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Pugaev DM, Lyubchenko LN, Ryabov AB, Kaprin AD. Early-onset gasrtric cancer (review). SIBERIAN JOURNAL OF ONCOLOGY 2024; 22:153-171. [DOI: 10.21294/1814-4861-2023-22-6-153-171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Objective. Early-onset gastric cancer (EOGC) constitutes a serious medical and social problem. Early-onset gastric cancer accounts for approximately 6% of all malignant epithelial neoplasms.Material and Methods. We reviewed retrospective and prospective randomized trials using Medline and Elibrary databases.Results. The applied significance of the molecular genetic classifications consist in the formation of groups for evaluating prognosis of the disease using multifactorial analysis. This classification indicates that EOGC diagnosed at a locally advanced stage and primary dissemination is most often caused by GS (TCGA) and MSS/EMT(ACRG) subtypes and is characterized by mutations in CDH1, RhoA, CLDN18-ARHGAP genes. These changes are accompanied by the prevalence of diffuse histological type of gastric cancer according to the Lauren classification and ulcerated or infiltrative type according to the Borrmann classification (type III and IV) with the presence of high-grade adenocarcinoma with a signet ring cell component.Conclusion. Considering the aggressiveness of gastric cancer in young patients, who more frequently present with locally advanced and metastatic disease at the time of diagnosis, there is a need for increased cancer alertness among physicians of other specialties, early endoscopic controls to detect cancer at early stages and benefit from both surgical and multimodal treatment.
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Affiliation(s)
- D. M. Pugaev
- Kommunarka Moscow Multidisciplinary Clinical Center, Moscow City Health Department
| | - L. N. Lyubchenko
- N.A. Lopatkin Research Institute of Urology and Interventional Radiology – branch National Medical Research Radiological Centre of the Ministry of Health of the Russia;
National Medical Research Radiological Centre of the Ministry of Health of the Russia
| | - A. B. Ryabov
- P.A. Hertsen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russia;
National Medical Research Radiological Centre of the Ministry of Health of the Russia
| | - A. D. Kaprin
- RUDN University;
P.A. Hertsen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russia;
National Medical Research Radiological Centre of the Ministry of Health of the Russia
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2
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Varga Z, Kolozsi P, Nagy K, Tóth D. Optimal extent of lymph node dissection in gastric cancer. Front Surg 2022; 9:1093324. [PMID: 36644530 PMCID: PMC9834278 DOI: 10.3389/fsurg.2022.1093324] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 12/15/2022] [Indexed: 12/31/2022] Open
Abstract
Gastric cancer still remains a major cause of cancer-related deaths globally. Stage-adapted, individualized treatment is crucial to achieving optimal oncological outcomes. Postoperative morbidity and accurate nodal staging are heavily influenced by the extent of lymph node dissection. On one hand, insufficient lymphadenectomy may result in understaging and undertreatment of a patient, on the other hand, unnecessary lymph node dissection may result in a higher rate of postoperative complications. Approximately one-third of patients with gastric cancer undergoes an avoidable lymph node dissection. Many of the recent treatment updates in the management of gastric cancer have a major influence on both surgical and oncological approaches. Currently, a wide range of endoscopic, minimally invasive, and hybrid surgical techniques are available. The concept of sentinel node biopsy and utilization of the Maruyama Computer Program are significant components of stage-adapted gastric cancer surgery. Likewise, centralization and application of national guidelines, widespread use of neoadjuvant therapy, and the stage migration phenomenon are serious concerns to be discussed. Our goal is to review the available surgical strategies for gastric cancer, with a primary focus on lymphadenectomy.
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Affiliation(s)
- Zsolt Varga
- Department of Surgery, University of Debrecen, Debrecen, Hungary
| | - Péter Kolozsi
- Department of Surgery, University of Debrecen, Debrecen, Hungary
| | - Kitti Nagy
- Department of Surgery, University of Debrecen, Debrecen, Hungary
| | - Dezső Tóth
- Department of Surgery, University of Debrecen, Debrecen, Hungary
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3
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Zheng L, Cai X, Song J, Shi H, Zhang J, Ke X, Li H, Chen Y. MicroRNA-30c-2-3p represses malignant progression of gastric adenocarcinoma cells via targeting ARHGAP11A. Bioengineered 2022; 13:14534-14544. [PMID: 35754342 PMCID: PMC9342190 DOI: 10.1080/21655979.2022.2090222] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
MicroRNAs are crucial tumor regulators to tumor development and progression. MiR-30c-2-3p can suppress malignant progression of tumor cells, but no study has reported the modulatory process of miR-30c-2-3p in gastric adenocarcinoma (GA). We herein investigated role of miR-30c-2-3p in GA cells. Here, we evaluated gene level in cancer cells by qRT-PCR. CCK-8, colony formation, flow cytometry, and transwell assays revealed biological functions of miR-30c-2-3p and ARHGAP11A. Genes downstream of miR-30c-2-3p were acquired through bioinformatics analysis. Our results suggested a low level of miR-30c-2-3p in GA tissue and cells, while its high expression could repress the malignant progression and promote cell cycle arrest and apoptosis of GA cells. Besides, ARHGAP11A was downstream of miR-30c-2-3p, with up-regulated ARHGAP11A facilitating malignant progression and repressing cell cycle arrest and apoptosis of GA cells. In addition, changes in GA cell functions caused by high ARHGAP11A expression could be partially offset by enhancing miR-30c-2-3p. Thus, our observations indicated that miR-30c-2-3p was a tumor repressor that could inhibit GA progression via modulating ARHGAP11A.
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Affiliation(s)
- Liang Zheng
- Department of Abdominal Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Xiongchao Cai
- Department of Abdominal Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Jintian Song
- Department of Abdominal Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Huaijing Shi
- Department of Gynecology Surgery, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Jiulong Zhang
- Department of Thoracic Surgical Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Xi Ke
- Department of Abdominal Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Hui Li
- Department of Abdominal Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, Fujian, China
| | - Yigui Chen
- Department of Abdominal Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, Fujian, China
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Huang M, Xu C, Yang S, Zhang Z, Wei Z, Wu M, Xue F. Vehicle-Free Nanotheranostic Self-Assembled from Clinically Approved Dyes for Cancer Fluorescence Imaging and Photothermal/Photodynamic Combinational Therapy. Pharmaceutics 2022; 14:1074. [PMID: 35631661 PMCID: PMC9145484 DOI: 10.3390/pharmaceutics14051074] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 05/04/2022] [Accepted: 05/14/2022] [Indexed: 02/01/2023] Open
Abstract
Phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT) has attracted growing attention as a noninvasive option for cancer treatment. At present, researchers have developed various "all-in-one" nanoplatforms for cancer imaging and PTT/PDT combinational therapy. However, the complex structure, tedious preparation procedures, overuse of extra carriers and severe side effects hinder their biomedical applications. In this work, we reported a nanoplatform (designated as ICG-MB) self-assembly from two different FDA-approved dyes of indocyanine green (ICG) and methylene blue (MB) without any additional excipients for cancer fluorescence imaging and combinational PTT/PDT. ICG-MB was found to exhibit good dispersion in the aqueous phase and improve the photostability and cellular uptake of free ICG and MB, thus exhibiting enhanced photothermal conversion and singlet oxygen (1O2) generation abilities to robustly ablate cancer cells under 808 nm and 670 nm laser irradiation. After intravenous injection, ICG-MB effectively accumulated at tumor sites with a near-infrared (NIR) fluorescence signal, which helped to delineate the targeted area for NIR laser-triggered phototoxicity. As a consequence, ICG-MB displayed a combinational PTT/PDT effect to potently inhibit tumor growth without causing any system toxicities in vivo. In conclusion, this minimalist, effective and biocompatible nanotheranostic would provide a promising candidate for cancer phototherapy based on current available dyes in clinic.
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Affiliation(s)
- Mingbin Huang
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, China; (M.H.); (C.X.); (Z.Z.)
- Department of Gastrointestinal Surgery, Fujian Provincial Hospital, Fuzhou 350001, China
| | - Chao Xu
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, China; (M.H.); (C.X.); (Z.Z.)
- Department of Gastrointestinal Surgery, Fujian Provincial Hospital, Fuzhou 350001, China
| | - Sen Yang
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China;
| | - Ziqian Zhang
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, China; (M.H.); (C.X.); (Z.Z.)
- Department of Gastrointestinal Surgery, Fujian Provincial Hospital, Fuzhou 350001, China
| | - Zuwu Wei
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China;
| | - Ming Wu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China;
| | - Fangqin Xue
- Shengli Clinical Medical College, Fujian Medical University, Fuzhou 350001, China; (M.H.); (C.X.); (Z.Z.)
- Department of Gastrointestinal Surgery, Fujian Provincial Hospital, Fuzhou 350001, China
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Graziosi L, Marino E, Bencivenga M, D’Ignazio A, Solaini L, Ministrini S, Caprioli M, Sacco M, Marrelli D, Mura G, Degiuli M, Morgagni P, Tiberio GAM, De Manzoni G, Roviello F, Donini A. Looking for a strategy in treating peritoneal gastric cancer carcinomatosis: an Italian multicenter Gastric Cancer Research group's analysis. World J Surg Oncol 2021; 19:334. [PMID: 34819103 PMCID: PMC8611869 DOI: 10.1186/s12957-021-02442-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 11/02/2021] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND The present study provides a snapshot of Italian patients with peritoneal metastasis from gastric cancer treated by surgery in Italian centers belonging to the Italian Research Group on Gastric Cancer. Prognostic factors affecting survival in such cohort of patients were evaluated with the final aim to identify patients who may benefit from radical intent surgery. METHODS It is a multicentric retrospective study based on a prospectively collected database including demographics, clinical, surgical, pathological, and follow-up data of patients with gastric cancer and synchronous macroscopic peritoneal metastases. Patients were surgically treated from January 2005 to January 2017. We focused on patients with macroscopic peritoneal carcinomatosis (PC) treated with upfront surgery in order to provide homogeneous evidences. RESULTS Our results show that patients with peritoneal carcinomatosis cannot be considered all lost. Strictly selected cases (R0/R1 and P1 patients) could benefit from an aggressive surgical approach performing an extended lymphadenectomy and HIPEC treatment. CONCLUSION The main result of the study is that GC patients with limited peritoneal involvement can have a survival benefit from a surgery with "radical oncological intent", that means extended lymphadenectomy and R0 resection. The retrospective nature of this study is an important bias, and for this reason, we have started a prospective multicentric study including Italian stage IV patients that hopefully will give us more answers.
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Affiliation(s)
- Luigina Graziosi
- General and Emergency Surgery, Santa Maria della Misericordia Hospital University of Perugia, Perugia, Italy
| | - Elisabetta Marino
- General and Emergency Surgery, Santa Maria della Misericordia Hospital University of Perugia, Perugia, Italy
| | - Maria Bencivenga
- General and Upper GI Surgery Division, University of Verona, Verona, Italy
| | - Alessia D’Ignazio
- Department of Surgery, Policlinico le Scotte, University of Siena, Siena, Italy
| | - Leonardo Solaini
- Department of Surgery, General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Via Forlanini 34, Forlì, Italy
| | - Silvia Ministrini
- Department of Experimental and Clinical Sciences, University of Brescia, Brescia, Italy
| | - Michela Caprioli
- Department of Experimental and Clinical Sciences, University of Brescia, Brescia, Italy
| | - Michele Sacco
- General and Upper GI Surgery Division, University of Verona, Verona, Italy
| | - Daniele Marrelli
- Department of Surgery, Policlinico le Scotte, University of Siena, Siena, Italy
| | - Gianni Mura
- Department of Surgery, Azienda USl Toscana SudEst—Arezzo, Arezzo, Italy
| | - Maurizio Degiuli
- Department of Oncology, Head, Digestive and Surgical Oncology, University of Torino, and San Luigi University Hospital, Orbassano, Italy
| | - Paolo Morgagni
- Department of Surgery, General and Oncologic Surgery, Morgagni-Pierantoni Hospital, Via Forlanini 34, Forlì, Italy
| | | | | | - Franco Roviello
- Department of Surgery, Policlinico le Scotte, University of Siena, Siena, Italy
| | - Annibale Donini
- General and Emergency Surgery, Santa Maria della Misericordia Hospital University of Perugia, Perugia, Italy
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Yan Y, Qian H, Cao Y, Zhu T. Nuclear factor-κB inhibitor Bay11-7082 inhibits gastric cancer cell proliferation by inhibiting Gli1 expression. Oncol Lett 2021; 21:301. [PMID: 33732377 PMCID: PMC7905653 DOI: 10.3892/ol.2021.12562] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 01/28/2021] [Indexed: 02/07/2023] Open
Abstract
Dysregulated nuclear factor (NF)-κB signaling pathway is involved in gastric carcinogenesis. The present study aimed to investigate the antitumor effects of the NF-κB inhibitor, Bay11-7082, on gastric cancer (GC) and elucidate its underlying molecular mechanisms. The MTT assay was performed to assess the effects of Bay11-7082 on the proliferation of HGC27 and MKN45 gastric cancer cells. In addition, the Transwell and wound healing assays were performed to determine cell migration and invasion, respectively. Reverse transcription-quantitative PCR and western blot analyses were performed to detect the mRNA and protein expression levels of the target genes. The results demonstrated that the half-maximal inhibitory concentration (IC50) of Bay11-7082 in HGC27 cells was 24.88, 6.72 and 4.23 nM at 24, 48 and 72 h, respectively. Furthermore, the IC50 of Bay11-7082 in MKN45 cells was 29.11, 11.22 and 5.88 nM at 24, 48 and 72 h, respectively. Treatment with Bay11-7082 significantly suppressed the cell migratory and invasive abilities compared with the control group. Notably, Bay11-7082 suppressed GLI Family Zinc Finger 1 (Gli1) mRNA and protein expression levels. Taken together, the results of the present study demonstrated that Bay11-7082 inhibited GC cell proliferation, at least in part through inhibition of Gli1.
