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Gut

Nearly a decade has elapsed since initial publication of a multicentre randomised trial of porfimer sodium photodynamic therapy (psPDT) for the treatment of Barrett's oesophagus (BO) containing high-grade dysplasia (HGD).1 With the addition of endoscopic mucosal resection (EMR) and radiofrequency ablation (RFA) to the therapeutic armamentarium, a seismic shift has now ensued in the treatment landscape of BO-associated mucosal neoplasia. An ever-increasing proportion of patients with BO HGD or T1 oesophageal adenocarcinoma (OAC), opt for endoscopic therapy rather than surgery.2 Durable disease remission is achievable for the majority of patients, with most instances of recurrence being amenable to further endoscopic management and with low rates of salvage oesophagectomy or oesophageal cancer-related mortality.3

Compared with a significant post-treatment stricture rate (>30% for PDT1) and prolonged duration of photosensitivity following psPDT, the relatively lower toxicity profile of newer-generation endoscopic therapies (<10% stricture rate...


Iron deficiency is a global health problem affecting likewise two billion people, and this condition is more prevalent in developing than in industrialised countries. Specifically, in childhood, iron deficiency and subsequent iron deficiency anaemia are considered to negatively affect the development of children causing growth and mental retardation.1 This is due to the fact that iron is essential for oxygen transport as being the central molecule in haemoglobin and referred to the metal's function as an essential compound of many vital enzymes in mitochondrial respiration, metabolism, hormone synthesis and DNA replication. In order to prevent the negative consequences of iron deficiency on children's development, several controlled clinical trials were initiated to study the effects of dietary fortification with iron and other micronutrients on children's health mostly in rural sites of developing countries where such nutrients are scarce and where iron deficiency is highly prevalent. However, the results...


Vitamin D is a prohormone that requires sequential enzymatic modification of 25 and 1a-hydroxylation in the liver and kidney respectively, leading to production of calcitriol (1,25(OH)2D3), the active form of vitamin D.1 Several studies have supported the notion that vitamin D, in addition to its classical action of maintaining systemic calcium homoeostasis and bone mineralisation, has non-classical extraskeletal actions including a potential capacity to inhibit fibrosis in various tissues. Murine lung fibroblasts treated with 1,25(OH)2D3, inhibited transforming growth factor (TGF)-β1-induced fibroblast proliferation, α-smooth-muscle actin expression, and diminished the upregulation of fibronectin and collagen expression. Furthermore, 1,25(OH)2D3 is able to inhibit the TGF-β1-dependent transdifferentiation of lung epithelial cells into myofibroblasts.2 Recent studies in mesenchymal multipotent cells showed that treatment with vitamin D led to an antiproliferative effect by inducing cell cycle arrest.3 Moreover, vitamin D reduced the collagen expression and other key profibrotic factors...


Objective

Reported malignant progression rates for low-grade dysplasia (LGD) in Barrett's oesophagus (BO) vary widely. Expert histological review of LGD is advised, but limited data are available on its clinical value. This retrospective cohort study aimed to determine the value of an expert pathology panel organised in the Dutch Barrett's Advisory Committee (BAC) by investigating the incidence rates of high-grade dysplasia (HGD) and oesophageal adenocarcinoma (OAC) after expert histological review of LGD.

Design

We included all BO cases referred to the BAC for histological review of LGD diagnosed between 2000 and 2011. The diagnosis of the expert panel was related to the histological outcome during endoscopic follow-up. Primary endpoint was development of HGD or OAC.

Results

293 LGD patients (76% men; mean 63 years±11.9) were included. Following histological review, 73% was downstaged to non-dysplastic BO (NDBO) or indefinite for dysplasia (IND). In 27% the initial LGD diagnosis was confirmed. Endoscopic follow-up was performed in 264 patients (90%) with a median follow-up of 39 months (IQR 16–72). For confirmed LGD, the risk of HGD/OAC was 9.1% per patient-year. Patients downstaged to NDBO or IND had a malignant progression risk of 0.6% and 0.9% per patient-year, respectively.

Conclusions

Confirmed LGD in BO has a markedly increased risk of malignant progression. However, the vast majority of patients with community LGD will be downstaged after expert review and have a low progression risk. Therefore, all BO patients with LGD should undergo expert histological review of the diagnosis for adequate risk stratification.


