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LuminalA global consensus report on fistulising peri-anal Crohn's disease

The World Congress of Gastroenterology 2013, held in Shanghai, called for the development of state-of-the-art, evidence based views for designated areas of gastroenterology. An expert consensus group was formed and developed a consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohn's disease (pCD), based on best available evidence (see page 1381). The group carried out a systematic literature review; statements were formed, discussed and approved in multiple rounds. Consensus was defined as at least 80% agreement among voters. Evidence was assessed using the modified GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria. Based on a multidisciplinary approach, items relevant for fistula management were identified and algorithms on diagnosis (see figure 1) and treatment of pCD were developed. This is an important document that is relevant to all clinicians involved in managing Crohn's...


IBD has been associated with an increased risk of osteoporosis and fracture.1 Current guidelines suggest using dual energy x-ray absorptiometry (DXA) to identify IBD patients with osteoporosis as candidates for possible therapy, but focus on IBD patients with established risk factors (ie, postmenopausal women, hypogonadal men or long term (≥3 month) users of glucocorticoids). While the exact role and timing for DXA in IBD is not fully defined, it is even more controversial to consider when therapeutic intervention is indicated. Among the possible choices, bisphosphonates remain the most commonly prescribed pharmacological osteoporosis intervention. While there is little debate when postmenopausal women have osteoporosis-related fractures or osteoporotic bone mineral density (BMD) (ie, T-scores –2.5 or lower),2 3 the use of bisphosphonates when patients with IBD are initiating a limited course of glucocorticoids, when T-scores are not in the osteoporotic range, in men or in premenopausal...


Apart from malabsorption and intestinal barrier dysfunction (via a ‘leak-flux’ mechanism), diarrhoea may reflect active ion secretion in the small intestine and/or colon. In recent years, our understanding about intestinal secretory mechanisms has increased enormously. Important new findings are (1) chloride, bicarbonate and potassium may be secreted simultaneously, but via independent transport processes and (2) movement of a specific ion across cell membranes may occur via several types of channels selective for that ion, but differing in their molecular structure and intrinsic biophysical properties. Additionally, Linley and coworkers now present evidence that (3) specific types of chloride and potassium channels involved in chloride and potassium secretion are differentially expressed in the apical membrane of enterocytes and goblet cells along the surface cell-crypt cell axis. Thus, we are now in a position to reconsider the ancient concept of exclusively secretory crypt cells and absorptive surface cells.1

In general,...


p21Waf1/Cip1 was originally identified as a crucial p53-regulated factor that controls cyclin-dependent kinase 1/2 (CDK1/CDK2) activities and sequesters proliferating cell nuclear antigen. The physical interaction with CDKs prevents binding and phosphorylation of retinoblastoma proteins which is required for the release of E2F transcription factors important for S-phase progression. Consequently, p21Waf1/Cip1 was classified as a tumour suppressor that interferes with cell cycle progression and DNA synthesis.1 2 Meanwhile, it has been realised that p21Waf1/Cip1 has a plethora of alternative functions in apoptosis, differentiation, migration, DNA repair, gene regulation, stem cell renewal and oncogenesis.1 2 Most of these functions are regulated in a dual and p53-independent manner. Cell proliferation is not exclusively inhibited but can also be promoted by p21Waf1/Cip1 when it is present at certain threshold concentrations. During apoptosis, the cytostatic effect of p21Waf1/Cip1 can protect cells from genotoxic insults (which require...


Among the primary hepatic malignant tumours, hepatocellular carcinoma (HCC) is the most common, while fibrolamellar carcinoma is a rare variant of HCC. In a recent article by Eggert et al examining the epidemiology of fibrolamellar hepatocellular carcinoma (fHCC) in the USA from 2000 to 2010,1 the authors reported better 5-year survival for fHCC compared with conventional HCC similar to previous studies.27 Even though several previous studies have advocated that fHCC is less aggressive than conventional HCC, some recent studies have failed to confirm the observation of a better outcome in fHCC.811 Cirrhosis is a well established poor prognostic factor in HCC.8 9 Since fHCC almost always arises in non-cirrhotic liver, the apparent better outcome in fHCC may be related to lack of cirrhosis....


