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Kim YS. Gastric Carcinoma. Curr Top Microbiol Immunol 2025. [PMID: 40423781 DOI: 10.1007/82_2025_303] [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: 05/28/2025]
Abstract
Epstein-Barr virus (EBV)-associated gastric cancers (EBVaGCs) account for about 10% of gastric cancers globally, with higher prevalence in East Asia and Latin America. These cancers develop through a "gastritis-infection-cancer sequence" and are characterized by unique molecular signatures, including CpG island methylator phenotype and mutations in ARID1A and PIK3CA genes. EBVaGCs typically present in the proximal stomach with diffuse-type histology and dense lymphocytic infiltration. Key viral proteins EBNA1 and LMP2A drive oncogenesis by altering cellular processes and immune responses. The IFN-γ signature and extensive epigenetic modifications contribute to their distinct profile. Despite often presenting at advanced stages, EBVaGCs generally have a more favorable prognosis. EBV employs sophisticated strategies to evade immune detection, utilizing latent proteins and noncoding RNAs. Paradoxically, despite an immune-hot environment, EBVaGCs demonstrate effective immune evasion, partly due to the expression of immune checkpoint molecules like PD-L1 and LAG3. Treatment approaches vary based on disease stage, from endoscopic resection for early-stage cancers to systemic therapies for advanced cases. Immunotherapy, particularly PD-1/PD-L1 inhibitors, shows promising results. Emerging research suggests combining these with LAG3 inhibitors may enhance efficacy. Ongoing research and advanced genomic techniques continue to reveal new insights, paving the way for personalized therapies and novel diagnostic approaches.
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Affiliation(s)
- Young-Sik Kim
- Department of Pathology, Korea University Ansan Hospital, Korea University College of Medicine, Seoul, Republic of Korea.
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Xiao Q, Liu Y, Li T, Wang C, He S, Zhai L, Yang Z, Zhang X, Wu Y, Liu Y. Viral oncogenesis in cancer: from mechanisms to therapeutics. Signal Transduct Target Ther 2025; 10:151. [PMID: 40350456 PMCID: PMC12066790 DOI: 10.1038/s41392-025-02197-9] [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: 08/16/2024] [Revised: 01/22/2025] [Accepted: 03/03/2025] [Indexed: 05/14/2025] Open
Abstract
The year 2024 marks the 60th anniversary of the discovery of the Epstein-Barr virus (EBV), the first virus confirmed to cause human cancer. Viral infections significantly contribute to the global cancer burden, with seven known Group 1 oncogenic viruses, including hepatitis B virus (HBV), human papillomavirus (HPV), EBV, Kaposi sarcoma-associated herpesvirus (KSHV), hepatitis C virus (HCV), human T-cell leukemia virus type 1 (HTLV-1), and human immunodeficiency virus (HIV). These oncogenic viruses induce cellular transformation and cancer development by altering various biological processes within host cells, particularly under immunosuppression or co-carcinogenic exposures. These viruses are primarily associated with hepatocellular carcinoma, gastric cancer, cervical cancer, nasopharyngeal carcinoma, Kaposi sarcoma, lymphoma, and adult T-cell leukemia/lymphoma. Understanding the mechanisms of viral oncogenesis is crucial for identifying and characterizing the early biological processes of virus-related cancers, providing new targets and strategies for treatment or prevention. This review first outlines the global epidemiology of virus-related tumors, milestone events in research, and the process by which oncogenic viruses infect target cells. It then focuses on the molecular mechanisms by which these viruses induce tumors directly or indirectly, including the regulation of oncogenes or tumor suppressor genes, induction of genomic instability, disruption of regular life cycle of cells, immune suppression, chronic inflammation, and inducing angiogenesis. Finally, current therapeutic strategies for virus-related tumors and recent advances in preclinical and clinical research are discussed.
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Affiliation(s)
- Qing Xiao
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Yi Liu
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Tingting Li
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Chaoyu Wang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Sanxiu He
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Liuyue Zhai
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Zailin Yang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China
| | - Xiaomei Zhang
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China.
| | - Yongzhong Wu
- Department of Radiation Oncology, Chongqing University Cancer Hospital, Chongqing, China.
| | - Yao Liu
- Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Department of Hematology-Oncology, Chongqing University Cancer Hospital, Chongqing, China.
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He MY, Liu M, Yuan J, Lv J, Li W, Yan Q, Tang Y, Wang L, Guo L, Liu F. Spatial transcriptomics reveals tumor microenvironment heterogeneity in EBV positive diffuse large B cell lymphoma. Sci Rep 2025; 15:15878. [PMID: 40335578 PMCID: PMC12058988 DOI: 10.1038/s41598-025-00410-x] [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: 12/13/2024] [Accepted: 04/28/2025] [Indexed: 05/09/2025] Open
Abstract
Accumulating research suggests that Epstein-Barr Virus-positive Diffuse Large B-cell Lymphoma (EBV+DLBCL) is associated with immune dysfunction and tumor microenvironment (TME) heterogeneity. While the prognostic role of the TME in EBV-DLBCL is established, its impact on EBV+DLBCL survival remains unclear. Here, we integrated 10X Visium spatial transcriptomics (ST) with single-cell RNA sequencing (scRNA-seq) to map TME heterogeneity in EBV+DLBCL. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses identified PD-1/PD-L1 signaling as a hallmark of EBV+DLBCL's immunosuppressive TME. Functional validation using the PD-1/PD-L1 inhibitor BMS202 revealed dose-dependent suppression of proliferation and enhanced apoptosis in EBV+Farage cells, with TLR4 emerging as a downstream effector showing EBV-status-dependent regulation. These findings not only link TME-driven PD-1/PD-L1 activation to EBV+DLBCL's poor prognosis but also provide preclinical evidence for PD-1/PD-L1 blockade as a therapeutic strategy.
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Affiliation(s)
- Mei-Yao He
- Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China
| | - Meng Liu
- School of Life and Health Technology, Dongguan University of Technology, Dongguan, 523808, People's Republic of China
| | - Jiayin Yuan
- Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China
| | - Jin Lv
- Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China
| | - Wei Li
- Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China
| | - Qianwen Yan
- Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China
| | - Yujiao Tang
- Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China
| | - Luyi Wang
- Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China
| | - Li Guo
- Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China
| | - Fang Liu
- Department of Pathology, The First People's Hospital of Foshan, Foshan, 528000, People's Republic of China.
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Abe H, Urabe M, Yagi K, Yamashita H, Seto Y, Ushiku T. Expression of therapy target molecules in esophagogastric junction and Barrett's adenocarcinoma. Gastric Cancer 2025; 28:264-274. [PMID: 39663311 DOI: 10.1007/s10120-024-01573-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 11/30/2024] [Indexed: 12/13/2024]
Abstract
BACKGROUND Recently, novel molecular targeted therapies have been developed for gastric and esophageal adenocarcinomas. We examined the status of therapeutic target molecules in esophagogastric junction (EGJ) and Barrett's adenocarcinoma. METHODS Tissue microarrays were constructed from 114 cases of non-Barrett's EGJ adenocarcinoma and 30 cases of Barrett's adenocarcinoma. Immunohistochemistry for mismatch repair proteins, PD-L1, HER2, CLDN18, FGFR2b, and EBER-ISH was performed. When HER2 immunohistochemistry was 2 + , gene amplification was examined using in situ hybridization. RESULTS EBER positivity, mismatch repair deficiency, PD-L1 combined positive score (CPS) ≥ 1, CLDN18 expression ≥ 75%, FGFR2b expression, and HER2 positivity were observed in 7 (6.1%), 11 (9.6%), 70 (61.4%), 38 (33.3%), 6 (5.3%), and 11 (9.6%) cases of EGJ adenocarcinoma as well as in 0 (0%), 0 (0%), 23 (76.7%), 7 (23.3%), 2 (6.7%), and 6 (20.0%) cases of Barrett's adenocarcinoma, respectively. PD-L1 CPS ≥ 1 cases had longer recurrence-free survival (P = 0.001) and overall survival (P = 0.003) than CPS < 1 cases. Other target molecules were not associated with survival. A total of 93/114 (81.6%) cases of EGJ adenocarcinoma and 26/30 (86.7%) cases of Barrett's adenocarcinomas expressed at least one target molecule. CONCLUSIONS Most EGJ and Barrett's adenocarcinomas may be eligible for molecular targeted therapy. Appropriate patient stratification based on these molecular tests will be important for precision medicine of the EGJ and Barrett's adenocarcinoma.
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Affiliation(s)
- Hiroyuki Abe
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
| | - Masayuki Urabe
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Gastrointestinal Surgery Division, Department of Surgery, Japanese Red Cross Omori Hospital, Tokyo, Japan
| | - Koichi Yagi
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroharu Yamashita
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Yasuyuki Seto
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
- Department of Esophageal/Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Tetsuo Ushiku
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Lee SH, Khoo ASB, Griffiths JR, Mat Lazim N. Metabolic regulation of the tumour and its microenvironment: The role of Epstein-Barr virus. Int J Cancer 2025; 156:488-498. [PMID: 39291683 DOI: 10.1002/ijc.35192] [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: 07/15/2024] [Revised: 09/03/2024] [Accepted: 09/05/2024] [Indexed: 09/19/2024]
Abstract
The Epstein-Barr virus (EBV), the first identified human tumour virus, infects over 95% of the individuals globally and has the potential to induce different types of cancers. It is increasingly recognised that EBV infection not only alters cellular metabolism, contributing to neoplastic transformation, but also utilises several non-cell autonomous mechanisms to shape the metabolic milieu in the tumour microenvironment (TME) and its constituent stromal and immune cells. In this review, we explore how EBV modulates metabolism to shape the interactions between cancer cells, stromal cells, and immune cells within a hypoxic and acidic TME. We highlight how metabolites resulting from EBV infection act as paracrine factors to regulate the TME, and how targeting them can disrupt barriers to immunotherapy.
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Affiliation(s)
- Shen-Han Lee
- Department of Otorhinolaryngology-Head & Neck Surgery, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
- Hospital Universiti Sains Malaysia, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
| | - Alan Soo-Beng Khoo
- School of Postgraduate Studies, International Medical University, Kuala Lumpur, Malaysia
- Department of Medical Oncology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - John R Griffiths
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK
| | - Norhafiza Mat Lazim
- Department of Otorhinolaryngology-Head & Neck Surgery, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
- Hospital Universiti Sains Malaysia, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia
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Nishiyama M, Miki Y, Tanaka H, Yoshii M, Kuroda K, Kasashima H, Fukuoka T, Tamura T, Shibutani M, Toyokawa T, Lee S, Maeda K. Immunological Analysis of Prognostic Factors in Conversion Surgery Cases for Gastric Cancer. J Surg Res 2025; 306:533-542. [PMID: 39889314 DOI: 10.1016/j.jss.2024.12.053] [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: 06/03/2024] [Revised: 12/04/2024] [Accepted: 12/30/2024] [Indexed: 02/02/2025]
Abstract
INTRODUCTION In order to clarify the optimal strategy regarding conversion surgery (CS) for gastric cancer (GC) patients, we focused on clinicopathological findings, including immunological factors, related to the favorable prognosis in patients with stage IV GC who underwent CS. MATERIALS AND METHODS A total of 25 patients with Stage IV GC who underwent induction chemotherapy (IC) and CS at our hospital between 2010 and 2021 were enrolled in this study. Biopsy specimens before IC and surgical specimens were collected. Immunohistochemical staining was performed using programmed death-ligand 1 (PD-L1) antibody, translationally controlled tumor protein (TCTP) antibody, and CD20 antibody. Prognostic factors were investigated using clinicopathological factors as well as immunological factors such as PD-L1, TCTP, and CD20 expression. RESULTS cN0, ycStage1-2, R0-1 surgery, D2 lymph node dissection, ypN0, and ypStage1-2 were significantly associated with favorable overall survival. Among patients who underwent R0/1 surgery, only histological type was a significant prognostic factor for recurrence-free survival. Low PD-L1 expression before IC and high TCTP expression after IC were significantly associated with favorable recurrence-free survival. CONCLUSIONS In addition to clinical factors, high TCTP expression after IC was identified as a significant favorable prognostic factor, which could help in identifying candidates for CS in the future.
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Affiliation(s)
- Masaki Nishiyama
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Yuichiro Miki
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
| | | | - Mami Yoshii
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Kenji Kuroda
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Hiroaki Kasashima
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Tatsunari Fukuoka
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Tatsuro Tamura
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Masatsune Shibutani
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Takahiro Toyokawa
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Shigeru Lee
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Kiyoshi Maeda
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
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Cozac-Szőke AR, Cozac DA, Negovan A, Tinca AC, Vilaia A, Cocuz IG, Sabău AH, Niculescu R, Chiorean DM, Tomuț AN, Cotoi OS. Immune Cell Interactions and Immune Checkpoints in the Tumor Microenvironment of Gastric Cancer. Int J Mol Sci 2025; 26:1156. [PMID: 39940924 PMCID: PMC11818890 DOI: 10.3390/ijms26031156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 01/26/2025] [Accepted: 01/27/2025] [Indexed: 02/16/2025] Open
Abstract
Gastric cancer (GC) ranks as the fifth most prevalent malignant neoplasm globally, with an increased death rate despite recent advancements in research and therapeutic options. Different molecular subtypes of GC have distinct interactions with the immune system, impacting the tumor microenvironment (TME), prognosis, and reaction to immunotherapy. Tumor-infiltrating lymphocytes (TILs) in the TME are crucial for preventing tumor growth and metastasis, as evidenced by research showing that patients with GC who have a significant density of TILs have better survival rates. But cancer cells have evolved a variety of mechanisms to evade immune surveillance, both sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) and Programmed Death-Ligand 1 (PD-L1) playing a pivotal role in the development of an immunosuppressive TME. They prevent T cell activation and proliferation resulting in a decrease in the immune system's capacity to recognize and eliminate malignant cells. These immune checkpoint molecules function via different but complementary mechanisms, the expression of Siglec-15 being mutually exclusive with PD-L1 and, therefore, providing a different therapeutic approach. The review explores how TILs affect tumor growth and patient outcomes in GC, with particular emphasis on their interactions within the TME and potential targeting of the PD-L1 and Siglec-15 pathways for immunotherapy.