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Affiliation(s)
- Yan Yan
- Department of Pharmacology, The Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, Jiangsu 215600, P.R. China
| | - Heya Qian
- Department of Oncology, The Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, Jiangsu 215600, P.R. China
| | - Ying Cao
- Department of Pharmacology, The Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, Jiangsu 215600, P.R. China
| | - Tao Zhu
- Department of Laboratory, The Affiliated Zhangjiagang Hospital of Soochow University, Zhangjiagang, Jiangsu 215600, P.R. China
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7
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Meng Y, Huang X, Liu J, Chen J, Bu Z, Wu G, Xie W, Jeen F, Huang L, Tian C, Mo X, Tang W. A Novel Nomogram for Individually Predicting of Vascular Invasion in Gastric Cancer. Technol Cancer Res Treat 2021; 20:15330338211004924. [PMID: 33929914 PMCID: PMC8111553 DOI: 10.1177/15330338211004924] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 01/22/2021] [Accepted: 02/25/2021] [Indexed: 02/03/2023] Open
Abstract
PURPOSE Vascular invasion (VI) is associated with recurrence and is an indicator of poor prognosis in gastric cancer (GC). Pre-operative identification of VI may guide the selection of the optimal surgical approach and assess the requirement for neoadjuvant therapy. METHODS A total of 271 patients were retrospectively collected and randomly allocated into the training and validation datasets. The least absolute shrinkage and selection operator regression model was used to select potentially relevant features, and multivariable logistic regression analysis was used to develop the nomogram. RESULTS The nomogram consisted of pre-operative serum complement C3 levels, duration of symptoms, pre-operative computed tomography stage, abdominal distension and undifferentiated carcinoma. The nomogram provided good calibration for both the training and the validation set, with area under the curve values of 0.792 and 0.774. Decision curve analysis revealed that the nomogram was clinically useful. CONCLUSION The present study constructed a nomogram for the pre-operative prediction of VI in patients with GC. The nomogram may aid the identification of high-risk patients and aid the optimization of pre-operative decision-making.
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Affiliation(s)
- Yongsheng Meng
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Xiaoliang Huang
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Jungang Liu
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Jianhong Chen
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Zhaoting Bu
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Guo Wu
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Weishun Xie
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Franco Jeen
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Lingxu Huang
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Chao Tian
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Xianwei Mo
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
| | - Weizhong Tang
- Division of Colorectal & Anal Surgery, Department of Gastrointestinal Surgery, Guangxi Medical University Cancer Hospital, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
- Guangxi Clinical Research Center for Colorectal Cancer, Nanning, Guangxi Zhuang Autonomous Region, People’s Republic of China
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MicroRNA-1297 inhibits proliferation and promotes apoptosis in gastric cancer cells by downregulating CDC6 expression. Anticancer Drugs 2020; 30:803-811. [PMID: 31419217 DOI: 10.1097/cad.0000000000000776] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Gastric cancer (GC), one of the most common malignant tumors and the second most common leading cause of cancer-related death worldwide, is a biologically heterogeneous disease accompanied by various genetic and epigenetic alterations. However, the molecular mechanisms underlying this disease are complex and not completely understood. Increasing studies have shown that aberrant microRNA (miRNA) expression is associated with GC tumorigenesis and growth. MiR-1297 has been confirmed to be a cancer suppressor in diverse tumors in humans. However, to date, the function and mechanism of miR-1297 in GC have not been determined. Here, we found that the expression of miR-1297 was significantly reduced in GC tissues or GC cell lines compared with paracarcinoma normal tissue or normal cell lines. Exogenic overexpression of miR-1297 in GC cell lines can inhibit cell proliferation and colony formation and induce apoptosis, and inhibition of miR-1297 in GC cell lines can promote cell proliferation and colony formation, and reduce apoptosis in vitro. We further confirmed that miR-1297 acted as a tumor suppressor through targeting cell division control protein 6 (CDC6) in GC. Moreover, the inverse relationship between miR-1297 and CDC6 was verified in GC cell lines. Our results indicated that miR-1297 is a potent tumor suppressor in GC, and its antiproliferative and gene-regulatory effects are, in part, mediated through its downstream target gene, CDC6. These findings implied that miR-1297 might be used as a novel therapeutic target of GC.
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p53/Mieap-regulated mitochondrial quality control plays an important role as a tumor suppressor in gastric and esophageal cancers. Biochem Biophys Res Commun 2020; 529:582-589. [PMID: 32736677 DOI: 10.1016/j.bbrc.2020.05.168] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 05/24/2020] [Indexed: 12/17/2022]
Abstract
Mitochondria-eating protein (Mieap) plays a critical role in mitochondrial quality control (MQC) and functions as a p53-inducible tumor suppressor. This study aimed to examine its role in gastric cancer (GC) and esophageal cancer (EC). GC cells were infected with Mieap-overexpressing adenovirus (Ad-Mieap) and subjected to fluorescence-activated cell sorting (FACS), western blotting, and caspase assays. Thereafter, we evaluated the potential disruption of the p53/Mieap-regulated MQC pathway in vivo. Methylation-specific PCR (MSP) for Mieap, NIX, and BNIP3 promoters was performed and p53 mutations were detected using cryopreserved surgical specimens. Exogenous Mieap in GC cells induced the formation of vacuole-like structures (called MIVs, Mieap-induced vacuoles) and caspase-dependent cell death, with the activation of both caspase-3 and caspase-9. Of the 47 GC patients, promoter methylation in Mieap, BNIP3, and NIX was identified in two (4.3%), 29 (61.7%), and zero (0%) specimens, respectively. In total, 33 GC patients (70.2%) inactivated this MQC pathway. Amazingly, BNIP3 promoter in the normal epithelium was highly methylated in 18 of the 47 GC patients (38.3%). In EC patients, this MQC pathway was also inactivated in ten of 12 patients (83.3%). These results indicate that p53/Mieap-regulated MQC plays an important role in upper gastrointestinal (GI) tumor suppression, possibly, in part, through the mitochondrial apoptotic pathway.
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10
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Fernandes E, Freitas R, Ferreira D, Soares J, Azevedo R, Gaiteiro C, Peixoto A, Oliveira S, Cotton S, Relvas-Santos M, Afonso LP, Palmeira C, Oliveira MJ, Ferreira R, Silva AMN, Lara Santos L, Ferreira JA. Nucleolin-Sle A Glycoforms as E-Selectin Ligands and Potentially Targetable Biomarkers at the Cell Surface of Gastric Cancer Cells. Cancers (Basel) 2020; 12:cancers12040861. [PMID: 32252346 PMCID: PMC7226152 DOI: 10.3390/cancers12040861] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 03/24/2020] [Accepted: 03/28/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Gastric cancer (GC) is a major health burden worldwide, with half of patients developing metastases within 5 years after treatment, urging novel biomarkers for diagnosis and efficient therapeutic targeting. Sialyl-Lewis A (SLeA), a terminal glycoepitope of glycoproteins and glycolipids, offers tremendous potential towards this objective. It is rarely expressed in healthy tissues and blood cells, while it is present in highly metastatic cell lines and metastases. SLeA is also involved in E-selectin mediated metastasis, making it an ideal target to control disease dissemination. METHODS AND RESULTS To improve cancer specificity, we have explored the SLeA-glycoproteome of six GC cell models, with emphasis on glycoproteins showing affinity for E-selectin. A novel bioinformatics-assisted algorithm identified nucleolin (NCL), a nuclear protein, as a potential targetable biomarker potentially involved in metastasis. Several immunoassays, including Western blot and in situ proximity ligation reinforced the existence of cell surface NCL-SLeA glycoforms in GC. The NCL-SLeA glycophenotype was associated with decreased survival and was not reflected in relevant healthy tissues. CONCLUSIONS NCL-SLeA is a biomarker of poor prognosis in GC holding potential for precise cancer targeting. This is the first report describing SLeA in preferentially nuclear protein, setting a new paradigm for cancer biomarkers discovery and targeted therapies.
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Affiliation(s)
- Elisabete Fernandes
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, 4200-162 Porto, Portugal; (E.F.); (R.F.); (D.F.); (J.S.); (R.A.); (C.G.); (A.P.); (S.O.); (S.C.); (M.R.-S.); (L.P.A.); (C.P.); (L.L.S.)
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-013 Porto, Portugal
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal;
- Institute for Biomedical Engineering (INEB), Porto, Portugal, 4200-135 Porto, Portugal
- Digestive Cancer Research Group, 1495-161 Algés, Portugal
| | - Rui Freitas
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, 4200-162 Porto, Portugal; (E.F.); (R.F.); (D.F.); (J.S.); (R.A.); (C.G.); (A.P.); (S.O.); (S.C.); (M.R.-S.); (L.P.A.); (C.P.); (L.L.S.)
| | - Dylan Ferreira
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, 4200-162 Porto, Portugal; (E.F.); (R.F.); (D.F.); (J.S.); (R.A.); (C.G.); (A.P.); (S.O.); (S.C.); (M.R.-S.); (L.P.A.); (C.P.); (L.L.S.)
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal;
- Institute for Biomedical Engineering (INEB), Porto, Portugal, 4200-135 Porto, Portugal
- Digestive Cancer Research Group, 1495-161 Algés, Portugal
| | - Janine Soares
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, 4200-162 Porto, Portugal; (E.F.); (R.F.); (D.F.); (J.S.); (R.A.); (C.G.); (A.P.); (S.O.); (S.C.); (M.R.-S.); (L.P.A.); (C.P.); (L.L.S.)
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-013 Porto, Portugal
- REQUIMTE-LAQV, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal;
| | - Rita Azevedo
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, 4200-162 Porto, Portugal; (E.F.); (R.F.); (D.F.); (J.S.); (R.A.); (C.G.); (A.P.); (S.O.); (S.C.); (M.R.-S.); (L.P.A.); (C.P.); (L.L.S.)
| | - Cristiana Gaiteiro
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, 4200-162 Porto, Portugal; (E.F.); (R.F.); (D.F.); (J.S.); (R.A.); (C.G.); (A.P.); (S.O.); (S.C.); (M.R.-S.); (L.P.A.); (C.P.); (L.L.S.)
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-013 Porto, Portugal
| | - Andreia Peixoto
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, 4200-162 Porto, Portugal; (E.F.); (R.F.); (D.F.); (J.S.); (R.A.); (C.G.); (A.P.); (S.O.); (S.C.); (M.R.-S.); (L.P.A.); (C.P.); (L.L.S.)
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-013 Porto, Portugal
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal;
- Institute for Biomedical Engineering (INEB), Porto, Portugal, 4200-135 Porto, Portugal
| | - Sara Oliveira
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, 4200-162 Porto, Portugal; (E.F.); (R.F.); (D.F.); (J.S.); (R.A.); (C.G.); (A.P.); (S.O.); (S.C.); (M.R.-S.); (L.P.A.); (C.P.); (L.L.S.)
| | - Sofia Cotton
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, 4200-162 Porto, Portugal; (E.F.); (R.F.); (D.F.); (J.S.); (R.A.); (C.G.); (A.P.); (S.O.); (S.C.); (M.R.-S.); (L.P.A.); (C.P.); (L.L.S.)
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-013 Porto, Portugal
| | - Marta Relvas-Santos
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, 4200-162 Porto, Portugal; (E.F.); (R.F.); (D.F.); (J.S.); (R.A.); (C.G.); (A.P.); (S.O.); (S.C.); (M.R.-S.); (L.P.A.); (C.P.); (L.L.S.)
- Institute for Biomedical Engineering (INEB), Porto, Portugal, 4200-135 Porto, Portugal
- REQUIMTE-LAQV, Department of Chemistry and Biochemistry, Faculty of Sciences of the University of Porto, 4169-007 Porto, Portugal;
| | - Luis Pedro Afonso
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, 4200-162 Porto, Portugal; (E.F.); (R.F.); (D.F.); (J.S.); (R.A.); (C.G.); (A.P.); (S.O.); (S.C.); (M.R.-S.); (L.P.A.); (C.P.); (L.L.S.)
