Natural history study of patients with familial platelet disorder with associated myeloid malignancy.

ABSTRACT: Deleterious germ line RUNX1 variants cause the autosomal dominant familial platelet disorder with associated myeloid malignancy (FPDMM), characterized by thrombocytopenia, platelet dysfunction, and a predisposition to hematologic malignancies (HMs). We launched a FPDMM natural history study and, from January 2019 to December 2021, enrolled 214 participants, including 111 patients with 39 different RUNX1 variants from 45 unrelated families. Seventy of 77 patients had thrombocytopenia, 18 of 18 had abnormal platelet aggregometry, 16 of 35 had decreased platelet dense granules, and 28 of 55 had abnormal bleeding scores. Nonmalignant bone marrows showed increased numbers of megakaryocytes in 12 of 55 patients, dysmegakaryopoiesis in 42 of 55, and reduced cellularity for age in 30 of 55 adult and 17 of 21 pediatric cases. Of 111 patients, 19 were diagnosed with HMs, including myelodysplastic syndrome, acute myeloid leukemia, chronic myelomonocytic leukemia, acute lymphoblastic leukemia, and smoldering myeloma. Of those 19, 18 were relapsed or refractory to upfront therapy and referred for stem cell transplantation. In addition, 28 of 45 families had at least 1 member with HM. Moreover, 42 of 45 patients had allergic symptoms, and 24 of 30 had gastrointestinal (GI) symptoms. Our results highlight the importance of a multidisciplinary approach, early malignancy detection, and wider awareness of inherited disorders. This actively accruing, longitudinal study will genotype and phenotype more patients with FPDMM, which may lead to a better understanding of the disease pathogenesis and clinical course, which may then inform preventive and therapeutic interventions. This trial was registered at www.clinicaltrials.gov as #NCT03854318.

Association of CDH1 Germline Variants and Colon Polyp Phenotypes in Patients with Hereditary Diffuse Gastric Cancer.

Background and Aims: Germline CDH1 variants resulting in E-cadherin loss of function result in an increased risk of diffuse type gastric cancer and lobular type breast cancer. However, the risk of developing other epithelial neoplasms, specifically colorectal cancer, is unknown. Methods: Patients enrolled in a prospective natural history study of hereditary gastric cancer who underwent at least one colonoscopy were evaluated. Results: Out of 300 patients with CDH1 pathogenic or likely pathogenic variants, 85 underwent colonoscopy. More than half of patients (56%, 48/85) had at least one colorectal polyp. Most of those patients (83%, 40/48) had at least one precancerous polyp (adenoma or sessile serrated lesion). More than half (56%) of patients younger than age 45 had a colorectal polyp. Of those with polyps, the most frequent CDH1 variant type was canonical splice site (27%, 13/48) followed by nonsense (21%, 10/48). There was no association between CDH1 variant type and increased likelihood of colorectal polyps. Conclusions: In summary, a majority of CDH1 variant carriers who underwent colonoscopy had colorectal polyps detected, and most subjects were less than 45 years old. This study of colorectal cancer risk based on the prevalence of colorectal polyps in the CDH1 population requires further investigation to appropriately counsel patients on colorectal cancer screening. Clinical trial registry website: https://clinicaltrials.gov/. Clinical trial number: NCT03030404.

Visualizing endoscopy-generated aerosols with laser light scattering (with videos).

BACKGROUND AND AIMS: Upper GI endoscopy is speculated to be an aerosol-generating procedure (AGP). Robust evidence exists for aerosol transmission of severe acute respiratory syndrome coronavirus 2. The quality of data available confirming aerosol generation during GI endoscopy is limited. We aimed to objectively demonstrate that GI endoscopy is an AGP and illustrate the mechanism by which the greatest risk for aerosolization of droplets during endoscopy may occur. METHODS: Aerosolized droplets generated during insertion and withdrawal of an endoscope and with passage of various tools through the endoscopic working channel using 2 experimental apparatuses modeling an upper GI tract (ie, a fluid-filled tube and a lamb esophagus) were qualitatively assessed by laser light scattering. RESULTS: Insertion and withdrawal of the upper endoscope into the upper GI tract models generated numerous aerosolized particles. A large number of brightly scattering particles were observed at the site of insertion and withdrawal of the endoscope. Passage of a cytology brush, biopsy forceps, and hemostatic clip through the working endoscope channel also generated aerosolized particles but in fewer numbers. There was no significant variation in quantity or brightness of droplets generated on testing different biopsy valve cap models or when suctioning fluid with an open versus closed biopsy valve cap. These results were reproducible over several trials. CONCLUSIONS: We illustrate in an objective manner that upper GI endoscopy is an AGP. These findings may have implications for transmission of infectious airborne pathogens outside of severe acute respiratory syndrome coronavirus 2 and can help to inform guidance on appropriate personal protective equipment use and other measures for transmission risk mitigation during GI endoscopy.

