Transarterial Chemoembolization Combined with Atezolizumab Plus Bevacizumab versus Transarterial Chemoembolization Alone in Intermediate-stage Hepatocellular Carcinoma: A Multicenter Retrospective Study.

Purpose: Combining transarterial chemoembolization (TACE) with systemic therapy has shown significant efficacy for intermediate-stage hepatocellular carcinoma (HCC) patients. This study aimed to validate the therapeutic efficacy of TACE combined with atezolizumab and bevacizumab (TACE + Atez/Bev) compared to TACE alone. Methods: A retrospective study was conducted across three centers in China, encompassing 155 patients at the intermediate-stage of HCC. Propensity Score Matching (PSM) was used to minimize selection bias, with a ratio of 1:1. Primary outcomes were TACE-specific Progression-Free Survival (PFS) and Overall Survival (OS). Objective Response Rate (ORR) and Disease Control Rate (DCR) were assessed based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Adverse events (AEs) related to treatment were analyzed to evaluate safety. Results: Before PSM, the TACE + Atez/Bev group demonstrated extended median OS (not reached vs 20.3 months, P = 0.004) and PFS (20.0 months vs 9.8 months, P = 0.029) compared to the TACE-alone group. The TACE + Atez/Bev group also had a higher ORR (60.9% vs 41.3%, P = 0.026) and DCR (89.1% vs 58.7%, P < 0.001) than the TACE-alone group. After applying the PSM, the study included 42 pairs of patients. Compared to the TACE-alone group, the combination therapy group also showed significantly longer median OS (not reached vs 21.4 months, P = 0.008) and PFS (21.7 vs 9.7 months, P = 0.009). The combination therapy group also had a higher ORR (66.7% vs 38.1%, P = 0.009) and DCR (92.9% vs 57.1%, P < 0.001). AEs in the combination therapy group were mostly manageable, with the most common being elevated liver transaminase. Conclusion: In treating intermediate-stage HCC, the survival benefit of combining TACE with atezolizumab and bevacizumab was significantly higher than TACE alone, and the treatment was well-tolerated.

Adjuvant sintilimab in resected high-risk hepatocellular carcinoma: a randomized, controlled, phase 2 trial.

Hepatocellular carcinoma (HCC), particularly when accompanied by microvascular invasion (MVI), has a markedly high risk of recurrence after liver resection. Adjuvant immunotherapy is considered a promising avenue. This multicenter, open-label, randomized, controlled, phase 2 trial was conducted at six hospitals in China to assess the efficacy and safety of adjuvant sintilimab, a programmed cell death protein 1 inhibitor, in these patients. Eligible patients with HCC with MVI were randomized (1:1) into the sintilimab or active surveillance group. The sintilimab group received intravenous injections every 3 weeks for a total of eight cycles. The primary endpoint was recurrence-free survival (RFS) in the intention-to-treat population. Key secondary endpoints included overall survival (OS) and safety. From September 1, 2020, to April 23, 2022, a total of 198 eligible patients were randomly allocated to receive adjuvant sintilimab (n = 99) or undergo active surveillance (n = 99). After a median follow-up of 23.3 months, the trial met the prespecified endpoints. Sintilimab significantly prolonged RFS compared to active surveillance (median RFS, 27.7 versus 15.5 months; hazard ratio 0.534, 95% confidence interval 0.360-0.792; P = 0.002). Further follow-up is needed to confirm the difference in OS. In the sintilimab group, 12.4% of patients experienced grade 3 or 4 treatment-related adverse events, the most common of which were elevated alanine aminotransferase levels (5.2%) and anemia (4.1%). These findings support the potential of immune checkpoint inhibitors as effective adjuvant therapy for these high-risk patients. Chinese Clinical Trial Registry identifier: ChiCTR2000037655 .

XAF1 promotes colorectal cancer metastasis via VCP-RNF114-JUP axis.

