跨越新元 奔赴新愿
HAPPY NEW YEAY
01
Ann Oncol (IF: 56.7; Q1). 2024 Dec 3:S0923-7534(24)04953-6.
doi: 10.1016/j.annonc.2024.11.016. Online ahead of print.
Tremelimumab and durvalumab as neoadjuvant or non-operative management strategy of patients with microsatellite instability-high resectable gastric or gastroesophageal junction adenocarcinoma: the INFINITY study by GONO
Tremelimumab 和 durvalumab 作为微卫星高度不稳定的可切除胃或胃食管连接部腺癌患者的新辅助或非手术治疗策略：GONO 的 INFINITY 研究
Background: In resectable gastric/gastroesophageal junction adenocarcinoma (GAC/GEJAC), microsatellite instability (MSI-H) confers improved survival, but limited benefit from chemotherapy. Immunotherapy may eliminate the need of chemotherapy or surgery.
Patients and methods: INFINITY is a multicentre, multicohort phase II trial (NCT04817826) investigating in Cohort 1 the activity and safety of tremelimumab+durvalumab (T300/D) as neoadjuvant treatment for dMMR/MSI-H, resectable GAC/GEJAC. Primary endpoint was pathologic complete response (pCR) rate; Secondary endpoints: progression-free survival (PFS), overall survival (OS), quality of life (QoL), and translational analyses. In Cohort 2, the activity and safety of T300/D was explored as definitive treatment in patients achieving clinical complete response (cCR). Primary endpoint was 2-year cCR rate, Secondary endpoints: PFS, OS, QoL, gastrectomy-free survival (GFS) and translational analyses.
Results: In Cohort 1, 18 patients were recruited and 15 evaluable. pCR and major-complete pathological response were 60% and 80%. Since pCR rate in T4 tumors was 17%, this subgroup of patients was excluded from enrollment in Cohort 2. At 28.1 months median follow-up, 24-month GC-specific PFS and OS rates were 85% and 92%. In Cohort 2, 18 patients were enrolled and 17 evaluable, 13 had cCR and started non-operative management (NOM). At 11.5 months median follow up, 1 patient had local regrowth and underwent salvage surgery, 12-month GFS was 64.2%.
Conclusions: The INFINITY study provided promising activity results of a chemo-free T300/D combination regimen as pre-operative treatment in dMMR/MSI GAC/GEJAC and the first available feasibility results of a NOM strategy in this disease setting, worth of further validation in larger cohorts.
02
Mol Cancer (IF: 27.7; Q1). 2024 Dec 30;23(1):284.
doi: 10.1186/s12943-024-02196-4.
Transcriptional landscape and predictive potential of long noncoding RNAs in peritoneal recurrence of gastric cancer
长链非编码 RNA 在胃癌腹膜复发中的转录图谱和预测潜力
Background: Long noncoding RNAs (lncRNAs) play a critical role in gastric cancer (GC) progression and metastasis. However, research comprehensively exploring tissue-derived lncRNAs for predicting peritoneal recurrence in patients with GC remains limited. This study aims to investigate the transcriptional landscape of lncRNAs in GC with peritoneal metastasis (PM) and to develop an integrated lncRNA-based score to predict peritoneal recurrence in patients with GC after radical gastrectomy.
Methods: We analyzed the transcriptome profile of lncRNAs in paired peritoneal, primary gastric tumor, and normal tissue specimens from 12 patients with GC in the Sun Yat-sen University Cancer Center (SYSUCC) discovery cohort. Key lncRNAs were identified via interactive analysis with the TCGA database and SYSUCC validation cohort. A score model was constructed using the LASSO regression model and nomogram COX regression and evaluated using receiver operating characteristic curves. The role of lncRNAs in the PM of GC was then examined through wound healing, Transwell, 3D multicellular tumor spheroid invasion, and peritoneal cavity xenograft tumorigenicity assays in mice.
Result: Five essential lncRNAs were screened and incorporated into the PM risk score to predict peritoneal recurrence-free survival (pRFS). We developed a comprehensive, integrated nomogram score, including the PM risk score, pT, pN, and tumor size, which could effectively predict the 5-year pRFS with an Area under the curve of 0.79 (95% CI: 0.71-0.88). Subsequently, we demonstrated that one of these lncRNAs, CASC15, promoted the invasion and migration of GC cells in vitro and facilitated the PM of GC cells in vivo, initially verifying that lncRNAs contribute to the PM of GC. Mechanistic analysis demonstrated that CASC15 promoted EMT and metastasis by activating the JNK and p38 pathways.
Conclusion: A lncRNA-based integrated score was constructed in this study to predict peritoneal recurrence in patients clinically.
03
Gastroenterology (IF: 25.7; Q1). 2024 Dec 23:S0016-5085(24)05663-4.
doi: 10.1053/j.gastro.2024.11.001. Online ahead of print.
AGA Clinical Practice Update on Screening and Surveillance in Individuals at Increased Risk for Gastric Cancer in the United States: Expert Review
AGA 临床实践更新，美国胃癌高危人群筛查和监测：专家评审
Description: Gastric cancer (GC) is a leading cause of preventable cancer and mortality in certain US populations. The most impactful way to reduce GC mortality is via primary prevention, namely Helicobacter pylori eradication, and secondary prevention, namely endoscopic screening and surveillance of precancerous conditions, such as gastric intestinal metaplasia (GIM). An emerging body of evidence supports the possible impact of these strategies on GC incidence and mortality in identifiable high-risk populations in the United States. Accordingly, the primary objective of this American Gastroenterological Association (AGA) Clinical Practice Update (CPU) Expert Review is to provide best practice advice for primary and secondary prevention of GC in the context of current clinical practice and evidence in the United States.
