A risk-based postresection follow-up strategy for hepatocellular carcinoma patients.

BACKGROUND: The optimal intervals for follow-up after hepatocellular carcinoma (HCC) patients undergo curative liver resection (LR) remain unclear. This study aimed to establish a risk-based post-resection follow-up strategy. METHODS: Patients that were diagnosed with HCC and received LR from three hospitals in China were included. The risk-based strategy was established based on the random survival forest model and compared with a fixed strategy both internally and externally. RESULTS: In total, 3447 patients from three hospitals were included. The authors' strategy showed superiority in the early detection of tumor relapse compared with fixed surveillance. Under fewer total visits, risk-based strategy achieved analogous survival time compared to the total 20 times follow-ups based on fixed strategy. Twelve total visits (five, three, one, two, and one visits in years 1-5, respectively) for American Joint Committee on Cancer/International Union Against Cancer T1a stage patients, 13 total visits (five, four, one, two, and one visits in years 1-5, respectively) for T1b stage patients, 15 total visits (eight, three, three, zero, and one visits in years 1-5, respectively) for T2 stage patients, and 15 total visits (eight, four, one, one, and one visits in years 1-5, respectively) for T3 stage patients were advocated. The detailed follow-up arrangements were available to the public through an interactive website (https://sysuccfyz.shinyapps.io/RiskBasedFollowUp/). CONCLUSION: This risk-based surveillance strategy was demonstrated to detect relapse earlier and reduce the total number of follow-ups without compromising on survival. Based on the strategy and methodology of the authors, surgeons or patients could choose more intensive or flexible schedules depending on the requirements and economic conditions. PLAIN LANGUAGE SUMMARY: A risk-based post-resection follow-up strategy was established by random survival forest model using a larger hepatocellular carcinoma population The strategy was demonstrated to detect tumor relapse earlier and reduce the total number of follow-ups without compromising on survival Our strategy and methodology could be widely applied by other surgeons and patients.

An integrated strategy for deciding open versus laparoscopic hepatectomy for resectable primary liver cancer.

BACKGROUND: Laparoscopic liver resection (LLR) is now widely performed in treating primary liver cancer (PLC) and yields equal long-term and superior short-term outcomes to those of open liver resection (OLR). The optimal surgical approach for resectable PLC (rPLC) remains controversial. Herein, we aimed to develop a nomogram to determine the most appropriate resection approach for the individual patient. METHODS: Patients with rPLC who underwent hepatectomy from January 2013 to December 2018 were reviewed. Prediction model for risky surgery during LLR was constructed. RESULTS: A total of 900 patients in the LLR cohort and 423 patients in the OLR cohort were included. A history of previous antitumor treatment, tumor diameter, tumor location and resection extent were independently associated with risky surgery of LLR. The nomogram which was constructed based on these risk factors demonstrated good accuracy in predicting risky surgery with a C index of 0.83 in the development cohort and of 0.76 in the validation cohort. Patients were stratified into high-, medium- or low-risk levels for receiving LLR if the calculated score was more than 0.8, between 0.2 and 0.8 or less than 0.2, respectively. High-risk patients who underwent LLR had more blood loss (441 ml to 417 ml) and a longer surgery time (183 min to 150 min) than those who received OLR. CONCLUSIONS: Patients classified into the high-risk level for LLR instead undergo OLR to reduce surgical risks and complications and patients classified into the low-risk level undergo LLR to maximize the advantages of minimally invasive surgery. TRIAL REGISTRATION: This study was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2100049446).

Survival benefit of liver resection following complete response to transarterial chemoembolization for intermediate-stage hepatocellular carcinoma: a retrospective, multicenter, cohort study.

BACKGROUND: High rate of tumor recurrence jeopardized the long-term survival of hepatocellular carcinoma (HCC) patients with complete response to transarterial chemoembolization (TACE). This study aims to evaluate the survival benefit of liver resection (LR) following the complete response to TACE for intermediate-stage HCC. METHODS: A total of 281 intermediate-stage HCC patients with complete response to TACE followed by persistent observation (TACE group) or LR (TLR group) from 01 January 2011 to 31 December 2021 from three institutions in China were included. Overall survival (OS) and disease-free survival (DFS) of patients were compared between the two groups by propensity score-matching (PSM). RESULTS: After PSM, the 1-year, 3-year, and 5-year OS rates were 91.4, 71.5, and 57.1% in the TACE group, and 96.6, 81.8, and 72.1% in the TLR group. The 1-year, 3-year, and 5-year DFS rates were 50.6, 22.6, and 6.8% in the TACE group, and 77.3, 56.3, and 38.7% in the TLR group. Compared with the TACE group, the TLR group showed significantly longer OS (HR, 0.528; 95% CI: 0.315-0.887; P =0.014) and DFS (HR, 0.388; 95% CI: 0.260-0.580; P <0.001). In patients beyond up-to-seven criterion, no difference was observed with OS (HR, 0.708; 95% CI: 0.354-1.419; P =0.329). LR following the complete response to TACE was safety. CONCLUSIONS: This study suggests that intermediate-stage HCC patients could benefit from LR following the complete response to TACE, resulting in longer OS and DFS. In addition, patients beyond up-to-seven could not benefit from the LR treatments.