Objective

Gastric cancer (GC) is a deadly malignancy for which new therapeutic strategies are needed. Three transcription factors, KLF5, GATA4 and GATA6, have been previously reported to exhibit genomic amplification in GC. We sought to validate these findings, investigate how these factors function to promote GC, and identify potential treatment strategies for GCs harbouring these amplifications.

Design

KLF5, GATA4 and GATA6 copy number and gene expression was examined in multiple GC cohorts. Chromatin immunoprecipitation with DNA sequencing was used to identify KLF5/GATA4/GATA6 genomic binding sites in GC cell lines, and integrated with transcriptomics to highlight direct target genes. Phenotypical assays were conducted to assess the function of these factors in GC cell lines and xenografts in nude mice.

Results

KLF5, GATA4 and GATA6 amplifications were confirmed in independent GC cohorts. Although factor amplifications occurred in distinct sets of GCs, they exhibited significant mRNA coexpression in primary GCs, consistent with KLF5/GATA4/GATA6 cross-regulation. Chromatin immunoprecipitation with DNA sequencing revealed a large number of genomic sites co-occupied by KLF5 and GATA4/GATA6, primarily located at gene promoters and exhibiting higher binding strengths. KLF5 physically interacted with GATA factors, supporting KLF5/GATA4/GATA6 cooperative regulation on co-occupied genes. Depletion and overexpression of these factors, singly or in combination, reduced and promoted cancer proliferation, respectively, in vitro and in vivo. Among the KLF5/GATA4/GATA6 direct target genes relevant for cancer development, one target gene, HNF4α, was also required for GC proliferation and could be targeted by the antidiabetic drug metformin, revealing a therapeutic opportunity for KLF5/GATA4/GATA6 amplified GCs.

Conclusions

KLF5/GATA4/GATA6 may promote GC development by engaging in mutual crosstalk, collaborating to maintain a pro-oncogenic transcriptional regulatory network in GC cells.


Objective

Helicobacter pylori strains that express the oncoprotein CagA augment risk for gastric cancer. However, the precise mechanisms through which cag+ strains heighten cancer risk have not been fully delineated and model systems that recapitulate the gastric niche are critical for understanding pathogenesis. Gastroids are three-dimensional organ-like structures that provide unique opportunities to study host-H. pylori interactions in a preclinical model. We used gastroids to inform and direct in vitro studies to define mechanisms through which H. pylori modulates expression of the cancer-associated tight junction protein claudin-7.

Design

Gastroids were infected by luminal microinjection, and MKN28 gastric epithelial cells were cocultured with H. pylori wild-type cag+ strains or isogenic mutants. β-catenin, claudin-7 and snail localisation was determined by immunocytochemistry. Proliferation was assessed using 5-ethynyl-2'-deoxyuridine, and levels of claudin-7 and snail were determined by western blot and flow cytometry.

Results

Gastroids developed into a self-organising differentiation axis and H. pylori induced mislocalisation of claudin-7 and increased proliferation in a CagA- and β-catenin-dependent manner. In MKN28 cells, H pylori-induced suppression of claudin-7 was regulated by β-catenin and snail. Similarly, snail expression was increased and claudin-7 levels were decreased among H. pylori-infected individuals.

Conclusions

H. pylori increase proliferation in a strain-specific manner in a novel gastroid system. H. pylori also alter expression and localisation of claudin-7 in gastroids and human epithelial cells, which is mediated by β-catenin and snail activation. These data provide new insights into molecular interactions with carcinogenic potential that occur between H. pylori and epithelial cells within the gastric niche.


Clinical presentation

A 31-year-old man visited our gastroenterology clinic owing to continuous epigastric pain lasting 3 months, diarrhoea during the previous month and an associated 10 kg weight loss. An ulcer in his antrum was discovered by oesophagogastroduodenoscopy (EGD), and he took a proton-pump inhibitor for a month. However, his clinical symptoms and ulcer worsened. He denied melena, haematemesis, fever, arthralgia, recurrent aphthous ulcer and genital ulcer. He had a >10-year history of asthma and eczema. Physical examination was unremarkable except for emaciation and upper abdominal tenderness. Laboratory test results were normal, including routine stool studies, serum amylase measurement, liver function tests, tumour marker measurements, 14C-urea breath test and parasite tests. A remarkable EGD finding was a giant ulcer in the antrum (figure 1A). Colonoscopy showed multiple shallow ulcers (0.2–0.4 cm) throughout the colon (figure 1B). Contrast-enhanced CT showed a markedly thickened gallbladder wall, with a...


