Treatment and prognosis of hepatic epithelioid hemangioendothelioma based on SEER data analysis from 1973 to 2014

Background: Hepatic epithelioid hemangioendothelioma (HEH) is a rare tumor of vascular origin with an unknown etiology, a low incidence, and a variable natural course. We evaluated the management and prognosis of HEH from the Surveillance, Epidemiology and End Results (SEER) program and changes in treatment modalities of HEH over 30 years. Methods: From 1973 to 2014 in the SEER database, we selected patients diagnosed with HEH. We analyzed the clinical characteristics, patterns of management, and clinical outcomes of patients with HEH. Results: We identi ed 79 patients with HEH (median age: 54.0 years;male to female ratio: 1:2.6). The initial extent of disease was local in 22 (27.8%) patients, regional metastasis in 22 (27.8%), distant metas-tasis in 31 (39.2%) and unknown in 4 (5.1%). The median size of primary tumor was 3.85 cm (interquartile range, 2.50 7.93 cm). Among 74 patients with available management data, the most common manage-ment was no treatment (29/74, 39.2%), followed by chemotherapy only (22/74, 29.7%), liver resection-based (13/74, 17.6%), and transplantation-based therapy (6/74, 8.1%). The 5-year cancer-speci c survival rate was 57.8%. Patients who underwent surgical treatment had signi cantly higher survival than those who underwent non-surgical treatment (5-year survival;88% vs. 49%, P=0.019). Multivariate analysis revealed that surgical therapy was the only independent prognostic factor for survival (hazard ratio: 0.20, P=0.040). Conclusions: Resection or liver transplantation is worth considering for treatment of patients with HEH.

Impact of guideline adherence on the prognosis of Barcelona clinic liver cancer stage B hepatocellular carcinoma

BACKGROUND Patients with Barcelona clinic liver cancer(BCLC)stage B hepatocellular carcinoma(HCC)are considerably heterogeneous in terms of tumor burden,liver function,and performance status.To improve the poor survival outcomes of these patients,treatment approaches other than transarterial chemoembolization(TACE),which is recommended by HCC guidelines,have been adopted in realworld clinical practice.We hypothesize that this non-adherence to treatment guidelines,particularly with respect to the use of liver resection,improves survival in patients with stage B HCC.AIM To assess guideline adherence in South Korean patients with stage B HCC and study its impact on survival.METHODS A retrospective analysis was conducted using data from 2008 to 2016 obtained from the Korea Central Cancer Registry.Patients with stage B HCC were categorized into three treatment groups,guideline-adherent,upward,and downward,based on HCC guidelines recommended by the Asian Pacific Association for the Study of the Liver(APASL),the European Association for the Study of the Liver(EASL),and the American Association for the Study of Liver Diseases(AASLD).The primary outcome was HCC-related deaths;tumor recurrence served as the secondary outcome.Survival among the groups was compared using the Kaplan-Meier method and the log-rank test.Predictors of survival outcomes were identified using multivariable Cox regression analysis.RESULTS In South Korea, over the study period from 2008 to 2016, a notable trend was observed in adherence to HCCguidelines. Adherence to the EASL guidelines started relatively high, ranging from 77% to 80% between 2008 and2012, but it gradually declined to 58.8% to 71.6% from 2013 to 2016. Adherence to the AASLD guidelines began at71.7% to 75.9% from 2008 to 2010, and then it fluctuated between 49.2% and 73.8% from 2011 to 2016. In contrast,adherence to the APASL guidelines remained consistently high, staying within the range of 90.14% to 94.5%throughout the entire study period. Upward treatment, for example with liver resection, liver transplantation, orradiofrequency ablation, significantly improved the survival of patients with BCLC stage B HCC compared to thatof patients treated in adherence to the guidelines (for patients analyzed according to the 2000 EASL guidelines, the5-year survival rates were 63.4% vs 27.2%, P < 0.001), although results varied depending on the guidelines.Progression-free survival rates were also significantly improved upon the use of upward treatments in certaingroups. Patients receiving upward treatments were typically < 70 years old, had platelet counts > 105/μL, andserum albumin levels ≥ 3.5 g/dL.CONCLUSIONAdherence to guidelines significantly influences survival in South Korean stage B HCC patients. Curativetreatments outperform TACE, but liver resection should be selected with caution due to disease heterogeneity.

Cancer-associated fibroblast-derived secreted phosphoprotein 1 contributes to resistance of hepatocellular carcinoma to sorafenib and lenvatinib

Background:Cancer-associated fibroblasts(CAFs)play an important role in the induction of chemo-resistance.This study aimed to clarify the mechanism underlying CAF-mediated resistance to two tyrosine kinase inhibitors(TKIs),sorafenib and lenvatinib,and to identify a novel therapeutic target for overcoming TKI resistance in hepatocellular carcinoma(HCC).Methods:We performed a systematic integrative analysis of publicly available gene expression datasets and whole-transcriptome sequencing data from 9 pairs of CAFs and para-cancer fibroblasts isolated from human HCC and para-tumor tissues,respectively,to identify key molecules that might induce resistance to TKIs.We then performed in vitro and in vivo experiments to validate selected targets and related mechanisms.The associations of plasma secreted phosphoprotein 1(SPP1)expression levels before sorafenib/lenvatinib treatment with progression-free survival(PFS)and overall survival(OS)of 54 patients with advanced HCC were evaluated using Kaplan-Meier and Cox regression analysis.Results:Bioinformatic analysis identified CAF-derived SPP1 as a candidate molecule driving TKI resistance.SPP1 inhibitors reversed CAF-induced TKI resistance in vitro and in vivo.CAF-derived SPP1 activated rapidly accelerated fibrosarcoma(RAF)/mitogen-activated protein kinase(MAPK)and phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR)through the integrin-protein kinase C-alpha(PKCα)signaling pathway and promoted epithelial-to-mesenchymal transition(EMT).A high plasma SPP1 level before TKI treatment was identified as an independent predictor of poor PFS(P=0.026)and OS(P=0.047)in patients with advanced HCC after TKI treatment.Conclusions:CAF-derived SPP1 enhances TKI resistance in HCC via bypass activation of oncogenic signals and EMT promotion.Its inhibition represents a promising therapeutic strategy against TKI resistance inHCC.Moreover,plasma SPP1 level before TKI treatment represents a potential biomarker for treatment response prediction.