随着十二月的寒风吹过，我们不由得感慨时光的飞逝，转眼间，我们已经走到了这一年的尾声。愿这个冬日的温暖阳光照亮每个人的心房，让我们的生活如这晴朗的天空般明朗；愿好运时刻相伴，伴随我们一起迈入新的一年。
01
Ann Oncol (IF: 56.7; Q1). 2024 Nov 12:S0923-7534(24)04906-8.
doi: 10.1016/j.annonc.2024.10.829. Online ahead of print.
Adjuvant immunotherapy in patients with resected gastric and oesophagogastric junction cancer following preoperative chemotherapy with high risk for recurrence (ypN+ and/or R1): European Organisation of Research and Treatment of Cancer (EORTC) 1707 VESTIGE study
复发高危（ypN+ 和/或 R1）已切除胃癌和食管胃连接部癌患者术前化疗后辅助免疫治疗：欧洲癌症研究与治疗组织 (EORTC) 1707 VESTIGE 研究
Background: Patients with gastroesophageal adenocarcinoma with tumour-positive lymph nodes (ypN+) or positive surgical margins (R1) following neoadjuvant chemotherapy and resection are at high risk of recurrence. Adjuvant nivolumab is effective in oesophageal/oesophagogastric junction cancer and residual pathological disease following chemoradiation and surgery. Immune checkpoint inhibition has shown efficacy in advanced gastroesophageal cancer. We hypothesised that nivolumab/ipilimumab would be more effective than adjuvant chemotherapy in high-risk (ypN+ and/or R1) patients with gastroesophageal adenocarcinoma following neoadjuvant chemotherapy and resection.
Patients and methods: VESTIGE was an academic international, multicentre, open-label, randomised phase II trial evaluating the efficacy of adjuvant nivolumab/ipilimumab versus chemotherapy in gastroesophageal adenocarcinoma at high risk of recurrence. Patients were randomised 1:1 to receive standard adjuvant chemotherapy (same regimen as neoadjuvant) or nivolumab 3 mg/kg IV every 2 weeks plus ipilimumab 1 mg/kg IV every 6 weeks for 1 year. Key inclusion criteria included ypN+ and/or R1 status after neoadjuvant chemotherapy plus surgery. The primary endpoint was disease-free survival in the intent-to-treat population. Secondary endpoints included overall survival, loco-regional and distant failure rates and safety according to NCI-CTCAE v5.0.
Findings: The independent Data Monitoring Committee reviewed data from 189 of the planned 240 patients in June 2022 and recommended stopping recruitment due to futility. At the time of final analysis, median follow-up was 25.3 months for 195 patients (98 nivolumab/ipilimumab and 97 chemotherapy). Median disease-free survival for the nivolumab/ipilimumab group was 11.4 months (95% confidence interval [CI], 8.4-16.8 months) versus 20.8 months (95% CI, 15.0-29.9 months) for the chemotherapy group, HR 1.55 (95% CI, 1.07- 2.25, one-sided P=0.99). The 12-month disease-free survival rates were 47.1% and 64.0%, respectively. There were no toxicity concerns or excess early discontinuations.
Interpretation: Nivolumab/ipilimumab did not improve disease-free survival compared to chemotherapy in patients with ypN+ and/or R1 gastroesophageal adenocarcinoma following neoadjuvant chemotherapy and surgery.
2
Lancet Oncol (IF: 41.6; Q1). 2024 Nov 15:S1470-2045(24)00580-1.
doi: 10.1016/S1470-2045(24)00580-1. Online ahead of print.
Ramucirumab plus paclitaxel as switch maintenance versus continuation of first-line oxaliplatin-based chemotherapy in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer (ARMANI): a randomised, open-label, multicentre, phase 3 trial
雷莫西尤单抗联合紫杉醇作为 HER2 阴性晚期胃癌或胃食管连接部癌患者的换药维持治疗对比继续一线奥沙利铂为基础的化疗（ARMANI）：一项随机、开放标签、多中心、3 期临床试验
Abstract
Background: Paclitaxel plus ramucirumab is recommended as a second-line treatment regimen in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer. We aimed to assess whether switch maintenance or early second-line therapy with paclitaxel plus ramucirumab improved outcomes compared with continuation of oxaliplatin and fluoropyrimidine doublet chemotherapy as a first-line strategy.
Methods: ARMANI was a multicentre, open-label, randomised, phase 3 trial done in 31 hospitals in Italy. We enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1 and locally advanced unresectable or metastatic HER2-negative gastric or gastro-oesophageal junction cancer, who had disease control after 3 months of FOLFOX (leucovorin, fluorouracil, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin). Patients were randomly assigned (1:1) to either paclitaxel 80 mg/m2 on days 1, 8, and 15 plus ramucirumab at 8 mg/kg on days 1 and 15 every 28 days intravenously (switch maintenance group) or continuation of oxaliplatin-based doublet chemotherapy (FOLFOX or CAPOX) for an additional 12 weeks, followed by fluoropyrimidine monotherapy maintenance (control group). Randomisation was stratified by previous gastrectomy (no vs yes), peritoneal carcinomatosis (yes vs no), and primary tumour location (gastro-oesophageal junction vs gastric). Treatment group allocation was done using a web-based system with a minimisation algorithm implementing a random component. The primary endpoint was progression-free survival, analysed on an intention-to-treat basis. The safety population included patients who received at least one dose of the study treatment. This study is registered with ClinicalTrials.gov, NCT02934464, and is complete.
