Clinical epidemiology of the endoscopic, laparoscopic, and surgical resection of malignant gastric tumors in Japan, 2014–2021: a retrospective study using open data from a national claims databaseSako, Akahito; Yada, Tomoyuki; Fujiya, Keiichi; Nakashima, Ryo; Yoshimura, Kensuke; Yanai, Hidekatsu; Uemura, Naomi
doi: 10.1007/s10120-024-01553-ypmid: 39333285
BackgroundGastric cancer is a common malignancy with a high incidence in East Asia. Gastric resection ranges from endoscopic resection to open total gastrectomy. However, nationwide data are lacking.MethodsThis observational study analyzed data from the publicly accessible National Database of Health Insurance Claims and Specific Health Checkups, which includes most national health insurance claims data in Japan. Trends in the types of resection performed for malignant gastric tumors between 2014 and 2021, patients’ age and sex distributions, and regional disparities were investigated.ResultsThe annual number of resections was highest in 2015 (109,000) and lowest in 2020 (90,000) after the COVID-19 pandemic. The proportion of endoscopic resections increased from 47% in 2014 to 57% in 2021 while that of total gastrectomies decreased from 17 to 10%. In 2021, 70% of patients who underwent resection were men. That year, 83.8% of all patients who underwent any type of gastric resection and 87.1% of those who underwent endoscopic submucosal dissection were aged ≥ 65 years. The annual incidence of gastric resection per million population was highest in Tottori (n = 1236) and lowest in Okinawa (n = 251). The proportion of endoscopic resections was highest in Miyagi (66%) and lowest in Aichi (45%) and that of open surgery was highest in Aomori (36%) and lowest in Wakayama (5%).ConclusionsGastric malignancy is increasingly treated by endoscopic submucosal dissection rather than open total gastrectomy. However, regional disparities remain in resection type. Standardization of treatment and a more even distribution of specialists are needed.
Decorin as a key marker of desmoplastic cancer-associated fibroblasts mediating first-line immune checkpoint blockade resistance in metastatic gastric cancerKim, Ki Tae; Lee, Min Hee; Shin, Su-Jin; Cho, In; Kuk, Jung Cheol; Yun, Jina; Choi, Yoon Young
doi: 10.1007/s10120-024-01567-6pmid: 39520589
BackgroundGastric cancer (GC) remains a significant cause of cancer-related mortality worldwide. Despite the transformative impact of immune checkpoint blockade (ICB) therapies across various cancers, only a minority of patients with metastatic GC (mGC) benefit, emphasizing the urgent need for precise biomarkers to predict therapeutic responses and optimize patient selection.MethodsIn this multi-omics study, we conducted whole exome and transcriptome sequencing on 12 tumors from mGC patients treated with nivolumab as first-line therapy. To validate our findings, we performed whole transcriptome sequencing on 17 additional tumors and analyzed 45 tumors from public dataset (PRJEB25780) of patients who received ICB therapy as second or third-line treatment. Comprehensive multi-omics analyses were conducted using single-cell RNA sequencing (n = 5, GSE167297) and spatial transcriptome sequencing (n = 2, independent internal dataset).ResultsICB-sensitive tumors exhibited robust activation of the interferon response pathway, while ICB-resistant tumors displayed epithelial–mesenchymal transition signatures. Intriguingly, at the single-cell level, genes associated with ICB sensitivity were predominantly expressed in immune cells, whereas genes associated with resistance were primarily found in cancer-associated fibroblasts (CAFs), particularly the desmoplastic CAF (dCAF) subtype. We identified DCN as a hallmark dCAF marker, and high DCN expression was inversely correlated with PD-L1 levels, ICB resistance, and poor prognosis in mGC (log-rank p = 0.027).ConclusionThis study elucidates the critical influence of the tumor microenvironment, specifically dCAFs, in mediating ICB resistance in mGC. Our findings highlight DCN as a representative marker for dCAF and a promising negative predictive biomarker for ICB response. These findings highlight the complex stromal-immune interactions and open avenues for personalized treatment for mGC.