Metastasis is the main cause of colorectal cancer (CRC)-related death, and the 5-year relative survival rate for CRC patients with distant metastasis is only 14%. X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1) is a zinc-rich protein belonging to the interferon (IFN)-induced gene family. Here, we report a metastasis-promoting role of XAF1 in CRC by acting as a novel adaptor of valosin-containing protein (VCP). XAF1 facilitates VCP-mediated deubiquitination of the E3 ligase RING finger protein 114 (RNF114), which promotes K48-linked ubiquitination and subsequent degradation of junction plakoglobin (JUP). The XAF1-VCP-RNF114-JUP axis is critical for the migration and metastasis of CRC cells. Moreover, we observe correlations between the protein levels of XAF1, RNF114, and JUP in clinical samples. Collectively, our findings reveal an oncogenic function of XAF1 in mCRC and suggest that the XAF1-VCP-RNF114-JUP axis is a potential therapeutic target for CRC treatment.

Discovery of distinct cancer cachexia phenotypes using an unsupervised machine-learning algorithm.

OBJECTIVES: Cancer cachexia is a debilitating condition with widespread negative effects. The heterogeneity of clinical features within patients with cancer cachexia is unclear. The identification and prognostic analysis of diverse phenotypes of cancer cachexia may help develop individualized interventions to improve outcomes for vulnerable populations. The aim of this study was to show that the machine learning-based cancer cachexia classification model generalized well on the external validation cohort. METHODS: This was a nationwide multicenter observational study conducted from October 2012 to April 2021 in China. Unsupervised consensus clustering analysis was applied based on demographic, anthropometric, nutritional, oncological, and quality-of-life data. Key characteristics of each cluster were identified using the standardized mean difference. We used logistic and Cox regression analysis to evaluate 1-, 3-, 5-y, and overall mortality. RESULTS: A consensus clustering algorithm was performed for 4329 patients with cancer cachexia in the discovery cohort, and four clusters with distinct phenotypes were uncovered. From clusters 1 to 4, the clinical characteristics of patients showed a transition from almost unimpaired to mildly, moderately, and severely impaired. Consistently, an increase in mortality from clusters 1 to 4 was observed. The overall mortality rate was 32%, 40%, 54%, and 68%, and the median overall survival time was 21.9, 18, 16.7, and 13.6 mo for patients in clusters 1 to 4, respectively. Our machine learning-based model performed better in predicting mortality than the traditional model. External validation confirmed the above results. CONCLUSIONS: Machine learning is valuable for phenotype classifications of patients with cancer cachexia. Detection of clinically distinct clusters among cachexic patients assists in scheduling personalized treatment strategies and in patient selection for clinical trials.

Preoperative and Prognostic Prediction of Microvascular Invasion in Hepatocellular Carcinoma: A Review Based on Artificial Intelligence.

Microvascular invasion of hepatocellular carcinoma is an important factor affecting tumor recurrence after liver resection and liver transplantation. There are many ways to classify microvascular invasion, however, an international consensus is urgently needed. Recently, artificial intelligence has emerged as an important tool for improving the clinical management of hepatocellular carcinoma. Many studies about microvascular invasion currently focus on preoperative and prognosis prediction of microvascular invasion using artificial intelligence. In this paper, we review the definition and staging of microvascular invasion, especially the diagnosis of it by using artificial intelligence. In preoperative prediction, deep learning based on multimodal data modeling of radiomics-screened features, clinical features, and medical images is currently the most effective means. In prognostic prediction, pathology is the gold standard, and the techniques used should more effectively utilize the global features of the pathology images.

Overall survival of patients with hepatocellular carcinoma treated with sintilimab and disease outcome after treatment discontinuation.

