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Xie RZ, Huang ZN, Zhang XQ, Sun YQ, Huang JB, Chen QY, Xie JW, Zheng CH, Huang CM, Lin JX, Li P. Long-term survival analysis after radical gastrectomy for Epstein-Barr virus-associated gastric cancer: A multicenter study. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2025; 51:109737. [DOI: 10.1016/j.ejso.2025.109737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2025]
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Morais R, Afonso J, Sousa N, Sousa-Pinto B, Libânio D, Marinho B, Sacramento ML, Simplício M, Faria-Ramos I, Azevedo L, Marques M, Silveira H, Gullo I, Carneiro F, Santos-Antunes J, Macedo G. Cost-utility and clinical impact of endoscopic screening for esophageal and gastric neoplasia in patients with head and neck neoplasms. Eur J Gastroenterol Hepatol 2025:00042737-990000000-00524. [PMID: 40359284 DOI: 10.1097/meg.0000000000002988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/15/2025]
Abstract
OBJECTIVE Patients with head and neck neoplasms (HNN) are at an increased risk of esophageal neoplasia (EN) and gastric neoplasia (GN). We aimed to assess the clinical impact and cost-utility of endoscopic screening in this population in the Western setting. METHODS In this single-center study HNN patients eligible for curative treatment underwent screening esophagogastroduodenoscopy. We assessed the frequency, clinical, and pathological outcomes of EN and GN. The cost-effectiveness of an annual endoscopic screening for EN was evaluated from a societal perspective, using a Markov model and probabilistic sensitivity analysis. In addition, we performed a sensitivity analysis using data on the prevalence of detected EN lesions in the four largest previous Western studies on this topic. RESULTS Forty-six HNN patients met the inclusion criteria and underwent endoscopic screening. Six EN were detected in five patients (10.9%, 95% confidence interval: 1.9-19.9%). Additionally, five GN were detected in five patients. Most patients had early-stage EN or GN (90%) and were treated with endoscopic resection (80%). Endoscopic screening strategy had an incremental cost-effectiveness ratio of 39 357.8 €/quality-adjusted life years gained, being cost-effective at a willingness-to-pay threshold of two times the Portuguese gross domestic product per capita. In the sensitivity analysis, it remained cost-effective when considering the prevalence of EN reported in Germany, France, and Brazil. CONCLUSION An endoscopic screening program identified EN or GN in a fifth of HNN patients, most presenting at an early stage. The program implementation appears to be cost-effective in Portugal. These results may be applicable to other medium-to-high-income Western countries.
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Affiliation(s)
- Rui Morais
- Department of Gastroenterology, Unidade Local de Saúde São João
- Faculty of Medicine
| | - João Afonso
- Department of Gastroenterology, Unidade Local de Saúde São João
- Faculty of Medicine
| | - Nuno Sousa
- Department of Gastroenterology, Unidade Local de Saúde São João
- Faculty of Medicine
| | - Bernardo Sousa-Pinto
- MEDCIDS, Department of Community Medicine, Information and Health Decision Sciences
- CINTESIS@RISE-Health Research Network, Faculty of Medicine, University of Porto
| | - Diogo Libânio
- MEDCIDS, Department of Community Medicine, Information and Health Decision Sciences
- Gastroenterology Department, RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto) and Porto Comprehensive Cancer Center (Porto CCC)
| | | | | | | | | | | | - Margarida Marques
- Department of Gastroenterology, Unidade Local de Saúde São João
- Faculty of Medicine
| | - Helena Silveira
- Faculty of Medicine
- Department of Otorhinolaryngology and Head and Neck Surgery, Unidade Local de Saúde São João
| | - Irene Gullo
- Faculty of Medicine
- Department of Pathology
- IPATIMUP/i3S, University of Porto, Porto, Portugal
| | - Fátima Carneiro
- Faculty of Medicine
- Department of Pathology
- IPATIMUP/i3S, University of Porto, Porto, Portugal
| | - João Santos-Antunes
- Department of Gastroenterology, Unidade Local de Saúde São João
- Faculty of Medicine
- IPATIMUP/i3S, University of Porto, Porto, Portugal
| | - Guilherme Macedo
- Department of Gastroenterology, Unidade Local de Saúde São João
- Faculty of Medicine
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Gullo I, Sacramento ML, Morais R, Kim Y, Eijk PP, Rocha AM, Baptista D, Santos-Antunes J, Ylstra B, Carneiro F. Epstein-Barr virus status drives morphological and molecular intra-tumour heterogeneity in gastric cancer: insights from a case report and literature review. Virchows Arch 2025:10.1007/s00428-025-04035-3. [PMID: 39873739 DOI: 10.1007/s00428-025-04035-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 01/15/2025] [Accepted: 01/17/2025] [Indexed: 01/30/2025]
Abstract
This case report describes a rare case of bi-phenotypic gastric cancer with two distinct, but clonally related, histological components. The first component, associated with Epstein-Barr virus (EBV) infection, exhibited the morphological features of gastric carcinoma with lymphoid stroma, suggesting that EBV, as an effective immunogenic factor, may trigger a prominent immune response within the tumour microenvironment. The second component, which was EBV-negative, displayed tubular/papillary morphology and features of increased biological aggressiveness, such as high-grade areas and lymphatic invasion. Immunohistochemical and molecular studies confirmed that, despite the differing morphologies and immunophenotypes, both components were clonally related, with the EBV-negative area showing more complex DNA aberrations, reminiscent of chromosomally instable (CIN) lesions. This case describes clonally related EBV-positive and -negative components within a single gastric cancer, contributing to a better understanding of EBV role in tumour heterogeneity and progression and highlights the impact of EBV loss on tumour behaviour.
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Affiliation(s)
- Irene Gullo
- Department of Pathology, Unidade Local de Saúde São João, Porto, Portugal.
- Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal.
- Instituto de Investigação E Inovação Em Saúde (i3S) & Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal.
| | - Maria Luísa Sacramento
- Department of Pathology, Unidade Local de Saúde São João, Porto, Portugal
- Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
| | - Rui Morais
- Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
- Department of Gastroenterology, Unidade Local de Saúde São João, Porto, Portugal
| | - Yongsoo Kim
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Paul P Eijk
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Ana Mafalda Rocha
- Instituto de Investigação E Inovação Em Saúde (i3S) & Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal
| | - Diana Baptista
- Department of Pathology, Unidade Local de Saúde São João, Porto, Portugal
- Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
| | - João Santos-Antunes
- Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
- Instituto de Investigação E Inovação Em Saúde (i3S) & Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal
- Department of Gastroenterology, Unidade Local de Saúde São João, Porto, Portugal
| | - Bauke Ylstra
- Instituto de Investigação E Inovação Em Saúde (i3S) & Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal
- Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC Location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Fátima Carneiro
- Department of Pathology, Unidade Local de Saúde São João, Porto, Portugal
- Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal
- Instituto de Investigação E Inovação Em Saúde (i3S) & Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal
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Morais R, Moreira J, Gaspar R, Santos-Antunes J, Marques M, Coelho R, Alves R, Ferreira-Silva J, Dias E, Pereira P, Lopes S, Cardoso H, Sousa-Pinto B, Faria-Ramos I, Gullo I, Carneiro F, Liberal R, Macedo G. Higher frequency of gastric neoplasia in advanced chronic liver disease patients: Impact of screening endoscopy in an intermediate-high risk country. Dig Liver Dis 2024; 56:2133-2142. [PMID: 38811247 DOI: 10.1016/j.dld.2024.04.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 04/28/2024] [Accepted: 04/29/2024] [Indexed: 05/31/2024]
Abstract
BACKGROUND The Baveno VII guidelines were proposed to identify which patients could safely avoid screening esophagogastroduodenoscopy (EGD) for gastroesophageal varices. We aimed to evaluate the frequency of gastric neoplasia in compensated advanced chronic liver disease (cACLD) patients who underwent EGD for screening of gastroesophageal varices (GOEV) compared to a healthy population. METHODS Retrospective study that enrolled all cACLD patients who underwent EGD for GOEV screening (January 2008-June 2018) in a tertiary reference center. cACLD patients were compared with asymptomatic healthy individuals who underwent EGD in a private hospital setting (April 2017-March 2018). RESULTS We evaluated 1845 patients (481 cACLD patients, 1364 healthy individuals). A significantly higher frequency of gastric neoplasia was observed in patients with cACLD compared to healthy individuals (4.0% vs. 1.0 %; p < 0.001). Rare histopathological subtypes (WHO Classification) accounted for 28.7 % of gastric carcinoma cases in the cACLD cohort. Seven cases of gastric neoplasia (36.8 % of gastric neoplasia cases in the cACLD patients) were diagnosed in patients who, according to the Baveno VII criteria, would have not been submitted to EGD. CONCLUSION We found an increased frequency of gastric neoplasia in patients with cACLD in comparison with healthy individuals. In countries with intermediate-high risk for GC, continuing to perform EGD could be beneficial.
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Affiliation(s)
- Rui Morais
- Faculty of Medicine of the University of Porto (FMUP), Portugal; Gastroenterology Department, Centro Hospitalar Universitário São João, Porto, Portugal.
| | - João Moreira
- Faculty of Medicine of the University of Porto (FMUP), Portugal
| | - Rui Gaspar
- Faculty of Medicine of the University of Porto (FMUP), Portugal; Gastroenterology Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | - João Santos-Antunes
- Faculty of Medicine of the University of Porto (FMUP), Portugal; Gastroenterology Department, Centro Hospitalar Universitário São João, Porto, Portugal; i3S - Instituto de Investigação e Inovação em Saúde and Institute of Molecular Pathology and Immunology, University of Porto (Ipatimup), Portugal
| | - Margarida Marques
- Faculty of Medicine of the University of Porto (FMUP), Portugal; Gastroenterology Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Rosa Coelho
- Faculty of Medicine of the University of Porto (FMUP), Portugal; Gastroenterology Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Rosa Alves
- Internal Medicine Department, Centro Hospitalar Barreiro Montijo, Portugal
| | - Joel Ferreira-Silva
- Faculty of Medicine of the University of Porto (FMUP), Portugal; Gastroenterology Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Emanuel Dias
- Faculty of Medicine of the University of Porto (FMUP), Portugal; Gastroenterology Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Pedro Pereira
- Faculty of Medicine of the University of Porto (FMUP), Portugal; Gastroenterology Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Susana Lopes
- Faculty of Medicine of the University of Porto (FMUP), Portugal; Gastroenterology Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Hélder Cardoso
- Faculty of Medicine of the University of Porto (FMUP), Portugal; Gastroenterology Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Bernardo Sousa-Pinto
- MEDCIDS-Department of Community Medicine, Information and Health Decision Sciences; Faculty of Medicine, University of Porto, Porto, Portugal; CINTESIS@RISE-Health Research Network, Faculty of Medicine, University of, Porto, Porto, Portugal
| | - Isabel Faria-Ramos
- Gastroenterology Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Irene Gullo
- Faculty of Medicine of the University of Porto (FMUP), Portugal; Department of Pathology, Centro Hospitalar Universitário de São João, Portugal; i3S - Instituto de Investigação e Inovação em Saúde and Institute of Molecular Pathology and Immunology, University of Porto (Ipatimup), Portugal
| | - Fátima Carneiro
- Faculty of Medicine of the University of Porto (FMUP), Portugal; Department of Pathology, Centro Hospitalar Universitário de São João, Portugal; i3S - Instituto de Investigação e Inovação em Saúde and Institute of Molecular Pathology and Immunology, University of Porto (Ipatimup), Portugal
| | - Rodrigo Liberal
- Faculty of Medicine of the University of Porto (FMUP), Portugal; Gastroenterology Department, Centro Hospitalar Universitário São João, Porto, Portugal
| | - Guilherme Macedo
- Faculty of Medicine of the University of Porto (FMUP), Portugal; Gastroenterology Department, Centro Hospitalar Universitário São João, Porto, Portugal
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McMiller TL, Besharati S, Yarchoan M, Zhu Q, Ünsal-Kaçmaz K, Xu K, Lee J, Bhaijee F, Engle LL, Taube JM, Berger AE, Anders RA, Topalian SL. Immune microenvironment of Epstein-Barr virus (EBV)-negative compared to EBV-associated gastric cancers: implications for immunotherapy. J Immunother Cancer 2024; 12:e010201. [PMID: 39572160 PMCID: PMC11580252 DOI: 10.1136/jitc-2024-010201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 10/29/2024] [Indexed: 11/24/2024] Open
Abstract
BACKGROUND Gastric carcinomas (GC) are aggressive malignancies, and only ~15% of patients respond to anti-programmed cell death (ligand) 1 (PD-(L)1) monotherapy. However, Epstein-Barr virus (EBV)-associated GCs (~5-10% of GCs) often harbor PD-L1 and PD-L2 chromosomal amplifications and robust CD8+ T cell infiltrates, and respond at a high rate to anti-PD-1. The current study compares the tumor immune microenvironments (TiMEs) of EBV+ versus EBV(-) GCs. METHODS Over 1000 cases of primary invasive GCs were screened to identify 25 treatment-naïve specimens for study (11 EBV+, 14 EBV(-)). Quantitative immunohistochemistry (IHC) was conducted for markers of immune cell subsets and co-regulatory molecules. Gene expression profiling (GEP) was performed on RNAs isolated from macrodissected areas of CD3+ T cell infiltrates abutting PD-L1+ stromal/tumor cells, using multiplex quantitative reverse transcriptase PCR for a panel of 122 candidate immune-related genes. RESULTS IHC revealed that 17/25 GCs contained PD-L1+ stromal cells, with no significant difference between EBV+/- specimens; however, only 3/25 specimens (all EBV+) contained PD-L1+ tumor cells. CD8+ T cell densities were higher in EBV+ versus EBV(-) tumors (p=0.044). With GEP normalized to the pan-leukocyte marker PTPRC/CD45, EBV+ GCs overexpressed ITGAE (CD103, marking intraepithelial T cells and a dendritic cell subset) and the interferon-inducible genes CXCL9 and IDO1. In contrast, EBV(-) tumors overexpressed several functionally-related gene groups associated with myeloid cells (CD163, IL1A, NOS2, RIGI), immunosuppressive cytokines/chemokines (CXCL2, CXCR4, IL10, IL32), coinhibitory molecules (HAVCR2/TIM-3 and VSIR/VISTA), and adenosine pathway components (ENTPD1/ CD39 and NT5E/CD73). Notably, compared with EBV+ GCs, EBV(-) GCs also overexpressed components of the cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) pathway associated with cancer-promoting inflammation, including PTGS2/COX-2 (most highly upregulated gene, 32-fold, p=0.005); prostaglandin receptors PTGER1 (EP1; up 21-fold, p=0.015) and PTGER4 (EP4; up twofold, p=0.022); and the major COX-2-inducing cytokine IL1B (up 11-fold, p=0.019). Consistent with these findings, COX-2 protein expression trended higher in EBV(-) versus EBV+ GCs (p=0.068). CONCLUSIONS While certain markers of immunosuppression are found in the GC TiME regardless of EBV status, EBV(-) GCs, which are much more common than EBV+ GCs, overexpress components of the COX-2/PGE2 pathway. These findings provide novel insights into the immune microenvironments of EBV+ and EBV(-) GC, and offer potential targets to overcome resistance to anti-PD-(L)1 therapies.
