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Gou M, Zhang H, Qian N, Zhang Y, Sun Z, Li G, Wang Z, Dai G. Deep learning radiomics analysis for prediction of survival in patients with unresectable gastric cancer receiving immunotherapy. Eur J Radiol Open 2025; 14:100626. [PMID: 39807092 PMCID: PMC11728962 DOI: 10.1016/j.ejro.2024.100626] [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: 10/28/2024] [Revised: 12/03/2024] [Accepted: 12/14/2024] [Indexed: 01/16/2025] Open
Abstract
Objective Immunotherapy has become an option for the first-line therapy of advanced gastric cancer (GC), with improved survival. Our study aimed to investigate unresectable GC from an imaging perspective combined with clinicopathological variables to identify patients who were most likely to benefit from immunotherapy. Method Patients with unresectable GC who were consecutively treated with immunotherapy at two different medical centers of Chinese PLA General Hospital were included and divided into the training and validation cohorts, respectively. A deep learning neural network, using a multimodal ensemble approach based on CT imaging data before immunotherapy, was trained in the training cohort to predict survival, and an internal validation cohort was constructed to select the optimal ensemble model. Data from another cohort were used for external validation. The area under the receiver operating characteristic curve was analyzed to evaluate performance in predicting survival. Detailed clinicopathological data and peripheral blood prior to immunotherapy were collected for each patient. Univariate and multivariable logistic regression analysis of imaging models and clinicopathological variables was also applied to identify the independent predictors of survival. A nomogram based on multivariable logistic regression was constructed. Result A total of 79 GC patients in the training cohort and 97 patients in the external validation cohort were enrolled in this study. A multi-model ensemble approach was applied to train a model to predict the 1-year survival of GC patients. Compared to individual models, the ensemble model showed improvement in performance metrics in both the internal and external validation cohorts. There was a significant difference in overall survival (OS) among patients with different imaging models based on the optimum cutoff score of 0.5 (HR = 0.20, 95 % CI: 0.10-0.37, P < 0.001). Multivariate Cox regression analysis revealed that the imaging models, PD-L1 expression, and lung immune prognostic index were independent prognostic factors for OS. We combined these variables and built a nomogram. The calibration curves showed that the C-index of the nomogram was 0.85 and 0.78 in the training and validation cohorts. Conclusion The deep learning model in combination with several clinical factors showed predictive value for survival in patients with unresectable GC receiving immunotherapy.
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Affiliation(s)
- Miaomiao Gou
- Department of Medical Oncology, The Fifth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, PR China
| | - Hongtao Zhang
- Department of Medical Oncology, The Fifth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, PR China
| | - Niansong Qian
- Department of Thoracic Oncology, The Eighth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, PR China
| | - Yong Zhang
- Department of Medical Oncology, The Second Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, PR China
| | - Zeyu Sun
- R&D Center, Keya Medical Technology Co., Ltd, Beijing, PR China
| | - Guang Li
- R&D Center, Keya Medical Technology Co., Ltd, Beijing, PR China
| | - Zhikuan Wang
- Department of Medical Oncology, The Fifth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, PR China
| | - Guanghai Dai
- Department of Medical Oncology, The Fifth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, PR China
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Li TH, Sun X, Li CG, Yin YP, Tao KX. Hypercoagulation after neoadjuvant immunochemotherapy as a new prognostic indicator in patients with locally advanced gastric cancer undergoing surgery. World J Gastrointest Oncol 2025; 17:100927. [DOI: 10.4251/wjgo.v17.i3.100927] [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: 08/30/2024] [Revised: 12/06/2024] [Accepted: 12/25/2024] [Indexed: 02/14/2025] Open
Abstract
BACKGROUND Coagulation status is closely related to the progression of malignant tumors. In the era of neoadjuvant immunochemotherapy (NICT), the prognostic utility of coagulation indicators in patients with locally advanced gastric cancer (LAGC) undergoing new treatments remains to be determined.
AIM To determine whether hypercoagulation is an effective prognostic indicator in patients with LAGC who underwent radical resection after NICT.
METHODS A retrospective analysis of clinical data from 104 patients with LAGC, who underwent radical resection after NICT between 2020 and 2023, was performed. D-dimer and fibrinogen concentrations were measured one week before NICT, and again one week before surgery, to analyze the association between these two indicators and their combined indices [non-hypercoagulation (D-dimer and fibrinogen concentrations within the upper limit of normal) vs hypercoagulation (D-dimer or fibrinogen concentrations above the upper limit of normal)] with prognosis. After radical resection, patients were followed-up periodically. The median follow-up duration was 21 months.
RESULTS Data collected after NICT revealed that the three-year overall survival (OS) and disease-free survival (DFS) rates the non-hypercoagulation group were significantly better than those in the hypercoagulation group [94.4% vs 78.0% (P = 0.019) and 87.0% vs 68.0% (P = 0.027), respectively]. Multivariate analysis indicated that hypercoagulation after NICT was an independent factor for poor postoperative OS [hazard ratio (HR) 4.436, P = 0.023] and DFS (HR 2.551, P = 0.039). Pre-NICT data demonstrated no statistically significant difference in three-year OS between the non-hypercoagulation and hypercoagulation groups (88.3% vs 84.1%, respectively; P = 0.443).
CONCLUSION Hypercoagulation after NICT is an effective prognostic indicator in patients with LAGC undergoing radical gastrectomy.
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Affiliation(s)
- Tian-Hao Li
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Xiong Sun
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Cheng-Guo Li
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Yu-Ping Yin
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
| | - Kai-Xiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, Hubei Province, China
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Gao W, Li F, Wu T, Ji L. Prognostic stratification of gastric cancer patients by intratumoral microbiota-mediated tumor immune microenvironment. Microb Pathog 2025; 200:107296. [PMID: 39809345 DOI: 10.1016/j.micpath.2025.107296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 11/19/2024] [Accepted: 01/10/2025] [Indexed: 01/16/2025]
Abstract
Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide, and therapeutic options for advanced GC are limited. Here, we observe that intratumoral microbiota controls chemokine expression, which in turn recruits immune cells into the tumor, and that immune infiltration is strongly associated with patient survival and disease attributes. Furthermore, microbiota regulation of chemokines is differentiated in GC patients with different survival risks. As seen in gastric tumors, in high-survival-risk patients, Pseudomonas regulates CCL4, CXCL9, CXCL10, and CXCL11 accumulation to recruit immune cells such as CD4+ T cells, CD8+ T cells, and M1 macrophages. In low-survival-risk patients, Leptospira regulates CCL4, CCL5, CXCL9, and CXCL10 accumulation to recruit multiple types of immune cells. An independent single-cell dataset of GC verified the relationship between chemokines and immune cells. What's more, chemokines, including CCL4, CCL5, CXCL9, CXCL10, and CXCL11, strongly influence the sensitivity of GC patients to potential drug candidates. This study demonstrates that intratumoral microbiota closely influences the gastric immune microenvironment and that this molding has prognostic heterogeneity, opening avenues for cancer prevention and therapy.
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Affiliation(s)
- Wei Gao
- Departments of Medical Oncology, Fujian Cancer Hospital, Fuzhou, Fujian, 350014, PR China; Clinical Oncology School of Fujian Medical University, Fuzhou, Fujian, 350014, PR China; Department of Medical Oncology, Fujian Medical University Union Hospital, No.29, Xinquan Road, Gulou District, Fuzhou, Fujian province, 350001, PR China
| | - Feifei Li
- Geneis Beijing Co., Ltd., Beijing, 100102, PR China
| | - Tao Wu
- Department of Medical Oncology, The Second Affiliated Hospital of Dalian Medical University, Dalian, 116021, PR China.
| | - Lei Ji
- Geneis Beijing Co., Ltd., Beijing, 100102, PR China.
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Zhang X, Wang J, Wang G, Zhang Y, Fan Q, Lu C, Hu C, Sun M, Wan Y, Sun S, Wang J, Zhang L, Shu Y, Luo J, Zhu D, Shen Z, Yao S, Shi Q, Yang J, Shen L. First-Line Sugemalimab Plus Chemotherapy for Advanced Gastric Cancer: The GEMSTONE-303 Randomized Clinical Trial. JAMA 2025:2830739. [PMID: 39992668 DOI: 10.1001/jama.2024.28463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/26/2025]
Abstract
Importance Gastric cancer, including gastroesophageal junction cancer, is one of the most commonly diagnosed cancers worldwide, with high mortality. Sugemalimab is a fully human anti-programmed death-ligand 1 (PD-L1) antibody. The combination of sugemalimab and chemotherapy showed promising antitumor activity and safety in a phase 1b study among patients with treatment-naive, unresectable, locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. This combination was further evaluated in the GEMSTONE-303 phase 3 trial. Objective To evaluate the efficacy of sugemalimab in combination with capecitabine and oxaliplatin (CAPOX) compared with placebo plus CAPOX as first-line treatment for patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with PD-L1 combined positive score (CPS) of 5 or greater. Design, Setting, and Participants GEMSTONE 303 is a phase 3, randomized, double-blind, placebo-controlled study conducted at 54 sites in China that enrolled patients from April 9, 2019, through December 29, 2021, with follow-up to July 9, 2023. A total of 479 eligible patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma with PD-L1 CPS of 5 or greater who did not receive any prior systemic therapy were randomized. Intervention Patients received sugemalimab (1200 mg intravenously) (n = 241) or placebo (n = 238) every 3 weeks for up to 24 months, plus CAPOX every 3 weeks for up to 6 cycles. Main outcomes and Measures Primary outcomes were overall survival and investigator-assessed progression-free survival. Results Baseline characteristics were well balanced between the 2 groups. Most patients were male (71.4% in sugemalimab group, 74.8% in placebo group). Median follow-up was 25.1 months in the sugemalimab group and 26.3 months in the placebo group. The sugemalimab group demonstrated significant improvements in overall survival (median, 15.6 months [95% CI, 13.3-17.8] vs 12.6 months [95% CI, 10.6-14.1]; hazard ratio, 0.75 [95% CI, 0.61-0.92]; P = .006) and progression-free survival (median, 7.6 months [95% CI, 6.4-7.9] vs 6.1 months [95% CI, 5.1-6.4]; hazard ratio, 0.66 [95% CI, 0.54-0.81]; P < .001). Grade 3 or higher treatment-related adverse events occurred in 53.9% of patients in the sugemalimab group and 50.6% in the placebo group. Conclusions and Relevance Sugemalimab plus chemotherapy significantly prolonged overall survival and progression-free survival with a manageable safety profile in previously untreated patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma. Trial Registration ClinicalTrials.gov Identifier: NCT03802591.
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Affiliation(s)
- Xiaotian Zhang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China
| | - Jufeng Wang
- Gastroenterology Department, Henan Cancer Hospital, Zhengzhou, China
| | - Gang Wang
- Cancer Chemotherapy Department, Anhui Provincial Hospital, Hefei, China
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Qingxia Fan
- Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chuangxin Lu
- Medical Oncology Department, Henan Provincial People's Hospital, Zhengzhou, China
| | - Changlu Hu
- Medical Oncology Department, Anhui Provincial Cancer Hospital, Hefei, China
| | - Meili Sun
- Oncology Department, Jinan Central Hospital, Jinan, China
| | - Yiye Wan
- Department of Gastroenterology and Medical Oncology, Jiangxi Cancer Hospital, Nanchang, China
| | - Sanyuan Sun
- Oncology Department, Xuzhou Central Hospital, Xuzhou, China
| | - Junye Wang
- Oncology Department, Affiliated Hospital of Jining Medical University, Jining, China
| | - Li Zhang
- Oncology Department, Chongqing University Three Gorges Hospital, Chongqing, China
| | - Yongqian Shu
- Oncology Department, The First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital), Nanjing, China
| | - Jie Luo
- Clinical Development, CStone Pharmaceuticals Co Ltd, Shanghai, China
| | - Dan Zhu
- Clinical Development, CStone Pharmaceuticals Co Ltd, Shanghai, China
| | - Zhenwei Shen
- Clinical Development, CStone Pharmaceuticals Co Ltd, Shanghai, China
| | - Sheng Yao
- Clinical Development, CStone Pharmaceuticals Co Ltd, Shanghai, China
| | - Qingmei Shi
- Clinical Development, CStone Pharmaceuticals Co Ltd, Shanghai, China
| | - Jason Yang
- Clinical Development, CStone Pharmaceuticals Co Ltd, Shanghai, China
| | - Lin Shen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China
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Li Z, Li Z, Sun C, Zhang X, Fei H, Xing C, Zhao D. Association between adjuvant radiotherapy in adults with gastric cancer and risk of second primary malignancy: a retrospective cohort study using the Surveillance, Epidemiology and End Results database. BMJ Open 2025; 15:e086349. [PMID: 39938963 PMCID: PMC11822440 DOI: 10.1136/bmjopen-2024-086349] [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: 03/12/2024] [Accepted: 01/27/2025] [Indexed: 02/14/2025] Open
Abstract
OBJECTIVES This study aims to assess the association between adjuvant radiotherapy and the development of second primary malignancies (SPMs) and identify its determinants in patients who have undergone surgical treatment for gastric cancer. DESIGN Retrospective cohort study using the Surveillance, Epidemiology and End Results (SEER) database. SETTING Cohorts (18 registries, 2000-2018, from SEER) were screened for any malignancy that developed after sufficient latency from diagnosis of surgically treated non-metastatic gastric cancer. PARTICIPANTS 24 777 surgically treated gastric cancer cases were included in the cohort. Among them, 6128 patients underwent adjuvant radiotherapy. OUTCOME MEASURES The cumulative incidence of SPMs was estimated using Fine and Gray's competing risk model and the radiotherapy-correlated risks were calculated using Poisson regression analysis. RESULTS Among patients with sufficient latency, there was no significant association between radiotherapy and the risk of developing second primary solid malignancies (relative risk=1.05, 95% CI 0.83 to 1.33) or haematological malignancies (relative risk=1.17, 95% CI 0.62 to 2.11). Interestingly, radiotherapy was associated with a reduced cumulative incidence of second lung and bronchus cancer compared with no radiotherapy, with a 15-year incidence of 1.4%-3.17% (p<0.05). Radiotherapy was not associated with a significant increase in standardised incidence ratios of SPMs. CONCLUSIONS Adjuvant radiotherapy was not associated with an increased risk of developing SPMs in surgically treated patients with gastric cancer. Clinical trials are warranted to further verify the findings.
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Affiliation(s)
- Zheng Li
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/ National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zefeng Li
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/ National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chongyuan Sun
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/ National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaojie Zhang
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/ National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - He Fei
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/ National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Cheng Xing
- Department of General Surgery, Beijing Hospital, Beijing, China
| | - Dongbing Zhao
- Department of Pancreatic and Gastric Surgical Oncology, National Cancer Center/ National Clinical Research for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Song J, Zhu J, Jiang Y, Guo Y, Liu S, Qiao Y, Du Y, Li J. Advancements in immunotherapy for gastric cancer: Unveiling the potential of immune checkpoint inhibitors and emerging strategies. Biochim Biophys Acta Rev Cancer 2025; 1880:189277. [PMID: 39938663 DOI: 10.1016/j.bbcan.2025.189277] [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: 06/10/2024] [Revised: 01/08/2025] [Accepted: 02/04/2025] [Indexed: 02/14/2025]
Abstract
Gastric cancer (GC) is linked to high morbidity and mortality rates. Approximately two-thirds of GC patients are diagnosed at an advanced or metastatic stage. Conventional treatments for GC, including surgery, radiotherapy, and chemotherapy, offer limited prognostic improvement. Recently, immunotherapy has gained attention for its promising therapeutic effects in various tumors. Immunotherapy functions by activating and regulating the patient's immune cells to target and eliminate tumor cells, thereby reducing the tumor burden in the body. Among immunotherapies, immune checkpoint inhibitors (ICIs) are the most advanced. ICIs disrupt the inhibitory protein-small molecule (PD-L1, CTLA4, VISTA, TIM-3 and LAG3) interactions produced by immune cells, reactivating these cells to recognize and attack tumor cells. However, adverse reactions and resistance to ICIs hinder their further clinical and experimental development. Therefore, a comprehensive understanding of the advancements in ICIs for GC is crucial. This article discusses the latest developments in clinical trials of ICIs for GC and examines combination therapies involving ICIs (targeted therapy, chemotherapy, radiotherapy), alongside ongoing clinical trials. Additionally, the review investigates the tumor immune microenvironment and its role in non-responsiveness to ICIs, highlighting the function of tumor immune cells in ICI efficacy. Finally, the article explores the prospects and limitations of new immunotherapy-related technologies, such as tumor vaccines, nanotechnologies, and emerging therapeutic strategies, aiming to advance research into personalized and optimized immunotherapy for patients with locally advanced gastric cancer.
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Affiliation(s)
- Jiawei Song
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China; Department of Experimental Surgery, Xijing Hospital, Xi'an 710038, China
| | - Jun Zhu
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China
| | - Yu Jiang
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China
| | - Yajie Guo
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China
| | - Shuai Liu
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China
| | - Yihuan Qiao
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China
| | - Yongtao Du
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China
| | - Jipeng Li
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Air force Medical University, Xi'an 710038, China; Department of Experimental Surgery, Xijing Hospital, Xi'an 710038, China.
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Zhang J, Yuan C, Ma X. Efficacy and safety of different drugs in patients with HER2-positive gastric cancer: network meta-analysis. Syst Rev 2025; 14:40. [PMID: 39930467 PMCID: PMC11808970 DOI: 10.1186/s13643-025-02777-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Accepted: 01/25/2025] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND In the past decade, there has been a significant advancement in targeted therapy and immunotherapy, leading to the discovery of new drugs and changes in the treatment approach for patients with HER2-positive gastric cancer. Although several drugs are available for treating these patients, there is still no consensus on their selection, and there has been limited direct or indirect comparison among them. OBJECTIVE To address this gap, a network meta-analysis was conducted to assess the efficacy and safety of different drugs used in the treatment of HER2-positive gastric cancer. METHODS By searching through databases such as PubMed, Embase, Web of Science, and Cochrane Library, we identified 16 randomized controlled trials that involved a total of 4485 patients and utilized 9 different intervention measures. RESULTS Based on the current evidence, compared with chemotherapy alone, the hazard ratio (HR) of overall survival (OS) and progression-free survival (PFS) in gastric cancer patients treated with nivolumab were [hazard ratio (HR): 2.61 95%confidence interval (CI) (1.51, 4.51)] and [hazard ratio (HR): 2.01 95% confidence interval (CI) (1.18, 3.42)], respectively. Compared with chemotherapy alone, the hazard ratio (HR) of overall survival (OS) and progression-free survival (PFS) in gastric cancer patients treated with trastuzumab deruxtecan were [hazard ratio (HR): 1.7 95% confidence interval (CI) (1.13, 2.56)] and [hazard ratio (HR): 2.13 95% confidence interval (CI) (1.42, 3.22)], respectively. It is suggested that nivolumab and trastuzumab deruxtecan can effectively prolong overall survival (OS) and progression-free survival(PFS) in patients with HER2-positive gastric cancer, while also reducing the risk of adverse events to some extent. Therefore, these two regimens, nivolumab and trastuzumab deruxtecan, are considered to be effective and safe options for the treatment of patients with HER2-positive gastric cancer. CONCLUSIONS In previous studies, trastuzumab-based chemotherapy has been a common treatment for HER2-positive gastric cancer. To a certain extent, our study provides a reliable direction for future treatment options for HER2-positive gastric cancer. SYSTEMATIC REVIEW REGISTRATION PROSPERO CRD42023420941.