BACKGROUND: The use of Anti-PD-1 therapy has yielded promising outcomes in hepatocellular carcinoma (HCC). However, limited research has been conducted on the overall survival (OS) of patients with varying tumor responses and treatment duration. METHODS: This retrospective study analyzed HCC patients who received sintilimab between January 2019 and December 2020 at four centers in China. The evaluation of tumor progression was based on Response Evaluation Criteria in Solid Tumors version 1.1. The study investigated the correlation between tumor response and OS, and the impact of drug use on OS following progressive disease (PD). RESULTS: Out of 441 treated patients, 159 patients satisfied the inclusion criteria. Among them, 77 patients with disease control exhibited a significantly longer OS compared to the 82 patients with PD (median OS 26.0 vs. 11.3 months, P < 0.001). Additionally, the OS of patients with objective response (OR) was better than that of patients with stable disease (P = 0.002). Among the 47 patients with PD who continued taking sintilimab, the OS was better than the 35 patients who discontinued treatment (median OS 11.4 vs. 6.9 months, P = 0.042). CONCLUSIONS: In conclusion, the tumor response in HCC patients who received sintilimab affects OS, and patients with PD may benefit from continued use of sintilimab.

Combination of alpha-fetoprotein and neutrophil-to-lymphocyte ratio to predict treatment response and survival outcomes of patients with unresectable hepatocellular carcinoma treated with immune checkpoint inhibitors.

BACKGROUND: Immune-checkpoint inhibitors (ICIs) have revolutionized the treatment of hepatocellular carcinoma (HCC). However, long-term survival outcomes and treatment response of HCC patients undergoing immunotherapy is unpredictable. The study aimed to evaluate the role of alpha-fetoprotein (AFP) combined with neutrophil-to-lymphocyte ratio (NLR) to predict the prognosis and treatment response of HCC patients receiving ICIs. METHODS: Patients with unresectable HCC who received ICI treatment were included. The HCC immunotherapy score was developed from a retrospective cohort at the Eastern Hepatobiliary Surgery Hospital to form the training cohort. The clinical variables independently associated with overall survival (OS) were identified using univariate and multivariate Cox regression analysis. Based on multivariate analysis of OS, a predictive score based on AFP and NLR was constructed, and patients were stratified into three risk groups according to this score. The clinical utility of this score to predict progression-free survival (PFS) and differentiate objective response rate (ORR) and disease control rate (DCR) was also performed. This score was validated in an independent external validation cohort at the First Affiliated Hospital of Wenzhou Medical University. RESULTS: Baseline AFP ≤ 400 ng/ml (hazard ratio [HR] 0.48; 95% CI, 0.24-0.97; P = 0.039) and NLR ≤ 2.77 (HR 0.11; 95% CI, 0.03-0.37; P<0.001) were found to be independent risk factors of OS. The two labolatory values were used to develop the score to predict survival outcomes and treatment response in HCC patients receiving immunotherapy, which assigned 1 point for AFP > 400 ng/ml and 3 points for NLR > 2.77. Patients with 0 point were classified as the low-risk group. Patients with 1-3 points were categorized as the intermediate-risk group. Patients with 4 points were classified as the high-risk group. In the training cohort, the median OS of the low-risk group was not reached. The median OS of the intermediate-risk group and high-risk group were 29.0 (95% CI 20.8-37.3) months and 16.0 (95% CI 10.8-21.2) months, respectively (P < 0.001). The median PFS of the low-risk group was not reached. The median PFS of the intermediate-risk group and high-risk group were 14.6 (95% CI 11.3-17.8) months and 7.6 (95% CI 3.6-11.7) months, respectively (P < 0.001). The ORR and DCR were highest in the low-risk group, followed by the intermediate-risk group and the high-risk group (P < 0.001, P = 0.007, respectively). This score also had good predictive power using the validation cohort. CONCLUSION: The HCC immunotherapy score based on AFP and NLR can predict survival outcomes and treatment response in patients receiving ICI treatments, suggesting that this score could serve as a useful tool for identification of HCC patients likely to benefit from immunotherapy.

Gemcitabine and cisplatin or oxaliplatin chemotherapy combined with atezolizumab plus bevacizumab for advanced biliary tract cancers: a single-arm trial.

