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OBJECTIVE Diabetes that arises from chronic pancreatitis (CP) is associated with increased morbidity and mortality. Methods to predict which patients with CP are at greatest risk for diabetes are urgently needed. We aimed to examine independent risk factors for diabetes in a large cohort of patients with CP. RESEARCH DESIGN AND METHODS This cross-sectional study comprised 645 individuals with CP enrolled in the PROCEED study, of whom 276 had diabetes. We conducted univariable and multivariable regression analyses of potential risk factors for diabetes. Model performance was assessed by area under the receiver operating characteristic curve (AUROC) analysis, and accuracy was evaluated by cross validation. Exploratory analyses were stratified according to the timing of development of diabetes relative to the diagnosis of pancreatitis. RESULTS Independent correlates of diabetes in CP included risk factors for type 2 diabetes (older age, overweight/obese status, male sex, non-White race, tobacco use) as well as pancreatic disease–related factors (history of acute pancreatitis complications, nonalcoholic etiology of CP, exocrine pancreatic dysfunction, pancreatic calcification, pancreatic atrophy) (AUROC 0.745). Type 2 diabetes risk factors were predominant for diabetes occurring before pancreatitis, and pancreatic disease–related factors were predominant for diabetes occurring after pancreatitis. CONCLUSIONS Multiple factors are associated with diabetes in CP, including canonical risk factors for type 2 diabetes and features associated with pancreatitis severity. This study lays the groundwork for the future development of models integrating clinical and nonclinical data to identify patients with CP at risk for diabetes and identifies modifiable risk factors (obesity, smoking) on which to focus for diabetes prevention.

Background & Aims Chronic pancreatitis (CP) is associated with osteopathy (osteoporosis or osteopenia). However, existing literature is mostly limited to retrospective or administrative studies that have not clearly defined the prevalence and risk factors. Our aim was to identify patient- and disease-related associations with osteopathy in a prospective cohort study of CP. Methods We studied 282 subjects with definitive CP enrolled in the PROCEED study who had a baseline dual-energy X-ray absorptiometry (DXA) scan. Osteopenia and osteoporosis were defined using the lowest T-scores. Clinical data were collected using standardized case report forms. Comparisons were performed with a multivariate logistic regression model with forward selection to identify risk factors for osteopathy. Results The majority of subjects had osteopathy on DXA scan (56.0%; 17.0% osteoporosis; 39.0% osteopenia). Subjects with osteopathy had a higher prevalence of traumatic (40.0% vs 26.4%; P = .02) and spontaneous fractures (3.9% vs 0; P = .04). On multivariate analysis, older age (odds ratio [OR], 1.29 per 5 years; 95% confidence interval [CI], 1.15–1.45), female sex (OR, 3.08; 95% CI, 1.75–5.43), white race (OR, 2.68; 95% CI, 1.20–6.01), and underweight body mass index category (OR, 7.40; 95% CI, 1.56–34.99) were associated with higher probability of osteopathy. There were no significant associations between osteopathy and other patient and disease-related features of CP. Conclusion In the largest study of patients with CP who underwent DXA screening, the majority had osteopathy. There are overlapping risk factors with osteopathy in the general population, but the high prevalence in men and younger women supports the need for future investigations into the mechanisms of bone loss in CP. ClinicalTrials.gov number, NCT03099850.

OBJECTIVES: The metabolic abnormalities that lead to diabetes mellitus (DM) following an episode of acute pancreatitis (AP) have not been extensively studied. This manuscript describes the objectives, hypotheses, and methods of mechanistic studies of glucose metabolism that comprise secondary outcomes of the Diabetes RElated to Acute pancreatitis and its Mechanisms (DREAM) Study. METHODS: Three months after an index episode of AP, participants without pre-existing DM will undergo baseline testing with an oral glucose tolerance test. Participants will be followed longitudinally in three sub-cohorts with distinct metabolic tests. In the first and largest subcohort, oral glucose tolerance tests will be repeated 12 months after AP and annually to assess changes in β-cell function, insulin secretion, and insulin sensitivity. In the second, mixed meal tolerance tests will be performed at 3 and 12 months, then annually, and following incident DM to assess incretin and pancreatic polypeptide responses. In the third, frequently-sampled intravenous glucose tolerance tests will be performed at 3 months and 12 months to assess the first-phase insulin response and more precisely measure β-cell function and insulin sensitivity. CONCLUSIONS: The DREAM study will comprehensively assess the metabolic and endocrine changes that precede and lead to the development of DM after AP.

Acute pancreatitis (AP) is a disease characterized by an acute inflammatory phase followed by a convalescent phase. Diabetes mellitus (DM) was historically felt to be a transient phenomenon related to acute inflammation; however, it is increasingly recognized as an important late and chronic complication. There are several challenges that have prevented precisely determining the incidence rate of DM following AP and understanding the underlying mechanisms. The Diabetes RElated to Acute Pancreatitis and its Mechanisms (DREAM) Study is a prospective cohort study designed to address these and other knowledge gaps to provide the evidence needed to screen for, prevent, and treat DM following AP. In the following article, we summarize literature regarding the epidemiology of DM following AP, and provide the rationale and an overview of the DREAM study.

BACKGROUND: Garcinia cambogia, either alone or with green tea, is commonly promoted for weight loss. Sporadic cases of liver failure from G. cambogia have been reported, but its role in liver injury is controversial. METHODS: Among 1418 patients enrolled in the Drug-Induced Liver Injury Network (DILIN) from 2004 to 2018, we identified 22 cases (adjudicated with high confidence) of liver injury from G. cambogia either alone (n=5) or in combination with green tea (n=16) or Ashwagandha (n=1). Control groups consisted of 57 patients with liver injury from herbal and dietary supplements (HDS) containing green tea without G. cambogia and 103 patients from other HDS. RESULTS: Patients who took G. cambogia were between 17 to 54 years, with liver injury arising 13 to 223 days (median = 51) after the start. One patient died, one required liver transplantation, and 91% were hospitalized. The liver injury was hepatocellular with jaundice. Although the peak values of aminotransferases were significantly higher (2001 ± 1386 U/L) in G. cambogia group (p

BACKGROUND AND AIMS Herbal supplements, and particularly multi-ingredient products, have become increasingly common causes of acute liver injury. Green tea is a frequent component in implicated products, but its role in liver injury is controversial. The aim of this study was to better characterize the clinical features, outcomes, and pathogenesis of green tea-associated liver injury. APPROACH AND RESULTS Among 1,414 patients enrolled in the U.S. Drug-Induced Liver Injury Network who underwent formal causality assessment, 40 cases (3%) were attributed to green tea, 202 to dietary supplements without green tea, and 1,142 to conventional drugs. The clinical features of green tea cases and representation of human leukocyte antigen (HLA) class I and II alleles in cases and control were analyzed in detail. Patients with green tea-associated liver injury ranged in age from 17 to 69 years (median = 40) and developed symptoms 15-448 days (median = 72) after starting the implicated agent. The liver injury was typically hepatocellular (95%) with marked serum aminotransferase elevations and only modest increases in alkaline phosphatase. Most patients were jaundiced (83%) and symptomatic (88%). The course was judged as severe in 14 patients (35%), necessitating liver transplantation in 3 (8%), but rarely resulting in chronic injury (3%). In three instances, injury recurred upon re-exposure to green tea with similar clinical features, but shorter time to onset. HLA typing revealed a high prevalence of HLA-B*35:01, found in 72% (95% confidence interval [CI], 58-87) of green tea cases, but only 15% (95% CI, 10-20) caused by other supplements and 12% (95% CI, 10-14) attributed to drugs, the latter rate being similar to population controls (11%; 95% CI, 10.5-11.5). CONCLUSIONS Green tea-related liver injury has distinctive clinical features and close association with HLA-B*35:01, suggesting that it is idiosyncratic and immune mediated.

The National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases initiated the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) in 2015 (the CPDPC's origin, structure, governance, and research objectives are described in another article in this journal). One of the key objectives of CPDPC is to assemble a cohort of 10,000 subjects 50 years or older with new-onset diabetes, called the NOD cohort. Using a define, enrich, and find early detection approach, the aims of the NOD study are to (a) estimate the 3-year probability of pancreatic ductal adenocarcinoma (PDAC) in NOD (define), (b) establish a biobank of clinically annotated biospecimens from presymptomatic PDAC and control new-onset type 2 diabetes mellitus subjects, (c) conduct phase 3 validation studies of promising biomarkers for identification of incident PDAC in NOD patients (enrich), and (d) provide a platform for development of a future interventional screening protocol for early detection of PDAC in patients with NOD that incorporates imaging studies and/or clinical algorithms (find). It is expected that 85 to 100 incidences of PDAC will be diagnosed during the study period in this cohort of 10,000 patients.

