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  • Efficacy of Sox10 Promoter Methylation in the Diagnosis of Intestinal Neuronal Dysplasia From the Peripheral Blood.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : null
    Yu-Rong Liu,Fang Ba,Lan-Jie Cheng,Xu Li,Shi-Wei Zhang,Shu-Cheng Zhang

    OBJECTIVES Intestinal neuronal dysplasia (IND) is a common malformation of the enteric nervous system. Diagnosis requires a full-thickness colonic specimen and an experienced pathologist, emphasizing the need for noninvasive analytical methods. Recently, the methylation level of the Sox10 promoter has been found to be critical for enteric nervous system development. However, whether it can be used for diagnostic purposes in IND is unclear. METHODS Blood and colon specimens were collected from 32 patients with IND, 60 patients with Hirschsprung disease (HD), and 60 controls. Sox10 promoter methylation in the blood and the Sox10 expression level in the colon were determined, and their correlation was analyzed. The diagnostic efficacy of blood Sox10 promoter methylation was analyzed by receiver operating characteristic curve. RESULTS The blood level of Sox10 promoter methylation at the 32nd locus was 100% (90%-100%; 95% confidence interval [CI], 92.29%-96.37%) in control, 90% (80%-90%; 95% CI, 82.84%-87.83%) in HD, and 60% (50%-80%; 95% CI, 57.12%-69.76%) in IND specimens. Sox10 promoter methylation in the peripheral blood was negatively correlated with Sox10 expression in the colon, which was low in control, moderate in HD, and high in IND specimens (r = -0.89). The area under the curve of Sox10 promoter methylation in the diagnosis of IND was 0.94 (95% CI, 0.874-1.000, P = 0.000), with a cutoff value of 85% (sensitivity, 90.6%; specificity, 95.0%). By applying a cutoff value of 65%, promoter methylation was more indicative of IND than HD. DISCUSSION The analysis of Sox10 promoter methylation in the peripheral blood can be used as a noninvasive method for IND diagnosis.

    更新日期:2019-11-01
  • Inflammation-Associated Microsatellite Alterations Caused by MSH3 Dysfunction Are Prevalent in Ulcerative Colitis and Increase With Neoplastic Advancement.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : null
    Koji Munakata,Minoru Koi,Takahito Kitajima,Stephanie Tseng-Rogenski,Mamoru Uemura,Hiroshi Matsuno,Kenji Kawai,Yuki Sekido,Tsunekazu Mizushima,Yuji Toiyama,Takuya Yamada,Masayuki Mano,Eiji Mita,Masato Kusunoki,Masaki Mori,John M Carethers

    OBJECTIVES Inflammation-associated microsatellite alterations (also known as elevated microsatellite alterations at selected tetranucleotide repeats [EMAST]) result from IL-6-induced nuclear-to-cytosolic displacement of the DNA mismatch repair (MMR) protein MSH3, allowing frameshifts of dinucleotide or longer microsatellites within DNA. MSH3 also engages homologous recombination to repair double-strand breaks (DSBs), making MSH3 deficiency contributory to both EMAST and DSBs. EMAST is observed in cancers, but given its genesis by cytokines, it may be present in non-neoplastic inflammatory conditions. We examined ulcerative colitis (UC), a preneoplastic condition from prolonged inflammatory duration. METHODS We assessed 70 UC colons without neoplasia, 5 UC specimens with dysplasia, 14 UC-derived colorectal cancers (CRCs), and 19 early-stage sporadic CRCs for microsatellite instability (MSI) via multiplexed polymerase chain reaction capable of simultaneous detection of MSI-H, MSI-L, and EMAST. We evaluated UC specimens for MSH3 expression via immunohistochemistry. RESULTS UC, UC with dysplasia, and UC-derived CRCs demonstrated dinucleotide or longer microsatellite frameshifts, with UC showing coincident reduction of nuclear MSH3 expression. No UC specimen, with or without neoplasia, demonstrated mononucleotide frameshifts. EMAST frequency was higher in UC-derived CRCs than UC (71.4% vs 31.4%, P = 0.0045) and higher than early-stage sporadic CRCs (66.7% vs 26.3%, P = 0.0426). EMAST frequency was higher with UC duration >8 years compared with ≤8 years (40% vs 16%, P = 0.0459). DISCUSSION Inflammation-associated microsatellite alterations/EMAST are prevalent in UC and signify genomic mutations in the absence of neoplasia. Duration of disease and advancement to neoplasia increases frequency of EMAST. MSH3 dysfunction is a potential contributory pathway toward neoplasia in UC that could be targeted by therapeutic intervention.

    更新日期:2019-11-01
  • Three Cases of Alcohol-Induced Acute-On-Chronic Liver Failure With Successful Support by Adipose-Derived Stem Cells.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : null
    Tobias Götze,Michael Krueger,Juliane Meutsch,Max Dörfel,Stephan Born,Jan-Peter Sowa,Ali Canbay

    OBJECTIVES Acute liver failure (ALF) and acute-on-chronic liver failure (AOCLF) are critical medical conditions with urgent therapy requirements. When ALF or AOCLF are due to alcohol intoxication or based on chronic alcohol abuse, virtually, no therapeutic options are available as liver transplantation is prohibited. In this case series, treatment of alcohol-induced ALF/AOCLF with adipose--derived stem cells (ASC) was tested under compassionate use. METHODS ASC from 2 donors were isolated, cultured, and expanded by established protocols. ASC were administered to 3 individuals with either ALF or AOCLF due to alcohol abuse under compassionate use. Clinical presentation, serum measurements, and other diagnostic methods were compiled before ASC treatment and during the disease course after ASC administration. RESULTS Three patients were admitted to the Department of Gastroenterology, Hepatology, and Infectious Diseases (University Hospital Magdeburg) with acute or AOCLF due to alcohol abuse. All 3 patients presented in impaired general condition and with elevated, in 1 case drastically elevated, serum liver enzyme concentrations. Treatment with ASC led to improvements in general condition and reduction of serum transaminases. In 2 cases, reduction of liver stiffness and increase of liver function by the C methacetin breath test were observed after ASC treatment. Recovery to a normal condition was achieved between 1 and 2 months after ASC treatment. No adverse effects associated to ASC treatment were observed. DISCUSSION ASC treatment may be a feasible option to enhance recovery from alcohol-induced ALF or AOCLF. ASC treatment seems safe in the presented cases.

    更新日期:2019-11-01
  • Molecular Biomarkers of Sessile Serrated Adenoma/Polyps.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : null
    Priyanka Kanth,Katherine E Boylan,Mary P Bronner,Kenneth M Boucher,Mark W Hazel,Ruoxin Yao,Stelian Pop,Philip S Bernard,Don A Delker

    OBJECTIVES Sessile serrated adenoma/polyps (SSA/Ps) contribute up to 30% of all colon cancers. There is considerable histological overlap between SSA/Ps and hyperplastic polyps. Inadequate consensus exists among pathologists, and no molecular biomarkers exist to differentiate these lesions with high accuracy. Lack of reliable diagnosis adversely affects clinical care. We previously defined a novel 7-gene panel by RNA sequencing that differentiates SSA/Ps from hyperplastic polyps. Here, we use the 7-gene panel as a molecular approach to differentiate SSA/Ps and HPs with higher sensitivity and specificity in a large sample set from a tertiary health care center. METHODS Reverse transcription quantitative polymerase chain reaction of the 7-gene panel was performed on 223 formalin-fixed, paraffin-embedded serrated polyp and normal colon samples. We compare the sensitivity and specificity of the 7-gene panel with the BRAF and KRAS mutation incidence in differentiating SSA/Ps and HPs. We also evaluate the clinical data of patients with SSA/Ps showing high and low expression of the gene panel. RESULTS The 7-gene RNA expression panel differentiates SSA/Ps and HPs with 89.2% sensitivity and 88.4% specificity. The gene panel outperforms BRAF mutation in identification of SSA/Ps. Clinical data suggest that expression of the 7-gene panel correlates with the development of SSA/Ps in the future. DISCUSSION This study describes a novel 7-gene panel that identifies SSA/Ps with improved accuracy. Our data show that RNA markers of SSA/Ps advance the distinction of serrated lesions and contribute to the study of the serrated pathway to colon cancer.

    更新日期:2019-11-01
  • Sex Differences in the Association Between Frailty and Sarcopenia in Patients With Cirrhosis.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : null
    Laila Fozouni,Connie W Wang,Jennifer C Lai

    OBJECTIVES Frailty is prevalent in patients with cirrhosis and is hypothesized to result in part from sarcopenia, but the precise contribution of sarcopenia to frailty in this population is poorly understood. METHODS Included were patients with cirrhosis from 2011 to 2014 who had an ambulatory frailty assessment and abdominal computed tomography scan within 3 months. Logistic regression assessed the associations between frailty (=Liver Frailty Index ≥4.5), and sarcopenia (=skeletal muscle index of <39 cm/m for women and <50 cm/m for men). RESULTS Two hundred ninety-one participants were included: 33% were female. The median (interquartile range) Liver Frailty Index was 3.7 (3.3-4.2); 19% were frail. The median (interquartile range) skeletal muscle index was 49 cm/m (31-69); 36% had sarcopenia. Among the 54 frail participants, 48% had sarcopenia. In univariable logistic regression, sarcopenia was associated with a 1.86× increased odds of being frail (95% confidence interval [CI], 1.02-3.38). After adjusting for sex, etiology, hepatocellular carcinoma, MELDNa, ascites, encephalopathy, and hypertension, sarcopenia was associated with a 2.38× increased odds of being frail (95% CI, 1.17-4.85). After stratifying by sex and adjusting for MELDNa, sarcopenia among males was associated with a significantly increased odds of frailty (odds ratio 2.81, 95% CI, 1.19-6.67), whereas sarcopenia among females was not (odds ratio 1.38; 95% CI, 0.45-4.25). DISCUSSION In patients with cirrhosis, sarcopenia was associated with a nearly 2-fold increased odds of being frail. Two-thirds of frail men displayed sarcopenia compared with only one-quarter of frail women. Contributors to the frail phenotype may differ by sex and support the need for sex-specific strategies to reduce frailty in this population.

    更新日期:2019-11-01
  • A Novel Allergen-Specific Immune Signature-Directed Approach to Dietary Elimination in Eosinophilic Esophagitis.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : null
    Evan S Dellon,Rishu Guo,Sarah J McGee,Deanna K Hamilton,Emily Nicolai,Jacquelyn Covington,Susan E Moist,Ashley Arrington,Benjamin L Wright,A Wesley Burks,Brian P Vickery,Michael Kulis

    OBJECTIVES Dietary elimination for treatment of eosinophilic esophagitis (EoE) is limited by lack of accuracy in current allergy tests. We aimed to develop an immunologic approach to identify dietary triggers and prospectively test allergen-specific immune signature-guided dietary elimination therapy. METHODS In the first phase, we developed and assessed 2 methods for determining selected food triggers using samples from 24 adults with EoE: a CD4+ T-cell proliferation assay in peripheral blood and food-specific tissue IgG4 levels in esophageal biopsies. In the second phase, we clinically tested elimination diets created from these methods in a prospective cohort treated for 6 weeks (NCT02722148). Outcomes included peak eosinophil counts (eos/hpf), endoscopic findings (measured by the EoE Endoscopic Reference Score), and symptoms (measured by the EoE Symptom Activity Index). RESULTS Parameters were optimized with a positive test on either assay, yielding agreements of 60%, 75%, 53%, 58%, and 53% between predicted and known triggers of peanut, egg, soy, wheat, and milk, respectively. In clinical testing, the mean number of foods eliminated based on the assays was 3.4, and 19 of 22 subjects were compliant with treatment. After treatment, median peak eosinophil counts decreased from 75 to 35 (P = 0.007); there were 4 histologic responders (21%). The EoE Endoscopic Reference Score and EoE Symptom Activity Index score also decreased after treatment (4.6 vs 3.0; P = 0.002; and 32.5 vs 25.0; P = 0.06, respectively). DISCUSSION We successfully developed a new testing approach using CD4 T-cell proliferation and esophageal food-specific IgG4 levels, with promising accuracy rates. In clinical testing, this led to improvement in eosinophil counts, endoscopic severity, and symptoms of dysphagia, but a smaller than expected number of patients achieved histologic remission.

    更新日期:2019-11-01
  • Factors That Affect Prevalence of Small Intestinal Bacterial Overgrowth in Chronic Pancreatitis: A Systematic Review, Meta-Analysis, and Meta-Regression.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-09-14
    Bara El Kurdi,Sumbal Babar,Mahmoud El Iskandarani,Adam Bataineh,Markus M Lerch,Mark Young,Vijay P Singh

    OBJECTIVES Small intestinal bacterial overgrowth (SIBO) can complicate chronic pancreatitis (CP) and interfere with management. Its predisposing factors in CP and treatment response are unknown. In this review, we evaluated factors affecting disease burden. METHODS A computerized search of PubMed and EMBASE databases from inception through May 2019 was done for studies correlating SIBO with CP. Studies were screened, and relevant data were extracted and analyzed. Pooled prevalence, odds ratio (OR), and meta-regression were performed using the random effects model as classically described by Borenstein et al. (2009). SIBO's relation to diabetes mellitus (DM), pancreatic exocrine insufficiency (PEI), narcotic use, and proton-pump inhibitor use was investigated. Treatment response was pooled across studies. P value < 0.05 was considered significant. RESULTS In 13 studies containing 518 patients with CP, SIBO prevalence was 38.6% (95% confidence interval [CI] 25.5-53.5). OR for SIBO in CP vs controls was 5.58 (95% CI 2.26-13.75). Meta-regression showed that PEI and the diagnostic test used were able to explain 54% and 43% of the variance in SIBO prevalence across studies, respectively. DM and PEI were associated with increased SIBO in CP with OR (2.1, 95% CI 1.2-3.5) and OR (2.5, 95% CI 1.3-4.8), respectively. Symptomatic improvement was reported in 76% of patients after SIBO treatment. DISCUSSION SIBO complicates 38% of CP with OR of 5.58 indicating a predisposition for this condition. PEI correlates with SIBO in CP and might play a role in pathophysiology. DM and PEI are associated with increased SIBO in CP. Treatment of SIBO may lead to symptomatic improvement.

