Long-term Survival Of Hepatocellular Carcinoma Patients Research Articles

Exploration of Key Genes Combining with Immune Infiltration Level andTumor Mutational Burden in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a lethal malignancy due to its heterogeneity and aggressive behavior. Recently, somatic mutations and tumor cell interactions with the surrounding tumor immune microenvironment (TIME) have been reported to participate in HCC carcinogenesis and predict HCC progression. In this study, we aimed to investigate the association between tumor mutational burden (TMB) and TIME in HCC. Additionally, we sought to identify differentially expressed genes (DEGs) associated with HCC prognosis and progression. The expression, clinical, and mutational data were downloaded from the cancer genome atlas (TCGA) database. The immune infiltration levels and TMB levels of the HCC samples were estimated and the samples were divided into immune cluster (ICR)-1 and 2 based on immune infiltration score and high and low TMB groups based on TMB score. Thereafter, differential gene expression analysis was conducted to identify the DEGs in the ICR1/2 and high/low TMB groups, and the intersecting DEGs were selected. Thereafter, Cox regression analysis was performed on 89 significant DEGs, among which 19 were associated with prognosis. These 19 DEGs were then used to construct a prognostic model based on their expression levels and regression coefficients. Thereafter, we analyzed the DEGs in mutant and wildtype TP53 HCC samples and identified high BCL10 and TRAF3 expression in the mutant TP53 samples. BCL10 and TRAF3 expression was detected by real-time quantitative reverse transcription PCR and immunohistochemistry, and their clinical correlation, biological function, and immune infiltration levels were analyzed by chi-square analyses, Gene Set Enrichment Analysis (GSEA), and "ssGSEA", respectively. The results of our study revealed that immune infiltration level was correlated with TMB and that they synergistically predicted poor prognosis of HCC patients. DEGs enriched in immune-related pathways could serve as indicators of immunotherapy response in HCC. Among these DEGs, BCL10 and TRAF3 were highly expressed in HCC tissues, especially in the mutant TP53 group, and they co-operatively exhibited immunological function, thereby affecting HCC progression and prognosis. In this study, we identified BCL10 and TRAF3 as potential prognostic indicators in HCC patients. Additionally, we found that BCL10 and TRAF3 influence TMB and TIME in HCC patients and can be used for the development of immune-based therapies for improving the long-term survival of HCC patients.

Predictors of short-term death and long-term survival in advanced hepatocellular carcinoma (HCC) treated with contemporary tyrosine kinase inhibitors (TKI) or immunotherapy: A multicenter analysis from the HCC-CHORD consortium.

4098 Background: Advances in systemic therapy for HCC have increased treatment options, including TKIs and immunotherapy combinations. Variables that predict patient outcomes may be helpful in personalizing treatment decisions. The aim of this study was to identify predictors of short-term death (STD) and long-term survival (LTS) for HCC patients. Methods: Retrospective review of patients with advanced HCC who received a TKI or immunotherapy combinations was conducted between Aug 2018 to Aug 2022 in the Canadian provinces of British Columbia, Alberta, Nova Scotia, Manitoba, as well as from select institutions in Ontario (n = 2). Prior locoregional therapies were permitted. Variables examined were: Barcelona Clinic Liver Cancer (BCLC) stage, Child-Pugh class, albumin-bilirubin (ALBI) grade, alpha fetoprotein (AFP) level, microvascular invasion (MVI), and distant metastases. Multivariate logistic regression was used to determine independent predictors of STD (patient survival < 6 months vs others) and LTS (patient survival > 18 months vs others). Results: 520 patients with the following baseline characteristics were included: median age 66, 84.6% male, 87.4% ECOG performance status 0-1, 69.7% BCLC stage C, and 88.7% Child-Pugh A. First-line treatments were primarily: lenvatinib 57.3%, sorafenib 8.1%, and atezolizumab/bevacizumab 31.7%. Median progression-free survival was 7.4 months (95% CI: 6.2 to 8.4), and overall survival was 17.1 months (95% CI:, 15.1 to 18.8). Independent predictors of STD were (odds ratio): ALBI grade (2.26), MVI (2.13), and distant metastases (2.14). These three factors were also predictive for LTS: ALBI grade (0.45), MVI (0.49), and distant metastases (0.36). Child-Pugh class, AFP, and BCLC stage were not predictive of STD nor LTS (Table). Conclusions: This study supports higher ALBI grade, MVI and distant metastases as predictors of STD, while lower ALBI grade, absence of MVI and lack of distant metastases were predictive of LTS in HCC patients treated with contemporary TKIs or immunotherapy combination regimens. These predictors may help guide treatment decisions in patient populations underrepresented in clinical trials, including patients with Child-Pugh B7 score who are often excluded. [Table: see text]

