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Maruyama Y, Saito M, Nakajima S, Saito K, Suzuki H, Kanoda R, Okayama H, Hanayama H, Sakamoto W, Saze Z, Momma T, Mimura K, Goto A, Kono K. Lenvatinib suppress FGF19-FGFR4 signaling to enhance antitumor immune response in gastric cancer. Gastric Cancer 2025; 28:397-408. [PMID: 39948303 DOI: 10.1007/s10120-025-01596-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2024] [Accepted: 01/31/2025] [Indexed: 04/13/2025]
Abstract
BACKGROUND Fibroblast growth factor receptor (FGFR) 4 is overexpressed in gastric cancer (GC) and is a potential therapeutic target for GC. Since the FGF/FGFR signaling is involved in tumor microenvironment inducing the formation of an immunosuppression, lenvatinib is expected to inhibit FGFR4 leading to reduced tumor PD-L1 levels and regulatory T cell (Treg) infiltration, improving pembrolizumab efficacy. This study explored the background of the molecular mechanisms underlying the therapeutic efficacy of lenvatinib plus pembrolizumab. METHODS Expression of FGFR4 and its specific ligand FGF19 was assessed by immunohistochemical staining and clinicopathological relevance was also examined. The effect of lenvatinib on FGF19-FGFR4 signaling was evaluated using cellular experiments. Lastly, the expression of FGFR4 on Treg cells was evaluated by immunostaining and flow cytometry. The Cancer Genome Atlas cBioPortal and Gene Expression Omnibus microarray databases were accessed to support these results. RESULTS High FGFR4 expression was associated with histological type and venous invasion and predominantly detected in human epidermal growth factor receptor 2 and Epstein-Barr virus-positive GC. Bioinformatics data suggested that FGF19-FGFR4 signaling was activated in GC, and cellular experiments showed that lenvatinib reduced FGFR4 and PD-L1 expression in GC cells. Results of integrating various analyses suggested that FGFR4 did not seem to be enough expressed on Treg cells in GC. CONCLUSIONS The FGF19-FGFR4 signaling has a pivotal role in gastric tumorigenesis and may be involved in immunosuppression through PD-L1 modification. But, lenvatinib may not regulate immune editing by directly inhibiting FGFR4 on Treg cells.
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Affiliation(s)
- Yuya Maruyama
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
| | - Motonobu Saito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan.
| | - Shotaro Nakajima
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
- Department of Multidisciplinary Treatment of Cancer and Regional Medical Support, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Katsuharu Saito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
| | - Hiroya Suzuki
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
| | - Ryo Kanoda
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
| | - Hirokazu Okayama
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
| | - Hiroyuki Hanayama
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
| | - Wataru Sakamoto
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
| | - Zenichiro Saze
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
| | - Tomoyuki Momma
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
| | - Kosaku Mimura
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
- Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Akiteru Goto
- Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, Akita, Japan
| | - Koji Kono
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, 960-1295, Japan
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Guo Y, Yu H, Li J, Liu K, Han M, Tang Y, Su L, Li X, Wu H, Chen D. DNA-methylation eraser TET2 activates WTIP expression to suppress an AKT-dependent chemoresistance of gastric cancer. Neoplasia 2025; 65:101166. [PMID: 40279682 DOI: 10.1016/j.neo.2025.101166] [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: 02/22/2025] [Revised: 03/28/2025] [Accepted: 04/09/2025] [Indexed: 04/27/2025]
Abstract
Chemoresistance is one of the major causes of the failure in gastric cancer (GC) treatment and leads to poor clinical outcomes. Ten-eleven translocation (TET) 2 expression and activity are frequently reduced in solid tumors. However, whether TET2 participants in GC chemoresistance remains poorly understood. In this study, we demonstrated that the TET2 acts as a novel suppressor of GC chemoresistance. TET2 and transcription factor PATZ1 work together to promote the expression of WTIP. WTIP interacts with PP2A to inhibit the T308 phosphorylation and kinase activity of AKT, thereby suppressing stemness and chemoresistance of GC. Thus, the novel TET2-WTIP transcriptional axis, which is frequently silenced, suppresses an AKT-dependent chemoresistance of GC. TET2, combined with WTIP and AKT-pT308, can synergistically serve as a biomarker for predicting chemotherapy response in GC patients. Furthermore, we highlight that combining AKT inhibitor with chemotherapy is a promising therapeutic strategy for TET2-silenced GCs with chemoresistance in clinic.
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Affiliation(s)
- Yan Guo
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, China
| | - Hongyang Yu
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, China
| | - Jinyang Li
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, China
| | - Kewei Liu
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, China
| | - Mengyi Han
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, China
| | - Yuxin Tang
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, China
| | - Li Su
- Department of Oncology and Hematology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Xianfeng Li
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, China
| | - Haixia Wu
- School of Medical Technology, Chongqing Medical and Pharmaceutical College, Chongqing, China.
| | - Dongfeng Chen
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, China.
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Zhan C, Qiu B, Wang J, Li Y, Yu J. Temporal and spatial trends in gastric cancer burden in the USA from 1990 to 2021: findings from the global burden of disease study 2021. Front Oncol 2024; 14:1499384. [PMID: 39744003 PMCID: PMC11688243 DOI: 10.3389/fonc.2024.1499384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 11/25/2024] [Indexed: 01/04/2025] Open
Abstract
Background Gastric cancer (GC) is a significant public health concern in the USA, and its burden is on the rise. Methods This study utilized the latest data from the Global Burden of Disease (GBD) study. We provided descriptive statistics on the incidence, prevalence, mortality, disability-adjusted life years (DALYs), and age-standardized rates (ASRs) of GC across the USA and states. By calculating percentage changes and average annual percentage changes (AAPC), along with conducting age-period-cohort analysis, we assessed the trends in the burden of GC. Decomposition analysis was then performed, followed by the application of an autoregressive integrated moving average (ARIMA) model to forecast changes in ASRs through 2036. Results From 1990 to 2021, the number of incidence and prevalence of GC in the USA increased, but age-standardized incidence rates (ASIR) trended downward (AAPC = -0.73, 95% confidence interval [CI]: -0.77 to -0.68) and age-standardized prevalence rates (ASPR) (AAPC = -0.99, 95% CI: -1.08 to -0.9) showed a decreasing trend. In addition, the number of deaths, DALYs, age-standardized mortality rates (ASMR) and age-standardized DALYs rates (ASDR) in GC showed a decreasing trend. The burden of GC was significantly higher in males compared to females. In addition, we found that the highest incidence and prevalence in females was in the age group of 75-79 years, whereas the highest incidence and prevalence in males was in the age group of 70-74 years. Conclusion GC is a major public health issue in the USA. Although ASIR, ASPR, ASMR, and ASDR for GC are decreasing, the number of incidence and prevalence of GC in the USA remains high, and the disease burden of GC in the USA remains high. Strengthening preventive interventions, particularly for men and patients over the age of 60, will be crucial in the future.
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Affiliation(s)
- Chengwei Zhan
- Daytime Observation Unit, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Binxu Qiu
- Department of Laboratory Medicine, Med+X Center for Manufacturing, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Department of General Surgery, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Breast Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Jun Wang
- Department of Critical Care Medicine, The First Hospital of Harbin Medical University, Harbin, China
| | - Yanhua Li
- Daytime Observation Unit, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Jinhai Yu
- Department of Gastric and Colorectal Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun, Jilin, China
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Mamun TI, Younus S, Rahman MH. Gastric cancer-Epidemiology, modifiable and non-modifiable risk factors, challenges and opportunities: An updated review. Cancer Treat Res Commun 2024; 41:100845. [PMID: 39357127 DOI: 10.1016/j.ctarc.2024.100845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 08/27/2024] [Accepted: 09/20/2024] [Indexed: 10/04/2024]
Abstract
Gastric cancer represents a significant global health challenge due to its high mortality and incidence rates, particularly in Eastern Asia, Eastern Europe, and South America. This comprehensive review synthesizes the latest epidemiological data and explores both modifiable and non-modifiable risk factors associated with gastric cancer, aiming to delineate the multifactorial etiology of this disease. Modifiable risk factors include Helicobacter pylori infection, obesity, dietary habits, smoking and alcohol consumption, whereas nonmodifiable factors comprise genetic predispositions, age, family history and male gender. The interplay of these factors significantly impacts the risk and progression of gastric cancer, suggesting potential preventive strategies. The challenges in treating gastric cancer are considerable, largely because of the late-stage diagnosis and the heterogeneity of the disease, which complicate effective treatment regimens. Current treatment strategies involve a combination of surgery, chemotherapy, radiotherapy, and targeted therapies. The FLOT regimen (5-FU, Leucovorin, Oxaliplatin and Docetaxel) is now a standard for resectable cases in Europe and the US, showing superior survival and response rates over ECF and ECX regimens. For HER2-positive gastric cancer, trastuzumab combined with chemotherapy improves overall survival, as demonstrated by the ToGA trial. Additionally, immune checkpoint inhibitors like pembrolizumab and nivolumab offer promising results. However, the five-year survival rate remains low, underscoring the urgency for improved therapeutic approaches. Recent advancements in molecular biology and cancer genomics have begun to pave the way for personalized medicine in gastric cancer care, focusing on molecular targeted therapies and immunotherapy. This review also highlights the critical need for better screening methods that could facilitate early detection and treatment, potentially improving the prognosis. By integrating epidemiological insights with new therapeutic strategies, this article aims to thoroughly understand of gastric cancer's dynamics and outline a framework for future research and clinical management, advocating for a multidisciplinary approach to tackle this formidable disease.
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Affiliation(s)
- Tajul Islam Mamun
- Department of Epidemiology and Public Health, Sylhet Agricultural University, Sylhet 3100, Bangladesh.
| | - Sabrina Younus
- Department of Pharmacy, University of Chittagong, Chattogram 4331, Bangladesh
| | - Md Hashibur Rahman
- Department of Physiology, Bangladesh Agricultural University, Mymensingh 2202, Bangladesh
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Wang Y, Gan X, Cheng X, Jia Y, Wang G, Tang X, Du H, Li X, Liu X, Xing X, Ji J, Li Z. ABCC2 induces metabolic vulnerability and cellular ferroptosis via enhanced glutathione efflux in gastric cancer. Clin Transl Med 2024; 14:e1754. [PMID: 39095325 PMCID: PMC11296884 DOI: 10.1002/ctm2.1754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 05/30/2024] [Accepted: 06/16/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Although it is traditionally believed that ATP binding cassette subfamily C member 2 (ABCC2) is a multidrug resistance-associated protein correlated with a worse prognosis, our previous and several other studies demonstrated the contrary to be true in gastric cancer (GC). We aim to explore the underlying mechanism of this discovery. METHODS Our study utilized whole-exome sequencing (WES), RNA sequencing, and droplet digital PCR (ddPCR) analysis of 80 gastric cancer samples, along with comprehensive immunohistochemical (IHC) analysis of 1044 human GC tissue samples.By utilizing CRISPRCas9 to genetically modify cell lines with the ABCC2-24C > T (rs717620) point mutation and conducting dual-luciferase reporter assays, we identified that transcription factors SOX9 and ETS1 serve as negative regulators of ABCC2 expression. Seahorse assay and mass spectrometry were used to discover altered metabolic patterns. Gain and loss-of-function experiments in GC cell lines and preclinical models were carried out to validate ABCC2 biological function. RESULTS ABCC2 high expression correlated with better prognosis, and rs717620 can influence ABCC2 expression by disrupting the binding of ETS1 and SOX9. Gain and loss-of-function experiments in GC cell lines demonstrated amino acid deprivation reduces proliferation, migration, and drug resistance in ABCC2-high GC cells. ABCC2 leads to reduced intracellular amino acid pools and disruption of cellular energy metabolism. This phenomenon depended on ABCC2-mediated GSH extrusion, resulting in alterations in redox status, thereby increasing the cell's susceptibility to ferroptosis. Furthermore, patient-derived organoids and patient-derived tumor-like cell clusters were used to observe impact of ABCC2 on therapeutic effect. In the xenograft model with high ABCC2 expression, we observed that constricting amino acid intake in conjunction with GPX4 inactivation resulted in notable tumor regression. CONCLUSIONS Our findings demonstrate a significant role of ABCC2 in amino acid metabolism and ferroptosis by mediating GSH efflux in GC. This discovery underlines the potential of combining multiple ferroptosis targets as a promising therapeutic strategy for GC with high ABCC2 expression. HIGHLIGHTS ABCC2 plays a crucial role in inducing metabolic vulnerability and ferroptosis in gastric cancer through enhanced glutathione efflux. The ABCC2 24C > T polymorphism is a key factor influencing its expression. These results highlight the potential of ABCC2 as a predictive biomarker and therapeutic target in gastric cancer.
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Affiliation(s)
- Yiding Wang
- Department of Gastrointestinal Cancer Translational ResearchKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer Hospital & InstituteBeijingP.R. China
- Department of Gastrointestinal Cancer CenterWard IPeking University Cancer Hospital & InstituteBeijingP.R. China
| | - Xuejun Gan
- Department of Gastrointestinal Cancer Translational ResearchKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer Hospital & InstituteBeijingP.R. China
- Department of Gastrointestinal Cancer CenterWard IPeking University Cancer Hospital & InstituteBeijingP.R. China
| | - Xiaojing Cheng
- Department of Gastrointestinal Cancer Translational ResearchKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer Hospital & InstituteBeijingP.R. China
| | - Yongning Jia
- Department of Gastrointestinal Cancer CenterWard IPeking University Cancer Hospital & InstituteBeijingP.R. China
| | - Gangjian Wang
- Department of Gastrointestinal Cancer Translational ResearchKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer Hospital & InstituteBeijingP.R. China
- Department of Gastrointestinal Cancer CenterWard IPeking University Cancer Hospital & InstituteBeijingP.R. China
| | - Xiaohuan Tang
- Department of Gastrointestinal Cancer Translational ResearchKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer Hospital & InstituteBeijingP.R. China
- Department of Gastrointestinal Cancer CenterWard IPeking University Cancer Hospital & InstituteBeijingP.R. China
| | - Hong Du
- Department of Gastrointestinal Cancer Translational ResearchKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer Hospital & InstituteBeijingP.R. China
| | - Xiaomei Li
- Department of Gastrointestinal Cancer Translational ResearchKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer Hospital & InstituteBeijingP.R. China
| | - Xijuan Liu
- Department of Central LaboratoryKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing)Peking University Cancer Hospital & InstituteBeijingChina
| | - Xiaofang Xing
- Department of Gastrointestinal Cancer Translational ResearchKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer Hospital & InstituteBeijingP.R. China
| | - Jiafu Ji
- Department of Gastrointestinal Cancer Translational ResearchKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer Hospital & InstituteBeijingP.R. China
- Department of Gastrointestinal Cancer CenterWard IPeking University Cancer Hospital & InstituteBeijingP.R. China
| | - Ziyu Li
- Department of Gastrointestinal Cancer Translational ResearchKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education)Peking University Cancer Hospital & InstituteBeijingP.R. China
- Department of Gastrointestinal Cancer CenterWard IPeking University Cancer Hospital & InstituteBeijingP.R. China
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Gupta K, Roy AM, Attwood K, Nipp RD, Mukherjee S. Effects of Immunotherapy on Quality-of-Life Outcomes in Patients with Gastroesophageal Cancers: A Meta-Analysis of Randomized Controlled Trials. Healthcare (Basel) 2024; 12:1496. [PMID: 39120199 PMCID: PMC11311609 DOI: 10.3390/healthcare12151496] [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: 06/11/2024] [Revised: 07/16/2024] [Accepted: 07/23/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have revolutionized cancer care, with increasing data demonstrating improved survival outcomes using ICIs among patients with advanced gastroesophageal cancer (GEC). ICIs are also associated with a lower incidence of grade ≥ 3 adverse events (AEs) compared to chemotherapy, suggesting that ICIs may have favorable effects on health-related quality of life (HRQoL). This meta-analysis sought to evaluate the effects of ICIs on the HRQoL of patients with advanced GEC. METHODS We conducted an online bibliographic search on Medline via PubMed using MeSH-based terms to retrieve randomized controlled trials (RCTs) that evaluated the effects of ICIs on HRQoL in patients with advanced GEC (we searched for all studies between 2018 and 2021). We included RCTs that incorporated ICIs as part of the intervention arm either as monotherapy (first or second line) or as a combination therapy (first-line) with another ICI or chemotherapy. We combined the HRQoL measures into a meta-analysis using standard random effects models, from which estimates of the average mean difference (MD) were obtained with 95% confidence intervals. We assessed the heterogeneity of the study outcomes using the Q and I2 statistics. RESULTS We identified 11 phase 3 RCTs that met the inclusion criteria, with a mean enrollment of 820 patients. Eight RCTs used an ICI plus chemotherapy combination in the intervention arm, three had ICIs as monotherapy, and one had doublet ICI therapy in the intervention arm. All RCTs used chemotherapy for the control arm. Collectively, the trials reported 37 HRQoL measures using five different HRQoL tools. The pooled analysis favored the intervention over the control arm in terms of the Functional Assessment of Cancer Therapy-Esophageal (FACT-E) scores [MD 2.7 (95% CI 0.1 to 5.3), p < 0.041]. In a subgroup analysis of eight RCTs comparing combination therapy with ICIs plus chemotherapy versus chemotherapy alone, the effect estimates favored the ICI arm regarding the FACT-E [MD 2.7 (95% CI 0.1 to 5.3), p < 0.041] and the EORTC QLQ-OES18 pain scale [MD -2.2 (95% CI -4.3 to -0.2), p < 0.030]. Likewise, the effect estimates favored the ICI monotherapy arm over the chemotherapy arm regarding the QLQ-STO22 hair loss subscale [MD -23.2 (95% CI -29.7 to -16.7), p < 0.001], QLQ-STO22 dysphagia subscale [MD 6.7 (95% CI 1.7 to 11.7), p = 0.009], EQ-5D pain scale [MD 6.9 (95% CI 2.9 to 10.9), p < 0.001], and QLQ-OES18 saliva subscale [MD 5.8 (95% CI 0.1 to 11.6), p = 0.046]. CONCLUSIONS In this meta-analysis, we found that the inclusion of ICIs as a first-line treatment for advanced GEC yielded better HRQoL outcomes than chemotherapy alone. Further research on the impact of ICIs on HRQoL is needed, with increasing evidence that ICIs improve the survival outcomes in patients with advanced GEC.