Risk of hepatitis B virus reactivation and its effect on survival in advanced hepatocellular carcinoma patients treated with hepatic arterial infusion chemotherapy and lenvatinib plus programmed death receptor-1 inhibitors.

Background: Hepatitis B virus (HBV) reactivation is a common complication in hepatocellular carcinoma (HCC) patients treated with chemotherapy or immunotherapy. This study aimed to evaluate the risk of HBV reactivation and its effect on survival in HCC patients treated with HAIC and lenvatinib plus PD1s. Methods: We retrospectively collected the data of 213 HBV-related HCC patients who underwent HAIC and lenvatinib plus PD1s treatment between June 2019 to June 2022 at Sun Yat-sen University, China. The primary outcome was the risk of HBV reactivation. The secondary outcomes were overall survival (OS), progression-free survival (PFS), and treatment-related adverse events. Results: Sixteen patients (7.5%) occurred HBV reactivation in our study. The incidence of HBV reactivation was 5% in patients with antiviral prophylaxis and 21.9% in patients without antiviral prophylaxis, respectively. The logistic regression model indicated that for HBV reactivation, lack of antiviral prophylaxis (P=0.003) and tumor diameter (P=0.036) were independent risk factors. The OS and PFS were significantly shorter in the HBV reactivation group than the non-reactivation group (P=0.0023 and P=0.00073, respectively). The number of AEs was more in HBV reactivation group than the non-reactivation group, especially hepatic AEs. Conclusion: HBV reactivation may occur in HCC patients treated with HAIC and lenvatinib plus PD1s. Patients with HBV reactivation had shorter survival time compared with non-reactivation. Therefore, HBV-related HCC patients should undergo antiviral therapy and HBV-DNA monitoring before and during the combination treatment.

Efficacy of additional locoregional therapy based on systemic therapy after intrahepatic progression for BCLC stage B/C hepatocellular carcinoma: A real-world study.

BACKGROUND: The leading course of death in patients with advanced hepatocellular carcinoma (HCC) is intrahepatic progression and associated hepatic failure. The study aimed to evaluate the efficacy of locoregional therapy targeting intrahepatic lesions after intrahepatic progression for advanced HCC. METHODS: Consecutive 263 HCC patients who received lenvatinib combined with immunotherapy were reviewed. Until to last follow-up, 178 patients had disease progression:107 patients had intrahepatic progression (IP group) with or without extrahepatic progression, and 71 patients only had extrahepatic progression (EP group). After intrahepatic progression, 47 patients received systemic therapy (Systemic group), 23 patients received locoregional-systemic therapy (Loco-systemic group), and 37 patients received best supportive therapy (Supportive group). RESULTS: The EP group showed significantly longer OS (overall survival) than the IP group (not reached vs 16.2 months, P = 0.009). Median OS was significantly longer in the Loco-systemic group (20.3 v 8.8 months; P = 0.03) than in the Systemic group. The median PFS (progression-free survival) was 11.7 months in the Loco-systemic group and 5.3 months in the Systemic group (P = 0.046). In patients who progressed fast in first-line treatment, there was no significant difference in OS and PFS between the two groups. CONCLUSION: Intrahepatic progression was associated with a poorer survival outcome compared with extrahepatic progression in advanced HCC. After intrahepatic progression, additional locoregional therapy based on systemic therapy may offer clinical benefits on OS and PFS in second-line treatment, the benefits were limited to patients who had once achieved tumor control during their first-line treatments.

Dynamic changes of serum α-fetoprotein predict the prognosis of bevacizumab plus immunotherapy in hepatocellular carcinoma.

