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Pancreatic exocrine insufficiency (PEI) is a common condition in patients with pancreatic cancer (PC). PEI can be due to the tumor, which, if located in the head, causes obstruction of the pancreatic duct with subsequent atrophy of the pancreatic parenchyma, or it can be the consequence of pancreatic surgical resection. The standard treatment of PEI is pancreatic enzyme replacement therapy (PERT). Clinical data to support the use of PERT in PC are however limited. There are very few randomized clinical trials that evaluated PERT in PC. Most data come from observational studies. Despite this limited clinical evidence, PERT treatment for PEI is an essential part of supportive therapy to ensure optimal nutritional status in PC patients who will receive surgery, neoadjuvant/adjuvant or palliative treatment. The objective of this review is to increase the awareness about PEI in PC patients and to provide expert recommendations on the use of PERT in resected, borderline resectable and unresectable patients, based on clinical experience and literature review. ispartof: ESMO OPEN vol:7 issue:1 ispartof: location:England status: published

The most important causes of hereditary colorectal cancer are Lynch syndrome (LS) and the adenomatous polyposis syndromes (familial adenomatous poly- posis syndrome or FAP, attenuated FAP or AFAP and MUTYH associated polyposis syndrome or MAP). The aim of this study was to investigate whether all patients with a hereditary syndrome within one center receive uniform advice regarding surveillance and treatment.A retrospective analysis was performed of all electronic patient health records of patients with LS, FAP, AFAP and MAP who received genetic counselling or were followed by a health care specialist at the University Hospital in Ghent.Data from 122 patients were collected. For all patients, recommendations from the medical genetics department were highly consistent. Adherence to their recommendations was good within the center for the management of colon polyps. There was a lack of consistency in the screening and surveillance advice for other tumors in departments other than gastroenterology. Only 33 patients had systematic follow-up consultations to check results and organize surveillance.Previously, small studies have suggested that patients with hereditary gastrointestinal cancer syndromes infrequently have surveillance as specified in the guidelines. This study shows almost uniform recommendations and good adherence for surveillance of the colon, but incomplete or contradictory advice for surveillance of other organs. The need for an integrated approach from a multidisciplinary team will only increase in the future, because more families with hereditary cancer are likely to be found due to the increased use of next generation sequencing in cancer diagnostics.

Objectives Anti-Hu antibodies (Hu-Abs) are the most frequent onconeural antibodies associated with paraneoplastic neurologic syndromes (PNS). PNS include a variety of neurological syndromes, affecting less than 1/10,000 patients with cancer. In the majority of cases, PNS will manifest before the malignancy is diagnosed. We found a case in which PNS was diagnosed without finding a primary malignancy after extensive work-up and even post-mortem autopsy. Patient and methods We present a case report of a 58-year-old man. This article includes extensive clinical work-up, full-body autopsy and brain autopsy with classical histochemical and myelin stainings and immunohistochemistry was performed. Results The patient developed a progressive trigeminal neuropathy over a period of 5 years, in combination with cerebellar degeneration, asymmetrical brainstem and limbic encephalitis. Serum showed repeatedly high anti-Hu antibodies. Comprehensive cancer screening could not demonstrate any primary malignancy. Therapy with corticosteroids, plasma exchange, cyclophosphamide and rituximab showed no beneficial effect. He died from the complications of enteric ganglionitis 5 years after onset of the first symptoms. A postmortem autopsy could not detect a primary malignancy either. Brain morphology is described in detail. Conclusion Paraneoplastic anti-Hu encephalitis cases associated with SCLC or other primary neoplasms are well known. An adult with a progressive multifocal neurological syndrome in the presence of positive anti-Hu antibodies, but without any primary neoplasm after a follow-up over 5 years is unusual.

In Nederland en Belgie wordt jaarlijks bij 21.000–25.000 patienten een colorectaal carcinoom gediagnosticeerd. Colorectale carcinomen geven over het algemeen pas laat symptomen. Met de start van het bevolkingsonderzoek naar darmkanker wordt een deel van de tumoren en premaligne poliepen tegenwoordig opgespoord door het uitvoeren van een occult-bloedtest. Coloscopie wordt beschouwd als de referentiestandaard voor de detectie van een carcinoom. CT-colografie of MR-colografie als alternatief kan worden overwogen. Wanneer de diagnose colorectaal carcinoom is gesteld, is het TNM-stadium van belang voor het bepalen van het behandelplan. De behandeling van het colorectaal carcinoom omvat meerdere modaliteiten. Chirurgie is nog altijd de hoeksteen en bestaat uit het verwijderen van de tumor, inclusief het bijbehorende lymfedrainagegebied. Bij rectumcarcinomen wordt er eveneens gebruikgemaakt van neoadjuvante radio(chemo)therapie. Een deel van de patienten met een coloncarcinoom dient nog adjuvant behandeld te worden met chemotherapie. Ook bij gemetastaseerde tumoren worden de voor- en nadelen van de verschillende modaliteiten: chemotherapie, radiotherapie en chirurgie, afgewogen. De huisarts speelt een belangrijke rol bij de opsporing van darmkanker, bij de begeleiding tijdens de behandeling, in de nazorgfase en bij eventueel palliatieve zorg.