Methods: This CPU Expert Review was commissioned and approved by the AGA Institute CPU Committee and the AGA Governing Board to provide timely guidance on a topic of high clinical importance to the AGA membership, and underwent internal peer review by the CPU Committee and external peer review through standard procedures of Gastroenterology. These best practice advice statements were drawn from a review of the published literature and expert opinion. Because systematic reviews were not performed, these best practice advice statements do not carry formal ratings regarding the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: There are identifiable high-risk groups in the United States who should be considered for GC screening. These include first-generation immigrants from high-incidence GC regions and possibly other non-White racial and ethnic groups, those with a family history of GC in a first-degree relative, and individuals with certain hereditary gastrointestinal polyposis or hereditary cancer syndromes. BEST PRACTICE ADVICE 2: Endoscopy is the best test for screening or surveillance in individuals at increased risk for GC. Endoscopy enables direct visualization to endoscopically stage the mucosa and identify areas concerning for neoplasia, as well as enables biopsies for further histologic examination and mucosal staging. Both endoscopic and histologic staging are key for risk stratification and determining whether ongoing surveillance is indicated and at what interval. BEST PRACTICE ADVICE 3: High-quality upper endoscopy for the detection of premalignant and malignant gastric lesions should include the use of a high-definition white-light endoscopy system with image enhancement, gastric mucosal cleansing, and insufflation to achieve optimal mucosal visualization, in addition to adequate visual inspection time, photodocumentation, and use of a systematic biopsy protocol for mucosal staging when appropriate. BEST PRACTICE ADVICE 4: H pylori eradication is essential and serves as an adjunct to endoscopic screening and surveillance for primary and secondary prevention of GC. Opportunistic screening for H pylori infection should be considered in individuals deemed to be at increased risk for GC (refer to Best Practice Advice 1). Screening for H pylori infection in adult household members of individuals who test positive for H pylori (so-called "familial-based testing") should also be considered. BEST PRACTICE ADVICE 5: In individuals with suspected gastric atrophy with or without intestinal metaplasia, gastric biopsies should be obtained according to a systematic protocol (eg, updated Sydney System) to enable histologic confirmation and staging. A minimum of 5 total biopsies should be obtained, with samples from the antrum/incisura and corpus placed in separately labeled jars (eg, jar 1, "antrum/incisura" and jar 2, "corpus"). Any suspicious areas should be described and biopsied separately. BEST PRACTICE ADVICE 6: GIM and dysplasia are endoscopically detectable. However, these findings often go undiagnosed when endoscopists are unfamiliar with the characteristic visual features; accordingly, there is an unmet need for improved training, especially in the United States. Artificial intelligence tools appear promising for the detection of early gastric neoplasia in the adequately visualized stomach, but data are too preliminary to recommend routine use. BEST PRACTICE ADVICE 7: Endoscopists should work with their local pathologists to achieve consensus for consistent documentation of histologic risk-stratification parameters when atrophic gastritis with or without metaplasia is diagnosed. At a minimum, the presence or absence of H pylori infection, severity of atrophy and/or metaplasia, and histologic subtyping of GIM, if applicable, should be documented to inform clinical decision making. BEST PRACTICE ADVICE 8: If the index screening endoscopy performed in an individual at increased risk for GC (refer to Best Practice Advice 1) does not identify atrophy, GIM, or neoplasia, then the decision to continue screening should be based on that individual's risk factors and preferences. If the individual has a family history of GC or multiple risk factors for GC, then ongoing screening should be considered. The optimal screening intervals in such scenarios are not well defined. BEST PRACTICE ADVICE 9: Endoscopists should ensure that all individuals with confirmed gastric atrophy with or without GIM undergo risk stratification. Individuals with severe atrophic gastritis and/or multifocal or incomplete GIM are likely to benefit from endoscopic surveillance, particularly if they have other risk factors for GC (eg, family history). Endoscopic surveillance should be considered every 3 years; however, intervals are not well defined and shorter intervals may be advisable in those with multiple risk factors, such as severe GIM that is anatomically extensive. BEST PRACTICE ADVICE 10: Indefinite and low-grade dysplasia can be difficult to reproducibly identify by endoscopy and accurately diagnose on histopathology. Accordingly, all dysplasia should be confirmed by an experienced gastrointestinal pathologist, and clinicians should refer patients with visible or nonvisible dysplasia to an endoscopist or center with expertise in the diagnosis and management of gastric neoplasia. Individuals with indefinite or low-grade dysplasia who are infected with H pylori should be treated and have eradication confirmed, followed by repeat endoscopy and biopsies by an experienced endoscopist, as visual and histologic discernment may improve once inflammation subsides. BEST PRACTICE ADVICE 11: Individuals with suspected high-grade dysplasia or early GC should undergo endoscopic submucosal dissection with the goal of en bloc, R0 resection to enable accurate pathologic staging with curative intent. Eradication of active H pylori infection is essential, but should not delay endoscopic intervention. Endoscopic submucosal dissection should be performed at a center with endoscopic and pathologic expertise. BEST PRACTICE ADVICE 12: Individuals with a history of successfully resected gastric dysplasia or cancer require ongoing endoscopic surveillance. Suggested surveillance intervals exist, but additional data are required to refine surveillance recommendations, particularly in the United States. BEST PRACTICE ADVICE 13: Type I gastric carcinoids in individuals with atrophic gastritis are typically indolent, especially if <1 cm. Endoscopists may consider resecting gastric carcinoids <1 cm and should endoscopically resect lesions measuring 1-2 cm. Individuals with type I gastric carcinoids >2 cm should undergo cross-sectional imaging and be referred for surgical resection, given the risk of metastasis. Individuals with type I gastric carcinoids should undergo surveillance, but the intervals are not well defined. BEST PRACTICE ADVICE 14: In general, only individuals who are fit for endoscopic or potentially surgical treatment should be screened for GC and continued surveillance of premalignant gastric conditions. If a person is no longer fit for endoscopic or surgical treatment, then screening and surveillance should be stopped. BEST PRACTICE ADVICE 15: To achieve health equity, a personalized approach should be taken to assess an individual's risk for GC to determine whether screening and surveillance should be pursued. In conjunction, modifiable risk factors for GC should be distinctly addressed, as most of these risk factors disproportionately impact people at high risk for GC and represent health care disparities.