Background

In-home iron fortification for infants in developing countries is recommended for control of anaemia, but low absorption typically results in >80% of the iron passing into the colon. Iron is essential for growth and virulence of many pathogenic enterobacteria. We determined the effect of high and low dose in-home iron fortification on the infant gut microbiome and intestinal inflammation.

Methods

We performed two double-blind randomised controlled trials in 6-month-old Kenyan infants (n=115) consuming home-fortified maize porridge daily for 4 months. In the first, infants received a micronutrient powder (MNP) containing 2.5 mg iron as NaFeEDTA or the MNP without iron. In the second, they received a different MNP containing 12.5 mg iron as ferrous fumarate or the MNP without the iron. The primary outcome was gut microbiome composition analysed by 16S pyrosequencing and targeted real-time PCR (qPCR). Secondary outcomes included faecal calprotectin (marker of intestinal inflammation) and incidence of diarrhoea. We analysed the trials separately and combined.

Results

At baseline, 63% of the total microbial 16S rRNA could be assigned to Bifidobacteriaceae but there were high prevalences of pathogens, including Salmonella Clostridium difficile, Clostridium perfringens, and pathogenic Escherichia coli. Using pyrosequencing, +FeMNPs increased enterobacteria, particularly Escherichia/Shigella (p=0.048), the enterobacteria/bifidobacteria ratio (p=0.020), and Clostridium (p=0.030). Most of these effects were confirmed using qPCR; for example, +FeMNPs increased pathogenic E. coli strains (p=0.029). +FeMNPs also increased faecal calprotectin (p=0.002). During the trial, 27.3% of infants in +12.5 mgFeMNP required treatment for diarrhoea versus 8.3% in –12.5 mgFeMNP (p=0.092). There were no study-related serious adverse events in either group.

Conclusions

In this setting, provision of iron-containing MNPs to weaning infants adversely affects the gut microbiome, increasing pathogen abundance and causing intestinal inflammation.

Trial registration number

NCT01111864.


Objective

Several pathogenic roles attributed over the past two decades to either T helper (Th)1 or Th2 cells are increasingly becoming associated with interleukin (IL)-17 and most recently IL-9 signalling. However, the implication of IL-9 in IBD has not been addressed so far.

Design

We investigated the expression of IL-9 and IL-9R by using peripheral blood, biopsies and surgical samples. We addressed the functional role of IL-9 signalling by analysis of downstream effector proteins. Using Caco-2 cell monolayers we followed the effect of IL-9 on wound healing.

Results

IL-9 mRNA expression was significantly increased in inflamed samples from patients with UC as compared with controls. CD3+ T cells were major IL-9-expressing cells and some polymorphonuclear leucocytes (PMN) also expressed IL-9. IL-9 was co-localised with the key Th9 transcription factors interferon regulatory factor 4 and PU.1. Systemically, IL-9 was abundantly produced by activated peripheral blood lymphocytes, whereas its receptor was overexpressed on gut resident and circulating PMN. IL-9 stimulation of the latter induced IL-8 production in a dose-dependent manner and rendered PMN resistant to apoptosis suggesting a functional role for IL-9R signalling in the propagation of gut inflammation. Furthermore, IL-9R was overexpressed on gut epithelial cells and IL-9 induced STAT5 activation in these cells. Moreover, IL-9 inhibited the growth of Caco-2 epithelial cell monolayers in wound healing experiments.

Conclusions

Our results provide evidence that IL-9 is predominantly involved in the pathogenesis of UC suggesting that targeting IL-9 might become a therapeutic option for patients with UC.


Objectives

To evaluate molecular profiles in the small bowel (SB) mucosa proximal to the pouch in ulcerative colitis (UC) patients after pouch surgery.