Este articulo es una traduccion del articulo publicado en Journal of Crohn’s and Colitis, Vol. 6, Dignass A, et al. Second European evidence-based Consensus on the diagnosis and management of ulcerative colitis Part 1: Definitions and diagnosis, 965--990 © 2012 European Crohn’s and Colitis Organisation. Publicado por Elsevier B.V. Todos los derechos reservados. http://dx.doi.org/10.1016/j.crohns.2012.09.003 Citar este articulo como: Dignass A, et al., Second EUROPEAN evidence-based Consensus on the diagnosis and management of ulcerative colitis: Definitions and diagnosis, Journal of Crohn’s and Colitis (2012), http://dx.doi.org/10.1016/j.crohns.2012.09.003 ∗ Autor para correspondencia. Department of Medicine 1, Agaplesion Markus Hospital, Wilhelm-Epstein-Str. 4, D-60431 Frankfurt/Main, Alemania. Telefono: +49 69 95332201; fax: +49 69 95332291. ∗∗ Autor para correspondencia. Division of Gastroenterology, Department of Medicine, Mt. Sinai Hospital and University Health Network; University of Toronto and University of Leuven, 600 University Avenue, Toronto, ON, Canada M5G 1X5. Correos electronicos: axel.dignass@fdk.info (A. Dignass), gvanassche@mtsinai.on.ca (G. van Assche). ♦ La afiliacion en nombre de la ECCO puede encontrarse en el anexo 1 al final del manuscrito. Definiciones

Background Involvement of the lymphatic system in inflammatory bowel disease (IBD) has been suggested. Aims To examine the density and distribution of lymphatic vessels (LV) within inflamed and non-inflamed wall sections of IBD patients compared with controls, and to evaluate expression of major lymphangiogenic factors. Methods Ileal and colon specimens of 22 patients with Crohn’s disease (CD), 16 patients with ulcerative colitis (UC) and 11 controls were studied. Quantification of LV was performed using immunohistochemistry with podoplanin and D2-40 antibodies on seven randomly selected fields. Mucosal expression of podoplanin and lymphangiogenic factor mRNA was measured using PCR. Results In CD patients, lymphatic density was significantly increased in noninflamed and inflamed ileal (P < 0.01 and P < 0.001) and colonic (P < 0.01 and P < 0.001) mucosa compared to controls. Podoplanin mRNA levels were similar in non-inflamed mucosal areas and controls, whereas a fourand sixfold increase was seen in inflamed ileal and colonic areas (P < 0.05). In UC, lymphatic density increased fourfold in non-inflamed (P < 0.001) and fivefold in inflamed colonic mucosa (P < 0.001) compared with controls. An increase in podoplanin mRNA levels was seen in both noninflamed and inflamed areas (P < 0.01) compared with controls. In CD and UC, lymphatics were found throughout the inflamed mucosa, including the upper half of the lamina propria. Expression of lymphangiogenic factors was similar in patients and controls. Conclusions Increased density of lymphatic vessels is a constant feature of IBD and is present in non-inflamed areas. It is transmural in CD and confined to the mucosa in UC. Its origin remains unclear

Aliment Pharmacol Ther 2011; 34: 526–532 Summary Background Butyrate, a colonic metabolite of carbohydrates, is considered as the major energy source for the colonic mucosa. An impaired butyrate metabolism has been reported in ulcerative colitis (UC), however, the cause still remains unknown. Aim In the present study, we investigated whether higher butyrate concentrations could normalise the oxidation rate in UC. Furthermore, it was investigated whether carnitine could enhance the butyrate oxidation. Methods Mucosal biopsies from a total of 26 UC patients and 25 controls were incubated with 14C-labelled Na-butyrate and the produced 14CO2 was measured. First, the rate of oxidative metabolism was compared at three different concentrations of Na-butyrate (0.05 mm, 1 mm and 10 mm). Then, incubations of biopsies were performed with carnitine alone or combined with ATP. Results Overall, butyrate oxidation in UC was significantly lower than that in controls. The maximum rate of butyrate oxidation was achieved in UC and control subjects from 1 mm onwards. Increasing the butyrate concentration to a level to be present in the colonic lumen, i.e. 10 mm, did not increase the rate of butyrate oxidation in UC to the rate observed in controls. Addition of carnitine alone or combined with ATP caused no effects. Conclusions Saturation of butyrate kinetics was achieved from 1 mm in UC and control subjects. The rate of butyrate metabolism was significantly impaired in active ulcerative colitis. The addition of compounds interfering with the β-oxidation pathway had no effect on the butyrate metabolism in UC.

BACKGROUND AND AIMS: Infliximab is an effective treatment for ulcerative colitis with over 60% of patients responding to treatment and up to 30% reaching remission. The mechanism of resistance to anti-tumour necrosis factor alpha (anti-TNFalpha) is unknown. This study used colonic mucosal gene expression to provide a predictive response signature for infliximab treatment in ulcerative colitis. METHODS: Two cohorts of patients who received their first treatment with infliximab for refractory ulcerative colitis were studied. Response to infliximab was defined as endoscopic and histological healing. Total RNA from pre-treatment colonic mucosal biopsies was analysed with Affymetrix Human Genome U133 Plus 2.0 Arrays. Quantitative RT-PCR was used to confirm microarray data. RESULTS: For predicting response to infliximab treatment, pre-treatment colonic mucosal expression profiles were compared for responders and non-responders. Comparative analysis identified 179 differentially expressed probe sets in cohort A and 361 in cohort B with an overlap of 74 probe sets, representing 53 known genes, between both analyses. Comparative analysis of both cohorts combined, yielded 212 differentially expressed probe sets. The top five differentially expressed genes in a combined analysis of both cohorts were osteoprotegerin, stanniocalcin-1, prostaglandin-endoperoxide synthase 2, interleukin 13 receptor alpha 2 and interleukin 11. All proteins encoded by these genes are involved in the adaptive immune response. These markers separated responders from non-responders with 95% sensitivity and 85% specificity. CONCLUSION: Gene array studies of ulcerative colitis mucosal biopsies identified predictive panels of genes for (non-)response to infliximab. Further study of the pathways involved should allow a better understanding of the mechanisms of resistance to infliximab therapy in ulcerative colitis. ClinicalTrials.gov number, NCT00639821. ispartof: Gut vol:58 issue:12 pages:1612-1619 ispartof: location:England status: published