04
Gut (IF: 23.0; Q1). 2024 Dec 10;74(1):26-34.
doi: 10.1136/gutjnl-2024-333227.
Epidemiology of gastrointestinal cancers: a systematic analysis from the Global Burden of Disease Study 2021
胃肠道肿瘤流行病学：2021 年全球疾病负担研究的系统分析
Background: Gastrointestinal cancers comprise nearly one-third of global mortality from cancer, yet the comprehensive global burden of these cancers remains uninvestigated.
Objective: We aimed to assess the global, regional and national burden of gastrointestinal cancers.
Designs: Data on oesophagus, gastric, colorectal, liver, pancreas and biliary tract cancers were extracted from the Global Burden of Disease 2021 database. Age-standardised incidence rate (ASIR) and age-standardised death rate (ASDR) were calculated by sex, region and Sociodemographic Index (SDI).
Results: In 2021, there were 5.26 million incidences and 3.70 million deaths from gastrointestinal cancer. The greatest burden is from colorectal, followed by gastric, oesophageal, pancreatic, liver and biliary tract cancer. We noted geographical and socioeconomic differences in ASIR and ASDR across all types of cancers. From 2000 to 2021, ASIR increased for colorectal cancer (annual percent change (APC): 0.10%, 95% CI 0.05% to 0.14%), pancreatic cancer (APC: 0.27%, 95% CI 0.14% to 0.41%), and liver cancer from metabolic dysfunction-associated steatotic liver disease (APC: 0.62%, 95% CI 0.58% to 0.67%) and alcohol-related liver disease (APC: 0.26%, 95% CI 0.22% to 0.30%). ASDR increased for pancreatic cancer (APC: 0.18%, 95% CI 0.02% to 0.34%). Higher SDI countries had higher incidence rates for most types of gastrointestinal cancer.
Conclusions: Although the ASIR of oesophageal, gastric and biliary tract cancer has decreased, the ASIR still increased in colorectal, pancreatic and liver cancer from steatotic liver disease. Public policies are important for controlling gastrointestinal cancers-most importantly, reducing alcohol consumption, hepatitis B immunisation and tackling the burden of metabolic diseases.
05
Cancer Commun (Lond) (IF: 20.1; Q1). 2024 Dec 10.
doi: 10.1002/cac2.12627. Online ahead of print.
Cancer situation in China: an analysis based on the global epidemiological data released in 2024
中国癌症状况：基于2024年全球流行病学数据的分析
Background: Cancer remains a major cause of mortality and a significant economic burden in China. Exploring the disparities in cancer patterns and control strategies between China and developed countries may offer valuable insights for policy formulation and enhance cancer management efforts. This study examined the incidence, mortality, and disability-adjusted life year (DALY) burden of cancer in China, and compared these metrics with those observed in the United States (US) and the United Kingdom (UK).
Methods: Data on cancer incidence, mortality, and DALYs for China, the US, and the UK were sourced from the GLOBOCAN 2022 online database and the Global Burden of Disease 2021 study (GBD 2021). We utilized Joinpoint regression models to analyze trends in cancer incidence and mortality across these countries, calculating annual percent changes (APCs) and determining the optimal joinpoints.
Results: In 2022, China recorded around 4,824,703 new cancer cases and 2,574,176 cancer-related deaths, contributing to 71,037,170 DALYs. China exhibited a lower cancer incidence rate compared to the US and the UK. Although cancer-related mortality in China is slightly lower than that in the UK, it is significantly higher than that in the US. Additionally, China experienced significantly higher DALY rates compared to both the US and UK. The cancer landscape in China was also undergoing significant changes, with a rapid rise in the incidence and burden of lung, colorectal, breast, cervical, and prostate cancers. Meanwhile, the incidence and burden of stomach cancer continued to decline. Although the incidence of liver and esophageal cancers was decreasing, the burden of liver cancer was increasing, while the burden of esophageal cancer remained largely unchanged.
Conclusions: The cancer profile of China is shifting from that of a developing country to one more typical of a developed country. The ongoing population aging and the rise in unhealthy lifestyles are expected to further escalate the cancer burden in China. Consequently, it is crucial for Chinese authorities to revise the national cancer control program, drawing on successful strategies from developed countries, while also accounting for the regional diversity in cancer types across China.