Design

Patients were prospectively recruited and stratified according to disease behaviour: normal pouch (NP), chronic pouchitis (CP), and Crohn's-like disease of the pouch (CLDP). Biopsies obtained from the pouch and the normal-appearing proximal SB (40 cm proximal to the anal verge) were compared to ileal biopsies from normal controls (NC). A histopathological score based on the degree of polymorphonuclear and mononuclear infiltrates was used to assess inflammation in the pouch and the proximal SB. Gene expression analysis was performed using microarrays, and validated by real-time PCR. Gene ontology and clustering were evaluated by bioinformatics.

Results

Thirty-six subjects were recruited (age 18–71 years, 16 males). Histopathology scores demonstrated minimal differences in the normal-appearing proximal SB of all groups. Nonetheless, significant (fold change ≥2, corrected p [FDR] ≤ 0.05) molecular alterations in the proximal SB were detected in all groups (NP n=9; CP n=80; and CLDP n=230) compared with NC. The magnitude of DUOX2 alteration in the proximal SB was highest. An increase of 6.0, 9.8 and 21.7 folds in DUOX2 expression in NP, CP, CLDP, respectively was observed. This was followed by alterations in MMP1, SLC6A14 and PGC. Gene alterations in the proximal SB overlapped with alterations within the pouch (76% and 97% overlap in CP and CLDP, respectively). Gene ontology analysis in the proximal SB and pouch were comparable.

Conclusions

Significant gene expression alterations exist in an apparently unaffected proximal SB. Alterations in the pouch and the proximal SB were comparable, suggesting that inflammation may not be limited to the pouch, but that it extends to the proximal SB.


Objective

The soluble preligand assembly domain (PLAD) of tumour necrosis factor receptor 1 (TNFR1) interferes with receptor trimerisation to block downstream signalling, and mediates Th17 suppression. We explored the therapeutic potential of recombinant PLAD.Fc protein on a spontaneous experimental colitis.

Design

A T-cell-specific BLIMP-1 knockout mouse model with mixed Th1/Th17 responses, resembling human Crohn's disease (CD) was established, and its colitogenic phenotype was characterised. Mice, 9 weeks old, were treated with PLAD.Fc protein at 5 mg/kg of body weight twice per week for 16 weeks, and presence of colitis was monitored by the appearance of diarrhoea, weight loss, and by histological colonic scoring. Activation status, cytokine profiles, and transcription factors in T cells were further analysed.

Results

The colitogenic phenotype in BLIMP-1 knockout mice was alleviated when an interleukin (IL)-23 knockdown transgene was introduced, indicating a therapeutic potential by downregulating IL-23-Th17 axis in these knockout mice. In PLAD.Fc-treated group, the mouse body weight remained stable and only mild disease scores were revealed. The percentage of naive CD4 T cells was increased and that of effector/memory CD4 T cells was decreased after PLAD.Fc-treatment. Moreover, the levels of IFN-, IL-17, IL-21, IL-22, IL-23R, granulocyte-macrophage colony-stimulating factor (GM-CSF) and TNF-α were diminished. Strikingly, Th2-associated cytokines (IL-4, IL-13 and IL-10) in sera, as well as percentages of Th2 cells, were increased in PLAD.Fc-treated mice. However, PLAD.Fc-mediated suppression of effector phenotypes in Th1/Th17 was abrogated after neutralising IL-10.

Conclusions

The Th2 cytokine milieu induced by PLAD.Fc rebalanced T-helper cell subsets and conferred a protection against colitis in BLIMP-1 knockout mice.


Objective

To compare the performance of existing sigmoidoscopy-based strategies in predicting advanced proximal neoplasia (APN) in an asymptomatic Chinese cohort.

Design

We included all screening participants aged 50–70 years who received colonoscopy between 2008 and 2014 in Hong Kong. Sigmoidoscopy yield was estimated from the colonoscopic findings based on the: (1) UK flexible sigmoidoscopy; (2) Screening for COlon REctum (SCORE); (3) NORwegian Colorectal Cancer Prevention (NORCCAP) trials and (4) US clinical index based on age, gender and distal findings. The sensitivity, specificity, the number of subjects needed to screen (NNS) and the number of subjects needed to refer (NNR) for colonoscopy to detect one APN were evaluated. Binary logistic regression modelling identified the distal findings associated with APN.