1.1 Introduction Ulcerative colitis is a life long disease arising from an interaction between genetic and environmental factors, but observed predominantly in the developed countries of the world. The precise aetiology is unknown and therefore medical therapy to cure the disease is not yet available. Within Europe there is a North–South gradient, but the incidence appears to have increased in Southern and developing countries in recent years.1,2 Patients may live with a considerable symptom burden despite medical treatment (66% describe interference with work and 73% with leisure activities3) in the hope that the aetiology of ulcerative colitis will shortly be revealed and a cure emerges. Although this is conceivable in the next decade, clinicians have to advise patients on the basis of information available today. Despite randomized trials there will always be many questions that can only be answered by the exercise of judgement and opinion. This leads to differences in practice between clinicians, which may be brought into sharp relief by differences in emphasis between countries. The Consensus endeavours to address these differences. The Consensus is not meant to supersede the guidelines of different countries (such as those from the UK,4 or Germany5), which reach broadly the same conclusions since they are, after all, based on the same evidence. Rather, the aim of the Consensus is to promote a European perspective on the management of ulcerative colitis (UC) and its dilemmas. Since the development of guidelines is an expensive and time-consuming process, it may help to avoid duplication of effort in the future. A European Consensus is also considered important because an increasing number of therapeutic trials recruit from Central and Eastern European countries where practice guidelines have yet to be published. This document sets out the current European Consensus on the diagnosis and management …

Summary Background Approximately 20% of primary sclerosing cholangitis (PSC) patients with concomitant inflammatory bowel disease (IBD) have Crohn's disease (CD). Aim To compare PSC/CD with other PSC patients. Methods Retrospective study of 240 PSC patients diagnosed between 1975 and 2012 (median follow-up 12 years). Activity of PSC at diagnosis was assessed by liver biopsy, Mayo risk and ERC scores. Survival without liver transplantation, number of transplantations and liver-related death were endpoints. Results Sixty-three per cent of patients had IBD: 105 UC, 32 CD and 14 IBD unclassified (IBDu). IBD was diagnosed before PSC in 50%. The yearly development of PSC after diagnosing IBD was similar in UC, CD or IBDu. Small-duct PSC was present in 28% of PSC/CD compared to 3% of PSC/UC. Small-duct PSC had a markedly better survival than large-duct PSC: no patient developed cholangiocarcinoma or liver-related death, but colorectal cancer occurred in three patients. In large-duct PSC, a more favourable outcome was evident in patients with CD. The liver disease was less progressive: one patient underwent liver transplantation compared to 28% and liver-related deaths were absent compared to 7% in the other PSC groups. Conclusions The prevalence of PSC with concomitant Crohn's disease is relatively rare, but the outcome is more benign than PSC with UC or without IBD. Approximately one-fourth has small-duct PSC. In large-duct PSC/CD, liver disease is less aggressive and the outcome is much better. The outcome of PSC patients with UC resembled that of PSC without IBD.

Myofibroblasts expressing α-smooth muscle actin (α-SMA) are the key cellular mediator of fibrosis. Fibrovascular epiretinal membranes from patients with proliferative diabetic retinopathy (PDR) are characterized by the accumulation of a large number of myofibroblasts. We explored the hypothesis that proliferating endothelial cells via endothelial-to-mesenchymal transition (EndoMT) and/or bone marrow-derived circulating fibrocytes contribute to the myofibroblast population present in PDR epiretinal membranes. Epiretinal membranes from 14 patients with PDR were studied by immunohistochemistry. All membranes contained neovessels expressing the endothelial cell marker CD31. CD31(+) endothelial cells co-expressed the fibroblast/myofibroblast markers fibroblast-specific protein-1 (FSP-1) and α-SMA, indicative for the occurrence of endoMT. In the stroma, cells expressing FSP-1, α-SMA, the leukocyte common antigen CD45, and the myelomonocytic marker CD11b were detected. Double labeling showed co-localization of CD45 with FSP-1 and α-SMA and co-localization of CD11b with α-SMA and matrix metalloproteinase-9, demonstrating the presence of infiltrating fibrocytes. In addition, we investigated the phenotypic changes that take place in human retinal microvascular endothelial cells following exposure to transforming growth factor-β1 (TGF-β1), connective tissue growth factor (CTGF) and the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Retinal microvascular endothelial cells changed morphology upon cytokine exposure, lost the expression of endothelial cell markers (endothelial nitric oxide synthase and vascular endothelial-cadherin) and started to express mesenchymal markers (calponin, snail, transgelin and FSP-1). These results suggest that endothelial cells as well as circulating fibrocytes may differentiate into myofibroblasts in the diabetic eye and contribute to pathologic fibrosis in PDR. publisher: Elsevier articletitle: Myofibroblasts in proliferative diabetic retinopathy can originate from infiltrating fibrocytes and through endothelial-to-mesenchymal transition (EndoMT) journaltitle: Experimental Eye Research articlelink: http://dx.doi.org/10.1016/j.exer.2015.01.023 content_type: article copyright: Copyright © 2015 Elsevier Ltd. All rights reserved. ispartof: Experimental Eye Research vol:132 pages:179-189 ispartof: location:England status: published

The purpose of this review was to explore issues relating to the nature of oesophageal injury in gastro-oesophageal reflux disease. Several structural and functional elements of the oesophageal epithelium provide for an inherent resistance against refluxed material. It is only when this defence is overcome that reflux-induced damage ensues. The light microscopic changes in reflux oesophagitis are manifold. Early changes are confined to the epithelium and consist of reactive changes and inflammatory cell infiltration. When the epithelial integrity can no longer be maintained, erosions and ulcers develop. Recently, dilatation of the intercellular spaces was described as a sensitive early marker for gastro-oesophageal reflux disease. This parameter was first identified by electron microscopy but can also be assessed by light microscopy in routinely stained tissue sections. Some of the changes occurring in early gastro-oesophageal reflux disease can be reproduced by incubating oesophageal mucosal biopsies in gastrointestinal fluids or their components. Activated pepsin, trypsin and conjugated bile acids at an acidic pH have been identified as probable causes of reflux-induced damage.