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Affiliation(s)
- Andreea-Raluca Cozac-Szőke
- Doctoral School of Medicine and Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.-R.C.-S.); (A.H.S.); (R.N.); (D.M.C.)
- Pathophysiology Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.C.T.); (I.-G.C.); (O.S.C.)
- Pathology Department, Mures Clinical County Hospital, 540011 Targu Mures, Romania
| | - Dan Alexandru Cozac
- Doctoral School of Medicine and Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.-R.C.-S.); (A.H.S.); (R.N.); (D.M.C.)
- Emergency Institute for Cardiovascular Diseases and Transplantation Targu Mures, 540142 Targu Mures, Romania
| | - Anca Negovan
- Department of Clinical Science-Internal Medicine, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania;
| | - Andreea Cătălina Tinca
- Pathophysiology Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.C.T.); (I.-G.C.); (O.S.C.)
- Pathology Department, Mures Clinical County Hospital, 540011 Targu Mures, Romania
| | - Alexandra Vilaia
- Department of Infectious Diseases I, Doctoral School of Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Iuliu-Gabriel Cocuz
- Pathophysiology Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.C.T.); (I.-G.C.); (O.S.C.)
- Pathology Department, Mures Clinical County Hospital, 540011 Targu Mures, Romania
| | - Adrian Horațiu Sabău
- Doctoral School of Medicine and Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.-R.C.-S.); (A.H.S.); (R.N.); (D.M.C.)
- Pathophysiology Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.C.T.); (I.-G.C.); (O.S.C.)
- Pathology Department, Mures Clinical County Hospital, 540011 Targu Mures, Romania
| | - Raluca Niculescu
- Doctoral School of Medicine and Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.-R.C.-S.); (A.H.S.); (R.N.); (D.M.C.)
- Pathophysiology Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.C.T.); (I.-G.C.); (O.S.C.)
- Pathology Department, Mures Clinical County Hospital, 540011 Targu Mures, Romania
| | - Diana Maria Chiorean
- Doctoral School of Medicine and Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.-R.C.-S.); (A.H.S.); (R.N.); (D.M.C.)
- Pathophysiology Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.C.T.); (I.-G.C.); (O.S.C.)
- Pathology Department, Mures Clinical County Hospital, 540011 Targu Mures, Romania
| | - Alexandru Nicușor Tomuț
- Faculty of Medicine, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania;
| | - Ovidiu Simion Cotoi
- Pathophysiology Department, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 540142 Targu Mures, Romania; (A.C.T.); (I.-G.C.); (O.S.C.)
- Pathology Department, Mures Clinical County Hospital, 540011 Targu Mures, Romania
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Zong R, Ma X, Shi Y, Geng L. Can Machine Learning Models Based on Computed Tomography Radiomics and Clinical Characteristics Provide Diagnostic Value for Epstein-Barr Virus-Associated Gastric Cancer? J Comput Assist Tomogr 2024; 48:859-867. [PMID: 38924393 DOI: 10.1097/rct.0000000000001636] [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: 06/28/2024]
Abstract
OBJECTIVE The aim of this study was to explore whether machine learning model based on computed tomography (CT) radiomics and clinical characteristics can differentiate Epstein-Barr virus-associated gastric cancer (EBVaGC) from non-EBVaGC. METHODS Contrast-enhanced CT images were collected from 158 patients with GC (46 EBV-positive, 112 EBV-negative) between April 2018 and February 2023. Radiomics features were extracted from the volumes of interest. A radiomics signature was built based on radiomics features by the least absolute shrinkage and selection operator logistic regression algorithm. Multivariate analyses were used to identify significant clinicoradiological variables. We developed 6 ML models for EBVaGC, including logistic regression, Extreme Gradient Boosting, random forest (RF), support vector machine, Gaussian Naive Bayes, and K-nearest neighbor algorithm. The area under the receiver operating characteristic curve (AUC), the area under the precision-recall curves (AP), calibration plots, and decision curve analysis were applied to assess the effectiveness of each model. RESULTS Six ML models achieved AUC of 0.706-0.854 and AP of 0.480-0.793 for predicting EBV status in GC. With an AUC of 0.854 and an AP of 0.793, the RF model performed the best. The forest plot of the AUC score revealed that the RF model had the most stable performance, with a standard deviation of 0.003 for AUC score. RF also performed well in the testing dataset, with an AUC of 0.832 (95% confidence interval: 0.679-0.951), accuracy of 0.833, sensitivity of 0.857, and specificity of 0.824, respectively. CONCLUSIONS The RF model based on clinical variables and Rad_score can serve as a noninvasive tool to evaluate the EBV status of gastric cancer.
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Affiliation(s)
- Ruilong Zong
- From the Department of Radiology, Xuzhou Central Hospital, Xuzhou, China
| | - Xijuan Ma
- From the Department of Radiology, Xuzhou Central Hospital, Xuzhou, China
| | - Yibing Shi
- From the Department of Radiology, Xuzhou Central Hospital, Xuzhou, China
| | - Li Geng
- Department of Radiology, The Affiliated Hospital of Xuzhou Medical University
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Zeng Z, Zhu Q. Progress and prospects of biomarker-based targeted therapy and immune checkpoint inhibitors in advanced gastric cancer. Front Oncol 2024; 14:1382183. [PMID: 38947886 PMCID: PMC11211377 DOI: 10.3389/fonc.2024.1382183] [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: 02/05/2024] [Accepted: 05/24/2024] [Indexed: 07/02/2024] Open
Abstract
Gastric cancer and gastroesophageal junction cancer represent the leading cause of tumor-related death worldwide. Although advances in immunotherapy and molecular targeted therapy have expanded treatment options, they have not significantly altered the prognosis for patients with unresectable or metastatic gastric cancer. A minority of patients, particularly those with PD-L1-positive, HER-2-positive, or MSI-high tumors, may benefit more from immune checkpoint inhibitors and/or HER-2-directed therapies in advanced stages. However, for those lacking specific targets and unique molecular features, conventional chemotherapy remains the only recommended effective and durable regimen. In this review, we summarize the roles of various signaling pathways and further investigate the available targets. Then, the current results of phase II/III clinical trials in advanced gastric cancer, along with the superiorities and limitations of the existing biomarkers, are specifically discussed. Finally, we will offer our insights in precision treatment pattern when encountering the substantial challenges.
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Affiliation(s)
| | - Qing Zhu
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
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10
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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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11
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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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12
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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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13
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Miyama Y, Kato T, Sato M, Yabuno A, Hasegawa K, Yasuda M. Cervical lymphoepithelioma-like carcinoma with deficient mismatch repair and loss of SMARCA4/BRG1: a case report and five related cases. Diagn Pathol 2024; 19:6. [PMID: 38178127 PMCID: PMC10765828 DOI: 10.1186/s13000-023-01429-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 12/13/2023] [Indexed: 01/06/2024] Open
Abstract
BACKGROUND We encountered a cervical lymphoepithelial carcinoma (LEC) possessing a predominantly solid architecture with deficient mismatch repair (dMMR) and loss of expression of the SWI/SNF (SWItch/Sucrose Non-Fermentable) chromatin remodeling complex subunit. This is the first case report of LEC with dMMR and loss of SWI/SNF complex subunit. CASE PRESENTATION A 34-year-old woman presented at our hospital with menstrual irregularities and abnormal vaginal bleeding. Magnetic resonance imaging revealed an exophytic mass in the posterior uterine cervix. Biopsy specimens confirmed squamous cell carcinoma with a 2018 International Federation of Gynecology and Obstetrics (FIGO) uterine cervical cancer stage of IB2. In a subsequent conization specimen, the tumor appeared exophytic. Microscopically, the tumor cells formed a predominant solid architecture. Abundant lymphocytic infiltration was observed. The pathological diagnosis indicated human papillomavirus (HPV)-associated squamous cell carcinoma with LEC pattern and pT1b2. Immunohistochemically, high programmed death-ligand 1 (PD-L1) expression, dMMR, and loss of the switch/sucrose non-fermentable family-related, matrix-associated, actin-dependent regulator of chromatin subfamily member 4 (SMARCA4)/BRG1, an SWI/SNF complex subunit, were observed. The patient underwent a radical hysterectomy and is alive without disease one year and five months later. Our analysis of five additional LEC cases revealed a consistent association with high-risk HPV and elevated PD-L1 expression. In addition to the present case, another patient exhibited dMMR. The SWI/SNF complex was retained except in the present case. The prognosis was favorable in all cases. CONCLUSIONS This unique case of LEC with dMMR suggests a distinct clinical entity with potential immunotherapy implications. Analysis of the other five LEC cases revealed that LEC was immune hot, and immune checkpoint inhibitors may be effective. The two dMMR cases showed loss of MLH1 and PMS2 expressions, and prominently high tumor PD-L1 expression. In those cases, dMMR might have contributed to the morphological characteristics of LEC.
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Affiliation(s)
- Yu Miyama
- Department of Pathology, Saitama Medical University International Medical Center, 1397-1, Yamane, Hidaka, Saitama, 350-1298, Japan.
| | - Tomomi Kato
- Department of Pathology, Saitama Medical University International Medical Center, 1397-1, Yamane, Hidaka, Saitama, 350-1298, Japan
| | - Masayasu Sato
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, 1397-1, Yamane, Hidaka, Saitama, 350-1298, Japan
| | - Akira Yabuno
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, 1397-1, Yamane, Hidaka, Saitama, 350-1298, Japan
| | - Kosei Hasegawa
- Department of Gynecologic Oncology, Saitama Medical University International Medical Center, 1397-1, Yamane, Hidaka, Saitama, 350-1298, Japan
| | - Masanori Yasuda
- Department of Pathology, Saitama Medical University International Medical Center, 1397-1, Yamane, Hidaka, Saitama, 350-1298, Japan
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14
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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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15
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Al-Nattah S, Matkovic E, Schwalbe M, Matkowskyj KA. Pathologic Features of Esophageal and Gastric Malignancies. Cancer Treat Res 2024; 192:19-48. [PMID: 39212914 DOI: 10.1007/978-3-031-61238-1_2] [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: 09/04/2024]
Abstract
Esophageal cancer is the eighth most common cancer globally, affecting approximately 570,000 people worldwide and currently ranking sixth among cancer-related mortality (Uhlenhopp et al. in, Clin J Gastroenterol 13:1010-1021, 2020). The prognosis is poor as many patients present with locally incurable or metastatic disease. In spite of advancements in treatment, the overall 5-year survival rates are in the realm of 10% whereas the 5-year post-esophagectomy survival rates are in the realm of 15-40% [2]. The incidence rates vary dramatically worldwide, which can be attributed to demographic and socioeconomic factors. Although the vast majority of esophageal neoplasms arise from the epithelial layer and include squamous cell carcinoma (SCC) and adenocarcinoma (AC), a subset of neuroendocrine and soft tissue tumors can also occur in the esophagus. Several tasks are presented to the surgical pathologist when dealing with esophageal carcinoma that include rendering a diagnosis, classifying the histological type, and assessing prognostic factors. This narrative review aims to evaluate current literature on various esophageal neoplasms and highlight pathological factors that impact clinical decision making and prognosis.
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Affiliation(s)
- Sanaa Al-Nattah
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
- Quest Diagnostics, Las Vegas, NV, USA
| | - Eduard Matkovic
- School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
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16
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Li J, Zhang Y, Luo B. The programed death-1/programed death ligand-1 axis and its potential as a therapeutic target for virus-associated tumours. Rev Med Virol 2024; 34:e2486. [PMID: 37905387 DOI: 10.1002/rmv.2486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2023] [Revised: 10/07/2023] [Accepted: 10/22/2023] [Indexed: 11/02/2023]
Abstract
As an important and serious condition impacting human health, the diagnosis, and treatment of tumours is clinically vital because tumour cell immune escape sustains tumour development. Programed death ligand-1 (PD-L1) on tumour cell surfaces binds to the programed death-1 (PD-1), inhibits T cell activation, and induces apoptosis, and incapacitates cells. This allows tumour cells to evade recognition and clearance by the immune system, thereby permitting tumour occurrence, and development and poor prognosis outcomes in patients with tumours. Currently, anti-PD-1/PD-L1 immunotherapy has become pivotal in tumour treatment. Pathogens, especially viruses, are important factors which induce many tumours. In this article, we examine associations between Epstein-Barr virus, human papilloma virus, hepatitis B virus, hepatitis C virus, and human immunodeficiency virus type 1-related tumours and PD-1/PD-L1 axis.