Efficacy and tolerability of colonoscopies in overweight and obese patients: Results from a national database on gastrointestinal endoscopic outcomes.

Background and study aims Gastroenterologists are encountering a rising number of obese patients requiring colonoscopy. Existing literature regarding colonoscopy outcomes in this population is scant and conflicting. We analyzed a nationwide cohort of patients to identify the effects of body mass index (BMI) on colonoscopy success, efficacy, and tolerability. Patients and methods The Clinical Outcomes Research Initiative (CORI) endoscopic database was queried for all colonoscopies in adults between 2008-2014. Patients were stratified into four cohorts based on BMI classification for comparison. Multivariable analysis was performed to identify the effect of BMI on procedure outcome, efficacy and tolerability. Results Of 41,401 procedures, 27,696 met study inclusion criteria. Of these, 49.4 % were performed for colorectal cancer screening, most commonly under anesthesia directed sedation. Patient discomfort was the reason for an incomplete colonoscopy in 18.7 % of all cases, and more frequent among the overweight and obese cohorts. An inadequate bowel preparation was most common in the class III obesity cohort. Compared to the normal BMI group, a BMI ≥ 30 and < 40 kg/m 2 was associated with an increased odds of an incomplete colonoscopy ( P  = 0.001for overweight, P  = 0.0004 for class I/II obesity), longer procedure ( P  < 0.05 for all) and poorer tolerance ( P  < 0.0001 for class I/II obesity, P  = 0.016 for class III obesity). Anesthesia-administered sedation was more commonly used than endoscopist directed sedation amongst the obese cohort compared with the normal BMI cohort ( P  < 0.0001). Conclusions Endoscopists should consider the increased odds of incomplete colonoscopy, longer procedures, and poorer tolerance when performing colonoscopy in obese patients to improve clinical management and procedural outcome.

Identifying who best tolerates moderate sedation: Results from a national database of gastrointestinal endoscopic outcomes.

BACKGROUND: With increasing volume and cost of gastrointestinal endoscopic procedures, the proper selection of patients for moderate sedation becomes increasingly relevant. The current literature lacks consistent findings that allow for appropriate selection of patients for moderate sedation. AIM: To analyze a nationwide registry of patients to identify patient and procedural factors associated with lower sedation requirements for endoscopy. METHODS: The Clinical Outcomes Research Initiative National Endoscopic Database was queried to assess adult patients undergoing moderate sedation for esophagogastroduodenoscopy (EGD) and colonoscopy from 2008 to 2014. Patients were stratified into two groups [low dose (LD) and high dose sedation] based on sedation requirements. Anthropometric, procedural, and anesthesia data were compared, and multivariable analysis was performed to identify factors associated with LD sedation. RESULTS: Of the 371102 patients included in the study, 63137 where stratified into the LD sedation group and 307965 were in the high dose group. Moderate sedation was managed primarily by endoscopists (50%) and anesthesia providers (47%). Patients undergoing EGDs and procedures performed in the inpatient setting, in ambulatory surgery centers, intensive care units or hospital wards, required less sedation than colonoscopies, outpatient procedures and procedures done in endoscopy suites, respectively (P < 0.0001 for all). On multivariable analysis, factors predictive of tolerance with lower sedation requirements for EGDs and colonoscopies were female gender, age ≥ 50, non-White race, Hispanic descent, body mass index ≤ 25 kg/m2, and higher American Society of Anesthesia Class (P < 0.0001 for all). CONCLUSION: Clinicians should consider these patient profiles in determining which patients will better tolerate moderate sedation vs those better suited for alternative sedation methods.

Social Media and Research Publication Activity During Early Stages of the COVID-19 Pandemic: Longitudinal Trend Analysis.