Findings: Between Jan 1, 2017, and Oct 2, 2023, 280 patients were randomly assigned to receive paclitaxel plus ramucirumab (switch maintenance group; n=144) or to continue FOLFOX or CAPOX (control group; n=136). All patients were White. 180 (64%) of 280 patients were male and 100 (36%) were female. At a median follow-up of 43·7 months (IQR 24·0-57·9), 253 (90%) of 280 patients had a progression-free survival event: 131 (91%) of 144 patients in the switch maintenance group and 122 (90%) of 136 patients in the control group. Median progression-free survival was 6·6 months (95% CI 5·9-7·8) in the switch maintenance group and 3·5 months (2·8-4·2) in the control group (HR 0·61, 95% CI 0·48-0·79; p=0·0002). The assumption of proportional hazards was violated; in an analysis of 24-month restricted mean survival time, restricted mean progression-free survival was 8·8 months (95% CI 7·7-9·9) in the switch maintenance group and 6·1 months (5·0-7·2) in the control group (p=0·0010). The most frequent grade 3-4 treatment-related adverse events were neutropenia (37 [26%] patients in the switch maintenance group vs 13 [10%] patients in the control group), peripheral neuropathy (eight [6%] vs nine [7%]) and arterial hypertension (nine [6%] vs none). Serious adverse events occurred in 28 (20%) of 141 patients in the experimental group and 15 (11%) of 135 patients in the control group; these events were treatment-related in two (1%) patients in the switch maintenance group (pulmonary embolism) and two (1%) patients in the control group (mucositis and anaemia). No treatment-related deaths occurred.
Interpretation: Paclitaxel and ramucirumab switch maintenance could be a potential treatment strategy in patients with advanced HER2-negative gastric or gastro-oesophageal junction cancer who are not eligible for immunotherapy or targeted agents.
3
Signal Transduct Target Ther (IF: 40.8; Q1). 2024 Nov 4;9(1):300.
doi: 10.1038/s41392-024-02006-9.
First-in-human, phase 1 dose-escalation and dose-expansion study of a RET inhibitor SY-5007 in patients with advanced RET-altered solid tumors
RET 抑制剂 SY-5007 在晚期 RET 变异实体瘤患者中的首次人体 1 期剂量递增和剂量扩展研究
Abstract
Oncogenic RET alteration is an important, tissue-agnostic therapeutic target across diverse cancers. We conducted a first-in-human phase 1 study on SY-5007, a potent and selective RET inhibitor, in patients with RET-altered solid tumors. Primary endpoints were safety, maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D). Secondary endpoints included pharmacokinetics and preliminary anti-tumor activity. A total of 122 patients were enrolled (17 in dose-escalation phase and 105 in dose-expansion phase), including 91 with non-small cell lung cancer, 23 with medullary thyroid cancer, 7 with papillary thyroid cancer and 1 with gastric cancer. Treatment-related adverse events (TRAEs) were reported in 96.7% of patients, with the most common grade ≥ 3 TRAEs being hypertension (22.1%), diarrhea (16.4%), hypertriglyceridemia (6.6%), and neutropenia (6.6%). The exposure to SY-5007 was dose proportional. Among the 116 efficacy-evaluable patients, the overall objective response rate (ORR) was 57.8%, with 70.0% in treatment-naïve patients and 51.3% in previously treated patients. The median progression-free survival (PFS) was 21.1 months. Efficacy was observed regardless of tumor types and previous therapies. Biomarker analysis of 61 patients with circulating tumor DNA (ctDNA)-detectable RET alterations showed an ORR of 57.4% and median PFS of 13.8 months. Rapid ctDNA clearance of RET alteration correlated with faster responses and improved outcomes. In relapsed patients, off-target induced resistance was observed in 57.1% (12/21), with no on-target RET alterations identified. In conclusion, SY-5007 was well-tolerated and showed promising efficacy in patients with RET-altered solid tumors. Serial ctDNA monitoring may unveil treatment response and potential resistance mechanisms (NCT05278364).
4
Cancer Discov (IF: 29.7; Q1). 2024 Nov 1;14(11):2051-2054.
doi: 10.1158/2159-8290.CD-24-0835.