We created the INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE (INSPPIRE 2) cohort to study the risk factors, natural history, and outcomes of pediatric acute recurrent pancreatitis and chronic pancreatitis (CP). Patient and physician questionnaires collect information on demographics, clinical history, family and social history, and disease outcomes. Health-related quality of life, depression, and anxiety are measured using validated questionnaires. Information entered on paper questionnaires is transferred into a database managed by Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer's Coordinating and Data Management Center. Biosamples are collected for DNA isolation and analysis of most common pancreatitis-associated genes.Twenty-two sites (18 in the United States, 2 in Canada, and 1 each in Israel and Australia) are participating in the INSPPIRE 2 study. These sites have enrolled 211 subjects into the INSPPIRE 2 database toward our goal to recruit more than 800 patients in 2 years. The INSPPIRE 2 cohort study is an extension of the INSPPIRE cohort study with a larger and more diverse patient population. Our goals have expanded to include evaluating risk factors for CP, its sequelae, and psychosocial factors associated with pediatric acute recurrent pancreatitis and CP.

PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and translational stuDies (PROCEED) is the first prospective, observational cohort study of chronic pancreatitis in the US. The primary goals of PROCEED are to define disease progression, test the predictive capability of candidate biomarkers, and develop a platform to conduct translational and mechanistic studies in chronic pancreatitis. Using objective and consensus-driven criteria, PROCEED will enroll adults at different stages of chronic pancreatitis - controls, Suspected chronic pancreatitis and Definite chronic pancreatitis. In addition to collecting detailed information using structured case report forms and protocol-mandated evaluations at baseline and during follow-up, PROCEED will establish a linked biorepository of blood, urine, saliva, stool, pancreatic fluid and pancreatic tissue. Enrollment for PROCEED began in June 2017. As of July 1, 2018, nine clinical centers of the Consortium to study Chronic Pancreatitis, Diabetes and Pancreatic Cancer (CPDPC) are enrolling, and 350 subjects have completed baseline evaluation. In conclusion, PROCEED will provide the most accurate and reliable estimates to date on progression of chronic pancreatitis. The established cohort and biorepository will facilitate numerous analyses, leading to new strategies for diagnosis, methods to monitor disease progression, and treatment of chronic pancreatitis.

Background The aim of this study was to clarify the pathophysiology of functional dyspepsia (FD), a highly prevalent gastrointestinal syndrome, and its relationship with the better-understood syndrome of gastroparesis. Methods Adult patients with chronic upper gastrointestinal symptoms were followed up prospectively for 48 weeks in multi-center registry studies. Patients were classified as having gastroparesis if gastric emptying was delayed; if not, they were labeled as having FD if they met Rome III criteria. Study analysis was conducted using analysis of covariance and regression models. Results Of 944 patients enrolled during a 12-year period, 720 (76%) were in the gastroparesis group and 224 (24%) in the FD group. Baseline clinical characteristics and severity of upper gastrointestinal symptoms were highly similar. The 48-week clinical outcome was also similar but at this time 42% of patients with an initial diagnosis of gastroparesis were reclassified as FD based on gastric-emptying results at this time point; conversely, 37% of patients with FD were reclassified as having gastroparesis. Change in either direction was not associated with any difference in symptom severity changes. Full-thickness biopsies of the stomach showed loss of interstitial cells of Cajal and CD206+ macrophages in both groups compared with obese controls. Conclusions A year after initial classification, patients with FD and gastroparesis, as seen in tertiary referral centers at least, are not distinguishable based on clinical and pathologic features or based on assessment of gastric emptying. Gastric-emptying results are labile and do not reliably capture the pathophysiology of clinical symptoms in either condition. FD and gastroparesis are unified by characteristic pathologic features and should be considered as part of the same spectrum of truly "organic" gastric neuromuscular disorders. ClinicalTrials.gov Identifier NCT00398801, NCT01696747

We would like to extend our gratitude to the all the patients and the healthy volunteers who participated in the study, as well as the University of Granada, Biomedicine PhD program. This work was supported by Roche Spain, the PhD grant from the University of Granada (DdMP) (2014) and the PhD grant from the Spanish Government (ARM) (FPU) 2014, REF FPU14/05461., Disseminated disease is present in ≈50% of colorectal cancer patients upon diagnosis, being responsible for most of cancer deaths. Addition of biological drugs, as Bevacizumab, to chemotherapy, has increased progression free survival and overall survival of metastatic colorectal cancer (mCRC) patients. However, these benefits have been only reported in a small proportion of patients. To date, there are not biomarkers that could explain the heterogeneity of this disease and would help in treatment selection. Recent findings demonstrated that microRNAs (miRNAs) play an important role in cancer and they can be encapsulated with high stability into extracellular vesicles (EVs) that are released in biological fluids. EVs can act as cell-to-cell communicators, transferring genetic information, such as miRNAs. In this context, we aimed to investigate serum EV associated miRNAs (EV-miRNAs) as novel non-invasive biomarkers for the diagnosis and prognosis of Bevacizumab-treated mCRC patients. We observed that baseline miRNA-21 and 92a outperformed carcinoembryonic antigen levels in the diagnosis of our 44 mCRC patients, compared to 17 healthy volunteers. In addition, patients who died presented higher levels of miRNA-92a and 222 at 24 weeks. However, in the multivariate Cox analysis, higher levels of miRNA-222 at 24 weeks were associated with lower overall survival. Altogether, these data indicate that EV-miRNAs have a strong potential as liquid biopsy biomarkers for the identification and prognosis of mCRC., Roche Spain, University of Granada (DdMP), Spanish Government REF FPU14/05461

The use of circulating tumor cells (CTCs) as indicators of treatment response in metastatic colorectal cancer (mCRC) needs to be clarified. The objective of this study is to compare the Response Evaluation Criteria in Solid Tumors (RECIST) with the Cytologic Criteria Assessing Response (CyCAR), based on the presence and phenotypic characterization of CTCs, as indicators of FOLFOX–bevacizumab treatment response. We observed a decrease of CTCs (42.8 vs. 18.2%) and VEGFR positivity (69.7% vs. 41.7%) after treatment. According to RECIST, 6.45% of the patients did not show any clinical benefit, whereas 93.55% patients showed a favorable response at 12 weeks. According to CyCAR, 29% had a non-favorable response and 71% patients did not. No significant differences were found between the response assessment by RECIST and CyCAR at 12 or 24 weeks. However, in the multivariate analysis, RECIST at 12 weeks and CyCAR at 24 weeks were independent prognostic factors for OS (HR: 0.1, 95% CI 0.02–0.58 and HR: 0.35, 95% CI 0.12–0.99 respectively). CyCAR results were comparable to RECIST in evaluating the response in mCRC and can be used as an alternative when the limitation of RECIST requires additional response analysis techniques., This work was supported by Roche Spain and a Ph.D. grant from the University of Granada.

Contains fulltext : 215317.pdf (Publisher’s version ) (Closed access) OBJECTIVES: In patients with acute recurrent pancreatitis (ARP), pancreas divisum, and no other etiologic factors, endoscopic retrograde cholangiopancreatography (ERCP) with minor papilla endoscopic sphincterotomy (miES) is often performed to enlarge the minor papillary orifice, based on limited data. The aims of this study are to describe the rationale and methodology of a sham-controlled clinical trial designed to test the hypothesis that miES reduces the risk of acute pancreatitis. METHODS: The SpHincterotomy for Acute Recurrent Pancreatitis (SHARP) trial is a multicenter, international, sham-controlled, randomized trial comparing endoscopic ultrasound + ERCP with miES versus endoscopic ultrasound + sham for the management of ARP. A total of 234 consented patients having 2 or more discrete episodes of acute pancreatitis, pancreas divisum confirmed by magnetic resonance cholangiopancreatography, and no other clear etiology for acute pancreatitis will be randomized. Both cohorts will be followed for a minimum of 6 months and a maximum of 48 months. RESULTS: The trial is powered to detect a 33% risk reduction of acute pancreatitis frequency. CONCLUSIONS: The SHARP trial will determine whether ERCP with miES benefits patients with idiopathic ARP and pancreas divisum. Trial planning has informed the importance of blinded outcome assessors and long-term follow-up.