    更新日期:2019-11-01
  • Role of Autoimmune Gastritis in Gastric Cancer.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-09-14
    Helge L Waldum,Reidar Fossmark

    更新日期:2019-11-01
  • IgG4-Related Disease: A Growing Appreciation of Follicular Helper T Cell Expansion.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-09-14
    Mitsuhiro Akiyama,Katsuya Suzuki,Yuko Kaneko,Tsutomu Takeuchi

    更新日期:2019-11-01
  • Metabolically Healthy Obesity and the Risk of Erosive Esophagitis: A Cohort Study.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-09-10
    Tae Jun Kim,Hyuk Lee,Sun-Young Baek,Kyunga Kim,Yang Won Min,Byung-Hoon Min,Jun Haeng Lee,Hee Jung Son,Poong-Lyul Rhee,Jae J Kim

    OBJECTIVES Obesity is an established risk factor of erosive esophagitis, and metabolic unhealthiness has been implicated in the pathogenesis of erosive esophagitis. Yet, the risk of erosive esophagitis among obese individuals without obesity-related metabolic unhealthiness, a condition referred to as "metabolically healthy obese (MHO)", remains unclear. We examined the association between body mass index (BMI) categories and the development of erosive esophagitis in a cohort of metabolically healthy individuals. METHODS We conducted a cohort study of 14,725 asymptomatic adults free of erosive esophagitis and metabolic abnormalities, who underwent repeated health checkups including screening endoscopy. A metabolically healthy state was defined as having no metabolic syndrome components and a homeostasis model assessment of insulin resistance <2.5. The presence of erosive esophagitis was determined using endoscopy. RESULTS During 81,385.2 person-years of follow-up, 1,865 participants developed erosive esophagitis (incidence rate, 22.9 per 1,000 person-years). The multivariable adjusted hazard ratios (95% confidence intervals) for incident erosive esophagitis comparing overweight (BMI 23.0-24.9) and obese (≥25) with normal-weight participants (18.5-22.9) were 1.12 (1.00-1.25) and 1.29 (1.14-1.47), respectively. In dose-response analyses, increasing BMI also showed positive association with overall and LA-B grade or higher. The association persisted in MHO individuals without central obesity. The association between waist circumference categories and the development of erosive esophagitis was also evident. DISCUSSION In a large cohort of strictly defined metabolically healthy men and women, the MHO phenotype was associated with an increased incidence of erosive esophagitis, providing evidence that the MHO phenotype is not protective from gastroesophageal reflux disease.

    更新日期:2019-11-01
  • Development and Validation of a Model to Predict Acute Kidney Injury in Hospitalized Patients With Cirrhosis.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-09-04
    Kavish R Patidar,Chenjia Xu,Hani Shamseddeen,Yao-Wen Cheng,Marwan S Ghabril,V V Pavan K Mukthinuthalapati,Zachary P Fricker,Samuel Akinyeye,Lauren D Nephew,Archita P Desai,Melissa Anderson,Tarek M El-Achkar,Naga P Chalasani,Eric S Orman

    OBJECTIVES Acute kidney injury (AKI) is a common complication in hospitalized patients with cirrhosis which contributes to morbidity and mortality. Improved prediction of AKI in this population is needed for prevention and early intervention. We developed a model to identify hospitalized patients at risk for AKI. METHODS Admission data from a prospective cohort of hospitalized patients with cirrhosis without AKI on admission (n = 397) was used for derivation. AKI development in the first week of admission was captured. Independent predictors of AKI on multivariate logistic regression were used to develop the prediction model. External validation was performed on a separate multicenter cohort (n = 308). RESULTS In the derivation cohort, the mean age was 57 years, the Model for End-Stage Liver Disease score was 17, and 59 patients (15%) developed AKI after a median of 4 days. Admission creatinine (OR: 2.38 per 1 mg/dL increase [95% CI: 1.47-3.85]), international normalized ratio (OR: 1.92 per 1 unit increase [95% CI: 1.92-3.10]), and white blood cell count (OR: 1.09 per 1 × 10/L increase [95% CI: 1.04-1.15]) were independently associated with AKI. These variables were used to develop a prediction model (area underneath the receiver operator curve: 0.77 [95% CI: 0.70-0.83]). In the validation cohort (mean age of 53 years, Model for End-Stage Liver Disease score of 16, and AKI development of 13%), the area underneath the receiver operator curve for the model was 0.70 (95% CI: 0.61-0.78). DISCUSSION A model consisting of admission creatinine, international normalized ratio, and white blood cell count can identify patients with cirrhosis at risk for in-hospital AKI development. On further validation, our model can be used to apply novel interventions to reduce the incidence of AKI among patients with cirrhosis who are hospitalized.

    更新日期:2019-11-01
  • Long-Term Natural History of Microscopic Colitis: A Population-Based Cohort.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-09-04
    Julien Loreau,Dana Duricova,Corinne Gower-Rousseau,Guillaume Savoye,Olivier Ganry,Hajer Ben Khadhra,Hélène Sarter,Clara Yzet,Jean-Philippe Le Mouel,Mathieu Kohut,Franck Brazier,Denis Chatelain,Eric Nguyen-Khac,Jean-Louis Dupas,Mathurin Fumery

    OBJECTIVES Data on long-term natural history of microscopic colitis (MC), including collagenous (CC) and lymphocytic colitis (LC), are lacking. METHODS All new cases of MC diagnosed in the Somme area, France, between January 1, 2005, and December 31, 2007, were prospectively included. Colonic biopsies from all patients were reviewed by a group of 4 gastrointestinal pathologist experts to assess the diagnosis of CC or LC. Demographic and clinical data were retrospectively collected from diagnosis to February 28, 2017. RESULTS One hundred thirty cases of MC, 87 CC and 43 LC, were included (median age at diagnosis: 70 [interquartile range, 61-77] and 48 [IQR, 40-61] years, respectively). The median follow-up was 9.6 years (7.6; 10.6). By the end of the follow-up, 37 patients (28%) relapsed after a median time of 3.9 years (1.2; 5.0) since diagnosis, without significant difference between CC and LC (30% vs 26%; P = 0.47). Twenty patients (15%) were hospitalized for a disease flare, and 32 patients (25%) presented another autoimmune disease. Budesonide was the most widely used treatment (n = 74, 59%), followed by 5-aminosalicylic acid (n = 31, 25%). The median duration of budesonide treatment was 92 days (70; 168), and no adverse event to budesonide was reported. Sixteen patients (22%) developed steroid dependency and 4 (5%) were corticoresistant. No difference in the risk of digestive and extradigestive cancer was observed compared with the general population. None of the death (n = 25) observed during the follow-up were linked to MC. In multivariate analysis, age at diagnosis (HR, 1.03; 95% confidence interval, 1.00-1.06; P = 0.02) and budesonide exposure (HR, 2.50; 95% confidence interval, 1.11-5.55; P = 0.03) were significantly associated with relapse. DISCUSSION This population-based study showed that after diagnosis, two-third of the patients with MC observed long-term clinical remission. Age at diagnosis and budesonide exposure were associated with a risk of relapse.

    更新日期:2019-11-01
  • Metformin Is Associated With Reduced Odds for Colorectal Cancer Among Persons With Diabetes.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : null
    Joshua Demb,Armaan Yaseyyedi,Lin Liu,Ranier Bustamante,Ashley Earles,Pradipta Ghosh,J Silvio Gutkind,Andrew J Gawron,Tonya R Kaltenbach,Maria Elena Martinez,Samir Gupta

    INTRODUCTION Metformin may be associated with reduced colorectal cancer (CRC) risk, but findings from previous studies have been inconsistent and had insufficient sample sizes to examine whether the association differs by anatomic site. This study examined whether metformin was associated with reduced CRC risk, both overall and stratified by anatomic site, in a large sample of persons with diabetes who underwent colonoscopy. METHODS We performed a case-control study of US Veterans with prevalent diabetes who underwent colonoscopy between 1999 and 2014 using Department of Veterans Affairs electronic health record data. Cases were defined by presence of CRC at colonoscopy, while controls had normal colonoscopy. The primary exposure was metformin use at time of colonoscopy (yes/no). Association of metformin exposure with CRC (further stratified by proximal, distal, or rectal subsite) was examined using multivariable and multinomial logistic regression and summarized by odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS We included 6,650 CRC patients and 454,507 normal colonoscopy patients. CRC cases were older and had lower metformin exposure. Metformin was associated with 8% relative reduction in CRC odds (OR: 0.92, 95% CI: 0.87-0.96). By subsite, metformin was associated with a 14% statistically significant reduced rectal cancer odds (OR: 0.86, 95% CI: 0.78-0.94) but no reduced distal or proximal cancer odds. DISCUSSION Metformin was associated with reduced CRC odds-particularly rectal cancer-in a large sample of persons with diabetes undergoing colonoscopy.

    更新日期:2019-11-01
  • Response to Liu et al.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : null
    Mark O Goodarzi,David C Whitcomb

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Quality of Life Is Associated With Wearable-Based Physical Activity in Patients With Inflammatory Bowel Disease: A Prospective, Observational Study.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : null
    Miriam Wiestler,Fabian Kockelmann,Momme Kück,Arno Kerling,Uwe Tegtbur,Michael P Manns,Masoumeh Attaran-Bandarabadi,Oliver Bachmann

    OBJECTIVES Patient-reported outcomes such as quality of life are gaining importance in the assessment of patients suffering from inflammatory bowel disease (IBD). The association of objectively measured physical activity and quality of life in patients with IBD has not been studied in depth. To investigate the association of disease-specific quality of life and physical activity as well as clinical and biochemical disease activity in patients with IBD. METHODS A total of 91 patients with IBD were stratified into 4 groups (Crohn's disease and ulcerative colitis, in remission and with moderate-severe activity, respectively) and evaluated in terms of disease-specific quality of life (Inflammatory Bowel Disease Questionnaire [IBDQ]), physical activity (accelerometry), body composition (bioelectrical impedance analysis), as well as clinical (Harvey-Bradshaw Index and Simple Clinical Colitis Activity Index) and biochemical (C-reactive protein and fecal calprotectin) parameters of disease activity. RESULTS In patients with moderate-severe disease activity, the IBDQ was significantly lower as compared to patients in remission (Mann-Whitney U test and Kruskal-Wallis test, P < 0.001). The physical activity level was higher in remission than in active disease (Mann-Whitney U test, P < 0.05). The IBDQ was significantly correlated with the duration of strenuous physical activity per day (P = 0.029178, r = 0.235), skeletal muscle mass (P = 0.033829, r = 0.229), and biomarkers of inflammation (C-reactive protein: P < 0.005, r = -0.335 and fecal calprotectin: P < 0.005, r = -0.385). DISCUSSION In this prospective, cross-sectional study, disease-specific quality of life was significantly associated with accelerometrically determined physical activity and disease activity in patients with IBD. This may be related to a reciprocal impact of these factors (DRKS00011370).

    更新日期:2019-11-01
  • Efficacy and Safety of Vonoprazan in Patients With Nonerosive Gastroesophageal Reflux Disease: A Randomized, Placebo-Controlled, Phase 3 Study.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : null
    Yoshikazu Kinoshita,Yuuichi Sakurai,Nobuyoshi Takabayashi,Kentaro Kudou,Takahiro Araki,Takuya Miyagi,Katsuhiko Iwakiri,Kiyoshi Ashida

    OBJECTIVES To assess the efficacy and safety of vonoprazan on heartburn symptoms in patients with nonerosive reflux disease (NERD) (ClinicalTrials.gov: NCT02954848). METHODS This phase 3, double-blind, placebo-controlled study included Japanese patients aged 20 years and older with grade N/M NERD and recurrent heartburn. Patients received placebo (n = 245) or vonoprazan 10 mg (n = 238) for 4 weeks. The primary efficacy outcome was frequency of heartburn experienced by patients during the treatment period (proportion of days without heartburn). Other outcomes included cumulative improvement rates of heartburn, proportion of patients with complete heartburn resolution in the fourth week of treatment, and safety. RESULTS Compared with placebo, the proportion of days without heartburn was not significantly higher in the vonoprazan group in the full analysis (primary end point, 72.55% vs 61.50%, vonoprazan vs placebo, P = 0.0643) but was significantly higher in the per-protocol-set sensitivity analysis (P = 0.0341). Early onset of response and significantly greater cumulative improvement rates of heartburn were observed in the vonoprazan group (P = 0.0003). In a post hoc analysis, a greater proportion of patients with complete heartburn resolution in the fourth week of treatment were reported in the vonoprazan group (P = 0.0023). Incidence of treatment-emergent adverse events was similar between treatment groups (23.5% vs 23.3%); most treatment-emergent adverse events were mild in severity. DISCUSSION Although vonoprazan 10 mg was not superior to placebo with respect to proportion of days without heartburn in Japanese patients with NERD, vonoprazan had a significantly higher cumulative rate of heartburn resolution and was well tolerated.

