Single cell analyses reveal the PD-1 blockade response-related immune features in hepatocellular carcinoma.

Background: Immunotherapy has demonstrated its potential to improve the prognosis of patients with hepatocellular carcinoma (HCC); however, patients' responses to immunotherapy vary a lot. A comparative analysis of the tumor microenvironment (TME) in responders and non-responders is expected to unveil the mechanisms responsible for the immunotherapy resistance and provide potential treatment targets. Methods: We performed sequencing analyses using 10x Genomics technology on six HCC patients who responded to anti-PD-1 therapy and one HCC patient who did not respond. Additionally, we obtained single cell data from untreated, responsive, and nonresponsive HCC patients from public databases, and used part of the datasets as a validation cohort. These data were integrated using algorithms such as Harmony. An independent validation cohort was established. Furthermore, we performed spatial transcriptomic sequencing on the tumor adjacent tissues of three HCC responsive patients using 10x Genomics spatial transcriptomic technology. Additionally, we analyzed data about three HCC patients obtained from public databases. Finally, we validated our conclusions using immunofluorescence, flow cytometry, and in vivo experiments. Results: Our findings confirmed the presence of "immune barrier" partially accounting for the limited efficacy of immunotherapy. Our analysis revealed a significant increase in TREM2+ Macrophages among non-responsive patients expressing multiple immunosuppressive signals. anti-Csf1r monoclonal antibodies effectively eliminated these macrophages and augmented the therapeutic effects of anti-PD-1 therapy. TCR+ Macrophages possessed direct tumor-killing capabilities. IL1B+ cDC2 was the primary functional subtype of cDC2 cells. Absence of THEMIShi CD8+ T subtypes might diminish immunotherapeutic effects. Furthermore, CD8+ T cells entered a state of stress after anti-PD-1 treatment, which might be associated with CD8+ T cell exhaustion and senescence. Conclusions: The profiles of immune TMEs showed differences in HCC patients responsive, non-responsive and untreated. These differences might explain the discounted efficacy of immunotherapy in some HCC patients. The cells and molecules, which we found to carry unique capabilities, may be targeted to enhance immunotherapeutic outcomes in patients with HCC.

YBX1 promotes stemness and cisplatin insensitivity in intrahepatic cholangiocarcinoma via the AKT/ß-catenin axis.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy characterized by a poor prognosis and closely linked to tumor stemness. However, the key molecules that regulate ICC stemness remain elusive. Although Y-box binding protein 1 (YBX1) negatively affects prognosis in various cancers by enhancing stemness and chemoresistance, its effect on stemness and cisplatin sensitivity in ICC remains unclear. METHODS: Three bulk and single-cell RNA-seq datasets were analyzed to investigate YBX1 expression in ICC and its association with stemness. Clinical samples and colony/sphere formation assays validated the role of YBX1 in stemness and sensitivity to cisplatin. AZD5363 and KYA1979K explored the interaction of YBX1 with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) and WNT/ß-catenin pathways. RESULTS: YBX1 was significantly upregulated in ICC, correlated with worse overall survival and shorter postoperative recurrence time, and was higher in chemotherapy-non-responsive ICC tissues. The YBX1-high group exhibited significantly elevated stemness scores, and genes linked to YBX1 upregulation were enriched in multiple stemness-related pathways. Moreover, YBX1 expression is significantly correlated with several stemness-related genes (SOX9, OCT4, CD133, CD44 and EPCAM). Additionally, YBX1 overexpression significantly enhanced the colony- and spheroid-forming abilities of ICC cells, accelerated tumor growth in vivo and reduced their sensitivity to cisplatin. Conversely, the downregulation of YBX1 exerted the opposite effect. The transcriptomic analysis highlighted the link between YBX1 and the PI3K/AKT and WNT/ß-catenin pathways. Further, AZD5363 and KYA1979K were used to clarify that YBX1 promoted ICC stemness through the regulation of the AKT/ß-catenin axis. CONCLUSIONS: YBX1 is upregulated in ICC and promotes stemness and cisplatin insensitivity via the AKT/ß-catenin axis. Our study describes a novel potential therapeutic target for improving ICC prognosis.