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Affiliation(s)
- Tracee L McMiller
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Sepideh Besharati
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Mark Yarchoan
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Qingfeng Zhu
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | - Ke Xu
- Bristol Myers Squibb Co, Princeton, New Jersey, USA
| | - Junghwa Lee
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Feriyl Bhaijee
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Logan L Engle
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Janis M Taube
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Alan E Berger
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Robert A Anders
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Suzanne L Topalian
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Kim TS, An JY, Choi MG, Lee JH, Sohn TS, Bae JM, Min YW, Lee H, Lee JH, Rhee PL, Kim JJ, Kim KM, Min BH. Clinicopathological Characteristics and Lymph Node Metastasis Rates in Early Gastric Lymphoepithelioma-Like Carcinoma: Implications for Endoscopic Resection. Gut Liver 2024; 18:807-813. [PMID: 39054912 PMCID: PMC11391134 DOI: 10.5009/gnl240006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 03/22/2024] [Accepted: 04/08/2024] [Indexed: 07/27/2024] Open
Abstract
Background/Aims Lymphoepithelioma-like carcinoma (LELC) is a rare subtype of gastric cancer. We aimed to identify the clinicopathological features and rate of lymph node metastasis (LNM) to investigate the feasibility of endoscopic submucosal dissection for early gastric LELC confined to the mucosa or submucosa. Methods We compared the clinicopathological characteristics of 116 early gastric LELC patients and 5,753 early gastric well- or moderately differentiated (WD or MD) tubular adenocarcinoma patients treated by gastrectomy. Results Compared to WD or MD early gastric cancer (EGC) patients, early LELC patients were younger and had a higher prevalence of proximally located tumors. Despite more frequent deep submucosal invasion (86.2% vs 29.8%), lymphatic invasion was less frequent (6.0% vs 16.2%) in early LELC patients than in WD or MD EGC patients. Among tumors with deep submucosal invasion, the tumor size was smaller, lymphatic invasion was less frequent (6.0% vs 40.2%) and the rate of LNM was lower (10.0% vs 19.4%) in patients with LELC than in those with WD or MD EGC. The overall rate of LNM in early LELC patients was 8.6% (10/116). The risk of LNM in patients with mucosal, shallow submucosal invasive, or deep submucosal invasive LELC was 0% (0/6), 0% (0/10), and 10% (10/100), respectively. Conclusions Early LELC is a distinct subtype of EGC with more frequent deep submucosal invasion but less lymphatic invasion and LNM than WD or MD EGCs. Endoscopic submucosal dissection may be considered curative for patients with early LELC confined to the mucosa or shallow submucosa, given its negligible rate of LNM.
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Affiliation(s)
- Tae-Se Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ji Yeong An
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Min Gew Choi
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jun Ho Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Tae Sung Sohn
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Moon Bae
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yang Won Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyuk Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jun Haeng Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Poong-Lyul Rhee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae J Kim
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Byung-Hoon Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Ooki A, Osumi H, Yoshino K, Yamaguchi K. Potent therapeutic strategy in gastric cancer with microsatellite instability-high and/or deficient mismatch repair. Gastric Cancer 2024; 27:907-931. [PMID: 38922524 PMCID: PMC11335850 DOI: 10.1007/s10120-024-01523-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 06/12/2024] [Indexed: 06/27/2024]
Abstract
Gastric cancer (GC) is a common malignancy that presents challenges in patient care worldwide. The mismatch repair (MMR) system is a highly conserved DNA repair mechanism that protects genome integrity during replication. Deficient MMR (dMMR) results in an increased accumulation of genetic errors in microsatellite sequences, leading to the development of a microsatellite instability-high (MSI-H) phenotype. Most MSI-H/dMMR GCs arise sporadically, mainly due to MutL homolog 1 (MLH1) epigenetic silencing. Unlike microsatellite-stable (MSS)/proficient MMR (pMMR) GCs, MSI-H/dMMR GCs are relatively rare and represent a distinct subtype with genomic instability, a high somatic mutational burden, favorable immunogenicity, different responses to treatment, and prognosis. dMMR/MSI-H status is a robust predictive biomarker for treatment with immune checkpoint inhibitors (ICIs) due to high neoantigen load, prominent tumor-infiltrating lymphocytes, and programmed cell death ligand 1 (PD-L1) overexpression. However, a subset of MSI-H/dMMR GC patients does not benefit from immunotherapy, highlighting the need for further research into predictive biomarkers and resistance mechanisms. This review provides a comprehensive overview of the clinical, molecular, immunogenic, and therapeutic aspects of MSI-H/dMMR GC, with a focus on the impact of ICIs in immunotherapy and their potential as neoadjuvant therapies. Understanding the complexity and diversity of the molecular and immunological profiles of MSI-H/dMMR GC will drive the development of more effective therapeutic strategies and molecular targets for future precision medicine.
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Affiliation(s)
- Akira Ooki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan.
| | - Hiroki Osumi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Koichiro Yoshino
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
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Lu Y, Liu H, Shang J, Mao Y, Meng L, Gao C. Effects of Weizhuan'an on rats with precancerous lesions of gastric cancer based on regulating gastric mucosal microflora and inflammatory factors. Front Pharmacol 2024; 15:1446244. [PMID: 39221149 PMCID: PMC11361960 DOI: 10.3389/fphar.2024.1446244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Accepted: 07/24/2024] [Indexed: 09/04/2024] Open
Abstract
Objectives This study aimed to observe the intervention of Weizhuan'an prescription on rats with precancerous lesions of gastric cancer (PLGC) as well as its regulation on gastric mucosal microflora and inflammatory factors and explore the pharmacodynamic mechanisms of Weizhuan'an Formula. Methods The rats were classified into the blank control group (BCG); low-, medium-, and high-dose groups of Weizhuan'an prescription (LDG, MDG, and HDG, respectively); and natural recovery group (NRG) at random. The rats in the traditional Chinese medicine (TCM) group were given corresponding doses of Weizhuan'an formula, while the rats in the NRG and BCG were given an equivalent volume of distilled water for 12 weeks. After that, gastric mucosa samples of rats were collected to observe the general and pathological changes in the gastric mucosa; the changes in gastric mucosal microflora were detected by 16S rDNA amplicon sequencing, and the inflammatory factors were analyzed by cytokine antibody microarray and Western blotting. Results The results suggest that compared with the BCG, the pathology of gastric mucosa and gastric mucosal microflora and inflammatory factors in rats with PLGC have changed significantly, while Weizhuan'an formula effectively improved them, especially in the MDG and HDG (p < 0.05). Compared with the NRG, the abundance of probiotics such as Lactobacillus and Veillonella were increased, while the abundance of pathogens such as Proteobacteria and Pseudomonas was decreased (p < 0.05, p < 0.01), and the relative contents of IL-2, IL-4, IL-13, and MCP-1 in gastric mucosa were decreased (p < 0.05). Moreover, it can upregulate the DNA-binding transcriptional regulator, ABC type multidrug transport system, and related enzymes and affect the signaling pathways such as viral protein interaction with cytokine and cytokine receptor and T cell receptor signaling pathway significantly (p < 0.05, p < 0.01), which can promote drug absorption and utilization and repair damaged gastric mucosa. Conclusion The study confirmed that Weizhuan'an prescription can treat rats with PLGC by regulating gastric mucosal microflora and inflammatory factors.
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Affiliation(s)
- Yuting Lu
- Guangdong Second Provincial General Hospital, Integrated Chinese and Western Medicine Postdoctoral Research Station, School of Medicine, Jinan University, Guangzhou, Guangdong, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Huayi Liu
- Department of Digestion, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China
| | - Jiaju Shang
- Department of Digestion, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China
| | - Yijia Mao
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Department of Digestion, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China
| | - Lingkai Meng
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Department of Digestion, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital, Tianjin, China
| | - Changbai Gao
- Department of Nephropathy, Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
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9
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Bos J, Groen-van Schooten TS, Brugman CP, Jamaludin FS, van Laarhoven HWM, Derks S. The tumor immune composition of mismatch repair deficient and Epstein-Barr virus-positive gastric cancer: A systematic review. Cancer Treat Rev 2024; 127:102737. [PMID: 38669788 DOI: 10.1016/j.ctrv.2024.102737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Revised: 04/16/2024] [Accepted: 04/19/2024] [Indexed: 04/28/2024]
Abstract
BACKGROUND Gastric cancer (GC), known for its unfavorable prognosis, has been classified in four distinct molecular subtypes. These subtypes not only exhibit differences in their genome and transcriptome but also in the composition of their tumor immune microenvironment. The microsatellite instable (MSI) and Epstein-Barr virus (EBV) positive GC subtypes show clear clinical benefits from immune checkpoint blockade, likely due to a neoantigen-driven and virus-driven antitumor immune response and high expression of immune checkpoint molecule PD-L1. However, even within these subtypes response to checkpoint inhibition is variable, which is potentially related to heterogeneity in the tumor immune microenvironment (TIME) and expression of co-inhibitory molecules. We conducted a systematic review to outline the current knowledge about the immunological features on the TIME of MSI and EBV + GCs. METHODS A systematic search was performed in PubMed, EMBASE and Cochrane Library. All articles from the year 1990 and onwards addressing immune features of gastric adenocarcinoma were reviewed and included based on predefined in- and exclusion criteria. RESULTS In total 5962 records were screened, of which 139 were included that reported immunological data on molecular GC subtypes. MSI and EBV + GCs were reported to have a more inflamed TIME compared to non-MSI and EBV- GC subtypes. Compared to microsatellite stable (MSS) tumors, MSI tumors were characterized by higher numbers of CD8 + and FoxP3 + T cells, and tumor infiltrating pro- and anti-inflammatory macrophages. HLA-deficiency was most common in MSI tumors compared to other molecular GC subtypes and associated with lower T and B cell infiltrates compared to HLA-proficient tumors. EBV + was associated with a high number of CD8 + T cells, Tregs, NK cells and macrophages. Expression of PD-L1, CTLA-4, Granzyme A and B, Perforin and interferon-gamma was enriched in EBV + tumors. Overall, MSI tumors harbored a more heterogeneous TIME in terms of immune cell composition and immune checkpoints compared to the EBV + tumors. DISCUSSION AND CONCLUSION MSI and EBV + GCs are highly Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration.; 2019pro-inflammatory immune cell populations. Although studies on the direct comparison of EBV + and MSI tumors are limited, EBV + tumors show less intra-subgroup heterogeneity compared to MSI tumors. More studies are needed to identify how Intra-subgroup heterogeneity impacts response to immunotherapy efficacy.
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Affiliation(s)
- J Bos
- Amsterdam UMC Location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - T S Groen-van Schooten
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Medical Oncology, De Boelelaan 1117, Amsterdam, the Netherlands
| | - C P Brugman
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Medical Oncology, De Boelelaan 1117, Amsterdam, the Netherlands
| | - F S Jamaludin
- Amsterdam UMC Location University of Amsterdam, Medical Library AMC, Meibergdreef 9, Amsterdam, the Netherlands
| | - H W M van Laarhoven
- Amsterdam UMC Location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam, the Netherlands; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands
| | - S Derks
- Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands; Amsterdam UMC Location Vrije Universiteit Amsterdam, Department of Medical Oncology, De Boelelaan 1117, Amsterdam, the Netherlands.
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10
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Dokanei S, Minai‐Tehrani D, Moghoofei M, Rostamian M. Investigating the relationship between Epstein-Barr virus infection and gastric cancer: A systematic review and meta-analysis. Health Sci Rep 2024; 7:e1976. [PMID: 38505684 PMCID: PMC10948593 DOI: 10.1002/hsr2.1976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 02/06/2024] [Accepted: 02/28/2024] [Indexed: 03/21/2024] Open
Abstract
Background and Aims Gastric cancer (GC) is a common cancer type worldwide, and various factors can be involved in its occurrence. One of these factors is Epstein-Barr virus (EBV) infection. In this regard, a systematic review and meta-analysis was conducted to achieve a better understanding of the EBV prevalence in GC samples. Methods English databases were searched and studies that reported the prevalence and etiological factors of EBV related to GC from July 2007 to November 2022 were retrieved. The reported data were selected based on the inclusion and exclusion criteria. The pooled prevalence of EBV infection with 95% confidence intervals was calculated. Quality assessment, heterogeneity testing, and publication bias assessment were also performed. The literature search showed 953 studies, of which 87 studies met our inclusion criteria and were used for meta-analysis. Results The pooled prevalence of EBV infection related to GC was estimated to be 9.5% (95% confidence interval [CI]: 8.2%-11%) in the general population. The prevalence of EBV infection related to GC by gender was 13.5% (95% CI: 11.1%-16.3%) in males and 7.6% (95% CI: 5.4%-10.6%) in females. No significant differences were observed in terms of geographical region. Out of the 87 studies included in the meta-analysis, the most common diagnostic test was in situ hybridization (58 cases). Conclusions Altogether, the results indicated that EBV infection is one of the important factors in the development of GC. However, this does not necessarily mean that EBV infection directly causes GC since other factors may also be involved in the development of GC. Therefore, it is recommended to conduct extensive epidemiological studies on various aspects of the relationship between this virus and GC, which can provide valuable information for understanding the relationship between EBV and GC.
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Affiliation(s)
- Saman Dokanei
- Faculty of Life Sciences and BiotechnologyShahid Beheshti University (GC)TehranIran
| | | | - Mohsen Moghoofei
- Department of Microbiology, Faculty of MedicineKermanshah University of Medical SciencesKermanshahIran
| | - Mosayeb Rostamian
- Infectious Diseases Research Center, Health InstituteKermanshah University of Medical SciencesKermanshahIran
- Student Research CommitteeKermanshah University of Medical SciencesKermanshahIran
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11
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Nowak KM, Chetty R. Predictive and prognostic biomarkers in gastrointestinal tract tumours. Pathology 2024; 56:205-213. [PMID: 38238239 DOI: 10.1016/j.pathol.2023.12.412] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 12/28/2023] [Accepted: 12/30/2023] [Indexed: 02/18/2024]
Abstract
Tumours of the gastrointestinal tract represent nearly a quarter of all newly diagnosed tumours diagnosed in 2019. Various treatment modalities for gastrointestinal cancers exist, some of which may be guided by biomarkers. Biomarkers act as gauges of either normal or pathogenic processes or responses to an exposure or intervention. They come in many forms. This review explores established and potential molecular/immunohistochemical (IHC) predictive and prognostic biomarkers of the gastrointestinal tract.