- Pathology Department, Portuguese Institute of Oncology of Porto, 4200-162 Porto, Portugal
| | - Carlos Palmeira
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, 4200-162 Porto, Portugal; (E.F.); (R.F.); (D.F.); (J.S.); (R.A.); (C.G.); (A.P.); (S.O.); (S.C.); (M.R.-S.); (L.P.A.); (C.P.); (L.L.S.)
- Immunology Department, Portuguese Institute of Oncology of Porto, 4200-162 Porto, Portugal
- Health Science Faculty, University of Fernando Pessoa, 4249-004 Porto, Portugal
| | - Maria José Oliveira
- Institute for Research and Innovation in Health (i3S), University of Porto, 4200-135 Porto, Portugal;
- Institute for Biomedical Engineering (INEB), Porto, Portugal, 4200-135 Porto, Portugal
| | - Rita Ferreira
- REQUIMTE-LAQV, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal;
| | - André M. N. Silva
- REQUIMTE-LAQV, Department of Chemistry and Biochemistry, Faculty of Sciences of the University of Porto, 4169-007 Porto, Portugal;
| | - Lúcio Lara Santos
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, 4200-162 Porto, Portugal; (E.F.); (R.F.); (D.F.); (J.S.); (R.A.); (C.G.); (A.P.); (S.O.); (S.C.); (M.R.-S.); (L.P.A.); (C.P.); (L.L.S.)
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-013 Porto, Portugal
- Digestive Cancer Research Group, 1495-161 Algés, Portugal
- Health Science Faculty, University of Fernando Pessoa, 4249-004 Porto, Portugal
- Department of Surgical Oncology, Portuguese Institute of Oncology of Porto, 4200-162 Porto, Portugal
- Department, Porto Comprehensive Cancer Centre (P.ccc), 4200-162 Porto, Portugal
| | - José Alexandre Ferreira
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, 4200-162 Porto, Portugal; (E.F.); (R.F.); (D.F.); (J.S.); (R.A.); (C.G.); (A.P.); (S.O.); (S.C.); (M.R.-S.); (L.P.A.); (C.P.); (L.L.S.)
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-013 Porto, Portugal
- Department, Porto Comprehensive Cancer Centre (P.ccc), 4200-162 Porto, Portugal
- Correspondence: ; Tel.: +351-225084000 (ext. 5111)
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Zhang F, Huang X, Song Y, Gao P, Zhou C, Guo Z, Shi J, Wu Z, Wang Z. Conversion Surgery for Stage IV Gastric Cancer. Front Oncol 2019; 9:1158. [PMID: 31788445 PMCID: PMC6854003 DOI: 10.3389/fonc.2019.01158] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 10/17/2019] [Indexed: 12/24/2022] Open
Abstract
The prognosis of stage IV gastric cancer (GC) is poor, with palliative chemotherapy remaining the main therapeutic option. Studies increasingly indicate that patients with unresectable stage IV GC, who undergo gastrectomy with radical intention after responding to several regimens of combined chemotherapy, can achieve good survival outcomes. Thus, surgery aiming at radical resection for unresectable stage IV GC after combined chemotherapy has received increasing attention in recent years. This novel therapeutic strategy was defined as conversion surgery in patients with unresectable stage IV GC and it can associate with significant improved survival when R0 resection can be achieved. Despite the recent advances in conversion surgery for patients with unresectable stage IV GC, selection criteria for combination chemotherapy regimens, indications for conversion surgery, optimal timing to surgery, and postoperative chemotherapy all remain controversial. This article reviews the current state of conversion surgery for unresectable stage IV GC.
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Affiliation(s)
- Fei Zhang
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xuanzhang Huang
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yongxi Song
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Peng Gao
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Cen Zhou
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhexu Guo
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jinxin Shi
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhonghua Wu
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhenning Wang
- Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
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12
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Zhao L, Li J, Bai C, Nie Y, Lin G. Multi-Modality Treatment for Patients With Metastatic Gastric Cancer: A Real-World Study in China. Front Oncol 2019; 9:1155. [PMID: 31737573 PMCID: PMC6839024 DOI: 10.3389/fonc.2019.01155] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 10/16/2019] [Indexed: 12/26/2022] Open
Abstract
Introduction: People with metastatic gastric cancer (GC) have a poor prognosis. The study aims to investigate the efficacy of multi-modality treatment for patients with metastatic GC. Methods: We retrospectively identified 267 patients with stage IV gastric cancer who were treated with systemic chemotherapy: 114 received multi-modality treatments, 153 received systematic chemotherapy alone. The survival of these two groups was compared by log rank test, the independent prognostic factors were investigated using univariate and multivariate analyses. Results: The median survival of metastatic GC patients who received multi-modality treatment was significantly longer than those who received systematic chemotherapy alone (18.4 vs. 11.4 months, P < 0.001). Multivariate analysis identified tumor histologic differentiation, CA19–9 level, previous curative resection, palliative gastrectomy, and metastasectomy as independent prognostic factors for overall survival. In the multimodality treatment group, patients who received palliative gastrectomy or metastasectomy had a longer survival than those who only received intraperitoneal chemotherapy or radiotherapy (21.6 vs. 15.2 months, P = 0.014). Conclusion: Multi-modality treatments offer a survival benefit for patients with metastatic GC. Future prospective studies are needed to confirm the result.
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Affiliation(s)
- Lin Zhao
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jiarui Li
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chunmei Bai
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongdu Nie
- Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guole Lin
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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13
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Sato S, Kunisaki C, Tanaka Y, Sato K, Miyamoto H, Yukawa N, Kosaka T, Akiyama H, Endo I, Misumi T. Curative-Intent Surgery for Stage IV Advanced Gastric Cancer: Who Can Undergo Surgery and What Are the Prognostic Factors for Long-Term Survival? Ann Surg Oncol 2019; 26:4452-4463. [PMID: 31529308 DOI: 10.1245/s10434-019-07790-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND A retrospective study was performed to evaluate the predictive factors for performing curative-intent surgery and prognostic factors for long-term survival of patients undergoing surgery for stage IV gastric cancer. PATIENTS AND METHODS Between 2001 and 2017, 271 patients with stage IV gastric cancer with distant metastasis who underwent systemic chemotherapy were enrolled. Logistic regression analysis was performed to evaluate predictive factors for curative-intent surgery. Cox proportional hazards regression model was applied for patients who were subsequently treated with curative-intent surgery to identify prognostic factors for long-term survival. RESULTS Curative-intent surgery was performed in 48 patients (17.7%). Median survival time was significantly longer in the surgery group than in the nonsurgery group (53 vs. 11 months, p < 0.0001). R0 resection was performed in 35 patients (72.9%). The three-year overall survival (OS) rates of the R0, R1, and R2 surgery groups were 75.4%, 33.3%, and 25.0%, respectively (p = 0.0002). Logistic regression analysis revealed that lymphogenous distant metastasis alone (odds ratio = 3.276, p = 0.004), positive lavage cytology alone (6.394, 0.014), doublet or triplet chemotherapy (4.064, 0.034), and high Glasgow prognostic score (0.276, 0.001) were independent predictive factors for performing curative-intent surgery. Among patients undergoing surgery, the Cox proportional hazards regression model for OS showed that R0 surgery was an independent prognostic factor for favorable OS (hazard ratio 0.188, p = 0.022). CONCLUSIONS Patients with lymphogenous distant metastasis alone, P0CY1 alone, good immunonutritional status, and doublet/triplet chemotherapy are candidates for performing effective curative-intent surgery. R0 surgery is crucial for improving long-term survival after surgery.
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Affiliation(s)
- Sho Sato
- Department of Surgery, Gastroenterological Center, Yokohama City University, Yokohama City, Kanagawa, Japan.,Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama City, Kanagawa, Japan
| | - Chikara Kunisaki
- Department of Surgery, Gastroenterological Center, Yokohama City University, Yokohama City, Kanagawa, Japan.
| | - Yusaku Tanaka
- Department of Surgery, Gastroenterological Center, Yokohama City University, Yokohama City, Kanagawa, Japan
| | - Kei Sato
- Department of Surgery, Gastroenterological Center, Yokohama City University, Yokohama City, Kanagawa, Japan
| | - Hiroshi Miyamoto
- Department of Surgery, Gastroenterological Center, Yokohama City University, Yokohama City, Kanagawa, Japan
| | - Norio Yukawa
- Department of Surgery, Gastroenterological Center, Yokohama City University, Yokohama City, Kanagawa, Japan
| | - Takashi Kosaka
- Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama City, Kanagawa, Japan
| | - Hirotoshi Akiyama
- Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama City, Kanagawa, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Graduate School of Medicine, Yokohama City University, Yokohama City, Kanagawa, Japan
| | - Toshihiro Misumi
- Department of Biostatistics, School of Medicine, Yokohama City University, Yokohama City, Kanagawa, Japan
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14
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Kim IH. Current status of adjuvant chemotherapy for gastric cancer. World J Gastrointest Oncol 2019; 11:679-685. [PMID: 31558973 PMCID: PMC6755106 DOI: 10.4251/wjgo.v11.i9.679] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 07/18/2019] [Accepted: 08/21/2019] [Indexed: 02/05/2023] Open
Abstract
Although radical gastrectomy is a standard treatment for advanced gastric cancer, recurrence remains high. After several large-scale controlled studies have shown the beneficial effects of adjuvant chemotherapy, that treatment emerged as a standard option for advanced gastric cancer after gastrectomy. However, various guidelines from different countries have suggested different adjuvant chemotherapies. Understanding the differences between guidelines is very important for investigating further therapeutic strategies. Fortunately, because there are many ongoing studies about new regimens for adjuvant treatment, it is expected that patients with gastric cancer after surgery will have better outcome.
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Affiliation(s)
- In-Hwan Kim
- Department of Surgery, Catholic University of Daegu, Daegu 42472, South Korea
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Maki H, Yuasa Y, Fujiwara S, Fukuta M, Takeuchi T, Fujimoto K, Tsuneki T, Matsuo Y, Mori O, Eto S, Tomibayashi A, Ishikura H. Unresectable Advanced Gastric Cancer with Skin Invasion followed by Total Gastrectomy after Second-Line Chemotherapy. Case Rep Oncol 2019; 12:671-680. [PMID: 31572157 PMCID: PMC6751414 DOI: 10.1159/000502415] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 07/25/2019] [Indexed: 11/24/2022] Open
Abstract
Conversion surgery has been reported but few cases have undergone surgical R0 resection after second-line chemotherapy. We report a case of an unresectable locally advanced gastric cancer in a patient who finally underwent the operation (R0) after second-line chemotherapy. The 77-year-old male was diagnosed with gastric cancer (cT4 [SI; Skin, Liver] N0M0 c Stage IIIA) with invasion to the skin of the abdominal wall, and chemotherapy was initially performed because of his poor performance status and due to the large defect in the abdominal wall that might occur if an operation was performed. Partial response (PR) was observed after S-1+CDDP (SP) therapy, which was then stopped after which progressive disease (PD) was observed. Ramucirumab+Paclitaxel (RAM/PTX) therapy was chosen as second-line therapy, and PR was obtained again, following which total gastrectomy was performed (D2 dissection of lymph nodes, Roux-en-Y reconstruction, and combined resection of the partial skin and the affected region of the liver). At 30 months postoperatively, no recurrence has occurred and the patient is alive after the operation without chemotherapy.
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Affiliation(s)
- Hidenori Maki
- Department of Surgery, Tokushima Red Cross Hospital, Komatsushima City, Japan
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Chen Z, Wei H, Zhao X, Xin X, Peng L, Ning Y, Wang Y, Lan Y, Zhang Q. Metformin treatment alleviates polycystic ovary syndrome by decreasing the expression of MMP‐2 and MMP‐9 via H19/miR‐29b‐3p and AKT/mTOR/autophagy signaling pathways. J Cell Physiol 2019; 234:19964-19976. [PMID: 30989649 DOI: 10.1002/jcp.28594] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Revised: 03/01/2019] [Accepted: 03/06/2019] [Indexed: 12/27/2022]
Affiliation(s)
- Zhilan Chen
- Department of Obstetrics and Gynecology The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Huafang Wei
- Department of Obstetrics and Gynecology Central Theater General Hospital of PLA Wuhan China
| | - Xiaoling Zhao
- Department of Obstetrics and Gynecology Central Theater General Hospital of PLA Wuhan China
| | - Xin Xin
- Department of Obstetrics and Gynecology The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Ling Peng
- Department of Obstetrics and Gynecology The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Yang Ning
- Department of Obstetrics and Gynecology The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Yapei Wang
- Department of Obstetrics and Gynecology The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
| | - Yanli Lan
- Department of Obstetrics and Gynecology Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science Xiangyang China
| | - Qinghua Zhang
- Department of Obstetrics and Gynecology The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology Wuhan China
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Chelakkot PG, Ravind R, Sruthi K, Menon D. Treatment in resectable non-metastatic adenocarcinoma of stomach: Changing paradigms. Indian J Cancer 2019; 56:74-80. [PMID: 30950450 DOI: 10.4103/ijc.ijc_375_18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
Adjuvant treatment in gastric adenocarcinoma has been a challenge for the treating specialists, and despite several trials, a clear consensus is yet to be defined. The higher propensity for lymph nodal involvement and locoregional recurrences led to the hypothesis that locoregional and systemic treatments need to be equally aggressive to achieve better outcomes in the management of gastric adenocarcinoma. Regional, ethnic, and biological differences between the Eastern and Western population are also found to reflect in the tumor behavior and its response to treatment. The MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy), Intergroup 0116, ACTS-GC (Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer), CLASSIC (Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer), ARTIST (Adjuvant Chemoradiation Therapy in Stomach Cancer), and the recently published CRITICS (Chemoradiotherapy after Induction Chemotherapy in Cancer of the Stomach) trials were a few of the randomized controlled trials that tried to give a clearer perspective of this tumor, though it still remains a dilemma. A study incorporating the tumor and demographic factors along with the availability of skilled talent and resources might generate an answer.
