Effect of bile duct resection on the prognosis of patients with hepatocellular carcinoma combined with extrahepatic bile duct tumor thrombus.

BACKGROUND: Surgical therapy is the most optimal treatment for hepatocellular carcinoma (HCC) combined with bile duct tumor thrombus (BDTT) patients. However, whether to perform bile duct resection (BDR) is still controversial. The purpose of this multicenter research is to compare the effect of BDR on the prognosis of extrahepatic BDTT patients. METHODS: We collected the data of 111 HCC patients combined with extrahepatic BDTT who underwent radical hepatectomy from June 1, 2004 to December 31, 2021. Those patients had either received hepatectomy with extrahepatic bile duct resection (BDR group) or hepatectomy without bile duct resection (NBDR group). Inverse probability of treatment weighting (IPTW) was used to reduce the potential bias between two groups and balance the influence of confounding factors in baseline data. Then compare the prognosis between the two groups of patients. Cox regression model was used for univariate and multivariate analysis to further determine the independent risk factors that influence the prognosis of HCC-BDTT patients. RESULTS: There were 38 patients in the BDR group and 73 patients in the NBDR group. Before and after IPTW, there were no statistical significance in OS, RFS and intraoperative median blood loss between the two groups (all P > 0.05). Before IPTW, the median postoperative hospital stay in the NBDR group was shorter (P = 0.046) and the grade of postoperative complications was lower than BDR group (P = 0.014). After IPTW, there was no difference in postoperative hospital stay between the two groups (P > 0.05). The complication grade in the NBDR group was still lower than that in the BDR group (P = 0.046). The univariate analysis showed that TNM stage and portal vein tumor thrombus (PVTT) were significantly correlated with OS (both P < 0.05). Preoperative AFP level, TNM stage and prognostic nutritional index (PNI) were significantly correlated with postoperative RFS (all P < 0.05). Multivariate analysis showed that tumor TNM stage was an independent risk factor for the OS rate (P = 0.014). TNM stage, PNI and AFP were independent predictors of RFS after radical hepatectomy (all P < 0.05). CONCLUSIONS: For HCC-BDTT patients, hepatocellular carcinoma resection combined with choledochotomy to remove the tumor thrombus may benefit more.

FASN-mediated fatty acid biosynthesis remodels immune environment in Clonorchis sinensis infection-related intrahepatic cholangiocarcinoma.

BACKGROUND & AIMS: Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver cancer and is highly lethal. Clonorchis sinensis (C. sinensis) infection is an important risk factor for iCCA. Here we investigated the clinical impact and underlying molecular characteristics of C. sinensis infection-related iCCA. METHODS: We performed single-cell RNA sequencing, whole-exome sequencing, RNA sequencing, metabolomics and spatial transcriptomics in 251 patients with iCCA from three medical centers. Alterations in metabolism and the immune microenvironment of C. sinensis-related iCCAs were validated through an in vitro co-culture system and in a mouse model of iCCA. RESULTS: We revealed that C. sinensis infection was significantly associated with iCCA patients' overall survival and response to immunotherapy. Fatty acid biosynthesis and the expression of fatty acid synthase (FASN), a key enzyme catalyzing long-chain fatty acid synthesis, were significantly enriched in C. sinensis-related iCCAs. iCCA cell lines treated with excretory/secretory products of C. sinensis displayed elevated FASN and free fatty acids. The metabolic alteration of tumor cells was closely correlated with the enrichment of tumor-associated macrophage (TAM)-like macrophages and the impaired function of T cells, which led to formation of an immunosuppressive microenvironment and tumor progression. Spatial transcriptomics analysis revealed that malignant cells were in closer juxtaposition with TAM-like macrophages in C. sinensis-related iCCAs than non-C. sinensis-related iCCAs. Importantly, treatment with a FASN inhibitor significantly reversed the immunosuppressive microenvironment and enhanced anti-PD-1 efficacy in iCCA mouse models treated with excretory/secretory products from C. sinensis. CONCLUSIONS: We provide novel insights into metabolic alterations and the immune microenvironment in C. sinensis infection-related iCCAs. We also demonstrate that the combination of a FASN inhibitor with immunotherapy could be a promising strategy for the treatment of C. sinensis-related iCCAs. IMPACT AND IMPLICATIONS: Clonorchis sinensis (C. sinensis)-infected patients with intrahepatic cholangiocarcinoma (iCCA) have a worse prognosis and response to immunotherapy than non-C. sinensis-infected patients with iCCA. The underlying molecular characteristics of C. sinensis infection-related iCCAs remain unclear. Herein, we demonstrate that upregulation of FASN (fatty acid synthase) and free fatty acids in C. sinensis-related iCCAs leads to formation of an immunosuppressive microenvironment and tumor progression. Thus, administration of FASN inhibitors could significantly reverse the immunosuppressive microenvironment and further enhance the efficacy of anti-PD-1 against C. sinensis-related iCCAs.

