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Thank you to our reviewers 2017

2018-02-08T08:00:42-08:00

The Editor would like to publicly acknowledge the people listed below who served as reviewers on the journal during 2017. Without their efforts, the quality of the journal could not be sustained.

Abraham, Clara

Abreu, Maria

Acosta, Andres

Adachi, Yasushi

Adams, Leon

Adan, Roger

Aden, Konrad

Adolph, Timon

Agace, William

Agarwal, Kosh

Aghemo, Alessio

Aguirre-Ghiso, Julio

Ainsworth, Mark

Ajani, Jaffer

Albano, Emmanuel

Aldini, Giancarlo

Alfa, Michelle

Algül, Hana

Allavena, Paola

Allen, Heather

Allez, Matthieu

Almeida, Raquel

Amieva, Manuel

Ananthakrishnan, Ashwin

Anderson, John

Andrea, De Gottardi

Andrisani, Ourania

Angeli, Paolo

Anhê, Fernando

Annese, Vito

Annicotte, Jean-Sébastien

Antoine, Daniel

Antoniades, Charalambos

Apte, Udayan

Arabzadeh, Azadeh

Armuzzi, Alessandro

Arvanitakis, Marianna

Asaka, Masahiro

Aspichueta, Patricia

Asselah, Tarik

Atreya, Raja

Augustin Recio, Salvador

Bae, Jin-Woo

Baek, Moo-Jun

Baines, John

Baio, Gabriella

Baird, D M

Bajaj, Jasmohan

Bantel, Heike

Barbara, Giovanni

Bardou, Marc

Barnich, Nicolas

Barrett, Kim

Bartenschlager, Ralf

Bartfeld, Sina

Barth-Jaeggi, Tanja

Bartosch, Birke

...



Non-coding regulatory variations: the dark matter of pancreatic cancer genomics

2018-02-08T08:00:42-08:00

Pancreatic ductal adenocarcinoma (PDAC) is the seventh cause of death for cancer worldwide and the third in the USA, where it is expected to become the second by year 2030. Unlike other cancers, little progress has been made when it comes to therapeutic options other than surgery, which is possible only for a small fraction (~20%) of patients presenting with localised disease.1 2

For the above reasons, large efforts have been undertaken to get a deeper understanding of the molecular alterations and their effects on cancer cells and tumour microenvironment, by exploiting both innovative disease models and high-throughput studies for genomic and transcriptomic profiling of PDAC.3 4 In the meanwhile, genome-wide association studies, and the study of familial pancreatic cancer, have been looking for and found genetic variations associated to PDAC onset and outcome.5 6

At the...




Chronic hepatitis B: divide and conquer?

2018-02-08T08:00:42-08:00

Chronic hepatitis B (CHB) puts 250 million people or more at a greatly increased risk to develop terminal liver disease.1 The causative agent, hepatitis B virus (HBV), is a small hepatotropic DNA virus that replicates via reverse transcription.2 Persistence of infection is the combined result of an inadequate host immune response3 and the stability of a special episomal form of the virus genome termed covalently closed circular (ccc) DNA.4 5 Associating with host and viral proteins into a minichromosome, cccDNA serves as template for all viral RNAs and thus progeny virions (figure 1). A true cure of CHB would thus require elimination of cccDNA from a patient’s liver; this is rarely achieved by current CHB therapies with type I interferon or nucleos(t)ide analogues (NAs) which inhibit HBV reverse transcription. Also, none of the new anti-HBV drugs in clinical...




Can we prevent and modify cardiometabolic disorders by controlling HCV infection?

2018-02-08T08:00:42-08:00

What is known about HCV comorbidities and viral clearance?

HCV infection has an estimated global prevalence of 1.0%, corresponding to roughly 71.1 million of infected individuals in 2015, with major geographical heterogeneity.1 Due to the large burden of infected individuals in the general population, the likelihood of co-occurrence of chronic HCV infection and common comorbidities is substantial regardless of causal linkages. Population-based studies show a higher overall mortality, both for liver-related and unrelated causes in HCV infected subjects compared with those uninfected, and cross-sectional and cohort studies identify HCV as an independent risk factor for extrahepatic manifestations.2 These issues are summarised in two meta-analyses reporting that HCV-infected patients are at higher risk of mixed cryoglobulinaemia, lymphoma, lichen planus, Sjögren’s syndrome, porphyria cutanea tarda, rheumatoid-like arthritis, depression, chronic kidney or end-stage renal disease, type 2 diabetes and cardiovascular disorders/mortality.3 4 While the...