Background Restorative proctocolectomy (RPC) is considered the preferred surgical choice for patient with ulcerative colitis (UC) who have failed medical therapy and in some patients with familial adenomatous polyposis (FAP). It has been shown through metabolic profiling of urine that CD patients have higher levels of formate and lower levels of hippurate and 4-cresol sulfate when compared to healthy controls. To date, extensive metabolic profiling in RPC has yet to be studied. This study aimed to determine compounds found in urine that are associated with treatment response in patients that have been treated for pouchitis Methods Patients with pouchitis were recruited from a single centre. Pouchitis was defined using the pouch disease activity index (PDAI) and pouchitis was considered when the score was ³7. Response to antibiotics was defined as either a 2 points reduction in PDAI. Mid-stream morning urine samples were collected. Samples we stored at -80°C until analysis. 1H-NMR profile was recorded using the Bruker® Avance III 600 MHz spectrometer, with a Samplejet 96 well autosampler. The full resolution 1H NMR spectra were imported into the SIMCA-P software package, and multivariate data analyses were carried out. Metabolite assignment was performed by comparing chemical shifts, Jres coupling, and peaks multiplicity with information in databases (such as Human Metabolome DataBase, HMDB). Results There were 21 patients. The median age of the cohort was 50 years (range 28–79). A total of 11 patients were on antibiotics and 10 patients were off antibiotics. Nine were responders. On multivariate modelling there were significant differences found between responders and non-responders (CV-ANOVA p=0.05) (figure 1). Significant spectral differences that corresponded to the multivariate model correlated with Formate (8.84 PPM) Trigonelline (4.45PPM) and Glycine 3.57(PPM) all of which were higher in responders. Conclusions Trigonelline, formate and glycine may help differentiate patients with pouchitis who will respond to treatments versus those that do not. It is currently unclear as to the mechanism as to why these metabolites are reduced in non-responders and further work is required to understand this and validate our findings.

Background Restorative proctocolectomy is a surgical option in patients with ulcerative colitis who become refractory to medical therapy. Short chain fatty acids (SCFA) are organic fatty acids with 1–6 carbons which arise from bacterial metabolism from carbohydrates entering the colon. Various studies have implicated SCFA in both the development of IBD and flares of IBD. Furthermore, it has been shown that SCFA concentrations are significantly lower in faecal samples from patients with pouchitis when compared with healthy controls. Our study aimed to assess longitudinal changes in SCFA that occur in a pouch to determine if they can predict or are associated with the development of pouchitis. To date no study has analysed short chain fatty acids in mucosal biopsy tissue from these patients. Methods Patients who underwent restorative proctocolectomy at a single centre underwent pouchoscopy at the time of restoration of continuity and then every 6 months for a year. Biopsies from the pouch were retrieved from the pouch body. Pouchitis was defined using the pouch disease activity index. The development of pouchitis was assessed at months 6 and 12 months. Biopsies samples were snap frozen at time of biopsy and stored in -80°C. Samples were thawed and weighed. Sterile water and Methyl tertiary-butyl ether with internal standard (IS) were added with a ratio of 20 mg of sample:50µL of H20:250µL of MTBE and IS with a further 4µL of hydrochloric acid added to each sample. 30µL of the polar phase was then placed into silanized Eppendorf tubes. 150µL of derivatiser was added to each sample and the cap of the tube applied immediately. These were then incubated for 45 minutes at 60°C in an oven. 70µL from the silanised vial was placed into vial inserts and analysed in the gas chromatography mass spectrometry machine. (GC-MS). SCFA were measured using an Agilent 7000C Triple Quadrupole GC/MS-MS System according to a previously published method. Simca was used for multivariate analysis and T-tests were used for univariate analysis. Results There were 56 biopsy samples. There were 22 patients (17 males); 16 UC and 6 FAP patients with longitudinal follow up. The median age of the cohort was 40 years (range 20–60 years). Of the UC patients four developed pouchitis within one year. When comparing UC patients at the time of closure of ileostomy, there were there were significant decreases in caproic acid (4674µM vs 12217µM p Conclusion The study has suggested that a decrease in SCFA found in the mucosal tissue at time of closure of ileostomy may predict onset of pouchitis within a year. This study is the first to demonstrate that SCFA can be analysed from biopsies. Future studies need to determine factors that may contribute to tissue SCFA levels which may help develop a potential therapeutic target to optimise and potentially reduce the incidence of pouchitis.

Background Restorative proctocolectomy is a surgical option in patients with ulcerative colitis who become refractory to medical therapy. Various studies have implicated SCFA in both the development of IBD and flares of IBD. Furthermore, it has been shown that SCFA concentrations are significantly lower in faecal samples from patients with pouchitis when compared with healthy controls. Our study aimed to assess longitudinal changes in SCFA that occur in a pouch to determine if they can predict or are associated with the development of pouchitis. To date no study has analysed short chain fatty acids in mucosal biopsy tissue from these patients. Methods Patients who underwent restorative proctocolectomy at a single centre underwent pouchoscopy at the time of restoration of continuity and then every 6 months for a year. Biopsies were retrieved from the pouch body. Pouchitis was defined using the pouch disease activity index. The development of pouchitis was assessed at 6 and 12 months.SCFA were measured using an Agilent 7000C Triple Quadrupole GC/MS-MS System. Simca was used for multivariate analysis and T-tests were used for univariate analysis. Results There were 56 biopsy samples. There were 22 patients (17 males); 16 UC and 6 FAP patients. Median age of the cohort was 40 years (range 20–60 years). Of the UC patients four developed pouchitis within one year. Comparing UC patients at the time of closure of ileostomy, there were significant decreases in caproic acid (4674uM vs 12217uM p Conclusions A decrease in SCFA found in the mucosal tissue at time of closure of ileostomy may predict onset of pouchitis within a year. This study is the first to demonstrate that SCFA can be analysed from biopsies. Future studies need to determine factors that may contribute to tissue SCFA levels which may help reduce the incidence of pouchitis.

Background Bodybuilding supplements can cause a profound cholestatic syndrome. Aim To describe the drug-Induced liver injury network's experience with liver injury due to bodybuilding supplements. Methods Liver injury pattern, severity and outcomes, potential genetic associations, and exposure to anabolic steroids by product analysis were analysed in prospectively enrolled subjects with bodybuilding supplement-induced liver injury with causality scores of probable or higher. Results Forty-four males (mean age 33 years) developed liver injury with a median latency of 73 days. Forty-one per cent presented with hepatocellular pattern of liver injury as defined by the R > 5 ([Fold elevation of ALT] ÷ [Fold elevation of Alk Phos] (mean, range = 6.4, 0.5-31.4, n = 42) despite all presenting with clinical features of cholestatic liver injury (100% with jaundice and 84% with pruritus). Liver biopsy (59% of subjects) demonstrated a mild hepatitis and profound cholestasis in most without bile duct injury, loss or fibrosis. Seventy-one per cent were hospitalised, and none died or required liver transplantation. In some, chemical analysis revealed anabolic steroid controlled substances not listed on the label. No enrichment of genetic variants associated with cholestatic syndromes was found, although mutations in ABCB11 (present in up to 20%) were significantly different than in ethnically matched controls. Conclusions Patients with bodybuilding supplements liver injury uniformly presented with cholestatic injury, which slowly resolved. The ingested products often contained anabolic steroids not identified on the label, and no enrichment in genetic variants was found, indicating a need for additional studies.

High-quality and well-annotated biorepositories are needed to better understand the pathophysiology and biologic mechanisms of chronic pancreatitis (CP) and its consequences. We report a methodology for the development of a robust standard operating procedure (SOP) for a biorepository based on the experience of the clinical centers within the consortium to study Chronic Pancreatitis, Diabetes and Pancreas Cancer Clinical Centers (CPDPC), supported by the National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases as a unique multidisciplinary model to study CP, diabetes, and pancreatic cancer in both children and adults. Standard operating procedures from the CPDPC centers were evaluated and consolidated. The literature was reviewed for standard biorepository operating procedures that facilitated downstream molecular analysis. The existing literature on biobanking practices was harmonized with the SOPs from the clinical centers to produce a biorepository for pancreatic research. This article reports the methods and basic principles behind the creation of SOPs to develop a biorepository for the CPDPC. These will serve as a guide for investigators developing biorepositories in pancreas research. Rigorous and meticulous adherence to standardized biospecimen collection will facilitate investigations to better understand the pathophysiology and biologic mechanisms of CP, diabetes, and pancreatic cancer.

Background & Aims Many patients with gastroparesis are prescribed opioids for pain control, but indications for opioid prescriptions and the relationship of opioid use to gastroparesis manifestations are undefined. We characterized associations of use of potent vs weaker opioids and presentations of diabetic and idiopathic gastroparesis. Methods We collected data on symptoms, gastric emptying, quality of life, and health care resource use from 583 patients with gastroparesis (>10% 4-h scintigraphic retention) from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Consortium, from January 2007 through November 2016. Patients completed medical questionnaires that included questions about opioid use. The opioid(s) were categorized for potency relative to oral morphine. Symptom severities were quantified by Patient Assessment of Upper Gastrointestinal Disorders Symptoms questionnaires. Subgroup analyses compared patients on potent vs weaker opioids and opioid effects in diabetic vs idiopathic etiologies. Results Forty-one percent of patients were taking opioids; 82% of these took potent agents (morphine, hydrocodone, oxycodone, methadone, hydromorphone, buprenorphine, or fentanyl). Abdominal pain was the reason for prescription for 61% of patients taking opioids. Mean scores for gastroparesis, nausea/vomiting, bloating/distention, abdominal pain, and constipation scores were higher in opioid users (P ≤ .05). Opioid use was associated with greater levels of gastric retention, worse quality of life, increased hospitalization, and increased use of antiemetic and pain modulator medications compared with nonusers (P ≤ .03). Use of potent opioids was associated with worse gastroparesis, nausea/vomiting, upper abdominal pain, and quality-of-life scores, and more hospitalizations compared with weaker opioids (tapentadol, tramadol, codeine, or propoxyphene) (P ≤ .05). Opioid use was associated with larger increases in gastric retention in patients with idiopathic vs diabetic gastroparesis (P = .008). Conclusions Opioid use is prevalent among patients with diabetic or idiopathic gastroparesis, and is associated with worse symptoms, delays in gastric emptying, and lower quality of life, as well as greater use of resources. Potent opioids are associated with larger effects than weaker agents. These findings form a basis for studies to characterize adverse outcomes of opioid use in patients with gastroparesis and to help identify those who might benefit from interventions to prevent opioid overuse.

