Clinical, Endoscopic, and Histopathologic Gastrointestinal Disease in an American Cohort With Behçet's Disease.

INTRODUCTION: Behçet's disease (BD) is a chronic systemic vasculitis characterized by oral and genital ulcers, uveitis, and skin lesions. Patients with BD may develop gastrointestinal (GI) disease; however, characterization of GI disease in American cohorts is lacking. In this article, we present clinical, endoscopic, and histopathologic GI findings in an American cohort of patients with BD. METHODS: Patients with established BD were evaluated prospectively at the National Institutes of Health. Demographic and clinical data were collected including BD manifestations and GI symptoms. Endoscopy with histopathologic sampling was performed for both clinical and research indications with written consent. RESULTS: Eighty-three patients were evaluated. The majority were female (83.1%) and white (75.9%). Mean age was 36 ± 14.8 years. GI symptoms were reported in 75% of cohort with nearly half of reporting abdominal pain (48.2%) and significant numbers reporting acid reflux, diarrhea, and nausea/vomiting. Esophagogastroduodenoscopy was performed in 37 patients; erythema and ulcers were the most common found abnormalities. Colonoscopy was performed in 32 patients with abnormalities including polyps, erythema, and ulcers. Endoscopy was normal in 27% of esophagogastroduodenoscopies and 47% of colonoscopies. Vascular congestion was demonstrated on the majority of random biopsies throughout the GI tract. Inflammation was not highly prevalent on random biopsies except in the stomach. Wireless capsule endoscopy was performed on 18 patients; ulcers and strictures were the most common abnormalities. DISCUSSION: GI symptoms were common in this cohort of American patients with BD. Endoscopic examination was often normal; however, histopathologic examination demonstrated vascular congestion throughout the GI tract.

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.

Organizing and Developing a GI Motility Lab in Community Practice: Challenges and Rewards.

PURPOSE OF REVIEW: Neurogastroenterology and motility is a rapidly evolving subspecialty that encompasses over 33% of gastroenterological disorders, and up to 50% of referrals to gastroenterology practice. It includes common problems such as dysphagia, gastroesophageal reflux disease, irritable bowel syndrome, chronic constipation, gastroparesis, functional dyspepsia, gas/bloating, small intestinal bacterial overgrowth, food intolerance and fecal incontinence Standard diagnostic tests such as endoscopy or imaging are normal in these conditions. To define the underlying mechanism(s)/etiology of these disorders, diagnostic motility tests are often required. These are best performed by well-trained personnel in a dedicated motility laboratory. Our purpose is to provide an up-to-date overview on how to organize and develop a motility laboratory based on our collective experiences in setting up such facilities in academia and community practice. RECENT FINDINGS: A lack of knowledge, training and facilities for providing diagnostic motility tests has led to suboptimal patient care. A motility laboratory is the hub for diagnostic and therapeutic motility procedures. Common procedures include esophageal function tests such as esophageal manometry and pH monitoring, anorectal function tests suchlike anorectal manometry, neurophysiology and balloon expulsion, dysbiosis and food intolerance tests such as hydrogen/methane breath tests, and gastrointestinal transit assessment. These tests provide an accurate diagnosis and guide clinical management including use of medications, biofeedback therapy, neuromodulation, behavioral therapies, evidence-based dietary interventions and endoscopic or surgical procedures. Further, there have been recent developments in billing and coding of motility procedures and training requirements that are not well known. This review provides a stepwise approach on how to set-up a motility laboratory in the community or academic practice and includes the rationale, infrastructure, staffing needs, commonly performed motility tests and their clinical utility, billing and coding strategies, training needs and economic considerations for setting up this service.

Evaluation of confocal laser endomicroscopy for detection of occult gastric carcinoma in CDH1 variant carriers.