Redefining the Gastric Microbes in Promoting Gastric Tumorigenesis: The Rise of the Non-H. pylori Microbiome
重新定义促进胃肿瘤发生的胃微生物：非幽门螺杆菌的兴起
Abstract
Gastric cancer remains one of the top cancers in China compared with Western countries, mainly attributed to the high rates of Helicobacter pylori infection. However, recent discoveries on the non-H. pylori gastric microbiome have led to a paradigm shift in our understanding of microbial risk factors driving gastric cancer, which will impact future screening and prevention strategies.
5
Gut (IF: 23.0; Q1). 2024 Nov 12:gutjnl-2024-333617.
doi: 10.1136/gutjnl-2024-333617. Online ahead of print.
CAF-macrophage crosstalk in tumour microenvironments governs the response to immune checkpoint blockade in gastric cancer peritoneal metastases
肿瘤微环境中的 CAF-巨噬细胞相互作用介导胃癌腹膜转移对免疫检查点阻断的反应
Abstract
Background: Peritoneal metastasis is the most common metastasis pattern of gastric cancer. Patients with gastric cancer peritoneal metastasis (GCPM) have a poor prognosis and respond poorly to conventional treatments. Recently, immune checkpoint blockade (ICB) has demonstrated favourable efficacy in the treatment of GCPM. Stratification of best responders and elucidation of resistance mechanisms of ICB therapies are highly important and remain major clinical challenges.
Design: We performed a phase II trial involving patients with GCPM treated with ICB (sintilimab) combined with chemotherapy. The samples of primary tumours, GCPMs and peripheral blood from patients were collected for single-cell sequencing to comprehensively interpret the tumour microenvironment of GCPM and its impacts on immunotherapy efficacy.
Results: The GCPM ecosystem coordinates a unique immunosuppressive pattern distinct from that of primary GC, which is dominated by a stroma-myeloid niche composed of SPP1+tumour-associated macrophages (TAMs) and Thrombospondin 2 (THBS2)+matrix cancer-associated fibroblasts (mCAFs). Consequently, this stroma-myeloid crosstalk is the major mediator of ICB resistance in patients with GCPM. Mechanistically, the accumulated THBS2+mCAFs facilitate the recruitment of peritoneum-specific tissue-resident macrophages and their transformation into SPP1+TAMs via the complement C3 and its receptor C3a receptor 1 (C3AR1), thereby forming a protumoral stroma-myeloid niche. Blocking the C3-C3AR1 axis disrupts the stroma-myeloid crosstalk and thereby significantly improves the benefits of ICB in in vivo models.
Conclusion: Our findings provide a new molecular portrait of cell compositions associated with ICB resistance in patients with GCPM and aid in the prioritisation of therapeutic candidates to potentiate immunotherapy.
6
JAMA Surg (IF: 15.7; Q1). 2024 Nov 27.
doi: 10.1001/jamasurg.2024.5227. Online ahead of print.
Prophylactic Drain Placement and Postoperative Invasive Procedures After Gastrectomy: The Abdominal Drain After Gastrectomy (ADIGE) Randomized Clinical Trial
胃切除术后预防性引流和术后侵入性手术：胃切除术后腹部引流 (ADIGE) 随机临床研究
Abstract
Importance: Evidence suggests that prophylactic abdominal drainage after gastrectomy for cancer may reduce postoperative morbidity and hospital stay but this evidence comes from small studies with a high risk of bias. Further research is needed to determine whether drains safely meet their primary purpose of identifying and managing postoperative intraperitoneal collections without the need for reoperation or additional percutaneous drainage.
Objective: To determine whether avoiding routine abdominal drainage increased postoperative invasive procedures.
Design, setting, and participants: The Abdominal Drain in Gastrectomy (ADIGE) Trial was a multicenter prospective randomized noninferiority trial. Enrollment spanned from December 2019 to January 2023. Follow-up evaluations were completed at 30 and 90 days. Eleven centers within the Italian Research Group for Gastric Cancer, encompassing both academic medical centers and community hospitals, were included. Patients with gastric cancer undergoing subtotal or total gastrectomy with curative intent were eligible, excluding those younger than 18 years, with serious comorbidities, or undergoing procedure types outside the scope of the study. Of 803 patients assessed for eligibility, 404 were randomized and 390 were included in final analyses.
Interventions: Patients were randomized 1:1 into prophylactic drain or no drain arms.
Main outcomes and measures: The primary end point was a modified intention-to-treat (mITT) analysis measuring reoperation or percutaneous drainage within 30 postoperative days. The null hypothesis was rejected when the 90% CI upper limit of the proportion difference did not exceed 3.56%. The calculated sample size to achieve 80% power with a 10% dropout rate was 404 patients (202 in each group). Surgeons and patients were blinded until gastrointestinal reconstruction.
