Rawad Mounzer

A Randomized Double-Blind Placebo-Controlled Trial of Rifaximin in Patients with Abdominal Bloating and Flatulence

AIMS:To study the efficacy of rifaximin, a nonabsorbable antibiotic, in relieving chronic functional symptoms of bloating and flatulence.METHODS:Randomized double-blind placebo-controlled trial consisting of three 10-day phases: baseline (phase 1), treatment with rifaximin 400 mg b.i.d. or placebo (phase 2), and post-treatment period (phase 3). Primary efficacy variable was subjective global symptom relief at the end of each phase. A symptom score was calculated from a symptom diary. Lactulose H2-breath test (LHBT) was performed at baseline and end of study.RESULTS:One hundred and twenty-four patients were enrolled (63 rifaximin and 61 placebo). Baseline characteristics were comparable and none had an abnormal baseline LHBT. Rome II criteria were met in 58.7% and 54.1%, respectively. At the end of phase 2, there was a significant difference in global symptom relief with rifaximin versus placebo (41.3%vs 22.9%, p= 0.03). This improvement was maintained at the end of phase 3 (28.6%vs 11.5%, p= 0.02). Mean cumulative and bloating-specific scores dropped significantly in the rifaximin group (p <0.05). Among patients with IBS, a favorable response to rifaximin was noted (40.5%vs 18.2%; p= 0.04) persisting by the end of phase 3 (27%vs 9.1%; p= 0.05). H2-breath excretion dropped significantly among rifaximin responders and correlated with improvement in bloating and overall symptom scores (p= 0.01). No adverse events were reported.CONCLUSIONS:Rifaximin is a safe and effective treatment for abdominal bloating and flatulence, including in IBS patients. Symptom improvement correlates with reduction in H2-breath excretion. Future trials are needed to examine the efficacy of long-term or cyclic rifaximin in functional colonic disorders.

Comparison of Existing Clinical Scoring Systems to Predict Persistent Organ Failure in Patients With Acute Pancreatitis

BACKGROUND & AIMS It is important to identify patients with acute pancreatitis who are at risk for developing persistent organ failure early in the course of disease. Several scoring systems have been developed to predict which patients are most likely to develop persistent organ failure. We head-to-head compared the accuracy of these systems in predicting persistent organ failure, developed rules that combined these scores to optimize predictive accuracy, and validated our findings in an independent cohort. METHODS Clinical data from 2 prospective cohorts were used for training (n = 256) and validation (n = 397). Persistent organ failure was defined as cardiovascular, pulmonary, and/or renal failure that lasted for 48 hours or more. Nine clinical scores were calculated when patients were admitted and 48 hours later. We developed 12 predictive rules that combined these scores, in order of increasing complexity. RESULTS Existing scoring systems showed modest accuracy (areas under the curve at admission of 0.62-0.84 in the training cohort and 0.57-0.74 in the validation cohort). The Glasgow score was the best classifier at admission in both cohorts. Serum levels of creatinine and blood urea nitrogen provided similar levels of discrimination in each set of patients. Our 12 predictive rules increased accuracy to 0.92 in the training cohort and 0.84 in the validation cohort. CONCLUSIONS The existing scoring systems seem to have reached their maximal efficacy in predicting persistent organ failure in acute pancreatitis. Sophisticated combinations of predictive rules are more accurate but cumbersome to use, and therefore of limited clinical use. Our ability to predict the severity of acute pancreatitis cannot be expected to improve unless we develop new approaches.

Tertiary Lymphoid Tissues Generate Effector and Memory T Cells That Lead to Allograft Rejection

Tertiary lymphoid tissues are lymph node‐like cell aggregates that arise at sites of chronic inflammation. They have been observed in transplanted organs undergoing chronic rejection, but it is not known whether they contribute to the rejection process by supporting local activation of naïve lymphocytes. To answer this question, we established a murine transplantation model in which the donor skin contains tertiary lymphoid tissues due to transgenic expression of lymphotoxin‐α(RIP‐LTα), whereas the recipient lacks all secondary lymphoid organs and does not mount primary alloimmune responses. We demonstrate in this model that RIP‐LTα allografts that harbor tertiary lymphoid tissues are rejected, while wild‐type allografts that lack tertiary lymphoid tissues are accepted. Wild‐type allografts transplanted at the same time as RIP‐LTα skin or 60 days later were also rejected, suggesting that tertiary lymphoid tissues, similar to secondary lymphoid organs, generate both effector and memory immune responses. Consistent with this observation, naive T cells transferred to RIP‐LTα skin allograft but not syngeneic graft recipients proliferated and differentiated into effector and memory T cells. These findings provide direct evidence that tertiary lymphoid structures perpetuate the rejection process by supporting naïve T‐cell activation.

