Chinese Medicine Prolongs Overall Survival of Chinese Patients with Advanced Gastric Cancer: Treatment Pattern and Survival Analysis of a 20-Year Real-World Study.

OBJECTIVE: To describe the treatment patterns and survival status of advanced gastric cancer (AGC) in China in the past two decades, and objectively evaluate the impact of standardized Chinese medicine (CM) treatment on the survival of AGC patients. METHODS: This multicenter registry designed and propensity score analysis study described the diagnosis characteristics, treatment-pattern development and survival status of AGC from 10 hospitals in China between January 1, 2000 and July 31, 2021. Overall survival (OS) was evaluated between non-CM cohort (standard medical treatment) and CM cohort (integrated standard CM treatment ≥3 months). Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to adjust any difference in average outcomes for bias. RESULTS: A total of 2,001 patients histologically confirmed locally advanced and/or metastasis stomach and gastroesophageal junction adenocarcinoma were enrolled. Among them, 1,607 received systemic chemotherapy, 215 (10.74%) accepted molecular targeted therapy, 44 (2.2%) received checkpoint inhibitor therapy, and 769 (38.43%) received CM. Two-drug regimen was the main choice for first-line treatment, with fluoropyrimidine plus platinum as the most common regimen (530 cases, 60.09%). While 45.71% (16 cases) of patients with HER2 amplification received trastuzumab in first-line. The application of apatinib increased (33.33%) in third-line. The application of checkpoint inhibitors has increased since 2020. COX analysis showed that Lauren mixed type (P=0.017), cycles of first-line treatment >6 (P=0.000), CM (P=0.000), palliative gastrectomy (P=0.000), trastuzumab (P=0.011), and apatinib (P=0.008) were independent prognostic factors for the OS of AGC. After PSM and IPTW, the median OS of CM cohort and non-CM cohort was 18.17 and 12.45 months, respectively (P<0.001). CONCLUSIONS: In real-world practice for AGC in China, therapy choices consisted with guidelines. Two-drug regimen was the main first-line choice. Standardized CM treatment was an independent prognostic factor and could prolong the OS of Chinese patients with AGC. (Registration No. NCT02781285).

Prognostic Implications of LRP1B and Its Relationship with the Tumor-Infiltrating Immune Cells in Gastric Cancer.

BACKGROUND: Recent studies have shown that low-density lipoprotein receptor-related protein 1b (LRP1B), as a potential tumor suppressor, is implicated in the response to immunotherapy. The frequency of LRP1B mutation gene is high in many cancers, but its role in gastric cancer (GC) has not been determined. METHODS: The prognostic value of LRP1B mutation in a cohort containing 100 patients having received radical gastrectomy for stage II-III GC was explored. By analyzing the data of LRP1B mRNA, the risk score of differentially expressed genes (DEGs) between LRP1B mutation-type and wild-type was constructed based on the TCGA-STAD cohort. The infiltration of tumor immune cells was evaluated by the CYBERSORT algorithm and verified by immunohistochemistry. RESULTS: LRP1B gene mutation was an independent risk factor for disease-free survival (DFS) in GC patients (HR = 2.57, 95% CI: 1.28-5.14, p = 0.008). The Kaplan-Meier curve demonstrated a shorter survival time in high-risk patients stratified according to risk score (p < 0.0001). CYBERSORT analysis showed that the DEGs were mainly concentrated in CD4+ T cells and macrophages. TIMER analysis suggested that LRP1B expression was associated with the infiltration of CD4+ T cells and macrophages. Immunohistochemistry demonstrated that LRP1B was expressed in the tumor cells (TCs) and immune cells in 16/89 and 26/89 of the cohort, respectively. LRP1B-positive TCs were associated with higher levels of CD4+ T cells, CD8+ T cells, and CD86/CD163 (p < 0.05). Multivariate analysis showed that LRP1B-positive TCs represented an independent protective factor of DFS in GC patients (HR = 0.43, 95% CI: 0.10-0.93, p = 0.042). CONCLUSIONS: LRP1B has a high prognostic value in GC. LRP1B may stimulate tumor immune cell infiltration to provide GC patients with survival benefits.

Prognostic Value of ANXA8 in Gastric Carcinoma.

Gastric carcinoma (GC) remains one of the most common and deadly cancers worldwide. In China, the incidence and mortality rates related to GC were quite high. Annexin A8 (ANXA8) is a member of the annexins family of calcium-dependent membrane phospholipid binding proteins. According to recent research, the up-regulation of ANXA8 is closely associated with various types of tumors. However, the specific role of ANXA8 in GC remains unclear. In our study, we explored the prognostic value of ANXA8 in GC. Here, with the data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets (GSE19826 and GSE13861) analyzed, we further performed quantitative real-time polymerase chain reaction (qRT-PCR) using 58 pairs of fresh-frozen tissues. We also subjected 152 pairs of formalin-fixed, paraffin-embedded GC tumor tissues from patients, and the adjacent normal gastric tissues (ANGTs) to immunohistochemical (IHC) analysis. Hence, we found an elevated expression of ANXA8 in tumor tissues with bioinformatics analyses, qRT-PCR, western blot and IHC. Over-expression of ANXA8 was strongly correlated with TNM stages and differentiation grades. Kaplan-Meier and cox proportional-hazard analyses showed that the increased expression of ANXA8 was strongly associated with overall survival (OS) and disease-free survival (DFS) in GC patients. Moreover, we found that ANXA8 is an independent prognostic factor of GC patients' OS and DFS. In brief, those results suggest that ANXA8 can act as an oncogene of GC development and can serve as a potential prognostic biomarker for GC treatment.

CSN6 inhibition suppresses pancreatic adenocarcinoma metastasis via destabilizing the c-Fos protein.

Deubiquitinase (DUB) can reverse the ubiquitin signal, and participate in virtually all aspects of cancer progression. Thus, DUB represents an attractive target for development of anticancer drugs. However, little is known about DUB which can be used as drug targets. Here, we found that the constitutive photomorphogenic 9 (COP9) signalosome complex subunit 6 (COPS6/CSN6), a DUB belongs to JAMM/MPN domain-associated metallopeptidases(JAMMs) class, was highly expressed in pancreatic adenocarcinoma(PAAD) tissues. High expression of CSN6 was associated with tumor TNM stage and metastasis in PAAD patients. Moreover, we demonstrated that CSN6 promoted invasion and metastasis through regulating forkhead box protein A1 (FOXA1) in PAAD cells. Re-expression of FOXA1 rescued the decreased invasion and metastasis caused by CSN6 knockdown, whereas inhibition of FOXA1 alleviated the pro-metastasis effect induced by CSN6 overexpression. Further, CSN6 regulated the expression of FOXA1 via c-Fos in PAAD cells. Mechanistically, CSN6 stabilized c-Fos protein by binding to it and decreasing its ubiquitination. Our work identified CSN6 as a targeting-permissible deubiquitinase, and CSN6 inhibition maybe a potential treatment strategy for PAAD.