Management of patients on antithrombotic agents undergoing emergency and elective endoscopy: joint Asian Pacific Association of Gastroenterology (APAGE) and Asian Pacific Society for Digestive Endoscopy (APSDE) practice guidelines

2018-02-08T08:00:42-08:00

This Guideline is a joint official statement of the Asian Pacific Association of Gastroenterology (APAGE) and the Asian Pacific Society for Digestive Endoscopy (APSDE). It was developed in response to the increasing use of antithrombotic agents (antiplatelet agents and anticoagulants) in patients undergoing gastrointestinal (GI) endoscopy in Asia. After reviewing current practice guidelines in Europe and the USA, the joint committee identified unmet needs, noticed inconsistencies, raised doubts about certain recommendations and recognised significant discrepancies in clinical practice between different regions. We developed this joint official statement based on a systematic review of the literature, critical appraisal of existing guidelines and expert consensus using a two-stage modified Delphi process. This joint APAGE-APSDE Practice Guideline is intended to be an educational tool that assists clinicians in improving care for patients on antithrombotics who require emergency or elective GI endoscopy in the Asian Pacific region.




Cancer incidence and mortality risks in a large US Barrett's oesophagus cohort

2018-02-08T08:00:42-08:00

Objective

Barrett's oesophagus (BE) increases the risk of oesophageal adenocarcinoma by 10–55 times that of the general population, but no community-based cancer-specific incidence and cause-specific mortality risk estimates exist for large cohorts in the USA.

Design

Within Kaiser Permanente Northern California (KPNC), we identified patients with BE diagnosed during 1995–2012. KPNC cancer registry and mortality files were used to estimate standardised incidence ratios (SIR), standardised mortality ratios (SMR) and excess absolute risks.

Results

There were 8929 patients with BE providing 50 147 person-years of follow-up. Compared with the greater KPNC population, patients with BE had increased risks of any cancer (SIR=1.40, 95% CI 1.31 to 1.49), which slightly decreased after excluding oesophageal cancer. Oesophageal adenocarcinoma risk was increased 24 times, which translated into an excess absolute risk of 24 cases per 10 000 person-years. Although oesophageal adenocarcinoma risk decreased with time since BE diagnosis, oesophageal cancer mortality did not, indicating that the true risk is stable and persistent with time. Relative risks of cardia and stomach cancers were increased, but excess absolute risks were modest. Risks of colorectal, lung and prostate cancers were unaltered. All-cause mortality was slightly increased after excluding oesophageal cancer (SMR=1.24, 95% CI 1.18 to 1.31), but time-stratified analyses indicated that this was likely attributable to diagnostic bias. Cause-specific SMRs were elevated for ischaemic heart disease (SMR=1.39, 95% CI 1.18 to 1.63), respiratory system diseases (SMR=1.51, 95% CI 1.29 to 1.75) and digestive system diseases (SMR=2.20 95% CI 1.75 to 2.75).

Conclusions

Patients with BE had a persistent excess risk of oesophageal adenocarcinoma over time, although their absolute excess risks for this cancer, any cancer and overall mortality were modest.




Global prevalence of, and risk factors for, gastro-oesophageal reflux symptoms: a meta-analysis

2018-02-08T08:00:42-08:00

Objectives

Gastro-oesophageal reflux symptoms are common in the community, but there has been no definitive systematic review and meta-analysis of data from all studies to estimate their global prevalence, or potential risk factors for them.

Design

Medline, Embase and Embase Classic were searched (until September 2016) to identify population-based studies that reported the prevalence of gastro-oesophageal reflux symptoms in adults (≥15 years); gastro-oesophageal reflux was defined using symptom-based criteria or questionnaires. The prevalence was extracted for all studies, and according to the criteria used to define it. Pooled prevalence, according to study location and certain other characteristics, OR and 95% CIs were calculated.

Results

Of the 14 132 citations evaluated, 102 reported the prevalence of gastro-oesophageal reflux symptoms in 108 separate study populations, containing 460 984 subjects. Prevalence varied according to country (from 2.5% in China to 51.2% in Greece) and criteria used to define gastro-oesophageal reflux symptoms. When only studies using a weekly frequency of heart burn or regurgitation to define presence were considered, pooled prevalence was 13.3% (95% CI 12.0% to 14.6%). Prevalence was higher in subjects ≥50 years (OR 1.32; 95% CI 1.12 to 1.54), smokers (OR 1.26; 95% CI 1.04 to 1.52), non-steroidal anti-inflammatory drug (NSAID)/aspirin users (OR 1.44; 95% CI 1.10 to 1.88) and obese individuals (OR 1.73; 95% CI 1.46 to 2.06).

Conclusions

The prevalence of gastro-oesophageal reflux symptoms varied strikingly among countries, even when similar definitions were used to define their presence. Prevalence was significantly higher in subjects ≥50 years, smokers, NSAID users and obese individuals, although these associations were modest.




Development of a Microscopic Colitis Disease Activity Index: a prospective cohort study

2018-02-08T08:00:42-08:00

Objective

Microscopic colitis (MC) is a common cause of chronic diarrhoea, often with additional symptoms. No validated instruments exist to assess disease activity in MC, making it difficult to compare efficacy of treatments between clinical trials. We aimed to identify clinical features that independently predicted disease severity and create a Microscopic Colitis Disease Activity Index (MCDAI).

Design

Patients with MC were prospectively administered a survey assessing their GI symptoms and the IBD Questionnaire (IBDQ). A single investigator also scored a physician global assessment (PGA) of disease severity on a 10-point scale. Multiple linear regression identified which symptoms best predicted the PGA. These symptoms were then combined in a weighted formula to create the MCDAI. The relationship between MCDAI and the IBDQ was investigated.