Sarcopenia Imperils Postoperative Long-Term Survival in HCC Patients with Metabolic Dysfunction-Associated Fatty Liver Disease: A Propensity Score Matching Analysis.

Recent research has suggested that sarcopenia may have an impact on postoperative outcomes. The number of hepatocellular carcinoma (HCC) patients with metabolic dysfunction-associated fatty liver disease (MAFLD) has increased significantly over time. The main objective of this study was to investigate the impact of sarcopenia on the prognosis of HCC patients with MAFLD after hepatectomy. A multivariate Cox proportional hazards model and a propensity score matching (PSM) analysis were conducted to ensure that the baseline characteristics were similar. Kaplan‒Meier survival curves were used to compare the prognosis of the two groups. This study involved 112 HCC patients with MAFLD undergoing hepatectomy. Sarcopenia was indicated as a risk factor for both recurrence-free survival (RFS) and overall survival (OS) in HCC patients with MAFLD after multivariate analysis (p=0.002 and 0.022, respectively). After conducting PSM analysis, Kaplan‒Meier survival curve analysis revealed significant differences in both the RFS and OS between the two groups (p=0.0002 and p=0.0047, respectively). All results showed that sarcopenia had a poor prognosis for HCC patients with MAFLD undergoing hepatectomy. In summary, our study suggests that sarcopenia might be a risk factor for OS and RFS in HCC patients with MAFLD who underwent hepatectomy through multivariate analysis and PSM analysis. Sarcopenia imperils postoperative survival rates and this finding can guide clinical decision-making. For postoperative patients, preventing or treating sarcopenia can potentially improve survival outcomes for patients with HCC and MAFLD.

Super‐stable homogeneous embolic agents advance the treatment of hepatocellular carcinoma

Super‐stable homogeneous embolic agents advance the treatment of hepatocellular carcinoma

Wide surgical margins improve prognosis for HCC with microvascular invasion.

Hepatocellular carcinoma (HCC) is the sixth leading cause of malignant tumors worldwide. Liver resection is a pivotal treatment modality for HCC. Surgical margin plays an important role in decreasing recurrence and improving prognosis for HCC patients. This paper aimed to perform a systematic review of the literature in regard to surgical margin in HCC patients with microvascular invasion (MVI). Residual MVI due to insufficient surgical margins is the main origin of postoperative recurrence and metastasis in HCC patients. A wide surgical margin (WSM) significantly improves oncological outcomes and long-term survival in HCC patients with MVI. Progress in the preoperative prediction of MVI may contribute to precise surgical decision-making in the future. WSM was associated with better outcomes in HCC patients with MVI. WSM is recommended for well-preserved liver function HCC patients who are predicted to have a high risk of MVI preoperatively.

Prognostic Prediction for Patients with Hepatocellular Carcinoma and Ascites: Role of Albumin-Bilirubin (ALBI) Grade and Easy (EZ)-ALBI Grade.