06
Sci Transl Med (IF: 15.8; Q1). 2024 Dec 11;16(777):eadn7218.
doi: 10.1126/scitranslmed.adn7218. Epub 2024 Dec 11.
Development of a fibrin-targeted theranostic for gastric cancer
纤维蛋白靶向治疗胃癌的研究进展
Patients with advanced gastric cancer (GCa) have limited treatment options, and alternative treatment approaches are necessary to improve their clinical outcomes. Because fibrin is abundant in gastric tumors but not in healthy tissues, we hypothesized that fibrin could be used as a high-concentration depot for a high-energy beta-emitting cytotoxic radiopharmaceutical delivered to tumor cells. We showed that fibrin is present in 64 to 75% of primary gastric tumors and 50 to 100% of metastatic gastric adenocarcinoma cores. First-in-human 64Cu-FBP8 fibrin-targeted positron emission tomography (PET) imaging in seven patients with gastric or gastroesophageal junction cancer showed high probe uptake in all target lesions with tumor-to-background (muscle) uptake ratios of 9.9 ± 6.6 in primary (n = 7) and 11.2 ± 6.6 in metastatic (n = 45) tumors. Using two mouse models of human GCa, one fibrin-high (SNU-16) and one fibrin-low (NCI-N87), we showed that PET imaging with a related fibrin-specific peptide, CM500, labeled with copper-64 (64Cu-CM500) specifically bound to and precisely quantified tumor fibrin in both models. We then labeled the fibrin-specific peptide CM600 with yttrium-90 and showed that 90Y-CM600 effectively decreased tumor growth in these mouse models. Mice carrying fibrin-high SNU-16 tumors experienced tumor growth inhibition and prolonged survival in response to either a single high dosage or fractionated lower dosage of 90Y-CM600, whereas mice carrying fibrin-low NCI-N87 tumors experienced prolonged survival in response to a fractionated lower dosage of 90Y-CM600. These results lay the foundation for a fibrin-targeted theranostic that may expand options for patients with advanced GCa.
07
Int J Surg (IF: 12.5; Q1). 2024 Dec 24.
doi: 10.1097/JS9.0000000000002184. Online ahead of print.
Predicting early recurrence in locally advanced gastric cancer after gastrectomy Using CT-based deep learning model: a multicenter study
使用基于 CT 的深度学习模型预测胃切除术后局部晚期胃癌的早期复发：一项多中心研究
Background: Early recurrence in patients with locally advanced gastric cancer (LAGC) portends aggressive biological characteristics and a dismal prognosis. Prediction of early recurrence may help determine treatment strategies for LAGC. To develop a deep learning model for early recurrence prediction (DLER) based on preoperative multiphase computed tomography (CT) images and further explore the underlying biological basis of the proposed model.
Materials and methods: In this retrospective study, 620 LAGC patients from January 2015 to March 2023 were included in three medical centres and The Cancer Image Archive (TCIA). The DLER model was developed using DenseNet169 and multiphase 2.5D CT images, and then crucial clinical factors of early recurrence were integrated into the multilayer perceptron classifier (MLP) model (DLERMLP). The area under the receiver operating characteristic curve (AUC), accuracy, sensitivity and specificity were applied to measure the performance of different models. The log-rank test was used to analyze survival outcomes. The genetic analysis was performed using RNA-sequencing data from TCIA.
Results: Using the MLP classifier combined with clinical factors, DLRMLP showed higher performance than DLER and clinical models in predicting early recurrence in internal validation set (AUC: 0.891 vs 0.797, 0.752), two external test set1 (0.814 vs. 0.666, 0.808) and external test2 (0.834 vs. 0.756, 0.766). Early recurrence-free survival, disease-free survival, and overall survival can be stratified using the DLERMLP (all P < .001). High DLERMLP score is associated with upregulated tumour proliferation pathways (WNT, MYC, and KRAS signalling) and immune cell infiltration in the tumour microenvironment.
Conclusion: The DLERMLP based on CT images was able to predict early recurrence of patients with LAGC and served as a useful tool for optimizing treatment strategies and monitoring.
08
Int J Surg (IF: 12.5; Q1). 2024 Dec 26.
doi: 10.1097/JS9.0000000000002185. Online ahead of print.
Robotic vs. laparoscopic gastrectomy for patients with locally advanced gastric cancer: a meta-analysis of randomized controlled trials and propensity-score-matched studies
机器人与腹腔镜胃切除术治疗局部晚期胃癌患者：随机对照试验和倾向评分匹配研究的荟萃分析
Background: The role of robotic surgery for the treatment of locally advanced gastric cancer remains controversial. This meta-analysis aimed to compare the short-term outcomes between robotic gastrectomy (RG) and laparoscopic gastrectomy (LG) for patients with locally advanced gastric cancer using data collected from randomized controlled trials (RCTs) and propensity score-matched (PSM) studies.
Materials and methods: We searched PubMed, Cochrane Library, Embase, and Web of Science databases for RCTs and PSM studies comparing RG and LG. Risk ratios (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were calculated.
