Vous êtes ici : Accueil > Espace Médecin > La revue de Presse > GUT

Mise à jour le : 28-02-2017




Les derniers abstracts de la revue Gut current issue :


    Date de mise en ligne : Mercredi 15 février 2017
    Sugarman, J., Revill, P., Zoulim, F., Yazdanpanah, Y., Janssen, H. L. A., Lim, S. G., Lewin, S. R.
    Ethics and hepatitis B cure research

    Recent scientific advances, including the development of curative therapies for HCV and the establishment of global cure initiatives for HIV, have led to international calls seeking a cure for chronic infection with HBV.1 2 Over 240 million people live with chronic HBV, resulting in up to 780 000 deaths annually due to hepatic fibrosis/cirrhosis and hepatocellular carcinoma (HCC).3 4 Persons chronically infected with HBV who do not receive treatment have a lifelong risk of developing HCC, the third most common cause of disease globally.5–7 Along with scaled-up approaches to preventing and treating chronic HBV infection, having a safe and effective cure for HBV infection promises to minimise the global burden of HBV-related morbidity and mortality and reduce the economic and other burdens of lifelong treatment. Nevertheless, as HBV cure research proceeds, it is critical to anticipate...


    Date de mise en ligne : Mercredi 15 février 2017
    Wills, E. S., Drenth, J. P. H.
    Building pancreatic organoids to aid drug development

    Comment on: gutjnl-2016-312423 ‘Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling’

    Much of our understanding of human diseases comes from the study of model systems such as cell lines. Cell lines are derived from cells that have obtained the property to proliferate indefinitely, often by immortalisation or isolation from cancerous tissues. They have the great advantage that they are easy to work with and can be kept in culture almost endlessly. The disadvantage is that they have lost the genetic signature of healthy primary cells, thwarting the interpretation of test results. This has led to the search for human cell systems that accurately recapitulate healthy or diseased human primary tissues. Advances in stem cell technology have made it possible to create, maintain and expand induced or adult stem cells while they retain multilineage potential. This has led to the development of...


    Date de mise en ligne : Mercredi 15 février 2017
    Hart, P. A., Chari, S. T.
    Preventing disease relapses in autoimmune pancreatitis with maintenance steroids: are we there yet?

    Autoimmune pancreatitis (AIP) is a fibro-inflammatory disease, which has defining histopathology and is characterised by a dramatic response to steroid treatment.1 Type 1 AIP describes the pancreatic manifestation of a multiorgan syndrome, currently referred to as IgG4-related disease and is frequently associated with an elevated serum IgG4 antibody level.2 This is a chronic disease with relapses occurring in 30–50% of patients within 3 years of disease onset.3 4 Published data suggest that low-dose maintenance steroids may decrease the risk for future disease relapse; however, this has not been demonstrated in a prospective clinical trial.5 In the present study, Masamune et al6 present their findings from a randomised controlled trial (RCT) examining the efficacy of low-dose steroids for maintenance of disease remission. We discuss this article in the context of the existing literature and identify future opportunities to improve...


    Date de mise en ligne : Mercredi 15 février 2017
    Kuntzen, C., Schwabe, R. F.
    Gut microbiota and Toll-like receptors set the stage for cytokine-mediated failure of antibacterial responses in the fibrotic liver

    The gut–liver axis is increasingly recognised as a key contributor to chronic liver disease. A failing gut barrier contributes to increased bacterial translocation, which results in an elevated risk of bacterial infection and a chronic inflammatory state that may promote the progression of chronic liver disease and the development of long-term complications such as fibrosis and HCC.1 2 The most important clinical consequence of increased translocation is acute bacterial infection, a common cause of hospital admissions and a major contributor to morbidity and mortality in patients with cirrhosis. Moreover, bacterial infections can lead to acute decompensation, often triggering acute-on-chronic liver injury.3 On top of a leaky gut, patients with liver cirrhosis have severe defects in the innate immune system, affecting macrophages, neutrophils and the complement system.4 The liver itself represents an important immunological organ and is the first target of gut-derived...


    Date de mise en ligne : Mercredi 15 février 2017
    Fisher, O. M., Lord, S. J., Falkenback, D., Clemons, N. J., Eslick, G. D., Lord, R. V.
    The prognostic value of TP53 mutations in oesophageal adenocarcinoma: a systematic review and meta-analysis
    Objective

    To clarify the prognostic role of tumour protein 53 (TP53) mutations in patients with oesophageal adenocarcinoma (OAC) as there is a need for biomarkers that assist in guiding management for patients with OAC.

    Design

    A systematic review was conducted using MEDLINE, Embase, PubMed and Current Contents Connect to identify studies published between January 1990 and February 2015 of oesophageal cancer populations (with OAC diagnoses >50% of cases) that measured tumoural TP53 status and reported hazard ratios (HR), or adequate data for estimation of HR for survival for TP53-defined subgroups. Risk of bias for HR estimates was assessed using prespecified criteria for the appraisal of relevant domains as defined by the Cochrane Prognosis Methods Group including adherence to Grading of Recommendations, Assessment, Development and Evaluation and REporting recommendations for tumor MARKer prognostic studies guidelines, as well as assay method used (direct TP53 mutation assessment vs immunohistochemistry) and adjustment for standard prognostic factors. A pooled HR and 95% CI were calculated using a random-effects model.