Results

Of the 175 patients enrolled, 13 (7.4%) did not complete the survey. The remaining 162 had a median age of 66 years (range, 57–73) and 74% were female. Several clinical features were independently associated with PGA (number of unformed stools daily, presence of nocturnal stools, abdominal pain, weight loss, faecal urgency and faecal incontinence). These parameters were combined to create the MCDAI, which strongly predicted the PGA (R2=0.80). A 1-unit decrease in disease activity (MCDAI) was associated with a 9-unit increase in quality of life (IBDQ).

Conclusions

The MCDAI strongly predicted the PGA and correlated with a validated measure of quality of life. Several symptoms in addition to diarrhoea are associated with disease severity in MC.




Double somatic mutations in mismatch repair genes are frequent in colorectal cancer after Hodgkin's lymphoma treatment

2018-02-08T08:00:42-08:00

Objective

Hodgkin's lymphoma survivors who were treated with infradiaphragmatic radiotherapy or procarbazine-containing chemotherapy have a fivefold increased risk of developing colorectal cancer (CRC). This study aims to provide insight into the development of therapy-related CRC (t-CRC) by evaluating histopathological and molecular characteristics.

Design

54 t-CRCs diagnosed in a Hodgkin's lymphoma survivor cohort were analysed for mismatch repair (MMR) proteins by immunohistochemistry, microsatellite instability (MSI) and KRAS/BRAF mutations. MSI t-CRCs were evaluated for promoter methylation and mutations in MMR genes. Pathogenicity of MMR gene mutations was evaluated by in silico predictions and functional analyses. Frequencies were compared with a general population cohort of CRC (n=1111).

Results

KRAS and BRAF mutations were present in 41% and 15% t-CRCs, respectively. Compared with CRCs in the general population, t-CRCs had a higher MSI frequency (24% vs 11%, p=0.003) and more frequent loss of MSH2/MSH6 staining (13% vs 1%, p<0.001). Loss of MLH1/PMS2 staining and MLH1 promoter methylation were equally common in t-CRCs and the general population. In MSI CRCs without MLH1 promoter methylation, double somatic MMR gene mutations (or loss of heterozygosity as second hit) were detected in 7/10 (70%) t-CRCs and 8/36 (22%) CRCs in the general population (p=0.008). These MMR gene mutations in t-CRCs were classified as pathogenic. MSI t-CRC cases could not be ascribed to Lynch syndrome.

Conclusions

We have demonstrated a higher frequency of MSI among t-CRCs, which results from somatic MMR gene mutations. This suggests a novel association of somatic MMR gene mutations with prior anticancer treatment.




Modifiable lifestyle factors associated with risk of sessile serrated polyps, conventional adenomas and hyperplastic polyps

2018-02-08T08:00:42-08:00

Objective

To identify modifiable factors associated with sessile serrated polyps (SSPs) and compare the association of these factors with conventional adenomas (ADs) and hyperplastic polyps (HPs).

Design

We used data from the Tennessee Colorectal Polyp Study, a colonoscopy-based case–control study. Included were 214 SSP cases, 1779 AD cases, 560 HP cases and 3851 polyp-free controls.

Results

Cigarette smoking was associated with increased risk for all polyps and was stronger for SSPs than for ADs (OR 1.74, 95% CI 1.16 to 2.62, for current vs never, ptrend=0.008). Current regular use of non-steroidal anti-inflammatory drugs was associated with a 40% reduction in SSP risk in comparison with never users (OR 0.68, 95% CI 0.48 to 0.96, ptrend=0.03), similar to the association with AD. Red meat intake was strongly associated with SSP risk (OR 2.59, 95% CI 1.41 to 4.74 for highest vs lowest intake, ptrend<0.001) and the association with SSP was stronger than with AD (ptrend=0.003). Obesity, folate intake, fibre intake and fat intake were not associated with SSP risk after adjustment for other factors. Exercise, alcohol use and calcium intake were not associated with risk for SSPs.

Conclusions

SSPs share some modifiable risk factors for ADs, some of which are more strongly associated with SSPs than ADs. Thus, preventive efforts to reduce risk for ADs may also be applicable to SSPs. Additionally, SSPs have some distinctive risk factors. Future studies should evaluate the preventive strategies for these factors. The findings from this study also contribute to an understanding of the aetiology and biology of SSPs.




Meat intake and risk of diverticulitis among men

2018-02-08T08:00:42-08:00

Objective

Diverticulitis is a common disease with a substantial clinical and economic burden. Besides dietary fibre, the role of other foods in the prevention of diverticulitis is underexplored.

Design

We prospectively examined the association between consumption of meat (total red meat, red unprocessed meat, red processed meat, poultry and fish) with risk of incident diverticulitis among 46 461 men enrolled in the Health Professionals Follow-Up Study (1986–2012). Cox proportional hazards models were used to compute relative risks (RRs) and 95% CIs.

