Abstract Background Intestinal metaplasia (IM) is considered a key pivot point in the Correa model of gastric cancer (GC). It is histologically subtyped into the complete and incomplete subtypes, the latter being associated with a greater risk of progression. However, the clinical utility of IM subtyping remains unclear, partially due to the absence of reliable defining biomarkers. Methods Based on gene expression data and existing literature, we selected CD10 and Das1 as candidate biomarkers to distinguish complete and incomplete IM glands in tissues from patients without GC (IM-GC) and patients with GC (IM + GC). Immunohistochemical staining of individually subtyped IM glands was scored after blinding by two researchers using tissue belonging to both IM-GC and IM + GC patients. Whole tissue Das1 staining was further assessed using digital image quantification (cellSens Dimension, Olympus). Results Across both cohorts CD10 stained the IM brush border and was shown to have a high sensitivity (87.5% and 94.9% in IM-GC and IM + GC patients respectively) and specificity (100.0% and 96.7% respectively) with an overall AUROC of 0.944 for complete IM glands. By contrast Das1 stained mainly goblet cells and the apical membrane of epithelial cells, mostly of incomplete IM glands with a low sensitivity (28.6% and 29.3% in IM-GC and IM + GC patients respectively) but high specificity (98.3% and 85.1% respectively) and an overall AUROC of 0.603 for incomplete IM glands. A combined logistic regression model showed a significant increase in AUROC for detecting complete IM glands (0.955 vs 0.970). Whole tissue digital quantification of Das1 staining showed a significant association with incomplete IM compared to complete IM, both in IM-GC and in IM + GC patients (p = 0.016 and p = 0.009 respectively, Mann–Whitney test and unpaired t test used). Additionally, complete IM in IM + GC patients exhibited significantly more Das1 staining than in IM-GC patients (p = 0.019, Mann–Whitney test). Conclusions These findings suggest that CD10 is an outstanding biomarker for complete IM and Das1 may be useful as a secondary biomarker for IM glands at greater risk of progression irrespective of IM subtype. Overall, the clinical use of these biomarkers could lead to improved patient stratification and targeted surveillance.

Although the incidence of gastric cancer (GC) is declining, it remains a significant global problem. GC is thought to arise via a series of histologically distinct premalignant stages and triggered by chronic Helicobacter pylori infection. Key to this pathway is intestinal metaplasia (IM), an intermediate stage immediately preceding dysplasia and a known risk factor in the progression to GC. This chapter focuses primarily on IM, its histological subtypes, clinical implications, and role in GC progression, and discusses the global surveillance and management guidelines for individuals with IM. The latter part of the chapter addresses the diagnosis and treatment of early GC which is a developing field in Western countries where GC is often diagnosed at an advanced stage.

Gastric cancer (GC) patients are mainly asymptomatic and present at an advanced stage with a 5-year survival rate of only 20-30% in most countries. It is crucial to gain greater insight into the process of gastric carcinogenesis in order to develop tools that will allow improved patient stratification and targeted surveillance. The relationship between intestinal metaplasia (IM), a key premalignant lesion in gastric carcinogenesis, and the diffuse type of gastric cancer (DGC) was investigated using data mining of GC patient pathology reports and existing gene expression data. IM and DGC were shown to be associated both histologically and molecularly in a proportion of cases suggesting that IM might be a precursor lesion to a subset of DGC cases. Complete and incomplete IM subtypes, the latter being associated with a greater risk of progression, were characterised at the molecular level using gene expression data acquired from macro-dissected IM tissue. Complete IM was associated with genes highly expressed in the small intestine whereas incomplete IM was associated with genes expressed both in the colon and in GC suggesting it is molecularly closer to a state of malignancy. Using OPAL multiplex immunohistochemistry, the macrophage and T cell landscape in IM was investigated. In addition to traditional “M1-like” (IRF8) and “M2-like” (CD163, CD206) macrophage populations, a novel hybrid subgroup “M1/2” containing macrophages expressing both M1 and M2 markers in different combinations was identified. Overall, complete IM was characterised by M2 macrophages and greater levels of T cell infiltration whereas incomplete IM was characterised by M1/2 macrophages and fewer CD8 and double negative (DN) T cells. Spatial cell analysis showed significantly fewer CD8 and DN T cells in the vicinity of incomplete IM epithelial cells suggesting reduced immune-surveillance may play a key role in progression to dysplasia. IM subtyping is affected by intra-observer and inter-observer variation. To address this, the potential of CD10 and Das1 as biomarkers for subtyping complete and incomplete IM was investigated. Overall CD10 was shown to be an outstanding biomarker for complete IM and Das1 was shown to have potential as an additional risk associated biomarker. GC animal models are associated with long duration and high cost. Optimised protocols for growing and characterising gastrointestinal organoids from gastroscopy biopsies were developed. IM organoid cultures were successfully established and characterised. Additionally a human gastrointestinal organoid biobank was created. In conclusion this thesis offers potential evidence of IM as a precursor lesion to DGC, characterises the molecular differences between complete and incomplete IM and shows key differences in the innate and adaptive immune system between IM subtypes and how these may play a role in progression to GC. It also identifies two biomarkers with potential clinical utility for subtyping IM and describes the methodology for growing IM organoids with future potential as a model for studying gastric carcinogenesis. Finally future studies are required to gain further insight into the cellular and molecular evolution of gastric carcinogenesis which should lead to better management of patients with premalignant lesions and ultimately to the prevention of GC.