This study was designed to evaluate the safety of fontolizumab, a humanised anti-interferon gamma antibody, in patients with moderate to severe Crohn's disease (CD). Forty five patients with a CD activity index (CDAI) of 250-450 were randomised in a double blind, placebo controlled, dose escalating fashion to receive single doses of fontolizumab (0.1, 1.0, and 4.0 mg/kg) or placebo. By day 29, patients with clinical response were re-randomised to receive three additional doses of one half their initial fontolizumab dose or placebo at four weekly intervals. Primary objectives were safety and tolerability. Secondary outcomes included assessments of immunogenicity, clinical activity, and potential pharmacodynamic surrogates. Treatment was generally well tolerated. There were slightly more reports of chills, flu-like syndrome, asthenia, nausea, and vomiting in the 1.0 mg and 4.0 mg/kg fontolizumab cohorts. Two serious adverse events rated as worsening of CD occurred under fontolizumab. Antibodies to fontolizumab were confirmed in one patient. No differences in clinical activity parameters were noted between any of the active treatment groups and placebo, with the placebo group having a particularly favourable outcome (60% response and 40% remission). By day 29, a more enhanced decrease in median Crohn's disease endoscopic index of severity (p = 0.02) and serum C reactive protein (p

The intestine is constantly challenged by food antigens and pathogens and is therefore in need of a good working innate and adaptive immune response. Chemokines are important modulators as they assure the directed movement of immune cells within the body. In addition, chemokines play an important role in hematopoiesis, angiogenesis and tumor metastasis. This review focuses on chemokines and gastrointestinal disorders, more particularly on inflammatory bowel diseases and gastrointestinal tumors. In a first part, the current knowledge on chemokine expression in inflammatory bowel diseases is summarized. Idiopathic inflammatory bowel diseases are characterized by an uncontrolled immune response. The resulting chronic inflammation of the intestine involves massive infiltration of immune cells, causing intestinal damage by the release of cytokines and proteolytic enzymes. Chemokines are believed to be key mediators in this process of aberrant leukocyte recruitment. Chemokine expression in inflammatory bowel disease strongly correlates with the grade of disease activity. The potential therapeutic use of chemokines in gastrointestinal tumors by the use of gene therapy is also reviewed. Chemokines have therapeutic potential in anti-tumor therapy by their angiostatic effect. On the other hand, chemokines can augment the cell-mediated adaptive immune response and thereby exert anti-tumor activity. However, chemokines can passively favor escape of tumor cells by stimulating the release of tissue degrading matrix metalloproteinases and can actively promote metastasis of chemokine receptor-expressing tumor cells.

Les cancers colorectaux sont une cause importante de mortalite et de morbidite au monde. Il est actuellement bien etabli que la plupart des cancers colorectaux proviennent d’adenomes. Ces lesions se presentent sous differents aspects microscopiques — tubuleux, villeux ou festonnes — et sont le siege d’atypies intra-epitheliales de degres de severite variables. La conduite a tenir concernant les lesions precurseurs dans le cadre de maladies inflammatoires coliques (MICI), est legerement differente de la conduite a tenir lorsqu’on met en evidence des lesions precurseurs isolees.

Les tumeurs malignes de l’intestin grele sont relativement rares, ne representant que 1 a 5 % des tumeurs malignes du tractus gastrointestinal. Cependant, leur incidence est en augmentation et differentes maladies sont actuellement associees a une augmentation du risque de cancerisation [1]. Le diagnostic d’un cancer primitif de l’intestin grele est difficile et en general pose tardivement car les symptomes cliniques sont peu specifiques. L’adenocarcinome, les tumeurs neuro-endocrines, les lymphomes et les tumeurs stromales gastro-intestinales (GIST) representent les types histologiques les plus frequents. Le traitement chirurgical est le traitement de choix des adenocarcinomes, des tumeurs endocrines et des GIST alors que les lymphomes sont traites par chimiotherapie. L’apport des chimiotherapies adjuvantes ou palliatives dans le cadre des adenocarcinomes, des tumeurs neuro-endocrines ou des GIST reste decevant. Le pronostic des tumeurs malignes de l’intestin grele est mauvais etant donne le caractere metastatique de ces tumeurs au moment du diagnostic [2]. Un diagnostic precoce et precis est important pour ameliorer la prise en charge de ces patients et par la, leur survie. Aussi, le follow-up apparait fondamental chez les patients qui ont une pathologie a haut risque de cancerisation, telle que l’enteropathie au gluten, la maladie de Crohn, la polypose familiale et une immunodeficience.