HCV has chronically infected an estimated number of 160 million individuals worldwide.1 In the course of 10–20 years of persistent infection, approximately 20% of these patients are at risk of developing severe liver disease, including fibrosis, cirrhosis and hepatocellular carcinoma.2 Besides the ability to establish chronic infection, the pronounced genetic variability of HCV and the diverse course of chronic infection ranging from relatively benign to exacerbating liver disease are hallmarks of hepatitis C. Moreover, response to classical antiviral treatment based on pegylated interferon alpha (PEG-IFN-α) and ribavirin is substantially influenced by viral and host factors, since viral genotypes 1 and 4 are more resilient to therapy compared with genotypes 2 and 3 and as polymorphisms in the vicinity of the IFN28B locus predict the chances to naturally clear HCV infection and of response to IFN-based therapies.3 4 The high degree of virus...


Integrins and chemokines are critical for immune cell recruitment to tissue under homeostatic and pathological conditions.1 The heterodimeric integrin α4β7, expressed on T cells, specifies the recruitment of T cells to the intestinal mucosa upon its interaction with its ligand MAdCAM-1.1 Intestinal specificity is imprinted in T cells via upregulation of α4β7 integrin upon their interaction with CD103 dendritic cells (DCs) in the mesenteric lymph node when their cognate antigen is being presented by the major histocompatibility complex.2 The vitamin A metabolite retinoic acid (RA), produced by CD103 DCs via the enzyme retinaldehyde dehydrogenase 2 (encoded by Aldh1a2 gene), acting on T cells plays a critical role in this intestinal imprinting,3 and DCs with this capacity can be identified by an assay that detects this enzymatic activity (ALDE+).4

Pharmacological intervention in tissue-specific recruitment of T cells has the...


The oft-repeated statistics are dismal: pancreatic ductal adenocarcinoma (PDA) has only a 6% 5-year survival rate that has not changed significantly in 30 years and the vast majority of PDA patients perish within 6 months of diagnosis. Several possible reasons contribute to these grim results. PDA is difficult to detect, it is recalcitrant to most targeted treatments and conventional therapies only have a modest effect on survival. Compared with other cancers, PDA was revealed to be remarkably genetically homogenous with 95% or more of PDA harbouring oncogenic mutations in the Kras gene,1 generating hope that finding effective ways of interrupting Kras signalling would increase survival for PDA patients. However, Kras-targeted therapies have proven elusive thus far, leaving its downstream effectors as the most obvious potential targets.

The true genetic heterogeneity of PDA has just begun to be appreciated2 3 within a background of the...


Objective

To develop a consensus on the classification, diagnosis and multidisciplinary treatment of perianal fistulising Crohn's disease (pCD), based on best available evidence.

Methods

Based on a systematic literature review, statements were formed, discussed and approved in multiple rounds by the 20 working group participants. Consensus was defined as at least 80% agreement among voters. Evidence was assessed using the modified GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria.

Results

Highest diagnostic accuracy can only be established if a combination of modalities is used. Drainage of sepsis is always first line therapy before initiating immunosuppressive treatment. Mucosal healing is the goal in the presence of proctitis. Whereas antibiotics and thiopurines have a role as adjunctive treatments in pCD, anti-tumour necrosis factor (anti-TNF) is the current gold standard. The efficacy of infliximab is best documented although adalimumab and certolizumab pegol are moderately effective. Oral tacrolimus could be used in patients failing anti-TNF therapy. Definite surgical repair is only of consideration in the absence of luminal inflammation.

Conclusions

Based on a multidisciplinary approach, items relevant for fistula management were identified and algorithms on diagnosis and treatment of pCD were developed.


Background

Centralisation of healthcare, especially for advanced cancer surgery, has been a matter of debate. Clear short-term mortality benefits have been described for oesophageal cancer surgery conducted at high-volume hospitals and by high-volume surgeons.

Objective

To clarify the association between hospital volume, surgeon volume and hospital type in relation to long-term survival after oesophagectomy for cancer, by a meta-analysis.

Design

The systematic literature search included PubMed, Web of Science, Cochrane library, EMBASE and Science Citation Index, for the period 1990–2013. Eligible articles were those which reported survival (time to death) as HRs after oesophagectomy for cancer by hospital volume, surgeon volume or hospital type. Fully adjusted HRs for the longest follow-up were the main outcomes. Results were pooled by a meta-analysis, and reported as HRs and 95% CIs.