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Affiliation(s)
- Jie Zhang
- Department of Oncology, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, 222000, China
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210008, China
| | - Chunluan Yuan
- Department of Oncology, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, 222000, China.
| | - Xiao Ma
- Department of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210008, China.
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Morikawa N, Sato Y, Iwama N, Kubota-Nakayama F, Onaka Y, Kondo Y, Kumagai F, Motoyama K. Confirmed Pathological Response to Nivolumab Combined with Chemotherapy for Advanced Gastric Cancer with Left Subclavicular Lymph Node Metastasis: A Case Report. TOHOKU J EXP MED 2025; 264:215-219. [PMID: 39198148 DOI: 10.1620/tjem.2024.j077] [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: 09/01/2024]
Abstract
We report the case of a 44-year-old male with advanced gastric cancer with distal lymph node metastasis who achieved a pathological complete response to chemotherapy combined with nivolumab. After five months of treatment, the patient underwent total gastrectomy with D2 lymph node dissection, and histological examination revealed the absence of malignant cells not only in the resected specimen but also in the harvested lymph nodes. At present, more than 1 year after the initial surgery, the patient is still alive without any recurrence. This case highlights the potential of chemotherapy combined with nivolumab to induce a complete response in advanced gastric cancer patients.
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Affiliation(s)
| | - Yuko Sato
- Department of Medical Oncology, Tohoku Rosai Hospital
- Department Medical House Call, Soshukai Okabe Clinic Sendai
| | - Noriyuki Iwama
- Department of Diagnostic Pathology, Tohoku Rosai Hospital
| | | | - Yuta Onaka
- Department of Diagnostic Radiology, Tohoku Rosai Hospital
| | - Yutaka Kondo
- Department of Gastroenterology, Tohoku Rosai Hospital
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Dong D, Yu X, Liu H, Xu J, Guo J, Guo W, Li X, Wang F, Zhang D, Liu K, Sun Y. Study of immunosenescence in the occurrence and immunotherapy of gastrointestinal malignancies. Semin Cancer Biol 2025; 111:16-35. [PMID: 39929408 DOI: 10.1016/j.semcancer.2025.01.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 01/18/2025] [Accepted: 01/26/2025] [Indexed: 02/25/2025]
Abstract
In human beings heterogenous, pervasive and lethal malignancies of different parts of the gastrointestinal (GI) tract viz., tumours of the oesophagus, stomach, small intestine, colon, and rectum, represent gastrointestinal malignancies. Primary treatment modality for gastric cancer includes chemotherapy, surgical interventions, radiotherapy, monoclonal antibodies and inhibitors of angiogenesis. However, there is a need to improve upon the existing treatment modality due to associated adverse events and the development of resistance towards treatment. Additionally, age has been found to contribute to increasing the incidence of tumours due to immunosenescence-associated immunosuppression. Immunosenescence is the natural process of ageing, wherein immune cells as well as organs begin to deteriorate resulting in a dysfunctional or malfunctioning immune system. Accretion of senescent cells in immunosenescence results in the creation of a persistent inflammatory environment or inflammaging, marked with elevated expression of pro-inflammatory and immunosuppressive cytokines and chemokines. Perturbation in the T-cell pools and persistent stimulation by the antigens facilitate premature senility of the immune cells, and senile immune cells exacerbate inflammaging conditions and the inefficiency of the immune system to identify the tumour antigen. Collectively, these conditions contribute positively towards tumour generation, growth and eventually proliferation. Thus, activating the immune cells to distinguish the tumour cells from normal cells and invade them seems to be a logical strategy for the treatment of cancer. Consequently, various approaches to immunotherapy, viz., programmed death ligand-1 (PD-1) inhibitors, Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors etc are being extensively evaluated for their efficiency in gastric cancer. In fact, PD-1 inhibitors have been sanctioned as late late-line therapy modality for gastric cancer. The present review will focus on deciphering the link between the immune system and gastric cancer, and the alterations in the immune system that incur during the development of gastrointestinal malignancies. Also, the mechanism of evasion by tumour cells and immune checkpoints involved along with different approaches of immunotherapy being evaluated in different clinical trials will be discussed.
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Affiliation(s)
- Daosong Dong
- Department of Pain, The First Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Xue Yu
- Department of Surgical Oncology and General Surgery, The First Hospital of China Medical University, Key Laboratory of Molecular Pathology and Epidemiology of Gastric Cancer in the Universities of Liaoning Province, Shenyang, Liaoning 110001, China
| | - Haoran Liu
- Department of Breast Surgery, The First Hospital of China Medical University, Shenyang 110001, China
| | - Jingjing Xu
- Department of Rheumatology and Immunology, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110001, China
| | - Jiayan Guo
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang 110001, China
| | - Wei Guo
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang 110001, China
| | - Xiang Li
- Department of Pancreatic-Biliary Surgery, The First Hospital of China Medical University, Shenyang 110001, China
| | - Fei Wang
- Department of Otolaryngology, The First Hospital of China Medical University, Shenyang 110001, China.
| | - Dongyong Zhang
- Department of Neurosurgery, The First Hospital of China Medical University, Shenyang 110001, China.
| | - Kaiwei Liu
- Department of Ultrasound, Shengjing Hospital of China Medical University, Shenyang, China.
| | - Yanbin Sun
- Department of Thoracic Surgery, The First Hospital of China Medical University, Shenyang 110001, China.
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Cao Z, Wang Z, Yang L, Li T, Tao X, Niu X. Reshaping the immune microenvironment and reversing immunosenescence by natural products: prospects for immunotherapy in gastric cancer. Semin Cancer Biol 2025:S1044-579X(25)00012-4. [PMID: 39923925 DOI: 10.1016/j.semcancer.2025.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 01/25/2025] [Accepted: 02/03/2025] [Indexed: 02/11/2025]
Abstract
Gastric cancer (GC) represents a global health-care challenge. Recent progress in immunotherapy has elicited attracted considerable attention as a viable treatment option through modulating the host immune system and unleashing pre-existing immunity, which has profoundly revolutionized oncology, especially GC. Nonetheless, low clinical response and intrinsic and acquired resistance remain persistently challenging. The microenvironment of GC comprising multifarious stromal cell types has remarkable immunosuppressive elements that may impact the efficacy of immunotherapy. Immunosenescence is increasingly regarded as a factor that contributes to cancer development, remodels the tumor microenvironment and affects the efficacy of immunotherapy. Natural products are at the forefront of traditional medicine. Senotherapeutics is a class of drugs and natural products capable of delaying, preventing, or reversing the senescence process (i.e., senolytics) or suppressing senescence-associated secretory phenotype (i.e., senomorphics). Emerging evidence supports that natural products can improve the efficacy of existing immunotherapy and expand their indications in GC mainly based upon remodeling the immunosuppressive microenvironment and reversing immunosenescence. The review provides an integrated review of previously reported and ongoing clinical trials with immunotherapeutic regimens in GC and discusses current challenges. Next, we focus on natural compounds that exert anti-GC functions and possess immunomodulatory properties. More attention is paid to the potential of these natural compounds in modulating the immune microenvironment and immunosenescence. Lastly, we discuss the nanomedicine that can overcome the deficiencies of natural products. Altogether, our review suggests the enormous potential of natural compounds in GC immunotherapy, and provides an important direction for future research.
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Affiliation(s)
- Zhipeng Cao
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang 110122, Liaoning, China
| | - Zhilin Wang
- Department of Pain Medicine, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning, China
| | - Li Yang
- Department of Anesthesiology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, Liaoning, China
| | - Tian Li
- Tianjin Key Laboratory of Acute Abdomen Disease-Associated Organ Injury and ITCWM Repair, Institute of Integrative Medicine of Acute Abdominal Diseases, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China.
| | - Xueshu Tao
- Department of Pain Medicine, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning, China.
| | - Xing Niu
- Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang 110122, Liaoning, China.
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11
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Luo D, Zhou J, Ruan S, Zhang B, Zhu H, Que Y, Ying S, Li X, Hu Y, Song Z. Overcoming immunotherapy resistance in gastric cancer: insights into mechanisms and emerging strategies. Cell Death Dis 2025; 16:75. [PMID: 39915459 PMCID: PMC11803115 DOI: 10.1038/s41419-025-07385-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 01/07/2025] [Accepted: 01/22/2025] [Indexed: 02/09/2025]
Abstract
Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with limited treatment options in advanced stages. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) targeting PD1/PD-L1, has emerged as a promising therapeutic approach. However, a significant proportion of patients exhibit primary or acquired resistance, limiting the overall efficacy of immunotherapy. This review provides a comprehensive analysis of the mechanisms underlying immunotherapy resistance in GC, including the role of the tumor immune microenvironment, dynamic PD-L1 expression, compensatory activation of other immune checkpoints, and tumor genomic instability. Furthermore, the review explores GC-specific factors such as molecular subtypes, unique immune evasion mechanisms, and the impact of Helicobacter pylori infection. We also discuss emerging strategies to overcome resistance, including combination therapies, novel immunotherapeutic approaches, and personalized treatment strategies based on tumor genomics and the immune microenvironment. By highlighting these key areas, this review aims to inform future research directions and clinical practice, ultimately improving outcomes for GC patients undergoing immunotherapy.
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Affiliation(s)
- Dingtian Luo
- Gastroenterology Department, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Jing Zhou
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Shuiliang Ruan
- Gastroenterology Department, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Binzhong Zhang
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Huali Zhu
- Gastroenterology Department, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Yangming Que
- Gastroenterology Department, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Shijie Ying
- Gastroenterology Department, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Xiaowen Li
- Pathology Department, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China
| | - Yuanmin Hu
- Intensive Care Unit, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China.
| | - Zhengwei Song
- Department of Surgery, the Second Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, China.
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12
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Ke H, Li P, Li Z, Zeng X, Zhang C, Luo S, Chen X, Zhou X, Dong S, Chen S, Huang J, Yuan M, Yu R, Ye S, Hu T, Tang Z, Liu D, Wu K, Wu X, Lan P. Immune profiling of the macroenvironment in colorectal cancer unveils systemic dysfunction and plasticity of immune cells. Clin Transl Med 2025; 15:e70175. [PMID: 39934971 DOI: 10.1002/ctm2.70175] [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: 06/21/2024] [Revised: 10/01/2024] [Accepted: 12/29/2024] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND Tumour immune macroenvironment is comprised of tumour and surrounding organs responding to tumourigenesis and immunotherapy. The lack of comprehensive analytical methods hinders its application for prediction of survival and treatment response in colorectal cancer (CRC) patients. METHODS Cytometry by time-of-flight (CyTOF) and RNA-seq was applied to characterise immune cell heterogeneity in a discovery cohort including tumour, blood and intestinal architecture comprising epithelium, lamina propria, submucosa, muscularis propria of normal bowel and tumour-adjacent bowel tissues. Immunoprofiling was also validated by a validation cohort using single-cell RNA sequencing, spatial transcription, CyTOF and multiplex immunofluorescent staining. RESULTS Based on cell phenotype and transcription, we identify distinct immunotypes in the CRC macroenvironment including blood, tumour and different intestinal architecture, showing disturbed immune cell compositions, increasing expression of immunosuppressive markers and cell-cell interactions contributing to immunosuppressive regulation. Furthermore, we evaluate immune macroenvironment influencing factors including tertiary lymphoid structures (TLSs), consensus molecular subtypes (CMSs) and immune checkpoint inhibitors (ICIs). TLS presence fuels anti-tumour immunity by promoting CD8+ T cell infiltration and altering activation or suppression of T cell systematically. TLS presence correlates with patient survival, intrinsic CMS and therapeutic efficacy of ICI. PD-1 and CD69 expressed in effector memory CD8+ T cells from blood can predict TLS presence in the CRC macroenvironment, serving as potential biomarkers for stratifying CRC patients into immunotherapy. CONCLUSIONS Our findings provide insights into the CRC immune macroenvironment, highlighting immune cell suppression and activation in tumourigenesis. Our study illustrates the potential utility of blood for predicting immunotherapy response. KEY POINTS Distinct immunotypes are identified in the CRC macroenvironment. TLS and immunotherapy exert influence on the immune macroenvironment. TLS presence correlates with patient survival, CMS and therapeutic efficacy of ICI. PD-1 and CD69 expressed in CD8+ Tem from blood can predict TLS presence in the CRC macroenvironment.
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Affiliation(s)
- Haoxian Ke
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Peisi Li
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Zhihao Li
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Department of Colorectal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xian Zeng
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Chi Zhang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Department of Colorectal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shuzhen Luo
- HIM-BGI Omics Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, BGI Research, Hangzhou, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI Research, Shenzhen, China
- BGI Genomics, Harbin, China
| | - Xiaofang Chen
- HIM-BGI Omics Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, BGI Research, Hangzhou, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI Research, Shenzhen, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Xinlan Zhou
- HIM-BGI Omics Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, BGI Research, Hangzhou, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI Research, Shenzhen, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Shichen Dong
- BGI Research, Shenzhen, China
- Shenzhen Key Laboratory of Single-Cell Omics, BGI Research, Shenzhen, China
| | - Shaopeng Chen
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Department of Colorectal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Junfeng Huang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Department of Colorectal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ming Yuan
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Department of Colorectal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Runfeng Yu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Department of Colorectal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shubiao Ye
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Tuo Hu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Department of Colorectal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zhonghui Tang
- Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China
| | - Dongbin Liu
- HIM-BGI Omics Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, BGI Research, Hangzhou, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI Research, Shenzhen, China
- BGI Genomics, Harbin, China
| | - Kui Wu
- HIM-BGI Omics Center, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, BGI Research, Hangzhou, China
- Guangdong Provincial Key Laboratory of Human Disease Genomics, Shenzhen Key Laboratory of Genomics, BGI Research, Shenzhen, China
- BGI Genomics, Harbin, China
| | - Xianrui Wu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ping Lan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Department of Gastrointestinal Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Biomedical Innovation Center, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Department of Colorectal Surgery, Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
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13
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Pavlakis N, Shitara K, Sjoquist K, Martin A, Jaworski A, Tebbutt N, Bang YJ, Alcindor T, O'Callaghan C, Strickland A, Rha SY, Lee KW, Kim JS, Bai LY, Hara H, Oh DY, Yip S, Zalcberg J, Price T, Simes J, Goldstein D. INTEGRATE IIa Phase III Study: Regorafenib for Refractory Advanced Gastric Cancer. J Clin Oncol 2025; 43:453-463. [PMID: 39365958 DOI: 10.1200/jco.24.00055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 06/07/2024] [Accepted: 07/17/2024] [Indexed: 10/06/2024] Open
Abstract
PURPOSE Treatment options for refractory advanced gastric and esophagogastric junction cancer (AGOC) are limited. Regorafenib, an oral multikinase inhibitor, prolonged progression-free survival (PFS) versus placebo in the INTEGRATE I phase II trial. INTEGRATE IIa was designed to examine whether regorafenib improved overall survival (OS). METHODS A double-blind placebo-controlled phase III trial compared regorafenib and best supportive care (BSC) versus placebo and BSC for participants with confirmed evaluable metastatic/advanced AGOC who failed ≥two prior therapies on a 2:1 random assignment, stratified by tumor location, geographic region (Asia v rest of world), and prior vascular endothelial growth factor inhibitors. The primary end point was OS. Treatment efficacy on OS was first tested in the pooled INTEGRATE I + INTEGRATE IIa cohort and, if significant, then in the INTEGRATE IIa cohort. Secondary end points were PFS, objective response rate, safety, and quality of life (QoL). RESULTS INTEGRATE IIa enrolled 251 participants: 157 from Asia and 94 from rest of world and 169 received regorafenib and 82 received placebo. No significant heterogeneity was observed between INTEGRATE I and INTEGRATE IIa studies on OS. Pooled OS analysis hazard ratio (HR) was 0.70 (95% CI, 0.56 to 0.87; P = .001; 361 events). INTEGRATE IIa alone OS HR was 0.68 (95% CI, 0.52 to 0.90; P = .006; 238 events), the median OS was 4.5 months versus 4.0 months, and 12-month survival rates were 19% and 6%, for regorafenib versus placebo, respectively. After a preplanned adjustment for multiplicity, there were no statistically significant differences across regions or other prespecified subgroups. Regorafenib improved PFS (HR, 0.53 [95% CI, 0.40 to 0.70]; P < .0001) and delayed deterioration in global QoL (HR, 0.68 [95% CI, 0.52 to 0.89]; P = .0043). The toxicity profile was consistent with that of previous reports. CONCLUSION Regorafenib improves survival compared with placebo in refractory AGOC.