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Affiliation(s)
- Klaudia M Nowak
- Laboratory Medicine Program, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.
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12
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Shin J, Park YS. Unusual or Uncommon Histology of Gastric Cancer. J Gastric Cancer 2024; 24:69-88. [PMID: 38225767 PMCID: PMC10774758 DOI: 10.5230/jgc.2024.24.e7] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 12/06/2023] [Accepted: 12/07/2023] [Indexed: 01/17/2024] Open
Abstract
This review comprehensively examines the diverse spectrum of gastric cancers, focusing on unusual or uncommon histology that presents significant diagnostic and therapeutic challenges. While the predominant form, tubular adenocarcinoma, is well-characterized, this review focuses on lesser-known variants, including papillary adenocarcinoma, micropapillary carcinoma, adenosquamous carcinoma, squamous cell carcinoma (SCC), hepatoid adenocarcinoma, gastric choriocarcinoma, gastric carcinoma with lymphoid stroma, carcinosarcoma, gastroblastoma, parietal cell carcinoma, oncocytic adenocarcinoma, Paneth cell carcinoma, gastric adenocarcinoma of the fundic gland type, undifferentiated carcinoma, and extremely well-differentiated adenocarcinoma. Although these diseases have different nomenclatures characterized by distinct histopathological features, these phenotypes often overlap, making it difficult to draw clear boundaries. Furthermore, the number of cases was limited, and the unique histopathological nature and potential pathogenic mechanisms were not well defined. This review highlights the importance of understanding these rare variants for accurate diagnosis, effective treatment planning, and improving patient outcomes. This review emphasizes the need for ongoing research and case studies to enhance our knowledge of these uncommon forms of gastric cancer, which will ultimately contribute to more effective treatments and better prognostic assessments. This review aimed to broaden the pathological narrative by acknowledging and addressing the intricacies of all cancer types, regardless of their rarity, to advance patient care and improve prognosis.
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Affiliation(s)
- Jinho Shin
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Young Soo Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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13
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Silva JR, Mascarenhas-Lemos L, Neto do Nascimento C, Sousa Marques D, Wen X, Pinho L, Maio R, Pontes P, Cirnes L, Cravo M, Carneiro F, Gullo I. Role of Endoscopic Biopsies and Morphologic Features in Predicting Microsatellite Instability Status in Gastric Cancer: A Multicenter Comparative Study of Endoscopic Biopsies and Surgical Specimens. Am J Surg Pathol 2023; 47:990-1000. [PMID: 37366224 DOI: 10.1097/pas.0000000000002085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/28/2023]
Abstract
Evaluation of mismatch repair (MMR) protein and microsatellite instability (MSI) status plays a pivotal role in the management of gastric cancer (GC) patients. In this study, we aimed to evaluate the accuracy of gastric endoscopic biopsies (EBs) in predicting MMR/MSI status and to uncover histopathologic features associated with MSI. A multicentric series of 140 GCs was collected retrospectively, in which EB and matched surgical specimens (SSs) were available. Laurén and WHO classifications were applied and detailed morphologic characterization was performed. EB/SS were analyzed by immunohistochemistry (IHC) for MMR status and by multiplex polymerase chain reaction (mPCR) for MSI status. IHC allowed accurate evaluation of MMR status in EB (sensitivity: 97.3%; specificity: 98.0%) and high concordance rates between EB and SS (Cohen κ=94.5%). By contrast, mPCR (Idylla MSI Test) showed lower sensitivity in evaluating MSI status (91.3% vs. 97.3%), while maintaining maximal specificity (100.0%). These results suggest a role of IHC as a screening method for MMR status in EB and the use of mPCR as a confirmatory test. Although Laurén/WHO classifications were not able to discriminate GC cases with MSI, we identified specific histopathologic features that are significantly associated with MMR/MSI status in GC, despite the morphologic heterogeneity of GC cases harboring this molecular phenotype. In SS, these features included the presence of mucinous and/or solid components ( P =0.034 and <0.001) and the presence of neutrophil-rich stroma, distant from tumor ulceration/perforation ( P <0.001). In EB, both solid areas and extracellular mucin lakes were also discriminating features for the identification of MSI-high cases ( P =0.002 and 0.045).
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Affiliation(s)
- João R Silva
- Faculty of Medicine of the University of Porto (FMUP)
| | - Luís Mascarenhas-Lemos
- Departments of Pathology
- Faculty of Medicine, Catholic University of Portugal
- NOVA Medical School, Universidade NOVA Lisbon
| | | | | | - Xiaogang Wen
- i3S (Instituto de Investigação e Inovação em Saúde) and Ipatimup (Institute of Molecular Pathology and Immunology of the University of Porto)
- Department of Pathology, Centro Hospitalar Universitário do Porto (CHUP)
| | - Lídia Pinho
- i3S (Instituto de Investigação e Inovação em Saúde) and Ipatimup (Institute of Molecular Pathology and Immunology of the University of Porto)
| | - Rui Maio
- Surgery
- NOVA Medical School, Universidade NOVA Lisbon
| | - Patrícia Pontes
- Department of Pathology, University Hospital Center of São João (CHUSJ)
| | - Luís Cirnes
- i3S (Instituto de Investigação e Inovação em Saúde) and Ipatimup (Institute of Molecular Pathology and Immunology of the University of Porto)
| | - Marília Cravo
- Gastroenterology, Hospital da Luz Lisbon
- Faculty of Medicine, University of Lisbon (FMUL), Lisbon
| | - Fátima Carneiro
- i3S (Instituto de Investigação e Inovação em Saúde) and Ipatimup (Institute of Molecular Pathology and Immunology of the University of Porto)
- Department of Pathology, University Hospital Center of São João (CHUSJ)
- Department of Pathology, FMUP, Porto
| | - Irene Gullo
- i3S (Instituto de Investigação e Inovação em Saúde) and Ipatimup (Institute of Molecular Pathology and Immunology of the University of Porto)
- Department of Pathology, University Hospital Center of São João (CHUSJ)
- Department of Pathology, FMUP, Porto
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14
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Seo JW, Park KB, Chin HM, Jun KH. Does Epstein-Barr virus-positive gastric cancer establish a significant relationship with the multiple genes related to gastric carcinogenesis? PLoS One 2023; 18:e0283366. [PMID: 37285389 DOI: 10.1371/journal.pone.0283366] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 03/07/2023] [Indexed: 06/09/2023] Open
Abstract
Gastric cancer has been categorized into molecular subtypes including Epstein-Barr virus (EBV)-positive tumors, which provide clinicopathological and prognostic information. In this study, we investigated the EBV infection status of patients with gastric cancer and its correlation with the clinicopathological characteristics and multiple genes related to gastric carcinogenesis. The data of 460 gastric cancer patients who underwent curative gastrectomy with D2 lymph node dissection between January 2017 and February 2022 were analyzed. The clinicopathological features and prognosis of the patients with EBV-positive gastric cancers were compared with those of EBV-negative gastric cancers. Immunohistochemistry for epidermal growth factor receptor (EGFR), C-erb B2, Ki-67, and p53 was performed. Additionally, in situ hybridization was conducted to detect EBV, and microsatellite instability (MSI) analysis was used to assess the deficiency in mismatch repair (MMR) genes. EBV-positivity and MSI were identified in 10.4% and 37.3% of gastric cancer patients, respectively. EBV positivity was associated with male gender (P = 0.001), proximal location (P = 0.004), poorly differentiated histological type (P = 0.048), moderate to severe lymphoid stroma (P = 0.006), high Ki-67 expression (P = 0.02), and a shorter resection margin. EGFR was more often expressed in EBV-negative gastric cancers (P < 0.001). MSI tumors were associated with older age (P = 0.01), the presence of lymphatic invasion (P = 0.02), less perineural invasion (P = 0.05), and the presence of H. pylori infection (P = 0.05). EBV positive gastric cancer is associated with increased Ki-67 and decreased EGFR expression and a shorter resection margin due to the prominent lymphoid stroma. However, MMR deficiency is not associated with EBV status even though MSI gastric cancer is related to H. pylori status.
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Affiliation(s)
- Ji Won Seo
- Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Ki Bum Park
- Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyung Min Chin
- Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Kyong Hwa Jun
- Department of Surgery, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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15
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Angerilli V, Fassan M, Parente P, Gullo I, Campora M, Rossi C, Sacramento ML, Pennelli G, Vanoli A, Grillo F, Mastracci L. A practical approach for PD-L1 evaluation in gastroesophageal cancer. Pathologica 2023; 115:57-70. [PMID: 36537078 PMCID: PMC10462995 DOI: 10.32074/1591-951x-836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 12/01/2022] [Indexed: 12/24/2022] Open
Abstract
PD-L1 is an established predictive immunohistochemical biomarker of response to immune checkpoint inhibitors. At present, PD-L1 is routinely assessed on biopsy samples of advanced gastroesophageal cancer patients before initiating first-line treatment. However, PD-L1 is still a suboptimal biomarker, due to changing cut-off values and scoring systems, interobserver and interlaboratory variability. This practical illustrated review discusses the range of staining patterns of PD-L1 and the potential pitfalls and challenges that can be encountered when evaluating PD-L1, focusing on gastric and gastroesophageal adenocarcinoma (G/GEA) and esophageal squamous cell carcinoma (ESCC).
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Affiliation(s)
- Valentina Angerilli
- Department of Medicine (DIMED), Surgical Pathology Unit, University Hospital of Padua, Padua (PD), Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology Unit, University Hospital of Padua, Padua (PD), Italy
- Veneto Institute of Oncology IOV - IRCCS, Padua (PD), Italy
| | - Paola Parente
- Unit of Pathology, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Irene Gullo
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ), Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Portugal
- i3S - Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Portugal
| | - Michela Campora
- Public Healthcare Trust of the Autonomous Province of Trento, Santa Chiara Hospital, Department of Laboratory Medicine, Pathology Unit, Trento, Italy
| | - Chiara Rossi
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia, and IRCCS San Matteo Hospital, Pavia, Italy
| | - Maria Luisa Sacramento
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ), Porto, Portugal
| | - Gianmaria Pennelli
- Department of Medicine (DIMED), Surgical Pathology Unit, University Hospital of Padua, Padua (PD), Italy
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia, and IRCCS San Matteo Hospital, Pavia, Italy
| | - Federica Grillo
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Italy
| | - Luca Mastracci
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Italy
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16
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EBV and MSI Status in Gastric Cancer: Does It Matter? Cancers (Basel) 2022; 15:cancers15010074. [PMID: 36612071 PMCID: PMC9817503 DOI: 10.3390/cancers15010074] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/13/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022] Open
Abstract
We investigated the impactof microsatellite instability (MSI) and Epstein-Barr virus (EBV) status in gastric cancer (GC), regarding response to perioperative chemotherapy (POPChT), overall survival (OS), and progression-free survival (PFS). We included 137 cases of operated GC, 51 of which were submitted to POPChT. MSI status was determined by multiplex PCR and EBV status by EBV-encoded RNA in situ hybridization. Thirty-seven (27%) cases presented as MSI-high, and seven (5.1%) were EBV+. Concerning tumor regression after POPChT, no differences were observed between the molecular subtypes, but females were more likely to respond (p = 0.062). No significant differences were found in OS or PFS between different subtypes. In multivariate analysis, age (HR 1.02, IC 95% 1.002-1.056, p = 0.033) and positive lymph nodes (HR 1.82, IC 95% 1.034-3.211, p = 0.038) were the only prognostic factors for OS. However, females with MSI-high tumors treated with POPChT demonstrated a significantly increased OS compared to females with MSS tumors (p = 0.031). In conclusion, we found a high proportion of MSI-high cases. MSI and EBV status did not influence OS or PFS either in patients submitted to POPChT or surgery alone. However, superior survival of females with MSI-high tumors suggests that sex disparities and molecular classification may influence treatment options in GC.
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17
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Mastracci L, Grillo F, Parente P, Gullo I, Campora M, Angerilli V, Rossi C, Sacramento ML, Pennelli G, Vanoli A, Fassan M. PD-L1 evaluation in the gastrointestinal tract: from biological rationale to its clinical application. Pathologica 2022; 114:352-364. [PMID: 36305021 PMCID: PMC9614301 DOI: 10.32074/1591-951x-803] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 09/20/2022] [Indexed: 11/06/2022] Open
Abstract
Immune-checkpoint inhibitors targeting the PD-1/PD-L1 axis have brought significant clinical benefit in many solid cancer types, including gastrointestinal malignancies. However, it has been estimated that only 20-40% of patients respond to treatment. The pattern of expression and potential predictive value of PD-L1 as an immunohistochemical biomarker has been extensively studied in gastrointestinal neoplasms. Until now, its predictive value has been demonstrated, and is currently in use only in upper gastrointestinal malignancies (gastroesophageal adenocarcinoma and esophageal squamous cell carcinoma). In this Review, we describe the technical aspects and challenges related to PD-L1 immunohistochemical assays, the current role of PD-L1 as a biomarker in clinical practice and we outline the main studies and clinical trials analyzing the prognostic and predictive value of PD-L1 in gastrointestinal cancers.
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Affiliation(s)
- Luca Mastracci
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Italy
| | - Federica Grillo
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Italy
| | - Paola Parente
- Unit of Pathology, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Irene Gullo
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ), Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Portugal
- i3S - Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Portugal
| | - Michela Campora
- Public Healthcare Trust of the Autonomous Province of Trento, Santa Chiara Hospital, Department of Laboratory Medicine, Pathology Unit, Trento, Italy
| | - Valentina Angerilli
- Department of Medicine (DIMED), Surgical Pathology Unit, University Hospital of Padua, Padua (PD), Italy
| | - Chiara Rossi
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia, and IRCCS San Matteo Hospital, Pavia, Italy
| | - Maria Luisa Sacramento
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ), Porto, Portugal
| | - Gianmaria Pennelli
- Department of Medicine (DIMED), Surgical Pathology Unit, University Hospital of Padua, Padua (PD), Italy
| | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia, and IRCCS San Matteo Hospital, Pavia, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology Unit, University Hospital of Padua, Padua (PD), Italy
- Veneto Institute of Oncology IOV - IRCCS, Padua (PD), Italy
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18
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Abstract
Gastric cancer (GC) is one of the most common lethal malignant neoplasms worldwide, with limited treatment options for both locally advanced and/or metastatic conditions, resulting in a dismal prognosis. Although the widely used morphological classifications may be helpful for endoscopic or surgical treatment choices, they are still insufficient to guide precise and/or personalized therapy for individual patients. Recent advances in genomic technology and high-throughput analysis may improve the understanding of molecular pathways associated with GC pathogenesis and aid in the classification of GC at the molecular level. Advances in next-generation sequencing have enabled the identification of several genetic alterations through single experiments. Thus, understanding the driver alterations involved in gastric carcinogenesis has become increasingly important because it can aid in the discovery of potential biomarkers and therapeutic targets. In this article, we review the molecular classifications of GC, focusing on The Cancer Genome Atlas (TCGA) classification. We further describe the currently available biomarker-targeted therapies and potential biomarker-guided therapies. This review will help clinicians by providing an inclusive understanding of the molecular pathology of GC and may assist in selecting the best treatment approaches for patients with GC.