Results

Sixteen studies from seven countries met the inclusion criteria. These studies reported hospital volume (N=13), surgeon volume (N=4) or hospital type (N=4). A survival benefit was found for high-volume hospitals (HR=0.82, 95% CI 0.75 to 0.90), and possibly also, for high-volume surgeons (HR=0.87, 95% CI 0.74 to 1.02) compared with their low-volume counterparts. No association with survival remained for hospital volume after adjustment for surgeon volume (HR=1.01, 95% CI 0.97 to 1.06; N=2), while a survival benefit was found in favour of high-volume surgeons after adjustment for hospital volume (HR=0.91, 95% CI 0.85 to 0.98; N=2).

Conclusions

This meta-analysis demonstrated better long-term survival (even after excluding early deaths) after oesophagectomy with high-volume surgery, and surgeon volume might be more important than hospital volume. These findings support centralisation with fewer surgeons working at large centres.


Clinical presentation

A 23-years-old Caucasian man was admitted to our institution for progressive weight loss and dysphagia. His past medical history was apparently unremarkable, including his laboratory tests, except for the presence of uninvestigated episodes of dysphagia he had since childhood.

The patient performed a barium oesophagogram which showed oesophageal dysmotility (figure 1A) followed by an oesophagogastroduodenoscopy, demonstrating the presence of multiple tubular duplications of the middle and distal third of the oesophagus, with a contextual stricture of the lumen crossable only with ultrathin endoscope (GIF XP160; Olympus, Tokyo, Japan) (figure 2 and see online supplementary video 1). The gastroduodenal mucosa appeared regular. Multiple biopsies of the proximal two-thirds of the oesophagus were performed. A thoracic CT scan, with virtual oesophagoscopy, was also carried out and confirmed the oesophageal duplication without any airways malformations (figure 1B and see online supplementary video 2).

...

Background

Idiopathic achalasia is a rare motor disorder of the oesophagus characterised by neuronal loss at the lower oesophageal sphincter. Achalasia is generally accepted as a multifactorial disorder with various genetic and environmental factors being risk-associated. Since genetic factors predisposing to achalasia have been poorly documented, we assessed whether single nucleotide polymorphisms (SNPs) in genes mediating immune response and neuronal function contribute to achalasia susceptibility.

Methods

391 SNPs covering 190 immune and 67 neuronal genes were genotyped in an exploratory cohort from Central Europe (589 achalasia patients, 794 healthy volunteers (HVs)). 24 SNPs (p<0.05) were validated in an Italian (160 achalasia patients, 278 HVs) and Spanish cohort (281 achalasia patients, 296 HVs). 16 SNPs in linkage disequilibrium (LD) with rs1799724 (r2>0.2) were genotyped in the exploratory cohort. Genotype distributions of patients (1030) and HVs (1368) were compared using Cochran–Armitage trend test.

Results

The rs1799724 SNP located between the lymphotoxin-α (LTA) and tumour necrosis factor-α (TNFα) genes was significantly associated with achalasia and withstood correction for testing multiple SNPs (p=1.17E-4, OR=1.41 (1.18 to 1.67)). SNPs in high LD with rs1799724 were associated with achalasia. Three SNPs located in myosin-5B, adrenergic receptor-β-2 and interleukin-13 (IL13) showed nominally significant association to achalasia that was strengthened by replication.

Conclusions

Our study provides evidence for rs1799724 at the LTA/TNFα locus as a susceptibility factor for idiopathic achalasia. Additional studies are needed to dissect which genetic variants in the LTA/TNFα locus are disease-causing and confirm other variants as potential susceptibility factors for achalasia.


Objective

Treatments with sequential therapy (SEQ) or bismuth quadruple (QUAD) therapy have been proposed as empirical firstline regimens for Helicobacter pylori. We compared the efficacy and tolerability of 10 day SEQ with 10 day modified QUAD as both firstline and secondline treatments for H pylori in a randomised crossover study.

Design

H pylori positive and treatment naïve patients were randomly assigned to receive either 10 day SEQ (esomeprazole for 10 days, amoxicillin for an initial 5 days, followed by clarithromycin and metronidazole for a subsequent 5 days) or modified QUAD (esomeprazole, bismuth subcitrate, tetracycline and metronidazole). H pylori eradication was confirmed by urea breath test at 8 weeks. Patients who failed the initial assigned treatment were crossed over to receive the alternate regimen. The primary outcome was eradication rates of firstline treatment by intention to treat (ITT) and per protocol (PP) analyses.