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Affiliation(s)
- Jing Li
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China
| | - Yan Zhang
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China
- Department of Clinical Laboratory, Zibo Central Hospital, Zibo, China
| | - Bing Luo
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao, China
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17
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Huang W, Bai L, Tang H. Epstein-Barr virus infection: the micro and macro worlds. Virol J 2023; 20:220. [PMID: 37784180 PMCID: PMC10546641 DOI: 10.1186/s12985-023-02187-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Accepted: 09/19/2023] [Indexed: 10/04/2023] Open
Abstract
Epstein‒Barr virus (EBV) is a DNA virus that belongs to the human B lymphotropic herpesvirus family and is highly prevalent in the human population. Once infected, a host can experience latent infection because EBV evades the immune system, leading to hosts harboring the virus for their lifetime. EBV is associated with many diseases and causes significant challenges to human health. This review first offers a description of the natural history of EBV infection, clarifies the interaction between EBV and the immune system, and finally focuses on several major types of diseases caused by EBV infection.
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Affiliation(s)
- Wei Huang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Lang Bai
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China.
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Hong Tang
- Center of Infectious Diseases, West China Hospital of Sichuan University, Chengdu, 610041, China.
- Division of Infectious Diseases, State Key Laboratory of Biotherapy and Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, 610041, China.
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18
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Lei Y, Cao P, Zheng X, Wei J, Cheng M, Liu M. Perspectives for immunotherapy of EBV-associated GLELC: A relatively "hot" tumor microenvironment. Cancer Med 2023; 12:19838-19849. [PMID: 37732493 PMCID: PMC10587976 DOI: 10.1002/cam4.6555] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 09/01/2023] [Accepted: 09/08/2023] [Indexed: 09/22/2023] Open
Abstract
BACKGROUND Epstein-Barr virus (EBV)-associated gastric lymphoepithelioma-like carcinoma (EBVaGLELC) represents a small number of gastric cancer (GC), and research on tumor microenvironment (TME) and treatment strategy are still lacking. AIMS Here, we aim to elucidate the immune features of this rare disease and further help to develop more effective treatment options. MATERIALS & METHODS A retrospective analysis was conducted between 2019 to 2022 in West China Hospital to reveal the immunological characteristics of EBV-positive GLELC. The difference of immune cell subset and tumor vascular structure between gastric denocarcinoma (GAC) and EBVaGLELC will be pointed out. DISCUSSION 13 patients with GELEC and 8 patients with GAC were retrospectively studied. The heterogeneity of the immune cell profile was then confirmed through multiplexed immunofluorescence staining (mIF), which revealed a higher proportion of CD3+ T cells, CD8+ T cells, and Treg cells in the EBV-associated GLELC group. Such a distinct TME may provide therapeutic advantages, and patients with this rare subtype of GC could be good candidates for immune checkpoint inhibitors (ICIs). Angiogenesis in EBV-positive GLELC may be less intense than that in gastric adenocarcinoma (GAC), a feature that might decrease their susceptibility to antiangiogenic therapy. Furthermore, we reported a 52-year-old male with advanced EBV-positive GLELC who showed a favorable response to the combined therapy with . A repeat evaluation showed sustained partial response (PR), and the progression-free survival (PFS) was more than 34 months until now. CONCLUSION Compared with GAC, EBVaGLELC revealed higher T cell infiltration and less intense of angiogenesis. It displays relatively "hot" TME that may provide the rationality to treat with immunotherapy in EBV-related GLELC.
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Affiliation(s)
- Yanna Lei
- Department of Gastric Cancer Center, West China HospitalSichuan UniversityChengduSichuanChina
- Department of Abdominal Oncology, West China HospitalSichuan UniversityChengduSichuanChina
| | - Peng Cao
- Department of Abdominal Oncology, West China HospitalSichuan UniversityChengduSichuanChina
- Department of Colorectal Cancer Center, West China HospitalSichuan UniversityChengduSichuanChina
| | - Xiufeng Zheng
- Department of Gastric Cancer Center, West China HospitalSichuan UniversityChengduSichuanChina
- Department of Abdominal Oncology, West China HospitalSichuan UniversityChengduSichuanChina
| | - Jing Wei
- Department of Gastric Cancer Center, West China HospitalSichuan UniversityChengduSichuanChina
- Department of Abdominal Oncology, West China HospitalSichuan UniversityChengduSichuanChina
| | - Mo Cheng
- Department of Gastric Cancer Center, West China HospitalSichuan UniversityChengduSichuanChina
- Department of Abdominal Oncology, West China HospitalSichuan UniversityChengduSichuanChina
| | - Ming Liu
- Department of Gastric Cancer Center, West China HospitalSichuan UniversityChengduSichuanChina
- Department of Abdominal Oncology, West China HospitalSichuan UniversityChengduSichuanChina
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19
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Wang Z, Liu Y, Niu X. Application of artificial intelligence for improving early detection and prediction of therapeutic outcomes for gastric cancer in the era of precision oncology. Semin Cancer Biol 2023; 93:83-96. [PMID: 37116818 DOI: 10.1016/j.semcancer.2023.04.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 04/12/2023] [Accepted: 04/24/2023] [Indexed: 04/30/2023]
Abstract
Gastric cancer is a leading contributor to cancer incidence and mortality globally. Recently, artificial intelligence approaches, particularly machine learning and deep learning, are rapidly reshaping the full spectrum of clinical management for gastric cancer. Machine learning is formed from computers running repeated iterative models for progressively improving performance on a particular task. Deep learning is a subtype of machine learning on the basis of multilayered neural networks inspired by the human brain. This review summarizes the application of artificial intelligence algorithms to multi-dimensional data including clinical and follow-up information, conventional images (endoscope, histopathology, and computed tomography (CT)), molecular biomarkers, etc. to improve the risk surveillance of gastric cancer with established risk factors; the accuracy of diagnosis, and survival prediction among established gastric cancer patients; and the prediction of treatment outcomes for assisting clinical decision making. Therefore, artificial intelligence makes a profound impact on almost all aspects of gastric cancer from improving diagnosis to precision medicine. Despite this, most established artificial intelligence-based models are in a research-based format and often have limited value in real-world clinical practice. With the increasing adoption of artificial intelligence in clinical use, we anticipate the arrival of artificial intelligence-powered gastric cancer care.
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Affiliation(s)
- Zhe Wang
- Department of Digestive Diseases 1, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang 110042, Liaoning, China
| | - Yang Liu
- Department of Gastric Surgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, Shenyang 110042, Liaoning, China.
| | - Xing Niu
- China Medical University, Shenyang 110122, Liaoning, China.
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20
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Reyes ME, Zanella L, Riquelme I, Buchegger K, Mora-Lagos B, Guzmán P, García P, Roa JC, Ili CG, Brebi P. Exploring the Genetic Diversity of Epstein-Barr Virus among Patients with Gastric Cancer in Southern Chile. Int J Mol Sci 2023; 24:11276. [PMID: 37511034 PMCID: PMC10378801 DOI: 10.3390/ijms241411276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/30/2023] [Accepted: 07/06/2023] [Indexed: 07/30/2023] Open
Abstract
The Epstein-Barr virus (EBV) has been associated with gastric cancer (GC), one of the deadliest malignancies in Chile and the world. Little is known about Chilean EBV strains. This study aims to investigate the frequency and genetic diversity of EBV in GC in patients in southern Chile. To evaluate the prevalence of EBV in GC patients from the Chilean population, we studied 54 GC samples using the gold standard detection method of EBV-encoded small RNA (EBER). The EBV-positive samples were subjected to amplification and sequencing of the Epstein-Barr virus nuclear protein 3A (EBNA3A) gene to evaluate the genetic diversity of EBV strains circulating in southern Chile. In total, 22.2% of the GC samples were EBV-positive and significantly associated with diffuse-type histology (p = 0.003). Phylogenetic analyses identified EBV-1 and EBV-2 in the GC samples, showing genetic diversity among Chilean isolates. This work provides important information for an epidemiological follow-up of the different EBV subtypes that may cause GC in southern Chile.
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Affiliation(s)
- María Elena Reyes
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Temuco 4810101, Chile
| | - Louise Zanella
- Doctorado en Ciencias Médicas, Universidad de La Frontera, Temuco 4811230, Chile
- Núcleo Milenio de Sociomedicina, Santiago 7560908, Chile
| | - Ismael Riquelme
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Temuco 4810101, Chile
| | - Kurt Buchegger
- Laboratory of Integrative Biology (LIBi), Millennium Institute on Immunology and Immunotherapy, Center of Excellence in Translational Medicine-Scientific and Technological Bioresource Nucleus-(-CEMT-BIOREN), Universidad de La Frontera, Temuco 4810296, Chile
- Departamento de Ciencias Básicas, Facultad de Medicina, Universidad de La Frontera, Temuco 4811322, Chile
| | - Bárbara Mora-Lagos
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Temuco 4810101, Chile
| | - Pablo Guzmán
- Pathology Department, School of Medicine, Universidad de La Frontera, Temuco 4781176, Chile
| | - Patricia García
- Millennium Institute on Immunology and Immunotherapy, Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Juan C Roa
- Millennium Institute on Immunology and Immunotherapy, Department of Pathology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330024, Chile
| | - Carmen Gloria Ili
- Laboratory of Integrative Biology (LIBi), Millennium Institute on Immunology and Immunotherapy, Center of Excellence in Translational Medicine-Scientific and Technological Bioresource Nucleus-(-CEMT-BIOREN), Universidad de La Frontera, Temuco 4810296, Chile
| | - Priscilla Brebi
- Laboratory of Integrative Biology (LIBi), Millennium Institute on Immunology and Immunotherapy, Center of Excellence in Translational Medicine-Scientific and Technological Bioresource Nucleus-(-CEMT-BIOREN), Universidad de La Frontera, Temuco 4810296, Chile
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21
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Comprehensive characterization of B7 family members in NSCLC and identification of its regulatory network. Sci Rep 2023; 13:4311. [PMID: 36922519 PMCID: PMC10017798 DOI: 10.1038/s41598-022-26776-w] [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: 12/06/2021] [Accepted: 12/20/2022] [Indexed: 03/17/2023] Open
Abstract
B7 family members act as co-stimulatory or co-inhibitory molecules in the adaptive immune system. Thisstudy aimed to investigate the dysregulation, prognostic value and regulatory network of B7 family members in non-small cell lung cancer (NSCLC). Data for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients were extracted from public databases. Patient prognosis was determined by Kaplan-Meier analysis. The downstream signaling pathways of B7 family were identified via GO and KEGG analysis. The key B7 related genes were selected by network, correlation and functional annotation analysis. Most B7 family members were dysregulated in LUAD and LUSC. The expression of B7-1/2/H3 and B7-H5 were significantly associated with overall survival in LUAD and LUSC, respectively. The major pathway affected by B7 family was the EGFR tyrosine kinase inhibitor resistance and ErbB signaling pathway. MAPK1, MAPK3 and MAP2K1 were pivotal B7 related genes in both LUAD and LUSC. This study reveals an overall dysregulation of B7 family members in NSCLC and highlights the potential of combination use of tyrosine kinase inhibitors or MEK/ERK inhibitors with B7 member blockade for NSCLC treatment.