BACKGROUND: Hereditary diffuse gastric cancer syndrome, attributed to inactivating germline CDH1 variants, is associated with an elevated lifetime risk of gastric cancer. We sought to evaluate cancer detection using probe-based confocal laser endomicroscopy (pCLE) during endoscopic surveillance. METHODS: A prospective, single-institution study was conducted in asymptomatic adults with pathogenic or likely pathogenic (P/LP) CDH1 variants. Subjects received endoscopic gastric surveillance using pCLE in conjunction with the Cambridge method (CM). Abnormalities visualized by pCLE were biopsied, followed by non-targeted mucosal biopsies according to the CM. Primary endpoint was to determine pCLE sensitivity for detection of occult SRC carcinoma compared to CM. RESULTS: Thirty-six patients with P/LP CDH1 variants underwent endoscopy using pCLE and CM. Majority were female (75%) with median age 47 years. Targeted biopsies of focal abnormalities on WLE were negative for carcinoma. Overall, 19.4% (7/36) patients had SRC detected on ≥1 biopsy. Non-targeted CM biopsies revealed SRC in 11.1% (4/36), whereas pCLE revealed SRC in 16.7% (6/36). Fifteen patients underwent total gastrectomy; all 15 explants contained occult carcinoma. In those 15 patients, the false-negative SRC detection rates for pCLE and CM were 67% and 87%, respectively. CONCLUSIONS: Confocal endomicroscopy alone has low sensitivity for occult cancer detection in CDH1 variant carriers, although it appeared no worse than the current recommended method and required fewer biopsies per patient. A more reliable endoscopic surveillance is needed as a viable alternative to surgery in this high-risk population (ClinicalTrials.gov, Number: NCT03648879).

Single-Organ and Multisystem Hypereosinophilic Syndrome Patients with Gastrointestinal Manifestations Share Common Characteristics.

BACKGROUND: Eosinophilic gastrointestinal diseases (EGIDs) are defined by marked eosinophilia in the gastrointestinal (GI) tract resulting in a wide variety of GI symptoms. When accompanied by blood hypereosinophilia (HE; absolute eosinophil count ≥1500/mm3), EGID can occur as an isolated GI disorder (hypereosinophilic syndrome [HES]/EGID overlap) or as part of a multisystem hypereosinophilic syndrome (Multisystem HES). OBJECTIVE: To describe the GI disease of patients categorized as those with HES/EGID overlap versus those with Multisystem HES. METHODS: Consecutively enrolled patients on a natural history protocol to study eosinophilia with biopsy-proven EGID involving the esophagus, stomach, small-bowel, and/or colon were evaluated for clinical, histopathologic, and endoscopic features by retrospective chart review. RESULTS: Among the 56 patients with EGID and HE, 34 were categorized as HES/EGID overlap and 22 as Multisystem HES. Demographics, GI symptoms, and associated comorbidities were similar between the 2 groups. Multisegment GI eosinophilia was present in 20 of 30 (67%) patients who underwent tissue sampling of all 4 GI segments. Tissue eosinophilia in all 4 GI segments was found in 5 of 30 (17%) patients. Dietary therapy was more common in patients with HES/EGID overlap (65% vs 23%, P = .0028). Patients with Multisystem HES were more likely to receive glucocorticoids (100% vs 79%, P = .0349) and nonglucocorticoid systemic therapies (77% vs 38%, P = .0061). One-third (8 of 22) of patients with Multisystem HES presented with isolated GI symptoms before developing extraintestinal manifestations at a median of 1 year (range, 0.25-15 years). CONCLUSION: There are striking clinical similarities between patients with Multisystem HES and those with HES/EGID overlap, despite differing treatment approaches. Moreover, Multisystem HES can present with isolated GI involvement. Larger prospective studies are needed to confirm these findings.

Characteristics of Clostridium difficile infection in patients hospitalized with myelodysplastic syndrome or acute myelogenous leukemia.

AIM: To evaluate factors associated with Clostridium difficile infection (CDI) and outcomes of CDI in the myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) population. METHODS: After IRB approval, all MDS/AML patients hospitalized at the University of Maryland Greenebaum Comprehensive Cancer Center between August 2011 and December 2013 were identified. Medical charts were reviewed for demographics, clinical information, development of CDI, complications of CDI, and mortality. Patients with CDI, defined as having a positive stool PCR done for clinical suspicion of CDI, were compared to those without CDI in order to identify predictors of disease. A t-test was used for comparison of continuous variables and chi-square or Fisher's exact tests were used for categorical variables, as appropriate. RESULTS: Two hundred and twenty-three patients (60.1% male, mean age 61.3 years, 13% MDS, 87% AML) had 594 unique hospitalizations during the study period. Thirty-four patients (15.2%) were diagnosed with CDI. Factors significantly associated with CDI included lower albumin at time of hospitalization (P < 0.0001), prior diagnosis of CDI (P < 0.0001), receipt of cytarabine-based chemotherapy (P = 0.015), total days of neutropenia (P = 0.014), and total days of hospitalization (P = 0.005). Gender (P = 0.10), age (P = 0.77), proton-pump inhibitor use (P = 0.73), receipt of antibiotics (P = 0.66), and receipt of DNA hypomethylating agent-based chemotherapy (P = 0.92) were not significantly associated with CDI. CONCLUSION: CDI is common in the MDS/AML population. Factors significantly associated with CDI in this population include low albumin, prior CDI, use of cytarabine-based chemotherapy, and prolonged neutropenia. In this study, we have identified a subset of patients in which prophylaxis studies could be targeted.