Results: Fifteen studies encompassing one RCT and 14 PSM studies were included, with a total of 5,079 patients (RG group: 2,279 patients; LG group: 2,800 patients). Although RG was associated with a longer operative time (MD, 19.82 mins), patients may benefit from reduced blood loss (MD, - 28.91 mL), shorter length of stay (MD, - 0.69 days), lower morbidity (RR, 0.82), major complications (RR, 0.71), blood transfusion rate (RR, 0.60), conversion rate (RR, 0.38), and higher number of harvested lymph nodes (MD, 3.25). There were no significant differences observed in readmission (RR, 0.89), mortality (RR, 0.75), reoperation (RR, 0.71), and R0 resection (RR, 0.99) between the groups. In addition, RG shortened the time to to first flatus (MD, - 0.38 days), the time to first liquid intake (MD, - 0.31 days), and the time to first soft diet intake (MD, - 0.20 days).
Conclusions: RG seem associated with improved short-term outcomes and enhanced postoperative recovery in locally advanced gastric cancer compared to LG. In the future, RG may become a safe and effective alternative to LG. Further research is needed to investigate long-term outcomes and confirm the promising advantages of RG in locally advanced gastric cancer.
09
Cell Rep Med (IF: 11.7; Q1). 2024 Dec 17;5(12):101848.
doi: 10.1016/j.xcrm.2024.101848. Epub 2024 Dec 4.
Interpretable multi-modal artificial intelligence model for predicting gastric cancer response to neoadjuvant chemotherapy
用于预测胃癌对新辅助化疗反应的可解释多模态人工智能模型
Neoadjuvant chemotherapy assessment is imperative for prognostication and clinical management of locally advanced gastric cancer. We propose an incremental supervised contrastive learning model (iSCLM), an interpretable artificial intelligence framework integrating pretreatment CT scans and H&E-stained biopsy images, for improved decision-making regarding neoadjuvant chemotherapy. We have constructed and tested iSCLM using retrospective data from 2,387 patients across 10 medical centers and evaluated its discriminative ability in a prospective cohort (132 patients; ChiCTR2300068917). iSCLM achieves areas under receiver operating characteristic curves of 0.846-0.876 across different test cohorts. Computed tomography (CT) and pathological attention heatmaps from Shapley additive explanations and global sort pooling illustrate additional benefits for capturing morphological features through supervised contrastive learning. Specifically, pathological top-ranked tiles exhibit decreased distances to tumor-invasive borders and increased inflammatory cell infiltration in responders compared with non-responders. Moreover, CD11c expression is elevated in responders. The developed interpretable model at the molecular pathology level accurately predicts chemotherapy efficacy.
10
J Exp Clin Cancer Res (IF: 11.4; Q1). 2024 Dec 19;43(1):326.
doi: 10.1186/s13046-024-03245-y.
FOLR2+ macrophage depletion from intestinal metaplasia to early gastric cancer: single-cell sequencing insight into gastric cancer progression
从肠上皮化生到早期胃癌的FOLR2+ 巨噬细胞耗竭：单细胞测序洞察胃癌进展
Background: The immune landscape associated with different subtypes of intestinal metaplasia (IM) and early gastric cancer (EGC) remains unclear. This study aimed to investigate the immune landscape of complete intestinal metaplasia (CIM), incomplete intestinal metaplasia (IIM), and EGC, as well as the underlying mechanisms of EGC progression.
Methods: Gastric biopsy samples were collected from five patients with CIM, six patients with IIM, and four patients with EGC, followed by single-cell RNA sequencing. Multiplex immunohistochemical staining was employed to validate the samples from the aforementioned patients. To elucidate the potential mechanisms involved, in vitro coculture experiments were conducted using FOLR2+/FOLR2-macrophages and CD8+ T cells. Flow cytometry was utilized to investigate the biological functions of FOLR2+ macrophages in the progression of EGC.
Results: Five subpopulations of macrophages were identified in CIM, IIM and EGC samples. FOLR2+ macrophages possess antitumor immune potential, and the proportion of FOLR2+ macrophage gradually decreased from the CIM stage to the IIM and EGC stages. FOLR2+ macrophages were significantly positively correlated with CD8+ T cells and activated the cytotoxicity of CD8+ T cells via antigen cross-presentation. Additionally, during the progression of EGC, epithelial cells progressively upregulated APP expression, thus inducing necroptosis of FOLR2+ macrophages via the APP‒TNFRSF21 axis.
Conclusions: Our work provides an understanding of the potential mechanisms underlying the malignant transformation of IM mediated by FOLR2+ macrophages.
11
J Immunother Cancer (IF: 10.3; Q1). 2024 Dec 9;12(12):e010041.
doi: 10.1136/jitc-2024-010041.
Multiomics reveals tumor microenvironment remodeling in locally advanced gastric and gastroesophageal junction cancer following neoadjuvant immunotherapy and chemotherapy
多组学揭示局部晚期胃癌和胃食管连接部癌在新辅助免疫治疗和化疗后肿瘤微环境重塑
Background: Perioperative chemotherapy is the standard of care for patients with locally advanced gastric and gastroesophageal junction cancer. Recent evidence demonstrated the addition of programmed cell death protein 1 (PD-1) inhibitors enhanced therapeutic efficacy. However, the mechanisms of response and resistance remain largely undefined. A detailed multiomic investigation is essential to elucidate these mechanisms.
Methods: We performed whole-exome sequencing, whole-transcriptome sequencing, multiplex immunofluorescence and single-cell RNA sequencing on matched pretreatment and post-treatment samples from 30 patients enrolled in an investigator-initiated Phase 2 clinical trial (NCT04908566). All patients received neoadjuvant PD-1 inhibitors in combination with chemotherapy. A major pathologic response (MPR) was defined as the presence of no more than 10% residual viable tumor cells following treatment.
