Development of diagnostic criteria and a prognostic score for hepatitis B virus-related acute-on-chronic liver failure Gut (IF 16.658) Pub Date : 2017-09-28 Tianzhou Wu, Jiang Li, Li Shao, Jiaojiao Xin, Longyan Jiang, Qian Zhou, Dongyan Shi, Jing Jiang, Suwan Sun, Linfeng Jin, Ping Ye, Lingling Yang, Yinyun Lu, Tan Li, Jianrong Huang, Xiaowei Xu, Jiajia Chen, Shaorui Hao, Yuemei Chen, Shaojie Xin, Zhiliang Gao, Zhongping Duan, Tao Han, Yuming Wang, Jianhe Gan, Tingting Feng, Chen Pan, Yongping Chen, Hai Li, Yan Huang, Qing Xie, Shumei Lin, Lanjuan Li, Jun Li
Objective The definition of acute-on-chronic liver failure (ACLF) based on cirrhosis, irrespective of aetiology, remains controversial. This study aimed to clarify the clinicopathological characteristics of patients with hepatitis B virus-related ACLF (HBV-ACLF) in a prospective study and develop new diagnostic criteria and a prognostic score for such patients. Design The clinical data from 1322 hospitalised patients with acute decompensation of cirrhosis or severe liver injury due to chronic hepatitis B (CHB) at 13 liver centres in China were used to develop new diagnostic and prognostic criteria. Results Of the patients assessed using the Chronic Liver Failure Consortium criteria with the exception of cirrhosis, 391 patients with ACLF were identified: 92 with non-cirrhotic HBV-ACLF, 271 with cirrhotic HBV-ACLF and 28 with ACLF with cirrhosis caused by non-HBV aetiologies (non-HBV-ACLF). The short-term (28/90 days) mortality of the patients with HBV-ACLF were significantly higher than those of the patients with non-HBV-ACLF. Total bilirubin (TB) ≥12 mg/dL and an international normalised ratio (INR) ≥1.5 was proposed as an additional diagnostic indicator of HBV-ACLF, and 19.3% of patients with an HBV aetiology were additionally diagnosed with ACLF. The new prognostic score (0.741×INR+0.523×HBV-SOFA+0.026×age+0.003×TB) for short-term mortality was superior to five other scores based on both discovery and external validation studies. Conclusions Regardless of the presence of cirrhosis, patients with CHB, TB ≥12 mg/dL and INR ≥1.5 should be diagnosed with ACLF. The new criteria diagnosed nearly 20% more patients with an HBV aetiology with ACLF, thus increasing their opportunity to receive timely intensive management.
International development and validation of a classification system for the identification of Barrett’s neoplasia using acetic acid chromoendoscopy: the Portsmouth acetic acid classification (PREDICT) Gut (IF 16.658) Pub Date : 2017-09-28 Kesavan Kandiah, Fergus J Q Chedgy, Sharmila Subramaniam, Gaius Longcroft-Wheaton, Paul Bassett, Alessandro Repici, Prateek Sharma, Oliver Pech, Pradeep Bhandari
Background Barrett’s oesophagus is an established risk factor for developing oesophageal adenocarcinoma. However, Barrett’s neoplasia can be subtle and difficult to identify. Acetic acid chromoendoscopy (AAC) is a simple technique that has been demonstrated to highlight neoplastic areas but lesion recognition with AAC remains a challenge, thereby hampering its widespread use. Objective To develop and validate a simple classification system to identify Barrett’s neoplasia using AAC. Design The study was conducted in four phases: phase 1—development of component descriptive criteria; phase 2—development of a classification system; phase 3—validation of the classification system by endoscopists; and phase 4—validation of the classification system by non-endoscopists. Results Phases 1 and 2 led to the development of a simplified AAC classification system based on two criteria: focal loss of acetowhitening and surface patterns of Barrett’s mucosa. In phase 3, the application of PREDICT (Portsmouth acetic acid classification) by endoscopists improved the sensitivity and negative predictive value (NPV) from 79.3% and 80.2% to 98.1% and 97.4%, respectively (p<0.001). In phase 4, the application of PREDICT by non-endoscopists improved the sensitivity and NPV from 69.6% and 75.5% to 95.9% and 96.0%, respectively (p<0.001). Conclusion We developed and validated a classification system known as PREDICT for the diagnosis of Barrett’s neoplasia using AAC. The improvement seen in the sensitivity and NPV for detection of Barrett’s neoplasia in phase 3 demonstrates the clinical value of PREDICT and the similar improvement seen among non-endoscopists demonstrates the potential for generalisation of PREDICT once proven in real time.
Covered TIPS versus endoscopic band ligation plus propranolol for the prevention of variceal rebleeding in cirrhotic patients with portal vein thrombosis: a randomised controlled trial Gut (IF 16.658) Pub Date : 2017-09-28 Yong Lv, Xingshun Qi, Chuangye He, Zhengyu Wang, Zhanxin Yin, Jing Niu, Wengang Guo, Wei Bai, Hongbo Zhang, Huahong Xie, Liping Yao, Jianhong Wang, Tao Li, Qiuhe Wang, Hui Chen, Haibo Liu, Enxing Wang, Dongdong Xia, Bohan Luo, Xiaomei Li, Jie Yuan, Na Han, Ying Zhu, Jielai Xia, Hongwei Cai, Zhiping Yang, Kaichun Wu, Daiming Fan, Guohong Han
Objective Limited data are available on the prevention of variceal rebleeding in cirrhotic patients with portal vein thrombosis (PVT). This study aimed to compare transjugular intrahepatic portosystemic shunt (TIPS) with covered stents versus endoscopic band ligation (EBL) plus propranolol for the prevention of variceal rebleeding among patients with cirrhosis and PVT. Design Consecutive cirrhotic patients (94% Child-Pugh class A or B) with PVT who had variceal bleeding in the past 6 weeks were randomly assigned to TIPS group (n=24) or EBL plus propranolol group (EBL+drug, n=25), respectively. Primary endpoint was variceal rebleeding. Secondary endpoints included survival, overt hepatic encephalopathy (OHE), portal vein recanalisation and rethrombosis, other complications of portal hypertension and adverse events. Results During a median follow-up of 30 months in both groups, variceal rebleeding was significantly less frequent in the TIPS group (15% vs 45% at 1 year and 25% vs 50% at 2 years, respectively; HR=0.28, 95% CI 0.10 to 0.76, p=0.008), with a significantly higher portal vein recanalisation rate (95% vs 70%; p=0.03) and a relatively lower rethrombosis rate (5% vs 33%; p=0.06) compared with the EBL+drug group. There were no statistically significant differences in survival (67% vs 84%; p=0.152), OHE (25% vs 16%; p=0.440), other complications of portal hypertension and adverse events between groups. Conclusion Covered TIPS placement in patients with PVT and moderately decompensated cirrhosis was more effective than EBL combined with propranolol for the prevention of rebleeding, with a higher probability of PVT resolution without increasing the risk of OHE and adverse effects, but this benefit did not translate into improved survival. Trial registration number ClinicalTrials.gov: [NCT01326949]. : /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01326949&atom=%2Fgutjnl%2Fearly%2F2017%2F09%2F28%2Fgutjnl-2017-314634.atom
Resection of pancreatic cancer in Europe and USA: an international large-scale study highlighting large variations Gut (IF 16.658) Pub Date : 2017-11-20 Lei Huang, Lina Jansen, Yesilda Balavarca, Esther Molina-Montes, Masoud Babaei, Lydia van der Geest, Valery Lemmens, Liesbet Van Eycken, Harlinde De Schutter, Tom B Johannesen, Claus W Fristrup, Michael B Mortensen, Maja Primic-Žakelj, Vesna Zadnik, Nikolaus Becker, Thilo Hackert, Margit Mägi, Tiziana Cassetti, Romano Sassatelli, Robert Grützmann, Susanne Merkel, Ana F Gonçalves, Maria J Bento, Péter Hegyi, Gábor Lakatos, Andrea Szentesi, Michel Moreau, Tony van de Velde, Annegien Broeks, Milena Sant, Pamela Minicozzi, Vincenzo Mazzaferro, Francisco X Real, Alfredo Carrato, Xavier Molero, Marc G Besselink, Núria Malats, Markus W Büchler, Petra Schrotz-King, Hermann Brenner
Objective Resection can potentially cure resectable pancreatic cancer (PaC) and significantly prolong survival in some patients. This large-scale international study aimed to investigate variations in resection for PaC in Europe and USA and determinants for its utilisation. Design Data from six European population-based cancer registries and the US Surveillance, Epidemiology, and End Results Program database during 2003–2016 were analysed. Age-standardised resection rates for overall and stage I–II PaCs were computed. Associations between resection and demographic and clinical parameters were assessed using multivariable logistic regression models. Results A total of 153 698 records were analysed. In population-based registries in 2012–2014, resection rates ranged from 13.2% (Estonia) to 21.2% (Slovenia) overall and from 34.8% (Norway) to 68.7% (Denmark) for stage I–II tumours, with great international variations. During 2003–2014, resection rates only increased in USA, the Netherlands and Denmark. Resection was significantly less frequently performed with more advanced tumour stage (ORs for stage III and IV versus stage I–II tumours: 0.05–0.18 and 0.01–0.06 across countries) and increasing age (ORs for patients 70–79 and ≥80 versus those <60 years: 0.37–0.63 and 0.03–0.16 across countries). Patients with advanced-stage tumours (stage III–IV: 63.8%–81.2%) and at older ages (≥70 years: 52.6%–59.5%) receiving less frequently resection comprised the majority of diagnosed cases. Patient performance status, tumour location and size were also associated with resection application. Conclusion Rates of PaC resection remain low in Europe and USA with great international variations. Further studies are warranted to explore reasons for these variations.
Proton pump inhibitors and gastric cancer: a long expected side effect finally reported also in man Gut (IF 16.658) Pub Date : 2017-11-20 Helge Lyder Waldum, Reidar Fossmark
We read with interest the report by Cheung et al describing increased risk of gastric cancer in patients treated long-term proton pump inhibitor (PPI) after Helicobacter pylori eradication.1 On the same day, a Swedish study also reported increased risk of gastric cancer in patients having been treated long-term with PPI.2 Since cancers in general most often require decades to develop, the magnitude of the PPI-related cancer risk cannot be foreseen. For 30 years, we have worked with the role of gastrin and the risk of PPI treatment with respect to gastric cancer and published more than 200 papers and letters in this field. However, our publications have for one reason or the other been overseen and not discussed. On the other hand, since we always have concluded that PPI treatment in the long term would cause gastric cancer, it is strange that producers of PPIs have not done studies to dismiss our results. However, the …
Coeliac biopsies: numbers are valid, alphabets not Gut (IF 16.658) Pub Date : 2017-11-20 Kamran Rostami, Arzu Ensari, Carolina Ciacci, Amitabh Srivastava, Umberto Volta, Vincenzo Villanacci, Michael N Marsh
We thank Gut for requesting responses to this letter from Oberhuber and colleagues.1 We were amazed that they chose to dismiss our intraepithelial lymphocytes (IEL) data as invalid2 on grounds of not being age/gender matched with controls. But this disregards all the other data of clinicians and pathologists in the field, and the rigorous reviewing processes that our article went through before publication in Gut . This dismissal reflects an aberrant viewpoint1 lacking widespread support. In real life, pathologists do sign off biopsies, while diagnoses are rendered without full clinical details, although with appropriately worded caveats. We aimed, specifically, to reduce the enormous …
Modifiable factors associated with patient-reported pain during and after screening colonoscopy Gut (IF 16.658) Pub Date : 2017-09-28 Marek Bugajski, Paulina Wieszczy, Geir Hoff, Maciej Rupinski, Jaroslaw Regula, Michal Filip Kaminski
Objective Pain associated with colonoscopy is a major burden for patients. We investigated modifiable factors associated with patient-reported pain during and after colonoscopy. Design This cross-sectional analysis included database records from 23 centres participating in a population-based colonoscopy screening programme in Poland. Colonoscopies were performed under three sedation modalities: none, benzodiazepine-opioid sedation or propofol sedation. We used Gastronet (a validated tool) to assess patients’ pain during and after colonoscopy; pain was scored on a four-point scale (no, little, moderate or severe pain), with moderate to severe defined as painful. We used multivariate logistic regression models to estimate ORs for painful colonoscopy and calculated risk-adjusted ratios of painful colonoscopies per endoscopist and compared it to the mean rate. Results Of 35 216 screening colonoscopies in 2014 and 2015 included in our study, 22 725 (64.5%) patients returned valid Gastronet questionnaires. The proportion of examinations described as causing pain during (after) the procedure was 22.5% (14.2%) for unsedated, 19.9% (13.5%) for benzodiazepine-opioid sedation and 2.5% (7.5%) for propofol sedation. Propofol sedation, higher case volume of endoscopists, newest endoscope generation and adequate bowel preparation were significantly associated with lower odds of painful colonoscopy. Pain scores after colonoscopy showed similar associations. Adjusted pain rates during and after colonoscopy varied 11 and over 23-fold, respectively, between endoscopists. Conclusion We identified several independent, modifiable factors associated with pain during and after colonoscopy, of which individual endoscopist was the most important. Dedicated training should be considered to decrease variability among endoscopists.