Unusually late-onset mycophenolate mofetil-related colitis.

PURPOSE: Serious gastrointestinal complications arising 13 years after the initiation of posttransplant immunosuppressant therapy with mycophenolate mofetil are reported. SUMMARY: Over a three-month period, a male heart transplant recipient who had taken oral mycophenolate mofetil (2 g daily) for 13 years as part of an immunosuppressant maintenance regimen developed diarrhea and weight loss leading to renal failure and metabolic acidosis. There was no evidence of opportunistic infection, and immunostaining for cytomegalovirus yielded negative results. Colonoscopy revealed areas of congested, erythematous, and nodular mucosa. Histological examination of mucosal biopsy specimens revealed pathological abnormalities typical of those seen in cases of mycophenolate mofetil-associated colitis. On discontinuation of mycophenolate mofetil use, the patient's diarrhea resolved and his renal function improved. Colitis, diarrhea, and other gastrointestinal complications are commonly reported in patients receiving mycophenolate mofetil, an immunosuppressant widely used to prevent rejection of solid organ or bone marrow transplants; however, the onset of such symptoms after more than a decade of continuous use of the drug has not been previously reported. This case suggests that mycophenolate mofetil toxicity should be considered in the evaluation of late-onset posttransplant diarrhea regardless of the duration of therapy. CONCLUSION: A 33-year-old man maintained on mycophenolate mofetil for 13 years after heart transplantation developed diarrhea, weight loss, and acute kidney injury over a three-month period. Colonoscopy and biopsy revealed pathological changes consistent with mycophenolate mofetil toxicity, and the patient's symptoms resolved after the drug was discontinued.

Clostridium difficile-associated disease: adherence with current guidelines at a tertiary medical center.

AIM: To assess adherence with the the Society for Healthcare Epidemiology of America (SHEA)/ the Infectious Diseases Society of America (IDSA) guidelines for management of Clostridium difficile (C. difficile)-associated disease (CDAD) at a tertiary medical center. METHODS: All positive C. difficile stool toxin assays in adults between May 2010 and May 2011 at the University of Maryland Medical Center were identified. CDAD episodes were classified as guideline adherent or non-adherent and these two groups were compared to determine demographic and clinical factors predictive of adherence. Logistic regression analysis was performed to assess the effect of multiple predictors on guideline adherence. RESULTS: 320 positive C. difficile stool tests were identified in 290 patients. Stratified by disease severity criteria set forth by the SHEA/IDSA guidelines, 42.2% of cases were mild-moderate, 48.1% severe, and 9.7% severe-complicated. Full adherence with the guidelines was observed in only 43.4% of cases. Adherence was 65.9% for mild-moderate CDAD, which was significantly better than in severe cases (25.3%) or severe-complicated cases (35.5%) (P < 0.001). There was no difference in demographics, hospitalization, ICU exposure, recurrence or 30-d mortality between adherent and non-adherent groups. A multivariate model revealed significantly decreased adherence for severe or severe-complicated episodes (OR = 0.18, 95%CI: 0.11-0.30) and recurrent episodes (OR = 0.46, 95%CI: 0.23-0.95). CONCLUSION: Overall adherence with the SHEA/IDSA guidelines for management of CDAD at a tertiary medical center was poor; this was most pronounced in severe, severe-complicated and recurrent cases. Educational interventions aimed at improving guideline adherence are warranted.

Resveratrol induces catalytic bioscavenger paraoxonase 1 expression and protects against chemical warfare nerve agent toxicity in human cell lines.

