Analysis of angiogenesis-related subtypes of hepatocellular carcinoma and tumor microenvironment infiltration feature in hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) is a highly vascularized tumor, and angiogenesis plays an important role in its progression. However, the role of angiogenesis in cell infiltration in the tumor microenvironment (TME) remains unclear. METHODS: We evaluated the associations of 35 angiogenesis-related genes (ARGs) with the clinicopathological features of 816 HCC patients. In addition, we assessed the associations between the ARGs and TME cell infiltration. A nomogram was constructed to determine the prognostic value of ARGs for HCC. The ARG score was used to distinguish angiogenic subtypes of HCC, and its usefulness for predicting the prognosis and treatment response of HCC patients was evaluated. RESULTS: We distinguished three ARG clusters differing in terms of TME cell infiltration, immune cell activation status, clinicopathological features, and clinical outcomes. There were significant associations of ARG expression with tumor immunity, the epithelial-mesenchymal transition (EMT), and transforming growth factor-ß expression. An ARG score model was constructed to generate a risk score for each patient based on differentially expressed genes between clusters. Furthermore, a high ARG score was associated with high expression of CTLA-4 and PD-L1/PD-1, and a low Tumor Immune Dysfunction and Exclusion score, indicating the usefulness of the ARG score for selecting patients for immunotherapy. Considering the relationship between ARGs and tumor immunity, immunotherapy combined with vascular-targeted therapy may be the best treatment for HCC. CONCLUSIONS: ARGs play an important role in TME diversity and complexity in HCC patients. The ARG score of HCC predicts TME invasion and can guide immunotherapy.

Association of tumor mutation burden and epidermal growth factor receptor inhibitor history with survival in patients with metastatic stage III/IV non-small-cell lung cancer: A retrospective study

OBJECTIVES: Lung cancer is the leading cause of cancer-related deaths worldwide. However, factors associated with the survival of patients with advanced non-small-cell lung cancer (NSCLC) who received only hospice care are largely unclear. In this study, we aimed to determine the prognostic factors correlated with survival in patients with advanced NSCLC who had undergone hospice care only. METHODS: A total of 102 patients with recurrent stage III/IV NSCLC after traditional treatment failure were investigated. Survival was measured from the date of enrollment to December 2019 or the time of death. Tumor tissues were collected, and DNA sequencing was performed to identify somatic mutations. Data on clinical factors of patients were collected and analyzed by univariate and multivariate analyses. Overall survival analysis was conducted using the Kaplan-Meier method. RESULTS: The 6-month, 1-year, and 2-year overall survival rates of the 102 patients with metastatic NSCLC were 17.65%, 3.92%, and 0.98%, respectively. The median overall survival of the 102 patients was 3.15 months. Tumor location in the peripheral lung, epidermal growth factor receptor (EGFR) inhibitor history, low tumor mutation load, adenocarcinoma, and poor performance status score were associated with prolonged survival compared with tumor location in the central lung, no EGFR inhibitor history, high tumor mutation load, squamous cell carcinoma, and good performance status score (p=0.045, p=0.003, p=0.045, p=0.021, and p=0.0003, respectively). CONCLUSIONS: EGFR inhibitor treatment history and tumor mutation load are risk factors for the overall survival of patients with stage III/IV NSCLC who have undergone only hospice care. These results provide a critical clinical basis for further study of nontraditional anti-tumor responses induced by EGFR inhibitors.

Regional differences in gallbladder cancer pathogenesis: Insights from a multi-institutional comparison of tumor mutations.

BACKGROUND: Although rare in the United States, gallbladder cancer (GBCA) is a common cause of cancer death in some parts of the world. To investigate regional differences in pathogenesis and outcomes for GBCA, tumor mutations were analyzed from a sampling of specimens. METHODS: Primary tumors from patients with GBCA who were treated in Chile, Japan, and the United States between 1999 and 2016 underwent targeted sequencing of known cancer-associated genes. Fisher exact and Kruskal-Wallis tests assessed differences in clinicopathologic and genetic factors. Kaplan-Meier methods evaluated differences in overall survival from the time of surgery between mutations. RESULTS: A total of 81 patients were included. Japanese patients (11 patients) were older (median age, 72 years [range, 54-81 years]) compared with patients from Chile (21 patients; median age, 59 years [range, 32-73 years]) and the United States (49 patients; median age, 66 years [range, 46-87 years]) (P = .002) and had more well-differentiated tumors (46% vs 0% for Chile/United States; P < .001) and fewer gallstone-associated cancers (36% vs 67% for Chile and 69% for the United States; P = .13). Japanese patients had a median mutation burden of 6 (range, 1-23) compared with Chile (median mutation burden, 7 [range, 3-20]) and the United States (median mutation burden, 4 [range, 0-27]) (P = .006). Tumors from Japanese patients lacked AT-rich interaction domain 1A (ARID1A) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations, whereas Chilean tumors lacked Erb-B2 receptor tyrosine kinase 3 (ERBB3) and AT-rich interaction domain 2 (ARID2) mutations. SMAD family member 4 (SMAD4) was found to be mutated similarly across centers (38% in Chile, 36% in Japan, and 27% in the United States; P = .68) and was univariately associated with worse overall survival (median, 10 months vs 25 months; P = .039). At least one potentially actionable gene was found to be altered in 80% of tumors. CONCLUSIONS: Differences in clinicopathologic variables suggest the possibility of distinct GBCA pathogenesis in Japanese patients, which may be supported by differences in mutation pattern. Among all centers, SMAD4 mutations were detected in approximately one-third of patients and may represent a converging factor associated with worse survival. The majority of patients carried mutations in actionable gene targets, which may inform the design of future trials.