Results: Of the 404 patients randomized 226 (57.8%) were male; the median (IQR) age was 71 (62-78) years. Intraoperative identification of nonresectable disease occurred in 14 patients, leading to their exclusion from the study, leaving 390 patients. In the mITT analysis, 15 patients (7.7%) in the drain group needed reoperation or percutaneous drainage by postoperative day 30 vs 29 (15%) in the no drain group, favoring the drain group (difference, 7.2%; 90% CI, 2.1-12.4; P = .02). Of note, the difference in the primary composite end point was entirely due to a similar difference in reoperation (5.1% in the drain group vs 12.4% in the no drain group; P = .01). Drain-related complications occurred in 4 patients.
Conclusions and relevance: The findings of this study indicate that refraining from prophylactic drain use after gastrectomy heightened the risk of postoperative invasive procedures, discouraging its avoidance. Future studies identifying high-risk groups could optimize prophylactic drainage decisions.
Trial registration: ClinicalTrials.gov Identifier: NCT04227951.
7
JAMA Surg (IF: 15.7; Q1). 2024 Nov 13:e245077.
doi: 10.1001/jamasurg.2024.5077. Online ahead of print.
Vagus Nerve Preservation for Early Distal Gastric Cancer With Monitoring and Indocyanine Green Labeling: A Randomized Clinical Trial
迷走神经保留治疗早期远端胃癌并进行监测和吲哚菁绿标记：一项随机临床试验
Abstract
Importance: Radical gastric cancer surgery can cause functional and physiological disorders due to the resection of perigastric vagus nerves. Few studies have used intraoperative neurophysiological monitoring and indocyanine green (ICG) labeling to preserve the perigastric vagus nerve and to evaluate the corresponding effects.
Objective: To assess the feasibility and effects of vagus nerve preservation using neurophysiologic monitoring and ICG labeling during laparoscopic distal gastrectomy in patients with early distal gastric cancer.
Design, setting, and participants: This open-label, prospective randomized clinical trial initially enrolled 285 patients with clinical stage cT1N0M0 distal gastric cancer from May 2022 to May 2023. This trial was conducted at Qilu Hospital of Shandong University in Jinan, China, and enrolled patients aged 18 to 80 years with histologically proven gastric adenocarcinoma scheduled for distal gastrectomy. The final follow-up examination was performed May 1, 2024.
Interventions: Eligible participants were randomly assigned 1:1 to vagus nerve preservation distal gastrectomy (VPG) or vagus nerve resection distal gastrectomy (VRG).
Main outcomes and measures: The primary outcome was the incidence of postsurgical gastroparesis. Secondary outcomes included postoperative gallstone formation, quality of life, morbidity, mortality, overall survival, and disease-free survival up to 12 months postoperatively. All analyses were based on both intention-to-treat and per-protocol analyses.
Results: Of 264 patients included in the intention-to-treat analysis, the median (IQR) patient age was 58.0 (52.0-67.0) years, and 67 patients (25.4%) were female. Both the VPG and VRG groups included 132 patients. Postoperative gastroparesis occurred in 1 patient (0.8%) in the VPG group and in 10 patients (7.6%) in the VRG group. Gallstones developed in 0 patients in the VPG group and in 9 patients (6.8%) in the VRG group. As assessed by mean (SD) score on the 30-item European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, the VRG group experienced more nausea and vomiting at 6 months postsurgery (19.38 [7.62]) than the VPG group (17.15 [9.21]) (P = .03) and had significantly higher rates of persistent appetite loss, reflux symptoms, and eating difficulties at both 6 months and 12 months than the VPG group. Differences in postoperative complications and metastasis were not significant.
Conclusions and relevance: Neurophysiologic monitoring and ICG labeling during distal laparoscopic gastrectomy for vagus nerve preservation in patients with early distal gastric cancer are safe and feasible. Preserving the perigastric vagus nerve may retain the function of the remnant stomach and improve quality of life.
Trial registration: Chictr.org.cn Identifier: ChiCTR2200059489.
8
Adv Sci (Weinh) (IF: 14.3; Q1). 2024 Nov 18:e2406276.
doi: 10.1002/advs.202406276. Online ahead of print.
Transcriptomics-Based Liquid Biopsy for Early Detection of Recurrence in Locally Advanced Gastric Cancer
基于转录组学的液体活检用于早期检测局部晚期胃癌复发
Abstract
The study presents a transcriptomics-based liquid biopsy approach for early recurrence detection in locally advanced gastric cancer (LAGC). Four mRNA biomarkers (AGTR1, DNER, EPHA7, and SUSD5) linked to recurrence are identified through transcriptomic data analysis. A Risk Stratification Assessment (RSA) model combining these biomarkers with clinical features showed superior predictive accuracy for postoperative recurrence, with AUCs of 0.919 and 0.935 in surgical and liquid biopsy validation cohorts, respectively. Functional studies using human gastric cancer cell lines AGS and HGC-27 demonstrated that silencing the identified mRNA panel genes impaired cell migration, invasion, and proliferation. In vivo experiments further showed reduced tumor growth, metastasis, and lymphangiogenesis in mice, possibly mediated by the cAMP signaling pathway. This non-invasive approach offers significant potential for enhancing recurrence detection and enabling personalized treatment strategies, thereby improving patient outcomes in the management of LAGC.