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22
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Kondo A, Shinozaki-Ushiku A, Rokutan H, Kunita A, Ikemura M, Yamashita H, Seto Y, Nagae G, Tatsuno K, Aburatani H, Koinuma D, Ushiku T. Loss of viral genome with altered immune microenvironment during tumour progression of Epstein-Barr virus-associated gastric carcinoma. J Pathol 2023; 260:124-136. [PMID: 36806225 DOI: 10.1002/path.6067] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 01/15/2023] [Accepted: 02/15/2023] [Indexed: 02/20/2023]
Abstract
Epstein-Barr virus (EBV) is one of the major drivers of gastric carcinogenesis. EBV infection is established before tumour initiation and is generally maintained throughout tumour development; however, the significance of EBV in tumour maintenance and progression remains to be elucidated. Here, we report eight cases of EBV-associated gastric carcinoma (EBVaGC) with intratumoural heterogenous expression of EBV-encoded small RNA (EBER), a highly expressed latent gene of EBV, and demonstrate clinicopathological characteristics of these rare cases. By performing detailed histological assessment of EBER-positive and -negative components of each case, detection of EBV genome in tumour cells by fluorescence in situ hybridisation, TP73 methylation analysis, whole exome sequencing, and targeted gene panel sequencing, we identified tumours in two patients to be collision tumours of different origins. In the other six patients, some genetic/epigenetic alterations were shared between EBER-positive and -negative components, suggesting that EBV was eliminated from tumour cells during progression. Interestingly, in both tumour types, programmed death ligand 1 and intratumoural infiltration of CD8+ T lymphocytes were lower in EBER-negative than in EBER-positive components, suggesting an immunogenic role of EBV. To the best of our knowledge, this study is the first to demonstrate the detailed histological features and genetic/epigenetic alterations in EBVaGC with heterogenous EBER expression; the loss of EBV may benefit tumour progression and immune evasion and might be clinically important for selecting treatment strategies for such cancers. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Atsushi Kondo
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Aya Shinozaki-Ushiku
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Division of Integrative Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hirofumi Rokutan
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Akiko Kunita
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Next-Generation Precision Medicine Development Laboratory, and Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masako Ikemura
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroharu Yamashita
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Yasuyuki Seto
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Genta Nagae
- Genome Science and Medicine Laboratory, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Kenji Tatsuno
- Genome Science and Medicine Laboratory, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Aburatani
- Genome Science and Medicine Laboratory, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Daizo Koinuma
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Tetsuo Ushiku
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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23
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CD47-targeted immunotherapy unleashes antitumour immunity in Epstein-Barr virus-associated gastric cancer. Clin Immunol 2023; 247:109238. [PMID: 36690192 DOI: 10.1016/j.clim.2023.109238] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 01/11/2023] [Accepted: 01/13/2023] [Indexed: 01/21/2023]
Abstract
The aims of this study were to enhance the antitumour immunity in Epstein-Barr virus-associated gastric cancer (EBVaGC). We performed RNA-seq analysis to compare the differential expression genes between EBVaGC and EBV-negative gastric cancer (EBVnGC) patients. The expression levels of CD68, CD163 and CD47 were analyzed by immunohistochemistry. Different subsets of macrophages were investigated by a coincubation model. The effects of CD47 blockade were also detected. The expression levels of CD68, CD163 and CD47 were significantly higher in EBVaGC, and were associated with poor prognoses. Macrophages coincubated with EBV+ AGS cells tended to be immunosuppressed, which could be reversed by CD47 deficiency or blocking CD47. EBV resulted in cGAS-STING pathway activation, which stimulated CD47 expression and inhibited macrophage phagocytosis. Anti-CD47 therapy activated cGAS-STING signaling, which was responsible for production of IFN-β, resulting in activation of antitumour immunity. Our results provide a promising new strategy for CD47-targeted immunotherapy in EBVaGC.
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24
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Xue Y, Balci S, Pehlivanoglu B, Muraki T, Memis B, Saka B, Kim G, Bandyopadhyay S, Knight J, El-Rayes B, Kooby D, Maithel SK, Sarmiento J, Basturk O, Reid MD, Adsay V. Medullary carcinoma of the ampulla has distinct clinicopathologic characteristics including common association with microsatellite instability and PD-L1 expression. Hum Pathol 2023; 131:38-46. [PMID: 36502926 DOI: 10.1016/j.humpath.2022.12.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 11/13/2022] [Accepted: 12/05/2022] [Indexed: 12/14/2022]
Abstract
Medullary carcinomas have not yet been fully characterized in the ampulla. Here, 359 ampullary carcinomas (ACs) were reviewed and 11 medullary-type carcinomas (3%) were found and analyzed. In addition to the diagnostic medullary pattern, 6 showed focal mucinous and 8 had focal abortive gland-like formations. They occurred in younger patients (57 versus 65 y; P = .02), had larger invasion size (mean, 3.2 versus 1.9 cm; P = .01), formed nodular polypoid or plaque-like tumors, and often lacked preinvasive component. In addition to the lymphoplasmacytic infiltrates, they also had prominent eosinophils in 5 of 11 cases. Eight were papilla Vateri-NOS (not otherwise specified) tumors, 2 were ampullary-duodenal origin, 1 had a minor intra-ampullary papillary tubular neoplasm component, and none were ampullary-ductal. Although they had pushing-border infiltration, perineural and vascular invasion was common. They were strongly associated with DNA mismatch repair (MMR) protein deficient (7/11, 64%). The 5-yr survival rate (53%) appeared to be comparable with, and perhaps even better than that of nonmedullary ACs (47%), although this did not reach statistical significance (P = .47). Programmed cell death ligand-1 (PD-L1) expression levels were assessed in 8, and all 4 that were MMR deficient were positive both by combined positive score (CPS) ≥1 and tumor proportion score (TPS) ≥1, and of the 4 MMR proficient cases, 3 were positive by CPS; 2 by TPS. Overall, only 1 of the 8 available for analysis failed to show PD-L1 positivity by CPS. In contrast, nonmedullary MMR-deficient carcinomas expressed PD-L1 in only 33% of tumors by CPS, and none by TPS. One medullary carcinoma was also EBV associated. Unlike 'medullary carcinomas' of the kidney, INI1 was retained in all 8 cases tested. In conclusion, medullary carcinomas are 3% of ACs, have a strong association with MMR-D, and may be less aggressive despite their larger size. PD-L1 expression appears to be closely associated with medullary ACs regardless of MMR status, and thus targeted therapies can be considered for all medullary carcinomas of this site.
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Affiliation(s)
- Yue Xue
- Department of Pathology, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Serdar Balci
- Department of Pathology, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Burcin Pehlivanoglu
- Department of Pathology, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Takashi Muraki
- Department of Pathology, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Bahar Memis
- Department of Pathology, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Burcu Saka
- Department of Pathology, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Grace Kim
- Department of Pathology, University of California San Francisco, San Francisco, CA, 94143, USA
| | | | - Jessica Knight
- Department of Epidemiology and Biostatistics, University of Georgia, Athens, GA, 30606, USA
| | - Bassel El-Rayes
- Department of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - David Kooby
- Department of Surgery, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Shishir K Maithel
- Department of Surgery, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Juan Sarmiento
- Department of Surgery, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Olca Basturk
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, 10065, USA
| | - Michelle D Reid
- Department of Pathology, School of Medicine, Emory University, Atlanta, GA, 30322, USA
| | - Volkan Adsay
- Department of Pathology, Koc University Hospital, Davutpasa Caddesi No. 4, 34010 Topkapi, Istanbul, Turkey.
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25
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Möller K, Knöll M, Bady E, Schmerder MJ, Rico SD, Kluth M, Hube-Magg C, Blessin NC, Mandelkow T, Lennartz M, Menz A, Luebke AM, Höflmayer D, Fraune C, Bernreuther C, Lebok P, Uhlig R, Contreras H, Weidemann S, Gorbokon N, Jacobsen F, Clauditz TS, Steurer S, Burandt E, Minner S, Sauter G, Simon R, Marx AH, Krech T. PD-L1 expression and CD8 positive lymphocytes in human neoplasms: A tissue microarray study on 11,838 tumor samples. Cancer Biomark 2023; 36:177-191. [PMID: 36683495 PMCID: PMC9986704 DOI: 10.3233/cbm-220030] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Programmed death ligand 1 (PD-L1) is the target of immune checkpoint inhibitor therapies in a growing number of tumor types, but a unanimous picture on PD-L1 expression across cancer types is lacking. MATERIALS AND METHODS We analyzed immunohistochemical PD-L1 expression in 11,838 samples from 118 human tumor types and its relationship with tumor infiltrating CD8 positive lymphocytes. RESULTS At a cut-off level of 10% positive tumor cells, PD-L1 positivity was seen in 85 of 118 (72%) tumor types, including thymoma (100% positive), Hodgkin's lymphoma (93%), anaplastic thyroid carcinoma (76%), Kaposi sarcoma (71%), sarcomatoid urothelial carcinoma (71%), and squamous cell carcinoma of the penis (67%), cervix (65%), floor of the mouth (61%), the lung (53%), and pharynx (50%). In immune cells, PD-L1 positivity was detectable in 103 (87%) tumor types, including tumors of haematopoetic and lymphoid tissues (75% to 100%), Warthin tumors of the parotid glands (95%) and Merkel cell carcinoma (82%). PD-L1 positivity in tumor cells was significantly correlated with the number of intratumoral CD8 positive lymphocytes across all tumor types as well as in individual tumor types, including serous carcinoma of the ovary, invasive breast carcinoma of no special type, intestinal gastric adenocarcinoma, and liposarcoma (p< 0.0001 each). CONCLUSIONS PD-L1 expression in tumor and inflammatory cells is found in a wide range of human tumor types. Higher rates of tumor infiltrating CD8 positive lymphocytes in PD-L1 positive than in PD-L1 negative cancers suggest that the antitumor immune response may trigger tumoral PD-L1 expression.
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Affiliation(s)
- Katharina Möller
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Madeleine Knöll
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Elena Bady
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | | | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Niclas C Blessin
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Tim Mandelkow
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Maximilian Lennartz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anne Menz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas M Luebke
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Doris Höflmayer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Bernreuther
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Patrick Lebok
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ria Uhlig
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Hendrina Contreras
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sören Weidemann
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Natalia Gorbokon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Till S Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas H Marx
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.,Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
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26
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Yoshida T, Ogura G, Tanabe M, Hayashi T, Ohbayashi C, Azuma M, Kunisaki C, Akazawa Y, Ozawa S, Matsumoto S, Suzuki T, Mitoro A, Fukunaga T, Shimizu A, Fujimoto G, Yao T. Clinicopathological features of PD-L1 protein expression, EBV positivity, and MSI status in patients with advanced gastric and esophagogastric junction adenocarcinoma in Japan. Cancer Biol Ther 2022; 23:191-200. [PMID: 35220884 PMCID: PMC8890430 DOI: 10.1080/15384047.2022.2038002] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
This real-world study examined the prevalence of programmed death ligand-1 (PD-L1) expression and assessed the frequency of microsatellite instability-high (MSI-H) status and Epstein-Barr virus (EBV) positivity in Japanese patients with advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. This multicenter (5 sites), retrospective, observational study (November 2018–March 2019) evaluated Japanese patients with advanced gastric and GEJ adenocarcinoma after surgical resection (Stage II/III at initial diagnosis) or unresectable advanced cancer (Stage IV). The primary objectives were prevalence of PD-L1 expression (combined positive score [CPS] ≥1), MSI status, and EBV positivity. Tumor specimens of 389/391 patients were analyzed (male, 67.1%; mean age, 67.6 ± 12.2 years); 241/389 (62%) were PD-L1 positive, 24/379 (6.3%) had MSI-H tumors, and 13/389 (3.3%) were EBV positive. PD-L1 expression was higher in tumor-infiltrating immune cells than in tumor cells for lower CPS cutoffs. Among patients with MSI-H tumors and EBV-positive tumors, 19/24 (79.2%) and 9/13 (69.2%), respectively, were PD-L1 positive. A greater proportion of patients with MSI-H tumors (83.3% [20/24]) were PD-L1 positive than those with MSI-low/stable tumors (60.8% [216/355]; p = .0297); similarly, an association was observed between history of H pylori infection and PD-L1 expression. A higher proportion of patients with MSI-H tumors demonstrated PD-L1 expression with a CPS ≥10 (66.7% [16/24]) vs those with MSI-low/stable tumors (24.8% [88/355]; p < .0001). The prevalence of PD-L1 positivity among Japanese patients was comparable to that in previous pembrolizumab clinical trials and studies in gastric cancer. Particularly, higher PD-L1 expression was observed in MSI-H tumors.
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Affiliation(s)
- Tsutomu Yoshida
- Department of Pathology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Go Ogura
- Department of Pathology, Tokai University School of Medicine, Isehara, Japan
| | - Mikiko Tanabe
- Division of Diagnostic Pathology, Yokohama City University Medical Center, Yokohama, Japan
| | - Takuo Hayashi
- Department of Diagnostic Pathology, Main Hospital, Juntendo University, Tokyo, Japan
| | - Chiho Ohbayashi
- Department of Diagnostic Pathology, Nara Medical University, Kashihara, Japan
| | - Mizutomo Azuma
- Department of Gastroenterology, Kitasato University School of Medicine, Sagamihara, Japan
| | - Chikara Kunisaki
- Department of Surgery, Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
| | - Yoichi Akazawa
- Department of Gastroenterology, School of Medicine, Juntendo University, Tokyo, Japan
| | - Soji Ozawa
- Department of Gastroenterological Surgery, Tokai University School of Medicine, Isehara, Japan
| | - Sohei Matsumoto
- Department of Surgery, Nara Medical University, Kashihara, Japan
| | - Takayoshi Suzuki
- Division of Gastroenterology and Hepatology, Tokai University School of Medicine, Tokai University, Isehara, Japan
| | - Akira Mitoro
- Department of Gastroenterology, Nara Medical University, Kashihara, Japan
| | - Tetsu Fukunaga
- Department of Gastroenterology and Minimally Invasive Surgery, School of Medicine, Juntendo University, Tokyo, Japan
| | | | | | - Takashi Yao
- Department of Human Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
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27
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Zhou H, Jing S, Liu Y, Wang X, Duan X, Xiong W, Li R, Peng Y, Ai Y, Fu D, Wang H, Zhu Y, Zeng Z, He Y, Ye Q. Identifying the key genes of Epstein-Barr virus-regulated tumour immune microenvironment of gastric carcinomas. Cell Prolif 2022; 56:e13373. [PMID: 36519208 PMCID: PMC9977676 DOI: 10.1111/cpr.13373] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Revised: 11/15/2022] [Accepted: 11/21/2022] [Indexed: 12/23/2022] Open
Abstract
The Epstein-Barr virus (EBV) is involved in the carcinogenesis of gastric cancer (GC) upon infection of normal cell and induces a highly variable composition of the tumour microenvironment (TME). However, systematic bioinformatics analysis of key genes associated with EBV regulation of immune infiltration is still lacking. In the present study, the TCGA and GEO databases were recruited to analyse the association between EBV infection and the profile of immune infiltration in GC. The weighted gene co-expression analysis (WGCNA) was applied to shed light on the key gene modules associated with EBV-associated immune infiltration in GC. 204 GC tissues were used to analysed the expression of key hub genes by using the immunohistochemical method. Real-time PCR was used to evaluate the association between the expression of EBV latent/lytic genes and key immune infiltration genes. Our results suggested that EBV infection changed the TME of GC mainly regulates the TIICs. The top three hub genes of blue (GBP1, IRF1, and LAP3) and brown (BIN2, ITGAL, and LILRB1) modules as representative genes were associated with EBV infection and GC immune infiltration. Furthermore, EBV-encoded LMP1 expression is account for the overexpression of GBP1 and IRF1. EBV infection significantly changes the TME of GC, and the activation of key immune genes was more dependent on the invasiveness of the whole EBV virion instead of single EBV latent/lytic gene expression.