Revised Atlanta and Determinant-Based Classification: Application in a Prospective Cohort of Acute Pancreatitis Patients

OBJECTIVES:Atlanta classification (Atlanta 1992) of acute pancreatitis (AP) has several limitations. Two new classification systems were recently proposed: the Atlanta reclassification (Atlanta 2012) and the determinant-based classification (DBC). The aim of our study was to: (i) determine the association between different severity categories and clinical outcomes and (ii) perform a head-to-head comparison between Atlanta 1992, Atlanta 2012, and DBC in predicting these clinical outcomes.METHODS:A total of 256 prospectively enrolled patients were assigned a severity category for all three classifications. Five clinical outcomes were evaluated: mortality, intensive care unit (ICU) admission and length of stay (LOS), need for interventions, and hospital LOS. Pairwise testing between severity grades within a classification system was performed using Fishers exact and Kruskal–Wallis tests. Predictive accuracies were evaluated using area under the ROC curve (AUC) and Somers D co-efficient.RESULTS:Overall, higher grades of severity were associated with worse clinical outcomes for all three classification systems. Atlanta 2012 and DBC performed better than Atlanta 1992 and were comparable in predicting mortality (AUC 0.89 for both vs. 0.76, P<0.001), ICU admission (AUC 0.91 for both vs. 0.80, P<0.001), and ICU LOS (Somers D 0.21 and 0.28 vs. 0.07, P<0.05). DBC performed better in predicting need for interventions (AUC 0.93 vs. 0.85, P<0.001), whereas Atlanta 2012 performed better in predicting hospital LOS (Somers D 0.43 vs. 0.37, P=0.04).CONCLUSIONS:Atlanta 2012 and DBC severity categories accurately reflected clinical outcomes in our cohort and were superior to Atlanta 1992. These novel classification systems can guide the selection of homogeneous patient populations for clinical research and provide an accurate spectrum of disease severity categories in the clinical setting.

Lymphotoxin-alpha contributes to lymphangiogenesis

Lymphotoxin-α (LTα), lymphotoxin-β (LTβ), and tumor necrosis factor-α (TNFα) are inflammatory mediators that play crucial roles in lymphoid organ development. We demonstrate here that LTα also contributes to the function of lymphatic vessels and to lymphangiogenesis during inflammation. LTα(-/-) mice exhibited reduced lymph flow velocities and increased interstitial fluid pressure. Airways of LTβ(-/-) mice infected with Mycoplasma pulmonis had significantly more lymphangiogenesis than wild type (WT) or LTα(-/-) mice, as did the skin draining immunization sites of LTβ(-/-) mice. Macrophages, B cells, and T cells, known sources of LT and TNFα, were apparent in the skin surrounding the immunization sites as were LTα, LTβ, and TNFα mRNAs. Ectopic expression of LTα led to the development of LYVE-1 and Prox1-positive lymphatic vessels within tertiary lymphoid organs (TLOs). Quantification of pancreatic lymphatic vessel density in RIPLTαLTβ(-/-) and WT mice revealed that LTα was sufficient for inducing lymphangiogenesis and that LTβ was not required for this process. Kidneys of inducible LTα transgenic mice developed lymphatic vessels before the appearance of obvious TLOs. These data indicate that LTα plays a significant role in lymphatic vessel function and in inflammation-associated lymphangiogenesis.