Current advances in enzyme bioscavenger prophylactic therapy against chemical warfare nerve agent (CWNA) exposure are moving towards the identification of catalytic bioscavengers that can degrade large doses of organophosphate (OP) nerve agents without self destruction. This is a preferred method compared to therapy with the purified stoichiometric bioscavenger, butyrylcholinesterase, which binds OPs 1:1 and would thus require larger doses for treatment. Paraoxonase-1 (PON-1) is one such catalytic bioscavenger that has been shown to hydrolyze OP insecticides and contribute to detoxification in animals and humans. Here we investigated the effects of a common red wine ingredient, Resveratrol (RSV), to induce the expression of PON-1 in the human hepatic cell line HC04 and evaluated the protection against CWNA simulants. Dose-response curves showed that a concentration of 20 microM RSV was optimal in inducing PON-1 expression in HC04 cells. RSV at 20 microM increased the extracellular PON-1 activity approximately 150% without significantly affecting the cells. Higher doses of RSV were cytotoxic to the cells. Resveratrol also induced PON-1 in the human lung cell line A549. RSV pre-treatment significantly (P = 0.05) protected the hepatic cells against exposure to 2x LD(50) of soman and sarin simulants. However, lung cells were protected against soman simulant exposure but not against sarin simulant exposure following RSV treatment. In conclusion, these studies indicate that dietary inducers, such as RSV, can up-regulate PON-1, a catalytic bioscavenger, which can then hydrolyze and protect against CWNA-induced toxicity, providing a prospective new method to protect against CWNA exposure.

Forskolin, an inducer of cAMP, up-regulates acetylcholinesterase expression and protects against organophosphate exposure in neuro 2A cells.

Bioscavenger prophylactic therapy using purified human acetylcholinesterase (AChE) or butylcholinesterase (BChE) is a promising treatment for future protection against chemical warfare nerve agent exposure. Potential immune response due to the complex structure of cholinesterases, mutations, post-translational modifications, and genetic variation is a limiting factor against purified enzyme therapy. We investigated an alternative bioscavenger approach using forskolin, an inducer of intracellular cyclic AMP (cAMP), which activates AChE promoter and up-regulates its expression. A mouse neuronal cell line, Neuro 2A, was treated with various doses of forskolin and analysis of the expressed enzyme indicates that the AChE activity was significantly increased in cells exposed to repeated administration of the drug every other day for 7-10 days. Cholinesterase enzyme assays showed that the enzyme activity was increased approximately 2-fold for the extracellular enzyme and 3-fold for the intracellular enzyme. The optimal dose found for extracellular enzyme production was 12-24 microM forskolin, while the optimal dose for intracellular was 12 microM. In parallel with the rise in the AChE level, the morphology of forskolin-treated cells showed neurite growth with increasing doses. Forskolin treatment protects Neuro 2A cells from diisopropylflurophophate (DFP), a surrogate of the organophosphate chemical warfare agents soman and sarin, induced toxicity in Neuro 2A cells. These results indicate that transcriptional inducers, such as forskolin, can sufficiently up-regulate cellular AChE production and protect cells against organophosphate toxicity.

Histone acetylase inhibitor trichostatin A induces acetylcholinesterase expression and protects against organophosphate exposure.

The biological effects of organophosphorous (OP) chemical warfare nerve agents (CWNAs) are exerted by inhibition of acetylcholinesterase (AChE), which prevents the hydrolysis of the neurotransmitter acetylcholine, leading to hypercholinergy, seizures/status epilepticus, respiratory/cardiovascular failure, and potentially death. Current investigations show that bioscavenger therapy using purified fetal bovine AChE in rodents and non-human primates and the more recently tested human butyrylcholinesterase, is a promising treatment for protection against multiple LD(50) CWNA exposures. Potential impediments, due to the complex structure of the enzyme, purification effort, resources, and cost have necessitated alternative approaches. Therefore, we investigated the effects of transcriptional inducers to enhance the expression of AChE to achieve sufficient protection against OP poisoning. Trichostatin A (TSA), an inhibitor of histone deacetylase that de-condenses the chromatin, thereby increasing the binding of transcription factors and mRNA synthesis, was evaluated for induction of AChE expression in various neuronal cell lines. Dose-response curves showed that a concentration of 333 nM TSA was optimal in inducing AChE expression. In Neuro-2A cells, TSA at 333 nM increased the extracellular AChE activity approximately 3-4 fold and intracellular enzyme activity 10-fold. Correlating with the AChE induction, TSA pre-treatment significantly protected the cells against exposure to the organophosphate diisopropylfluorophosphate, a surrogate for the chemical warfare agents soman and sarin. These studies indicate that transcriptional inducers such as TSA up-regulate AChE, which then can bioscavenge any organophosphates present, thereby protecting the cells from OP-induced cytotoxicity. In conclusion, transcriptional inducers are prospective new methods to protect against CWNA exposure.