Background Providing adjuvant chemotherapy in locally advanced rectal cancer after neoadjuvant chemoradiation is currently a matter of debate. Recommendations from clinical guidelines range from offering no treatment to oxaliplatin-based combinations. We present a risk-adapted approach based on the response to initial chemoradiation as the strongest prognostic factor for disease-free survival (DFS). Patients and Methods One hundred one patients were treated at a single institution with preoperative long-course radiotherapy plus concurrent fluoropyrimidines. Patients with disease downstaged to pT0-2N0 received adjuvant fluoropyrimidines alone, while the remaining received an oxaliplatin-based combination. The primary study end point was 5-year DFS. Results Overall, the disease of 54 patients was downstaged to pT0-2N0 (53.5%), while that of 47 patients was staged as pT3-4 or N+ (46.5%) after surgery. In the intention-to-treat analysis, 5-year DFS for patients in the good-prognosis group (downstaging to pT0-2 N0) and for those with poor prognosis (pT3-4 or N+) were 79.4% and 66.3%, respectively (hazard ratio, 0.489; P = .043). Downstaging and pN+ were independent prognostic factors for DFS. Conclusion A risk-adapted adjuvant therapy strategy based on pathologic stage after neoadjuvant chemoradiation is feasible and achieves high rates of 5-year DFS. Patients with good prognostic factors can be treated with adjuvant fluoropyrimidines alone, thus permitting the avoidance of oxaliplatin-derived toxicities.

Introduction: Sleep disturbances and night time symptoms are associated with the level of control of ashtma symptoms and quality of life Aims and objectives: Main aim: validate the Sleep Jenkins Questionnaire (SJQ) into Spanish. Secondary aim: assess quality of sleep in asthmatic patients using the SJQ and the Medical Outcome Study (MOS) sleep scale and analyse the metric properties of the SJQ Method: A multicentric prospective study with an intervention group of asthmatic patients and a control group. A total of 90 cases and 90 controls were included. The questionnaires were administered during 3 successive visits at a 3 weeks and 3 months interval Results: The test re-test of SJQ between V1 and V2 in the 90 cases showed temporary stability. Patients who had exacerbation of asthma between V2 and V3 had higher scores in SJQ (worse quality of sleep) at V3 than V2, which shows the sensivity to change of the test. A good correlation between the two measurament scales was observed at V1. The SJQ score between cases and controls during V1 showed significant differences in quality of sleep in both grooups. No statistically significant differences were found in quality of sleep depending on the severity of asthma but statistically significant differences were observed according to the control of asthma. The overall quality of sleep of our patients was good Conclusions: The SJQ showed temporary stability in the test-retest, sensitivity to change and validity criteria

Pancreatogenic diabetes mellitus is most commonly the result of chronic pancreatitis, but can also occur secondary to pancreatic cancer. The early identification of pancreatogenic diabetes and distinction from the more prevalent type 2 diabetes is clinically significant; however, currently there is no validated method to differentiate these diabetes subtypes. We describe a study, “Evaluation of a Mixed Meal Test for Diagnosis and Characterization of PancrEaTogEniC DiabeTes Secondary to Pancreatic Cancer and Chronic Pancreatitis: the DETECT study,” which seeks to address this knowledge gap. The DETECT study is a multicenter study that will examine differences in hormone and glucose excursions following a mixed meal test. The study will also create a biorepository that will be used to evaluate novel diagnostic biomarkers for differentiating these diabetes subtypes.

Changes in levels of cytokines and chemokines have been proposed as possible biomarkers of tissue injury, including liver injury due to drugs. Recently, in acute drug-induced liver injury (DILI), we showed that 19 of 27 immune analytes were differentially expressed and that disparate patterns of immune responses were evident. Lower values of serum albumin (< 2.8 g/dL) and lower levels of only four analytes, namely, IL-9, IL-17, PDGF-bb, and RANTES, were highly predictive of early death [accuracy = 96%]. The goals of this study were to assess levels of the same 27 immune analytes in larger numbers of subjects to learn whether the earlier findings would be confirmed in new and larger cohorts of subjects, compared with a new cohort of healthy controls. We studied 127 subjects with acute DILI enrolled into the US DILIN. We also studied 118 subjects with severe acute liver injury of diverse etiologies, enrolled into the ALF SG registry of subjects. Controls comprised 63 de-identified subjects with no history of liver disease and normal liver tests. Analytes associated with poor outcomes [death before 6 months, n = 32 of the total of 232 non-acetaminophen (Apap) subjects], were lower serum albumin [2.6 vs 3.0 g/dL] and RANTES [6,458 vs 8,999 pg/mL] but higher levels of IL-6 [41 vs 18], IL-8 [78 vs 48], and MELD scores [30 vs 24]. Similar patterns were observed for outcome of death/liver transplant within 6 months. A model that included only serum albumin < 2.8 g/dL and RANTES below its median value of 11,349 had 83% (or 81%) accuracy for predicting early death (or early death/liver transplant) in 127 subjects from DILIN. No patterns of serum immune analytes were reflective of the etiologies of acute liver failure, but there were cytokine patterns that predicted prognosis in both acute DILI and ALF.

Background & Aims There are few effective treatments for nausea and other symptoms in patients with gastroparesis and related syndromes. We performed a randomized trial of the ability of the neurokinin-1 receptor antagonist aprepitant to reduce symptoms in patients with chronic nausea and vomiting caused by gastroparesis or gastroparesis-like syndrome. Methods We conducted a 4-week multicenter, double-masked trial of 126 patients with at least moderate symptoms of chronic nausea and vomiting of presumed gastric origin for a minimum of 6 months. Patients were randomly assigned to groups given oral aprepitant (125 mg/day, n = 63) or placebo (n = 63). The primary outcome from the intention-to-treat analysis was reduction in nausea, defined as a decrease of 25 mm or more, or absolute level below 25 mm, on a daily patient-reported 0-to-100 visual analog scale (VAS) of nausea severity. We calculated relative risks of nausea improvement using stratified Cochran-Mental-Haenszel analysis. Results Aprepitant did not reduce symptoms of nausea, based on the primary outcome measure (46% reduction in the VAS score in the aprepitant group vs 40% reduction in the placebo group; relative risk, 1.2; 95% CI, 0.8–1.7) ( P = .43). However, patients in the aprepitant group had significant changes in secondary outcomes such as reduction in symptom severity (measured by the 0–5 Gastroparesis Clinical Symptom Index) for nausea (1.8 vs 1.0; P = .005), vomiting (1.6 vs 0.5; P = .001), and overall symptoms (1.3 vs 0.7; P = .001). Adverse events, predominantly mild or moderate in severity grade, were more common in aprepitant (22 of 63 patients, 35% vs 11 of 63, 17% in the placebo group) ( P = .04). Conclusions In a randomized trial of patients with chronic nausea and vomiting caused by gastroparesis or gastroparesis-like syndrome, aprepitant did not reduce the severity of nausea when reduction in VAS score was used as the primary outcome. However, aprepitant had varying effects on secondary outcomes of symptom improvement. These findings support the need to identify appropriate patient outcomes for trials of therapies for gastroparesis, including potential additional trials for aprepitant. ClinicalTrials.gov no: NCT01149369.