    更新日期:2019-11-01
  • Identification of a Novel Candidate Gene for Serrated Polyposis Syndrome Germline Predisposition by Performing Linkage Analysis Combined With Whole-Exome Sequencing.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : null
    Claudio Toma,Marcos Díaz-Gay,Yasmin Soares de Lima,Coral Arnau-Collell,Sebastià Franch-Expósito,Jenifer Muñoz,Bronwyn Overs,Laia Bonjoch,Sabela Carballal,Teresa Ocaña,Miriam Cuatrecasas,Aránzazu Díaz de Bustamante,Antoni Castells,Luis Bujanda,Joaquín Cubiella,Francesc Balaguer,Daniel Rodríguez-Alcalde,Janice M Fullerton,Sergi Castellví-Bel

    OBJECTIVES Serrated polyposis syndrome (SPS) is a complex disorder with a high risk of colorectal cancer for which the germline factors remain largely unknown. Here, we combined whole-exome sequencing (WES) and linkage studies in families with multiple members affected by SPS to identify candidate genes harboring rare variants with higher penetrance effects. METHODS Thirty-nine affected subjects from 16 extended SPS families underwent WES. Genome-wide linkage analysis was performed under linear and exponential models. The contribution of rare coding variants selected to be highly pathogenic was assessed using the gene-based segregation test. RESULTS A significant linkage peak was identified on chromosome 3p25.2-p22.3 (maxSNP = rs2293787; LODlinear = 2.311, LODexp = 2.11), which logarithm of the odds (LOD) score increased after fine mapping for the same marker (maxSNP = rs2293787; LODlinear = 2.4, LODexp = 2.25). This linkage signal was replicated in 10 independent sets of random markers from this locus. To assess the contribution of rare variants predicted to be pathogenic, we performed a family-based segregation test with 11 rare variants predicted to be deleterious from 10 genes under the linkage intervals. This analysis showed significant segregation of rare variants with SPS in CAPT7, TMEM43, NGLY1, and FBLN2 genes (weighted P value > 0.007). DISCUSSION Protein network analysis suggested FBLN2 as the most plausible candidate genes for germline SPS predisposition. Etiologic rare variants implicated in disease predisposition may be identified by combining traditional linkage with WES data. This powerful approach was effective for the identification of a new candidate gene for hereditary SPS.

    更新日期:2019-11-01
  • Identification of Epigenetic Methylation Signatures With Clinical Value in Crohn's Disease.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : null
    Inés Moret-Tatay,Elena Cerrillo,Esteban Sáez-González,David Hervás,Marisa Iborra,Juan Sandoval,Enrique Busó,Luis Tortosa,Pilar Nos,Belén Beltrán

    INTRODUCTION DNA methylation is an epigenetic mechanism that regulates gene expression and represents an important link between genotype, environment, and disease. It is a reversible and inheritable mechanism that could offer treatment targets. We aimed to assess the methylation changes on specific genes previously associated with Crohn's disease (CD) and to study their possible associations with the pathology. METHODS We included 103 participants and grouped them into 2 cohorts (a first [n = 31] and a second validation [n = 72] cohort), with active CD (aCD) and inactive CD (iCD) and healthy participants (CTR). DNA was obtained from the peripheral blood and analyzed by the Agena platform. The selected genes were catalase (CAT), α-defensin 5 (DEFA5), FasR, FasL, tumor necrosis factor (TNF), TNFRSF1A, TNFRSF1B, PPA2, ABCB1, NOD2, PPARγ, and PKCζ. We used the elastic net algorithm and R software. RESULTS We studied 240 CpGs. Sixteen CpGs showed differential methylation profiles among aCD, iCD, and CTR. We selected for validation those with the greatest differences: DEFA5 CpG_11; CpG_13; CAT CpG_31.32; TNF CpG_4, CpG_12; and ABCB1 CpG_21. Our results validated the genes DEFA5 (methylation gain) and TNF (methylation loss) with P values < 0.001. In both cases, the methylation level was maintained and did not change with CD activity (aCD vs iCD). The subanalysis comparison between aCD and iCD showed significant differential methylation profiles in other CpGs: TNF, FAS, ABCB1, CAT, and TNFRS1BF genes. DISCUSSION The methylation status of DEFA5 and TNF genes provides a signature biomarker that characterizes patients with CD and supports the possible implication of the environment and the immune system in CD pathogenesis.

    更新日期:2019-11-01
  • Influence of Gastric Emptying and Gut Transit Testing on Clinical Management Decisions in Suspected Gastroparesis.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : null
    William L Hasler,Satish S C Rao,Richard W McCallum,Richard A Krause,Linda A Nguyen,Michael I Schulman,Allen A Lee,Baharak Moshiree,John M Wo,Henry P Parkman,Irene Sarosiek,Gregory E Wilding,Braden Kuo

    INTRODUCTION Gastric emptying scintigraphy (GES) or wireless motility capsules (WMCs) can evaluate upper gastrointestinal symptoms in suspected gastroparesis; WMC tests can also investigate lower gut symptoms. We aimed to determine whether these tests impact treatment plans and needs for additional diagnostic evaluation. METHODS In a prospective, multicenter study, 150 patients with gastroparesis symptoms simultaneously underwent GES and WMC testing. Based on these results, investigators devised management plans to recommend changes in medications, diet, and surgical therapies and order additional diagnostic tests. RESULTS Treatment changes were recommended more often based on the WMC vs GES results (68% vs 48%) (P < 0.0001). Ordering of additional test(s) was eliminated more often with WMC vs GES (71% vs 31%) (P < 0.0001). Prokinetics (P = 0.0007) and laxatives (P < 0.0001) were recommended more often based on the WMC vs GES results. Recommendations for prokinetics and gastroparesis diets were higher and neuromodulators lower in subjects with delayed emptying on both tests (all P ≤ 0.0006). Laxatives and additional motility tests were ordered more frequently for delayed compared with normal WMC colonic transit (P ≤ 0.02). Multiple motility tests were ordered more often on the basis of GES vs WMC findings (P ≤ 0.004). Antidumping diets and transit slowing medications were more commonly recommended for rapid WMC gastric emptying (P ≤ 0.03). DISCUSSION WMC transit results promote medication changes and eliminate additional diagnostic testing more often than GES because of greater detection of delayed gastric emptying and profiling the entire gastrointestinal tract in patients with gastroparesis symptoms. TRANSLATIONAL IMPACT Gastric scintigraphy and WMCs have differential impact on management decisions in suspected gastroparesis.

    更新日期:2019-11-01
  • Development and Validation of a Nomogram for Early Detection of Malignant Gallbladder Lesions.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : null
    Mingyu Chen,Jiasheng Cao,Yang Bai,Chenhao Tong,Jian Lin,Vishal Jindal,Leandro Cardoso Barchi,Silvio Nadalin,Sherry X Yang,Antonio Pesce,Fabrizio Panaro,Arie Ariche,Keita Kai,Riccardo Memeo,Tanios Bekaii-Saab,Xiujun Cai,

    OBJECTIVES Preoperative decision-making for differentiating malignant from benign lesions in the gallbladder remains challenging. We aimed to create a diagnostic nomogram to identify gallbladder cancer (GBC), especially for incidental GBC (IGBC), before surgical resection. METHODS A total of 587 consecutive patients with pathologically confirmed gallbladder lesions from a hospital were randomly assigned to a training cohort (70%) and an internal validation cohort (30%), with 287 patients from other centers as an external validation cohort. Radiological features were developed by the least absolute shrinkage and selection operator logistic regression model. Significant radiological features and independent clinical factors, identified by multivariate analyses, were used to construct a nomogram. RESULTS A diagnostic nomogram was established by age, CA19.9, and 6 radiological features. The values of area under the curve in the internal and external validation cohorts were up to 0.91 and 0.89, respectively. The calibration curves for probability of GBC showed optimal agreement between nomogram prediction and actual observation. Compared with previous methods, it demonstrated superior sensitivity (91.5%) and accuracy (85.1%) in the diagnosis of GBC. The accuracy using the nomogram was significantly higher in GBC groups compared with that by radiologists in the training cohort (P < 0.001) and similarly in each cohort. Notably, most of the IGBC, which were misdiagnosed as benign lesions, were successfully identified using this nomogram. DISCUSSION A novel nomogram provides a powerful tool for detecting the presence of cancer in gallbladder masses, with an increase in accuracy and sensitivity. It demonstrates an unprecedented potential for IGBC identification.

    更新日期:2019-11-01
  • Novel Circulating Tumor Cell Assay for Detection of Colorectal Adenomas and Cancer.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : null
    Wen-Sy Tsai,Jeng-Fu You,Hsin-Yuan Hung,Pao-Shiu Hsieh,Ben Hsieh,Heinz-Josef Lenz,Gregory Idos,Shai Friedland,Jennifer Yi-Jiun Pan,Hung-Jen Shao,Jen-Chia Wu,Jr-Ming Lai,Shih-En Chang,Rui Mei,Drew Watson,Manana Javey,Ashish Nimgaonkar

    OBJECTIVES There is a significant unmet need for a blood test with adequate sensitivity to detect colorectal cancer (CRC) and adenomas. We describe a novel circulating tumor cell (CTC) platform to capture colorectal epithelial cells associated with CRC and adenomas. METHODS Blood was collected from 667 Taiwanese adults from 2012 to 2018 before a colonoscopy. The study population included healthy control subjects, patients with adenomas, and those with stage I-IV CRC. CTCs were isolated from the blood using the CellMax platform. The isolated cells were enumerated, and an algorithm was used to determine the likelihood of detecting adenoma or CRC. Nominal and ordinal logistic regression demonstrated that CTC counts could identify adenomas and CRC, including CRC stage. RESULTS The CellMax test demonstrated a significant association between CTC counts and worsening disease status (Cuzick's P value < 0.0001) with respect to the adenoma-carcinoma sequence. The test showed high specificity (86%) and sensitivity across all CRC stages (95%) and adenomatous lesions (79%). The area under the curve was 0.940 and 0.868 for the detection of CRC and adenomas, respectively. DISCUSSION The blood-based CTC platform demonstrated high sensitivity in detecting adenomas and CRC, as well as reasonable specificity in an enriched symptomatic patient population. TRANSLATIONAL IMPACT If these results are reproduced in an average risk population, this test has the potential to prevent CRC by improving patient compliance and detecting precancerous adenomas, eventually reducing CRC mortality.

    更新日期:2019-11-01
  • Influence of Gender and Reproductive Factors on Liver Fibrosis in Patients With Chronic Hepatitis B Infection.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-10-28
    Ming Xiong,Junying Li,Shuling Yang,Fansen Zeng,Yali Ji,Jiang Liu,Qiaoping Wu,Qingjun He,Ronglong Jiang,Fuyuan Zhou,Weiqun Wen,Jinjun Chen,Jinlin Hou

    INTRODUCTION The role of reproductive factors in the development of chronic hepatitis B (CHB) remains unknown. We assessed the potential contributions of gender, menopausal status, and menarche age to liver fibrosis in CHB. METHODS A cross-sectional prospective study included 716 women and 716 age-matched men with CHB who were not currently receiving antiviral therapy. Liver stiffness measurement using transient elastography was used to stage liver fibrosis as F0-F1 (<7.2 kPa), F ≥ 2 (7.2 kPa), F ≥ 3 (9.4 kPa), and F = 4 (12.2 kPa). Female patients were asked regarding their age at menarche and menopausal status using a questionnaire. RESULTS Of the 716 women, 121 (16.9%) were postmenopausal, and 80 (11.2%) had advanced liver fibrosis. Multivariate logistic regression analysis showed that the postmenopausal status compared with the premenopausal status (odds ratio [OR] = 3.65-8.83; P < 0.05) and age at menarche of >14 years compared with <13 years (OR = 2.85-3.95; P < 0.05) were significantly associated with advanced fibrosis. Compared with premenopausal women, age-matched men had a higher OR for advanced fibrosis (P < 0.05). Compared with postmenopausal women, age-matched men did not show a significant difference in the degree of liver fibrosis (P > 0.05). Longitudinal data analysis showed that postmenopausal women (n = 31) were significantly less likely to undergo regression of liver fibrosis after antiviral treatment vs premenopausal women (n = 19) (26.3% vs 74.2%, respectively; P < 0.001). DISCUSSION Menopause and late menarche aggravated liver fibrosis in untreated CHB, besides menopause delayed fibrosis regression under antiviral therapy. The protective effect of female gender against fibrosis was lost for postmenopausal women. TRANSLATIONAL IMPACT It is important to consider menopausal status and age at menarche in establishing surveillance strategies among CHB females. Postmenopausal estrogen therapy may be considered for the prevention or treatment of liver fibrosis.

    更新日期:2019-11-01
  • Colorectal Cancer Risks According to Sex Differences in Patients With Type II Diabetes Mellitus: A Korean Nationwide Population-Based Cohort Study.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-10-28
    Ji Min Lee,Kang-Moon Lee,Dae Bum Kim,Seung-Hyun Ko,Yong Gyu Park

    INTRODUCTION Developing colorectal cancer (CRC) poses challenges for patients with type II diabetes mellitus (T2DM). We investigated CRC risk factors in patients with T2DM. METHODS We retrospectively collected data from the National Health Insurance Corporation database, comprising approximately 97% of the Korean population. T2DM and CRC were defined according to International Classification of Disease codes (10th Revision) and claims data. Obesity was defined using body mass index (BMI); abdominal obesity was defined according to waist circumference. Other variables were defined using demographic, anthropometric, and laboratory data. RESULTS Overall, 2,591,149 patients with T2DM were analyzed. During the follow-up period (median, 5.4 years), 24,236 CRC cases were identified. Aging (≥70 years), male sex, smoking, alcohol consumption, hypertension, and insulin and/or sulfonylurea use were significant risk factors for CRC. In males, smoking and alcohol consumption were more likely to lead to CRC, whereas a BMI increase was a more significant risk factor in females. Females with a BMI ≥ 25 kg/m and abdominal obesity were associated with an 18% increased risk of CRC compared with patients with normal weight and normal waist circumference (hazard ratio = 1.184, 95% confidence interval 1.123-1.25), whereas male patients with a BMI ≥ 25 kg/m and abdominal obesity were associated with an 8% increased risk (hazard ratio = 1.087, 95% confidence interval 1.049-1.127). DISCUSSION Patients had CRC risk factors that differed according to sex. Smoking and heavy alcohol consumption were risks of CRC in males. Female patients with a BMI ≥ 25 kg/m and abdominal obesity were at a higher risk of developing CRC than males.