Results

From 5879 eligible subjects, 132 (2.2%) had APN. The US strategy achieved the highest sensitivity for APN detection (42.0%) and the UK criteria attained the highest specificity (96%). The US criteria led to the lowest NNS (92 vs 103–267) and the UK criteria required the least NNR (12 vs 16–21). Using the US strategy, the rates of APN detected were 1.4% (low-risk group), 2.2% (intermediate risk) and 5.9% (high risk). The c-statistics of the UK, SCORE, NORCCAP and the US criteria were 0.55±0.03; 0.59±0.03; 0.59±0.03 and 0.62±0.05 respectively.

Conclusions

The US criteria had the highest sensitivity for detection of APN and lowest NNS and the UK score had the highest specificity and the lowest NNR. The performance of all these four criteria to predict APN is limited, highlighting an urgent need to devise a novel APN prediction system for Asian subjects.


Objective

Colorectal cancer (CRC) screening programmes based on the guaiac faecal occult blood test (gFOBT) reduce CRC-specific mortality. Several studies have shown higher sensitivity with the faecal immunochemical test (FIT) compared with gFOBT. We carried out an ecological study to evaluate the impact of FIT-based screening programmes on CRC mortality.

Design

In the Veneto Region (Italy), biennial FIT-based screening programmes that invited 50–69-year-old residents were introduced in different areas between 2002 and 2009. We compared CRC mortality rates from 1995 to 2011 between the areas where screening started in 2002–2004 (early screening areas (ESA)) and areas that introduced the screening in 2008–2009 (late screening areas (LSA)) using Poisson regression models. We also compared available data on CRC incidence rates (1995–2007) and surgical resection rates (2001–2012).

Results

Before the introduction of screening, CRC mortality and incidence rates in the two areas were similar. Compared with 1995–2000, 2006–2011 mortality rates were 22% lower in the ESA than in the LSA (rate ratio (RR)=0.78; 95% CI 0.68 to 0.89). The reduction was larger in women (RR=0.64; CI 0.51 to 0.80) than in men (RR=0.87; CI 0.73 to 1.04). In the ESA, incidence and surgery rates peaked during the introduction of the screening programme and then returned to the baseline (2006–2007 incidence) or dropped below initial values (surgery after 2007).

Conclusions

FIT-based screening programmes were associated with a significant reduction in CRC mortality. This effect took place much earlier than reported by gFOBT-based trials and observational studies.


Objective

Non-alcoholic fatty liver disease (NAFLD) is closely linked to obesity and constitutes part of the metabolic syndrome, which have been associated with low serum vitamin D (VD). Due to known crosstalk between VD and transforming growth factor (TGF)-β signalling, VD has been proposed as an antifibrotic treatment.

Design

We evaluated the association between VD, the vitamin D receptor (VDR) and liver fibrosis in primary human hepatic stellate cells (phHSC) and 106 morbidly obese patients with NAFLD.

Results

Treating phHSC with VD ameliorated TGF-β-induced fibrogenesis via both VDR-dependent and VDR-independent mechanisms. Reduction of fibrogenic response was abolished in cells homozygous for GG at the A1012G single nucleotide polymorphisms within the VDR gene. Compared with healthy livers, NAFLD livers expressed higher levels of VDR mRNA and VDR fragments. VDR mRNA was lower in patients homozygous for GG at A1012G and expression of pro-fibrogenic genes was higher in patients carrying the G allele.

Conclusions

VD may be an antifibrotic treatment option early in the onset of fibrosis in specific genotypes for VDR. Known polymorphisms of the VDR may influence the response to VD treatment.


Objectives

We used a screening strategy of global serum microRNA (miRNA) profiling, followed by a second stage of independent replication and exploration of liver expression of selected miRNAs to study: (1) the circulating miRNA signature associated with non-alcoholic fatty liver disease (NAFLD) progression and predictive power, (2) the role of miRNAs in disease biology and (3) the association between circulating miRNAs and features of the metabolic syndrome.

Methods

The study used a case-control design and included patients with NAFLD proven through biopsy and healthy controls.