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Affiliation(s)
- Heng Zhou
- Center of Regenerative Medicine & Department of StomatologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Shuili Jing
- Center of Regenerative Medicine & Department of StomatologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Yu Liu
- College of Life and Health Sciences, Institute of Biology and MedicineWuhan University of Science and TechnologyWuhanHubeiChina
| | - Xuming Wang
- Department of PathologyGuilin Medical UniversityGuilinGuangxiChina
| | - Xingxiang Duan
- Center of Regenerative Medicine & Department of StomatologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Wei Xiong
- Center of Regenerative Medicine & Department of StomatologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Ruohan Li
- Center of Regenerative Medicine & Department of StomatologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Youjian Peng
- Center of Regenerative Medicine & Department of StomatologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Yilong Ai
- Foshan Hospital of Stomatology, School of Medicine, Foshan UniversityFoshanGuangdongChina
| | - Dehao Fu
- Department of Orthopaedics, Shanghai General HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Hui Wang
- Demonstration Center for Experimental Basic Medicine Education, Wuhan UniversityWuhanChina
| | - Yaoqi Zhu
- Institute of Regenerative and Translational MedicineTianyou Hospital of Wuhan University of Science and TechnologyWuhanHubeiChina,Department of oral and maxillofacial surgeryHospital of Taikang Tongji (Wuhan)WuhanChina
| | - Zhi Zeng
- Department of PathologyRenmin Hospital of Wuhan UniversityWuhanChina
| | - Yan He
- Institute of Regenerative and Translational MedicineTianyou Hospital of Wuhan University of Science and TechnologyWuhanHubeiChina,Department of oral and maxillofacial surgery, Massachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
| | - Qingsong Ye
- Center of Regenerative Medicine & Department of StomatologyRenmin Hospital of Wuhan UniversityWuhanChina,Department of oral and maxillofacial surgery, Massachusetts General HospitalHarvard Medical SchoolBostonMassachusettsUSA
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28
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Deep learning model to predict Epstein-Barr virus associated gastric cancer in histology. Sci Rep 2022; 12:18466. [PMID: 36323712 PMCID: PMC9630260 DOI: 10.1038/s41598-022-22731-x] [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: 03/30/2022] [Accepted: 10/18/2022] [Indexed: 11/20/2022] Open
Abstract
The detection of Epstein-Barr virus (EBV) in gastric cancer patients is crucial for clinical decision making, as it is related with specific treatment responses and prognoses. Despite its importance, the limited medical resources preclude universal EBV testing. Herein, we propose a deep learning-based EBV prediction method from H&E-stained whole-slide images (WSI). Our model was developed using 319 H&E stained WSI (26 EBV positive; TCGA dataset) from the Cancer Genome Atlas, and 108 WSI (8 EBV positive; ISH dataset) from an independent institution. Our deep learning model, EBVNet consists of two sequential components: a tumor classifier and an EBV classifier. We visualized the learned representation by the classifiers using UMAP. We externally validated the model using 60 additional WSI (7 being EBV positive; HGH dataset). We compared the model's performance with those of four pathologists. EBVNet achieved an AUPRC of 0.65, whereas the four pathologists yielded a mean AUPRC of 0.41. Moreover, EBVNet achieved an negative predictive value, sensitivity, specificity, precision, and F1-score of 0.98, 0.86, 0.92, 0.60, and 0.71, respectively. Our proposed model is expected to contribute to prescreen patients for confirmatory testing, potentially to save test-related cost and labor.
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29
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Chen S, Chen X, Zhang P, Chen S, Wang X, Luo Q, Cui Z, Huang Y, Wan L, Hou X, Yao H, Liu X, He A, Jiang Z, Qiu J, Li Y, Yu K, Zhuang J. Bioinformatics Analysis and Experimental Identification of Immune-Related Genes and Immune Cells in the Progression of Retinoblastoma. Invest Ophthalmol Vis Sci 2022; 63:28. [PMID: 36315123 PMCID: PMC9631497 DOI: 10.1167/iovs.63.11.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Purpose Retinoblastoma (RB) is the most common type of aggressive intraocular malignancy in children. The alteration of immunity during RB progression and invasion has not yet been well defined. This study investigated significantly altered immune-associated genes and cells related to RB invasion. Methods The differentially expressed immune-related genes (IRGs) in noninvasive RB and invasive RB were identified by analysis of two microarray datasets (GSE97508 and GSE110811). Hub IRGs were further identified by real time PCR. The single-sample gene set enrichment analysis algorithm and Pearson correlation analysis were used to define immune cell infiltration and the relationships between hub IRGs and immune cells. Cell viability and migration were evaluated by CCK-8 and Transwell assays. A xenograft mouse model was used to verify the relationship between Src homology 3 (SH3) domain GRB2-like 2 (SH3GL2) expression and myeloid-derived suppressor cells (MDSCs). Results Eight upregulated genes and six downregulated IRGs were identified in invasive RB. Seven IRGs were confirmed by real-time PCR. Moreover, the proportions of MDSCs were higher in invasive RB tissues than in noninvasive RB tissues. Furthermore, correlation analysis of altered immune genes and cells suggested that SH3GL2, Langerhans cell protein 1 (LCP1) and transmembrane immune signaling adaptor TYROBP have strong connections with MDSCs. Specifically, decreased SH3GL2 expression promoted the migration of RB cells in vitro, increased the tumor size and weight, and increased the numbers of MDSCs in the tumor and spleen in vivo. Conclusions This study indicated that SH3GL2 and MDSCs play a critical role in RB progression and invasion and provide candidate targets for the treatment of RB.
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Affiliation(s)
- Shuilian Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Xi Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Ping Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Shuxia Chen
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Xiao Wang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Qian Luo
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Zedu Cui
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Yuke Huang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Linxi Wan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Xiangtao Hou
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Huan Yao
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Xuan Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Anqi He
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Zihua Jiang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Jin Qiu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Yan Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Keming Yu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
| | - Jing Zhuang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou City, China
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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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31
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Deng SZ, Wang XX, Zhao XY, Bai YM, Zhang HM. Exploration of the Tumor Immune Landscape and Identification of Two Novel Immunotherapy-Related Genes for Epstein-Barr virus-associated Gastric Carcinoma via Integrated Bioinformatics Analysis. Front Surg 2022; 9:898733. [PMID: 36090326 PMCID: PMC9450882 DOI: 10.3389/fsurg.2022.898733] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 04/27/2022] [Indexed: 11/17/2022] Open
Abstract
Epstein–Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a specific molecular subtype of gastric carcinoma with a high proportion of tumor-infiltrating lymphocytes. It is a highly immunogenic tumor that may benefit from immunotherapy. Hence, it is imperative to analyze the immune landscape and identify immunotherapy biomarkers for EBVaGC. In our study, we investigated the immune landscape and identified 10 hub genes for EBVaGC via integrated bioinformatics analysis. We found that EBVaGC expressed more immune-related genes, including common immune checkpoints and human leukocyte antigen (HLA) genes than EBV-negative gastric carcinoma (EBVnGC). The immune score in EBVaGC was higher, which means EBVaGC has greater immune cell infiltration. Ten hub genes (CD4, STAT1, FCGR3A, IL10, C1QA, CXCL9, CXCL10, CXCR6, PD-L1, and CCL18) were detected as candidate biomarkers for EBVaGC. Two hub genes, CXCL9 and CXCR6, were identified as novel immunotherapy-related genes. Taken together, the results of our comprehensive analysis of the immune microenvironment of EBVaGC revealed its unique immune landscape, demonstrating that it is a highly immunogenic tumor. Moreover, we identified hub genes that may serve as potential immunotherapy biomarkers for EBVaGC.
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Affiliation(s)
- Shi-Zhou Deng
- Department of Clinical Oncology, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Xiang-Xu Wang
- Department of Clinical Oncology, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Xing-Yu Zhao
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Air Force Medical University, Xi’an, China
| | - Yin-Miao Bai
- Department of Clinical Oncology, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Hong-Mei Zhang
- Department of Clinical Oncology, Xijing Hospital, Air Force Medical University, Xi’an, China
- Correspondence: Hong-Mei Zhang
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32
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A deep learning model and human-machine fusion for prediction of EBV-associated gastric cancer from histopathology. Nat Commun 2022; 13:2790. [PMID: 35589792 PMCID: PMC9120175 DOI: 10.1038/s41467-022-30459-5] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 05/03/2022] [Indexed: 11/22/2022] Open
Abstract
Epstein–Barr virus-associated gastric cancer (EBVaGC) shows a robust response to immune checkpoint inhibitors. Therefore, a cost-efficient and accessible tool is needed for discriminating EBV status in patients with gastric cancer. Here we introduce a deep convolutional neural network called EBVNet and its fusion with pathologists for predicting EBVaGC from histopathology. The EBVNet yields an averaged area under the receiver operating curve (AUROC) of 0.969 from the internal cross validation, an AUROC of 0.941 on an external dataset from multiple institutes and an AUROC of 0.895 on The Cancer Genome Atlas dataset. The human-machine fusion significantly improves the diagnostic performance of both the EBVNet and the pathologist. This finding suggests that our EBVNet could provide an innovative approach for the identification of EBVaGC and may help effectively select patients with gastric cancer for immunotherapy. Epstein–Barr virus-associated gastric cancer shows a robust response to immune checkpoint inhibitors. Here the authors introduce a deep convolutional neural network and its fusion with pathologists for predicting it from histopathology.
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33
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Immunosuppressive Tumor Microenvironment and Immunotherapy of Epstein–Barr Virus-Associated Malignancies. Viruses 2022; 14:v14051017. [PMID: 35632758 PMCID: PMC9146158 DOI: 10.3390/v14051017] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/03/2022] [Accepted: 05/09/2022] [Indexed: 02/07/2023] Open
Abstract
The Epstein–Barr virus (EBV) can cause different types of cancer in human beings when the virus infects different cell types with various latent patterns. EBV shapes a distinct and immunosuppressive tumor microenvironment (TME) to its benefit by influencing and interacting with different components in the TME. Different EBV-associated malignancies adopt similar but slightly specific immunosuppressive mechanisms by encoding different EBV products to escape both innate and adaptive immune responses. Strategies reversing the immunosuppressive TME of EBV-associated malignancies have been under evaluation in clinical practice. As the interactions among EBV, tumor cells, and TME are intricate, in this review, we mainly discuss the epidemiology of EBV, the life cycle of EBV, the cellular and molecular composition of TME, and a landscape of different EBV-associated malignancies and immunotherapy by targeting the TME.
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34
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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: 25] [Impact Index Per Article: 8.3] [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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35
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Chen Q, Hu J, Hu X, Koh K, Chen H. Current methods and emerging approaches for detection of programmed death ligand 1. Biosens Bioelectron 2022; 208:114179. [PMID: 35364526 DOI: 10.1016/j.bios.2022.114179] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 02/21/2022] [Accepted: 03/08/2022] [Indexed: 02/08/2023]
Abstract
Various tumor cells overexpress programmed death ligand 1 (PD-L1), a main immune checkpoint protein (ICP) embedded in the tumor cells membrane, to evade immune recognition through the interaction between PD-L1 and its receptor programmed death 1 (PD-1) which is from T-cells for maintaining immune tolerance. So inhibitors targeting the PD-1 or PD-L1 can block the PD-1/PD-L1 signaling pathway to restore the recognition activity of the immune system to tumor cells, which also have been utilized as a novel approach to improve the clinical therapeutic effect for cancer patients. Since not all cancer patients can respond to these inhibitors effectively, previous diagnosis of PD-L1 is significant to target the right treatments for cancer patients. This review pays attention to the PD-L1 detection and recent progress in the measurement of PD-L1 concentration, including various detection methods based on optical sensors as well as electrochemical assays. Apart from above those, we also focus on the prospects of PD-L1 detection in precision medicine.
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Affiliation(s)
- Qiang Chen
- School of Life Sciences, Shanghai University, Shanghai, 200444, PR China; School of Medicine, Shanghai University, Shanghai, 200444, PR China
| | - Junjie Hu
- School of Life Sciences, Shanghai University, Shanghai, 200444, PR China
| | - Xiaojun Hu
- School of Life Sciences, Shanghai University, Shanghai, 200444, PR China
| | - Kwangnak Koh
- Institute of General Education, Pusan National University, Busan, 609-735, Republic of Korea
| | - Hongxia Chen
- School of Life Sciences, Shanghai University, Shanghai, 200444, PR China.
