九月，既是盛夏的终曲，又开启了初秋的序幕。学生们满怀憧憬地开启新学期的篇章，而职场人士则步入一个充满挑战的新阶段，准备迎接年终的冲刺。
秋风送爽，丰收在望。在这个收获与启程交织的季节，愿每一位踏上新征程的朋友，都能在秋天这片丰收的土地上，收获属于自己的丰盈果实。
01
J Clin Oncol (IF: 42.1; Q1). 2024 Aug 1:JCO2302626.
doi: 10.1200/JCO.23.02626. Online ahead of print.
2
Signal Transduct Target Ther (IF: 40.8; Q1). 2024 Aug 26;9(1):222.
doi: 10.1038/s41392-024-01932-y.
Abstract
3
J Hematol Oncol (IF: 29.5; Q1). 2024 Aug 9;17(1):65.
doi: 10.1186/s13045-024-01578-x.
Recent developments in immunotherapy for gastrointestinal tract cancers
胃肠道肿瘤免疫治疗的最新进展
Abstract
4
Mol Cancer (IF: 27.7; Q1). 2024 Aug 20;23(1):169.
doi: 10.1186/s12943-024-02085-w.
Implications of PD-L1 expression on the immune microenvironment in HER2-positive gastric cancer
PD-L1表达对HER2阳性胃癌免疫微环境的影响
Abstract
In the KEYNOTE-811 study, anti-HER2 and immunotherapy treatments resulted in longer survival in HER2-positive gastric cancer patients with CPS ≥ 1, whereas CPS < 1 patients lacked notable benefits. We studied this in a real-world cohort of 106 HER2-positive, CPS < 1 patients and found no survival differences between those treated with anti-HER2 therapy alone or with added immunotherapy. Thus, we investigate the tumor microenvironment variations in 160 HER2-positive patients, CPS ≥ 1 cases exhibited elevated spatial effective scores of immune cells, including CD4, CD8 subtypes, and NK cells, compared to CPS < 1. Furthermore, through single-cell sequencing in eight HER2-positive individuals, gene expressions revealed regulation of T-cell co-stimulation in CPS ≥ 1 and IL-1 binding in CPS < 1 cases. Notably, we discovered a CPS < 1 subtype marked by CXCR4+M2 macrophages, associated with poor prognosis, whose proportion and expression were reduced when benefiting from anti-HER2 therapy. These findings suggest CPS ≥ 1 patients, due to their immune microenvironment composition, may respond better to anti-PD-1/PD-L1 therapy.
5
Mol Cancer (IF: 27.7; Q1). 2024 Aug 20;23(1):170.
doi: 10.1186/s12943-024-02084-x.
The role of microRNAs in the gastric cancer tumor microenvironment
microRNA在胃癌肿瘤微环境中的作用
Abstract
Background: Gastric cancer (GC) is one of the deadliest malignant tumors with unknown pathogenesis. Due to its treatment resistance, high recurrence rate, and lack of reliable early detection techniques, a majority of patients have a poor prognosis. Therefore, identifying new tumor biomarkers and therapeutic targets is essential. This review aims to provide fresh insights into enhancing the prognosis of patients with GC by summarizing the processes through which microRNAs (miRNAs) regulate the tumor microenvironment (TME) and highlighting their critical role in the TME.
Main text: A comprehensive literature review was conducted by focusing on the interactions among tumor cells, extracellular matrix, blood vessels, cancer-associated fibroblasts, and immune cells within the GC TME. The role of noncoding RNAs, known as miRNAs, in modulating the TME through various signaling pathways, cytokines, growth factors, and exosomes was specifically examined. Tumor formation, metastasis, and therapy in GC are significantly influenced by interactions within the TME. miRNAs regulate tumor progression by modulating these interactions through multiple signaling pathways, cytokines, growth factors, and exosomes. Dysregulation of miRNAs affects critical cellular processes such as cell proliferation, differentiation, angiogenesis, metastasis, and treatment resistance, contributing to the pathogenesis of GC.
Conclusions: miRNAs play a crucial role in the regulation of the GC TME, influencing tumor progression and patient prognosis. By understanding the mechanisms through which miRNAs control the TME, potential biomarkers and therapeutic targets can be identified to improve the prognosis of patients with GC.
6
Gastroenterology (IF: 25.7; Q1). 2024 Aug 1:S0016-5085(24)05297-1.
doi: 10.1053/j.gastro.2024.07.038. Online ahead of print.
