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Intrahepatic cholangiocarcinoma (iCCA) is a lethal malignant neoplasm with limited therapeutic options. Previous studies have found that Notch1 overexpression alone suffices to induce iCCA in the mouse, albeit after long latency. The current study found that activation of the Yes-associated protein (Yap) proto-oncogene occurs during Notch1-driven iCCA progression. After co-expressing activated Notch1 intracellular domain (Nicd) and Yap (YapS127A) in the mouse liver, rapid iCCA formation and progression occurred in Nicd/Yap mice. Mechanistically, an increased expression of amino acid transporters and activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway was detected in Nicd/Yap mouse liver tumors. Significantly, the genetic deletion of Raptor, the major mTORC1 component, completely suppressed iCCA development in Nicd/Yap mice. Elevated expression of Notch1, YAP, amino acid transporters, and members of the mTORC1 pathway was also detected ubiquitously in a collection of human iCCA specimens. Their levels were associated with a poor patient outcome. This study demonstrates that Notch and YAP concomitant activation is frequent in human cholangiocarcinogenesis. Notch and YAP synergize to promote iCCA formation by activating the mTORC1 pathway.

Purpose: To retrospectively compare the efficacy and safety of combined radiofrequency ablation and percutaneous ethanol injection (RFA-PEI) with repeat hepatectomy for elderly patients with initial recurrent hepatocellular carcinoma (HCC) after hepatic surgery. Methods: From January 2009 to June 2015, 105 elderly patients (≥70 years) who underwent RFA-PEI (n = 57) or repeated hepatectomy (n = 48) for recurrent HCC ≤ 5.0 cm were included in the study. The overall survival (OS) and recurrence-free survival (RFS) were analysed with the Kaplan-Meier method and compared by the log-rank test. Non-tumour-related death, complications and hospital stays were assessed. Univariate and multivariate analyses were performed to identify the prognostic significance of the variables in predicting the OS and RFS. Results: OS rates were 78.2%, 40.8% and 36.7% at 1, 3 and 5 years after RFA-PEI and 76.3%, 52.5% and 42.6% after repeat hepatectomy, respectively (p = 0.413). Correspondingly, the 1-, 3- and 5-year RFS rates after RFA-PEI and repeat hepatectomy were 69.5%, 37.8%, 33.1% and 73.1%, 49.7%, 40.7%, respectively (p = 0.465). Non-tumour-related deaths in the RFA-PEI group (2/57) were significantly fewer than those in the repeat hepatectomy group (10/48) (p = 0.016). RFA-PEI was superior to repeat hepatectomy regarding the major complication rates and length of in-hospital stay (both p < 0.001). Multivariate analysis showed that the tumour number was the significant prognostic factor for the OS (hazard ratio (HR) = 1.961, 95% CI = 1.043-3.686, p = 0.037) and RFS (HR = 1.866, 95% CI = 1.064-3.274, p = 0.030). Conclusion: RFA-PEI provides comparable OS and RFS to repeat hepatectomy for elderly patients with small recurrent HCC after hepatectomy but with fewer non-tumour-related deaths, major complications and shorter hospital stays. [ABSTRACT FROM AUTHOR]

Objectives: To compare combined percutaneous radiofrequency ablation and ethanol injection (RFA-PEI) with hepatic resection (HR) in the treatment of resectable solitary hepatocellular carcinoma (HCC) with 2.1-5.0 cm diameter.Methods: From June 2009 to December 2015, 271 patients whom underwent RFA-PEI (n = 141) or HR (n = 130) in three centres were enrolled. The overall survival (OS) and recurrence-free survival (RFS) between groups were compared with Kaplan-Meier method and log-rank tests. Complications, hospital stay and cost were assessed.Results: The OS rates at 1, 3 and 5 years were 93.5%, 72.7%, 58.6% in RFA-PEI group and 82.3%, 57.5%, 51.8% in HR group (p = 0.021). The corresponding 1-, 3- and 5-year RFS rates were 65.8%, 41.3%, 34.3% in RFA-PEI group and 50.5%, 33.8%, 28.4% in HR group (p = 0.038). For patients with 2.1-3.0 cm tumours, the 1-, 3- and 5-year OS after RFA-PEI and HR were 98.0%, 82.3%, 74.2% and 89.4%, 65.1%, 61.9%, respectively (p = 0.024). The corresponding RFS were 79.6%, 54.7%, 45.1% in RFA-PEI group, and 57.6%, 43.9%, 31.7% in HR group, respectively (p = 0.020). RFA-PEI was superior to HR in major complication rates, length of hospital stay and cost (all p < 0.001).Conclusion: RFA-PEI had a survival benefit over HR in the treatment of solitary HCCs, especially for those with 2.1-3.0 cm in diameter.Key Points: • RFA-PEI provided superior survival to HR in solitary HCC with 2.1-5.0 cm in diameter. • RFA-PEI is superior to HR in complications, length of hospital stay and cost. • RFA-PEI might be an alternative treatment for solitary HCC within 5.0 cm in diameter. [ABSTRACT FROM AUTHOR]