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Affiliation(s)
- Moonsik Kim
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea.
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Abstract
Like most solid tumours, the microenvironment of epithelial-derived gastric adenocarcinoma (GAC) consists of a variety of stromal cell types, including fibroblasts, and neuronal, endothelial and immune cells. In this article, we review the role of the immune microenvironment in the progression of chronic inflammation to GAC, primarily the immune microenvironment driven by the gram-negative bacterial species Helicobacter pylori. The infection-driven nature of most GACs has renewed awareness of the immune microenvironment and its effect on tumour development and progression. About 75-90% of GACs are associated with prior H. pylori infection and 5-10% with Epstein-Barr virus infection. Although 50% of the world's population is infected with H. pylori, only 1-3% will progress to GAC, with progression the result of a combination of the H. pylori strain, host susceptibility and composition of the chronic inflammatory response. Other environmental risk factors include exposure to a high-salt diet and nitrates. Genetically, chromosome instability occurs in ~50% of GACs and 21% of GACs are microsatellite instability-high tumours. Here, we review the timeline and pathogenesis of the events triggered by H. pylori that can create an immunosuppressive microenvironment by modulating the host's innate and adaptive immune responses, and subsequently favour GAC development.
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20
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Prevalence of Epstein-Barr Virus Infection and Mismatch Repair Protein Deficiency and the Correlation of Immune Markers in Tibetan Patients with Gastric Cancer. BIOMED RESEARCH INTERNATIONAL 2022; 2022:2684065. [PMID: 35734348 PMCID: PMC9208987 DOI: 10.1155/2022/2684065] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 05/13/2022] [Accepted: 05/24/2022] [Indexed: 11/23/2022]
Abstract
Background Gastric cancer (GC) is a major cause of cancer-related death in China. Immunotherapies based on PD-1/PD-L1 inhibitors have improved the survival of some patients with GC. Epstein–Barr virus (EBV) infection, mismatch repair (MMR) deficiency, and tumor immune microenvironment (TIME) markers (such as CD3, CD8, and PD-L1) may help to identify specific patients who will respond to PD-1/PD-L1 inhibitors. Considering racial heterogeneity, the pattern of TIME markers in Tibetan patients with GC is still unclear. We aimed to identify the prevalence of EBV infection and the MMR status and their association with immune markers in Tibetan GC to aid in patient selection for immunotherapy. Materials and Methods From 2001 to 2015, we retrospectively collected 120 tissue samples from consecutive Tibetan GC patients and constructed tissue microarrays. EBV infection was assessed by Epstein–Barr-encoded RNA (EBER) in situ hybridization, and MMR protein levels were measured. Immune markers (including CD3 and CD8) in intraepithelial, stromal, and total areas were detected by immunohistochemistry (IHC). PD-L1 expression was assessed by the combined positive score (CPS). We also analyzed the relationships of EBV infection and MMR status with immune markers. Results Of the 120 samples, 11 (9.17%) were EBV positive (+), and 6 (5%) were MMR deficient (dMMR). PD-L1 CPS ≥1% was found in 32.5% (39/120) of Tibetan GC patients. EBV infection was associated with higher numbers of CD3+ T cells (P < 0.05) and CD8+ T cells (P < 0.05) and higher PD-L1 expression (P < 0.05). For the limited number of dMMR patients, no significant relationship was observed between dMMR and TIME markers (P > 0.05). Conclusions In Tibetan GC patients, the rates of EBV infection, dMMR, and positive PD-L1 expression were 9.17%, 5%, and 32.5%, respectively. EBV infection was associated with the numbers of CD3+ T cells and CD8+ T cells and PD-L1 expression within the tumor. These markers may guide the selection of Tibetan GC patients for immunotherapy.
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Yamashita S, Nishi M, Yoshikawa K, Nakao T, Tokunaga T, Takasu C, Kashihara H, Wada Y, Yoshimoto T, Iwakawa Y, Oya T, Tsuneyama K, Shimada M. Gastric carcinoma with lymphoid stroma derived from hamartomatous inverted polyp with osteoclast-like giant cells: a case report. Int Cancer Conf J 2022; 11:196-200. [PMID: 35669900 PMCID: PMC9163280 DOI: 10.1007/s13691-022-00547-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/21/2022] [Indexed: 10/18/2022] Open
Abstract
Gastric carcinomas with lymphoid stroma (GCLS) are characterized by prominent stromal infiltration of lymphocyte and account for 1-4% of gastric cancers. Although, osteoclast-like giant cells (OGC) have been reported in some GCLS, OGCs in gastric tumors is exceedingly rare. A 60-year-old woman presented to our hospital after the finding of a positive fecal blood test during a routine medical check. Esophagogastroduodenoscopy revealed a Type 0-III + IIc tumor in the middle part of the gastric body. Biopsy revealed a poorly differentiated tumor and she was referred to our department. Early phase computed tomography showed thickening of the wall in the middle of the gastric body and enlargement of nearby lymph nodes. Laparoscopic total gastrectomy was performed. Pathological examination revealed a hamartomatous inverted polyp (HIP) in the submucosal layer with tub2-por1 tumor in the HIP. Prominent lymphocytic infiltration and OGCs were found around the tumor. Immunohistochemical analysis showed that the tumor cells were negative for EBER, MLH-1, and MSH2, 6. These findings suggest that this tumor was a non-microsatellite instability (MSI)-high GCLS without Epstein-Barr virus (EBV) infection. The patient's postoperative course was uneventful and she was discharged 11 days after surgery. She remains well 3 years after surgery.
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Wei Y, Gao L, Yang X, Xiang X, Yi C. Inflammation-Related Genes Serve as Prognostic Biomarkers and Involve in Immunosuppressive Microenvironment to Promote Gastric Cancer Progression. Front Med (Lausanne) 2022; 9:801647. [PMID: 35372408 PMCID: PMC8965837 DOI: 10.3389/fmed.2022.801647] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 02/15/2022] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) is a typical inflammatory-related malignant tumor which is closely related to helicobacter pylori infection. Tumor inflammatory microenvironment plays a crucial role in tumor progression and affect the clinical benefit from immunotherapy. In recent years, immunotherapy for gastric cancer has achieved promising outcomes, but not all patients can benefit from immunotherapy due to tumor heterogeneity. In our study, we identified 29 differentially expressed and prognostic inflammation-related genes in GC and normal samples. Based on those genes, we constructed a prognostic model using a least absolute shrinkage and selection operator (LASSO) algorithm, which categorized patients with GC into two groups. The high-risk group have the characteristics of "cold tumor" and have a poorer prognosis. In contrast, low-risk group was "hot tumor" and had better prognosis. Targeting inflammatory-related genes and remodeling tumor microenvironment to turn "cold tumor" into "hot tumor" may be a promising solution to improve the efficacy of immunotherapy for patients with GC.
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Affiliation(s)
- Yuanfeng Wei
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Limin Gao
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Xi Yang
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoyu Xiang
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, China
| | - Cheng Yi
- Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, China
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Dislich B, Mertz KD, Gloor B, Langer R. Interspatial Distribution of Tumor and Immune Cells in Correlation with PD-L1 in Molecular Subtypes of Gastric Cancers. Cancers (Basel) 2022; 14:cancers14071736. [PMID: 35406506 PMCID: PMC8996833 DOI: 10.3390/cancers14071736] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 03/24/2022] [Indexed: 12/16/2022] Open
Abstract
(1) Background: EBV-positive and mismatch repair-deficient (MMRd) gastric cancers (GCs) show higher levels of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression and thus a more profound response to immunotherapy. However, the majority of GCs are EBV-negative (EBV−) and MMR proficient (MMRp). We analyzed PD-L1 expression and TILs in EBV-MMRpGCs in comparison to EBV-positive (EBV+) and MMRdGCs to identify an immunogenic phenotype susceptible to immunotherapy. (2) Methods: A next-generation tissue microarray of 409 primary resected GCs was analyzed by Epstein-Barr encoding region (EBER) in situ hybridization for MSH1, PMS2, MSH2, MSH6, PD-L1, and CD8 immunohistochemistry. PD-L1 positivity was defined as a combined positive score (CPS) of ≥1. CD8+ TILs and their proximity to cancer cells were digitally analyzed on the HALO™ image analysis platform. (3) Results: Eleven cases were EBV+, 49 cases MMRd, and 349 cases EBV-MMRpGCs. The highest rate of PD-L1 positivity was seen in EBV+GCs, followed by MMRdGCs and EBV-MMRpGCs (81.8%, 73.5%, and 27.8%, respectively). EBV+ and MMRdGCs also demonstrated increased numbers and proximity of CD8+ TILs to tumor cells compared to EBV-MMRpGCs (p < 0.001 each). PD-L1 status positively correlated with the total numbers of CD8+ TILs and their proximity to tumor cells in all subtypes, including EBV-MMRpGCs (p < 0.001 each). A total of 28.4% of EBV-MMRpGCs showed high CD8+ TILs independent of PD-L1. (4) Conclusions: PD-L1 and CD8 immunohistochemistry, supplemented by digital image analysis, may identify EBV-MMRpGCs with high immunoreactivity indices, indicating susceptibility to immunotherapy.
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Affiliation(s)
- Bastian Dislich
- Institute of Pathology, University of Bern, 3008 Bern, Switzerland
- Correspondence:
| | - Kirsten D. Mertz
- Institute of Pathology, Cantonal Hospital Baselland, 4410 Liestal, Switzerland;
| | - Beat Gloor
- Department of Visceral Surgery and Medicine, Inselspital Bern, University of Bern, 3010 Bern, Switzerland;
| | - Rupert Langer
- Institute of Clinical Pathology and Molecular Pathology, Kepler University Hospital, Johannes Kepler University, 4021 Linz, Austria;
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Lima Á, Sousa H, Medeiros R, Nobre A, Machado M. PD-L1 expression in EBV associated gastric cancer: a systematic review and meta-analysis. Discov Oncol 2022; 13:19. [PMID: 35318527 PMCID: PMC8941030 DOI: 10.1007/s12672-022-00479-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 03/04/2022] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES The aim of this systematic review and meta-analysis is to the summarize the evidence on programmed cell death protein ligand 1 (PD-L1) in Epstein-Barr virus associated gastric cancer (EBVaGC) and to estimate the expression rate of PD-L1 among this subtype of Gastric Cancer (GC). MATERIALS AND METHODS For this study, PubMed®, EMBASE® and Web of Science® databases were searched for articles published until 1st November 2021. A total of 43 eligible publications with a total of 11,327 patients were included analysis based on inclusion and exclusion criteria. A total of 41 publications present data for proportion estimation and 33 for comparison of PD-L1 between EBV positive and negative GC. DerSimonian-Laird random-effects model was used for meta-analysis. RESULTS The analysis showed that in EBVaGC the pooled positivity rate for PD-L1 was 54.6% (p < 0.001), with a high heterogeneity between the included studies, which was associated with variation on positivity criteria for PD-L1 expression. Overall, the study reveals an increased association between PD-L1 and EBVaGC (OR = 6.36, 95% CI 3.91-10.3, p < 0.001). Furthermore, the study revealed that GC with lymphoid stroma (GCLS) is highly associated with EBV (OR = 17.4, 95% CI 6.83-44.1, p < 0.001), with a pooled EBV positivity rate of 52.9% (p < 0.001). CONCLUSIONS Patients with EBVaGC tend to show higher PD-L1 expression, which enhances EBV positivity as a promising marker for patient selection for immunotherapy targeted agents. A uniform criteria for PD-L1 positivity in tumor cells is needed, as well as further prospective studies to validate our findings and their prognostic significance.
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Affiliation(s)
- Áurea Lima
- Serviço de Oncologia Médica do Centro Hospitalar de Entre o Douro e Vouga, Unidade de Santa Maria da Feira, Rua Dr. Cândido Pinho 5, 4520-211, Santa Maria da Feira, Portugal.
- CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde (IINFACTS), Rua Central de Gandra 1317, 4585-116, Gandra PRD, Portugal.
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
| | - Hugo Sousa
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
- Serviço de Virologia, Instituto Português de Oncologia do Porto FG EPE (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
- Early Phase Clinical Trials Unit - Clinical Research Unit &/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, Research Center of IPO Porto (CI-IPOP)/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center (Porto.CCC), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
- Serviço de Virologia, Instituto Português de Oncologia do Porto FG EPE (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Amanda Nobre
- Serviço de Oncologia Médica do Centro Hospitalar de Entre o Douro e Vouga, Unidade de Santa Maria da Feira, Rua Dr. Cândido Pinho 5, 4520-211, Santa Maria da Feira, Portugal
| | - Manuela Machado
- Serviço de Oncologia Médica do Centro Hospitalar de Entre o Douro e Vouga, Unidade de Santa Maria da Feira, Rua Dr. Cândido Pinho 5, 4520-211, Santa Maria da Feira, Portugal
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Bai Y, Xie T, Wang Z, Tong S, Zhao X, Zhao F, Cai J, Wei X, Peng Z, Shen L. Efficacy and predictive biomarkers of immunotherapy in Epstein-Barr virus-associated gastric cancer. J Immunother Cancer 2022; 10:jitc-2021-004080. [PMID: 35241494 PMCID: PMC8896035 DOI: 10.1136/jitc-2021-004080] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/31/2022] [Indexed: 12/14/2022] Open
Abstract
Background Epstein-Barr virus (EBV)-associated gastric cancer (GC) (EBVaGC) is a distinct molecular subtype of GC with a favorable prognosis. However, the exact effects and potential mechanisms of EBV infection on immune checkpoint blockade (ICB) efficacy in GC remain to be clarified. Additionally, EBV-encoded RNA (EBER) in situ hybridization (ISH), the traditional method to detect EBV, could cause false-positive/false-negative results and not allow for characterizing other molecular biomarkers recommended by standard treatment guidelines for GC. Herein, we sought to investigate the efficacy and potential biomarkers of ICB in EBVaGC identified by next-generation sequencing (NGS). Design An NGS-based algorithm for detecting EBV was established and validated using two independent GC cohorts (124 in the training cohort and 76 in the validation cohort). The value of EBV infection for predicting ICB efficacy was evaluated among 95 patients with advanced or metastatic GC receiving ICB. The molecular predictive biomarkers for ICB efficacy were identified to improve the prediction accuracy of ICB efficacy in 22 patients with EBVaGC. Results Compared with orthogonal assay (EBER-ISH) results, the NGS-based algorithm achieved high performance with a sensitivity of 95.7% (22/23) and a specificity of 100% (53/53). EBV status was identified as an independent predictive factor for overall survival and progression-free survival in patients with DNA mismatch repair proficient (pMMR) GC following ICB. Moreover, the patients with EBV+/pMMR and EBV−/MMR deficient (dMMR) had comparable and favorable survival following ICB. Twenty-two patients with EBV+/pMMR achieved an objective response rate of 54.5% (12/22) on immunotherapy. Patients with EBVaGC with a high cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) level were less responsive to anti-programmed death-1/ligand 1 (PD-1/L1) monotherapy, and the combination of anti-CTLA-4 plus anti-PD-1/L1 checkpoint blockade benefited patients with EBVaGC more than anti-PD-1/L1 monotherapy with a trend close to significance (p=0.074). There were nearly significant differences in tumor mutational burden (TMB) level and SMARCA4 mutation frequency between the ICB response and non-response group. Conclusions We developed an efficient NGS-based EBV detection strategy, and this strategy-identified EBV infection was as effective as dMMR in predicting ICB efficacy in GC. Additionally, we identified CTLA-4, TMB, and SMARCA4 mutation as potential predictive biomarkers of ICB efficacy in EBVaGC, which might better inform ICB treatment for EBVaGC.