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Affiliation(s)
- Prameela G Chelakkot
- Department of Oncology, Sevana Hospital and Research Centre, Pattambi, Palakkad District, Kerala, India
| | - Rahul Ravind
- Department of Medical Oncology, Tata Memorial Hospital, Mumbai, Maharashtra, India
| | - K Sruthi
- Department of Radiation Oncology, Amrita Institute of Medical Sciences, Amrita Vishwa Vidyapeetham, Amrita University, Cochin, Kerala, India
| | - Durgapoorna Menon
- Department of Radiation Oncology, Aster Hospital, Cochin, Kerala, India
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18
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Plastin3 is associated with epithelial-mesenchymal transition and poor prognosis in gastric cancer. Oncol Lett 2018; 17:2393-2399. [PMID: 30675305 PMCID: PMC6341793 DOI: 10.3892/ol.2018.9819] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 12/04/2018] [Indexed: 01/26/2023] Open
Abstract
The plastin3 (PLS3) gene, which encodes an actin bundling protein known to inhibit cofilin-mediated depolymerization of actin fiber, has been previously reported to serve an important role in the epithelial-mesenchymal transition (EMT) in cancer. The aim of the present study was to determine the clinical significance of PLS3 and its role in regulating EMT, as well as in promoting cell invasion and migration in gastric cancer. The expression of plastin3 mRNA was measured in 163 resected gastric cancer specimens, in order to determine the clinicopathological significance. Furthermore, in vitro invasion and migration assays were performed on gastric cancer cells, which revealed that PLS3 expression was suppressed. The high PLS3 expression group had a higher incidence of advanced tumour stage, cancer differentiation, tumour invasion depth and distant metastases compared with the low PLS3 expression group (P<0.05). In addition, the high PLS3 expression group had a significantly poorer prognosis than the low expression group (P=0.012). Multivariate analysis indicated that high PLS3 expression was an independent prognostic factor for survival. The present study also identified that suppression of PLS3 in gastric cancer cells was associated with decreased cell invasion and migration. The findings from the present study indicate that high expression of PLS3 in gastric cancer is independently associated with a poor prognosis, and that PL3 serves an important role in EMT.
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19
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Tang CT, Liang Q, Yang L, Lin XL, Wu S, Chen Y, Zhang XT, Gao YJ, Ge ZZ. RAB31 Targeted by MiR-30c-2-3p Regulates the GLI1 Signaling Pathway, Affecting Gastric Cancer Cell Proliferation and Apoptosis. Front Oncol 2018; 8:554. [PMID: 30534536 PMCID: PMC6275292 DOI: 10.3389/fonc.2018.00554] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 11/08/2018] [Indexed: 12/13/2022] Open
Abstract
Background: Gastric cancer (GC), one of the most common cancers worldwide, is highly malignant and fatal. Ras-related protein in brain 31 (RAB31), a member of the RAB family of oncogenes, participates in the process of carcinogenesis and cancer development; however, its role in GC progression is unknown. Methods: In our study, 90 pairs of tissue microarrays were used to measure the levels of RAB31 protein by immunochemistry, and 22 pairs of fresh tissue were used to measure the levels of RAB31 mRNA by quantitative PCR. We also investigated the effects of RAB31 on tumor growth both in vitro and in vivo. Results: RAB31 was overexpressed in GC tissues, and its overexpression predicted poor survival in patients. In a nude mouse model, depletion of RAB31 inhibited tumor growth. In vitro, silencing of RAB31 suppressed cell viability, promoted cell cycle arrest, enhanced apoptosis, and affected the expression of cell cycle and apoptotic proteins; these effects were mediated by glioma-associated oncogene homolog 1 (GLI1). Co-immunoprecipitation and immunofluorescence assays confirmed that RAB31 interacted with GLI1. In addition, luciferase reporter assays and Western blotting showed that microRNA-30c-2-3p modulated the RAB31/GLI1 pathway by targeting the 3′-untranslated region of RAB31. Conclusions: Collectively, these data show that RAB31 is regulated by microRNA-30c-2-3p, and functions as an oncogene in GC tumorigenesis and development by interacting with GLI1. Therefore, targeting the miR-30c-2-3p/RAB31/GLI1 axis may be a therapeutic intervention for gastric cancer.
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Affiliation(s)
- Chao-Tao Tang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Qian Liang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Li Yang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xiao-Lu Lin
- Department of Digestive Endoscopy, Provincial Clinic Medical College, Fujian Medical University, Fujian Provincial Hospital, Fuzhou, China
| | - Shan Wu
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yong Chen
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xin-Tian Zhang
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yun-Jie Gao
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhi-Zheng Ge
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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20
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Song Y, Zhao N, Jiang K, Zheng Z, Wang B, Kong D, Li S. Occurrence of metachronous multiple primary cancers occurred in different parts of the stomach with 2 pathologic features: A case report. Medicine (Baltimore) 2018; 97:e10803. [PMID: 29768377 PMCID: PMC5976309 DOI: 10.1097/md.0000000000010803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
RATIONALE With the increasing survival rate of gastric cancer, more multiple primary cancers (MPC) have been reported. However, few cases involve metachronous multiple primary cancers which both occurred in the stomach. PATIENT CONCERNS An 83-year-old Chinese male had been diagnosed with gastric cardia cancer and underwent proximal gastrectomy. The pathological result was gastric adenocarcinoma. 13 years later the patient's gastroscope result deteriorated. The biopsy of the antrum revealed dysplasia with doubtful focal cancerization. DIAGNOSES Metachronous multiple primary cancers in the stomach. INTERVENTIONS Endoscopic submucosal dissection (ESD) was performed. The pathological result showed an intra-mucosal signet-ring carcinoma. OUTCOMES After treatment, the patient is alive with good condition until now. LESSONS This is an unusual case of MPC with different pathological features in different parts of the same organ in an interval of more than ten years and undergoing different operations.
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Affiliation(s)
- Yan Song
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin
| | - Ningning Zhao
- Department of Gastroenterology and Hepatology, Hebei Province Cangzhou Hospital of Integrated Traditional and Western Medicine, Cangzhou, Hebei Province
| | - Kui Jiang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin
| | - Zhongqing Zheng
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin
| | - Bangmao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin
| | - Dalu Kong
- Department of Hepatobiliary Surgery, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Shu Li
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin
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21
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Kim IH, Park SS, Lee CM, Kim MC, Kwon IK, Min JS, Kim HI, Lee HH, Lee SI, Chae H. Efficacy of Adjuvant S-1 Versus XELOX Chemotherapy for Patients with Gastric Cancer After D2 Lymph Node Dissection: A Retrospective, Multi-Center Observational Study. Ann Surg Oncol 2018; 25:1176-1183. [PMID: 29450755 DOI: 10.1245/s10434-018-6375-z] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND After curative resection of gastric cancer with D2 lymph node dissection, postoperative adjuvant chemotherapy with S-1 or capecitabine plus oxaliplatin (XELOX) is considered to be standard therapy in Eastern countries. This study aimed to compare the efficacies of adjuvant S-1 and XELOX chemotherapy for gastric cancer patients after D2 dissection based on disease-free survival (DFS). METHODS This retrospective observational study was conducted at 29 tertiary hospitals in Korea. Of 1898 patients who underwent curative resection and received adjuvant chemotherapy for gastric cancer between February 2012 and December 2013, 1088 patients who met the eligibility criteria were enrolled in the study. After propensity score-matching, the 3-year disease-free survival rate (DFS) was used to compare efficacies directly between adjuvant XELOX and S-1 chemotherapies for patients with stage 2 or 3 gastric cancer after D2 gastrectomy. RESULTS The 3-year DFS rates for the S-1 and XELOX groups did not differ significantly among disease stages 2A, 2B, and 3A (all p > 0.05). However, the survival rates for the S-1 group were significantly lower than for the XELOX group for stage 3B (65.8% vs. 68.6%; p = 0.019) and stage 3C (48.4% vs. 66.7%; p = 0.002) gastric cancer. The hazard ratios (HRs) of S-1 chemotherapy for recurrence compared with XELOX for stages 3B and 3C were respectively 2.030 [95% confidence interval (CI), 1.110-3.715; p = 0.022] and 2.732 (95% CI 1.427-5.234; p = 0.002). CONCLUSIONS Adjuvant XELOX chemotherapy was more effective than S-1 for patients with stage 3B or 3C gastric cancer after D2 lymph node dissection.
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Affiliation(s)
- In-Hwan Kim
- Department of Surgery, Daegu Catholic University School of Medicine, Daegu, South Korea
| | - Sung-Soo Park
- Department of Surgery, Korea University College of Medicine and School of Medicine, Seoul, South Korea
| | - Chang-Min Lee
- Department of Surgery, Korea University College of Medicine and School of Medicine, Seoul, South Korea
| | - Min Chan Kim
- Department of Surgery, Dong-A University School of Medicine, Busan, South Korea
| | - In-Kyu Kwon
- Department of Surgery, Keimyung University School of Medicine, Daegu, South Korea
| | - Jae-Seok Min
- Department of Surgery, Dongnam Institute of Radiological and Medical Sciences, Busan, South Korea
| | - Hyoung-Il Kim
- Department of Surgery, Yonsei University School of Medicine, Seoul, South Korea
| | - Han Hong Lee
- Department of Surgery, Seoul St. Mary's Hospital, Seoul, South Korea
| | - Sang-Il Lee
- Department of Surgery, Chungnam National University School of Medicine, Daejeon, South Korea
| | - Hyundong Chae
- Department of Surgery, Daegu Catholic University School of Medicine, Daegu, South Korea.
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22
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Yamaguchi K, Yoshida K, Tanahashi T, Takahashi T, Matsuhashi N, Tanaka Y, Tanabe K, Ohdan H. The long-term survival of stage IV gastric cancer patients with conversion therapy. Gastric Cancer 2018; 21:315-323. [PMID: 28616743 PMCID: PMC5846815 DOI: 10.1007/s10120-017-0738-1] [Citation(s) in RCA: 105] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 06/05/2017] [Indexed: 02/07/2023]
Abstract
PURPOSE A retrospective study was performed to clarify the role of conversion therapy (surgery with a prospect of R0 resection performed in initially unresectable metastatic cancer that responded to the chemotherapy) in stage IV gastric cancer (GC). PATIENTS AND METHODS We treated 259 stage IV GC patients with systemic chemotherapy at Gifu and Hiroshima University Hospitals between 2001-2013. Of these, 84 patients who were subsequently treated by surgery were classified into four categories according to our previously published classification of stage IV GC, and short- and long-term outcomes were analyzed. RESULTS Surgery was performed in 84 patients, of which 7 were performed following the neoadjuvant chemotherapy, whereas the other 77 that excluded neoadjuvant chemotherapy cases were considered the conversion therapy. The postoperative mortality and morbidity were comparable with those reported clinical trials. The MSTs of the patients with/without surgery for each category were 28.3/5.8 months for category 1, 30.5/11.0 months for category 2, 31.0/18.5 months for category 3 and 24.7/10.0 months for category 4. The MST of the R0 resected patients (41.3 months) was far better than that of the R1-2 resected patients (21.2 months). The MSTs of the patients with R0/R1-2 resection were 56.2/16.3 months for category 2, 33.3/29.6 months for category 3 and 40.7/17.8 months for category 4. CONCLUSION There were long-term survivors who underwent conversion therapy for stage IV GC. Adequate selection of stage IV GC patients for conversion therapy may be an important role for the surgical oncologist in the new era.