Nomograms to predict long-term survival for patients with gallbladder carcinoma after resection.

BACKGROUND: Surgical resection remains the primary treatment option for gallbladder carcinoma (GBC). However, there is a pressing demand for prognostic tools that can refine patients' treatment choices and tailor personalized therapies accordingly. AIMS: The nomograms were constructed using the data of a training cohort (n = 378) of GBC patients at Eastern Hepatobiliary Surgery Hospital (EHBH) between 2008 and 2018. The model's performance was validated in GBC patients (n = 108) at Guangzhou Centre from 2007 to 2018. METHODS AND RESULTS: The 5-year overall survival (OS) rate in the training cohort was 24.4%. Multivariate analyses were performed using preoperative and postoperative data to identify independent predictors of OS. These predictors were then incorporated into preoperative and postoperative nomograms, respectively. The C-index of the preoperative nomogram was 0.661 (95% CI, 0.627 to 0.694) for OS prediction and correctly delineated four subgroups (5-year OS rates: 48.1%, 19.0%, 15.6%, and 8.1%, p < 0.001). The C-index of the postoperative nomogram was 0.778 (95%CI, 0.756 -0.800). Furthermore, this nomogram was superior to the 8th TNM system in both C-index and the net benefit on decision curve analysis. The results were externally validated. CONCLUSION: The two nomograms showed an optimally prognostic prediction in GBC patients after curative-intent resection.

Liver resection versus liver transplantation for hepatocellular carcinoma within the Milan criteria based on estimated microvascular invasion risks.

Background: Preoperative prediction of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) may optimize individualized treatment decision-making. This study aimed to investigate the prognostic differences between HCC patients undergoing liver resection (LR) and liver transplantation (LT) based on predicted MVI risks. Methods: We analysed 905 patients who underwent LR, including 524 who underwent anatomical resection (AR) and 117 who underwent LT for HCC within the Milan criteria using propensity score matching. A nomogram model was used to predict preoperative MVI risk. Results: The concordance indices of the nomogram for predicting MVI were 0.809 and 0.838 in patients undergoing LR and LT, respectively. Based on an optimal cut-off value of 200 points, the nomogram defined patients as high- or low-risk MVI groups. LT resulted in a lower 5-year recurrence rate and higher 5-year overall survival (OS) rate than LR among the high-risk patients (23.6% vs 73.2%, P < 0.001; 87.8% vs 48.1%, P < 0.001) and low-risk patients (19.0% vs 45.7%, P < 0.001; 86.5% vs 70.0%, P = 0.002). The hazard ratios (HRs) of LT vs LR for recurrence and OS were 0.18 (95% confidence interval [CI], 0.09-0.37) and 0.12 (95% CI, 0.04-0.37) among the high-risk patients and 0.37 (95% CI, 0.21-0.66) and 0.36 (95% CI, 0.17-0.78) among the low-risk patients. LT also provided a lower 5-year recurrence rate and higher 5-year OS rate than AR among the high-risk patients (24.8% vs 63.5%, P = 0.001; 86.7% vs 65.7%, P = 0.004), with HRs of LT vs AR for recurrence and OS being 0.24 (95% CI, 0.11-0.53) and 0.17 (95% CI, 0.06-0.52), respectively. The 5-year recurrence and OS rates between patients undergoing LT and AR were not significantly different in the low-risk patients (19.4% vs 28.3%, P = 0.129; 85.7% vs 77.8%, P = 0.161). Conclusions: LT was superior to LR for patients with HCC within the Milan criteria with a predicted high or low risk of MVI. No significant differences in prognosis were found between LT and AR in patients with a low risk of MVI.

Development and validation of prognostic dynamic nomograms for hepatitis B Virus-related hepatocellular carcinoma with microvascular invasion after curative resection.