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Affiliation(s)
- Yuezong Bai
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Tong Xie
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhenghang Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Shuang Tong
- Medical Affairs, 3D Medicines, Inc, Shanghai, China
| | | | - Feilong Zhao
- Medical Affairs, 3D Medicines, Inc, Shanghai, China
| | - Jinping Cai
- Medical Affairs, 3D Medicines, Inc, Shanghai, China
| | - Xiaofan Wei
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Zhi Peng
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
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Wang B, Du C, Li L, Xie Y, Hu C, Li Z, Zhu Y, Yuan Y, Liu X, Lu N, Xue L. New substituted molecular classifications of advanced gastric adenocarcinoma: characteristics and probable treatment strategies. JOURNAL OF THE NATIONAL CANCER CENTER 2022; 2:50-59. [PMID: 39035211 PMCID: PMC11256717 DOI: 10.1016/j.jncc.2021.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background Gastric adenocarcinoma (GA) is a heterogeneous tumor, and the accurate classification of GA is important. Previous classifications are based on molecular analysis and have not focused on GA with the primitive enterocyte phenotype (GAPEP), a unique subtype with a poor prognosis and frequent liver metastases. New substituted molecular (SM) classifications based on immunohistochemistry (IHC) are needed. Methods According to the IHC staining results, we divided 582 cases into six types: mismatch repair deficient (dMMR), Epstein-Barr virus associated (EBVa), the primitive enterocyte phenotype (PEP), the epithelial mesenchymal transition (EMT) phenotype, not otherwise specified/P53 mutated (NOS/P53m) and not otherwise specified/P53 wild-type (NOS/P53w). We analyzed the clinicopathological features, the immune microenvironment (PD-L1, CD8) and expression of HER2 and VEGFR2 of those types. Results There were 31 (5.3%) cases of the dMMR type, 13 (2.2%) cases of the EBVa type, 44 (7.6%) cases of the PEP type, 122 (21.0%) cases of the EMT type, 127 (21.8%) cases of the NOS/P53m type and 245 (42.1%) cases of the NOS/P53w type. Patients with the dMMR type had the best survival (P < 0.001). Patients with the EBVa type were younger (P < 0.001) and had higher PD-L1 and CD8 expression (P < 0.001) than other patients. Patients with the EMT type exhibited poor differentiation and a higher rate of abdominal metastasis. Patients with the NOS/P53m and PEP types had the worst survival rates and the highest PD-L1/HER2/VEGFR2 expression levels among all patients (P < 0.001). Conclusion Different SM classifications have different clinicopathological features and expression patterns, which indicate the probable clinical treatment strategies for these subtypes.
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Affiliation(s)
- Bingzhi Wang
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Chunxia Du
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Lin Li
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yibin Xie
- Department of Abdominal Surgical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Chunfang Hu
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zhuo Li
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yongjian Zhu
- Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yanling Yuan
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Xiuyun Liu
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Ning Lu
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Liyan Xue
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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Uner M, Isık A, Oztop S, Karabulut E, Demirkol-Canlı S, Akyol A. Gastric Carcinoma with Lymphoid Stroma: A Combination of Mismatch Repair Deficient Medullary Type and Epstein-Barr Virus-associated Gastric Carcinomas. Int J Surg Pathol 2022; 30:623-633. [PMID: 35188817 DOI: 10.1177/10668969221080062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Gastric carcinomas consist of a heterogeneous group of neoplasms with broad cytological and architectural variations. Gastric carcinomas with lymphoid stroma show poor correlation between their histomorphology and biological behavior. This contrast causes a need for more detailed analysis and molecular exploration of lymphoid stroma-rich gastric carcinomas with medullary like features and lack of glandular differentiation. In this study, we performed a detailed retrospective analysis of 53 gastric carcinomas among 654 gastric tumors from surgical resection specimens, all of which had no prominent glandular differentiation. Morphological and clinical data were compared with immunohistochemistry (MLH1, PMS2, MSH2 and MSH6 for mismatch repair mechanism deficiency; CD2, CD8 and CD163 for immune infiltration; and PD-1, PD-L1, LMP-1, ERBB2 and ki-67) besides EBER in situ hybridization and molecular studies (PCR based microsatellite instability and BRAF V600E mutation analysis). Morphological, immunohistochemical and molecular findings lead us to classify lymphoid stroma-rich advanced gastric carcinomas (n = 40/53) into two distinct entities originating from two different pathogenetic pathway: one is gastric carcinomas revealing predominantly medullary type morphology with defective DNA mismatch repair mechanism (n = 30/53) and the other is EBV associated carcinomas (n = 10/53). In addition, we suggest that biomarker based classification algorithms besides morphological evaluation are necessary to identify these two entities. Distinguishing these entities is crucial to apply different treatment strategies, including alternative treatments such as immunotherapy.
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Affiliation(s)
- Meral Uner
- 37515Department of Pathology, Hacettepe University Faculty of Medicine, Sıhhiye, Ankara, Turkey
| | - Aynur Isık
- Hacettepe University Transgenic Animal Technologies Research and Application Center, Sıhhiye, Ankara, Turkey
| | - Sıdıka Oztop
- Hacettepe University Transgenic Animal Technologies Research and Application Center, Sıhhiye, Ankara, Turkey.,175695Department of Immunology, Baskent University, Adana Dr. Turgut Noyan Medical and Research Center, Seyhan, Adana, Turkey
| | - Erdem Karabulut
- Department of Medical Biostatistics, Hacettepe University Faculty of Medicine, 37515Hacettepe University, Sıhhiye, Ankara, Turkey
| | - Secil Demirkol-Canlı
- 64005Molecular Pathology Application and Research Center, Hacettepe University, Sıhhiye, Ankara, Turkey
| | - Aytekin Akyol
- 37515Department of Pathology, Hacettepe University Faculty of Medicine, Sıhhiye, Ankara, Turkey.,Hacettepe University Transgenic Animal Technologies Research and Application Center, Sıhhiye, Ankara, Turkey.,64005Molecular Pathology Application and Research Center, Hacettepe University, Sıhhiye, Ankara, Turkey.,64005Tumor Pathology Division, Hacettepe University Cancer Institute, Sıhhiye, Ankara, Turkey
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Cheng N, Li P, Cheng H, Zhao X, Dong M, Zhang Y, Zhao P, Chen J, Shao C. Prognostic Value of Tumor-Infiltrating Lymphocytes and Tertiary Lymphoid Structures in Epstein-Barr Virus-Associated and -Negative Gastric Carcinoma. Front Immunol 2021; 12:692859. [PMID: 34276684 PMCID: PMC8281029 DOI: 10.3389/fimmu.2021.692859] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 06/14/2021] [Indexed: 01/22/2023] Open
Abstract
Background Tumor-infiltrating lymphocytes (TILs) are considered a manifestation of the host immune response against cancer and tertiary lymphoid structures (TLS) may contribute to lymphocytes recruitment. Both of them have been reported as potential prognostic parameters in some human malignancies. However, the roles of TILs, TLS, and their correlation in Epstein-Barr Virus-associated gastric carcinoma (EBVaGC) and EBV-negative gastric carcinoma (EBVnGC) are largely unknown. Methods To observe the correlation among TILs, TLS, and clinicopathological characteristics and their prognostic significance in EBVaGC and EBVnGC, respectively. TILs and TLS were assessed by morphology and/or immunohistochemistry, and accompanied by clinicopathological analysis from 846 gastric cancer patients in multiple institutions. Results Forty-two (5.0%) cases of EBVaGC and 804 cases of EBVnGC were identified by in situ hybridization, respectively. For EBVnGC, higher TILs grade was correlated with TLS-present. EBVnGC patients with high TILs grade and TLS-present exhibited survival benefits. TILs (P = 0.001) and TLS (P = 0.003), especially TILs & TLS (P < 0.001) were independent prognostic factors in EBVnGC. A nomogram was constructed and validated for predicting the probability of overall survival and performed well with a good calibration. No significant prognostic value was detected in EBVaGC. Conclusion TILs and TLS, especially TILs & TLS were promising prognostic indicators for overall survival in EBVnGC. TILs and TLS were highly overlapping in their extent and prognostic abilities, and may be considered as a coindicator of prognosis of gastric cancer. The evaluations of TILs and TLS are simple and can be assessed routinely in pathological diagnosis.
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Affiliation(s)
- Na Cheng
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Peng Li
- Department of Histology and Embryology of Basic Medical Department, Guangdong Medical University, Dongguan, China
| | - Huanhuan Cheng
- Department of Ophthalmology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiaoxiao Zhao
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
- Department of Pathology, The Central Hospital of Wuhan, Huazhong University of Science and Technology, Wuhan, China
| | - Min Dong
- Department of Medical Oncology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Yiwang Zhang
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Peizhen Zhao
- Dermatology Hospital, Southern Medical University, Guangzhou, China
| | - Jianning Chen
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Chunkui Shao
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
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Challoner BR, von Loga K, Woolston A, Griffiths B, Sivamanoharan N, Semiannikova M, Newey A, Barber LJ, Mansfield D, Hewitt LC, Saito Y, Davarzani N, Starling N, Melcher A, Grabsch HI, Gerlinger M. Computational Image Analysis of T-Cell Infiltrates in Resectable Gastric Cancer: Association with Survival and Molecular Subtypes. J Natl Cancer Inst 2021; 113:88-98. [PMID: 32324860 PMCID: PMC7781469 DOI: 10.1093/jnci/djaa051] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Revised: 03/05/2020] [Accepted: 04/02/2020] [Indexed: 01/08/2023] Open
Abstract
Background Gastric and gastro-esophageal junction cancers (GCs) frequently recur after resection, but markers to predict recurrence risk are missing. T-cell infiltrates have been validated as prognostic markers in other cancer types, but not in GC because of methodological limitations of past studies. We aimed to define and validate the prognostic role of major T-cell subtypes in GC by objective computational quantification. Methods Surgically resected chemotherapy-naïve GCs were split into discovery (n = 327) and validation (n = 147) cohorts. CD8 (cytotoxic), CD45RO (memory), and FOXP3 (regulatory) T-cell densities were measured through multicolor immunofluorescence and computational image analysis. Cancer-specific survival (CSS) was assessed. All statistical tests were two-sided. Results CD45RO-cell and FOXP3-cell densities statistically significantly predicted CSS in both cohorts. Stage, CD45RO-cell, and FOXP3-cell densities were independent predictors of CSS in multivariable analysis; mismatch repair (MMR) and Epstein–Barr virus (EBV) status were not statistically significant. Combining CD45RO-cell and FOXP3-cell densities into the Stomach Cancer Immune Score showed highly statistically significant (all P ≤ .002) CSS differences (0.9 years median CSS to not reached). T-cell infiltrates were highest in EBV-positive GCs and similar in MMR-deficient and MMR-proficient GCs. Conclusion The validation of CD45RO-cell and FOXP3-cell densities as prognostic markers in GC may guide personalized follow-up or (neo)adjuvant treatment strategies. Only those 20% of GCs with the highest T-cell infiltrates showed particularly good CSS, suggesting that a small subgroup of GCs is highly immunogenic. The potential for T-cell densities to predict immunotherapy responses should be assessed. The association of high FOXP3-cell densities with longer CSS warrants studies into the biology of regulatory T cells in GC.
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Affiliation(s)
- Benjamin R Challoner
- Translational Oncogenomics Laboratory, Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Katharina von Loga
- Translational Oncogenomics Laboratory, Division of Molecular Pathology, The Institute of Cancer Research, London, UK.,Translational Immuno-Oncology Team, Centre for Molecular Pathology, The Royal Marsden Hospital NHS Foundation Trust and The Institute of Cancer Research, Sutton, UK
| | - Andrew Woolston
- Translational Oncogenomics Laboratory, Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Beatrice Griffiths
- Translational Oncogenomics Laboratory, Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Nanna Sivamanoharan
- Translational Oncogenomics Laboratory, Division of Molecular Pathology, The Institute of Cancer Research, London, UK.,Translational Immuno-Oncology Team, Centre for Molecular Pathology, The Royal Marsden Hospital NHS Foundation Trust and The Institute of Cancer Research, Sutton, UK
| | - Maria Semiannikova
- Translational Oncogenomics Laboratory, Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Alice Newey
- Translational Oncogenomics Laboratory, Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Louise J Barber
- Translational Oncogenomics Laboratory, Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - David Mansfield
- Targeted Therapy Team, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK
| | - Lindsay C Hewitt
- Department of Pathology, Maastricht University Medical Center, Limburg, The Netherlands
| | - Yuichi Saito
- Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan
| | - Naser Davarzani
- Department of Pathology, Maastricht University Medical Center, Limburg, The Netherlands.,Biosystems Data Analysis, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, The Netherlands
| | - Naureen Starling
- Gastrointestinal Cancer Unit, The Royal Marsden Hospital NHS Foundation Trust, London, UK
| | - Alan Melcher
- Translational Immunotherapy Team, Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK
| | - Heike I Grabsch
- Department of Pathology, Maastricht University Medical Center, Limburg, The Netherlands.,Pathology & Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, St James's University Hospital, Leeds, UK
| | - Marco Gerlinger
- Translational Oncogenomics Laboratory, Division of Molecular Pathology, The Institute of Cancer Research, London, UK.,Gastrointestinal Cancer Unit, The Royal Marsden Hospital NHS Foundation Trust, London, UK
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30
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Hatano Y, Ideta T, Hirata A, Hatano K, Tomita H, Okada H, Shimizu M, Tanaka T, Hara A. Virus-Driven Carcinogenesis. Cancers (Basel) 2021; 13:2625. [PMID: 34071792 PMCID: PMC8198641 DOI: 10.3390/cancers13112625] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/22/2021] [Accepted: 05/25/2021] [Indexed: 12/13/2022] Open
Abstract
Cancer arises from the accumulation of genetic and epigenetic alterations. Even in the era of precision oncology, carcinogens contributing to neoplastic process are still an important focus of research. Comprehensive genomic analyses have revealed various combinations of base substitutions, referred to as the mutational signatures, in cancer. Each mutational signature is believed to arise from specific DNA damage and repair processes, including carcinogens. However, as a type of carcinogen, tumor viruses increase the cancer risk by alternative mechanisms, including insertional mutagenesis, viral oncogenes, and immunosuppression. In this review, we summarize virus-driven carcinogenesis to provide a framework for the control of malignant cell proliferation. We first provide a brief overview of oncogenic viruses and describe their implication in virus-related tumors. Next, we describe tumor viruses (HPV, Human papilloma virus; HBV, Hepatitis B virus; HCV, Hepatitis C virus; EBV, Epstein-Barr virus; Kaposi sarcoma herpesvirus; MCV, Merkel cell polyoma virus; HTLV-1, Human T-cell lymphotropic virus, type-1) and tumor virus-related cancers. Lastly, we introduce emerging tumor virus candidates, human cytomegalovirus (CMV), human herpesvirus-6 (HHV-6) and adeno-associated virus-2 (AAV-2). We expect this review to be a hub in a complex network of data for virus-associated carcinogenesis.