Results: Before treatment, the positive ratio of CD3+T cells in both the tumor parenchyma and stroma was significantly higher in the non-MPR group compared with the MPR group (p=0.042 and p=0.013, respectively). Least absolute shrinkage and selection operator regression was employed for feature gene selection and 13 genes were ultimately used to construct a predictive model for identifying MPR after surgery. The model exhibited a perfect area under curve (AUC) of 1.000 (95% CI: 1.000 to 1.000, p<0.001). Post-treatment analysis revealed a significant increase in CD3+T cells, CD8+T cells and NK cells in the tumor stroma of MPR patients. In the tumor parenchyma, aside from a marked increase in CD8+T cells and NK cells, a notable reduction in macrophage was also observed (all p<0.05). Importantly, forkheadbox protein 3 (FOXP3), the principal marker for regulatory T cells (Treg) cells, showed a significant decrease during treatment in MPR patients. FOXP3 expression in the non-MPR group was significantly higher than in the MPR group (p=0.0056) after treatment. Furthermore, single-cell RNA sequencing analysis confirmed that nearly all Treg cells were derived from the non-MPR group.
Conclusions: Our study highlights the critical role of dynamic changes within the tumor immune microenvironment in predicting the efficacy of neoadjuvant combined immunochemotherapy. We examined the disparities between MPR/non-MPR groups, shedding light on potential mechanisms of immune response and suppression. In addition to bolstering cytotoxic immune responses, specifically targeting Treg cells may be crucial for enhancing treatment outcomes.
12
Cancer Lett (IF: 9.1; Q1). 2024 Dec 3:611:217362.
doi: 10.1016/j.canlet.2024.217362. Online ahead of print.
Emerging targets in gastric and pancreatic cancer: Focus on claudin 18.2
胃癌和胰腺癌的新兴靶点：claudin 18.2
Recently, the molecular landscape of gastric and pancreatic cancers has advanced with Claudin 18.2 (CLDN18.2) emerging as a promising therapeutic target. Claudin 18.2, a tight junction protein, is selectively expressed in cancer cells and minimally in normal tissues, making it an attractive candidate for targeted therapy. Therapies like monoclonal antibodies (e.g., zolbetuximab), bispecific antibodies, and antibody-drug conjugates have shown significant potential in improving clinical outcomes. Early-phase clinical trials demonstrate robust antitumor activity, particularly in combination with chemotherapy and immunotherapy regimens. However, challenges such as patient selection, resistance mechanisms, and toxicity management remain critical. This review highlights the therapeutic landscape, clinical advancements, and future directions of targeting Claudin 18.2 in gastric and pancreatic cancer treatment.
13
Ann Surg (IF: 7.5; Q1). 2024 Dec 11.
doi: 10.1097/SLA.0000000000006603. Online ahead of print.
3-Year Survival Outcomes of Patients with Enhanced Recovery After Surgery vs. Conventional Care in Laparoscopic Distal Gastrectomy: The GISSG1901 Randomized Clinical Trial
腹腔镜远端胃切除术后加速康复患者与常规治疗患者的 3 年生存结果：GISSG1901 随机临床试验
Objectives: The efficacy of enhanced recovery after surgery (ERAS) to improve the prognosis of patients who undergo laparoscopic distal gastrectomy (LDG) for gastric cancer is uncertain. This randomized study compared oncological outcomes in LDG after ERAS or conventional care.
Background: At present, randomized controlled trials have confirmed that ERAS can improve the short-term clinical outcomes of patients undergoing LDG, but whether it improves survival has not been reported yet.
Methods: A multicenter, randomized, controlled trial was performed to compare oncological outcomes of ERAS versus conventional care in LDG. Between April 4, 2019, and March 18, 2020, 527 patients with locally advanced lower gastric adenocarcinoma were recruited from 13 centers in China. The primary endpoints were 3-year overall survival (OS) and disease-free survival (DFS). The secondary endpoints were complications, mortality, recovery, time of receiving adjuvant chemotherapy and medical expenses.
Results: The full analysis set included 186 cases in the ERAS group and 184 in conventional group, well balanced with respect to patient demographics and baseline characteristics (published before). Postoperative hospital stay and the interval before adjuvant chemotherapy were obviously shorter in the ERAS group compared to conventional group as reported previously and with lower medical expenses. Compared with the conventional group, ERAS group had fewer overall complications (21.0% vs. 30.4%, respectively; P=0.037). The median (IQR) follow-up for all cases was 42.17 (range, 3.12-48.50) months. The 3-year OS and DFS in the ERAS group and conventional group were 86.56% and 80.11% (log-rank P=0.025), 79.57% and 69.57% (log-rank P=0.027), respectively. In a subgroup analysis of stage I and II disease patients, 3-year OS and DFS were similar between the groups (P=0.901; P=0.859 for stage I and P=0.421; P=0.459 for stage II). However, in the stage III disease, the ERAS group exhibited longer 3-year OS and DFS than the conventional group (79.41% vs. 64.47% for OS, log-rank P=0.046; 70.59% vs. 53.95% for DFS, log-rank P=0.046).
Conclusions: Patients undergoing ERAS LDG had fewer overall complications, shorter hospital stay, decreased medical expenses, and improved 3-year OS and DFS rates, particularly in cases with stage III gastric cancer.
14
BMC Med (IF: 7.0; Q1). 2024 Dec 18;22(1):585.
doi: 10.1186/s12916-024-03801-5.