9
J Adv Res (IF: 11.4; Q1). 2024 Nov 23:S2090-1232(24)00548-4.
doi: 10.1016/j.jare.2024.11.028. Online ahead of print.
Trends, clinicopathological features, surgical treatment patterns and prognoses of early-onset versus late-onset gastric cancer: A retrospective cohort study
早发与晚发胃癌的趋势、临床病理特征、手术治疗模式和预后：一项回顾性队列研究
Abstract
Introduction: This study investigates the differences between early-onset gastric carcinoma (EOGC) and late-onset gastric carcinoma (LOGC) by examining trends, demographics, clinical and molecular features, treatments, and outcomes at a leading cancer center in China.
Objectives: To delineate the distinctions between EOGC and LOGC in terms of patient characteristics, disease progression, and treatment outcomes, and to suggest appropriate screening strategies.
Methods: We analyzed 18,877 gastric carcinoma cases treated at Fudan University Shanghai Cancer Center (FUSCC) from 2000 to 2022. Descriptive statistics were performed using IBM SPSS. Survival rates were assessed via the Kaplan-Meier method and log-rank test, while COX regression analysis identified factors affecting disease-free survival (DFS) and overall survival (OS).
Results: The average age of gastric cancer diagnosis has increased slightly since 2000, with a steady rise in both EOGC and LOGC cases, though EOGC's proportion has slightly decreased. EOGC had a higher proportion of female patients and was more common in the gastric body and antrum pylorus. EOGC cases showed lower levels of cancer biomarkers, HER2 expression, vascular and lymphatic invasion, and lower differentiation and invasion depth. They also exhibited more advanced N and TNM staging, Borrmann IV type, and low adhesive carcinoma. EOGC underwent more extensive D2 lymphadenectomy and neoadjuvant chemotherapy. There were no significant differences in Claudin18.2 and MMR protein status between EOGC and LOGC. EOGC had higher rates of ovarian and peritoneal metastases, with a better early prognosis but faster late-stage progression.
Conclusion: EOGC and LOGC cases have increased over the past two decades. EOGC presents unique clinical and pathological features, requiring thorough surgical treatment and has a better early prognosis but more rapid late-stage progression. Enhanced screening for younger adults is recommended to address the rising EOGC trend.
10
J Immunother Cancer (IF: 10.3; Q1). 2024 Nov 20;12(11):e010201.
doi: 10.1136/jitc-2024-010201.
Immune microenvironment of Epstein-Barr virus (EBV)-negative compared to EBV-associated gastric cancers: implications for immunotherapy
EBV 相关胃癌与 EBV 阴性胃癌的免疫微环境比较：对免疫治疗的意义
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.
11
J Immunother Cancer (IF: 10.3; Q1). 2024 Nov 3;12(11):e010174.
doi: 10.1136/jitc-2024-010174.
Myeloid subsets impede the efficacy of anti-PD1 therapy in patients with advanced gastric cancer (WJOG10417GTR study)
髓样亚群阻碍晚期胃癌患者抗 PD1 治疗的疗效（WJOG10417GTR 研究）
Background: Gastric cancer (GC) is one of the most common and deadly malignant diseases worldwide. Despite revolutionary advances, the therapeutic efficacy of anti-PD1/PDL1 monoclonal antibodies in advanced GC is still low due to the emergence of innate and acquired resistance to treatment. Myeloid cells represent the majority of human immune cells. Therefore, their increase, decrease, and abnormality could have a significant impact on the patient's immune system and the progression of cancer, and reprogramming, inhibiting, and eliminating the tumor-supportive types may improve the immunological situation and efficacy of immunotherapy. However, the significance of myeloid cells in anti-PD1/PDL1 therapy remains unclear in GC. In the WJOG10417GTR study on GC, we sought to identify myeloid determinants that could predict anti-PD1 therapeutic efficacy and also serve as potential therapeutic targets.
Methods: We collected tumor tissues and peripheral blood from 96 patients with advanced GC before and 1 month after anti-PD1 nivolumab monotherapy, and the isolated whole leucocytes were analyzed by flow cytometry for various immune cell populations, including many myeloid subsets. Then, the relationship between the cellular levels and progression-free survival (PFS) or overall survival (OS) was statistically analyzed.
Results: We found that high levels of several myeloid subsets expressing molecules that have been targeted in drug discovery but not yet approved for clinical use were significantly associated with shorter PFS/OS as compared with low levels: PDL1+ and CTLA4+ myeloid subsets within tumors at baseline, PDL1+, B7H3+ and CD115+ myeloid subsets in peripheral blood at baseline, and LAG3+, CD155+ and CD115+ myeloid subsets in peripheral blood at post-treatment.