Atlas of metastatic gastric cancer links ferroptosis to disease progression and immunotherapy response
转移性胃癌图谱将铁死亡与疾病进展和免疫治疗的疗效相关联
Abstract
Background & aims: Metastases from gastric adenocarcinoma (GAC) lead to high morbidity and mortality. Developing innovative and effective therapies requires a comprehensive understanding of the tumor and immune biology of advanced GAC. Yet, collecting matched specimens from advanced, treatment-naïve GAC patients poses a significant challenge, limiting the scope of current research, which has predominantly focused on localized tumors. This gap hinders a deeper insight into the metastatic dynamics of GAC.
Methods: We performed in-depth single-cell transcriptome and immune profiling on 68 paired, treatment-naïve, primary-metastatic tumors to delineate alterations in cancer cells and their tumor microenvironment (TME) during metastatic progression. To validate our observations, we conducted comprehensive functional studies both in vitro and in vivo, employing cell lines, multiple PDX and novel mouse models of GAC.
Results: Liver and peritoneal metastases exhibited distinct properties in cancer cells and dynamics of TME phenotypes, supporting the notion that cancer cells and their local TMEs co-evolve at metastatic sites. Our study also revealed differential activation of cancer meta-programs across metastases. We observed evasion of cancer cell ferroptosis via GPX4 upregulation during GAC progression. Conditional depletion of Gpx4 or pharmacological inhibition of ferroptosis resistance significantly attenuated tumor growth and metastatic progression. Additionally, ferroptosis-resensitizing treatments augmented the efficacy of CAR T-cell therapy.
Conclusions: This study represents the largest single-cell dataset of metastatic GACs to date. High-resolution mapping of the molecular and cellular dynamics of GAC metastasis has revealed a rationale for targeting ferroptosis defense in combination with CAR T-cell therapy as a novel therapeutic strategy with potential immense clinical implications.
7
Nat Commun (IF: 14.7; Q1). 2024 Aug 9;15(1):6833.
doi: 10.1038/s41467-024-51271-3.
Clinical outcomes and ctDNA correlates for CAPOX BETR: a phase II trial of capecitabine, oxaliplatin, bevacizumab, trastuzumab in previously untreated advanced HER2+ gastroesophageal adenocarcinoma
CAPOX BETR 的临床结果和 ctDNA 相关性：卡培他滨、奥沙利铂、贝伐珠单抗、曲妥珠单抗治疗既往未经治疗的晚期 HER2+ 胃食管腺癌的 II 期试验
Abstract
Preclinical studies suggest that simultaneous HER2/VEGF blockade may have cooperative effects in gastroesophageal adenocarcinomas. In a single-arm investigator initiated clinical trial for patients with untreated advanced HER2+ gastroesophageal adenocarcinoma, bevacizumab was added to standard of care capecitabine, oxaliplatin, and trastuzumab in 36 patients (NCT01191697). Primary endpoint was objective response rate and secondary endpoints included safety, duration of response, progression free survival, and overall survival. The study met its primary endpoint with an objective response rate of 81% (95% CI 65-92%). Median progression free and overall survival were 14.0 (95% CI, 11.3-36.4) and 23.2 months (95% CI, 16.6-36.4), respectively. The median duration of response was 14.9 months. The regimen was well tolerated without unexpected or severe toxicities. In post-hoc ctDNA analysis, baseline ctDNA features were prognostic: Higher tumor fraction and alternative MAPK drivers portended worse outcomes. ctDNA at resistance identified oncogenic mutations and these were detectable 2-8 cycles prior to radiographic progression. Capecitabine, oxaliplatin, trastuzumab and bevacizumab shows robust clinical activity in HER2+ gastroesophageal adenocarcinoma. Combination of VEGF inhibitors with chemoimmunotherapy and anti-PD1 regimens is warranted.
8
Int J Surg (IF: 12.5; Q1). 2024 Aug 26.
doi: 10.1097/JS9.0000000000002062. Online ahead of print.
Final results of a randomized controlled trial: comparison of the efficacy and safety between totally laparoscopic and laparoscopic-assisted total gastrectomy for advanced siewert III esophagogastric junction cancer and upper and middle third gastric cancer
随机对照试验的最终结果：完全腹腔镜与腹腔镜辅助全胃切除术治疗晚期 Siewert Ⅲ期食管胃连接部癌及上中三分之一胃癌的疗效和安全性比较
Abstract
Background: This study aimed to compare the efficacy and safety of TLTG with the overlap technique to LATG in patients with advanced Siewert III Esophagogastric Junction Cancer and upper and middle third gastric cancer.
Methods: This single-center RCT enrolled 292 patients with the mentioned cancers, randomly assigned to TLTG overlap (n=146) or LATG (n=146) groups. Data on demographics, pathology, intraoperative variables, postoperative complications, recovery parameters, and 3-year survival were collected. Main outcome: postoperative complications within 30 days. Secondary outcomes: 3-year disease-free and overall survival.
