MedStar Washington Hospital Center, USA; Georgetown University School of Medicine, USA.

The volume-activated chloride channel (VACC) serves vital cellular functions in secretion and cell volume regulation via regulatory volume decrease (RVD) in various epithelia. Previously, we have shown that RVD in primary CF mouse cholangiocytes is impaired. Thus, the effect of CFTR defect on VACC and RVD in CF human immortalized cholangiocyte cell (HBDC) was examined in comparison with those in normal HBDC by using cell volume measurement and whole-cell patch clamp techniques, respectively. The CF HBDC had an impaired RVD, which was not further inhibited by removing the extracellular calcium or administering BAPTA-AM, NPPB, or DIDS. When exposed to a hypotonic solution, CF HBDC exhibited large, outwardly rectified currents with time-dependent inactivation at a positive potential. The amplitude of the outward currents was about three times that of the inward currents. The amplitude and reversal potential of VACC was dependent on chloride concentration. The VACC was significantly inhibited by replacing chloride with gluconate, glutamate, sucrose, or acetate in the hypotonic solution as well as by an administration of NPPB or tamoxifen, classical VACC inhibitors. Surprisingly, the VACC amplitude is greater in CF HBDC than in normal HBDC, suggesting that the channel density or open probability of VACC is increased, thus CFTR may have inhibitory effects on VACC. On the contrary, the amplitude of the volume-activated potassium current is lower in CF HBDC, suggesting the potassium channel density or open probability is decreased in CF cholangiocytes and/or CFTR may have regulatory effects on volume-activated potassium current. In conclusion, RVD is impaired in CF human cholangiocytes. The VACC of CF human cholangiocytes has similar electrophysiological characteristics as that of normal cholangiocytes but its activity is augmented in CF cholangiocytes, while volume-activated potassium current is decreased in CF human cholangiocytes, providing a fundamental underlying pathophysiologic mechanism for the impaired RVD in CF cholangiocytes.

BACKGROUND Gastric cancer significantly contributes to cancer mortality globally. Gastric intestinal metaplasia (GIM) is a stage in the Correa cascade and a premalignant lesion of gastric cancer. The natural history of GIM formation and progression over time is not fully understood. Currently, there are no clear guidelines on GIM surveillance or management in the United States. AIM To investigate factors associated with GIM development over time in African American-predominant study population. METHODS This is a retrospective longitudinal study in a single tertiary hospital in Washington DC. We retrieved upper esophagogastroduodenoscopies (EGDs) with gastric biopsies from the pathology department database from January 2015 to December 2020. Patients included in the study had undergone two or more EGDs with gastric biopsy. Patients with no GIM at baseline were followed up until they developed GIM or until the last available EGD. Exclusion criteria consisted of patients age < 18, pregnancy, previous diagnosis of gastric cancer, and missing data including pathology results or endoscopy reports. The study population was divided into two groups based on GIM status. Univariate and multivariate Cox regression was used to estimate the hazard induced by patient demographics, EGD findings, and Helicobacter pylori (H. pylori) status on the GIM status. RESULTS Of 2375 patients who had at least 1 EGD with gastric biopsy, 579 patients were included in the study. 138 patients developed GIM during the study follow-up period of 1087 d on average, compared to 857 d in patients without GIM (P = 0.247). The average age of GIM group was 64 years compared to 56 years in the non-GIM group (P < 0.001). In the GIM group, adding one year to the age increases the risk for GIM formation by 4% (P < 0.001). Over time, African Americans, Hispanic, and other ethnicities/races had an increased risk of GIM compared to Caucasians with a hazard ratio (HR) of 2.12 (1.16, 3.87), 2.79 (1.09, 7.13), and 3.19 (1.5, 6.76) respectively. No gender difference was observed between the study populations. Gastritis was associated with an increased risk for GIM development with an HR of 1.62 (1.07, 2.44). On the other hand, H. pylori infection did not increase the risk for GIM. CONCLUSION An increase in age and non-Caucasian race/ethnicity are associated with an increased risk of GIM formation. The effect of H. pylori on GIM is limited in low prevalence areas.