Results

Among 84 circulating miRNAs analysed, miR-122, miR-192, miR-19a and miR-19b, miR-125b, and miR-375 were upregulated >2-fold (p<0.05) either in simple steatosis (SS) or non-alcoholic steatohepatitis (NASH). The most dramatic and significant fold changes were observed in the serum levels of miR-122 (7.2-fold change in NASH vs controls and 3.1-fold change in NASH vs SS) and miR-192 (4.4-fold change in NASH vs controls); these results were replicated in the validation set. The majority of serum miR-122 circulate in argonaute2-free forms. Circulating miR-19a/b and miR-125b were correlated with biomarkers of atherosclerosis. Liver miR-122 expression was 10-fold (p<0.03) downregulated in NASH compared with SS and was preferentially expressed at the edge of lipid-laden hepatocytes. In vitro exploration showed that overexpression of miR-122 enhances alanine aminotransferase activity.

Conclusions

miR-122 plays a role of physiological significance in the biology of NAFLD; circulating miRNAs mirror the histological and molecular events occurring in the liver. NAFLD has a distinguishing circulating miRNA profile associated with a global dysmetabolic disease state and cardiovascular risk.


Background

Chronic HCV infection is a leading cause of liver-related morbidity globally. The innate and adaptive immune responses are thought to be important in determining viral outcomes. Polymorphisms associated with the IFNL3 (IL28B) gene are strongly associated with spontaneous clearance and treatment outcomes.

Objective

This study investigates the importance of HLA genes in the context of genetic variation associated with the innate immune genes IFNL3 and KIR2DS3.

Design

We assess the collective influence of HLA and innate immune genes on viral outcomes in an Irish cohort of women (n=319) who had been infected from a single source as well as a more heterogeneous cohort (Swiss Cohort, n=461). In the Irish cohort, a number of HLA alleles are associated with different outcomes, and the impact of IFNL3-linked polymorphisms is profound.

Results

Logistic regression was performed on data from the Irish cohort, and indicates that the HLA-A*03 (OR 0.36 (0.15 to 0.89), p=0.027) -B*27 (OR 0.12 (0.03 to 0.45), p=<0.001), -DRB1*01:01 (OR 0.2 (0.07 to 0.61), p=0.005), -DRB1*04:01 (OR 0.31 (0.12 to 0.85, p=0.02) and the CC IFNL3 rs12979860 genotypes (OR 0.1 (0.04 to 0.23), p<0.001) are significantly associated with viral clearance. Furthermore, DQB1*02:01 (OR 4.2 (2.04 to 8.66), p=0.008), KIR2DS3 (OR 4.36 (1.62 to 11.74), p=0.004) and the rs12979860 IFNL3 ‘T’ allele are associated with chronic infection. This study finds no interactive effect between IFNL3 and these Class I and II alleles in relation to viral clearance. There is a clear additive effect, however. Data from the Swiss cohort also confirms independent and additive effects of HLA Class I, II and IFNL3 genes in their prediction of viral outcome.

Conclusions

This data supports a critical role for the adaptive immune response in the control of HCV in concert with the innate immune response.


Background and aim

Hepatocellular carcinoma (HCC) is the most common liver cancer. We characterised HCC associated with infection compared with non-HBV-related HCC to understand interactions between viral and hepatocyte genomic alterations and their relationships with clinical features.

Methods

Frozen HBV (n=86) or non-HBV-related (n=90) HCC were collected in two French surgical departments. Viral characterisation was performed by sequencing HBS and HBX genes and quantifying HBV DNA and cccDNA. Nine genes were screened for somatic mutations and expression profiling of 37 genes involved in hepatocarcinogenesis was studied.

Results

HBX revealed frequent non-sense, frameshift and deletions in tumours, suggesting an HBX inactivation selected in HCC. The number of viral copies was frequently lower in tumour than in non-tumour tissues (p=0.0005) and patients with low HBV copies in the non-tumour liver tissues presented additional risk factor (HCV, alcohol or non-alcoholic steato-hepatitis, p=0.006). P53 was the most frequently altered pathway in HBV-related HCC (47%, p=0.001). Furthermore, TP53 mutations were associated with shorter survival only in HBV-related HCC (p=0.02) whereas R249S mutations were identified exclusively in migrants. Compared with other aetiologies, HBV-HCC were more frequently classified in tumours subgroups with upregulation of genes involved in cell-cycle regulation and a progenitor phenotype. Finally, in HBV-related HCC, transcriptomic profiles were associated with specific gene mutations (HBX, TP53, IRF2, AXIN1 and CTNNB1).