    Results

    Sixteen eligible studies (11 with OAC only and 5 mixed histology cohorts) including 888 patients were identified. TP53 mutations were associated with reduced survival (HR 1.48, 95% CI 1.16 to 1.90, I2=33%). A greater prognostic effect was observed in a sensitivity analysis of those studies that reported survival for OAC-only cohorts and were assessed at low risk of bias (HR 2.11, 95% CI 1.35 to 3.31, I2=0%).

    Conclusions

    Patients with OAC and TP53 gene mutations have reduced overall survival compared with patients without these mutations, and this effect is independent of tumour stage.


    Date de mise en ligne : Mercredi 15 février 2017
    Ford, A. C., Luthra, P., Tack, J., Boeckxstaens, G. E., Moayyedi, P., Talley, N. J.
    Efficacy of psychotropic drugs in functional dyspepsia: systematic review and meta-analysis
    Objective

    Functional dyspepsia (FD) is a chronic gastroduodenal disorder. Individuals with FD demonstrate visceral hypersensitivity, abnormal central pain processing, and low mood, but it is unclear whether psychotropic drugs are an effective treatment for the condition. We performed a systematic review and meta-analysis of randomised controlled trials (RCTs).

    Design

    MEDLINE, EMBASE, EMBASE Classic, PsychINFO and the Cochrane Controlled Trials Register were searched (up to June 2015) for RCTs recruiting adults with FD comparing psychotropic drugs with placebo. We contacted authors directly to maximise trial eligibility and minimise risk of bias for studies. Dichotomous symptom data were pooled to obtain relative risk (RR) of remaining symptomatic after therapy, with 95% CIs.

    Results

    The search identified 2795 citations; 13 RCTs (1241 patients) were eligible. Ten trials were at low risk of bias. The RR of FD symptoms not improving with psychotropic drugs versus placebo was 0.78 (95% CI 0.68 to 0.91) (number needed to treat=6; 95% CI 4 to 16). However, benefit was limited to antipsychotics and tricyclic antidepressants. When only studies that excluded individuals with coexistent mood disorder were considered, there was no benefit. Total numbers of adverse events and adverse events leading to withdrawal were significantly more common, with a number needed to harm of 21 for both.

    Conclusions

    Psychotropic drugs may be an effective treatment for FD, but the effect appears to be limited to antipsychotics and tricyclic antidepressants with fewer trials for other agents, meaning that firm conclusions for efficacy cannot be made. More data from high quality RCTs are required to support their use in the treatment of FD.


    Date de mise en ligne : Mercredi 15 février 2017
    Westerlind, H., Mellander, M.-R., Bresso, F., Munch, A., Bonfiglio, F., Assadi, G., Rafter, J., Hübenthal, M., Lieb, W., Källberg, H., Brynedal, B., Padyukov, L., Halfvarson, J., Törkvist, L., Bjork, J., Andreasson, A., Agreus, L., Almer, S., Miehlke, S., Madisch, A., Ohlsson, B., Löfberg, R., Hultcrantz, R., Franke, A., D'Amato, M.
    Dense genotyping of immune-related loci identifies HLA variants associated with increased risk of collagenous colitis
    Objective

    Collagenous colitis (CC) is a major cause of chronic non-bloody diarrhoea, particularly in the elderly female population. The aetiology of CC is unknown, and still poor is the understanding of its pathogenesis. This possibly involves dysregulated inflammation and immune-mediated reactions in genetically predisposed individuals, but the contribution of genetic factors to CC is underinvestigated. We systematically tested immune-related genes known to impact the risk of several autoimmune diseases for their potential CC-predisposing role.

    Design

    Three independent cohorts of histologically confirmed CC cases (N=314) and controls (N=4299) from Sweden and Germany were included in a 2-step association analysis. Immunochip and targeted single nucleotide polymorphism (SNP) genotype data were produced, respectively, for discovery and replication purposes. Classical human leucocyte antigen (HLA) variants at 2-digit and 4-digit resolution were obtained via imputation from single marker genotypes. SNPs and HLA variants passing quality control filters were tested for association with CC with logistic regression adjusting for age, sex and country of origin.

    Results

    Forty-two markers gave rise to genome-wide significant association signals, all contained within the HLA region on chromosome 6 (best p=4.2x10–10 for SNP rs4143332). Among the HLA variants, most pronounced risk effects were observed for 8.1 haplotype alleles including DQ2.5, which was targeted and confirmed in the replication data set (p=2.3x10–11; OR=2.06; 95% CI (1.67 to 2.55) in the combined analysis).

    Conclusions

    HLA genotype associates with CC, thus implicating HLA-related immune mechanisms in its pathogenesis.


    Date de mise en ligne : Mercredi 15 février 2017
    Parseus, A., Sommer, N., Sommer, F., Caesar, R., Molinaro, A., Stahlman, M., Greiner, T. U., Perkins, R., Bäckhed, F.
    Microbiota-induced obesity requires farnesoid X receptor
    Objective

    The gut microbiota has been implicated as an environmental factor that modulates obesity, and recent evidence suggests that microbiota-mediated changes in bile acid profiles and signalling through the bile acid nuclear receptor farnesoid X receptor (FXR) contribute to impaired host metabolism. Here we investigated if the gut microbiota modulates obesity and associated phenotypes through FXR.