    更新日期:2019-11-01
  • Detection of Liver Steatosis With a Novel Ultrasound-Based Technique: A Pilot Study Using MRI-Derived Proton Density Fat Fraction as the Gold Standard.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-10-15
    Giovanna Ferraioli,Laura Maiocchi,Maria Vittoria Raciti,Carmine Tinelli,Annalisa De Silvestri,Mara Nichetti,Pasquale De Cata,Mariangela Rondanelli,Luca Chiovato,Fabrizio Calliada,Carlo Filice

    OBJECTIVES The primary aim of this study was to investigate the value of attenuation imaging (ATI), a novel ultrasound technique for detection of steatosis, by comparing the results to that obtained with controlled attenuation parameter (CAP) and by using MRI-derived proton density fat fraction (PDFF) as reference standard. METHODS From March to November 2018, 114 consecutive adult subjects potentially at risk of steatosis and 15 healthy controls were enrolled. Each subject underwent ATI and CAP assessment on the same day. MRI-PDFF was performed within a week. RESULTS The prevalence of steatosis, as defined by MRI-PDFF ≥ 5%, was 70.7%. There was a high correlation of ATI with MRI-PDFF (r = 0.81, P < 0.0001). The correlation of CAP with MRI-PDFF and with ATI, respectively, was moderate (r = 0.65, P < 0.0001 and r = 0.61, P < 0.0001). The correlation of ATI or CAP with PDFF was not affected by age, gender, or body mass index. Area under the receiver operating characteristics of ATI and CAP, respectively, were 0.91 (0.84-0.95; P < 0.0001) and 0.85 (0.77-0.91; P < 0.0001) for detecting S > 0 steatosis (MRI-PDFF ≥ 5%); 0.95 (0.89-0.98; P < 0.0001) and 0.88 (0.81-0.93; P < 0.0001) for detecting S > 1 steatosis (MRI-PDFF ≥ 16.3%). The cutoffs of ATI and CAP, respectively, were 0.63 dB/cm/MHz and 258 dB/m for detecting S > 0 liver steatosis; 0.72 dB/cm/MHz and 304 dB/m for detecting S > 1 steatosis. ATI performed better than CAP, and this improvement was statistically significant for S > 1 (P = 0.04). DISCUSSION This study shows that, in patients with no fibrosis/mild fibrosis, ATI is a very promising tool for the noninvasive assessment of steatosis.

    更新日期:2019-11-01
  • Gut Microbiota Functional Biomolecules With Immune-Lipid Metabolism for a Prognostic Compound Score in Epstein-Barr Virus-Associated Gastric Adenocarcinoma: A Pilot Study.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-10-15
    Fang Wang,Jingyi Wu,Yan Wang,Yufen Jin,Xin Jiang,Zhichao Qiu,Yan Qin,Yankui Liu,Xiaowei Qi,Xiaosong Ge,Yong Mao,Yang Cheng,Dong Hua

    OBJECTIVE Increasing evidence has indicated an association between gut microbiota in gastrointestinal cancer and clinical outcome. Herein, we aim to develop a prognosis-prediction tool based on an immune-lipid metabolism signature, tumor cell-associated immune microenvironment, and lipid metabolism proteins inferred from the function of gut microbiota. METHODS 16S gene ribosomal RNA sequencing was performed on 10 fecal samples obtained after tumor resection but before chemotherapy (EBVaGC = 4 and EBVnGC = 6). Least absolute shrinkage and selection operator (LASSO) Cox regression was applied to screening for highly accurate marker proteins. A compound score based on the fraction of screened markers was then constructed using a LASSO logistic regression model. RESULTS The Tax4Fun analysis based on Kyoto Encyclopedia of Genes and Genomes data indicated differentially expressed tumor pathway between EBVnGC and EBVaGC. Using the LASSO logistic model, a compound score was established consisting of 14 types of immune microenvironment and lipid metabolism proteins. In the training set (378 patients), significant differences were found between high- and low-compound score groups in overall survival across and within subpopulations with an identical EBV. Multivariable analysis revealed that the compound score was an independent prognostic factor (hazard ratio, 2.26; 95% confidence interval = 2.28-3.36). The prognostic value ;of the compound score was also confirmed in the validation (162 patients) and entire (540 patients) sets. DISCUSSION The proposed compound score is a promising signature for estimating overall survival in patients with gastric cancer having EBVaGCs or EBVnGCs.

    更新日期:2019-11-01
  • Metabolic Trifecta After Pancreatitis: Exocrine Pancreatic Dysfunction, Altered Gut Microbiota, and New-Onset Diabetes.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-10-15
    Maxim S Petrov

    Pancreatitis, a complex disease influenced by both genetic and environmental factors, often leads to metabolic sequelae (such as exocrine pancreatic dysfunction and new-onset diabetes). Several trillion micro-organisms inhabit the gastrointestinal tract, and this community plays an important role in the regulation of functions of not only the gut but also the pancreas. Studies to parse the underlying contributions of the gut microbiota to metabolic sequelae of pancreatitis will offer important translational insights with a view to preventing exocrine pancreatic dysfunction and new-onset diabetes after pancreatitis.

    更新日期:2019-11-01
  • Whole Exome Sequencing Among 26 Patients With Indeterminate Acute Liver Failure: A Pilot Study.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-10-15
    Jorge Rakela,Jody Rule,Daniel Ganger,Julie Lau,Julie Cunningham,Mrunal Dehankar,Saurabh Baheti,William M Lee,

    INTRODUCTION The etiology of acute liver failure (ALF) remains an important prognostic factor. The Acute Liver Failure Study Group recently reported that 150 of 2,718 adult patients with ALF (5.5%) had an indeterminate etiology. Our aim was to use whole exome sequencing to identify genetic variants associated with phenotypic, biochemical, and histologic features among patients with indeterminate ALF. METHODS This effort has defined a cohort of well-pedigreed patients with indeterminate ALF; DNA samples extracted from whole blood samples were obtained from 26 respective patients with indeterminate ALF. These samples were kept at the Acute Liver Failure Study Group repository at the NIDDK, Bethesda. Whole exome sequencing and bioinformatics analysis were performed at the Mayo Clinic Center of Individualized Medicine in Rochester, MN. RESULTS Of the 26 patients, 8 survived spontaneously, 6 died, and 12 underwent a liver transplantation; all those transplanted were alive at 21 days after enrollment in the study. Twenty-two of the 26 patients presented as ALF. We found 12 variants associated with 11 genes. The most common variant was rs4940595 in the SERPINB11 gene which was found in 23 of the 26 patients. This variant had a stop codon; no reports of disorders have been associated with this variant. The next most commonly found variant was rs1135840 in the CYP2D6 gene; this mutation is a missense_variant and has been reported to be associated with hepatotoxicity of antituberculous therapy. None of our patients were receiving this therapy. We also found a significant asymmetric distribution of rs1800754 of the CYP2D7 gene and rs1135840 of the CYP2D6 gene between patients who survived spontaneously (75%) and those who died or underwent liver transplantation (30.5% and 25%, respectively). DISCUSSION We found 12 variants of 11 genes significantly associated with ALF among adults with indeterminate etiology. We also found a significant asymmetric distribution of 2 variants belonging to the CYP2D7 and CYP2D6 genes, respectively, between those who survived spontaneously and those who died or underwent liver transplantation. The 2 most common variants, rs4940595 and rs1135840, of the SERPINB11 and CYP2D6 genes, respectively, found in our patients with ALF have been described as potentially important in the adaptive response combating the emergence of infectious diseases and associated with hepatotoxicity of antituberculous therapy, respectively. Our findings need to be expanded to include more patients with indeterminate ALF as well as viral, drug toxicity, and autoimmune etiologies to determine whether our findings are associated with the specific etiology, indeterminate, or with the overall ALF syndrome itself.

    更新日期:2019-11-01
  • Cold Snare Polypectomy in Patients Taking Dual Antiplatelet Therapy: A Randomized Trial of Discontinuation of Thienopyridines.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-10-11
    Dae Won,Joon Sung Kim,Jeong-Seon Ji,Byung-Wook Kim,Hwang Choi

    INTRODUCTION Cold snare polypectomy (CSP) is a safe and effective method for removing polyps ≤10 mm. The aim of this study was to compare the risk of clinically significant bleeding and thromboembolic events after CSP between stopping and continuing thienopyridines in patients taking dual antiplatelet therapy (DAPT). METHODS The study was a single-center, noninferiority, and randomized controlled study involving patients who received colonoscopy from October 2015 to October 2016. Patients receiving DAPT with polyps ≤10 mm were randomly assigned to either the DAPT group (patients continued DAPT) or the aspirin group (patients discontinued thienopyridines for 1 week). Primary outcome was clinically significant bleeding. Secondary outcomes included intraprocedural bleeding, nonsignificant hematochezia, and occurrence of thromboembolic events. RESULTS Forty-two patients with 104 eligible polyps were allocated to the DAPT group, and 45 patients with 101 eligible polyps were allocated to the aspirin group. Patient demographic characteristics including size, location, shape, and pathology of the removed polyps were similar in the 2 groups. Intraprocedural bleeding and nonsignificant hematochezia rates were also similar between the 2 groups (4.8% vs 2.2%, P = 0.608; 19.0% vs 8.9%, P = 0.170). No thromboembolic event occurred in either group. Only 1 patient (2.4%) in the DAPT group showed clinically significant bleeding. No significant bleeding was found in the aspirin group. DISCUSSION Clinically significant bleeding rate after CSP for polyps ≤10 mm in patients continuing to take DAPT was 2.4%. Therefore, CSP is a safe method for removing small polyps even in patients taking DAPT (ClincialTrials.gov number, NCT02865824).

    更新日期:2019-11-01
  • Fibrosis Mediators in the Colonic Mucosa of Acute and Healed Ulcerative Colitis.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-10-05
    Mona Dixon Gundersen,Rasmus Goll,Christopher Graham Fenton,Endre Anderssen,Sveinung Wergeland Sørbye,Jon Ragnar Florholmen,Ruth Hracky Paulssen

    OBJECTIVES A healed intestinal mucosa is the aim of therapy in acute ulcerative colitis (UC). Disruption of mucosal wound healing may lead to severe complications including intestinal fibrosis. This study examined mucosal gene expression in the healing process of acute UC with a special focus on known mediators of fibrosis. METHODS Endoscopic biopsies from patients with acute, moderate to severe UC were analyzed with a quantitative polymerase chain reaction array for 84 genes involved in fibrosis pathways. All patients were treated with infliximab (anti- tumor necrosis factor). Biopsies were taken before therapy and when disease remission was reached, defined as a Mayo score of ≤2, with an endoscopic subscore of 0 or 1. A healthy control group was included. Immunostaining of matrix metallopeptidase 9 and smooth muscle actin was performed. RESULTS Mucosal biopsies from acute UC (n = 28), remission UC (n = 28), and healthy controls (n = 13) were analyzed. Fibrosis and extracellular matrix-associated genes were upregulated in the endoscopically healed UC mucosa vs controls, with collagen type III alpha 1 chain, actin alpha 2, lysyl oxidase, TIMP metallopeptidase inhibitor 3, and caveolin 1 uniquely showing no overlap with acute disease. Pro- and antifibrotic mediators (interleukin [IL]13 receptor subunit alpha 2, IL1B, IL10, tumor necrosis factor, snail family transcriptional repressor 1, and C-C motif chemokine ligand 2) were upregulated in both acute and healed UC compared with controls. An attenuated pattern of the canonical transforming growth factor beta (TGFB) pathway was observed in acute UC and to a lesser extent in the healed mucosa, except for TGFB2, which was enhanced. DISCUSSION The endoscopically healed mucosa of UC showed a persisting dysregulation of fibrosis-associated mediators compared with controls, including extracellular matrix remodeling, profibrotic cytokines, and TGFB signaling pathways.

    更新日期:2019-11-01
  • Small Intestinal Bacterial Overgrowth: Clinical Features and Therapeutic Management.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-10-05
    Satish S C Rao,Jigar Bhagatwala

    Small intestinal bacterial overgrowth (SIBO) is a common, yet underrecognized, problem. Its prevalence is unknown because SIBO requires diagnostic testing. Although abdominal bloating, gas, distension, and diarrhea are common symptoms, they do not predict positive diagnosis. Predisposing factors include proton-pump inhibitors, opioids, gastric bypass, colectomy, and dysmotility. Small bowel aspirate/culture with growth of 10-10 cfu/mL is generally accepted as the "best diagnostic method," but it is invasive. Glucose or lactulose breath testing is noninvasive but an indirect method that requires further standardization and validation for SIBO. Treatment, usually with antibiotics, aims to provide symptom relief through eradication of bacteria in the small intestine. Limited numbers of controlled studies have shown systemic antibiotics (norfloxacin and metronidazole) to be efficacious. However, 15 studies have shown rifaximin, a nonsystemic antibiotic, to be effective against SIBO and well tolerated. Through improved awareness and scientific rigor, the SIBO landscape is poised for transformation.