Spontaneous Bacterial Peritonitis Before Liver Transplantation Does Not Affect Patient Survival

BACKGROUND & AIMS Spontaneous bacterial peritonitis (SBP) is a devastating complication of cirrhosis with high mortality. The impact of a prior episode of SBP on the outcome of liver transplantation (LT) is not well known. We aimed to determine the short- and long-term morbidity and mortality of patients who received LT, with and without a history of SBP. METHODS We reviewed the records of all adult patients who underwent LT at a single center between June 1999 and June 2009. Patients with SBP were compared with all other patients who underwent LT during the same time period, without prior episodes of SBP. RESULTS A total of 1491 adult patients underwent LT in the study period; 80 (5.4%) had at least 1 episode of SBP before LT. The mean follow-up time for all patients in the study was just over 4 years. Patients in the SBP cohort were more likely to be male (74%) and to have alcoholic liver disease. Patients with SBP had higher Child-Pugh and model for end-stage liver disease scores at the time of transplantation compared with controls, but there was no difference in long-term mortality between the 2 groups. Patients with SBP, however, were more likely to require surgery for complications related to LT within 1 year and were more likely to die of sepsis. CONCLUSIONS Despite higher Child-Pugh and model for end-stage liver disease score at the time of LT, survival times of patients with SBP before LT are similar to those patients without SBP.

Genetics of acute and chronic pancreatitis.

Purpose of review Acute pancreatitis, recurrent acute pancreatitis (RAP) and chronic pancreatitis are interrelated and progressive inflammatory disorders of the pancreas with highly variable and complex susceptibility, severity and outcomes. The role of genetics in acute pancreatitis, RAP and progression to chronic pancreatitis within a new framework is needed. Recent findings The first genome-wide association study in the pancreas has been published with genome-wide significance linked with noncoding variants at the PRSS1-PRSS2 locus on chromosome seven and the CLDN2 locus on the X chromosome. A new personalized medicine paradigm is being considered to facilitate organization of genetic and other susceptibility risk compared with the risk of disease progression or resolution and risk of complications. Summary A new framework for organizing multiple, complex data sets is emerging. The role of genetics in the context of other variables is important in understanding susceptibility to RAP and in the modification of disease severity and progression to chronic pancreatitis. Questions of when to order testing, what to order and how to use the data in real time remains an area for future research and development.

A Prospective Multicenter Study Evaluating Learning Curves and Competence in Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography Among Advanced Endoscopy Trainees: The Rapid Assessment of Trainee Endoscopy Skills Study

BACKGROUND & AIMS: On the basis of the Next Accreditation System, trainee assessment should occur on a continuous basis with individualized feedback. We aimed to validate endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) learning curves among advanced endoscopy trainees (AETs) by using a large national sample of training programs and to develop a centralized database that allows assessment of performance in relation to peers. METHODS: ASGE recognized training programs were invited to participate, and AETs were graded on ERCP and EUS exams by using a validated competency assessment tool that assesses technical and cognitive competence in a continuous fashion. Grading for each skill was done by using a 4‐point scoring system, and a comprehensive data collection and reporting system was built to create learning curves by using cumulative sum analysis. Individual results and benchmarking to peers were shared with AETs and trainers quarterly. RESULTS: Of the 62 programs invited, 20 programs and 22 AETs participated in this study. At the end of training, median number of EUS and ERCP performed/AET was 300 (range, 155–650) and 350 (125–500), respectively. Overall, 3786 exams were graded (EUS, 1137; ERCP‐biliary, 2280; ERCP‐pancreatic, 369). Learning curves for individual end points and overall technical/cognitive aspects in EUS and ERCP demonstrated substantial variability and were successfully shared with all programs. The majority of trainees achieved overall technical (EUS, 82%; ERCP, 60%) and cognitive (EUS, 76%; ERCP, 100%) competence at conclusion of training. CONCLUSIONS: These results demonstrate the feasibility of establishing a centralized database to report individualized learning curves and confirm the substantial variability in time to achieve competence among AETs in EUS and ERCP. ClinicalTrials.gov: NCT02509416.