    Design

    We fed germ-free (GF) and conventionally raised (CONV-R) wild-type and Fxr–/– mice a high-fat diet (HFD) for 10 weeks. We monitored weight gain and glucose metabolism and analysed the gut microbiota and bile acid composition, beta-cell mass, accumulation of macrophages in adipose tissue, liver steatosis, and expression of target genes in adipose tissue and liver. We also transferred the microbiota of wild-type and Fxr-deficient mice to GF wild-type mice.

    Results

    The gut microbiota promoted weight gain and hepatic steatosis in an FXR-dependent manner, and the bile acid profiles and composition of faecal microbiota differed between Fxr–/– and wild-type mice. The obese phenotype in colonised wild-type mice was associated with increased beta-cell mass, increased adipose inflammation, increased steatosis and expression of genes involved in lipid uptake. By transferring the caecal microbiota from HFD-fed Fxr–/– and wild-type mice into GF mice, we showed that the obesity phenotype was transferable.

    Conclusions

    Our results indicate that the gut microbiota promotes diet-induced obesity and associated phenotypes through FXR, and that FXR may contribute to increased adiposity by altering the microbiota composition.


    Date de mise en ligne : Mercredi 15 février 2017
    van Doorn, S., van der Vlugt, M., Depla, A., Wientjes, C., Mallant-Hent, R., Siersema, P., Tytgat, K., Tuynman, H., Kuiken, S., Houben, G., Stokkers, P., Moons, L., Bossuyt, P., Fockens, P., Mundt, M., Dekker, E.
    Adenoma detection with Endocuff colonoscopy versus conventional colonoscopy: a multicentre randomised controlled trial
    Background and aims

    Colonoscopy is the current reference standard for the detection of colorectal neoplasia, but nevertheless adenomas remain undetected. The Endocuff, an endoscopic cap with plastic projections, may improve colonic visualisation and adenoma detection. The aim of this study was to compare the mean number of adenomas per patient (MAP) and the adenoma detection rate (ADR) between Endocuff-assisted colonoscopy (EAC) and conventional colonoscopy (CC).

    Methods

    We performed a multicentre, randomised controlled trial in five hospitals and included fecal immonochemical test (FIT)-positive screening participants as well as symptomatic patients (>45 years). Consenting patients were randomised 1:1 to EAC or CC. All colonoscopies were performed by experienced colonoscopists (≥500 colonoscopies) who were trained in EAC. All colonoscopy quality indicators were prospectively recorded.

    Findings

    Of the 1063 included patients (52% male, median age 65 years), 530 were allocated to EAC and 533 to CC. More adenomas were detected with EAC, 722 vs 621, but the gain in MAP was not significant: on average 1.36 per patient in the EAC group versus 1.17 in the CC group (p=0.08). In a per-protocol analysis, the gain was 1.44 vs 1.19 (p=0.02), respectively. In the EAC group, 275 patients (52%) had one or more adenomas detected versus 278 in the CC group (52%; p=0.92). For advanced adenomas these numbers were 109 (21%) vs 117 (22%). The adjusted caecal intubation rate was lower with EAC (94% vs 99%; p<0.001), however when allowing crossover from EAC to CC, they were similar in both groups (98% vs 99%; p value=0.25).

    Interpretation

    Though more adenomas are detected with EAC, the routine use of Endocuff does not translate in a higher number of patients with one or more adenomas detected. Whether increased detection ultimately results in a lower rate of interval carcinomas is not yet known.

    Trial registration number

    http://www.trialregister.nl Dutch Trial Register: NTR3962.


    Date de mise en ligne : Mercredi 15 février 2017
    Gupta, S., Jacobs, E. T., Baron, J. A., Lieberman, D. A., Murphy, G., Ladabaum, U., Cross, A. J., Jover, R., Liu, L., Martinez, M. E.
    Risk stratification of individuals with low-risk colorectal adenomas using clinical characteristics: a pooled analysis
    Objective

    For individuals with 1–2 small (<1 cm) low-risk colorectal adenomas, international guidelines range from no surveillance to offering surveillance colonoscopy in 5–10 years. We hypothesised that the risks for metachronous advanced neoplasia (AN) among patients with low-risk adenomas differ based on clinical factors distinct from those currently used.

    Design

    We pooled data from seven prospective studies to assess the risk of metachronous AN. Two groups with 1–2 small adenomas were defined based on guidelines from the UK (n=4516) or the European Union (EU)/US (n=2477).

    Results

    Absolute risk of metachronous AN ranged from a low of 2.9% to a high of 12.2%, depending on specific risk factor and guideline used. For the UK group, the highest absolute risks for metachronous AN were found among individuals with a history of prior polyp (12.2%), villous histology (12.2%), age ≥70 years (10.9%), high-grade dysplasia (10.9%), any proximal adenoma (10.2%), distal and proximal adenoma (10.8%) or two adenomas (10.1%). For the EU/US group, the highest absolute risks for metachronous AN were among individuals with a history of prior polyp (11.5%) or the presence of both proximal and distal adenomas (11.0%). In multivariate analyses, strong associations for increasing age and history of prior polyps and odds of metachronous AN were observed, whereas more modest associations were shown for baseline proximal adenomas and those with villous features.