This study investigated the effects of intratumoral injection of immunoactivator after microwave ablation on antitumor immunity in a mouse model of hepatocellular carcinoma. Hepatocellular carcinoma cell line Hepa1-6 was subcutaneously injected into C57/B6 mice to establish a mouse model of hepatocellular carcinoma. When tumor diameter reached 8 mm, microwave ablation was performed for 3 min with temperature controlled at 55°C. Cytokine sustained-release microspheres (CytoMPS) containing human interleukin-2 (hIL-2) and mouse granulocyte macrophage colony-stimulating factor (mGM-CSF) were injected into the tumor of mice in the experimental group (n=5) at 3, 7 and 14 days after ablation, while sustained-release microspheres containing no cytokine were used in the control group (n=5). Mice were sacrificed on the 17th day after ablation, and CD4+ and CD8+ T cells in peripheral blood were counted by flow cytometry. Spleen was collected from the mice to isolate lymphocytes. Lactate dehydrogenase (LDH) release assay was used to determine the cytotoxicity of spleen cells to Hepal-6 cells. Injection of CytoMPS after ablation increased the percentage of CD4+ and CD8+ T cells in peripheral blood. Cytotoxicity of CD8+ CTL to Hepal-6 is significantly higher in experimental group than in control group (P<0.01). The results showed that intratumoral injection of CytoMPS containing hIL-2 and mGM-CSF can significantly increase the proportion of CD4+ and CD8+ T cells in blood and increase the cytotoxicity of CTL cells to tumor cells in mice with hepatocellular carcinoma. [ABSTRACT FROM AUTHOR]

Background & Aims We aimed to establish and validate a nomogram to predict survival at 2 and 5 years after recurrence of hepatocellular carcinoma (HCC) in patients who have undergone curative resection. Methods We developed a nomogram using data from a training cohort of 638 patients (most with hepatitis B virus infection) with recurrence of HCC after curative resection at Sun Yat-sen University Cancer Center, in Guangzhou, China from 2007 through 2013. The median follow-up time was 39.7 months. Patients were evaluated every 3–4 months for the first 2 years after resection and every 3–6 months thereafter. The nomogram was based on variables independently associated with survival after HCC recurrence, including antiviral treatment; albumin-bilirubin grade and alpha-fetoprotein level at recurrence; time from primary resection to recurrence; size, site, number of recurrences; and treatment for recurrence. We validated the nomogram using data from an independent internal cohort of 213 patients treated at the same institution and an external cohort of 127 patients treated at 2 other centers in China, from 2002 through 2009. The predictive accuracy of the nomogram was measured using Harrell’s concordance index (C index) and compared with the Barcelona Clinic Liver Cancer staging system of recurrence. Results Our nomogram predicted survival of patients in the training cohort with a C-index of 0.797 (95% CI, 0.765–0.830)—greater than that of the Barcelona Clinic Liver Cancer staging system for recurrence (C-index score, 0.713; 95% CI, 0.680–0.745) ( P < .001). This nomogram accurately stratified patients into subgroups with predicted long, medium, and short survival times: the proportions of patients in each group who survived 2 years after HCC recurrence were 91.2%, 67.6%, and 23.8%; the proportions of patients in each group who survived 5 years after HCC recurrence were 74.9%, 53.3%, and 9.1%. Our nomogram predicted patient survival times with C-index scores of 0.756 (95% CI, 0.703–0.808) in the internal validation cohort and 0.747 (95% CI, 0.701–0.794) in the external validation cohorts. Conclusions We developed a nomogram to determine the probability of survival, at different time points, of patients with recurrence of HCC (most with hepatitis B virus infection), after curative resection and validated it internally and externally. [ABSTRACT FROM AUTHOR]