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Affiliation(s)
- Yuichiro Hatano
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; (H.T.); (A.H.)
| | - Takayasu Ideta
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; (T.I.); (M.S.)
- Department of Laboratory Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Akihiro Hirata
- Laboratory of Veterinary Pathology, Joint Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, Gifu 501-1194, Japan;
| | - Kayoko Hatano
- Department of Obstetrics and Gynecology, Gifu University Hospital, Gifu 501-1194, Japan;
| | - Hiroyuki Tomita
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; (H.T.); (A.H.)
| | - Hideshi Okada
- Department of Emergency and Disaster Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan;
| | - Masahito Shimizu
- Department of Gastroenterology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; (T.I.); (M.S.)
| | - Takuji Tanaka
- Department of Diagnostic Pathology (DDP) and Research Center of Diagnostic Pathology (RC-DiP), Gifu Municipal Hospital, Gifu 500-8513, Japan;
| | - Akira Hara
- Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan; (H.T.); (A.H.)
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31
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Ulase D, Behrens HM, Krüger S, Zeissig S, Röcken C. Gastric Carcinomas with Stromal B7-H3 Expression Have Lower Intratumoural CD8+ T Cell Density. Int J Mol Sci 2021; 22:ijms22042129. [PMID: 33669921 PMCID: PMC7924590 DOI: 10.3390/ijms22042129] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/14/2021] [Accepted: 02/17/2021] [Indexed: 12/12/2022] Open
Abstract
CD8+ T cells are the main effector cells of anti-cancer immune response that can be regulated by various costimulatory and coinhibitory molecules, including members of the B7 family. B7 homolog 3 (B7-H3) appears as a promising marker for immunotherapy; however, its significance in gastric cancer (GC) is unclear yet. We evaluated the spatial distribution of CD8+ T cells in relation to the expression of B7-H3 by double immunohistochemical staining. The level of B7-H3 intensity was scored manually (0–3) and dichotomized into B7-H3-low and B7-H3-high groups. The distribution and density of CD8+ T cells was analysed using whole slide digital imaging. B7-H3 was expressed mainly in the stromal compartment of GC (n = 73, 76% of all cases). Tumours with high expression of B7-H3 showed larger spatial differences of CD8+ T cells (86.4/mm2 in tumour centre vs. 414.9/mm2 in invasive front) when compared to B7-H3-low group (157.7/mm2 vs. 218.7/mm2, respectively) (p < 0.001). This study provides insight into the expression pattern of B7-H3 in GC of Western origin. In GCs with higher level of B7-H3 expression, CD8+ T cells were spatially suppressed in the tumour centre suggesting that B7-H3 might be involved in tumour escape mechanisms from the immune response.
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Affiliation(s)
- Dita Ulase
- Department of Pathology, Christian-Albrechts-University, 24105 Kiel, Germany; (D.U.); (H.-M.B.); (S.K.)
- Department of Pathology, Riga Stradins University, LV-1007 Riga, Latvia
| | - Hans-Michael Behrens
- Department of Pathology, Christian-Albrechts-University, 24105 Kiel, Germany; (D.U.); (H.-M.B.); (S.K.)
| | - Sandra Krüger
- Department of Pathology, Christian-Albrechts-University, 24105 Kiel, Germany; (D.U.); (H.-M.B.); (S.K.)
| | - Sebastian Zeissig
- Department of Medicine I, University Medical Center Dresden, Technische Universität (TU) Dresden, 01307 Dresden, Germany;
- Center for Regenerative Therapies Dresden (CRTD), Technische Universität (TU) Dresden, 01307 Dresden, Germany
| | - Christoph Röcken
- Department of Pathology, Christian-Albrechts-University, 24105 Kiel, Germany; (D.U.); (H.-M.B.); (S.K.)
- Correspondence: ; Tel.: +49-431-50015501
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32
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Rocha S, Basto AP, Ijsselsteijn ME, Teles SP, Azevedo MM, Gonçalves G, Gullo I, Almeida GM, Maqueda JJ, Oliveira MI, Carneiro F, Barata JT, Graça L, de Miranda NFCC, Carvalho J, Oliveira C. Immunophenotype of Gastric Tumors Unveils a Pleiotropic Role of Regulatory T Cells in Tumor Development. Cancers (Basel) 2021; 13:cancers13030421. [PMID: 33498681 PMCID: PMC7865950 DOI: 10.3390/cancers13030421] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/19/2021] [Accepted: 01/20/2021] [Indexed: 01/26/2023] Open
Abstract
Gastric cancer (GC) patients display increased regulatory T cell (Tregs) numbers in peripheral blood and among tumor-infiltrating lymphocytes. Nevertheless, the role of Tregs in GC progression remains controversial. Here, we sought to explore the impact of Tregs in GCs with distinct histology, and whether Tregs can directly influence tumor cell behavior and GC development. We performed a comprehensive immunophenotyping of 82 human GC cases, through an integrated analysis of multispectral immunofluorescence detection of T cells markers and patient clinicopathological data. Moreover, we developed 3D in vitro co-cultures with Tregs and tumor cells that were followed by high-throughput and light-sheet imaging, and their biological features studied with conventional/imaging flow cytometry and Western blotting. We showed that Tregs located at the tumor nest were frequent in intestinal-type GCs but did not associate with increased levels of effector T cells. Our in vitro results suggested that Tregs preferentially infiltrated intestinal-type GC spheroids, induced the expression of IL2Rα and activation of MAPK signaling pathway in tumor cells, and promoted spheroid growth. Accumulation of Tregs in intestinal-type GCs was increased at early stages of the stomach wall invasion and in the absence of vascular and perineural invasion. In this study, we proposed a non-immunosuppressive mechanism through which Tregs might directly modulate GC cells and thereby promote tumor growth. Our findings hold insightful implications for therapeutic strategies targeting intestinal-type GCs and other tumors with similar immune context.
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Affiliation(s)
- Sara Rocha
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (S.R.); (S.P.T.); (M.M.A.); (I.G.); (G.M.A.); (J.J.M.); (F.C.); (J.C.)
- Ipatimup—Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal
- Doctoral Program on Cellular and Molecular Biotechnology Applied to Health Sciences, ICBAS—Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal
| | - Afonso P Basto
- iMM—Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisbon, Portugal; (A.P.B.); (J.T.B.); (L.G.)
- Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal
| | - Marieke E Ijsselsteijn
- Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (M.E.I.); (N.F.C.C.d.M.)
| | - Sara P Teles
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (S.R.); (S.P.T.); (M.M.A.); (I.G.); (G.M.A.); (J.J.M.); (F.C.); (J.C.)
- Ipatimup—Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal
| | - Maria M Azevedo
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (S.R.); (S.P.T.); (M.M.A.); (I.G.); (G.M.A.); (J.J.M.); (F.C.); (J.C.)
| | - Gilza Gonçalves
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal;
| | - Irene Gullo
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (S.R.); (S.P.T.); (M.M.A.); (I.G.); (G.M.A.); (J.J.M.); (F.C.); (J.C.)
- Ipatimup—Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal;
- Department of Pathology, Centro Hospitalar Universitário de São João, 4200-319 Porto, Portugal
| | - Gabriela M Almeida
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (S.R.); (S.P.T.); (M.M.A.); (I.G.); (G.M.A.); (J.J.M.); (F.C.); (J.C.)
- Ipatimup—Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal;
| | - Joaquín J Maqueda
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (S.R.); (S.P.T.); (M.M.A.); (I.G.); (G.M.A.); (J.J.M.); (F.C.); (J.C.)
- Ipatimup—Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal
| | - Marta I Oliveira
- International Iberian Nanotechnology Laboratory, 4715-330 Braga, Portugal;
| | - Fátima Carneiro
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (S.R.); (S.P.T.); (M.M.A.); (I.G.); (G.M.A.); (J.J.M.); (F.C.); (J.C.)
- Ipatimup—Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal;
- Department of Pathology, Centro Hospitalar Universitário de São João, 4200-319 Porto, Portugal
| | - João T Barata
- iMM—Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisbon, Portugal; (A.P.B.); (J.T.B.); (L.G.)
| | - Luís Graça
- iMM—Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisbon, Portugal; (A.P.B.); (J.T.B.); (L.G.)
- Instituto Gulbenkian de Ciência, 2780-156 Oeiras, Portugal
| | - Noel F C C de Miranda
- Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands; (M.E.I.); (N.F.C.C.d.M.)
| | - Joana Carvalho
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (S.R.); (S.P.T.); (M.M.A.); (I.G.); (G.M.A.); (J.J.M.); (F.C.); (J.C.)
- Ipatimup—Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal
| | - Carla Oliveira
- i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, 4200-135 Porto, Portugal; (S.R.); (S.P.T.); (M.M.A.); (I.G.); (G.M.A.); (J.J.M.); (F.C.); (J.C.)
- Ipatimup—Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal;
- Correspondence: ; Tel.: +351-225-570-785
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Cao Y, Xie L, Shi F, Tang M, Li Y, Hu J, Zhao L, Zhao L, Yu X, Luo X, Liao W, Bode AM. Targeting the signaling in Epstein-Barr virus-associated diseases: mechanism, regulation, and clinical study. Signal Transduct Target Ther 2021; 6:15. [PMID: 33436584 PMCID: PMC7801793 DOI: 10.1038/s41392-020-00376-4] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 09/30/2020] [Accepted: 10/15/2020] [Indexed: 12/11/2022] Open
Abstract
Epstein–Barr virus-associated diseases are important global health concerns. As a group I carcinogen, EBV accounts for 1.5% of human malignances, including both epithelial- and lymphatic-originated tumors. Moreover, EBV plays an etiological and pathogenic role in a number of non-neoplastic diseases, and is even involved in multiple autoimmune diseases (SADs). In this review, we summarize and discuss some recent exciting discoveries in EBV research area, which including DNA methylation alterations, metabolic reprogramming, the changes of mitochondria and ubiquitin-proteasome system (UPS), oxidative stress and EBV lytic reactivation, variations in non-coding RNA (ncRNA), radiochemotherapy and immunotherapy. Understanding and learning from this advancement will further confirm the far-reaching and future value of therapeutic strategies in EBV-associated diseases.
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Affiliation(s)
- Ya Cao
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China. .,Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, 410078, Changsha, China. .,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, 410078, Changsha, China. .,Research Center for Technologies of Nucleic Acid-Based Diagnostics and Therapeutics Hunan Province, 410078, Changsha, China. .,Molecular Imaging Research Center of Central South University, 410008, Changsha, Hunan, China. .,National Joint Engineering Research Center for Genetic Diagnostics of Infectious Diseases and Cancer, 410078, Changsha, China. .,Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China.
| | - Longlong Xie
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China.,Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, 410078, Changsha, China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, 410078, Changsha, China
| | - Feng Shi
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China.,Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, 410078, Changsha, China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, 410078, Changsha, China
| | - Min Tang
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China.,Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, 410078, Changsha, China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, 410078, Changsha, China.,Molecular Imaging Research Center of Central South University, 410008, Changsha, Hunan, China
| | - Yueshuo Li
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China.,Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, 410078, Changsha, China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, 410078, Changsha, China
| | - Jianmin Hu
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China.,Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, 410078, Changsha, China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, 410078, Changsha, China
| | - Lin Zhao
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China.,Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, 410078, Changsha, China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, 410078, Changsha, China
| | - Luqing Zhao
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China
| | - Xinfang Yu
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China.,Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, 410078, Changsha, China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, 410078, Changsha, China
| | - Xiangjian Luo
- Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China.,Cancer Research Institute and School of Basic Medical Science, Xiangya School of Medicine, Central South University, 410078, Changsha, China.,Key Laboratory of Carcinogenesis, Chinese Ministry of Health, 410078, Changsha, China.,Molecular Imaging Research Center of Central South University, 410008, Changsha, Hunan, China
| | - Weihua Liao
- Department of Radiology, Xiangya Hospital, Central South University, 410078, Changsha, China
| | - Ann M Bode
- The Hormel Institute, University of Minnesota, Austin, MN, 55912, USA
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Gullo I, van der Post RS, Carneiro F. Recent advances in the pathology of heritable gastric cancer syndromes. Histopathology 2020; 78:125-147. [PMID: 33382491 DOI: 10.1111/his.14228] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 08/04/2020] [Indexed: 02/06/2023]
Abstract
Despite the relative rarity of hereditary gastric cancer syndromes, the prompt recognition of their specific clinical features and histopathological characteristics is pivotal in offering patients the most appropriate treatment. In this article, we address the three major inherited syndromes that primarily affect the stomach: hereditary diffuse gastric cancer (HDGC), caused by germline variants in CDH1 and CTNNA1; gastric adenocarcinoma and proximal polyposis of the stomach, caused by germline mutations in promoter 1B of APC; and familial intestinal gastric cancer, which has a poorly defined genetic cause. The main focus will be on HDGC, in light of the recent publication of updated clinical practice guidelines and emerging concepts regarding HDGC histopathology. In particular, we describe the broad morphological spectrum of HDGC lesions, stressing the importance of recognising indolent and aggressive phenotypes. Moreover, we discuss the increased risk of gastric (pre)malignancies developing in patients with other well-defined hereditary cancer syndromes, such as familial adenomatous polyposis, Lynch syndrome, Peutz-Jeghers syndrome, juvenile polyposis, Li-Fraumeni syndrome, and hereditary breast and ovarian cancer syndrome.