BackgroundPrevious retrospective studies of paediatric ulcerative colitis have had limited ability to describe disease progression and identify predictors of treatment response. In this study, we aimed to identify characteristics associated with outcomes following standardised therapy after initial diagnosis.MethodsThe PROTECT multicentre inception cohort study was based at 29 centres in the USA and Canada and included paediatric patients aged 4-17 years who were newly diagnosed with ulcerative colitis. Guided by the Pediatric Ulcerative Colitis Activity Index (PUCAI), patients received initial standardised treatment with mesalazine (PUCAI 10-30) oral corticosteroids (PUCAI 35-60), or intravenous corticosteroids (PUCAI ≥65). The key outcomes for this analysis were week 12 corticosteroid-free remission, defined as PUCAI less than 10 and taking only mesalazine, and treatment escalation during the 12 study weeks to anti-tumour necrosis factor α (TNFα) agents, immunomodulators, or colectomy among those initially treated with intravenous corticosteroids. We identified independent predictors of outcome through multivariable logistic regression using a per-protocol approach. This study is registered with ClinicalTrials.gov, number NCT01536535.FindingsPatients were recruited between July 10, 2012, and April 21, 2015. 428 children initiated mesalazine (n=136), oral corticosteroids (n=144), or intravenous corticosteroids (n=148). Initial mean PUCAI was 31·1 (SD 13·3) in children initiating with mesalazine, 50·4 (13·8) in those initiating oral corticosteroids, and 66·9 (13·7) in those initiating intravenous corticosteroids (p

Minocycline hepatotoxicity can present with prominent autoimmune features in previously healthy individuals. The aim of this study was to identify genetic determinants of minocycline drug-induced liver injury (DILI) in a well-phenotyped cohort of patients.Caucasian patients with minocycline DILI underwent genome-wide genotyping and were compared to unexposed population controls. Human leukocyte antigen (HLA) binding of minocycline was assessed using AutoDock Vina.Among the 25 cases, 80% were female, median age was 19years and median latency from drug start to DILI onset was 318days. At presentation, 76% had acute hepatocellular liver injury, median ALT 1,077U/L (range: 63 to 2,333), median bilirubin 4.5mg/dl (range: 0.2 to 16.7), and 90% had a +ANA. During follow-up, 50% were treated with corticosteroids and no participants died or required a liver transplant. A significant association was noted between HLA-B∗35:02 and risk for minocycline DILI; a 16% carrier frequency in DILI cases compared to 0.6% in population controls (odds ratio: 29.6, 95% CI: 7.8-89.8, p=2.5×10HLA-B∗35:02 is a rare HLA allele that was more frequently identified in the 25 minocycline DILI cases compared to population controls. If confirmed in other cohorts, this HLA allele may prove to be a useful diagnostic marker of minocycline DILI.Development of liver injury following prolonged use of minocycline for acne is a rare but potentially severe form of drug-induced liver injury. Our study demonstrates that individuals who are HLA-B∗35:02 carriers are at increased risk of developing minocycline related liver injury. These results may help doctors more rapidly and confidently diagnose affected patients and possibly reduce the risk of liver injury in individuals receiving minocycline going forward.

Approximately half the US adult population consumes herbals and dietary supplements (HDS),(1,2) with recent reports showing their use to be increasing.(3,4) Supplement users are more commonly women, non-Hispanic whites, over age 40, and have higher levels of education than non-users.(4-7) NHANES III data indicate that multivitamins and minerals are the most common supplements used, followed by calcium and fish oils.(5) However, the range of HDS is far broader and includes numerous commercial products. Although dietary supplements are perceived as safe (8), the current regulatory framework established by the Dietary Supplement Health and Education Act of 1994 (9) requires less evidence of safety prior to marketing as assessed by the Food and Drug Administration (FDA) than is required for pharmaceuticals. The FDA and other regulatory bodies can take action against a manufacturer only if there is proven adulteration or injury from its supplement. Recent cases of life-threatening hepatotoxicity from the dietary supplement OxyElite Pro (10) underscore the potential adverse consequences of this oversight process. The Drug-Induced Liver Injury Network (DILIN), supported by the National Institutes of Diabetes and Digestive and Kidney Diseases, was established in 2003 to identify, enroll, and characterize cases of drug-induced liver injury attributable to medications (excluding acetaminophen) and HDS (ClinicalTrials.gov Identifier:NCT00345930).(11) The original DILIN report identified HDS as the second most common cause for liver injury. (12) Since that report, many more cases have been accrued by the DILIN. Thus, we examined the burden and characteristics of liver injury attributable to HDS in the DILIN, and compared this injury with that due to conventional medications.

Background Biliopancreatic-type postcholecystectomy pain, without significant abnormalities on imaging and laboratory test results, has been categorized as "suspected" sphincter of Oddi dysfunction (SOD) type III. Clinical predictors of "manometric" SOD are important to avoid unnecessary ERCP, but are unknown. Objective To assess which clinical factors are associated with abnormal sphincter of Oddi manometry (SOM). Design Prospective, cross-sectional. Setting Tertiary. Patients A total of 214 patients with suspected SOD type III underwent ERCP and pancreatic SOM (pSOM; 85% dual SOM), at 7 U.S. centers (from August 2008 to March 2012) as part of a randomized trial. Interventions Pain and gallbladder descriptors, psychosocial/functional disorder questionnaires. Main Outcome Measurements Abnormal SOM findings. Univariate and multivariate analyses assessed associations between clinical characteristics and outcome. Results The cohort was 92% female with a mean age of 38 years. Baseline pancreatic enzymes were increased in 5%; 9% had minor liver enzyme abnormalities. Pain was in the right upper quadrant (RUQ) in 90% (48% also epigastric); 51% reported daily abdominal discomfort. Fifty-six took narcotics an average of 33 days (of the past 90 days). Less than 10% experienced depression or anxiety. Functional disorders were common. At ERCP, 64% had abnormal pSOM findings (34% both sphincters, 21% biliary normal), 36% had normal pSOM findings, and 75% had at least abnormal 1 sphincter. Demographic factors, gallbladder pathology, increased pancreatobiliary enzymes, functional disorders, and pain patterns did not predict abnormal SOM findings. Anxiety, depression, and poorer coping were more common in patients with normal SOM findings (not significant on multivariate analysis). Limitations Generalizability. Conclusions Patient and pain factors and psychological comorbidity do not predict SOM results at ERCP in suspected type III SOD. (Clinical Trial registration number: NCT00688662.)

Patients with several painful functional gastrointestinal disorders (FGIDs) are reported to have a high prevalence of psychosocial disturbance. These aspects have not been studied extensively in patients with suspected Sphincter of Oddi dysfunction (SOD).A total of 214 patients with post-cholecystectomy pain and suspected SOD were enrolled in seven US centers in a multicenter-randomized trial (Evaluating Predictors and Interventions in Sphincter of Oddi Dysfunction). Baseline assessments included pain descriptors and burden, structured psychosocial assessments of anxiety/depression, coping, trauma, and health-related quality of life. Patients with high levels of depression, suicidal ideation, or psychosis were excluded.The study population (92% female, mean age 38) reported anxiety (9%), depression (8%), past sexual trauma (18%), and physical abuse (10%). Of the total screened population (n=1460), 3.9% of the patients were excluded because of the presence of defined severe psychological problems. The mean medical outcomes study short-form-36 (SF-36) physical and mental composite scores were 38.70 (s.d.=7.89) and 48.74 (s.d.=9.60), respectively. Most subjects reported symptoms of other FGIDs. There were no correlations between the extent of the pain burden in the 3 months before enrollment and the baseline anxiety scores or victimization history. However, those with greater pain burden were significantly more depressed. There were no meaningful differences in the psychosocial parameters in subjects with or without irritable bowel, and those who had cholecystectomy for stones or functional gallbladder disease. Those declining randomization were comparable to those randomized.Psychosocial comorbidity in SOD is high. However, it does not appear to differ significantly from that reported in surveys of age- and gender-matched general populations, and may be lower than reported with other FGIDs.

Background & Aims Drug induced liver injury (DILI) is challenging because of the lack of biomarkers to predict mortality. Our aim was to describe miRNA changes in sera of subjects with acute idiosyncratic DILI and determine if levels of miRNAs were associated with 6 month mortality. Methods Clinical data and sera were collected from subjects enrolled in the Drug Induced Liver Injury Network prospective study. miRNAs were isolated from serum obtained from 78 subjects within 2 weeks of acute DILI and followed up for 6 months or longer. miRNAs were compared to 40 normal controls and 6 month survivors vs non-survivors. Results The mean age of the DILI cohort was 48 years, and 55% were female. Eleven (14.1%) subjects died, 10 within 6 months of DILI onset, 5 (45%) liver related. Lower levels of miRNAs-122, -4463 and -4270 were associated with death within 6 months (P

CD133 has been associated with cell properties such as self renewal, migration and vasculogenic mimicry, potentially involved in generation of circulating tumor cells (CTCs). We characterized CD133 expression in CTCs of 98 nometastatic breast cancer (BC) patients. CTCs were isolated by immunomagnetic techniques using magnetic beads labeled with a multicytokeratin(CK)-specific antibody (CK3-11D5) and CTCs and CD133 detection through immunocytochemical methods. CK+/CD133+ CTCs were identified in 65% of patients at baseline and 47.8% after systemic therapy (p = 0.53). Correlation of CD133 status in CTCs with classical clinicopathological characteristics and response to therapy was performed. Her2 not amplified and low Ki-67 index were positively correlated with presence of CK+/CD133+ CTCs. Before any treatment, CK+/CD133+ CTCs were more frequently isolated in patients with luminal BC subtype. No statistically significant differences were found between proportion of CK+/CD133+ CTCs and BC subtypes after systemic therapy, implying a relative enrichment of CK+/CD133+ CTCs in triple negative and HER2-amplified tumors. While CK+/CTCs decreases after chemotherapy when analyzing the whole population, CK+/CD133+ CTCs were enriched in post-treatment samples in nonluminal BC subtypes. These findings suggest the potential role of CD133 as a promising marker of chemoresistance in nonluminal BC patients. Further prospective studies and extensive preclinical modeling will be needed to confirm whether CD133 is a marker of resistance to chemotherapy, and its role as a target for novel anticancer therapies targeting cancer stem cells and tumor vasculature.