Results

During 651 970 person-years of follow-up, we documented 764 cases of incident diverticulitis. Compared with men in the lowest quintile (Q1) of total red meat consumption, men in the highest quintile (Q5) had a multivariable RR of 1.58 (95% CI 1.19 to 2.11; p for trend=0.01). The increase in risk was non-linear, plateauing after six servings per week (p for non-linearity=0.002). The association was stronger for unprocessed red meat (RR for Q5 vs Q1: 1.51; 95% CI 1.12 to 2.03; p for trend=0.03) than for processed red meat (RR for Q5 vs Q1: 1.03; 95% CI 0.78 to 1.35; p for trend=0.26). Higher consumption of poultry or fish was not associated with risk of diverticulitis. However, the substitution of poultry or fish for one serving of unprocessed red meat per day was associated with a decrease in risk of diverticulitis (multivariable RR 0.80; 95% CI 0.63 to 0.99).

Conclusions

Red meat intake, particularly unprocessed red meat, was associated with an increased risk of diverticulitis. The findings provide practical dietary guidance for patients at risk of diverticulitis.




Protein and glycomic plasma markers for early detection of adenoma and colon cancer

2018-02-08T08:00:42-08:00

Objective

To discover and confirm blood-based colon cancer early-detection markers.

Design

We created a high-density antibody microarray to detect differences in protein levels in plasma from individuals diagnosed with colon cancer <3 years after blood was drawn (ie, prediagnostic) and cancer-free, matched controls. Potential markers were tested on plasma samples from people diagnosed with adenoma or cancer, compared with controls. Components of an optimal 5-marker panel were tested via immunoblotting using a third sample set, Luminex assay in a large fourth sample set and immunohistochemistry (IHC) on tissue microarrays.

Results

In the prediagnostic samples, we found 78 significantly (t-test) increased proteins, 32 of which were confirmed in the diagnostic samples. From these 32, optimal 4-marker panels of BAG family molecular chaperone regulator 4 (BAG4), interleukin-6 receptor subunit beta (IL6ST), von Willebrand factor (VWF) and CD44 or epidermal growth factor receptor (EGFR) were established. Each panel member and the panels also showed increases in the diagnostic adenoma and cancer samples in independent third and fourth sample sets via immunoblot and Luminex, respectively. IHC results showed increased levels of BAG4, IL6ST and CD44 in adenoma and cancer tissues. Inclusion of EGFR and CD44 sialyl Lewis-A and Lewis-X content increased the panel performance. The protein/glycoprotein panel was statistically significantly higher in colon cancer samples, characterised by a range of area under the curves from 0.90 (95% CI 0.82 to 0.98) to 0.86 (95% CI 0.83 to 0.88), for the larger second and fourth sets, respectively.

Conclusions

A panel including BAG4, IL6ST, VWF, EGFR and CD44 protein/glycomics performed well for detection of early stages of colon cancer and should be further examined in larger studies.




A comparative effectiveness trial of two faecal immunochemical tests for haemoglobin (FIT). Assessment of test performance and adherence in a single round of a population-based screening programme for colorectal cancer

2018-02-08T08:00:42-08:00

Aim

To compare acceptability and diagnostic accuracy of a recently available faecal immunochemical test (FIT) system (HM-JACKarc) with the FIT routinely used in an established screening programme (OC-Sensor).

Design

Randomised controlled trial (ISRCTN20086618) within a population-based colorectal cancer (CRC) screening programme. Subjects eligible for invitation in the Umbria Region (Italy) programme were randomised (ratio 1:1) to be screened using one of the FIT systems.

Results

Screening uptake among the 48 888 invitees was the same for both systems among subjects invited in the first round and higher with OC-Sensor than with HM-JACKarc (relative risk (RR): 1.03; 95% CI 1.02 to 1.04) among those invited in subsequent rounds. Positivity rate (PR) was similar with OC-Sensor (6.5%) as with HM-JACKarc (6.2%) among subjects performing their first FIT screening and higher with OC-Sensor (5.6%, RR: 1.25, 95% CI 1.12 to 1.40) than with HM-JACKarc (4.4%) among those screened in previous rounds. Positive predictive value (PPV) (OC-Sensor: 25.9%, HM-JACKarc: 25.6%) and detection rate (DR) (OC-Sensor: 1.40%; HM-JACKarc: 1.42%) for advanced neoplasia (AN: CRC + advanced adenoma) were similar among subjects performing their first FIT screening. The differences in the AN PPV (OC-Sensor: 20.3%, HM-JACKarc: 22.6%) and DR (OC-Sensor: 0.96%, HM-JACKarc: 0.83%) among those screened in previous rounds were not statistically significant. The number needed to scope to detect one AN was 3.9 (95% CI 5.8 to 2.9) and 3.9 (95% CI 5.5 to 2.9) at first and 4.9 (95% CI 5.8 to 4.2) and 4.4 (95% CI 5.3 to 3.7) at subsequent screening, with OC-Sensor and HM-JACKarc, respectively.