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Affiliation(s)
- Kazuya Yamaguchi
- Department of Surgical Oncology, Gifu University, 1-1 Yanagido, Gifu, 501-1194 Japan
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Gifu University, 1-1 Yanagido, Gifu, 501-1194 Japan
| | - Toshiyuki Tanahashi
- Department of Surgical Oncology, Gifu University, 1-1 Yanagido, Gifu, 501-1194 Japan
| | - Takao Takahashi
- Department of Surgical Oncology, Gifu University, 1-1 Yanagido, Gifu, 501-1194 Japan
| | - Nobuhisa Matsuhashi
- Department of Surgical Oncology, Gifu University, 1-1 Yanagido, Gifu, 501-1194 Japan
| | - Yoshihiro Tanaka
- Department of Surgical Oncology, Gifu University, 1-1 Yanagido, Gifu, 501-1194 Japan
| | - Kazuaki Tanabe
- Division of Frontier Medical Science, Department of Surgery, Graduate School of Biomedical Sciences Hiroshima University, Hiroshima, Japan
| | - Hideki Ohdan
- Division of Frontier Medical Science, Department of Surgery, Graduate School of Biomedical Sciences Hiroshima University, Hiroshima, Japan
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23
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Yeh JM, Tramontano AC, Hur C, Schrag D. Comparative effectiveness of adjuvant chemoradiotherapy after gastrectomy among older patients with gastric adenocarcinoma: a SEER-Medicare study. Gastric Cancer 2017; 20:811-824. [PMID: 28205057 PMCID: PMC5557693 DOI: 10.1007/s10120-017-0693-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 01/14/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Since the INT-0116 trial reported a survival advantage, postoperative chemoradiotherapy (CRT) has been a care standard for US patients in whom gastric adenocarcinoma has been diagnosed. We sought to estimate the association between treatment and survival among the older US Medicare population. METHODS This is a retrospective cohort study of Medicare beneficiaries aged 65-79 years with stage IB-III gastric adenocarcinoma diagnosed between 2002 and 2009 in a Surveillance, Epidemiology, and End Results region. Patients were categorized on the basis of treatment: (1) gastrectomy only and (2) gastrectomy plus adjuvant CRT. We examined factors associated with receipt of adjuvant CRT, including stage at diagnosis, comorbidity, and tumor subtype. Overall survival was measured from 90 days after gastrectomy until death or the censoring date of December 31, 2010. RESULTS Of the 1519 patients who underwent gastrectomy, 41.7% received adjuvant CRT. Factors associated with adjuvant CRT included age younger than 75 years at cancer diagnosis and stage II or stage III cancer. The median overall survival from the time of gastrectomy was 25.1 months (interquartile range 43.7 months) for gastrectomy only and 26.9 months (interquartile range 40.9 months) for adjuvant CRT. Multivariable and propensity-score-stratified models demonstrated a survival benefit associated with adjuvant CRT [hazard ratio (HR) 0.58; 95% confidence interval (CI) 0.50-0.67], although the magnitude was greater for stage II tumors (HR 0.50; 95% CI 0.39-0.61) and stage III tumors (HR 0.58; 95% CI 0.45-0.73) than for stage IB tumors (HR 1.02; 95% CI 0.71-1.45). CONCLUSIONS Adjuvant CRT, in conjunction with gastrectomy, was associated with a survival benefit among older patients with stage II or stage III tumors.
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Affiliation(s)
- Jennifer M. Yeh
- Division of General Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA,Center for Health Decision Science, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Angela C. Tramontano
- Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA, USA
| | - Chin Hur
- Institute for Technology Assessment, Massachusetts General Hospital, Boston, MA, USA
| | - Deborah Schrag
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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24
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Kataoka K, Kinoshita T, Moehler M, Mauer M, Shitara K, Wagner AD, Schrauwen S, Yoshikawa T, Roviello F, Tokunaga M, Boku N, Ducreux M, Terashima M, Lordick F. Current management of liver metastases from gastric cancer: what is common practice? New challenge of EORTC and JCOG. Gastric Cancer 2017; 20:904-912. [PMID: 28150070 DOI: 10.1007/s10120-017-0696-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Accepted: 01/18/2017] [Indexed: 02/07/2023]
Abstract
The role of multidisciplinary treatment including surgery for liver metastases from gastric cancer (LMGC) is controversial. Studies to answer this clinical question are increasing in number, but all published data thus far are based on retrospective analyses with limited sample sizes. Thus, the European Organisation for Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cancer Group (GITCG) and the Japan Clinical Oncology Group (JCOG) Stomach Cancer Study Group (SCSG) initiated a collaboration to develop an optimal treatment strategy for LMGC. Before planning a prospective study, a questionnaire was sent out to the network members of both groups in June 2016 to clarify current common practice in each region. Sixty-seven sites from 17 countries in the EORTC network and 55 sites from Japan responded. According to the survey, for patients with resectable LMGC without extrahepatic metastases, preoperative chemotherapy followed by resection of both primary (if still in place) and liver lesions was the preferred option for both the synchronous and the metachronous setting. For patients with unresectable LMGC, most of the sites recommended chemotherapy only. In this article, the detailed results of this survey are reported, shedding light on current community practice, and a joint EORTC-JCOG strategy of investigation is delineated.
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Affiliation(s)
- Kozo Kataoka
- European Organisation for Research and Treatment of Cancer (EORTC) Headquarters, Avenue E, Mounier 83/11, 1200, Brussels, Belgium.
| | - Takahiro Kinoshita
- Department of Gastric Surgery Division, National Cancer Center Hospital East, Chiba, Japan
| | - Markus Moehler
- First Department of Internal Medicine, Johannes Gutenberg-University of Mainz, Mainz, Germany
| | - Murielle Mauer
- European Organisation for Research and Treatment of Cancer (EORTC) Headquarters, Avenue E, Mounier 83/11, 1200, Brussels, Belgium
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, National Cancer Center Hospital East, Chiba, Japan
| | | | - Stefanie Schrauwen
- European Organisation for Research and Treatment of Cancer (EORTC) Headquarters, Avenue E, Mounier 83/11, 1200, Brussels, Belgium
| | - Takaki Yoshikawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Franco Roviello
- General Surgery and Surgical Oncology Department, University of Siena, Siena, Italy
| | - Masanori Tokunaga
- Division of Gastric Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Narikazu Boku
- Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan
| | - Michel Ducreux
- Department of Medical Oncology, Gustave Roussy, Villejuif, France
| | | | - Florian Lordick
- University Cancer Center Leipzig (UCCL), University Hospital Leipzig, Liebigstr. 20, 04103, Leipzig, Germany.
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25
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Qiu X, Zhu H, Liu S, Tao G, Jin J, Chu H, Wang M, Tong N, Gong W, Zhao Q, Qiang F, Zhang Z. Expression and prognostic value of microRNA-26a and microRNA-148a in gastric cancer. J Gastroenterol Hepatol 2017; 32:819-827. [PMID: 27529338 DOI: 10.1111/jgh.13533] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/10/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM In our previous study, we demonstrated that four microRNAs (miRNAs) (miR-26a, miR-142-3p, miR-148a, and miR-195) that were downregulated in both plasma and tumor tissues were confirmed to be promising non-invasive diagnostic biomarkers for gastric cancer (GC). METHODS We used the quantitative reverse transcription polymerase chain reaction to assess the expression levels of the four miRNAs from paraffin-embedded surgical specimens of GC patients. Kaplan-Meier curves and log-rank test were applied to predict the correlation between miRNAs and cumulative overall survival (OS) of patients with GC. Besides, we performed in vitro assays including cell proliferation, migration, invasion and colony formation, and apoptosis. RESULTS The median of miRNA expression in paraffin-embedded tissues were used as the cutoff value to classify patients into high or low expression groups. Down-regulation of miR-26a and miR-148a was significantly associated with shorter OS of GC patients either in the test set (miR-26a: P = 0.009; miR-148a: P = 0.005) or the validation set (miR-26a: P = 0.011; miR-148a: P = 0.024). When two sets were combined, Cox regression analysis demonstrated that both of miR-26a and miR-148a were independent prognostic factors for predicting OS of patients with GC (miR-26a: HR = 0.76, 95% CI = 0.61-0.94; miR-148a: HR = 0.73, 95% CI = 0.58-0.91). Furthermore, elevated expression of miR-26 significantly suppressed cell proliferation, migration, invasion and colony formation, and induced apoptosis of MGC-803 cells compared with negative control groups (P < 0.05). CONCLUSION These findings supported miR-26a and miR-148a could serve as potential prognostic biomarkers for GC.
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Affiliation(s)
- Xiaonan Qiu
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Haixia Zhu
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Core Laboratory, Nantong Tumor Hospital, Nantong, China
| | - Sang Liu
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Guoquan Tao
- Department of General Surgery, Huai-An First People's Hospital Affiliated to Nanjing Medical University, Huai-An, China
| | - Jing Jin
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Haiyan Chu
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Meilin Wang
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Na Tong
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Weida Gong
- Department of General Surgery, Yixing Cancer Hospital, Yixing, China
| | - Qinghong Zhao
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Fulin Qiang
- Core Laboratory, Nantong Tumor Hospital, Nantong, China
| | - Zhengdong Zhang
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
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26
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Yamaguchi K, Yoshida K, Tanaka Y, Matsuhashi N, Tanahashi T, Takahashi T. Conversion therapy for stage IV gastric cancer-the present and future. Transl Gastroenterol Hepatol 2016; 1:50. [PMID: 28138617 DOI: 10.21037/tgh.2016.05.12] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Accepted: 05/30/2016] [Indexed: 12/27/2022] Open
Affiliation(s)
- Kazuya Yamaguchi
- Department of Surgical Oncology, Gifu University, Graduate School of Medicine, Gifu, Japan
| | - Kazuhiro Yoshida
- Department of Surgical Oncology, Gifu University, Graduate School of Medicine, Gifu, Japan
| | - Yoshihiro Tanaka
- Department of Surgical Oncology, Gifu University, Graduate School of Medicine, Gifu, Japan
| | - Nobuhisa Matsuhashi
- Department of Surgical Oncology, Gifu University, Graduate School of Medicine, Gifu, Japan
| | - Toshiyuki Tanahashi
- Department of Surgical Oncology, Gifu University, Graduate School of Medicine, Gifu, Japan
| | - Takao Takahashi
- Department of Surgical Oncology, Gifu University, Graduate School of Medicine, Gifu, Japan
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27
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Is conversion therapy possible in stage IV gastric cancer: the proposal of new biological categories of classification. Gastric Cancer 2016; 19:329-338. [PMID: 26643880 PMCID: PMC4824831 DOI: 10.1007/s10120-015-0575-z] [Citation(s) in RCA: 216] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 11/06/2015] [Indexed: 02/07/2023]
Abstract
Conversion therapy for gastric cancer (GC) has been the subject of much recent attention. It is defined as a surgical treatment aiming at an R0 resection after chemotherapy for tumors that were originally unresectable or marginally resectable for technical and/or oncological reasons. However, the indications for resection remain to be clarified. In the present review, we focus on the biology and heterogeneous characteristics of stage IV GC and propose new categories of classification. Stage IV GC patients can be divided based on the absence (categories 1 and 2) or presence (categories 3 and 4) of macroscopically detectable peritoneal dissemination, which has a different biological outcome compared to hematological metastasis. Category 1 is defined oncologically as stage IV but the metastasis is technically resectable. Category 2 includes a marginally resectable metastasis or patients for whom the operation would not necessarily be the best choice. Category 3 includes a potentially unresectable metastasis of peritoneal dissemination that is only macroscopically detectable. Category 4 includes noncurable metastasis with peritoneal and other organ metastasis. The indications for conversion therapy might include the patients from category 2, some patients from category 3 and a very small number of patients from category 4. The longer survival can be expected for patients corresponding to categories 1, 2 and, to a lesser extent, 3, while the treatment of other patients focuses on "care." The provision of conversion therapy for stage IV GC patients might be one of the main roles of surgical oncologists in the near future.
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28
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Takano J, Morishita A, Fujihara S, Iwama H, Kokado F, Fujikawa K, Fujita K, Chiyo T, Tadokoro T, Sakamoto T, Nomura T, Tani J, Miyoshi H, Yoneyama H, Kobara H, Mori H, Niki T, Hirashima M, Masaki T. Galectin-9 suppresses the proliferation of gastric cancer cells in vitro. Oncol Rep 2015; 35:851-60. [PMID: 26717877 DOI: 10.3892/or.2015.4452] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 10/26/2015] [Indexed: 11/06/2022] Open
Abstract
Gastric cancer is the second-leading cause of cancer-related mortality worldwide, and the prognosis of advanced gastric cancer remains poor. Galectin-9 (Gal-9) is a tandem-repeat-type galectin that has recently been demonstrated to exert anti-proliferative effects on various types of cancer cells. The aim of our present study was to evaluate the effects of Gal-9 on human gastric cancer cells and the expression levels of microRNAs (miRNAs) associated with the antitumor effects of Gal-9 in vitro. In our initial experiments, Gal-9 suppressed the proliferation of gastric cancer cell lines in vitro. Our data further revealed that Gal-9 increased caspase-cleaved keratin 18 (CCK18) levels in gastric cancer cells. Additionally, Gal-9 reduced the phosphorylation of vascular endothelial growth factor receptor-3 (VEGFR-3) and insulin-like growth factor-1 receptor (IGF-1R). Furthermore, miRNA expression levels were markedly altered with Gal-9 treatment in vitro. In conclusion, Gal-9 suppressed the proliferation of human gastric cancer cells by inducing apoptosis. These findings suggest that Gal-9 could be a potential therapeutic target in the treatment of gastric cancer.