Advanced biliary tract cancer (BTC) has a poor prognosis, even after combined chemotherapy of gemcitabine and oxaliplatin (GEMOX). To investigate the efficacy and safety of GEMOX chemotherapy combining atezolizumab and bevacizumab in advanced BTC, the authors designed an open-label, single-arm, phase II clinical trial and will enroll patients with stage IV BTC. The participants will receive GEMOX chemotherapy combined with atezolizumab plus bevacizumab. The primary end point is objective response rate; the secondary end points are overall survival, disease control rate, progression-free survival, time to progression, duration of response and safety. The results of this trial are expected to provide novel, safe and effective treatment options for patients with advanced BTC, which could further improve their prognosis. Clinical Trial Registration: ChiCTR2100049830 (ChiCTR.org).

Camrelizumab plus gemcitabine and oxaliplatin for the treatment of advanced intrahepatic cholangiocarcinoma: a bi-centric observational retrospective study.

Background: Immune checkpoint inhibitor (ICI), coupled with systemic chemotherapy, may enhance the clinical benefit of cancer by potentiating antitumor immunity, but its efficacy and safety are not clear in advanced intrahepatic cholangiocarcinoma (ICC). This study aims to assess the efficacy and safety of camrelizumab plus gemcitabine and oxaliplatin (GEMOX) for the treatment of advanced ICC in the real world. Methods: Advanced ICC patients receiving at least one session of camrelizumab plus GEMOX combination treatment from March 2020 to February 2022 at two high-volume centers were considered eligible. Tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). The primary endpoint was objective response rate (ORR), disease control rate (DCR), time to response (TTR), and duration of response (DOR). The secondary end points included overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (TRAEs). Results: 30 eligible ICC patients were enrolled and analyzed in this observational retrospective study. The median follow-up time was 24.0 (21.5-26.5) months. The ORR and DCR were 40% and 73.3%, respectively. The median TTR was 2.4 months and the median DOR was 5.0 months. The median PFS and OS were 7.5 months and 17.0 months, respectively. The most common TRAEs were fever (83.3%), fatigue (73.3%), and nausea (70%). Of all TRAEs, thrombocytopenia, and neutropenia were the most frequent severe AE (both 10%). Conclusion: The combination of camrelizumab and GEMOX is a potentially efficacious and safe treatment modality for advanced ICC patients. Potential biomarkers are needed to identify patients who might benefit from this treatment option.

Laparoscopic and open liver resection for hepatocellular carcinoma with type 2 diabetes mellitus: multicenter propensity score-matched study.

PURPOSE: This study aimed at analyzing and comparing the perioperative results and long-term oncological outcomes of hepatocellular carcinoma (HCC) patients with type 2 diabetes mellitus (T2DM) treated with laparoscopic (LLR) versus open liver resection (OLR). METHODS: Clinicopathological data of HCC patients with T2DM who underwent LLR or OLR as initial treatment from four medical centers were retrospectively reviewed. The survival outcomes of patients who underwent laparoscopic liver resection (LLR) were compared with those of patients who underwent open liver resection (OLR). Using the Kaplan-Meier method, survival curves for the two groups of patients were generated, and the log-rank test was used to compare survival differences. Propensity score matching (PSM) analysis was used to match patients of the LLR and OLR groups in a 1:1 ratio. RESULTS: 230 HCC patients with T2DM were enrolled, including 101 patients in the LLR group and 129 patients in the OLR group. After PSM, 90 patients were matched in each of the study group. Compared with the OLR group, the LLR group had less blood loss, a shorter hospitalization and fewer postoperative complications. The LLR group had a significantly better overall survival (OS) and recurrence-free survival (RFS) than the OLR group before and after PSM. Subgroup analysis demonstrated that HCC patients with T2DM had survival benefits from LLR regardless of the course of T2DM. CONCLUSIONS: Laparoscopic liver resection for HCC patients with T2DM can be safely performed with favorable perioperative and long-term oncological outcomes at high-volume liver cancer centers, regardless of the course of T2DM.

Efficacy and safety of a triple combination of atezolizumab, bevacizumab plus GEMOX for advanced biliary tract cancer: a multicenter, single-arm, retrospective study.