Conclusions

Our results suggest that acceptability and diagnostic performance of HM-JACKarc and of OC-Sensor systems are similar in a screening setting.

Trial registration number

ISRCTN20086618; Results.




Fibroblast drug scavenging increases intratumoural gemcitabine accumulation in murine pancreas cancer

2018-02-08T08:00:42-08:00

Objective

Desmoplasia and hypovascularity are thought to impede drug delivery in pancreatic ductal adenocarcinoma (PDAC). However, stromal depletion approaches have failed to show clinical responses in patients. Here, we aimed to revisit the role of the tumour microenvironment as a physical barrier for gemcitabine delivery.

Design

Gemcitabine metabolites were analysed in LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre (KPC) murine tumours and matched liver metastases, primary tumour cell lines, cancer-associated fibroblasts (CAFs) and pancreatic stellate cells (PSCs) by liquid chromatography-mass spectrometry/mass spectrometry. Functional and preclinical experiments, as well as expression analysis of stromal markers and gemcitabine metabolism pathways were performed in murine and human specimen to investigate the preclinical implications and the mechanism of gemcitabine accumulation.

Results

Gemcitabine accumulation was significantly enhanced in fibroblast-rich tumours compared with liver metastases and normal liver. In vitro, significantly increased concentrations of activated 2',2'-difluorodeoxycytidine-5'-triphosphate (dFdCTP) and greatly reduced amounts of the inactive gemcitabine metabolite 2',2'-difluorodeoxyuridine were detected in PSCs and CAFs. Mechanistically, key metabolic enzymes involved in gemcitabine inactivation such as hydrolytic cytosolic 5'-nucleotidases (Nt5c1A, Nt5c3) were expressed at low levels in CAFs in vitro and in vivo, and recombinant expression of Nt5c1A resulted in decreased intracellular dFdCTP concentrations in vitro. Moreover, gemcitabine treatment in KPC mice reduced the number of liver metastases by >50%.

Conclusions

Our findings suggest that fibroblast drug scavenging may contribute to the clinical failure of gemcitabine in desmoplastic PDAC. Metabolic targeting of CAFs may thus be a promising strategy to enhance the antiproliferative effects of gemcitabine.




Pancreatic cancer cell lines as patient-derived avatars: genetic characterisation and functional utility

2018-02-08T08:00:42-08:00

Objective

Pancreatic ductal adenocarcinoma (PDAC) is a therapy recalcitrant disease with the worst survival rate of common solid tumours. Preclinical models that accurately reflect the genetic and biological diversity of PDAC will be important for delineating features of tumour biology and therapeutic vulnerabilities.

Design

27 primary PDAC tumours were employed for genetic analysis and development of tumour models. Tumour tissue was used for derivation of xenografts and cell lines. Exome sequencing was performed on the originating tumour and developed models. RNA sequencing, histological and functional analyses were employed to determine the relationship of the patient-derived models to clinical presentation of PDAC.

Results

The cohort employed captured the genetic diversity of PDAC. From most cases, both cell lines and xenograft models were developed. Exome sequencing confirmed preservation of the primary tumour mutations in developed cell lines, which remained stable with extended passaging. The level of genetic conservation in the cell lines was comparable to that observed with patient-derived xenograft (PDX) models. Unlike historically established PDAC cancer cell lines, patient-derived models recapitulated the histological architecture of the primary tumour and exhibited metastatic spread similar to that observed clinically. Detailed genetic analyses of tumours and derived models revealed features of ex vivo evolution and the clonal architecture of PDAC. Functional analysis was used to elucidate therapeutic vulnerabilities of relevance to treatment of PDAC.

Conclusions

These data illustrate that with the appropriate methods it is possible to develop cell lines that maintain genetic features of PDAC. Such models serve as important substrates for analysing the significance of genetic variants and create a unique biorepository of annotated cell lines and xenografts that were established simultaneously from same primary tumour. These models can be used to infer genetic and empirically determined therapeutic sensitivities that would be germane to the patient.




Characterising cis-regulatory variation in the transcriptome of histologically normal and tumour-derived pancreatic tissues

2018-02-08T08:00:42-08:00

Objective

To elucidate the genetic architecture of gene expression in pancreatic tissues.

Design

We performed expression quantitative trait locus (eQTL) analysis in histologically normal pancreatic tissue samples (n=95) using RNA sequencing and the corresponding 1000 genomes imputed germline genotypes. Data from pancreatic tumour-derived tissue samples (n=115) from The Cancer Genome Atlas were included for comparison.