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Affiliation(s)
- Nick Pavlakis
- Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW, Australia
- University of Sydney, Sydney, NSW, Australia
| | - Kohei Shitara
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa City, Japan
| | - Katrin Sjoquist
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
- Cancer Care Centre, St George Hospital, Kogarah, NSW, Australia
| | - Andrew Martin
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
| | - Anthony Jaworski
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
| | - Niall Tebbutt
- Olivia Newton-John Cancer Wellness & Research Centre, Melbourne, VIC, Australia
| | - Yung-Jue Bang
- Seoul National University College of Medicine, Seoul, South Korea
| | | | - Chris O'Callaghan
- Canadian Cancer Trials Group, Queens University, Kingston, ON, Canada
| | - Andrew Strickland
- Department of Medical Oncology, Monash Health, Monash University, Melbourne, VIC, Australia
| | - Sun Young Rha
- Yonsei Cancer Centre, Yonsei University Health System, Seoul, South Korea
| | - Keun-Wook Lee
- Seoul National University College of Medicine, Seoul, South Korea
- Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Jin-Soo Kim
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, South Korea
| | - Li-Yuan Bai
- Division of Hematology and Oncology, China Medical University Hospital, Taichung, Taiwan
- China Medical University, Taichung, Taiwan
| | | | - Do-Youn Oh
- Seoul National University Hospital, Cancer Research Institute, Jongno-gu, Seoul National University College of Medicine, South Korea
- Integrated Major in Innovative Medical Science, Seoul National University Graduate School, Seoul, South Korea
| | - Sonia Yip
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
| | - John Zalcberg
- Department of Medical Oncology, Alfred Health, Melbourne, VIC, Australia
- School of Public Health, Faculty of Medicine Monash University, Melbourne, VIC, Australia
| | - Tim Price
- The Queen Elizabeth Hospital, Adelaide, SA, Australia
| | - John Simes
- NHMRC Clinical Trials Centre, University of Sydney, Sydney, NSW, Australia
| | - David Goldstein
- Nelune Cancer Centre, Prince of Wales Hospital, Sydney, NSW, Australia
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14
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Ku G, Haag GM, Park H, Lam VK, George TJ, Kim SS, Gutierrez M, Shankaran V, Stein S, Denlinger CS, Elimova E, Nagrial A, He AR, Sawyer MB, Yoon HH, Geva R, Starr J, Curigliano G, Golan T, von Moos R, Fritsch R, Lim D, Wang Q, Patel A, Aoyama T, Lei M, Greenawalt D, Di Bartolomeo M. Nivolumab combination therapies in patients with advanced gastric and gastroesophageal junction cancer: the phase II FRACTION gastric cancer study. ESMO Open 2025; 10:104107. [PMID: 39798422 PMCID: PMC11772135 DOI: 10.1016/j.esmoop.2024.104107] [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: 07/31/2024] [Revised: 12/03/2024] [Accepted: 12/09/2024] [Indexed: 01/15/2025] Open
Abstract
BACKGROUND Nivolumab-based therapies are efficacious with acceptable safety in patients with gastric cancer (GC) and gastroesophageal junction cancer (GEJC). Novel nivolumab-based combination immunotherapies may offer enhanced efficacy in these indications. FRACTION-GC was a signal-seeking, randomized, open-label, phase II adaptive-design trial assessing efficacy and safety of nivolumab in combination with ipilimumab [cytotoxic T lymphocyte antigen-4 (CTLA-4) antibody], relatlimab (lymphocyte-activation gene 3 antibody), or IDO1i (BMS986205, an indoleamine-2,3-dioxygenase-1 inhibitor) in patients with unresectable, advanced/metastatic GC/GEJC. PATIENTS AND METHODS Previously treated patients with GC/GEJC were randomized to receive nivolumab + ipilimumab, nivolumab + relatlimab, or nivolumab + IDO1i across two tracks: anti-programmed death-(ligand) 1/anti-CTLA-4-naïve (track 1) and -experienced (track 2). Primary endpoints were objective response rate (ORR) by investigator per RECIST v1.1, duration of response, and progression-free survival (PFS) rate at 24 weeks. Secondary endpoint was safety. RESULTS Eighty-one patients in track 1 and 81 in track 2 received one combination therapy. With a median follow-up of 50.2 months, ORR [95% confidence interval (CI)] by investigator for nivolumab + ipilimumab, nivolumab + relatlimab, and nivolumab + IDO1i in track 1 was 4% (0.1% to 21.9%), 5% (0.1% to 24.9%), and 13% (4.4% to 28.1%), and for track 2 was 9% (1.1% to 28.0%), 6% (0.7% to 18.7%), and 0% (0% to 15.4%), respectively. PFS rate at 24 weeks (95% CI) was 24% (11% to 39%) for nivolumab + IDO1i track 1, 17% (16% to 32%) for nivolumab + relatlimab track 2, and not estimable for other treatment arms. Grade 3/4 treatment-related adverse events were reported in 22%, 5%, and 18% of patients receiving nivolumab + ipilimumab, nivolumab + relatlimab, and nivolumab + IDO1i in track 1 and in 35%, 11%, and 18% of patients in track 2, respectively. No treatment-related deaths were reported. CONCLUSIONS While ORR did not meet prespecified expansion criteria in any treatment arm, the safety profile of the combinations was manageable. FRACTION-GC represents a novel adaptive protocol for testing multiple combination immunotherapies.
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Affiliation(s)
- G Ku
- Memorial Sloan Kettering Cancer Center, New York, USA.
| | - G M Haag
- Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Hospital and Clinical Cooperation Unit Applied Tumor-Immunity, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - H Park
- Washington University School of Medicine, St Louis, USA
| | - V K Lam
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, USA
| | - T J George
- University of Florida Health Cancer Center, Gainesville, USA
| | - S S Kim
- Division of Medical Oncology, University of Colorado Cancer Center, Aurora, USA
| | - M Gutierrez
- John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, USA
| | - V Shankaran
- University of Washington School of Medicine, Seattle, USA
| | - S Stein
- Yale University School of Medicine, New Haven, USA
| | | | - E Elimova
- Princess Margaret Cancer Centre, Toronto, Canada
| | - A Nagrial
- Department of Medical Oncology, Westmead Hospital, University of Sydney, Sydney, Australia
| | - A R He
- Georgetown University Medical Center, Washington, USA
| | - M B Sawyer
- Cross Cancer Institute, University of Alberta, Edmonton, Canada
| | | | - R Geva
- Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - J Starr
- Mayo Clinic, Jacksonville, USA
| | - G Curigliano
- Department of Oncology and Hemato-Oncology, University of Milano, Milan, Italy; European Institute of Oncology, IRCCS, Milan, Italy
| | - T Golan
- Sheba Medical Center, Tel-Aviv University, Tel Aviv, Israel
| | - R von Moos
- Cancer Center, Kantonsspital Graubünden, Chur, Switzerland
| | - R Fritsch
- Department of Medical Oncology and Hematology, Universitätsspital Zürich, Zurich, Switzerland
| | - D Lim
- City of Hope National Medical Center, Duarte, USA
| | - Q Wang
- Bristol Myers Squibb, Princeton, USA
| | - A Patel
- Bristol Myers Squibb, Princeton, USA
| | - T Aoyama
- Bristol Myers Squibb, Princeton, USA
| | - M Lei
- Bristol Myers Squibb, Princeton, USA
| | | | - M Di Bartolomeo
- Fondazione IRCCS Istituto Nazionale Tumori Milano, Milan, Italy
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15
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Gao W, Wang X, Shi Y, Wu G, Zhou M, Lin X. Predictable regulation of gut microbiome in immunotherapeutic efficacy of gastric cancer. Genes Immun 2025; 26:1-8. [PMID: 39533019 DOI: 10.1038/s41435-024-00306-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 10/21/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024]
Abstract
Immunotherapy has showcased remarkable progress in the management of gastric cancer (GC), prompting the need to proactively identify and classify patients suitable for immunotherapy. Here, 30 patients were enrolled and stratified into three groups (PR, partial response; SD, stable disease; PD, progressive disease) based on efficacy assessment. 16S rRNA sequencing were performed to analyze the gut microbiome signature of patients at three timepoints. We found that immunotherapy interventions perturbed the gut microbiota of patients. Additionally, although differences at the enterotype level did not distinguish patients' immunotherapy response, we identified 6, 7, and 19 species that were significantly enriched in PR, SD, and PD, respectively. Functional analysis showed that betalain biosynthesis and indole alkaloid biosynthesis were significantly different between the responders and non-responders. Furthermore, machine learning model utilizing only bacterial biomarkers accurately predicted immunotherapy efficacy with an Area Under the Curve (AUC) of 0.941. Notably, Akkermansia muciniphila and Dorea formicigenerans played a significant role in the classification of immunotherapy efficacy. In conclusion, our study reveals that gut microbiome signatures can be utilized as effective biomarkers for predicting the immunotherapy efficacy for GC.
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Affiliation(s)
- Wei Gao
- Department of Medical Oncology, Fujian Medical University Union Hospital, No.29, Xinquan Road, Gulou District, Fuzhou, Fujian, 350001, China
- Department of Medical Oncology, Fujian Cancer Hospital, Fuzhou, Fujian, 350014, P.R. China
- Clinical Oncology School of Fujian Medical University, Fuzhou, Fujian, 350014, P.R. China
| | - Xinli Wang
- Department of Medical Oncology, Fujian Medical University Union Hospital, No.29, Xinquan Road, Gulou District, Fuzhou, Fujian, 350001, China
| | - Yi Shi
- Clinical Oncology School of Fujian Medical University, Fuzhou, Fujian, 350014, P.R. China
- Department of molecular pathology, Fujian Cancer Hospital, Fuzhou, Fujian, 350014, P.R. China
| | - Guangfeng Wu
- Department of Medical Oncology, Fujian Cancer Hospital, Fuzhou, Fujian, 350014, P.R. China
| | - Min Zhou
- Department of Medical Oncology, Fujian Cancer Hospital, Fuzhou, Fujian, 350014, P.R. China
| | - Xiaoyan Lin
- Department of Medical Oncology, Fujian Medical University Union Hospital, No.29, Xinquan Road, Gulou District, Fuzhou, Fujian, 350001, China.
- Clinical Oncology School of Fujian Medical University, Fuzhou, Fujian, 350014, P.R. China.
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16
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Nishiyama M, Miki Y, Tanaka H, Yoshii M, Kuroda K, Kasashima H, Fukuoka T, Tamura T, Shibutani M, Toyokawa T, Lee S, Maeda K. Immunological Analysis of Prognostic Factors in Conversion Surgery Cases for Gastric Cancer. J Surg Res 2025; 306:533-542. [PMID: 39889314 DOI: 10.1016/j.jss.2024.12.053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 12/04/2024] [Accepted: 12/30/2024] [Indexed: 02/02/2025]
Abstract
INTRODUCTION In order to clarify the optimal strategy regarding conversion surgery (CS) for gastric cancer (GC) patients, we focused on clinicopathological findings, including immunological factors, related to the favorable prognosis in patients with stage IV GC who underwent CS. MATERIALS AND METHODS A total of 25 patients with Stage IV GC who underwent induction chemotherapy (IC) and CS at our hospital between 2010 and 2021 were enrolled in this study. Biopsy specimens before IC and surgical specimens were collected. Immunohistochemical staining was performed using programmed death-ligand 1 (PD-L1) antibody, translationally controlled tumor protein (TCTP) antibody, and CD20 antibody. Prognostic factors were investigated using clinicopathological factors as well as immunological factors such as PD-L1, TCTP, and CD20 expression. RESULTS cN0, ycStage1-2, R0-1 surgery, D2 lymph node dissection, ypN0, and ypStage1-2 were significantly associated with favorable overall survival. Among patients who underwent R0/1 surgery, only histological type was a significant prognostic factor for recurrence-free survival. Low PD-L1 expression before IC and high TCTP expression after IC were significantly associated with favorable recurrence-free survival. CONCLUSIONS In addition to clinical factors, high TCTP expression after IC was identified as a significant favorable prognostic factor, which could help in identifying candidates for CS in the future.
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Affiliation(s)
- Masaki Nishiyama
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Yuichiro Miki
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
| | | | - Mami Yoshii
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Kenji Kuroda
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Hiroaki Kasashima
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Tatsunari Fukuoka
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Tatsuro Tamura
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Masatsune Shibutani
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Takahiro Toyokawa
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Shigeru Lee
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Kiyoshi Maeda
- Department of Gastroenterological Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
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Liao W, Wang Y, Wang R, Fu B, Chen X, Ouyang Y, Bai B, Jin Y, Lu Y, Liu F, Zhang Y, Shi D, Zhang D. Signature Construction Associated with Tumor-Infiltrating Macrophages Identifies IRF8 as a Novel Biomarker for Immunotherapy in Advanced Gastric Cancer. Int J Mol Sci 2025; 26:1089. [PMID: 39940857 PMCID: PMC11817691 DOI: 10.3390/ijms26031089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Revised: 01/16/2025] [Accepted: 01/22/2025] [Indexed: 02/16/2025] Open
Abstract
Advanced gastric cancer (AGC) is characterized by poor prognosis and limited responsiveness to immunotherapy. Tumor-associated macrophages (TAMs) play a pivotal role in cancer progression and therapeutic outcomes. In this study, we developed a novel gene signature associated with M1-like TAMs using data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) to predict prognosis and immunotherapy response. This gene signature was determined as an independent prognostic indicator for AGC, with high-risk patients exhibiting an immunosuppressive tumor immune microenvironment (TIME) and poorer survival outcomes. Furthermore, Interferon regulatory factor 8 (IRF8) was identified as a key gene and validated through in vitro and in vivo experiments. IRF8 overexpression reshaped the suppressive TIME, leading to an increased presence of M1-like TAMs, IFN-γ+ CD8+ T cells, and Granzyme B+ CD8+ T cells. Notably, the combination of IRF8 overexpression and anti-PD-1 therapy significantly inhibited tumor growth in syngeneic mouse models. AGC patients with elevated IRF8 expression were found to be more responsive to anti-PD-1 treatment. These findings highlight potential biomarkers for prognostic evaluation and immunotherapy in AGC, offering insights that could guide personalized treatment strategies.
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Affiliation(s)
- Wanqian Liao
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (W.L.); (Y.W.); (B.F.); (B.B.); (Y.J.); (Y.L.); (F.L.); (Y.Z.)
- Integrated Traditional Chinese and Western Medicine Research Center, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (R.W.); (X.C.); (Y.O.)
| | - Yu Wang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (W.L.); (Y.W.); (B.F.); (B.B.); (Y.J.); (Y.L.); (F.L.); (Y.Z.)
- Integrated Traditional Chinese and Western Medicine Research Center, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (R.W.); (X.C.); (Y.O.)
| | - Rui Wang
- Integrated Traditional Chinese and Western Medicine Research Center, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (R.W.); (X.C.); (Y.O.)
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Bibo Fu
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (W.L.); (Y.W.); (B.F.); (B.B.); (Y.J.); (Y.L.); (F.L.); (Y.Z.)
- Integrated Traditional Chinese and Western Medicine Research Center, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (R.W.); (X.C.); (Y.O.)
| | - Xiangfu Chen
- Integrated Traditional Chinese and Western Medicine Research Center, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (R.W.); (X.C.); (Y.O.)
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Ying Ouyang
- Integrated Traditional Chinese and Western Medicine Research Center, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (R.W.); (X.C.); (Y.O.)
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Bing Bai
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (W.L.); (Y.W.); (B.F.); (B.B.); (Y.J.); (Y.L.); (F.L.); (Y.Z.)
- Integrated Traditional Chinese and Western Medicine Research Center, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (R.W.); (X.C.); (Y.O.)
| | - Ying Jin
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (W.L.); (Y.W.); (B.F.); (B.B.); (Y.J.); (Y.L.); (F.L.); (Y.Z.)
- Integrated Traditional Chinese and Western Medicine Research Center, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (R.W.); (X.C.); (Y.O.)
| | - Yunxin Lu
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (W.L.); (Y.W.); (B.F.); (B.B.); (Y.J.); (Y.L.); (F.L.); (Y.Z.)
- Integrated Traditional Chinese and Western Medicine Research Center, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (R.W.); (X.C.); (Y.O.)
| | - Furong Liu
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (W.L.); (Y.W.); (B.F.); (B.B.); (Y.J.); (Y.L.); (F.L.); (Y.Z.)
- Integrated Traditional Chinese and Western Medicine Research Center, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (R.W.); (X.C.); (Y.O.)
| | - Yang Zhang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (W.L.); (Y.W.); (B.F.); (B.B.); (Y.J.); (Y.L.); (F.L.); (Y.Z.)
- Integrated Traditional Chinese and Western Medicine Research Center, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (R.W.); (X.C.); (Y.O.)
| | - Dongni Shi
- Integrated Traditional Chinese and Western Medicine Research Center, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (R.W.); (X.C.); (Y.O.)
- Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
| | - Dongsheng Zhang
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (W.L.); (Y.W.); (B.F.); (B.B.); (Y.J.); (Y.L.); (F.L.); (Y.Z.)
- Integrated Traditional Chinese and Western Medicine Research Center, Sun Yat-sen University Cancer Center, Guangzhou 510060, China; (R.W.); (X.C.); (Y.O.)
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Panahizadeh R, Panahi P, Asghariazar V, Makaremi S, Noorkhajavi G, Safarzadeh E. A literature review of recent advances in gastric cancer treatment: exploring the cross-talk between targeted therapies. Cancer Cell Int 2025; 25:23. [PMID: 39856676 PMCID: PMC11762578 DOI: 10.1186/s12935-025-03655-8] [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: 06/08/2024] [Accepted: 01/17/2025] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) ranks fourth in global mortality rates and fifth in prevalence, making it one of the most common cancers worldwide. Recent clinical studies have highlighted the potential of immunotherapies as a promising approach to treating GC. This study aims to shed light on the most impactful therapeutic strategies in the context of GC immunotherapy, highlighting both established and emerging approaches. MAIN BODY This review examines over 160 clinical studies conducted globally, focusing on the effectiveness of various immunotherapy modalities, including cancer vaccines, adoptive cell therapy, immune checkpoint inhibitors (ICIs), and monoclonal antibodies (mAbs). A comprehensive search of peer-reviewed literature was performed using databases such as Web of Science, PubMed, and Scopus. The selection criteria included peer-reviewed articles published primarily within the last 10 years, with a focus on studies that provided insights into targeted therapies and their mechanisms of action, clinical efficacy, and safety profiles. The findings indicate that these immunotherapy strategies can enhance treatment outcomes for GC, aligning with current treatment guidelines. ICIs like pembrolizumab and nivolumab have shown significant survival benefits in specific GC subgroups. Cancer vaccines and CAR-T cell therapies demonstrate potential, while mAbs targeting HER2 and VEGFR pathways enhance outcomes in combination regimens. We discuss the latest advancements and challenges in targeted therapy and immunotherapy for GC. Given the evolving nature of this field, this research emphasizes significant evidence-based therapies and those currently under evaluation rather than providing an exhaustive overview. Challenges include resistance mechanisms, immunosuppressive tumor environments, and inconsistent results from combination therapies. Biomarker-driven approaches and further research into emerging modalities like CAR-T cells and cancer vaccines are critical for optimizing treatments. CONCLUSIONS Immunotherapy is reshaping GC management by improving survival and quality of life. Ongoing research and clinical evaluations are crucial for refining personalized and effective therapies.
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Affiliation(s)
- Reza Panahizadeh
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
- Students Research Committee, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Padideh Panahi
- Student Research Committee, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Asghariazar
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Shima Makaremi
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Ghasem Noorkhajavi
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Elham Safarzadeh
- Cancer Immunology and Immunotherapy Research Center, Ardabil University of Medical Sciences, Ardabil, Iran.
- Department of Microbiology, Parasitology and Immunology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, 85991-56189, Iran.