Conclusions: This study revealed that these myeloid subsets are significant risk factors in nivolumab therapy for advanced GC. Targeting them may be useful as diagnostic biomarkers to predict potential anti-PD1 therapeutic efficacy, and also as therapeutic targets for accelerating the development of new drugs to improve clinical outcomes in immunotherapy for GC.
12
Clin Cancer Res (IF: 10.0; Q1). 2024 Nov 4.
doi: 10.1158/1078-0432.CCR-24-2436. Online ahead of print.
Intestinal subtype as a biomarker of response to neoadjuvant immunochemotherapy in locally advanced gastric adenocarcinoma: insights from a prospective phase II trial
肠型亚型作为新辅助免疫化疗治疗局部晚期胃腺癌疗效的生物标志物：来自前瞻性 II 期试验的见解
Purpose: Neoadjuvant immunochemotherapy (NAIC) markedly induces pathologic regression in locally advanced gastric adenocarcinoma (GAC). 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 GAC with NAIC (NCT05515796). Correlation between clinicopathological characteristics and neoadjuvant efficacy was investigated. Bulk RNA-seq data from 104 samples (from 75 patients in two independent cohorts) and scRNA-seq data from 105 treatment-naïve GACs were comprehensively analyzed to decipher the association of epithelial and microenvironmental characteristics and clinical responses.
Results: The pre-specified primary endpoints were achieved: pathological complete regression (pathCR) rate was 30%, major pathological regression (MPR) rate was 43%, while the regimen was well tolerated. Analysis of baseline clinical-pathological 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 (DDR)-active cancer cells and enrichment of CLEC9A+ dendritic cells (DCs) in the tumor microenvironment were associated with enhanced responsiveness of the intestinal subtype GAC 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 DDR-active cancer cells and CLEC9A+ DCs, which accurately predicted the efficacy of NAIC in multiple independent GAC cohorts.
Conclusions: Intestinal subtype is a histological biomarker of enhanced sensitivity of GAC to NAIC. The Intestinal-subtype specific signature model is applicable to guide NAIC for patients with locally advanced GAC.
13
Eur J Cancer (IF: 7.6; Q1). 2024 Nov 20:214:115137.
doi: 10.1016/j.ejca.2024.115137. Online ahead of print.
Patient access to perioperative chemotherapy with fluorouracil, leucovorin, oxaliplatin and docetaxel in patients with resectable gastric cancer in the Netherlands
荷兰可切除胃癌患者围手术期接受氟尿嘧啶、亚叶酸钙、奥沙利铂和多西他赛化疗的情况
Background: The FLOT4 trial demonstrated superior survival of perioperative chemotherapy with 5-fluorouracil, oxaliplatin, and docetaxel (FLOT) compared to anthracycline triplets for resectable gastric cancer. These results were presented at the American Society of Clinical Oncology (ASCO) congress in June 2017 and published in April 2019. However, adoption of novel treatments in clinical practice often encounters delays. This study assesses the patterns of perioperative chemotherapy utilization and FLOT uptake in clinical practice within the Netherlands.
Materials and methods: A retrospective cohort study was conducted with resectable gastric cancer patients (cT1-4a,XcNallcM0) between 2015-2020 from the Netherlands Cancer Registry. Descriptive statistics, Cochran-Armitage tests, Fisher's exact or unpaired T-tests, and Jonckheere-Terpstra tests were used to analyze chemotherapy trends and FLOT uptake across hospitals.
Results: Among 3290 included patients, 42.9 % received neoadjuvant treatment. In 2015, 43.6 % of patients received perioperative chemotherapy versus 43.5 % in 2020 (p = 0.63). 40 out of 62 hospitals (64.5 %) adopted FLOT between the ASCO presentation and the full publication. FLOT increased from 42.9 % before publication to 86.8 % after publication (p < 0.0001), while anthracycline triplet use decreased to 0.9 % (p < 0.0001). Higher hospital volume was associated with fewer days to adoption (p = 0.04) but not with adoption of FLOT before publication (p = 0.14).
Conclusion: Timing of FLOT adoption varied among Dutch hospitals, leading to unequal patient access to effective treatments. Establishing (inter)national guidelines on provisional treatment adjustment pending publication is crucial to reduce variation in access. Moreover, rapid publication of final trial results is imperative to reduce variation in practice and ensure fair patient treatment.
14
Acta Pharmacol Sin (IF: 6.9; Q1). 2024 Nov 26.
doi: 10.1038/s41401-024-01414-5. Online ahead of print.