Results

We identified 38 615 cis-eQTLs (in 484 genes) in histologically normal tissues and 39 713 cis-eQTL (in 237 genes) in tumour-derived tissues (false discovery rate <0.1), with the strongest effects seen near transcriptional start sites. Approximately 23% and 42% of genes with significant cis-eQTLs appeared to be specific for tumour-derived and normal-derived tissues, respectively. Significant enrichment of cis-eQTL variants was noted in non-coding regulatory regions, in particular for pancreatic tissues (1.53-fold to 3.12-fold, p≤0.0001), indicating tissue-specific functional relevance. A common pancreatic cancer risk locus on 9q34.2 (rs687289) was associated with ABO expression in histologically normal (p=5.8x10–8) and tumour-derived (p=8.3x10–5) tissues. The high linkage disequilibrium between this variant and the O blood group generating deletion variant in ABO (exon 6) suggested that nonsense-mediated decay (NMD) of the ‘O’ mRNA might explain this finding. However, knockdown of crucial NMD regulators did not influence decay of the ABO ‘O’ mRNA, indicating that a gene regulatory element influenced by pancreatic cancer risk alleles may underlie the eQTL.

Conclusions

We have identified cis-eQTLs representing potential functional regulatory variants in the pancreas and generated a rich data set for further studies on gene expression and its regulation in pancreatic tissues.




Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy

2018-02-08T08:00:42-08:00

Objective

A close relationship between gut microbiota and some chronic liver disorders has recently been described. Herein, we systematically performed a comparative analysis of the gut microbiome in primary biliary cholangitis (PBC) and healthy controls.

Design

We first conducted a cross-sectional study of 60 ursodeoxycholic acid (UDCA) treatment-naïve patients with PBC and 80 matched healthy controls. Second, an independent cohort composed of 19 treatment-naïve patients and 34 controls was used to validate the results. Finally, a prospective study was performed in a subgroup of 37 patients with PBC who underwent analysis before and after 6 months of UDCA treatment. Faecal samples were collected, and microbiomes were analysed by 16S ribosomal RNA gene sequencing.

Results

A significant reduction of within-individual microbial diversity was noted in PBC (p=0.03). A signature defined by decreased abundance of four genera and increased abundance of eight genera strongly correlated with PBC (area under curve=0.86, 0.84 in exploration and validation data, respectively). Notably, the abundance of six PBC-associated genera was reversed after 6 months of UDCA treatment. In particular, Faecalibacterium, enriched in controls, was further decreased in gp210-positive than gp210-negative patients (p=0.002). Of interest was the finding that the increased capacity for the inferred pathway, bacterial invasion of epithelial cells in PBC, highly correlated with the abundance of bacteria belonging to Enterobacteriaceae.

Conclusions

This study presents a comprehensive landscape of gut microbiota in PBC. Dysbiosis was found in the gut microbiome in PBC and partially relieved by UDCA. Our study suggests that gut microbiota is a potential therapeutic target and diagnostic biomarker for PBC.




Proliferation of primary human hepatocytes and prevention of hepatitis B virus reinfection efficiently deplete nuclear cccDNA in vivo

2018-02-08T08:00:42-08:00

Objective

The stability of the covalently closed circular DNA (cccDNA) in nuclei of non-dividing hepatocytes represents a key determinant of HBV persistence. Contrarily, studies with animal hepadnaviruses indicated that hepatocyte turnover can reduce cccDNA loads but knowledge on the proliferative capacity of HBV-infected primary human hepatocytes (PHHs) in vivo and the fate of cccDNA in dividing PHHs is still lacking. This study aimed to determine the impact of human hepatocyte division on cccDNA stability in vivo.

Methods

PHH proliferation was triggered by serially transplanting hepatocytes from HBV-infected humanised mice into naïve recipients. Cell proliferation and virological changes were assessed by quantitative PCR, immunofluorescence and RNA in situ hybridisation. Viral integrations were analysed by gel separation and deep sequencing.

Results

PHH proliferation strongly reduced all infection markers, including cccDNA (median 2.4 log/PHH). Remarkably, cell division appeared to cause cccDNA dilution among daughter cells and intrahepatic cccDNA loss. Nevertheless, HBV survived in sporadic non-proliferating human hepatocytes, so that virological markers rebounded as hepatocyte expansion relented. This was due to reinfection of quiescent PHHs since treatment with the entry inhibitor myrcludex-B or nucleoside analogues blocked viral spread and intrahepatic cccDNA accumulation. Viral integrations were detected both in donors and recipient mice but did not appear to contribute to antigen production.

Conclusions

We demonstrate that human hepatocyte division even without involvement of cytolytic mechanisms triggers substantial cccDNA loss. This process may be fundamental to resolve self-limiting acute infection and should be considered in future therapeutic interventions along with entry inhibition strategies.




Polypoid lesions from the oesophagus to colon

2018-02-08T08:00:42-08:00

Clinical presentation

A 73-year-old man presented with abdominal fullness for 2 months. He had lost 5 kg in the previous 2 months. He did not have fever or abdominal pain. He had a history of chronic hepatitis B. Physical examination showed enlarged lymph nodes over bilateral neck, axillary and inguinal areas. Laboratory study revealed leucocytosis with white cell counts 14.1x109/L; haemoglobin level 12.8 g/dL; platelet count 227x109/L; hypoalbuminaemia with albumin level 2.8 g/dL, as well as normal blood sugar, aminotransferase, urea, creatine, serum uric acid and lactic acid dehydrogenase levels. Tumour markers carcinoembryonic antigen, carbohydrate antigen 19–9 and alpha-fetoprotein were all within normal limits. The upper GI panendoscopy showed multiple whitish sessile polypoid lesions over the whole circumference of oesophagus, extending form upper third to the gastro-oesophageal junction (figure 1A). Enlarged gastric rugae with polypoid lesions were seen from the fundus to the body of the stomach, and numerous erosive lesions...