Results: TLTG versus LATG: TLTG had shorter incision, faster flatus/defecation, reduced analgesia, less opioid use, and shorter hospital stay. Similar operation time, anastomosis time, blood loss, and lymph node harvest. TLTG had lower overall post-op complication rate (P=0.047), no significant difference in serious complications (P=0.310). Variances in anastomotic stenosis occurrence at 3 months. No rehospitalization or mortality at 30 days. No significant differences in 3-month disease-free survival (P=0.058) or overall survival (P=0.236).
Conclusion: Overlap method for anastomosis in TLTG is safe and feasible for advanced middle-upper-third gastric cancer, with positive short-term outcomes. This technique has potential as the preferred esophagojejunostomy approach in TLTG.
9
Int J Surg (IF: 12.5; Q1). 2024 Aug 22.
doi: 10.1097/JS9.0000000000002056. Online ahead of print.
The safety and efficacy of neoadjuvant PD-1 inhibitor plus chemotherapy for patients with locally advanced gastric cancer: A systematic review and meta-analysis
新辅助PD-1抑制剂联合化疗治疗局部晚期胃癌的安全性和有效性：系统评价与荟萃分析
Abstract
Background: The extensive utilization of immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) has achieved significant advancements in the treatment of diverse solid tumors. The present meta-analysis aims to evaluate the safety and efficacy of neoadjuvant chemotherapy (NCT) plus PD-1 inhibitor for patients with locally advanced gastric cancer (LAGC).
Methods: An electronic search of PubMed, EmBase, and the Cochrane Library was performed to identify the clinical trials of NCT + PD-1 inhibitor vs. NCT in patients with LAGC. The retrieval period extended from the establishment of the corresponding database until April 2024, and meta-analysis was conducted using Stata (version 15) software. Subsequently, direct comparative analysis was used to compare pooled results of neoadjuvant immunochemotherapy (NICT) with NCT.
Results: After screening, 6 phase II/III randomized controlled trials (RCTs) and 9 retrospective studies with 2,953 patients were included. In meta-analysis, NICT group demonstrated a significantly higher rate of pathological complete response (pCR) (P<0.001) and R0 resection (P=0.001), and a lower 2-year recurrence rate (P=0.001) compared to the NCT group. The NICT group, however, exhibited a higher incidence of severe treatment-related adverse events (TRAEs) (P=0.044). Additionally, the NICT and NCT groups exhibited no statistical differences in terms of the number of harvested lymph nodes, the occurrence of total TRAEs and postoperative complications, as well as the duration of postoperative hospitalization.
Conclusions: The combination of PD-1 inhibitor + NCT in LAGC patients enhances the likelihood of achieving radical surgery and improves prognosis, albeit to some extent increasing the risk of severe TRAEs. NICT is anticipated to emerge as the preferred neoadjuvant therapy option for patients diagnosed with LAGC.
10
Clin Nucl Med (IF: 9.6; Q1). 2024 Aug 1. doi:10.1097/RLU.0000000000005394. Online ahead of print.
The Contribution of 68Ga-FAPI-04 PET/CT to Staging and Prognosis in Gastric Cancer
68Ga-FAPI-04 PET/CT对胃癌分期和预后的贡献
Aim: This study aimed to compare the diagnostic capabilities of 18F-FDG PET/CT and 68Ga-FAPI-04 PET/CT imaging in staging gastric carcinoma, exploring the impact of 68Ga-FAPI-04 PET/CT on treatment planning and its prognostic significance.
Methods: The research included 31 patients undergoing staging for gastric cancer, who received both 18F-FDG PET/CT and 68Ga-FAPI-04 PET/CT scans. We compared the SUVmax and SUVmean of the primary tumor and lymph nodes, the count of organ metastases, tumor-to-background ratios, and overall staging accuracy. Additionally, the study evaluated radiological progression-free survival and overall survival rates.
Results: The 68Ga-FAPI-04 PET/CT demonstrated superior efficacy in identifying the primary tumor compared with 18F-FDG PET/CT, particularly in cases of poorly cohesive, signet-ring cell, and mucinous subtypes, with detection rates of 96.7% versus 77.4% (P = 0.006 and P = 0.008, respectively). Analysis of lymph nodes showed a significantly higher detection of positive nodes with 68Ga-FAPI-04 (P = 0.026), although no significant differences were observed in SUVmax and tumor-to-background ratio on a patient basis (P > 0.05). SUVmax and tumor-to-background ratios for peritoneal involvement were notably higher with 68Ga-FAPI-04 PET/CT compared with 18F-FDG PET/CT (P = 0.04 for both). No significant differences were found in the detection of organ metastases and disease stage between the 2 imaging modalities (P > 0.05). Primary tumor uptake did not significantly impact radiological progression-free survival or overall survival in either modality.