Conclusions

Integrated genomic characterisation of HBV and non-HBV-related HCC emphasised the immense molecular diversity of HCC closely related to aetiologies that could impact clinical care of HCC patients.


Reversibility of hepatic fibrosis and cirrhosis following antiviral therapy for hepatitis B or C has advanced the prospect of developing antifibrotic therapies for patients with chronic liver diseases, especially non-alcoholic steatohepatitis. Mechanisms of fibrosis have focused on hepatic stellate cells, which become fibrogenic myofibroblasts during injury through ‘activation’, and are at the nexus of efforts to define novel drug targets. Recent studies have clarified pathways of stellate cell gene regulation and epigenetics, emerging pathways of fibrosis regression through the recruitment and amplification of fibrolytic macrophages, nuanced responses of discrete inflammatory cell subsets and the identification of the ‘ductular reaction’ as a marker of severe injury and repair. Based on our expanded knowledge of fibrosis pathogenesis, attention is now directed towards strategies for antifibrotic therapies and regulatory challenges for conducting clinical trials with these agents. New therapies are attempting to: 1) Control or cure the primary disease or reduce tissue injury; 2) Target receptor-ligand interactions and intracellular signaling; 3) Inhibit fibrogenesis; and 4) Promote resolution of fibrosis. Progress is urgently needed in validating non-invasive markers of fibrosis progression and regression that can supplant biopsy and shorten the duration of clinical trials. Both scientific and clinical challenges remain, however the past three decades of steady progress in understanding liver fibrosis have contributed to an emerging translational success story, with realistic hopes for antifibrotic therapies to treat patients with chronic liver disease in the near future.


The recent approval of two immune checkpoint inhibitors for the treatment of malignant melanoma has sparked great interest by physicians and basic scientists searching for novel therapeutics for GI cancer. Chronic inflammation is recognised as a major risk factor for the development of hepatocellular carcinoma (HCC) and makes this type of cancer a potentially ideal target for an immune based treatment approach. Further evidence for a critical role of immune responses in patients with HCC is derived from the fact that immune signatures and profiles predict patients’ outcome as well as the fact that tumour-induced spontaneous antitumour immunity can be detected. In addition ablative therapies can lead to changes in the number, phenotype and function of different immune cell subsets, which correlate with patients’ survival. Various HCC-specific mouse models have been developed, which improve our understanding of hepatocarcinogenesis and tumour-immune cell interactions, and lead to the development of novel immune based treatment approaches, which are currently being evaluated in preclinical and in early clinical settings. Immune checkpoint blockade along with adoptive immune cell therapy and vaccine approaches are currently being evaluated either alone or in combination with other treatments. Here, we provide an overview for the rationale of immunotherapy in HCC, summarise ongoing studies and provide a perspective for immune based approaches in patients with HCC.


Basic scienceThe intestinal virome in IBD

Norman JM, Handley SA, Baldridge MT, et al. Disease-specific alterations in the enteric virome in inflammatory bowel disease. Cell 2015;160:1–14.

Defining disease-specific changes in the gut microbiota has been the topic of great debate for many years in the context of IBD. Almost exclusively, studies have focused on defining changes in gut bacterial populations. Recently, the remit has broadened to assess the fungal component, the mycome, and also the viral component, the virome. The enteric virome consists mainly of bacteriophage belonging to Caudovirales and Microviridae, as well as some eukaryotic viruses. These interact with the host to potentially exacerbate IBD. In the case of the more abundant bacteriophage component, they are thought to play a direct role in intestinal physiology or to change the bacterial microbiome through predator-prey relationships. This study characterised the normal human and IBD enteric virome and...


We read the paper by Bajor et al with interest.1 The authors demonstrated that 18% of patients who meet criteria for IBS may have underlying bile acid diarrhoea (BAD), using 23-seleno-25-homo-tauro-cholic acid (SeHCAT) scanning. This issue has been the subject of a previous systematic review and meta-analysis2 which reported that up to 30% of individuals with IBS had evidence of idiopathic BAD. However, many of the included studies were retrospective, and few used accepted symptom-based criteria to define the presence of IBS, underlining the importance of the data from Bajor et al1 who recruited a well characterised and rigorously defined cohort of patients meeting the Rome II criteria for IBS.