BACKGROUND: Alpha-fetoprotein (AFP) has been established as a biomarker for hepatocellular carcinoma (HCC); however, whether its dynamic changes could predict the response to systemic therapy remains elusive. This study explored the AFP trajectory and the association with survival in patients received bevacizumab plus immunotherapy. METHODS: We retrospectively enrolled 536 HCC patients received bevacizumab plus immunotherapy between February 2021 and February 2023. Patients were divided into two groups according to AFP values before treatment (400 ng/ml). Dynamic changes of AFP were fitted using a latent class model to generate the AFP trajectories. Multivariable Cox models were utilized to compute hazard ratios (HRs) for survival. Inverse-probability-of-treatment weighted analyses were conducted to mitigate the influence of unmeasured confounding variables. The primary endpoint is progression free survival (PFS). The second endpoint is overall survival (OS). RESULTS: Three distinct trajectories were identified for AFP-low and AFP-high patients, respectively. In AFP-low group, compared with the high-rising class (25%; n=69), HRs of PFS were 0.39 and 0.2 for the low-stable class (59.1%; n=163) and sharp-falling class (15.9%; n=44), after adjusting by tumor diameter, tumor number, and extra-hepatic metastasis. In AFP-high group, compared with the high-stable class (18.5%; n=48), HRs of PFS were 0.3 and 0.04 for the middle-stable class (56.5%; n=147) and sharp-falling class (25%; n=65), after adjusting by tumor diameter, tumor number, and extra-hepatic metastasis. Furthermore, the AFP trajectories exhibited the utmost relative importance among all covariates regarding PFS and OS in the multivariable regression models. CONCLUSION: The AFP trajectories in HCC patients receiving bevacizumab and immunotherapy, constituted an independent biomarker indicative of clinical outcomes. Findings from this study hold potential clinical utility in dynamically forecasting the prognosis of systemic therapy in HCC patients and facilitating clinical decision-making. Rapid reduction of AFP post-treatment can lead to favorable patient prognoses.

Patients with hepatocellular carcinoma extrahepatic metastases can benefit from hepatic arterial infusion chemotherapy combined with lenvatinib plus programmed death-1 inhibitors.

BACKGROUND: Lenvatinib plus programmed death-1 (PD-1) inhibitors (LEN-P) have been recommended in China for patients with advanced hepatocellular carcinoma (HCC). However, they provide limited survival benefits to patients with extrahepatic metastases. We aimed to investigate whether combining hepatic arterial infusion chemotherapy (HAIC) with LEN-P could improve its efficacy. MATERIALS AND METHODS: This multicenter cohort study included patients with HCC extrahepatic metastases who received HAIC combined with LEN-P (HAIC-LEN-P group, n =127) or LEN-P alone ( n =103) as the primary systemic treatment between January 2019 and December 2022. Baseline data were balanced using a one-to-one propensity score matching (PSM) and inverse probability of treatment weighting (IPTW). RESULTS: After PSM, the HAIC-LEN-P group significantly extended the median overall survival (mOS) and median progression-free survival (mPFS), compared with the LEN-P group (mOS: 27.0 months vs. 9.0 months, P <0.001; mPFS: 8.0 months vs. 3.0 months, P =0.001). After IPTW, the mOS [hazard ratio (HR)=0.384, P <0.001] and mPFS (HR=0.507, P <0.001) were significantly higher in the HAIC-LEN-P group than in the LEN-P group. The HAIC-LEN-P group's objective response rate was twice as high as that of the LEN-P group (PSM cohort: 67.3% vs. 29.1%, P <0.001; IPTW cohort: 66.1% vs. 27.8%, P <0.001). Moreover, the HAIC-LEN-P group exhibited no noticeable increase in the percentages of grade 3 and 4 adverse events compared with the LEN-P group ( P >0.05). CONCLUSION: HAIC can improve the efficacy of LEN-P in patients with HCC extrahepatic metastases and may be an alternative treatment for advanced HCC management.

Comparison of resection, ablation and stereotactic body radiation therapy in treating solitary hepatocellular carcinoma ≤ 5 cm: a retrospective, multicenter, cohort study.