The novel BCL-2/BCL-XL inhibitor APG-1252-mediated cleavage of GSDME enhances the antitumor efficacy of HER2-targeted therapy in HER2-positive gastric cancer
新型 BCL-2/BCL-XL 抑制剂 APG-1252 介导的 GSDME 裂解增强了 HER2 阳性胃癌中 HER2 靶向治疗的抗肿瘤疗效
HER2-positive gastric cancer has a poor prognosis, with a high incidence of drug resistance and a lack of effective treatments for drug-resistant patients. The exploration of the mechanism of resistance to HER2-targeted therapy in HER2-positive gastric cancer and the identification of effective strategies to reverse it are urgently needed. In this study, we found that HER2-targeted agents upregulated the expression of GSDME and that the overexpression of GSDME attenuated the sensitivity of HER2-targeted agents. Furthermore, we observed that the BCL-2/BCL-XL inhibitor APG-1252 plus lapatinib promoted GSDME-mediated pyroptosis and exhibited remarkable antitumor activity both in vitro and in vivo. Mechanistically, APG-1252 combined with lapatinib synergistically induced GSDME-mediated pyroptosis in HER2-positive gastric cancer by activating caspase-dependent pathways and blocking the phospho-AKT/GSK-3β/MCL-1 signaling pathway. Our data indicated that the combination of lapatinib and APG-1252 had a synergistic antitumor effect on HER2-positive gastric cancer through the induction of caspase-3/GSDME-mediated apoptosis and pyroptosis.
15
J Gastroenterol (IF: 6.9; Q1). 2024 Nov 21.
doi: 10.1007/s00535-024-02170-3. Online ahead of print.
The landscape of 142 Epstein-Barr viral whole genomes in gastric cancer
胃癌中 142 个 Epstein-Barr 病毒全基因组概况
Background: A substantial portion of gastric cancer (GC) is linked to Epstein-Barr virus (EBV) infection. The characteristics of this viral genome, such as specific viral strains and large structural variations, influence the progression of diseases like nasopharyngeal carcinoma and hematological malignancy. However, the EBV genomes from GC have not been thoroughly characterized.
Methods: Our study involved 849 consecutive GC patients diagnosed at Nagoya City University Hospital, Japan (NCU cohort). We detected EBV from formalin-fixed, paraffin-embedded sections using a novel direct PCR-based rapid detection method. Additionally, we analyzed 142 EBV whole genomes (125 newly sequenced) from GC, comparing them with 205 genomes from other EBV-associated diseases.
Results: We identified 32 (3.8%) patients associated with EBVaGC in the NCU cohort. Moreover, the direct PCR identified several GC specimens containing EBV-infected lymphocytes or their follicles. The dominant viral strain in GC was type 1 EBV, prevalent in most parts of the world, and no GC-specific strain was identified. We found no significant associations between single-nucleotide variants in the viral genome and GC. Structural variations of the EBV genome were infrequent in GC (4 cases, 2.1%), contrasting with EBV-associated hematological malignancy, which frequently carries large deletions.
Conclusions: This study is the first to uncover the genomic variations of EBV in GC. While EBV is definitively linked to GC, the characteristics of its genomes do not strongly correlate with disease development or progression. Our findings on viral genomes supplement the current understanding of human genomes in EBVaGC.
16
Gastric Cancer (IF: 6.0; Q1). 2024 Nov 2.
doi: 10.1007/s10120-024-01560-z. Online ahead of print.
Prognostic and predictive factors for the efficacy and safety of trastuzumab deruxtecan in HER2-positive gastric or gastroesophageal junction cancer
德曲妥珠单抗在 HER2 阳性胃癌或胃食管交界癌中的疗效和安全性的预后和预测因素
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.
17
Gastric Cancer (IF: 6.0; Q1). 2024 Nov 5.
doi: 10.1007/s10120-024-01561-y. Online ahead of print.
Morbidity and quality of life of totally laparoscopic versus laparoscopy-assisted distal gastrectomy for early gastric cancer: a multi-center prospective randomized controlled trial (CKLASS01)
比较全腹腔镜与腹腔镜辅助远端胃切除术治疗早期胃癌的并发症和生活质量：一项多中心前瞻性随机对照试验（CKLASS01）
Background: There is a paucity of confirmatory randomized controlled trials (RCTs) comparing the effectiveness of totally laparoscopic distal gastrectomy (TLDG) vs laparoscopy-assisted distal gastrectomy (LADG) for early gastric cancer (EGC).
Methods: A phase III, prospective, multi-center RCT was conducted, wherein patients (n = 442) with clinical stage I gastric cancer eligible for laparoscopic distal gastrectomy were randomized 1:1 to the TLDG or the LADG group. Postoperative morbidity and quality of life (QoL) were compared.
Results: In total, 422 patients were assessed (TLDG, 216; LADG, 206) in the modified intention-to-treat (mITT) analysis. The morbidity rate did not differ significantly between the two groups (TLDG, 6.0%; LADG, 5.8%; P = 0.93). The 90-day mortality rate was comparable between the groups (TLDG, 0.5%; LADG, 0.0%; P > 0.99). TLDG was significantly associated with a lower pain score compared with LADG in patients with a BMI of ≥ 25 kg/m2 (P = 0.002) at 24 h postoperatively. Moreover, TLDG significantly improved QoL in terms of C30 social functioning at 3 and 6 months (P = 0.03 and P = 0.04), C30 global health status at 3 months (P = 0.02), and STO22 body image at 3 months (P = 0.01), with differences dissipating at 12 months.