Background Malnutrition and immunological status are associated with survival in many cancers. Prognostic nutritional index (PNI) and body mass index (BMI) are recognized immune-nutritional indices and associated with postoperative outcome in hepatocellular carcinoma (HCC) patients. However, this association is still controversial. Our aim was to determine whether the combination of PNI and BMI is better than either alone in HCC patients' prognosis. Material and methods Preoperative PNI and BMI, patient demographics, clinical and pathological data from 322 HCC patients were collected and analyzed. Results Low PNI was correlated with age, cirrhosis, total bilirubin (TBIL) ≥34.2 μmol/L, and recurrence. Likewise, low BMI was associated with TBIL ≥34.2 μmol/L, portal vein tumor thrombi (PVTT), tumor size, tumor differentiation, TNM stage, and recurrence. Multivariate analysis identified TNM stage, PVTT, tumor size, PNI, and BMI as independent predictors of outcome in HCC patients. Low PNI combined with BMI (PNI + BMI) accurately predicted poorer outcome, particularly in patients with TNM stage I HCC. The predictive range of PNI + BMI was more sensitive than that of either alone. Conclusions preoperative PNI/BMI is an independent predictor of outcome for HCC patients, especially in patients with early stage HCC. Intriguingly, the PNI + BMI combination can enhance the accuracy of prognosis. [ABSTRACT FROM AUTHOR]

Background Recently, increasing studies have revealed the association of inflammatory parameters, such as preoperative platelet count, and the prognosis of hepatocellular carcinoma (HCC). However, the link between the platelet count and the prognosis of patients with HCC after hepatic resection is still controversial. Methods We searched PubMed, Web of Science, EMBASE, and CBM for relevant trials and analyzed outcomes with random-effects model. The hazard ratio (HR) and its 95% confidence interval (CI) were calculated. Results In total, 31 studies, including a total of 10,730 patients, met our criteria. The results showed that thrombocytopenia in HCC patients was associated with poor overall survival (HR = 1.47, 95% CI: 1.21-1.78), disease-free survival (HR = 1.36, 95% CI: 1.08-1.72), and a high risk of cancer recurrence (HR = 1.41, 95% CI: 1.22-1.62), but a low risk of extrahepatic metastasis (HR = 0.55, 95% CI: 0.47-0.63). Conclusions The meta-analysis revealed that preoperative platelet count could act as a significant biomarker in the prognosis of HCC, especially a platelet count of <100 × 10 3 /mm 3 . Additional high-quality trials are needed, considering the low-quality studies analyzed. [ABSTRACT FROM AUTHOR]

Rapid progress and metastasis remain the major treatment failure modes of hepatocarcinoma (HCC). Unfortunately, the underlying molecular mechanisms of hepatoma cell proliferation and migration are poorly understood. Metabolic abnormalities play critical roles in tumorigenesis and progression. Hexokinase domain containing 1 (HKDC1) catalyzes the phosphorylation of glucose. However, the functions and mechanisms of HKDC1 in cancer remain unknown. In this study, real-time RT-PCR and Western blotting assays were used to detect the HKDC1 expression levels in HCC tissues and cell lines. The Oncomine™ Cancer Microarray Database was applied to analysis the correlations between HKDC1 expression and HCC clinical characteristics. MTT and Transwell migration assays were performed to determine the functions of HKDC1 in HCC cells. The effect of HKDC1 on Wnt/β-catenin signaling pathway was assessed using Western blotting assay. In this study, we found that HKDC1 expression levels were elevated in HCC tissues compared with the adjacent tissues. HCC patients with high expression levels of HKDC1 had poor overall survival (OS). Furthermore, higher HKDC1 levels also predicted a worse OS of patients within solitary, elevated pre-operated serum alpha fetoprotein (AFP) level and higher tumor diameter. Moreover, silencing HKDC1 suppressed HCC cells proliferation and migration in vitro . Downregulated HKDC1 expression repressed β-Catenin and c-Myc expression, which indicates that silencing HKDC1 may reduce proliferation and migration via inhibiting the Wnt/β-catenin signaling pathway in HCC. In summary, HKDC1 provides further insight into HCC tumor progression and may provide a novel prognostic biomarker and therapeutic target for HCC treatment. [ABSTRACT FROM AUTHOR]