Efficacy, safety, and biomarker analysis of first-line immune checkpoint inhibitors with chemotherapy versus chemotherapy for advanced gastric cancer: a multicenter, retrospective cohort study
一线免疫检查点抑制剂联合化疗对比化疗治疗晚期胃癌的疗效、安全性及生物标志物分析：一项多中心、回顾性队列研究
Background: Recent phase III randomized controlled trials have demonstrated that first-line immune checkpoint inhibitors (ICIs) improve prognosis in advanced HER-2-negative gastric cancer patients with programmed death ligand 1 (PD-L1) combined positive score (CPS) higher than 5. However, these findings are not confirmed in real-world settings, and the benefits in PD-L1 CPS < 5 patients remain controversial.
Methods: In this multicenter, retrospective cohort study, data from across thirteen medical centers were analyzed by inverse probability of treatment weighting for matching, alongside univariate and multivariate COX proportional hazard regression models. Genomic and transcriptomic analyses were conducted to identify efficacy prognostic models and resistance mechanisms.
Results: This study included 573 patients with advanced gastric cancer, 265 treated with chemotherapy and 308 with ICIs plus chemotherapy. In the overall cohort and HER-2-negative patients, the combination therapy significantly improved progression-free survival and overall survival, without marked increases in severe adverse events. Notably, patients with PD-L1 CPS 1-4 showed significant overall survival prolongation and a trend towards improved progression-free survival with combination therapy. Patients with unknown PD-L1 status also benefitted from ICIs. SMARCA4 and BRCA2 mutations were more frequent in patients with responses, while CCNE1 and ZFHX3 alternation, alongside high "ABC transporters" signatures, were more common in non-responsive patients. A novel risk model, PGFIC, outperformed traditional biomarkers in predicting treatment outcomes.
Conclusions: Adding ICIs to first-line treatment significantly prolongs survival in overall patients and in those with PD-L1 CPS 1-4 or unknown. This study also provides valuable insights into prognostic markers and resistance mechanisms, potentially guiding immunotherapy strategies.
15
Anal Chem (IF: 6.7; Q1). 2024 Dec 17;96(50):20015-20025.
doi: 10.1021/acs.analchem.4c04639. Epub 2024 Dec 6.
Highly Sensitive Multiplexed Sensing of miRNAs in a Gastric Cancer Patient's Liquid Biopsy
胃癌患者液体活检中 miRNA 的高灵敏度多重传感
Gastric cancer (GC) is one of the leading causes of cancer mortality in the world. Most patients are in the advanced stage of the disease at the time of diagnosis because the symptoms of early gastric cancer patients are not obvious. Early diagnosis of gastric cancer is still challenging due to the high cost, invasiveness, and low accuracy of traditional diagnostic methods such as endoscopy and biopsy. Herein, we develop clinically accurate and highly sensitive detection of multiple GC miRNA biomarkers in human serum using an isothermal nucleic acid primer exchange reaction (PER). The isothermal nucleic acid primer exchange reaction demonstrates high sensitivity and robustness, exemplified by a one-pot reaction achieving a detection limit of 28.71 fM. By quantifying the levels of three miRNA biomarkers selected through bioinformatics analysis in gastric cancer serum samples, the diagnostic approach effectively distinguished between clinical gastric cancer patients (n = 25) and noncancer controls (n = 10). The performance of our three-miRNA signature in discriminating between GC and controls was as follows: area under the curve (AUC): 0.808, sensitivity: 89%, specificity: 88%, positive predictive value (PPV): 96%, and negative predictive value (NPV): 70%.
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J Transl Med (IF: 6.1; Q1). 2024 Dec 27;22(1):1152.
doi: 10.1186/s12967-024-05867-4
Association of PD-1 + Treg/PD-1 + CD8 ratio and tertiary lymphoid structures with prognosis and response in advanced gastric cancer patients receiving preoperative treatment
PD-1 + Treg/PD-1 + CD8 比例及三级淋巴结构与接受术前治疗的晚期胃癌患者预后及疗效的关系
Background: Recent studies have highlighted the distinct ratio of PD-1 + Treg/PD-1 + CD8 for prognosis prediction. However, it remains unclear about the association of this ratio and tertiary lymphoid structures (TLS) with prognosis and response to neoadjuvant or conversion therapy in advanced gastric cancer.
Methods: Firstly, fresh postoperative samples from 68 gastric cancer patients in Renji Hospital were collected. Meanwhile, immune cell infiltration as well as clinical prognosis analysis were conducted. Subsequently, we further systematically evaluated flow cytometry analysis of tumor samples and TLS expression in 38 gastric cancer patients with different response situations after neoadjuvant therapy. Also, a Renji conversion therapy cohort including 10 patients with complete matching samples before and after treatment was established to receive RNA sequencing analysis and multiplex immunohistochemistry (mIHC) tests. The corresponding TLS score and immune cell infiltration were further compared based on therapeutic response variations.
Results: In general, the ratio of PD-1 + Treg/PD-1 + CD8>1 could be regarded as an independent predictor of prognosis in advanced gastric cancer patients. Moreover, PD-1 + Treg/PD-1 + CD8 < 1 and high expression of TLS could indicate better neoadjuvant therapy response and extended survival time in advanved gastric cancer patients. Besides, PD-1 + Treg/PD-1 + CD8 low &TLS high group could predict better progression free survival time (PFS) in complete response (CR) subgroup. In response group after conversion therapy, the number of PD-1 + CD8 + T cells significantly increased, mainly occurring outside the TLSs. Meanwhile, the TLSs were also considerably activated as we could observed.