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Yu C, Jiang H, Wang L, Jiang Z, Jin C. Baseline (derived) neutrophil-lymphocyte ratio associated with survival in gastroesophageal junction or gastric cancer treated with ICIs. Front Oncol 2025; 15:1404695. [PMID: 39926278 PMCID: PMC11802431 DOI: 10.3389/fonc.2025.1404695] [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: 03/21/2024] [Accepted: 01/06/2025] [Indexed: 02/11/2025] Open
Abstract
Objective We carried out the meta-analysis to determine the predictive value of baseline neutrophil to lymphocyte ratio (NLR) and derived neutrophil to lymphocyte ratio (dNLR) levels in patients with gastroesophageal junction or gastric cancer (GJGC) who underwent immune checkpoint inhibitor (ICI) treatment. Methods Eligible articles were obtained through PubMed, the Cochrane Library, EMBASE, and Google Scholar, until April 15, 2023. The clinical outcomes evaluated in this study encompassed overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Results A total of 24 articles with 2221 patients were included in this meta-analysis. The pooled results demonstrated that patients with high NLR levels had significantly poorer OS (HR: 1.860, 95% CI: 1.564-2.213, p < 0.001) and PFS (HR: 1.678, 95% CI: 1.354-2.079, p < 0.001), and lower ORR (OR: 0.754, 95% CI: 0.621-0.915, p = 0.004) and DCR (OR: 0.391, 95% CI: 0.262-0.582, p < 0.001). Besides, we also found that high dNLR levels were significantly associated with shorter OS (HR: 2.117, 95% CI: 1.590-2.820, p < 0.001) and PFS (HR: 1.803, 95% CI: 1.415-2.297, p < 0.001). Conclusion Low baseline (Derived) NLR has the potential to predict the good efficacy of ICIs and survival outcomes in patients with GJGC. (Derived) NLR could be useful in determining the optimal treatment strategies for these patients.
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Affiliation(s)
| | | | | | | | - Chong Jin
- Department of General Surgery, Taizhou Central Hospital, Taizhou University, Taizhou, Zhejiang, China
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20
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Huang JB, Zhou ZY, Lu J, Zhu JY, Lai B, Mao SX, Cao JQ. Inflammatory burden index as a prognostic marker in patients with advanced gastric cancer treated with neoadjuvant chemotherapy and immunotherapy. Front Immunol 2025; 15:1471399. [PMID: 39906738 PMCID: PMC11790653 DOI: 10.3389/fimmu.2024.1471399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2024] [Accepted: 12/23/2024] [Indexed: 02/06/2025] Open
Abstract
Background Blood inflammation index has been shown to correlate with the prognosis of patients with gastric cancer. However, few studies have compared the efficacy of existing blood inflammatory markers in predicting the prognosis of patients with locally advanced gastric cancer in combination with neoadjuvant chemotherapy and immunotherapy. Objective The objective of this study was to compare the prognostic value of existing commonly used blood inflammatory index in patients with advanced gastric cancer treated with neoadjuvant chemotherapy combined with immunotherapy. Methods The clinicopathological data of patients with advanced gastric cancer from three centers in China were analyzed retrospectively. Univariate COX regression analysis was used to analyze the independent risk factors of poor tumor regression and overall survival (OS) in this part of patients, and the predictive value of different inflammatory indexes on prognosis was compared by C-index index. Finally, Inflammatory burden index(IBI) was grouped by X-tile software, and Kaplan-Meier method was used to compare the survival difference between groups. Results A total of 163 patients were enrolled in this study. The median age was 63 years(56-68). The median cycle of neoadjuvant therapy was 4(3-4). The median survival time was 85.1%(1 years), 65.6%(2 years), and 47.4%(3 years).Univariate analysis showed that IBI was an independent risk factor for non-TR(residual tumor cells>50%) (HR=1.08,95%CI:1.00-1.45,p<0.001)and OS(HR=1.04,95%CI:1.03-1.05,p<0.001). IBI is the best predictor of OS (C-index: 0.82, 95% CI: 0.78-0.87) among all inflammatory indexes. The IBI cutoff value was 52.1. It was found that the high IBI group had a higher incidence of postoperative complications(32.1%vs14.3%, p=0.001), the proportion of non-TR patients was significantly higher than that of the low IBI group(64.3%vs35.7%, p =0.001), and the high IBI group had a significantly lower OS((47.6% vs 87.6%, p < 0.001). Conclusion IBI is the best inflammatory index to predict the prognosis of advanced gastric cancer treated with neoadjuvant chemotherapy combined with immunotherapy, which will help guide patients' treatment decisions. This result still needs to be verified by large prospective studies.
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Affiliation(s)
- Jiao-Bao Huang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Zhi-Yong Zhou
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jun Lu
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fuzhou, China
| | - Ji-Yun Zhu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, China
| | - Bin Lai
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Sheng-Xun Mao
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jia-Qing Cao
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, China
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21
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Dong S, Wei C, Wang X, Yang X, Shen W, Li S, Xu J, Ma Y, Bie L, Yu W, Li N. A retrospective multicenter study on the efficacy and safety of disitamab vedotin monotherapy versus combination with anti-PD-1 immunotherapy in advanced gastric cancer. Sci Rep 2025; 15:2232. [PMID: 39825061 PMCID: PMC11742410 DOI: 10.1038/s41598-025-86504-y] [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: 10/01/2024] [Accepted: 01/10/2025] [Indexed: 01/20/2025] Open
Abstract
Novel therapeutic agents including disitamab vedotin (RC48, an antibody-drug conjugate) and immune-checkpoint inhibitors (e.g., PD-1 inhibitors) have provided new hope as an advanced gastric-cancer (GC) treatment. This multicenter retrospective study studied RC48 monotherapy (MT)'s efficacy and safety against its combination with anti-PD-1 immunotherapy (IT) in advanced GC. Patients treated with RC48 MT or RC48 combined with anti-PD-1 IT from July 2021 to April 2023 were recruited for the study. The progression-free survival (PFS), overall survival (OS), objective-response rate (ORR), disease-control rate (DCR), and safety were studied. After propensity score matching (PSM) (1:1), this study included 34 in the RC48 plus anti-PD-1 IT group and 34 in the RC48 MT group. The median PFS was significantly longer in the combination-therapy (CT) group than in the MT group (5.3 versus 3.8 months, HR: 0.51, 95% CI: 0.31-0.85, p = 0.010), and the median OS was also notably increased (10.0 versus 6.8 months, HR: 0.45, 95% CI: 0.27-0.77, p = 0.003). The ORR and DCR were higher in the combination group (41.18% versus 14.71%, p = 0.031; 61.76% versus 35.30%, p = 0.052). Moreover, subgroup analyses further revealed that those in the CT group experienced a longer PFS and OS, particularly those with high HER2 expression or a PD-L1 CPS score of 1 or higher. The combination therapy (CT) achieved acceptable tolerability and manageable adverse events. Furthermore, the most common grade 3-5 treatment-related adverse events (TRAEs) included decreased white-blood-cell (WBC) count, decreased neutrophil count, and anemia. No new safety risks were observed. In sum, the RC48 and anti-PD-1 IT combination showed good efficacy and a manageable safety profile, indicating its strong potential as an advanced GC therapeutic option.
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Affiliation(s)
- Shuailei Dong
- Department of Gastrointestinal Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Chen Wei
- Department of Gastrointestinal Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Xueting Wang
- Department of Internal Medicine, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Xinyi Yang
- Phase I Clinical Research Center, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Wei Shen
- Department of Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453100, Henan, China
| | - Shuyi Li
- Department of Medical Oncology, Anyang Tumor Hospital & The Affiliated Anyang Tumor Hospital of Henan University of Science and Technology, Anyang, 455100, China
| | - Jiye Xu
- Department of Oncology, Zhoukou Central Hospital, Zhoukou, 466000, China
| | - Yijie Ma
- Department of Gastrointestinal Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Liangyu Bie
- Department of Gastrointestinal Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Wenyue Yu
- Department of Gastrointestinal Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Ning Li
- Department of Gastrointestinal Oncology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China.
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Wang Y, Li X, Wang Y, Qin J. Establishment and characterization of a new mouse gastric carcinoma cell line, MCC. Cancer Cell Int 2025; 25:9. [PMID: 39800685 PMCID: PMC11727671 DOI: 10.1186/s12935-024-03633-6] [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: 07/26/2024] [Accepted: 12/31/2024] [Indexed: 01/16/2025] Open
Abstract
BACKGROUND The aim of this study was to establish a primary mouse gastric carcinoma cell line. METHODS Gastric adenocarcinoma in the body region was induced in immunocompetent BALB/c mice using N-Methyl-N-nitrosourea and a 2% NaCl solution. Fresh gastric cancer tissue samples were cultured in 1640 medium supplemented with 10% fetal bovine serum for primary culture and subculture. Cellular morphology was assessed via light microscopy, and a cell growth curve was established. Genomic and proteomic analyses were conducted to characterize the molecular features of the cell lines. This cell line demonstrated a 100% success rate in forming subcutaneous tumors in BALB/c mice. By integrating proteomic profiles from clinical gastric cancer patients and the murine subcutaneous tumor model, several molecular targets suitable for preclinical investigation were identified. Trametinib, a MEK inhibitor, was employed as a model compound in our preclinical study. RESULTS A novel gastric carcinoma cell line, designated MCC, was established from BALB/c mice. This cell line exhibited a doubling time of approximately 33 h. Genomic and proteomic analyses identified mutations frequently observed in clinical gastric cancer patients, such as Kras, Egfr, and Ccnd3. Additionally, MCC overexpresses proteins, including SLC1A5, MCM6, and ITGA2, which are significantly upregulated in gastric cancer tissues compared to adjacent non-cancerous tissues. The MCC cell line demonstrated stable tumorigenicity in immunocompetent BALB/c mice, forming subcutaneous tumors that closely resemble the proteomic profile of clinical gastric cancer samples. This high concordance facilitated the identification of several potential therapeutic targets for gastric cancer. Preclinical studies with trametinib revealed that treatment effectively inhibited gastric cancer growth, likely mediated through the activation of immune cells, particularly neutrophils and T cells. CONCLUSIONS The MCC cell line serves as an indispensable model for gastric cancer research, offering a robust platform for investigating tumor development and progression. Its exceptional tumorigenic capacity and strong concordance with clinical proteomic profiles underscore its significance in translational research, facilitating the discovery of novel therapeutic targets and elucidation of molecular pathways critical for developing effective treatment strategies.
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Affiliation(s)
- Yushen Wang
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, People's Republic of China
| | - Xianju Li
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, People's Republic of China.
| | - Yi Wang
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, People's Republic of China.
| | - Jun Qin
- State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, People's Republic of China.
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Wang L, Sun M, Li J, Wan L, Tan Y, Tian S, Hou Y, Wu L, Peng Z, Hu X, Zhang Q, Huang Z, Han M, Peng S, Pan Y, Ren Y, Zhang M, Chen D, Liu Q, Li X, Qin ZY, Xiang J, Li M, Zhu J, Chen Q, Luo H, Wang S, Wang T, Li F, Bian XW, Wang B. Intestinal Subtype as a Biomarker of Response to Neoadjuvant Immunochemotherapy in Locally Advanced Gastric Adenocarcinoma: Insights from a Prospective Phase II Trial. Clin Cancer Res 2025; 31:74-86. [PMID: 39495175 DOI: 10.1158/1078-0432.ccr-24-2436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 09/22/2024] [Accepted: 10/31/2024] [Indexed: 11/05/2024]
Abstract
PURPOSE Neoadjuvant immunochemotherapy (NAIC) markedly induces pathologic regression in locally advanced gastric adenocarcinoma. However, specific biomarkers are still lacking to effectively identify the beneficiary patients for NAIC. PATIENTS AND METHODS A prospective, single-arm, phase II study was conducted to treat locally advanced gastric adenocarcinoma with NAIC (NCT05515796). Correlation between clinicopathologic characteristics and neoadjuvant efficacy was investigated. Bulk RNA sequencing data from 104 samples (from 75 patients in two independent cohorts) and single-cell RNA sequencing data from 105 treatment-naïve gastric adenocarcinomas were comprehensively analyzed to decipher the association of epithelial and microenvironmental characteristics and clinical responses. RESULTS The prespecified primary endpoints were achieved: pathologic complete regression rate was 30%, major pathologic regression rate was 43%, and the regimen was well tolerated. Analysis of baseline clinical-pathologic parameters revealed the intestinal subtype of Lauren's classification as a key feature stratifying patients with increased sensitivity to NAIC. Mechanistically, an increased pool of DNA damage repair-active cancer cells and enrichment of CLEC9A+ dendritic cells in the tumor microenvironment were associated with enhanced responsiveness of the intestinal subtype gastric adenocarcinoma to NAIC. More importantly, an intestinal subtype-specific signature model was constructed by the machine learning algorithm NaiveBayes via integrating the transcriptomic features of both DNA damage repair-active cancer cells and CLEC9A+ dendritic cells, which accurately predicted the efficacy of NAIC in multiple independent gastric adenocarcinoma cohorts. CONCLUSIONS Intestinal subtype is a histologic biomarker of enhanced sensitivity of gastric adenocarcinoma to NAIC. The intestinal subtype-specific signature model is applicable to guide NAIC for patients with locally advanced gastric adenocarcinoma.
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Affiliation(s)
- Lei Wang
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Mengting Sun
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Jinyang Li
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Linghong Wan
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Yuting Tan
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
- School of Medicine, Chongqing University, Chongqing, P.R. China
| | - Shuoran Tian
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Yongying Hou
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
- Department of Pathology, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Linyu Wu
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Ziyi Peng
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Xiao Hu
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
- School of Medicine, Chongqing University, Chongqing, P.R. China
| | - Qihua Zhang
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P.R. China
| | - Zening Huang
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, P.R. China
| | - Mengyi Han
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Shiyin Peng
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
- School of Medicine, Chongqing University, Chongqing, P.R. China
| | - Yuwei Pan
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
- School of Medicine, Chongqing University, Chongqing, P.R. China
| | - Yuanfeng Ren
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Mengsi Zhang
- Institute of Pathology and Southwest Cancer Center, and Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Dongfeng Chen
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Qin Liu
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Xianfeng Li
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Zhong-Yi Qin
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Junyv Xiang
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Mengxia Li
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Jianwu Zhu
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Qiyue Chen
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Key Laboratory of Ministry of Education of Gastrointestinal Cancer, Fujian Medical University, Fuzhou, P.R. China
| | - Huiyan Luo
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P.R. China
| | - Shunan Wang
- Department of Radiology, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Tao Wang
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Fan Li
- Division of Gastric and Colorectal Surgery, Department of General Surgery, Daping Hospital, Army Medical University, Chongqing, P.R. China
| | - Xiu-Wu Bian
- Institute of Pathology and Southwest Cancer Center, and Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
| | - Bin Wang
- Department of Gastroenterology, Chongqing Key Laboratory of Digestive Malignancies, Daping Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
- Institute of Pathology and Southwest Cancer Center, and Key Laboratory of Tumor Immunopathology of Ministry of Education of China, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, P.R. China
- Jinfeng Laboratory, Chongqing, P.R. China
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24
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Kaushik M, Kapoor A, Singh H, Suresh P, Mulajkar D, Rathore A, Nair R, Nihanthy D, Mehrotra A, Patel A. Real world experience on patterns of usage and toxicity profile of immunotherapy drugs in Indian patients: A prospective observational study. Med J Armed Forces India 2025; 81:39-45. [PMID: 39872179 PMCID: PMC11762613 DOI: 10.1016/j.mjafi.2023.07.007] [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: 03/30/2023] [Accepted: 07/16/2023] [Indexed: 01/29/2025] Open
Abstract
Background Immune checkpoint inhibitors (ICIs) are now considered revolutionary agents in the treatment of various cancers. Prospective data are limited on the patterns of usage and toxicity profile of these drugs. We planned this study for addressing the same in Indian patients. Methods This prospective study was conducted over a period of 2 years. All patients who were treated with Nivolumab, pembrolizumab, atezolizumab, and durvalumab were included. Immune-related adverse events were recorded. Toxicities were graded and number of patients experiencing dose limiting toxicities was recorded. Results A total of 53 patients received one of the above four agents. Majority of patients were less than 60 years of age. Carcinoma lung was the most frequent malignancy followed by renal cell carcinoma, Hodgkin's Lymphoma, Urinary Bladder cancers, Malignant Melanoma, and Recurrent/Metastatic Head and neck cancer. Nivolumab was used in most of the study population followed by pembrolizumab. Majority of agents were used in second line. The frequency of all grade adverse events for fatigue, anemia, pneumonitis, skin rash, dyspnea, diarrhea, and hypothyroidism were (in %) 73.58, 62.26, 16.9, 11.32, 9.43, 9.43, and 7.55, respectively. No grade 5 toxicity was observed. None of the grade 3 or 4 toxicities led to treatment discontinuation. Statistically, no difference was found for all grade toxicities among ICI drugs and among the various lines of use. Conclusion Nivolumab was the commonest drug used in our cohort. Most of ICIs were used in second-line setting. Toxicities are in line with the published literature.
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Affiliation(s)
- M.R. Kaushik
- Classified Specialist (Medicine) & Medical Oncologist, INHS Asvini, Mumbai, India
| | - Amul Kapoor
- Consultant (Medicine & Medical Oncology), Army Hospital (R&R), New Delhi, India
| | - H.P. Singh
- Consultant (Medicine & Medical Oncology), Capitol Hospital, Jalandhar, India
| | - P. Suresh
- Senior Adviser (Medicine) & Medical Oncologist, Army Hospital (R&R), New Delhi, India
| | - Deepak Mulajkar
- Senior Adviser (Medicine) & Medical Oncologist, Army Hospital (R&R), New Delhi, India
| | - Anvesh Rathore
- Senior Adviser (Medicine) & Medical Oncologist, Army Hospital (R&R), New Delhi, India
| | - Rajesh Nair
- Classified Specialist (Medicine) & Medical Oncologist, Command Hospital (Central Command), Lucknow, India
| | - D.S. Nihanthy
- Senior Resident (Medical Oncology), Army Hospital (R&R), New Delhi, India
| | - Aarty Mehrotra
- Senior Resident (Medical Oncology), Army Hospital (R&R), New Delhi, India
| | - Amol Patel
- Senior Adviser (Medicine) & Medical Oncologist, INHS Asvini, Mumbai, India
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25
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Jubashi A, Nakayama I, Koganemaru S, Sakamoto N, Oda S, Matsubara Y, Miyashita Y, Sato S, Ushiyama S, Kobayashi A, Okazaki U, Okemoto D, Yamamoto K, Mishima S, Kotani D, Kawazoe A, Hashimoto T, Nakamura Y, Kuboki Y, Bando H, Kojima T, Yoshino T, Miyaaki H, Nakao K, Shitara K. Prognostic and predictive factors for the efficacy and safety of trastuzumab deruxtecan in HER2-positive gastric or gastroesophageal junction cancer. Gastric Cancer 2025; 28:63-73. [PMID: 39487862 PMCID: PMC11706866 DOI: 10.1007/s10120-024-01560-z] [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: 07/24/2024] [Accepted: 10/08/2024] [Indexed: 11/04/2024]
Abstract
BACKGROUND Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate targeting HER2-positive gastric cancer or gastroesophageal junction cancer (GC/GEJC). Although effective, T-DXd has notable toxicities, including interstitial lung disease (ILD). This study evaluated the efficacy, safety, and prognostic factors associated with T-DXd for GC/GEJC. METHODS A retrospective observational study was conducted at our institution by reviewing medical records of patients treated with T-DXd until September 2023. Eligible patients had unresectable advanced or recurrent GC/GEJC, HER2 status of IHC 3 + or IHC 2 + /ISH-positive, and prior treatment with trastuzumab-containing regimen. RESULTS Among the 101 patients analyzed, the initial T-DXd dose was 6.4 mg/kg in 77 patients and 5.4 mg/kg in 24 patients. The objective response rate was 54.3%, with a median PFS of 5.4 months and a median OS of 11.4 months. The significant prognostic factors for shorter PFS and OS included ECOG PS ≥ 1, presence of primary lesion, and peritoneal metastasis but not the initial T-DXd dose. ILD occurred in 14.9% of patients. Notably, higher T-DXd dose and smaller tumor burden were associated with a higher incidence of ILD. CONCLUSIONS Several factors were associated with prognosis after T-DXd treatment in patients with GC/GEJC. Tumor burden is a potential risk factor for T-DXd-related ILD. Further studies are needed to optimize dosing based on tumor burden and to improve the therapeutic index.