Interobserver agreement among cytopathologists in the evaluation of pancreatic endoscopic ultrasound- guided fine needle aspiration cytology specimens *

Background and aims: Endoscopic ultrasound with fine needle aspiration (EUS-FNA) has become the standard of care in the evaluation of solid pancreatic lesions. Limited data exist on interobserver agreement (IOA) among cytopathologists in assessing solid pancreatic EUS-FNA specimens. This study aimed to evaluate IOA among cytopathologists in assessing EUS-FNA cytology specimens of solid pancreatic lesions using a novel standardized scoring system and to assess individual clinical and cytologic predictors of IOA. Methods: Consecutive patients who underwent EUS-FNA of solid pancreatic lesions at a tertiary care referral center were included. EUS-FNA slides were evaluated by four blinded cytopathologists using a standardized scoring system that assessed final cytologic diagnosis and quantitative (number of nucleated/diagnostic cells) and qualitative (bloodiness, inflammation/necrosis, contamination, artifact) cytologic parameters. Final clinical diagnosis was based on final cytology, surgical pathology, or 1-year clinical follow-up. IOA was calculated using multi-rater kappa (κ) statistics. Bivariate analyses were performed comparing cases with and without uniform agreement among the cytopathologists followed by logistic regression with backward elimination to model likelihood of uniform agreement. Results: Ninety-nine patients were included (49 % males, mean age 64 years, mean lesion size 26 mm). IOA for final diagnosis was moderate (κ = 0.45, 95 % confidence interval (CI) 0.4 – 0.49) with minimal improvement when combining suspicious and malignant diagnoses (κ = 0.54, 95 %CI 0.49 – 0.6). The weighted kappa value for overall diagnosis was 0.65 (95 %CI 0.54 – 0.76). IOA was slight to fair (κ = 0.04 – 0.32) for individual cytologic parameters. A final clinical diagnosis of malignancy was the most significant predictor of agreement [OR 3.99 (CI 1.52 – 10.49)]. Conclusions: Interobserver agreement among cytopathologists for pancreatic EUS-FNA specimens is moderate-substantial for the final cytologic diagnosis. The final clinical diagnosis of malignancy was the strongest predictor of agreement. These results have significant implications for patient management and need to be validated in future trials.

Suboptimal Agreement Among Cytopathologists in Diagnosis of Malignancy Based on Endoscopic Ultrasound Needle Aspirates of Solid Pancreatic Lesions: A Validation Study

Background & Aims: Despite the widespread use of endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA) to sample pancreatic lesions and the standardization of pancreaticobiliary cytopathologic nomenclature, there are few data on inter‐observer agreement among cytopathologists evaluating pancreatic cytologic specimens obtained by EUS‐FNA. We developed a scoring system to assess agreement among cytopathologists in overall diagnosis and quantitative and qualitative parameters, and evaluated factors associated with agreement. Methods: We performed a prospective study to validate results from our pilot study that demonstrated moderate to substantial inter‐observer agreement among cytopathologists for the final cytologic diagnosis. In the first phase, 3 cytopathologists refined criteria for assessment of quantity and quality measures. During phase 2, EUS‐FNA specimens of solid pancreatic lesions from 46 patients were evaluated by 11 cytopathologists at 5 tertiary care centers using a standardized scoring tool. Individual quantitative and qualitative measures were scored and an overall cytologic diagnosis was determined. Clinical and EUS parameters were assessed as predictors of unanimous agreement. Inter‐observer agreement (IOA) was calculated using multi‐rater kappa (&kgr;) statistics and a logistic regression model was created to identify factors associated with unanimous agreement. Results: The IOA for final diagnoses, based on cytologic analysis, was moderate (&kgr; = 0.56; 95% CI, 0.43–0.70). Kappa values did not increase when categories of suspicious for malignancy, malignant, and neoplasm were combined. IOA was slight to moderate for individual quantitative (&kgr; = 0.007; 95% CI, –0.03 to –0.04) and qualitative parameters (&kgr; = 0.5; 95% CI, 0.47–0.53). Jaundice was the only factor associated with agreement among all cytopathologists on multivariate analysis (odds ratio for unanimous agreement, 5.3; 95% CI, 1.1–26.89). Conclusions: There is a suboptimal level of agreement among cytopathologists in the diagnosis of malignancy based on analysis of EUS‐FNA specimens obtained from solid pancreatic masses. Strategies are needed to refine the cytologic criteria for diagnosis of malignancy and enhance tissue acquisition techniques to improve diagnostic reproducibility among cytopathologists.