Background: Anti-programmed cell death ligand 1/vascular endothelial growth factor inhibition, coupled with chemotherapy, may potentiate antitumor immunity leading to enhanced clinical benefit, but it has not been investigated in advanced biliary tract cancer (BTC). Objectives: We investigated the efficacy and safety of atezolizumab, bevacizumab, and gemcitabine plus oxaliplatin (GEMOX) in advanced BTC and explore the potential biomarkers related to the response. Design: Multicenter, single-arm, retrospective study. Methods: Advanced BTC patients, who received a triple combination therapy at three medical centers between 18 March 2020 and 1 September 2021, were included. Treatment response was evaluated via mRECIST and RECIST v1.1. Endpoints included the overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. The whole exome sequencing of pathological tissues was conducted for bioinformatic analysis. Results: In all, 30 patients were enrolled. The best ORR was 76.7% and the DCR was 90.0%. The median PFS was 12.0 months, and the median OS was not reached. During the treatment, 10.0% (3/30) of patients suffered from ⩾grade 3 treatment-related adverse events (TRAEs). Furthermore, fever (73.3%), neutropenia (63.3%), increased aspartate transaminase and alanine aminotransferase levels (50.0% and 43.3%, respectively) are the most common TRAEs. Bioinformatics analysis revealed patients with altered ALS2CL had a higher ORR. Conclusion: The triple combination of atezolizumab, bevacizumab, and GEMOX may be efficacious and safe for patients with advanced BTC. ALS2CL may be a potential predictive biomarker for the efficacy of triple combination therapy.

Early Experience of TACE Combined with Atezolizumab plus Bevacizumab for Patients with Intermediate-Stage Hepatocellular Carcinoma beyond Up-to-Seven Criteria: A Multicenter, Single-Arm Study.

Aim: Locoregional treatment, such as TACE, in combination with immunotherapy may elicit a synergistic anticancer effect. However, TACE combined with atezolizumab plus bevacizumab (atezo/bev) has not been investigated for patients with intermediate stage (BCLC B) HCC beyond the up-to-seven criteria. This study aims to evaluate the efficacy and safety of this treatment strategy in intermediate-stage HCC patients with large or multinodular tumors exceeding the up-to-seven criteria. Methods: This multicenter retrospective study included patients with intermediate stage (BCLC B) HCC beyond the up-to-seven criteria treated with TACE combined with atezo/bev from five centers in China from March to September 2021. The outcomes of this study included the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS). Treatment-related adverse events (TRAEs) were analyzed to assess safety. Results: A total of 21 patients were enrolled in this study, with a median follow-up duration of 11.7 months. According to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, the best ORR was 42.9% and the DCR was 100%. According to modified RECIST (mRECIST), the best ORR and DCR were 61.9% and 100%, respectively. The median PFS and OS were not reached. The most common TRAEs at all levels were fever (71.4%), and the most common grade 3/4 TRAE was hypertension (14.3%). Conclusions: TACE combined with atezo/bev showed encouraging efficacy and an acceptable safety profile, making it a promising treatment option for patients with BCLC B HCC beyond the up-to-seven criteria, which will be further investigated in a prospective single-arm trial.

A reasonable identification of the early recurrence time based on microvascular invasion for hepatocellular carcinoma after R0 resection: A multicenter retrospective study.

BACKGROUND: Early and late recurrence of hepatocellular carcinoma (HCC) have different clinical outcomes, especially for those accompanied by microvascular invasion (MVI), but the definition of early recurrence remains controversial. Therefore, a reasonable identification of the early recurrence time for HCC is urgently needed. METHODS: Resected recurrence patients were enrolled and divided into two cohorts, one for identification of the early recurrence time and another for verification of the accuracy of the point. Univariable and multivariable Cox regression analyses were adopted to identify the prognostic factors of recurrence HCC (rHCC) and Kaplan-Meier method was applied to analyze the overall survival (OS). The appropriate cutoff value was determined by the exhaustive method using different recurrence intervals from 1 to 24 months in turn. RESULTS: In total, 292 resected rHCC patients were analyzed to calculate the early recurrence interval, and another 421 resected rHCC patients with MVI were enrolled to verify the efficacy of adjuvant transarterial chemoembolization (TACE) in this recurrence interval. MVI was identified as an independent risk factor by multivariable analysis. The OS of rHCC patients without MVI is better than that of patients with MVI when the recurrence time was within 13 months, while not beyond 13 months. The verification cohort demonstrated that adjuvant TACE provided longer survival for rHCC with MVI when the recurrence time was within 13 months, while not beyond 13 months. CONCLUSION: For HCC patients with MVI who underwent R0 resection, 13 months may be a reasonable early recurrence time point, and within this interval, postoperative adjuvant TACE may result in longer survival compared with surgery alone.