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Affiliation(s)
- Kush Gupta
- Department of Internal Medicine, University of Massachusetts Chan Medical School-Baystate, Springfield, MA 01109, USA;
| | - Arya Mariam Roy
- Department of Hematology and Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA; (A.M.R.); (K.A.)
| | - Kristopher Attwood
- Department of Hematology and Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA; (A.M.R.); (K.A.)
| | - Ryan David Nipp
- OU Health Stephenson Cancer Center, Oklahoma City, OK 73104, USA;
| | - Sarbajit Mukherjee
- Department of Hematology and Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA; (A.M.R.); (K.A.)
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Wang Y, Li D, Xun J, Wu Y, Wang HL. Construction of prognostic markers for gastric cancer and comprehensive analysis of pyroptosis-related long non-coding RNAs. World J Gastrointest Surg 2024; 16:2281-2295. [PMID: 39087128 PMCID: PMC11287702 DOI: 10.4240/wjgs.v16.i7.2281] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 05/22/2024] [Accepted: 06/14/2024] [Indexed: 07/22/2024] Open
Abstract
BACKGROUND China's most frequent malignancy is gastric cancer (GC), which has a very poor survival rate, and the survival rate for patients with advanced GC is dismal. Pyroptosis has been connected to the genesis and development of cancer. The function of pyroptosis-related long non-coding RNAs (PRLs) in GC, on the other hand, remains uncertain. AIM To explore the construction and comprehensive analysis of the prognostic characteristics of long non-coding RNA (lncRNA) related to pyroptosis in GC patients. METHODS The TCGA database provided us with 352 stomach adenocarcinoma samples, and we obtained 28 pyroptotic genes from the Reactome database. We examined the correlation between lncRNAs and pyroptosis using the Pearson correlation coefficient. Prognosis-related PRLs were identified through univariate Cox analysis. A predictive signature was constructed using stepwise Cox regression analysis, and its reliability and independence were assessed. To facilitate clinical application, a nomogram was created based on this signature. we analyzed differences in immune cell infiltration, immune function, and checkpoints between the high-risk group (HRG) and low-risk group (LRG). RESULTS Five hundred and twenty-three PRLs were screened from all lncRNAs (absolute correlation coefficient > 0.4, P < 0.05). Nine PRLs were included in the risk prediction signature that was created through stepwise Cox regression analysis. We determined the risk score for GC patients and employed the median value as the dividing line between HRG and LRG. The ability of the risk signature to predict the overall survival (OS) of GC is demonstrated by the Kaplan-Meier analysis, risk curve, receiver operating characteristic curve, and decision curve analysis curve. The risk signature was shown to be an independent prognostic factor for OS in both univariate and multivariate Cox regression analyses. HRG showed a more efficient local immune response or modulation compared to LRG, as indicated by the predicted signal pathway analysis and examination of immune cell infiltration, function, and checkpoints (P < 0.05). CONCLUSION In general, we have created a brand-new prognostic signature using PRLs, which may provide ideas for immunotherapy in patients with GC.
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Affiliation(s)
- Yu Wang
- Department of Gastrointestinal Surgery, Hospital of Integrated Chinese and Western Medicine, Tianjin University, Tianjin 300100, China
| | - Di Li
- Department of Gastrointestinal Surgery, Hospital of Integrated Chinese and Western Medicine, Tianjin University, Tianjin 300100, China
| | - Jing Xun
- Department of Gastrointestinal Surgery, Hospital of Integrated Chinese and Western Medicine, Tianjin University, Tianjin 300100, China
| | - Yu Wu
- Department of Gastrointestinal Surgery, Hospital of Integrated Chinese and Western Medicine, Tianjin University, Tianjin 300100, China
| | - Hong-Lei Wang
- Department of Gastrointestinal Surgery, Hospital of Integrated Chinese and Western Medicine, Tianjin University, Tianjin 300100, China
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Bonner SN, Edwards MA. The Impact of Racial Disparities and the Social Determinants of Health on Esophageal and Gastric Cancer Outcomes. Surg Oncol Clin N Am 2024; 33:595-604. [PMID: 38789201 DOI: 10.1016/j.soc.2023.12.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/26/2024]
Abstract
Reducing long-standing inequities in gastric and esophageal cancers is a priority of patients, providers, and policy makers. Many social determinants of health influence risk factors for disease development, incidence, treatment, and outcomes of gastric and esophageal cancers.
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Affiliation(s)
- Sidra N Bonner
- Department of Surgery, University of Michigan, 1500 East Medical Center Drive, 2100 Taubman Center, Ann Arbor, MI 48109, USA
| | - Melanie A Edwards
- Trinity Health IHA Medical Group, Cardiovascular & Thoracic Surgery Ann Arbor, 5325 Elliott Drive, Suite 102, Ypsilanti, MI 48197, USA.
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9
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He Z, Yang H, Chen Q, Chen YPP, Qin H, He W, Chen Z. Role of TAP1 in the identification of immune-hot tumor microenvironment and its prognostic significance for immunotherapeutic efficacy in gastric carcinoma. J Gastrointest Oncol 2024; 15:890-907. [PMID: 38989426 PMCID: PMC11231864 DOI: 10.21037/jgo-24-28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 04/19/2024] [Indexed: 07/12/2024] Open
Abstract
Background Gastric cancer (GC), a multifaceted gastrointestinal malignancy, is the fourth most prevalent contributor to cancer-related fatalities globally. As a member of the ATP-binding cassette (ABC) family, transporter associated with antigen processing 1 (TAP1) is crucial for conveying antigen peptides from the cytoplasm to the lumen of the endoplasmic reticulum and subsequently loading them onto the major histocompatibility complex (MHC) class I molecules. Recent studies have established the biological significance of TAP1 in upholding tumor survival and facilitating immune evasion by remodeling the tumor microenvironment (TME) and orchestrating immune infiltration. The study was conducted to elucidate the association of TAP1 expression with immunological characteristics, and sought to exploit the value of TAP1 as a biomarker reflecting the inflamed TME and immunotherapeutic response. Methods RNA-sequencing profiles and clinical annotations were obtained from The Cancer Genome Atlas-stomach adenocarcinoma (TCGA-STAD) cohort and Gene Expression Omnibus (GEO) portal. Preprocessing was conducting using the limma package. Weighted gene co-expression network analysis (WGCNA) was used to identify gene modules and TAP1 co-expressed genes (CEGs) based on correlation patterns. Consensus clustering and silhouette analysis determined the optimal number of TAP1-related groups. Gene expression profiles were integrated and classified using the pamr package. The Estimation of STromal and Immune cells in MAlignant Tumors using Expression data (ESTIMATE) algorithm and single-sample gene set enrichment analysis (ssGSEA) were used to evaluate immunological characteristics. Differential expression analysis was conducted using the limma package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed. Single-cell RNA sequencing (scRNA-seq) datasets were analyzed using the Seurat toolkit to characterize cell types. Results Within this investigation, no significant differences in TAP1 expression were observed among patients exhibiting various clinicopathological features, indicating that TAP1 expression was not specific to molecular subtypes. Subsequent analysis revealed a positive correlation between TAP1 and diverse immunological traits, encompassing immunomodulators, tumor-infiltrating immune cells, as well as immune checkpoints across multiple datasets. Besides, within a GC immunotherapy cohort, individuals displaying high TAP1 expression demonstrated an increased likelihood of achieving complete remission (CR) post-treatment, suggesting heightened sensitivity to immunotherapy. In the clinical cohort, TAP1 overexpression in GC patients was positively correlated with CD8. Conclusions TAP1 appears linked to an inflamed TME and serves as a prospective biomarker for discerning immunological attributes and gauging immunotherapeutic responses in GC, particularly in identifying immune-reactive tumors.
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Affiliation(s)
- Zehua He
- Department of General Surgery, Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University, Nanning, China
| | - Hong Yang
- Department of Anesthesia Surgery Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qingfeng Chen
- School of Computer, Electronic and Information, Guangxi University, Nanning, China
| | - Yi-Ping Phoebe Chen
- Department of Computer Science and Information Technology, La Trobe University, Melbourne, Australia
| | - Huabo Qin
- Department of General Surgery, Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University, Nanning, China
| | - Wanrong He
- Department of Computer Science and Information Technology, La Trobe University, Melbourne, Australia
| | - Zhihui Chen
- Department of General Surgery, Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University, Nanning, China
- Department of Gastrointestinal Surgery Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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10
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Li W, Wan L. Cost-utility of sintilimab plus chemotherapy vs chemotherapy as first-line treatment of advanced gastric or gastroesophageal junction cancer in China. Expert Rev Pharmacoecon Outcomes Res 2024; 24:671-678. [PMID: 38594905 DOI: 10.1080/14737167.2024.2341859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 04/03/2024] [Indexed: 04/11/2024]
Abstract
OBJECTIVES ORIENT-16, a phase III clinical trial conducted at 62 hospitals in China, reported that add-on sintilimab (Sin) to chemotherapy (Chemo) had favorable efficacy (p < 0.05) for patients with advanced HER2-negative gastric or gastroesophageal junction cancer (GC/GEJC). This study aimed to evaluate the cost-utility of the Sin+Chemo based on results of ORIENT-16 from the perspective of Chinese healthcare payers. METHODS A three-state partitioned survival model was developed to simulate the 10-year life expectancy and total healthcare costs for patients with advanced HER2-negative GC/GEJC. Primary measure outcomes were: cost, quality-adjusted life-years (QALYs), and incremental cost-utility ratios (ICURs). Sensitivity/scenario analyses were conducted to assess the model robustness. RESULTS In all patients, Sin+Chemo vs Chemo increased costs by $6,472, additionally providing 0.61 QALYs, resulting in an ICUR of $10,610/QALY. While, in PD-L1 combined positive score ≥ 5 cohort, the ICUR was $9,738/QALYs. The ICUR was most sensitive to the utility of progression-free survival. The probabilistic sensitivity analysis showed that add-on Sin had a 100% probability of being cost-effective at a willingness-to-pay threshold of $18,625/QALY gained. CONCLUSIONS Sin+Chemo is a cost-effective first-line treatment option for advanced HER2-negative GC/GEJC in China. CLINICAL TRIAL REGISTRATION ORIENT-16, www.clinicaltrials.gov, identifier is NCT03745170.
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Affiliation(s)
- Wei Li
- Department of Pharmacy, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Li Wan
- Department of Pharmacy, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Kadono T, Iwasa S, Hirose T, Hirano H, Okita N, Shoji H, Takashima A, Kato K. Impact of immune checkpoint inhibitors on survival outcomes in advanced gastric cancer in Japan: A real-world analysis. Cancer Med 2024; 13:e7401. [PMID: 38899745 PMCID: PMC11187802 DOI: 10.1002/cam4.7401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Revised: 03/14/2024] [Accepted: 06/07/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND Nivolumab was approved for the treatment of advanced gastric cancer in 2017 in Japan. The aim of this study was to assess the impact of nivolumab in a real-world clinical setting. METHODS This single-institutional retrospective study included patients with advanced gastric or esophagogastric junction adenocarcinoma and a history of first-line chemotherapy with platinum-based doublet or triplet regimens between 2010 and 2020. To assess the impact of nivolumab on survival, the patients were divided based on the year of nivolumab approval into a pre-2017 (2010-2016) group and a post-2017 (2017-2020) group. RESULTS From a total of 1918 patients, 1093 were excluded. There were 533 patients in the pre-2017 group and 292 in the post-2017 group. Immune checkpoint inhibitors were used significantly more often in the post-2017 group than in the pre-2017 group (8.6% vs. 47.9%). Median overall survival was significantly longer in the post-2017 group (16.9 vs. 13.9 months; hazard ratio [HR] 0.75, 95% confidence interval [CI] 0.63-0.90; p < 0.01). The proportion of patients transitioning to third-line treatment was higher in the post-2017 group than in the pre-2017 group (56.3% vs. 43.8%, p < 0.01). Median survival outcomes following progression on second-line treatment were significantly longer in the post-2017 group (4.3 vs. 3.2 months; HR 0.70, 95% CI 0.57-0.86; p < 0.01). CONCLUSION The proportion of patients transitioning to third-line treatment and survival outcomes following progression on second-line treatment have improved since the approval of nivolumab. This drug might help to prolong overall survival in real-world practice.
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Affiliation(s)
- Toru Kadono
- Department of Gastrointestinal Medical OncologyNational Cancer Center HospitalTokyoJapan
- Cancer Chemotherapy CenterOsaka Medical and Pharmaceutical UniversityTakatsukiOsakaJapan
| | - Satoru Iwasa
- Department of Gastrointestinal Medical OncologyNational Cancer Center HospitalTokyoJapan
| | - Toshiharu Hirose
- Department of Gastrointestinal Medical OncologyNational Cancer Center HospitalTokyoJapan
| | - Hidekazu Hirano
- Department of Gastrointestinal Medical OncologyNational Cancer Center HospitalTokyoJapan
| | - Natsuko Okita
- Department of Gastrointestinal Medical OncologyNational Cancer Center HospitalTokyoJapan
| | - Hirokazu Shoji
- Department of Gastrointestinal Medical OncologyNational Cancer Center HospitalTokyoJapan
| | - Atsuo Takashima
- Department of Gastrointestinal Medical OncologyNational Cancer Center HospitalTokyoJapan
| | - Ken Kato
- Department of Gastrointestinal Medical OncologyNational Cancer Center HospitalTokyoJapan
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Zhizhilashvili S, Mchedlishvili I, Jankarashvili N, Camacho R, Mebonia N. Effect of Age at Diagnosis on the Prognosis of Gastric Cancer Patients: A Population-Based Study in Georgia. Cureus 2024; 16:e62154. [PMID: 38993440 PMCID: PMC11238615 DOI: 10.7759/cureus.62154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/11/2024] [Indexed: 07/13/2024] Open
Abstract
INTRODUCTION The national burden of gastric cancer (GC) is high in Georgia, which is determined by its high mortality and low survival. The study aimed to estimate the effect of age at diagnosis on the prognosis of GC patients diagnosed between 2015 and 2020 in Georgia. MATERIALS AND METHODS We obtained data for the study from the national population-based cancer registry. All patients 15 years of age or older, diagnosed during 2015-2020 with invasive GC (site codes C16.0 to C16.9, International Classification of Diseases for Oncology), were eligible for inclusion in the analysis. We produced survival curves using the Kaplan-Meier method, and the log-rank test was used to compare survival between groups. Hazard ratios (HR) were estimated using univariate Cox proportional models and multivariate Cox proportional hazard models. The endpoint of the study was overall survival (OS). The level of statistical significance of the study findings was estimated using p-values and 95% confidence intervals (CI). A p-value<0.05 was considered statistically significant. Results: A total of 1,828 gastric cancer cases were included in the statistical analysis. The average age of patients was 65 years. The bivariate Cox's regression analysis demonstrated that the risk of gastric cancer mortality increased gradually with the age of cancer patients. The HR and 95% CI were as follows: 1.5 (1.1-1.8) and 2.1 (1.5-2.5) in the 46-65 years and >65 years groups, respectively, with the <46 years group as a reference. Moreover, multivariable Cox's regression analysis proved that age is an independent risk factor for GC mortality (HR = 1.4; 95% CI = 1.2-1.8; p<.001). Conclusion: We found that age at diagnosis was a significant predictor of the worse survival of GC patients diagnosed between 2015 and 2020 in Georgia.
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Affiliation(s)
- Saba Zhizhilashvili
- Epidemiology and Biostatistics, Tbilisi State Medical University, Tbilisi, GEO
| | | | | | - Rolando Camacho
- Oncology (Non-communicable Diseases), World Health Organization, Mallorca, ESP
| | - Nana Mebonia
- Epidemiology and Biostatistics, Tbilisi State Medical University, Tbilisi, GEO
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Saleh RO, Al-Hawary SIS, Hammoud A, Hjazi A, Ayad Abdulrazzaq S, Rajput P, Alawsi T, Alnajar MJ, Alawadi A. The long non-coding RNAs (lncRNA) in the pathogenesis of gastric cancer cells: molecular mechanisms and involvement miRNAs. Mol Biol Rep 2024; 51:615. [PMID: 38704760 DOI: 10.1007/s11033-024-09546-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 04/11/2024] [Indexed: 05/07/2024]
Abstract
A complex sequence of occurrences, including host genetic vulnerability, Helicobacter pylori infection, and other environmental variables, culminate in gastric cancer (GC). The development of several genetic and epigenetic changes in oncogenes and tumor suppressor genes causes dysregulation of several signaling pathways, which upsets the cell cycle and the equilibrium between cell division and apoptosis, leading to GC. Developments in computational biology and RNA-seq technology enable quick detection and characterization of long non-coding RNAs (lncRNAs). Recent studies have shown that long non-coding RNAs (lncRNAs) have multiple roles in the development of gastric cancer. These lncRNAs interact with molecules of protein, RNA, DNA, and/or combinations. This review article explores several gastric cancer-associated lncRNAs, such as ADAMTS9-AS2, UCA1, XBP-1, and LINC00152. These various lncRNAs could change GC cell apoptosis, migration, and invasion features in the tumor microenvironment. This review provides an overview of the most recent research on lncRNAs and GC cell apoptosis, migration, invasion, and drug resistance, focusing on studies conducted in cancer cells and healthy cells during differentiation.
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Affiliation(s)
- Raed Obaid Saleh
- Department of Medical Laboratory Techniques, Al-Maarif University College, Al-Anbar, Iraq
| | | | - Ahmad Hammoud
- Department of Medical and Technical Information Technology, Bauman Moscow State Technical University, Moscow, Russia.
- Department of Mathematics and Natural Sciences, Gulf University for Science and Technology, Mishref Campus, Kuwait City, Kuwait.
