Background and Aims: Immunotherapy has become the standard‐of‐care treatment for hepatocellular carcinoma (HCC), but its efficacy remains limited. To identify immunotherapy‐susceptible HCC, we profiled the molecular abnormalities and tumor immune microenvironment (TIME) of rapidly increasing nonviral HCC. Approaches and Results: We performed RNA‐seq of tumor tissues in 113 patients with nonviral HCC and cancer genome sequencing of 69 genes with recurrent genetic alterations reported in HCC. Unsupervised hierarchical clustering classified nonviral HCCs into three molecular classes (Class I, II, III), which stratified patient prognosis. Class I, with the poorest prognosis, was associated with TP53 mutations, whereas class III, with the best prognosis, was associated with cadherin‐associated protein beta 1 (CTNNB1) mutations. Thirty‐eight percent of nonviral HCC was defined as an immune class characterized by a high frequency of intratumoral steatosis and a low frequency of CTNNB1 mutations. Steatotic HCC, which accounts for 23% of nonviral HCC cases, presented an immune‐enriched but immune‐exhausted TIME characterized by T cell exhaustion, M2 macrophage and cancer‐associated fibroblast (CAF) infiltration, high PD‐L1 expression, and TGF‐β signaling activation. Spatial transcriptome analysis suggested that M2 macrophages and CAFs may be in close proximity to exhausted CD8+ T cells in steatotic HCC. An in vitro study showed that palmitic acid‐induced lipid accumulation in HCC cells upregulated PD‐L1 expression and promoted immunosuppressive phenotypes of cocultured macrophages and fibroblasts. Patients with steatotic HCC, confirmed by chemical‐shift MR imaging, had significantly longer PFS with combined immunotherapy using anti–PD‐L1 and anti‐VEGF antibodies. Conclusions: Multiomics stratified nonviral HCCs according to prognosis or TIME. We identified the link between intratumoral steatosis and immune‐exhausted immunotherapy‐susceptible TIME.
Extensive gastrointestinal surgery surveillance data in Japan were analyzed to examine the differences in the risk factors for surgical site infection (SSI) between laparotomy and laparoscopic abdominal procedures. Surgical procedures investigated in the study were gastrectomy, cholecystectomy, colectomy, rectal resection, and appendectomy. A total of 32,629 patients were included in the study. The study participants were divided into two groups according to the year of surgery, 2003–2009 (first study period) and 2010–2015 (second study period), due to the increase in the number of laparoscopic surgeries in the second study period. The incidence of SSI was stratified by three SSI classifications (superficial incisional, deep incisional, and organ/space SSI). Multiple logistic regression analysis was performed to predict the risk factors for SSI. The percentage of laparoscopic surgeries performed has increased linearly since 2010. Patients in the second study period were significantly older and had a higher prevalence of SSI risk factors compared with those in the first study period. In addition, the predictive factors changed substantially in most surgical procedures between the two study periods. Wound class ≥ 3 was a ubiquitous risk factor for superficial incisional SSI (SI-SSI) and organ/space SSI (OS-SSI) in both open (laparotomy) and laparoscopic procedures in the first study period. Meanwhile, in the second study period, operative duration was a ubiquitous risk factor in both procedures. The risk factors for SI-SSI differed from those for OS-SSI in the five abdominal surgeries investigated in the study. Periodic examination of risk factors for SSI is recommended in an aging society.
Background Driver alterations may represent novel candidates for driver gene-guided therapy; however, intrahepatic cholangiocarcinoma (ICC) with multiple genomic aberrations makes them intractable. Therefore, the pathogenesis and metabolic changes of ICC need to be understood to develop new treatment strategies. We aimed to unravel the evolution of ICC and identify ICC-specific metabolic characteristics to investigate the metabolic pathway associated with ICC development using multiregional sampling to encompass the intra- and inter-tumoral heterogeneity. Methods We performed the genomic, transcriptomic, proteomic and metabolomic analysis of 39–77 ICC tumour samples and eleven normal samples. Further, we analysed their cell proliferation and viability. Results We demonstrated that intra-tumoral heterogeneity of ICCs with distinct driver genes per case exhibited neutral evolution, regardless of their tumour stage. Upregulation of BCAT1 and BCAT2 indicated the involvement of ‘Val Leu Ile degradation pathway’. ICCs exhibit the accumulation of ubiquitous metabolites, such as branched-chain amino acids including valine, leucine, and isoleucine, to negatively affect cancer prognosis. We revealed that this metabolic pathway was almost ubiquitously altered in all cases with genomic diversity and might play important roles in tumour progression and overall survival. Conclusions We propose a novel ICC onco-metabolic pathway that could enable the development of new therapeutic interventions.
Background: In this study, we aimed to develop and validate a nomogram to predict overall survival (OS) and recurrence-free survival (RFS) in patients who underwent curative resection of ampulla of Vater (AOV) cancer. This is the first study for nomograms in AOV cancer patients using retrospective data based on an international multicenter study.
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