An unusual gastric tumour with gastric outlet obstruction Gut (IF 16.658) Pub Date : 2017-09-28 I-Lin Frank Chen, Kai-Wen Liu, Tao-Qian Tang, Wen-Lun Wang
A 62-year-old male without significant medical history presented with intermittent epigastric pain and abdominal fullness for 2 months. He denied having bloody stool or weight loss. He visited the outpatient department, where the CT scan of abdomen was performed (figure 1). He then underwent oesophagogastroduodenoscopy (EGD), which revealed a subepithelial tumour at gastric antrum with obstruction of the pylorus (figure 2 and video in the online supplementary file 1). Endoscopic ultrasound sonography (EUS) was performed …
Gut roundtable meeting paper: selected recent advances in hepatocellular carcinoma Gut (IF 16.658) Pub Date : 2017-11-17 Alexander Gerbes, Fabien Zoulim, Herbert Tilg, Jean-François Dufour, Jordi Bruix, Valérie Paradis, Riad Salem, Markus Peck-Radosavljevic, Peter R Galle, Tim F Greten, Jean-Charles Nault, Matias A Avila
Hepatocellular carcinoma (HCC) ranks number three among the most frequent causes of death from solid tumors worldwide. With obesity and fatty liver diseases as risk factors on the rise, HCC represents an ever increasing challenge. While there is still no curative treatment for most patients numerous novel drugs have been proposed, but most ultimately failed in phase III trials. This manuscript targets therapeutic advances and most burning issues. Expert key point summaries and urgent research agenda are provided regarding risk factors, including microbiota, need for prognostic and predictive biomarkers and the equivocal role of liver biopsy. Therapeutic topics highlighted are locoregional techniques, combination therapies and the potential of immunotherapy. Finally the manuscript provides a critical evaluation of novel targets and strategies for personalized treatment of HCC.
Cumulative burden of inflammation predicts colorectal neoplasia risk in ulcerative colitis: a large single-centre study Gut (IF 16.658) Pub Date : 2017-11-17 Chang-Ho Ryan Choi, Ibrahim Al Bakir, Nik-Sheng (John) Ding, Gui-Han Lee, Alan Askari, Janindra Warusavitarne, Morgan Moorghen, Adam Humphries, Ana Ignjatovic-Wilson, Siwan Thomas-Gibson, Brian P Saunders, Matthew D Rutter, Trevor A Graham, Ailsa L Hart
Objective Ulcerative colitis (UC) is a dynamic disease with its severity continuously changing over time. We hypothesised that the risk of colorectal neoplasia (CRN) in UC closely follows an actuarial accumulative inflammatory burden, which is inadequately represented by current risk stratification strategies. Design This was a retrospective single-centre study. Patients with extensive UC who were under colonoscopic surveillance between 2003 and 2012 were studied. Each surveillance episode was scored for a severity of microscopic inflammation (0=no activity; 1=mild; 2=moderate; 3=severe activity). The cumulative inflammatory burden (CIB) was defined as sum of: average score between each pair of surveillance episodes multiplied by the surveillance interval in years. Potential predictors were correlated with CRN outcome using time-dependent Cox regression. Results A total of 987 patients were followed for a median of 13 years (IQR, 9–18), 97 (9.8%) of whom developed CRN. Multivariate analysis showed that the CIB was significantly associated with CRN development (HR, 2.1 per 10-unit increase in CIB (equivalent of 10, 5 or 3.3 years of continuous mild, moderate or severe active microscopic inflammation); 95% CI 1.4 to 3.0; P<0.001). Reflecting this, while inflammation severity based on the most recent colonoscopy alone was not significant (HR, 0.9 per-1-unit increase in severity; 95% CI 0.7 to 1.2; P=0.5), a mean severity score calculated from all colonoscopies performed in preceding 5 years was significantly associated with CRN risk (HR, 2.2 per-1-unit increase; 95% CI 1.6 to 3.1; P<0.001). Conclusion The risk of CRN in UC is significantly associated with accumulative inflammatory burden. An accurate CRN risk stratification should involve assessment of multiple surveillance episodes to take this into account.
A randomised trial of the effect of omega-3 polyunsaturated fatty acid supplements on the human intestinal microbiota Gut (IF 16.658) Pub Date : 2017-09-26 Henry Watson, Suparna Mitra, Fiona C Croden, Morag Taylor, Henry M Wood, Sarah L Perry, Jade A Spencer, Phil Quirke, Giles J Toogood, Clare L Lawton, Louise Dye, Paul M Loadman, Mark A Hull
Objective Omega-3 polyunsaturated fatty acids (PUFAs) have anticolorectal cancer (CRC) activity. The intestinal microbiota has been implicated in colorectal carcinogenesis. Dietary omega-3 PUFAs alter the mouse intestinal microbiome compatible with antineoplastic activity. Therefore, we investigated the effect of omega-3 PUFA supplements on the faecal microbiome in middle-aged, healthy volunteers (n=22).Design A randomised, open-label, cross-over trial of 8 weeks’ treatment with 4 g mixed eicosapentaenoic acid/docosahexaenoic acid in two formulations (soft-gel capsules and Smartfish drinks), separated by a 12-week ‘washout’ period. Faecal samples were collected at five time-points for microbiome analysis by 16S ribosomal RNA PCR and Illumina MiSeq sequencing. Red blood cell (RBC) fatty acid analysis was performed by liquid chromatography tandem mass spectrometry.Results Both omega-3 PUFA formulations induced similar changes in RBC fatty acid content, except that drinks were associated with a larger, and more prolonged, decrease in omega-6 PUFA arachidonic acid than the capsule intervention (p=0.02). There were no significant changes in α or β diversity, or phyla composition, associated with omega-3 PUFA supplementation. However, a reversible increased abundance of several genera, including Bifidobacterium , Roseburia and Lactobacillus was observed with one or both omega-3 PUFA interventions. Microbiome changes did not correlate with RBC omega-3 PUFA incorporation or development of omega-3 PUFA-induced diarrhoea. There were no treatment order effects.Conclusion Omega-3 PUFA supplementation induces a reversible increase in several short-chain fatty acid-producing bacteria, independently of the method of administration. There is no simple relationship between the intestinal microbiome and systemic omega-3 PUFA exposure.Trial registration number ISRCTN18662143.
DNA methylation defines regional identity of human intestinal epithelial organoids and undergoes dynamic changes during development Gut (IF 16.658) Pub Date : 2017-11-15 Judith Kraiczy, Komal M Nayak, Kate J Howell, Alexander Ross, Jessica Forbester, Camilla Salvestrini, Roxana Mustata, Sally Perkins, Amanda Andersson-Rolf, Esther Leenen, Anke Liebert, Ludovic Vallier, Philip C Rosenstiel, Oliver Stegle, Gordon Dougan, Robert Heuschkel, Bon-Kyoung Koo, Matthias Zilbauer
Objective Human intestinal epithelial organoids (IEOs) are increasingly being recognised as a highly promising translational research tool. However, our understanding of their epigenetic molecular characteristics and behaviour in culture remains limited.Design We performed genome-wide DNA methylation and transcriptomic profiling of human IEOs derived from paediatric/adult and fetal small and large bowel as well as matching purified human gut epithelium. Furthermore, organoids were subjected to in vitro differentiation and genome editing using CRISPR/Cas9 technology.Results We discovered stable epigenetic signatures which define regional differences in gut epithelial function, including induction of segment-specific genes during cellular differentiation. Established DNA methylation profiles were independent of cellular environment since organoids retained their regional DNA methylation over prolonged culture periods. In contrast to paediatric and adult organoids, fetal gut-derived organoids showed distinct dynamic changes of DNA methylation and gene expression in culture, indicative of an in vitro maturation. By applying CRISPR/Cas9 genome editing to fetal organoids, we demonstrate that this process is partly regulated by TET1, an enzyme involved in the DNA demethylation process. Lastly, generating IEOs from a child diagnosed with gastric heterotopia revealed persistent and distinct disease-associated DNA methylation differences, highlighting the use of organoids as disease-specific research models.Conclusions Our study demonstrates striking similarities of epigenetic signatures in mucosa-derived IEOs with matching primary epithelium. Moreover, these results suggest that intestinal stem cell-intrinsic DNA methylation patterns establish and maintain regional gut specification and are involved in early epithelial development and disease.
Adherent-invasive Escherichia coli in inflammatory bowel disease Gut (IF 16.658) Pub Date : 2017-11-15 Carolina Palmela, Caroline Chevarin, Zhilu Xu, Joana Torres, Gwladys Sevrin, Robert Hirten, Nicolas Barnich, Siew C Ng, Jean-Frederic Colombel
Intestinal microbiome dysbiosis has been consistently described in patients with IBD. In the last decades, Escherichia coli, and the adherent-invasive E coli (AIEC) pathotype in particular, has been implicated in the pathogenesis of IBD. Since the discovery of AIEC, two decades ago, progress has been made in unravelling these bacteria characteristics and its interaction with the gut immune system. The mechanisms of adhesion of AIEC to intestinal epithelial cells (via FimH and cell adhesion molecule 6) and its ability to escape autophagy when inside macrophages are reviewed here. We also explore the existing data on the prevalence of AIEC in patients with Crohn’s disease and UC, and the association between the presence of AIEC and disease location, activity and postoperative recurrence. Finally, we highlight potential therapeutic strategies targeting AIEC colonisation of gut mucosa, including the use of phage therapy, bacteriocins and antiadhesive molecules. These strategies may open new avenues for the prevention and treatment of IBD in the future.