    更新日期:2019-11-01
  • Machine Learning-Based Computational Models Derived From Large-Scale Radiographic-Radiomic Images Can Help Predict Adverse Histopathological Status of Gastric Cancer.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-10-03
    Qiong Li,Liang Qi,Qiu-Xia Feng,Chang Liu,Shu-Wen Sun,Jing Zhang,Guang Yang,Ying-Qian Ge,Yu-Dong Zhang,Xi-Sheng Liu

    INTRODUCTION Adverse histopathological status (AHS) decreases outcomes of gastric cancer (GC). With the lack of a single factor with great reliability to preoperatively predict AHS, we developed a computational approach by integrating large-scale imaging factors, especially radiomic features at contrast-enhanced computed tomography, to predict AHS and clinical outcomes of patients with GC. METHODS Five hundred fifty-four patients with GC (370 training and 184 test) undergoing gastrectomy were retrospectively included. Six radiomic scores (R-scores) related to pT stage, pN stage, Lauren & Borrmann (L&B) classification, World Health Organization grade, lymphatic vascular infiltration, and an overall histopathologic score (H-score) were, respectively, built from 7,000+ radiomic features. R-scores and radiographic factors were then integrated into prediction models to assess AHS. The developed AHS-based Cox model was compared with the American Joint Committee on Cancer (AJCC) eighth stage model for predicting survival outcomes. RESULTS Radiomics related to tumor gray-level intensity, size, and inhomogeneity were top-ranked features for AHS. R-scores constructed from those features reflected significant difference between AHS-absent and AHS-present groups (P < 0.001). Regression analysis identified 5 independent predictors for pT and pN stages, 2 predictors for Lauren & Borrmann classification, World Health Organization grade, and lymphatic vascular infiltration, and 3 predictors for H-score, respectively. Area under the curve of models using those predictors was training/test 0.93/0.94, 0.85/0.83, 0.63/0.59, 0.66/0.63, 0.71/0.69, and 0.84/0.77, respectively. The AHS-based Cox model produced higher area under the curve than the eighth AJCC staging model for predicting survival outcomes. Furthermore, adding AHS-based scores to the eighth AJCC staging model enabled better net benefits for disease outcome stratification. DISCUSSION The developed computational approach demonstrates good performance for successfully decoding AHS of GC and preoperatively predicting disease clinical outcomes.

    更新日期:2019-11-01
  • Correction: Plasma MicroRNA Signature Validation for Early Detection of Colorectal Cancer.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-03-27
    Marta Herreros-Villanueva,Saray Duran-Sanchon,Ana Carmen Martín,Rosa Pérez-Palacios,Elena Vila-Navarro,María Marcuello,Mireia Diaz-Centeno,Joaquín Cubiella,Maria Soledad Diez,Luis Bujanda,Angel Lanas,Rodrigo Jover,Vicent Hernández,Enrique Quintero,Juan José Lozano,Marta García-Cougil,Ibon Martínez-Arranz,Antoni Castells,Meritxell Gironella,Rocio Arroyo

    更新日期:2019-11-01
  • Plasma MicroRNA Signature Validation for Early Detection of Colorectal Cancer.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-02-01
    Marta Herreros-Villanueva,Saray Duran-Sanchon,Ana Carmen Martín,Rosa Pérez-Palacios,Elena Vila-Navarro,María Marcuello,Mireia Diaz-Centeno,Joaquín Cubiella,Maria Soledad Diez,Luis Bujanda,Angel Lanas,Rodrigo Jover,Vicent Hernández,Enrique Quintero,Juan José Lozano,Marta García-Cougil,Ibon Martínez-Arranz,Antoni Castells,Meritxell Gironella,Rocio Arroyo

    OBJECTIVES Specific microRNA (miRNA) signatures in biological fluids can facilitate earlier detection of the tumors being then minimally invasive diagnostic biomarkers. Circulating miRNAs have also emerged as promising diagnostic biomarkers for colorectal cancer (CRC) screening. In this study, we investigated the performance of a specific signature of miRNA in plasma samples to design a robust predictive model that can distinguish healthy individuals from those with CRC or advanced adenomas (AA) diseases. METHODS Case control study of 297 patients from 8 Spanish centers including 100 healthy individuals, 101 diagnosed with AA, and 96 CRC cases. Quantitative real-time reverse transcription was used to quantify a signature of miRNA (miRNA19a, miRNA19b, miRNA15b, miRNA29a, miRNA335, and miRNA18a) in plasma samples. Binary classifiers (Support Vector Machine [SVM] linear, SVM radial, and SVM polynomial) were built for the best predictive model. RESULTS Area under receiving operating characteristic curve of 0.92 (95% confidence interval 0.871-0.962) was obtained retrieving a model with a sensitivity of 0.85 and specificity of 0.90, positive predictive value of 0.94, and negative predictive value of 0.76 when advanced neoplasms (CRC and AA) were compared with healthy individuals. CONCLUSIONS We identified and validated a signature of 6 miRNAs (miRNA19a, miRNA19b, miRNA15b, miRNA29a, miRNA335, and miRNA18a) as predictors that can differentiate significantly patients with CRC and AA from those who are healthy. However, large-scale validation studies in asymptomatic screening participants should be conducted.

    更新日期:2019-11-01
  • Common NOD2 Risk Variants as Major Susceptibility Factors for Bacterial Infections in Compensated Cirrhosis.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-02-01
    Matthias Christian Reichert,Cristina Ripoll,Markus Casper,Robin Greinert,Edith Vandieken,Frank Grünhage,Beate Appenrodt,Alexander Zipprich,Frank Lammert

    OBJECTIVES Common nucleotide-binding oligomerization domain containing 2 (NOD2) gene variants have been associated with bacterial infections (BIs) in cirrhosis, in particular, spontaneous bacterial peritonitis, and mortality. Our aim was to evaluate the independent association of NOD2 variants with BI according to the decompensation stage. METHODS Consecutive patients with cirrhosis in 2 academic medical centers were included and genotyped for the NOD2 variants p.R702W, p.G908R, and c.3020insC. Electronic medical records were screened for BI (requiring antibiotic therapy) and past and present decompensation (as defined by variceal bleeding, encephalopathy, ascites, and/or jaundice). Clinically significant portal hypertension (CSPH) was assessed with liver stiffness and/or hepatic venous pressure gradient measurements. RESULTS Overall, 735 patients were recruited (men 65%; interquartile age range 53-68 years). Alcoholic cirrhosis was the predominant etiology (n = 406, 55%), and most patients were in the decompensated stage (n = 531, 72%). In total, 158 patients (21%) carried at least one NOD2 variant. BIs were detected in 263 patients (36%), and NOD2 variants were associated with BI (odds ratio = 1.58; 95% confidence interval 1.11-2.27; P = 0.02). In compensated patients, the combination of NOD2 variants and presence of CSPH was the best independent predictors of BI, whereas other factors, such as spleen size and hemoglobin, and decompensations including hepatic encephalopathy or jaundice, gained relevance in decompensated patients. CONCLUSIONS NOD2 risk variants are associated with BI in cirrhosis. The genetic effect on BI is strongest in compensated patients, whereas in decompensated patients their presence is less relevant. In this situation, CSPH becomes an independent factor associated with BI.

    更新日期:2019-11-01
  • Whole Genome Messenger RNA Profiling Identifies a Novel Signature to Predict Gastric Cancer Survival.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-02-01
    Jin Dai,Zhe-Xuan Li,Yang Zhang,Jun-Ling Ma,Tong Zhou,Wei-Cheng You,Wen-Qing Li,Kai-Feng Pan

    OBJECTIVES Molecular prognostic biomarkers for gastric cancer (GC) are still limited. We aimed to identify potential messenger RNAs (mRNAs) associated with GC prognosis and further establish an mRNA signature to predict the survival of GC based on the publicly accessible databases. METHODS Discovery of potential mRNAs associated with GC survival was undertaken for 441 patients with GC based on the Cancer Genome Atlas (TCGA), with information on clinical characteristics and vital status. Gene ontology functional enrichment analysis and pathway enrichment analysis were conducted to interrogate the possible biological functions. We narrowed down the list of mRNAs for validation study based on a significance level of 1.00 × 10, also integrating the information from the methylation analysis and constructing the protein-protein interaction network for elucidating biological processes. A total of 54 mRNAs were further studied in the validation stage, using the Gene Expression Omnibus (GEO) database (GSE84437, n = 433). The validated mRNAs were used to construct a risk score model predicting the prognosis of GC. RESULTS A total of 13 mRNAs were significantly associated with survival of GC, after the validation stage, including DCLK1, FLRT2, MCC, PRICKLE1, RIMS1, SLC25A15, SLCO2A1, CDO1, GHR, CD109, SELP, UPK1B, and CD36. Except CD36, DCLK1, and SLCO2A1, other mRNAs are newly reported to be associated with GC survival. The 13 mRNA-based risk score had good performance on distinguishing GC prognosis, with a higher score indicating worse survival in both TCGA and GEO datasets. CONCLUSIONS We established a 13-mRNA signature to potentially predict the prognosis of patients with GC, which might be useful in clinical practice for informing patient stratification.

    更新日期:2019-11-01
  • A Multicenter, Randomized, Controlled Trial of Rebamipide Plus Lansoprazole for the Treatment of Postendoscopic Submucosal Dissection Ulcers.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-02-01
    Bin Yan,Zhongsheng Lu,Zhizheng Ge,Side Liu,Xuegang Guo,Dean Tian,Yuxiu Yang,Xiaobo Li,Wei Gong,Zhiguo Liu,Mei Liu,Bingxi Zhou,Kabing Zhao,Fei Pan,Jing Yang,Yunsheng Yang

    OBJECTIVES To evaluate the healing efficacy of rebamipide and lansoprazole combination therapy with lansoprazole alone for endoscopic submucosal dissection (ESD)-induced ulcers and clarify the ulcer healing-associated factors. METHODS Three hundred patients were randomized into control and experimental groups after they underwent ESD. The patients received intravenous pantoprazole (30 mg) every 12 hours and oral rebamipide (100 mg, experimental group) or placebo (control group) 3 times daily on days 1-3. On days 4-56, patients received oral lansoprazole (30 mg daily) and rebamipide (100 mg) or placebo 3 times daily. Endoscopic evaluations were performed at postoperative weeks 4 and 8. RESULTS At week 4, the ulcer reduction rate was significantly higher in the experimental than in the control group (0.97 ± 0.034 vs. 0.94 ± 0.078; P < 0.001). The ulcer healing (18.2% vs 20.3%; P = 0.669) and ulcer improvement rates (94.2% vs 88.7%; P = 0.109) in the 2 groups were not significantly different. At week 8, the ulcer healing and ulcer improvement rates were 90.6% and 100%, respectively, in both groups. Multivariate analysis showed that the combination treatment was an independent factor associated with ulcer area reduction after ESD. The maximum diameter of the initial ulcer (≥35.5 mm vs <35.5 mm) was an independent factor associated with the ulcer improvement rate after ESD. CONCLUSIONS The rebamipide and lansoprazole combination therapy can help accelerate the reduction rate of post-ESD ulcer compared with the lansoprazole monotherapy at 4 weeks of therapy.

    更新日期:2019-11-01
  • Characterization of Proximal Small Intestinal Microbiota in Patients With Suspected Small Intestinal Bacterial Overgrowth: A Cross-Sectional Study.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-08-30
    Andrea S Shin,Xiang Gao,Matthew Bohm,Huaiying Lin,Anita Gupta,David E Nelson,Evelyn Toh,Sean Teagarden,Robert Siwiec,Qunfeng Dong,John M Wo

    OBJECTIVES The composition of the small intestinal microbiota has not yet been characterized thoroughly using culture-independent techniques. We compared small intestinal microbial communities in patients with and without small intestinal bacterial overgrowth (SIBO) using culture-dependent and culture-independent bacterial identification approaches. METHODS Small bowel aspirate and mucosal samples were collected from patients with suspected SIBO. The aspirates were cultured to diagnose SIBO, defined as ≥10 colony-forming units/mL coliform or ≥10 colony-forming units/mL upper aerodigestive tract bacteria. Bacteria in the aspirates and mucosa were identified using 16S rRNA gene sequencing. We compared small intestinal microbiome composition between groups with and without a culture-based SIBO diagnosis. RESULTS Analysis of the aspirate and mucosal microbial communities from 36 patients revealed decreased α-diversity but no differences in β-diversity in patients with SIBO compared with those without SIBO. There were no significant differences in the relative abundance of individual taxa from the aspirates or mucosa after adjustment for false discovery rate between patients with and without SIBO. Subgroup analysis revealed significant differences in mucosal β-diversity between the coliform and upper aerodigestive tract subgroups. Relative abundances of a mucosal Clostridium spp. (P = 0.05) and an aspirate Granulicatella spp. (P = 0.02) were higher in coliform SIBO vs non-SIBO subgroups. The microbial composition and relative abundance of multiple taxa significantly differed in the mucosal and aspirate specimens. DISCUSSION Culture-based results of small bowel aspirates do not correspond to aspirate microbiota composition but may be associated with species richness of the mucosal microbiota.