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Affiliation(s)
- Irene Gullo
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ), Porto, Portugal.,Department of Pathology, Faculty of Medicine of the University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal
| | - Rachel S van der Post
- Department of Pathology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Fátima Carneiro
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ), Porto, Portugal.,Department of Pathology, Faculty of Medicine of the University of Porto, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde (i3S), Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Porto, Portugal
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35
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Imyanitov EN, Ivantsov AO, Tsimafeyeu IV. Harmonization of Molecular Testing for Non-Small Cell Lung Cancer: Emphasis on PD-L1. Front Oncol 2020; 10:549198. [PMID: 33102215 PMCID: PMC7554524 DOI: 10.3389/fonc.2020.549198] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 08/14/2020] [Indexed: 12/23/2022] Open
Abstract
Comprehensive molecular testing plays a critical role in the choice of treatment for non-small lung cell cancer (NSCLC). The analysis of druggable alterations in EGFR, BRAF, MET, KRAS, ALK, ROS1, RET and NTRK1/2/3 genes is more or less standardized and can be achieved using a single diagnostic platform, e.g., next generation sequencing (NGS) or polymerase chain reaction (PCR). In contrast to above targets, PD-L1 testing requires the use of immunohistochemistry (IHC). There are multiple PD-L1 IHC assays, which utilize distinct antibodies and detection systems. These PD-L1 tests are tailored to distinct drugs, often rely on different thresholds and scoring guidelines, and are characterized by incomplete inter-laboratory and inter-observer reproducibility. Several studies evaluated the performance of PD-L1 RNA expression tests, as PCR-based RNA analysis is compatible with other NSCLC molecular testing platforms, can be performed in a semi-automated manner, and has a potential for proper standardization. These investigations revealed a correlation between PD-L1 protein and RNA expression; however, there were NSCLCs demonstrating decent amounts of PD-L1 transcript in the absence of PD-L1 IHC staining. Clinical studies are required to evaluate, which of the two PD-L1 testing approaches, i.e., RNA or protein expression measurement, has a better predictive value.
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Affiliation(s)
- Evgeny N Imyanitov
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St. Petersburg, Russia.,Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, Saint Petersburg, Russia
| | - Alexandr O Ivantsov
- Department of Tumor Growth Biology, N.N. Petrov Institute of Oncology, St. Petersburg, Russia.,Department of Clinical Genetics, St.-Petersburg Pediatric Medical University, Saint Petersburg, Russia
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36
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Huang L, Chen H, Xu Y, Chen J, Liu Z, Xu Q. Correlation of tumor-infiltrating immune cells of melanoma with overall survival by immunogenomic analysis. Cancer Med 2020; 9:8444-8456. [PMID: 32931642 PMCID: PMC7666744 DOI: 10.1002/cam4.3466] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 08/08/2020] [Accepted: 08/26/2020] [Indexed: 12/26/2022] Open
Abstract
AIMS Different types of tumor-infiltrating immune cells not only augment but also dampen antitumor immunity in the microenvironment of melanoma. Therefore, it is critical to provide an overview of tumor-infiltrating immune cells in melanoma and explore a novel strategy for immunotherapies. METHODS We analyzed the immune states of different stages in melanoma patients by the immune, stromal, and estimation of stromal and immune cells in malignant tumor tissues using expression data (ESTIMATE) scores. Immune cell types were identified by the estimating relative subsets of RNA transcripts (CIBERSORTx) algorithm in 471 melanoma and 324 healthy tissues. Moreover, we performed a gene set variation analysis (GSVA) to determine the differentially regulated pathways in the tumor microenvironment. RESULTS In melanoma cohorts, we found that ESTIMATE and immune scores were involved in survival or tumor clinical stage. Among the 22 immune cells, CD8+ T cells, M2 macrophages, and regulatory T cells (Tregs) showed significant differences using the CIBERSORTx algorithm. Furthermore, GSVA identified the immune cell-related pathways; the primary immunodeficiency pathway, intestinal immune network for IgA, and TGF-β pathways were identified as participants of the crosstalk in CD8+ T cells, Tregs, and M2 macrophages in the melanoma microenvironment. CONCLUSION These results reveal the cellular and molecular characteristics of immune cells in melanoma, providing a method for selecting targets of immunotherapies and promoting the efficacy of therapies for the treatment of melanoma.
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Affiliation(s)
- Lili Huang
- Department of Oncology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.,Tongji University Cancer Center, Shanghai, China.,Department of Oncology, Dermatology Hospital, Tongji University, Shanghai, China
| | - Hong Chen
- Department of Gastrointestinal Surgery, Fujian Provincial Hospital, Fuzhou, China
| | - Yu Xu
- Department of musculoskeletal Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jianhua Chen
- Department of Oncology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.,Tongji University Cancer Center, Shanghai, China.,Department of Oncology, Dermatology Hospital, Tongji University, Shanghai, China
| | - Zhuqing Liu
- Department of Oncology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.,Tongji University Cancer Center, Shanghai, China.,Department of Oncology, Dermatology Hospital, Tongji University, Shanghai, China
| | - Qing Xu
- Department of Oncology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.,Tongji University Cancer Center, Shanghai, China.,Department of Oncology, Dermatology Hospital, Tongji University, Shanghai, China
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37
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Ghasemi F, Tessier TM, Gameiro SF, Maciver AH, Cecchini MJ, Mymryk JS. High MHC-II expression in Epstein-Barr virus-associated gastric cancers suggests that tumor cells serve an important role in antigen presentation. Sci Rep 2020; 10:14786. [PMID: 32901107 PMCID: PMC7479113 DOI: 10.1038/s41598-020-71775-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Accepted: 08/18/2020] [Indexed: 02/06/2023] Open
Abstract
EBV-associated gastric adenocarcinomas (EBVaGCs) often exhibit better clinical outcomes than EBV negative gastric cancers (GCs), which could be related to their consistent expression of foreign viral antigens. Antigen-presenting cells (APCs) present peptide antigens in the context of the class-II major histocompatibility complex (MHC-II). During inflammatory conditions, epithelial cells express MHC-II and function as accessory APCs. Utilizing RNA-seq data from nearly 400 GC patients, we determined the impact of EBV-status on expression of MHC-II components, genes involved in their regulation, and T-cell co-stimulation. Virtually all MHC-II genes were significantly upregulated in EBVaGCs compared to normal tissues, or other GC subtypes. Genes involved in antigen presentation were also significantly upregulated in EBVaGCs, as were the key MHC-II transcriptional regulators CIITA and RFX5. This was unexpected as the EBV encoded BZLF1 protein can repress CIITA transcription and is expressed in many EBVaGCs. Furthermore, MHC-II upregulation was strongly correlated with elevated intratumoral levels of interferon-gamma. In addition, expression of co-stimulatory molecules involved in T-cell activation and survival was also significantly increased in EBVaGCs. Thus, gastric adenocarcinoma cells may functionally contribute to the highly immunogenic tumor microenvironment observed in EBVaGCs via a previously unappreciated role in interferon-induced antigen presentation.
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Affiliation(s)
- Farhad Ghasemi
- Department of Surgery, Western University, London, ON, N6A 4V2, Canada
| | - Tanner M Tessier
- Department of Microbiology and Immunology, Western University, London, ON, N6A 3K7, Canada
| | - Steven F Gameiro
- Department of Microbiology and Immunology, Western University, London, ON, N6A 3K7, Canada
| | - Allison H Maciver
- Department of Surgery, Western University, London, ON, N6A 4V2, Canada.,Department of Oncology, Western University, London, ON, N6A 3K7, Canada
| | - Matthew J Cecchini
- Department of Pathology and Laboratory Medicine, Western University and London Health Sciences Centre, London, ON, N6A 5C1, Canada
| | - Joe S Mymryk
- Department of Microbiology and Immunology, Western University, London, ON, N6A 3K7, Canada. .,Department of Oncology, Western University, London, ON, N6A 3K7, Canada. .,Department of Otolaryngology, Head & Neck Surgery, Western University, London, ON, N6A 5W9, Canada. .,London Regional Cancer Program, Lawson Health Research Institute, London, ON, N6C 2R5, Canada. .,London Regional Cancer Program, Room A4-837, 790 Commissioners Rd. East, London, ON, N6A 4L6, Canada.
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Gullo I, Grillo F, Mastracci L, Vanoli A, Carneiro F, Saragoni L, Limarzi F, Ferro J, Parente P, Fassan M. Precancerous lesions of the stomach, gastric cancer and hereditary gastric cancer syndromes. Pathologica 2020; 112:166-185. [PMID: 33179620 PMCID: PMC7931572 DOI: 10.32074/1591-951x-166] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 06/30/2020] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer accounts for about 6% of cancers worldwide, being the fifth most frequently diagnosed malignancy and the third leading cause of cancer related death. Gastric carcinogenesis is a multistep and multifactorial process and is the result of the complex interplay between genetic susceptibility and environmental factors. The identification of predisposing conditions and of precancerous lesions is the basis for screening programs and early stage treatment. Furthermore, although most gastric cancers are sporadic, familial clustering is observed in up to 10% of patients. Among them, hereditary cases, related to known cancer susceptibility syndromes and/or genetic causes are thought to account for 1-3% of all gastric cancers. The pathology report of gastric resections specimens therefore requires a standardized approach as well as in depth knowledge of prognostic and treatment associated factors.
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Affiliation(s)
- Irene Gullo
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ) & Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal and Instituto de Investigação e Inovação em Saúde (i3S) & Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Portugal
| | - Federica Grillo
- Correspondence Federica Grillo Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova and Ospedale Policlinico San Martino, IRCCS for Oncology and Neuroscience, Genova, Italy, largo Rosanna Benzi 10, 16132 Genova, Italy Tel. +39 010 5555957 Fax: +39 010 5556392 E-mail:
| | | | - Alessandro Vanoli
- Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital, Pavia, Italy
| | - Fatima Carneiro
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ) & Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), Porto, Portugal and Instituto de Investigação e Inovação em Saúde (i3S) & Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Portugal
| | - Luca Saragoni
- UO Anatomia Patologica, Ospedale G.B. Morgagni-L. Pierantoni, Forlì, Italy
| | - Francesco Limarzi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST/IRCCS), Meldola (FC), Italy
| | - Jacopo Ferro
- Anatomic Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics (DICS), University of Genova, Italy
| | - Paola Parente
- Pathology Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG) Italy
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, Italy
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Abstract
Gastric cancer is still one of the most prevalent and deadliest cancers in the world. Although our knowledge about the disease has progressed extraordinarily, this has not been accompanied by our capacity to effectively treat the disease. In the last years, immunotherapy made its way into the cancer field and was responsible for major changes in the treatment success rates for several cancer types. Although gastric cancer was not among the first successful targets of this type of therapy, the relationship between this type of cancer, immunosurveillance and immunotherapy is now being actively researched. In this article, we review the literature of the past year regarding the relationship between gastric cancer, its immune microenvironment and response to immunotherapy. Published data indicate that the immune microenvironment influences the clinical behaviour of gastric cancer, and is correlated with its histologic and molecular subtypes with an emphasis on the microsatellite- and EBV-positive tumour subgroups. Although the literature regarding response to immunotherapy is scarce, there is good evidence that patient stratification for immunotherapy is going to become a reality in gastric cancer.
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Affiliation(s)
- Carlos Resende
- i3S - Institute for Research and Innovation in Health and IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Carla Pereira Gomes
- i3S - Institute for Research and Innovation in Health and IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal
| | - Jose Carlos Machado
- i3S - Institute for Research and Innovation in Health and IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.,Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
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40
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Smyth EC, Nilsson M, Grabsch HI, van Grieken NC, Lordick F. Gastric cancer. Lancet 2020; 396:635-648. [PMID: 32861308 DOI: 10.1016/s0140-6736(20)31288-5] [Citation(s) in RCA: 2707] [Impact Index Per Article: 541.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 05/06/2020] [Accepted: 05/07/2020] [Indexed: 02/06/2023]
Abstract
Gastric cancer is the fifth most common cancer and the third most common cause of cancer death globally. Risk factors for the condition include Helicobacter pylori infection, age, high salt intake, and diets low in fruit and vegetables. Gastric cancer is diagnosed histologically after endoscopic biopsy and staged using CT, endoscopic ultrasound, PET, and laparoscopy. It is a molecularly and phenotypically highly heterogeneous disease. The main treatment for early gastric cancer is endoscopic resection. Non-early operable gastric cancer is treated with surgery, which should include D2 lymphadenectomy (including lymph node stations in the perigastric mesentery and along the celiac arterial branches). Perioperative or adjuvant chemotherapy improves survival in patients with stage 1B or higher cancers. Advanced gastric cancer is treated with sequential lines of chemotherapy, starting with a platinum and fluoropyrimidine doublet in the first line; median survival is less than 1 year. Targeted therapies licensed to treat gastric cancer include trastuzumab (HER2-positive patients first line), ramucirumab (anti-angiogenic second line), and nivolumab or pembrolizumab (anti-PD-1 third line).