Illusions regarding Helicobacter pylori clinical trials and treatment guidelines Gut (IF 16.658) Pub Date : 2017-12-01 David Y Graham
Identification of reliable Helicobacter pylori eradication therapy has proved difficult, in part because brief exposure of H. pylori to commonly used antimicrobials such as macrolides, nitroimidazoles or quinolones often results in resistance (bystander effect). Most treatment studies and meta-analyses contains major flaws preventing generalisability that making reliable treatment recommendations and guidelines an illusion (box 1).Box 1 ### Helicobacter pylori treatment illusions Development of H. pylori therapy differs from other infectious diseases. Since the advent of antibiotics, infectious diseases therapy has been susceptibility based, whereas most H. pylori treatment guidelines recommend susceptibility testing only after two empiric therapy failures. Increased penicillin resistance in the 1970s prompted rapid changes in recommendations and the development of antimicrobial surveillance programme to regularly update recommendations thus allowing empirical therapies to remain effective.1 Despite increasing resistance, H. pylori treatment guidelines have continued to recommend increasingly ineffective therapies and most new empiric therapies consist of variations using those same drugs (eg, sequential therapy). Treatment success has focused on comparisons between regimens irrespective of cure rates and without consideration of the antibiotic susceptibility profile of the infection, thus producing illusions of success. For example, sequential therapy consists of 5 days of dual proton pump inhibitor (PPI)–amoxicillin therapy followed by 5 days of PPI–clarithromycin and metronidazole triple therapy (Bazzoli’s triple therapy).2 Interestingly, sequential therapy …
Gastro-oesophageal reflux events: just another trigger in chronic cough? Gut (IF 16.658) Pub Date : 2017-12-01 L A Houghton, J A Smith
GORD is considered a common cause of chronic cough, either alone or in association with nasal disease and/or asthma.1 This, along with the fact that there are currently no specific therapies approved for the treatment of chronic cough, has led to extensive use of acid suppressants, such that one US study in patients with extraoesophageal manifestations of GORD, of which 50% had cough, estimated costs to be four to five times those associated with their use in typical GORD.2 Despite this widespread use, a significant proportion of patients with chronic cough thought to be due to GORD remain refractory to acid suppression. Indeed, multiple studies and meta-analyses have failed to document a therapeutic benefit of acid suppression in chronic cough.3 A growing number of studies suggest that in 30%–48% of patients, coughing episodes seem to be temporally linked to reflux events, irrespective of their acidity or the presence of other conditions contributing to coughing.1 ,4 ,5 Notably, patients exhibiting such associations, that is, a positive symptom association probability (SAP) for cough preceded by reflux (SAPR-C), appear to have no more erosive disease or oesophageal exposure to reflux, with little reaching the proximal oesophagus, than those with a negative SAPR-C.5 SAPR-C-positive patients, however, do have a heightened cough …
Janus-like monocytes regulate postoperative ileus Gut (IF 16.658) Pub Date : 2017-12-01 Allan McI Mowat
In Gut , Farro et al and Pohl et al present new findings on the role of myeloid cells in postoperative ileus (POI).1 2 POI is a frequent consequence of abdominal surgery that can lead to costly delays in patient recovery.3 The failure of peristalsis reflects paralysis of the smooth muscles of the intestine and several studies have suggested that this is dependent on macrophages in the muscularis externa (ME) layer of the gut wall that produce nitric oxide (NO).4 The intestine contains one of the largest pools of macrophages in the body, the majority of which is located in the lamina propria (LP) of the mucosa, near the epithelium. However macrophages are also present between the longitudinal and circular muscle layers of the ME, where they are in close proximity to the myenteric plexus.5 6 Recent studies indicate that LP and ME macrophages are phenotypically and functionally distinct under steady-state conditions.6 In particular, ME macrophages appear to have specialised tissue protection functions, including the production of factors such as bone morphogenic protein-2 (BMP2) that promote neuronal growth. In return, β2-adrenergic receptors on ME macrophages allow them to be sustained by sympathetic neurons and these two-way interactions are at least partly dependent on the local microbiota.6 …
SENP1 activity sustains cancer stem cell in hypoxic HCC Gut (IF 16.658) Pub Date : 2017-12-01 Alice Conigliaro, Marco Tripodi, Maurizio Parola
Hepatocellular carcinoma (HCC) represents the fifth most common cancer and the third leading cause of cancer mortality worldwide, with a minority of patients surviving at 5 years from diagnosis, despite treatment.1 HCC usually develops in conditions of chronic liver disease (CLD), mostly on the background of a cirrhotic liver, with liver transplantation at present being the only treatment strategy to cure both HCC and the specific CLD. All the other therapeutic strategies, because of the underlying liver cirrhosis, have to take into account, and may be limited in their feasibility, by the residual liver function of the individual patient, a critical parameter affecting the patient's prognosis.2 Indeed, even when the surgical intervention is feasible, according to current guidelines, efficient removal of the primary lesions is not often conclusive since intrahepatic recurrence, as well as extrahepatic metastasis, are very frequent and associated with poor prognosis for patients.3 Along these lines, current literature suggests that both the progression of CLD towards HCC development as well as HCC progression and acquisition of resistance to therapy are highly affected by the microenvironment, in which several cells (including tumour-associated macrophages or fibroblasts and cancer stem cells (CSCs)), inflammation, fibrosis as well as hypoxia, oxidative stress and autophagy are believed to play a critical role.4 In particular, hepatic hypoxia (ie, very common in CLD and HCC) and hypoxia-inducible factors (HIFs) are currently believed to be major determinant players that, in agreement with data in other tumours, can contribute to cancer development and progression by promoting and/or modulating transcriptional programmes (metabolic adaptation, …
Prioritising treatment among people who inject drugs in order to eliminate hepatitis C: addressing reluctance with sound economic analyses Gut (IF 16.658) Pub Date : 2017-12-01 Yvan J-F Hutin, Stefan Z Wiktor
In May 2016, the World Health Assembly, the governing body of WHO, endorsed the first-ever global hepatitis strategy.1 This document, termed the Global Health Sector Strategy on Viral Hepatitis (GHSS-VH), proposes ambitious prevention and treatment targets with the ultimate goal of eliminating hepatitis as a public health threat by 2030. The GHSS-VH defines elimination as a 90% reduction in incidence of chronic HBV and HCV infections and a 65% reduction in hepatitis-related mortality. Achieving the goals of the global strategy will require scaling up prevention and treatment services, which in turn will require increases in financial resources and political commitment. In addition, national health planners will need to decide how best to allocate these resources so that they have maximal impact. A solid understanding of the epidemiology of hepatitis infection in the country, in particular identifying groups at highest risk of infection and those at highest risk of death should be the basis of a sound national treatment plan that can meet the incidence and mortality goals of GHSS-VH. In this issue, Scott et al 2 developed a mathematical model to study which treatment strategies would most effectively and efficiently eliminate hepatitis C in Australia, based on the WHO strategy's goals. As in most high-income countries, HCV infection …
Lumen-apposing metal stents (LAMS) for pancreatic fluid collection (PFC) drainage: may not be business as usual Gut (IF 16.658) Pub Date : 2017-12-01 Ji Young Bang, Muhammad Hasan, Udayakumar Navaneethan, Robert Hawes, Shyam Varadarajulu
Lumen-apposing metal stents (LAMS) have been recently developed to improve treatment outcomes in the endoscopic management of pancreatic fluid collections (PFC), particularly in walled-off necrosis (WON), to facilitate better drainage of necrotic contents and minimise the risk of perforation and peritoneal leakage. In an ongoing randomised trial, we observed serious adverse events that included delayed bleeding, buried stent syndrome and biliary stricture that necessitated a change in the management protocol for patients with PFC treated with LAMS. Randomised trials comparing endoscopic and surgical techniques for the management of PFCs have favoured the endoscopic approach.1 ,2 Endoscopy is less expensive, associated with shorter hospital stay and the clinical outcomes are comparable. To compare the clinical outcomes of patients undergoing endoscopic drainage of WON using LAMS or plastic stents, a randomised trial (NCT02685865) was initiated at our institution. Included in the study were patients with symptomatic WON measuring >6 cm in size and located adjacent to the gastric or duodenal lumen. Excluded were patients with pseudocysts, WON inaccessible for endoscopic ultrasound-guided drainage and irreversible coagulopathy. The LAMS (Hot AXIOS, Boston Scientific) used in this trial had a single-step cautery-tipped delivery system with dimensions of 15 mm (diameter) by 10 mm (length). In the plastic stent cohort, two 7 Fr by 4 cm double pigtail stents were deployed after dilation of the transmural tract to 12 mm. Per study protocol, a follow-up CT was obtained at 4–6 weeks after the index intervention to assess treatment response with treatment success defined as resolution of WON to <3 cm in conjunction with symptom relief. The main outcome measure was to compare the median number of interventions required to achieve treatment success. The secondary outcome measures were to compare the rates of treatment success and clinical and stent-related adverse events. The total sample size was estimated at 62 patients. In this ongoing …
Determinants of reflux-induced chronic cough Gut (IF 16.658) Pub Date : 2017-12-01 Thomas V K Herregods, Ans Pauwels, Jafar Jafari, Daniel Sifrim, Albert J Bredenoord, Jan Tack, André J P M Smout
Objective Gastro-oesophageal reflux is considered to be an important contributing factor in chronic unexplained cough. It remains unclear why some reflux episodes in the same patient causes cough while others do not. To understand more about the mechanism by which reflux induces cough, we aimed to identify factors which are important in triggering cough. Design In this multicentre study, 49 patients with reflux-associated chronic cough were analysed using 24-hour pH-impedance-pressure monitoring. The characteristics of reflux episodes that were followed by cough were compared with reflux episodes not associated with cough. Results The majority (72.4%) of the reflux episodes were acidic (pH<4). Compared with reflux episodes that were not followed by cough, reflux episodes that were followed by a cough burst were associated with a higher proximal extent (p=0.0001), a higher volume clearance time (p=0.002) and a higher acid burden in the preceding 15 min window (p=0.019) and higher reflux burden in the preceding 30 min window (p=0.044). No significant difference was found between the two groups when looking at the nadir pH, the pH drop, the acid clearance time or the percentage of reflux episodes which were acidic. Conclusions The presence of a larger volume of refluxate and oesophageal exposure to reflux for a longer period of time seems to play an important role in inducing cough, while the acidity of the refluxate seems to be less relevant. This helps explain the observation that most patients with chronic cough tend not to benefit from acid inhibitory treatment.
Discrepancies between patient-reported outcomes, and endoscopic and histological appearance in UC Gut (IF 16.658) Pub Date : 2017-12-01 Jean-Frédéric Colombel, Mary E Keir, Alexis Scherl, Rui Zhao, Gert de Hertogh, William A Faubion, Timothy T Lu
Objective Both endoscopy and histology may be included in the definition of mucosal healing in UC. This study aimed to establish the association between patient-reported outcomes, specifically symptom measures, and the presence of inflammation as measured by endoscopy and histology in UC. Design Using patient data from an observational multicentre study of UC (n=103), rectal bleeding (RB) and stool frequency (SF) symptom subscores of the Mayo Clinic Score (MCS) were compared with the endoscopic subscore (MCSe) and histology. Faecal calprotectin and biopsy cytokine expression were also evaluated. Results When identifying UC patients with inactive disease, RB scores were superior to SF scores and the combination (sensitivity/specificity: MCSe=0/1, RB 77%/81%, SF 62%/95%, RB+SF 54%/95%; MCSe=0, RB 87%/66%, SF 76%/83%, RB+SF 68%/86%). Across different definitions of mucosal healing (MCSe≤1; 0; or 0 plus inactive histology), a larger subset of patients reported increased SF (39%, 25% and 27%, respectively) compared with RB (24%, 13% and 10%). Faecal calprotectin and inflammatory cytokine expression were higher in patients with active disease compared with patients with mucosal healing, but there were no differences between patients using increasingly stringent definitions of mucosal healing. Conclusions Endoscopically inactive disease is associated with absence of RB but not with complete normalisation of SF. Achieving histological remission did not improve symptomatic relief. In addition, in these patients, higher inflammatory biomarker levels were not observed. These data suggest that non-inflammatory changes, such as bowel damage, may contribute to SF in UC.
Alterations in the epithelial stem cell compartment could contribute to permanent changes in the mucosa of patients with ulcerative colitis Gut (IF 16.658) Pub Date : 2017-12-01 Isabella Dotti, Rut Mora-Buch, Elena Ferrer-Picón, Núria Planell, Peter Jung, M Carme Masamunt, Raquel Franco Leal, Javier Martín de Carpi, Josep Llach, Ingrid Ordás, Eduard Batlle, Julián Panés, Azucena Salas
Objective UC is a chronic inflammatory disease of the colonic mucosa. Growing evidence supports a role for epithelial cell defects in driving pathology. Moreover, long-lasting changes in the epithelial barrier have been reported in quiescent UC. Our aim was to investigate whether epithelial cell defects could originate from changes in the epithelial compartment imprinted by the disease. Design Epithelial organoid cultures (EpOCs) were expanded ex vivo from the intestinal crypts of non-IBD controls and patients with UC. EpOCs were induced to differentiate (d-EpOCs), and the total RNA was extracted for microarray and quantitative real-time PCR (qPCR) analyses. Whole intestinal samples were used to determine mRNA expression by qPCR, or protein localisation by immunostaining. Results EpOCs from patients with UC maintained self-renewal potential and the capability to give rise to differentiated epithelial cell lineages comparable with control EpOCs. Nonetheless, a group of genes was differentially regulated in the EpOCs and d-EpOCs of patients with UC, including genes associated with antimicrobial defence (ie, LYZ , PLA2G2A ), with secretory (ie, ZG16 , CLCA1 ) and absorptive (ie, AQP8 , MUC12 ) functions, and with a gastric phenotype (ie, ANXA10 , CLDN18 and LYZ ). A high rate of concordance was found in the expression profiles of the organoid cultures and whole colonic tissues from patients with UC. Conclusions Permanent changes in the colonic epithelium of patients with UC could be promoted by alterations imprinted in the stem cell compartment. These changes may contribute to perpetuation of the disease.