Patients with hepatocellular carcinoma (HCC) often have co-existing ascites, which is a hallmark of liver decompensation. The albumin-bilirubin (ALBI) grade and EZ (easy)-ALBI grade are used to assess liver functional reserve in HCC, but the predictive accuracy of these two models in HCC patients with ascites is unclear. We aimed to determine the prognostic role of ALBI and EZ-ALBI grades in these patients. A total of 4431 HCC patients were prospectively enrolled and retrospectively analyzed. Independent prognostic predictors were identified by the multivariate Cox proportional hazards model. Of all patients, 995 (22.5%) patients had ascites. Grade 1, 2, and 3 ascites were found in 16%, 4%, and 3% of them, respectively. A higher ascites grade was associated with higher ALBI and EZ-ALBI scores and linked with decreased overall survival. In the Cox multivariate analysis, serum bilirubin level > 1.1 mg/dL, creatinine level ≥ 1.2 mg/dL, α-fetoprotein ≥ 20 ng/mL, total tumor volume > 100 cm3, vascular invasion, distant metastasis, poor performance status, ALBI grade 2 and 3, EZ-ALBI grade 2 and 3, and non-curative treatments were independently associated with increased mortality (all p < 0.05) among HCC patients with ascites. The ALBI and EZ-ALBI grade can adequately stratify overall survival in both the entire cohort and specifically in patients with ascites. Ascites is highly prevalent and independently predict patient survival in HCC. The ALBI and EZ-ALBI grade are feasible markers of liver dysfunction and can stratify long-term survival in HCC patients with ascites.

Recent progress in molecular mechanisms of postoperative recurrence and metastasis of hepatocellular carcinoma.

Hepatectomy is currently considered the most effective option for treating patients with early and intermediate hepatocellular carcinoma (HCC). Unfortunately, the postoperative prognosis of patients with HCC remains unsatisfactory, predominantly because of high postoperative metastasis and recurrence rates. Therefore, research on the molecular mechanisms of postoperative HCC metastasis and recurrence will help develop effective intervention measures to prevent or delay HCC metastasis and recurrence and to improve the long-term survival of HCC patients. Herein, we review the latest research progress on the molecular mechanisms underlying postoperative HCC metastasis and recurrence to lay a foundation for improving the understanding of HCC metastasis and recurrence and for developing more precise prevention and intervention strategies.

107P Preliminary result of anatomical hepatectomy on recurrence based on preoperative circulating tumor cell status in hepatocellular carcinoma

Hepatocellular carcinoma (HCC), which comprises the majority of liver cancer was a leading cause of death worldwide. The high rate of recurrence severely hampers the long-term survival of HCC patients after hepatectomy. Early recurrence, which is mainly caused by intrahepatic dissemination, accounts for nearly 70% of all recurrent cases. Circulating tumor cells (CTC) has shown potential clinical implications. CTC was associated with the severity of microvascular invasion (mVI) in the peritumoral tissue.

720P Integrative genomic analysis of matched primary and recurrent tumors reveals molecular characteristics of hepatocellular carcinoma with short-term recurrence

High incidence of recurrence is a major challenge for the survival of hepatocellular carcinoma (HCC) patients. Few evidences are available to elucidate mechanisms of early recurrence in HCC patients. Exploring the genomic relation and evolutionary patterns between primary and recurrent tumors is important to prevent postoperative recurrence and improve long-term survival of HCC patients.

