Amar Mandalia

Hispanics With Primary Biliary Cirrhosis Are More Likely to Have Features of Autoimmune Hepatitis and Reduced Response to Ursodeoxycholic Acid Than Non-Hispanics

BACKGROUND & AIMS Primary biliary cirrhosis (PBC) is a cholestatic disease that predominantly affects middle-aged Caucasian women. Studies have suggested that PBC has a more aggressive course in individuals of Hispanic ancestry. We investigated the clinical presentation and progression of PBC in an ethnically diverse population. METHODS We performed a cross-sectional study, analyzing data from Hispanic (n = 70) and non-Hispanic patients (n = 134) with PBC seen at the University of Miami/Jackson Memorial Hospital from January 1, 2000, through December 31, 2011. We compared demographics, clinical presentation, response to therapy, and outcomes between the groups. RESULTS Age at diagnosis, antimitochondrial antibody positivity, frequency of advanced histologic stage, use and dose of ursodeoxycholic acid (UDCA), and the presence of pruritus or fatigue were similar between groups. Hypothyroidism was less frequent among Hispanics (16% vs 29% in non-Hispanics; P = .04). Hispanic subjects were more likely to have overlap syndrome of PBC and autoimmune hepatitis than non-Hispanics (31% vs 13%; P = .002). After a median follow-up period of 3.65 years, a greater percentage of Hispanics had ascites (24% vs 12%; P = .03) and variceal bleeding (20% vs 7%; P = .01), although there were no differences in the number of deaths or liver transplants. Of 204 total patients, 180 received UDCA for at least 1 year. A lower proportion of Hispanic patients had a biochemical response to treatment (60% vs 88%; P < .0001). Independent predictors of poor biochemical response were younger age at diagnosis and Hispanic ethnicity. CONCLUSIONS In a cross-sectional study, patients of Hispanic ethnicity with PBC had an increased prevalence of overlap syndrome, reduced response to UDCA treatment, and more frequent complications of portal hypertension than non-Hispanic patients.

Predictive factors for clinically actionable computed tomography findings in inflammatory bowel disease patients seen in the emergency department with acute gastrointestinal symptoms

BACKGROUND The wide use of abdomino-pelvic computed tomography (APCT) in emergency departments (ED) has raised the concern for radiation exposure, costs and potential reactions to contrast agents. The aim of this study was to determine the yield and predictive factors for clinically actionable findings (CAF) in APCTs performed in patients with inflammatory bowel disease (IBD) who visit the ED. METHODS We performed a cross-sectional study including patients with IBD who visited the ED. Variables considered were demographics, IBD phenotype, clinical symptoms, IBD medication use prior to ED visit, laboratory values, and imaging results. The primary outcome was a composite of CAF, defined as new, intra-abdominal abscess or tumor, bowel obstruction, fistulae, diverticulitis, choledocholithiasis, or appendicitis. RESULTS 354 patients were included. One or more CAF were reported in 26.6% of the APCTs (32.1% in CD and 12.8% in UC [p<0.01]). Independent predictive variables of CAF in CD were: CRP level ≥5mg/dl (p=0.04), previous history of IBD surgery (p=0.037), Black race (p<0.01) and low body mass index (p<0.01). None of the study variables predicted CAF in UC. CONCLUSIONS The yield for CAF with APCT in the ED was high for CD patients but minimal for those with UC and was not improved by the use of contrast. Elevated CRP, low BMI, Black race and previous history of IBD surgery predicted CAF in CD but no variables were predictive of CAF in UC.