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Affiliation(s)
- Jitsuko Takano
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Asahiro Morishita
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Shintaro Fujihara
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Hisakazu Iwama
- Life Science Research Center, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Fuyuko Kokado
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Keiko Fujikawa
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Koji Fujita
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Taiga Chiyo
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Tomoko Tadokoro
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Teppei Sakamoto
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Takako Nomura
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Joji Tani
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Hisaaki Miyoshi
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Hirohito Yoneyama
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Hirohito Mori
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Toshihiro Niki
- Department of Immunology and Immunopathology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Mitsuomi Hirashima
- Department of Immunology and Immunopathology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, Kagawa 761-0793, Japan
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29
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Stollfuss J, Landvogt N, Abenstein M, Ziegler S, Schwaiger M, Senekowitsch-Schmidtke R, Wieder H. Non-invasive imaging of implanted peritoneal carcinomatosis in mice using PET and bioluminescence imaging. EJNMMI Res 2015; 5:125. [PMID: 26337805 PMCID: PMC4559549 DOI: 10.1186/s13550-015-0125-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2015] [Accepted: 08/25/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Non-invasive imaging of peritoneal carcinomatosis remains challenging. The aim of this study was to compare positron emission tomography (PET) and bioluminescence imaging (BLI) for the early detection of peritoneal carcinomatosis in a mouse model. METHODS Female nude mice were inoculated intraperitoneally with 1×10(7) HSC45-M2-luc gastric cancer cells. The cells were stably transfected with the gene coding for firefly luciferase. Tumour development was monitored using PET and BLI and in two subgroups, on days 3 and 4 or on days 6 and 7 after tumour cell inoculation. Tumour nodules found on post mortem examination served as the reference standard for evaluating the images. RESULTS PET detected 58/82 lesions (sensitivity 71 %). This method detected all (100 %) nodules larger than 6 mm, 88 % of nodules in the range of >2-4 mm, and even 58 % of small nodules measuring only 1-2 mm. BLI identified a total of 40/82 lesions (sensitivity 49 %). The difference between PET and BLI was statistically significant at p < 0.05 (PET/BLI chi-square 8.2). CONCLUSIONS PET was more sensitive than BLI for the detection of early peritoneal carcinomatosis in our mouse model. The sensitivity of BLI largely depended on the site of the lesions in relation to the imaging device.
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Affiliation(s)
- J Stollfuss
- Department of Radiology and Nuclear Medicine, Klinikum Memmingen, Memmingen, Germany,
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Kim JW, Jang JY, Chang YW, Kim YH. Clinical features of second primary cancers arising in early gastric cancer patients after endoscopic resection. World J Gastroenterol 2015; 21:8358-8365. [PMID: 26217087 PMCID: PMC4507105 DOI: 10.3748/wjg.v21.i27.8358] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Revised: 04/07/2015] [Accepted: 05/21/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the incidence and distribution of second primary cancers (SPCs) in early gastric cancer (EGC) patients who underwent endoscopic resection (ER), compared to advanced gastric cancer (AGC) patients who underwent surgery.
METHODS: The medical records of 1021 gastric cancer (GC) patients were retrospectively reviewed from January 2006 to December 2010. The characteristics and incidence of SPCs were investigated in those with EGC that underwent curative ER (the EGC group) and those with AGC who underwent curative surgical resection (the AGC group).
RESULTS: We ultimately enrolled 184 patients in the EGC group and 229 patients in the AGC group. A total of 38 of the 413 (9.2%) GC patients had SPCs; the rate was identical in both groups. Of these 38 patients, 18 had synchronous and 20 had metachronous cancers. The most common SPC was lung cancer (18.4%), followed by colorectal cancer (13.2%) and esophageal cancer (13.2%). No significant risk factors were identified for the development of SPCs.
CONCLUSION: Endoscopists should provide close surveillance and establish follow-up programs to ensure SPC detection in GC patients undergoing curative resection regardless of their clinical characteristics.
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Deregulation between miR-29b/c and DNMT3A is associated with epigenetic silencing of the CDH1 gene, affecting cell migration and invasion in gastric cancer. PLoS One 2015; 10:e0123926. [PMID: 25874772 PMCID: PMC4398372 DOI: 10.1371/journal.pone.0123926] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Accepted: 03/09/2015] [Indexed: 12/26/2022] Open
Abstract
The de-regulation of the miR-29 family and DNA methyltransferase 3A (DNMT3A) is associated with gastric cancer (GC). While increasing evidence indicates miR-29b/c could regulate DNA methylation by targeting DNMT3A, it is currently unknown if epigenetic silencing of miR-29b/c via promoter hypermethylation in GC is caused by abnormal expression of DNMT3A. Thus, we aimed to evaluate whether cross-talk regulation exists between miR-29b/c and DNMT3A and whether it is associated with a malignant phenotype in GC. First, wound healing and Transwell assays revealed that miR-29b/c suppresses tumor metastasis in GC. A luciferase reporter assay demonstrated that DNMT3A is a direct target of miR-29b/c. We used bisulfite genomic sequencing to analyze the DNA methylation status of miR-29b/c. The percentage of methylated CpGs was significantly decreased in DNMT3A-depleted cells compared to the controls. Furthermore, the involvement of DNMT3A in promoting GC cell migration was associated with the promoter methylation-mediated repression of CDH1. In 50 paired clinical GC tissue specimens, decreased miR-29b/c was significantly correlated with the degree of differentiation and invasion of the cells and was negatively correlated with DNMT3A expression. Together, our preliminary results suggest that the following process may be involved in GC tumorigenesis. miR-29b/c suppresses the downstream gene DNMT3A, and in turn, miR-29b/c is suppressed by DNMT3A in a DNA methylation-dependent manner. The de-regulation of both of miR-29b/c and DNMT3A leads to the epigenetic silencing of CDH1 and contributes to the metastasis phenotype in GC. This finding reveals that DNA methylation-associated silencing of miR-29b/c is critical for GC development and thus may be a therapeutic target.
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Kwon IG, Cho I, Choi YY, Hyung WJ, Kim CB, Noh SH. Risk factors for complications during surgical treatment of remnant gastric cancer. Gastric Cancer 2015; 18:390-6. [PMID: 24705942 DOI: 10.1007/s10120-014-0369-8] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2013] [Accepted: 03/09/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Surgical treatment for remnant gastric cancer is related to high mortality and morbidity. The aim of this study was to identify risk factors that predispose to postoperative complications after gastrectomy for remnant gastric cancer. METHODS A total of 210 patients who underwent a gastrectomy for remnant gastric cancer between January 1998 and December 2012 were retrospectively analyzed. Surgical complications were reviewed and graded using the Clavien-Dindo classification. Univariate and multivariate analysis was performed to identify the risk factors for development of complications. RESULTS The incidence of postoperative complications was 46% (96/210), and major complications occurred in 14% (30/210). The operation-related mortality rate was 1.0%. Multivariate analysis revealed that only a BMI ≥25 (P = 0.001) and blood transfusion (P < 0.001) were significant independent risk factors for major complication. Indication for the initial gastrectomy and previous anastomosis type were not related to the development of surgical complications. CONCLUSIONS Although surgery for remnant gastric cancer is a complex procedure because of the previous operation, factors related to the previous operation do not affect the development of postoperative complications.
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Affiliation(s)
- In Gyu Kwon
- Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Korea
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Han G, Gong H, Wang Y, Guo S, Liu K. AMPK/mTOR-mediated inhibition of survivin partly contributes to metformin-induced apoptosis in human gastric cancer cell. Cancer Biol Ther 2015; 16:77-87. [PMID: 25456211 PMCID: PMC4622954 DOI: 10.4161/15384047.2014.987021] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 09/22/2014] [Accepted: 11/09/2014] [Indexed: 01/04/2023] Open
Abstract
Recent studies demonstrated that metformin exerts anti-neoplastic effect in a spectrum of malignancies. However, the mechanism whereby metformin affects various cancers, including gastric cancer, is poorly elucidated. Considering apoptosis plays critical role in tumorigenesis, we, in the present study, investigated the in vitro apoptotic effect of metformin on human gastric cancer cell and the underlying mechanism. Three differently-differentiated gastric cancer cell lines, MKN-28, SGC-7901 and BGC-823, along with one noncancerous gastric cell line GES-1 were used. We found that metformin treatment selectively induces apoptosis in the 3 cancer cell lines, but not the noncancerous one, as confirmed by flow cytometry, Caspase-Glo assay and western blotting against PARP and cleaved caspase 3. Moreover, the apoptotic effect of metformin seems to correlate negatively with the differentiation degree of gastric cancer. Metformin-induced apoptosis may be partially mediated through inhibition of anti-apoptotic survivin. Additionally, AMPK and mTOR, 2 important regulatory molecules responsible for metformin action, were investigated for their possible involvements in metformin-induced apoptosis of gastric cancer cell. AMPK knockdown by siRNA restores metformin-inhibited survivin expression and partially abolishes metformin-induced apoptosis. Similarly, forced overexpression of mTOR downstream effector p70S6K1 relieves metformin-induced inhibition of survivin and partly attenuates metformin-induced apoptosis. More importantly, survivin overexpression alleviates metformin-induced apoptosis. Xenograft nude mouse experiment also confirmed that AMPK/mTOR-mediated decrease of suvivin is in vivo implicated in metformin-induced apoptosis. Taken together, these evidences suggest that AMPK/mTOR-mediated inhibition of survivin may partly contribute to metformin-induced apoptosis of gastric cancer cell.
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Affiliation(s)
- Gang Han
- Department of General Surgery; The Affiliated Shanghai Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Hangjun Gong
- Department of General Surgery; The Affiliated Shanghai Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yidong Wang
- Department of General Surgery; The Affiliated Shanghai Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shaowen Guo
- Department of Pathology; The Affiliated Shanghai Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Kun Liu
- Department of Pathology; The Affiliated Shanghai Shuguang Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Ma JA, Hu C, Li W, Ren J, Zou F, Zhou D, Zou W, Wei Y, Zhou Y. Downregulation of c-Met expression does not enhance the sensitivity of gastric cancer cell line MKN-45 to gefitinib. Mol Med Rep 2014; 11:2269-75. [PMID: 25395073 DOI: 10.3892/mmr.2014.2948] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Accepted: 08/22/2014] [Indexed: 11/06/2022] Open
Abstract
The aim of the present study was to investigate the effect of downregulation of the c‑Met gene on signal transduction and apoptosis in gastric cancer MKN‑45 cells; furthermore, the study aimed to determine whether altered c‑Met gene expression affected MKN‑45 sensitivity to gefitinib. Three c‑Met‑specific small interfering RNAs (siRNAs) were synthesized and transfected into MKN‑45 cells. Messenger RNA (mRNA) and protein levels of c‑Met and its downstream signaling molecules [phosphoinositide 3‑kinase (PI3K) and AKT] were examined using reverse transcription polymerase chain reaction and western blot analysis 48 h following transfection. Cell apoptosis was evaluated using Annexin‑V/propidium iodide double staining and fluorescence‑activated cell sorting analysis. An MTT assay was performed in order to measure the 50% inhibitory concentration (IC50) of gefitinib on MKN‑45 cells. The results of the present study demonstrated that 48 h post‑transfection with c‑Met siRNA, MKN‑45 cells showed significantly downregulated expression of c‑Met mRNA and protein as well as an increased rate of apoptosis (P<0.05). In addition, following c‑Met siRNA transfection mRNA and protein levels of PI3K and AKT were not significantly altered in MKN‑45 cells (P>0.05); however, a marked decrease in the expression levels of phosphorylated (p)‑PI3K and p‑AKT was observed (P<0.05). Furthermore, the IC50 of gefitinib in MKN‑45 cells was not significantly decreased. In conclusion, knockdown of the c‑Met gene promoted gastric cancer cell apoptosis and inhibited downstream p‑PI3K and p‑AKT; however, the sensitivity of MKN‑45 cells to gefitinib was not increased.
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Affiliation(s)
- Jin-An Ma
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Chunhong Hu
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Wenjuan Li
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Jing Ren
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Fangwen Zou
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Dongai Zhou
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Wen Zou
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Yajun Wei
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Ying Zhou
- Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
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Li MZ, Deng L, Wang JJ, Xiao LB, Wu WH, Yang SB, Li WF. Surgical outcomes and prognostic factors of T4 gastric cancer patients without distant metastasis. PLoS One 2014; 9:e107061. [PMID: 25211331 PMCID: PMC4161379 DOI: 10.1371/journal.pone.0107061] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 08/05/2014] [Indexed: 12/04/2022] Open
Abstract
Objective To evaluate surgical outcomes and prognostic factors for T4 gastric cancer treated with curative resection. Methods Between January 1994 and December 2008, 94 patients diagnosed with histological T4 gastric carcinoma and treated with curative resection were recruited. Patient characteristics, surgical complications, survival, and prognostic factors were analyzed. Results Postoperative morbidity and mortality were 18.1% and 2.1%, respectively. Multivariate analysis indicated lymph node metastasis (hazard ratio, 2.496; 95% confidence interval, 1.218–5.115; p = 0.012) was independent prognostic factor. Conclusions For patients with T4 gastric cancer, lymph node metastasis was associated with poorer survival. Neoadjuvant chemotherapy or aggressive adjuvant chemotherapy after radical resection was strongly recommended for these patients.