    更新日期:2019-11-01
  • Multicenter Validation Study of a Diagnostic Algorithm to Detect NASH and Fibrosis in NAFLD Patients With Low NAFLD Fibrosis Score or Liver Stiffness.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-08-10
    Stephanie Liebig,Neele Stoeckmann,Andreas Geier,Monika Rau,Joern M Schattenberg,Matthias J Bahr,Michael P Manns,Elmar Jaeckel,Klaus Schulze-Osthoff,Heike Bantel

    OBJECTIVES Nonalcoholic steatohepatitis (NASH) and fibrosis play critical roles for the prognosis of patients with nonalcoholic fatty liver disease (NAFLD). Identification of patients at risk of NASH and fibrosis is therefore critical for disease management. NAFLD Fibrosis Score (NFS) and transient elastography (TE) have been suggested to exclude advanced fibrosis. However, there is increasing evidence that also patients with NASH and early fibrosis are at risk of disease progression and complications, emphasizing the need for improved noninvasive risk stratification in NAFLD. METHODS Because hepatocyte apoptosis plays an early role in NASH pathogenesis, we evaluated whether the apoptosis biomarker M30 might identify NAFLD patients who are at risk of NASH and fibrosis despite low NFS or TE values. Serum M30 levels were assessed by enzyme-linked immunosorbent assay in combination with NFS and/or TE in an exploration (n = 103) and validation (n = 100) cohort of patients with biopsy-proven NAFLD. RESULTS Most patients with low NFS (cutoff value < -1.455) revealed increased M30 levels (>200 U/L) in the exploration (62%) and validation (67%) cohort, and more than 70% of them had NASH, mostly with histological fibrosis. Vice versa, most patients with NFS < -1.455 but nonelevated M30 levels showed no NASH. NASH was also detected in most patients with indeterminate NFS (-1.455 to 0.676) but elevated M30 levels, from which ∼90% showed fibrosis. Similar results were obtained when using TE instead of NFS. DISCUSSION The combination of the M30 biomarker with NFS or TE enables a more reliable identification of patients with an increased risk of progressed NAFLD and improves patient stratification.

    更新日期:2019-11-01
  • Dysbiosis of the Duodenal Mucosal Microbiota Is Associated With Increased Small Intestinal Permeability in Chronic Liver Disease.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-08-03
    Ashok S Raj,Erin R Shanahan,Cuong D Tran,Purnima Bhat,Linda M Fletcher,David A Vesey,Mark Morrison,Gerald Holtmann,Graeme A Macdonald

    OBJECTIVES Chronic liver disease (CLD) is associated with both alterations of the stool microbiota and increased small intestinal permeability. However, little is known about the role of the small intestinal mucosa-associated microbiota (MAM) in CLD. The aim of this study was to evaluate the relationship between the duodenal MAM and both small intestinal permeability and liver disease severity in CLD. METHODS Subjects with CLD and a disease-free control group undergoing routine endoscopy underwent duodenal biopsy to assess duodenal MAM by 16S rRNA gene sequencing. Small intestinal permeability was assessed by a dual sugar (lactulose: rhamnose) assay. Other assessments included transient elastography, endotoxemia, serum markers of hepatic inflammation, dietary intake, and anthropometric measurements. RESULTS Forty-six subjects (35 with CLD and 11 controls) were assessed. In subjects with CLD, the composition (P = 0.02) and diversity (P < 0.01) of the duodenal MAM differed to controls. Constrained multivariate analysis and linear discriminate effect size showed this was due to Streptococcus-affiliated lineages. Small intestinal permeability was significantly higher in CLD subjects compared to controls. In CLD, there were inverse correlations between microbial diversity and both increased small intestinal permeability (r = -0.41, P = 0.02) and serum alanine aminotransferase (r = -0.35, P = 0.04). Hepatic stiffness was not associated with the MAM. DISCUSSION In CLD, there is dysbiosis of the duodenal MAM and an inverse correlation between microbial diversity and small intestinal permeability. TRANSLATIONAL IMPACT Strategies to ameliorate duodenal MAM dysbiosis may ameliorate intestinal barrier dysfunction and liver injury in CLD.

    更新日期:2019-11-01
  • Selection Between Liver Resection Versus Transarterial Chemoembolization in Hepatocellular Carcinoma: A Multicenter Study.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-08-03
    Sirui Fu,Jingwei Wei,Jie Zhang,Di Dong,Jiangdian Song,Yong Li,Chongyang Duan,Shuaitong Zhang,Xiaoqun Li,Dongsheng Gu,Xudong Chen,Xiaohan Hao,Xiaofeng He,Jianfeng Yan,Zhenyu Liu,Jie Tian,Ligong Lu

    OBJECTIVES Models should be developed to assist choice between liver resection (LR) and transarterial chemoembolization (TACE) for hepatocellular carcinoma. METHODS After separating 520 cases from 5 hospitals into training (n = 302) and validation (n = 218) data sets, we weighted the cases to control baseline difference and ensured the causal effect between treatments (LR and TACE) and estimated progression-free survival (PFS) difference. A noninvasive PFS model was constructed with clinical factors, radiological characteristics, and radiomic features. We compared our model with other 4 state-of-the-art models. Finally, patients were classified into subgroups with and without significant PFS difference between treatments. RESULTS Our model included treatments, age, sex, modified Barcelona Clinic Liver Cancer stage, fusion lesions, hepatocellular carcinoma capsule, and 3 radiomic features, with good discrimination and calibrations (area under the curve for 3-year PFS was 0.80 in the training data set and 0.75 in the validation data set; similar results were achieved in 1- and 2-year PFS). The model had better accuracy than the other 4 models. A nomogram was built, with different scores assigned for LR and TACE. Separated by the threshold of score difference between treatments, for some patients, LR provided longer PFS and might be the better option (training: hazard ratio [HR] = 0.50, P = 0.014; validation: HR = 0.52, P = 0.026); in the others, LR provided similar PFS with TACE (training: HR = 0.84, P = 0.388; validation: HR = 1.14, P = 0.614). TACE may be better because it was less invasive. DISCUSSION We propose an individualized model predicting PFS difference between LR and TACE to assist in the optimal treatment choice.

    更新日期:2019-11-01
  • Circulating Anti-cytolethal Distending Toxin B and Anti-vinculin Antibodies as Biomarkers in Community and Healthcare Populations With Functional Dyspepsia and Irritable Bowel Syndrome.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-07-30
    Nicholas J Talley,Gerald Holtmann,Marjorie M Walker,Grace Burns,Michael Potter,Ayesha Shah,Michael Jones,Natasha A Koloski,Simon Keely

    OBJECTIVES Anti-cytolethal distending toxin B (CdtB) and anti-vinculin antibodies have been proposed as biomarkers that discriminate irritable bowel syndrome (IBS) diarrhea from inflammatory bowel disease; however, it is unknown whether they can also discriminate patients with IBS and IBS subtypes and functional dyspepsia (FD) from healthy individuals in the general population. We aimed to determine whether anti-CdtB and anti-vinculin can discriminate IBS and FD from health and from organic gastrointestinal (GI) disease. METHODS Adults were enrolled from 2 Australian studies: (i) a random, population-based study (n = 331) with subjects diagnosed with IBS (n = 63) or FD (n = 61) by modified Rome III criteria or healthy control subjects (n = 246) who did not meet criteria for IBS and/or FD and (ii) an outpatient-based study with subjects diagnosed with IBS (n = 256) and/or FD (n = 55) or organic GI disease (n = 182) by an independent clinician. Serum levels of anti-CdtB/anti-vinculin antibodies were determined by enzyme-linked immunosorbent assay. RESULTS There was a significantly higher mean value of anti-CdtB in FD vs healthy controls (mean = 2.46 [SD = 0.72] vs mean = 2.14 [SD = 0.77]; P = 0.005) and IBS/FD overlap vs healthy controls (mean = 2.47 [SD = 0.78] vs mean = 2.14 [SD = 0.77]; P = 0.02). There were no significant differences in anti-CdtB in IBS and FD outpatients or IBS/FD subgroups compared with patients with organic GI disease. In terms of anti-vinculin, there were no significant differences between IBS and FD and healthy controls or between IBS and FD and organic GI disease controls. DISCUSSION We did not confirm that anti-CdtB/anti-vinculin discriminated IBS diarrhea from organic GI disease in Australian subjects. However, we did find higher anti-CdtB in FD and IBS/FD overlap vs healthy controls. Postinfectious FD may be more common than currently recognized.

    更新日期:2019-11-01
  • Increasing Economic Burden in Hospitalized Patients With Cirrhosis: Analysis of a National Database.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-07-26
    Archita P Desai,Prashanthinie Mohan,Brandon Nokes,Deekksha Sheth,Shannon Knapp,Malaz Boustani,Naga Chalasani,Michael B Fallon,Elizabeth A Calhoun

    INTRODUCTION The prevalence of cirrhosis is increasing despite advances in therapeutics, and it remains an expensive medical condition. Studies examining the healthcare burden of inpatient cirrhosis-related care regardless of etiology, stage, or severity are lacking. This study aims to describe the current drivers of cost, length of stay (LOS), and mortality in hospitalized patients with cirrhosis. METHODS Using the National Inpatient Sample (NIS) data from 2008 to 2014, we categorized admissions into decompensated cirrhosis (DC), compensated cirrhosis (CC), and NIS without cirrhosis. Descriptive statistics and regression analysis were used to analyze the association between patient characteristics, comorbidities, complications, and procedures with costs, LOS, and mortality in each group. RESULTS The hospitalization costs for patients with cirrhosis increased 30.2% from 2008 to 2014 to $7.37 billion. Cirrhosis admissions increased by 36% and 24% in the DC and CC groups, respectively, compared with 7.7% decrease in the NIS without cirrhosis group. DC admissions contributed to 58.6% of total cirrhotic admissions by 2014. Procedures increased costs in both DC and CC groups by 15%-152%, with mechanical ventilation being associated with high cost increase and mortality increase. Complications are also key drivers of costs and LOS, with renal and infectious complications being associated with the highest increases in the DC group and infections and nonportal hypertensive gastrointestinal bleeding for the CC group. DISCUSSION Economic burden of hospitalized patients with cirrhosis is increasing with more admissions and longer LOS in DC and CC groups. Important drivers include procedures and portal hypertensive and nonportal hypertensive complications.

    更新日期:2019-11-01
  • Weak Cytotoxic T Cells Activation Predicts Low-Grade Dysplasia Persistence in Ulcerative Colitis.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-07-26
    Andromachi Kotsafti,Renata DʼIncà,Melania Scarpa,Matteo Fassan,Imerio Angriman,Claudia Mescoli,Nicolò Bortoli,Paola Brun,Romeo Bardini,Massimo Rugge,Edoardo Savarino,Fabiana Zingone,Carlo Castoro,Ignazio Castagliuolo,Marco Scarpa

    INTRODUCTION In patients with ulcerative colitis (UC), dysplasia develops in 10%-20% of cases. The persistence of low-grade dysplasia (LGD) in UC in 2 consecutive observations is still an indication for restorative proctocolectomy. Our hypothesis is that in the case of weak cytotoxic activation, dysplasia persists. We aimed to identify possible immunological markers of LGD presence and persistence. METHODS We prospectively enrolled 112 UC patients who underwent screening colonoscopy (T0) who had biopsies taken from their sigmoid colon. Ninety of them had at least a second colonoscopy (T1) with biopsies taken in the sigmoid colon and 8 patients had dysplasia in both examinations suggesting a persistence of LGD in their colon. Immunohistochemistry and real time polymerase chain reaction for CD4, CD69, CD107, and CD8β messenger RNA (mRNA) expression and flow cytometry for epithelial cells expressing CD80 or HLA avidin-biotin complex were performed. Non-parametric statistics, receiver operating characteristic curves analysis, and logistic multiple regression analysis were used. RESULTS Thirteen patients had LGD diagnosed at T0. The mucosal mRNA expression of CD4, CD69, and CD8β was significantly lower than in patients without dysplasia (P = 0.033, P = 0.046 and P = 0.007, respectively). A second colonoscopy was performed in 90 patients after a median follow-up of 17 (12-25) months and 14 of the patients were diagnosed with LGD. In these patients, CD8β mRNA expression at T0 was significantly lower in patients without dysplasia (P = 0.004). A multivariate survival analysis in a model including CD8β mRNA levels and age >50 demonstrated that both items were independent predictors of dysplasia at follow-up (hazard ratio [HR] = 0.47 [95% confidence interval [CI]: 0.26-0.86], P = 0.014, and HR = 13.32 [95% CI: 1.72-102.92], P = 0.013). DISCUSSION These data suggest a low cytotoxic T cell activation in the colonic mucosa of UC patients who do not manage to clear dysplasia. Thus, low level of CD8β mRNA expression in non-dysplastic colonic mucosa might be considered in future studies about the decision making of management of LGD in UC.

    更新日期:2019-11-01
  • The Gut Microbiota in Collagenous Colitis Shares Characteristics With Inflammatory Bowel Disease-Associated Dysbiosis.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-07-26
    Adam Carstens,Johan Dicksved,Ronald Nelson,Mårten Lindqvist,Anna Andreasson,Johan Bohr,Curt Tysk,Nicholas J Talley,Lars Agréus,Lars Engstrand,Jonas Halfvarson

    INTRODUCTION In inflammatory bowel disease (IBD), an aberrant immune response to gut microbiota is important, but the role of the microbiota in collagenous colitis (CC) is largely unknown. We aimed to characterize the microbiota of patients with CC compared with that of healthy control and patients with IBD. METHODS Fecal samples were collected from patients with CC (n = 29), age- and sex-matched healthy controls (n = 29), patients with Crohn's disease (n = 32), and patients with ulcerative colitis (n = 32). Sequence data were obtained by 454 sequencing of 16S rRNA gene amplicons, and the obtained sequences were subsequently taxonomically classified. RESULTS Analysis of similarity statistics showed a segregation between patients with CC and healthy controls with increasing taxonomic resolution, becoming significant comparing operational taxonomic unit data (P = 0.006). CC had a lower abundance of 10 different taxa. Taxa-specific analyses revealed a consistent lower abundance of several operational taxonomic units belonging to the Ruminococcaceae family in patients with CC, q < 0.05 after false discovery rate correction. Loss of these taxa was seen in patients with CC with active disease and/or corticosteroid treatment only and resembled the findings in patients with IBD. DISCUSSION CC is associated with a specific fecal microbiome seen primarily in patients with active disease or ongoing corticosteroid treatment, whereas the microbiome of CC patients in remission resembled that of healthy controls. Notably, the shift in key taxa, including the Ruminococcaceae family, was also observed in IBD. There may be common mechanisms in the pathogenesis of CC and IBD.