Results

357 patients were randomised to receive either SEQ or QUAD. The PP eradication rates of the SEQ and QUAD groups were 95.2% and 98.8%, respectively (p=0.10). Based on ITT analysis, the corresponding eradication rates were 89.4% and 92.7%, respectively (p=0.36). Eight (4.8%) patients in the SEQ and two (1.2%) patients in the QUAD who failed the firstline treatment were crossed over to the alternate regimen with 100% retreatment success. The overall incidence of adverse events was higher in the QUAD (16.7%) than in the SEQ (8.1%; p=0.032) group.

Conclusions

Ten day sequential and modified bismuth quadruple therapies are both highly effective as empirical firstline therapies for H pylori in Chinese patients.

ClinicalTrials.gov

NCT 01760824


Objective

To explore the risk of new or recurrent cancer among patients with IBD and previous cancer, exposed or not to immunosuppressants.

Design

Among the 17 047 patients of the CESAME prospective observational cohort who were enrolled from May 2004 to June 2005, and followed-up until December 2007, we identified 405 patients with cancer diagnosed previous to study entry. We calculated the rates of incident cancer in patients with or without previous cancer, and we assessed by survival analysis and nested case-control study the impact of immunosuppressants on the risk of incident new or recurrent cancer in patients with previous cancer.

Results

The rate of incident cancer was 21.1/1000 patient-years (PY) and 6.1/1000 PY in patients with and without previous cancer, respectively. The multivariate-adjusted HR of incident cancer between patients with and without previous cancer was 1.9 (95% CI 1.2 to 3.0, p=0.003). Among patients with previous cancer, the rates of new and recurrent cancers were, respectively, 13.2/1000 PY and 6.0/1000 PY in the 312 patients who were not taking immunosuppressant at the time of study entry, and 23.1/1000 PY and 3.9/1000 PY in the 93 patients treated with immunosuppressants at study entry. There was no significant association between the exposure to immunosuppressants and the risk of new or recurrent cancer.

Conclusions

Patients with IBD with a history of cancer are at increased risk of developing any (new or recurrent) cancer, with a predominant incidence of new cancers. Treatment with immunosuppressants has no overall major impact per se on this risk.


Objective

Osteoporosis and fractures are frequently encountered in patients with Crohn's disease. In order to prevent fractures, treatment with bone protecting drugs appears warranted early in the course of bone disease when bone loss is not yet prominent. We therefore aimed to demonstrate a beneficial effect on bone density of the bisphosphonate risedronate in osteopenic Crohn's disease patients.

Methods

This double-blind, placebo-controlled randomised trial of risedronate with calcium and vitamin D supplementation was performed in osteopenic Crohn's disease patients. Patients were treated for 2 years with follow-up after 3 and after every 6 months. Disease characteristics and activity and bone turnover markers were assessed at all visits; dual x-ray absorptiometry was performed at baseline, 12 and 24 months; radiographs of the spine at baseline and 24 months.

Results

Of 132 consenting patients, 131 were randomised (67 placebo and 64 risedronate). Patient characteristics were similar in both groups, although the risedronate group was slightly heavier (body mass index 24.3 vs 23.0 kg/m2). Bone mineral density at lumbar spine increased 0.04 g/cm2 on average in the risedronate group versus 0.01 g/cm2 in the placebo group (p=0.007). The mean increase in total hip bone mineral density was 0.03 versus 0.01 g/cm2, respectively (p=0.071). Fracture prevalence and incidence were similar. Change of T-scores and concentrations of bone turnover markers were consistent with a beneficial effect of risedronate when compared with placebo. The effect of risedronate was primarily demonstrated in the first 12 months of treatment. No serious unexpected suspected adverse events were observed.

Conclusions

A 24-month treatment course with risedronate 35 mg once weekly, concomitant with calcium and vitamin D supplementation, in osteopenic Crohn's disease patients improved bone density at lumbar spine.

NTR 163 Dutch Trial Register.


Background and objective

While pro-inflammatory monocyte trafficking to the intestine has been partially characterised, the molecules required for migration of tolerogenic mononuclear phagocytes (dendritic cells (DC) and macrophages) are unknown. We hypothesised that the gut-homing receptor integrin α4β7 is required for this process.

Methods

We used a T cell-mediated colitis model to study the role of α4β7 in the innate immune compartment. We then performed competitive bone marrow (BM) reconstitution experiments to assess the requirement of α4β7 in the generation of intestinal retinoic acid (RA)-producing CD11chi DC (ALDE+DC) and CD64 macrophages. Using mixed BM chimeras we also asked whether α4β7 is required to give rise to tolerogenic mononuclear phagocytes.