BACKGROUND: The COVID-19 pandemic has highlighted the importance of rapid dissemination of scientific and medical discoveries. Current platforms available for the distribution of scientific and clinical research data and information include preprint repositories and traditional peer-reviewed journals. In recent times, social media has emerged as a helpful platform to share scientific and medical discoveries. OBJECTIVE: This study aimed to comparatively analyze activity on social media (specifically, Twitter) and that related to publications in the form of preprint and peer-reviewed journal articles in the context of COVID-19 and gastroenterology during the early stages of the COVID-19 pandemic. METHODS: COVID-19-related data from Twitter (tweets and user data) and articles published in preprint servers (bioRxiv and medRxiv) as well as in the PubMed database were collected and analyzed during the first 6 months of the pandemic, from December 2019 through May 2020. Global and regional geographic and gastrointestinal organ-specific social media trends were compared to preprint and publication activity. Any relationship between Twitter activity and preprint articles published and that between Twitter activity and PubMed articles published overall, by organ system, and by geographic location were identified using Spearman's rank-order correlation. RESULTS: Over the 6-month period, 73,079 tweets from 44,609 users, 7164 journal publications, and 4702 preprint publications were retrieved. Twitter activity (ie, number of tweets) peaked in March 2020, whereas preprint and publication activity (ie, number of articles published) peaked in April 2020. Overall, strong correlations were identified between trends in Twitter activity and preprint and publication activity (P<.001 for both). COVID-19 data across the three platforms mainly concentrated on pulmonology or critical care, but when analyzing the field of gastroenterology specifically, most tweets pertained to pancreatology, most publications focused on hepatology, and most preprints covered hepatology and luminal gastroenterology. Furthermore, there were significant positive associations between trends in Twitter and publication activity for all gastroenterology topics (luminal gastroenterology: P=.009; hepatology and inflammatory bowel disease: P=.006; gastrointestinal endoscopy: P=.007), except pancreatology (P=.20), suggesting that Twitter activity did not correlate with publication activity for this topic. Finally, Twitter activity was the highest in the United States (7331 tweets), whereas PubMed activity was the highest in China (1768 publications). CONCLUSIONS: The COVID-19 pandemic has highlighted the potential of social media as a vehicle for disseminating scientific information during a public health crisis. Sharing and spreading information on COVID-19 in a timely manner during the pandemic has been paramount; this was achieved at a much faster pace on social media, particularly on Twitter. Future investigation could demonstrate how social media can be used to augment and promote scholarly activity, especially as the world begins to increasingly rely on digital or virtual platforms. Scientists and clinicians should consider the use of social media in augmenting public awareness regarding their scholarly pursuits.

Enhanced endoscopic detection of occult gastric cancer in carriers of pathogenic CDH1 variants.

BACKGROUND: Germline inactivating variants in the CDH1 tumor suppressor gene impart an elevated lifetime risk of diffuse gastric cancer. The current endoscopic surveillance method depends upon random gastric biopsies for early cancer detection. METHODS: Asymptomatic adults with pathogenic or likely pathogenic CDH1 variants referred for endoscopic gastric cancer surveillance were included in this retrospective cohort. Upper gastrointestinal endoscopy was performed according to the consensus Cambridge method, in the early period, or a systematic (Bethesda) protocol as part of an ongoing natural history study. The primary outcome measure was cancer detection. RESULTS: Collectively, 135 endoscopic surveillance procedures were performed in 120 patients. Twenty-six (19%, 26/135) procedures were performed using Cambridge method and 109 (81%) using the Bethesda protocol. Gastric signet ring cell carcinomas were detected in 15% (4/26) using the Cambridge method and 36% (40/109) using the Bethesda protocol (p < 0.05). Almost half (44.2%, 53/120) of patients later elected for prophylactic total gastrectomy, of whom 51 (96%, 51/53) had a signet ring cell carcinoma (T1a) discovered by histopathology. On a per endoscopy basis, the false-negative rates of detection using Cambridge method and Bethesda protocol were 80% (12/15) and 37.7% (17/45), respectively (p < 0.01). CONCLUSIONS: Gastric cancer detection was more frequent with implementation of a systematic surveillance protocol in CDH1 variant carriers. Given the decision for prophylactic surgery is often made by patients in the context of family history and pathologic result of surveillance biopsies, we propose the Bethesda protocol offers patients an opportunity to make more informed decisions.

Pancreatic neuroendocrine tumor presenting in indolent systemic mastocytosis: A case report.

INTRODUCTION: Systemic mastocystosis, a disorder of clonal mast cell expansion presents with symptoms of flushing, pruritus, musculoskeletal pain, gastrointestinal cramping and vascular instability. Patients with neuroendocrine tumors may present with similar symptoms due to the release of vasoactive mediators in both diseases. We report the co-occurrence of systemic mastocytosis and a neuroendocrine pancreatic tumor for which the patient received disease-specific treatment. CASE PRESENTATION: A 58-year-old woman with a history of indolent systemic mastocytosis and a serum tryptase of 51 ng/mL was diagnosed with a solid pancreatic lesion on ultrasound when assessing for organomegaly. Lesional biopsy was consistent with a pancreatic neuroendocrine tumor which was successfully resected. DISCUSSION: Presenting symptoms such as skin rashes, flushing, fatigue and diarrhea, are similar for systemic mastocytosis and neuroendocrine tumors. The co-occurrence of both diseases has not been previously reported. Activating mutations in KIT, which are a hallmark of systemic mastocytosis, may drive neoplastic proliferation in neuroendocrine tumors. Furthermore, mast cells infiltrating pancreatic tissue may have a trophic effect on the development of pancreatic neuroendocrine tumors. CONCLUSION: While challenging to diagnose both diseases presenting with similar symptoms, recognition of these distinct diseases is necessary to ensure timely treatment.