BACKGROUND: Few studies have focused on the efficacy of stereotactic body radiation therapy (SBRT) in treating early hepatocellular carcinoma (HCC) for curative intention. This study aims to determine the best option among resection, ablation and SBRT in dealing with single HCC no more than 5 cm. MATERIALS AND METHODS: This multicenter retrospective cohort study included 985 patients from 3 hospitals: 495, 335 and 155 in the resection, ablation and SBRT groups, respectively between January 2014 and December 2021. Subgroup analysis and propensity score matching (PSM) were performed. RESULTS: The SBRT group had unfavorable clinical features including larger tumor size, poorer liver function and more relapsed tumors. The 1-, 3-, and 5-year recurrence free survival (RFS) rates were 84.3%, 66.8% and 56.2% with resection, 73.3%, 49.8% and 37.2% with ablation and 73.2%, 56.4% and 53.6% with SBRT, respectively (P<0.001). The 3-year overall survival (OS) rates were 89.0%, 89.2% and 88.8% in the resection, ablation and SBRT group, respectively (P=0.590). The three modalities resulted in similar RFS and OS after adjusting for clinical factors. Resection provided ideal local tumor control, successively followed by SBRT and ablation. SBRT led to comparable RFS time compared to resection for tumors < 3 cm (HR=0.75, P=0.205), relapsed tumors (HR=0.83, P=0.420) and patients with poor liver function (HR=0.70, P=0.330). In addition, SBRT was superior to ablation regarding RFS when tumors were adjacent to intra-hepatic vessels (HR=0.64, P=0.031). SBRT were more minimally invasive, however, gastrointestinal disorders, hepatic inflammation and myelosuppression occurred more frequently. CONCLUSION: All three approaches could be applied as curative options. Resection remains the best choice for preventing tumor recurrence, and SBRT showed advantages in treating small, recurrent and vascular-type lesions as well as patients with relatively poor liver function.

Survival benefit of neoadjuvant hepatic arterial infusion chemotherapy followed by hepatectomy for hepatocellular carcinoma with portal vein tumor thrombus.

Background/purpose: The prognosis of hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) is generally poor and hepatectomy is optional for these patients. This study aims to explore the survival benefits of neoadjuvant hepatic arterial infusion chemotherapy (HAIC) for resectable HCC with PVTT. Methods: This retrospective study included 120 resectable HCC patients with PVTT who underwent hepatectomy, from January 2017 to January 2021 at Sun Yat-sen University Cancer Center. Of these patients, the overall survival (OS) and recurrence-free survival (RFS) of 55 patients who received hepatectomy alone (Surgery group) and 65 patients who received neoadjuvant HAIC followed by hepatectomy (HAIC-Surgery group) were compared. Logistic regression analysis was conducted to develop a model predicting the response to neoadjuvant HAIC. Results: The OS rates for the HAIC-Surgery group at 1, 3, and 5 years were 94.9%, 78%, and 66.4%, respectively, compared with 84.6%, 47.6%, and 37.2% in the Surgery group (p < 0.001). The RFS rates were 88.7%, 56.2%, and 38.6% versus 84.9%, 38.3%, and 22.6% (p = 0.002). The subgroup analysis revealed that the survival benefit of neoadjuvant HAIC was limited to patients who responded to it. The logistic model, consisting of AFP and CRP, that predicted the response to neoadjuvant HAIC performed well, with an area under the ROC curve (AUC) of 0.756. Conclusion: Neoadjuvant HAIC followed by hepatectomy is associated with a longer survival outcome than hepatectomy alone for HCC patients with PVTT and the survival benefit is limited to patients who respond to neoadjuvant FOLFOX-HAIC.

Laparoscopic Hepatectomy versus Open Hepatectomy After Conversion Therapy Using Transarterial Chemoembolization or Hepatic Arterial Infusion Chemotherapy for Patients with Initially Unresectable Hepatocellular Carcinoma.

Background: Laparoscopic hepatectomy (LH) is more advantageous than open hepatectomy (OH) for hepatocellular carcinoma (HCC). However, surgical methods of conversion resection for patients with HCC have not been compared. We aimed to compare LH with OH for HCC after conversion therapy. Methods: We retrospectively reviewed the data of 334 patients who underwent conversion resection between January 2016 and December 2020 at Sun Yat-sen University, China. Propensity score matching (PSM) of patients in a ratio of 1:2 was conducted, and 62 patients and 121 patients who underwent LH and OH, respectively, were matched. Results: The LH and OH groups differed at baseline in terms of ALT (P=0.008), AFP (P=0.042), largest tumor size (P=0.028), macrovascular invasion (P=0.006), BCLC stages (P=0.021), and CNLC stages (P=0.048). The incidences of postoperative complications before and after PSM were lower in the LH group than in the OH group (P=0.007 and 0.003, respectively). There were no significant differences in the overall survival (OS) and recurrence-free survival (RFS) between the two groups (P=0.79 and 0.8, respectively). According to the multivariable Cox regression analyses, the largest tumor size (P<0.0001) and tumor number (P=0.004) were significant and independent prognostic factors of OS. Conclusion: In our study, we found that LH is technically feasible and safe in patients after conversion therapy. Compared with OH, LH showed similar OS and RFS and was associated with fewer postoperative complications.