Introduction: The association between inflammatory bowel disease (IBD) and risk of developing Hodgkin (HL) or non-Hodgkin lymphoma (NHL) is established in scientific literature. It is unclear if this risk is inherited in IBD or related to using immunomodulatory therapy in IBD. Here, we represent a study based on the National Inpatient Sample (NIS) database, the largest all-payer inpatient database in the USA, to analyse the trends of HL and NHL in IBD hospitalizations over time and examine the role of age, sex, and race on this association. Methods: We analysed the NIS data of adult hospitalizations for all IBD hospitalizations with lymphoma either as a primary or secondary discharge code from 2003-2017 using the validated ICD-9/10 codes. Age, sex and racial demographic factors were collected. Trend analysis of HL and NHL was performed with Cochran-Armitage and Jonckheere-Terpstra tests. Results: Overall Trends: From 2003 to 2017, a total of 734 (0.03%) and 8093 (0.36%) out of 2,235,413 ulcerative colitis (UC) hospitalizations and 1325 (0.1%) and 10803 (0.8%) out of 1,324,746 Crohn’s disease (CD) hospitalizations were related to HL and NHL respectively. Between 2003-2017, there has been a 25% and 32.56 % increase (PTrend < 0.007) in the rate of HL and NHL related admissions in UC group, and a 25% and 63.33% increase (PTrend < 0.02) in the rate of HL and NHL related admissions in CD group. Age: In NHL group, in both UC and CD cohorts, the age group > 65 had higher proportional prevalence than other age groups (P < 0.005), but similar finding was not seen in HL group, in both UC and CD cohorts. Sex: In NHL group, there was an increasing trend of female prevalence from 37.78% to 44.78% and 38.69% to 50.27% in UC and CD cohorts respectively (PTrend < 0.007). Similar trend was not seen in the HL group in both UC and CD. Ethnicity: In both UC and CD cohorts, HL and NHL related admissions appeared to be predominant in white patients, outweighing other races by at least 4 times. Conclusion: Our study demonstrates an increasing trend of HL and NHL related hospitalizations in IBD patients from 2003-2017. In both UC and CD cohorts, there appears to be an increasingly female predominance of NHL, but not HL. HL and NHL related admissions in both UC and CD was predominantly in white patients. While an increased use of immunomodulatory therapy may partly explain some of these findings, future studies are needed to validate these findings.Table 1.: Total number, trends, female and race proportion of hospitalized lymphoma in IBD population footnote: Number represent trend between 2003, and 2017, except female trend in Crohn’s with Hodgkins is between 2004 and 2017Figure 1.: Trends in annual prevalence of Hodgkin and non-Hodgkin lymphoma in Inflammatory bowel disease footnote: A: Trends in annual prevalence of Hodgkin lymphoma in Inflammatory bowel disease B: Trends in annual prevalence of non-Hodgkin lymphoma in Inflammatory bowel disease HL, Hodgkin lymphoma; NHL, non-Hodgkin lymphoma; UC, Ulcerative Colitis; CD, Crohn’s disease

Introduction: Whipple disease (WD) is a rare systemic disease that affects the gastrointestinal (GI) system. We used the National Inpatient Sample database to determine the most common reasons for admission in patients with WD, as well as to characterize epidemiologic factors associated with the disease. Methods: Patients with a primary or secondary ICD-10 diagnosis of WD (K90. 81) from 2016-2018 were included. Patients with a diagnosis of pancreatic malignancy were excluded as patients with Whipple procedure mislabeled as WD. Frequency rank procedures were used to determine the most common reasons for hospitalization. Continuous variable and categorical variables were compared between patients with Whipple disease and other hospitalizations using logistic regressions and Pearson chi-squared analysis, respectively. Results: An estimated 490 patients had a diagnosis of WD out of 107,001,355 inpatient encounters, a prevalence of 4.6 per 1 million inpatient encounters. In-hospital mortality of patients with WD was 3.1% (SE = 1.0%).Patients with Whipple disease were significantly older than other hospitalized patients (P < 0.001) with a mean age of 60.2 years (SE = 1.6) compared to 50.0 years (SE = 0.1), respectively (Table 1). Patients were more likely to be male (P < 0.001), with males composing 67.3% of Whipple disease encounters. About a quarter of patients were hospitalized for a gastrointestinal pathology (25.5%), most commonly a nonspecific diagnosis of WD (11.2%), inflammation of gastric mucosa (4.1%), abdominal pain (3.1%), GI obstruction (3.1%) or GI hemorrhage (3.1%), and rarely peritoneal adhesiolysis (1.0%) (Figure 1). Patients with Whipple disease were commonly hospitalized for septicaemia or sepsis (11.2%) or cardiovascular diseases (11.2%). Total joint replacement or revision (4.1%), respiratory disease (8.2%), and diseases of the nervous system (6.1%) were less common reasons for admission (Figure 1). Conclusion: We found that patients hospitalized with WD are older than, and more likely to be male compared to other hospitalized patients. Although gastrointestinal pathology is the most common reason for hospitalization, it is classified as the primary reason for admission in only 25% of inpatient encounters. Outpatient presentation of WD might differ significantly from our presented hospitalized WD data. Further studies are necessary to better understand WD but it is limited by the rarity of the disease.Table 1.: Whipple Disease hospitalizations characteristics and demographics in comparison with other hospitalizations footnote: SE : standard error.Figure 1.: A: Reasons for gastrointestinal admissions in Whipple Disease. B: Reasons for admissions in Whipple Disease.