COVID-19: An analysis of social media and research publication activity during the early stages of the pandemic.

Objectives: The COVID-19 pandemic has highlighted the importance of rapid dissemination of scientific and medical discovery. Social media (SoMe) has become an invaluable platform in science and medicine. This study analyzed activity of SoMe (Twitter), preprints, and publications related to COVID-19 and gastroenterology (GI) during the COVID-19 pandemic. Methods: Data from Twitter, preprint servers and PubMed was collected and analyzed from December 2019 through May 2020. Global and regional geographic and gastrointestinal organ specific social media trends were compared to preprint and publication activity; any associations were identified. Results: Over the 6-month period, there were 73,079 tweets from 44,609 users, 7,164 publications, and 4,702 preprints. Twitter activity peaked during March while preprints and publications peaked in April 2020. Strong correlations were identified between Twitter and both preprints and publications activity (p<0.001 for both). While COVID-19 data across the 3 platforms concentrated on pulmonology/critical care, the majority of GI tweets pertained to pancreatology, most publications focused on hepatology, and most preprints covered hepatology and luminal GI (LGI). There were significant associations between Twitter activity and research for all GI subfields (p=0.009 for LGI, p=0.006 for hepatology and IBD, p=0.007 for endoscopy), except pancreatology (p=0.2). Twitter activity was highest in the US (7,331 tweets) whereas PubMed activity was highest in China (1,768 publications). Conclusions: The COVID-19 pandemic has highlighted the utility of SoMe as a vehicle for disseminating scientific information during a public health crisis. Scientists and clinicians should consider the use of SoMe in augmenting public awareness of their scholarly pursuits.

Escalation of Immunosuppressive Therapy for Inflammatory Bowel Disease Is Not Associated With Adverse Outcomes After Infection With Clostridium difficile.

BACKGROUND: Clostridium difficile infection (CDI) is common in patients with inflammatory bowel disease (IBD), often leading to diagnostic confusion and delays in IBD therapy escalation. This study sought to assess outcomes after CDI in IBD patients exposed to new or escalated immunosuppressive therapy. METHODS: This multicenter retrospective cohort study included IBD patients with documented CDI at 4 academic medical centers. Data were abstracted from clinical databases at each institution. Outcomes at 30 and 90 days were compared between patients undergoing new or intensified immunosuppressive therapy and those without therapy escalation. Continuous variables were compared using t tests, and proportions using chi-square tests. Multivariable logistic regression was used to determine the association of individual variables with severe outcomes (including death, sepsis, and/or colectomy) within 90 days. Secondary outcomes included CDI recurrence, rehospitalization, worsening of IBD, and severe outcomes within 30 days. RESULTS: A total of 207 adult patients with IBD and CDI were included, of whom 62 underwent escalation to biologic or corticosteroid therapy (median time to escalation, 13 days). Severe outcomes within 90 days occurred in 21 (15.6%) nonescalated and 1 (1.8%) therapy-escalated patients. Serum albumin <2.5 mg/dL, lactate >2.2 mg/dL, intensive care unit admission, hypotension, and comorbid disease were associated with severe outcomes. Likelihood of severe outcomes was decreased in patients undergoing escalation of IBD therapy after CDI (adjusted odds ratio [aOR], 0.12) and increased among patients aged >65 years (aOR, 4.55). CONCLUSIONS: Therapy escalation for IBD within 90 days of CDI was not associated with worse clinical outcomes. Initiation of immunosuppression for active IBD may therefore be appropriate in carefully selected patients after treatment of CDI.

Inpatient Choledocholithiasis Requiring ERCP and Cholecystectomy: Outcomes of a Combined Single Inpatient Procedure Versus Separate-Session Procedures.