Background and Aim: The prediction models of postoperative survival for hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) with microvascular invasion (MVI) have not been well established. The study objective was the development of nomograms to predict disease recurrence and overall survival (OS) in these patients. Methods: Data were obtained from 1046 HBV-related MVI-positive HCC patients who had undergone curative resection from January 2014 to December 2017. The study was approved by the Eastern Hepatobiliary Surgery Hospital and Jinling Hospital ethics committee, and patients provided informed consent for the use of their data. Nomograms for recurrence and OS were created by Cox regression model in the training cohort (n=530). The modes were verified in an internal validation cohort (n= 265) and an external validation cohort (n= 251). Results: The nomograms of recurrence and OS based on preoperative serological indicators (HBV-DNA, neutrophil-lymphocyte ratio, a-fetoprotein), tumor clinicopathologic features (diameter, number), surgical margin and postoperative adjuvant TACE achieved high C-indexes of 0.722 (95% confidence interval [CI], 0.711-0.732) and 0.759 (95% CI, 0.747-0.771) in the training cohort, respectively, which were significantly higher than conventional HCC staging systems (BCLC, CNLC, HKLC).The nomograms were validated in the internal validation cohort (0.747 for recurrence, 0.758 for OS) and external validation cohort(0.719 for recurrence, 0.714 for OS) had well-fitted calibration curves. Our nomograms accurately stratified patients with HBV-HCC with MVI into low-, intermediate- and high-risk groups of postsurgical recurrence and mortality. Prediction models for recurrence-free survival (https://baishileiehbh.shinyapps.io/HBV-MVI-HCC-RFS/) and OS (https://baishileiehbh.shinyapps.io/HBV-MVI-HCC-OS/) were constructed. Conclusions: The two nomograms showed good predictive performance and accurately distinguished different recurrence and OS by the nomograms scores for HBV-HCC patients with MVI after resection.

The Comparison of Surgical Margins and Type of Hepatic Resection for Hepatocellular Carcinoma With Microvascular Invasion.

OBJECTIVE: The objective of this study was to investigate the impact of surgical margin and hepatic resection on prognosis and compare their importance on prognosis in patients with hepatocellular carcinoma (HCC). METHODS: The clinical data of 906 patients with HCC who underwent hepatic resection in our hospital from January 2013 to January 2015 were collected retrospectively. All patients were divided into anatomical resection (AR) (n = 234) and nonanatomical resection (NAR) group (n = 672) according to type of hepatic resection. The effects of AR and NAR and wide and narrow margins on overall survival (OS) and time to recurrence (TTR) were analyzed. RESULTS: In all patients, narrow margin (1.560, 1.278-1.904; 1.387, 1.174-1.639) is an independent risk factor for OS and TTR, and NAR is not. Subgroup analysis showed that narrow margins (2.307, 1.699-3.132; 1.884, 1.439-2.468), and NAR (1.481, 1.047-2.095; 1.372, 1.012-1.860) are independent risk factors for OS and TTR in patients with microvascular invasion (MVI)-positive. Further analysis showed that for patients with MVI-positive HCC, NAR with wide margins was a protective factor for OS and TTR compared to AR with narrow margins (0.618, 0.396-0.965; 0.662, 0.448-0.978). The 1, 3, and 5 years OS and TTR rate of the two group were 81%, 49%, 29% versus 89%, 64%, 49% (P = .008) and 42%, 79%, 89% versus 32%, 58%, 74% (P = .024), respectively. CONCLUSIONS: For patients with MVI-positive HCC, AR and wide margins were protective factors for prognosis. However, wide margins are more important than AR on prognosis. In the clinical setting, if the wide margins and AR cannot be ensured at the same time, the wide margins should be ensured first.

Surgical Margin Affects the Long-Term Prognosis of Patients With Hepatocellular Carcinoma Undergoing Radical Hepatectomy Followed by Adjuvant TACE.