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences , Prince Sattam bin Abdulaziz University, Al-Kharj, 11942, Saudi Arabia
| | | | - Pranchal Rajput
- School of Applied and Life Sciences, Divison of Research and Innovation, Uttaranchal University, Dehradun, India
| | - Taif Alawsi
- Scientific Research Center, Al-Ayen University, Thi-Qar, Iraq
- Department of Laser and Optoelectronics Engineering, University of Technology, Baghdad, Iraq
| | | | - Ahmed Alawadi
- College of Technical Engineering, The Islamic University, Najaf, Iraq
- College of Technical Engineering, The Islamic University of Al Diwaniyah, Al-Qadisiyyah, Iraq
- College of Technical Engineering, The Islamic University of Babylon, Babylon, Iraq
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14
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Fu M, Zhang X, Shen F, Ma J, Li Z. Prognostic value of peripheral blood neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, pan-immune-inflammation value and systemic immune-inflammation index for the efficacy of immunotherapy in patients with advanced gastric cancer. Immunotherapy 2024. [PMID: 38578121 DOI: 10.2217/imt-2024-0031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/06/2024] Open
Abstract
Aim: The study aimed to assess the value of pretreatment peripheral blood neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), pan-immune-inflammation value (PIV) and systemic immune-inflammation index (SII) for predicting immunotherapy prognosis and efficacy in advanced gastric cancer (GC). Methods: A total of 84 advanced GC patients received immunotherapy were retrospectively collected. The optimal cut-off values were determined by receiver operating characteristic curves. The univariate and multivariate analysis investigated the effects of NLR, PLR, PIV and SII on patients prognosis. Results: NLR, PLR, PIV and SII had predictive value of efficacy. NLR ≥3.65 was an independent risk factor for worse outcomes. Conclusion: NLR, PLR, PIV and SII have predictive value of efficacy and NLR ≥3.65 suggests a poor prognosis following immunotherapy in advanced GC.
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Affiliation(s)
- Maodong Fu
- Department of Integrated Traditional Chinese & Western Medicine, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, Fujian, 361015, People's Republic of China
- Xiamen Clinical Research Center for Cancer Therapy, Xiamen, Fujian, 361015, People's Republic of China
| | - Xiuping Zhang
- Department of Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, Fujian, 361015, People's Republic of China
- Xiamen Clinical Research Center for Cancer Therapy, Xiamen, Fujian, 361015, People's Republic of China
| | - Feng Shen
- Department of Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, Fujian, 361015, People's Republic of China
- Xiamen Clinical Research Center for Cancer Therapy, Xiamen, Fujian, 361015, People's Republic of China
| | - Jun Ma
- Department of Integrated Traditional Chinese & Western Medicine, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, Fujian, 361015, People's Republic of China
- Xiamen Clinical Research Center for Cancer Therapy, Xiamen, Fujian, 361015, People's Republic of China
| | - Zhiyong Li
- Department of Oncology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, Fujian, 361015, People's Republic of China
- Xiamen Clinical Research Center for Cancer Therapy, Xiamen, Fujian, 361015, People's Republic of China
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15
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Wang J, Zhang J, Liu H, Meng L, Gao X, Zhao Y, Wang C, Gao X, Fan A, Cao T, Fan D, Zhao X, Lu Y. N6-methyladenosine reader hnRNPA2B1 recognizes and stabilizes NEAT1 to confer chemoresistance in gastric cancer. Cancer Commun (Lond) 2024; 44:469-490. [PMID: 38512764 PMCID: PMC11024687 DOI: 10.1002/cac2.12534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Revised: 02/29/2024] [Accepted: 03/06/2024] [Indexed: 03/23/2024] Open
Abstract
BACKGROUND Chemoresistance is a major cause of treatment failure in gastric cancer (GC). Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is an N6-methyladenosine (m6A)-binding protein involved in a variety of cancers. However, whether m6A modification and hnRNPA2B1 play a role in GC chemoresistance is largely unknown. In this study, we aimed to investigate the role of hnRNPA2B1 and the downstream mechanism in GC chemoresistance. METHODS The expression of hnRNPA2B1 among public datasets were analyzed and validated by quantitative PCR (qPCR), Western blotting, immunofluorescence, and immunohistochemical staining. The biological functions of hnRNPA2B1 in GC chemoresistance were investigated both in vitro and in vivo. RNA sequencing, methylated RNA immunoprecipitation, RNA immunoprecipitation, and RNA stability assay were performed to assess the association between hnRNPA2B1 and the binding RNA. The role of hnRNPA2B1 in maintenance of GC stemness was evaluated by bioinformatic analysis, qPCR, Western blotting, immunofluorescence, and sphere formation assays. The expression patterns of hnRNPA2B1 and downstream regulators in GC specimens from patients who received adjuvant chemotherapy were analyzed by RNAscope and multiplex immunohistochemistry. RESULTS Elevated expression of hnRNPA2B1 was found in GC cells and tissues, especially in multidrug-resistant (MDR) GC cell lines. The expression of hnRNPA2B1 was associated with poor outcomes of GC patients, especially in those who received 5-fluorouracil treatment. Silencing hnRNPA2B1 effectively sensitized GC cells to chemotherapy by inhibiting cell proliferation and inducing apoptosis both in vitro and in vivo. Mechanically, hnRNPA2B1 interacted with and stabilized long noncoding RNA NEAT1 in an m6A-dependent manner. Furthermore, hnRNPA2B1 and NEAT1 worked together to enhance the stemness properties of GC cells via Wnt/β-catenin signaling pathway. In clinical specimens from GC patients subjected to chemotherapy, the expression levels of hnRNPA2B1, NEAT1, CD133, and CD44 were markedly elevated in non-responders compared with responders. CONCLUSION Our findings indicated that hnRNPA2B1 interacts with and stabilizes lncRNA NEAT1, which contribute to the maintenance of stemness property via Wnt/β-catenin pathway and exacerbate chemoresistance in GC.
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Affiliation(s)
- Jiayao Wang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
- The Air Force Hospital of Southern Theater CommandGuangzhouGuangdongP. R. China
| | - Jiehao Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
- The Air Force Hospital of Southern Theater CommandGuangzhouGuangdongP. R. China
| | - Hao Liu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Lingnan Meng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
- National Center for International Research of Bio‐targeting TheranosticsGuangxi Key Laboratory of Bio‐targeting TheranosticsGuangxi Medical UniversityNanningGuangxiP. R. China
| | - Xianchun Gao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Yihan Zhao
- Second Clinical CollegeShaanxi University of Traditional Chinese MedicineXianyangShaanxiP. R. China
| | - Chen Wang
- College of Life SciencesNorthwest UniversityXi'anShaanxiP. R. China
| | - Xiaoliang Gao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Ahui Fan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Tianyu Cao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Daiming Fan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Xiaodi Zhao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
| | - Yuanyuan Lu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive DiseasesXijing Hospital of Digestive DiseasesFourth Military Medical UniversityXi'anShaanxiP. R. China
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Rugge M, Genta RM, Malfertheiner P, Dinis-Ribeiro M, El-Serag H, Graham DY, Kuipers EJ, Leung WK, Park JY, Rokkas T, Schulz C, El-Omar EM. RE.GA.IN.: the Real-world Gastritis Initiative-updating the updates. Gut 2024; 73:407-441. [PMID: 38383142 DOI: 10.1136/gutjnl-2023-331164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 12/18/2023] [Indexed: 02/23/2024]
Abstract
At the end of the last century, a far-sighted 'working party' held in Sydney, Australia addressed the clinicopathological issues related to gastric inflammatory diseases. A few years later, an international conference held in Houston, Texas, USA critically updated the seminal Sydney classification. In line with these initiatives, Kyoto Global Consensus Report, flanked by the Maastricht-Florence conferences, added new clinical evidence to the gastritis clinicopathological puzzle.The most relevant topics related to the gastric inflammatory diseases have been addressed by the Real-world Gastritis Initiative (RE.GA.IN.), from disease definitions to the clinical diagnosis and prognosis. This paper reports the conclusions of the RE.GA.IN. consensus process, which culminated in Venice in November 2022 after more than 8 months of intense global scientific deliberations. A forum of gastritis scholars from five continents participated in the multidisciplinary RE.GA.IN. consensus. After lively debates on the most controversial aspects of the gastritis spectrum, the RE.GA.IN. Faculty amalgamated complementary knowledge to distil patient-centred, evidence-based statements to assist health professionals in their real-world clinical practice. The sections of this report focus on: the epidemiology of gastritis; Helicobacter pylori as dominant aetiology of environmental gastritis and as the most important determinant of the gastric oncogenetic field; the evolving knowledge on gastric autoimmunity; the clinicopathological relevance of gastric microbiota; the new diagnostic horizons of endoscopy; and the clinical priority of histologically reporting gastritis in terms of staging. The ultimate goal of RE.GA.IN. was and remains the promotion of further improvement in the clinical management of patients with gastritis.
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Affiliation(s)
- Massimo Rugge
- Department of Medicine-DIMED, University of Padova, Padua, Italy
- Azienda Zero, Veneto Tumour Registry, Padua, Italy
| | - Robert M Genta
- Gastrointestinal Pathology, Inform Diagnostics Research Institute, Dallas, Texas, USA
- Pathology, Baylor College of Medicine, Houston, Texas, USA
| | - Peter Malfertheiner
- Medizinische Klinik und Poliklinik II, Ludwig Maximilian Universität Klinikum München, Munich, Germany
- Klinik für Gastroenterologie, Hepatologie und Infektiologie, Otto-von-Guericke Universität Magdeburg, Magdeburg, Germany
| | - Mario Dinis-Ribeiro
- Porto Comprehensive Cancer Center & RISE@CI-IPO, University of Porto, Porto, Portugal
- Gastroenterology Department, Portuguese Institute of Oncology of Porto, Porto, Portugal
| | - Hashem El-Serag
- Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
- Houston VA Health Services Research & Development Center of Excellence, Michael E DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - David Y Graham
- Department of Medicine, Michael E DeBakey Veterans Affairs Medical Center, Houston, Texas, USA
| | - Ernst J Kuipers
- Erasmus University Medical Center, Rotterdam, The Netherlands
| | | | - Jin Young Park
- International Agency for Research on Cancer, Lyon, France
| | - Theodore Rokkas
- Gastroenterology, Henry Dunant Hospital Center, Athens, Greece
| | | | - Emad M El-Omar
- Microbiome Research Centre, University of New South Wales, Sydney, New South Wales, Australia
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Wen L, Xu K, Huang M, Pan Q. Identification of oxeiptosis-associated lncRNAs and prognosis-related signature to predict the immune status in gastric cancer. Medicine (Baltimore) 2024; 103:e37189. [PMID: 38363905 PMCID: PMC10869064 DOI: 10.1097/md.0000000000037189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 01/17/2024] [Indexed: 02/18/2024] Open
Abstract
As a novel form of cell death, oxeiptosis is mainly caused by oxidative stress and has been defined to contribute to the cellular death program in cancer. However, the precise involvement of oxeiptosis-related long non-coding RNAs (lncRNAs) within gastric cancer (GC) remains elusive. Thus, our study was aimed to elucidate the pivotal effect of hub oxeiptosis-related lncRNAs on GC by comprehensively analyzing lncRNA and gene expression data obtained from The Cancer Genome Atlas (TCGA) database. Subsequently, we constructed a risk signature (risk-sig) using lncRNAs and further evaluated its prognostic significance. We successfully identified thirteen lncRNAs closely related with oxeiptosis that exhibited significant relevance to the prognosis of GC, forming the foundation of our meticulously constructed risk-sig. Notably, our clinical analyses unveiled a strong correlation between the risk-sig and crucial clinical parameters including overall survival (OS), gender, TNM stage, grade, M stage, and N stage among GC patients. Intriguingly, the diagnostic accuracy of this risk-sig surpassed that of conventional clinicopathological characteristics, underscoring its potential as a highly informative prognostic tool. In-depth mechanistic investigations further illuminated a robust association between this risk-sig and fundamental biological processes such as tumor stemness, immune cell infiltration, and immune subtypes. These findings provide valuable insights into the complex interplay between oxeiptosis-related lncRNAs and the intricate molecular landscape of GC. Ultimately, leveraging the risk scores derived from our comprehensive analysis, we successfully developed a nomogram that enables accurate prediction of GC prognosis. Collectively, our study established a solid foundation for the integration of thirteen hub oxeiptosis-related lncRNAs into a clinically applicable risk-sig, potentially revolutionizing prognostic assessment in GC and facilitating the development of innovative therapeutic strategies.
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Affiliation(s)
- Li Wen
- Nursing Department, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Kaili Xu
- Department of Operating Room, The First People’s Hospital of Linping District, Hangzhou, China
| | - Min Huang
- Department of Medicine, Zhejiang Rehabilitation Hospital, Hangzhou, China
| | - Qin Pan
- Department of Operating Room, The First People’s Hospital of Linping District, Hangzhou, China
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Cui J, Ding R, Liu H, Ma M, Zuo R, Liu X. Trends in the incidence and survival of cancer in individuals aged 55 years and older in the United States, 1975-2019. BMC Public Health 2024; 24:72. [PMID: 38172749 PMCID: PMC10763484 DOI: 10.1186/s12889-023-17571-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Accepted: 12/22/2023] [Indexed: 01/05/2024] Open
Abstract
BACKGROUND In ageing societies such as the United States, evaluating the incidence and survival rates of cancer in older adults is essential. This study aimed to analyse the incidence and survival rates of cancer in individuals aged 55 years or older in the United States. METHODS This retrospective study (1975-2019) was conducted using combined registry data from the Surveillance, Epidemiology, and End Results database. Data from the 9, 12, and 17 Registries (Nov 2021 Sub) datasets were used. RESULTS In 2019, the incidence of cancer in individuals older than 55 years and the overall population was 1322.8 and 382.1 per 100,000 population, respectively. From 2000 to 2019, the incidence of cancer in individuals older than 55 years showed a decreasing trend, whereas their five-year survival rates showed an increasing trend. The incidence of cancer in the 75-79 and 80-84 year age groups was the highest among all age groups. CONCLUSIONS The incidence of colon cancer declined significantly, whereas that of intrahepatic bile duct cancer increased considerably. These trends may be due to increased screening for cancers with high incidence rates and improved control of the risk factors for cancer. Rapid development of targeted therapy and immunotherapy combined with early tumour detection may be an important reason for the improved survival rates.
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Affiliation(s)
- Junpeng Cui
- Department of General Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Rongmei Ding
- Department of Oncology, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Haifeng Liu
- Department of General Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Mingxiu Ma
- Department of General Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Ruixue Zuo
- Department of General Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China
| | - Xun Liu
- Department of General Surgery, Shengjing Hospital of China Medical University, No. 36 Sanhao Street, Heping District, Shenyang, 110004, Liaoning, China.
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19
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Gupta K, George A, Attwood K, Gupta A, Roy AM, Gandhi S, Siromoni B, Singh A, Repasky E, Mukherjee S. Association between Environmental Temperature and Survival in Gastroesophageal Cancers: A Population Based Study. Cancers (Basel) 2023; 16:74. [PMID: 38201502 PMCID: PMC10778299 DOI: 10.3390/cancers16010074] [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: 11/22/2023] [Revised: 12/18/2023] [Accepted: 12/21/2023] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND Cold stress suppresses antitumor response in animal models, leading to tumor growth. Recent studies have also shown a negative correlation between the average annual temperature (AAT) and cancer incidence. We hypothesized that esophageal cancer (EC) and gastric cancer (GC) patients living in warmer climates have improved survival outcomes than those living in colder climates. METHODS We conducted a retrospective analysis using the Surveillance, Epidemiology, and End Results (SEER) database from 1996 to 2015. We retrieved the National Centers for Environmental Information data to calculate the county-level AAT. Cox multivariate regression models were performed to measure the association between temperature (measured continuously at diagnosis and in 5-degree increments) and OS/DSS, adjusting for variables. All associations were compared at a significance level of 0.05. The OS and DSS were summarized using Kaplan-Meier methods. All statistics were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). RESULTS A total of 17,408 EC patients were analyzed. The average age of the cohort was 65 years, 79% of which were males and 21% were females. Of them, 61.6% had adenocarcinoma, and 37.6% were squamous. After adjusting for covariates, patients in regions with an AAT > 53.5 °F had an 11% improvement in OS [HR 0.89 (95% CI 0.86-0.92), p < 0.0001] and 13% in DSS [HR 0.87 (95% CI 0.84-0.90), p < 0.0001]. When the temperature was analyzed in 5 °F increments, with each increment, there was a 3% improvement in OS [HR 0.97 (95% CI 0.96-0.98), p < 0.0001] and 4% in DSS [HR 0.96 (95% CI 0.95-0.97), p < 0.0001]. Subgroup analysis of squamous and adenocarcinoma showed similar results. These findings were validated in 20,553 GC patients. After adjusting for covariates, patients in regions with an AAT > 53.5 had a 13% improvement in OS [HR 0.87 (95% CI 0.85-0.90), p < 0.0001] and 14% in DSS [HR 0.86 (95% CI 0.83-0.89), p < 0.0001]. When analyzed in 5 °F increments, with each increment, there was a 4% improvement in OS [HR 0.96 (95% CI 0.952-0.971), p < 0.0001] and 4% in DSS [HR 0.96 (95% CI 0.945-0.965), p < 0.0001]. CONCLUSION We showed for the first time that higher environmental temperatures are associated with significant improvements in OS and DSS in patients with gastro-esophageal cancers, notwithstanding the limitations of a retrospective database analysis. Further confirmatory and mechanistic studies are required to implement specific interventional strategies.