Introduction: Crohn’s disease is a chronic inflammatory disorder of the gut. It is assumed that a defective interaction between the bacterial flora of the gut and the innate immune system plays a key role in the pathogenesis of the disease. This may lead to specific histological lesions. The epithelioid granuloma is particularly interesting in this regard as it is also observed in several bacterial infections of the gut. Aims and methods: We hypothesised that genetic or environmental factors with a known influence on inflammation or immunity would lead to an increased prevalence of granulomas. Therefore, surgical specimens from 161 patients were evaluated for the presence of granulomas. Patients were genotyped for the three single nucleotide polymorphisms in caspase recruitment domain 15 (CARD15)/NOD2 associated with CD and for Asp299Gly in Toll-like receptor 4 (TLR4). Results: The overall prevalence of granulomas was 68.9%. We did not find a significant correlation between granulomas and TLR4 or CARD15 variants. The frequency of granulomas increased with more distal disease (63% small bowel, 72% right colon, 88% left colon, 90% rectum; p = 0.01). Granulomas were more frequent in younger patients (odds ratio 0.95 (95% confidence interval 0.92–0.98) p = 0.007). Conclusion: In this study of 161 well documented CD patients, we found no significant association between CARD15 and TLR4 variants and granulomas. This finding seems to refute our initial hypothesis. However, it may be that additional factors are needed for granuloma development. Granulomas may develop only when specific bacterial components are present. Therefore, future research on granuloma pathogenesis should be orientated towards detection and identification of bacterial components in these lesions.

SUMMARY Aim: To evaluate, using isotope techniques, the in vivo effectiveness of a pH-dependent colonic delivery system. Methods: In order to dispose of differently labelled substrates for measurement of orocaecal transit time, inulin- 14 C-carboxylic acid was evaluated as an alternative substrate to inulin and lactose- 13 C-ureide. Secondly, the time of release of 13 C- and 15 N-urea from the colonic delivery system was compared with the orocaecal transit time, measured using inulin and inulin- 14 Ccarboxylic acid. This study was repeated after a 2-week lactulose intake period. Results: The orocaecal transit time determined using inulin- 14 C-carboxylic acid (398 min) was not significantly different from the orocaecal transit time determined using inulin (420 min) or lactose- 13 C-ureide (396 min). Before lactulose intake, the 13 CO2 excretion time was 358 min and the orocaecal transit times determined with the inulin- 14 C-carboxylic acid and inulin breath test were 376 and 375 min respectively. After lactulose, the 13 CO2 excretion time was 383 min and orocaecal transit times were 354 min for inulin- 14 C-carboxylic acid and 392 min for inulin. A highly significant correlation was found. Good agreement was found between the urinary 15 N excretion and the appearance of 13 CO2 in breath. Conclusion: Isotope techniques provide an excellent noninvasive tool for the in vivo evaluation of a colonic delivery system.

SUMMARYAn imbalance of immunoregulatory factors and/or cells contributes to uncontrolled mucosal T cell activation and inflammation in Crohn's disease (CD). Bioactive interleukin (IL)-18 has been shown to be produced by macrophages in CD lesions. We report here that T cells freshly isolated from inflamed tissue of CD patients (and not T cells from control intestinal tissue) were responsive to IL-18. In the presence of IL-18, these T cells produced more interferon (IFN)-γ and less IL-10. To analyse further the role of IL-18 in this disease, an acute and a chronic model of murine colitis were used. IL-18 mRNA was significantly enhanced in trinitrobenzene sulphonic acid (TNBS) induced colitis, and treatment with IL-18 binding protein (IL-18BPa), which neutralizes IL-18 bioactivity, significantly reduced the severity of colitis. However, IL-18BPa did not affect the course of chronic colitis in CD45RBhighCD4+ T cell reconstituted SCID mice. Production of IFN-γ in lamina propria mononuclear cell cultures from IL-18BPa-treated SCID mice was decreased, but at the same time fewer lamina propria CD4+ T cells harvested from IL-18BPa-treated mice compared to non-treated mice were in apoptosis. We conclude that IL-18 clearly has a modulatory role in the inflammatory cascade of CD and experimental colitis by affecting IFN-γ and IL-10 production, and apoptosis. In view of the divergent effects of IL-18 neutralization in the two different murine colitis models, it is unlikely that IL-18 is at the top of this cascade.

Surgical treatment and prognosis is different in esophageal, cardiac and distal gastric adenocarcinomas. Determination of the origin, in particular of adenocarcinomas situated at the gastroesophageal junction, may be difficult. It has been suggested that esophageal adenocarcinomas are characterized by a specific cytokeratin pattern, namely the CK7+/CK20- pattern. According to the same authors, this cytokeratin pattern is absent in gastric adenocarcinomas. The aim of our study is to evaluate if this cytokeratin pattern CK7+/CK20- is absent in cardiac and distal gastric adenocarcinomas. Therefore, we evaluated the combined immunohistochemical expression of CK7 and CK20 on paraffin-embedded material of 214 resection specimens for adenocarcinoma, comprising 66 esophageal, 73 cardiac and 75 distal gastric adenocarcinomas (UICC-classification). The adenocarcinomas were subtyped into intestinal- and diffuse-type according to the Lauren classification. The immunohistochemical staining was considered as positive if 50% or more of the tumor cells were stained. Statistical analysis has been performed applying the chi2-test. The tumors situated at the gastroesophageal junction, esophageal as well as cardiac adenocarcinomas, showed predominantly a CK7+/CK20- expression pattern (67 vs 68%), whereas this cytokeratin pattern is rather uncommon in distal gastric adenocarcinomas (31%, P4 x 10(-5)). Independent of their localization, intestinal- as well as diffuse-type adenocarcinomas have a similar cytokeratin pattern. Our data show that the combined expression of CK7 and CK20 is different for the adenocarcinomas situated on both sides of the gastroesophageal junction compared to the distal gastric adenocarcinomas. However, in contrast to data in the literature, the combined expression of CK7 and CK20 has a low specificity in the distinction between esophageal and cardiac adenocarcinomas. This may suggest a similar origin (cell lineage) and thus may have an impact on therapeutic strategies.