We therefore congratulate the authors on conducting this study. The concept that underlying organic GI disease may explain symptoms compatible with IBS is not novel. The current gold standard for diagnosing IBS, the...


We thank Dr Aziz et al1 for expressing their interest in our recent paper, where we demonstrate that bile acids entering the colon may be an important factor for generation of part of the symptoms in patients who fulfil current diagnostic criteria for IBS.2 We agree with their comment that clinicians managing patients with IBS should be aware of the fact that an abnormal 75Se-labelled homocholic acid-taurine (75SeHCAT) test is quite a common finding in patients with non-constipated IBS, and that treating patients with IBS and an abnormal 75SeHCAT test with a bile acid binding agent may improve some of the key symptoms in these patients, especially diarrhoeal symptoms. However, we do not think that an abnormal 75SeHCAT test in a patient with typical IBS symptoms, that is, abdominal pain and/or discomfort associated with bowel habit disturbance, excludes an IBS diagnosis. In our study, it...


Sir,

We read with interest the paper by Amaddeo et al1 describing a comprehensive and integrative study to understand the molecular characteristics of HBV-related hepatocellular carcinoma (HCC). Chronic HBV infection is one of the most common causes of HCC. Although integration of viral gene into host genome has been implicated as an important oncogenic mechanism, a series of studies have reported that both direct and indirect hepatocarcinogenic actions of HBV infection exist. Amaddeo et al1 found a frequent inactivation of p53 and overexpression of stem cell-related genes in HBV-infected HCC tumours. Most importantly, TP53 mutations were shown to be associated with poor prognosis exclusively in HBV-related patients. This is probably an indirect oncogenic mechanism resulting from HBV infection.

In parallel, in a very recent Cancer Cell paper, Lau et al2 reported a direct oncogenic mechanism of HBV in that insertion of viral gene...


We acknowledge Cao et al1 for being interested in our recent study on molecular features of hepatitis B related hepatocellular carcinoma (HBV-related HCC).2 As they suggested, we searched for the HBx-LINE1 chimerical transcript recently identified in a Chinese population of HBV-related HCC by Lau et al3 in our series of HCC treated in France.2 To this aim, we have selected and analysed 50 HBV-related HCC tumours which were included in our last report.2 Total RNAs were extracted using Trizol (Invitrogen) from frozen tissues and converted into cDNA by SuperScript VILO cDNA Synthesis Kit (Life Technologies). Reverse-transcribed cDNA equivalent to 40 ng of RNA were amplified by hemi-nested PCR using the primers and the protocol designed by Lau et al.3 In our laboratory, no HBX fusion transcripts were previously amplified or cloned. Each sample was screened for the detection...


Recent publications in Gut1 2 have highlighted the beneficial role of the National Institute for Health Research (NIHR) Clinical Research Network in supporting clinical gastroenterology research in the UK.3 On an European level, the European Clinical Research Infrastructures Network provides integrated support to multinational clinical research projects in partner countries. The overarching aim of the NIHR Clinical Research Network is to maximise clinical research delivery by providing the infrastructure that allows high-quality studies to be undertaken in the NHS. The support available encompasses many aspects of the study life-cycle, including study set-up, researcher training and aiding study delivery, for example by providing protected clinician research time and research nurse support at individual study sites in NHS institutions. All clinical gastroenterology research studies entered onto the NIHR Clinical Research Network Portfolio are eligible for support.3

The performance of the NIHR Clinical Research...


We appreciate the suggestion by Dr Rhodes to further evaluate the link between oral contraceptive (OC) use and risk of Crohn's disease according to the anatomical location of disease involvement.1 We agree that a plausible mechanism for the link between OC use and risk of Crohn's disease may be through the effect of oestrogen on subacute thrombosis, leading to the development of multifocal ischaemia and infarction of the colon that manifests as colitis. In our study,2 we documented 315 incident cases of Crohn's disease through 2007 in Nurses’ Health Study II (NHS II) and 2008 in NHS I. Among these cases, 141 (45%) were isolated colonic disease and 82 (26%) were ileal Crohn's disease. Compared with never users of OC, the multivariate-adjusted HRs of Crohn's disease confined to the ileum were 2.99 (95% CI 1.06 to 8.49) for current OC use and 1.46 (95% CI...