    Conclusions

    Risks of metachronous AN among individuals with 1–2 small adenomas vary according to readily available clinical characteristics. These characteristics may be considered for recommending colonoscopy surveillance and require further investigation.


    Date de mise en ligne : Mercredi 15 février 2017
    Mennonna, D., Maccalli, C., Romano, M. C., Garavaglia, C., Capocefalo, F., Bordoni, R., Severgnini, M., De Bellis, G., Sidney, J., Sette, A., Gori, A., Longhi, R., Braga, M., Ghirardelli, L., Baldari, L., Orsenigo, E., Albarello, L., Zino, E., Fleischhauer, K., Mazzola, G., Ferrero, N., Amoroso, A., Casorati, G., Parmiani, G., Dellabona, P.
    T cell neoepitope discovery in colorectal cancer by high throughput profiling of somatic mutations in expressed genes
    Objective

    Patient-specific (unique) tumour antigens, encoded by somatically mutated cancer genes, generate neoepitopes that are implicated in the induction of tumour-controlling T cell responses. Recent advancements in massive DNA sequencing combined with robust T cell epitope predictions have allowed their systematic identification in several malignancies.

    Design

    We undertook the identification of unique neoepitopes in colorectal cancers (CRCs) by using high-throughput sequencing of cDNAs expressed by standard cancer cell cultures, and by related cancer stem/initiating cells (CSCs) cultures, coupled with a reverse immunology approach not requiring human leukocyte antigen (HLA) allele-specific epitope predictions.

    Results

    Several unique mutated antigens of CRC, shared by standard cancer and related CSC cultures, were identified by this strategy. CD8+ and CD4+ T cells, either autologous to the patient or derived from HLA-matched healthy donors, were readily expanded in vitro by peptides spanning different cancer mutations and specifically recognised differentiated cancer cells and CSC cultures, expressing the mutations. Neoepitope-specific CD8+ T cell frequency was also increased in a patient, compared with healthy donors, supporting the occurrence of clonal expansion in vivo.

    Conclusions

    These results provide a proof-of-concept approach for the identification of unique neoepitopes that are immunogenic in patients with CRC and can also target T cells against the most aggressive CSC component.


    Date de mise en ligne : Mercredi 15 février 2017
    Moller, P., Seppälä, T., Bernstein, I., Holinski-Feder, E., Sala, P., Evans, D. G., Lindblom, A., Macrae, F., Blanco, I., Sijmons, R., Jeffries, J., Vasen, H., Burn, J., Nakken, S., Hovig, E., Rodland, E. A., Tharmaratnam, K., de Vos tot Nederveen Cappel, W. H., Hill, J., Wijnen, J., Green, K., Lalloo, F., Sunde, L., Mints, M., Bertario, L., Pineda, M., Navarro, M., Morak, M., Renkonen-Sinisalo, L., Frayling, I. M., Plazzer, J.-P., Pylvanainen, K., Sampson, J. R., Capella, G., Mecklin, J.-P., Möslein, G., in collaboration with The Mallorca Group ()
    Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database
    Objective

    Estimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance.

    Design

    We undertook a multicentre study of patients carrying Lynch syndrome-associated mutations affecting MLH1, MSH2, MSH6 or PMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle relational database and analysed by age, sex and mutated gene.

    Results

    1942 mutation carriers without previous cancer had follow-up including colonoscopic surveillance for 13 782 observation years. 314 patients developed cancer, mostly colorectal (n=151), endometrial (n=72) and ovarian (n=19). Cancers were detected from 25 years onwards in MLH1 and MSH2 mutation carriers, and from about 40 years in MSH6 and PMS2 carriers. Among first cancer detected in each patient the colorectal cancer cumulative incidences at 70 years by gene were 46%, 35%, 20% and 10% for MLH1, MSH2, MSH6 and PMS2 mutation carriers, respectively. The equivalent cumulative incidences for endometrial cancer were 34%, 51%, 49% and 24%; and for ovarian cancer 11%, 15%, 0% and 0%. Ten-year crude survival was 87% after any cancer, 91% if the first cancer was colorectal, 98% if endometrial and 89% if ovarian.

    Conclusions

    The four Lynch syndrome-associated genes had different penetrance and expression. Colorectal cancer occurred frequently despite colonoscopic surveillance but resulted in few deaths. Using our data, a website has been established at http://LScarisk.org enabling calculation of cumulative cancer risks as an aid to genetic counselling in Lynch syndrome.


    Date de mise en ligne : Mercredi 15 février 2017
    Hohwieler, M., Illing, A., Hermann, P. C., Mayer, T., Stockmann, M., Perkhofer, L., Eiseler, T., Antony, J. S., Müller, M., Renz, S., Kuo, C.-C., Lin, Q., Sendler, M., Breunig, M., Kleiderman, S. M., Lechel, A., Zenker, M., Leichsenring, M., Rosendahl, J., Zenke, M., Sainz, B., Mayerle, J., Costa, I. G., Seufferlein, T., Kormann, M., Wagner, M., Liebau, S., Kleger, A.
    Human pluripotent stem cell-derived acinar/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling
    Objective

    The generation of acinar and ductal cells from human pluripotent stem cells (PSCs) is a poorly studied process, although various diseases arise from this compartment.