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Affiliation(s)
- Amane Jubashi
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki City, Nagasaki, 852-8501, Japan
| | - Izuma Nakayama
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
| | - Shigehiro Koganemaru
- Department of Experimental Therapeutics, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Naoya Sakamoto
- Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Chiba, 277-8577, Japan
| | - Shioto Oda
- Department of Diagnostic Radiology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Yuki Matsubara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Yu Miyashita
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Seiya Sato
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Shinpei Ushiyama
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Akinori Kobayashi
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Ukyo Okazaki
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Dai Okemoto
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Kazumasa Yamamoto
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Saori Mishima
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Daisuke Kotani
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Akihito Kawazoe
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Tadayoshi Hashimoto
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Translational Research Support Section, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Yoshiaki Nakamura
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Translational Research Support Section, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Yasutoshi Kuboki
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
- Department of Experimental Therapeutics, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Hideaki Bando
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Takashi Kojima
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
| | - Hisamitsu Miyaaki
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki City, Nagasaki, 852-8501, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki City, Nagasaki, 852-8501, Japan
| | - Kohei Shitara
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan
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26
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Hayashi H, Yasufuku I, Sato Y, Fujibayashi S, Chikaishi W, Endo M, Horaguchi T, Yokoi R, Matsumoto K, Kuno M, Sengoku Y, Fukada M, Asai R, Tajima JY, Makiyama A, Kiyama S, Tanaka Y, Murase K, Ishihara T, Matsuhashi N. Neutrophil‑to‑lymphocyte ratio and risk of disease progression in patients with nivolumab‑treated unresectable or recurrent gastric cancer. Oncol Lett 2025; 29:20. [PMID: 39492934 PMCID: PMC11526420 DOI: 10.3892/ol.2024.14766] [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: 06/16/2024] [Accepted: 08/29/2024] [Indexed: 11/05/2024] Open
Abstract
Studies have associated neutrophil-to-lymphocyte ratio (NLR) with overall survival (OS) and progression-free survival (PFS) in patients with gastric cancer (GC). The present study aimed to examine the relationship between dynamic changes in NLR during treatment and disease progression in patients with unresectable or recurrent GC treated with nivolumab monotherapy as a third-line or later regimen. Patients treated with nivolumab as a third-line or later therapy for unresectable or recurrent GC at Gifu University Hospital (Gifu, Japan) from April 2017 to December 2021 were included. Pretreatment data and those obtained every 2 weeks after the treatment commenced were evaluated. The association between all NLR values and disease progression for each patient was evaluated using a time-dependent Cox proportional hazards model and restricted cubic spline (RCS) curves. The study included 44 patients (23 men and 21 women). The response and disease control rates were 6.8 and 27.3%, respectively. The median PFS and OS of all patients were 1.84 months [95% confidence interval (CI), 1.32-2.14] and 5.93 months (95% CI, 3.75-10.75), respectively. The risk for progressive disease (PD) increased with higher NLR (hazard ratio, 2.25; 95% CI, 1.3-3.87). The RCS curves also indicated that the higher the NLR, the higher the risk for PD, especially if the NLR value was <3.0. NLR during treatment could predict the risk of PD, suggesting that NLR could be integrated with tumor markers, computed tomographic images and other modalities to enable treatment selection without delay.
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Affiliation(s)
- Hirokatsu Hayashi
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Itaru Yasufuku
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Yuta Sato
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Seito Fujibayashi
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Wakana Chikaishi
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Masahide Endo
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Takeshi Horaguchi
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Ryoma Yokoi
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Keita Matsumoto
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Masashi Kuno
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Yuki Sengoku
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Masahiro Fukada
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Ryuichi Asai
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Jesse Yu Tajima
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Akitaka Makiyama
- Cancer Center, Gifu University Hospital, Gifu, Gifu 501-1194, Japan
| | - Shigeru Kiyama
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Yoshihiro Tanaka
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Katsutoshi Murase
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
| | - Takuma Ishihara
- Innovative and Clinical Research Promotion Center, Gifu University Hospital, Gifu, Gifu 501-1194, Japan
| | - Nobuhisa Matsuhashi
- Department of Gastroenterological Surgery and Pediatric Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu 501-1194, Japan
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27
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Kim HD, Shin J, Hyung J, Lee H, Moon M, Ma J, Park YS, Ryu MH. Survival outcomes of patients with gastric cancer treated with first-line nivolumab plus chemotherapy based on claudin 18.2 expression. Gastric Cancer 2025; 28:74-82. [PMID: 39528778 DOI: 10.1007/s10120-024-01566-7] [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: 07/23/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND Claudin 18.2 has emerged as a viable therapeutic target in gastric cancer; however, its clinical relevance in the context of immune checkpoint inhibitor-based chemotherapy is not known. This study aimed to investigate the efficacy of nivolumab plus chemotherapy according to claudin 18.2 expression in patients with gastric cancer. METHODS This single-center study included patients with advanced gastric cancer who were treated with first-line nivolumab plus chemotherapy (n = 204) or chemotherapy alone (n = 183) whose claudin 18.2 immunohistochemistry results were available. Claudin 18.2 positivity (moderate-to-strong expression in ≥ 75% by the 43-14A clone) was analyzed in terms of efficacy outcomes. RESULTS Among patients treated with nivolumab plus chemotherapy, 96 (47.1%) were assessed to have claudin 18.2-positive tumors. Between patients with claudin 18.2-positive and -negative tumors, objective response rate with nivolumab plus chemotherapy was comparable. Progression-free survival (PFS) and overall survival (OS) with nivolumab plus chemotherapy were comparable between those with claudin 18.2-positive and -negative tumors. For both subgroups with PD-L1 combined positive score ≥ 5 and < 5, PFS and OS with nivolumab plus chemotherapy were also comparable between patients with claudin 18.2-positive and -negative tumors. A consistent trend of favorable PFS and OS was observed with nivolumab plus chemotherapy compared to that of chemotherapy alone in both claudin 18.2-positive and -negative subgroups. CONCLUSION The efficacy of nivolumab plus chemotherapy did not vary according to claudin 18.2 positivity. The clinical benefit of nivolumab plus chemotherapy over chemotherapy was consistently observed in claudin 18.2-positive and -negative gastric cancer cases.
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Affiliation(s)
- Hyung-Don Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jinho Shin
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Jaewon Hyung
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Hyungeun Lee
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Meesun Moon
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jeongeun Ma
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Young Soo Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-gu, Seoul, 05505, Republic of Korea
| | - Min-Hee Ryu
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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28
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Chen T, Xu M, Xu J, Zhan X, Zhang Y, Ying M, Wu M. The application of immunotherapy combined with taxanes in second‑line treatment of advanced HER2 negative gastric cancer. Mol Clin Oncol 2025; 22:11. [PMID: 39640912 PMCID: PMC11618035 DOI: 10.3892/mco.2024.2806] [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: 07/22/2024] [Accepted: 11/12/2024] [Indexed: 12/07/2024] Open
Abstract
Human epidermal growth factor receptor-2 (HER2) negative advanced gastric cancer (GC) has a high global incidence and mortality rate with limited options for second-line treatment. Monotherapy is not effective and the combination of chemotherapy and immunotherapy has not yet been included in the guidelines. The present study aimed to explore a new treatment approach by conducting a single-center, retrospective, observational real-world study. A total of 21 patients with advanced HER2-negative GC, who had progressed after receiving standard first-line regimens [tegafur, gimeracil and oteracil potassium capsules (S-1) or capecitabine plus oxaliplatin], were selected. The application of programmed cell death-1 (PD-1) inhibitor combined with taxanes was selected as the second-line treatment. The primary outcomes measured were progression-free survival (PFS), pathological complete response, objective response rate (ORR), disease control rate (DCR) and adverse reactions in the present patient cohort. The median (m)PFS in the overall population was 7.1 months, with a 95% confidence interval (CI) of 6.0-8.2 months and the median overall survival (mOS) was 11.3 months, with a 95% CI of 4.5-18.2 months. The ORR was 9.5% and the DCR was 90.5%. Univariate and multivariate analyses indicated that Ki67 <70% and tumor marker-positive status [one or two increases among carcinoembryogenic antigen (CEA), cancer antigen (CA) 199 and CA125] were independent prognostic factors for PFS and overall survival (OS) in second-line treatment. Significant statistical differences were noted in PFS (mPFS=5.3 months, 95% CI: 3.1-7.5 months vs. mPFS=9.1 months, 95% CI: 6.2-12.0 months; P=0.002) and OS (mOS=8.8 months, 95% CI: 7.0-10.7 months vs. mOS=17.2 months, 95% CI: 16.0-18.5 months; P=0.013) between the Ki67-high group (Ki67 ≥70%) and the Ki67-low group (Ki67 <70%). Significant statistical differences were noted in OS between tumor marker-negative status (CEA, CA199 and CA125 within normal range) and tumor marker-positive status (one or two increases among CEA, CA199 and CA125; mOS=17.2 months, 95% CI: 16.0-18.4 months vs. mOS=8.8 months, 95% CI: 5.3-12.4 months; P=0.018); however, no significant differences were noted in PFS between these two groups. The present study retrospectively analyzed the new second-line approach of PD-1 inhibitor combined with taxanes for HER2 negative GC which effectively improved patient PFS and OS compared with single-agent chemotherapy. The expression levels of Ki67 and the tumor marker-negative status possess potential clinical value in monitoring prognosis and guiding future individualized use of chemotherapy combined with immunotherapy.
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Affiliation(s)
- Tianran Chen
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, P.R. China
| | - Meng Xu
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, P.R. China
| | - Jiajun Xu
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, P.R. China
| | - Xianbao Zhan
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, P.R. China
| | - Yingyi Zhang
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, P.R. China
| | - Mingzhen Ying
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, P.R. China
| | - Meihong Wu
- Department of Oncology, Shanghai Changhai Hospital, Naval Medical University, Shanghai 200433, P.R. China
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29
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Suzuki N, Odawara N, Fujisawa G, Ishibashi R, Hata M, Oya Y, Tamada K, Hayashi T, Abe S, Miyakawa Y, Hayakawa Y, Shinozaki-Ushiku A, Ushiku T, Boku N, Fujishiro M. Sustained Clinical Complete Response after Discontinuation of Trastuzumab-deruxetecan Due to Interstitial Pneumonia for HER2-positive Gastric Adenocarcinoma with Enteroblastic Differentiation (GAED). Intern Med 2025; 64:101-107. [PMID: 38839335 PMCID: PMC11781934 DOI: 10.2169/internalmedicine.3155-23] [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: 11/05/2023] [Accepted: 04/17/2024] [Indexed: 06/07/2024] Open
Abstract
Trastuzumab deruxtecan (T-DXd) has demonstrated remarkable efficacy as a third- or later-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-positive advanced gastric and gastroesophageal junction adenocarcinomas. However, it may cause pneumonitis, and its efficacy in rare histologies such as gastric adenocarcinoma with enteroblastic differentiation (GAED) remains unclear. A 74-year-old woman with unresectable HER2-positive GAED and lung metastasis received T-DXd as a fifth-line chemotherapy. Treatment was discontinued after 15 cycles owing to drug-induced pneumonitis; however, the patient achieved a sustained complete response for 14 months without subsequent chemotherapy or the exacerbation of pneumonitis. T-DXd was effective in HER2-positive GAED.
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Affiliation(s)
- Nobumi Suzuki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Nariaki Odawara
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Gota Fujisawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Rei Ishibashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Masahiro Hata
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Yukiko Oya
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Kenji Tamada
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Takeshi Hayashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Sohei Abe
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Yu Miyakawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan
| | - Yoku Hayakawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan
| | | | - Tetsuo Ushiku
- Department of Pathology, The University of Tokyo Hospital, Japan
| | - Narikazu Boku
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan
- Department of Oncology and General Medicine, IMSUT Hospital, Institute of Medical Science, The University of Tokyo, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Japan
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30
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Kim IH, Kang SJ, Choi W, Seo AN, Eom BW, Kang B, Kim BJ, Min BH, Tae CH, Choi CI, Lee CK, An HJ, Byun HK, Im HS, Kim HD, Cho JH, Pak K, Kim JJ, Bae JS, Yu JI, Lee JW, Choi J, Kim JH, Choi M, Jung MR, Seo N, Eom SS, Ahn S, Kim SJ, Lee SH, Lim SH, Kim TH, Han HS. Korean Practice Guidelines for Gastric Cancer 2024: An Evidence-based, Multidisciplinary Approach (Update of 2022 Guideline). J Gastric Cancer 2025; 25:5-114. [PMID: 39822170 PMCID: PMC11739648 DOI: 10.5230/jgc.2025.25.e11] [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: 12/24/2024] [Accepted: 12/24/2024] [Indexed: 01/19/2025] Open
Abstract
Gastric cancer is one of the most common cancers in both Korea and worldwide. Since 2004, the Korean Practice Guidelines for Gastric Cancer have been regularly updated, with the 4th edition published in 2022. The 4th edition was the result of a collaborative work by an interdisciplinary team, including experts in gastric surgery, gastroenterology, endoscopy, medical oncology, abdominal radiology, pathology, nuclear medicine, radiation oncology, and guideline development methodology. The current guideline is the 5th version, an updated version of the 4th edition. In this guideline, 6 key questions (KQs) were updated or proposed after a collaborative review by the working group, and 7 statements were developed, or revised, or discussed based on a systematic review using the MEDLINE, Embase, Cochrane Library, and KoreaMed database. Over the past 2 years, there have been significant changes in systemic treatment, leading to major updates and revisions focused on this area. Additionally, minor modifications have been made in other sections, incorporating recent research findings. The level of evidence and grading of recommendations were categorized according to the Grading of Recommendations, Assessment, Development and Evaluation system. Key factors for recommendation included the level of evidence, benefit, harm, and clinical applicability. The working group reviewed and discussed the recommendations to reach a consensus. The structure of this guideline remains similar to the 2022 version. Earlier sections cover general considerations, such as screening, diagnosis, and staging of endoscopy, pathology, radiology, and nuclear medicine. In the latter sections, statements are provided for each KQ based on clinical evidence, with flowcharts supporting these statements through meta-analysis and references. This multidisciplinary, evidence-based gastric cancer guideline aims to support clinicians in providing optimal care for gastric cancer patients.
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Affiliation(s)
- In-Ho Kim
- Division of Medical Oncology, Department of Internal Medicine, Seoul St. Mary's Hospital, The College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung Joo Kang
- Department of Internal Medicine, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea
| | - Wonyoung Choi
- Center for Gastric Cancer, National Cancer Center, Goyang, Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Bang Wool Eom
- Center for Gastric Cancer, National Cancer Center, Goyang, Korea
| | - Beodeul Kang
- Division of Medical Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, Korea
| | - Bum Jun Kim
- Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University Medical Center, Hallym University College of Medicine, Anyang, Korea
| | - Byung-Hoon Min
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Chung Hyun Tae
- Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Korea
| | - Chang In Choi
- Department of Surgery, Pusan National University Hospital, Busan, Korea
| | - Choong-Kun Lee
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Ho Jung An
- Division of Oncology, Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
| | - Hwa Kyung Byun
- Department of Radiation Oncology, Yongin Severance Hospital, Yonsei University College of Medicine, Yongin, Korea
| | - Hyeon-Su Im
- Department of Hematology and Oncology, Ulsan University Hospital, Ulsan University College of Medicine, Ulsan, Korea
| | - Hyung-Don Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jang Ho Cho
- Division of Medical Oncology, Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Kyoungjune Pak
- Department of Nuclear Medicine and Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Jae-Joon Kim
- Division of Hematology and Oncology, Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan, Korea
| | - Jae Seok Bae
- Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Korea
| | - Jeong Il Yu
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea
| | - Jeong Won Lee
- Department of Nuclear Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Jungyoon Choi
- Division of Oncology/Hematology, Department of Internal Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, Korea
| | - Jwa Hoon Kim
- Division of Medical Oncology, Department of Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
| | - Miyoung Choi
- National Evidence-based Healthcare Collaborating Agency (NECA), Seoul, Korea
| | - Mi Ran Jung
- Department of Surgery, Chonnam National University Medical School, Gwangju, Korea
| | - Nieun Seo
- Department of Radiology, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Soo Eom
- Department of Surgery, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Soomin Ahn
- Department of Pathology and Translational Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Soo Jin Kim
- Department of Radiology, National Cancer Center, Goyang, Korea
| | - Sung Hak Lee
- Department of Hospital Pathology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Sung Hee Lim
- Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Seoul, Korea
| | - Tae-Han Kim
- Department of Surgery, Gyeongsang National University Changwon Hospital, Changwon, Korea.
| | - Hye Sook Han
- Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea.