Conclusion: 68Ga-FAPI-04 PET/CT imaging surpasses 18F-FDG PET/CT in detecting the primary tumor, especially in poorly cohesive and signet-ring cell gastric cancer types, and offers improved accuracy in disease staging. This indicates its potential to enhance treatment management and prognostic assessment in gastric cancer patients.
11
EMBO Mol Med (IF: 9.0; Q1). 2024 Aug 20.
doi: 10.1038/s44321-024-00120-3. Online ahead of print.
Immunotherapies targeting the oncogenic fusion gene CLDN18-ARHGAP in gastric cancer
针对胃癌致癌融合基因 CLDN18-ARHGAP 的免疫疗法
The CLDN18-ARHGAP fusion gene is an oncogenic driver newly discovered in gastric cancer. It was detected in 9% (8/87) of gastric cancer patients in our center. An immunogenic peptide specifically targeting CLDN18-ARHGAP fusion gene was generated to induce neoantigen-reactive T cells, which was proved to have specific and robust anti-tumor capacity both in in vitro coculture models and in vivo xenograft gastric cancer models. Apart from the immunogenic potential, CLDN18-ARHGAP fusion gene was also found to contribute to immune suppression by inducing a regulatory T (Treg) cell-enriched microenvironment. Mechanistically, gastric cancer cells with CLDN18-ARHGAP fusion activate PI3K/AKT-mTOR-FAS signaling, which enhances free fatty acid production of gastric cancer cells to favor the survival of Treg cells. Furthermore, PI3K inhibition could effectively reverse Treg cells upregulation to enhance anti-tumor cytotoxicity of neoantigen-reactive T cells in vitro and reduce tumor growth in the xenograft gastric cancer model. Our study identified the CLDN18-ARHGAP fusion gene as a critical source of immunogenic neoepitopes, a key regulator of the tumor immune microenvironment, and immunotherapeutic applications specific to this oncogenic fusion.
12
Chin Med J (Engl) (IF: 7.5; Q1). 2024 Aug 2.
doi: 10.1097/CM9.0000000000003232. Online ahead of print.
Feasibility and long-term survival of proximal gastrectomy after neoadjuvant therapy for locally advanced proximal gastric cancer: A propensity-score-matched analysis
局部晚期近端胃癌新辅助治疗后近端胃切除术的可行性和长期生存：倾向得分匹配分析
Background: Neoadjuvant therapy enhances the possibility of achieving radical resection and improves the prognosis for locally advanced gastric cancer (GC). However, there is a lack of evidence regarding the optimal extent of resection for locally advanced proximal GC after neoadjuvant therapy.
Methods: In this study, 330 patients underwent resection in Peking University Cancer Hospital, with curative intent after neoadjuvant therapy for histologically confirmed proximal GC from January 2009 to December 2022. Among them, 45 patients underwent proximal gastrectomy (PG), while 285 underwent total gastrectomy (TG).
Results: In this study, 45 patients underwent proximal gastrectomy (PG), while 285 underwent total gastrectomy (TG). After propensity-score matching, 110 patients (71 TG and 39 PG) were included in the analysis. No significant differences between PG and TG regarding short-term outcomes and long-term prognosis were found. Specifically, PG demonstrated comparable overall survival to TG (P = 0.47). Subgroup analysis revealed that although not statistically significant, PG showed a potential advantage over TG in overall survival for patients with tumor-long diameters less than 4 cm (P = 0.31). However, for those with a long diameter larger than 4 cm, TG had a better survival probability (P = 0.81). No substantial differences were observed in baseline characteristics, surgical safety, postoperative recovery, and postoperative complications.
Conclusion: For locally advanced proximal GC with objective response to neoadjuvant therapy (long diameter <4 cm), PG is an alternative surgical procedure. Further research and prospective studies are warranted to validate these findings and guide clinical decision-making.
13
Chin Med J (Engl) (IF: 7.5; Q1). 2024 Aug 15.
doi: 10.1097/CM9.0000000000003259. Online ahead of print.
Emerging trends in early-onset gastric cancer
早发性胃癌的新趋势
The incidence of early-onset gastric cancer (EOGC) is consistently increasing, and its etiology is notably complex. This increase may be attributed to distinctive factors that differ from those associated with late-onset gastric cancer (LOGC), including genetic predispositions, dietary factors, gastric microbiota dysbiosis, and screening of high-risk cases. These factors collectively contribute to the onset of cancer. EOGC significantly differs from LOGC in terms of clinicopathological and molecular characteristics. Moreover, multiple differences in prognosis and clinical management also exist. This study aimed to systematically review the latest research advancements in the epidemiological characteristics, etiological factors, clinicopathological and molecular features, prognosis, and treatment modalities of EOGC.