    Design

    We designed a straightforward approach to direct human PSCs towards pancreatic organoids resembling acinar and ductal progeny.

    Results

    Extensive phenotyping of the organoids not only shows the appropriate marker profile but also ultrastructural, global gene expression and functional hallmarks of the human pancreas in the dish. Upon orthotopic transplantation into immunodeficient mice, these organoids form normal pancreatic ducts and acinar tissue resembling fetal human pancreas without evidence of tumour formation or transformation. Finally, we implemented this unique phenotyping tool as a model to study the pancreatic facets of cystic fibrosis (CF). For the first time, we provide evidence that in vitro, but also in our xenograft transplantation assay, pancreatic commitment occurs generally unhindered in CF. Importantly, cystic fibrosis transmembrane conductance regulator (CFTR) activation in mutated pancreatic organoids not only mirrors the CF phenotype in functional assays but also at a global expression level. We also conducted a scalable proof-of-concept screen in CF pancreatic organoids using a set of CFTR correctors and activators, and established an mRNA-mediated gene therapy approach in CF organoids.

    Conclusions

    Taken together, our platform provides novel opportunities to model pancreatic disease and development, screen for disease-rescuing agents and to test therapeutic procedures.


    Date de mise en ligne : Mercredi 15 février 2017
    Masamune, A., Nishimori, I., Kikuta, K., Tsuji, I., Mizuno, N., Iiyama, T., Kanno, A., Tachibana, Y., Ito, T., Kamisawa, T., Uchida, K., Hamano, H., Yasuda, H., Sakagami, J., Mitoro, A., Taguchi, M., Kihara, Y., Sugimoto, H., Hirooka, Y., Yamamoto, S., Inui, K., Inatomi, O., Andoh, A., Nakahara, K., Miyakawa, H., Hamada, S., Kawa, S., Okazaki, K., Shimosegawa, T., for the Research Committee of Intractable Pancreas Diseases in Japan
    Randomised controlled trial of long-term maintenance corticosteroid therapy in patients with autoimmune pancreatitis
    Objective

    Corticosteroid has been established as the standard therapy for autoimmune pancreatitis (AIP), but the requirement for maintenance corticosteroid therapy is controversial. We conducted a randomised controlled trial to clarify the efficacy of maintenance corticosteroid therapy in patients with AIP.

    Design

    We conducted a multicentre, tertiary setting, randomised controlled trial. After the induction of remission with the initial oral prednisolone (PSL) treatment, maintenance therapy with PSL at 5–7.5 mg/day was continued for 3 years or withdrawn at 26 weeks. The primary endpoint was relapse-free survival over 3 years and the secondary endpoint was serious corticosteroid-related complications. All analyses were performed on an intention-to-treat basis.

    Results

    Between April 2009 and March 2012, 49 patients with AIP were randomly assigned to the maintenance therapy group (n=30) or the cessation group (n=19). Baseline characteristics were not different between the two groups. Relapses occurred within 3 years in 11 out of 19 (57.9%) patients assigned to the cessation group, and in 7 of 30 (23.3%) patients in the maintenance therapy group. The relapse rate over 3 years was significantly lower in the maintenance therapy group than that in the cessation group (p=0.011). The relapse-free survival was significantly longer in the maintenance therapy group than that in the cessation group (p=0.007). No serious corticosteroid-related complications requiring discontinuation of PSL were observed.

    Conclusions

    Maintenance corticosteroid therapy for 3 years may decrease relapses in patients with AIP compared with those who discontinued the therapy at 26 weeks.

    Trial registration number

    UMIN000001818; Results.


    Date de mise en ligne : Mercredi 15 février 2017
    Crippa, S., Bassi, C., Salvia, R., Malleo, G., Marchegiani, G., Rebours, V., Levy, P., Partelli, S., Suleiman, S. L., Banks, P. A., Ahmed, N., Chari, S. T., Fernandez-del Castillo, C., Falconi, M.
    Low progression of intraductal papillary mucinous neoplasms with worrisome features and high-risk stigmata undergoing non-operative management: a mid-term follow-up analysis
    Objective

    To evaluate mid-term outcomes and predictors of survival in non-operated patients with pancreatic intraductal papillary mucinous neoplasms (IPMNs) with worrisome features or high-risk stigmata as defined by International Consensus Guidelines for IPMN. Reasons for non-surgical options were physicians’ recommendation, patient personal choice or comorbidities precluding surgery.

    Methods

    In this retrospective, multicentre analysis, IPMNs were classified as branch duct (BD) and main duct (MD), the latter including mixed IPMNs. Univariate and multivariate analysis for overall survival (OS) and disease-specific survival (DSS) were obtained.

    Results

    Of 281 patients identified, 159 (57%) had BD-IPMNs and 122 (43%) had MD-IPMNs; 50 (18%) had high-risk stigmata and 231 (82%) had worrisome features. Median follow-up was 51 months. The 5-year OS and DSS for the entire cohort were 81% and 89.9%. An invasive pancreatic malignancy developed in 34 patients (12%); 31 had invasive IPMNs (11%) and 3 had IPMN-distinct pancreatic ductal adenocarcinoma (1%). Independent predictors of poor DSS in the entire cohort were age >70 years, atypical/malignant cyst fluid cytology, jaundice and MD >15 mm. Compared with MD-IPMNs, BD-IPMNs had significantly better 5-year OS (86% vs 74.1%, p=0.002) and DSS (97% vs 81.2%, p<0.0001). Patients with worrisome features had better 5-year DSS compared with those with high-risk stigmata (96.2% vs 60.2%, p<0.0001).