    更新日期:2019-11-01
  • Primer on Precision Medicine for Complex Chronic Disorders.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-07-25
    David C Whitcomb

    Precision medicine promises patients with complex disorders the right treatment for the right patient at the right dose at the right time with expectation of better health at a lower cost. The demand for precision medicine highlights the limitations of modern Western medicine. Modern Western medicine is a population-based, top-down approach that uses pathology to define disease. Precision medicine is a bottom-up approach that identifies predisease disorders using genetics, biomarkers, and modeling to prevent disease. This primer demonstrates the contrasting strengths and limitations of each paradigm and why precision medicine will eventually deliver on the promises.

    更新日期:2019-11-01
  • A Low FODMAP Diet May Reduce Symptoms in Patients With Fecal Incontinence.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-07-25
    Stacy B Menees,Deepa Chandhrasekhar,Ee Lane Liew,William D Chey

    INTRODUCTION Fecal incontinence (FI) is a common complaint and is often associated with diarrhea and urgency. Foods high in fermentable oligo-, di-, and mono-saccharides and polyols (FODMAP) cause symptoms of diarrhea and urgency. Therefore, this study assesses the impact of a low FODMAP diet on the occurrence of FI due to loose stool. METHODS This study is a retrospective chart review of patients with FI seen in the Michigan Bowel Control Program clinic between August 2012 and December 2017. Patients who had FI with loose stool without red flag signs and who were recommended a low FODMAP diet and underwent formal dietary instruction with a Michigan Medicine dietician were included. RESULTS Sixty-five patients with FI who underwent formal dietary teaching were included in this study. Eighty-eight percent of the patients were white, and 87% were women with a mean age of 62 years (±14 years). Additionally, the chart review showed that 35% of the patients had FI daily, 21.5% had FI weekly, and 5% had FI monthly. About 64.6% of the patients (42) had reported a reduction in their FI symptoms with the low FODMAP diet. There was no demographic or clinical characteristic that predicted the response to a low FODMAP diet. DISCUSSION In this case series, dietary manipulation with a low FODMAP diet was a useful tool to treat patients who suffer from FI due to loose stool. Further confirmatory, prospective randomized controlled trials are required to see the true efficacy of a low FODMAP diet in patients who suffer with FI.

    更新日期:2019-11-01
  • Blunted Evoked Prouroguanylin Endocrine Secretion in Chronic Constipation.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-07-19
    Scott A Waldman,Renata Tenenbaum,Henry C Foehl,Peter Winkle,Patrick Griffin

    OBJECTIVES Prouroguanylin (ProUGN) in the intestine is cleaved to form uroguanylin (UGN), which stimulates guanylate cyclase C (GUCY2C), inducing cyclic guanosine monophosphate signaling. Paracrine release regulates fluid secretion, contributing to bowel function, whereas endocrine secretion evoked by eating forms a gut-brain axis, controlling appetite. Whereas hormone insufficiency contributes to hyperphagia in obesity, its contribution to the pathophysiology of constipation syndromes remains unexplored. Here, we compared circulating ProUGN and UGN in healthy subjects and in patients with chronic idiopathic constipation (CIC) and patients with irritable bowel syndrome with constipation (IBS-C). METHODS Circulating ProUGN and UGN levels were measured in 60 healthy subjects, 53 patients with CIC, and 54 patients with IBS-C. After an overnight fast, the participants ingested a standardized meal; blood samples were drawn at fasting and at 30, 60, and 90 minutes thereafter, and hormone levels were quantified by enzyme-linked immunosorbent assay. RESULTS Fasting ProUGN levels were >30% lower in patients with CIC and those with IBS-C compared with healthy subjects regardless of age, sex, or disease state. After eating, ProUGN levels increased compared with fasting levels, although the rate of change was slower and maximum levels were lower in patients with CIC and those with IBS-C. Similarly, fasting UGN levels were lower in patients with CIC and those with IBS-C compared with healthy subjects. However, unlike ProUGN levels, UGN levels did not increase after eating. DISCUSSION These observations support a novel pathophysiologic model in which CIC and IBS-C reflect a contribution of ProUGN insufficiency dysregulating intestinal fluid and electrolyte secretion. TRANSLATIONAL IMPACT This study suggests that CIC and IBS-C can be treated by oral GUCY2C hormone replacement. Indeed, these observations provide a mechanistic framework for the clinical utility of oral GUCY2C ligands like plecanatide (Trulance) and linaclotide (Linzess) to treat CIC and IBS-C.

    更新日期:2019-11-01
  • Correction: Activated T-Follicular Helper 2 Cells Are Associated With Disease Activity in IgG4-Related Sclerosing Cholangitis and Pancreatitis.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-07-18
    Tamsin Cargill,Mateusz Makuch,Ross Sadler,Laura C Lighaam,Rory Peters,Marieke van Ham,Paul Klenerman,Adrian Bateman,Theo Rispens,Eleanor Barnes,Emma L Culver

    更新日期:2019-11-01
  • A Phase 2 Study of Galunisertib (TGF-β1 Receptor Type I Inhibitor) and Sorafenib in Patients With Advanced Hepatocellular Carcinoma.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-07-12
    R K Kelley,E Gane,E Assenat,J Siebler,P R Galle,P Merle,I O Hourmand,A Cleverly,Y Zhao,I Gueorguieva,M Lahn,S Faivre,K A Benhadji,G Giannelli

    INTRODUCTION Inhibition of tumor growth factor-β (TGF-β) receptor type I potentiated the activity of sorafenib in preclinical models of hepatocellular carcinoma (HCC). Galunisertib is a small-molecule selective inhibitor of TGF-β1 receptor type I, which demonstrated activity in a phase 2 trial as second-line HCC treatment. METHODS The combination of galunisertib and sorafenib (400 mg BID) was tested in patients with advanced HCC and Child-Pugh A liver function without prior systemic therapy. Galunisertib dose was administered 80 or 150 mg b.i.d. orally for 14 days every 28 days in safety lead-in cohorts; in the expansion cohort, all patients received galunisertib 150 mg b.i.d. Objectives included time-to-tumor progression, changes in circulating alpha fetoprotein and TGF-β1, safety, overall survival (OS), response rate, and pharmacokinetics (PK). RESULTS Patients (n = 47) were enrolled from 5 non-Asian countries; 3 and 44 patients received the 80 mg and 150 mg b.i.d. doses of galunisertib, respectively. The pharmacokinetics and safety profiles were consistent with monotherapy of each drug. For the 150 mg b.i.d. galunisertib cohort, the median time-to-tumor progression was 4.1 months; the median OS was 18.8 months. A partial response was seen in 2 patients, stable disease in 21, and progressive disease in 13. TGF-β1 responders (decrease of >20% from baseline) vs nonresponders had longer OS (22.8 vs 12.0 months, P = 0.038). DISCUSSION The combination of galunisertib and sorafenib showed acceptable safety and a prolonged OS outcome.

    更新日期:2019-11-01
  • Immunologic Features of Patients With Advanced Hepatocellular Carcinoma Before and During Sorafenib or Anti-programmed Death-1/Programmed Death-L1 Treatment.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-07-12
    Zuzana Macek Jilkova,Caroline Aspord,Keerthi Kurma,Anouck Granon,Christian Sengel,Nathalie Sturm,Patrice N Marche,Thomas Decaens

    INTRODUCTION Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Today, a promising treatment strategy is focused on the enhancement of antitumor immune responses by immune checkpoint modification. However, as only 20% of patients with HCC are responders, identification of predictive factors is urgently required. Therefore, for the first time, the features of the intrahepatic and circulating immune system in patients with advanced-stage HCC, before and during the treatment, were analyzed. METHODS We collected fresh HCC biopsies, along with adjacent tumor-free liver tissues and peripheral blood samples, from 21 patients with advanced HCC. Furthermore, we performed an extensive immunomonitoring of patients with HCC treated with sorafenib or programmed death (PD)-1/PD-L1 pathway blockade using multiparametric flow cytometry. RESULTS We observed that regardless of the treatment, low baseline intratumoral CD4/CD8 T-cell ratio was associated with better overall survival (P = 0.0002). The baseline frequency of intratumoral PD-1 CD8 T cells was significantly lower in patients responding to sorafenib treatment than in the nonresponders (P = 0.0117), and the frequency of circulating PD-1 T cells increased with tumor progression (P = 0.0329). By contrast, responders to PD-1/PD-L1 pathway blockade showed a trend of high baseline frequency of intratumoral PD-1 CD8 T cells. Moreover, we observed a trend of LAG3 and TIM3 upregulation on circulating T cells in nonresponding patients to PD-1/PD-L1 pathway blockade. DISCUSSION Immunosuppressive state, characterized by an enhanced intratumoral CD4/CD8 T-cell ratio, was associated with poor prognosis. Additionally, our results suggest that the frequency of intratumoral PD-1 CD8 T cells may serve as a biomarker to identify which individuals will benefit from which treatment and support the use of combination strategies.

    更新日期:2019-11-01
  • Variable Features of Juvenile Polyposis Syndrome With Gastric Involvement Among Patients With a Large Genomic Deletion of BMPR1A.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-07-02
    Sari Lieberman,Rachel Beeri,Tom Walsh,Menachem Schechter,Dan Keret,Elizabet Half,Suleyman Gulsuner,Ariela Tomer,Harold Jacob,Shlomi Cohen,Lina Basel-Salmon,Mahmud Mansur,Rachel Berger,Lior H Katz,Eliahu Golomb,Tamar Peretz,Zohar Levy,Inbal Kedar,Mary-Claire King,Ephrat Levy-Lahad,Yael Goldberg

    OBJECTIVES Loss-of-function mutations of BMPR1A cause juvenile polyposis syndrome (JPS), but large genomic deletions in BMPR1A are rare, reported in few families only, and data regarding the associated phenotype are limited. METHODS We investigated clinical features and genomic data of 7 extended seemingly unrelated families with a genomic deletion of the entire coding region of BMPR1A. We defined mutation size, mutation prevalence, and tumor pathogenesis using whole-genome sequencing, targeted genotyping, and haplotype analysis. RESULTS Patients with JPS from 7 families of Bukharin Jewish ancestry carried a deletion of 429 kb, encompassing the BMPR1A coding sequence and 8 downstream genes. Haplotype analysis and testing controls identified this as a common founder mutation occurring in 1/124 individuals of Bukharin origin. Tumor testing did not demonstrate loss of heterozygosity. Among carriers, JPS was almost fully penetrant, but clinical features varied widely, ranging from mild to very severe, including pan-enteric polyps, gastritis, and colorectal, esophageal, and testicular cancer, and carriers with phenotypes, which would not have raised suspicion of JPS. DISCUSSION The phenotype in this large cohort was extremely variable, although all carriers shared the same variant and the same genetic background. New observations include a preponderance of adenomatous rather than juvenile polyps, possible association with testicular cancer, and unexpected upper gastrointestinal involvement.

    更新日期:2019-11-01
  • Clinicopathologic and Racial/Ethnic Differences of Colorectal Cancer Among Adolescents and Young Adults.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-07-02
    Andreana N Holowatyj,Mark A Lewis,Samantha T Pannier,Anne C Kirchhoff,Sheetal Hardikar,Jane C Figueiredo,Lyen C Huang,David Shibata,Stephanie L Schmit,Cornelia M Ulrich

    OBJECTIVES Despite overall reductions in colorectal cancer burden, incidence rates continue to rise among younger patients, and causes remain unknown. We examined differences in clinicopathologic and racial/ethnic characteristics within the adolescent and young adult (AYA) population diagnosed with colorectal cancer in the United States. METHODS Using the National Cancer Institute's Surveillance, Epidemiology, and End Results program data, we identified individuals diagnosed with first primary colorectal cancer between ages 15 and 39 years from 2010 to 2015. Adjusted multivariable logistic regression models were used to quantify clinicopathologic and racial/ethnic differences across age at onset subgroups (15-19, 20-24, 25-29, 30-34, and 35-39 years). RESULTS We identified 5,350 AYA patients diagnosed with colorectal cancer. Of note, 28.6% of AYA cases were diagnosed with right-sided tumors (cecum to transverse colon). The proportion of right-sided colorectal cancers differed significantly by age group at diagnosis (38.3% vs 27.3% of AYAs aged 15-19 vs 35-39 years, respectively; P trend = 0.01). Proportions of cases with mucinous adenocarcinoma and signet ring cell carcinoma histopathologic subtypes significantly increased with younger age at onset (P trends = 0.01 and 0.03, respectively). Differences in clinical stage were observed across AYA age groups, with stage II disease increasing with younger age (P trend = 0.01). The proportion of Hispanic AYAs was higher within younger patients, accounting for 21.0% of the AYA population aged 35-39 years up to 28.3% of 15-19-year-old individuals (P trend = 0.003). DISCUSSION Within the AYA population, colorectal cancers differ by clinicopathologic and racial/ethnic characteristics. Further investigation of the clinical and biologic diversity of colorectal cancers that partially underlie age- and race-related differences in cancer susceptibility and outcomes is warranted.