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36
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Saleh RR, Scott JL, Meti N, Perlon D, Fazelzad R, Ocana A, Amir E. Prognostic Value of Programmed Death Ligand-1 Expression in Solid Tumors Irrespective of Immunotherapy Exposure: A Systematic Review and Meta-Analysis. Mol Diagn Ther 2022; 26:153-168. [PMID: 35106739 DOI: 10.1007/s40291-022-00576-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/04/2022] [Indexed: 10/19/2022]
Abstract
BACKGROUND The programmed cell death-1/programmed cell death ligand-1 (PD-L1) pathway, which plays a crucial role in cancer immune surveillance, is the target of several approved immunotherapeutic agents and is used as a predictive biomarker in some solid tumors. However, its use as a prognostic marker (i.e., regardless of therapy used) is not established clearly with available data demonstrating inconsistent prognostic impact of PD-L1 expression in solid tumors. METHODS We conducted a systematic literature search of electronic databases and identified publications exploring the effect of PD-L1 expression on overall survival and/or disease-free survival. Hazard ratios were pooled in a meta-analysis using generic inverse-variance and random-effects modeling. We used the Deeks method to explore subgroup differences based on disease site, stage of disease, and method of PD-L1 quantification. RESULTS One hundred and eighty-six studies met the inclusion criteria. Programmed cell death ligand-1 expression was associated with worse overall survival (hazard ratio 1.33, 95% confidence interval 1.26-1.39; p < 0.001). There was significant heterogeneity between disease sites (subgroup p = 0.002) with pancreatic, hepatocellular, and genitourinary cancers associated with the highest magnitude of adverse outcomes. Programmed cell death ligand-1 was also associated with worse overall disease-free survival (hazard ratio 1.19, 95% confidence interval 1.09-1.30; p < 0.001). Stage of disease did not significantly affect the results (subgroup p = 0.52), nor did the method of quantification via immunohistochemistry or messenger RNA (subgroup p = 0.70). CONCLUSIONS High expression of PD-L1 is associated with worse survival in solid tumors albeit with significant heterogeneity among tumor types. The effect is consistent in early-stage and metastatic disease and is not sensitive to method of PD-L1 quantification. These data can provide additional information for the counseling of patients with cancer about prognosis.
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Affiliation(s)
- Ramy R Saleh
- Department of Medical Oncology, McGill University, Montreal, QC, Canada
| | - Jordan L Scott
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, ON, Canada
| | - Nicholas Meti
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, ON, Canada
| | - Danielle Perlon
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, ON, Canada
| | - Rouhi Fazelzad
- Information Specialist, Library and Information Services, Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Alberto Ocana
- Hospital Clinico San Carlos and Instituto de Investigación Sanitaria San Carlos (IdISSC), and Centro Regional de Investigaciones Biomedicas (CRIB), Centro de Investigación Biomédica en Red Cáncerci (CIBERONC), Universidad Castilla La Mancha (UCLM), Madrid, Spain
| | - Eitan Amir
- Division of Medical Oncology and Hematology, Department of Medicine, Princess Margaret Cancer Centre and the University of Toronto, Toronto, ON, Canada.
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37
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Paschold L, Binder M. Circulating Tumor DNA in Gastric and Gastroesophageal Junction Cancer. Curr Oncol 2022; 29:1430-1441. [PMID: 35323320 PMCID: PMC8947276 DOI: 10.3390/curroncol29030120] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 02/15/2022] [Accepted: 02/20/2022] [Indexed: 12/21/2022] Open
Abstract
Tumor cells shed DNA into the plasma. “Liquid biopsy” analysis of mutations or other genomic alterations in circulating cell-free DNA (cfDNA) may provide us with a tool to detect minimal residual cancer, comprehensively profile the genomic tumor landscape in search of druggable targets, and monitor cancers non-invasively over time for treatment failure or emerging treatment-resistant tumor subclones. While liquid biopsies have not yet entered routine clinical management in patients with gastric and gastroesophageal junction cancers, this group of diseases may benefit from such advanced diagnostic tools due to their pronounced genetic spatiotemporal heterogeneity and limitations in imaging sensitivity. Moreover, as the armamentarium of targeted treatment approaches and immunotherapies expands, cfDNA analyses may reveal their utility not only as a biomarker of response but also for precision monitoring. In this review, we discuss the different applications of cfDNA analyses in patients with gastric and gastroesophageal junction cancer and the technical challenges that such liquid biopsies have yet to overcome.
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Affiliation(s)
| | - Mascha Binder
- Correspondence: ; Tel.: +49-345-557-4972; Fax: +49-345-557-2950
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38
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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: 4] [Impact Index Per Article: 1.3] [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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39
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Watson S, Cyrta J, Lefevre M, Planchon JM, Louvet C, Servois V, Vaflard P, Bidard FC, Bieche I, Soularue E. Hyperprogressive Disease After Pembrolizumab Treatment in Advanced Epstein-Barr Virus-Associated Gastric Adenocarcinoma With ERBB2 Amplification. JCO Precis Oncol 2022; 5:370-377. [PMID: 34994599 DOI: 10.1200/po.20.00272] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Sarah Watson
- Institut Curie, PSL Research University, Department of Medical Oncology, Paris, France.,Institut Curie, PSL Research University, INSERM U830, Cancer, Heterogeneity, Instability and Plasticity (CHIP), Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France
| | - Joanna Cyrta
- Institut Curie, PSL Research University, Department of Pathology, Paris, France
| | - Marine Lefevre
- Institut Mutualiste Montsouris, Department of Pathology, Paris, France
| | | | - Christophe Louvet
- Institut Mutualiste Montsouris, Department of Medical Oncology, Paris, France
| | - Vincent Servois
- Institut Curie, PSL Research University, Department of Radiology, Paris, France
| | - Pauline Vaflard
- Institut Curie, PSL Research University, Department of Medical Oncology, Paris, France
| | | | - Ivan Bieche
- Institut Curie, PSL Research University, Department of Genetics, Paris, France
| | - Emilie Soularue
- Institut Mutualiste Montsouris, Department of Medical Oncology, Paris, France
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40
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Yu HY, Li CP, Huang YH, Hsu SJ, Wang YP, Hsieh YC, Fang WL, Huang KH, Li AFY, Lee RC, Lee KL, Wu YH, Lai IC, Yang WC, Hung YP, Wang YC, Chen SH, Chen MH, Chao Y. Microsatellite Instability, Epstein-Barr Virus, and Programmed Cell Death Ligand 1 as Predictive Markers for Immunotherapy in Gastric Cancer. Cancers (Basel) 2022; 14:218. [PMID: 35008382 PMCID: PMC8750088 DOI: 10.3390/cancers14010218] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/28/2021] [Accepted: 12/30/2021] [Indexed: 12/17/2022] Open
Abstract
Immunotherapy benefits selected cases of gastric cancer (GC), but the correlation between biomarkers and prognosis is still unclear. Fifty-two patients with GC who underwent immunotherapy were enrolled from June 2016 to December 2020. Their clinical features and biomarkers-microsatellite instability-high (MSI-H), programmed cell death ligand 1 (PD-L1) combined positive score (CPS), and Epstein-Barr encoding region (EBER)-were analyzed. Eight patients had MSI-H, five patients had EBER, 29 patients had CPS ≥ 1, and 20 patients had no biomarker. The overall response rates (ORRs) of the MSI-H, EBER, PD-L1 CPS ≥ 1, and all-negative group were 75%, 60%, 44.8%, and 15%, respectively. Compared with that of the all-negative group, progression-free survival (PFS) was better in the MSI-H (p = 0.018), CPS ≥ 5 (p = 0.012), and CPS ≥ 10 (p = 0.006) groups, but not in the EBER (p = 0.2) and CPS ≥ 1 groups (p = 0.35). Ten patients had combined biomarkers, CPS ≥ 1 with either MSI-H or EBER. The ORRs were 66.7% for CPS ≥ 1 and MSI-H and 75% for CPS ≥ 1 and EBER. PFS was better in patients with combined biomarkers (p = 0.01). MSI-H, EBER, and CPS are useful biomarkers for predicting the efficacy of immunotherapy.
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Affiliation(s)
- Hung-Yuan Yu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (H.-Y.Y.); (C.-P.L.); (Y.-H.H.); (S.-J.H.); (Y.-P.W.); (Y.-C.H.)
- Hospitalist Ward, Department of Medicine, Taipei Veterans General Hospital, Taipei 112201, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (W.-L.F.); (K.-H.H.); (A.F.-Y.L.); (R.-C.L.); (K.-L.L.); (Y.-H.W.); (I.-C.L.); (W.-C.Y.); (Y.-P.H.)
| | - Chung-Pin Li
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (H.-Y.Y.); (C.-P.L.); (Y.-H.H.); (S.-J.H.); (Y.-P.W.); (Y.-C.H.)
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (W.-L.F.); (K.-H.H.); (A.F.-Y.L.); (R.-C.L.); (K.-L.L.); (Y.-H.W.); (I.-C.L.); (W.-C.Y.); (Y.-P.H.)
- Division of Clinical Skills Training, Department of Medical Education, Taipei Veterans General Hospital, Taipei 112201, Taiwan
| | - Yi-Hsiang Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (H.-Y.Y.); (C.-P.L.); (Y.-H.H.); (S.-J.H.); (Y.-P.W.); (Y.-C.H.)
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (W.-L.F.); (K.-H.H.); (A.F.-Y.L.); (R.-C.L.); (K.-L.L.); (Y.-H.W.); (I.-C.L.); (W.-C.Y.); (Y.-P.H.)
| | - Shao-Jung Hsu
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (H.-Y.Y.); (C.-P.L.); (Y.-H.H.); (S.-J.H.); (Y.-P.W.); (Y.-C.H.)
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (W.-L.F.); (K.-H.H.); (A.F.-Y.L.); (R.-C.L.); (K.-L.L.); (Y.-H.W.); (I.-C.L.); (W.-C.Y.); (Y.-P.H.)
| | - Yen-Po Wang
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (H.-Y.Y.); (C.-P.L.); (Y.-H.H.); (S.-J.H.); (Y.-P.W.); (Y.-C.H.)
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (W.-L.F.); (K.-H.H.); (A.F.-Y.L.); (R.-C.L.); (K.-L.L.); (Y.-H.W.); (I.-C.L.); (W.-C.Y.); (Y.-P.H.)
| | - Yun-Cheng Hsieh
- Division of Gastroenterology and Hepatology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112201, Taiwan; (H.-Y.Y.); (C.-P.L.); (Y.-H.H.); (S.-J.H.); (Y.-P.W.); (Y.-C.H.)
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (W.-L.F.); (K.-H.H.); (A.F.-Y.L.); (R.-C.L.); (K.-L.L.); (Y.-H.W.); (I.-C.L.); (W.-C.Y.); (Y.-P.H.)
| | - Wen-Liang Fang
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (W.-L.F.); (K.-H.H.); (A.F.-Y.L.); (R.-C.L.); (K.-L.L.); (Y.-H.W.); (I.-C.L.); (W.-C.Y.); (Y.-P.H.)
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112201, Taiwan
| | - Kuo-Hung Huang
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (W.-L.F.); (K.-H.H.); (A.F.-Y.L.); (R.-C.L.); (K.-L.L.); (Y.-H.W.); (I.-C.L.); (W.-C.Y.); (Y.-P.H.)
- Division of General Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112201, Taiwan
| | - Anna Fen-Yau Li
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (W.-L.F.); (K.-H.H.); (A.F.-Y.L.); (R.-C.L.); (K.-L.L.); (Y.-H.W.); (I.-C.L.); (W.-C.Y.); (Y.-P.H.)
- Department of Pathology, Taipei Veterans General Hospital, Taipei 112201, Taiwan
| | - Rheun-Chuan Lee
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (W.-L.F.); (K.-H.H.); (A.F.-Y.L.); (R.-C.L.); (K.-L.L.); (Y.-H.W.); (I.-C.L.); (W.-C.Y.); (Y.-P.H.)
- Department of Radiology, Taipei Veterans General Hospital, Taipei 112201, Taiwan
| | - Kang-Lung Lee
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (W.-L.F.); (K.-H.H.); (A.F.-Y.L.); (R.-C.L.); (K.-L.L.); (Y.-H.W.); (I.-C.L.); (W.-C.Y.); (Y.-P.H.)
- Department of Radiology, Taipei Veterans General Hospital, Taipei 112201, Taiwan
| | - Yuan-Hung Wu
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (W.-L.F.); (K.-H.H.); (A.F.-Y.L.); (R.-C.L.); (K.-L.L.); (Y.-H.W.); (I.-C.L.); (W.-C.Y.); (Y.-P.H.)
- Department of Oncology, Taipei Veterans General Hospital, Taipei 112201, Taiwan
| | - I-Chun Lai
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (W.-L.F.); (K.-H.H.); (A.F.-Y.L.); (R.-C.L.); (K.-L.L.); (Y.-H.W.); (I.-C.L.); (W.-C.Y.); (Y.-P.H.)