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Affiliation(s)
- Kush Gupta
- Department of Internal Medicine, Umass Chan Medical School—Baystate, Springfield, MA 01199, USA;
| | - Anthony George
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA (K.A.)
| | - Kristopher Attwood
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA (K.A.)
| | - Ashish Gupta
- Department of Hematology and Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA (A.M.R.)
| | - Arya Mariam Roy
- Department of Hematology and Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA (A.M.R.)
| | - Shipra Gandhi
- Department of Hematology and Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA (A.M.R.)
| | - Beas Siromoni
- School of Health Sciences, University of South Dakota, Vermillion, SD 57069, USA
| | - Anurag Singh
- Department of Hematology and Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA (A.M.R.)
| | - Elizabeth Repasky
- Department of Hematology and Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA (A.M.R.)
| | - Sarbajit Mukherjee
- Department of Hematology and Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA (A.M.R.)
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20
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Song Z, Su M, Li X, Xie J, Han F, Yao J. A novel endoplasmic reticulum stress-related lncRNA signature for prognosis prediction and immune response evaluation in Stomach adenocarcinoma. BMC Gastroenterol 2023; 23:432. [PMID: 38066437 PMCID: PMC10709857 DOI: 10.1186/s12876-023-03001-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Accepted: 10/16/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND Stomach adenocarcinoma (STAD) is a significant contributor to cancer-related mortality worldwide. Although previous research has identified endoplasmic reticulum stress (ERS) as a regulator of various tumor-promoting properties of cancer cells, the impact of ERS-related long non-coding RNAs (lncRNAs) on STAD prognosis has not yet been investigated. Therefore, our study aims to develop and validate an ERS-related lncRNA signature that can accurately predict the prognosis of STAD patients. METHODS We collected RNA expression profiles and clinical data of STAD patients from The Cancer Genome Atlas (TCGA) and identified ERS-related genes from the Molecular Signature Database (MSigDB). Co-expression analysis enabled us to identify ERS-related lncRNAs, and we applied univariate Cox, least absolute shrinkage, and selection operator (LASSO), and multivariate Cox regression analyses to construct a predictive signature comprising of 9 ERS-related lncRNAs. We assessed the prognostic accuracy of our signature using Kaplan-Meier survival analysis, and validated our predictive signature in an independent gene expression omnibus (GEO) cohort. We also performed tumor mutational burden (TMB) and tumor immune microenvironment (TIME) analyses. Enrichment analysis was used to investigate the functions and biological processes of the signature, and we identified two distinct STAD patient subgroups through consensus clustering. Finally, we performed drug sensitivity analysis and immunologic efficacy analysis to explore further insights. RESULTS The 9 ERS related-lncRNAs signature demonstrated satisfactory predictive performance as an independent prognostic marker and was significantly associated with STAD clinicopathological characteristics. Furthermore, patients in the high-risk group displayed a worse STAD prognosis than those in the low-risk group. Notably, gene set enrichment analysis (GSEA) revealed significant enrichment of extracellular matrix pathways in the high-risk group, indicating their involvement in STAD progression. Additionally, the high-risk group exhibited significantly lower TMB expression levels than the low-risk group. Consensus clustering revealed two distinct STAD patient subgroups, with Cluster 1 exhibiting higher immune cell infiltration and more active immune functions. Drug sensitivity analysis suggested that the low-risk group was more responsive to oxaliplatin, epirubicinl, and other drugs. CONCLUSION Our study highlights the crucial regulatory roles of ERS-related lncRNAs in STAD, with significant clinical implications. The 9-lncRNA signature we have constructed represents a reliable prognostic indicator that has the potential to inform more personalized treatment decisions for STAD patients. These findings shed new light on the pathogenesis of STAD and its underlying molecular mechanisms, offering opportunities for novel therapeutic strategies to be developed for STAD patients.
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Affiliation(s)
- Zhaoxiang Song
- Depratment of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Mengge Su
- Depratment of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiangyu Li
- Depratment of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jinlin Xie
- Depratment of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Fei Han
- Depratment of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianning Yao
- Depratment of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
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21
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Cao LL, Lu H, Soutto M, Bhat N, Chen Z, Peng D, Gomaa A, Wang JB, Xie JW, Li P, Zheng CH, Nomura S, Datta J, Merchant N, Chen ZB, Villarino A, Zaika A, Huang CM, El-Rifai W. Multivalent tyrosine kinase inhibition promotes T cell recruitment to immune-desert gastric cancers by restricting epithelial-mesenchymal transition via tumour-intrinsic IFN-γ signalling. Gut 2023; 72:2038-2050. [PMID: 37402563 PMCID: PMC10592091 DOI: 10.1136/gutjnl-2022-329134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 06/11/2023] [Indexed: 07/06/2023]
Abstract
OBJECTIVE Gastric cancer (GC) ranks fifth in incidence and fourth for mortality worldwide. The response to immune checkpoint blockade (ICB) therapy in GC is heterogeneous due to tumour-intrinsic and acquired immunotherapy resistance. We developed an immunophenotype-based subtyping of human GC based on immune cells infiltration to develop a novel treatment option. DESIGN A algorithm was developed to reclassify GC into immune inflamed, excluded and desert subtypes. Bioinformatics, human and mouse GC cell lines, syngeneic murine gastric tumour model, and CTLA4 blockade were used to investigate the immunotherapeutic effects by restricting receptor tyrosine kinase (RTK) signalling in immune desert (ICB-resistant) type GC. RESULTS Our algorithm restratified subtypes of human GC in public databases and showed that immune desert-type and excluded-type tumours are ICB-resistant compared with immune-inflamed GC. Moreover, epithelial-mesenchymal transition (EMT) signalling was highly enriched in immune desert-type GC, and syngeneic murine tumours exhibiting mesenchymal-like, compared with epithelial-like, properties are T cell-excluded and resistant to CTLA4 blockade. Our analysis further identified a panel of RTKs as potential druggable targets in the immune desert-type GC. Dovitinib, an inhibitor of multiple RTKs, strikingly repressed EMT programming in mesenchymal-like immune desert syngeneic GC models. Dovitinib activated the tumour-intrinsic SNAI1/2-IFN-γ signalling axis and impeded the EMT programme, converting immune desert-type tumours to immune inflamed-type tumours, sensitising these mesenchymal-like 'cold' tumours to CTLA4 blockade. CONCLUSION Our findings identified potential druggable targets relevant to patient groups, especially for refractory immune desert-type/ 'cold' GC. Dovitinib, an RTK inhibitor, sensitised desert-type immune-cold GC to CTLA4 blockade by restricting EMT and recruiting T cells.
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Affiliation(s)
- Long Long Cao
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Heng Lu
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Mohammed Soutto
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Nadeem Bhat
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Zheng Chen
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Dunfa Peng
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Ahmed Gomaa
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Jia Bin Wang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Jian Wei Xie
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Ping Li
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Chao Hui Zheng
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Sachiyo Nomura
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Jashodeep Datta
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Nipun Merchant
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Zhi Bin Chen
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Alejandro Villarino
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Alexander Zaika
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA
- Department of Veterans Affairs, Miami Healthcare System, Miami, Florida, USA
| | - Chang Ming Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
- Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, China
| | - Wael El-Rifai
- Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
- Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA
- Department of Veterans Affairs, Miami Healthcare System, Miami, Florida, USA
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22
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Désilets A, Elkhoury R, Gebai A, Tehfe M. Current and Emerging Role of Monoclonal Antibody-Based First-Line Treatment in Advanced Gastro-Esophageal and Gastric Cancer. Curr Oncol 2023; 30:9304-9316. [PMID: 37887572 PMCID: PMC10605724 DOI: 10.3390/curroncol30100672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/12/2023] [Accepted: 10/19/2023] [Indexed: 10/28/2023] Open
Abstract
Gastric cancer is the fifth most common malignancy worldwide and one of the main causes of cancer-related death. While surgical treatment is the only curative option for early disease, many have inoperable or advanced disease at diagnosis. Treatment in this case would be a combination of chemotherapy and immunotherapy. Gastro-esophageal (GEJ) and gastric cancer (GC) genetic profiling with current molecular diagnostic techniques has significantly changed the therapeutic landscape in advanced cancers. The identification of key players in GEJ and GC survival and proliferation, such as human epidermal growth factor 2 (HER2), vascular endothelial growth factor (VEGF), and programmed cell death protein 1 (PD-1)/programmed cell death ligand-1 (PD-L1), has allowed for the individualization of advanced cancer treatment and significant improvement in overall survival and progression-free survival of patients. This review comprehensively examines the current and emerging role of monoclonal antibody-based first-line treatments in advanced GEJ and GC. We explore the impact of monoclonal antibodies targeting HER2, VEGF, PD-1/PD-L1, and Claudin 18.2 (CLDN18.2) on the first-line treatment landscape by talking about key clinical trials. This review emphasizes the importance of biomarker testing for optimal treatment selection and provides practical recommendations based on ASCO guidelines.
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Affiliation(s)
- Audrey Désilets
- Department of Medicine, Université de Montreal, Montreal, QC H3T 1J4, Canada
| | - Reem Elkhoury
- Department of Medicine, Université de Montreal, Montreal, QC H3T 1J4, Canada
- Hematology-Oncology, Oncology Center-Centre Hospitalier de l’Universite de Montreal, Montreal, QC H2X 0C1, Canada
| | - Ahmad Gebai
- Department of Medicine, Université de Montreal, Montreal, QC H3T 1J4, Canada
| | - Mustapha Tehfe
- Department of Medicine, Université de Montreal, Montreal, QC H3T 1J4, Canada
- Hematology-Oncology, Oncology Center-Centre Hospitalier de l’Universite de Montreal, Montreal, QC H2X 0C1, Canada
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23
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Zhang P, Tong Y, Huang X, Chen Y, Li Y, Luan D, Li J, Wang C, Li P, Du L, Wang J. The Dual-Response-Single-Amplification Fluorescent Nanomachine for Tumor Imaging and Gastric Cancer Diagnosis. ACS NANO 2023; 17:16553-16564. [PMID: 37527488 DOI: 10.1021/acsnano.3c02148] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/03/2023]
Abstract
Gastric cancer (GC) is one of the most common tumors worldwide and is the leading cause of tumor-related mortality. Traditional biomarkers and screening methods cannot meet the clinical demands. There is an urgent need for highly sensitive diagnostic markers as well as accurate quantification methods for early gastric cancer (EGC) screening. Here a dual-target cooperatively responsive fluorescent nanomachine by the innovative application of two targets─responsive strand migration system with a single-amplification-cycle element was developed for the simultaneous detection of GC biomarkers miR-5585-5p and PLS3 mRNA, which were selected by next-generation sequencing and RT-qPCR. It was also an RNA extraction-free, PCR-free, and nonenzymatic biosensor to achieve tumor cell imaging and serum diagnosis. Requiring only a 20 μL serum sample and 20 min incubation time, the nanomachine achieved an ultrasensitive detection limit of fM level with a broad linear range from fM to nM. More importantly, a higher AUC value (0.884) compared to the clinically used biomarker CA 72-4 was obtained by the nanomachine to distinguish GC patients successfully. Notably, for the key concerns of diagnosis of EGC patients, the nanomachine also achieved a satisfactory AUC value of 0.859. Taken together, this work has screened and obtained multiple biomarkers and developed a fluorescent nanomachine for combination diagnosis of GC, providing an ingenious design of a functionalized DNA nanomachine and a feasible strategy for the transformation of serum biomarkers into clinical diagnosis.
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Affiliation(s)
- Peng Zhang
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan 250033, China
- Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan 250033, China
- Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan 250033, China
| | - Yao Tong
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan 250033, China
- Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan 250033, China
- Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan 250033, China
| | - Xiaowen Huang
- State Key Laboratory of Biobased Material and Green Papermaking, Department of Bioengineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan 250300, China
| | - Yuqing Chen
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan 250033, China
- Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan 250033, China
- Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan 250033, China
| | - Yanru Li
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan 250033, China
- Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan 250033, China
- Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan 250033, China
| | - Dongrui Luan
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan 250033, China
- Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan 250033, China
- Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan 250033, China
| | - Juan Li
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan 250033, China
- Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan 250033, China
- Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan 250033, China
| | - Chuanxin Wang
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan 250033, China
- Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan 250033, China
- Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan 250033, China
| | - Peilong Li
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan 250033, China
- Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan 250033, China
- Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan 250033, China
| | - Lutao Du
- Department of Clinical Laboratory, The Second Hospital of Shandong University, Jinan 250033, China
- Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, Jinan 250033, China
- Shandong Engineering & Technology Research Center for Tumor Marker Detection, Jinan 250033, China
| | - Jiayi Wang
- Department of Clinical Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
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Yanagimoto Y, Kurokawa Y, Doki Y. Essential updates 2021/2022: Perioperative and surgical treatments for gastric and esophagogastric junction cancer. Ann Gastroenterol Surg 2023; 7:698-708. [PMID: 37663969 PMCID: PMC10472390 DOI: 10.1002/ags3.12711] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 06/05/2023] [Accepted: 06/13/2023] [Indexed: 09/05/2023] Open
Abstract
In recent years, important clinical trials for gastric cancer (GC) and esophagogastric junction cancer (EGJC) have been reported, changing the strategies of surgical and perioperative treatment. Although laparoscopic gastrectomy has already been shown to be effective for early-stage cancer, recent evidence from both Asia (JLSSG0901, CLASS-01 and KLASS-02) and Europe (LOGICA and STOMACH trials) has demonstrated that it is useful for advanced GC. Robotic surgery has been rapidly gaining popularity in recent years, and randomized controlled trials are ongoing to evaluate its efficacy. A prospective nationwide multicenter study mapped sites with frequent metastasis and revealed lymphatic flow specific to EGJC, thus establishing the optimal lymph node dissection area and surgical approach based on esophageal involvement. Perioperative chemotherapy, the mainstay of treatment in Europe, also has been established in Asia by the PRODIGY and RESOLVE studies. New clinical trials have been conducted to evaluate the efficacy of combining immunotherapy or molecular-targeted therapy with perioperative chemotherapy or chemoradiotherapy. In this review, we present important recent clinical trials regarding the treatment of GC and EGJC published in 2021 or 2022.
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Affiliation(s)
| | - Yukinori Kurokawa
- Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineOsakaJapan
| | - Yuichiro Doki
- Department of Gastroenterological SurgeryOsaka University Graduate School of MedicineOsakaJapan
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25
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Kendrick P, Kelly YO, Baumann MM, Compton K, Blacker BF, Daoud F, Li Z, Mouhanna F, Nassereldine H, Schmidt C, Sylte DO, Force LM, Hay SI, Rodriquez EJ, Mensah GA, Nápoles AM, Pérez-Stable EJ, Murray CJ, Mokdad AH, Dwyer-Lindgren L. The burden of stomach cancer mortality by county, race, and ethnicity in the USA, 2000-2019: a systematic analysis of health disparities. LANCET REGIONAL HEALTH. AMERICAS 2023; 24:100547. [PMID: 37600165 PMCID: PMC10435837 DOI: 10.1016/j.lana.2023.100547] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 06/14/2023] [Accepted: 06/16/2023] [Indexed: 08/22/2023]
Abstract
Background There are persistent disparities in stomach cancer mortality among racial-ethnic groups in the USA, but the extent to which these patterns vary geographically is not well understood. This analysis estimated age-standardised mortality for five racial-ethnic groups, in 3110 USA counties over 20 years, to describe spatial-temporal variations in stomach cancer mortality and disparities between racial-ethnic groups. Methods Redistribution methods for insufficient cause of death codes and validated small area estimation methods were applied to death registration data from the US National Vital Statistics System and population data from the US National Center for Health Statistics to estimate annual stomach cancer mortality rates. Estimates were stratified by county and racial-ethnic group (non-Latino and non-Hispanic [NL] American Indian or Alaska Native [AIAN], NL Asian or Pacific Islander [Asian], NL Black [Black], Latino or Hispanic [Latino], and NL White [White]) from 2000 to 2019. Estimates were corrected for misreporting of racial-ethnic group on death certificates using published misclassification ratios. We masked (ie, did not display) estimates for county and racial-ethnic group combinations with a mean annual population of less than 1000; thus, we report estimates for 3079 (of 3110) counties for the total population, and 474, 667, 1488, 1478, and 3051 counties for the AIAN, Asian, Black, Latino, and White populations, respectively. Findings Between 2000 and 2019, national age-standardised stomach cancer mortality was lowest among the White population in every year. Nationally, stomach cancer mortality declined for all racial-ethnic groups across this time period, with the most rapid declines occurring among the Asian (percent decline 48.3% [45.1-51.1]) and Black populations (42.6% [40.2-44.6]). Mortality among the other racial-ethnic groups declined more moderately, decreasing by 36.7% (35.3-38.1), 35.1% (32.2-37.7), and 31.6% (23.9-38.0) among the White, Latino, and AIAN populations, respectively. Similar patterns were observed at the county level, although with wide geographic variation. In 2019, a majority of counties had higher mortality rates among minoritised racial-ethnic populations compared to the White population: 81.1% (377 of 465 counties with unmasked estimates for both racial-ethnic groups) among the AIAN population, 88.2% (1295 of 1469) among the Latino population, 99.4% (663 of 667) among the Asian population, and 99.9% (1484 of 1486) among the Black population. However, the size of these disparities ranged widely across counties, with the largest range from 0.3 to 17.1 among the AIAN population. Interpretation Stomach cancer mortality has decreased substantially across populations and geographies in the USA. However, disparities in stomach cancer mortality among racial-ethnic groups are widespread and have persisted over the last two decades. Local-level data are crucial to understanding the scope of this unequal burden among minoritised groups in the USA. Funding National Institute on Minority Health and Health Disparities; National Heart, Lung, and Blood Institute; National Cancer Institute; National Institute on Aging; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Office of Disease Prevention; and Office of Behavioral and Social Sciences Research, National Institutes of Health (contract #75N94019C00016).