Introduction: Colonic wall thickening (CWT) is a common incidental finding on abdominal computed tomography (CT). Previous data has suggested a significant prevalence of colorectal cancer (CRC) in subjects with CWT, but predictors of CRC in those patients remain unclear. The aim of this study was to identify clinical factors associated with and predictive of colorectal cancer in subjects with CWT. Methods: Subjects with an abnormal abdominal CT and a follow-up colonoscopy between 2010-2020 were retrospectively reviewed. Patients with CWT in the CT were included in this study. Subjects with age < 18 or pre-existing gastrointestinal malignancy were excluded from this study. Focal CWT was defined as CWT that was localized and present in only one site. Pearson chi-square test and Mann-Whitney U test were used to compare categorical and continuous variables, respectively. A multivariable logistic regression model was performed to assess for factors independently associated with colorectal carcinoma in CWT subjects. Receiver operating characteristic (ROC) curve analysis was used to examine significant parameters in multivariable analysis. Area under the curve (AUC) > 0.7 was used for significant predictive value. Results: Overall, 1184 patients with abnormal abdominal CT underwent a colonoscopy with biopsy and 269 subjects (23%) with CWT on abdominal CT were identified and included in the analysis. In total, 36 subjects (13%) were found to have CRC on pathology. Distinct characteristics for patients with CRC included older age (68 vs 56; p< 0.05), lower hematocrit (29 vs 36; p< 0.05), higher platelet count (340 vs 249; p< 0.05), lower albumin (2.8 vs 3.3; p< 0.05), and more frequent focal CWT (92 vs 72%; p< 0.05) compared to those without CRC. No significant differences were found in terms of gender, race, BMI, tobacco use, BUN, AST, and ALT levels (all p >0.05). Based on the multivariable logistic regression, low hematocrit (OR 0.86; CI 0.80-0.92), elevated platelets (OR 1.003; CI 1.001-1.005), and focal CWT (OR 4.31; CI 1.06-17.59) were independently associated with CRC in subjects with CWT (all p< 0.05). In ROC curve analysis of the independent variables, AUC for hematocrit, platelets, and focal CWT was 0.773, 0.732, and 0.600 respectively. Conclusion: Based on this study, low hematocrit, elevated platelets, and focal CWT were independently associated with CRC in patients with CWT. In addition, low hematocrit and elevated platelets could potentially be used as predictors of CRC in these subjects.Figure 1.: Receiver operating characteristic (ROC) curve analysis of significant parameters associated with colorectal cancer in patients with colonic wall thickening.Table 1.: Baseline characteristics and laboratory findings of patients with incidental colonic wall thickening with malignancy vs no malignancy

loss of appetite, abdominal cramping, bloating, and diarrhea were assessed using a daily electronic patient-reported outcome questionnaire to generate weekly TSS. Patients underwent upper endoscopy with biopsy at screening, week 14 of ENIGMA, and 2 timepoints during the OLE study. Histopathologic analyses were performed by a blinded central pathologist; EG and EoD were defined as $30 eos/hpf in $5 gastric hpfs and $30 eos/hpf in $3 duodenal hpfs, respectively. Results: As of March 2021, 13 patients with EG6EoD and 12 patients with EoD without EG received 94 weeks of lirentelimab (ENIGMA1OLE). At week 94, mean TSS was reduced by 70% in patients with EG6EoD and 81% in patients EoD without EG compared with baseline (Table 1). TSS decreased significantly from baseline through week 94 regardless of EG6EoD or EoD without EG (Figure 1). Gastro-duodenal eosinophil counts were significantly reduced. There were no drug-related serious adverse events. The most common adverse events were mild–moderate infusion-related reactions, mostly during the first infusion. Conclusion: In an OLE study, patients with EG6EoD or EoD without EG receiving lirentelimab for up to 94 weeks had sustained and similar reductions in TSS and eosinophil counts in gastric and duodenal biopsies—patients benefited regardless of whether the stomach was involved. Long-term treatment with lirentelimab (AK002) was well tolerated and holds promise for patients with EG and/ or EoD.