- Department of Oncology, Taipei Veterans General Hospital, Taipei 112201, Taiwan
| | - Wan-Chin Yang
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (W.-L.F.); (K.-H.H.); (A.F.-Y.L.); (R.-C.L.); (K.-L.L.); (Y.-H.W.); (I.-C.L.); (W.-C.Y.); (Y.-P.H.)
- Department of Oncology, Taipei Veterans General Hospital, Taipei 112201, Taiwan
| | - Yi-Ping Hung
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (W.-L.F.); (K.-H.H.); (A.F.-Y.L.); (R.-C.L.); (K.-L.L.); (Y.-H.W.); (I.-C.L.); (W.-C.Y.); (Y.-P.H.)
- Department of Oncology, Taipei Veterans General Hospital, Taipei 112201, Taiwan
| | - Yu-Chao Wang
- Institute of Biomedical Informatics, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan;
| | - Shu-Hui Chen
- Department of Nursing, Taipei Veterans General Hospital, Taipei 112201, Taiwan;
| | - Ming-Huang Chen
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (W.-L.F.); (K.-H.H.); (A.F.-Y.L.); (R.-C.L.); (K.-L.L.); (Y.-H.W.); (I.-C.L.); (W.-C.Y.); (Y.-P.H.)
- Department of Oncology, Taipei Veterans General Hospital, Taipei 112201, Taiwan
| | - Yee Chao
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112201, Taiwan; (W.-L.F.); (K.-H.H.); (A.F.-Y.L.); (R.-C.L.); (K.-L.L.); (Y.-H.W.); (I.-C.L.); (W.-C.Y.); (Y.-P.H.)
- Department of Oncology, Taipei Veterans General Hospital, Taipei 112201, Taiwan
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Amirmoezi F, Geramizadeh B. Molecular Classification of Gastric Cancer With Emphasis on PDL-1 Expression: The First Report From Iran. CLINICAL PATHOLOGY (THOUSAND OAKS, VENTURA COUNTY, CALIF.) 2022; 15:2632010X221096378. [PMID: 35651850 PMCID: PMC9149623 DOI: 10.1177/2632010x221096378] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/25/2022] [Indexed: 11/17/2022]
Abstract
BACKGROUND Gastric cancer is one of the lethal cancers and there is no effective treatment for these patients and still, 5-year survival rate is about 25% to 30%. Finding reliable biomarkers for early-stage diagnosis, targeted therapy, and survival prediction is a priority in this cancer. OBJECTIVES In this study we were trying to know about the molecular classification of gastric cancers in a group of patients from the South of Iran. PATIENTS AND METHODS In a cross sectional study, 50 specimens of gastric cancer were selected that have enough tissue to be stained by immunohistochemistry (IHC). IHC was performed for Her-2, mismatch repair genes (MLH-1, MSH-2, MSH-6, and PMS-2), and PDL-1. Frequency of positive makers was compared with survival and outcome. RESULTS AND CONCLUSION In our study, deficient MMR (dMMR) was detected in 4 patients (8.0%). PD-L1 expression in tumor cells (TC) was observed in 1 of 4 cases (25%) with PMS2 loss. However, PD-L1 in TCs and TILs (tumor infiltrating lymphocytes) was negative in 1 case with MLH1 loss and in 3 of 4 cases with PMS2 loss, which was not statistically significant. All of our 50 cases were positive for MSH2 and MSH6, 24% of which showed TCs with PDL-1 expression and 32% of them in TIL. HER2 was positive in 2 (2/50, 4.0%) cases, among which all of the cases were positive for PD-L1 expression in TCs and TILs, respectively. However, in HER2-negative group, 26.2% (11/42) and 28.6% (12/42) of tumors were positive for PD-L1 in TCs and TILs, respectively. The expression rate of PD-L1 in HER2 negative TCs was significantly higher than that in HER2 positive TCs (P = .033). Immunohistochemistry for Her-2 was equivocal in 6 cases (12.0%) none of which expressed PD-L1 in tumor cells. In our study minimum and maximum survival times from detection of gastric cancer were 1 and 87 months, respectively. The mean ± SD and median ± SD of overall survival time were 30.69 ± 4.88 and 18 ± 1.45 months, respectively. One and 3-year survival rates of 40% and 24%, respectively. PD-L1 expression was not associated with survival, but its expression was associated with intestinal type Lauren classification and negative HER-2. PD-L1 positivity in tumor cells or tumor infiltrating lymphocytes was not an independent prognostic factor in gastric cancer.
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Affiliation(s)
- Fatemeh Amirmoezi
- Department of Pathology, Medical School
of Shiraz University, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Bita Geramizadeh
- Department of Pathology, Medical School
of Shiraz University, Shiraz University of Medical Sciences, Shiraz, Iran
- Transplant Research Center, Shiraz
University of Medical Sciences, Shiraz, Iran
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Du XZ, Wen B, Liu L, Wei YT, Zhao K. Role of immune escape in different digestive tumours. World J Clin Cases 2021; 9:10438-10450. [PMID: 35004976 PMCID: PMC8686128 DOI: 10.12998/wjcc.v9.i34.10438] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 08/15/2021] [Accepted: 10/18/2021] [Indexed: 02/06/2023] Open
Abstract
A counterbalance between immune cells and tumour cells is key to fighting tumours, and immune escape is an important mechanism for the survival of tumour cells in the body. Tumor cells and their cytokines impair the activity of T cells, NK cells, macrophages and other immune cells through various ways, and change the expression of their own surface antigens so as to avoid the clearance of the immune system. Changes in major histocompatibility complex molecules, high expression of programmed death-ligand 1, and the presence of immunosuppressive cells in the tumor microenvironment (TME) are main means by which tumors impair the function of immune cells. During the development of tumours of the digestive system, different mechanisms acting on tumour cells, the TME, and immune cells lead to immune escape and promote tumour progression. In this paper, the mechanisms of immune escape in tumour cells of the digestive system are reviewed to provide a theoretical basis for the immunotherapy of gastrointestinal tumours.
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Affiliation(s)
- Xin-Zhu Du
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Bin Wen
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Lin Liu
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Ying-Ting Wei
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
| | - Kui Zhao
- Department of Gastroenterology, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
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Chen ZD, Zhang PF, Xi HQ, Wei B, Chen L, Tang Y. Recent Advances in the Diagnosis, Staging, Treatment, and Prognosis of Advanced Gastric Cancer: A Literature Review. Front Med (Lausanne) 2021; 8:744839. [PMID: 34765619 PMCID: PMC8575714 DOI: 10.3389/fmed.2021.744839] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 09/30/2021] [Indexed: 01/06/2023] Open
Abstract
Gastric cancer is one of the most common cause of cancer related deaths worldwide which results in malignant tumors in the digestive tract. The only radical treatment option available is surgical resection. Recently, the implementation of neoadjuvant chemotherapy resulted in 5-year survival rates of 95% for early gastric cancer. The main reason of treatment failure is that early diagnosis is minimal, with many patients presenting advanced stages. Hence, the greatest benefit of radical resection is missed. Consequently, the main therapeutic approach for advanced gastric cancer is combined surgery with neoadjuvant chemotherapy, targeted therapy, or immunotherapy. In this review, we will discuss the various treatment options for advanced gastric cancer. Clinical practice and clinical research is the most practical way of reaching new advents in terms of patients' characteristics, optimum drug choice, and better prognosis. With the recent advances in gastric cancer diagnosis, staging, treatment, and prognosis, we are evident that the improvement of survival in this patient population is just a matter of time.
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Affiliation(s)
- Zhi-da Chen
- Department of General Surgery, First Medical Center of Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
| | - Peng-Fei Zhang
- Department of Oncology, First Medical Center of Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
| | - Hong-Qing Xi
- Department of General Surgery, First Medical Center of Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
| | - Bo Wei
- Department of General Surgery, First Medical Center of Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
| | - Lin Chen
- Department of General Surgery, First Medical Center of Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
| | - Yun Tang
- Department of General Surgery, First Medical Center of Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
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Zhang Q, Cheng L, Qin Y, Kong L, Shi X, Hu J, Li L, Ding Z, Wang T, Shen J, Yang Y, Yu L, Liu B, Liu C, Qian X. SLAMF8 expression predicts the efficacy of anti-PD1 immunotherapy in gastrointestinal cancers. Clin Transl Immunology 2021; 10:e1347. [PMID: 34729183 PMCID: PMC8546794 DOI: 10.1002/cti2.1347] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 07/29/2021] [Accepted: 09/25/2021] [Indexed: 12/19/2022] Open
Abstract
Objectives Epstein–Barr virus (EBV) infection is associated with a better response to anti‐PD1 immunotherapy. We hypothesised that genetic alterations induced by EBV infection are responsible for the activation of key immune responses and hence are predictive of anti‐PD1 efficacy. Methods With transcriptome data of gastric cancer (GC), we explored differentially expressed genes (DEGs) specific for EBV infection and performed coexpression network analysis using the DEGs to identify the consistent coexpression genes (CCGs) between EBV‐positive and EBV‐negative GC tissues. We selected the tag genes of the CCGs and validated them using RNA sequencing and immunohistochemistry. We established murine models and collected tissues from clinical patients to test the value of SLAMF8 in predicting anti‐PD1 treatment. The location and expression of SLAMF8 were characterised by multiplex immunofluorescence and quantitative PCR. Moreover, exogenous overexpression and RNA‐sequencing analysis were used to test the potential function of SLAMF8. Results We identified 290 CCGs and validated the tag gene SLAMF8 in transcriptome data of gastrointestinal cancer (GI). We observed that the T‐cell activation pathway was significantly enriched in high‐expression SLAMF8 GI cancers. Higher SLAMF8 expression was positively associated with CD8 expression and a better response to anti‐PD1 treatment. We further observed dynamically increased expression of SLAMF8 in murine models relatively sensitive to anti‐PD1 treatment. SLAMF8 was mainly expressed on the surface of macrophages. Exogenous overexpression of SLAMF8 in macrophages resulted in enrichment of positive regulation of multiple immune‐related pathways. Conclusion Higher SLAMF8 expression may predict better anti‐PD1 immunotherapy efficacy in GI cancer.
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Affiliation(s)
- Qun Zhang
- The Comprehensive Cancer Center Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital Clinical Cancer Institute of Nanjing University Nanjing China
| | - Lei Cheng
- Department of Pulmonary Medicine Shanghai Chest Hospital Shanghai Jiao Tong University Shanghai China
| | - Yanmei Qin
- Department of Respiratory and Critical Care Medicine Affiliated Hospital of Nantong University Nantong China
| | - Linghui Kong
- The Comprehensive Cancer Center Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital Clinical Cancer Institute of Nanjing University Nanjing China
| | - Xiao Shi
- The Comprehensive Cancer Center Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital Clinical Cancer Institute of Nanjing University Nanjing China
| | - Jing Hu
- The Comprehensive Cancer Center Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital Clinical Cancer Institute of Nanjing University Nanjing China
| | - Li Li
- The Comprehensive Cancer Center Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital Clinical Cancer Institute of Nanjing University Nanjing China
| | - Zhou Ding
- The Comprehensive Cancer Center Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital Clinical Cancer Institute of Nanjing University Nanjing China
| | - Ting Wang
- Department of Pathology Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital Nanjing China
| | - Jie Shen
- The Comprehensive Cancer Center Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital Clinical Cancer Institute of Nanjing University Nanjing China
| | - Yang Yang
- The Comprehensive Cancer Center Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital Clinical Cancer Institute of Nanjing University Nanjing China
| | - Lixia Yu
- The Comprehensive Cancer Center Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital Clinical Cancer Institute of Nanjing University Nanjing China
| | - Baorui Liu
- The Comprehensive Cancer Center Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital Clinical Cancer Institute of Nanjing University Nanjing China
| | - Chenchen Liu
- Department of Gastric Surgery Fudan University Shanghai Cancer Center Shanghai China
| | - Xiaoping Qian
- The Comprehensive Cancer Center Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital Clinical Cancer Institute of Nanjing University Nanjing China
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Yeh YC, Ho HL, Lin CI, Chou TY, Wang YC. Whole-exome Sequencing of Epstein-Barr Virus-associated Pulmonary Carcinoma With Low Lymphocytic Infiltration Shows Molecular Features Similar to Those of Classic Pulmonary Lymphoepithelioma-like Carcinoma: Evidence to Support Grouping Together as One Disease Entity. Am J Surg Pathol 2021; 45:1476-1486. [PMID: 33927156 DOI: 10.1097/pas.0000000000001722] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Pulmonary lymphoepithelioma-like carcinoma (LELC) is a distinct type of Epstein-Barr virus (EBV)-associated non-small cell carcinoma characterized by a syncytial growth pattern with heavy lymphocytic infiltration. We recently identified a group of non-small cell carcinomas, which are also associated with EBV but lack significant lymphocytic infiltration. These EBV-associated pulmonary carcinomas with low lymphocytic infiltration morphologically resemble nonkeratinizing squamous cell carcinoma, but their patient characteristics are more similar to those of LELC, including female sex and nonsmoking status. To clarify the relationships between these disease entities, in this study, we explored the molecular characteristics of the EBV-associated carcinomas with low lymphocytic infiltration using whole-exome sequencing and compared their molecular profiles with those of classic LELC and pulmonary squamous cell carcinoma. We demonstrate that the molecular characteristics of EBV-associated carcinomas with low lymphocytic infiltration are highly similar to those of classic LELC. Both show low tumor mutational burden, lack of commonly mutated driver genes in other types of non-small cell lung cancer, similar mutational signature involving APOBEC-related mutations, and enrichment of CD274 (programmed death-ligand 1) amplification. These molecular characteristics are very different from those of pulmonary squamous cell carcinoma. The unique patient demographics and molecular characteristics shared by EBV-associated carcinomas with low lymphocytic infiltration and classic LELC suggest that these tumors represent one single disease entity defined by EBV association. This study supports the proposal for the usage of the term "EBV-associated pulmonary carcinoma" to encompass the entire morphologic spectrum of this distinct EBV-associated disease entity.