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Otsuka K, Nishiyama H, Kuriki D, Kawada N, Ochiya T. Connecting the dots in the associations between diet, obesity, cancer, and microRNAs. Semin Cancer Biol 2023; 93:52-69. [PMID: 37156343 DOI: 10.1016/j.semcancer.2023.05.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 04/27/2023] [Accepted: 05/01/2023] [Indexed: 05/10/2023]
Abstract
The prevalence of obesity has reached pandemic levels worldwide, leading to a lower quality of life and higher health costs. Obesity is a major risk factor for noncommunicable diseases, including cancer, although obesity is one of the major preventable causes of cancer. Lifestyle factors, such as dietary quality and patterns, are also closely related to the onset and development of obesity and cancer. However, the mechanisms underlying the complex association between diet, obesity, and cancer remain unclear. In the past few decades, microRNAs (miRNAs), a class of small non-coding RNAs, have been demonstrated to play critical roles in biological processes such as cell differentiation, proliferation, and metabolism, highlighting their importance in disease development and suppression and as therapeutic targets. miRNA expression levels can be modulated by diet and are involved in cancer and obesity-related diseases. Circulating miRNAs can also mediate cell-to-cell communications. These multiple aspects of miRNAs present challenges in understanding and integrating their mechanism of action. Here, we introduce a general consideration of the associations between diet, obesity, and cancer and review the current knowledge of the molecular functions of miRNA in each context. A comprehensive understanding of the interplay between diet, obesity, and cancer could be valuable for the development of effective preventive and therapeutic strategies in future.
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Affiliation(s)
- Kurataka Otsuka
- Tokyo NODAI Research Institure, Tokyo University of Agriculture, 1-1-1 Sakuragaoka, Setagaya, Tokyo 156-8502, Japan; R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan; Division of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1, Nishishinjyuku, Shinjuku-ku, Tokyo 160-0023, Japan; Division of Molecular and Cellular Medicine, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
| | - Hiroshi Nishiyama
- R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan
| | - Daisuke Kuriki
- R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan
| | - Naoki Kawada
- R&D Division, Kewpie Corporation, 2-5-7, Sengawa-cho, Chofu-shi, Tokyo 182-0002, Japan
| | - Takahiro Ochiya
- Division of Molecular and Cellular Medicine, Institute of Medical Science, Tokyo Medical University, 6-7-1, Nishishinjyuku, Shinjuku-ku, Tokyo 160-0023, Japan
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Nguyen Wenker T, Peng FB, Emelogu I, Mallepally N, Kanwal F, El-Serag HB, Tan MC. The Predictive Performance of Contemporary Guideline Recommendations for Helicobacter pylori Testing in a United States Population. Clin Gastroenterol Hepatol 2023; 21:1771-1780. [PMID: 36270616 PMCID: PMC10110767 DOI: 10.1016/j.cgh.2022.10.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Revised: 09/27/2022] [Accepted: 10/01/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND The Houston Consensus Conference and American College of Gastroenterology (ACG) have recommended Helicobacter pylori screening in United States populations with specific risk factors. However, the performance of these guidelines in clinical practice is not known. METHODS We identified consecutive patients undergoing upper endoscopy with gastric biopsies for any indication in a safety-net hospital in Houston, TX during January 2015-December 2016. We tested the association between the presence of H pylori (histopathology, stool antigen, urea breath test, immunoglobulin G serology, or prior treatment) and H pylori risk factors using logistic regression models, reported as odds ratios and 95% confidence intervals (CIs). We evaluated the area under the receiver operating characteristic (AUROC) curve for predictive ability of individual risk factors identified by the Houston Consensus Conference and ACG. RESULTS Of 942 patients, the prevalence of H pylori infection was 51.5%. The risk factors with the highest predictive performance included first-generation immigrant (AUROC, 0.59) and Hispanic or black race/ethnicity (AUROC, 0.57), whereas the remaining 7 risk factors/statements had low predictive value. A model that combined first-generation immigrant status, black or Hispanic race/ethnicity, dyspepsia, and reflux had higher predictive ability for H pylori infection (AUROC, 0.64; 95% CI, 0.61-0.68) than any individual risk factor. CONCLUSIONS In this contemporary U.S. cohort, the performance of individual risk factors identified by the Houston Consensus Conference and ACG was generally low for predicting H pylori infection except for black or Hispanic race/ethnicity and first-generation immigrant status. A risk prediction model combining several risk factors had improved diagnostic performance and should be validated in future studies.
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Affiliation(s)
- Theresa Nguyen Wenker
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Frederick B Peng
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Ikenna Emelogu
- Division of Digestive Diseases, Emory University, Atlanta, Georgia
| | - Niharika Mallepally
- Division of Gastrointestinal and Liver Diseases, University of Southern California, Los Angeles, California
| | - Fasiha Kanwal
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Hashem B El-Serag
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas; Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas
| | - Mimi C Tan
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas.
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Yu Y, Wang Y, Xi D, Wang N, Gao L, Shi Q, Yu R, Li H, Xiang L, Maswikiti EP, Chen H. A novel adenosine signalling-based prognostic signature in gastric cancer and its association with cancer immune features and immunotherapy response. Cell Biol Int 2023. [PMID: 37366248 DOI: 10.1002/cbin.12053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 04/10/2023] [Accepted: 05/21/2023] [Indexed: 06/28/2023]
Abstract
Reliable prognostic signatures that can reflect the intrinsic characteristics of gastric cancer (GC) are still rare. Here, we developed an adenosine-based prognostic signature and explored its association with the tumour immune in GC patients, aiming at confirming the prognostic value of adenosine-related genes and guiding the GC risk stratification and immunotherapeutic response prediction. We collected adenosine pathway-related genes from STRING websites and manual searching. We enrolled the The Cancer Genome Atlas cohort and four gene expression omnibus cohorts of GC for generating and validating the adenosine pathway-based signature using the Cox regression method. Gene expression in the signature was verified using polymerase chain reaction. We also performed gene set enrichment analysis, immune infiltration assessment and immunotherapy response prediction based on this signature. Our study resulted in a six-gene adenosine signature (GNAS, CXCR4, PPP1R1B, ADCY6, NT5E and NOS3) for risk stratification of GC prognosis, with the highest area under the receiver operating characteristic curve up to 0.767 for predicting 10-year overall survival (OS). In the training cohort, patients with signature-defined high risk had significantly poorer OS than those with low risk (p < .001). Multivariate analysis identified the signature as an independent prognostic factor (hazard ratio 2.863, 95% confidence interval [1.871-4.381], p < .001). These findings were confirmed in four independent cohorts. Expression detection showed that all signature genes were upregulated in both GC tissues and cell lines. Further analysis revealed that the signature-defined high-risk patients were characterised by immunosuppressive states and associated with a poor immunotherapy response. In conclusion, the adenosine pathway-based signature represents a promising risk stratification tool for GC in guiding individualised prognostication and immunotherapy.
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Affiliation(s)
- Yang Yu
- The Department of Tumor Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Yidian Wang
- Department of Joint Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Dayong Xi
- The Department of Tumor Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Na Wang
- The Department of Tumor Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Lei Gao
- The Department of Tumor Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Qianling Shi
- The First Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Rong Yu
- The Department of Tumor Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Haiyuan Li
- The Department of Tumor Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Lin Xiang
- The Department of Tumor Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Ewetse Paul Maswikiti
- The Department of Tumor Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
- The Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, China
| | - Hao Chen
- The Department of Tumor Surgery, Lanzhou University Second Hospital, Lanzhou, Gansu, China
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Leowattana W, Leowattana P, Leowattana T. Immunotherapy for advanced gastric cancer. World J Methodol 2023; 13:79-97. [PMID: 37456977 PMCID: PMC10348086 DOI: 10.5662/wjm.v13.i3.79] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 05/11/2023] [Accepted: 05/31/2023] [Indexed: 06/20/2023] Open
Abstract
Gastric cancer (GC) is believed to be the fifth most common cancer and the third most common cause of death worldwide. Treatment techniques include radiation, chemotherapy, gastrectomy, and targeted treatments are often employed. Some hopeful results from the development of GC immunotherapy have already changed treatment approaches. Along with previous combination medicines, new immunotherapies have been developed that target distinct molecules. Despite ongoing studies into the current therapeutic options and significant improvements in this field, the prognosis for the ailment is poor. Since there are few treatment options and a delay in detection, the illness actually advances, spreads, and metastasizes. The bulk of immunotherapies in use today rely on cytotoxic immune cells, monoclonal antibodies, and gene-transferred vaccines. Immune checkpoint inhibitors have become more popular. In this review, we sought to examine the viewpoint and development of several immunotherapy treatment modalities for advanced GC, as well as the clinical results thus far reported. Additionally, we outlined tumor immune escape and tumor immunosurveillance.
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Affiliation(s)
- Wattana Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
| | - Pathomthep Leowattana
- Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Rachatawee 10400, Bangkok, Thailand
| | - Tawithep Leowattana
- Department of Medicine, Faculty of Medicine, Srinakharinwirot University, Wattana 10110, Bangkok, Thailand
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Levin AA, Klimov DD, Nechunaev AA, Prokhorenko LS, Mishchenkov DS, Nosova AG, Astakhov DA, Poduraev YV, Panchenkov DN. Assessment of experimental OpenCV tracking algorithms for ultrasound videos. Sci Rep 2023; 13:6765. [PMID: 37185281 PMCID: PMC10130022 DOI: 10.1038/s41598-023-30930-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 03/03/2023] [Indexed: 05/17/2023] Open
Abstract
This study aims to compare the tracking algorithms provided by the OpenCV library to use on ultrasound video. Despite the widespread application of this computer vision library, few works describe the attempts to use it to track the movement of liver tumors on ultrasound video. Movements of the neoplasms caused by the patient`s breath interfere with the positioning of the instruments during the process of biopsy and radio-frequency ablation. The main hypothesis of the experiment was that tracking neoplasms and correcting the position of the manipulator in case of using robotic-assisted surgery will allow positioning the instruments more precisely. Another goal of the experiment was to check if it is possible to ensure real-time tracking with at least 25 processed frames per second for standard definition video. OpenCV version 4.5.0 was used with 7 tracking algorithms from the extra modules package. They are: Boosting, CSRT, KCF, MedianFlow, MIL, MOSSE, TLD. More than 5600 frames of standard definition were processed during the experiment. Analysis of the results shows that two algorithms-CSRT and KCF-could solve the problem of tumor tracking. They lead the test with 70% and more of Intersection over Union and more than 85% successful searches. They could also be used in real-time processing with an average processing speed of up to frames per second in CSRT and 100 + frames per second for KCF. Tracking results reach the average deviation between centers of neoplasms to 2 mm and maximum deviation less than 5 mm. This experiment also shows that no frames made CSRT and KCF algorithms fail simultaneously. So, the hypothesis for future work is combining these algorithms to work together, with one of them-CSRT-as support for the KCF tracker on the rarely failed frames.
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Affiliation(s)
- A A Levin
- Moscow State University of Medicine and Dentistry Named After A.I. Evdokimov, 20/1 Delegatskaya ul., Moscow, Russian Federation, 127473.
| | - D D Klimov
- Moscow State University of Medicine and Dentistry Named After A.I. Evdokimov, 20/1 Delegatskaya ul., Moscow, Russian Federation, 127473
| | - A A Nechunaev
- Moscow State University of Medicine and Dentistry Named After A.I. Evdokimov, 20/1 Delegatskaya ul., Moscow, Russian Federation, 127473
| | - L S Prokhorenko
- Moscow State University of Medicine and Dentistry Named After A.I. Evdokimov, 20/1 Delegatskaya ul., Moscow, Russian Federation, 127473
| | - D S Mishchenkov
- Moscow State University of Medicine and Dentistry Named After A.I. Evdokimov, 20/1 Delegatskaya ul., Moscow, Russian Federation, 127473
| | - A G Nosova
- Moscow State University of Medicine and Dentistry Named After A.I. Evdokimov, 20/1 Delegatskaya ul., Moscow, Russian Federation, 127473
| | - D A Astakhov
- Moscow State University of Medicine and Dentistry Named After A.I. Evdokimov, 20/1 Delegatskaya ul., Moscow, Russian Federation, 127473
| | - Y V Poduraev
- Moscow State University of Technology "STANKIN", 1 Vadkovsky per., Moscow, Russian Federation, 127055
| | - D N Panchenkov
- Moscow State University of Medicine and Dentistry Named After A.I. Evdokimov, 20/1 Delegatskaya ul., Moscow, Russian Federation, 127473
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31
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Ren L, Deng H, Jiang Y, Liu C. Dual-Regulated Mechanism of EZH2 and KDM6A on SALL4 Modulates Tumor Progression via Wnt/β-Catenin Pathway in Gastric Cancer. Dig Dis Sci 2023; 68:1292-1305. [PMID: 36877334 DOI: 10.1007/s10620-022-07790-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 12/06/2022] [Indexed: 03/07/2023]
Abstract
BACKGROUND SALL4 has been demonstrated in many cancers and participated in tumorigenesis and tumor progression, however, its expression and function still remain ambiguous in GC, especially its upstream mechanistic modulators. PURPOSE We explored whether the dual mediation of EZH2 and KDM6A could be involved in upstream regulation of SALL4, which promotes GC cell progression via the Wnt/β-catenin pathway. METHOD Analysis of discrepant gene expression in GC and normal gastric tissues from The Cancer Genome Atlas (TCGA) dataset. GC cell lines were transfected by siEZH2 and siKDM6A, the transduction molecules of KDM6A/EZH2-SALL4-β-catenin signaling were quantified in the GC cells. RESULTS Here, we showed that only SALL4 levels of SALL family members were upregulated in nonpaired and paired GC tissues than those in corresponding normal tissues and were associated with its histological types, pathological stages, TNM stages including T stage (local invasion), N stage (lymph node metastasis), M stage (distant metastasis), and overall survival from the TCGA dataset. SALL4 level was elevated in GC cells compared to normal gastric epithelial cell line (GES-1) and was correlated to cancer cell progression and invasion through the Wnt/β-catenin pathway in GC, which levels would be separately upregulated or downregulated by KDM6A or EZH2. CONCLUSION We first proposed and demonstrated that SALL4 promoted GC cell progression via the Wnt/β-catenin pathway, which was mediated by the dual regulation of EZH2 and KDM6A on SALL4. This mechanistic pathway in gastric cancer represents a novel targetable pathway.
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Affiliation(s)
- Lei Ren
- Department of General Surgery (Gastrointestinal Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Department of Surgery, Klinikum Rechts Der Isar, Technical University of Munich, School of Medicine, Munich, Germany
| | - Hong Deng
- Department of General Surgery (Gastrointestinal Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yu Jiang
- Department of General Surgery (Hepatobiliary Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, China
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Taiping Str. 25, Luzhou, 646000, China
| | - Chunfeng Liu
- Department of Respiratory and Critical Care Medicine, The Affiliated Hospital of Southwest Medical University, Taiping Str. 25, Luzhou, 646000, China.
- Inflammation & Allergic Diseases Research Unit, The Affiliated Hospital of Southwest Medical University, Taiping Str. 25, Luzhou, 646000, China.
- Experimental and Molecular Pathology, Institute of Pathology, Ludwig-Maximilians-University, Thalkirchner Str. 36, 80337, Munich, Germany.
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ARID1A deficiency is targetable by AKT inhibitors in HER2-negative gastric cancer. Gastric Cancer 2023; 26:379-392. [PMID: 36811690 DOI: 10.1007/s10120-023-01373-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 02/10/2023] [Indexed: 02/24/2023]
Abstract
BACKGROUND The PI3K/AKT signaling pathway is frequently activated in gastric cancer (GC); however, AKT inhibitors are not effective in unselected GC patients in clinical trials. Mutations in AT-rich interactive domain 1A (ARID1A), which are found in approximately 30% of GC patients, activate PI3K/AKT signaling, suggesting that targeting the ARID1A deficiency-activated PI3K/AKT pathway is a therapeutic candidate for ARID1A-deficient GC. METHODS The effect of AKT inhibitors was evaluated using cell viability and colony formation assays in ARID1A-deficient and ARID1A knockdown ARID1A-WT GC cells as well as in HER2-positive and HER2-negative GC. The Cancer Genome Atlas cBioPortal and Gene Expression Omnibus microarray databases were accessed to determine the extent of dependence of GC cell growth on the PI3K/AKT signaling pathway. RESULTS AKT inhibitors decreased the viability of ARID1A-deficient cells and the inhibitory effect was greater in ARID1A-deficient/HER2-negative GC cells. Bioinformatics data suggested that PI3K/AKT signaling plays a greater role in proliferation and survival in ARID1A-deficient/HER2-negative GC cells than in ARID1A-deficient/HER2-positive cells, supporting the higher therapeutic efficacy of AKT inhibitors. CONCLUSIONS The effect of AKT inhibitors on cell proliferation and survival is affected by HER2 status, providing a rationale for exploring targeted therapy using AKT inhibitors in ARID1A-deficient/HER2-negative GC.
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Zhu S, Al-Mathkour M, Cao L, Khalafi S, Chen Z, Poveda J, Peng D, Lu H, Soutto M, Hu T, McDonald OG, Zaika A, El-Rifai W. CDK1 bridges NF-κB and β-catenin signaling in response to H. pylori infection in gastric tumorigenesis. Cell Rep 2023; 42:112005. [PMID: 36681899 PMCID: PMC9973518 DOI: 10.1016/j.celrep.2023.112005] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 10/31/2022] [Accepted: 01/03/2023] [Indexed: 01/22/2023] Open
Abstract
Infection with Helicobacter pylori (H. pylori) is the main risk factor for gastric cancer, a leading cause of cancer-related death worldwide. The oncogenic functions of cyclin-dependent kinase 1 (CDK1) are not fully understood in gastric tumorigenesis. Using public datasets, quantitative real-time PCR, western blot, and immunohistochemical (IHC) analyses, we detect high levels of CDK1 in human and mouse gastric tumors. H. pylori infection induces activation of nuclear factor κB (NF-κB) with a significant increase in CDK1 in in vitro and in vivo models (p < 0.01). We confirm active NF-κB binding sites on the CDK1 promoter sequence. CDK1 phosphorylates and inhibits GSK-3β activity through direct binding with subsequent accumulation and activation of β-catenin. CDK1 silencing or pharmacologic inhibition reverses these effects and impairs tumor organoids and spheroid formation. IHC analysis demonstrates a positive correlation between CDK1 and β-catenin. The results demonstrate a mechanistic link between infection, inflammation, and gastric tumorigenesis where CDK1 plays a critical role.