Conclusions: This study underlined that combining PD-1 + Treg/PD-1 + CD8 ratio and TLS were significantly associated with prognosis and preoperative treatment response in advanced gastric cancer. Inspiringly, these indicators have the potential to elucidate the immune balance of advanced gastric cancer patients and can accurately guide subsequent therapeutic strategies.
17
Gastric Cancer (IF: 6.0; Q1). 2024 Dec 26.
doi: 10.1007/s10120-024-01576-5. Online ahead of print.
Hazard rates of recurrence for gastric cancer after curative resection: implications for postoperative surveillance
胃癌根治性切除术后复发的风险率：术后监测的意义
Background: Identifying the most effective postoperative surveillance interval in patients with gastric cancer (GC) remains challenging. To elucidate a logical and effective surveillance schedule, we analyzed GC recurrence risk trends after gastrectomy using the hazard function.
Methods: We retrospectively reviewed the medical records of 2503 patients who underwent curative GC resection between 2000 and 2018. We examined recurrence risk over time and the influence of clinicopathological variables on it.
Results: Overall, GC recurred in 291 patients (11.6%) over a median of 64.6 months. Recurrence risk was highest at approximately 11-months postoperatively (hazard rate [HR]: 0.0045), decreasing to half the peak at approximately 39-months postoperatively. Patients with Stage I GC maintained a low risk. In Stage II patients, the risk peaked at 16-months postoperatively (HR: 0.006) and gradually declined thereafter. Stage III patients had the highest risk at 11 months postoperatively (HR: 0.019), plateauing at 40 months.
Conclusions: We demonstrated significant cancer stage-dependent differences in postsurgical GC recurrence risk by using the hazard function. Reductions in surveillance intensity might be acceptable according to the individual risk of recurrence.
18
Gastric Cancer (IF: 6.0; Q1). 2024 Dec 10.
doi: 10.1007/s10120-024-01572-9. Online ahead of print.
SUSD2+ cancer-associated fibroblasts in gastric cancer mediate the effect of immunosuppression and predict overall survival and the effectiveness of neoadjuvant immunotherapy
胃癌中的 SUSD2+ 癌症相关成纤维细胞介导免疫抑制作用并预测总体生存期和新辅助免疫治疗的有效性
Background: The expression patterns and functions of Sushi Domain Containing 2 (SUSD2) differ among various malignancies. This research aims to investigate the expression of SUSD2 and the role of the SUSD2+ cancer-associated fibroblasts (CAFs) for immunotherapy in gastric cancer.
Methods: The expression of SUSD2 and specific markers (CD4, CD8, PD-1, TIGIT, TIM-3 and CD163) was determined using immunohistochemistry and multiplex immunofluorescence (mIHC) on paraffin sections. Flow cytometry and western blot were used to assess the expression of SUSD2 in fibroblasts from fresh samples. Also, analysis of single-cell and bulk RNA sequencing was employed to confirm the presence and characterize the function of SUSD2+ CAFs. The predictive power of indicators for neoadjuvant immunotherapy was evaluated via ROC curve analysis. Animal experiment was employed to validate the immunosuppressive effect of SUSD2+ CAFs.
Results: SUSD2 is mainly expressed on fibroblasts within the tumors and the high infiltration of SUSD2+ CAFs went together with a poor survival and a more advanced tumor stage. Significantly, the joint use of SUSD2+ CAFs and CD8+ T cells demonstrated a remarkable ability to predict the efficacy of neoadjuvant immunotherapy superior to PD-L1 combined positive score. High SUSD2+ CAFs was correlated with resistance to immunotherapy as well as low CD8+ T infiltration and high exhausted T cell infiltration.
Conclusions: We have identified a novel subset of CAFs that could predict the survival and response to neoadjuvant immunotherapy of patients. The SUSD2+ CAFs have the potential to serve as a predictive biomarker and a promising target for immunotherapy.
19
Gastric Cancer (IF: 6.0; Q1). 2024 Dec 10.
doi: 10.1007/s10120-024-01571-w. Online ahead of print.
Nationwide survey on HER2 and PD-L1 testing practices in gastric cancer across Japan
日本胃癌 HER2 和 PD-L1 检测实践调查
Background: Since HER2 and PD-L1 testing are key to selecting drugs for first-line treatments in advanced gastric cancer, evaluating differences in these tests among institutions is necessary to standardize treatment.
Methods: A questionnaire survey was conducted targeting institutions certified by the Japanese Gastric Cancer Association.
Results: Responses were obtained from 155 institutions. Most institutions performed HER2 testing in-house, while PD-L1 tests were largely outsourced. HER2 scores and PD-L1 CPS rates showed greater variability across institutions than anticipated. In the pre-analytic phase, 10% neutral buffered formalin was commonly used, with fixation practices generally following guidelines. Overall, the impact of fixation-related factors was limited, but in surgical specimens, longer fixation was associated with a higher proportion of score 0/1+ and a lower proportion of score 3+. When examining HER2 scores by institution, if a particular score had a high (or low) frequency in biopsy, the same trend was also seen in surgical specimens.
Conclusions: These findings suggest that not only factors related to specimen preparation, but also biases in evaluation criteria among pathologists may contribute to the significant variability among institutions. Standardization of pre- and post-analytic phases, coupled with appropriate training, is essential to achieve consistent gastric cancer therapy.
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