Fecal transplant is as effective and safe in immunocompromised as non-immunocompromised patients for Clostridium difficile

Dear Editor: Clostridium difficile infection (CDI) is a leading cause of nosocomial infection and is associated with significant morbidity andmortality. Immunocompromised (IC) patients are particularly at higher risk. Recurrence rates of up to 60 % have been reported after the third episode despite treatment with antibiotics. Recent published reports of fecalmicrobiota transplantation (FMT) in the IC population have shed light that the procedure proves to be effective and safe. No studies that compare the efficacy and adverse event rate of FMT between IC and non-IC patients currently exist. The aim of our study is to compare the response and serious adverse event (SAE) rates of FMT for recurrent or refractory CDI (RCDI) between IC patients and non-IC patients. We performed a single-center retrospective study on patients who received FMT for RCDI in a single tertiary care center. Donor stool was obtained from a universal donor, friend, or relative. We used a standardized protocol for preparation of stool used for FMT. Patients received FMT through the upper gastrointestinal route or by colonoscopy. Those who failed initial FMTwere eligible to receive additional FMT. Patients were considered IC as a result of one or more of the following: HIV infection (any CD4 count), AIDS-defining diagnosis or CD4<200/mm, inherited or primary immune disorders, active malignancy, and immunodeficient or immunosuppressed from a medical condition/medication including current or recent (<3 months) treatment with anti-neoplastic agent or immunosuppressant medications. Immunosuppressant medications included but were not limited tomonoclonal antibodies to B and T cells, anti-tumor necrosis factor agents, glucocorticoids, antimetabolites (azathioprine, 6-mercaptopurine, methotrexate), calcineurin inhibitors (tacrolimus and cyclosporine), and mycophenolate mofetil. Outcomes compared between the two populations included rates of overall and primary 12-week CDI response post-FMT and percentage of patients who experienced SAEs within 12 weeks of FMT. Overall response was defined as lack of relapse with diarrhea associated with a positive C difficile PCR within 12 weeks of the last FMT (patients were eligible to have up to three FMT prior to being considered as a FMT non-responder). Primary response was defined as lack of relapse with diarrhea associated with a positive C. difficile PCR testing within 12 weeks post single FMT. SAEs were defined as any death, life-threatening experience, hospitalization, or important medical event such as infection of inflammatory bowel disease flare within 12 weeks post-FMT. Patients were excluded from efficacy analysis if they did not have a minimum of 12 weeks post-FMT follow up. Data was collected from a total of 122 FMTs performed on 107 patients. Six patients were excluded due to loss of follow up during the post-FMT follow up period. Six were excluded from the efficacy analysis due to * Tanvi Dhere tdhere@emory.edu

Diverticulitis after fecal microbiota transplant for C. difficile infection.

and further molecular analysis. Follow-up at 4 years showed a normal psychomotor, social and intellectual development, scoliosis of the thoracic part of the backbone, and no facial or hand and feet dysmorphism. Using the comparative genomic hybridization technique we revealed deletions of 7q11.1–7q11.2, 16p11.2–16p13.2, 16p13.3, 16q11.2–16q12.2 and 19p13.1–19p13.3 chromosomal regions in the esophagus ( Figure 1 ) and no chromosomal aberrations in blood ( Figure 2 ) in the same patient resulting in somatic mosaicism. No other tissues were analyzed. We validated 19p13 deletion using quantitative real-time PCR and MLPA. Recent scientifi c reports suggest that in the process of cell diff erentiation genome rearrangements may occur ( 5–7 ). Th is somatic cell mosaicism can be formed aft er fertilization in the early stages of embryonic development, being one of the mechanisms for the diff erentiation of various tissues ( 8 ). More and more reports in the literature describe somatic mosaicism as well as the cause of various diseases ( 9 ). Th e chromosome deletions described by us in this paper are large DNA losses and may be pathogenic alterations with signifi cance in the etiology of this developmental defect. We suspect that 7q11.1–7q11.2, 16p11.2– 16p13.2, 16p13.3, 16q11.2–16q12.2 and 19p13.1–19p13.3 chromosomal regions may contain key genes, regulatory seque nces, or other genetic elements playing an important role in esophagus development. For example, the 19p13 chromosomal region contains the LDLR gene, which is involved in cholesterol metabolism. Cholesterol acts in the proper functioning of the Sonic Hedgehog signaling pathway, which is instrumental in patterning of the early embryo and is essential to foregut development ( 10 ). We hypothesize that genetic mosaicism may be the cause of the EA and this readily explains the diffi culty in identifying pathogenic mutations in patients with isolated EA.