Results

Lack of β7 integrins in the innate immune compartment (β7–/–RAG2–/– mice) markedly accelerated T cell-mediated colitis, which was correlated with lower numbers and frequencies of ALDE+DC in mesenteric lymph nodes. Consistent with a role of α4β7 in the generation of intestinal mononuclear phagocytes, BM cells from β7–/– mice poorly reconstituted small intestine ALDE+DC and M when compared to their wild type counterparts. In addition, mice lacking β7 integrins in the CD11chi compartment showed decreased ability to induce Foxp3+ TREG and IL-10-producing T cells.

Conclusions

Mice lacking β7 integrins in the innate immune compartment are more susceptible to intestinal inflammation, which is correlated with a requirement of β7 integrins to reconstitute gut mononuclear phagocytes with tolerogenic potential.


Background and aims

Rectal sensory and motor interactions in patients with IBS have not been studied in detail. The aim of this study was to evaluate fasting and postprandial rectal sensorimotor characteristics and their interactions in IBS compared with healthy controls.

Design

We included 274 patients with IBS and 34 controls. All subjects underwent a rectal barostat study before and 60 min after a standardised liquid meal (800 kcal; 60% fat). Sensory thresholds, intensity of sensations, viscerosomatic referral and compliance were measured. During 15 min before the first distension sequence and until 50 min after meal intake, rectal balloon volumes were registered in 5 min intervals at operating pressure to quantify rectal tone. Mixed models were used to analyse the rectal tone response over time.

Results

Rectal sensory thresholds and compliance were decreased and viscerosomatic referral areas increased in patients with IBS compared with controls. Meal intake increased rectal sensitivity, compliance and referral areas in patients and controls and the same proportions of patients were hypersensitive to distension before and after meal intake. There was a higher basal rectal tone in IBS and a significantly different rectal tone response after meal intake in patients with IBS compared with controls and, interestingly, also in IBS with rectal hypersensitivity (defined in the preprandial state), compared with normosensitive patients.

Conclusions

Meal intake affects rectal sensorimotor function in IBS and health. Importantly, the rectal tone responses to a high-caloric meal are different between patients with IBS and controls, as well as between hypersensitive and normosensitive patients with IBS.


Background

Previous prospective studies have found the incidence of intestinal diverticular disease decreased with increasing intakes of dietary fibre, but associations by the fibre source are less well characterised. We assessed these associations in a large UK prospective study of middle-aged women.

Methods and findings

During 6 (SD 1) years follow-up of 690 075 women without known diverticular disease who had not changed their diet in the last 5 years, 17 325 were admitted to hospital or died with diverticular disease. Dietary fibre intake was assessed using a validated 40-item food questionnaire and remeasured 1 year later in 4265 randomly-selected women. Mean total dietary fibre intake at baseline was 13.8 (SD 5.0) g/day, of which 42% came from cereals, 22% from fruits, 19% from vegetables (not potatoes) and 15% from potatoes. The relative risk (95% CI) for diverticular disease per 5 g/day fibre intake was 0.86 (0.84 to 0.88). There was significant heterogeneity by the four main sources of fibre (p<0.0001), with relative risks, adjusted for each of the other sources of dietary fibre of 0.84 (0.81 to 0.88) per 5 g/day for cereal, 0.81 (0.77 to 0.86) per 5 g/day for fruit, 1.03 (0.93 to 1.14) per 5 g/day for vegetable and 1.04 (1.02 to 1.07) per 1 g/day for potato fibre.

Conclusions

A higher intake of dietary fibre is associated with a reduced risk of diverticular disease. The associations with diverticular disease appear to vary by fibre source, and the reasons for this variation are unclear.


Objective

Gene expression profiling provides an opportunity to develop robust prognostic markers of colorectal carcinoma (CRC). However, the markers have not been applied for clinical decision making. We aimed to develop an immunohistochemistry signature using microarray data for predicting CRC prognosis.

Design

We evaluated 25 CRC gene signatures in independent microarray datasets with prognosis information and constructed a subnetwork using signatures with high concordance and repeatable prognostic values. Tumours were examined immunohistochemically for the expression of network-centric and the top overlapping molecules. Prognostic values were assessed in 682 patients from Shanghai, China (training cohort) and validated in 343 patients from Guangzhou, China (validation cohort). Median follow-up duration was 58 months. All p values are two-sided.

