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Genetic locus controls bacteria-induced colitis and associated cancer
▸ Boulard O, Kirchberger S, Royston DJ, et al. Identification of a genetic locus controlling bacteria-driven colitis and associated cancer through effects on innate inflammation. J Exp Med 2012;209:1309–24.
While many genetic studies have identified pathways that contribute to inflammatory bowel disease (IBD) susceptibility, the genetic factors involved in progression from colon inflammation to colitis-associated colorectal cancer (CAC) are not known. In this study by Boulard et al, the authors identify a major susceptibility locus for Helicobacter hepaticus-induced innate colitis and CAC in the 129S6.Rag−/− mouse strain. The locus, designated Hiccs, renders susceptible mice resistant to colitis and reduces colon tumour formation. Hiccs was mapped to a 1.71-Mb interval on chromosome 3, and found to include altered expression of three genes and differences in non-synonymous single nucleotide polymorphisms between resistant and susceptible strains. Analysis of colonic lamina propria leukocytes showed that resistance to colitis correlates with reduced secretion of pro-inflammatory cytokines. Bone marrow chimaera experiments demonstrated that Hiccs acts specifically in innate haematopoietic cells to confer resistance to H hepaticus-induced colitis. Innate inflammation without proper immune regulation plays a key role in inflammation-induced cancer. In order to identify how Hiccs controls the early inflammatory response, kinetic analyses of the innate response following H hepaticus infection were performed. Inflammatory cytokine production (TNF, IL-1β, and IFN-γ) and granulocyte recruitment driven by innate lymphoid cells are both controlled by Hiccs. The authors used a novel tumour induction protocol combining administration of the carcinogen azoxymethane with H hepaticus infection to explore whether the Hiccs locus is involved in CAC development. The Hiccs locus dramatically reduced frequency of colitis-associated invasive adenocarcinoma from 75% to 29%. This study along with further research on molecular pathways involved in increasing susceptibility to colitis and CAC could promote new insights into human IBD and into cancer caused by inflammation, as well as provide novel therapeutic targets for treatment.
Loss of Myofibroblasts by inactivation: a new concept in liver fibrosis regression
▸ Kisseleva T, Cong M, Paik Y, et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc Natl Acad Sci USA 2012;109:9448–53.
Fibrosis is the generic wound healing response of the liver to chronic injury of any form and can progress to cirrhosis. Whilst long thought of as irreversible, it is now widely accepted that liver fibrosis is a dynamic process and the removal of the causative agent can result in resolution of the hepatic scar in both animal models and human disease. A greater understanding of the mechanisms responsible for fibrosis regression will inform badly needed anti-fibrotic therapies. A key feature of fibrosis resolution is the loss of activated myofibroblasts, which are derived from activation of quiescent hepatic stellate cells (qHSCs) and represent the principal scar producing cells in the injured liver. Previously, this cell loss has largely been attributed to apoptosis. In this study by Kisseleva et al, the authors have identified a novel pathway which may be important in fibrosis resolution. Using a series of transgenic murine models which enable lineage tracing of activated myofibroblasts, they demonstrated that during fibrosis resolution, a proportion of these cells actually revert to an inactive HSC (iHSC) phenotype which persist in the liver long after cessation of injury. This was reproduced in two separate models of hepatic injury. Phenotyping these iHSCs revealed that they adopt a quiescent-like state but remain primed, activating more strongly than standard qHSCs in response to further fibrogenic stimuli. This results in increased fibrosis to a second insult, even in animals that have apparently fully recovered. Using gene expression profiling, they identified increased heat shock protein expression in iHSCs as a potential anti-apoptotic mechanism in this population. Thus, a greater understanding of the mechanisms controlling the fate of activated myofibroblasts following cessation of hepatic injury will enable the development of therapies aimed at promoting HSC apoptosis rather than quiescence and result in removal of a potentially pro-fibrotic population from the injured liver.
Integrated molecular analysis provides insights into colorectal cancer pathogenesis
▸ The Cancer Genome Atlas Network. Comprehensive molecular characterisation of human colon and rectal cancer. Nature 2012;487:330–7.