A 64-year-old man with a history of persistent atrial fibrillation presented 2 weeks after pulmonary vein isolation radiofrequency ablation (RFA) with progressive weakness, altered mental status, and seizures. The patient underwent unsuccessful RFA for atrial fibrillation at an outside facility and

Thyroid-stimulating hormone (TSH) is an important regulator of the hypothalamic-pituitary-thyroid (HPT) axis in Xenopus laevis. To evaluate the role of this hormone on developing tadpoles, immunologically-based Western blots and sandwich ELISAs were developed for measuring intracellular (within pituitaries), secreted (ex vivo pituitary culture), and circulating (serum) amounts. Despite the small size of the tadpoles, these methods were able to easily measure intracellular and secreted TSH, and circulating TSH was measurable in situations where high levels were induced. The method was validated after obtaining a highly purified and enriched TSH sample using anti-TSH-β antibodies conjugated to magnetic beads. Subsequent mass-spectrometric analysis of the bands from SDS-PAGE and Western procedures identified the presence of amino acid sequences corresponding to TSH subunits. The purified sample was also used to prepare standard curves for quantitative analysis. The Western and ELISA methods had limits of detection in the low nanogram range. While the majority of the developmental work for these methods was done with X. laevis, the methods also detected TSH in Xenopus tropicalis. To our knowledge this is the first report of a specific detection method for TSH in these species, and the first to measure circulating TSH in amphibians. Examples of the utility of the methods include measuring a gradual increase in pituitary TSH at key stages of development, peaking at stages 58-62; the suppression of TSH secretion from cultured pituitaries in the presence of thyroid hormone (T4); and increases in serum TSH following thyroidectomy.

BACKGROUND & AIMS: The relationship between alcohol consumption and idiosyncratic drug induced liver injury (DILI) is not well understood. We investigated the relationship between heavy consumption of alcohol and characteristics and outcomes of patients with DILI enrolled in the Drug-induced Liver Injury Network (DILIN) prospective study. METHODS: We collected data from 1198 individuals with definite, highly likely, or probable DILI enrolled in the DILIN study from September 2004 through April 2016. At enrollment, all participants were asked about alcohol consumption; those with any alcohol consumption during previous 12 months were asked to complete the Skinner questionnaire to assess drinking history. Heavy consumption of alcohol was defined as more than 3 drinks, on average, per day by men or more than 2 drinks, on average, per day by women. RESULTS: Of the 601 persons who reported consuming at least 1 alcoholic drink in the preceding 12 months, 348 completed the Skinner questionnaire and 80 reported heavy consumption of alcohol. Heavy drinkers were younger (average age, 42 years) than non-drinkers (average age, 49 years) and a higher proportion were men (63% of heavy drinkers vs 35% of nondrinkers) (P

The long-term outcomes of patients with drug induced liver injury (DILI) are not well described. The aim of this study was to determine the frequency and severity of persistent liver biochemistry abnormalities in DILI patients followed over 2 years.Subjects with evidence of liver injury at 6 months after DILI onset were offered a month 12 and 24 study visit.Amongst the 99 patients with definite, probable, or very likely DILI and available laboratory data at 12 months after DILI onset, 74 (75%) had persistent liver injury (persisters) defined as a serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT)1.5 × upper limit of normal (ULN) or an alkaline phosphataseULN, while 25 (25%) had resolved liver injury (resolvers). On multivariate analysis, month 12 persisters were significantly older (52.6 vs. 43.7 years, P=0.01) and more likely to have a cholestatic lab profile at DILI onset (54 vs. 20%, P0.01) than resolvers. The month 12 persisters also had significantly poorer SF-36 physical summary scores at DILI onset and throughout follow-up compared with the resolvers (P0.01). Amongst the 17 subjects with a liver biopsy obtained at a median of 387 days after DILI onset, 9 had chronic cholestasis, 3 had steatohepatitis, and 3 had chronic hepatitis.In all, 75% of subjects with liver injury at 6 months after DILI onset have laboratory evidence of persistent liver injury during prolonged follow-up. Higher serum alkaline phosphatase levels at presentation and older patient age were independent predictors of persistent liver injury. Subjects with persistent liver injury at 12 months after DILI onset should be carefully monitored and assessed for liver disease progression.

In two-thirds of patients with Zollinger-Ellison syndrome (ZES), fasting serum gastrin (FSG) levels overlap with values seen in other conditions. In these patients, gastrin provocative tests are needed to establish the diagnosis of ZES. Whereas numerous gastrin provocative tests have been proposed, only the secretin, calcium, and meal tests are widely used today. Many studies have analyzed gastrin provocative test results in ZES, but they are limited by small patient numbers and methodologic differences. To address this issue, we report the results of a prospective National Institutes of Health (NIH) study of gastrin provocative tests in 293 patients with ZES and compare these data with those from 537 ZES and 462 non-ZES patients from the literature. In 97%-99% of gastrinoma patients, an increase in serum gastrin post secretin (Delta secretin) or post calcium (Delta calcium) occurred. In NIH ZES patients with or =200 pg/mL (83%/100%), Delta secretin >50% (86%/93%), Delta calcium > or =395 pg/mL (54%/100%), and Delta calcium >50% (78%/83%). A systematic analysis of the sensitivity and specificity of other possible criteria for a positive secretin or calcium test allowed us to identify a new criterion for secretin testing (Delta > or =120 pg/mL) with the highest sensitivity/specificity (94%/100%) and to confirm the commonly used criterion for calcium tests (Delta > or =395 pg/mL) (62%/100%). This analysis further showed that the secretin test was more sensitive than the calcium test (94% vs. 62%). Our results suggest that secretin stimulation should be used as the first-line provocative test because of its greater sensitivity and simplicity and lack of side effects. In ZES patients with a negative secretin test, 38%-50% have a positive calcium test. Therefore the calcium test should be considered in patients with a strong clinical suspicion of ZES but a negative secretin test. Furthermore, we found that some clinical (diarrhea, duration of medical treatment), laboratory (basal acid output), and tumoral (size, extent) characteristics correlate with the serum gastrin increase post secretin and post calcium. However, using the proposed criteria, the result of these provocative tests (that is, positive or negative) is minimally influenced by these factors, so secretin and calcium provocative tests are reliable in patients with different clinical, laboratory, and tumor characteristics. A systematic analysis of meal testing showed that 54%-77% of ZES patients have a 100% increase post meal, causing significant overlap with antral syndromes. Furthermore, we could not confirm the usefulness of meal tests for localization of duodenal gastrinomas. We conclude that the secretin test is a crucial element in the diagnosis of most ZES patients, the calcium test may be useful in selected patients, but the meal test is not helpful in the management of ZES. For secretin testing, the criterion with the highest sensitivity and specificity is an increase of > or =120 pg/mL, which should replace other criteria commonly used today.

Multiple endocrine neoplasm type 1 (MEN1) is associated with parathyroid, pancreatic, and pituitary tumors. Although most patients present with hyperparathyroidism, the diagnosis can be difficult, because a significant proportion present with other endocrinopathies or may lack a family history, and other MEN1 manifestations may be mild. Recently, multiple cutaneous lesions (angiofibromas and collagenomas) were reported to be frequent in MEN1 patients, and it was proposed that their discovery suggested the diagnosis of MEN1. The purpose of this study was to prospectively assess the frequency and sensitivity/specificity of various cutaneous criteria for MEN1 in 110 consecutive patients with gastrinomas with or without MEN1. All patients had hormonal and functional studies to determine MEN1 status (48 with MEN1, 62 without MEN1), dermatological evaluation, and tumor imaging studies. Angiofibromas and collagenomas were more frequent in MEN1 patients (64% vs. 8% and 62% vs. 5%; P < 0.00001) and were multiple in 77-81% of the MEN1 patients. Lipomas occurred in 17%. The presence of these skin lesions did not correlate with age, disease duration, or other MEN1 features. Angiofibromas or collagenomas (single or multiple) had 50-65% sensitivity for MEN1 and 92-100% specificity. The combination criterion of multiple angiofibromas (more than three) and any collagenomas had the highest sensitivity (75%) and specificity (95%). This criterion has greater sensitivity than pituitary or adrenal disease and is comparable to hyperparathyroidism in some studies of patients with MEN1 with gastrinoma. This criterion should have sufficient sensitivity/specificity to be clinically useful.