BACKGROUND: The aim of this study was to investigate whether postoperative adjuvant transcatheter arterial chemoembolization (TACE) treatment in wide- and narrow-margin groups could improve the long-term prognosis of patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: A total of 670 patients with HCC who underwent radical hepatectomy from January 2016 to December 2017 were enrolled, including 397 patients and 273 patients in the wide- and narrow-margin groups. Recurrence-free survival (RFS) and overall survival (OS) outcomes were compared in the wide-margin and narrow-margin groups with and without adjuvant TACE postoperatively, respectively. Propensity score matching (PSM) analysis was used to match patients between TACE and no TACE groups in a 1:1 ratio. RESULTS: The wide-margin resection was associated with better RFS and OS rates than narrow-margin resection for patients with HCC. Patients with postoperative adjuvant TACE had a better RFS and OS than patients without postoperative adjuvant TACE in the narrow-margin group and reduced the intrahepatic recurrence rate (39.1% vs. 52.6%, P = .036) and the local recurrence rate in the liver (11.2% vs. 21.4%, P = .032). But postoperative adjuvant TACE did not alter recurrence and survival outcomes in the wide-margin group. Similar results were noted after propensity score matching (PSM). CONCLUSION: The wide-margin resection had better RFS and OS than the narrow-margin resection for patients with HCC. Postoperative adjuvant TACE was associated with reduced recurrence and improved OS after narrow-margin resection, but was not effective in the wide-margin resection.

Genomic landscape of Chinese patients with hepatocellular carcinoma using next-generation sequencing and its association with the prognosis.

INTRODUCTION AND OBJECTIVES: The occurrence of hepatocellular carcinoma (HCC) is not entirely clear at present. This study comprehensively described the landscape of genetic aberrations in Chinese HCC patients using next-generation sequencing (NGS) and investigated the association of genetic aberrations with clinicopathological characteristics and prognosis. MATERIALS AND METHODS: The clinicopathological data of 78 HCC patients undergoing surgery were retrospectively analyzed. The genomic DNA extracted from tumor samples was detected using a NGS-based gene panel. RESULTS: Mutations in TP53 (55%), TERT (37%), MUC16 (29%) and CTNNB1 (27%) were most common in HCC. The co-occurrences between frequently mutated genes occurring ≥10% were relatively common in HCC. Forty-eight (61.5%) cases harbored DNA damage repair gene mutations, mainly including PRKDC (11.5%), SLX4 (9.0%), ATM (7.7%), MSH6 (7.7%), and PTEN (6.4%), and 39 (50.0%) patients had at least one actionable mutation. FH amplification (odds ratio: 3.752, 95% confidence interval: 1.170-12.028, p=0.026) and RB1 mutations (odds ratio: 13.185, 95% confidence interval: 1.214-143.198, p=0.034) were identified as the independent risk factors for early postoperative recurrence in HCC. CONCLUSIONS: Our study provides a novel insight into the genomic profiling of Chinese HCC patients. FH amplification and RB1 mutations may be associated with an increased risk of early postoperative recurrence in HCC.

Surgical Strategies Affect the Long-Term Prognosis of Patients with Hepatocellular Carcinoma Adjacent to the Left Branch of the Portal Vein.

Purpose: When hepatocellular carcinoma (HCC) is closely associated with the left branch of the portal vein, there is still controversy regarding the surgical approach. Methods: This study enrolled 330 HCC patients with tumors adjacent to the left branch of the portal vein. Among them, 85 patients underwent left hemihepatectomy (LH), while the remaining 235 underwent liver lobectomy (LL), which included left medial segmentectomy or left lateral sectionectomy. Perioperative complications, time to recurrence and overall survival (OS) were compared using propensity score matching. Results: LH resulted in a lower 5-year recurrence rate and higher 5-year OS rate than LL (56.5% vs 74.0%, p=0.002; 67.4% vs 53.5%, p=0.029). The LL group showed a higher tendency for early recurrence (ER) and intrahepatic recurrence (IR). The cumulative IR rates at 1- 3-, and 5-years for the LH group and the LL group were 17.0%, 36.7%, 45.1% and 33.8%, 57.1%, 63.7%, respectively, with a p-value of 0.007. There was no statistically significant difference in the cumulative ER rates between the two groups at 1-, 3-, and 5- years. Furthermore, the LH group and the LL group had similar perioperative complications, and no cases of liver failure occurred. Conclusion: LH, compared to LL, reduced the IR rate and ER rate in HCC patients with tumor adjacent to the left branch of the portal vein. It improved the OS outcome of the patients, and there was no significant difference in perioperative complications between the two groups.

Elevated serum neutrophil-lymphocyte ratio is associated with worse long-term survival in patients with HBV-related intrahepatic cholangiocarcinoma undergoing resection.