Concurrent radiotherapy with carboplatin and cetuximab for the treatment of medically compromised patients with locoregionally advanced head and neck squamous cell carcinoma

Background: Cetuximab (Cx) + radiation therapy (RT) is well-tolerated and has improved survival in patients (pts) with locoregionally advanced head and neck squamous cell carcinomas (LA-HNSCC). However, its efficacy when compared to HD-DDP + RT has been questioned. At our institution, low-dose weekly carboplatin is added to Cx + RT for patients unsuitable for HD-DDP. Methods: We reviewed records of 16 patients with LA-HNSCC treated with definitive Cx + carboplatin + RT at the University of Miami from 2007 to 2011. Median follow-up was 24 months (range: 1–69 months). Results: Median age: 71.5 years (range: 57–90 years); 15 male, 1 female. ECOG PS 0 = 15, 1 = 1. TNM staging was: T1 = 1, T2 = 5, T3 = 8, T4 = 2; N stage: N0 = 8, N1 = 5, N2a = 2, N2b = 1. All patients received weekly carboplatin (AUC 1.5–2), Cx given conventionally and daily conventionally fractionated RT. Median total weeks of concurrent systemic therapy = 7 (range: 3–8 weeks). RT was delivered to a median total dose of 70 Gy (range 30–74 Gy). Of the 15 evaluable patients, there were: 12 CR, 2 PR, and 1 PD. There were three local in-field failures, two regional failures, and three distant failures. At last follow-up, 8/15 patients remained with NED. Three-year locoregional recurrence was 28.3% (95% CI: 7.7–53.9%). Mean percentage of weight loss was 14% (range: 6–26%). Two patients required systemic therapy dose reduction. Three patients experienced a treatment delay and three did not finish RT as planned including a patient who received only 30 Gy due to death secondary to MI during treatment. Conclusion: In this small retrospective series, carboplatin/Cx/RT was well-tolerated and efficacious in patients unsuitable for HD-DDP having LA-HNSCC. Acute toxicities were similar to Cx + RT, likely due to the non-overlapping toxicity profiles of the two systemic agents. We hypothesize that the addition of a well-tolerated cytotoxic chemotherapy agent may improve the therapeutic ratio of Cx + RT in patients who are poor candidates for more aggressive therapies and warrants evaluation in a prospective manner.

74 Fecal Metabolites Associated With Nitrergic Myenteric Neuronal Impairment and Gastrointestinal Motility Disorders in Western Diet-Fed Mice

Introduction: Western-diet (WD) is associated with reduced stool frequency in humans. High-fat fed mice exhibit delayed gastrointestinal (GI) transit associated with reduced number of nitrergic myenteric neurons. Mechanisms of these alterations are still unknown. Our aim was to investigate if WD feeding leads to modifications of fecal metabolites associated with the development of enteric neurodegeneration and the role played by the gut microbiota in such phenomenon. Methods: C57Bl/6 mice were fed a WD (34.5% kcal from fat, representative of the typical American diet fat calorie intake, n=5) or a Regular diet (RD, 16.9% kcal from fat, n=5). 6 weeks post feeding, fecal metabolites were analyzed by high-resolution mass spectrometry (LTQ-FT). 12 weeks post feeding, nitrergic myenteric neurons were quantified in the proximal colon by NADPH-diaphorase staining and GI and colonic transit were measured. Citrulline was measured by ELISA in germ-free (GF) mice stools fed a WD or a RD for 6 weeks (n=3 per group). Data are presentedas mean ± SEM and are significant to p < 0.05. Results: After 12 weeks of feeding, WD mice exhibited a reduced stool frequency in comparison to RD mice (1.5±0.5 and 4.4±0.3 stools/min, respectively) and this was associated with a delayed intestinal transit time (281.5±57.5 and 152.8±15.7 min). In addition, WD mice had a longer colonic transit time (as measured by bead expulsion time: WD: 127.5±52.5 min; RD: 13.2±2.0 min) associated with reduced number of nitrergic myenteric neurons in the proximal colon (113.0±5.6 and 64.2±7.4 neurons/field). Together, these data demonstrate an altered colonic motor function after 12 weeks of WD. We quantified 3730 metabolites in the feces but only 185 were significantly higher in WD mice compared to RD mice. In addition to palmitate, we found increased concentrations of citrulline (associated with enhanced nitric oxide synthase activity), 3-hydroxykynurenine (reflecting neuroinflammation) and bacterial muramic acid [Figure 1]. In order to understand the possible role of the gut microbiota in these changes, we measured fecal citrulline in GF mice fed a WD or a RD for 6 weeks and found similar concentrations (3.0±0.5 and 2.6±0.3 ng/mg). Conclusion: Our results show that long-term WD consumption is associated with nitrergic myenteric neuronal loss contributing to delayed GI transit. These alterations were preceded by gut dysbiosis and elevated fecal citrulline, potentially reflecting higher plasma concentrations that lead to oxidative stress and apoptosis in NO producing neurons. Importantly, fecal citrulline was not affected by a WD feeding under germfree conditions, suggesting that the gut microbiota is required for such effects. Fecal citrulline may be considered as a marker of myenteric neuronal impairments responsible for the motor alterations observed during WD feeding.