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Affiliation(s)
- Ming-zhe Li
- Department of Gastrointestinal and Pancreatic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Liang Deng
- Department of General Surgery I, the Eastern Hospital of the First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jing-jing Wang
- Department of laboratory, Hexian Memory Hospital of Panyu District, Guangzhou, China
| | - Long-bin Xiao
- Department of Gastrointestinal and Pancreatic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- * E-mail:
| | - Wen-hui Wu
- Department of Gastrointestinal and Pancreatic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shi-bin Yang
- Department of Gastrointestinal and Pancreatic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wen-feng Li
- Department of Gastrointestinal and Pancreatic Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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Nakajima T, Fujii M. What make differences in the outcome of adjuvant treatments for resected gastric cancer? World J Gastroenterol 2014; 20:11567-11573. [PMID: 25206264 PMCID: PMC4155350 DOI: 10.3748/wjg.v20.i33.11567] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 01/09/2014] [Accepted: 04/09/2014] [Indexed: 02/06/2023] Open
Abstract
After a long history of Dark Age of adjuvant chemotherapy for gastric cancer, definite evidences of survival benefit from adjuvant treatment have been reported since 2000s. These survival benefits are likely attributed to something new approach different from pervious studies. In 2001, South West Oncology Group INT0116 trial yielded survival benefit in curatively resected gastric cancer patients with postoperative chemoradiotherapy [5-fluorouracil (5-FU) + Leucovorin + radiotherapy], followed by positive result by MAGIC Trial, employing peri-operative(pre- and postoperative chemotherapy with Epirubicin, cisplatin (CDDP), 5-fluorouracil (ECF) regimen in patients with curative resection. A novel drug [S1: ACTS-GC (Adjuvant chemotherapy trial of TS-1 for gastric cancer) in 2007], or new drug combination chemotherapys [CDDP + 5-FU: FNCLCC/FFCD (Federation Nationale des Centres de Lutte contre le cancer/Federation Francophone de Cancerologie Digestive) in 2011, Capecitabine + Oxaliplatin: CLASSIC in 2012] also produced positive results in terms of improved prognosis. Neoadjuvant or perioperative chemotherapy, novel anti-cancer drugs, and chemoradiotherapy might be the key words to develop further improvement in the adjuvant treatment of resectable gastric cancer. Moreover, it is not new but still true to stress the importance of D2 surgery as the baseline treatment in order to minimize the amount of residual tumor after surgery.
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Minimally invasive surgery for remnant gastric cancer: a comparison with open surgery. Surg Endosc 2014; 28:2452-8. [PMID: 24622766 DOI: 10.1007/s00464-014-3496-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 02/17/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Completion total gastrectomy for remnant gastric cancer (RGC) is technically challenging, especially using the minimally invasive approach. Only a few small case series have reported the technical feasibility of completion total gastrectomy by minimally invasive surgery (MIS). The aim of this study was to compare the efficacy and safety of MIS and open surgery for RGC. METHODS We retrospectively analyzed 76 completion total gastrectomies for RGC between 2005 and 2012. Indications for MIS were limited to no evidence of serosa invasion or lymph node metastasis to extraperigastric areas on preoperative evaluation. We compared patient characteristics, intraoperative factors, post-operative outcomes, and survival for the MIS and open surgery groups. RESULTS Eighteen patients underwent completion total gastrectomy with MIS (10 laparoscopic, 8 robotic) and 58 patients underwent open surgery. Operation time was longer in the MIS than the open group (266 vs. 203 min, P = 0.004), but the groups had similar estimated blood loss, frequency of unplanned other organ resection, and number of retrieved lymph nodes. The MIS group had a significantly earlier initiation of soft diet, shorter hospital stay, and fewer pain medication injections. Complication rates, recurrence, and overall 5-year survival were similar for the two groups. When we compared laparoscopy with robotic, similar result was shown in all parameters except operation time. CONCLUSIONS Compared to open surgery, MIS for RGC demonstrated better short-term outcome and comparable oncologic results. MIS for RGC is feasible and safe and maintains advantages of minimal invasiveness. Both laparoscopic and robotic approaches are reasonable to the management of RGC.
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Kim C, Chon H, Kang B, Kim K, Jeung HC, Chung H, Noh S, Rha S. Prediction of metachronous multiple primary cancers following the curative resection of gastric cancer. BMC Cancer 2013; 13:394. [PMID: 23967865 PMCID: PMC3765265 DOI: 10.1186/1471-2407-13-394] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2012] [Accepted: 08/19/2013] [Indexed: 02/06/2023] Open
Abstract
Background Due to improved survival rate, gastric cancer (GC) patients have an increased risk of developing multiple primary cancer (MPC). The purpose of this study is to evaluate the clinicopathological features of MPC and to generate useful tools for the prediction of metachronous MPC following gastrectomy. Methods 3066 patients who underwent curative resection of GC were reviewed retrospectively, based on the clinical information and the medical record. Results The 5-year incidence of MPC was 2.5%. Of these, 54.3% had a metachronous MPC, while 45.7% had a synchronous MPC. The most prevalent site of metachronous MPC was the colorectum (26.3%), followed by lung (23.7%) and liver (18.4%). Multivariate logistic regression analysis revealed that old age at the time of GC diagnosis (≥60 years), early stage of GC (stage I and II), and multiplicity of GC at the time of gastrectomy were independent predictive factors for metachronous MPC. GC patients with either metachronous or synchronous MPC showed poorer survival than patients without MPC. In addition, patients with a metachronous MPC showed late survival disadvantage, while patients with a synchronous MPC showed early survival disadvantage. Furthermore, we were able to develop and internally validate a nomogram to predict the metachronous MPC after curative gastrectomy (C-index = 0.72). Conclusion Patients at high risk of developing metachronous MPC after curative resection of GC were identified. Individual risk of developing metachronous MPC could be predicted by a novel nomogram. Further external validation with independent patient cohorts is required to improve the accuracy of prediction.
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Abstract
This review presents the current status of adjuvant and neoadjuvant treatment options for primary resectable gastric cancer in the East, with updated data from recent studies. Marked disparities between the East and the West in standard surgical procedures (D2 vs. D1/0 lymphadenectomy) and their outcomes result in significant geographical variation in preferred adjuvant treatments. Currently, oral fluoropyrimidine-based postoperative adjuvant chemotherapy, 1 year of S-1 chemotherapy, or capecitabine plus oxaliplatin for 6 months are the standards of care after curative resection with D2 lymphadenectomy for stage II/III gastric cancer in the East, though there is still some room for improvement. The role of postoperative adjuvant chemoradiotherapy (CRT) following curative D2 gastrectomy has long been debated in the East. However, the first prospective randomized controlled trial comparing CRT with chemotherapy alone failed to demonstrate a survival benefit, thus further studies are required. Chemotherapy has been pursued as a neoadjuvant approach in East Asia because of a rare locoregional recurrence after curative D2 gastrectomy. Locally advanced, marginally resectable gastric cancer with poor prognosis, such as large type 3 or 4 tumors, para-aortic and/or bulky nodal disease, and serosa-positive gastric cancer, is the main target of neoadjuvant chemotherapy. Promising efficacy has been demonstrated in several phase II studies with the safe use of D2 or more extended surgery following neoadjuvant chemotherapy. Although the results of ongoing phase III trials are awaited, Asian findings could be relevant and generalizable to other regions when D2 surgery is performed by experienced surgeons.
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Affiliation(s)
- Kazumasa Fujitani
- Department of Surgery, Osaka National Hospital, Osaka 540-006, Japan.
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Knight G, Earle CC, Cosby R, Coburn N, Youssef Y, Malthaner R, Wong RKS. Neoadjuvant or adjuvant therapy for resectable gastric cancer: a systematic review and practice guideline for North America. Gastric Cancer 2013; 16:28-40. [PMID: 22467061 DOI: 10.1007/s10120-012-0148-3] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2011] [Accepted: 02/16/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric cancer is a global health problem accounting for 10% of all new cancer cases and 12% of all cancer deaths worldwide. Many clinical trials and meta-analyses have explored the value of neoadjuvant or adjuvant chemotherapy and radiation therapy in gastric cancer; however, these studies have produced conflicting results. The purpose of this guidance document was to determine whether patients with resectable gastric cancer should receive neoadjuvant or adjuvant therapy in addition to surgery. Outcomes of interest were overall survival, disease-free survival, and adverse events. METHODS A systematic review was undertaken to inform recommendations regarding neoadjuvant and adjuvant therapy in resectable gastric cancer in Ontario, Canada. MEDLINE and EMBASE databases, as well as American Society of Clinical Oncology (ASCO) annual meeting proceedings and American Society for Therapeutic Radiology and Oncology (ASTRO) proceedings were systematically searched from 2002 to 2010. Oral fluoropyrimidine trials were excluded owing to the unavailability of these agents in North America. RESULTS Overall, 22 randomized controlled trials (RCTs), 13 meta-analyses, and two secondary analyses were included. The systematic review informed the development of a clinical practice guideline with the following recommendations. Postoperative 5-fluorouracil-based chemoradiotherapy based on the Macdonald approach or perioperative ECF (epirubicin, cisplatin, fluorouracil) chemotherapy based on the Cunningham/MAGIC (Medical Research Council Adjuvant Gastric Infusional Chemotherapy) approach are both acceptable standards of care in North America. Choice of treatment should be made on a case-by-case basis. Adjuvant chemotherapy is a reasonable option for those patients for whom the Macdonald and MAGIC protocols are contraindicated. All patients with resectable gastric cancer should undergo a pretreatment multidisciplinary assessment to determine the best plan of care. CONCLUSIONS Overall survival in patients with resectable gastric cancer is significantly improved with the use of either postoperative chemoradiation (Macdonald approach) or perioperative ECF (MAGIC protocol).
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Affiliation(s)
- Greg Knight
- Grand River Regional Cancer Centre, 835 King Street West, P O Box 9056, Kitchener, ON, N2G 1G3, Canada.
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Bauer L, Langer R, Becker K, Hapfelmeier A, Ott K, Novotny A, Höfler H, Keller G. Expression profiling of stem cell-related genes in neoadjuvant-treated gastric cancer: a NOTCH2, GSK3B and β-catenin gene signature predicts survival. PLoS One 2012; 7:e44566. [PMID: 22970250 PMCID: PMC3438181 DOI: 10.1371/journal.pone.0044566] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2012] [Accepted: 08/08/2012] [Indexed: 12/20/2022] Open
Abstract
Cancer stem cell (CSC) based gene expression signatures are associated with prognosis in various tumour types and CSCs are suggested to be particularly drug resistant. The aim of our study was first, to determine the prognostic significance of CSC-related gene expression in residual tumour cells of neoadjuvant-treated gastric cancer (GC) patients. Second, we wished to examine, whether expression alterations between pre- and post-therapeutic tumour samples exist, consistent with an enrichment of drug resistant tumour cells. The expression of 44 genes was analysed in 63 formalin-fixed, paraffin embedded tumour specimens with partial tumour regression (10-50% residual tumour) after neoadjuvant chemotherapy by quantitative real time PCR low-density arrays. A signature of combined GSK3B(high), β-catenin (CTNNB1)(high) and NOTCH2(low) expression was strongly correlated with better patient survival (p<0.001). A prognostic relevance of these genes was also found analysing publically available gene expression data. The expression of 9 genes was compared between pre-therapeutic biopsies and post-therapeutic resected specimens. A significant post-therapeutic increase in NOTCH2, LGR5 and POU5F1 expression was found in tumours with different tumour regression grades. No significant alterations were observed for GSK3B and CTNNB1. Immunohistochemical analysis demonstrated a chemotherapy-associated increase in the intensity of NOTCH2 staining, but not in the percentage of NOTCH2. Taken together, the GSK3B, CTNNB1 and NOTCH2 expression signature is a novel, promising prognostic parameter for GC. The results of the differential expression analysis indicate a prominent role for NOTCH2 and chemotherapy resistance in GC, which seems to be related to an effect of the drugs on NOTCH2 expression rather than to an enrichment of NOTCH2 expressing tumour cells.