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31
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Maruyama S, Imamura Y, Toihata T, Haraguchi I, Takamatsu M, Yamashita M, Nakashima Y, Oki E, Taguchi K, Yamamoto M, Mine S, Okamura A, Kanamori J, Nunobe S, Sano T, Kitano S, Noda T, Watanabe M. FOXP3+/CD8+ ratio associated with aggressive behavior in RUNX3-methylated diffuse esophagogastric junction tumor. Cancer Sci 2025; 116:178-191. [PMID: 39440906 PMCID: PMC11711055 DOI: 10.1111/cas.16373] [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: 06/05/2024] [Revised: 09/21/2024] [Accepted: 10/03/2024] [Indexed: 10/25/2024] Open
Abstract
The tumor immune microenvironment is increasingly becoming a key consideration in developing treatment regimens for aggressive cancers, with evidence that regulatory T cells (Tregs) attenuate the antitumor response by interrupting cytotoxic T cells (CD8+). Here, we hypothesized the prognostic relevance of the proportions of Tregs (marked by forkhead box protein 3 [FOXP3]) and CD8+ cells in diffuse, non-Epstein-Barr virus (EBV)/non-microsatellite instability (MSI)-high gastroesophageal adenocarcinomas (GEAs), which are clinically characterized as more aggressive, immunologically inactive tumors as compared with their intestinal counterparts. Cell-count ratios of FOXP3+/CD8+ expression were calculated at the intratumoral region and invasive margin discretely on digital images from 303 chemo-naive non-EBV/non-MSI-high esophagogastric junction (EGJ) adenocarcinomas. A significant modifying prognostic effect of tumor histology was observed between 5-year EGJ cancer-specific survival and the FOXP3+/CD8+ ratio at the invasive margin in pStage I-III tumors (p for interaction = 0.022; hazard ratio [HR] = 8.47 and 95% confidence interval [CI], 2.04-35.19 for high ratio [vs. low] for diffuse; HR = 1.57 and 95% CI, 0.88-2.83 for high ratio [vs. low] for intestinal). A high FOXP3+/CD8+ ratio at the invasive margin was associated with RUNX3 methylation (p = 0.035) and poor prognosis in RUNX3-methylated diffuse histological subtype (5-year EGJ cancer-specific survival, 52.3% for high and 100% for low, p = 0.015). Multiomics data from The Cancer Genome Atlas linked CCL28 with RUNX3-suppressed diffuse histological subtypes of non-EBV/non-MSI-high GEA. Our data suggest that a high FOXP3+/CD8+ ratio at the invasive margin might indicate tumor immune escape via CCL28, particularly in the RUNX3-methylated diffuse histological subtype.
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Affiliation(s)
- Suguru Maruyama
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yu Imamura
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tasuku Toihata
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Ikumi Haraguchi
- Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Manabu Takamatsu
- Department of Pathology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Makiko Yamashita
- Advanced Medical Development Center, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Yuichiro Nakashima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenichi Taguchi
- Department of Pathology, Kyushu Cancer Center, National Hospital Organization, Fukuoka, Japan
| | - Manabu Yamamoto
- Department of Gastroenterological Surgery, Kyushu Cancer Center, National Hospital Organization, Fukuoka, Japan
| | - Shinji Mine
- Department of Esophageal and Gastroenterological Surgery, Juntendo University Hospital, Tokyo, Japan
| | - Akihiko Okamura
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Jun Kanamori
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Souya Nunobe
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Takeshi Sano
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Shigehisa Kitano
- Advanced Medical Development Center, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Tetsuo Noda
- Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Masayuki Watanabe
- Department of Gastroenterological Surgery, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
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32
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Eom SS, Ryu KW, Han HS, Kong SH. A Comprehensive and Comparative Review of Global Gastric Cancer Treatment Guidelines: 2024 Update. J Gastric Cancer 2025; 25:153-176. [PMID: 39822173 PMCID: PMC11739642 DOI: 10.5230/jgc.2025.25.e10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2024] [Revised: 12/19/2024] [Accepted: 12/20/2024] [Indexed: 01/19/2025] Open
Abstract
Differences in demographics, medical expertise, and patient healthcare resources across countries have led to significant variations in guidelines. In light of these differences, in this review, we aimed to explore and compare the most recent updates to gastric cancer treatment from five guidelines that are available in English. These English-version guidelines, which have been recently published and updated for journal publication, include those published in South Korea in 2024, Japan in 2021, China in 2023, the United States in 2024, and Europe in 2024. The South Korean and Japanese guidelines provide a higher proportion of content to endoscopic and surgical treatments, reflecting their focus on minimally invasive techniques, function-preserving surgeries, and systemic therapy. The Chinese guidelines provide recommendations addressing not only surgical approaches but also perioperative chemotherapy and palliative systemic therapy. Meanwhile, in the United States and European guidelines, a higher proportion of the content is dedicated to perioperative and palliative systemic therapy, aligning with their approaches to advanced-stage disease management. All guidelines address surgical and systemic chemotherapy treatments; however, the proportion and emphasis of content vary based on the patient distribution and treatment approaches specific to each country. With emerging research findings on gastric cancer treatment worldwide, the national guidelines are being progressively revised and updated. Understanding the commonalities and differences among national guidelines, along with the underlying evidence, can provide valuable insights into the treatment of gastric cancer.
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Affiliation(s)
- Sang Soo Eom
- Department of Surgery, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
| | - Keun Won Ryu
- Center for Gastric Cancer, National Cancer Center, Goyang, Korea
| | - Hye Sook Han
- Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea.
| | - Seong-Ho Kong
- Department of Surgery, Seoul National University Hospital and Seoul National University College of Medicine Cancer Research Institute, Seoul, Korea.
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33
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Guo M, Zhao W, Chen Y, Zou D, Peng W, Sha H, Zhou G, Fang Y, Shen B. Efficacy of rechallenge after first-line immunotherapy for advanced gastric cancer: A retrospective real-world study. Hum Vaccin Immunother 2024; 20:2423479. [PMID: 39494935 PMCID: PMC11540071 DOI: 10.1080/21645515.2024.2423479] [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: 07/19/2024] [Revised: 10/15/2024] [Accepted: 10/28/2024] [Indexed: 11/05/2024] Open
Abstract
We aimed to explore the efficacy of rechallenge after first-line immunotherapy in advanced gastric cancer (AGC) and to analyze the factors affecting prognosis based on clinical characteristics. Eighty-five AGC patients who underwent rechallenged after the failure of first-line treatment with immune checkpoint inhibitors (ICIs) were retrospectively collected from July 2019 to December 2022 in Jiangsu Cancer Hospital. Potential factors affecting prognosis were analyzed by univariate and multivariate Cox analysis. Survival analysis was performed by Kaplan-Meier method and Log rank test. Stratified factors included human epidermal growth factor receptor 2 (HER-2) and programmed cell death-ligand 1 combined positive score (PD-L1 CPS). The objective response rate (ORR) was 15.3%, and the disease control rate (DCR) was 74.1%. The median progression-free survival (PFS) was 4.8 months. Results showed that patients in the I + C group had the best response. The ORR was 20.0% VS 8.7% in the I + C group and I + C + AAD group. The DCR was 78.0% VS 65.2%, and the median PFS was 6.7 VS 4.7 months [hazard ratio (HR): 0.55, 95% confidence interval (CI): 0.30-1.00, p = .022]. The ORR was 20.0% VS 8.3% in the I + C group and I + C + ADC group. The DCR was 78.0% VS 75.0%, and the median PFS was 6.7 VS 4.4 months (HR: 0.59, 95%CI: 0.26-1.30, p = .112). The median PFS was 4.7 VS 4.4 months in the I + C + AAD group and I + C + ADC group (HR: 1.21, 95%CI: 0.60-2.47, p = .580). Adverse events (AEs) were found in 34 patients, mainly including leukopenia 9 (10.6%), and neutropenia 8 (9.4%). The incidence of grade 3-4 AEs was 8.2%. There were no drug-related deaths and all AEs were manageable. Rechallenge after first-line immunotherapy showed good survival benefit and acceptable safety in the therapy of AGC. Especially for patients with HER-2-positive and PD-L1 CPS ≥ 1%, rechallenge may be an effective treatment modality.
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Affiliation(s)
- Mengya Guo
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wenhui Zhao
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yue Chen
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Dan Zou
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Weiwei Peng
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Huanhuan Sha
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Guoren Zhou
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | | | - Bo Shen
- Department of Oncology, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
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Pan Y, Ma Y, Guan H, Dai G. Pre-treatment of hyponatremia as a biomarker for poor immune prognosis in advanced or metastatic gastric cancer: A retrospective case analysis. Hum Vaccin Immunother 2024; 20:2414546. [PMID: 39411929 PMCID: PMC11486141 DOI: 10.1080/21645515.2024.2414546] [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: 05/17/2024] [Revised: 09/22/2024] [Accepted: 10/07/2024] [Indexed: 10/19/2024] Open
Abstract
Hyponatremia, a prevalent electrolyte imbalance among tumor patients, has often been overlooked regarding its prognostic significance for immunotherapy. In this study, we delved into the prognostic ramifications of hyponatremia in advanced gastric cancer (AGC) patients undergoing immunotherapy. Enrolling AGC patients diagnosed between December 2014 and May 2021, we extracted pertinent data from electronic medical records, with a median follow-up of 35.8 months. Kaplan-Meier curves illuminated patients' progression-free survival (PFS) and overall survival (OS), while survival disparities were tested using the Mantel-Haenszel log rank test. COX and logistic regressions were employed to scrutinize the correlation between serum sodium levels and prognosis in 268 AGC patients, both at baseline and during treatment. Notably, patients with hyponatremia exhibited shorter PFS (4.7 vs 2.1 months, p = .001*) and OS (12.5 vs 3.9 months, p < .001*). Serum sodium emerged as an independent prognostic factor for both PFS (HR = 1.773; 95% CI 1.067-2.945; p = .001*) and OS (HR = 1.773; 95% CI 1.067-2.945; p = .003*). Subgroup analysis revealed that AGC patients with hyponatremia derived no benefit from immunotherapy in terms of PFS and OS. Strikingly, a decrease in serum sodium during immunotherapy was associated with early relapse and mortality. Based on these findings, we hypothesize that hyponatremia portends poor prognostic outcomes in AGC patients treated with immunotherapy and may serve as a valuable prognostic biomarker. However, further large-scale prospective studies are warranted to validate these observations.
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Affiliation(s)
- Yuting Pan
- Department of Medical Oncology, Medical School of Chinese PLA, Beijing, China
- Department of Medical Oncology, The First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Yue Ma
- Department of Medical Oncology, Medical School of Chinese PLA, Beijing, China
- Department of Medical Oncology, The First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Huafang Guan
- External Relations Office, Yingtan City People’s Hospital, Yingtan, China
| | - Guanghai Dai
- Department of Medical Oncology, The First Medical Centre, Chinese PLA General Hospital, Beijing, China
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35
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Lee SM, Oh H. Association of PD-L1 positivity with Epstein Barr virus infection and microsatellite instability in gastric carcinomas with lymphoid stroma. Sci Rep 2024; 14:30932. [PMID: 39730741 DOI: 10.1038/s41598-024-81764-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 11/28/2024] [Indexed: 12/29/2024] Open
Abstract
Gastric carcinoma with lymphoid stroma (GCLS) is characterized by dense intra-and peritumoral lymphocytic infiltration and a high rate of Epstein Barr Virus (EBV) infection, suggesting being a promising candidate for immunotherapy. We investigated correlations between PD-L1 expression and clinicopathologic factors, including EBV positivity and microsatellite instability (MSI) status in GCLSs. The study included resected 214 GCLSs and 300 gastric adenocarcinomas (GACs) for control. Epstein Barr Virus encoding region in situ hybridization (EBER ISH), immunohistochemistry for PD-L1 and HER2, dual-colored in situ hybridization for HER2, and MSI analysis were performed. EBV positivity was found in 181 (85%) of 214 GCLSs. MSI analysis demonstrated that 0.6% of EBV + GCLSs and 54.5% of EBV-GCLSs were MSI-high compared to 7% of EBV-GACs. Approximately 3% and 3.9% of HER2 amplifications were found in EBV- and EBV + GCLSs compared to 13% of EBV-GACs. PD-L1 expression with ≥ 1, ≥ 5, and ≥ 10 combined positive scores (CPS) were observed in 81.8%, 70.2%, and 55.3% of EBV + GCLSs. PD-L1 expression with ≥ 10 CPS was observed in 21.2% of EBV-GCLSs, predominantly in MSI-H tumors (85.7%). EBV positivity and MSI are associated with PD-L1 positivity rates in patients with GCLS who may respond better to PD-1/PD-L1 inhibitors but not anti-HER2 inhibitors.
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Affiliation(s)
- Sun Mi Lee
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 350 W. 11th street, Indianapolis, IN, 46202, USA.
- Department of Pathology, Jeju National University Hospital, Jeju-si, South Korea.
| | - Hyunjoo Oh
- Department of Internal Medicine, Jeju National University Hospital, Jeju-si, South Korea
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Ma X, Lu T, Yang Y, Qin D, Tang Z, Cui Y, Wang R. DEAD-box helicase family proteins: emerging targets in digestive system cancers and advances in targeted drug development. J Transl Med 2024; 22:1120. [PMID: 39707322 DOI: 10.1186/s12967-024-05930-0] [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: 08/24/2024] [Accepted: 11/30/2024] [Indexed: 12/23/2024] Open
Abstract
Cancer has become one of the major diseases threatening human health in the twenty-first century due to its incurability. In 2022, new cases of esophageal and gastrointestinal cancers accounted for 17.1% of all newly diagnosed cancer cases worldwide. Despite significant improvements in early cancer screening, clinical diagnostics, and treatments in recent years, the overall prognosis of digestive system cancer patients remains poor. The DEAD-box helicase family, a crucial member of the RNA helicase family, participates in almost every aspect of RNA metabolism, including transcription, splicing, translation, and degradation, and plays a key role in the occurrence and progression of various cancers. This article aims to summarize and discuss the role and potential clinical applications of DEAD-box helicase family proteins in digestive system cancers. The discussion includes the latest progress in the occurrence, development, and treatment of esophageal and gastrointestinal tumors; the main functions of DEAD-box helicase family proteins; their roles in digestive system cancers, including their relationships with clinical factors; effects on cancer proliferation, migration, and invasion; and involved signaling pathways; as well as the existing inhibitory strategies targeting DDX family proteins, are discussed. Additionally, outlooks on future research directions are provided.
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Affiliation(s)
- Xiaochao Ma
- Department of Thoracic Surgery, Organ Transplantation Center, the First Hospital of Jilin University, 1 Ximin Street, ChangchunJilin, 130021, China
| | - Tianyu Lu
- Department of Thoracic Surgery, Organ Transplantation Center, the First Hospital of Jilin University, 1 Ximin Street, ChangchunJilin, 130021, China
| | - Yue Yang
- Department of Thoracic Surgery, Organ Transplantation Center, the First Hospital of Jilin University, 1 Ximin Street, ChangchunJilin, 130021, China
| | - Da Qin
- Department of Thoracic Surgery, Organ Transplantation Center, the First Hospital of Jilin University, 1 Ximin Street, ChangchunJilin, 130021, China
| | - Ze Tang
- Department of Thoracic Surgery, Organ Transplantation Center, the First Hospital of Jilin University, 1 Ximin Street, ChangchunJilin, 130021, China
| | - Youbin Cui
- Department of Thoracic Surgery, Organ Transplantation Center, the First Hospital of Jilin University, 1 Ximin Street, ChangchunJilin, 130021, China.
| | - Rui Wang
- Department of Thoracic Surgery, Organ Transplantation Center, the First Hospital of Jilin University, 1 Ximin Street, ChangchunJilin, 130021, China
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Fujii H. Pharmacist intervention and identification of adverse events related to treatment efficacy in cancer chemotherapy to improve clinical outcomes. J Pharm Health Care Sci 2024; 10:81. [PMID: 39696667 DOI: 10.1186/s40780-024-00403-4] [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: 10/11/2024] [Accepted: 12/07/2024] [Indexed: 12/20/2024] Open
Abstract
Adverse events (AEs) induced by cancer chemotherapy reduce not only patient quality of life (QOL) but also the efficacy of treatment. Management of AEs can therefore improve both the efficacy and safety of cancer chemotherapy. This review describes the contribution of pharmacists to the management of adverse events aimed at improving the treatment efficacy of cancer chemotherapy. Efforts to improve the evidence-practice gap are a useful approach to countermeasures against AEs. Pharmacists can intervene in these efforts in the course of their daily practice. Here, we made undertook to improve the evidence-practice gap in prophylaxis pharmacotherapy for chemotherapy-induced nausea and vomiting (CINV) and anti-EGFR antibody-induced acneiform rash. After intervention by pharmacists, the rate of adherence to prophylaxis pharmacotherapy for these AEs was significantly improved, and the incidence of CINV and acneiform rash was significantly decreased. Notably, time to treatment failure (TTF) with anti-EGFR antibody therapy tended to be increased, and may have contributed to an improvement in therapeutic effect. Next, we examined adverse events associated with anti-cancer drugs related to the therapeutic effect of cancer chemotherapy. Incidence of hypomagnesemia in patients receiving anti-EGFR antibodies and neutropenia in patients receiving TAS-102 was significantly associated with the therapeutic effect of cancer chemotherapy. Moreover, we examined the impact of cancer cachexia, a cancer-associated AE, on the therapeutic effect of immune checkpoint inhibitors. In patients receiving nivolumab, the presence of cancer cachexia prior to treatment initiation was associated with shorter OS and TTF. In summary, pharmacist management of AEs was shown to improve treatment response. Further, AEs which are predictive of treatment response in cancer chemotherapy were identified. Management of these AEs is an important role for pharmacists aiming to improve patient QOL and treatment efficacy.
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Affiliation(s)
- Hironori Fujii
- Department of Pharmacy, Gifu University Hospital, 1-1 Yanagido, Gifu, 501-1194, Japan.
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Ning Y, Fang S, Zhang R, Fang J, Lin K, Ding Y, Nie H, Zhou J, Zhao Q, Ke H, Wang H, Wang F. Simvastatin induces ferroptosis and activates anti-tumor immunity to sensitize anti-PD-1 immunotherapy in microsatellite stable gastric cancer. Int Immunopharmacol 2024; 142:113244. [PMID: 39317047 DOI: 10.1016/j.intimp.2024.113244] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 09/08/2024] [Accepted: 09/19/2024] [Indexed: 09/26/2024]
Abstract
BACKGROUND Gastric cancer (GC), especially the case with microsatellite stability (MSS) phenotype, has limited efficacy for immune checkpoint blockade (ICB) therapy. Metabolism reprogramming is newly recognized to affect tumor immune microenvironment (TIME). However, the relationship between metabolism reprogramming and immunotherapy for MSS GC has not been reported. METHODS A metabolic stratification for GC was developed based on the glycolysis/cholesterol synthesis axis using the R package "ConsensusClusterPlus". The T cell inflamed score was used to define "immune-hot" and "immune-cold" phenotypes in MSS GC. The anti-tumor and immunological effects of simvastatin were explored using in vitro and in vivo experiments. RESULTS Three metabolic subtypes were identified in GC patients, including cholesterol, glycolysis and quiescent subtypes. The cholesterol subtype was associated with poorer clinical features and higher tumor purity. Correspondingly, we demonstrated that simvastatin, a specific inhibitor of cholesterol synthesis, significantly inhibited the proliferation, migration, and induced ferroptosis in GC cells. Interestingly, simvastatin markedly inhibited tumor growth in immunocompetent mice, while no significant effect in immunodeficient mice. Upregulation of chemokines and increased recruitment of CD8+ T cells were observed after simvastatin treatment. Consistently, the cholesterol subtype exhibited a less inflamed TIME and coincided significantly with the "immune-cold" phenotype of MSS GC. Finally, we confirmed simvastatin enhanced PD-1 blockade efficacy via modulating the TIME and activating anti-tumor immunity in tumor-bearing mice. CONCLUSION Our data revealed the significance of cholesterol synthesis in GC and demonstrated simvastatin served as a promising sensitizer for ICB therapy by inducing ferroptosis and anti-tumor immunity in MSS GC patients.