ROC-king onwards: intraepithelial lymphocyte counts, distribution & role in coeliac disease mucosal interpretation Gut (IF 16.658) Pub Date : 2017-12-01 Kamran Rostami, Michael N Marsh, Matt W Johnson, Hamid Mohaghegh, Calvin Heal, Geoffrey Holmes, Arzu Ensari, David Aldulaimi, Brigitte Bancel, Gabrio Bassotti, Adrian Bateman, Gabriel Becheanu, Anna Bozzola, Antonio Carroccio, Carlo Catassi, Carolina Ciacci, Alexandra Ciobanu, Mihai Danciu, Mohammad H Derakhshan, Luca Elli, Stefano Ferrero, Michelangelo Fiorentino, Marilena Fiorino, Azita Ganji, Kamran Ghaffarzadehgan, James J Going, Sauid Ishaq, Alessandra Mandolesi, Sherly Mathews, Roxana Maxim, Chris J Mulder, Andra Neefjes-Borst, Marie Robert, Ilaria Russo, Mohammad Rostami-Nejad, Angelo Sidoni, Masoud Sotoudeh, Vincenzo Villanacci, Umberto Volta, Mohammad R Zali, Amitabh Srivastava
Objectives Counting intraepithelial lymphocytes (IEL) is central to the histological diagnosis of coeliac disease (CD), but no definitive ‘normal’ IEL range has ever been published. In this multicentre study, receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off between normal and CD (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens. Design The study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centres, eight countries of three continents, recruited 198 patients with Marsh III histology and 203 controls and used one agreed protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. Demographic and serological data were also collected. Results The mean ages of CD and control groups were 45.5 (neonate to 82) and 38.3 (2–88) years. Mean IEL count was 54±18/100 enterocytes in CD and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the subclassification of the Marsh III lesion. Conclusion Our ROC curve analyses demonstrate that for Marsh III lesions, a cut-off of 25 IEL/100 enterocytes optimises discrimination between normal control and CD biopsies. No differences in IEL counts were found between Marsh III a, b and c lesions. There was an indication of a continuously graded dose–response by IEL to environmental (gluten) antigenic influence.
Uncoupling of mucosal gene regulation, mRNA splicing and adherent microbiota signatures in inflammatory bowel disease Gut (IF 16.658) Pub Date : 2017-12-01 Robert Häsler, Raheleh Sheibani-Tezerji, Anupam Sinha, Matthias Barann, Ateequr Rehman, Daniela Esser, Konrad Aden, Carolin Knecht, Berenice Brandt, Susanna Nikolaus, Sascha Schäuble, Christoph Kaleta, Andre Franke, Christoph Fretter, Werner Müller, Marc-Thorsten Hütt, Michael Krawczak, Stefan Schreiber, Philip Rosenstiel
Objective An inadequate host response to the intestinal microbiota likely contributes to the manifestation and progression of human inflammatory bowel disease (IBD). However, molecular approaches to unravelling the nature of the defective crosstalk and its consequences for intestinal metabolic and immunological networks are lacking. We assessed the mucosal transcript levels, splicing architecture and mucosa-attached microbial communities of patients with IBD to obtain a comprehensive view of the underlying, hitherto poorly characterised interactions, and how these are altered in IBD. Design Mucosal biopsies from Crohn's disease and patients with UC, disease controls and healthy individuals (n=63) were subjected to microbiome, transcriptome and splicing analysis, employing next-generation sequencing. The three data levels were integrated by different bioinformatic approaches, including systems biology-inspired network and pathway analysis. Results Microbiota, host transcript levels and host splicing patterns were influenced most strongly by tissue differences, followed by the effect of inflammation. Both factors point towards a substantial disease-related alteration of metabolic processes. We also observed a strong enrichment of splicing events in inflamed tissues, accompanied by an alteration of the mucosa-attached bacterial taxa. Finally, we noted a striking uncoupling of the three molecular entities when moving from healthy individuals via disease controls to patients with IBD. Conclusions Our results provide strong evidence that the interplay between microbiome and host transcriptome, which normally characterises a state of intestinal homeostasis, is drastically perturbed in Crohn's disease and UC. Consequently, integrating multiple OMICs levels appears to be a promising approach to further disentangle the complexity of IBD.
CCR2-dependent monocyte-derived macrophages resolve inflammation and restore gut motility in postoperative ileus Gut (IF 16.658) Pub Date : 2017-12-01 Giovanna Farro, Michelle Stakenborg, Pedro J Gomez-Pinilla, Evelien Labeeuw, Gera Goverse, Martina Di Giovangiulio, Nathalie Stakenborg, Elisa Meroni, Francesca D’Errico, Yvon Elkrim, Damya Laoui, Zofia M Lisowski, Kristin A Sauter, David A Hume, Jo A Van Ginderachter, Guy E Boeckxstaens, Gianluca Matteoli
Objective Postoperative ileus (POI) is assumed to result from myeloid cells infiltrating the intestinal muscularis externa (ME) in patients undergoing abdominal surgery. In the current study, we investigated the role of infiltrating monocytes in a murine model of intestinal manipulation (IM)-induced POI in order to clarify whether monocytes mediate tissue damage and intestinal dysfunction or they are rather involved in the recovery of gastrointestinal (GI) motility. Design IM was performed in mice with defective monocyte migration to tissues (C-C motif chemokine receptor 2, Ccr2−/ − mice) and wild-type (WT) mice to study the role of monocytes and monocyte-derived macrophages (MΦs) during onset and resolution of ME inflammation. Results At early time points, IM-induced GI transit delay and inflammation were equal in WT and Ccr2 − / − mice. However, GI transit recovery after IM was significantly delayed in Ccr2 − / − mice compared with WT mice, associated with increased neutrophil-mediated immunopathology and persistent impaired neuromuscular function. During recovery, monocyte-derived MΦs acquire pro-resolving features that aided in the resolution of inflammation. In line, bone marrow reconstitution and treatment with MΦ colony-stimulating factor 1 enhanced monocyte recruitment and MΦ differentiation and ameliorated GI transit in Ccr2 − / − mice. Conclusion Our study reveals a critical role for monocyte-derived MΦs in restoring intestinal homeostasis after surgical trauma. From a therapeutic point of view, our data indicate that inappropriate targeting of monocytes may increase neutrophil-mediated immunopathology and prolong the clinical outcome of POI, while future therapies should be aimed at enhancing MΦ physiological repair functions.
Irf4-dependent CD103+CD11b+ dendritic cells and the intestinal microbiome regulate monocyte and macrophage activation and intestinal peristalsis in postoperative ileus Gut (IF 16.658) Pub Date : 2017-12-01 Judith-Mira Pohl, Sebastian Gutweiler, Stephanie Thiebes, Julia K Volke, Ludger Klein-Hitpass, Denise Zwanziger, Matthias Gunzer, Steffen Jung, William W Agace, Christian Kurts, Daniel Robert Engel
Objective Postoperative ileus (POI), the most frequent complication after intestinal surgery, depends on dendritic cells (DCs) and macrophages. Here, we have investigated the mechanism that activates these cells and the contribution of the intestinal microbiota for POI induction. Design POI was induced by manipulating the intestine of mice, which selectively lack DCs, monocytes or macrophages. The disease severity in the small and large intestine was analysed by determining the distribution of orally applied fluorescein isothiocyanate-dextran and by measuring the excretion time of a retrogradely inserted glass ball. The impact of the microbiota on intestinal peristalsis was evaluated after oral antibiotic treatment. Results We found that Cd11c-Cre+ Irf4flox/flox mice lack CD103+CD11b+ DCs, a DC subset unique to the intestine whose function is poorly understood. Their absence in the intestinal muscularis reduced pathogenic inducible nitric oxide synthase (iNOS) production by monocytes and macrophages and ameliorated POI. Pathogenic iNOS was produced in the jejunum by resident Ly6C– macrophages and infiltrating chemokine receptor 2-dependent Ly6C+ monocytes, but in the colon only by the latter demonstrating differential tolerance mechanisms along the intestinal tract. Consistently, depletion of both cell subsets reduced small intestinal POI, whereas the depletion of Ly6C+ monocytes alone was sufficient to prevent large intestinal POI. The differential role of monocytes and macrophages in small and large intestinal POI suggested a potential role of the intestinal microbiota. Indeed, antibiotic treatment reduced iNOS levels and ameliorated POI. Conclusions Our findings reveal that CD103+CD11b+ DCs and the intestinal microbiome are a prerequisite for the activation of intestinal monocytes and macrophages and for dysregulating intestinal motility in POI.
Stress activates pronociceptive endogenous opioid signalling in DRG neurons during chronic colitis Gut (IF 16.658) Pub Date : 2017-12-01 Raquel Guerrero-Alba, Eduardo E Valdez-Morales, Nestor N Jimenez-Vargas, Cintya Lopez-Lopez, Josue Jaramillo-Polanco, Takanobu Okamoto, Yasmin Nasser, Nigel W Bunnett, Alan E Lomax, Stephen J Vanner
Aims and background Psychological stress accompanies chronic inflammatory diseases such as IBD, and stress hormones can exacerbate pain signalling. In contrast, the endogenous opioid system has an important analgesic action during chronic inflammation. This study examined the interaction of these pathways. Methods Mouse nociceptive dorsal root ganglia (DRG) neurons were incubated with supernatants from segments of inflamed colon collected from patients with chronic UC and mice with dextran sodium sulfate (cDSS)-induced chronic colitis. Stress effects were studied by adding stress hormones (epinephrine and corticosterone) to dissociated neurons or by exposing cDSS mice to water avoidance stress. Changes in excitability of colonic DRG nociceptors were measured using patch clamp and Ca2+ imaging techniques. Results Supernatants from patients with chronic UC and from colons of mice with chronic colitis caused a naloxone-sensitive inhibition of neuronal excitability and capsaicin-evoked Ca2+ responses. Stress hormones decreased signalling induced by human and mouse supernatants. This effect resulted from stress hormones signalling directly to DRG neurons and indirectly through signalling to the immune system, leading to decreased opioid levels and increased acute inflammation. The net effect of stress was a change endogenous opioid signalling in DRG neurons from an inhibitory to an excitatory effect. This switch was associated with a change in G protein-coupled receptor excitatory signalling to a pathway sensitive to inhibitors of protein kinase A-protein, phospholipase C-protein and G protein βϒ subunits. Conclusions Stress hormones block the inhibitory actions of endogenous opioids and can change the effect of opioid signalling in DRG neurons to excitation. Targeting these pathways may prevent heavy opioid use in IBD.
Subclonal diversity arises early even in small colorectal tumours and contributes to differential growth fates Gut (IF 16.658) Pub Date : 2017-12-01 Chelsie K Sievers, Luli S Zou, Perry J Pickhardt, Kristina A Matkowskyj, Dawn M Albrecht, Linda Clipson, Jeffery W Bacher, B Dustin Pooler, Fouad J Moawad, Brooks D Cash, Mark Reichelderfer, Tien N Vo, Michael A Newton, Bret R Larget, Richard B Halberg
Objective and design The goal of the study was to determine whether the mutational profile of early colorectal polyps correlated with growth behaviour. The growth of small polyps (6–9 mm) that were first identified during routine screening of patients was monitored over time by interval imaging with CT colonography. Mutations in these lesions with known growth rates were identified by targeted next-generation sequencing. The timing of mutational events was estimated using computer modelling and statistical inference considering several parameters including allele frequency and fitness. Results The mutational landscape of small polyps is varied both within individual polyps and among the group as a whole but no single alteration was correlated with growth behaviour. Polyps carried 0–3 pathogenic mutations with the most frequent being in APC , KRAS/NRAS , BRAF , FBXW7 and TP53 . In polyps with two or more pathogenic mutations, allele frequencies were often variable, indicating the presence of multiple populations within a single tumour. Based on computer modelling, detectable mutations occurred at a mean polyp size of 30±35 crypts, well before the tumour is of a clinically detectable size. Conclusions These data indicate that small colon polyps can have multiple pathogenic mutations in crucial driver genes that arise early in the existence of a tumour. Understanding the molecular pathway of tumourigenesis and clonal evolution in polyps that are at risk for progressing to invasive cancers will allow us to begin to better predict which polyps are more likely to progress into adenocarcinomas and which patients are at greater risk of developing advanced disease.