Efficacy and safety of TACE combined with lenvatinib and PD-1 inhibitors for unresectable recurrent HCC: A multicenter, retrospective study.

BACKGROUND: There is no consensus on the optimal regimen for unresectable recurrent hepatocellular carcinoma (HCC), so this retrospective study aimed to evaluate the efficacy and safety of transarterial chemoembolization (TACE) combined with lenvatinib and PD-1 inhibitors (T-L-P) versus TACE combined with lenvatinib (T-L) or TACE alone. METHOD: Data were collected from 204 patients with unresectable recurrent HCC who received T-L-P, T-L, or TACE alone at three medical centers from January, 2019 to December, 2020 for analysis. The survival outcomes, tumor response, and adverse events were compared between three groups, and risk factors were further investigated. RESULTS: The median overall survival in the T-L-P, T-L, and TACE alone groups were not reached, 25.6, and 15.7 months, respectively (p < 0.001). The median progression-free survival in the T-L-P, T-L, and TACE alone groups were 24.1, 17.3, and 13.7 months, respectively (p < 0.001). The best objective response rate in the T-L-P, T-L, and TACE alone groups were 70.4%, 48.9%, and 42.5%, respectively. The best disease control rate in the T-L-P, T-L, and TACE alone groups were 100.0%, 97.8%, and 87.5%, respectively. There was no significant difference between the T-L-P and T-L groups for Grade 3/4 adverse events. CONCLUSION: T-L-P regimen was safe and superior to T-L or TACE alone in improving survival for unresectable recurrent HCC patients.

Intensity-modulated radiotherapy combined with systemic atezolizumab and bevacizumab in treatment of hepatocellular carcinoma with extrahepatic portal vein tumor thrombus: A preliminary multicenter single-arm prospective study.

Background and aims: The efficacy and safety of systemic atezolizumab and bevacizumab (atezo/bev) in treatment of patients with unresectable hepatocellular carcinoma (HCC) have been demonstrated. However, the efficacy of this treatment in patients with HCC and extrahepatic portal vein tumor thrombus (ePVTT) is not satisfactory. This study aimed to study the efficacy and safety of combining intensity-modulated radiotherapy (IMRT) with systemic atezo/bev in treatment of these patients. Methods: This multicenter prospective study included patients with ePVTT treated with IMRT combined with atezo/bev from March to September 2021 in three centers in China. The outcomes of this study included objective response rate (ORR), overall survival (OS), progression-free survival (PFS), time to progression (TTP), and association between response and tumor mutational burden (TMB). Treatment-related adverse events (TRAEs) were analyzed to assess safety. Results: Of 30 patients in this study, the median follow-up was 7.4 months. Based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, the ORR was 76.6%, the median OS for the entire cohort was 9.8 months, the median PFS was 8.0 months, and the median TTP was not reached. This study failed to establish a significant correlation between TMB with any of the following outcomes, including ORR, OS, PFS or TTP. The most common TRAEs at all levels were neutropenia (46.7%), and the most common grade 3/4 TRAE was hypertension (16.7%). There was no treatment-related deaths. Conclusions: IMRT combined with atezo/bev showed encouraging treatment efficacy with an acceptable safety profile, making this treatment to be a promising option for HCC patients with ePVTT. Further studies are required to support the findings of this preliminary study. Clinical trial registration: http://www.chictr.org.cn, Identifier ChiCTR2200061793.