Identification of genetic and epigenetic aberrations in colorectal cancer has contributed substantially to our understanding of the pathogenesis of this common malignancy. The Cancer Genome Atlas project now reports results of a genome-scale analysis of 276 colon and rectal cancers by exome capture sequencing, copy number analysis, DNA methylation analysis, mRNA and miRNA expression analysis and, in a subset of 97 specimens, low-depth whole-genome sequencing. The majority (84%) of cancers had a mutation rate of <8.24 per 106, however, the remainder were hypermutated. Hypermutated cancers were most commonly due to genomic instability in the form of high microsatellite instability (MSI-H), associated with MLH1 methylation, however, a smaller proportion (23%) were not MSI-H, and had somatic mutations in MMR genes or polymerase ε. In non-hypermutated cancers, 24 genes were recurrently mutated. In addition to anticipated mutations (eg, APC, KRAS, TP53, P53, etc), mutations were frequently observed in ARID1A and FAM123B (a WNT pathway regulator), and novel mutations were identified in SOX9 (a cell differentiation factor). In addition to CIMP-high and CIMP-low epigenotypes, clustering analysis of methylation data identified two additional subgroups that differed by tumour subsite. Interestingly, gene expression patterns did not differ between rectal and non-hypermethylated colon cancers. Copy number analysis revealed that 4% of tumours harbour an amplicon containing ERBB2. A frequent focal amplification was a chromosomal region including IGF2. IGF2 was also overexpressed in 15% of tumours without IGF2 amplification. IGF2 overexpression was mutually exclusive with genomic events that activate the PIK3 pathway (eg, overexpression of IRS2). Pathways analysis revealed alterations in the WNT pathway in 93% of tumours. TGFβ pathways abnormalities occurred commonly in hypermutated cancers and almost 100% of total cancers had alterations in MYC transcriptional targets. In addition to significantly contributing to understanding of the molecular pathology of colorectal cancer, these findings identify potential therapeutic targets, such as ERBB2 and IGF2 signalling to PIK3, which may lead to personalised therapy in subsets of patients with colorectal cancer.
Can placement of a pancreatic duct stent reduce risk of post-ERCP pancreatitis (PEP)?
▸ Lee TH, Moon JH, Choi HJ, et al. Prophylactic temporary 3F pancreatic duct stent to prevent post-ERCP PEP in patients with a difficult biliary cannulation: a multicenter, prospective, randomised study. Gastrointest Endosc Published Online First: 6 Jul 2012. doi:10.1016/j.gie.2012.05.001.
PEP is the most common ERCP related complication and causes significant rates of morbidity and mortality. Risk factors for post-ERCP PEP include known or suspected sphincter of Oddi dysfunction (SOD), papillectomy, precut sphincterotomy, pancreatic sphincterotomy, previous history of PEP, young age, female sex and difficult biliary cannulation. Various strategies have been employed to minimise the rates of PEP including the use of pharmacological agents. Placement of a temporary prophylactic pancreatic duct stent is another option in high risk patients. This prospective randomised trial assessed the usefulness of small calibre 3F pancreatic duct stents (PS) in preventing PEP in patients with a difficult biliary cannulation. This was defined as failure to achieve selective biliary access despite 10 min of attempted cannulation, more than five attempted unintentional pancreatic cannulations, or frequent papillary contact of more than 10 times (sustained contact between the catheter and the ampulla of Vater for at least 3–5 s). Of the 101 patients enrolled, 50 received a prophylactic PS following biliary sphincterotomy. The incidence rate of PEP in the PS group was 12% (6/50), predominantly mild self-limiting disease. In the non-stented group PEP occurred in 29% (15/51) with two cases of moderate and one case of severe disease. Rates of successful stent placement were very high (96%) and spontaneous stent dislodgement occurred within 1 week in all but three patients, minimising the need for further endoscopic procedures. For problematic biliary cannulation prophylactic PS seems an increasingly sensible option, and smaller diameter stents may have a practical advantage in terms of spontaneous dislodgement. However in this particular study it should be noted that the study population was of overall low risk—only two patients had suspected SOD—and the endoscopists were highly skilled practitioners, each performing more that 500 procedures per year on average, so the results demonstrated here may not translate easily to centres with a lower volume of work.
Should cirrhotic patients drive?
▸ Bajaj JS, Pinkerton SD, Sanyal AJ, et al. Diagnosis and treatment of minimal hepatic encephalopathy (MHE) to prevent motor vehicle accidents (MVA): a cost-effectiveness analysis. Hepatology 2012;55:1164–71.