    更新日期:2019-11-01
  • Transjugular Liver Biopsy: Safe Even in Patients With Severe Coagulopathies and Multiple Biopsies.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-07-02
    Megan J Sue,Edward W Lee,Sammy Saab,Justin P McWilliams,Francisco Durazo,Mohamed El-Kabany,Fady Kaldas,Ronald W Busuttil,Stephen T Kee

    OBJECTIVES To investigate the safety profile and diagnostic efficacy of transjugular liver biopsy (TJLB), with a focus on patients with severe coagulopathies and with multiple biopsies. METHODS Clinical, laboratory, and demographic information was collected on 1,321 TJLBs in 932 patients (mean age 43.5 ± 23.2 years) performed between January 2009 and May 2017 to determine the diagnostic success rate and incidence of both major and minor complications in the 3-day and 30-day period post-biopsies. These outcomes were also analyzed for severely coagulopathic patients and a subgroup of patients who underwent multiple biopsies. RESULTS The overall success rate (diagnostic yield) of the TJLB procedure was 97.7% (1,291/1,321). Overall, the major and minor complication rates were 1.0% (13/1,321) and 9.5% (126/1,321), respectively. In patients with multiple biopsies, the overall complication rate was similar to the entire study cohort, which was 10.4% (57/550). Patients were also stratified according to the platelet counts of 0-50, 51-100, 101-200, 201-300 and >300 × 10 platelets/μL. The overall complication rates were 8.0% (10/124), 11.6% (36/310), 9.9% (54/547), 11.9% (28/235), and 14.3% (11/77), respectively, and these were not statistically significant from each other. Patients were also stratified by international normalized ratio into 0-1, 1.1-2, 2.1-3, and >3. The overall complication rates of these patients were 8.0% (19/237), 11.8% (113/954), 16.3% (7/43), and 0% (0/9), respectively, and were not statistically significant from each other. DISCUSSION TJLB is a highly efficacious, well-tolerated and safe procedure. It can be safely performed multiple times in the same patient or in critically ill, severely coagulopathic patients with no significant increase in the rate of complication while maintaining an extremely favorable diagnostic yield.

    更新日期:2019-11-01
  • Clinical Potential of Circulating Tumor Cells in Colorectal Cancer: A Prospective Study.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-06-28
    Dong Hoon Baek,Gwang Ha Kim,Geun Am Song,In Sub Han,Eun Young Park,Hyun Sung Kim,Hong Jae Jo,Sang Hwa Ko,Do Youn Park,Yoon-Kyung Cho

    OBJECTIVES Circulating tumor cells (CTCs) in the blood have been used as diagnostic markers in patients with colorectal cancer (CRC). In this study, we evaluated a CTC detection system based on cell size to assess CTCs and their potential as early diagnostic and prognostic biomarkers for CRC. METHODS From 2014 to 2015, 88 patients with newly diagnosed CRC, who were scheduled for surgery, and 31 healthy volunteers were enrolled and followed up in Pusan National University Hospital. CTCs were enriched using a centrifugal microfluidic system with a new fluid-assisted separation technique (FAST) and detected by cytomorphological evaluation using fluorescence microscopy. RESULTS Two or more CTCs were detected using FAST in 74 patients and 3 healthy volunteers. The number of CTCs in the CRC group was significantly higher than that in the healthy volunteers (P < 0.001). When a receiver operating characteristic curve was created to differentiate patients with CRC from healthy volunteers, the sensitivity and specificity were almost optimized when the critical CTC value was 5/7.5 mL of blood. When this value was used, the sensitivity and specificity in differentiating patients with CRC from the healthy controls were 75% and 100%, respectively. In patients with CRC with ≥5 CTCs, vascular invasion was frequently identified (P = 0.035). All patients with stage IV were positive for CTCs. Patients with ≥5 CTCs showed a trend toward poor overall and progression-free survival. DISCUSSION Our study demonstrated promising results with the use of FAST-based CTC detection for the early diagnosis and prognosis of CRC.

    更新日期:2019-11-01
  • Genetic Risk Score in Diabetes Associated With Chronic Pancreatitis Versus Type 2 Diabetes Mellitus.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-06-25
    Mark O Goodarzi,Tanvi Nagpal,Phil Greer,Jinrui Cui,Yii-Der I Chen,Xiuqing Guo,James S Pankow,Jerome I Rotter,Samer Alkaade,Stephen T Amann,John Baillie,Peter A Banks,Randall E Brand,Darwin L Conwell,Gregory A Cote,Christopher E Forsmark,Timothy B Gardner,Andres Gelrud,Nalini Guda,Jessica LaRusch,Michele D Lewis,Mary E Money,Thiruvengadam Muniraj,Georgios I Papachristou,Joseph Romagnuolo,Bimaljit S Sandhu,Stuart Sherman,Vikesh K Singh,C Mel Wilcox,Stephen J Pandol,Walter G Park,Dana K Andersen,Melena D Bellin,Phil A Hart,Dhiraj Yadav,David C Whitcomb,

    INTRODUCTION Diabetes mellitus (DM) is a complication of chronic pancreatitis (CP). Whether pancreatogenic diabetes associated with CP-DM represents a discrete pathophysiologic entity from type 2 DM (T2DM) remains uncertain. Addressing this question is needed for development of specific measures to manage CP-DM. We approached this question from a unique standpoint, hypothesizing that if CP-DM and T2DM are separate disorders, they should be genetically distinct. To test this hypothesis, we sought to determine whether a genetic risk score (GRS) based on validated single nucleotide polymorphisms for T2DM could distinguish between groups with CP-DM and T2DM. METHODS We used 60 T2DM single nucleotide polymorphisms to construct a weighted GRS in 1,613 subjects from the North American Pancreatitis Study 2 and 2,685 subjects from the Multi-Ethnic Study of Atherosclerosis, all of European origin. RESULTS The mean GRS was identical between 321 subjects with CP-DM and 423 subjects with T2DM (66.53 vs 66.42, P = 0.95), and the GRS of both diabetic groups was significantly higher than that of nondiabetic controls (n = 3,554, P < 0.0001). Exploratory analyses attempting to enrich the CP-DM group for pancreatogenic diabetes, such as eliminating diabetes diagnosed before CP, requiring pancreas-specific comorbidities, or removing those with a family history of diabetes, did not improve the ability of the GRS to distinguish between CP-DM and T2DM. DISCUSSION Recognizing that we lacked a gold standard to define CP-DM, our study suggests that CP-DM may be a subtype of T2DM, a notion that should be tested in future, large prospective studies.

    更新日期:2019-11-01
  • Correction: Activated T-Follicular Helper 2 Cells Are Associated With Disease Activity in IgG4-Related Sclerosing Cholangitis and Pancreatitis.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-05-15
    Michael Camilleri,Paula Carlson,Victor Chedid,Priya Vijayvargiya,Duane Burton,Irene Busciglio

    更新日期:2019-11-01
  • Aquaporin Expression in Colonic Mucosal Biopsies From Irritable Bowel Syndrome With Diarrhea.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-04-30
    Michael Camilleri,Paula Carlson,Victor Chedid,Priya Vijayvargiya,Duane Burton,Irene Busciglio

    INTRODUCTION Aquaporin (AQP) channels are involved in regulating fluid homeostasis in the colon. Several AQP channels were detected in human colon epithelial cells. In a previous study, rats fed 1% (wt/wt) sodium cholate had increased AQP3, 7, and 8 levels, suggesting AQP involvement in bile acid diarrhea (BAD). Our aim was to compare AQP expressions in rectosigmoid mucosal (RSM) biopsies from patients with irritable bowel syndrome-diarrhea (IBS-D) (divided into those with normal or high fecal BA excretion) and in patients with IBS-constipation (IBS-C) compared with healthy controls. METHODS In RSM biopsies from 44 patients with IBS-D (with normal (<) or high (>2,337 μmol/48 hours (BAD)) fecal BA excretion), 10 patients with IBS-C, and 17 healthy controls, we measured expressions of AQP1, 3, 7, and 8, with RT-PCR (housekeeper gene GAPDH). We analyzed RNA for expression by RT-PCR assays, with expression calculated using 2-based fold-change. Comparisons of IBS groups were corrected for false detection rate (Bonferroni correction for 12 comparisons; P < 0.0042). AQP protein measurements on biopsies from 3 healthy controls, 3 patients with IBS-D, and 3 patients with BAD were performed by western blots (GAPDH housekeeping protein). RESULTS In RSM from patients with IBS-D (but not IBS-C), mRNA expression of AQP3 was decreased, and AQP7 and 8 were increased relative to controls. Fold differences were not different in IBS-D with or without BAD. Western blots confirmed increased expression of AQP7 and 8 and decreased AQP3 proteins in biopsies from patients with IBS-D compared with controls. CONCLUSIONS Increased AQP7 and 8 and decreased AQP3 expressions in RSM suggest that further studies on AQPs' potential role in the pathophysiology of diarrhea in IBS-D are warranted.

    更新日期:2019-11-01
  • Activated T-Follicular Helper 2 Cells Are Associated With Disease Activity in IgG4-Related Sclerosing Cholangitis and Pancreatitis.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-04-30
    Tamsin Cargill,Mateusz Makuch,Ross Sadler,Laura C Lighaam,Rory Peters,Marieke van Ham,Paul Klenerman,Adrian Bateman,Theo Rispens,Eleanor Barnes,Emma L Culver

    OBJECTIVES Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) and autoimmune pancreatitis (AIP) are characterized by an abundance of circulating and tissue IgG4-positive plasma cells. T-follicular helper (Tfh) cells are necessary for B-cell differentiation into plasma cells. We aimed at elucidating the presence and phenotype of Tfh cells and their relationship with disease activity in IgG4-SC/AIP. METHODS Circulating Tfh-cell subsets were characterized by multiparametric flow cytometry in IgG4-SC/AIP (n = 18), disease controls with primary sclerosing cholangitis (n = 8), and healthy controls (HCs, n = 9). Tissue Tfh cells were characterized in IgG4-SC/AIP (n = 12) and disease control (n = 10) specimens. Activated PD1+ Tfh cells were cocultured with CD27+ memory B cells to assess their capacity to support B-cell differentiation. Disease activity was assessed using the IgG4-responder index and clinical parameters. RESULTS Activated circulating PD-1+CXCR5+ Tfh cells were expanded in active vs inactive IgG4-SC/AIP, primary sclerosing cholangitis, and HC (P < 0.01), with enhanced PD-1 expression on all Tfh-cell subsets (Tfh1, P = 0.003; Tfh2, P = 0.0006; Th17, P = 0.003). Expansion of CD27+CD38+CD19lo plasmablasts in active disease vs HC (P = 0.01) correlated with the PD-1+ Tfh2 subset (r = 0.69, P = 0.03). Increased IL-4 and IL-21 cytokine production from stimulated cells of IgG4-SC/AIP, important in IgG4 class switch and proliferation, correlated with PD-1+ Tfh2 (r = 0.89, P = 0.02) and PD-1+ Tfh17 (r = 0.83, P = 0.03) subsets. Coculture of PD1+ Tfh with CD27+ B cells induced higher IgG4 expression than with PD1- Tfh (P = 0.008). PD-1+ Tfh2 cells were strongly associated with clinical markers of disease activity: sIgG4 (r = 0.70, P = 0.002), sIgE (r = 0.66, P = 0.006), and IgG4-responder index (r = 0.60, P = 0.006). Activated CXCR5+ Tfh cells homed to lymphoid follicles in IgG4-SC/AIP tissues. CONCLUSIONS Circulating and tissue-activated Tfh cells are expanded in IgG4-SC/AIP, correlate with disease activity, and can drive class switch and proliferation of IgG4-committed B cells. PD1+ Tfh2 cells may be a biomarker of active disease and a potential target for immunotherapy.

    更新日期:2019-11-01
  • Cyclooxygenase-2 and Cytosolic Phospholipase A2 Are Overexpressed in Mucinous Pancreatic Cysts.
    Clin. Transl. Gastroen. (IF 4.803) Pub Date : 2019-04-23
    Elsie T Mensah,Thomas Smyrk,Lizhi Zhang,Benjamin Bick,Christina M Wood-Wentz,Navtej Buttar,Suresh T Chari,Ferga C Gleeson,Michael Kendrick,Michael Levy,Randall Pearson,Bret T Petersen,Santhi Vege,Felicity Enders,Paul Limburg,Mark Topazian

    OBJECTIVES Expression of prostaglandin biosynthetic pathway enzymes in mucinous pancreatic cysts is unknown. Cyclooxygenase-2 (COX-2) inhibition is a potential cancer chemoprevention strategy for these lesions. We evaluated the expression of COX-2, cytosolic phospholipase A2 (cPLA2), and protein kinase B (AKT) in the epithelium of pancreatic cysts and correlated enzyme expression with aspirin (ASA) use and cyst fluid prostaglandin E2 (PGE2) concentration. METHODS Pathology of 80 resected pancreatic cysts was reviewed. Expression of COX-2, cPLA2, and AKT was quantified by tissue immunohistochemistry immunoreactivity scores (IRSs). IRS values were compared between cyst types and (in 30 cases) with matched cyst fluid PGE2 concentrations. RESULTS The mean IRS was higher in the epithelium of mucinous vs nonmucinous cysts for COX-2 (6.1 ± 4.7 vs 3.2 ± 2.8, P = 0.01) and cPLA2 (6.9 ± 3.0 vs 2.9 ± 2.9, P < 0.001). Cyst epithelial COX-2 expression was higher in mucinous cysts with low-grade dysplasia vs those with high-grade dysplasia or invasive carcinoma (IRS 8.0 ± 3.9 vs 1.5 ± 2.9, P < 0.001), whereas the opposite was found for cPLA2 (6.2 ± 3.0 vs 8.6 ± 2.3, P = 0.005). Cyst fluid PGE2 concentrations did not correlate with either the IRS or a history of low- to moderate-dose ASA use. CONCLUSIONS COX-2 and cPLA2 are overexpressed in the epithelium of mucinous pancreatic cysts. COX-2 and/or cPLA2 inhibition might prevent the emergence or progression of mucinous pancreatic cysts, but higher doses of ASA or nonsteroidal anti-inflammatory drugs may be necessary to substantially inhibit cyst epithelial COX-2 activity.

    更新日期:2019-11-01
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