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Affiliation(s)
- Yumei Ning
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Shilin Fang
- Department of Infectious Disease, Zhongnan Hospital of Wuhan University, Hubei AIDS Clinical Training Center, China
| | - Runan Zhang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Jun Fang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Kun Lin
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Yang Ding
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Haihang Nie
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Jingkai Zhou
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China.
| | - Hengning Ke
- Department of Infectious Disease, Zhongnan Hospital of Wuhan University, Hubei AIDS Clinical Training Center, China.
| | - Haizhou Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China.
| | - Fan Wang
- Department of Gastroenterology, Zhongnan Hospital of Wuhan University, Wuhan, China; Hubei Clinical Center and Key Lab of Intestinal and Colorectal Diseases, Wuhan, China.
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He Y, Fan Z, Sun W, Ouyang L, Wang C. Clinical features, treatment, and outcome of nivolumab-induced cholangitis. Immunopharmacol Immunotoxicol 2024; 46:757-762. [PMID: 39245799 DOI: 10.1080/08923973.2024.2402338] [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: 01/18/2024] [Accepted: 09/03/2024] [Indexed: 09/10/2024]
Abstract
BACKGROUND Cholangitis is an uncommon and severe adverse reaction of nivolumab with unclear clinical features. The purpose of this study was to investigate the clinicopathological features, imaging, and treatment of nivolumab-induced cholangitis. METHODS Case reports, case series, and clinical studies of nivolumab-induced cholangitis were retrospectively analyzed by searching Chinese and English databases from January 1, 2017 to December 31, 2023. RESULTS Thirty-eight patients entered the study. The median number of cycles of cholangitis onset was seven cycles after administration (range 1, 28) and the median time was 11 days (range 78, 390). Abdominal pain (42.1%) and fever (18.4%) were the most important initial symptoms. Some patients (15.8%) showed elevated liver enzymes without any clinical symptoms. The median alkaline phosphatase level was 1721 IU/L (range 126, 9118), and the median γ-glutamyltranspeptidase level was 829 IU/L (range 104, 3442). Anti-nuclear antibodies, anti-mitochondrial antibodies, and IgG4 typically show negative results. Imaging shows extrahepatic bile duct and intrahepatic bile duct dilation, hypertrophy, and stenosis. Liver biopsy and biliary tract biopsy mainly found CD8 inflammatory cell infiltration. Systemic steroids (84.2%) and ursodeoxycholic acid (UDCA) (34.2%) were administered, and 24 patients (63.2%) had poor to moderate response to steroids. Thirty-one patients (81.6%) improved and seven patients (18.4%) did not improve. CONCLUSIONS Clinicians must remain vigilant for patients experiencing cholestasis while on nivolumab and should assess for cholangitis and carry out appropriate imaging tests. Considering the excellent efficacy of UCDA in cholangitis, steroids combined with UDCA may be a viable treatment option in cases where steroids are ineffective for cholangitis.
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Affiliation(s)
- Yang He
- Department of pharmacy, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
- College of Pharmacy, Changsha Medical University, Changsha, Hunan, China
| | - Zhiqiang Fan
- Department of pharmacy, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Wei Sun
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Linqi Ouyang
- Department of pharmacy, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China
| | - Chunjiang Wang
- Department of Pharmacy, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
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Schäfer H, Idrissi-Yaghir A, Arzideh K, Damm H, Pakull TM, Schmidt CS, Bahn M, Lodde G, Livingstone E, Schadendorf D, Nensa F, Horn PA, Friedrich CM. BioKGrapher: Initial evaluation of automated knowledge graph construction from biomedical literature. Comput Struct Biotechnol J 2024; 24:639-660. [PMID: 39502384 PMCID: PMC11536026 DOI: 10.1016/j.csbj.2024.10.017] [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: 08/28/2024] [Revised: 10/11/2024] [Accepted: 10/11/2024] [Indexed: 11/08/2024] Open
Abstract
Background The growth of biomedical literature presents challenges in extracting and structuring knowledge. Knowledge Graphs (KGs) offer a solution by representing relationships between biomedical entities. However, manual construction of KGs is labor-intensive and time-consuming, highlighting the need for automated methods. This work introduces BioKGrapher, a tool for automatic KG construction using large-scale publication data, with a focus on biomedical concepts related to specific medical conditions. BioKGrapher allows researchers to construct KGs from PubMed IDs. Methods The BioKGrapher pipeline begins with Named Entity Recognition and Linking (NER+NEL) to extract and normalize biomedical concepts from PubMed, mapping them to the Unified Medical Language System (UMLS). Extracted concepts are weighted and re-ranked using Kullback-Leibler divergence and local frequency balancing. These concepts are then integrated into hierarchical KGs, with relationships formed using terminologies like SNOMED CT and NCIt. Downstream applications include multi-label document classification using Adapter-infused Transformer models. Results BioKGrapher effectively aligns generated concepts with clinical practice guidelines from the German Guideline Program in Oncology (GGPO), achievingF 1 -Scores of up to 0.6. In multi-label classification, Adapter-infused models using a BioKGrapher cancer-specific KG improved microF 1 -Scores by up to 0.89 percentage points over a non-specific KG and 2.16 points over base models across three BERT variants. The drug-disease extraction case study identified indications for Nivolumab and Rituximab. Conclusion BioKGrapher is a tool for automatic KG construction, aligning with the GGPO and enhancing downstream task performance. It offers a scalable solution for managing biomedical knowledge, with potential applications in literature recommendation, decision support, and drug repurposing.
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Affiliation(s)
- Henning Schäfer
- Institute for Transfusion Medicine, University Hospital Essen, Hufelandstraße 55, Essen, 45147, Germany
- Department of Computer Science, University of Applied Sciences and Arts Dortmund (FHDO), Emil-Figge Str. 42, Dortmund, 44227, Germany
| | - Ahmad Idrissi-Yaghir
- Department of Computer Science, University of Applied Sciences and Arts Dortmund (FHDO), Emil-Figge Str. 42, Dortmund, 44227, Germany
- Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital Essen, Hufelandstraße 55, Essen, 45147, Germany
| | - Kamyar Arzideh
- Institute for AI in Medicine (IKIM), University Hospital Essen, Girardetstraße 2, Essen, 45131, Germany
| | - Hendrik Damm
- Department of Computer Science, University of Applied Sciences and Arts Dortmund (FHDO), Emil-Figge Str. 42, Dortmund, 44227, Germany
- Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital Essen, Hufelandstraße 55, Essen, 45147, Germany
| | - Tabea M.G. Pakull
- Institute for Transfusion Medicine, University Hospital Essen, Hufelandstraße 55, Essen, 45147, Germany
- Department of Computer Science, University of Applied Sciences and Arts Dortmund (FHDO), Emil-Figge Str. 42, Dortmund, 44227, Germany
| | - Cynthia S. Schmidt
- Institute for Transfusion Medicine, University Hospital Essen, Hufelandstraße 55, Essen, 45147, Germany
- Institute for AI in Medicine (IKIM), University Hospital Essen, Girardetstraße 2, Essen, 45131, Germany
| | - Mikel Bahn
- Institute for AI in Medicine (IKIM), University Hospital Essen, Girardetstraße 2, Essen, 45131, Germany
| | - Georg Lodde
- Department of Dermatology, University Hospital Essen, Hufelandstraße 55, Essen, 45147, Germany
| | - Elisabeth Livingstone
- Department of Dermatology, University Hospital Essen, Hufelandstraße 55, Essen, 45147, Germany
| | - Dirk Schadendorf
- Department of Dermatology, University Hospital Essen, Hufelandstraße 55, Essen, 45147, Germany
| | - Felix Nensa
- Institute for AI in Medicine (IKIM), University Hospital Essen, Girardetstraße 2, Essen, 45131, Germany
- Institute of Interventional and Diagnostic Radiology and Neuroradiology, University Hospital Essen, Hufelandstraße 55, Essen, 45147, Germany
| | - Peter A. Horn
- Institute for Transfusion Medicine, University Hospital Essen, Hufelandstraße 55, Essen, 45147, Germany
| | - Christoph M. Friedrich
- Department of Computer Science, University of Applied Sciences and Arts Dortmund (FHDO), Emil-Figge Str. 42, Dortmund, 44227, Germany
- Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University Hospital Essen, Hufelandstraße 55, Essen, 45147, Germany
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Manne A, Tounkara F, Min E, Samuel P, Benson K, Noonan AM, Mittra A, Hays J, Roychowdhury S, Malalur P, Rahman S, Jin N, Pitter K, Miller E, Diaz A, He K. Risk Factors Predicting Outcomes in Advanced Upper Gastrointestinal Cancers Treated With Immune Checkpoint Inhibitors. Gastroenterology Res 2024; 17:195-204. [PMID: 39802925 PMCID: PMC11711034 DOI: 10.14740/gr1768] [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: 08/07/2024] [Accepted: 09/07/2024] [Indexed: 01/16/2025] Open
Abstract
Background Immune checkpoint inhibitors (ICIs) have moved to the frontline in recent years to manage upper gastrointestinal (UGI) tumors, such as esophageal and gastric cancers. This retrospective review sheds light on real-world data on ICI-treated UGI tumors to identify risk factors (clinical and pathological) impacting the outcome other than traditional biomarkers (programmed cell death ligand 1 (PD-L1) or microsatellite instability status). Methods Patients with UGI tumors who received at least one dose of ICI for stage IV or recurrent disease between January 1, 2015, and July 31, 2021, at The Ohio State University were included in the study. The patients' baseline characteristics, labs, and blood counts (even at disease progression) were extracted with survival outcomes (progression-free survival (PFS) and overall survival (OS)). Descriptive statistics, log-rank test and Cox proportional hazard model for survival outcomes, Fisher exact test for categorical variables, were conducted using JMP Pro 16 (SAS Institute Inc., Cary, NC). Results We had 64 patients (84% males) included in the study, with the racial distribution as follows: 88% Caucasian, 5% African American, 1% Asian, and 6% from other racial groups. Men and the use of ICI in third lines or more had a positive impact on PFS and OS. For OS, 1) history of surgery positively impacted the outcome, while bone metastases worsened it; 2) baseline red blood cell count (RBC), hemoglobin, and thyroid-stimulating hormone (TSH) negatively impacted the OS. For PFS, 1) PD-L1 positivity, baseline lymphocyte count, and aspartate transferase levels had a positive impact; 2) human epidermal growth factor receptor 2 (HER2) positivity, baseline RBC, TSH, alkaline phosphatase, and alanine transferase (AST) levels had a negative impact. A slight increase in white blood cell (WBC) count (by 1.54, P = 0.02) and a drop in lymphocyte count (by 0.1907, P = 0.003) was significantly associated with disease progression. Conclusions Baseline risk factors and monitoring blood counts can help predict outcomes in ICI-treated UGI tumors. We need larger studies to confirm this.
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Affiliation(s)
- Ashish Manne
- Division of Medical Oncology, Department of Internal Medicine, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Fode Tounkara
- Department of Biostatistics, The Ohio State University, Columbus, OH 432120, USA
| | - Eric Min
- Division of Medical Oncology, Department of Internal Medicine, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Paul Samuel
- Division of Medical Oncology, Department of Internal Medicine, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Katherine Benson
- Division of Medical Oncology, Department of Internal Medicine, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Anne M. Noonan
- Division of Medical Oncology, Department of Internal Medicine, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Arjun Mittra
- Division of Medical Oncology, Department of Internal Medicine, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - John Hays
- Division of Medical Oncology, Department of Internal Medicine, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Sameek Roychowdhury
- Division of Medical Oncology, Department of Internal Medicine, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Pannaga Malalur
- Division of Medical Oncology, Department of Internal Medicine, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Shafia Rahman
- Division of Medical Oncology, Department of Internal Medicine, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Ning Jin
- Division of Medical Oncology, Department of Internal Medicine, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Kenneth Pitter
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Eric Miller
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Alexandra Diaz
- Department of Radiation Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Kai He
- Division of Medical Oncology, Department of Internal Medicine, The Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
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Shimoyama R, Imamura Y, Uryu K, Mase T, Ohtaki M, Ohtani K, Shiragami M, Fujimura Y, Hayashi M, Shinozaki N, Minami H. Inflammation‑based prognostic markers in patients with advanced or recurrent gastric cancer treated with nivolumab: Tokushukai REAl‑world Data project 02 (TREAD 02). Mol Clin Oncol 2024; 21:90. [PMID: 39421231 PMCID: PMC11484223 DOI: 10.3892/mco.2024.2788] [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: 06/12/2024] [Accepted: 09/03/2024] [Indexed: 10/19/2024] Open
Abstract
In addition to blood test data, inflammation-based prognostic markers have been used to predict the prognosis of various types of cancer. However, several of these previous studies may be outdated, as they were conducted prior to the widespread adoption of immune checkpoint inhibitors, leading to limited reports on their efficacy. The present study aimed to assess the accuracy of different inflammation-based prognostic markers in patients with advanced or recurrent gastric cancer undergoing nivolumab monotherapy as salvage-line chemotherapy. In a retrospective cohort study across Japan, a total of 159 patients with advanced or recurrent gastric cancer who were treated with nivolumab between September 2017 and March 2020 were selected. Blood test data were collected within 14 days of the start of chemotherapy and 17 inflammation-based prognostic markers were evaluated. Cox regression analysis was performed using all patient background factors. Subsequently, model selection was performed using backward elimination based on the Akaike information criterion (AIC) to obtain effective background factors which could be assessed for their impact on patient survival. For each marker, the magnitude of the impact on the survival rate, after adjusting for the background factors, was assessed using concordance and AIC analyses. A total of 159 patients (female, 30.2%; median age, 70 years) were included in the present study. Most patients received platinum, fluoropyrimidine and taxane treatment, with a median of three prior lines of systemic therapy. With a median follow-up of 3.3 months (95% CI, 2.5-3.8), median overall survival and time to treatment failure were 3.8 months (95% CI, 3.3-4.5) and 1.8 months (95% CI, 1.8-2.3), respectively. Amongst the 17 markers analyzed, the modified Glasgow prognostic score (mGPS) was classed as the most useful factor that affected the survival rate of patients. Real-world data showed that mGPS, an inflammation-based prognostic marker, had the strongest correlation with prognosis in patients with advanced or recurrent gastric cancer receiving nivolumab monotherapy. The present study was registered as a clinical trial with the UMIN Clinical Trial Registry (http://www.umin.ac.jp/ctr/index.htm) under the trial registration number UMIN000050590 on 15th March 2023.
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Affiliation(s)
- Rai Shimoyama
- Department of General Surgery, Shonan Kamakura General Hospital, Kamakura, Kanagawa 247-8533, Japan
| | - Yoshinori Imamura
- Cancer Care Promotion Center, University of Fukui Hospital, Eiheiji, Fukui 910-1193, Japan
- Department of Hematology and Oncology, University of Fukui Hospital, Eiheiji, Fukui 910-1193, Japan
- Department of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
| | - Kiyoaki Uryu
- Department of Medical Oncology, Yao Tokushukai General Hospital, Yao, Osaka 581-0011, Japan
| | - Takahiro Mase
- Department of Breast Surgery, Ogaki Tokushukai Hospital, Ogaki, Gifu 503-0015, Japan
| | - Megu Ohtaki
- deCult Co., Ltd., Hatsukaichi, Hiroshima 739-0413, Japan
| | - Keiko Ohtani
- deCult Co., Ltd., Hatsukaichi, Hiroshima 739-0413, Japan
| | - Megumi Shiragami
- Development Division, Tokushukai Information System Inc., Osaka 530-0001, Japan
| | - Yoshiaki Fujimura
- Development Division, Tokushukai Information System Inc., Osaka 530-0001, Japan
| | - Maki Hayashi
- Oncology Project Secretariat, Mirai Iryo Research Center Inc., Tokyo 102-0074, Japan
| | - Nobuaki Shinozaki
- Department of General Surgery, Shonan Kamakura General Hospital, Kamakura, Kanagawa 247-8533, Japan
| | - Hironobu Minami
- Department of Medical Oncology and Hematology, Kobe University Graduate School of Medicine, Kobe, Hyogo 650-0017, Japan
- Cancer Center, Kobe University Hospital, Kobe, Hyogo 650-0017, Japan
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Xia T, Zhang Y, Peng H, Jia X, Yang D, Wei L, Li T, Yao W. EVA1B facilitates esophageal squamous carcinoma progression and recruitment of immunosuppressive myeloid-derived suppressor cells in the tumor microenvironment. Pharmacol Res 2024; 210:107521. [PMID: 39603573 DOI: 10.1016/j.phrs.2024.107521] [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: 09/07/2024] [Revised: 11/18/2024] [Accepted: 11/22/2024] [Indexed: 11/29/2024]
Abstract
Eva-1 Homolog B (EVA1B) has been preliminarily found to be associated with prognostic outcomes and immune microenvironment in several human cancer types, but the implications of EVA1B in ESCC remain unclear. Human ESCC and paracancerous tissues were gathered in this study, and EVA1B expression was measured via immunoblotting. EC109 and KYSE-180 ESCC cells were stably infected by sh-EVA1B lentivirus, and functional experiments were subsequently implemented. Syngeneic mouse models were built, and the expansion and recruitment of myeloid-derived suppressor cells (MDSCs) were then evaluated. The results showed that EVA1B presented the notable up-regulation in clinical ESCC tissues versus controls, and was connected to more advanced stages and the abundance of MDSCs. Silencing EVA1B notably attenuated proliferation of ESCC cells and tumor growth in syngeneic mouse models. Moreover, EVA1B suppression resulted in apoptosis and cell cycle arrest, and impaired ESCC cell aggressiveness. Among ESCC patients, EVA1B was strongly correlated to EMT pathway activity. Targeted suppression of EVA1B mitigated the expression of Wnt3a, β-catenin and LRP6 in ESCC cells and tumor xenografts. Additionally, inhibition of EVA1B attenuated the expansion and recruitment of MDSCs within the immune microenvironment based upon the reduction in the percentage of CD11b+Gr-1+ immunosuppressive MDSCs as well as the expression of MDSC expansion stimulators (S100A8, S100A9, Arg-1, and VEGF). Collectively, our findings unveiled the contribution of high expression of EVA1B to ESCC progression and MDSCs expansion and recruitment, indicating that targeted suppression of EVA1B may be a potential treatment choice for ESCC patients.