Background: This study aimed to examine the influence of serum inflammatory marker levels on long-term outcomes after liver resection in patients with intrahepatic cholangiocarcinoma (ICC). Methods: Data from 1189 consecutive ICC patients who underwent liver resection were reviewed. The serum neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and prognostic nutritional index (PNI) were measured before surgery. Overall survival (OS) and tumour recurrence were analysed using the Kaplan-Meier method and compared using the log-rank test. Independent risk factors for OS and tumour recurrence were analysed using the Cox hazard regression model. Results: We identified elevated serum NLR (≥ 2.15) as an independent risk factor for both OS and tumour recurrence (hazard ratio [HR]: 1.327, 95% confidence interval [CI]: 1.105-1.593; HR: 1.274, 95% CI: 1.074-1.510) among the three inflammatory markers assessed. Elevated NLR was associated with higher carbohydrate antigen 19-9 (CA19-9) and carcinoembryonic antigen (CEA) levels, larger tumour size, multiple tumours, lymph node metastasis, vascular invasion, and more advanced tumour node metastasis (TNM) stage (III/IV). Subgroup analysis showed that elevated NLR was an independent risk factor for OS and tumour recurrence in patients with hepatitis B virus (HBV) infection compared with patients without HBV infection (HR: 1.347, 95% CI: 1.073-1.690; HR: 1.386, 95% CI: 1.112-1.726). Conclusions: Elevated serum NLR was associated with worse prognosis among ICC patients who underwent liver resection, especially in patients with HBV infection.

Spontaneous bacterial peritonitis in hepatocellular carcinoma after PD-1 inhibitor therapy: two clinical cases.

With the recent advances in immunotherapy, especially programmed cell death protein 1 (PD-1) inhibitors, the treatment of hepatocellular carcinoma (HCC) patients has entered a new stage. However, few reports have focused on spontaneous bacterial peritonitis (SBP) after PD-1 inhibitor treatment of intermediate-to advanced-stage HCC. In this article, we report two clinical cases of SBP after successful PD-1 inhibitor therapy. The patient's condition was assessed as a complete response (CR) according to the mRECIST criteria. Based on these two cases, we found that patients with large or giant HCC who have large tumour diameter should be closely monitored for SBP after successful PD-1 inhibitor therapy, especially when the imaging shows the rapid development of marked necrosis and depression at the tumour site. Early and active treatment is necessary to reduce the suffering caused by SBP.

Prognostic Nomograms Combined Adjuvant Lenvatinib for Hepatitis B Virus-related Hepatocellular Carcinoma With Microvascular Invasion After Radical Resection.

Background and Aim: Microvascular invasion (MVI) has been established as one of the most important contributors to the prognosis of primary hepatocellular carcinoma (HCC). The objective of this study was to investigate the potential effect of postoperative adjuvant therapy with lenvatinib on the long-term prognosis after radical resection in hepatitis B virus (HBV)-related HCC patients with MVI, as well as to predict the long-term survival based on nomograms. Methods: Data from 293 HBV-related hepatocellular carcinoma patients with histologically confirmed MVI who underwent R0 resection at Eastern Hepatobiliary Surgery Hospital (EHBH) was retrospectively analyzed. 57 patients received postoperative adjuvant therapy with lenvatinib, while 236 patients did not. The survival outcome of patients who received postoperative adjuvant lenvatinib versus those who did not was analyzed. Results: The 1-year, 2-year recurrence rates and survival rates of the lenvatinib group were improved compared to the non-lenvatinib group (15.9%, 43.2% vs 40.1%, 57.2%, P=0.002; 85.8%, 71.2% vs 69.6%, 53.3%, P=0.009, respectively). Similar findings were also observed after Propensity Score Matching (PSM) compared to non-PSM analyses The 1-year, 2-year recurrence rates and survival rates were more favorable for the lenvatinib group compared to the non-lenvatinib group (15.9%, 43.2% vs 42.1%, 57.4%, P=0.028; 85.8%, 71.2% vs 70.0%, 53.4%, P=0.024, respectively). As shown by univariate and multivariate analyses, absence of adjuvant lenvatinib treatment was identified as an independent risk factor for recurrence and survival. The established nomograms displayed good performance for the prediction of recurrence and survival, with a C-index of 0.658 and 0.682 respectively. Conclusions: Postoperative adjuvant therapy with lenvatinib was associated with improved long-term prognosis after R0 Resection in HBV-related HCC patients with MVI, which could be accurately predicted from nomograms.