14
ESMO Open (IF: 7.1; Q1). 2024 Aug 22;9(9):103679.
doi: 10.1016/j.esmoop.2024.103679. Online ahead of print.
HER2-low gastric cancer: is the subgroup targetable?
HER2 低表达胃癌：该亚组可以靶向治疗吗？
Therapeutic developments in the targeting of human epidermal growth factor receptor 2 (HER2)-expressing gastric cancer have followed the dramatic success of HER2-expressing breast cancer treatment, which has facilitated the expansion of indications for anti-HER2 agents to include not only conventional HER2-positive breast cancer, but also HER2-low and HER2-ultralow subgroups. The targetability of HER2-low gastric cancer, however, has yet to be established. Hence, further studies are needed to comprehensively understand the clinicopathological features, specific gene alterations, and distinct tumor immune microenvironment of HER2-low gastric cancer and compare them with those for HER2-positive or -negative gastric cancer. Antibody-drug conjugates for HER2 play an important role in making HER2-low gastric cancer targetable. In this context, a deeper understanding of the novel anti-HER2 agents, including antibody-drug conjugates, bispecific T-cell engager antibodies, and a combination of these agents, as well as new forms of immunomodulatory agents are also required. Redefining and re-categorizing HER2 status through not only immunohistochemistry/fluorescence in situ hybridization but also evaluating ERRB2 copy number gain or protein overexpression levels measured using DNA or RNA sequencing might be helpful for identifying populations with HER2-expressing tumors who would ideally benefit from anti-HER2 treatment. The current paper reviewed recent clinical trials, focusing particularly on HER2-low gastric cancer together with basic/translational findings, and discuss perspectives on further therapeutic development in the treatment of this distinct subgroup.
15
Mod Pathol (IF: 7.1; Q1). 2024 Aug 2:100589.
doi: 10.1016/j.modpat.2024.100589. Online ahead of print.
Claudin-18.2 immunohistochemical evaluation in gastric and gastroesophageal junction adenocarcinomas to direct targeted therapy: a practical approach
Claudin-18.2 免疫组织化学评估胃和胃食管交界腺癌以指导靶向治疗：一种实用方法
Claudin-18.2 (CLDN18.2) expression evaluated by immunohistochemistry is a new biomarker for gastric and gastroesophageal junction adenocarcinomas that will soon have market authorization for implementation into routine clinical practice. Despite successful testing in the setting of clinical trials, no specific practical testing guidelines have been proposed. Several pre-analytical and analytical variables may interfere with adequate CLDN18.2 staining interpretation, thus this article provides practical guidance on CLDN18.2 testing and scoring in gastric/gastroesophageal junction adenocarcinomas in order to identify patients who may respond to targeted therapy with monoclonal antibodies directed against CLDN18.2. Based on available data, moderate to strong (2+/3+) membrane staining in ≥75% of adenocarcinoma cells is the proposed cut-off for clinical use of the monoclonal antibody anti-CLDN18.2 (zolbetuximab).
16
ESMO Open (IF: 7.1; Q1). 2024 Aug 14;9(8):103663.
doi: 10.1016/j.esmoop.2024.103663. Online ahead of print.
Health-related quality of life in patients with CLDN18.2-positive, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma: results from the SPOTLIGHT and GLOW clinical trials
CLDN18.2 阳性、局部晚期不可切除或转移性胃或胃食管交界腺癌患者的健康相关生活质量：SPOTLIGHT 和 GLOW 临床试验的结果
Background: First-line zolbetuximab plus chemotherapy (SPOTLIGHT, mFOLFOX6; GLOW, CAPOX) significantly improved progression-free survival (PFS) and overall survival (OS) versus placebo plus chemotherapy in patients with human epidermal growth factor receptor 2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors were claudin 18 isoform 2-positive in the phase III SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies. We present patient-reported outcomes (PROs) from these studies.
Materials and methods: Health-related quality of life (HRQoL) was measured in the full analysis sets using the European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients Core Questionnaire (QLQ-C30) and Oesophago-Gastric Module (QLQ-OG25), Global Pain, and 5-level EQ-5D (EQ-5D-5L) questionnaires. Analyses focused on key PRO domains: global health status (GHS)/QoL, physical functioning, abdominal pain and discomfort, and nausea/vomiting. Least squares mean (LSM) changes from baseline and time to first definitive deterioration (TTDD) were evaluated combined across SPOTLIGHT and GLOW and for individual studies. Time to confirmed deterioration (TTCD) was evaluated independently for SPOTLIGHT and GLOW.