Tu1241 Does Race Play a Role in Medication Adherence in Inflammatory Bowel Disease Patients

Background: High quality care in inflammatory bowel disease (IBD) includes complex medical therapies that require adherence to treatment plans and frequent monitoring. Studies of IBD patients in the United States have identified race-based differences in healthcare delivery and utilization. Prior investigations of race and medication adherence in IBD have relied on survey tools and self-reporting. Our aim was to compare medication adherence between African American (AA) and Caucasian (C) IBD patients using objective pharmacy refill data. Methods: After Emory IRB approval, we retrospectively reviewed the charts of IBD patients treated in a tertiary centers subspecialty IBD clinic between 10/2013 and 12/ 2013. Medication adherence was determined using electronic pharmacy refill data (including all pharmacies used by the patient) for the 6 months following a visit to the IBD clinic. Poor adherence was defined as a medication possession ratio of <0.8 during the periods that the patient was prescribed the medication. Data was collected on rates of disease flares over this 6-month period. Statistical analysis included Mann-Whitney U for continuous variables and Chi-square testing for categorical variables, as well as a logistic regression analysis. Results: One hundred and sixty IBD patient charts were reviewed (53% F, mean age 44.1 ± 1.3). In this cohort, 23% were AA, 69.4% C, and 6.6% other races (33% UC, 65% CD, and 2% indeterminate colitis). Twenty-five percent were new patients and 75% established patients. Among AA patients, 81.1% were adherent to medications (n=30/37), as compared to 88.3% of C patients (n=98/111). This differencewas not statistically significant (p=0.3). No difference was seen in anti-TNF therapy prescriptions, where 33.3% of C patients and 43.2% of AA were prescribed biologics (p=0.2). Patients who were non-adherent to medical therapy were more likely to be younger than adherent patients (age 33 vs.46, p= 0.001). In a logistic regression model adjusting for sex, race, prior surgery, and prior hospital admission, younger age was the only significant predictor of poor adherence to IBD therapies (OR= 0.9, 95% CI 0.9-0.98, p<0.01). Non-adherent patients had more flares (0.8 vs.0.4 flares/patient in 6 months, p=0.014), and were prescribed a larger number of IBDmedications (1.6 vs.1 medication, p<0.01). Conclusions: An objective evaluation of medication refills in AA and C IBD patients seen in the same clinic revealed no significant differences in medication adherence. The only significant predictor of poor adherence was younger age. Lower medication adherence was associated with increased IBD flares, as well as being prescribed a larger number of IBD medications. While prospective validation is needed, this suggests that race-based disparities in medication adherence are decreased with similar access to care.