Clinical practice status of the adjuvant therapy in hepatocellular carcinoma (HCC): A survey of Chinese hepatobiliary surgeons.

e16127 Background: There are different views on the scope of indications for surgical treatment of HCC worldwide. Unlike the Barcelona Clinic Liver Cancer, the European Association for Study of the Liver, and the American Association for the Study of Liver Diseases which recommend surgical resection as the first choice only for early HCC, it is also recommended as the first treatment for selected patients with intermediate or advanced HCC in China. However, in any case, postoperative recurrence is an important issue affecting the long-term survival of HCC patients, and to date, there is no globally recognized treatment algorithm for adjuvant therapy. We performed a survey to understand the patient characteristics and clinical status of hepatobiliary surgeons’ decision aids for adjuvant treatment. Methods: This survey was conducted among senior hepatobiliary surgeons who work at high-volume hospitals in China. Surgeons were asked to fill out an online questionnaire by scanning the QR code. Results: From September to November 2021, 511 surgeons from 55 cities responded. Among them, 70.3% worked in general hospitals, 26.8% in cancer hospitals, and 2.9% in integrative medicine hospitals. The majority of the institutions were tertiary hospitals (91.2 %). When determining whether a patient was suitable or not for adjuvant therapy, surgeons mainly considered tumor factors (chosen by 92.8% and 81.6%) and patient factors (chosen by 80.8% and 75.3%). The analysis showed that the patients whom surgeons considered for adjuvant therapy had one or more of the following characteristics: Tumor factors including China liver cancer (CNLC) stage Ia-IIIb (preoperative), R1 resection, Child-Pugh A or B liver function, well recovery from surgery, presence of ≥1 high-risk recurrence factors (i.e. microvascular invasion, macrovascular tumor thrombus, and hilar lymph node metastasis); Patient factors which were hepatocarcinoma-related medical history (e.g., HBV/HCV) and affordability. Most surgeons used targeted therapy (83.8%, mainly anti-angiogenic multi-kinase inhibitors), TACE (72.8%), or combination therapy (60.3%, mainly targeted drugs combined with immunotherapy or TACE) as adjuvant therapy. When asked to choose the two most related factors impacting treatment compliance, 52.1% chose patients' financial status, and 51.7% considered adverse reactions. Less adverse reactions (71.0% of surgeons), better efficacy (66.7%), and a higher reimbursement ratio (53.3%) were the top 3 unmet need for future adjuvant therapy. Conclusions: This survey presented a patient portrait that Chinese hepatobiliary surgeons considered for adjuvant therapy and the practice patterns in adjuvant therapy for HCC. However, the patient group that can benefit from adjuvant therapy remains to be explored and validated in prospective clinical studies.

Update results from ALTER-H004 study: Anlotinib combined with TACE as adjuvant therapy in hepatocellular carcinoma patients at high risk of recurrence after surgery—A single-arm, multicenter, phase II clinical trial.

e16120 Background: Hepatectomy is considered to be an effective curative treatment for hepatocellular carcinoma (HCC), however, high recurrence rate after curative resection severely reduces the long-term survival of HCC patients (pts). Transarterial chemoembolization (TACE) as adjuvant therapy has been proved to improve clinical outcomes for pts with high recurrence risk factors after hepatectomy, but the effect is still unsatisfactory. ALTER-H004 trial was designed to evaluate the efficacy and safety of anlotinib as maintenance adjuvant treatment following inductional TACE in pts with HCC. Here we updated the results at the data cutoff of January 20, 2022. Methods: This single arm, multicenter, phase II trial of ALTER-H004 was planned to enroll 30 pts which with histologically confirmed HCC and undertook hepatectomy within 1-2 months. The recruited pts who did not recieve any previous tumor-related treatment must have any of the following high risk factors: ≥5 cm and &lt; 10 cm of tumor diameter, tumor number ≥3, tumor microvascular invasion M1 or M2, portal vein tumor thrombus resection (Cheng's classification I/II). Eligible pts received conventional TACE treatment within 1-2 months after hepatectomy. On the 3-5th day after TACE treatment, oral anlotinib (12mg, qd, d1-d14, q3w) was given until disease recurrence or unacceptable toxicity. The primary endpoint was disease free survival (DFS). Secondary endpoints included 1-year DFS rate, time to recurrence and safety. Results: By the cutoff date of January 20, 2022, 26 pts were enrolled and 25 pts received at least once tumor assessment. According to RECIST 1.1, 14 of 25 did not progress were still on treatment and 7 relapsed. One withdrew the consent and 3 discontinued because of intolerable adverse events. The longest duration of treatment is 16.53 months. The DFS were not mature and the 6-month DFS rates were 77.45% (95% CI: 53.83̃89.99). 12 of 25 pts (48.0%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 5 pts (20.0%) included hypertension (8.0%), leukocytopenia (8.0%) and ascites (4.0%). No grade 4 or 5 TRAEs occurred. Conclusions: The update results suggested that anlotinib combined with TACE as adjuvant therapy in HCC pts at high recurrence risk exhibited promising clinical benefit and favorable safety profile, and the results needed to be confirmed in trials continued subsequently. Clinical trial information: NCT04213118.