Results: The combined analysis set included 1072 patients (zolbetuximab plus chemotherapy, 537; placebo plus chemotherapy, 535). Compliance rates were similar between treatment arms. Similar trends were observed in the zolbetuximab versus placebo arms for LSM changes from baseline in key PRO domains, with no clinically meaningful deterioration. Nausea/vomiting worsened during the first few zolbetuximab cycles but later returned to baseline levels. Overall TTCD and TTDD results were similar between arms in both studies.
Conclusions: Patients in SPOTLIGHT and GLOW maintained measured HRQoL relative to baseline when treated with first-line zolbetuximab added to chemotherapy. Zolbetuximab plus chemotherapy improved PFS and OS without negatively affecting HRQoL in key PRO domains compared with placebo plus chemotherapy.
17
Biomed Pharmacother (IF: 6.9; Q1). 2024 Aug 2:178:117229.
doi: 10.1016/j.biopha.2024.117229. Online ahead of print.
Harnessing cytokines to optimize chimeric antigen receptor-T cell therapy for gastric cancer: Current advances and innovative strategies
利用细胞因子优化胃癌嵌合抗原受体 T 细胞疗法：当前进展和创新策略
Enormous patients with gastric cancer (GC) are insensitive to chemotherapy and targeted therapy without the chance of radical surgery, so immunotherapy may supply a novel choice for them. Chimeric antigen receptor (CAR)-T cell therapy has the advantages of higher specificity, stronger lethality, and longer-lasting efficacy, and it has the potential for GC in the future. However, its application still faces numerous obstacles in terms of accuracy, efficacy, and safety. Cytokines can mediate the migration, proliferation, and survival of immune cells, regulate the duration and strength of immune responses, and are involved in the occurrence of severe side effects in CAR-T cell therapy. The expression levels of specific cytokines are associated with the genesis, invasion, metastasis, and prognosis of GC. Applications of cytokines and their receptors in CAR-T cell therapy have emerged, and various cytokines and their receptors have contributed to improving CAR-T cell anti-tumor capabilities. Large amounts of central cytokines in this therapy include chemokines, interleukins (ILs), transforming growth factor-β (TGF-β), and colony-stimulating factors (CSFs). Meanwhile, researchers have explored the combination therapy in treating GC, and several approaches applied to other malignancies can also be considered as references. Therefore, our review comprehensively outlines the biological functions and clinical significance of cytokines and summarizes current advances and innovative strategies for harnessing cytokines to optimize CAR-T cell therapy for GC.
18
Gastric Cancer (IF: 6.0; Q1). 2024 Aug 20.
doi: 10.1007/s10120-024-01535-0. Online ahead of print.
Nivolumab plus chemotherapy in patients with HER2-negative, previously untreated, unresectable, advanced, or recurrent gastric/gastroesophageal junction cancer: 3-year follow-up of the ATTRACTION-4 randomized, double-blind, placebo-controlled, phase 3 trial
纳武利尤单抗联合化疗治疗 HER2 阴性、既往未经治疗、不可切除、晚期或复发性胃/胃食管交界癌患者：ATTRACTION-4 随机、双盲、安慰剂对照 3 期研究的 3 年随访结果
Background: Nivolumab + chemotherapy is now a standard of care for HER2-negative, previously untreated, unresectable or recurrent gastric/gastroesophageal junction cancer (advanced gastric cancer), but long-term follow-up data of clinical trials are limited.
Methods: ATTRACTON-4 was a phase 3, double-blind, placebo-controlled trial in Japan, South Korea, and Taiwan. Patients were randomized to either nivolumab or placebo, both combined with the physician's choice of SOX (oral S-1 [tegafur-gimeracil-oteracil potassium] + oxaliplatin) or CAPOX (capecitabine + oxaliplatin). We report the primary endpoints-centrally assessed progression-free survival (PFS) and overall survival (OS)-and landmark analyses of OS among patients alive using 3-year follow-up data.
Results: At the cutoff date (May 10, 2021), 17/359 patients in the nivolumab + chemotherapy group and 6/358 in the placebo + chemotherapy group were continuing study treatment. PFS (centrally assessed) was longer in the nivolumab + chemotherapy group (median 10.94 vs. 8.48 months; hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.55-0.82). Although OS did not differ between the two groups (median 17.45 vs. 17.15 months; HR 0.89, 95% CI 0.75-1.05), the landmark analysis of OS, calculating HRs at each landmark time point (every month), was getting numerically better in the nivolumab + chemotherapy group over time. Approximately 80% of patients who achieved complete response in the nivolumab + chemotherapy group were alive at 3 years. No new safety signals or major late-onset select treatment-related adverse events were observed for nivolumab + chemotherapy.