Background: Anti-TNFα therapy with infliximab is effective for Crohn’s disease. Infliximab neutralizes the biological activities of TNFα, a cytokine involved in host-defence against certain infections. Aim: To evaluate the effects of infliximab on the gut and peripheral immune system functions. Methods: Biopsies and blood samples from three clinical trials of infliximab in Crohn’s disease were analysed. Pharmacokinetics, changes in leucocyte counts and T cell subsets, T cell function, and cytokine profiles of lamina propria mononuclear cells (LPMC) and peripheral blood mononuclear cells (PBMC) were analysed. Results: Infliximab has a serum half-life of 9.5 days and is still detectable in serum 8 weeks after infusion. Leucocyte counts showed consistent changes from baseline toward normal values after therapy. Monocytes and lymphocytes were modestly increased, while neutrophils were decreased 4 weeks after treatment. Lymphocyte subsets and T cell proliferative responses were not altered after therapy. The proportion of PBMCs capable of producing IFNγ and TNFα did not change, while Th1 cytokine production by stimulated LPMC was decreased after infliximab therapy. Conclusion: The clinical efficacy of infliximab is based on local anti-inflammatory and immunomodulatory effects in the bowel mucosa, without generalized suppression of systemic immune functions in Crohn’s disease patients.

Une vascularite localisee pourrait rendre compte des lesions initiales de recidive de la maladie de Crohn apres chirurgie. Cette etude avait pour but d'etudier par endoscopie de fluorescence la microcirculation muqueuse de l'ileon pre-anastomotique, chez des malades ayant eu une resection ileocolique droite pour une maladie de Crohn, relativement a la recidive endoscopique. Dix malades ont ete inclus dans un protocole prospectif de suivi endoscopique un an apres chirurgie. L'ileon preanastomotique etait examine en endoscopie standard et en fluorescence. Des biopsies etaient realisees en zones fluorescentes et nonfluorescentes pour rechercher des lesions inflammatoires et vasculaires en microscopie optique et en immunohistochimie. Une recidive endoscopique a ete observee chez huit malades. En fluorescence, la muqueuse prenait un aspect heterogene avec a) des zones fluorescentes correspondant aux lesions aphtoides, b) des anneaux fluorescents centrant des zones sombres correspondant a des ulceres plus profonds « en carte de geographie » et c) des petits spots brillants disperses sur la muqueuse normale en endoscopie standard. L'examen histologique des biopsies des spots fluorescents a revele sur 79% d'entre elles des alterations inflammatoires interessant les vaisseaux. La recidive endoscopique de la maladie de Crohn est associee a des aspects fluorescents qui peuvent rendre compte soit d'une vasodilatation associee a une inflammation soit d'une authentique atteinte de la microvascularisation. L'etude histologique suggere que les lesions vasculaires sont plutot secondaires a l'atteinte inflammatoire.

The incidence of adenocarcinoma of the esophagus has been increasing in developing countries over the last three decades and probably reflects a genuine increase in the incidence of its recognized precursor lesion, Barrett’s metaplasia. Despite advances in multimodality therapy, the prognosis for invasive esophageal adenocarcinoma is poor. An improved understanding of the molecular biology of this disease may allow improved diagnosis, therapy, and prognosis. We focus on recent developments in the molecular and cell biology of Barrett’s metaplasia, a heterogeneous lesion affecting the transitional zone of the gastro-esophageal junction whose associated molecular alterations may vary both in nature and temporally. Early premalignant clones produce biological and genetic heterogeneity as seen by multiple p53 mutations, p16 mutations, aneuploidy, and abnormal methylation resulting in stepwise changes in differentiation, proliferation, and apoptosis, allowing disease progression under selective pressure. Abnormalities in expression of growth factors of the epidermal growth factor family and cell adhesion molecules, especially cadherin/catenin complexes, may occur early in invasion. Exploitation of these molecular events may lead to a more appropriate diagnosis and understanding of these lesions in the future.

Summary Congenital oesophageal stenosis due to tracheobronchial remnants is a very rare condition characterized by the presence of tracheobronchial tissue in the oesophageal wall. The most common symptoms are dysphagia, regurgitation and hypersalivation. These usually appear in early infancy when solid food is introduced into the diet. Clinical diagnosis is difficult. Conventional radiology shows a dilated oesophagus without peristalsis, incomplete expansion of the gastro-oesophageal transition zone and delayed oesophageal emptying. Lesions suggesting oesophagitis may be present at endoscopy but pH-metry may be normal. The combination of stenosis with or without oesophagitis with normal pH-metry suggests that the patient's symptoms may be due to factors other than intraluminal and that further investigation is needed. The treatment of this condition requires surgical resection of the stenosis with little morbidity or mortality. The presence of tracheobronchial remnants is confirmed upon histopathological examination of the resected bowel segment.

OBJECTIVES Intestinal metaplasia is associated with gastric carcinomas, in particular intestinal-type carcinomas. According to the literature, intestinal metaplasia, especially the sulphomucin-rich incomplete type (type IIb or III) can be considered as a precancerous lesion. Intestinal metaplasia is not uncommon in gastric lymphomas, and the purpose of this study was to determine its prevalence and extent, its different subtypes and the distribution of sulphomucin and to compare these findings with those in gastric carcinomas. DESIGN The prevalence and grade of intestinal metaplasia were investigated in surgical specimens from 160 patients with gastric carcinoma (102) [intestinal type (69), diffuse type (33)] and gastric lymphoma (58) [marginal zone cell (29), diffuse large cell (29)]. Intestinal metaplasia is analysed by specific mucin stains. METHODS Intestinal metaplasia was described according to the Updated Sydney system. Using periodic acid-Schiff Alcian Blue pH 2.5 and high iron-diamine/Alcian Blue staining, the intestinal metaplasia was classified (Jass classification) and its sulphomucin content was determined. RESULTS The prevalence and extent of intestinal metaplasia are significantly higher in intestinal-type carcinomas than all other gastric malignancies. Subtyping of intestinal metaplasia is independent of the different types of gastric neoplasia. High sulphomucin positivity in the metaplastic epithelium is only seen in intestinal-type carcinomas, although in a small number of cases (21.5%). CONCLUSION Prevalence, extent and sulphomucin content of intestinal metaplasia are significantly higher in intestinal-type gastric carcinoma compared to diffuse-type carcinoma, marginal zone cell and diffuse large cell lymphomas in the stomach.