Conclusions: TLDG is not superior to LADG in terms of postoperative morbidity and mortality, but it provides better C30 social functioning at 3 and 6 months, C30 global health status and STO22 body image at 3 months, and reduces early postoperative pain for patients with a BMI of ≥ 25 kg/m2.
Trial registration: ClinicalTrials.gov: NCT03393182.
18
Cancer Cell Int (IF: 5.3; Q1). 2024 Nov 15;24(1):380.
doi: 10.1186/s12935-024-03553-5.
Expression of HECTD2 predicts peritoneal metastasis of gastric cancer and reconstructs immune microenvironment
HECTD2表达预测胃癌腹膜转移并重建免疫微环境
Peritoneal metastasis (PM) is a common metastasis site and death cause of gastric cancer, which is a complex biological process, but there is currently a lack of effective prediction and treatment targets. In this study, we first analyzed the differential gene expression of gastric cancer patients with or without peritoneal metastasis, and identified the HECT domain E3 ubiquitin protein ligase 2 (HECTD2) as the core gene of PM in gastric cancer. The current study shows that the role of HECTD2 in tumor is contradictory. In this study, our results show that the low expression of HECTD2 indicates that the survival rate of overall survival (OS), progression-free survival (PFS), disease-specific survival (DSS), and disease-free survival (DFS) are better, and can be used as an important component of prognostic indicators. In addition, through pathway enrichment analysis, we found that HECTD2 was mainly involved in metastasis related pathways such as extracellular matrix remodeling and cell adhesion in gastric cancer, and high expression of HECTD2 could activate epithelial-mesenchymal transition (EMT) metastasis related pathways in gastric cancer. In regulating the metastasis of gastric cancer cells, HECTD2 can also change the surrounding microenvironment, induce the enrichment of interstitial components and build an immune microenvironment conducive to tumor progression, while patients with low expression of HECTD2 may be more likely to benefit from immunotherapy. In conclusion, HECTD2 may be a novel biomarker for the diagnosis and prognosis of peritoneal metastasis of gastric cancer, providing basis for the mechanism of peritoneal metastasis of cancer and clinical medication.
19
Cell Biol Toxicol (IF: 5.3; Q1). 2024 Nov 20;40(1):101.
doi: 10.1007/s10565-024-09943-9.
Advancing gastric cancer treatment: nanotechnology innovations and future prospects
推进胃癌治疗：纳米技术创新和未来前景
Gastric cancer (GC) is the fifth most common cancer worldwide, particularly prevalent in Asia, especially in China, where both its incidence and mortality rates are significantly high. Meanwhile, nanotechnology has demonstrated great potential in the treatment of GC. In particular, nanodrug delivery systems have improved therapeutic efficacy and targeting through various functional modifications, such as targeting peptides, tumor microenvironment responsiveness, and instrument-based methods. For instance, silica (SiO2) has excellent biocompatibility and can be used as a drug carrier, with its porous structure enhancing drug loading capacity. Polymer nanoparticles regulate drug release rates and mechanisms by altering material composition and preparation methods. Lipid nanoparticles efficiently encapsulate hydrophilic drugs and promote cellular uptake, while carbon-based nanoparticles can be used in biosensors and drug delivery. Targets such as integrins, HER2 receptors, and the tumor microenvironment have been used to improve drug efficacy in GC treatment. Nanodrug delivery techniques not only enhance drug efficacy and delivery capabilities but also selectively target tumor cells. Currently, there is a lack of systematic summarization and synthesis regarding the relationship between nanodrug delivery systems and GC treatment, which to some extent hinders researchers and clinicians from efficiently searching for and referencing related studies, thereby reducing work efficiency. This study aims to systematically summarize the existing research on the relationship between nanodrug delivery systems and GC treatment, making it easier for professionals to search and reference, and thereby promoting further research on the role of nanodrug delivery systems and their clinical applications in GC. This review discusses the applications of functionalized nanocarriers in the treatment of GC in recent years, including surface modifications with targeted markers, the combination of phototherapy, chemotherapy, and immunotherapy, along with their advantages and challenges. It also examines the future prospects of targeted nanomaterials in GC treatment. The review particularly focuses on the combined application of nanocarriers in multiple treatment modalities, such as phototherapy, chemotherapy, and immunotherapy, demonstrating their potential in multimodal treatments. Furthermore, it thoroughly explores the specific challenges that nanocarriers face in GC treatment, such as biocompatibility, drug release control, and clinical translation issues, while providing a systematic outlook on future developments. Additionally, this study emphasizes the potential value and feasibility of nanocarriers in clinical applications, contrasting with most reviews that focus on basic research. Through these innovations, we offer new perspectives and directions for the development of nanotechnology in the treatment of GC.
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