BCL-2 system analysis identifies high-risk colorectal cancer patients Gut (IF 16.658) Pub Date : 2017-12-01 Andreas U Lindner, Manuela Salvucci, Clare Morgan, Naser Monsefi, Alexa J Resler, Mattia Cremona, Sarah Curry, Sinead Toomey, Robert O'Byrne, Orna Bacon, Michael Stühler, Lorna Flanagan, Richard Wilson, Patrick G Johnston, Manuel Salto-Tellez, Sophie Camilleri-Broët, Deborah A McNamara, Elaine W Kay, Bryan T Hennessy, Pierre Laurent-Puig, Sandra Van Schaeybroeck, Jochen H M Prehn
Objective The mitochondrial apoptosis pathway is controlled by an interaction of multiple BCL-2 family proteins, and plays a key role in tumour progression and therapy responses. We assessed the prognostic potential of an experimentally validated, mathematical model of BCL-2 protein interactions (DR_MOMP) in patients with stage III colorectal cancer (CRC). Design Absolute protein levels of BCL-2 family proteins were determined in primary CRC tumours collected from n=128 resected and chemotherapy-treated patients with stage III CRC. We applied DR\_MOMP to categorise patients as high or low risk based on model outputs, and compared model outputs with known prognostic factors (T-stage, N-stage, lymphovascular invasion). DR\_MOMP signatures were validated on protein of n=156 patients with CRC from the Cancer Genome Atlas (TCGA) project. Results High-risk stage III patients identified by DR\_MOMP had an approximately fivefold increased risk of death compared with patients identified as low risk (HR 5.2, 95% CI 1.4 to 17.9, p=0.02). The DR\_MOMP signature ranked highest among all molecular and pathological features analysed. The prognostic signature was validated in the TCGA colon adenocarcinoma (COAD) cohort (HR 4.2, 95% CI 1.1 to 15.6, p=0.04). DR_MOMP also further stratified patients identified by supervised gene expression risk scores into low-risk and high-risk categories. BCL-2-dependent signalling critically contributed to treatment responses in consensus molecular subtypes 1 and 3, linking for the first time specific molecular subtypes to apoptosis signalling. Conclusions DR_MOMP delivers a system-based biomarker with significant potential as a prognostic tool for stage III CRC that significantly improves established histopathological risk factors.
SENP1 promotes hypoxia-induced cancer stemness by HIF-1α deSUMOylation and SENP1/HIF-1α positive feedback loop Gut (IF 16.658) Pub Date : 2017-12-01 Chun-Ping Cui, Carmen Chak-Lui Wong, Alan Ka-Lun Kai, Daniel Wai-Hung Ho, Eunice Yuen-Ting Lau, Yu-Man Tsui, Lo-Kong Chan, Tan-To Cheung, Kenneth Siu-Ho Chok, Albert C Y Chan, Regina Cheuk-Lam Lo, Joyce Man-Fong Lee, Terence Kin-Wah Lee, Irene Oi Lin Ng
Objective We investigated the effect and mechanism of hypoxic microenvironment and hypoxia-inducible factors (HIFs) on hepatocellular carcinoma (HCC) cancer stemness. Design HCC cancer stemness was analysed by self-renewal ability, chemoresistance, expression of stemness-related genes and cancer stem cell (CSC) marker-positive cell population. Specific small ubiquitin-like modifier (SUMO) proteases 1 (SENP1) mRNA level was examined with quantitative PCR in human paired HCCs. Immunoprecipitation was used to examine the binding of proteins and chromatin immunoprecipitation assay to detect the binding of HIFs with hypoxia response element sequence. In vivo characterisation was performed in immunocompromised mice and stem cell frequency was analysed. Results We showed that hypoxia enhanced the stemness of HCC cells and hepatocarcinogenesis through enhancing HIF-1α deSUMOylation by SENP1 and increasing stabilisation and transcriptional activity of HIF-1α. Furthermore, we demonstrated that SENP1 is a direct target of HIF-1/2α and a previously unrecognised positive feedback loop exists between SENP1 and HIF-1α. Conclusions Taken together, our findings suggest the significance of this positive feedback loop between HIF-1α and SENP1 in contributing to the increased cancer stemness in HCC and hepatocarcinogenesis under hypoxia. Drugs that specifically target SENP1 may offer a potential novel therapeutic approach for HCC.
Lysophosphatidylcholine acyltransferase 1 is downregulated by hepatitis C virus: impact on production of lipo-viro-particles Gut (IF 16.658) Pub Date : 2017-12-01 Frauke Beilstein, Matthieu Lemasson, Véronique Pène, Dominique Rainteau, Sylvie Demignot, Arielle R Rosenberg
Objective HCV is intimately linked with the liver lipid metabolism, devoted to the efflux of triacylglycerols stored in lipid droplets (LDs) in the form of triacylglycerol-rich very-low-density lipoproteins (VLDLs): (i) the most infectious HCV particles are those of lowest density due to association with triacylglycerol-rich lipoproteins and (ii) HCV-infected patients frequently develop hepatic steatosis (increased triacylglycerol storage). The recent identification of lysophosphatidylcholine acyltransferase 1 (LPCAT1) as an LD phospholipid-remodelling enzyme prompted us to investigate its role in liver lipid metabolism and HCV infectious cycle. Design Huh-7.5.1 cells and primary human hepatocytes (PHHs) were infected with JFH1-HCV. LPCAT1 depletion was achieved by RNA interference. Cells were monitored for LPCAT1 expression, lipid metabolism and HCV production and infectivity. The density of viral particles was assessed by isopycnic ultracentrifugation. Results Upon HCV infection, both Huh-7.5.1 cells and PHH had decreased levels of LPCAT1 transcript and protein, consistent with transcriptional downregulation. LPCAT1 depletion in either naive or infected Huh-7.5.1 cells resulted in altered lipid metabolism characterised by LD remodelling, increased triacylglycerol storage and increased secretion of VLDL. In infected Huh-7.5.1 cells or PHH, LPCAT1 depletion increased production of the viral particles of lowest density and highest infectivity. Conclusions We have identified LPCAT1 as a modulator of liver lipid metabolism downregulated by HCV, which appears as a viral strategy to increase the triacylglycerol content and hence infectivity of viral particles. Targeting this metabolic pathway may represent an attractive therapeutic approach to reduce both the viral titre and hepatic steatosis.
A genetic roadmap of pancreatic cancer: still evolving Gut (IF 16.658) Pub Date : 2017-12-01 Faiyaz Notta, Stephan A Hahn, Francisco X Real
A diagnosis of pancreatic ductal adenocarcinoma (PDA) is often fatal. PDA is widely recognised as one of the ‘incurable cancers’ because therapies against this tumour type are generally ineffective. The fatal nature of this tumour is due to its aggressive clinical course. Pancreatic cancer commonly presents at the metastatic stage; even in cases where tumours are localised to the pancreas at diagnosis, metastatic seeds have often been invariably been spawned off, frustrating surgical attempts to cure the cancer. The key principles of pancreatic cancer mutational development were outlined nearly two decades ago using the genetics of precursor lesions to position the various stages of tumour progression. Since then, there has been a cavalcade of new data. How these recent studies impact the classical perceptions of pancreatic cancer development is a work in progress. Given that significant improvements in patient outcomes are not in sight for this disease, it is likely that broadening the current perspectives and acquiring deeper biological insights into the morphogenetic route of tumour development will be needed to foster new strategies for more effective cancer control.
Early intervention in Crohn’s disease: towards disease modification trials Gut (IF 16.658) Pub Date : 2017-12-01 Silvio Danese, Gionata Fiorino, Laurent Peyrin-Biroulet
Crohn’s disease (CD) is a chronic progressive destructive inflammatory bowel disease. As in rheumatoid arthritis, there is increasing evidence that early treatment initiation with disease-modifying agents, such as biological drugs, may lead to complete disease control, prevention of disease progression thus protecting against irreversible damage and restoration of normal quality of life. Data from randomised clinical trials with immunosuppressants and biologics suggest that treating patients with a disease duration of <2 years and an absence of complications may significantly reduce the risk for complications and increase time in remission in patients with CD. Moreover, rapid disease control may effectively prevent disease progression and allow dose reduction or even withdrawal of treatment, reducing the risk of long-term adverse events and healthcare costs. However, prospective disease modification trials are needed to confirm these initial results. Here we review the literature regarding early intervention in adult patients with CD and propose criteria for future disease modification trials.
The principles and practice of nutritional support Gut (IF 16.658) Pub Date : 2017-12-01 Simon Lal
Stephen JD O'Keefe. Spring-Verlag New York Inc. New York, USA. ISBN: 1493917781. This book provides exactly what it says on the cover: a useful practical guide for multidisciplinary health professionals in nutrition support. It is, of course, strengthened by the expertise and reputation of Dr O'Keefe in the field, and I agree with Dr O'Keefe that the book's single authorship avoids overlap and allows focus on the common principles of nutritional support that are applicable to various disease states. The book is divided into three parts: ‘the principles' and ‘the practice’ of general nutrition support and a final part that reviews nutritional support in different diseases, along with a succinct overview of the more complex conditions of intestinal failure and small bowel transplantation. Part …
GI highlights from the literature Gut (IF 16.658) Pub Date : 2017-12-01 Mairi H McLean
### Cigarettes and IBD: it’s in your genes Yadav P, Ellinghaus D, Rémy G, et al . Genetic factors interact with tobacco smoke to modify risk for inflammatory bowel disease in humans and mice. Gastroenterology 2017;153:550–565. The relationship between smoking and IBD risk is unclear. Gene–smoking interactions in IBD were explored at a genome-wide level in this paper using data from the International IBD Genetics Consortium. Immunochip custom array data from 20 000 IBD cases were compared with control cases in a meta-analysis of smokers versus non-smokers. Sixty-four single nucleotide polymorphisms (SNPs) were identified for which the associated risk of IBD was affected by smoking. Nearly half of these SNPs were close to SNPs known to be related to IBD, and many were located near genes linked with mucosal barrier regulation and immune response. Twenty SNPs were within the human leucocyte antigen region at 6p21, so the effect on adaptive immunity may be an explanation for the gene–smoking interaction. Seven SNPs interacted with smoking in opposite directions in Crohn’s disease and UC. There was also a contrast between former, ever and current smokers. Two genes identified as potentially interacting with smoking, Il10 and Nod2 , were evaluated in genetic knockout mouse models exposed to smoke in ventilated smoking chambers, equivalent to five cigarettes per day for 8 weeks. Il10 -deficient mice developed accelerated colitis as well as ileitis. Nod2 -deficient mice developed ileitis. In wild type mice exposed to smoke, there was no sign of IBD. Hence, there is a protective role of Il10 and Nod2 in response to smoking and may have a role in disease location. In summary, the effect of smoking in the pathogenesis of IBD depends on patient-specific genetic variants. ### Intestinal fungal dysbiosis and systemic fungal translocation promote the progression of alcohol-related liver disease Yang AM, Inamine T, Hochrath K, et al . Intestinal fungi contribute to development of alcoholic liver disease. J Clin Invest 2017;127:2829–41. Alterations in the …
Re-evaluation of the role of lumen-apposing metal stents (LAMS) for pancreatic ﬂuid collection drainage Gut (IF 16.658) Pub Date : 2017-12-01 Huiyun Zhu, Han Lin, Zhendong Jin, Yiqi Du
We read with great interest the recent endoscopy news reported by Bang et al ,1 discussing the lumen-apposing metal stents (LAMS) for pancreatic fluid collection (PFC) drainage. Patients with walled-off necrosis (WON) treated by using LAMS in their centre occurred a 50% (6/12) rate of adverse events including delayed bleeding (3/12), buried stent syndrome (2/12) and biliary stricture (1/12), which is higher than we expected on our experiences. As the authors reported all three patients presented with severe bleeding were confirmed with pseudoaneurysms. But another data from Sharaiha et al 2 showed that LAMS method was safe for PFC. In 124 patients with WON underwent endoscopic …
Response to letter to the editor Gut (IF 16.658) Pub Date : 2017-12-01 Ji Young Bang, Shyam Varadarajulu
Dear editor, Adverse events are captured more accurately during the conduct of a randomised trial1 than when an audit is performed and reported retrospectively.2 As observed in our study, the majority of adverse events were encountered beyond the 4-week time frame …
