applicants using the Qualtrics software. At the end of the interview season, we e-mailed both survey links to all PDs and requested that they forward the applicant survey to their interviewed candidates. Surveys were voluntary and anonymous. Descriptive statistics were used to analyze the data with results presented as percentages. RESULTS: A total of 29.7% of PDs completed the survey. Compared to traditional interviews, VI were viewed by 46.5% of PDs to be very suboptimal or suboptimal. Yet, 69.1% envisioned a role for VI in the future. A total of 14.2% of applicants completed the survey. Compared to traditional interviews, VI were viewed by 42.3% of applicants to be very suboptimal or suboptimal. However, 61.8% saw a future role for VI. While both applicants and PDs reported that establishing an interpersonal connection was a disadvantage with VI, applicants placed more emphasis on this need for connection (p = 0.001). CONCLUSION: Overall, PDs and applicants report mixed views with regard to VI but anticipate that it may continue to have a future role. VI may augment future recruitment cycles with care taken to not disadvantage applicants, who rely heavily on the interview process to create personal connections with programs.

Modelling to Quantify the Likelihood that Local Elimination of Transmission has Occurred Using Routine Gambiense Human African Trypanosomiasis Surveillance Data.

BACKGROUND: The gambiense human African trypanosomiasis (gHAT) elimination programme in the Democratic Republic of Congo (DRC) routinely collects case data through passive surveillance and active screening, with several regions reporting no cases for several years, despite being endemic in the early 2000s. METHODS: We use mathematical models fitted to longitudinal data to estimate the probability that selected administrative regions have already achieved elimination of transmission (EOT) of gHAT. We examine the impact of active screening coverage on the certainty of model estimates for transmission and therefore the role of screening in the measurement of EOT. RESULTS: In 3 example health zones of Sud-Ubangi province, we find there is a moderate (>40%) probability that EOT has been achieved by 2018, based on 2000-2016 data. Budjala and Mbaya reported zero cases during 2017-18, and this further increases our respective estimates to 99.9% and 99.6% (model S) and to 87.3% and 92.1% (model W). Bominenge had recent case reporting, however, that if zero cases were found in 2021, it would substantially raise our certainty that EOT has been met there (99.0% for model S and 88.5% for model W); this could be higher with 50% coverage screening that year (99.1% for model S and 94.0% for model W). CONCLUSIONS: We demonstrate how routine surveillance data coupled with mechanistic modeling can estimate the likelihood that EOT has already been achieved. Such quantitative assessment will become increasingly important for measuring local achievement of EOT as 2030 approaches.