Volume of hepatoid component and intratumor M2 macrophages predict prognosis in patients with hepatoid adenocarcinoma of the stomachTaniguchi, Yoshiaki; Kiyozawa, Daisuke; Kohashi, Kenichi; Kawatoko, Shinichiro; Yamamoto, Takeo; Torisu, Takehiro; Yoshizumi, Tomoharu; Nakamura, Masafumi; Kitazono, Takanari; Oda, Yoshinao
doi: 10.1007/s10120-024-01562-xpmid: 39488822
BackgroundHepatoid adenocarcinoma of the stomach (HAS), a subtype of gastric cancer (GC), includes multiple tumor components, such as enteroblastic and tubular adenocarcinoma components. However, which component mostly contributes to the aggressive behavior of HAS remains unclear. Moreover, the role of tumor-associated macrophages (TAMs) has not been explored in HAS. This study evaluated the clinical significance of the proportion of the hepatoid component within the tumor, CD163 + macrophages, and macrophage colony-stimulating factor-1 (CSF-1) in HAS.MethodsIn total, 56 cases of primary HAS were analyzed. In each case, hepatoid (HC), enteroblastic (EC), and tubular (TC) components were identified, and the ratio of HC to the entire tumor (hepatoid component ratio, HCR) was assessed to examine the correlation between HCR and clinicopathological features. Immunohistochemical staining for CD163 and CSF-1 was performed, and differences in immunohistochemical results among the three tumor components were analyzed. In each tumor component, the prognostic impact of CD163 and CSF-1 was examined.ResultsA high HCR was associated with worse overall survival (OS). CD163 + TAMs and CSF-1 immunoreactivity score in HC were significantly higher than those in the other components. High infiltration of CD163 + TAMs and a high CSF-1 immunoreactivity score in HC were associated with an aggressive course and worse OS. Multivariate analysis revealed the proportion of HC in HAS as an independent prognostic factor (HR = 3.176, p = 0.006).ConclusionsThe HCR and CD163 + TAMs may be useful prognostic predictors, and TAMs may be novel therapeutic targets of HAS.
Survival outcomes of patients with gastric cancer treated with first-line nivolumab plus chemotherapy based on claudin 18.2 expressionKim, Hyung-Don; Shin, Jinho; Hyung, Jaewon; Lee, Hyungeun; Moon, Meesun; Ma, Jeongeun; Park, Young Soo; Ryu, Min-Hee
doi: 10.1007/s10120-024-01566-7pmid: 39528778
BackgroundClaudin 18.2 has emerged as a viable therapeutic target in gastric cancer; however, its clinical relevance in the context of immune checkpoint inhibitor-based chemotherapy is not known. This study aimed to investigate the efficacy of nivolumab plus chemotherapy according to claudin 18.2 expression in patients with gastric cancer.MethodsThis single-center study included patients with advanced gastric cancer who were treated with first-line nivolumab plus chemotherapy (n = 204) or chemotherapy alone (n = 183) whose claudin 18.2 immunohistochemistry results were available. Claudin 18.2 positivity (moderate-to-strong expression in ≥ 75% by the 43-14A clone) was analyzed in terms of efficacy outcomes.ResultsAmong patients treated with nivolumab plus chemotherapy, 96 (47.1%) were assessed to have claudin 18.2-positive tumors. Between patients with claudin 18.2-positive and -negative tumors, objective response rate with nivolumab plus chemotherapy was comparable. Progression-free survival (PFS) and overall survival (OS) with nivolumab plus chemotherapy were comparable between those with claudin 18.2-positive and -negative tumors. For both subgroups with PD-L1 combined positive score ≥ 5 and < 5, PFS and OS with nivolumab plus chemotherapy were also comparable between patients with claudin 18.2-positive and -negative tumors. A consistent trend of favorable PFS and OS was observed with nivolumab plus chemotherapy compared to that of chemotherapy alone in both claudin 18.2-positive and -negative subgroups.ConclusionThe efficacy of nivolumab plus chemotherapy did not vary according to claudin 18.2 positivity. The clinical benefit of nivolumab plus chemotherapy over chemotherapy was consistently observed in claudin 18.2-positive and -negative gastric cancer cases.
Neoadjuvant chemotherapy in relation to long-term mortality in individuals cured of gastric adenocarcinomaLeijonmarck, Wilhelm; Mattsson, Fredrik; Lagergren, Jesper
doi: 10.1007/s10120-024-01558-7pmid: 39387985
BackgroundLate effects of chemotherapy could affect mortality amongst cancer survivors. This study aimed to clarify if neoadjuvant chemotherapy for gastric adenocarcinoma influences the long-term survival in individuals cured of this tumour.MethodsThis was a nationwide and population-based cohort study that included all individuals who underwent gastrectomy for gastric adenocarcinoma in Sweden between 2006 and 2015 and survived for ≥ 5 years after surgery. The cohort was followed up until death or end of study period (31 December 2020). Multivariable Cox proportional hazards regression was used to provide hazard ratios (HR) with 95% confidence intervals (CI). The HR were adjusted for age, sex, comorbidity, education, calendar year, tumour sub-location, in-hospital complications, and splenectomy. Data came from medical records and nationwide registers.ResultsAmongst 613 gastric adenocarcinoma survivors, neoadjuvant chemotherapy (used in 269 patients; 43.9%) was associated with a decreased crude mortality rate (HR 0.66, 95% CI 0.46–0.96). However, the association attenuated and became statistically non-significant after adjustment for all confounders (HR 0.83, 95% CI 0.56–1.23) and after adjustments solely for age and comorbidity (HR 0.82, 95% CI 0.56–1.20). Stratified analyses did not reveal any statistically significant associations between neoadjuvant chemotherapy and long-term mortality in categories of age, sex, comorbidity, calendar year and tumour sub-location.ConclusionNeoadjuvant chemotherapy did not decrease the long-term survival amongst gastric adenocarcinoma survivors. Patients who received neoadjuvant chemotherapy were a selected group characterised by younger age and fewer severe comorbidities and therefore with better chances of long-term survival.