Epithelial organoid cultures from patients with ulcerative colitis and Crohn's disease: a truly long-term model to study the molecular basis for inflammatory bowel disease? Gut (IF 16.658) Pub Date : 2017-12-01 Manuel Noben, Bram Verstockt, Magali de Bruyn, Nikolai Hendriks, Gert Van Assche, Séverine Vermeire, Catherine Verfaillie, Marc Ferrante
With great interest we read the paper by Dotti et al ,1 who identified a set of differentially expressed genes in epithelial organoid cultures (EpOCs) derived from patients with UC compared with EpOCs from healthy controls. Similarly, we created an EpOC library from patients with UC (n=17), Crohn's disease (CD, n=12) and healthy controls (n=10). First, we assessed the potential of isolated intestinal crypts to grow into organoids (colony forming units). We observed that a similar percentage of organoids was formed from intestinal crypts isolated from controls and patients with UC or CD. Moreover, intestinal crypts isolated from macroscopically inflamed and non-inflamed tissue had similar potential to form organoids (figure 1A). Although we used a slightly divergent differentiation medium,2 the expansion and differentiation capacity of our organoids was similar as demonstrated by Dotti et al . Figure 1 (A) Colony forming units (CFUs) determined by quantification of the number of seeded crypts at the day of isolation and organoid formation after 7 days. CFUs are expressed as a percentage of organoids representative to the original number of seeded crypts. (B) Relative mRNA expression levels of leucine-rich repeat-containing G-protein coupled receptor 5 ( LGR5 ), mucin2 ( MUC2 ) and protein atonal homologue 1 ( ATOH1 ). mRNA levels were …
In vitro and in silico evidence against a significant effect of the SPINK1 c.194G>A variant on pre-mRNA splicing Gut (IF 16.658) Pub Date : 2017-12-01 Hao Wu, Arnaud Boulling, David N Cooper, Zhao-Shen Li, Zhuan Liao, Jian-Min Chen, Claude Férec
We read with interest the recent publication of Beer and Sahin-Tóth1 reporting that exonic variants affecting pre-mRNA splicing contribute to the genetic burden in chronic pancreatitis. One particular variant, affecting the last nucleotide of exon 3 of the SPINK1 gene, c.194G>A, was found to cause an ∼80% reduction in SPINK1 mRNA expression as compared with the wild type in a minigene assay performed in human embryonic kidney 293T (HEK293T) cells. The SPINK1 sequence inserted into the minigene expression vector however comprised only exon 1, exon 2, exon 3, intron 3 and exon 4 of the four-exon gene.1 It should be noted that the potential effect of c.194G>A as a missense mutation (p.Arg65Gln) on protein function has previously been analysed; engineered expression of the full-length mutant coding sequence in Chinese hamster ovary cells and HEK293T cells showed a consistent 50%–60% reduction in protein secretion as compared with the wild type.2 ,3 We recently analysed the functional consequences of 24 SPINK1 intronic variants in relation to their associated mRNA splicing phenotypes4 ,5 by means of a full-gene splicing assay in which the full-length 7 kb SPINK1 genomic sequence (including all four exons plus all three introns of the gene) was cloned into the pcDNA3.1/V5-His-TOPO vector.6 This full-length gene expression system has already proved itself in practice by accurately representing the in vivo situation in the context …
Thinking out of the Gut: a case of obscure lower GI bleeding Gut (IF 16.658) Pub Date : 2017-12-01 Frederick H Koh, Hian-Li Chan, Fredrik Petersson, Choon-Seng Chong
Clinical presentation A middle-aged man was admitted for episodes of fresh per-rectal bleeding, which were not associated with defecation. He was recently investigated for macrocytic anaemia in the outpatient haematology clinic. Examination of the perineum revealed grade 1 internal haemorrhoids with no signs of bleeding. Initial laboratory tests revealed macrocytic anaemia (haemoglobin 10.5 g/dL, normal 12.9–17.0 g/dL; mean corpuscular haemoglobin 95.3 fL, normal 80.0–95.0 fL). Peripheral blood film showing blasts, dysplastic neutrophils, nucleated red blood cells and hypogranular platelets. The patient underwent a sigmoidoscopy and rubber band ligation of the internal haemorrhoids after persistent fresh per-rectal bleeding. The bleeding persisted with the development of hypotension and a significant drop of haemoglobin to 4.8 g/dL requiring blood transfusions and intensive care monitoring. Repeated endoscopy, including intubation of the terminal ileum, revealed uncomplicated right-sided diverticulosis. CT mesenteric angiography performed during an episode of significant bleeding revealed extravasation of contrast in the ileum, but mesenteric angiography was unsuccessful, possibly due to a temporary cessation of bleeding. Bleeding subsequently recurred and in light of the persistent bleeding with no clear source and with a total of 12 units of packed cell transfused, exploratory laparotomy, on-table enteroscopy ([figure 1]) with small bowel resection was performed. Histopathological examination of the specimen was performed ([figures 2][⇓]–). ![Figure 1] Figure 1 Multiple ileal lesions with stigmata of recent bleed. ![Figure 2] Figure 2 Area of ulceration associated with atypical mononuclear infiltrate. ![Figure 3] Figure 3 Atypical mononuclear infiltrate composed of cells with enlarged, irregular nuclei containing variably prominent nucleoli. ![Figure 4] Figure 4 Atypical cells displayed cytoplasmic expression of myeloperoxidase. Question What is the diagnosis? : #F1 : #F2 : #F3 : #F4 : pending:yes
Correction: Quality standards in upper gastrointestinal endoscopy: a position statement of the British Society of Gastroenterology (BSG) and Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland (AUGIS) Gut (IF 16.658) Pub Date : 2017-12-01 BMJ Publishing Group Ltd and British Society of Gastroenterology
Beg S, Ragunath K, Wyman A, et al . Quality …
Wide-field endoscopic mucosal resection versus endoscopic submucosal dissection for laterally spreading colorectal lesions: a cost-effectiveness analysis Gut (IF 16.658) Pub Date : 2017-10-07 Farzan F Bahin, Steven J Heitman, Khalid N Rasouli, Hema Mahajan, Duncan McLeod, Eric Y T Lee, Stephen J Williams, Michael J Bourke
Objective To compare the cost-effectiveness of endoscopic submucosal dissection (ESD) and wide-field endoscopic mucosal resection (WF-EMR) for removing large sessile and laterally spreading colorectal lesions (LSLs) >20 mm. Design An incremental cost-effectiveness analysis using a decision tree model was performed over an 18-month time horizon. The following strategies were compared: WF-EMR, universal ESD (U-ESD) and selective ESD (S-ESD) for lesions highly suspicious for containing submucosal invasive cancer (SMIC), with WF-EMR used for the remainder. Data from a large Western cohort and the literature were used to inform the model. Effectiveness was defined as the number of surgeries avoided per 1000 cases. Incremental costs per surgery avoided are presented. Sensitivity and scenario analyses were performed. Results 1723 lesions among 1765 patients were analysed. The prevalence of SMIC and low-risk-SMIC was 8.2% and 3.1%, respectively. Endoscopic lesion assessment for SMIC had a sensitivity and specificity of 34.9% and 98.4%, respectively. S-ESD was the least expensive strategy and was also more effective than WF-EMR by preventing 19 additional surgeries per 1000 cases. 43 ESD procedures would be required in an S-ESD strategy. U-ESD would prevent another 13 surgeries compared with S-ESD, at an incremental cost per surgery avoided of US$210 112. U-ESD was only cost-effective among higher risk rectal lesions. Conclusion S-ESD is the preferred treatment strategy. However, only 43 ESDs are required per 1000 LSLs. U-ESD cannot be justified beyond high-risk rectal lesions. WF-EMR remains an effective and safe treatment option for most LSLs. Trial registration number NCT02000141.
Response to ‘Analysis of learning curves in gastroscopy training: the need for composite measures for defining competence’ by Siau et al Gut (IF 16.658) Pub Date : 2017-09-26 Stephen Thomas Ward, Paul Dunckley
We are thankful for the letter of Siau et al 1 in response to our article describing the learning curve to satisfactory completion rates in upper GI endoscopy.2We agree that D2 intubation and successful J manoeuvre are insufficient to define competence. Our article’s title stated that we focused on completion rates. We specifically mentioned in our discussion that it is necessary to comply with a host of other measures to be competent. For example, procedural completion and successful J manoeuvre do not ensure complete inspection of the mucosa, nor do they result in correct identification of pathology. We welcome the introduction by Joint Advisory Group of assessment of endoscopic non-technical skills and support direct observation of procedural skills …
Prospective study on the incidence, prevalence and 5-year pancreatic-related mortality of pancreatic cysts in a population-based study Gut (IF 16.658) Pub Date : 2017-09-23 Marie-Luise Kromrey, Robin Bülow, Jenny Hübner, Christin Paperlein, Markus M Lerch, Till Ittermann, Henry Völzke, Julia Mayerle, Jens-Peter Kühn
Objective To analyse the prevalence, incidence and clinical relevance of pancreatic cysts detected as incidental finding in a population-based longitudinal study.Design A total of 1077 participants (521 men, mean age 55.8±12.8 years) of 2333 participants from the population-based Study of Health in Pomerania (SHIP) underwent magnetic resonance cholangiopancreaticography (MRCP) at baseline (2008–2012). MRCP was analysed for pancreatic cysts with a diameter ≥2 mm. 676/1077 subjects received a 5-year follow-up (2014–2016). The prevalence and incidence of pancreatic cysts (weighted for study participation) were assessed in association to age, gender and suspected epidemiological risk factors. Mortality follow-up was performed in 2015 for all SHIP participants (mean follow-up period 5.9 years, range 3.2–7.5 years).Results At baseline pancreatic cysts had a weighted prevalence of 49.1%, with an average number of 3.9 (95% CI 3.2 to 4.5) cysts per subject in the subgroup harbouring cysts. Cyst size ranged from 2 to 29 mm. Prevalence (p<0.001), number (p=0.001) and maximum size (p<0.001) increased significantly with age. The 5-year follow-up revealed a weighted incidence of 12.9% newly detected pancreatic cysts. 57.1% of the subjects initially harbouring pancreatic cysts showed an increase in number and/or maximum cyst size. Of all subjects undergoing MRCP, no participant died of pancreatic diseases within mortality follow-up.Conclusion The prevalence of pancreatic cysts in the general population is unexpectedly high, and their number and size increase with age. Overall, no pancreatic cancer was observed in this collective during a 5-year follow-up. Nevertheless, prospective follow-up imaging showed minimal progress in more than 50%. Only about 6% of cysts and 2.5% of the study group initially presented with cysts of more than 1 cm and thus might be clinically meaningful.
High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B Gut (IF 16.658) Pub Date : 2017-10-21 Gi-Ae Kim, Young-Suk Lim, Seungbong Han, Jonggi Choi, Ju Hyun Shim, Kang Mo Kim, Han Chu Lee, Yung Sang Lee
Objective High serum HBV DNA levels are associated with high risks of hepatocellular carcinoma (HCC) and cirrhosis in patients with chronic hepatitis B (CHB). Although the immune-tolerant (IT) phase is characterised by high circulating HBV DNA levels, it remains unknown whether antiviral treatment reduces risks of HCC and mortality.Design This historical cohort study included HBeAg-positive patients with CHB with high HBV DNA levels (≥20 000 IU/mL) and no evidence of cirrhosis at a tertiary referral hospital in Korea from 2000 to 2013. The clinical outcomes of 413 untreated IT-phase patients with normal alanine aminotransferase (ALT) levels (females, <19 IU/mL; males, <30 IU/mL) were compared with those of 1497 immune-active (IA)-phase patients (ALT ≥80 IU/mL) treated with nucleos(t)ide analogues.Results The IT group was significantly younger than the IA group (mean age, 38 vs 40 years at baseline, p=0.04). The 10-year estimated cumulative incidences of HCC (12.7% vs 6.1%; p=0.001) and death/transplantation (9.7% vs 3.4%; p<0.001) were significantly higher in the IT group than the IA group. In multivariable analyses, the IT group showed a significantly higher risk of HCC (HR 2.54; 95% CI 1.54 to 4.18) and death/transplantation (HR 3.38; 95% CI 1.85 to 6.16) than the IA group, which was consistently identified through inverse probability treatment weighting, propensity score-matched and competing risks analyses.Conclusions Untreated IT-phase patients with CHB had higher risks of HCC and death/transplantation than treated IA-phase patients. Unnecessary deaths could be prevented through earlier antiviral intervention in select IT-phase patients.