Over the last two decades there has been a broad paradigm shift in our understanding of gastric cancer (GC) and its premalignant states from gross histological models to increasingly precise molecular descriptions. In this review we reflect upon the historic approaches to describing premalignant lesions and GC, highlight the current molecular landscape and how this could inform future risk assessment prevention strategies.

AimsTo characterize the microenvironment of classical Hodgkin lymphoma (cHL) in people living with human immunodeficiency virus (PLWH). The objective was to identify and then quantify the immune cells present in the microenvironment.Methods and resultsTen samples of cHL from PLWH were compared with 10 samples of cHL from the general population using tissue microarray technology and immunohistochemistry. Sections were immunostained with antibodies for CD30, CD3, CD4, CD8, CD20, CD68R, CD56, CD57, CD123, FoxP3 and granzyme B. A statistically significant reduction of CD4(+) T cells, CD56(+) cells, CD57(+) cells, CD123(+) cells and B cells and an increase in numbers in FoxP3(+)CD8(+) cells was observed in cHL diagnosed in PLWH. No significant differences were seen in the number of CD8(+) T cells, CD4(+)FoxP3(+) T cells and macrophages.ConclusionThere are considerable differences in the microenvironment of cHL occurring with and without HIV.

Research Articles| October 03 2008 Lymphoma-like Lesions Induced in the Hamster Cheek Pouch with Topical Vitamin A Palmitate Subject Area: Further Areas , Oncology , Pathology and Cell Biology I.S. Levij; I.S. Levij Department of Pathology, Rothschild Hadassah University Hospital, Jerusalem Search for other works by this author on: This Site PubMed Google Scholar A. Polliack A. Polliack Department of Pathology, Rothschild Hadassah University Hospital, Jerusalem Search for other works by this author on: This Site PubMed Google Scholar Pathologia et Microbiologia (1969) 34 (5): 282–288. https://doi.org/10.1159/000162172 Article history Received: September 19 1969 Published Online: October 03 2008 Content Tools Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation I.S. Levij, A. Polliack; Lymphoma-like Lesions Induced in the Hamster Cheek Pouch with Topical Vitamin A Palmitate. Pathologia et Microbiologia 1 May 1969; 34 (5): 282–288. https://doi.org/10.1159/000162172 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsPathobiology Search Advanced Search Article PDF first page preview Close Modal This content is only available via PDF. 1969Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. You do not currently have access to this content.

Clinical & Experimental AllergyVolume 30, Issue 6 p. 747-750 The anti-inflammatory effects of interleukin-10 in allergic disease Koulis, Koulis Allergy and Clinical Immunology, Imperial College School of Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, UKSearch for more papers by this author Robinson, Robinson Allergy and Clinical Immunology, Imperial College School of Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, UKSearch for more papers by this author Koulis, Koulis Allergy and Clinical Immunology, Imperial College School of Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, UKSearch for more papers by this author Robinson, Robinson Allergy and Clinical Immunology, Imperial College School of Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, UKSearch for more papers by this author First published: 24 December 2001 https://doi.org/10.1046/j.1365-2222.2000.00839.xCitations: 35AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume30, Issue6June 2000Pages 747-750 RelatedInformation

Somatic hypermutation is the most critical mechanism underlying the diversification of Ig genes. Although mutation occurs specifically in B cells during the germinal center reaction, it remains a matter of debate whether the mutation machinery also targets non-Ig genes. We have studied mutations in the 5′ noncoding region of the Bcl6 gene in different subtypes of lymphomas. We found frequent hypermutation in follicular lymphoma (25 of 59 = 42%) (germinal center cell origin) and mucosa-associated lymphoid tissue (MALT) lymphoma (19 of 45 = 42%) (postgerminal center), but only occasionally in mantle cell lymphoma (1 of 21 = 4.8%) (pregerminal center). Most mutations were outside the motifs potentially important for transcription, suggesting they were not important in lymphomagenesis but may, like Ig mutation, represent an inherent feature of the lymphoma precursor cells. Therefore, we investigated their normal cell counterparts microdissected from a reactive tonsil. Bcl6 mutation was found in 13 of 24 (54%) clones from the germinal centre but only in 1 of 24 (4%) clones from the naive B cells of the mantle zone. The frequency, distribution, and nature of these mutations were similar to those resulting from the Ig hypermutation process. The results show unequivocal evidence of non-Ig gene hypermutation in germinal center B cells and provide fresh insights into the process of hypermutation and lymphomagenesis.