Levels of pretreatment serum lipids predict responses to PD-1 inhibitor treatment in advanced intrahepatic cholangiocarcinoma.

BACKGROUND: It has been identified that serum lipids can be used as prognostic biomarkers in several types of cancer and are associated with patient survival. We aimed to clarify the prognostic value of the serum lipids and to establish a novel effective nomogram for overall survival (OS) in intrahepatic cholangiocarcinoma (iCCA) patients receiving anti-PD1 therapy. METHODS: Pretreatment serum lipids were retrospectively analyzed for prognostic value, including apolipoprotein B (APOB), apolipoproteinA-1 (APOA1), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG), which were assessed for prediction accuracy using Kaplan-Meier survival curves and time-dependent receiver operating characteristic (ROC). Cox regression analysis with univariate and multivariate factors was used to identify prognostic factors predictive of OS, and prognostic nomograms were constructed. RESULTS: All the serum lipids showed good discriminatory ability in terms of OS (all P < 0.05), the higher the lipid levels, the better the prognosis, while APOA1 and TG were remarkable independent predictors for OS in multivariate analysis (hazard ratio, 2.177,2.035; confidence interval, 1.393-3.402, 1.184-3.498; P = 0.001, P = 0.01). Four (CA19-9, APOA1, tumor number and TG) independent prognostic factors were chosen to generate the nomogram for OS. The area under the ROC curve at 1-year and 2-year consistently demonstrated that the predictive value of the nomogram was superior to serum lipids. CONCLUSION: In our study, serum lipid levels were used as a prognostic nomogram in the prediction of anti-PD-1 therapy efficacy in patients with iCCA.

Survival benefit of preoperative hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin followed by hepatectomy for hepatocellular carcinoma.

Background: Hepatic arterial infusion chemotherapy (HAIC) with cisplatin, fluorouracil, and leucovorin (FOLFOX) demonstrated promising efficacy against advanced hepatocellular carcinoma (HCC) as an alleviative treatment. We aimed to explore the survival benefit of preoperative FOLFOX-HAIC and establish a predictive nomogram. Methods: This study retrospectively reviewed data from 1251 HCC patients who underwent liver resection. 1027 patients received liver resection alone (LR group), and 224 patients were treated with FOLFOX-HAIC followed by liver resection (HLR group). Propensity score matching (PSM) was conducted between the two groups. The nomogram was established based on the findings of the multivariable Cox regression analysis. Results: After Propensity score matching according to initial tumor characteristics, the 1-, 2-, and 3-year overall survival rates were 85.4, 72.0, and 67.2% in the LR group and 95.2, 84.7, and 75.9% in the HLR group, respectively (p = 0.014). After PSM according to preoperative tumor characteristics, the 1-, 2-, and 3-year OS rates were 87.9, 76.6, and 72.3% in the LR group and 95.4, 84.4, and 75.1% in the HLR group, respectively (p = 0.24). Harrell's C-indexes of the nomogram for OS prediction in patients with preoperative FOLFOX-HAIC were 0.82 (95% CI 0.78-0.86) in the training cohort and 0.87 (95% CI 0.83-0.93) in the validation cohort and the nomogram performed well-fitted calibration curves. Conclusion: Preoperative FOLFOX-HAIC is associated with a longer survival outcome for HCC patients. The novel nomogram efficiently predicted the OS of patients who underwent preoperative FOLFOX-HAIC.

Comparison of hepatic arterial infusion chemotherapy with mFOLFOX vs. first-line systemic chemotherapy in patients with unresectable intrahepatic cholangiocarcinoma.