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Affiliation(s)
- Tian Xia
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, China.
| | - Yongkang Zhang
- Department of Thoracic Surgery, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China.
| | - Haodong Peng
- Department of Thoracic Surgery, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China.
| | - Xiangbo Jia
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, China.
| | - Dong Yang
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, China.
| | - Li Wei
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, China.
| | - Tian Li
- Tianjin Medical University, Tianjin 300102, China.
| | - Wenjian Yao
- Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan 450003, China.
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Wang Z, Chen H, Sun L, Wang X, Xu Y, Tian S, Liu X. Uncovering the potential of APOD as a biomarker in gastric cancer: A retrospective and multi-center study. Comput Struct Biotechnol J 2024; 23:1051-1064. [PMID: 38455068 PMCID: PMC10918487 DOI: 10.1016/j.csbj.2024.02.015] [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: 10/21/2023] [Revised: 02/16/2024] [Accepted: 02/16/2024] [Indexed: 03/09/2024] Open
Abstract
Gastric cancer (GC) poses a significant health challenge worldwide, necessitating the identification of predictive biomarkers to improve prognosis. Dysregulated lipid metabolism is a well-recognized hallmark of tumorigenesis, prompting investigation into apolipoproteins (APOs). In this study, we focused on apolipoprotein D (APOD) following comprehensive analyses of APOs in pan-cancer. Utilizing data from the TCGA-STAD and GSE62254 cohorts, we elucidated associations between APOD expression and multiple facets of GC, including prognosis, tumor microenvironment (TME), cancer biomarkers, mutations, and immunotherapy response, and identified potential anti-GC drugs. Single-cell analyses and immunohistochemical staining confirmed APOD expression in fibroblasts within the GC microenvironment. Additionally, we independently validated the prognostic significance of APOD in the ZN-GC cohort. Our comprehensive analyses revealed that high APOD expression in GC patients was notably associated with unfavorable clinical outcomes, reduced microsatellite instability and tumor mutation burden, alterations in the TME, and diminished response to immunotherapy. These findings provide valuable insights into the potential prognostic and therapeutic implications of APOD in GC.
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Affiliation(s)
- Zisong Wang
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
- School of Basic Medical Sciences, Wuhan University, Wuhan 430071, Hubei Province, China
| | - Hongshan Chen
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Le Sun
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Xuanyu Wang
- Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Yihang Xu
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Sufang Tian
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
| | - Xiaoping Liu
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
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Yang W, Zhou M, Li G, Zhou C, Wang L, Xia F, Zhang H, Shen L, Wang Y, Wan J, Wang Y, Zhao G, Zhang Z. Adjuvant chemoradiotherapy plus PD-1 inhibitor for pN3 gastric cancer: a randomized, multicenter, Phase III trial. Future Oncol 2024; 20:3389-3396. [PMID: 39545610 PMCID: PMC11776863 DOI: 10.1080/14796694.2024.2421156] [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: 04/05/2024] [Accepted: 10/22/2024] [Indexed: 11/17/2024] Open
Abstract
D2 surgery followed by adjuvant chemotherapy has been established as the standard of care for patients with locally advanced gastric cancer in Asian countries. However, its efficacy is still unsatisfactory, especially for pathological N3 disease. The RACING trial is a randomized, multicenter, Phase III trial designed to compare the efficacy and safety of chemotherapy alone versus chemotherapy in combination with PD-1 inhibitor and radiotherapy in patients with pN3 gastric or gastroesophageal junction adenocarcinoma. A total of 433 patients will be assigned at a 1:1 ratio to the two arms. The primary end point is the 3-year disease-free survival rate. The secondary end points include the 3-year overall survival rate, 3-year local recurrence-free survival rate, treatment-related adverse events and quality of life.Clinical Trial Registration: NCT04997837 (ClinicalTrials.gov).
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Affiliation(s)
- Wang Yang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center
- Department of Oncology, Shanghai Medical College, Fudan University
| | - Menglong Zhou
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center
- Department of Oncology, Shanghai Medical College, Fudan University
| | - Guichao Li
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center
- Department of Oncology, Shanghai Medical College, Fudan University
| | - Changming Zhou
- Department of Oncology, Shanghai Medical College, Fudan University
- Department of Cancer Prevention, Fudan University Shanghai Cancer Center
| | - Lei Wang
- Department of Oncology, Shanghai Medical College, Fudan University
- Department of Pathology, Fudan University Shanghai Cancer Center
| | - Fan Xia
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center
- Department of Oncology, Shanghai Medical College, Fudan University
| | - Hui Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center
- Department of Oncology, Shanghai Medical College, Fudan University
| | - Lijun Shen
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center
- Department of Oncology, Shanghai Medical College, Fudan University
| | - Yan Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center
- Department of Oncology, Shanghai Medical College, Fudan University
| | - Juefeng Wan
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center
- Department of Oncology, Shanghai Medical College, Fudan University
| | - Yaqi Wang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center
- Department of Oncology, Shanghai Medical College, Fudan University
| | - Guangfa Zhao
- Department of Oncology, Shanghai Medical College, Fudan University
- Department of Gastric Surgery, Fudan University Shanghai Cancer Center
| | - Zhen Zhang
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center
- Department of Oncology, Shanghai Medical College, Fudan University
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46
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Li G, Li Z, Shen J, Ma X, Zheng S, Zheng Y, Cao K, Dong N. Identifying and validating angiogenesis-related genes remodeling tumor microenvironment and suppressing immunotherapy response in gastric cancer. Gene 2024; 928:148796. [PMID: 39067544 DOI: 10.1016/j.gene.2024.148796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 07/18/2024] [Accepted: 07/22/2024] [Indexed: 07/30/2024]
Abstract
Angiogenesis significantly correlates with tumor microenvironment remodeling and immunotherapy response. Our study aimed to construct a prognostic angiogenesis-related model for gastric cancer. Using public database, a angiogenetic related five-gene (FGF1, GRB14, PAK3, PDGFRA, and PRKD1) model was identified. The top 25 % of patients were defined as high-risk, and the remaining as low-risk. The area under the curve for 1-, 3-, and 5-year overall survival (OS) were 0.646, 0.711, and 0.793, respectively. Survival analysis showed a better 10-year OS in low-risk patients in the construction (HR = 0.57, p = 0.002) and validation cohorts. GO and GSEA revealed that DEGs were enriched in extracellular matrix receptor interactions, dendritic cell antigen processing/presentation regulation, and angiogenesis pathways. CIBERSORT analysis revealed abundant naïve B cells, resting mast cells, resting CD4+ memory T cells, M2 macrophages, and monocytes in high-risk subgroups. The TIMER database showed strong positive correlations between PAK3, FGF1, PRKD1, and PDGFRA expression levels and the infiltration of CD4+ T cells and macrophages. The IOBR analysis revealed an immunosuppressive environment in the high-risk subgroup. Low-risk patients show a higher response rate to anti-PD1 treatment. TMA showed that FGF1 overexpression was associated with poor prognosis and CD4+ T cells and macrophage infiltration. In vivo study based on the 615 mice indicated that inhibiting FGF1 function could suppress tumor growth and enhance anti-PD1 therapeutic efficacy. In summary, we established a five-angiogenesis-related gene model to predict survival outcomes and immunotherapy responses in patients with gastric cancer and identified FGF1 as a prognostic gene and potential target for improving immune treatment.
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Affiliation(s)
- Guiyuan Li
- Department of Oncology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zhe Li
- Department of Liver Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, China
| | - Jing Shen
- Department of Information, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiaolong Ma
- Department of Radiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shaoqiang Zheng
- Department of Radiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yunlu Zheng
- Department of Information, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
| | - KaiMing Cao
- Department of Radiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
| | - Ningxin Dong
- Department of Radiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
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Liu J, Zhang X, Ren Q, Song C, Yu J, Cai Y, Chen D. Negative response to immunotherapy in dMMR or MSI-H gastric cancer with APC and PTEN mutations: a case report. Front Oncol 2024; 14:1484802. [PMID: 39669365 PMCID: PMC11634749 DOI: 10.3389/fonc.2024.1484802] [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: 08/22/2024] [Accepted: 11/11/2024] [Indexed: 12/14/2024] Open
Abstract
Background Microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) represents a distinct molecular phenotype observed in malignant tumors. These tumors typically exhibit high levels of programmed cell death 1 ligand 1 (PD-L1) expression and high tumor mutational burden (TMB), resulting in an enhanced response to immune checkpoint inhibitors (ICI) therapy. The emergence of ICI has transformed the therapeutic strategy of gastric cancer (GC). Immune checkpoint blockade significantly improves the survival of gastric cancer patients, especially those with MSI-H or dMMR. However, it's worth noting that not all patients with MSI-H respond favorably to this treatment. It has been reported that factors such as tumor heterogeneity, alterations in the tumor microenvironment, and aberrant activation of tumor-related signaling pathways have been linked with resistance to ICI therapy. Case presentation Here, we describe a case of dMMR and MSI-H GC with adenomatous polyposis coli (APC) and phosphatase and tensin homolog deleted on chromosome ten (PTEN) mutations that failed to respond to anti-PD-1 combined with anti-HER2 (human epidermal growth factor receptor-2) therapy and chemotherapy. We attempted to elucidate the underlying causes and mechanisms behind this lack of response, and to provide new insights into treatment options for these patients. Conclusions Mutations of key genes within tumor-related signaling pathways and the infiltration of CD8+T cells in the tumor microenvironment may influence the efficacy of immunotherapy for MSI-H solid tumors.
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Affiliation(s)
- Jiang Liu
- *Correspondence: Jiang Liu, ; Dadong Chen,
| | | | | | | | | | | | - Dadong Chen
- Department of Oncology, The Affiliated Xinghua People’s Hospital, Medical School of Yangzhou University, Xinghua, Jiangsu, China
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Li CF, Lian LL, Li QR, Jiao Y. Immunotherapy for metastatic gastric cancer. World J Gastrointest Surg 2024; 16:3408-3412. [PMID: 39649204 PMCID: PMC11622096 DOI: 10.4240/wjgs.v16.i11.3408] [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: 06/17/2024] [Revised: 08/20/2024] [Accepted: 08/26/2024] [Indexed: 10/30/2024] Open
Abstract
This editorial discusses the article written by Chen et al that was published in the latest edition of the World Journal of Gastrointestinal Surgery. The current study found that programmed cell death 1 ligand 1 (PD-L1) expression is considered as one of the pan-cancer biomarkers of immune checkpoint inhibitors (ICIs) treatment response. Four molecular subtypes are widely used to guide and evaluate the prognosis and diagnosis and treatment of gastric cancer (GC) patients. Clinical trials of ICI treatment including Nivolumab, Pembrolizumab, Avelumab have been conducted for metastatic GC (mGC). The effects of various single agent ICIs on mGC therapy varied. ICIs combined with chemotherapy can indeed bring survival benefits to patients with mGC. Combining ICIs with chemotherapy can give more patients the chance of surgery in the treatment of GC transformation. However, not all PD-L1 positive patients can benefit from it. It is urgent to find better biomarkers to predict the response of ICIs for more precise clinical treatment.
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Affiliation(s)
- Chang-Fei Li
- Department of Patient Service Center, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Li-Li Lian
- Department of Neurology, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Qiu-Ru Li
- Department of Neurology, The Second Hospital of Jilin University, Changchun 130000, Jilin Province, China
| | - Yan Jiao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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Hamada Y, Tanoue K, Arigami T, Yamakuchi M, Okawa M, Matsushita D, Takenouchi K, Yamada S, Maywar DN, Nakayama C, Oyama Y, Higashi S, Fujisaki C, Hozaka Y, Kita Y, Hashiguchi T, Ohtsuka T. The Vascular Endothelial Growth Factor-A121/Vascular Endothelial Growth Factor-A165 Ratio as a Predictor of the Therapeutic Response to Immune Checkpoint Inhibitors in Gastric Cancer. Cancers (Basel) 2024; 16:3958. [PMID: 39682145 DOI: 10.3390/cancers16233958] [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: 10/24/2024] [Revised: 11/14/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
BACKGROUND/OBJECTIVES The response rate to immune checkpoint inhibitor (ICI) therapy is limited. Further, there is a need to discover biomarkers to predict therapeutic efficacy. The vascular endothelial growth factor (VEGF) is strongly associated with intra-tumoral immunity; however, its utility as a marker remains unknown. Therefore, our objectives were to examine the isoforms of VEGF and determine whether VEGF levels predict ICI efficacy. METHODS Levels of VEGF isoforms VEGF-A121 and VEGF-A165 were measured in stored serum samples obtained from 30 patients with advanced or recurrent gastric cancer who received nivolumab monotherapy at Kagoshima University Hospital, and the association with prognosis and treatment efficacy was retrospectively analyzed. RESULTS The serum levels of the total VEGF, VEGF-A121, and VEGF-A165 were not significantly associated with prognosis. However, the ratio of VEGF-A121/VEGF-A165 (VEGF-A121/165) exhibited a statistically significant (p = 0.0088) difference in progression-free survival (PFS) with the low-ratio group having a 67-day prolonged median PFS time. Under univariable analysis, only VEGF-A121/165 values exhibited reduced progression-free survival with statistical significance. When comparing treatment responses in the low (n = 15) and high (n = 15) serum VEGF-A-121/165 groups, RECIST evaluation was 3 to 0 for complete response (CR), 2 to 0 for partial response (PR), 3 to 2 for stable disease (SD), and 3 to 10 for progressive disease (PD). Patients with clinically unsettled PR or SD were classified as non-CR/non-PD (4 vs. 3), with a disease control rate of 80% vs. 33%. CONCLUSIONS The serum VEGF-A121/165 ratio may represent a new, easily measured biomarker for predicting the therapeutic response to ICIs.
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Affiliation(s)
- Yuki Hamada
- Department of Digestive Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Kiyonori Tanoue
- Department of Digestive Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Takaaki Arigami
- Department of Digestive Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Munekazu Yamakuchi
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Masashi Okawa
- Department of Cardiovascular and Gastroenterological Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Daisuke Matsushita
- Department of Digestive Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Kazunori Takenouchi
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | | | - Drew N Maywar
- Department of Electrical and Computer Engineering Technology, Rochester Institute of Technology, Rochester, NY 14623, USA
| | - Chieri Nakayama
- Department of Digestive Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Yoko Oyama
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Sadayuki Higashi
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Chieko Fujisaki
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Yuto Hozaka
- Department of Digestive Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Yoshiaki Kita
- Department of Digestive Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Teruto Hashiguchi
- Department of Laboratory and Vascular Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
| | - Takao Ohtsuka
- Department of Digestive Surgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
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50
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McMiller TL, Besharati S, Yarchoan M, Zhu Q, Ünsal-Kaçmaz K, Xu K, Lee J, Bhaijee F, Engle LL, Taube JM, Berger AE, Anders RA, Topalian SL. Immune microenvironment of Epstein-Barr virus (EBV)-negative compared to EBV-associated gastric cancers: implications for immunotherapy. J Immunother Cancer 2024; 12:e010201. [PMID: 39572160 PMCID: PMC11580252 DOI: 10.1136/jitc-2024-010201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 10/29/2024] [Indexed: 11/24/2024] Open
Abstract
BACKGROUND Gastric carcinomas (GC) are aggressive malignancies, and only ~15% of patients respond to anti-programmed cell death (ligand) 1 (PD-(L)1) monotherapy. However, Epstein-Barr virus (EBV)-associated GCs (~5-10% of GCs) often harbor PD-L1 and PD-L2 chromosomal amplifications and robust CD8+ T cell infiltrates, and respond at a high rate to anti-PD-1. The current study compares the tumor immune microenvironments (TiMEs) of EBV+ versus EBV(-) GCs. METHODS Over 1000 cases of primary invasive GCs were screened to identify 25 treatment-naïve specimens for study (11 EBV+, 14 EBV(-)). Quantitative immunohistochemistry (IHC) was conducted for markers of immune cell subsets and co-regulatory molecules. Gene expression profiling (GEP) was performed on RNAs isolated from macrodissected areas of CD3+ T cell infiltrates abutting PD-L1+ stromal/tumor cells, using multiplex quantitative reverse transcriptase PCR for a panel of 122 candidate immune-related genes. RESULTS IHC revealed that 17/25 GCs contained PD-L1+ stromal cells, with no significant difference between EBV+/- specimens; however, only 3/25 specimens (all EBV+) contained PD-L1+ tumor cells. CD8+ T cell densities were higher in EBV+ versus EBV(-) tumors (p=0.044). With GEP normalized to the pan-leukocyte marker PTPRC/CD45, EBV+ GCs overexpressed ITGAE (CD103, marking intraepithelial T cells and a dendritic cell subset) and the interferon-inducible genes CXCL9 and IDO1. In contrast, EBV(-) tumors overexpressed several functionally-related gene groups associated with myeloid cells (CD163, IL1A, NOS2, RIGI), immunosuppressive cytokines/chemokines (CXCL2, CXCR4, IL10, IL32), coinhibitory molecules (HAVCR2/TIM-3 and VSIR/VISTA), and adenosine pathway components (ENTPD1/ CD39 and NT5E/CD73). Notably, compared with EBV+ GCs, EBV(-) GCs also overexpressed components of the cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) pathway associated with cancer-promoting inflammation, including PTGS2/COX-2 (most highly upregulated gene, 32-fold, p=0.005); prostaglandin receptors PTGER1 (EP1; up 21-fold, p=0.015) and PTGER4 (EP4; up twofold, p=0.022); and the major COX-2-inducing cytokine IL1B (up 11-fold, p=0.019). Consistent with these findings, COX-2 protein expression trended higher in EBV(-) versus EBV+ GCs (p=0.068). CONCLUSIONS While certain markers of immunosuppression are found in the GC TiME regardless of EBV status, EBV(-) GCs, which are much more common than EBV+ GCs, overexpress components of the COX-2/PGE2 pathway. These findings provide novel insights into the immune microenvironments of EBV+ and EBV(-) GC, and offer potential targets to overcome resistance to anti-PD-(L)1 therapies.
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Affiliation(s)
- Tracee L McMiller
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Sepideh Besharati
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Mark Yarchoan
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Qingfeng Zhu
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | - Ke Xu
- Bristol Myers Squibb Co, Princeton, New Jersey, USA
| | - Junghwa Lee
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Feriyl Bhaijee
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Logan L Engle
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Janis M Taube
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Alan E Berger
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Robert A Anders
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Suzanne L Topalian
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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