Results

Five signatures were selected to construct a subnetwork. The expression of GRB2, PTPN11, ITGB1 and POSTN in cancer cells, each significantly associated with disease-free survival, were selected to construct an immunohistochemistry signature. Patients were dichotomised into high-risk and low-risk subgroups with an optimal risk score (1.55). Compared with low-risk patients, high-risk patients had shorter disease-specific survival (DSS) in the training (HR=6.62; 95% CI 3.70 to 11.85) and validation cohorts (HR=3.53; 95% CI 2.13 to 5.84) in multivariate Cox analyses. The signature better predicted DSS than did tumour-node-metastasis staging in both cohorts. In those who received postoperative chemotherapy, high-risk score predicted shorter DSS in the training (HR=6.35; 95% CI 3.55 to 11.36) and validation cohorts (HR=5.56; 95% CI 2.25 to 13.71).

Conclusions

Our immunohistochemistry signature may be clinically practical for personalised prediction of CRC prognosis.


Background and objective

High calcium concentrations are an established risk factor for pancreatitis. We have investigated whether increasing magnesium concentrations affect pathological calcium signals and premature protease activation in pancreatic acini, and whether dietary or intraperitoneal magnesium administration affects the onset and course of experimental pancreatitis.

Methods

Pancreatic acini were incubated with up to 10 mM magnesium; [Ca2+]i (fura-2AM) and intracellular protease activation (fluorogenic substrates) were determined over 60 min. Wistar rats received chow either supplemented or depleted for magnesium (<300 ppm to 30 000 ppm) over two weeks before pancreatitis induction (intravenous caerulein 10 µg/kg/h/4 h); controls received 1 µg/kg/h caerulein or saline. C57BL6/J mice received four intraperitoneal doses of magnesium (NaCl, Mg2+ 55 192 or 384 mg/kg bodyweight) over 72 h, then pancreatitis was induced by up to eight hourly supramaximal caerulein applications. Pancreatic enzyme activities, protease activation, morphological changes and the immune response were investigated.

Results

Increasing extracellular Mg2+ concentration significantly reduced [Ca2+]i peaks and frequency of [Ca2+]i oscillations as well as intracellular trypsin and elastase activity. Magnesium administration reduced pancreatic enzyme activities, oedema, tissue necrosis and inflammation and somewhat increased Foxp3-positiv T-cells during experimental pancreatitis. Protease activation was found in animals fed magnesium-deficient chow—even with low caerulein concentrations that normally cause no damage.

Conclusions

Magnesium supplementation significantly reduces premature protease activation and the severity of pancreatitis, and antagonises pathological [Ca2+]i signals. Nutritional magnesium deficiency increases the susceptibility of the pancreas towards pathological stimuli. These data have prompted two clinical trials on the use of magnesium in patients at risk for pancreatitis.


Objective

Pancreatic cancer is a leading cause of cancer-related death in the Western world. Current chemotherapy regimens have modest survival benefit. Thus, novel, effective therapies are required for treatment of this disease.

Design

Activating KRAS mutation almost always drives pancreatic tumour initiation, however, deregulation of other potentially druggable pathways promotes tumour progression. PTEN loss leads to acceleration of KrasG12D-driven pancreatic ductal adenocarcinoma (PDAC) in mice and these tumours have high levels of mammalian target of rapamycin (mTOR) signalling. To test whether these KRAS PTEN pancreatic tumours show mTOR dependence, we compared response to mTOR inhibition in this model, to the response in another established model of pancreatic cancer, KRAS P53. We also assessed whether there was a subset of pancreatic cancer patients who may respond to mTOR inhibition.

Results

We found that tumours in KRAS PTEN mice exhibit a remarkable dependence on mTOR signalling. In these tumours, mTOR inhibition leads to proliferative arrest and even tumour regression. Further, we could measure response using clinically applicable positron emission tomography imaging. Importantly, pancreatic tumours driven by activated KRAS and mutant p53 did not respond to treatment. In human tumours, approximately 20% of cases demonstrated low PTEN expression and a gene expression signature that overlaps with murine KRAS PTEN tumours.

Conclusions

KRAS PTEN tumours are uniquely responsive to mTOR inhibition. Targeted anti-mTOR therapies may offer clinical benefit in subsets of human PDAC selected based on genotype, that are dependent on mTOR signalling. Thus, the genetic signatures of human tumours could be used to direct pancreatic cancer treatment in the future.