Nomogram for prediction of long-term survival with hepatocellular carcinoma based on NK cell counts

IntroductionAmong all immune cells, natural killer (NK) cells play an important role as the first line of defense against tumor. The purpose of our study is to observe whether the NK cell counts can predict the overall survival of patients with hepatocellular carcinoma (HCC). MethodsTo develop a novel model, from January 2010 to June 2015, HCC patients enrolled in Beijing Ditan hospital were divided into training and validation cohort. Cox multiple regression analysis was used to analyze the independent risk factors for 1-year, 3-year and 5-year overall survival (OS) of patients with HCC, and the nomogram was used to establish the prediction model. In addition, the decision tree was established to verify the contribution of NK cell counts to the survival of patients with HCC. ResultsThe model used in predicting overall survival of HCC included six variables (namely, NK cell counts, albumin (ALB) level, alpha-fetoprotein (AFP) level, portal vein tumor thrombus (PVTT), tumor number and treatment). The C-index of nomogram model in HCC patients predicting 1-year, 3-year and 5-year overall survival was 0.858, 0.788 and 0.782 respectively, which was higher than tumor–lymph node–metastasis (TNM) staging system, Okuda, model for end-stage liver disease (MELD), MELD-Na, the Chinese University Prognostic Index (CUPI) and Japan Integrated Staging (JIS) scores (p < 0.001). The decision tree showed the specific 5-year OS probability of HCC patients under different risk factors, and found that NK cell counts were the third in the column contribution. ConclusionsOur study emphasizes the utility of NK cell counts for exploring interactions between long-term survival of HCC patients and predictor variables.

944P Adjuvant camrelizumab combined with apatinib treatment after resection of hepatocellular carcinoma in CNLC II and III stage: A single-center prospective phase II trial

Hepatocellular carcinoma (HCC) is a common tumor worldwide and a leading cause of tumor-related death. Surgical resection is one of the most effective treatments with curative potential. However, high recurrence rate (up to 50-70% in 5 years) after curative resection severely reduces the long-term survival of HCC patients. Especially, survival after resection of HCC in China liver cancer (CNLC) stage II-III remains poor. Anti-PD-1 antibody Camrelizumab combined with apatinib has been shown to be safe and effective in patients with advanced HCC.

Surveillance as Determinant of Long-Term Survival in Non-Transplanted Hepatocellular Carcinoma Patients.