Abdominal pain after cholecystectomy is common and may be attributed to sphincter of Oddi dysfunction. Management often involves endoscopic retrograde cholangiopancreatography (ERCP) with manometry and sphincterotomy.To determine whether endoscopic sphincterotomy reduces pain and whether sphincter manometric pressure is predictive of pain relief.Multicenter, sham-controlled, randomized trial involving 214 patients with pain after cholecystectomy without significant abnormalities on imaging or laboratory studies, and no prior sphincter treatment or pancreatitis randomly assigned (August 6, 2008-March 23, 2012) to undergo sphincterotomy or sham therapy at 7 referral medical centers. One-year follow-up was blinded. The final follow-up visit was March 21, 2013.After ERCP, patients were randomized 2:1 to sphincterotomy (n = 141) or sham (n = 73) irrespective of manometry findings. Those randomized to sphincterotomy with elevated pancreatic sphincter pressures were randomized again (1:1) to biliary or to both biliary and pancreatic sphincterotomies. Seventy-two were entered into an observational study with conventional ERCP managemeny.Success of treatment was defined as less than 6 days of disability due to pain in the prior 90 days both at months 9 and 12 after randomization, with no narcotic use and no further sphincter intervention.Twenty-seven patients (37%; 95% CI, 25.9%-48.1%) in the sham treatment group vs 32 (23%; 95% CI, 15.8%-29.6%) in the sphincterotomy group experienced successful treatment (adjusted risk difference, -15.6%; 95% CI, -28.0% to -3.3%; P = .01). Of the patients with pancreatic sphincter hypertension, 14 (30%; 95% CI, 16.7%-42.9%) who underwent dual sphincterotomy and 10 (20%; 95% CI, 8.7%-30.5%) who underwent biliary sphincterotomy alone experienced successful treatment. Thirty-seven treated patients (26%; 95% CI,19%-34%) and 25 patients (34%; 95% CI, 23%-45%) in the sham group underwent repeat ERCP interventions (P = .22). Manometry results were not associated with the outcome. No clinical subgroups appeared to benefit from sphincterotomy more than others. Pancreatitis occurred in 15 patients (11%) after primary sphincterotomies and in 11 patients (15%) in the sham group. Of the nonrandomized patients in the observational study group, 5 (24%; 95% CI, 6%-42%) who underwent biliary sphincterotomy, 12 (31%; 95% CI, 16%-45%) who underwent dual sphincterotomy, and 2 (17%; 95% CI, 0%-38%) who did not undergo sphincterotomy had successful treatment.In patients with abdominal pain after cholecystectomy undergoing ERCP with manometry, sphincterotomy vs sham did not reduce disability due to pain. These findings do not support ERCP and sphincterotomy for these patients.clinicaltrials.gov Identifier: NCT00688662.

Background: Proton pump inhibitors are potent acid suppressants which, at normal doses, can result in hypergastrinaemia in patients with idiopathic oesophageal reflux disease and in the control of symptoms in most patients with gastrinomas. Therefore, their use could delay or mask the diagnosis of gastrinoma. Aim: To investigate whether the widespread use of proton pump inhibitors masks or complicates the diagnosis of gastrinoma. Subjects and methods: Data from two centres with different referral criteria for suspected gastrinomas were analysed (Gastroenterology Unit, Rome, Italy and National Institutes of Health, Bethesda, MD, USA). The number of referrals and the number of new patients with gastrinoma diagnosed in the years prior to the widespread use of proton pump inhibitors (1986–1992) were compared with the numbers since proton pump inhibitors became widely available (1993–1998). Results: The decrease in referral rate (P=0.0009) and the decrease in the annual rate of gastrinoma diagnosis (P=0.0020) at both centres correlated with the increased use of proton pump inhibitors. At the Italian centre, there was a 62% decrease in annual referrals (P

It is not known whether specific characteristics of medication are associated with type of drug-induced liver injury (DILI) or outcome. We examined the relationships among select characteristics of medications and DILI phenotype and outcome.We analyzed 383 cases of DILI caused by a single orally administered prescription agent from the DILI Network Prospective Study with causalities of definite, highly likely, or probable. Relationship of daily dosage (≥50 mg vs ≤49 mg), preponderance of hepatic metabolism (≥50% vs50%), or Biopharmaceutics Drug Disposition Classification System (BDDCS) class (1-4, based on solubility and metabolism of the drug) were compared with clinical characteristics and outcomes.Compared with cases of DILI in the ≤49 mg/day group, those associated with daily dosages ≥50 mg had shorter latency (median, 38 days vs 56 days; P = .03) and a different biochemical pattern of liver injury (P = .04); no differences in recovery, severity, or outcome were observed. Patients with DILI caused by medications with or without preponderant hepatic metabolism did not differ in clinical characteristics or outcomes. Compared with other classes of BDDCS, DILI caused by BDDCS class 1 medications had significantly longer latency (P.001) and greater proportion of hepatocellular injury (P = .001). However, peak liver biochemical values and patients' time to recovery, disease severity, and outcomes did not differ among the 4 BDDCS classes.Characteristics of medications (dosage, hepatic metabolism, and solubility) are associated with features of DILI such as latency and pattern of liver injury, but not with recovery, severity, or outcome.

Background & Aims Little is known about the incidence of drug-induced liver injury (DILI) and risk factors for adverse outcomes. We evaluated short-term outcomes of a large cohort of patients with DILI enrolled in an ongoing multicenter prospective study. Methods Data were collected from 660 adults with definite, highly likely, or probable DILI. Regression methods were used to identify risk factors for early liver-related death or liver transplantation and chronic liver injury. Results Patients' median age was 51.4 years; 59.5% were female and 59.1% required hospitalization. Within 6 months of DILI onset, 30 patients received liver transplants (4.5%; 95% confidence interval [CI], 3.0%–6.1%) and 32 died (5%; 95% CI, 3.2%–6.5%); 53% of the deaths were liver related. Asian race, absence of itching, lung disease, low serum albumin levels, low platelet counts, and high serum levels of alanine aminotransferase and total bilirubin at presentation were independent risk factors for reduced times to liver-related death or liver transplantation (C-statistic = 0.87). At 6 months after DILI onset, 18.9% of the 598 evaluable subjects had persistent liver damage. African-American race, higher serum levels of alkaline phosphatase, and prior heart disease or malignancy requiring treatment were independent risk factors for chronic DILI (C-statistic = 0.71). Conclusions Nearly 1 in 10 patients die or undergo liver transplantation within 6 months of DILI onset and nearly 1 in 5 of the remaining patients have evidence of persistent liver injury at 6 months. The profile of liver injury at presentation, initial severity, patient's race, and medical comorbidities are important determinants of the likelihood of death/transplantation or persistent liver injury within 6 months.

Extracellular calcium levels are able to influence the secretion of gastrin by gastrinomas and possibly affect the growth pattern. The molecular mechanisms of these functions are not known. The purpose of the present study was to investigate the presence of the calcium-sensing receptor (CaR) in 10 gastrinomas and determine the extent of expression in the tumors. The amounts of CaR messenger ribonucleic acid in eight tumors were determined by quantitative RT-PCR. Protein expression was analyzed by Western blot and immunohistochemistry using a monoclonal antibody (ADD). CaR messenger ribonucleic acid was detected in all gastrinomas with levels ranging from 0.04–3.16 times the amount of β-actin transcripts. The Western blot showed a major immunoreactive band at 250 kDa and a minor at 140 kDa, corresponding to the receptor dimer and monomer, respectively. Immunohistochemistry demonstrated variable membranous staining in all gastrinomas and normal pancreatic islets. No staining was observed in the normal liver, lymph node, or exocrine pancreas. We conclude that the CaR is present in all gastrinomas, with expression varying by 80-fold. It probably contributes to the calcium-stimulated gastrin release by gastrinomas. Whether the density of the CaR is a determining factor of the magnitude of this gastrin release or plays a role in regulating the growth pattern of the gastrinoma, as it does in other cells, remains unclear at present.