La reversibilite d'un grand nombre de lesions histologiques peut etre obtenue apres eradication d'Helicobacter pylori. Cette reversibilite n'est demontree qu'a la premiere etape de la carcinogenese selon la sequence de Correa, c'est-a-dire le stade de la gastrite chronique superficielle. L'atrophie glandulaire semble etre un aboutissement sans retour. D'une maniere analogue, PG Isaacson a decrit une sequence lymphomagenese [69]. Ici encore une transition entre reversibilite et irreversibilite a ete introduite. La detection de cette transition est probablement situee a un niveau moleculaire-genetique plutot qu'au niveau morphologique. Le Groupe d'Etude Europeen d'Helicobacter pylori et le groupe de contact belge d'Helicobacter pylori ont organise des conferences de consensus respectivement en septembre 1996 et fevrier 1998. Le role potentiel d'Helicobacter pylori en pratique courante a ete examine de facon approfondie et les recommandations relatives au traitement des patients ont ete formulees [70]. Il a ete decide que le lymphome MALT (de faible degre), la gastrite (avec anomalies severes), et que la surveillance apres resection locale pour cancer gastrique superficiel constituent des indications majeures de traitement d'eradication d'Helicobacter pylori. En ce qui concerne les lymphomes MALT le poids des arguments en faveur de cette decision la rend indiscutable, tandis que pour les deux autres indications, l'evidence est consideree comme un simple argument.

Nous avons developpe une technique sensible et reproductible d’hybridationin situ (HIS) en utilisant des sondes d’ARNc (ARN complementaire) marquees a la digoxigenine pour localiser l’ARNm (ARM messager) de cytokeratines (CK) sur des specimens de muqueuse œsophagienne fixes ou inclus en paraffine, y compris des biopsies prelevees en endoscopie. Comme le profil d’expression de CK est une caracteristique reconnue d’un type de cellule epitheliale donne ou d’un tissu, des changements specifiques dans ce profil d’expression de CK ou dans l’expression d’ARNm-CK individuels peuvent etre lies au developpement precoce de pathologies epitheliales particulieres telles que dysplasie et cancer. Etant donne que les modifications moleculaires precedent souvent les changements morphologiques, la technique d’HIS decrite ici peut etre extrapolee a la detection de modifications de l’expression de certains genes et de la neo-expression d’autres marqueurs moleculaires, connus pour ou suspectes d’accompagner le processus cancereux. En outre, ce protocole d’HIS bien etabli peut etre facilement realise et devenir un outil utile en histologie de routine, en recherche clinique ou pour le diagnostic clinique.

Standardized added metabolic activity (SAM) is a PET parameter for assessing the total metabolic load of malignant processes, avoiding partial volume effects and lesion segmentation. The potential role of this parameter in the assessment of response to chemotherapy and bevacizumab was tested in patients with metastatic colorectal cancer with potentially resectable liver metastases (mCRC).(18)F-FDG PET/CT was performed in 18 mCRC patients with liver metastases before treatment and after five cycles of FOLFOX/FOLFIRI and bevacizumab. Of the 18 patients, 16 subsequently underwent resection of liver metastases. Baseline and follow-up SUVmax, and SAM as well as reduction in SUVmax (∆SUVmax) and SAM (∆SAM) of all liver metastases were correlated with morphological response, and progression-free and overall survival (PFS and OS).A significant reduction in metabolic activity of the liver metastases was seen after chemotherapy with a median ∆SUVmax of 25.3% and ∆SAM of 94.5% (p = 0.033 and 0.003). Median baseline SUVmax and SAM values were significantly different between morphological responders and nonresponders (3.8 vs. 7.2, p = 0.021; and 34 vs. 211, p = 0.002, respectively), but neither baseline PET parameters nor morphological response was correlated with PFS or OS. Follow-up SUVmax and SAM as well as ∆SAM were found to be prognostic factors. The median PFS and OS in the patient group with a high follow-up SUVmax were 10.4 months and 32 months, compared to a median PFS of 14.7 months and a median OS which had not been reached in the group with a low follow-up SUVmax (p = 0.01 and 0.003, respectively). The patient group with a high follow-up SAM and a low ∆SAM had a median PFS and OS of 9.4 months and 32 months, whereas the other group had a median PFS of 14.7 months and a median OS which had not been reached (p = 0.002 for both PFS and OS).(18)F-FDG PET imaging is a useful tool to assess treatment response and predict clinical outcome in patients with mCRC who undergo chemotherapy before liver metastasectomy. Follow-up SUVmax, follow-up SAM and ∆SAM were found to be significant prognostic factors for PFS and OS.