The effect of sustained virological response on the risk of extrahepatic manifestations of hepatitis C virus infection

2018-02-08T08:00:42-08:00

Background and aim

Chronic HCV infection is associated with several extrahepatic manifestations (EHMs). Data on the effect of sustained virological response (SVR) on the risk of EHMs are limited.

Methods

We conducted a retrospective cohort study using data of patients from the US Veterans Affairs HCV Clinical Case Registry who had a positive HCV RNA test (10/1999-08/2009). Patients receiving interferon-based antiviral therapy (AVT) were identified. SVR was defined as negative HCV RNA at least 12 weeks after end of AVT. Risks of eight incident EHMs were evaluated in Cox regression models.

Results

Of the 160 875 HCV-infected veterans, 31 143 (19.4%) received AVT, of whom 10 575 (33.9%) experienced SVR. EHM risk was reduced in the SVR group compared with untreated patients for mixed cryoglobulinaemia (adjusted HR (aHR)=0.61; 95% CI 0.39 to 0.94), glomerulonephritis (aHR=0.62; 95% CI 0.48 to 0.79), porphyria cutanea tarda (PCT) (aHR=0.41; 95% CI 0.20 to 0.83), non-Hodgkin’s lymphoma (NHL) (aHR=0.64; 95% CI 0.43 to 0.95), diabetes (aHR=0.82; 95% CI 0.76 to 0.88) and stroke (aHR=0.84; 95% CI 0.74 to 0.94), but not for lichen planus (aHR=1.11; 95% CI 0.78 to 1.56) or coronary heart disease (aHR=1.12; 95% CI 0.81 to 1.56). Risk reductions were also observed when patients with SVR were compared with treated patients without SVR for mixed cryoglobulinaemia, glomerulonephritis, PCT and diabetes. Significant reductions in the magnitude of aHRs towards the null with increasing time to initiation of AVT after HCV diagnosis were observed for glomerulonephritis, NHL and stroke.

Conclusions

Risks of several EHMs of HCV infection are reduced after AVT with SVR. However, early initiation of AVT may be required to reduce the risk of glomerulonephritis, NHL and stroke.




Oncolytic reovirus as a combined antiviral and anti-tumour agent for the treatment of liver cancer

2018-02-08T08:00:42-08:00

Objective

Oncolytic viruses (OVs) represent promising, proinflammatory cancer treatments. Here, we explored whether OV-induced innate immune responses could simultaneously inhibit HCV while suppressing hepatocellular carcinoma (HCC). Furthermore, we extended this exemplar to other models of virus-associated cancer.

Design and results

Clinical grade oncolytic orthoreovirus (Reo) elicited innate immune activation within primary human liver tissue in the absence of cytotoxicity and independently of viral genome replication. As well as achieving therapy in preclinical models of HCC through the activation of innate degranulating immune cells, Reo-induced cytokine responses efficiently suppressed HCV replication both in vitro and in vivo. Furthermore, Reo-induced innate responses were also effective against models of HBV-associated HCC, as well as an alternative endogenous model of Epstein–Barr virus-associated lymphoma. Interestingly, Reo appeared superior to the majority of OVs in its ability to elicit innate inflammatory responses from primary liver tissue.

Conclusions

We propose that Reo and other select proinflammatory OV may be used in the treatment of multiple cancers associated with oncogenic virus infections, simultaneously reducing both virus-associated oncogenic drive and tumour burden. In the case of HCV-associated HCC (HCV-HCC), Reo should be considered as an alternative agent to supplement and support current HCV-HCC therapies, particularly in those countries where access to new HCV antiviral treatments may be limited.




Adherent-invasive Escherichia coli in inflammatory bowel disease

2018-02-08T08:00:42-08:00

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.




GI highlights from the literature

2018-02-08T08:00:42-08:00

Basic scienceShould we target the microbiota in the treatment of colorectal cancer?

Bullman S, Pedamallu C, Sicinska E, et al. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science 2017. pii: eaal5240. doi: 10.1126/science.aal5240. [Epub ahead of print 23 Nov 2017].

The gut microbiota has emerged as a key driver of colorectal cancer (CRC) development and progression. Several recent studies have shown that higher levels of Fusobacterium species are present in human CRC tissue compared with adjacent normal mucosa. Fusobacteria can protect the tumour through suppression of immunity and tumour cell killing, leading to the suggestion that Fusobacteria may actually promote tumour growth and survival. This recent study investigated the role of Fusobacterium and its associated microbiome in CRC. Analysing five independent patient cohorts, they demonstrated that the microbiota associated with Fusobacterium-positive CRC was also seen in distal metastases, reported as microbiota similarity between paired...




The role of hepatokines in NAFLD-related extrahepatic diseases: culprit or accomplice?