    Conclusions

    In elderly patients with IPMNs that have worrisome features, the 5-year DSS is 96%, suggesting that conservative management is appropriate. By contrast, presence of high-risk stigmata is associated with a 40% risk of IPMN-related death, reinforcing that surgical resection should be offered to fit patients.


    Date de mise en ligne : Mercredi 15 février 2017
    Hackstein, C.-P., Assmus, L. M., Welz, M., Klein, S., Schwandt, T., Schultze, J., Förster, I., Gondorf, F., Beyer, M., Kroy, D., Kurts, C., Trebicka, J., Kastenmüller, W., Knolle, P. A., Abdullah, Z.
    Gut microbial translocation corrupts myeloid cell function to control bacterial infection during liver cirrhosis
    Objective

    Patients with liver cirrhosis suffer from increased susceptibility to life-threatening bacterial infections that cause substantial morbidity.

    Methods

    Experimental liver fibrosis in mice induced by bile duct ligation or CCl4 application was used to characterise the mechanisms determining failure of innate immunity to control bacterial infections.

    Results

    In murine liver fibrosis, translocation of gut microbiota induced tonic type I interferon (IFN) expression in the liver. Such tonic IFN expression conditioned liver myeloid cells to produce high concentrations of IFN upon intracellular infection with Listeria that activate cytosolic pattern recognition receptors. Such IFN-receptor signalling caused myeloid cell interleukin (IL)-10 production that corrupted antibacterial immunity, leading to loss of infection-control and to infection-associated mortality. In patients with liver cirrhosis, we also found a prominent liver IFN signature and myeloid cells showed increased IL-10 production after bacterial infection. Thus, myeloid cells are both source and target of IFN-induced and IL-10-mediated immune dysfunction. Antibody-mediated blockade of IFN-receptor or IL-10-receptor signalling reconstituted antibacterial immunity and prevented infection-associated mortality in mice with liver fibrosis.

    Conclusions

    In severe liver fibrosis and cirrhosis, failure to control bacterial infection is caused by augmented IFN and IL-10 expression that incapacitates antibacterial immunity of myeloid cells. Targeted interference with the immune regulatory host factors IL-10 and IFN reconstitutes antibacterial immunity and may be used as therapeutic strategy to control bacterial infections in patients with liver cirrhosis.


    Date de mise en ligne : Mercredi 15 février 2017
    Vergis, N., Khamri, W., Beale, K., Sadiq, F., Aletrari, M. O., Moore, C., Atkinson, S. R., Bernsmeier, C., Possamai, L. A., Petts, G., Ryan, J. M., Abeles, R. D., James, S., Foxton, M., Hogan, B., Foster, G. R., O'Brien, A. J., Ma, Y., Shawcross, D. L., Wendon, J. A., Antoniades, C. G., Thursz, M. R.
    Defective monocyte oxidative burst predicts infection in alcoholic hepatitis and is associated with reduced expression of NADPH oxidase
    Objective

    In order to explain the increased susceptibility to serious infection in alcoholic hepatitis, we evaluated monocyte phagocytosis, aberrations of associated signalling pathways and their reversibility, and whether phagocytic defects could predict subsequent infection.

    Design

    Monocytes were identified from blood samples of 42 patients with severe alcoholic hepatitis using monoclonal antibody to CD14. Phagocytosis and monocyte oxidative burst (MOB) were measured ex vivo using flow cytometry, luminometry and bacterial killing assays. Defects were related to the subsequent development of infection. Intracellular signalling pathways were investigated using western blotting and PCR. Interferon- (IFN-) was evaluated for its therapeutic potential in reversing phagocytic defects. Paired longitudinal samples were used to evaluate the effect of in vivo prednisolone therapy.

    Results

    MOB, production of superoxide and bacterial killing in response to Escherichia coli were markedly impaired in patients with alcoholic hepatitis. Pretreatment MOB predicted development of infection within two weeks with sensitivity and specificity that were superior to available clinical markers. Accordingly, defective MOB was associated with death at 28 and 90 days. Expression of the gp91phox subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase was reduced in patients with alcoholic hepatitis demonstrating defective MOB. Monocytes were refractory to IFN- stimulation and showed high levels of a negative regulator of cytokine signalling, suppressor of cytokine signalling-1. MOB was unaffected by 7 days in vivo prednisolone therapy.

    Conclusions

    Monocyte oxidative burst and bacterial killing is impaired in alcoholic hepatitis while bacterial uptake by phagocytosis is preserved. Defective MOB is associated with reduced expression of NADPH oxidase in these patients and predicts the development of infection and death.


    Date de mise en ligne : Mercredi 15 février 2017
    Tovar, V., Cornella, H., Moeini, A., Vidal, S., Hoshida, Y., Sia, D., Peix, J., Cabellos, L., Alsinet, C., Torrecilla, S., Martinez-Quetglas, I., Lozano, J. J., Desbois-Mouthon, C., Sole, M., Domingo-Domenech, J., Villanueva, A., Llovet, J. M.
    Tumour initiating cells and IGF/FGF signalling contribute to sorafenib resistance in hepatocellular carcinoma
    Objective

    Sorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterise the role of tumour-initiating cells (T-ICs) and signalling pathways involved in sorafenib resistance.