Objective

Adult primary human hepatocytes (PHHs) support the complete infection cycle of natural HCV from patients’ sera. The molecular details underlying sera infectivity towards these cells remain largely unknown. Therefore, we sought to gain a deeper comprehension of these features in the most physiologically relevant culture system.

Design

Using kinetic experiments, we defined the optimal conditions to infect PHH and explored the link between cell organisation and permissivity. Based on their infectivity, about 120 sera were classified in three groups. Concentration of 52 analytes was measured in 79 selected sera using multiplexed immunobead-based analyte profiling.

Results

PHH permissivity towards HCV infection negatively correlated with cell polarisation and formation of functional bile canaliculi. PHH supported HCV replication for at least 2 weeks with de novo virus production. Depending on their reactivity, sera could be classified in three groups of high, intermediate or low infectivity toward PHH. Infectivity could not be predicted based on the donors’ clinical characteristics, viral load or genotype. Interestingly, highly infectious sera displayed a specific cytokine profile with low levels of most of the 52 tested analytes. Among them, 24 cytokines/growth factors could impact hepatocyte biology and infection efficiency.

Conclusions

We identified critical factors leading to efficient PHH infection by HCV sera in vitro. Overall, we showed that this cellular model provides a useful tool for studying the mechanism of HCV infection in its natural host cell, selecting highly infectious isolates, and determining the potency of drugs towards various HCV strains.


Background and aims

The cyclin-dependent kinase inhibitor p21 has been implicated as a tumour suppressor. Moreover, recent genetic studies suggest that p21 might be a potential therapeutic target to improve regeneration in chronic diseases. The aim of this study was to delineate the role of p21 in chronic liver injury and to specify its role in hepatocarcinogenesis in a mouse model of chronic cholestatic liver injury.

Methods

The degree of liver injury, regeneration and tumour formation was assessed in Mdr2–/– mice and compared with Mdr2/ p21–/– mice. Moreover, the role of p21 was evaluated in hepatoma cells in vitro and in human hepatocellular carcinoma (HCC).

Results

Mdr2–/– mice developed HCCs as a consequence of chronic inflammatory liver injury. In contrast, tumour development was profoundly delayed in Mdr2/ p21–/– mice. Delayed tumour development was accompanied by markedly impaired liver regeneration in Mdr2/ p21–/– mice. Moreover, the regenerative capacity of the Mdr2/ p21–/– livers in response to partial hepatectomy declined with age in these mice. Hepatocyte transplantation experiments revealed that impaired liver regeneration was due to intrinsic factors within the cells and changes in the Mdr2/ p21–/– microenvironment. In human HCCs, a subset of tumours expressed p21, which was associated with a significant shorter patient survival.

Conclusions

We provide experimental evidence that p21 is required for sustained liver regeneration and tumour development in chronic liver injury indicating that p21 needs to be tightly regulated in order to balance liver regeneration and cancer risk. Moreover, we identify p21 as a negative prognostic marker in human HCC.


The gut microbiota affects numerous biological functions throughout the body and its characterisation has become a major research area in biomedicine. Recent studies have suggested that gut bacteria play a fundamental role in diseases such as obesity, diabetes and cardiovascular disease. Data are accumulating in animal models and humans suggesting that obesity and type 2 diabetes (T2D) are associated with a profound dysbiosis. First human metagenome-wide association studies demonstrated highly significant correlations of specific intestinal bacteria, certain bacterial genes and respective metabolic pathways with T2D. Importantly, especially butyrate-producing bacteria such as Roseburia intestinalis and Faecalibacterium prausnitzii concentrations were lower in T2D subjects. This supports the increasing evidence, that butyrate and other short-chain fatty acids are able to exert profound immunometabolic effects. Endotoxaemia, most likely gut-derived has also been observed in patients with metabolic syndrome and T2D and might play a key role in metabolic inflammation. A further hint towards an association between microbiota and T2D has been derived from studies in pregnancy showing that major gut microbial shifts occurring during pregnancy affect host metabolism. Interestingly, certain antidiabetic drugs such as metformin also interfere with the intestinal microbiota. Specific members of the microbiota such as Akkermansia muciniphila might be decreased in diabetes and when administered to murines exerted antidiabetic effects. Therefore, as a ‘gut signature’ becomes more evident in T2D, a better understanding of the role of the microbiota in diabetes might provide new aspects regarding its pathophysiological relevance and pave the way for new therapeutic principles.