Simple SummarySome patients with hepatocellular carcinoma (HCC) obtain a very long survival, irrespective of any prediction. In this study, we looked for the impact of surveillance in long-term survival of HCC patients. After adjustment for confounders in multivariable logistic regression analysis, diagnosis under surveillance remained an independent predictor of long-term survival. In the surveillance group, observed and lead-time corrected survivals were significantly longer than in patients with casual/symptomatic diagnosis. However, when adjusted for baseline characteristics with inverse probability weights, surveillance and no surveillance groups demonstrated a similar survival, suggesting that the beneficial effect of surveillance is mediated by early stage diagnosis, which allows higher applicability of curative treatments. Surveillance is a major determinant of long-term survival and a wide implementation of surveillance programs should be pursued in order to improve the still poor prognosis of HCC patients.Purpose: We aimed at assessing the impact of surveillance on long-term survival in HCC patients. Methods: From the ITA.LI.CA database, we selected 1028 cases with long (≥5 years, LS group) and 2721 controls with short-term survival (<5 years, SS group). The association between surveillance and LS was adjusted for confounders by multivariable logistic regression analysis. Survival of surveilled patients was presented both as observed and corrected for the lead-time bias, and the comparison of survival between surveillance and no surveillance groups was also performed after balancing the baseline characteristics with inverse probability weights (IPW). Results: LS patients were more frequently diagnosed under surveillance (p < 0.0001), and had more favorable baseline characteristics. Surveillance was an independent predictor of LS (OR = 1.413, 95% CI 1.195–1.671; p < 0.0001). The observed and the lead-time corrected survival of surveilled patients were significantly longer compared to the survival of not surveilled patients (p < 0.0001 and p = 0.0008, respectively). In IPW adjusted populations, no survival differences were demonstrated between the two groups (p = 0.30). Conclusions: Surveillance, increasing early-stage diagnosis and applicability of curative treatments, is a fundamental determinant of long-term survival in HCC patients. A wide implementation of surveillance programs should be pursued in order to improve HCC patients’ prognosis.

Impact of splenomegaly and splenectomy on prognosis in hepatocellular carcinoma with portal vein tumor thrombus treated with hepatectomy.

BackgroundHepatocellular carcinoma (HCC) commonly occurs in patients with splenomegaly. This study aimed to investigate the impact of splenomegaly with or without splenectomy on long-term survival of HCC patients with portal vein tumor thrombus (PVTT) treated with liver resection (LR).MethodsHCC patients with PVTT who underwent LR from 2005 to 2012 from 6 hospitals were retrospectively studied. The long-term overall survival (OS) and recurrence-free survival (RFS) were compared between patients with or without splenomegaly, and between patients who did or did not undergo splenectomy for splenomegaly. Propensity score matching (PSM) analysis was performed to match patients in a 1:1 ratio.ResultsOf 716 HCC patients with PVTT who underwent LR, 140 patients had splenomegaly (SM group) and 576 patients had no splenomegaly (non-SM group). The SM group was further subdivided into 49 patients who underwent splenectomy (SPT group), and 91 patients who did not received splenectomy (non-SPT group). PSM matched 140 patients in the SM group, and 49 patients in the SPT group. Splenomegaly was an independent risk factor of poor RFS and OS. The OS and RFS rates were significantly better for patients in the non-SM group than the SM group (OS: P<0.001; RFS: P<0.001), and for patients in the SPT group than the non-SPT group (OS: P<0.001; RFS: P<0.001).ConclusionsPatients who had splenomegaly had significantly worse survival in HCC patients with PVTT. Splenectomy for splenomegaly significantly improved long-term survival in these patients.

Salinomycin-Loaded Small-Molecule Nanoprodrugs Enhance Anticancer Activity in Hepatocellular Carcinoma.

BackgroundThere is currently no effective treatment for advanced hepatocellular carcinoma (HCC), and chemotherapy has little effect on long-term survival of HCC patients, largely due to the cancer stem cell (CSC) chemoresistance of HCC.MethodsWe constructed a small-molecule nanometer-sized prodrug (nanoprodrug) loaded with salinomycin (SAL) for the treatment of HCC. SAL was encapsulated by the prodrug LA-SN38 (linoleic acid modified 7-ethyl-10-hydroxycamptothecin) to construct a self-assembled nanoprodrug further PEGylated with DSPE-PEG2000. We characterized this codelivered nanoprodrug and its antitumor activity both in vitro in human HCC cell lines and in vivo in mice.ResultsDelivery of the SAL- and LA-SN38-based nanoprodrugs effectively promoted apoptosis of HCC cells, exerted inhibition of HCC tumor-sphere formation as well as HCC cell motility and invasion, and reduced the proportion of CD133+ HCC-CSC cells. In nude mice, the nanoprodrug suppressed growth of tumor xenografts derived from human cell lines and patient.ConclusionOur results show that SAL-based nanoprodrugs are a promising platform for treating patients with HCC and a novel strategy for combination therapy of cancers.