High Bile Titer and High Bile to Serum Ratio of CYFRA 21 - 1 Reliably Discriminate Malignant Biliary Obstruction Caused by Cholangiocarcinoma.

INTRODUCTION: Previously we demonstrated that elevated serum CYFRA 21 - 1 is a reliable diagnostic and prognostic biomarker for biliary tract cancers. This study aims to explore the diagnostic performance of bile CYFRA 21 - 1 (bCYFRA 21 - 1) in discriminating malignant biliary obstruction (MBO) caused by cholangiocarcinoma (CCA). METHODS: 77 CCA patients ((17 intrahepatic CCA (iCCA), 49 perihilar CCA (pCCA) and 11 distal CCA (dCCA)) and 43 benign patients with biliary obstruction were enrolled. Serum and bile levels of CYFRA 21 - 1, carcinoembryonic antigen (CEA) and carbohydrate antigen 19 - 9 (CA19-9) were quantified. Diagnostic performances of these biomarkers were estimated by receiver operator characteristic curves. Subgroups analysis of these tumor markers among CCA subtypes was performed. RESULTS: High bCYFRA 21 - 1 (cut-off value of 59.25 ng/mL with sensitivity of 0.889 and specificity of 0.750) and high bile to serum ratio of CYFRA 21 - 1 (b/sCYFRA 21 - 1, cut-off value of 31.55 with sensitivity of 0.741 and specificity of 0.778) achieved better diagnostic performance than any other biomarker in discriminating MBO. Subgroup analysis revealed that bCYFRA 21 - 1 was significantly elevated in all CCA subtypes; moreover b/sCYFRA 21 - 1 was upregulated in pCCA and dCCA (the mean b/sCYFRA 21 - 1 of pCCA was highest among CCA subtypes: 57.90, IQR 29.82-112.27). CONCLUSIONS: Both high biliary CYFRA 21 - 1 and high bile to serum ratio of CYFRA 21 - 1 were reliable diagnostic biomarkers for MBO caused by CCA.

Hepatic Resection Provides Survival Benefit for Selected Intermediate-Stage (BCLC-B) Hepatocellular Carcinoma Patients / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The intermediate stage of hepatocellular carcinoma (HCC) (Barcelona Clinic Liver Cancer [BCLC] B) comprises a highly heterogeneous population, and the treatment strategy is still controversial. Because of the heterogeneity, a subclassification of intermediate-stage HCCs was put forward by Bolondi according to the ‘beyond Milan and within up-to-7' criteria and Child-Pugh score. In this study, we aim to analyze the prognosis of BCLC-B stage HCC patients who received hepatic resection according to the Bolondi's subclassification. MATERIALS AND METHODS: One thousand and one hundred three patients diagnosedwith HCC and treatedwith hepatic resectionwere enrolled in our hospital between 2006 and 2012. According to Bolondi's subclassification, the BCLC-B patients were divided into four groups. Recurrence-free survival (RFS) and overall survival (OS) were analyzed. RESULTS: According to Bolondi's subclassification, the BCLC-B patients were divided into four groups: B1 (n=41, 18.7%), B2 (n=160, 73.1%), B3 (n=11, 5.0%), and B4 (n=7, 3.2%). Significant difference was observed between B1 and other groups (B1 vs. B2, p=0.022; B1 vs. B3, p < 0.001; B1 vs. B4, p < 0.001), but no difference for B2 vs. B4 (p=0.542) and B3 vs. B4 (p=0.542). In addition, no significant differences were observed between BCLC-A and BCLC-B1 group for both RFS (p=0.087) and OS (p=0.643). In multivariate analysis, BCLC-B subclassification was not a risk factor for both OS (p=0.263) and RFS (p=0.892). CONCLUSION: In our study, HCC patients at B1 stagewere benefited from hepatic resection and had similar survival to BCLC-A stage patients. Our study provided rationality of hepatic resection for selected BCLC-B stage HCC patients instead of routine transarterial chemoembolization.