Transarterial chemoembolization plus immune checkpoint inhibitor as postoperative adjuvant therapy for hepatocellular carcinoma with portal vein tumor thrombus: A multicenter cohort study.

PURPOSE: This study aimed to assess the efficacy and safety of postoperative adjuvant transarterial chemoembolization (PA-TACE) plus immune checkpoint inhibitor (ICI) for hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). PATIENTS AND METHODS: This study was conducted on three centers from June 2018 to December 2020. Patients were divided into the PA-TACE (n = 48) and PA-TACE plus ICI groups (n = 42). The recurrence-free survival (RFS) and overall survival (OS) curves were depicted by Kaplan-Meier method, and the differences between the two groups were compared using log-rank test. Univariate and multivariate Cox analyses were performed to identify independent risk factors for RFS and OS. Adverse events (AEs) were assessed according to the Common Terminology Criteria for AEs (CTCAE) version 5.0. RESULTS: The median RFS of the PA-TACE plus ICI group was significantly longer than the PA-TACE group (12.76 months vs. 8.11 months; P = 0.038). The median OS of the PA-TACE plus ICI group was also significanfly better than the PA-TACE group (24.5 months vs. 19.1 months; P = 0.032). PA-TACE plus ICI treatment was an independent prognostic factor for RFS (HR: 0.54, 95% CI: 0.32-0.9, P = 0.019) and OS (HR: 0.47, 95% CI: 0.26-0.86, P = 0.014). Only one patient experienced grade ≥3 immune-related AEs in the PA-TACE plus ICI group. CONCLUSIONS: PA-TACE plus ICI treatment had better efficacy in preventing recurrence and prolonging survival than PA-TACE alone for HCC patients with PVTT after R0 resection. This novel treatment modality may be an appropriate option for HCC with PVTT.

Efficacy and safety of radiotherapy combined with atezolizumab plus bevacizumab in treating hepatocellular carcinoma with portal vein tumour thrombus: a study protocol.

INTRODUCTION: Vascular invasion and metastasis are poor prognostic factors in patients with hepatocellular carcinoma (HCC). The efficacy of available therapeutic regimens for unresectable HCC is not satisfactory in HCC with portal vein tumour thrombosis (PVTT). Therefore, this open-label, single-arm phase II clinical trial aims to investigate the efficacy and safety of radiotherapy combined with atezolizumab plus bevacizumab in treating HCC patients with PVTT. METHODS AND ANALYSIS: We plan to enrol patients diagnosed with unresectable HCC complicated by PVTT. Intensity-modulated radiotherapy (IMRT) combined with atezolizumab plus bevacizumab will be administered for treatment. Patients will initially receive radiotherapy, with each IMRT cycle lasting for 28 days and the total dose of tumour (DT) of 40 Gy/20 f/26 d. CT scan will be performed again, and the treatment plan will be reformulated after field constriction. The treatment will continue until the total DT is up to 54-56 Gy/27-28 f. The treatment with atezolizumab plus bevacizumab will be started at 3±1 days after the initiation of radiotherapy and will continue until unacceptable toxicity or disease progression. The primary endpoint is objective response rate (ORR), while the secondary endpoints include overall survival, disease control rate, progression-free survival, time to progression, duration of response and the rate of surgical conversions. Assuming an ORR of 47%, with a two-sided alpha error of 0.1, 90% power, and a 10% drop-out rate, the required number of evaluable patients is 42. ETHICS AND DISSEMINATION: This study will be conducted according to the standards of Good Clinical Practice and in compliance with the principles of the Declaration of Helsinki. The Ethics Committee of our Hospital has approved the protocol (EHBHKY2021-K-017). All participants are required to provide written informed consent. The results of the trial will be published in peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2100049831.

Efficacy and safety of transarterial chemoembolization plus antiangiogenic- targeted therapy and immune checkpoint inhibitors for unresectable hepatocellular carcinoma with portal vein tumor thrombus in the real world.