Guidelines on the management of abnormal liver blood tests Gut (IF 16.658) Pub Date : 2017-11-09 Philip N Newsome, Rob Cramb, Suzanne M Davison, John F Dillon, Mark Foulerton, Edmund M Godfrey, Richard Hall, Ulrike Harrower, Mark Hudson, Andrew Langford, Anne Mackie, Robert Mitchell-Thain, Karen Sennett, Nicholas C Sheron, Julia Verne, Martine Walmsley, Andrew Yeoman
These updated guidelines on the management of abnormal liver blood tests have been commissioned by the Clinical Services and Standards Committee (CSSC) of the British Society of Gastroenterology (BSG) under the auspices of the liver section of the BSG. The original guidelines, which this document supersedes, were written in 2000 and have undergone extensive revision by members of the Guidelines Development Group (GDG). The GDG comprises representatives from patient/carer groups (British Liver Trust, Liver4life, PBC Foundation and PSC Support), elected members of the BSG liver section (including representatives from Scotland and Wales), British Association for the Study of the Liver (BASL), Specialist Advisory Committee in Clinical Biochemistry/Royal College of Pathology and Association for Clinical Biochemistry, British Society of Paediatric Gastroenterology, Hepatology and Nutrition (BSPGHAN), Public Health England (implementation and screening), Royal College of General Practice, British Society of Gastrointestinal and Abdominal Radiologists (BSGAR) and Society of Acute Medicine. The quality of evidence and grading of recommendations was appraised using the AGREE II tool. These guidelines deal specifically with the management of abnormal liver blood tests in children and adults in both primary and secondary care under the following subheadings: (1) What constitutes an abnormal liver blood test? (2) What constitutes a standard liver blood test panel? (3) When should liver blood tests be checked? (4) Does the extent and duration of abnormal liver blood tests determine subsequent investigation? (5) Response to abnormal liver blood tests. They are not designed to deal with the management of the underlying liver disease.
Real-time differentiation of adenomatous and hyperplastic diminutive colorectal polyps during analysis of unaltered videos of standard colonoscopy using a deep learning model Gut (IF 16.658) Pub Date : 2017-10-23 Michael F Byrne, Nicolas Chapados, Florian Soudan, Clemens Oertel, Milagros Linares Pérez, Raymond Kelly, Nadeem Iqbal, Florent Chandelier, Douglas K Rex
Background In general, academic but not community endoscopists have demonstrated adequate endoscopic differentiation accuracy to make the ‘resect and discard’ paradigm for diminutive colorectal polyps workable. Computer analysis of video could potentially eliminate the obstacle of interobserver variability in endoscopic polyp interpretation and enable widespread acceptance of ‘resect and discard’.Study design and methods We developed an artificial intelligence (AI) model for real-time assessment of endoscopic video images of colorectal polyps. A deep convolutional neural network model was used. Only narrow band imaging video frames were used, split equally between relevant multiclasses. Unaltered videos from routine exams not specifically designed or adapted for AI classification were used to train and validate the model. The model was tested on a separate series of 125 videos of consecutively encountered diminutive polyps that were proven to be adenomas or hyperplastic polyps.Results The AI model works with a confidence mechanism and did not generate sufficient confidence to predict the histology of 19 polyps in the test set, representing 15% of the polyps. For the remaining 106 diminutive polyps, the accuracy of the model was 94% (95% CI 86% to 97%), the sensitivity for identification of adenomas was 98% (95% CI 92% to 100%), specificity was 83% (95% CI 67% to 93%), negative predictive value 97% and positive predictive value 90%.Conclusions An AI model trained on endoscopic video can differentiate diminutive adenomas from hyperplastic polyps with high accuracy. Additional study of this programme in a live patient clinical trial setting to address resect and discard is planned.
Differential preventive activity of sulindac and atorvastatin in Apc+/Min-FCCCmice with or without colorectal adenomas Gut (IF 16.658) Pub Date : 2017-11-09 Wen-Chi L Chang, Christina Jackson, Stacy Riel, Harry S Cooper, Karthik Devarajan, Harvey H Hensley, Yan Zhou, Lisa A Vanderveer, Minhhuyen T Nguyen, Margie L Clapper
Objective The response of subjects to preventive intervention is heterogeneous. The goal of this study was to determine if the efficacy of a chemopreventive agent differs in non-tumour-bearing animals versus those with colorectal tumours. Sulindac and/or atorvastatin was administered to Apc+/Min-FCCC mice with known tumour-bearing status at treatment initiation.Design Male mice (6–8 weeks old) underwent colonoscopy and received control chow or chow with sulindac (300 ppm), atorvastatin (100 ppm) or sulindac/atorvastatin. Tissues were collected from mice treated for 14 weeks (histopathology) or 7 days (gene expression). Cell cycle analyses were performed on SW480 colon carcinoma cells treated with sulindac, atorvastatin or both.Results The multiplicity of colorectal adenomas in untreated mice bearing tumours at baseline was 3.6-fold higher than that of mice that were tumour free at baseline (P=0.002). Atorvastatin completely inhibited the formation of microadenomas in mice that were tumour free at baseline (P=0.018) and altered the expression of genes associated with stem/progenitor cells. Treatment of tumour-bearing mice with sulindac/atorvastatin led to a 43% reduction in the multiplicity of colorectal adenomas versus untreated tumour-bearing mice (P=0.049). Sulindac/atorvastatin increased the expression of Hoxb13 and Rprm significantly, suggesting the importance of cell cycle regulation in tumour inhibition. Treatment of SW480 cells with sulindac/atorvastatin led to cell cycle arrest (G0/G1).Conclusions The tumour status of animals at treatment initiation dictates response to therapeutic intervention. Atorvastatin eliminated microadenomas in tumour-free mice. The tumour inhibition observed with Sul/Atorva in tumour-bearing mice was greater than that achieved with each agent.
Genome-wide association studies identified loci contribute to phenotypic variance of gastric cancer Gut (IF 16.658) Pub Date : 2017-09-22 Caiwang Yan, Meng Zhu, Tongtong Huang, Fei Yu, Guangfu Jin
We read with great interest the article by Mocellin et al ,1 who conducted a comprehensive meta-analysis that nominated 11 germline variants at nine loci significantly associated with gastric cancer (GC) with high level of summary evidence. Moreover, they also identified 38 single nucleotide polymorphisms (SNPs) with intermediate quality significant associations. Most of these loci were resulted from hypothesis-driven studies based on biological relevance, but most of these studies were small sample size and might lead to publication bias. In order to further evaluate their relevance with GC in individual large studies, we analysed these variants directly or their strong linkage disequilibrium SNPs using existing genome-wide association study (GWAS) datasets (including 2631 cases and 4373 controls) in Chinese populations, including those from Nanjing and Beijing populations conducted by our group2 and from Henan and Shanxi populations conducted by the USA National Cancer …
Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy Gut (IF 16.658) Pub Date : 2017-09-22 Jingying Zhou, Man Liu, Hanyong Sun, Yu Feng, Liangliang Xu, Anthony W H Chan, Joanna H Tong, John Wong, Charing Ching Ning Chong, Paul B S Lai, Hector Kwong-Sang Wang, Shun-Wa Tsang, Tyler Goodwin, Rihe Liu, Leaf Huang, Zhiwei Chen, Joseph JY Sung, King Lau Chow, Ka Fai To, Alfred Sze-Lok Cheng
Objective Myeloid-derived suppressor cells (MDSCs) contribute to tumour immunosuppressive microenvironment and immune-checkpoint blockade resistance. Emerging evidence highlights the pivotal functions of cyclin-dependent kinases (CDKs) in tumour immunity. Here we elucidated the role of tumour-intrinsic CDK20, or cell cycle-related kinase (CCRK) on immunosuppression in hepatocellular carcinoma (HCC).Design Immunosuppression of MDSCs derived from patients with HCC and relationship with CCRK were determined by flow cytometry, expression analyses and co-culture systems. Mechanistic studies were also conducted in liver-specific CCRK -inducible transgenic (TG) mice and Hepa1–6 orthotopic HCC models using CRISPR/Cas9-mediated Ccrk depletion and liver-targeted nanoparticles for interleukin (IL) 6 trapping. Tumorigenicity and immunophenotype were assessed on single or combined antiprogrammed death-1-ligand 1 (PD-L1) therapy.Results Tumour-infiltrating CD11b+CD33+HLA-DR− MDSCs from patients with HCC potently inhibited autologous CD8+T cell proliferation. Concordant overexpression of CCRK and MDSC markers (CD11b/CD33) positively correlated with poorer survival rates. Hepatocellular CCRK stimulated immunosuppressive CD11b+CD33+HLA-DR− MDSC expansion from human peripheral blood mononuclear cells through upregulating IL-6. Mechanistically, CCRK activated nuclear factor-κB (NF-κB) via enhancer of zeste homolog 2 (EZH2) and facilitated NF-κB-EZH2 co-binding to IL-6 promoter. Hepatic CCRK induction in TG mice activated the EZH2/NF-κB/IL-6 cascade, leading to accumulation of polymorphonuclear (PMN) MDSCs with potent T cell suppressive activity. In contrast, inhibiting tumorous Ccrk or hepatic IL-6 increased interferon γ+tumour necrosis factor-α+CD8+ T cell infiltration and impaired tumorigenicity, which was rescued by restoring PMN-MDSCs. Notably, tumorous Ccrk depletion upregulated PD-L1 expression and increased intratumorous CD8+ T cells, thus enhancing PD-L1 blockade efficacy to eradicate HCC.Conclusion Our results delineate an immunosuppressive mechanism of the hepatoma-intrinsic CCRK signalling and highlight an overexpressed kinase target whose inhibition might empower HCC immunotherapy.
SRSF6-regulated alternative splicing that promotes tumour progression offers a therapy target for colorectal cancer Gut (IF 16.658) Pub Date : 2017-11-07 Ledong Wan, Wenying Yu, Enhui Shen, Wenjie Sun, Yuan Liu, Jianlu Kong, Yihua Wu, Fengyan Han, Lei Zhang, Tianze Yu, Yuwei Zhou, Sunzhe Xie, Enping Xu, Honghe Zhang, Maode Lai
Objective To investigate the molecular function of splicing factor SRSF6 in colorectal cancer (CRC) progression and discover candidate chemicals for cancer therapy through targeting SRSF6.Design We performed comprehensive analysis for the expression of SRSF6 in 311 CRC samples, The Cancer Genome Atlas and Gene Expression Omnibus (GEO) database. Functional analysis of SRSF6 in CRC was performed in vitro and in vivo . SRSF6-regulated alternative splicing (AS) and its binding motif were identified by next-generation RNA-sequencing and RNA immunoprecipitation sequencing (RIP-seq), which was validated by gel shift and minigene reporter assay. ZO-1 exon23 AS was investigated to mediate the function of SRSF6 in vitro and in vivo . Based on the analysis of domain-specific role, SRSF6-targeted inhibitor was discovered de novo by virtual screening in 4855 FDA-approved drugs and its antitumour effects were evaluated in vitro and in vivo .Results SRSF6 was frequently upregulated in CRC samples and associated with poor prognosis, which promoted proliferation and metastasis in vitro and in vivo . We identified SRSF6-regulated AS targets and discovered the SRSF6 binding motif. Particularly, SRSF6 regulates ZO-1 aberrant splicing to function as an oncogene by binding directly to its motif in the exon23. Based on the result that SRSF6 RRM2 domain plays key roles in regulating AS and biological function, indacaterol, a β2-adrenergic receptor agonist approved for chronic obstructive pulmonary disease treatment, is identified as the inhibitor of SRSF6 to suppress CRC tumourigenicity.Conclusions SRSF6 functions the important roles in mediating CRC progression through regulating AS, and indacaterol is repositioned as an antitumour drug through targeting SRSF6.Accession numbers The accession numbers for sequencing data are SRP111763 and SRP111797.