    Design

    HCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: (1) role of T-ICs by in vitro sphere formation and in vivo tumourigenesis assays using NOD/SCID mice, (2) activation of alternative signalling pathways and (3) efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, quantitative real-time PCR (qRT-PCR)) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in two independent cohorts.

    Results

    Sorafenib-acquired resistant tumours showed significant enrichment of T-ICs (164 cells needed to create a tumour) versus sorafenib-sensitive tumours (13 400 cells) and non-treated tumours (1292 cells), p<0.001. Tumours with sorafenib-acquired resistance were enriched with insulin-like growth factor (IGF) and fibroblast growth factor (FGF) signalling cascades (false discovery rate (FDR)<0.05). In vitro, cells derived from sorafenib-acquired resistant tumours and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumour growth and improved survival in sorafenib-resistant tumours. A sorafenib-resistance 175 gene signature was characterised by enrichment of progenitor cell features, aggressive tumorous traits and predicted poor survival in two cohorts (n=442 patients with HCC).

    Conclusions

    Acquired resistance to sorafenib is driven by T-ICs with enrichment of progenitor markers and activation of IGF and FGF signalling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression.


    Date de mise en ligne : Mercredi 15 février 2017
    Hernaez, R., Sola, E., Moreau, R., Gines, P.
    Acute-on-chronic liver failure: an update

    Acute-on-chronic liver failure (ACLF) is a syndrome characterised by acute decompensation of chronic liver disease associated with organ failures and high short-term mortality. Alcohol and chronic viral hepatitis are the most common underlying liver diseases. Up to 40%–50% of the cases of ACLF have no identifiable trigger; in the remaining patients, sepsis, active alcoholism and relapse of chronic viral hepatitis are the most common reported precipitating factors. An excessive systemic inflammatory response seems to play a crucial role in the development of ACLF. Using a liver-adapted sequential organ assessment failure score, it is possible to triage and prognosticate the outcome of patients with ACLF. The course of ACLF is dynamic and changes over the course of hospital admission. Most of the patients will have a clear prognosis between day 3 and 7 of hospital admission and clinical decisions such as evaluation for liver transplant or discussion over goals of care could be tailored using clinical scores. Bioartificial liver support systems, granulocyte-colony stimulating factors or stem-cell transplant are in the horizon of medical care of this patient population; however, data are too premature to implement them as standard of care.


    Date de mise en ligne : Mercredi 15 février 2017
    Tian-Zhi, L., Leong Qi Hui, F., Tan, K.-K.
    Don't mistake it as a polyp!
    CLINICAL PRESENTATION

    A middle-aged woman first presented with vague abdominal symptoms of bloatedness and change in bowel habits. Physical examination was otherwise unremarkable. A colonoscopic evaluation was performed, which demonstrated a possible appendiceal mass (figure 1). A CT scan of the abdomen and pelvis was performed, which confirmed the bulky appendix (figure 2).

    In view of the indeterminate nature of the lesion and inability to rule out an underlying neoplastic process, the patient was counselled for surgical resection of the appendix, with the possibility of a limited right hemicolectomy.

    Intraoperatively, the right ovary and fallopian tube were densely adherent to the caecal pole (figure 3). The appendix was not discernable even with open dissection, although a palpable mass was present in the caecum. As such, an ileo-caecectomy was performed. The specimen was cut open which revealed a bulky appendiceal prominence in the...


    Date de mise en ligne : Mercredi 15 février 2017
    McLean, M. H.
    GI highlights from the literature
    Basic scienceMutation burden in cancer cells

    Blokzijl F, de Ligt J, Jager M, et al. Tissue-specific mutation accumulation in human adult stem cells during life. Nature 2016;538:260–4.

    In cancer, stem cells are thought to be the primary target for genetic defects due to the fact that they live far longer than any differentiated cells; however, no accurate estimation of the mutation rate in human tissue stem cells (particularly colon, small intestine and liver) has been established. Here, the authors have generated 45 organoid cultures, from 19 donors ranging in age from 3 to 87 years, from stem cells extracted from colon, small intestine and liver specimens. There is a much higher rate of cancer incidence in the human colon compared with small intestine and liver and the authors test whether this is reflected in the mutation burden and pattern in the organoids. They performed whole genome sequencing...


    Date de mise en ligne : Mercredi 15 février 2017
    Friedman, S., Larsen, P. V., Fedder, J., Norgard, B. M.
    The reduced chance of a live birth in women with IBD receiving assisted reproduction is due to a failure to achieve a clinical pregnancy

    We recently reported that for women with UC receiving assisted reproductive technology (ART) treatment, the chance of a live birth after each embryo transfer cycle decreased significantly. In women with Crohn's disease (CD), the chance of a live birth after each embryo transfer cycle also decreased but was not significant in the fully adjusted regression model.1 In our study, we chose the outcome live birth because it was the most important clinical outcome for patients with UC and CD undergoing ART. After demonstrating the negative effects of UC and CD on chances of live birth, we wish to update our readers by exploring where along the process from fertilisation through pregnancy the risk of delivering a live born child decreases. Is the reduced chance of live birth due to (1) a reduced chance of conceiving after an ART cycle? and/or (2) a reduced chance of maintaining a...