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MESH Headings
- Aged
- Biomarkers, Tumor/genetics
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/immunology
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Non-Small-Cell Lung/virology
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/immunology
- Carcinoma, Squamous Cell/pathology
- Carcinoma, Squamous Cell/virology
- DNA Copy Number Variations
- DNA Mutational Analysis
- Epstein-Barr Virus Infections/virology
- Female
- Gene Dosage
- Herpesvirus 4, Human/pathogenicity
- Humans
- Lung Neoplasms/genetics
- Lung Neoplasms/immunology
- Lung Neoplasms/pathology
- Lung Neoplasms/virology
- Lymphocytes, Tumor-Infiltrating/immunology
- Middle Aged
- Mutation
- Predictive Value of Tests
- Terminology as Topic
- Exome Sequencing
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Affiliation(s)
- Yi-Chen Yeh
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital
- School of Medicine
- Institute of Biomedical Informatics
| | - Hsiang-Ling Ho
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital
- Department of Biotechnology and Laboratory Science in Medicine
| | - Chia-I Lin
- Department of Pathology, Taipei Hospital, Ministry of Health and Welfare, Taipei, Taiwan
| | - Teh-Ying Chou
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital
- Institute of Clinical Medicine, National Yang Ming Chiao Tung University
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Bauer M, Jasinski-Bergner S, Mandelboim O, Wickenhauser C, Seliger B. Epstein-Barr Virus-Associated Malignancies and Immune Escape: The Role of the Tumor Microenvironment and Tumor Cell Evasion Strategies. Cancers (Basel) 2021; 13:cancers13205189. [PMID: 34680337 PMCID: PMC8533749 DOI: 10.3390/cancers13205189] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 10/06/2021] [Accepted: 10/11/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary The Epstein–Barr virus, also termed human herpes virus 4, is a human pathogenic double-stranded DNA virus. It is highly prevalent and has been linked to the development of 1–2% of cancers worldwide. EBV-associated malignancies encompass various structural and epigenetic alterations. In addition, EBV-encoded gene products and microRNAs interfere with innate and adaptive immunity and modulate the tumor microenvironment. This review provides an overview of the characteristic features of EBV with a focus on the intrinsic and extrinsic immune evasion strategies, which contribute to EBV-associated malignancies. Abstract The detailed mechanisms of Epstein–Barr virus (EBV) infection in the initiation and progression of EBV-associated malignancies are not yet completely understood. During the last years, new insights into the mechanisms of malignant transformation of EBV-infected cells including somatic mutations and epigenetic modifications, their impact on the microenvironment and resulting unique immune signatures related to immune system functional status and immune escape strategies have been reported. In this context, there exists increasing evidence that EBV-infected tumor cells can influence the tumor microenvironment to their own benefit by establishing an immune-suppressive surrounding. The identified mechanisms include EBV gene integration and latent expression of EBV-infection-triggered cytokines by tumor and/or bystander cells, e.g., cancer-associated fibroblasts with effects on the composition and spatial distribution of the immune cell subpopulations next to the infected cells, stroma constituents and extracellular vesicles. This review summarizes (i) the typical stages of the viral life cycle and EBV-associated transformation, (ii) strategies to detect EBV genome and activity and to differentiate various latency types, (iii) the role of the tumor microenvironment in EBV-associated malignancies, (iv) the different immune escape mechanisms and (v) their clinical relevance. This gained information will enhance the development of therapies against EBV-mediated diseases to improve patient outcome.
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Affiliation(s)
- Marcus Bauer
- Department of Pathology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 14, 06112 Halle (Saale), Germany; (M.B.); (C.W.)
| | - Simon Jasinski-Bergner
- Department of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle (Saale), Germany;
| | - Ofer Mandelboim
- Department of Immunology, Faculty of Medicine, The Hebrew University of Jerusalem, En Kerem, P.O. Box 12271, Jerusalem 91120, Israel;
| | - Claudia Wickenhauser
- Department of Pathology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 14, 06112 Halle (Saale), Germany; (M.B.); (C.W.)
| | - Barbara Seliger
- Department of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle (Saale), Germany;
- Fraunhofer Institute for Cell Therapy and Immunology, Perlickstr. 1, 04103 Leipzig, Germany
- Correspondence: ; Tel.: +49-(345)-557-1357
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Xie T, Peng Z, Liu Y, Zhang Z, Zhang X, Li J, Lu M, Gong J, Qi C, Ji J, Shen L. Clinicopathological Characteristics and Response to Chemotherapy in Treatment-Naive Epstein-Barr Virus Associated Gastric Cancer: A Retrospective Study. Front Oncol 2021; 11:611676. [PMID: 34631508 PMCID: PMC8495155 DOI: 10.3389/fonc.2021.611676] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 08/31/2021] [Indexed: 01/08/2023] Open
Abstract
Background Epstein–Barr virus associated gastric cancer (EBVaGC) is a special subtype of gastric cancer. However, the perioperative treatment plan and the response to chemotherapy are still uncertain. Methods We retrospectively enrolled patients diagnosed with EBVaGC from March 2013 to July 2020 in Beijing Cancer Hospital. Clinicopathological characteristics were recorded. Disease-free survival (DFS) were then calculated, and variants affecting DFS were tested in a Cox proportional regression model. Results One hundred sixty consecutive patients were finally included in our study. Of the patients, 96.9% had adenocarcinoma, while five had squamous cell carcinoma component. Most (70.9%) of them were poorly differentiated. Prevalent programmed death-ligand 1 (PD-L1) (69%) and minor HER-2 (3.8%) expression were noticed; all of the patients were MMR proficient (pMMR) or microsatellite stable (MSS). Among 33 patients who experienced neoadjuvant therapy, the number of tumor regression grade (TRG) 1, TRG 2, and TRG 3 was 5, 16, and 12, respectively. Patients with advanced tumor stage and T stage showed poorer response. Thirty-one patients experienced first-line chemotherapy; ORR was 33.3%, and DCR was 61.9%. One hundred forty-seven patients underwent surgery, and 27 of them showed disease recurrence; the 3-year DFS rate was 71.0%. Tumor stage, neoadjuvant chemotherapy, vascular invasion, and negative PD-L1 expression were associated with poorer DFS. Vascular invasion was the independent risk factor of DFS. Only seven patients reached OS with median follow-up time of 14 months. Conclusion EBVaGC exhibits unique clinicopathological characteristics. Neoadjuvant chemotherapy may not be suitable for EBVaGC, and EBVaGC exhibited relatively poor response to chemotherapy.
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Affiliation(s)
- Tong Xie
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, 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
| | - Yiqiang Liu
- Department of Pathology , Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Zhening Zhang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Xiaotian Zhang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jian Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Ming Lu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jifang Gong
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Changsong Qi
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing, China
| | - Jiafu Ji
- Department of Gastrointestinal Surgery, 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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Iwasaki A, Shinozaki-Ushiku A, Kunita A, Yamazawa S, Sato Y, Yamashita H, Fukayama M, Seto Y, Ushiku T. Human Leukocyte Antigen Class I Deficiency in Gastric Carcinoma: An Adaptive Immune Evasion Strategy Most Common in Microsatellite Instable Tumors. Am J Surg Pathol 2021; 45:1213-1220. [PMID: 34310369 DOI: 10.1097/pas.0000000000001779] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Immune checkpoint inhibitor therapy is effective only for a subset of patients with gastric cancer. Impaired neoantigen presentation caused by deficiency of human leukocyte antigen class I (HLA-I) has been reported as a common mechanism of immune evasion which is associated with resistance to immune checkpoint blockade. To elucidate the significance of HLA-I deficiency in gastric cancer with special focus on microsatellite instable (MSI) and Epstein-Barr virus (EBV)-positive tumors, we examined HLA-I expression on tumor cells and correlated the results with clinicopathologic features, programmed death-ligand 1 (PD-L1) expression, and degree of tumor-infiltrating immune cells. This study included 58 MSI, 44 EBV-positive, and 107 non-EBV non-MSI tumors for comparison. The frequency of HLA-I deficiency (≥1% tumor cells) was significantly higher in MSI tumors (52%) compared with EBV-positive tumors (23%) and the other tumors (28%). In contrast, PD-L1 expression levels were highest in EBV-positive tumors, followed by MSI tumors, with the lowest prevalence in the other tumors in both Tumor Proportion Score and Combined Positive Score. HLA-I deficiency was significantly more frequent in advanced tumors (pT2-4) than in early tumors (pT1) in MSI and non-EBV non-MSI subtypes. In addition, the degree of CD8-positive cells infiltration was significantly reduced in HLA-I deficient tumor areas compared with HLA-I preserved tumor area within a tumor. Based on our observations, HLA-I, as well as PD-L1, should be considered as a common mechanism of immune escape especially in the MSI subtype, and therefore could be a biomarker predicting response to immune checkpoint inhibitor therapy in gastric cancer.
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Affiliation(s)
| | | | | | | | | | - Hiroharu Yamashita
- Department of Digestive Surgery, Nihon University School of Medicine, Tokyo
| | - Masashi Fukayama
- Asahi TelePathology Center, Asahi General Hospital, Asahi, Chiba Prefecture, Japan
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Olnes MJ, Martinson HA. Recent advances in immune therapies for gastric cancer. Cancer Gene Ther 2021; 28:924-934. [PMID: 33664460 PMCID: PMC8417143 DOI: 10.1038/s41417-021-00310-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/28/2021] [Accepted: 02/11/2021] [Indexed: 01/31/2023]
Abstract
Gastric cancer (GC) is an aggressive malignancy that is the third leading cause of cancer mortality worldwide. Localized GC can be cured with surgery, but most patients present with more advanced non-operable disease. Until recently, treatment options for relapsed and refractory advanced GC have been limited to combination chemotherapy regimens, HER-2 directed therapy, and radiation, which lead to few durable responses. Over the past decade, there have been significant advances in our understanding of the molecular and immune pathogenesis of GC. The infectious agents Epstein-Barr virus and Helicobacter pylori perturb the gastric mucosa immune equilibrium, which creates a microenvironment that favors GC tumorigenesis and evasion of immune surveillance. Insights into immune mechanisms of GC have translated into novel therapeutics, including immune checkpoint inhibitors, which have become a treatment option for select patients with GC. Furthermore, chimeric antigen receptor T-cell therapies have emerged as a breakthrough treatment for many cancers, with recent studies showing this to be a potential therapy for GC. In this review, we summarize the current state of knowledge on immune mechanisms of GC and the status of emerging immunotherapies to treat this aggressive cancer, as well as outline current challenges and directions for future research.
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Affiliation(s)
- Matthew J Olnes
- Hematology and Medical Oncology, Alaska Native Tribal Health Consortium, Anchorage, AK, USA.
- WWAMI School of Medical Education, University of Alaska Anchorage, Anchorage, AK, USA.
| | - Holly A Martinson
- WWAMI School of Medical Education, University of Alaska Anchorage, Anchorage, AK, USA
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PD-L1 Expression Is a Favorable Prognostic Marker in Gastric Carcinoma. Appl Immunohistochem Mol Morphol 2021; 28:748-754. [PMID: 32205740 DOI: 10.1097/pai.0000000000000834] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Gastric cancer (GC) is the fifth most common cancer and the third leading cause of cancer-related mortality worldwide. Although multidisciplinary therapeutic strategies have improved treatment outcomes, the overall prognosis for patients with GC remains poor. Recently, immunotherapeutic agents targeting immunosuppressive proteins such as anti-programmed death-1 receptor and anti-programmed death ligand-1 (PD-L1) have emerged as effective treatment options for various cancers, including GC. In addition to their therapeutic role, the expression of PD-L1 has been used as a predictive biomarker for programmed death-1/PD-L1 treatment response and has been shown to have a prognostic role in certain cancers. This study aims to evaluate the expression of PD-L1 in GC samples from Jordanian patients and assess its prognostic role as well as its correlation with clinicopathologic variables. Gastrectomy samples from 96 patients diagnosed with gastric adenocarcinoma were included in the study. Immunohistochemistry assay was employed for PD-L1 testing, and the scoring was based on a combined positive score (CPS). It was found that 66.7% of the study samples were positive for PD-L1 (CPS≥1). The expression of PD-L1 was not significantly associated with any of the assessed clinicopathologic variables; however, it was found to be an independent favorable prognostic factor for overall survival (hazard ratio: 0.481; 95% confidence interval: 0.231-1.001; P=0.050).
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