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Affiliation(s)
- Shoumin Zhu
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Marwah Al-Mathkour
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Longlong Cao
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Shayan Khalafi
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Zheng Chen
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Julio Poveda
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Dunfa Peng
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Heng Lu
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Mohammed Soutto
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Tianling Hu
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Oliver G McDonald
- Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Alexander Zaika
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Veterans Affairs, Miami Healthcare System, Miami, FL, USA
| | - Wael El-Rifai
- Department of Surgery, Miller School of Medicine, University of Miami, Miami, FL, USA; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA; Department of Veterans Affairs, Miami Healthcare System, Miami, FL, USA.
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He L, Li Y, Qu L, Zhang F. Prognostic and clinicopathological value of the geriatric nutritional risk index in gastric cancer: A meta-analysis of 5,834 patients. Front Surg 2023; 9:1087298. [PMID: 36684163 PMCID: PMC9852775 DOI: 10.3389/fsurg.2022.1087298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Accepted: 11/22/2022] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Recent studies have explored the prognostic value of the geriatric nutritional risk index (GNRI) in patients with gastric cancer (GC), but the results are controversial. We aimed to systemically identify the association between the GNRI and prognosis in GC using a meta-analysis. METHODS The databases of PubMed, Web of Science, Cochrane Library, and Embase were searched until September 25, 2022. Pooled hazard ratios and the corresponding 95% confidence intervals (CIs) were used to estimate the prognostic value of the GNRI in GC. Odds ratios (ORs) and 95% CIs were used to assess the correlation between the GNRI and clinicopathological characteristics of GC. RESULTS Ten studies including 5,834 patients with GC were included in this meta-analysis. The merged results indicated that a low pretreatment GNRI was associated with inferior overall survival (hazard ratio = 1.21, 95% CI = 1.12-1.30, P < 0.001) and worse cancer-specific survival (hazard ratio = 2.21, 95% CI = 1.75-2.80, P < 0.001) for GC. Moreover, a low GNRI was significantly associated with an advanced pathological stage (OR = 2.27, 95% CI = 1.33-3.85, P = 0.003), presence of adjuvant chemotherapy (OR = 1.25, 95% CI = 1.01-1.55, P = 0.040), and tumor location in the lower stomach (OR = 1.33, 95% CI = 1.06-1.65, P = 0.012) in GC. However, there was no significant association between GNRI and sex, tumor differentiation, or lymph node metastasis in patients with GC. CONCLUSION Our meta-analysis identified that the pretreatment GNRI level was a significant prognostic factor for patients with GC. A low GNRI is associated with worse overall survival and inferior cancer-specific survival in patients with GC.
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Affiliation(s)
- Liang He
- Department of Gastrointestinal Surgery, The First Hospital of Jilin University, Changchun, China
| | - Ying Li
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
| | - Linlin Qu
- Department of Clinical Laboratory, The First Hospital of Jilin University, Changchun, China
| | - Fan Zhang
- Department of Gastroenterology, The First Hospital of Jilin University, Changchun, China
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Hong X, Zhuang K, Xu N, Wang J, Liu Y, Tang S, Zhao J, Huang Z. An integrated analysis of prognostic mRNA signature in early- and progressive-stage gastric adenocarcinoma. Front Mol Biosci 2023; 9:1022056. [PMID: 36660425 PMCID: PMC9846543 DOI: 10.3389/fmolb.2022.1022056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 11/28/2022] [Indexed: 01/06/2023] Open
Abstract
The pathogenesis and vital factors of early and progressive stages of stomach adenocarcinoma (STAD) have not been fully elucidated. In order to discover novel and potential targets to guide effective treatment strategies, a comprehensive bioinformatics study was performed, and the representative results were then validated by quantitative polymerase chain reaction (qPCR) and immunohistochemical (IMC) staining in clinical samples. A total of 4,627, 4,715, and 3,465 differentially expressed genes (DEGs) from overall-, early-, and progressive-stage STAD were identified, respectively. Prognostic models of 5-year OS were established for overall-, early-, and progressive-stage STAD, and ROC curves demonstrated AUC values for each model were 0.73, 0.87, and 0.92, respectively. Function analysis revealed that mRNAs of early-stage STAD were enriched in chemical stimulus-related pathways, whereas remarkable enrichment of mRNAs in progressive-stage STAD mainly lay in immune-related pathways. Both qPCR and IHC data confirmed the up-regulation of IGFBP1 in the early-stage and CHAF1A in progressive-stage STAD compared with their matched normal tissues, indicating that these two representative targets could be used to predict the prognostic status of the patients in these two distinct STAD stages, respectively. In addition, seven mRNAs (F2, GRID2, TF, APOB, KIF18B, INCENP, and GCG) could be potential novel biomarkers for STAD at different stages from this study. These results contributed to identifying STAD patients at high-risk, thus guiding targeted treatment with efficacy in these patients.
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Affiliation(s)
- Xiaoling Hong
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China,Key Laboratory of Big Data Mining and Precision Drug Design, Guangdong Medical University, Dongguan, China,Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Medical University, Dongguan, China,Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, Guangdong Medical University, Dongguan, China,The Second School of Clinical Medicine, Guangdong Medical University, Zhanjiang, China
| | - Kai Zhuang
- Key Laboratory of Big Data Mining and Precision Drug Design, Guangdong Medical University, Dongguan, China,Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Medical University, Dongguan, China,Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, Guangdong Medical University, Dongguan, China,School of Public Health, Guangdong Medical University, Dongguan, China
| | - Na Xu
- Key Laboratory of Big Data Mining and Precision Drug Design, Guangdong Medical University, Dongguan, China,Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Medical University, Dongguan, China,Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, Guangdong Medical University, Dongguan, China
| | - Jiang Wang
- School of Biomedical Engineering, Guangdong Medical University, Zhanjiang, China
| | - Yong Liu
- Key Laboratory of Big Data Mining and Precision Drug Design, Guangdong Medical University, Dongguan, China,Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Medical University, Dongguan, China,Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, Guangdong Medical University, Dongguan, China
| | - Siqi Tang
- Key Laboratory of Big Data Mining and Precision Drug Design, Guangdong Medical University, Dongguan, China,Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Medical University, Dongguan, China,Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, Guangdong Medical University, Dongguan, China,The Second School of Clinical Medicine, Guangdong Medical University, Zhanjiang, China
| | - Junzhang Zhao
- Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangdong, Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, National Key Clinical Discipline, Guangzhou, China,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou, China,*Correspondence: Junzhang Zhao, ; Zunnan Huang,
| | - Zunnan Huang
- The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China,Key Laboratory of Big Data Mining and Precision Drug Design, Guangdong Medical University, Dongguan, China,Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Medical University, Dongguan, China,Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, Guangdong Medical University, Dongguan, China,Marine Medical Research Institute of Guangdong Zhanjiang, Zhanjiang, China,*Correspondence: Junzhang Zhao, ; Zunnan Huang,
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Jiang F, Lin H, Yan H, Sun X, Yang J, Dong M. Construction of mRNA prognosis signature associated with differentially expressed genes in early stage of stomach adenocarcinomas based on TCGA and GEO datasets. Eur J Med Res 2022; 27:205. [PMID: 36253873 PMCID: PMC9578190 DOI: 10.1186/s40001-022-00827-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 09/11/2022] [Indexed: 12/24/2022] Open
Abstract
Background Stomach adenocarcinomas (STAD) are the most common malignancy of the human digestive system and represent the fourth leading cause of cancer-related deaths. As early-stage STAD are generally mild or asymptomatic, patients with advanced STAD have short overall survival. Early diagnosis of STAD has a considerable influence on clinical outcomes. Methods The mRNA expression data and clinical indicators of STAD and normal tissues were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database. The gene expression differences were analyzed by R packages, and gene function enrichment analysis was performed. Kaplan–Meier method and univariate Cox proportional risk regression analysis were used to screen differential expressed genes (DEGs) related to survival of STAD patients. Multivariate Cox proportional risk regression analysis was used to further screen and determine the prognostic DEGs in STAD patients, and to construct a multigene prognostic prediction signature. The accuracy of predictive signature was tested by receiver operating characteristic (ROC) curve software package, and the nomogram of patients with STAD was drawn. Cox regression was used to investigate the correlation between multigene prognostic signature and clinical factors. The predictive performance of this model was compared with two other models proposed in previous studies using KM survival analysis, ROC curve analysis, Harrell consistency index and decision curve analysis (DCA). qRT-PCR and Western blot were used to verify the expression levels of prognostic genes. The pathways and functions of possible involvement of features were predicted using the GSEA method. Results A total of 569 early-stage specific DEGs were retrieved from TCGA-STAD dataset, including 229 up-regulated genes and 340 down-regulated genes. Enrichment analysis showed that the early-stage specific DEGs were associated with cytokine–cytokine receptor interaction, neuroactive ligand–receptor interaction, and calcium signaling pathway. Multiple Cox regression algorithm was used to identify 10 early-stage specific DEGs associated with overall survival (P < 0.01) of STAD patients, and a multi-mRNA prognosis signature was established. The patients were divided into high-risk group and low-risk group according to the risk score. In the training set, the prognostic signature was positively correlated with tumor size and stage (P < 0.05), survival curve (P < 0.001) and time-dependent ROC (AUC = 0.625). In the training dataset and test dataset, the both signatures had good predictive efficiencies. Cox regression and DCA analysis revealed that the prognostic signature was an independent factor and had a better predict effect than the conventional TNM stage classification method and the earlier published biomarkers on the prognosis of STAD patients. Conclusion In this study, based on the early-stage specifically expressed genes, the prognostic signature constructed through TCGA and GEO datasets may become an indicator for clinical prognosis assessment of STAD and a new strategy for targeted therapy in the future. Supplementary Information The online version contains supplementary material available at 10.1186/s40001-022-00827-4.
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Affiliation(s)
- Fuquan Jiang
- Department of General Surgery, PLA Strategic Support Force Characteristic Medical Center, Beijing, 100101, People's Republic of China
| | - Haiguan Lin
- Department of General Surgery, PLA Strategic Support Force Characteristic Medical Center, Beijing, 100101, People's Republic of China
| | - Hongfeng Yan
- Department of General Surgery, PLA Strategic Support Force Characteristic Medical Center, Beijing, 100101, People's Republic of China
| | - Xiaomin Sun
- Department of General Surgery, PLA Strategic Support Force Characteristic Medical Center, Beijing, 100101, People's Republic of China
| | - Jianwu Yang
- Department of General Surgery, PLA Strategic Support Force Characteristic Medical Center, Beijing, 100101, People's Republic of China.
| | - Manku Dong
- Department of General Surgery, PLA Strategic Support Force Characteristic Medical Center, Beijing, 100101, People's Republic of China.
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Cerrato-Izaguirre D, Chirino YI, Prada D, Quezada-Maldonado EM, Herrera LA, Hernández-Guerrero A, Alonso-Larraga JO, Herrera-Goepfert R, Oñate-Ocaña LF, Cantú-de-León D, Meneses-García A, Basurto-Lozada P, Robles-Espinoza CD, Camacho J, García-Cuellar CM, Sánchez-Pérez Y. Somatic Mutational Landscape in Mexican Patients: CDH1 Mutations and chr20q13.33 Amplifications Are Associated with Diffuse-Type Gastric Adenocarcinoma. Int J Mol Sci 2022; 23:11116. [PMID: 36232418 PMCID: PMC9570354 DOI: 10.3390/ijms231911116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 09/15/2022] [Accepted: 09/19/2022] [Indexed: 12/04/2022] Open
Abstract
The Hispanic population, compared with other ethnic groups, presents a more aggressive gastric cancer phenotype with higher frequency of diffuse-type gastric adenocarcinoma (GA); this could be related to the mutational landscape of GA in these patients. Using whole-exome sequencing, we sought to present the mutational landscape of GA from 50 Mexican patients who were treated at The Instituto Nacional de Cancerología from 2019 to 2020. We performed a comprehensive statistical analysis to explore the relationship of the genomic variants and clinical data such as tumor histology and presence of signet-ring cell, H. pylori, and EBV. We describe a potentially different mutational landscape between diffuse and intestinal GA in Mexican patients. Patients with intestinal-type GA tended to present a higher frequency of NOTCH1 mutations, copy number gains in cytobands 13.14, 10q23.33, and 12q25.1, and copy number losses in cytobands 7p12, 14q24.2, and 11q13.1; whereas patients with diffuse-type GA tended to present a high frequency of CDH1 mutations and CNV gains in cytobands 20q13.33 and 22q11.21. This is the first description of a mutational landscape of GA in Mexican patients to better understand tumorigenesis in Hispanic patients and lay the groundwork for discovering potential biomarkers and therapeutic targets.
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Affiliation(s)
- Dennis Cerrato-Izaguirre
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del I.P.N. (CINVESTAV), Avenida Instituto Politécnico Nacional No. 2508, Ciudad de México CP. 07360, Mexico
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), San Fernando No. 22, Tlalpan, Ciudad de México CP. 14080, Mexico
| | - Yolanda I. Chirino
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Los Reyes Iztacala, Tlalnepantla de Baz, Estado de México CP. 54090, Mexico
| | - Diddier Prada
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), San Fernando No. 22, Tlalpan, Ciudad de México CP. 14080, Mexico
| | - Ericka Marel Quezada-Maldonado
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), San Fernando No. 22, Tlalpan, Ciudad de México CP. 14080, Mexico
| | - Luis A Herrera
- Instituto Nacional de Medicina Genómica (INMEGEN), Periférico Sur No. 4809, Arenal Tepepan, Tlalpan, Ciudad de México CP. 14610, Mexico
| | - Angélica Hernández-Guerrero
- Servicio de Endoscopía, Instituto Nacional de Cancerología (INCan), San Fernando No. 22, Tlalpan, Ciudad de México CP. 14080, Mexico
| | - Juan Octavio Alonso-Larraga
- Servicio de Endoscopía, Instituto Nacional de Cancerología (INCan), San Fernando No. 22, Tlalpan, Ciudad de México CP. 14080, Mexico
| | - Roberto Herrera-Goepfert
- Departamento de Patología, Instituto Nacional de Cancerología (INCan), San Fernando No. 22, Tlalpan, Ciudad de México CP. 14080, Mexico
| | - Luis F. Oñate-Ocaña
- Subdirección de Investigación Clínica, Instituto Nacional de Cancerología (INCan), San Fernando No. 22, Tlalpan, Ciudad de México CP. 14080, Mexico
| | - David Cantú-de-León
- Dirección de Investigación, Instituto Nacional de Cancerología (INCan), San Fernando No. 22, Tlalpan, Ciudad de México CP. 14080, Mexico
| | - Abelardo Meneses-García
- Dirección General, Instituto Nacional de Cancerología (INCan), San Fernando No. 22, Tlalpan, Ciudad de México CP. 14080, Mexico
| | - Patricia Basurto-Lozada
- Laboratorio Internacional de Investigación Sobre el Genoma Humano, Universidad Nacional Autónoma de México, Santiago de Querétaro CP. 76010, Mexico
| | - Carla Daniela Robles-Espinoza
- Laboratorio Internacional de Investigación Sobre el Genoma Humano, Universidad Nacional Autónoma de México, Santiago de Querétaro CP. 76010, Mexico
- Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK
| | - Javier Camacho
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del I.P.N. (CINVESTAV), Avenida Instituto Politécnico Nacional No. 2508, Ciudad de México CP. 07360, Mexico
| | - Claudia M. García-Cuellar
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), San Fernando No. 22, Tlalpan, Ciudad de México CP. 14080, Mexico
| | - Yesennia Sánchez-Pérez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), San Fernando No. 22, Tlalpan, Ciudad de México CP. 14080, Mexico
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Feng Y, Zhang C, Wu Z, Xu H, Zhang X, Feng C, Shao J, Xie M, Yang Y, Zhang Y, Ma T. Incorporation of liver chemistry score in predicting survival of liver-involved advanced gastric cancer patients who received palliative chemotherapy. Cancer Med 2022; 12:2831-2841. [PMID: 36057969 PMCID: PMC9939141 DOI: 10.1002/cam4.5179] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 05/17/2022] [Accepted: 05/28/2022] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Gastric cancer liver metastasis (GCLM) patients usually accompany by abnormal serum liver function tests (LFTs) more or less; however, the prognostic value of LFTs is not fully understood. This study aimed to develop a liver chemistry score (LCS) based on LFTs and incorporate it into prognosis determination for GCLM patients who received palliative chemotherapy. METHODS Data were derived from hospitalized GCLM patients in two general hospitals in China. LCS was generated based on the results of LFTs by LASSO regression. Cutoff value of the score was determined by restricted cubic spline. The score was then incorporated into Cox regression analysis to construct a predictive nomogram; the model was then evaluated internally and externally by AUC of time-dependent receiver operating characteristic curves (ROC) and calibration curves. RESULTS Three hundred and thirty-six and 72 patients were included in development and validation cohort, respectively. LASSO regression analysis in development cohort finally reached a two-parametric LCS calculated on AST and ALP levels as 0.03343515 × ln (AST, U/L) + 0.02687997 × ln (ALP, U/L), and 0.232 was set as optimal cutoff value. Patients in low (LCS < 0.232) or high (LCS ≥ 0.232) score group experienced different survival times; median OS was 13.54 (95% CI: 11.1-15.6) months in the low LCS group and 7.3 (6.6-9.3) months in the high LCS group (p < 0.001). A nomogram including LCS and other clinical parameters was constructed and showed superior performance than model not including LCS. AUC of 6-month ROC improved from 0.647 (95% CI: 0.584-0.711) to 0.699 (0.638-0.759) in internal validation, and 0.837 (0.734-0.940) to 0.875 (0.784-0.966) in external validation. CONCLUSIONS Liver chemistry score is useful in determining the prognosis of gastric cancer patients with liver metastasis and may be helpful to clinicians in decision-making.