Down-regulation of small nuclear RNA (snRNA) RNU5E-1 in hepatocellular carcinoma presents with vital clinical significance.

For lack of accurate diagnosis and ideal prognosis assessment, hepatocellular carcinoma (HCC) has become the fourth cancers-related death malignant diseases. Small nuclear RNAs (snRNAs) have been investigated as a new class of regulators associated with pathogenesis and clinical evaluation of tumors such as HCC. As for RNU5E-1, one newly identified snRNA, may have similar functions. However, the relationship between RNU5E-1 expression and HCC tumorigenesis remains unclear. The relative RNU5E-1 expression was measured in several HCC cell lines and HCC tissues of 100 patients using quantitative real-time PCR. All patients were grouped according to individual RNU5E-1 expression. Then, the potential association between RNU5E-1 expression in HCC clinical characteristics and prognostic information of patients was evaluated. Compared to human normal hepatocyte cell line QSG-7701, the RNU5E-1 expression in HCC cell lines (fold change: SK-HEP-1, 0.417; Hep 3B, 0.313; Huh-7, 0.189) were significantly down-regulated (P<0.05). Similarly, its expression levels were remarkably lower in HCC tissue than that in corresponding adjacent liver tissues (average fold change: 0.322, P=0.002). Besides, the expression level of RNU5E-1 was remarkably related to tumor size, vessel carcinoma embolus, differentiation level, TNM stages and tumor recurrence rate as well as long-term survival in HCC patients (P<0.05). Moreover, in Kaplan-Meier and Cox regression analysis, RNU5E-1 expression was remarkably correlated to postoperative tumor-free as well as long-term survival in HCC patients as independent factors (P<0.05). The research revealed that RNU5E-1 was down-regulated in HCC and it could be one of indicators for diagnosis and prognostic prediction of HCC patients.

Actual long-term survival in HCC patients with portal vein tumor thrombus after liver resection: a nationwide study.

Liver resection for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) offers a chance of cure, although survival is often limited. The actual 3-year survival and its associated prognostic factors have not been reported. A nationwide database of HCC patients with PVTT who underwent liver resection with 'curative' intent was analyzed. The clinicopathologic characteristics, the perioperative, and survival outcomes for the actual long-term survivors were compared with the non-long-term survivors (patients who died within 3years of surgery). Univariable and multivariable regression analyses were performed to identify predictive factors associated with long-term survival outcomes. The study included 1590 patients with an actuarial 3-year survival of 16.6%, while the actual 3-year survival rate was 11.7%. There were 171 patients who survived for at least 3years after surgery and 1290 who died within 3years of surgery. Multivariable regression analysis revealed that total bilirubin > 17.1μmol/l, AFP > 400ng/ml, types of hepatectomy, extent of PVTT, intraoperative blood loss > 400ml, tumor diameter > 5cm, tumor encapsulation, R0 resection, liver cirrhosis, adjuvant TACE, postoperative early recurrence (< 1year), and recurrence treatments were independent prognostic factors associated with actual long-term survival. One in nine HCC patients with PVTT reached the long-term survival milestone of 3years after resection. Major hepatectomy, controlling intraoperative blood loss, R0 resection, adjuvant TACE, and 'curative' treatment for initial recurrence should be considered for patients to achieve better long-term survival outcomes.