Comparison of the safety and prognosis of sequential regorafenib after sorafenib and lenvatinib treatment failure in patients with unresectable hepatocellular carcinoma: a retrospective cohort study.

Background: There is lack of studies on sequential regorafenib after sorafenib and lenvatinib treatment failure in patients with unresectable hepatocellular carcinoma (HCC). This study was to explore the safety and prognosis of sequential regorafenib after sorafenib and lenvatinib failure in HCC patients. Methods: This study was a retrospective, real-world study that included 50 HCC patients who received sequential regrafinib after sorafenib and lenvatinib failure. The safety and prognosis of two groups were compared. Results: The incidence of all grade and III/IV adverse events were 68% and 24%. According to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 and modified (m) RECIST standards, the objective response rates (ORRs) after receiving regorafenib were 14.0% and 22.0%, respectively. The disease control rates (DCRs) were 62.0% and 60.0%, respectively. Based on different first-line targeted drugs, 50 patients were divided into sorafenib (n=22) and lenvatinib group (n=28). There was no differences between two groups except age and bilirubin. And there was no differences in other treatments before or after regorafenib. The baseline between two groups was basically same and had good comparability. There was no difference in incidence of all grade and III/IV adverse events, ORR and DCR between two groups (P>0.05). On long-term prognosis, total overall survival (TOS) in sorafenib and lenvatinib group were 23.0 (95% CI: 15.1-30.9) vs. 29.7 (95% CI: 21.4-38.1) months. The difference was statistically significant (P=0.041). Besides, regorafenib overall survival (ROS) in sorafenib and lenvatinib group were 11.7 (95% CI: 7.1-16.3) vs. 15.9 (95% CI: 8.3-23.5) months. The difference was statistically significant ( P=0.045). The regorafenib progression-free survival (RPFS) was 5.6 (95% CI: 1.9-9.2) vs. 8.0 (95% CI: 5.1-10.9) months in sorafenib and lenvatinib group, respectively, and difference was not statistically significant (P=0.380). Conclusions: Regorafenib is an effective drug for second-line treatment of HCC, with fewer severe adverse events, ORR and DCR was 14-22% and 62-60%, respectively. Both TOS and ROS in lenvatinib group were better than those in sorafenib group. For HCC patients whose first-line targeted drug is lenvatinib, it is safe and effective to accept regorafenib after disease progresses.

Simultaneous versus staged major hepatectomy (≥3 liver segments) for outcomes of synchronous colorectal liver metastases: A systematic review and meta-analysis.

BACKGROUND: Hepatectomy is an effective treatment for synchronous colorectal liver metastases (SCLM) patients. However, whether to choose simultaneous hepatectomy (SIH) or staged hepatectomy (STH) is still controversial, especially during major hepatectomy (≥3 liver segments). AIMS: Compare the difference between the SCLM patients underwent SIH and STH, especially during major hepatectomy (≥3 liver segments). METHODS AND RESULTS: A meta-analysis was conducted by analyzing the published data on the outcomes of SCLM patients underwent SIH or STH from January 2010 to December 2020 from the electronic databases. A random-effects model was used to derive pooled estimates of odds ratio (OR) with 95% confidence interval (CI) for the explored outcomes. Eventually, 18 studies, including 5101 patients, were included this study. The result of meta-analysis showed that SIH did not increase postoperative complications (pooled OR: 1.037; 95% CI: 0.897-1.200), perioperative mortality (pooled OR: 0.942; 95% CI: 0.552-1.607), 3-year mortality (pooled OR: 1.090; 95% CI: 0.903-1.316) or 5-year mortality (pooled OR: 1.077; 95% CI: 0.926-1.253), as compared with STH. Subgroup analysis showed that, simultaneous major hepatectomy (SIMH) also did not increase postoperative complications (pooled OR: 0.863; 95% CI: 0.627-1.188) or perioperative mortality (pooled OR: 0.689; 95% CI: 0.290-1.637) as compared with staged major hepatectomy (STMH). CONCLUSION: Postoperative complications, perioperative mortality and long-term prognosis had no significant difference between SIH and STH for SCLM patients. Besides, postoperative complications and perioperative mortality also had no significant difference between SIMH and STMH.