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Affiliation(s)
- Lukas Bauer
- Institute of Pathology, Technische Universität München, München, Germany
| | - Rupert Langer
- Institute of Pathology, Technische Universität München, München, Germany
| | - Karen Becker
- Institute of Pathology, Technische Universität München, München, Germany
| | - Alexander Hapfelmeier
- Institute of Medical Statistics and Epidemiology, Technische Universität München, München, Germany
| | - Katja Ott
- Department of Surgery, Universität Heidelberg, Heidelberg, Germany
| | - Alexander Novotny
- Department of Surgery, Technische Universität München, München, Germany
| | - Heinz Höfler
- Institute of Pathology, Technische Universität München, München, Germany
- Institute of Pathology, Helmholtz-Zentrum München, Neuherberg, Germany
| | - Gisela Keller
- Institute of Pathology, Technische Universität München, München, Germany
- * E-mail:
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Kato K, Gong J, Iwama H, Kitanaka A, Tani J, Miyoshi H, Nomura K, Mimura S, Kobayashi M, Aritomo Y, Kobara H, Mori H, Himoto T, Okano K, Suzuki Y, Murao K, Masaki T. The antidiabetic drug metformin inhibits gastric cancer cell proliferation in vitro and in vivo. Mol Cancer Ther 2012; 11:549-60. [PMID: 22222629 DOI: 10.1158/1535-7163.mct-11-0594] [Citation(s) in RCA: 185] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Recent studies suggest that metformin, which is commonly used as an oral anti-hyperglycemic agent of the biguanide family, may reduce cancer risk and improve prognosis, but the mechanisms by which metformin affects various cancers, including gastric cancer, remains unknown. The goal of the present study was to evaluate the effects of metformin on human gastric cancer cell proliferation in vitro and in vivo and to study microRNAs (miRNA) associated with antitumor effect of metformin. We used MKN1, MKN45, and MKN74 human gastric cancer cell lines to study the effects of metformin on human gastric cancer cells. Athymic nude mice bearing xenograft tumors were treated with or without metformin. Tumor growth was recorded after 4 weeks, and the expression of cell-cycle-related proteins was determined. In addition, we used miRNA array tips to explore the differences among miRNAs in MKN74 cells bearing xenograft tumors treated with or without metformin in vitro and in vivo. Metformin inhibited the proliferation of MKN1, MKN45, and MKN74 in vitro. Metformin blocked the cell cycle in G(0)-G(1)in vitro and in vivo. This blockade was accompanied by a strong decrease of G(1) cyclins, especially in cyclin D1, cyclin-dependent kinase (Cdk) 4, Cdk6 and by a decrease in retinoblastoma protein (Rb) phosphorylation. In addition, metformin reduced the phosphorylation of epidermal growth factor receptor and insulin-like growth factor-1 receptor in vitro and in vivo. The miRNA expression was markedly altered with the treatment of metformin in vitro and in vivo. Various miRNAs altered by metformin also may contribute to tumor growth in vitro and in vivo.
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Affiliation(s)
- Kiyohito Kato
- Department of Gastroenterology and Neurology, Kagawa University School of Medicine, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
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Berg D, Wolff C, Langer R, Schuster T, Feith M, Slotta-Huspenina J, Malinowsky K, Becker KF. Discovery of new molecular subtypes in oesophageal adenocarcinoma. PLoS One 2011; 6:e23985. [PMID: 21966358 PMCID: PMC3179464 DOI: 10.1371/journal.pone.0023985] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2011] [Accepted: 07/28/2011] [Indexed: 12/22/2022] Open
Abstract
A large number of patients suffering from oesophageal adenocarcinomas do not respond to conventional chemotherapy; therefore, it is necessary to identify new predictive biomarkers and patient signatures to improve patient outcomes and therapy selections. We analysed 87 formalin-fixed and paraffin-embedded (FFPE) oesophageal adenocarcinoma tissue samples with a reverse phase protein array (RPPA) to examine the expression of 17 cancer-related signalling molecules. Protein expression levels were analysed by unsupervised hierarchical clustering and correlated with clinicopathological parameters and overall patient survival. Proteomic analyses revealed a new, very promising molecular subtype of oesophageal adenocarcinoma patients characterised by low levels of the HSP27 family proteins and high expression of those of the HER family with positive lymph nodes, distant metastases and short overall survival. After confirmation in other independent studies, our results could be the foundation for the development of a Her2-targeted treatment option for this new patient subgroup of oesophageal adenocarcinoma.
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Affiliation(s)
- Daniela Berg
- Institute of Pathology, Technische Universität München, Munich, Germany
| | - Claudia Wolff
- Institute of Pathology, Technische Universität München, Munich, Germany
| | - Rupert Langer
- Institute of Pathology, Technische Universität München, Munich, Germany
| | - Tibor Schuster
- Institute of Medical Statistics and Epidemiology, Technische Universität München, Munich, Germany
| | - Marcus Feith
- Department of Surgery, Technische Universität München, Munich, Germany
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Mutze K, Langer R, Schumacher F, Becker K, Ott K, Novotny A, Hapfelmeier A, Höfler H, Keller G. DNA methyltransferase 1 as a predictive biomarker and potential therapeutic target for chemotherapy in gastric cancer. Eur J Cancer 2011; 47:1817-25. [PMID: 21458988 DOI: 10.1016/j.ejca.2011.02.024] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2010] [Revised: 02/18/2011] [Accepted: 02/28/2011] [Indexed: 12/11/2022]
Abstract
PURPOSE DNA methylation contributes to carcinogenesis by mediating transcriptional regulation and chromatin remodelling, which may influence the effect of DNA-damaging drugs. We examined the prognostic and predictive impact of DNA methyltransferase (DNMT) 1 and 3b expression in gastric carcinomas (GC) treated by neoadjuvant chemotherapy. In vitro, DNMT1 expression and chemosensitivity were investigated for a functional relationship and the DNMT inhibitor decitabine (DAC) was tested as an alternative treatment option. PATIENTS AND METHODS DNMT1/3b expression was analysed immunohistochemically in 127 pretherapeutic biopsies of neoadjuvant (platinum/5-fluorouracil)-treated GC patients and correlated with response and overall survival (OS). Short hairpin RNA technology was used to knockdown DNMT1 in the GC cell line, AGS. The chemosensitivity of GC cell lines to DAC alone and to DAC in combination with cisplatin was analysed by XTT or colony formation assays. RESULTS High DNMT1 and DNMT3b expression was found in 105/127 (83%) and 79/127 (62%) carcinomas, respectively. Patients with low DNMT1 expression demonstrated a significantly better histopathological/clinical response (P=0.03/P=0.008) and OS (P(log-rank)=0.001). In vitro, knockdown of DNMT1 caused an increased chemosensitivity towards cisplatin. Combined treatment with cisplatin and DAC showed a synergistic effect leading to increased cytotoxicity in the cisplatin-resistant cell line AGS. CONCLUSION Low DNMT1 expression defines a subgroup of GC patients with better outcomes following platinum/5FU-based neoadjuvant chemotherapy. In vitro data support a functional relationship between DNMT1 and cisplatin sensitivity. Besides its potential use as a predictive biomarker, DNMT1 may represent a promising target for alternative therapeutic strategies for a subset of GC patients.
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Affiliation(s)
- Kathrin Mutze
- Institute of Pathology, Technische Universität München, Trogerstr. 18, 81675 München, Germany
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Guidelines for preclinical and early phase clinical assessment of novel radiosensitisers. Br J Cancer 2011; 105:628-39. [PMID: 21772330 PMCID: PMC3188925 DOI: 10.1038/bjc.2011.240] [Citation(s) in RCA: 120] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
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Maduekwe UN, Yoon SS. An evidence-based review of the surgical treatment of gastric adenocarcinoma. J Gastrointest Surg 2011; 15:730-41. [PMID: 21399886 DOI: 10.1007/s11605-011-1477-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2011] [Accepted: 02/23/2011] [Indexed: 01/31/2023]
Abstract
The management of gastric adenocarcinoma continues to evolve. Chemotherapy is being increasingly used in both the neoadjuvant and adjuvant setting. Surgical resection of the stomach and regional lymph nodes remains the mainstay of potentially curative therapy, but significant regional differences persist in the surgical management. This review provides an update on the current literature regarding the preoperative evaluation and staging, extent of gastric resection, extent of lymph node resection, and adjuvant therapy for patients with gastric adenocarcinoma.
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Affiliation(s)
- Ugwuji N Maduekwe
- Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Yawkey 7B, 55 Fruit St., Boston, MA 02114, USA
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Mutze K, Langer R, Becker K, Ott K, Novotny A, Luber B, Hapfelmeier A, Göttlicher M, Höfler H, Keller G. Histone deacetylase (HDAC) 1 and 2 expression and chemotherapy in gastric cancer. Ann Surg Oncol 2010; 17:3336-43. [PMID: 20585871 DOI: 10.1245/s10434-010-1182-1] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2010] [Indexed: 12/20/2022]
Abstract
BACKGROUND Histone deacetylases (HDACs) modulate chromatin and may influence the effect of DNA-damaging drugs. We investigated HDAC1 and -2 expression in gastric carcinomas (GCs) for an association of patient outcome with conventional neoadjuvant chemotherapy. In vitro, HDAC inhibitors were evaluated as alternative treatment options. METHODS HDAC1/2 expression was analyzed immunohistochemically in 127 pretherapeutic biopsy samples of neoadjuvant (platinum/5-fluorouracil) chemotherapy-treated GC patients and correlated with response and overall survival (OS). Chemosensitivity of four GC cell lines to cisplatin and the HDAC inhibitors suberoylanilide hydroxamic acid (SAHA) and valproic acid was determined by XTT assays. Efficiencies of combined drug schedules were analyzed. RESULTS High expression of HDAC1/2 was found in 69 (54%) of 127 and 108 (85%) of 127 carcinomas, respectively, and was not associated with response or OS. In patients whose disease responded to therapy, high HDAC1 expression was associated with worse OS (P = 0.005). In cell lines, sequential treatment with SAHA and cisplatin showed synergistic effects irrespective of the initial cisplatin sensitivity. CONCLUSIONS HDAC1 and -2 expression is not suitable to predict response or survival for neoadjuvant-treated GC patients, but HDAC1 expression may be used for risk stratification in patients whose disease responds to therapy. Sequential treatment with SAHA and cisplatin may represent an alternative treatment option for GC patients.
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Affiliation(s)
- Kathrin Mutze
- Institute of Pathology, Technische Universität München, Munich, Germany
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Abstract
The extent of lymphadenectomy that should be performed for gastric adenocarcinoma has been a topic of persistent debate. In countries such as Japan and Korea, where the incidence of gastric adenocarcinoma is high, more extensive (e.g., D2) lymphadenectomies are routinely performed, usually by experienced surgeons with low morbidity and mortality. In western countries such as the U.S., where the incidence of gastric adenocarcinoma is tenfold lower, the performance of more extensive lymphadenectomies is generally limited to specialized centers, and quite possibly the majority of patients are treated at nonreferral centers with less than a D1 lymphadenectomy. There is little disagreement among gastric cancer experts that the minimum lymphadenectomy that should be performed for gastric adenocarcinoma should be at least a D1 lymphadenectomy. Two large, prospective randomized trials performed in the United Kingdom and the Netherlands failed to demonstrate a survival benefit of D2 over D1 lymphadenectomy, but these trials have been criticized for high surgical morbidity and mortality rates in the D2 group. More recent studies have demonstrated that western surgeons can be trained to perform D2 lymphadenectomies on western patients with low morbidity and mortality. Retrospective analyses and one prospective, randomized trial suggest that there may be some benefits to more extensive lymphadenectomies when performed safely, but this assertion requires further validation. This article provides an update on the current literature regarding the extent of lymphadenectomy for gastric adenocarcinoma.
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Affiliation(s)
- Sam S Yoon
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
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Abstract
Worldwide, gastric cancer is one of the top three leading causes of cancer mortality, but incidence and presentation vary geographically. Currently, surgery is the only possible cure. Nodal status is an important prognostic indicator for gastric cancer, and despite results of randomized controlled trials, debate continues over the importance of aggressive lymphadenectomy.
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Affiliation(s)
- Natalie G Coburn
- Division of Surgical Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
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Cross talk between hedgehog and epithelial-mesenchymal transition pathways in gastric pit cells and in diffuse-type gastric cancers. Br J Cancer 2008; 100:389-98. [PMID: 19107131 PMCID: PMC2634717 DOI: 10.1038/sj.bjc.6604846] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
We previously reported hedgehog (Hh) signal activation in the mucus-secreting pit cell of the stomach and in diffuse-type gastric cancer (GC). Epithelial–mesenchymal transition (EMT) is known to be involved in tumour malignancy. However, little is known about whether and how both signallings cooperatively act in diffuse-type GC. By microarray and reverse transcription–PCR, we investigated the expression of those Hh and EMT signalling molecules in pit cells and in diffuse-type GCs. How both signallings act cooperatively in those cells was also investigated by the treatment of an Hh-signal inhibitor and siRNAs of Hh and EMT transcriptional key regulator genes on a mouse primary culture and on human GC cell lines. Pit cells and diffuse-type GCs co-expressed many Hh and EMT signalling genes. Mesenchymal-related genes (WNT5A, CDH2, PDGFRB, EDNRA, ROBO1, ROR2, and MEF2C) were found to be activated by an EMT regulator, SIP1/ZFHX1B/ZEB2, which was a target of a primary transcriptional regulator GLI1 in Hh signal. Furthermore, we identified two cancer-specific Hh targets, ELK1 and MSX2, which have an essential role in GC cell growth. These findings suggest that the gastric pit cell exhibits mesenchymal-like gene expression, and that diffuse-type GC maintains expression through the Hh–EMT pathway. Our proposed extensive Hh–EMT signal pathway has the potential to an understanding of diffuse-type GC and to the development of new drugs.
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