2018-02-08T08:00:42-08:00

We recently read with great interest a review by Adams et al1 showing that non-alcoholic fatty liver disease (NAFLD) has a profound impact on the onset of extrahepatic diseases, such as cardiovascular diseases and kidney diseases. We fully agree with this conclusion, and the authors have fully elucidated the relationship between NAFLD and extrahepatic diseases. We think that hepatokines produced and secreted by liver may play a critical role in NAFLD-related extrahepatic diseases, which would deepen the understanding of this disease.

Fibroblast growth factor 21 (FGF21), a hepatokine that is mainly secreted by the liver, has beneficial effects for improving metabolic processes.2 It has been well recognised that FGF21 plays a pivotal role in the pathogenesis and therapeutic mechanisms of NAFLD.3 Abnormality in FGF21 would prompt the development of NAFLD. Coincidentally, dysfunctional FGF21 in peripheral blood is highly associated with cardiovascular and cerebrovascular diseases.4...




Randomised controlled trial of long-term maintenance corticosteroid therapy in patients with autoimmune pancreatitis

2018-02-08T08:00:42-08:00

We read with great interest the article by Masamune et al1 regarding the role of long-term maintenance corticosteroids in patients with autoimmune pancreatitis (AIP).1 AIP is a steroid responsive disorder, which has two distinct entities with overlapping features, classified as type I and type II AIP. While type I AIP is a part of a spectrum of IgG4-related disease with extrapancreatic manifestations, type II is a pancreas-specific disease. The diagnostic criteria, treatment approach and prognosis are different between the two types. Masamune et al demonstrated that corticosteroid treatment for a prolonged period of 3 years reduces rates of relapse when compared with patients who discontinued steroid treatment at 26 weeks. The authors have showed that the two treatment groups are comparable at baseline with regard to clinical, radiological and serological characteristics. However, the authors do not reveal the distribution of the two different types of...




PRSS1 copy number variants and promoter polymorphisms in pancreatitis: common pathogenetic mechanism, different genetic effects

2018-02-08T08:00:42-08:00

We have read with interest three related papers that were recently published in this journal.1–3 Taken together, the findings reported in these papers (summarised in online ) suggest that loss-of-function PRSS1 promoter variants can protect against pancreatitis. The other side of the coin is however that gain-of-function PRSS1 promoter variants predispose to pancreatitis. It therefore follows that the risk-associated [rs4726576C; rs10273639C] allele shares a common pathogenetic mechanism with the previously reported trypsinogen duplication and triplication copy number variants (CNVs)4 5 as both types of variant predispose to pancreatitis by increasing PRSS1 expression; this mechanism is quite distinct from either the increased activation and/or stability of trypsin(ogen) or misfolding-induced endoplasmic reticulum stress caused by disease-associated PRSS1 missense mutations.6 However, despite both serving to increase PRSS1 expression, the promoter variant and the CNVs differ significantly in terms of the...




Quantitative liver MRI including extracellular volume fraction for non-invasive quantification of liver fibrosis: a prospective proof-of-concept study

2018-02-08T08:00:42-08:00

We read with interest the recent reviews published in Gut, emphasising that even though the understanding of the pathobiology of liver fibrosis has been improved in the last three decades,1 novel and easy to implement diagnostic and therapeutic approaches are required.2 Indeed, fibrosis is the most important histological feature of patients with chronic liver disease (CLD), such as non-alcoholic fatty liver disease, and is associated with long-term overall mortality, liver transplantation and liver-related events.3 Diagnostic and therapeutic approaches,2 therefore, require accurate measurements that ideally allow non-invasive fibrosis quantification, representing the whole liver free of bias and easily integrated in clinical routine.

A liver biopsy, still the reference standard, has substantial drawbacks (complications, intraobserver and interobserver variabilities).4 Transient elastography (TE), suggested for population-wide screens (eg, patients with diabetes),5 requires additional expensive devices and trained personnel. However, contrast-enhanced MRI is routinely performed...




Correction: Gut roundtable meeting paper: selected recent advances in hepatocellular carcinoma

2018-02-08T08:00:42-08:00

Gerbes A, Zoulim F, Tilg H, et al. Gut roundtable meeting paper: selected recent advances in hepatocellular carcinoma. Gut 2018;67:380–388. doi: 10.1136/gutjnl-2017-315068.

Figures 1, 3 and 4 of the above paper were published without acknowledgement of the original source. The legends should include the following information:

Figure 1. Adapted from Kurmann A, Wanner B, Martens F et al. Hepatic steatosis is associated with surgical-site infection after hepatic and colorectal surgery. Surgery 2014;156:109–16. With permission from Elsevier.

Figure 3. Reused from Villanueva A. Rethinking future development of molecular therapies in hepatocellular carcinoma: a bottom-up approach. J Hepatol 2013;59:392–5. With permission from Elsevier.

Figure 4. Adapted from Duffy AG, Ulahannan SV, Makorova-Rusher O et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma. J Hepatol 2017;66:545–551. With permission from Elsevier.

The publisher apologises for the omission.