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Affiliation(s)
- Ying Feng
- Department of OncologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiPeople's Republic of China
| | - Cheng Zhang
- Department of OncologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiPeople's Republic of China,Anhui Provincial Cancer Institute/Anhui Provincial Office for Cancer Prevention and ControlHefeiPeople's Republic of China
| | - Zhijun Wu
- Department of OncologyMa'anshan Municipal People's HospitalMa'anshanPeople's Republic of China
| | - Hui Xu
- Department of OncologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiPeople's Republic of China,Anhui Provincial Cancer Institute/Anhui Provincial Office for Cancer Prevention and ControlHefeiPeople's Republic of China
| | - Xiaopeng Zhang
- Department of Noncommunicable Diseases and Health EducationHefei Center for Disease Control and PreventionHefeiPeople's Republic of China
| | - Chong Feng
- Department of Noncommunicable Diseases and Health EducationHefei Center for Disease Control and PreventionHefeiPeople's Republic of China
| | - Jingyi Shao
- Department of OncologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiPeople's Republic of China
| | - Minmin Xie
- Department of OncologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiPeople's Republic of China
| | - Yahui Yang
- Department of OncologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiPeople's Republic of China
| | - Yi Zhang
- Department of OncologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiPeople's Republic of China
| | - Tai Ma
- Department of OncologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiPeople's Republic of China
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Yang W, Fang Y, Niu Y, Sun Y. A predictive model for early death in elderly patients with gastric cancer: A population-based study. Front Oncol 2022; 12:972639. [PMID: 36072801 PMCID: PMC9444320 DOI: 10.3389/fonc.2022.972639] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 07/28/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundThe mean age of gastric cancer (GC) patients has increased due to the aging society. Elderly GC patients with poor physical status tend to develop complications during the treatment courses, which cause early death. This study aimed to identify risk factors and establish nomograms for predicting total early death and cancer-specific early death in elderly GC patients.MethodsData for elderly GC patients were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. These patients were randomly assigned to a training cohort and a validation cohort. The univariate logistic regression model and backward stepwise logistic regression model were used to identify independent risk factors for early death. Nomograms were constructed to predict the overall risk of early death and their performance was validated by receiver operating characteristic (ROC) curve, calibration curve, decision curve analyses (DCA), integrated discrimination improvement (IDI), and net reclassification improvement (NRI) in both training and validation cohorts.ResultsAmong the 3102 enrolled patients, 1114 patients died within three months from the first diagnosis and 956 of them died due to cancer-specific causes. Non-Asian or Pacific Islander (API) race, non-cardia/fundus or lesser/greater curvature, higher AJCC stage, no surgery and no chemotherapy were all related to a high risk of both all-cause early death and cancer-specific early death. Higher T stage and N0 stage were only positively related to total early mortality, while liver metastasis was only positively related to cancer-specific early mortality. Based on these identified factors, two nomograms were developed for predicting the risk of all-cause and cancer-specific early death, which showed good performance with the AUC of the nomograms were 0.775 and 0.766, respectively. The calibration curves, DCAs, NRI, and IDI also confirmed the value of these nomograms.ConclusionsThese nomogram models were considered a practical tool to identify the early death of elderly GC patients and help provide a more individualized treatment strategy.
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Affiliation(s)
- Wenwei Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yuting Fang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yaru Niu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yongkun Sun
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Hebei Cancer Hospital, Chinese Academy of Medical Sciences, Langfang, China
- *Correspondence: Yongkun Sun,
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Arnold M, Morgan E, Bardot A, Rutherford MJ, Ferlay J, Little A, Møller B, Bucher O, De P, Woods RR, Saint-Jacques N, Gavin AT, Engholm G, Achiam MP, Porter G, Walsh PM, Vernon S, Kozie S, Ramanakumar AV, Lynch C, Harrison S, Merrett N, O'Connell DL, Mala T, Elwood M, Zalcberg J, Huws DW, Ransom D, Bray F, Soerjomataram I. International variation in oesophageal and gastric cancer survival 2012-2014: differences by histological subtype and stage at diagnosis (an ICBP SURVMARK-2 population-based study). Gut 2022; 71:1532-1543. [PMID: 34824149 DOI: 10.1136/gutjnl-2021-325266] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Accepted: 11/04/2021] [Indexed: 02/05/2023]
Abstract
OBJECTIVE To provide the first international comparison of oesophageal and gastric cancer survival by stage at diagnosis and histological subtype across high-income countries with similar access to healthcare. METHODS As part of the ICBP SURVMARK-2 project, data from 28 923 patients with oesophageal cancer and 25 946 patients with gastric cancer diagnosed during 2012-2014 from 14 cancer registries in seven countries (Australia, Canada, Denmark, Ireland, New Zealand, Norway and the UK) were included. 1-year and 3-year age-standardised net survival were estimated by stage at diagnosis, histological subtype (oesophageal adenocarcinoma (OAC) and oesophageal squamous cell carcinoma (OSCC)) and country. RESULTS Oesophageal cancer survival was highest in Ireland and lowest in Canada at 1 (50.3% vs 41.3%, respectively) and 3 years (27.0% vs 19.2%) postdiagnosis. Survival from gastric cancer was highest in Australia and lowest in the UK, for both 1-year (55.2% vs 44.8%, respectively) and 3-year survival (33.7% vs 22.3%). Most patients with oesophageal and gastric cancer had regional or distant disease, with proportions ranging between 56% and 90% across countries. Stage-specific analyses showed that variation between countries was greatest for localised disease, where survival ranged between 66.6% in Australia and 83.2% in the UK for oesophageal cancer and between 75.5% in Australia and 94.3% in New Zealand for gastric cancer at 1-year postdiagnosis. While survival for OAC was generally higher than that for OSCC, disparities across countries were similar for both histological subtypes. CONCLUSION Survival from oesophageal and gastric cancer varies across high-income countries including within stage groups, particularly for localised disease. Disparities can partly be explained by earlier diagnosis resulting in more favourable stage distributions, and distributions of histological subtypes of oesophageal cancer across countries. Yet, differences in treatment, and also in cancer registration practice and the use of different staging methods and systems, across countries may have impacted the comparisons. While primary prevention remains key, advancements in early detection research are promising and will likely allow for additional risk stratification and survival improvements in the future.
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Affiliation(s)
- Melina Arnold
- Cancer Surveillance Branch, International Agency for Research on Cancer, Lyon, France
| | - Eileen Morgan
- Cancer Surveillance Branch, International Agency for Research on Cancer, Lyon, France
| | - Aude Bardot
- Cancer Surveillance Branch, International Agency for Research on Cancer, Lyon, France
| | - Mark J Rutherford
- Cancer Surveillance Branch, International Agency for Research on Cancer, Lyon, France
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Jacques Ferlay
- Cancer Surveillance Branch, International Agency for Research on Cancer, Lyon, France
| | - Alana Little
- Cancer Institute New South Wales, Alexandria, New South Wales, Australia
| | | | | | - Prithwish De
- Surveillance and Cancer Registry, Cancer Care Ontario, Toronto, Ontario, Canada
| | | | - Nathalie Saint-Jacques
- Registry & Analytics, Nova Scotia Health Authority Cancer Care Program, Halifax, Nova Scotia, Canada
| | - Anna T Gavin
- Northern Ireland Cancer Registry, Queen's University Belfast, Belfast, UK
| | - Gerda Engholm
- Cancer Prevention & Documentation, Danish Cancer Society, Copenhagen, Denmark
| | - Michael P Achiam
- Danish EsophagoGastric Cancer group, Department of Surgical Gastroenterology, Rigshospitalet, Copenhagen, Denmark
| | - Geoff Porter
- Canadian Partnership Against Cancer, Toronto, Ontario, Canada
| | | | | | - Serena Kozie
- Saskatchewan Cancer Agency, Regina, Saskatchewan, Canada
| | | | - Charlotte Lynch
- International Cancer Benchmarking Partnership (ICBP), Policy & Information, Cancer Research UK, London, UK
| | - Samantha Harrison
- International Cancer Benchmarking Partnership (ICBP), Policy & Information, Cancer Research UK, London, UK
| | - Neil Merrett
- Department of Upper Gastrointestinal Surgery, Bankstown-Lidcombe Hospital and School of Medicine, Western Sydney University, Sydney, New South Wales, Australia
| | - Dianne L O'Connell
- The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, New South Wales, Australia
| | - Tom Mala
- Department of Gastrointestinal Surgery, Oslo University Hospital, Oslo, Norway
| | - Mark Elwood
- School of Population Health, The University of Auckland, Auckland, New Zealand
| | - John Zalcberg
- School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
| | - Dyfed W Huws
- Swansea University, Swansea, Wales, UK
- Welsh Cancer Intelligence and Surveillance Unit, Public Health Wales, Cardiff, Wales, UK
| | - David Ransom
- WA Cancer and Palliative Care Network Policy Unit, Health Networks Branch, Department of Health, Perth, WA, Australia
| | - Freddie Bray
- Cancer Surveillance Branch, International Agency for Research on Cancer, Lyon, France
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Cerrato-Izaguirre D, Chirino YI, García-Cuellar CM, Santibáñez-Andrade M, Prada D, Hernández-Guerrero A, Larraga OA, Camacho J, Sánchez-Pérez Y. Mutational landscape of gastric adenocarcinoma in Latin America: A genetic approach for precision medicine. Genes Dis 2022; 9:928-940. [PMID: 35685475 PMCID: PMC9170608 DOI: 10.1016/j.gendis.2021.04.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 04/01/2021] [Indexed: 02/07/2023] Open
Abstract
Latin-America (LATAM) is the second region in gastric cancer incidence; gastric adenocarcinoma (GA) represents 95% of all cases. We provide a mutational landscape of GA highlighting a) germline pathogenic variants associated with hereditary GA, b) germline risk variants associated with sporadic GA, and c) somatic variants present in sporadic GA in LATAM, and analyze how this landscape can be applied for precision medicine. We found that Brazil, Chile, Colombia, Mexico, Peru, and Venezuela are the countries with more published studies from LATAM explicitly related to GA. Our analysis displayed that different germline pathogenic variants for the CDH1 gene have been identified for hereditary GA in Brazilian, Chilean, Colombian, and Mexican populations. An increased risk of developing somatic GA is associated with the following germline risk variants: IL-4, IL-8, TNF-α, PTGS2, NFKB1, RAF1, KRAS and MAPK1 in Brazilian; IL-10 in Chilean; IL-10 in Colombian; EGFR and ERRB2 in Mexican, TCF7L2 and Chr8q24 in Venezuelan population. The path from mutational landscape to precision medicine requires four development levels: 1) Data compilation, 2) Data analysis and integration, 3) Development and approval of clinical approaches, and 4) Population benefits. Generating local genomic information is the initial padlock to overcome to generate and apply precision medicine.
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Affiliation(s)
- Dennis Cerrato-Izaguirre
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), Tlalpan, Ciudad de México, CP 14080, Mexico
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del I.P.N. (CINVESTAV), Ciudad de México, CP 07360, Mexico
| | - Yolanda I. Chirino
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Los Reyes Iztacala, Tlalnepantla de Baz, Estado de México, CP 54090, Mexico
| | - Claudia M. García-Cuellar
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), Tlalpan, Ciudad de México, CP 14080, Mexico
| | - Miguel Santibáñez-Andrade
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), Tlalpan, Ciudad de México, CP 14080, Mexico
| | - Diddier Prada
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), Tlalpan, Ciudad de México, CP 14080, Mexico
- Departamento de Informática Biomédica, Facultad de Medicina, Universidad Nacional Autónoma de México, Coyoacán, Ciudad de México, CP 04510, Mexico
- Department of Environmental Health Science, Mailman School of Public Health, Columbia University, New York, NY 10027, USA
| | - Angélica Hernández-Guerrero
- Servicio de Endoscopía, Instituto Nacional de Cancerología (INCan), Tlalpan, Ciudad de México, CP 14080, Mexico
| | - Octavio Alonso Larraga
- Servicio de Endoscopía, Instituto Nacional de Cancerología (INCan), Tlalpan, Ciudad de México, CP 14080, Mexico
| | - Javier Camacho
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del I.P.N. (CINVESTAV), Ciudad de México, CP 07360, Mexico
| | - Yesennia Sánchez-Pérez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), Tlalpan, Ciudad de México, CP 14080, Mexico
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Huang L, Jansen L, Verhoeven RHA, Ruurda JP, Van Eycken L, De Schutter H, Johansson J, Lindblad M, Johannesen TB, Zadnik V, Žagar T, Lagarde SM, van de Velde CJH, Schrotz-King P, Brenner H. Survival trends of patients with non-metastatic gastric adenocarcinoma in the US and European countries: the impact of decreasing resection rates. Cancer Commun (Lond) 2022; 42:648-662. [PMID: 35666080 PMCID: PMC9257984 DOI: 10.1002/cac2.12318] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Revised: 03/13/2022] [Accepted: 05/26/2022] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND We previously observed decreasing resection rates of non-metastatic gastric adenocarcinoma (GaC) in the US and some European countries. If and to what extent these trends affect the trends in overall survival (OS) of patients with non-metastatic GaC at the population level remain unclear. This large international population-based cohort study aimed to assess the impact of the previously observed decreasing resection rates on multivariable-adjusted trends in the long-term OS of patients with non-metastatic GaC. METHODS Individual-level data of patients with non-metastatic GaC were obtained from the national cancer registries of the Netherlands, Belgium, Sweden, Norway, and Slovenia, and the US Surveillance, Epidemiology, and End Results database. We analyzed data for each country separately. Associations between year of diagnosis and OS were assessed using Cox proportional hazards regression model with adjustment for multiple prognostic variables, with and without including resection and chemotherapy as potential explanatory variables. RESULTS A total of 66,398 non-metastatic GaC patients diagnosed in 2003-2016 were analyzed, with an accumulated follow-up of 172,357 person-years. Without adjustment for resection, OS was improved only slightly in the US [hazard ratio (HR)per year = 0.99; HR≥ vs. <2010 = 0.96], and no improvement was observed in the investigated European countries, with OS even worsening in Sweden (HRper year = 1.03; HR≥ vs. <2010 = 1.17). After adjusting for resection, the increasing OS trend became stronger in the US (HRper year = 0.98; HR≥ vs. <2010 = 0.88), and the temporal trend became insignificant in Sweden. In Slovenia (HRper year = 0.99; HR≥ vs. <2010 = 0.92) and Norway (HRper year = 0.97; HR≥ vs. <2010 = 0.86), improved OS over time emerged after resection adjustment. Improved OS in patients undergoing resection was observed in the US, the Netherlands, and Norway. Adjustment for chemotherapy did not alter the observed associations. Stratified analyses by tumor location showed mostly similar results with the findings in all patients with non-metastatic GaCs regarding the associations between year of diagnosis and survival. CONCLUSIONS OS of patients with non-metastatic GaC mostly did not improve in selected European countries and was even worsened in Sweden, while it was slightly increased in the US in the early 21st century. Progress in OS of patients with non-metastatic GaC seems to have been impeded to a large extent by decreasing rates of resection.
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Affiliation(s)
- Lei Huang
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.,Medical Faculty Heidelberg of Heidelberg University, Heidelberg, 69120, Germany
| | - Lina Jansen
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.,German Cancer Consortium, German Cancer Research Center, Heidelberg, 69120, Germany
| | - Rob H A Verhoeven
- Department of Research & Development, Netherlands Comprehensive Cancer Organization, Utrecht, 3501 DB, The Netherlands.,Department of Medical Oncology, Amsterdam University Medical Centers, Amsterdam, 1105 AZ, The Netherlands
| | - Jelle P Ruurda
- Department of Surgery, University Medical Center Utrecht, Utrecht, 3508 GA, The Netherlands
| | | | | | - Jan Johansson
- Department of Esophageal and Gastric Surgery, Lund University Hospital, Lund, 221 85, Sweden
| | - Mats Lindblad
- Department of Clinical Science, Intervention, and Technology, Division of Surgery, Karolinska University Hospital, Stockholm, 171 76, Sweden
| | - Tom B Johannesen
- Registry Department, The Cancer Registry of Norway, Oslo, 0379, Norway
| | - Vesna Zadnik
- Epidemiology and Cancer Registry, Institute of Oncology Ljubljana, Ljubljana, 1000, Slovenia
| | - Tina Žagar
- Epidemiology and Cancer Registry, Institute of Oncology Ljubljana, Ljubljana, 1000, Slovenia
| | - Sjoerd M Lagarde
- Department of Surgery, Erasmus Medical Centre-University Medical Centre Rotterdam, Rotterdam, 3015 CE, The Netherlands
| | | | - Petra Schrotz-King
- Division of Preventive Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, 69120, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, 69120, Germany.,German Cancer Consortium, German Cancer Research Center, Heidelberg, 69120, Germany.,Division of Preventive Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, 69120, Germany
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Antigen-Specific T Cell Immunotherapy Targeting Claudin18.2 in Gastric Cancer. Cancers (Basel) 2022; 14:cancers14112758. [PMID: 35681738 PMCID: PMC9179507 DOI: 10.3390/cancers14112758] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 05/30/2022] [Accepted: 05/30/2022] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Claudin18.2 is expressed in the primary and metastatic gastric cancer, making Claudin18.2 a suitable target for antigen-specific T cell immunotherapy. In this study, we first identified 12 Claudin18.2 peptides that had immunogenicity, and found that T cells stimulated by Claudin18.2 peptides had stronger anti-tumor activity and higher effective cytokine-secreting ability in vitro. We also found that Claudin18.2 peptide reactivity was associated with older age and higher Claudin18.2 expression, which helped to screen appropriate patients. The value of Claudin18.2 in the T cell-based GC immunotherapy has been affirmed in this study. Abstract T cell-based immunotherapy has led to many breakthroughs in the treatment of solid tumors. In this study, we found that membrane protein Claudin18.2 was a promising antigen in T cell-based immunotherapy for gastric cancer (GC). Firstly, we identified five HLA-A*0201- and seven HLA-A*1101-restricted T cell epitopes of Claudin18.2. Peripheral blood mononuclear cells (PBMCs) stimulated by Claudin18.2 peptides showed progressive anti-tumor ability and higher effective cytokine secretion than unstimulated PBMCs in vitro. In total, 81.8% of GC patients were Claudin18.2-positive by immunohistochemical (IHC) detection, and a positive correlation between Claudin18.2 expression and peptide reactivity (p = 0.002) was found. Clinicopathological features analyses demonstrated that Claudin18.2 expression did not correlate with gender, age, stage or Lauren classification. Survival analysis showed that a longer median progression-free survival (mPFS) was not related to peptide reactivity (p = 0.997), but related to a lower Claudin18.2 expression level (p = 0.047). These findings establish a foundation for the clinical application of Claudin18.2 targeted T cell-based immunotherapy in GC.