Preoperative Estimated Risk of Microvascular Invasion is Associated with Prognostic Differences Following Liver Resection Versus Radiofrequency Ablation for Early Hepatitis B Virus-Related Hepatocellular Carcinoma.

OBJECTIVES: The aim of this study was to examine prognostic differences between liver resection (LR) and percutaneous radiofrequency ablation (PRFA) for hepatocellular carcinoma (HCC) based on preoperative predicted microvascular invasion (MVI) risk. METHODS: Data on consecutive patients who underwent LR (n = 1344) or PRFA (n = 853) for hepatitis B virus-related HCC within the Milan criteria (MC) were analyzed. A preoperative nomogram was used to estimate MVI risk. Overall survival (OS), time to recurrence, and patterns of recurrence were compared using propensity score matching. RESULTS: The concordance indices of the nomogram to predict MVI were 0.813 and 0.781 among LR patients with HCC within the MC or ≤ 3 cm, respectively. LR and PRFA resulted in similar 5-year recurrence and OS for patients with nomogram-predicted low-risk of MVI. LR provided better 5-year recurrence and OS versus PRFA for patients with high-risk of MVI (71.6% vs. 80.7%, p = 0.013; 47.9% vs. 34.0%, p = 0.002, for HCC within the MC; 62.3% vs. 78.8%, p = 0.020; 63.6% vs. 38.3%, p = 0.015, for HCC ≤ 3 cm). Among high-risk patients, LR was associated with lower recurrence and improved OS compared with PRFA, on multivariate analysis [hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.63-0.97, and HR 0.68, 95% CI 0.52-0.88, for HCC within the MC; HR 0.51, 95% CI 0.32-0.81, and HR 0.47, 95% CI 0.26-0.84, for HCC ≤ 3 cm], and resulted in less early and local recurrence than PRFA (42.4% vs. 54.8%, p = 0.007, and 31.2% vs. 46.1%, p = 0.007, for HCC within the MC; 27.9% vs. 50.8%, p = 0.016, and 15.6% vs. 39.5%, p = 0.046, for HCC ≤ 3 cm). CONCLUSIONS: LR was oncologically superior over PRFA for early HCC patients with predicted high-risk of MVI. LR was associated with better local disease control than PRFA in these patients.

PD-L1 combined with HDAC9 is a useful prognostic predictor in hepatocellular carcinoma.

BACKGROUND: The expression of programmed death-ligand 1 (PD-L1) is associated with the response of patients to PD-1/PD-L1 blockade immunotherapy. It has been demonstrated that histone deacetylase (HDAC) inhibitors may alter the expression of PD-L1/PD-L2 and enhance the antitumor immune responses. However, the profile of PD-L1 expression and its association with HDACs in hepatocellular carcinoma (HCC) has not been accurately investigated. METHODS: The expression of PD-L1 and HDACs were examined by immunohistochemical (IHC) staining using tissue microarray (TMA) of 109 HCC specimens. Expression data from TCGA database and IHC staining of TMA were used for correlation analysis. Survival rates were analyzed based on data from 109 HCC patients. RESULTS: We found that PD-L1 was upregulated in the majority of HCC samples. Furthermore, correlation analysis revealed that PD-L1 expression was positively correlated with HDAC9 and HDAC2 expression in HCC. Survival analysis showed that high levels of PD-L1 combined with increased expression of HDAC9 decreased overall survival (OS) in patients with HCC. In addition, univariate and multivariate analysis further suggested that the increased PD-L1/HDAC9 expression was an independent prognostic biomarker in HCC. HDAC9 overexpression promoted HCC growth and PD-L1 expression. CONCLUSIONS: The results of the current study highlighted the strong association between HDACs with immunotherapy, thus providing a rational basis for combining HDAC9 specific inhibitors and PD-1 blockade in a future clinical approach for HCC.

Prognostic significance of combining high mobility group Box-1 and OV-6 expression in hepatocellular carcinoma.