Background: Systemic chemotherapy (SC) remains the only first-line treatment for unresectable intrahepatic cholangiocarcinoma (iCCA). Hepatic arterial infusion chemotherapy (HAIC) has been recently proven to be effective in managing hepatocellular carcinoma (HCC). Hence, our study aims to investigate the safety and efficacy of HAIC in treating unresectable iCCA patients. Methods: We reviewed 146 patients with unresectable iCCA who had received HAIC or SC between March 2016 and March 2022 in a retrospective manner. Outcomes of patients and safety were compared between the HAIC and SC groups. Results: There were 75 and 71 patients in the HAIC and SC groups, respectively. The median OS in the HAIC and SC groups was 18.0 and 17.8 months (p = 0.84), respectively. The median PFS in the HAIC and SC groups was 10.8 and 11.4 months (p = 0.59), respectively. However, the HAIC group had significantly longer intrahepatic progression-free survival (IPFS) than the SC group (p = 0.035). The median IPFS in the HAIC and SC groups was 13.7 and 11.4 months, respectively. According to the OS (p = 0.047) and PFS (p = 0.009), single-tumor patients in the HAIC group appeared to benefit more. In addition, the overall incidence of adverse events (AEs) was lower in the HAIC group than that in the SC group. Conclusion: Our study revealed that HAIC was a safe and effective therapeutic regimen for unresectable iCCA with better intrahepatic tumor control when compared to SC. Meanwhile, patients with single tumor were more likely to benefit from HAIC than SC.

Cholesterol and C-reactive protein prognostic score predicted prognosis of immune checkpoint inhibitors based interventional therapies for intermediate-to-advanced hepatocellular carcinoma patients.

Serum cholesterol (CHO) and C-reactive protein (CRP) have been successfully used as prognostic predictors for several malignancies, respectively. However, the clinicopathological significance of CHO and CRP levels in hepatocellular carcinoma (HCC) patients treated with ICIs-based hepatic artery infusion chemotherapy (HAIC) remains unclear. Serum CHO and CRP levels were measured for a total of 152 HCC patients that had been treated with ICIs-based HAIC from February 2019 to April 2020. Efficacy was evaluated according to tumor response and survival. The median OS was not reached in the CHO-low subgroup and 17.7 months in the CHO-high subgroup (P = 0.015). The median OS was not reached in the CRP-low subgroup and 20.0 months in the CRP-high subgroup (P = 0.010). Univariate and multivariate Cox regression analysis demonstrated that both serum CHO and CRP levels were independent risk factors for the OS of HCC patients treated with ICIs-based HAIC (P < 0.05). Moreover, Cox regression analysis after Propensity Score Matching showed the similar results. CHO and CRP prognostic score (CCPS) combining CHO and CRP levels could significantly stratify HCC patients receiving ICIs-based HAIC into low-, intermediate-, and high-risk subgroups (P < 0.001). Patients in the risk subgroups reported similar disease control rates (P = 0.121) and significantly different overall response rates (low- vs intermediate- vs high-risk groups: 70.6 % vs 46.6 % vs 44.1 %, respectively, P = 0.038) according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). The results of this study support the association between CCPS high risk with the response and OS for HCC patients receiving ICIs-based HAIC.

Induction therapy with hepatic arterial infusion chemotherapy enhances the efficacy of lenvatinib and pd1 inhibitors in treating hepatocellular carcinoma patients with portal vein tumor thrombosis.

BACKGROUND: Hepatic arterial infusion chemotherapy (HAIC) with fluorouracil, leucovorin, and oxaliplatin (FOLFOX), lenvatinib and programmed death receptor-1 signaling inhibitors (PD1s) all alone have been proven effective in treating advanced hepatocellular carcinoma (HCC), yet the efficacy and safety of the tri-combination therapy in treating HCC patients with portal vein tumor thrombosis (PVTT) remains unknown. METHODS: In this retrospective study, HCC patients with PVTT received either induction therapy of HAIC and lenvatinib plus PD1s in the initial period of treatment and then dual maintenance therapy of lenvatinib and PD1s (HAIC-Len-PD1) or continuous lenvatinib combined with PD1s (Len-PD1). RESULTS: In total, 53 and 89 patients were enrolled into the Len-PD1 group and HAIC-Len-PD1 group, respectively. The median overall survival times were 13.8 months in the Len-PD1 group and 26.3 months in the HAIC-Len-PD1 group (hazard ratio (HR) = 0.43, P < 0.001). The median progression-free survival (PFS) time was significantly longer in the HAIC-Len-PD1 group than in the Len-PD1 group (11.5 months versus 5.5 months, HR = 0.43, P < 0.001). Induction therapy showed an objective response rate (ORR) 3 times higher than lenvatinib combined with PD1s therapy (61.8% versus 20.8%, P < 0.001), and exhibited inspiring intra- and extra-hepatic tumor control ability. Induction therapy led to more adverse events than lenvatinib combined with PD1s therapy, most of which were tolerable and controllable. CONCLUSION: The induction therapy of FOLFOX-HAIC and lenvatinib plus PD1s is an effective and safe treatment for HCC patients with PVTT. The concept of induction therapy could be applied to other local-regional treatments and drugs combinations in HCC management.