Basic scienceNod2: —a key component of the microbial intestinal crypt interface

 Nigro G, Rossi R, Commere P-H, et al. The cytosolic bacterial peptidoglycan sensor Nod2 affords stem cell protection and links microbes to gut epithelial regeneration. Cell Host Microbe 15, 792–8.

Genetic factors play an important role in the pathogenesis of Crohn's disease (CD). The most significant of these implicates aberrant immune responses central to microbial sensing/signalling and mucosa-initiated effector responses. Nucleotide oligomerisation domain 2 (Nod2) is a member of the Nod-like receptor (NLR) family of intracellular microbe sensors that are strongly involved in innate immunity. Nod2 is known to be expressed by paneth cells within intestinal crypts. However due to the complexity of this site in terms of the differing cell types present and the potential interactions with microbes, there has been debate as to the precise functions of each cell type. Nigro and colleagues used...


We are grateful for the opportunity to reply to Dr Njei's letter, which raised the question of whether a better 5-year survival for patients with fibrolamellar hepatocellular carcinoma (fHCC) versus patients with hepatocellular carcinoma (HCC) (that we recently reported), was real or an artefact of research methodology.1 In the letter, results of a meta-analysis were presented which were interpreted to show that the survival of fHCC and HCC do not differ in non-cirrhotic patients. We disagree with this interpretation of the results.

In the meta-analysis, 11 studies were included in the overall analysis, while three of the 11 were included in a subset analysis of non-cirrhotic patients. The overall analysis resulted in an OR=2.09, 95% CI1.38 to 3.16, while the subset analysis resulted in an OR=1.69, 95% CI 0.69 to 4.17. Based on these results, it was concluded that the survival of fHCC was significantly better in...


We read with great interest the letter by Eggert et al, in response to our recently published article which raised concerns about the better 5-year survival of fibrolamellar hepatocellular carcinoma (fHCC) compared with conventional hepatocellular carcinoma (HCC-NOS).1 2 In the letter, the authors pointed out that it cannot be concluded from our meta-analysis that ‘survival in fHCC is similar to conventional HCC in non-cirrhotic liver patients’, given the overlap in the CIs of the subgroup analyses (limited to non-cirrhotic liver patients) and the overall analysis of all cases. The authors further report findings of their recently published follow-up article suggesting that fHCC patients experience better survival despite larger tumour size distribution, with survival benefits limited to cases younger than 40 years of age.2 3

With the aim of providing a more focused answer to these interesting disparities in results, we also examined...


Dear Sir,

In June 2013, the Mallorca Group published revised guidelines for the clinical management of Lynch syndrome.1 In the title, HNPCC (Hereditary NonPolyposis Colorectal Cancer) is equated with Lynch syndrome, continuing a misuse of terms that has fuelled confusion for many years. The two terms describe different, although overlapping, diseases: the distinction is critical to an accurate understanding of hereditary colorectal cancer.

HNPCC is defined clinically, usually as families satisfying Amsterdam I or II criteria.2 Lynch syndrome is defined genetically, by the presence of a germline mutation in DNA mismatch repair (MMR) or EPCAM genes.3 Not all HNPCC families have Lynch syndrome and not all Lynch syndrome families have HNPCC. To determine the extent of the misuse of terms, we searched PubMed and Medline databases in 2013 for the keywords ‘Lynch syndrome’ and ‘HNPCC’. One hundred and sixty-seven unique references were found,...


In 1991 Wotherspoon et al1 showed a close association between Helicobacter pylori infection and gastric mucosa-associated lymphoid tissue (MALT) lymphoma (GML) with the organism present in 92% of cases. Other studies have shown this association to be varying between 42% and 100%. In vitro studies at that time showed that lymphoma cell proliferation was associated with the presence of H. pylori mediated through specific tumour infiltrating T cells in a contact dependant manner. In the light of this finding Wotherspoon et al1 were able to demonstrate that eradication of H. pylori induced lymphoma regression.

In a recent Gut article, Nakamura et al2 demonstrated that H. pylori eradication therapy can result in durable lymphoma regression in the majority of cases. However, absence of H. pylori infection is a known predictive factor for eradication resistance.3

Prevalence of H. pylori has shown signs of...


V Mukhekat, I Ahmad, Y Merali, et al. PTU-078 The Application Of A Markov Model For Evauating Asa Therapy For Ulcerative Colitis. Gut 2014;63:Suppl 1 A73. The first author's name was published incorrectly. The correct name is Vinaykumar Mukhekar.