MHE is a diagnosis that is not often pursued whilst managing patients with cirrhosis, even by trained hepatologists, reflecting the difficulty in performing diagnostic tests for MHE and obtaining standardised results from them. It is estimated that 55% of patients with cirrhosis have MHE and nearly 19% of these patients progress to overt encephalopathy annually. MHE is associated with impaired driving skills and increased incidence of MVA but does not figure in the list of conditions that needs guidance from the Driver and Vehicle Licensing Agency. This article used a Markov model on a theoretical cohort of 1000 cirrhotic patients followed up for a period of 5 years and calculated societal costs involved, including patient time, assessment costs and treatment (Lactulose or Rifaximin) and also the costs as a result of MVAs. The diagnostic strategies were (1) presumptive treatment of all cirrhosis patients; (2) diagnosis by neuropsychological exam (NPE) with treatment; (3) diagnosis by standard psychometric tests (SPTs) with treatment; (4) diagnosis by rapid screening using inhibitory control test (ICT) with treatment; and (5) no MHE diagnosis or treatment (status quo). The societal cost of a single MVA was estimated at $ 42 100. The cost per accident prevented was least using ICT and treatment with lactulose ($ 24 454) as opposed to SPT and treatment with lactulose ($ 25 470), presumptive treatment ($ 30 469) and NPE and treatment with lactulose ($ 33 742). Rifaximin treatment was not cost effective with any of the diagnostic regimens. The net programme savings over 5 years ranged from $ 1.7 to 3.6 million depending on the strategy. There are several intrinsic difficulties on accepting these findings at face value but it is definitely food for thought. The lack of a gold standard hampers the diagnosis of MHE and impacts on the calculated sensitivity and specificity of diagnostic tests, thereby rendering several of the ‘facts’ as mere assumptions. Of course, in real life, there can be several reasons for cognitive decline in cirrhotic patients, for example, when alcohol and drug usage are factored in.
Targeting T cells—the ongoing search for novel therapeutics for the treatment of IBD
▸ Sandborn WJ, Colombel J-F, Sands BE, et al. Abatacept for Crohn's disease and ulcerative colitis. Gastroenterology 2012;143:62–9.
▸ Sands BE, Sandborn WJ, Creed TJ, et al. Basiliximab Does not increase efficacy of corticosteroids in patients with steroid-refractory ulcerative colitis. Gastroenterology 2012;143;356–64.
Despite increased understanding of the pathogenesis of IBD, and the introduction of biologic therapy, there are still a significant proportion of patients with considerable morbidity and ongoing disease activity resistant to currently available treatment. Two recent papers report the findings of two multi-centre randomised placebo controlled trials of potential novel treatment strategies; the first by Sandborn et al assessed abatacept—a recombinant fusion protein consisting of a fragment of IgG1 and cytotoxic T-lymphocyte antigen-4 (CTLA-4). This competes for cell surface receptor binding, inhibiting the CD28 T cell receptor interaction with CD80/CD86 on the antigen presenting cell that creates the co-stimulatory signalling required for T cell activation. This has been successful in rheumatoid arthritis and animal models of IBD. The study recruited approximately 1000 patients with moderate-severe IBD (including both CD (Crohn's disease) and UC (ulcerative colitis)) despite conventional therapy, to receive differing doses of drug or placebo. Disappointingly, there was no difference in clinical response or remission at 8 or 12 weeks. There was no effect on mucosal healing at 12 weeks for UC patients. It was deemed generally safe, however, two patients in the high dose abatacept group died of severe infections. The second paper by Sands et al assessed basiliximab, a monoclonal antibody that binds CD25, a chain of the IL-2 receptor, inhibiting T cell proliferation and survival. IL-2 is known to be implicated in steroid resistance. A previous open labelled study showed that a single dose achieved high rates of clinical remission in steroid refractory UC, and this present paper reports on the subsequent randomised placebo controlled trial to assess whether addition of this agent to ongoing corticosteroid therapy could render UC patients sensitive to steroid therapy and achieve remission. Unfortunately, this predicted response was not achieved with no significant effect on clinical response, clinical remission or mucosal healing within 8 weeks. The binding affinity of this drug to CD25 was impaired by the formation of neutralising antibodies from week 4 in a proportion of patients. Therefore the search for a rescue therapy to avoid colectomy for this particular patient cohort still continues.
Contributors Dr Miranda Hanson, Dr Prakash Ramachandran, Dr Paul Lochhead, Dr Jonathan MacDonald, Dr Ashis Mukhopadhya, Dr Mairi McLean.
Competing interests None.
Journals reviewed Journal of Experimental Medicine, Proceedings of the National Academy of Science USA, Nature, Gastrointestinal Endoscopy, Hepatology, Gastroenterology.
Provenance and peer review Not commissioned; internally peer reviewed.
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