Multiple endocrine neoplasia type 1 (MEN1) gene mutations are reported in some gastrinomas occurring in patients without MEN1 as well as in some other pancreatic endocrine tumors (PETs). In some inherited syndromes phenotype-genotype correlations exist for disease severity, location, or other manifestations. The purpose of the present study was to correlate mutations of the MEN1 gene in a large cohort of patients with sporadic gastrinomas to disease activity, tumor location, extent, and growth pattern. DNA was extracted from frozen gastrinomas from 51 patients and screened by dideoxyfinger-printing (ddF) for abnormalities in the 9 coding exons and adjacent splice junctions of the MEN1 gene. Tumor DNA exhibiting abnormal ddF patterns was sequenced for mutations. The findings were correlated with clinical manifestations of the disease, primary tumor site, disease extent, and tumor growth postoperatively. Tumor growth was determined by serial imaging studies. Sixteen different MEN1 gene mutations in the 51 sporadic gastrinomas (31%) were identified (11 truncating, 4 missense, and 1 in-frame deletion). Nine of the 16 mutations were located in exon 2 compared to 7 of 16 in the remaining 8 coding exons (P = 0.005 on a per nucleotide basis). Primary pancreatic or lymph node gastrinomas with a mutation had only exon 2 mutations, whereas duodenal tumors uncommonly harbored exon 2 mutations (P = 0.011). Similarly, small primary tumors (

BACKGROUND Serum chromogranin A levels (CgA) are reported by some authors to be of clinical utility for assessing the presence or absence of a pancreatic endocrine tumor and tumor extent or growth. The aim of the current study was to assess this finding and compare the results with those from serum gastrin determinations (FSG) in a large cohort of patients with gastrinomas. METHODS In 112 consecutive patients with the Zollinger–Ellison syndrome serum CgA and FSG levels were measured and correlated with disease activity, extent of disease, and the presence of multiple endocrine neoplasia type-1 (MEN-1) or gastric carcinoid tumors. RESULTS Serum CgA levels drawn on 2 consecutive days correlated closely (P < 0.00001) as did serum gastrin levels. Serum CgA levels correlated significantly with FSG levels (P < 0.00001). Serum CgA and FSG levels were significantly higher in patients with active disease than in disease free patients (P < 0.00001). The sensitivity for the presence of disease was higher for CgA compared with FSG (92% vs. 80%; P = 0.021). However, the specificity of CgA was 67%. Serum CgA levels were not significantly different in the four disease categories (stable extrahepatic disease, increasing extrahepatic disease, stable liver metastases, and increasing liver metastases). FSG levels were significantly lower in patients with stable extrahepatic disease compared with those with increasing extrahepatic disease. However, both tumor markers decreased significantly with a gastrinoma resection in five patients. The presence of MEN-1 or a gastric carcinoid tumor did not influence the results. CONCLUSIONS The results of the current study showed that serum CgA and FSG levels both are sensitive tumor markers for the detection of a gastrinoma; however, CgA levels have a relatively low specificity. Neither the magnitude of the serum CgA nor gastrin level correlated with tumor growth or tumor extent and therefore cannot be used to determine these variables. However, in contrast to some other studies, the results of the current study show that changes in serum CgA or gastrin in a given patient with time are related to the tumor extent and not to gastric mucosal changes due to hypergastrinemia. Cancer 1999;85:1470–83. © 1999 American Cancer Society.

Background: Gastric acid secretion is important for absorption of dietary non-haem iron, and iron deficiency is common in gastric hyposecretory states such as after gastric resection. It is not known if prolonged, continuous treatment with potent acid suppressants such as omeprazole will lead to iron deficiency or lower body iron stores. Aim: To assess iron stores and the occurrence of iron deficiency anaemia in patients with Zollinger–Ellison syndrome (ZES) treated long-term with gastric antisecretory drugs. Methods: One hundred and nine patients with ZES but without previous gastric resections were studied. All patients underwent assessment of acid control on antisecretory agents, determination of tumour extent, evaluation of haematological parameters (Hct, haemoglobin, WBC, MCV, MCHC), and determination of serum iron parameters (iron, ferritin, transferrin, iron/transferrin ratio). Acid control values for the last 4 years were reviewed, the presence or absence of acid hyposecretion determined using three different criteria and this result correlated with haematological and iron parameters. Results: Eighty-nine patients were taking omeprazole, nine patients were taking histamine H2-antagonists and 11 patients were taking no drugs following curative resection. The mean duration of omeprazole treatment was 5.7 years (range 0.7–12.5 years) and total duration of any treatment was 10.1 years (range 0.7–21 years). Acid hyposecretion was present by at least one criterion in 45% of patients. There were no significant differences between patients with or without acid hyposecretion, taking or not taking omeprazole, having different durations of omeprazole treatment or different durations of total time receiving any antisecretory treatment, for any serum iron parameter, haematological parameter, or for the frequency of iron deficiency. Males and females did not differ in percentage with low ferritin levels or percentage with iron deficiency. Conclusions: Continuous treatment with omeprazole for 6 years or continuous treatment with any gastric antisecretory drug for 10 years does not cause decreased body iron stores or iron deficiency. These results suggest that, in contrast to recent results which show yearly monitoring of vitamin B12 in such patients is needed, such monitoring for iron parameters is not necessary.

PURPOSE The growth pattern of untreated metastatic neuroendocrine tumors is unknown. This uncertainty contributes to the disagreement regarding timing and could effect evaluation of the efficacy of antitumor treatment. The purpose of this study was to determine the growth rate of untreated hepatic metastatic gastrinoma and to identify its predictors. PATIENTS AND METHODS Nineteen patients with histologically proven metastatic gastrinoma in the liver with Zollinger-Ellison syndrome were studied. Conventional imaging studies were performed initially and at 4- to 6-month intervals before any treatment. Metastases growth rates were calculated and correlated with laboratory and clinical parameters, as well as tumor extent on initial tumor assessment. RESULTS Twenty-six percent of patients (five of 19) demonstrated no growth over a mean follow-up time of 29 months, 32% (six of 19) had slow growth (1% to 50% increase in volume per month) over a 19-month period, and 42% (eight of 19) had rapid growth (> 50% volume increase per month) over an 11-month period. In patients with rapid growth, 62% died; 0% of the no-growth or slow-growth group died. No clinical or laboratory parameter correlated with growth rate, except the rate increase in fasting serum gastrin and the presence of bilobar liver or bone metastases. The growth rate was highly predictive of death from tumor. CONCLUSION The growth rate of metastatic gastrinoma varies markedly in different patients and 26% demonstrate no growth. The growth rate needs to considered in the determination of when and in whom antitumor therapy is initiated, as well as in the assessment of response to tumoricidal therapies.

Many herbal dietary supplements (HDS) contain green tea extract (GTE) and its component catechins, although their presence may not always be indicated on the product label. Because GTE and catechins have been implicated in human hepatotoxicity in several case reports, our objective was to determine whether catechins were present in HDS that were implicated in hepatotoxicity, even if not identified among the labeled ingredients, and whether these compounds could be associated with liver injury. We assayed 97 HDS implicated in human hepatotoxicity for catechins. We found that 29 of 73 HDS (39.7 %) that did not identify GTE or any of its component catechins on their label contained catechins. Among patients with confirmed hepatotoxicity, there was no statistically significant association between the presence of catechin or the dose consumed and liver injury causality score, severity, or pattern of liver injury. Catechin levels tended to be highest in products used for weight loss, although catechin concentrations were low in most products. Many HDS commonly contain catechins that are implicated in hepatotoxicity, although their presence may not be indicated on the product label. Although our results did not establish an association between GTE or catechins with hepatotoxicity, they highlight some of the many complexities and uncertainties that surround the attribution of drug-induced liver injury (DILI) to HDS.

The conference “Advances in Acute and Chronic Pancreatitis: From Development to Inflammation and Repair” was held June 25–26, 2012, on the NIH campus, in Bethesda, Maryland (http://www2.niddk.nih.gov/News/Calendar/Pancreatitis2012.htm).

Idiosyncratic drug-induced liver injury (DILI) is an important but relatively infrequent cause of potentially severe acute and chronic liver injury. The aim of this clinical research workshop was to review and attempt to standardize the current nomenclature and terminology used in DILI research. Because DILI is a diagnosis of exclusion, selected elements of the medical history, laboratory tests, and previous reports were proposed to improve causality assessment. Definitions and diagnostic criteria regarding the onset of DILI, evolution of liver injury, risk factors, and mandatory testing versus optional testing for competing causes were reviewed. In addition, the role of intentional and inadvertent rechallenge, liver histology, and host genetic polymorphisms in establishing the diagnosis and prognosis of DILI were reviewed. Consensus was established regarding the need to develop a web-of-knowledge database that provides concise, reliable, and updated information on cases of liver injury due to drugs and herbal and dietary supplements. In addition, the need to develop drug-specific computerized causality assessment methods that are derived from prospectively phenotyped cases was a high priority. Proposed scales for grading DILI severity and assessing the likelihood of an agent causing DILI and written criteria for improving the reliability, accuracy, and reproducibility of expert opinion were reviewed. Finally, the unique challenges of assessing causality in children, patients with underlying liver disease, and subjects taking herbal and dietary supplements were discussed. Conclusion: Workshop participants concluded that multicenter referral networks enrolling patients with suspected DILI according to standardized methodologies are needed. These networks should also collect biological samples that may provide crucial insights into the mechanism(s) of DILI with the ultimate aim of preventing future cases of DILI. (HEPATOLOGY 2010)