INTRODUCTION: Mycophenolate mofetil (MMF) is a commonly used immunosuppressive medication to prevent allograft rejection in solid organ transplant recipients. Undesirable gastrointestinal effects of MMF are mild and include nausea, vomiting, and diarrhea. However, more serious complications such as gastrointestinal hemorrhage have been reported. We present a rare case of MMF-induced ileocolitis leading to hemorrhagic shock. CASE DESCRIPTION/METHODS: A 50-year-old man with orthotopic heart transplant 3 months prior (on MMF 1000mg BID, tacrolimus 3mg qAM+2mg qPM, and prednisone 10 daily) presented with a two-week history of nausea, vomiting, abdominal pain, and bloody diarrhea. His hemoglobin was 9 mg/dL and CRP was 55 mg/L. CT imaging showed ileal wall thickening (Figure 1) and subsequent colonoscopy revealed multiple large ulcerations in the terminal ileum (Figure 2). Biopsies showed active chronic ileocolitis with ulceration and focal acute cryptitis, and were negative for HSV, CMV, fungi, and tuberculosis. His MMF was then suspected to be the cause of his symptoms and was discontinued along with tacrolimus. He was started on IV methylprednisolone 40 mg daily and cyclosporine. Although his diarrhea soon resolved, he developed recurrent hematochezia leading to hemorrhagic shock 14 days after discontinuation of MMF requiring IR embolization of branches of the ileocolic artery. These were most likely secondary to erosion of the large terminal ileal ulcers into the vasculature. Unfortunately, the patient continued to have bleeding which was complicated by peritonitis. He was taken urgently to surgery where resection of multiple areas of ischemic-appearing bowel from the terminal ileum and cecum. Pathology revealed hemorrhage, vascular congestion, and serositis. After surgery, the patient improved, and no further bleeding occurred. DISCUSSION: MMF in solid organ transplant patients can be associated with serious gastrointestinal complications, such as ileocolitis, ulcerations, and hemorrhage. Our patient had no prior history of IBD, infectious, or vascular etiologies that could explain the findings of terminal ileum ulcerations; therefore, it was determined that MMF was the cause of his ileocolitis. Endoscopic and histological features have been reported to mimic acute colitis, similar to IBD, graft versus host disease, or intestinal ischemia. Treatment involves discontinuing the offending agent and treatment of complications, such as hemorrhage with endoscopy, embolization, or surgical resection.Figure 1.: Terminal ileum wall thickening (arrows) shown on the transverse section of the CT scan abdomen (A) and the coronal section of MR enterorrhaphy (B).Figure 2.: Colonoscopy images showing multiple large terminal ileum ulcers (arrows in A and yellow square in B).

Introduction: Studies have shown that male patients have a significantly higher prevalence of adenomatous polyps (AP) compared to female patients, but the effect of gender on the prevalence of proximal serrated polyps (PSP) is relatively unknown. In addition, there is limited data in the literature that African Americans (AA) have a higher prevalence of advanced AP compared to Caucasians (C), but no definitive data on the effect of race on the prevalence of PSP. The aim of this study was to investigate and compare the effect of gender and race on the prevalence of AP and PSP found on screening colonoscopies in 2 tertiary hospitals with differing patient populations. Methods: All complete screening colonoscopies for patients with age > 50 years, either AA or C, with good to excellent bowel preparation performed by endoscopists with more than 5 years of experience, were reviewed at Medstar Washington Hospital Center (MWHC) from June 2015 to June 2017. Pathology reports were manually reviewed. PSPs included sessile serrated adenoma and hyperplastic polyps from the cecum to the splenic flexure. To validate the findings from MWHC, similar data was collected from Medstar Georgetown University Hospital (MGUH) from June 2016 to June 2017, with 75 consecutive cases for each endoscopist. Results: At MWHC, 1935 colonoscopies were performed by 15 endoscopists. The proportion of females (F) to males (M) was 53% vs 47%. 83% of the patients were AA and 17% were C. The prevalence of AP found on screening colonoscopy was significantly higher for M compared to F, 43% vs 35% (p<0.005), consistent with the existing literature. No difference in the prevalence of PSP was found between the two groups (M: 0.14% vs F: 8.75%, p=0.29). There was no difference in the prevalence of AP between the AA and C, 38% vs 39% (p=0.76), nor in the prevalence of PSP between the two groups, 9.28% vs 9.96%, (p=0.72). At MGUH, 675 colonoscopies were performed by 9 endoscopists. The proportion of F:M was 57% vs 43%. 31% were AA and 69% were C. The prevalence of AP was significantly higher for M compared to F, 34% vs 23% (p 0.05). 31% were AA and 69% were C. No difference was noted between the two races in the prevalence of AP (25% vs 28%, p=0.39) or PSP (4% vs 6%, p=0.32) Conclusion: Although the 2 different academic centers had different patient populations, AP was consistently higher in males than females. The prevalence of AP was not affected by the race. The prevalence of PSP was not affected by either race or gender.163_A Figure 1. Prevalence of adenomatous polyps and proximal serrated polyps in males and females at two tertiary care centers.163_B Figure 2. Prevalence of adenomatous polyps and proximal serrated polyps in African Americans and Caucasians at two tertiary care centers.