Purpose: This study aimed to assess the efficacy and safety of a triple therapy that comprises transarterial chemoembolization (TACE), antiangiogenic-targeted therapy, and programmed death-1 (PD-1) inhibitors in a real-world cohort of patients with unresectable hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT). Methods: Consecutive patients treated with TACE combined with antiangiogenic therapy and PD-1 inhibitors at the Eastern Hepatobiliary Surgery Hospital between June 2019 and May 2021 were enrolled. The baseline characteristics and treatment course of the patients were recorded. The tumor response was evaluated based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and HCC-specific modified RECIST (mRECIST). The overall survival (OS) and progression-free survival (PFS) of the patients were analyzed using the Kaplan-Meier method. Adverse events (AEs) were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Results: As of the data cutoff on 30 August 2021, the median follow-up time was 10.0 (3.9-28.4) months. A total of 39 eligible patients were included. The objective response rate (ORR) and the disease control rate (DCR) were 35.9% and 74.4% according to the RECIST 1.1, and 48.7% and 84.6% according to mRECIST criteria, respectively. The median OS and PFS were 14.0 and 9.2 months, respectively. Moreover, 34 (87.2%) patients experienced at least one treatment-related AE and 8 (20.5%) patients experienced grade 3/4 treatment-related AEs. The most common treatment- and laboratory-related AEs were hypertension (46.2%) and decreased albumin (53.8%), respectively. No treatment-related mortality occurred during the study period. Conclusions: TACE combined with antiangiogenic-targeted therapy and immune checkpoint inhibitors may have promising anticancer activity in unresectable HCC patients with PVTT. AEs were manageable, with no unexpected overlapping toxicities.

A deep learning model with incorporation of microvascular invasion area as a factor in predicting prognosis of hepatocellular carcinoma after R0 hepatectomy.

INTRODUCTION: Microvascular invasion (MVI) is a known risk factor for prognosis after R0 liver resection for hepatocellular carcinoma (HCC). The aim of this study was to develop a deep learning prognostic prediction model by incorporating a new factor of MVI area to the other independent risk factors. METHODS: Consecutive patients with HCC who underwent R0 liver resection from January to December 2016 at the Eastern Hepatobiliary Surgery Hospital were included in this retrospective study. For patients with MVI detected on resected specimens, they were divided into two groups according to the size of the maximal MVI area: the small-MVI group and the large-MVI group. RESULTS: Of 193 patients who had MVI in the 337 HCC patients, 130 patients formed the training cohort and 63 patients formed the validation cohort. The large-MVI group of patients had worse overall survival (OS) when compared with the small-MVI group (p = 0.009). A deep learning model was developed based on the following independent risk factors found in this study: MVI stage, maximal MVI area, presence/absence of cirrhosis, and maximal tumor diameter. The areas under the receiver operating characteristic of the deep learning model for the 1-, 3-, and 5-year predictions of OS were 80.65, 74.04, and 79.44, respectively, which outperformed the traditional COX proportional hazards model. CONCLUSION: The deep learning model, by incorporating the maximal MVI area as an additional prognostic factor to the other previously known independent risk factors, predicted more accurately postoperative long-term OS for HCC patients with MVI after R0 liver resection.

Transcatheter arterial chemoembolization plus atezolizumab and bevacizumab for unresectable hepatocellular carcinoma: a single-arm, phase II trial.

The therapeutic effect of transcatheter arterial chemoembolization (TACE) is limited for patients with hepatocellular carcinoma (HCC). Herein, we designed an open-label, single-arm phase II clinical trial to investigate the efficacy and safety of TACE combined with atezolizumab plus bevacizumab for patients with Barcelona Clinic Liver Cancer (BCLC) stage-B HCC. Patients will initially receive TACE. Atezolizumab and bevacizumab will be initiated 2-14 days after the first TACE session. TACE will be repeated on demand. The primary endpoint is the objective response rate. The secondary end points include overall survival, disease control rate, progression-free survival, time-to-progression and safety. The study results will provide evidence for establishing a novel therapeutic regimen for patients with unresectable HCC. Clinical Trial Registration: ChiCTR2100049829 (ChiCTR.org).