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Affiliation(s)
- Elizabeth C Smyth
- Department of Oncology, Cambridge University Hospitals National Health Service Foundation Trust, Hill's Road, Cambridge, UK.
| | - Magnus Nilsson
- Division of Surgery, Department of Clinical Science, Intervention and Technology, Karolinska Institute, Stockholm, Sweden; Department of Upper Abdominal Diseases, Karolinska University Hospital, Stockholm, Sweden
| | - Heike I Grabsch
- Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center+, Maastricht, Netherlands; Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - Nicole Ct van Grieken
- Department of Pathology, Amsterdam University Medical Centre, Cancer Center Amsterdam, VU University, Amsterdam, Netherlands
| | - Florian Lordick
- University Cancer Center Leipzig, Leipzig University Medical Center, Leipzig, Germany
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Gullo I, Costa C, Silva SL, Ferreira C, Motta A, Silva SP, Ferreira RD, Rosmaninho P, Faria E, da Costa JT, Câmara R, Gonçalves G, Santos-Antunes J, Oliveira C, Machado JC, Carneiro F, Sousa AE. The Dysfunctional Immune System in Common Variable Immunodeficiency Increases the Susceptibility to Gastric Cancer. Cells 2020; 9:1498. [PMID: 32575504 PMCID: PMC7349552 DOI: 10.3390/cells9061498] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 06/16/2020] [Accepted: 06/17/2020] [Indexed: 02/06/2023] Open
Abstract
Gastric carcinoma (GC) represents the most common cause of death in patients with common variable immunodeficiency (CVID). However, a limited number of cases have been characterised so far. In this study, we analysed the clinical features, bacterial/viral infections, detailed morphology and immune microenvironment of nine CVID patients with GC. The study of the immune microenvironment included automated digital counts of CD20+, CD4+, CD8+, FOXP3+, GATA3+ and CD138+ immune cells, as well as the evaluation of PD-L1 expression. Twenty-one GCs from non-CVID patients were used as a control group. GC in CVID patients was diagnosed mostly at early-stage (n = 6/9; 66.7%) and at younger age (median-age: 43y), when compared to non-CVID patients (p < 0.001). GC pathogenesis was closely related to Helicobacter pylori infection (n = 8/9; 88.9%), but not to Epstein-Barr virus (0.0%) or cytomegalovirus infection (0.0%). Non-neoplastic mucosa (non-NM) in CVID-patients displayed prominent lymphocytic gastritis (100%) and a dysfunctional immune microenvironment, characterised by higher rates of CD4+/CD8+/Foxp3+/GATA3+/PD-L1+ immune cells and the expected paucity of CD20+ B-lymphocytes and CD138+ plasma cells, when compared to non-CVID patients (p < 0.05). Changes in the immune microenvironment between non-NM and GC were not equivalent in CVID and non-CVID patients, reflecting the relevance of immune dysfunction for gastric carcinogenesis and GC progression in the CVID population.
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Affiliation(s)
- Irene Gullo
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ), 4200-319 Porto, Portugal; (I.G.); (C.C.); (G.G.)
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal; (C.O.); (J.C.M.)
- Institute of Molecular Pathology and Immunology, University of Porto (Ipatimup), 4200-135 Porto, Portugal
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal
| | - Catarina Costa
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ), 4200-319 Porto, Portugal; (I.G.); (C.C.); (G.G.)
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal; (C.O.); (J.C.M.)
| | - Susana L. Silva
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; (C.F.); (A.M.); (S.P.S.); (R.D.F.); (P.R.); (A.E.S.)
- Centro de Imunodeficiências Primárias do Centro Académico de Medicina de Lisboa, 1649-028 Lisbon, Portugal
- Centro Hospitalar Universitário Lisboa Norte, 1600-190 Lisbon, Portugal
| | - Cristina Ferreira
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; (C.F.); (A.M.); (S.P.S.); (R.D.F.); (P.R.); (A.E.S.)
- Centro de Imunodeficiências Primárias do Centro Académico de Medicina de Lisboa, 1649-028 Lisbon, Portugal
- Centro Hospitalar Universitário Lisboa Norte, 1600-190 Lisbon, Portugal
| | - Adriana Motta
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; (C.F.); (A.M.); (S.P.S.); (R.D.F.); (P.R.); (A.E.S.)
- Centro de Imunodeficiências Primárias do Centro Académico de Medicina de Lisboa, 1649-028 Lisbon, Portugal
| | - Sara P. Silva
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; (C.F.); (A.M.); (S.P.S.); (R.D.F.); (P.R.); (A.E.S.)
- Centro de Imunodeficiências Primárias do Centro Académico de Medicina de Lisboa, 1649-028 Lisbon, Portugal
- Centro Hospitalar Universitário Lisboa Norte, 1600-190 Lisbon, Portugal
| | - Rúben Duarte Ferreira
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; (C.F.); (A.M.); (S.P.S.); (R.D.F.); (P.R.); (A.E.S.)
- Centro de Imunodeficiências Primárias do Centro Académico de Medicina de Lisboa, 1649-028 Lisbon, Portugal
| | - Pedro Rosmaninho
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; (C.F.); (A.M.); (S.P.S.); (R.D.F.); (P.R.); (A.E.S.)
- Centro de Imunodeficiências Primárias do Centro Académico de Medicina de Lisboa, 1649-028 Lisbon, Portugal
| | - Emília Faria
- Serviço de Imunoalergologia, Centro Hospitalar Hospitalar e Universitário de Coimbra, 3004-561 Coimbra, Portugal;
| | - José Torres da Costa
- Serviço de Imunoalergologia, Centro Hospitalar Hospitalar Universitário de São João (CHUSJ), 4200-319 Porto, Portugal;
| | - Rita Câmara
- Serviço de Imunoalergologia, Hospital Dr Nélio Mendonça, 9000-177 Funchal, Portugal;
| | - Gilza Gonçalves
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ), 4200-319 Porto, Portugal; (I.G.); (C.C.); (G.G.)
- Institute of Molecular Pathology and Immunology, University of Porto (Ipatimup), 4200-135 Porto, Portugal
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal
| | - João Santos-Antunes
- Department of Gastroenterology, Centro Hospitalar Universitário de São João (CHUSJ), 4200-319 Porto, Portugal;
| | - Carla Oliveira
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal; (C.O.); (J.C.M.)
- Institute of Molecular Pathology and Immunology, University of Porto (Ipatimup), 4200-135 Porto, Portugal
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal
| | - José C. Machado
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal; (C.O.); (J.C.M.)
- Institute of Molecular Pathology and Immunology, University of Porto (Ipatimup), 4200-135 Porto, Portugal
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal
| | - Fátima Carneiro
- Department of Pathology, Centro Hospitalar Universitário de São João (CHUSJ), 4200-319 Porto, Portugal; (I.G.); (C.C.); (G.G.)
- Department of Pathology, Faculty of Medicine of the University of Porto (FMUP), 4200-319 Porto, Portugal; (C.O.); (J.C.M.)
- Institute of Molecular Pathology and Immunology, University of Porto (Ipatimup), 4200-135 Porto, Portugal
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, 4200-135 Porto, Portugal
| | - Ana E. Sousa
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal; (C.F.); (A.M.); (S.P.S.); (R.D.F.); (P.R.); (A.E.S.)
- Centro de Imunodeficiências Primárias do Centro Académico de Medicina de Lisboa, 1649-028 Lisbon, Portugal
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Huan C, Xiaoxu C, Xifang R. Zinc Finger Protein 521, Negatively Regulated by MicroRNA-204-5p, Promotes Proliferation, Motility and Invasion of Gastric Cancer Cells. Technol Cancer Res Treat 2020; 18:1533033819874783. [PMID: 31526099 PMCID: PMC6749787 DOI: 10.1177/1533033819874783] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
OBJECTIVE This study aims to investigate the expression, role, and detailed mechanism of microRNA-204-5p and zinc finger protein 521 in gastric cancer. METHODS Immunohistochemistry was adopted to detect the expressions of zinc finger protein 521 in 82 cases of gastric cancer tissues. Western blot was used to detect the expressions of zinc finger protein 521 in gastric cancer cells and adjacent cells. Moreover, the correlation between zinc finger protein 521 and the prognosis of patients were also evaluated. Cell Counting Kit 8 assay and colony formation assay were performed to figure out the impact of zinc finger protein 521 on the proliferation of gastric cancer cells. By conducting flow cytometry, the effect of zinc finger protein 521 on the apoptosis of gastric cancer cells was determined. The scratch wound healing assay and transwell invasion assay were carried out to determine the effect of zinc finger protein 521 on regulating the motility and invasion of gastric cancer cells. Ultimately, the targeting relationship and interaction between microRNA-204-5p and zinc finger protein 521 were verified by real-time polymerase chain reaction, Western blot, and dual luciferase reporter gene assay. RESULTS Compared with adjacent cells, zinc finger protein 521 was highly expressed in gastric cancer cells, which was related to TNM stage (P = .0388), tumor size (P = .0168), and local lymph node metastasis (P = .0024). Overexpressed zinc finger protein 521 can promote the proliferation, migration, and invasion of gastric cancer cells and inhibit the apoptosis. Zinc finger protein 521 is a target gene of microRNA-106-5p, and there was a negative correlation between the expression of zinc finger protein 521 and microRNA-204-5p. CONCLUSION Zinc finger protein 521 can arrest the apoptosis and enhance the proliferation, migration, and invasion of gastric cancer cells via regulating microRNA-204-5p. Our study may provide novel clues for the treatment of patients with gastric cancer.
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Affiliation(s)
- Chen Huan
- Department of Gastroenterology, The First People's Hospital of Yichang, Yichang, Hubei, China.,Department of Gastroenterology, The People's Hospital of Three Gorges University, Yichang, Hubei, China
| | - Cai Xiaoxu
- Department of Gastroenterology, The People's Hospital of Three Gorges University, Yichang, Hubei, China.,Department of Oncology, The First People's Hospital of Yichang, Yichang, Hubei, China
| | - Ren Xifang
- Department of Gastroenterology, The First People's Hospital of Yichang, Yichang, Hubei, China.,Department of Gastroenterology, The People's Hospital of Three Gorges University, Yichang, Hubei, China
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43
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Huss R, Coupland SE. Software‐assisted decision support in digital histopathology. J Pathol 2020; 250:685-692. [DOI: 10.1002/path.5388] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 01/09/2020] [Accepted: 01/17/2020] [Indexed: 12/16/2022]
Affiliation(s)
- Ralf Huss
- Institute of Pathology and Molecular Diagnostics University Hospital Augsburg Augsburg Germany
| | - Sarah E Coupland
- Department of Cellular and Molecular Pathology University of Liverpool Liverpool UK
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44
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Thirty years of Epstein-Barr virus-associated gastric carcinoma. Virchows Arch 2019; 476:353-365. [PMID: 31836926 DOI: 10.1007/s00428-019-02724-4] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/18/2019] [Accepted: 11/25/2019] [Indexed: 12/13/2022]
Abstract
Thirty years have passed since a possible association of Epstein-Barr virus (EBV) with gastric carcinoma was reported. We now know EBV-associated gastric carcinoma to be a specific subtype of gastric carcinoma. Global epigenetic methylation and counteraction of the antitumour microenvironment are two major characteristics of this subtype of gastric carcinoma. Recent development of therapeutic modalities for gastric carcinoma, such as endoscopic mucosal dissection and immune checkpoint inhibitor therapy, has made the presence of EBV infection a biomarker for the treatment of gastric carcinoma. This review presents a portrait of EBV-associated gastric carcinoma from initiation to maturity that we define as the 'gastritis-infection-cancer sequence', followed by its molecular abnormalities and interactions with immune checkpoint molecules and the microenvironment. EBV non-coding RNAs (microRNA and circular RNA) and exosomes derived from EBV-infected cells that were previously behind the scenes are now recognized for their roles in EBV-associated gastric carcinoma. The virus utilizes cellular machinery skilfully to control infected cells and their microenvironment. We should thus strive to understand virus-host interactions more fully in the following years to overcome this virus-driven subtype of gastric carcinoma.
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Trist BG, Hare DJ, Double KL. Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease. Aging Cell 2019; 18:e13031. [PMID: 31432604 PMCID: PMC6826160 DOI: 10.1111/acel.13031] [Citation(s) in RCA: 440] [Impact Index Per Article: 73.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 07/05/2019] [Accepted: 08/07/2019] [Indexed: 12/13/2022] Open
Abstract
Parkinson's disease prevalence is rapidly increasing in an aging global population. With this increase comes exponentially rising social and economic costs, emphasizing the immediate need for effective disease‐modifying treatments. Motor dysfunction results from the loss of dopaminergic neurons in the substantia nigra pars compacta and depletion of dopamine in the nigrostriatal pathway. While a specific biochemical mechanism remains elusive, oxidative stress plays an undeniable role in a complex and progressive neurodegenerative cascade. This review will explore the molecular factors that contribute to the high steady‐state of oxidative stress in the healthy substantia nigra during aging, and how this chemical environment renders neurons susceptible to oxidative damage in Parkinson's disease. Contributing factors to oxidative stress during aging and as a pathogenic mechanism for Parkinson's disease will be discussed within the context of how and why therapeutic approaches targeting cellular redox activity in this disorder have, to date, yielded little therapeutic benefit. We present a contemporary perspective on the central biochemical contribution of redox imbalance to Parkinson's disease etiology and argue that improving our ability to accurately measure oxidative stress, dopaminergic neurotransmission and cell death pathways in vivo is crucial for both the development of new therapies and the identification of novel disease biomarkers.
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Affiliation(s)
- Benjamin G. Trist
- Brain and Mind Centre and Discipline of Pharmacology, Faculty of Medical and Health The University of Sydney Sydney NSW Australia
| | - Dominic J. Hare
- The Florey Institute of Neuroscience and Mental Health The University of Melbourne Parkville Vic. Australia
- Elemental Bio‐imaging Facility University of Technology Sydney Broadway NSW Australia
| | - Kay L. Double
- Brain and Mind Centre and Discipline of Pharmacology, Faculty of Medical and Health The University of Sydney Sydney NSW Australia
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The Transcriptomic Landscape of Gastric Cancer: Insights into Epstein-Barr Virus Infected and Microsatellite Unstable Tumors. Int J Mol Sci 2018; 19:ijms19072079. [PMID: 30018250 PMCID: PMC6073163 DOI: 10.3390/ijms19072079] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 07/12/2018] [Accepted: 07/13/2018] [Indexed: 12/31/2022] Open
Abstract
Background: Epstein-Barr Virus (EBV) positive and microsatellite unstable (MSI-high) gastric cancer (GC) are molecular subgroups with distinctive molecular profiles. We explored the transcriptomic differences between EBV+ and MSI-high GCs, and the expression of current GC immunotherapy targets such as PD-1, PD-L1, CTLA4 and Dies1/VISTA. Methods: Using Nanostring Technology and comparative bioinformatics, we analyzed the expression of 499 genes in 46 GCs, classified either as EBV positive (EBER in situ hybridization) or MSI-high (PCR/fragment analysis). PD-L1 protein expression was assessed by immunohistochemistry. Results: From the 46 GCs, 27 tested MSI-high/EBV−, 15 tested MSS/EBV+ and four tested MSS/EBV−. The Nanostring CodeSet could segregate GCs according to MSI and, to a lesser extent, EBV status. Functional annotation of differentially expressed genes associated MSI-high/EBV− GCs with mitotic activity and MSS/EBV+ GCs with immune response. PD-L1 protein expression, evaluated in stromal immune cells, was lower in MSI-high/EBV− GCs. High mRNA expression of PD-1, CTLA4 and Dies1/VISTA and distinctive PD-1/PD-L1 co-expression patterns (PD-1high/PD-L1low, PD-1high/PDL1high) were associated with MSS/EBV+ molecular subtype and gastric cancer with lymphoid stroma (GCLS) morphological features. Conclusions: EBV+ and MSI-high GCs present distinct transcriptomic profiles. GCLS/EBV+ cases frequently present co-expression of multiple immunotherapy targets, a finding with putative therapeutic implications.
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