    Date de mise en ligne : Mercredi 15 février 2017
    Lankelma, J. M., Schuijt, T. J., Wiersinga, W. J.
    Reply to letter to the editor of Gut by Dickson and Cox

    Dear editor,

    We are thankful for the letter of Drs Dickson and Cox in response to our paper on the effect of the intestinal microbiota on host responses during pneumococcal pneumonia.1 We do agree that we cannot rule out that the antibiotics we used in our experiments could have influenced the microbiota in the airways and we do underwrite the importance of studying local host–microbe interactions within the respiratory tract during pneumonia. However, some points need to be addressed.

    The relative importance of the microbiota of the lower airways, the area where alveolar macrophages reside, is a matter of debate. A study in humans showed that the microbiota that was sampled from the lower airways was mostly a reflection of contamination of the bronchoscope during passage through the upper airways.2 We think the articles cited by Dickson et al are of importance, but do not...


    Date de mise en ligne : Mercredi 15 février 2017
    Jansen, C., Bogs, C., Krag, A., Francque, S., Trebicka, J.
    Sequential shear-wave elastography of liver and spleen rules out clinically significant portal hypertension in compensated advanced chronic liver disease

    With interest we read the letter entitled ‘Ruling in and ruling out with elastography in compensated advanced chronic liver disease’ by Agustin et al1 to our study ‘Algorithm to rule-out clinically significant portal hypertension combining Shear-wave elastography of liver and spleen: a prospective multi-centre study’.2 Indeed, we would like to thank our colleagues for their interest in our study and deciphering the strengths and weaknesses of this study. Besides acknowledging the merits of the study, the colleagues commented on the selection of patients regarding severity and aetiology of advanced chronic liver disease (ACLD), as well as the clinical importance of ruling out or ruling in clinically significant portal hypertension (CSPH).

    The criticism about the selection of patients stimulated us to perform new calculations. Even though the algorithm was calculated including patients with decompensated ACLD (dACLD), it performed much better in patients with compensated ACLD (


    Date de mise en ligne : Mercredi 15 février 2017
    Hadizadeh, F., Walter, S., Belheouane, M., Bonfiglio, F., Heinsen, F.-A., Andreasson, A., Agreus, L., Engstrand, L., Baines, J. F., Rafter, J., Franke, A., D'Amato, M.
    Stool frequency is associated with gut microbiota composition

    We read with great interest the two recent communications by Vandeputte et al1 and Tigchelaar et al,2 which reported an association between stool consistency and gut microbiota composition. Both studies focused on stool consistency, based on the Bristol Stool Scale (BSS) as the main trait, due to its reported correlation with colonic transit time (CTT) that is of clinical relevance for several GI conditions. However, stool frequency, another feature of human bowel function that is easy to measure and record, has also been shown to correlate with CTT,3 4 although to a lesser extent than stool form, and has not yet been investigated in relation to microbiota composition.

    We examined the association between gut microbiota and stool frequency in the Population-based Colonoscopy study, a general population-based cohort from Stockholm, Sweden, previously described in detail.5 Sixty-nine individuals (21 males and...


    Date de mise en ligne : Mercredi 15 février 2017
    Veitch, A., Dumonceau, J.-M.
    Author response to letter: colonic stenting in patients on P2Y12 receptor antagonists and direct oral anticoagulants--are current BSG/ESGE guidelines practical?

    We thank the authors for their interest in the recently published British Society of Gastroenterology and European Society of Gastrointestinal Endoscopy (ESGE) guidelines on endoscopy in patients on antiplatelet or anticoagulant therapy.1 As stated in the summary of recommendations, these guidelines refer to the management of elective endoscopic procedures. For elective palliative colonic stenting, there is often adequate time to discontinue antithrombotic therapy, including P2Y12 antagonists. In an emergency situation, we agree with the authors that the balance of risk between haemorrhage due to stenting versus death due to colonic obstruction would favour endoscopic stenting. Importantly, stenting in this context is controversial, and ESGE guidelines recommend this only for those at high risk of postoperative mortality.2 The patient should be consented accordingly in this high-risk situation.

    We are also grateful to the authors for highlighting the potential use of idarucizumab as a reversal agent for...


    Date de mise en ligne : Mercredi 15 février 2017
    Wang, L., Xia, J., Wang, L., Wang, Y.
    Experimental infection of rabbits with genotype 3 hepatitis E virus produced both chronicity and kidney injury

    Dear Editor,

    We read with great interest the elegant work of Sayed et al,1 which established a mouse model for chronic hepatitis E virus (HEV) infections. The study showed that mice with humanised livers could be infected with both HEV-1 and HEV-3 and develop a chronic viral infection. The establishment of this model meets the urgent need for a research animal model to study chronic hepatitis E infection as increasing cases of such infections have been reported in immunocompromised patients.2 We have recently reported on a chronic hepatitis E case caused by HEV-4 in a woman with nephritic syndrome.3 HEV RNA and antigen were detected in the patient's urine and HEV RNA-positive urine successfully induced infection in Cynomolgus monkeys.3 We agree with the claim made by Sayed et al1 that their model may allow the unravelling of the potential...