The inflammatory environment and existence of cancer stem cells are critical for progression and intrahepatic recurrence of hepatocellular carcinoma (HCC) after curative resections. Here, we investigated the prognostic significance of combining high mobility group box 1 (HMGB1) expression and hepatic progenitor marker OV6 in hepatocellular carcinoma. Expression of HMGB1 and OV6 was evaluated using immunohistochemistry profiling in tissue microarrays containing samples from 208 HCC patients. Invasive clinical or pathological factors were found in patients with high expression of HMGB1 or OV6. Higher HMGB1 was associated with poorer clinical outcomes, and independently related to elevated 5-year recurrence incidence (85.5% vs. 62.4%, P<0.001). We also found that more OV6 positive staining was correlated with poor prognosis of HCC patients (P<0.001). Notably, expression of HMGB1 was positively correlated with OV6 in density (R2=0.032, P<0.001) and reversely related to HCC outcomes. Abnormal expression of HMGB1 in combination with positive staining of OV6 displayed poorer prognostic performance than single biomarker alone (area under curve (AUC) survival=0.696). Therefore, HMGB1 and OV6 positive staining are promising prognostic parameters for HCC, and we propose that HMGB1 and OV6 may cooperate with each other and predict poor prognosis of HCC.

Actual over 10-year survival after liver resection for patients with intrahepatic cholangiocarcinoma.

Partial hepatectomy is a potentially curative therapy for intrahepatic cholangiocarcinoma (ICC). Unfortunately, the overall surgical prognosis remains dismal and the actual 10-year survival has not been reported. This study aimed to document 10-year actual survival rates, identify the prognostic factors associated with 10-year survival rate, and analyze the characteristics of patients who survived ≥ 10 years. Among 251 patients who underwent curative liver resection for ICC between 2003 and 2006 at the Eastern Hepatobiliary Surgery Hospital, 21 patients (8.4%) survived ≥ 10 years. The 5-, 7-, and 10-year overall survival rates were 32.3%, 22.3% and 8.4%, respectively. The 10-year cumulative incidence of ICC-related death and recurrence were 80.9% and 85.7%, respectively. Multivariate analysis based on competing risk survival analysis identified that tumor > 5 cm was independently associated with ICC-related death and recurrence (hazard ratios: 1.369 and 1.445, respectively), in addition to carcinoembryonic antigen (CEA) >10 U/mL, carbohydrate antigen 19-9 (CA19-9) >39 U/mL, multiple nodules, vascular invasion, nodal metastasis and local extrahepatic invasion. Patients who survived ≥ 10 years had a longer time to first recurrence, lower levels of CEA, CA19-9 and alkaline phosphatase, less perioperative blood loss, solitary tumor, smaller tumor size, and absence of nodal metastasis or local extrahepatic invasion. In conclusion, a 10-year survival after liver resection for ICC is possible and can be expected in approximately 8.4% of patients.

Hepatitis B virus X protein stimulates high mobility group box 1 secretion and enhances hepatocellular carcinoma metastasis.

Hepatitis B virus X protein (HBx) plays an important role in the progression of hepatocellular carcinoma. Here we reported that overexpression of HBx in hepatocellular carcinoma (HCC) cells could induce the secretion of high-mobility group box 1 (HMGB1) to promote invasion and metastasis of HCC in an autocrine/paracrine manner. HBx triggered an increase of cytoplasmic calcium and activated CAMKK/CAMKIV pathway, leading to subsequent translocation and release of HMGB1. HMGB1 neutralizing antibody, as well as calcium chelator or inhibitors of CAMKK/CAMKIV, could remarkably reduce invasion and metastasis of HCC cells in vitro and in a murine HCC metastasis model in vivo. Furthermore, the level of HMGB1 in patient serum and tumor tissues was positively correlated with HBV DNA load. We demonstrate an inverse relationship between HMGB1 in tumor cytoplasm and overall prognosis of HCC patients. CONCLUSION: HBx promotes the progression of HCC through translocation and secretion of HMGB1 from tumor cells via calcium dependent cascades. These data indicates that HMGB1 could serve as a novel prognostic biomarker and potential therapeutic target for HBV-related HCC.