Post-transplant infection improves outcome of hepatocellular carcinoma patients after orthotopic liver transplantation

BACKGROUNDTumor recurrence after orthotopic liver transplantation (OLT) remains a serious threat for long-term survival of the recipients with hepatocellular carcinoma (HCC), since very few factors or measures have shown impact on overcoming HCC recurrence after OLT. Postoperative infection suppresses tumor recurrence and improves patient survival in lung cancer and malignant glioma probably via stimulating the immune system. Post-transplant infection (PTI), a common complication, is deemed to be harmful for the liver transplant recipients from a short-term perspective. Nevertheless, whether PTI inhibits HCC recurrence after OLT and prolongs the long-term survival of HCC patients needs to be clarified.AIMTo investigate the potential influence of PTI on the survival and tumor recurrence of patients with HCC after OLT.METHODSA total of 238 patients with HCC who underwent OLT between August 2002 and July 2016 at our center were retrospectively included and accordingly subdivided into a PTI group (53 patients) and a non-PTI group (185 patients). Univariate analyses, including the differences of overall survival (OS), recurrence-free survival (RFS), and post-recurrence survival (PRS), between the PTI and non-PTI subgroups as well as survival curve analysis were performed by the Kaplan-Meier method, and the differences were compared using the log rank test. The variables with a P-value < 0.1 in univariate analyses were included in the multivariate survival analysis by using a Cox proportional-hazards model.RESULTSThe 1-, 3-, and 5-year OS and RFS rates of the whole cohort were 86.6%, 69.0%, and 63.6%, and 75.7%, 60.0%, and 57.3%, respectively. The 1-, 3-, and 5-year OS rates for the PTI patient group (96.0%, 89.3%, and 74.0%) were significantly higher than those for the non-PTI group (84.0%, 63.4%, and 60.2%) (P = 0.033). The absence of PTI was an independent risk factor for dismal OS (relative risk [RR] = 2.584, 95%CI: 1.226-5.449) and unfavorable RFS (RR = 2.683, 95%CI: 1.335-5.390). Subgroup analyses revealed that PTI remarkably improved OS (P = 0.003) and RFS (P = 0.003) rates of HCC patients with vascular invasion (IV), but did not impact on OS (P = 0.404) and RFS (P = 0.304) of patients without VI. Among the patients who suffered post-transplant tumor recurrence, patients with PTI showed significantly better OS (P = 0.026) and PRS (P = 0.042) rates than those without PTI.CONCLUSIONPTI improves OS and RFS of the transplant HCC patients at a high risk for post-transplant death and tumor recurrence, which is attributed to suppressive effect of PTI on HCC recurrence.

Concomitant Inhibition of Cytoprotective Autophagy Augments the Efficacy of Withaferin A in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related mortality, and despite recent advances in early diagnosis and therapeutics, HCC related morbidity and mortality rate continue to rise. Clearly, it is imperative to develop novel effective therapies for HCC to improve long-term survival of HCC patients. We found that Withaferin A (WFA), a bioactive compound derived from Withania somnifera, is an effective agent for HCC inhibition. Interestingly, we observed that in addition to inducing apoptotic cell death, WFA also induces autophagy in HCC cells. Utilizing mRFP-EGFP-LC3B, LC3B-GFP/Lysotracker and LC3B-GFP/Rab7-RFP, we show that WFA induces autophagosomes-lysosomes fusion. WFA-induced autolysosomes exhibit intact protein degradation activity as evident with cathepsin-D activation and DQ-BSA assays. Importantly, we present that inhibiting WFA-induced autophagy either by blocking autophagosome-formation or by elevating lysosomal pH (Chloroquine and Bafilomycin) enhances WFA-induced growth-inhibition and apoptosis, indicating the presence of cytoprotective autophagy. Indeed, WFA and CQ combination shows synergism and higher efficacy in comparison to either monotherapy. Collectively, we reveal that the efficacy of WFA is somewhat diminished by the concomitant induction of cytoprotective autophagy which can be successfully conquered by cotreatment with CQ, and we pave the way for development of a novel combination therapeutic strategy for HCC.