Conclusion: This 3-year follow-up of ATTRACTION-4 confirmed the long-term clinical benefit and manageable safety of nivolumab + chemotherapy in patients with previously untreated advanced gastric cancer.
Trial registration: NCT02746796.
19
Gastric Cancer (IF: 6.0; Q1). 2024 Aug 22.
doi: 10.1007/s10120-024-01546-x. Online ahead of print.
Oncological similarities between large type 3 and type 4 tumors in patients with resectable gastric cancer: a propensity score-matched analysis of a multi-institutional dataset
可切除胃癌患者 3 型和 4 型大肿瘤之间的肿瘤学相似性：多机构数据集的倾向评分匹配分析
Abstract
Background: Large type 3 (diameter ≥ 8 cm) and type 4 gastric cancers have been arbitrarily combined in Japan as a single entity. However, whether these two types are oncologically similar remain unclear. This study aimed to clarify this issue.
Methods: In this retrospective study, we analyzed a database of 3,575 patients from nine institutions who underwent gastrectomy between 2010 and 2014. Using propensity scores to balance significant variables, we compared prognoses and tumor recurrences.
Results: Of patients with clinical T3/T4 who underwent R0 resection, 75 and 73 had large type 3 and 4 tumors, respectively. Patients with type 4 tumors had significantly lower overall survival rates than those of patients with large type 3 tumors (hazard ratio [HR] 1.77; 95% confidence interval [CI] 1.14-2.74). However, among the large type 3 tumors, a remarkable difference in prognosis was observed between the differentiated and undifferentiated histological types. A comparison was made between large type 3 with undifferentiated phenotype and type 4, each with 39 patients after propensity score matching. Outcomes in both groups were similar in terms of overall survival (HR 1.28; 95% CI 0.73-2.25) and relapse-free survival (HR 1.34; 95% CI 0.80-2.27). No statistically significant differences were observed in the incidence of peritoneal recurrence (35.9% vs. 46.1%, P = 0.36) and lymph node recurrence (25.6% vs. 12.8%, P = 0.15).
Conclusions: Large type 3 tumors with undifferentiated phenotype and type 4 tumors were oncologically similar. This subgroup could be considered as a new entity for future clinical trials.
20
Gastric Cancer (IF: 6.0; Q1). 2024 Aug 7.
doi: 10.1007/s10120-024-01542-1. Online ahead of print.
Landscape of homologous recombination deficiency in gastric cancer and clinical implications for first-line chemotherapy
胃癌同源重组缺陷的现状及其对一线化疗的临床意义
Abstract
Background: Homologous recombination deficiency (HRD) is one of the crucial hallmarks of cancer. It is associated with a favorable response to platinum-based chemotherapy. We explored the distinctive clinicopathological features of gastric cancer (GC) with HRD and the clinical significance of HRD in platinum-based first-line chemotherapy for unresectable metastatic GC.
Methods: We enrolled 160 patients with GC in this study. Their tumor samples were subjected to genomic profiling utilizing targeted tumor sequencing. HRD was defined as the presence of alterations in any of 16 HR genes (BARD1, BLM, BRCA1, BRCA2, BRIP1, MRE11A, NBN, PALB2, PARP1, POLD1, RAD50, RAD51, RAD51C, RAD51D, WRN, and XRCC2). The clinicopathological features and treatment outcomes of first-line chemotherapy for unresectable metastatic GC were compared between HRD and non-HRD groups.
Results: Forty-seven patients (29.4%) were classified into the HRD group. This group had a significantly lower proportion of macroscopic type 3 or 4 tumors and higher TMB than the non-HRD group. Among patients who underwent platinum-based first-line chemotherapy, the HRD group had a greater response rate and longer progression-free survival after treatment (median 8.0 months vs. 3.0 months, P = 0.010), with an adjusted hazard ratio of 0.337 (95% confidence interval 0.151-0.753). HRD status was not associated with treatment outcomes in patients who did not undergo platinum-based chemotherapy.
Conclusions: Low proportion of macroscopic type 3 or 4 tumors and a high TMB are distinctive features of GC with HRD. HRD status is a potential predictive marker in platinum-based first-line chemotherapy for unresectable metastatic GC.
21
Gastric Cancer (IF: 6.0; Q1). 2024 Aug 8.
doi: 10.1007/s10120-024-01544-z. Online ahead of print.