Size-Tunable Nanoregulator-Based Radiofrequency Ablation Suppresses MDSCs and Their Compensatory Immune Evasion in Hepatocellular Carcinoma.

Radiofrequency ablation (RFA) is a widely used therapy for hepatocellular carcinoma (HCC). However, in cases of insufficient RFA (iRFA), nonlethal temperatures in the transition zone increase the risk of postoperative relapse. The pathological analysis of HCC tissues shows that iRFA-induced upregulation of myeloid-derived suppressor cells (MDSCs) in residual tumors is critical for postoperative recurrence. Furthermore, this study demonstrates, for the first time, that combining MDSCs suppression strategy during iRFA can unexpectedly lead to a compensatory increase in PD-L1 expression on the residual MDSCs, attributed to relapse due to immune evasion. To address this issue, a novel size-tunable hybrid nano-microliposome is designed to co-deliver MDSCs inhibitors (IPI549) and αPDL1 antibodies (LPIP) for multipathway activation of immune responses. The LPIP is triggered to release immune regulators by the mild heat in the transition zone of iRFA, selectively inhibiting MDSCs and blocking the compensatory upregulation of PD-L1 on surviving MDSCs. The combined strategy of LPIP + iRFA effectively ablates the primary tumor by activating immune responses in the transition zone while suppressing the compensatory immune evasion of surviving MDSCs. This approach avoids the relapse of the residual tumor in a post-iRFA incomplete ablation model and appears to be a promising strategy in RFA for the eradication of HCC.

Development and Validation of Prognostic Nomograms for Hepatocellular Carcinoma After Hepatectomy Based on Inflammatory Markers.

Background: The value of lactate dehydrogenase (LDH) compared with other inflammation-based scores in predicting the outcomes of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients after curative resection remains unknown. This study aims to evaluate the predictive value of LDH and develop novel nomograms to predict postoperative recurrence and survival in these patients. Methods: This study retrospectively collected 1560 patients with HBV-related HCC who underwent curative resection from four institutions in China. In total, 924 patients were recruited from our center and randomly divided into the training cohort (n = 616) and internal validation (n = 308) cohorts. Additionally, 636 patients were selected from three other centers as the external validation cohort. The C index of inflammation-based scores was calculated and compared in the training cohort. Novel models were developed according to multivariable Cox regression analysis in the training cohort and validated in the internal and external validation cohorts. Results: LDH showed a higher C-index than other inflammation-based scores for recurrence survival (RFS, 0.60, 95% CI, 0.58-0.61) and overall survival (OS, 0.65, 95% CI, 0.63-0.68). The nomograms of RFS and OS were developed based on tumor diameter, macrovascular invasion, AFP, operative hemorrhage, tumor differentiation, tumor number and LDH and achieved a high C-index (0.78, 95% CI, 0.76-0.79 and 0.81, 95% CI, 0.79-0.83), which were remarkably higher than the C-indexes of the five conventional HCC staging systems (0.52-0.62 for RFS and 0.53-0.67 for OS). The nomograms were validated in the internal validation cohort (0.77 for RFS, 0.78 for OS) and external validation cohort (0.80 for RFS, 0.81 for OS) and performed well-fitted calibration curves. Conclusion: The two nomograms based on inflammatory markers achieved optimal prediction for RFS and OS of patients with HBV-related HCC after hepatectomy.

Antiviral Treatments Eliminate the Adverse Impacts of High Baseline HBV Loads on the Survival of HBV-Related HCC Patients.