Introduction Recent studies have demonstrated that the protective effect of colonoscopy against colorectal cancer is lower in the proximal colon. Proximal serrated polyps, including sessile serrated adenomas and proximal hyperplastic polyps, can be frequently missed and pose a risk of interval cancers. Aim To investigate the overall adenoma detection rate (ADR) and the proximal serrated polyp detection rate (PSPDR) among academic gastroenterologists, community gastroenterologists, and colorectal surgeons from a single institution, all of whom have received formal training in colonoscopy during their fellowship. Methods All complete screening colonoscopies for patients aged 50 or older with a good to excellent bowel preparation performed by different endoscopists at Medstar Washington Hospital Center (Washington, DC) from July 2015 to December 2017 were reviewed. Pathology reports of the resected polyps were manually reviewed. Results A total of 2850 screening colonoscopies meeting the inclusion criteria were performed by 18 endoscopists (6 academic, 7 community, and 5 colorectal surgeons). There was no significant difference in the mean ADR among the three groups of endoscopists: academic gastroenterologists, community gastroenterologists, and colorectal surgeons (40.3% vs 36.0% vs 39.6%, respectively). However, academic gastroenterologists had a significantly higher PSPDR compared to community gastroenterologists or colorectal surgeons (12.3% vs 5.4% vs 4.5%, respectively, ANOVA p = 0.006). Conclusion Our novel data show that academic gastroenterologists had a significantly higher PSPDR compared to community gastroenterologists or colorectal surgeons despite a comparable overall ADR among the three groups. PSPDR may be considered as an important quality indicator for colonoscopy, apart from ADR.

Metoclopramide, the only FDA-approved drug for gastroparesis, is widely used by patients with multiple medical conditions, such as diabetes, that put them at increased risk for cardiac events.Since metoclopramide tablets and injection were approved in 1980, there have been very few reports of torsades de pointes, cardiac arrest, and/or sudden death associated with the use of the FDA-approved doses of the oral formulation.Literature reports of cardiac events are primarily associated with parenteral administration in patients who are medically compromised, but there has been a lack of information for prescribing physicians regarding the effects of metoclopramide on the QT interval.Evoke Pharma is developing a nasal spray formulation of metoclopramide for patients with diabetic gastroparesis and performed the first metoclopramide thorough electrocardiogram (ECG) study.Aims: The primary objective of the study was to define the ECG effects of an 80 mg supratherapeutic dose of metoclopramide nasal spray administered to healthy adult male and female subjects.The secondary objectives were to define the ECG effects of a 20 mg metoclopramide nasal spray dose, and to assess assay sensitivity with an active control, moxifloxacin.In addition, the safety and pharmacokinetics of both doses of metoclopramide nasal spray were evaluated.Methods: The study was conducted using a double-blind, double-dummy, randomized, four-period crossover design.Subjects were randomized to receive placebo nasal spray, 20 mg metoclopramide nasal spray, 80 mg metoclopramide nasal spray, and 400 mg of oral moxifloxacin under fasting conditions in a random sequence separated by a minimum fourday washout period between doses.Safety was evaluated by adverse events, clinical laboratory test results, vital sign measurements, 12-lead safety ECG results, and physical and nasal examination findings.Results: Metoclopramide nasal spray did not increase the corrected QT interval at the therapeutic and supratherapeutic doses tested while the expected extent and pattern of change during moxifloxacin treatment was observed.Heart rate and PR interval increased modestly in the moxifloxacin arm, but there were no consistent or clinically significant changes associated with any of the treatments.Mean metoclopramide plasma PK exposure parameters (Cmax and AUC0-t) were approximately dose proportional across the 20 to 80 mg dose range of the nasal spray.There were no SAEs, no drops due to AE, and all 48 subjects completed the study.Conclusions: These negative ECG results for metoclopramide nasal spray at 80 mg (8 times the clinical dose) provide useful clinical information for prescribing physicians and their patients with acute or recurrent symptoms of diabetic gastroparesis who will most often be dosed with 10 mg of metoclopramide nasal spray before meals and at bedtime for 28 days. Mo1608