Management challenges and the role of adjuvant chemotherapy in remnant gastric cancer: an analysis of 313 patients from the KEGG multicenter observational study
残余胃癌的管理挑战和辅助化疗的作用：KEGG 多中心观察研究中 313 名患者的分析
Abstract
Background: Clinical findings and postoperative follow-up data on remnant gastric cancer (RGC) are limited due to its rarity. Additionally, the preoperative staging, radical surgery, and managing recurrence in RGC present significant clinical challenges.
Methods: We analyzed the clinicopathological findings, adjuvant chemotherapy, and patterns of postoperative recurrence of 313 consecutive patients who underwent curative surgery for RGC at 17 Japanese institutions. This study investigated the optimal management of RGC and the impact of adjuvant chemotherapy (AC) on recurrence-free survival (RFS).
Results: Pathological stages I, II, and III were observed in 55.9% (N = 175), 24.9% (N = 78), and 19.2% (N = 60) of the patients, respectively. The overall concordance rate between clinical and pathological T staging was 58.3%, with a clinical T4 sensitivity of 41.4% for diagnosing pathological T4. During the median follow-up period of 4.6 years, disease recurrence occurred in 24.3% of patients. Most recurrences (over 80%) occurred within 2.5 years, and 96.1% within 5 years after RGC surgery. Peritoneal recurrence was the most common in patients with advanced RGC, accounting for 14.1% in stage II and 28.3% in stage III. Multivariable regression analysis showed that AC was significantly associated with a longer RFS, with a hazard ratio of 0.45 (95% confidence interval: 0.26-0.76).
Conclusions: Our study underscores the importance of early detection, accurate preoperative staging, and postoperative surveillance in managing advanced RGC cases. Despite some limitations, our findings indicate that AC may provide survival benefits comparable to those seen in primary gastric cancer.
22
Cancer Biol Med (IF: 5.6; Q1). 2024 Aug 7:j.issn.2095-3941.2024.0159.
doi: 10.20892/j.issn.2095-3941.2024.0159. Online ahead of print.
Global, regional, and national burden of early-onset gastric cancer
早发性胃癌的全球、地区和国家负担
Abstract
Objective: The burden of gastric cancer (GC) across different age groups needs updating. We determined the GC global, regional, and national burden profiles and changes in incidence for 3 sequential 5-year intervals from 2003 to 2017.
Methods: The latest incidence and mortality estimates of GC from 185 countries and regions were extracted from the GLOBOCAN 2022 database. The 5-year interval age-standardised incidence rates (ASIRs) were evaluated using cancer registry data from volumes X-XII of the Cancer Incidence in Five Continents (CI5). Correlation analysis was used to evaluate the relationship between ASIR or the age-standardised mortality rate (ASMR) and the Human Development Index (HDI).
Results: There was an estimated global 968,000 new GC cases and 660,000 deaths in 2022, with male predominance. GC ASIRs and ASMRs were 9.2 and 6.1 per 100,000 persons, respectively. East Asia had the highest burden, with 53.8% of cases and 48.2% of deaths among all geographic regions. There was a significant correlation between ASIR and HDI. Over three 5-year intervals from 2003 to 2017, the incidence of GC notably decreased in most countries but peaked at 2008-2012 in New Zealand, Turkey, and South Africa. Several countries in Europe, Oceania, and America suggest an increasingly concerning trend among younger individuals, especially females.
Conclusions: GC is a significant health issue, especially among males and in geographic regions with an HDI, such as eastern Asia. While the incidence of GC is decreasing in many countries due to prevention efforts and improved treatments, a rising trend persists among younger individuals. Comprehensive prevention strategies tailored to different age patterns are clearly needed.
23
Crit Rev Oncol Hematol (IF: 5.5; Q1). 2024 Aug 6:202:104470.
doi: 10.1016/j.critrevonc.2024.104470. Online ahead of print.
Genomic biology and therapeutic strategies of liver metastasis from gastric cancer
胃癌肝转移的基因组生物学及治疗策略
Abstract
The liver is a frequent site of metastasis in advanced gastric cancer (GC). Despite significant advancements in diagnostic and therapeutic techniques, the overall survival rate for patients afflicted with gastric cancer liver metastasis (GCLM) remains dismally low. Precision oncology has made significant progress in identifying therapeutic targets and enhancing our understanding of metastasis mechanisms through genome sequencing and molecular characterization. Therefore, it is crucial to have a comprehensive understanding of the various molecular processes involved in GCLM and the fundamental principles of systemic therapy to develop new treatment approaches. This paper aims to review recent findings on the diagnosis, potential biomarkers, and therapies targeting the multiple molecular processes of GCLM, with the goal of improving treatment strategies for patients with GCLM.
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