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Li YT, Zhou XS, Han XM, Tian J, Qin Y, Zhang T, Liu JL. Pretreatment serum albumin-to-alkaline phosphatase ratio is an independent prognosticator of survival in patients with metastatic gastric cancer. World J Gastrointest Oncol 2022; 14:1002-1013. [PMID: 35646278 PMCID: PMC9124991 DOI: 10.4251/wjgo.v14.i5.1002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/26/2021] [Accepted: 04/21/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Previous studies have suggested that a low albumin-to-alkaline phosphatase ratio (AAPR) is associated with a lower survival rate in patients with various malignancies. However, the relationship between pretreatment AAPR and the prognosis of patients with gastric cancer (GC) remains unclear.
AIM To investigate the prognostic value of AAPR in distant metastatic GC.
METHODS A total of 191 patients with distant metastatic cancer from a single institute were enrolled in this study. Pretreatment clinical data, including serum albumin and alkaline phosphatase levels, were collected. A chi-square test or Fisher’s exact test was applied to evaluate the correlations between AAPR and various clinical parameters in GC patients. The Kaplan–Meier method and Cox proportional hazards regression model were used to evaluate the prognostic efficacy of AAPR in metastatic GC patients. A two-sided P value lower than 0.05 was considered statistically significant.
RESULTS A receiver operating characteristic curve indicated that 0.48 was the optimal threshold value for AAPR. AAPR ≤ 0.48 was significantly associated with bone (P < 0.05) and liver metastasis (P < 0.05). Patients with high levels of AAPR had better survival in terms of overall survival (OS) and progression-free survival (PFS), regardless of the presence of liver/bone metastasis. Pretreatment AAPR was found to be a favorable predictor of OS and PFS based on a multivariate cox regression model. AAPR-M system, constructed based on AAPR and number of metastatic sites, showed superior predictive ability relative to the number of metastatic sites for predicting survival.
CONCLUSION Pretreatment AAPR may serve as an independent prognostic factor for predicting PFS and OS in patients with metastatic GC. Furthermore, AAPR may assist clinicians with individualizing treatment.
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Affiliation(s)
- Yu-Ting Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Xiao-Shu Zhou
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Xiao-Ming Han
- Department of Ultrasound Medicine, Jingmen Second People’s Hospital, Jingchu University of Technology Affiliated Central Hospital, Jingmen 448000, Hubei Province, China
| | - Jing Tian
- Department of Oncology, Hubei Cancer Hospital, The Seventh Clinical School Affiliated of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430000, Hubei Province, China
| | - You Qin
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Tao Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Jun-Li Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
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Wang Z, Cao L, Zhou S, Lyu J, Gao Y, Yang R. Construction and Validation of a Novel Pyroptosis-Related Four-lncRNA Prognostic Signature Related to Gastric Cancer and Immune Infiltration. Front Immunol 2022; 13:854785. [PMID: 35392086 PMCID: PMC8980360 DOI: 10.3389/fimmu.2022.854785] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 03/01/2022] [Indexed: 12/31/2022] Open
Abstract
Increasing evidence has demonstrated that pyroptosis, a type of inflammatory programmed cell death, plays an important role in the pathogenesis and progression of gastric cancer. However, it remains unclear whether pyroptosis-related long non-coding RNAs (lncRNAs) can be used to predict the diagnosis and prognosis of gastric adenocarcinoma. This study aimed to evaluate and test the role of the lncRNA signature associated with pyroptosis as a prognostic tool for stomach adenocarcinoma (STAD) and to ascertain their immune value. Relative RNA-sequencing data were extracted from The Cancer Genome Atlas database (TCGA), and data preprocessing was performed for STAD. Pearson correlation analysis was used to determine whether lncRNAs were significantly correlated with pyroptosis based on 23 genes related to pyroptosis. Univariate Cox regression and least absolute shrinkage and selection operator(LASSO) analyses were both adopted to select features and establish the pyroptosis-related lncRNA (PRL) prognostic signature. Kaplan–Meier(KM) survival analysis of the different risk groups was conducted according to the risk scores. We further examined the functional enrichment, tumor microenvironment, and landscape of mutation status among the different risk groups, and these analyses further explained the reasons for the differences in the prediction as well as survival value of the different risk groups. Four lncRNAs, including HAND2-AS1, LINC01354, RP11-276H19.1, and PGM5-AS1, were involved in the PRL signature and used to split STAD patients into two risk groups. Overall survival time(OS) was significantly higher in the low-risk group than in the high-risk group in both the training and validation groups. Functional enrichment analysis was further employed to analyze differentially expressed genes in high- and low-risk groups to identify potential molecular functions and pathways associated with pyroptosis in the gastric cancer microenvironment. Protein-protein interaction (PPI) and Friends analysis identified hub genes that may play a key role in differentially expressed genes in high- and low-risk groups. In addition, there were remarkable discrepancies between the different risk groups in the tumor stage (P < 0.01) and histologic grade (P < 0.05). Furthermore, drug-susceptibility testing indicated potential sensitive chemotherapeutic drugs for each risk group. This study is the first to establish and validate STAD-associated PRLs that can effectively guide the prognosis and the immune microenvironment in STAD patients and provide evidence for the development of molecularly targeted therapies related to pyroptosis.
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Affiliation(s)
- Zhengguang Wang
- Department of Orthopedics, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Lei Cao
- Department of General Surgery, Tianjin Union Medical Center, Tianjin, China.,Tianjin Key Laboratory of General Surgery in Construction, Tianjin Union Medical Center, Tianjin, China
| | - Sitong Zhou
- Department of Dermatology, The First People's Hospital of Foshan, Foshan, China
| | - Jin Lyu
- Department of Pathology, The First People's Hospital of Foshan, Foshan, China
| | - Yang Gao
- Department of Molecular Pharmacology, School of Medicine, Nankai University, Tianjin, China
| | - Ronghua Yang
- Department of Burn and Plastic Surgery, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
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Gaps in Providers' Knowledge Delays Gastric Cancer Diagnosis. J Gastrointest Surg 2022; 26:750-756. [PMID: 34978028 DOI: 10.1007/s11605-021-05209-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 11/13/2021] [Indexed: 01/31/2023]
Abstract
BACKGROUND Previous studies have suggested that symptomatic cancer patients often experience delays in diagnosis (DD). However, DD of gastric cancer within the USA and etiology of those delays are not understood. Our study quantifies the proportion of gastric cancer patients experiencing DD and contributing barriers of care. METHODS We conducted a single institution retrospective review of 256 gastric cancer patients treated between 2015 and 2020. Patients with an interval from symptom onset to diagnosis of > 90 days were classified as having DD and categorized into one of the following barriers of care: access, provider knowledge/skills, and patient factors. Chi-square tests were used to analyze categorical group differences. Non-pooled t-tests and ANOVA were used to compare differences in group means. RESULTS A total of 59 patients (23%) had DD. Among patients with DD, the mean time from symptom onset to diagnosis was 229 days vs 30 days in the non-delayed group (p < 0.0001). The most common barrier of care was provider knowledge/skills gaps (44%), followed by access (36%) and patient-related factors (20%). Only 5% of patients who experienced delays reported abdominal pain alone, with the remaining 95% of patients reporting more than one symptom including obstruction, gastrointestinal bleeding, or weight loss. CONCLUSION Patients often face lengthy delays in gastric cancer diagnosis which arise from healthcare system factors such as access barriers or gaps in provider knowledge/skills. Understanding concerning alarm symptoms and addressing identified barriers will expedite patient diagnosis and are prime opportunities to improve outcomes for gastric cancer patients.
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Parmar C, Zakeri R, Abouelazayem M, Shin TH, Aminian A, Mahmoud T, Abu Dayyeh BK, Wee MY, Fischer L, Daams F, Mahawar K. Esophageal and gastric malignancies after bariatric surgery: a retrospective global study. Surg Obes Relat Dis 2022; 18:464-472. [PMID: 35065887 DOI: 10.1016/j.soard.2021.11.024] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 10/27/2021] [Accepted: 11/20/2021] [Indexed: 01/19/2023]
Abstract
BACKGROUND Bariatric surgery can influence the presentation, diagnosis, and management of gastrointestinal cancers. Esophagogastric (EG) malignancies in patients who have had a prior bariatric procedure have not been fully characterized. OBJECTIVE To characterize EG malignancies after bariatric procedures. SETTING University Hospital, United Kingdom. METHODS We performed a retrospective, multicenter observational study of patients with EG malignancies after bariatric surgery to characterize this condition. RESULTS This study includes 170 patients from 75 centers in 25 countries who underwent bariatric procedures between 1985 and 2020. At the time of the bariatric procedure, the mean age was 50.2 ± 10 years, and the mean weight 128.8 ± 28.9 kg. Women composed 57.3% (n = 98) of the population. Most (n = 64) patients underwent a Roux-en-Y gastric bypass (RYGB) followed by adjustable gastric band (AGB; n = 46) and sleeve gastrectomy (SG; n = 43). Time to cancer diagnosis after bariatric surgery was 9.5 ± 7.4 years, and mean weight at diagnosis was 87.4 ± 21.9 kg. The time lag was 5.9 ± 4.1 years after SG compared to 9.4 ± 7.1 years after RYGB and 10.5 ± 5.7 years after AGB. One third of patients presented with metastatic disease. The majority of tumors were adenocarcinoma (82.9%). Approximately 1 in 5 patients underwent palliative treatment from the outset. Time from diagnosis to mortality was under 1 year for most patients who died over the intervening period. CONCLUSION The Oesophago-Gastric Malignancies After Obesity/Bariatric Surgery study presents the largest series to date of patients developing EG malignancies after bariatric surgery and attempts to characterize this condition.
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Affiliation(s)
- Chetan Parmar
- Department of Surgery, Whittington Health NHS Trust, London, UK.
| | - Roxanna Zakeri
- Department of Surgery, Whittington Health NHS Trust, London, UK; Centre for Obesity Research, University College, London, UK
| | - Mohamed Abouelazayem
- Department of Surgery, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Thomas H Shin
- Bariatric and Metabolic Institute, Department of General Surgery, Cleveland Clinic, Cleveland, Ohio
| | - Ali Aminian
- Bariatric and Metabolic Institute, Department of General Surgery, Cleveland Clinic, Cleveland, Ohio
| | - Tala Mahmoud
- Department of Gastroenterology, Mayo Clinic, Rochester, Minnesota
| | | | - Melissa Y Wee
- Department of Oesophagogastric Surgery, Flinders Medical Centre, Adelaide, Australia
| | - Laura Fischer
- Department of Surgery, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma
| | - Freek Daams
- Department of Surgery, Amsterdam UMC, VUmc, Amsterdam, The Netherlands
| | - Kamal Mahawar
- Department of Surgery, South Tyneside and Sunderland NHS Foundation Trust, Sunderland, UK
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Cao T, Lu Y, Wang Q, Qin H, Li H, Guo H, Ge M, Glass SE, Singh B, Zhang W, Dong J, Du F, Qian A, Tian Y, Wang X, Li C, Wu K, Fan D, Nie Y, Coffey RJ, Zhao X. A CGA/EGFR/GATA2 positive feedback circuit confers chemoresistance in gastric cancer. J Clin Invest 2022; 132:154074. [PMID: 35289315 PMCID: PMC8920335 DOI: 10.1172/jci154074] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 01/26/2022] [Indexed: 12/24/2022] Open
Abstract
De novo and acquired resistance are major impediments to the efficacy of conventional and targeted cancer therapy. In unselected gastric cancer (GC) patients with advanced disease, trials combining chemotherapy and an anti-EGFR monoclonal antibody have been largely unsuccessful. In an effort to identify biomarkers of resistance so as to better select patients for such trials, we screened the secretome of chemotherapy-treated human GC cell lines. We found that levels of CGA, the α-subunit of glycoprotein hormones, were markedly increased in the conditioned media of chemoresistant GC cells, and CGA immunoreactivity was enhanced in GC tissues that progressed on chemotherapy. CGA levels in plasma increased in GC patients who received chemotherapy, and this increase was correlated with reduced responsiveness to chemotherapy and poor survival. Mechanistically, secreted CGA was found to bind to EGFR and activate EGFR signaling, thereby conferring a survival advantage to GC cells. N-glycosylation of CGA at Asn52 and Asn78 is required for its stability, secretion, and interaction with EGFR. GATA2 was found to activate CGA transcription, whose increase, in turn, induced the expression and phosphorylation of GATA2 in an EGFR-dependent manner, forming a positive feedback circuit that was initiated by GATA2 autoregulation upon sublethal exposure to chemotherapy. Based on this circuit, combination strategies involving anti-EGFR therapies or targeting CGA with microRNAs (miR-708-3p and miR-761) restored chemotherapy sensitivity. These findings identify a clinically actionable CGA/EGFR/GATA2 circuit and highlight CGA as a predictive biomarker and therapeutic target in chemoresistant GC.
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Affiliation(s)
- Tianyu Cao
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Yuanyuan Lu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Qi Wang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Hongqiang Qin
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
| | - Hongwei Li
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Hao Guo
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.,State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, China
| | - Minghui Ge
- State Key Laboratory of Translational Medicine and Innovative Drug Development, Jiangsu Simcere Diagnostics Co., Ltd., Nanjing, China
| | - Sarah E Glass
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Bhuminder Singh
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Wenyao Zhang
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Jiaqiang Dong
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Feng Du
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Airong Qian
- Key Laboratory for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Ye Tian
- Key Laboratory for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an, China
| | - Xin Wang
- Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, China
| | - Cunxi Li
- Beijing Institute of Human Reproduction and Genetics Medicine, Beijing, China.,Jiaen Genetics Laboratory, Beijing Jiaen Hospital, Beijing, China
| | - Kaichun Wu
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Daiming Fan
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | - Robert J Coffey
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Xiaodi Zhao
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
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Yin X, He XK, Wu LY, Yan SX. Effect of prior malignancy on the prognosis of gastric cancer and somatic mutation. World J Clin Cases 2022; 10:1485-1497. [PMID: 35211586 PMCID: PMC8855248 DOI: 10.12998/wjcc.v10.i5.1485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Revised: 11/08/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Cancer survivors have a higher risk of developing secondary cancer, with previous studies showing heterogeneous effects of prior cancer on cancer survivors.
AIM To describe the features and clinical significance of a prior malignancy in patients with gastric cancer (GC).
METHODS We identified eligible patients from the Surveillance, Epidemiology, and End Results (SEER) database, and compared the clinical features of GC patients with/without prior cancer. Kaplan-Meier curves and Cox analyses were used to assess the prognostic impact of prior cancer on overall survival (OS) and cancer-specific survival (CSS) outcomes. We also validated our results in The Cancer Genome Atlas (TCGA) cohort and compared mutation patterns.
RESULTS In the SEER dataset, of the 35492 patients newly diagnosed with GC between 2004 and 2011, 4,001 (11.3%) had at least one prior cancer, including 576 (1.62%) patients with multiple cancers. Patients with a prior cancer history tended to be elderly, with a more localized stage and less positive lymph nodes. The prostate (32%) was the most common initial cancer site. The median interval from initial cancer diagnosis to secondary GC was 68 mo. By using multivariable Cox analyses, we found that a prior cancer history was not significantly associated with OS (hazard ratio [HR]: 1.01, 95% confidence interval [CI]: 0.97–1.05). However, a prior cancer history was significantly associated with better GC-specific survival (HR: 0.82, 95% CI: 0.78–0.85). In TCGA cohort, no significant difference in OS was observed for GC patients with or without prior cancer. Also, no significant differences in somatic mutations were observed between groups.
CONCLUSION The prognosis of GC patients with previous diagnosis of cancer was not inferior to that of primary GC patients.
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Affiliation(s)
- Xin Yin
- Department of Radiation Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Xing-Kang He
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Hangzhou 310000, Zhejiang Province, China
| | - Ling-Yun Wu
- Department of Radiation Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
| | - Sen-Xiang Yan
- Department of Radiation Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310000, Zhejiang Province, China
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+HOXA10-AS Promotes Malignant Phenotypes of Gastric Cancer via Upregulating HOXA10. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:1846687. [PMID: 35222681 PMCID: PMC8866012 DOI: 10.1155/2022/1846687] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Revised: 12/16/2021] [Accepted: 12/29/2021] [Indexed: 12/07/2022]
Abstract
Objective To study the role of long noncoding RNA HOXA10-AS in gastric cancer (GC) and its underlying mechanism which is one of the most common and fetal malignancies. Long noncoding RNA HOXA10-AS is highly expressed and acts in an oncogenic role in cancers. However, its roles in GC are still unknown. Methods The expression of HOXA10-AS and HOXA10 in GC tissues from the TCGA database was analyzed. Western blot and qRT-PCR assays were applied to examine the expression of HOXA10-AS and HOXA10. Cell proliferation was evaluated with CCK-8 and EdU incorporation assays. Cell apoptosis was analyzed by flow cytometry. Migratory and invasive capacities were evaluated with wound healing and transwell assays. Results HOXA10-AS and HOXA10 were upregulated in GC, and their expressions were positively correlated. Knockdown of HOXA10-AS inhibited HOXA10 expression in GC cells. Furthermore, knockdown of HOXA10-AS restrained GC cell proliferation, migration, and invasion but promoted apoptosis. In addition, overexpression of HOXA10-AS promoted malignant phenotypes of GC cells, but all these effects could be reversed by knockdown of HOXA10. Conclusion HOXA10-AS promoted GC cell proliferation, migration and invasion and enhanced apoptosis via upregulating HOXA10. Our study implies a novel regulatory mechanism of malignant phenotypes and provides potential therapeutic targets for GC.
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