B-cell lymphomas of mucosa-associated lymphoid tissue invariably contain large numbers of reactive tumor-infiltrating T cells. In the stomach, these lymphomas develop secondary to Helicobacter pylori infection, and clinical and in vitro studies have shown that their growth depends on help provided by H. pylori-specific T cells. In this study we characterized tumor-infiltrating T cells in low- and high-grade B-cell lymphomas of mucosa-associated lymphoid tissue using immunohistochemistry. In most cases, CD4+ T cells dominated and almost all T cells were CD45RO+ memory cells. In 11 of 13 cases studied, the proliferating T cells were CD4+ and no proliferation was observed in the CD8+ subset. In low-grade lymphomas, between 7 and 24% of T cells expressed CD40L whereas no CD40L expression was observed in the majority of high-grade tumors. Examination of homing receptor profile showed that both alpha 4 beta 7 integrin+ and L-selectin+ T cells were present. Examination of T cell diversity by a panel of antibodies against different T-cell receptor V beta regions and by analysis of T-cell receptor genes using polymerase chain reaction suggested that the T cells in these tumors were polyclonal. These results show that low-grade B-cell lymphomas of mucosa-associated lymphoid tissue contain a significant population of activated helper T cells that may be important in supporting tumor growth.

In this study, we examined lymphocyte homing receptor and vascular addressin expression in a case of primary gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) with a secondary intestinal spread. We compared the findings with that observed in B cells of normal MALT and MALT acquired as a consequence of Helicobacter pylori-associated gastritis and other low-grade gastric B-cell MALT lymphomas. The neoplastic B cells in the gastric tumor were alpha 4 beta 7-, CD62L+, whereas the intestinal secondary was alpha 4 beta 7+, CD62L-. Incubation of isolated tumor cells from the stomach by H. pylori generated T-cell-dependent proliferation of neoplastic B cells and induced expression of alpha 4 beta 7 integrin similar to the intestinal tumor. These observations indicate that reversal of homing receptor profile in the gastric tumor by antigen specific stimulation may be responsible for secondary intestinal dissemination. In normal stomach and normal MALT, alpha 4 beta 7 and CD62L expression reflected the differentiation of the B cell. Plasma cells were alpha 4 beta 7+, CD62L-, whereas a subset of memory B cells were alpha 4 beta 7-, CD62L+. Homing receptor expression in MALT lymphoma B cells was heterogeneous, however, in line with their memory B-cell phenotype in the majority of cases, the neoplastic B cells were alpha 4 beta 7-, CD62L+. Neoplastic plasma cells were always alpha 4 beta 7+, CD62L-. The venules in normal gastric mucosa expressed mucosal addressin cell adhesion molecule-1 but not peripheral lymph node addressin. In normal MALT, H. pylori-associated follicular gastritis and MALT lymphomas high endothelial venules coexpressed mucosal addressin cell adhesion molecule-1 and peripheral lymph node addressin. These findings suggest expression of lymphocyte homing receptors by B cells and vascular addressins by mucosal venules are similar in normal MALT and MALT lymphomas, and factors controlling normal mucosal B-cell traffic are also operational in MALT lymphomas.

Hyperthermophiles exist in conditions which present an increased threat to the informational integrity of their DNA, particularly by hydrolytic damage. As in mesophilic organisms, specific activities must exist to restore and protect this template function of DNA. In this study we have demonstrated the presence of thermally stable uracil-DNA glycosylase activities in seven hyperthermophiles; one bacterial: Thermotoga maritima, and six archaeal: Sulfolobus solfataricus, Sulfolobus shibatae, Sulfolobus acidocaldarius, Thermococcus litoralis, Pyrococcus furiosus and Pyrobaculum islandicum. Uracil-DNA glycosylase inhibitor protein of the Bacillus subtilis bacteriophage PBS1 shows activity against all of these, suggesting a highly conserved tertiary structure between hyperthermophilic and mesophilic uracil-DNA glycosylases.