Background: In consideration of no standard exclusion criteria for hepatitis B virus (HBV) loads in hepatocellular carcinoma (HCC)-related clinical trials, this study aimed to investigate the prevalence of HBV-related exclusion criteria among current clinical trials and evaluate whether antiviral treatments could eliminate the adverse effects from high HBV loads for HCC patients. Methods: This is a retrospective study including 772 HCC clinical trials on ClinicalTrials.gov and 1784 HCC patients receiving antiviral treatment. The Kaplan-Meier (K-M) method was used to compare the progression-free survival (PFS) and overall survival (OS) between different groups, and Cox regression analyses were performed to validate possible risk factors on PFS and overall survival OS. Results: Among 772 clinical trials, 58.3% did not adopt baseline HBV loads as exclusion criteria, 18.0% was 2000 IU/mL, and 10.5% was receiving antiviral therapy. We observed baseline HBV loads had no significant impact on PFS (p = 0.491, 0.155, 0.119, 0.788, 0.280, 0.683 respectively) and OS (p = 0.478, 0.741, 0.263, 0.039, 0.999, 0.581 respectively) in all patients or each treatment group including hepatectomy, radiofrequency ablation, interventional therapy, targeted drugs and anti-programmed cell death immunotherapy, except for the OS of interventional therapy group, where patients with high HBV loads had higher BCLC stage, serum AFP level and ALBI grade (p = 0.009, 0.015 and 0.003, respectively). Conclusion: Antiviral treatments could eliminate the adverse impacts of high HBV loads on the survival of HCC patients. Simplified eligibility criteria can be adopted for HCC patients with HBV infection where regular antiviral therapy should be enough.

Inflammation-Based Scores Predict Responses to PD-1 Inhibitor Treatment in Intrahepatic Cholangiocarcinoma.

Purpose: Inflammatory response is related to tumor progression and patient survival. We aimed to clarify the prognostic value of the inflammation-based scores in intrahepatic cholangiocarcinoma (ICC) patients receiving anti-PD1 therapy. Patients and Methods: A total of 73 patients who received anti-PD-1 therapy from February 2019 to February 2021 were included in the study. Representative inflammation-based prognostic scores, including C-reactive protein (CRP), the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-CRP ratio (LCR), lymphocyte-to-monocyte ratio (LMR), systemic immune inflammation index (SII), CRP-to-albumin ratio (CAR), prognostic nutritional index (PNI), Glasgow Prognostic Score (GPS), and prognostic index (PI), were assessed for prediction accuracy using Kaplan-Meier survival curves and time-dependent receiver operating characteristic (ROC). All the ten inflammation-based prognostic scores were measured before receiving anti-PD1 therapy. Results: All the ten inflammation-based prognostic scores showed good discriminatory ability in terms of overall survival (OS) (all P < 0.01), the higher the score, the worse the prognosis, while the CRP score was a remarkable independent predictor for OS in multivariate analysis (hazard ratio, 6.032; confidence interval, 2.467-14.752; P < 0.001). The area under the ROC curve at 6 months, 12 months, 18 months and 24 months consistently demonstrated that the predictive value of the CRP score was superior to other inflammation-based scores. Conclusion: Inflammation-based scores predict the efficacy of anti-PD-1 therapy in patients with ICC and CRP score superior to the other inflammation-based prognostic scores in terms of predictive ability.

Preoperative serum ctDNA predicts early hepatocellular carcinoma recurrence and response to systemic therapies.

BACKGROUND: Circulating tumor DNA (ctDNA) can be useful in tumor diagnosis and surveillance. However, its value in hepatocellular carcinoma (HCC) patients receiving curative resection remains unknown. Here, we aim to determine the prognostic value of ctDNA in HCC patients. METHODS: A prospective cohort enrolled 258 HCC patients who underwent curative liver resection from April 1, 2019, to September 31, 2020. Blood samples were collected before surgery for the detection of ctDNA. RESULTS: The number of total mutant genes in ctDNA was associated with early tumor relapse (HR = 2.2, p < 0.001). We defined a gene set consisting of APC, ARID1A, CDKN2A, FAT1, LRP1B, MAP3K1, PREX2, TERT and TP53 as high-risk genes (HRGs) associated with early recurrence. Patients were classified into low-, median- and high-risk levels based on the number of mutant genes in the HRGs. High-risk patients had worse recurrence free survival, especially single-tumor patients (HR = 13.0, p < 0.001). The risk level and TNM stage were independently associated with tumor recurrence. A preoperative recurrence estimation nomogram based on those two factors was constructed and demonstrated good accuracy with a C index of 0.76 (95% CI 0.70-0.82). Patients preserved FAT1 or LRP1B variants but without TP53 variants had worse progression free survival for receiving lenvatinib combined with immune checkpoint inhibitors after recurrence (HR = 17.1, p < 0.001). Furthermore, RNA sequencing data revealed that ctDNA status was associated with tumor immune infiltration. CONCLUSION: Preoperative serum ctDNA can be a practical noninvasive approach to predict recurrence after surgery and response to systemic therapies. ctDNA-guided HCC management should be recommended.