Human papillomaviruses (HPV) are associated with benign lesions and show specificity towards the location or tissues that they infect. HPVs are responsible for warts. Among more than 60 different HPV types known to occur in humans, a strong association has been found between types 16 and 18 and cervical cancer, and such an association is also suspected for types 31, 33, 35, 45, 51, 52, and 56. We describe the effects of (S)-1-(3-hydroxy-2-phosphonyl-methoxypropy Dcytosine (HPMPC), following local intratumoral injection, in a 69-year-old woman with hypopharyngeal and esophageal papillomatous lesions, polymerase chain reaction (PCR) positive for HPV types 16 and 18, that relapsed after surgery and that also failed to respond to Nd-Yag laser photocoagulation and al-pha-interferon treatment (6 × 106 U five times a week for 4 weeks followed by three times a week for 2 months). HPMPC was given at 1.25 mg/kg, with a sclerosing needle, through the biopsy channel of a video-endoscope, directly into the tumor, from March until July 1993 at seven different occasions. The first four injections were given at an interval of 1 week at the level of the hypopharynx. The next three injections were given at an interval of 3 to 5 weeks. During the fourth to the seventh session, half of the dose was injected into the hypopharyngeal and the other half into the esophageal tumor. Three further injections of HPMPC were administered at the level of the esophageal tumor in September 1993 with 2-week intervals. After HPMPC treatment, the lesions became smaller and flat until they completely disappeared. Endoscopic examination in February 1994 did not show any sign of papilloma in the esophagus or hypopharynx. These results suggest an in vivo efficacy of HPMPC for the treatment of papillomatous lesions due to HPV. © 1995 Wiley-Liss, Inc.

Serrated polyps of the colorectum have received much attention in recent literature. Several classifications have been proposed and created considerable confusion. Morphology and molecular biology have greatly contributed to the better identification of these entity. The recently published WHO classification, proposed using the term of "serrated polyp" as a generic term and defined sporadic serrated polyps as "a heterogeneous group" of lesions characterized morphologically by a serrated (sawtooth or stellate) architecture of the epithelial component which include hyperplastic polyps (HP), sessile serrated adenomas/polyps (SSA/P) and traditional serrated adenomas (TSA). With the development of molecular biology, it is now clear that the serrated pathway is one of the new carcinogenic pathways in the colon. There is now strong evidence that some serrated polyps correspond to precursors of some sporadic colorectal cancer (CRC). The aim of this article is to summarize the present data concerning the morphological and molecular characteristics of these serrated lesions and to give some recommendations for the management of such lesions.

Permeability tests are widely used to investigate the pathogenesis of various gastrointestinal diseases including coeliac disease, infectious diarrhoea, and inflammatory bowel disease. In Crohn's disease they are used as activity parameters by some investigators. Lack of standardisation, however, makes it very difficult to compare data reported in different studies. The aim of this study was to gather permeation data in well controlled test conditions to standardise the methods. Nine healthy volunteers each received five consecutive permeability tests by mouth using polyethylene glycol-400 (PEG-400) and 51Cr-EDTA as probe molecules. The probes were dissolved in water, a glucose solution, a starch solution, a hyperosmolar lactulose-mannitol solution, and a liquid meal. A significantly decreased permeation for both probes was found when given with the hyperosmolar solution. The 51Cr-EDTA permeation was also decreased with water. The permeability index, 51Cr-EDTA/PEG-400, corrected for influencing factors, confirmed that the lactulose-mannitol solution and plain water yield lower values of macro-molecule permeation than starch, glucose or liquid meal. Hyperosmolarity was clearly accompanied by a decrease in permeability probably caused by reversed solvent drag. Interindividual variability of probe permeation and permeability index is very low with a standard liquid meal. It is proposed that for permeability studies a standard liquid meal is always used.

Involvement of the lymphatic system in inflammatory bowel disease (IBD) has been suggested.To examine the density and distribution of lymphatic vessels (LV) within inflamed and non-inflamed wall sections of IBD patients compared with controls, and to evaluate expression of major lymphangiogenic factors.Ileal and colon specimens of 22 patients with Crohn's disease (CD), 16 patients with ulcerative colitis (UC) and 11 controls were studied. Quantification of LV was performed using immunohistochemistry with podoplanin and D2-40 antibodies on seven randomly selected fields. Mucosal expression of podoplanin and lymphangiogenic factor mRNA was measured using PCR.In CD patients, lymphatic density was significantly increased in non-inflamed and inflamed ileal (P0.01 and P0.001) and colonic (P0.01 and P0.001) mucosa compared to controls. Podoplanin mRNA levels were similar in non-inflamed mucosal areas and controls, whereas a four- and sixfold increase was seen in inflamed ileal and colonic areas (P0.05). In UC, lymphatic density increased fourfold in non-inflamed (P0.001) and fivefold in inflamed colonic mucosa (P0.001) compared with controls. An increase in podoplanin mRNA levels was seen in both non-inflamed and inflamed areas (P0.01) compared with controls. In CD and UC, lymphatics were found throughout the inflamed mucosa, including the upper half of the lamina propria. Expression of lymphangiogenic factors was similar in patients and controls.Increased density of lymphatic vessels is a constant feature of IBD and is present in non-inflamed areas. It is transmural in CD and confined to the mucosa in UC. Its origin remains unclear.

Background Patients with gastrointestinal neuromuscular diseases may undergo operative procedures that yield tissue appropriate to diagnosis of underlying neuromuscular pathology. Critical to accurate diagnosis is the determination of limits of normality based on the study of control human tissues. Although robust diagnostic criteria exist for many qualitative alterations in the neuromuscular apparatus, these do not include quantitative values due to lack of adequate control data. Purpose The aim of this report was to summarize all relevant available published quantitative data for elements of the human enteric nervous system (neuronal cell bodies, glial cells, and nerve fibers) from the perspective of the practicing pathologist. Forty studies meeting inclusion criteria were systematically reviewed with data tabulated in detail and discussed in the context of methodological variations and limitations. The results reveal a lack of concordance between observations of different investigators resulting in data insufficient to produce robust normal ranges. This diversity highlights the need to standardize the way pathologists collect, process, and quantitate neuronal and glial elements in enteric neuropathologic samples, as suggested by recent international guidelines on gastrointestinal neuromuscular pathology. (Less)