OBJECTIVES: Separate-session endoscopic retrograde cholangiography (ERCP) and laparoscopic cholecystectomy (LC) is the usual method for management of inpatient choledocholithiasis. Our goal was to compare single operative-session LC and ERCP to a multi-session approach for both the same hospitalization and within 30 days after; there is limited data comparing the three groups. METHODS: A retrospective review on inpatients with choledocholithiasis that underwent ERCP and LC was performed. Single operative-session ERCP + LC (SOS group) and separate hospitalization ERCP + LC (DH group) were compared against the control cohort: separate-session ERCP + LC performed during the same hospitalization (SH group). RESULTS: Among the 214 cases, 37 (17%) had LC + ERCP performed under a single operative session (SOS), 130 (60.7%) cases had LC + ERCP performed in separate operative sessions during the same hospitalization (SH), and 47 (22%) cases had LC + ERCP performed in different hospitalizations, within 30 days (DH). There was no statistically significant difference in efficacy or adverse events. The SOS group had a statistically significant mean shorter length of hospital stay as compared to the SH and DH groups (5.46 vs 7.15 vs 9.38; p = 0.05 and 0.02). There was a statistically significant reduction in the total cost of care in the SOS group versus the SH group ($59,221 vs $75, 808; p = 0.007). CONCLUSION: The SOS approach is safe, efficacious, and cost-efficient when compared to separate operative sessions. This approach can be considered in situations where it is preferable for the patient to undergo a single session of anesthesia, without compromising technical success and safety.

A Prospective Evaluation of Ileocecal Valve Dysfunction and Intestinal Motility Derangements in Small Intestinal Bacterial Overgrowth.

BACKGROUND: Small intestinal bacterial overgrowth (SIBO) is an increasingly recognized clinical syndrome; however, its etiophathogenesis is poorly understood. We hypothesized that loss of gastric acid, a delayed intestinal transit, and ileocecal valve dysfunction may contribute to the genesis of this syndrome. AIMS: Our primary aim was to assess these parameters using wireless motility capsule (WMC) testing and to correlate them with the presence or absence of SIBO. METHODS: We prospectively evaluated 30 consecutive patients at a tertiary care center with suspected SIBO, diagnosed by lactulose hydrogen breath testing (LBT), and small bowel aspirate microbiology. Patients underwent WMC testing to assess ileocecal junction pressure (ICJP), small bowel transit time (SBTT), and regional gastrointestinal pH. RESULTS: Thirty patients completed testing; 15 had a positive LBT, and 11 had a positive aspirate culture. As compared with LBT-negative patients, ICJP was lower (27.8 vs. 72.7 mmHg, p = 0.027), SBTT was longer (10.0 vs. 1.1 h, p = 0.004), gastric pH was higher (3.63 vs. 2.42, p < 0.01), and small bowel pH was higher (6.96 vs. 6.61, p = 0.05). A hypotensive ICJP (<46.61 mmHg) was more prevalent in LBT-positive patients as compared with LBT-negative patients (73.3 vs. 14.29%, p = 0.003). Logistic regression models were used to assess the magnitude of each measured WMC parameter and the presence of SIBO. p values ≤0.05 were considered statistically significant. CONCLUSIONS: Patients with SIBO have significantly lower ICJP, prolonged SBTT, and a higher gastrointestinal pH as compared to those without SIBO. These abnormalities may play different roles in the pathogenesis of SIBO, facilitating more targeted treatment to prevent recurrences of SIBO.

Rectal indomethacin is protective against post-ERCP pancreatitis in high-risk patients but not average-risk patients: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Rectal indomethacin is a popular chemopreventive agent to help prevent post-ERCP pancreatitis (PEP). Previous meta-analyses have shown an overall protective effect for PEP in average-risk and high-risk patients. However, these meta-analyses are limited by a small number of studies. Recently, more trials have been published addressing this issue. The aim is to determine whether rectal indomethacin prevents PEP in average-risk and high-risk groups, after incorporating these new data. METHODS: A comprehensive search of multiple literature databases in April 2016 was performed. Human prospective randomized controlled trials with placebo controls that examined the effect of rectally administered indomethacin on the incidence of PEP were included. RESULTS: A total of 8 trials between 2007 and 2016 (n = 3778) were included. No significant publication bias existed. All studies used similar criteria to detect pancreatitis. Random effects model meta-analysis showed that the rate of PEP was significantly lower using indomethacin compared with placebo (relative risk, 0.43; 95% confidence interval, 0.28-0.65; P < .001) in high-risk patients. There was no significant statistical or clinical heterogeneity. Among average-risk patients, the rate of PEP was similar (non-significant) between the indomethacin and placebo groups (relative risk, 0.74; 95% confidence interval, 0.52-1.07; P = .115). The result of the main outcome remained robust in multiple sensitivity analyses. CONCLUSIONS: Rectal indomethacin given before or after ERCP is protective against PEP in high-risk patients versus placebo; however, it is not protective in average-risk patients versus placebo.