Enterochromaffin cells in the gut: a distant regulator of brain function? Gut (IF 16.658) Pub Date : 2017-10-28 Chun Yang, Jie Gao, Jie Zhang, Ai-Lin Luo
We read with great interest the recent excellent work by Stevens et al ,1 in which the authors showed that zonulin and fatty acid-binding protein 2 have a relationship with the increase in lipopolysaccharide (LPS) and abnormal composition of gut microbiota in patients with anxiety or depression. We appreciate these findings and would like to discuss the role of enterochromaffin cells (ECs) in brain function in this context.Accumulating evidence has shown that neuropsychiatric diseases are frequently associated with gut microbiota disorders.2 It has been widely recognised that toxins within the human body mainly stem from the gut.3 The opening of intercellular tight junctions in the gut allow many toxins into the bloodstream that then have a deleterious effect on the brain, finally resulting in a series of neuropsychiatric symptoms. …
Improving future studies in chronic pancreatitis: a paradigm shift in our understanding? Gut (IF 16.658) Pub Date : 2017-09-22 Andrew D Hopper, Jennifer A Campbell
We read with interest the study by de la Iglesia-García et al 1 The authors present a detailed, well-conducted meta-analysis of the efficacy of pancreatic enzyme replacement therapy (PERT) in patients with chronic pancreatitis (CP) who also have evidence of exocrine pancreatic insufficiency (EPI). Using level 1 evidence studies, the primary endpoint of fat absorption is shown to increase with PERT, with additional improvements shown in GI symptoms and quality of life. The authors should be commended for their work clarifying the beneficial use of PERT in this group of patients, but they and the preceding commentary by Windsor2 highlight the heterogenicity of the criteria used to diagnose CP and the greater need for a clear consensus to help target and guide dosing of PERT. Although a recent consensus to produce a mechanistic definition for …
Illusions regarding Helicobacter pylori clinical trials and treatment guidelines Gut (IF 16.658) Pub Date : 2017-09-21 David Y Graham
Identification of reliable Helicobacter pylori eradication therapy has proved difficult, in part because brief exposure of H. pylori to commonly used antimicrobials such as macrolides, nitroimidazoles or quinolones often results in resistance (bystander effect). Most treatment studies and meta-analyses contains major flaws preventing generalisability that making reliable treatment recommendations and guidelines an illusion (box 1).Box 1 ### Helicobacter pylori treatment illusionsDevelopment of H. pylori therapy differs from other infectious diseases. Since the advent of antibiotics, infectious diseases therapy has been susceptibility based, whereas most H. pylori treatment guidelines recommend susceptibility testing only after two empiric therapy failures. Increased penicillin resistance in the 1970s prompted rapid changes in recommendations and the development of antimicrobial surveillance programme to regularly update recommendations thus allowing empirical therapies to remain effective.1 Despite increasing resistance, H. pylori treatment guidelines have continued to recommend increasingly ineffective therapies and most new empiric therapies consist of variations using those same drugs (eg, sequential therapy). Treatment success has focused on comparisons between regimens irrespective of cure rates and without consideration of the antibiotic susceptibility profile of the infection, thus producing illusions of success. For example, sequential therapy consists of 5 days of dual proton pump inhibitor (PPI)–amoxicillin therapy followed by 5 days of PPI–clarithromycin and metronidazole triple therapy (Bazzoli’s triple therapy).2 Interestingly, sequential therapy …
Novel device for measuring polyp size: an ex vivo animal study Gut (IF 16.658) Pub Date : 2017-09-21 Omer Goldstein, Ori Segol, Peter D Siersema, Harold Jacob, Seth A Gross
In situ assessment of polyp size during colonoscopy is of clinical importance for optimal treatment and follow-up. In this initial study, we evaluated the accuracy and usability of a virtual tape measure, a novel device providing quantitative measurements, as compared with current practice of unassisted assessment and using biopsy forceps as scale.The virtual tape-measure prototype was shown to provide submillimetre accuracy, almost an order of magnitude better than current practice. It has the potential of becoming the standard for quantitative in situ polyp size measurement; however, further studies in a clinical setting are needed.In colonoscopy, there is clinical importance for in situ assessment of polyp size.1 To date, no commercially available medical endoscope has the capability of performing measurements. There are several mechanical devices designed to perform these measurements, such as a calibrated hood2 and a ruler snare,3 but these are mainly used in research, as they are limited in their capacity and are difficult to operate.Therefore, in current practice, endoscopist estimates are based on acquired expertise and/or an approximate scale (eg, using biopsy forceps), …
Pan-genomic analyses identify key Helicobacter pylori pathogenic loci modified by carcinogenic host microenvironments Gut (IF 16.658) Pub Date : 2017-09-18 Jennifer M Noto, Abha Chopra, John T Loh, Judith Romero-Gallo, M Blanca Piazuelo, Mark Watson, Shay Leary, Amber C Beckett, Keith T Wilson, Timothy L Cover, Simon Mallal, Dawn A Israel, Richard M Peek
Objective Helicobacter pylori is the strongest risk factor for gastric cancer; however, the majority of infected individuals do not develop disease. Pathological outcomes are mediated by complex interactions among bacterial, host and environmental constituents, and two dietary factors linked with gastric cancer risk are iron deficiency and high salt. We hypothesised that prolonged adaptation of H. pylori to in vivo carcinogenic microenvironments results in genetic modification important for disease.Design Whole genome sequencing of genetically related H. pylori strains that differ in virulence and targeted H. pylori sequencing following prolonged exposure of bacteria to in vitro carcinogenic conditions were performed.Results A total of 180 unique single nucleotide polymorphisms (SNPs) were identified among the collective genomes when compared with a reference H. pylori genome. Importantly, common SNPs were identified in isolates harvested from iron-depleted and high salt carcinogenic microenvironments, including an SNP within fur (FurR88H). To investigate the direct role of low iron and/or high salt, H. pylori was continuously cultured in vitro under low iron or high salt conditions to assess fur genetic variation. Exposure to low iron or high salt selected for the FurR88H variant after only 5 days. To extend these results, fur was sequenced in 339 clinical H. pylori strains. Among the isolates examined, 17% (40/232) of strains isolated from patients with premalignant lesions harboured the FurR88H variant, compared with only 6% (6/107) of strains from patients with non-atrophic gastritis alone (p=0.0034).Conclusion These results indicate that specific genetic variation arises within H. pylori strains during in vivo adaptation to conditions conducive for gastric carcinogenesis.
ROC-king onwards: intraepithelial lymphocyte counts, distribution & role in coeliac disease mucosal interpretation Gut (IF 16.658) Pub Date : 2017-09-16 Kamran Rostami, Michael N Marsh, Matt W Johnson, Hamid Mohaghegh, Calvin Heal, Geoffrey Holmes, Arzu Ensari, David Aldulaimi, Brigitte Bancel, Gabrio Bassotti, Adrian Bateman, Gabriel Becheanu, Anna Bozzola, Antonio Carroccio, Carlo Catassi, Carolina Ciacci, Alexandra Ciobanu, Mihai Danciu, Mohammad H Derakhshan, Luca Elli, Stefano Ferrero, Michelangelo Fiorentino, Marilena Fiorino, Azita Ganji, Kamran Ghaffarzadehgan, James J Going, Sauid Ishaq, Alessandra Mandolesi, Sherly Mathews, Roxana Maxim, Chris J Mulder, Andra Neefjes-Borst, Marie Robert, Ilaria Russo, Mohammad Rostami-Nejad, Angelo Sidoni, Masoud Sotoudeh, Vincenzo Villanacci, Umberto Volta, Mohammad R Zali, Amitabh Srivastava
Objectives Counting intraepithelial lymphocytes (IEL) is central to the histological diagnosis of coeliac disease (CD), but no definitive ‘normal’ IEL range has ever been published. In this multicentre study, receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off between normal and CD (Marsh III lesion) duodenal mucosa, based on IEL counts on >400 mucosal biopsy specimens.Design The study was designed at the International Meeting on Digestive Pathology, Bucharest 2015. Investigators from 19 centres, eight countries of three continents, recruited 198 patients with Marsh III histology and 203 controls and used one agreed protocol to count IEL/100 enterocytes in well-oriented duodenal biopsies. Demographic and serological data were also collected.Results The mean ages of CD and control groups were 45.5 (neonate to 82) and 38.3 (2–88) years. Mean IEL count was 54±18/100 enterocytes in CD and 13±8 in normal controls (p=0.0001). ROC analysis indicated an optimal cut-off point of 25 IEL/100 enterocytes, with 99% sensitivity, 92% specificity and 99.5% area under the curve. Other cut-offs between 20 and 40 IEL were less discriminatory. Additionally, there was a sufficiently high number of biopsies to explore IEL counts across the subclassification of the Marsh III lesion.Conclusion Our ROC curve analyses demonstrate that for Marsh III lesions, a cut-off of 25 IEL/100 enterocytes optimises discrimination between normal control and CD biopsies. No differences in IEL counts were found between Marsh III a, b and c lesions. There was an indication of a continuously graded dose–response by IEL to environmental (gluten) antigenic influence.
Regulatory NK cells mediated between immunosuppressive monocytes and dysfunctional T cells in chronic HBV infection Gut (IF 16.658) Pub Date : 2017-09-12 Haijun Li, Naicui Zhai, Zhongfeng Wang, Hongxiao Song, Yang Yang, An Cui, Tianyang Li, Guangyi Wang, Junqi Niu, Ian Nicholas Crispe, Lishan Su, Zhengkun Tu
Background and aims HBV infection represents a major health problem worldwide, but the immunological mechanisms by which HBV causes chronic persistent infection remain only partly understood. Recently, cell subsets with suppressive features have been recognised among monocytes and natural killer (NK) cells. Here we examine the effects of HBV on monocytes and NK cells.Methods Monocytes and NK cells derived from chronic HBV-infected patients and healthy controls were purified and characterised for phenotype, gene expression and cytokines secretion by flow cytometry, quantitative real-time (qRT)-PCR, ELISA and western blotting. Culture and coculture of monocytes and NK cells were used to determine NK cell activation, using intracellular cytokines staining.Results In chronic HBV infection, monocytes express higher levels of PD-L1, HLA-E, interleukin (IL)-10 and TGF-β, and NK cells express higher levels of PD-1, CD94 and IL-10, compared with healthy individuals. HBV employs hepatitis B surface antigen (HBsAg) to induce suppressive monocytes with HLA-E, PD-L1, IL-10 and TGF-β expression via the MyD88/NFκB signalling pathway. HBV-treated monocytes induce NK cells to produce IL-10, via PD-L1 and HLA-E signals. Such NK cells inhibit autologous T cell activation.Conclusions Our findings reveal an immunosuppressive cascade, in which HBV generates suppressive monocytes, which initiate regulatory NK cells differentiation resulting in T cell inhibition.
Gastric microbial community profiling reveals a dysbiotic cancer-associated microbiota Gut (IF 16.658) Pub Date : 2017-11-04 Rui M Ferreira, Joana Pereira-Marques, Ines Pinto-Ribeiro, Jose L Costa, Fatima Carneiro, Jose C Machado, Ceu Figueiredo
Objective Gastric carcinoma development is triggered by Helicobacter pylori . Chronic H. pylori infection leads to reduced acid secretion, which may allow the growth of a different gastric bacterial community. This change in the microbiome may increase aggression to the gastric mucosa and contribute to malignancy. Our aim was to evaluate the composition of the gastric microbiota in chronic gastritis and in gastric carcinoma.Design The gastric microbiota was retrospectively investigated in 54 patients with gastric carcinoma and 81 patients with chronic gastritis by 16S rRNA gene profiling, using next-generation sequencing. Differences in microbial composition of the two patient groups were assessed using linear discriminant analysis effect size. Associations between the most relevant taxa and clinical diagnosis were validated by real-time quantitative PCR. Predictive functional profiling of microbial communities was obtained with PICRUSt.Results The gastric carcinoma microbiota was characterised by reduced microbial diversity, by decreased abundance of Helicobacter and by the enrichment of other bacterial genera, mostly represented by intestinal commensals. The combination of these taxa into a microbial dysbiosis index revealed that dysbiosis has excellent capacity to discriminate between gastritis and gastric carcinoma. Analysis of the functional features of the microbiota was compatible with the presence of a nitrosating microbial community in carcinoma. The major observations were confirmed in validation cohorts from different geographic origins.Conclusions Detailed analysis of the gastric microbiota revealed for the first time that patients with gastric carcinoma exhibit a dysbiotic microbial community with genotoxic potential, which is distinct from that of patients with chronic gastritis.
Assessment of liver fibrosis with the gamma-glutamyl transpeptidase to platelet ratio: a multicentre validation in patients with HBV infection Gut (IF 16.658) Pub Date : 2017-11-03 Xiao-Jie Lu, Xiu-Hui Li, Zhao-Xin Yuan, Hai-Ying Sun, Xiao-Chen Wang, Xiaolong Qi, Xin Zhang, Beicheng Sun
We read with interest the study by Lemoine et al 1 in which the gamma-glutamyl transpeptidase (GGT) to platelet ratio (GPR) was developed to stage fibrosis in patients with chronic hepatitis B (CHB). This study concluded that GPR is more accurate than the aspartate aminotransferase to platelet ratio index (APRI) and Fib-4 to stage liver fibrosis in patients with CHB. As China is a highly endemic area of CHB with estimated >74 million hepatitis B surface antigen (HBsAg)-positive patients,2 3 we conducted this multicentre study to validate the diagnostic performance of GPR in Chinese patients with CHB.Treatment-naïve patients with positive HBsAg who underwent liver biopsy, Fibroscan (FS402, Echosens, France) and blood tests were included from three centres (Huai’an Fourth People’s Hospital, Huai’an, China (January 2012–April 2016), Beijing You-An Hospital, Capital Medical University, Beijing, China (January 2014–June 2016) and Hepatology Hospital of Jilin …
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