A novel engineered IL-21 receptor arms T-cell receptor-engineered T cells (TCR-T cells) against hepatocellular carcinoma.

Strategies to improve T cell therapy efficacy in solid tumors such as hepatocellular carcinoma (HCC) are urgently needed. The common cytokine receptor γ chain (γc) family cytokines such as IL-2, IL-7, IL-15 and IL-21 play fundamental roles in T cell development, differentiation and effector phases. This study aims to determine the combination effects of IL-21 in T cell therapy against HCC and investigate optimized strategies to utilize the effect of IL-21 signal in T cell therapy. The antitumor function of AFP-specific T cell receptor-engineered T cells (TCR-T) was augmented by exogenous IL-21 in vitro and in vivo. IL-21 enhanced proliferation capacity, promoted memory differentiation, downregulated PD-1 expression and alleviated apoptosis in TCR-T after activation. A novel engineered IL-21 receptor was established, and TCR-T armed with the novel engineered IL-21 receptors (IL-21R-TCR-T) showed upregulated phosphorylated STAT3 expression without exogenous IL-21 ligand. IL-21R-TCR-T showed better proliferation upon activation and superior antitumor function in vitro and in vivo. IL-21R-TCR-T exhibited a less differentiated, exhausted and apoptotic phenotype than conventional TCR-T upon repetitive tumor antigen stimulation. The novel IL-21 receptor in our study programs powerful TCR-T and can avoid side effects induced by IL-21 systemic utilization. The novel IL-21 receptor creates new opportunities for next-generation TCR-T against HCC.

Transarterial chemoembolization with/without immune checkpoint inhibitors plus tyrosine kinase inhibitors for unresectable hepatocellular carcinoma: a single center, propensity score matching real-world study.

OBJECTIVES: To explore the efficacy and safety of Transarterial chemoembolization (TACE) in combination with immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) in patients with unresectable hepatocellular carcinoma (uHCC). METHODS: 456 patients with HCC receiving either TACE in combination with ICIs and TKIs (combination group, n = 139) or TACE monotherapy (monotherapy group, n = 317) were included from Apr 2016 to Dec 2021 in this retrospective study. We employed propensity score matching (PSM), performed 1:2 optimal pair matching, to balance potential bias. RESULTS: The mean follow-up time is 24.7 months (95% CI 22.6-26.8) for matched patients as of March 2022. After matching, the combination group achieved longer OS and PFS (median OS:21.9 vs. 16.3 months, P = 0.022; median PFS: 8.3 vs. 5.1 months, P < 0.0001) than TACE monotherapy group. The combination group had better objective response rate (ORR) and disease control rate (DCR) (ORR: 52.5% vs. 32.8%, P < 0.001; DCR: 82.7% vs. 59.6%, P < 0.001). Subgroup analysis showed that patients who received "TKIs + ICIs" after the first TACE procedure (after TACE group) achieved longer OS than those before the first TACE procedure (before TACE group) (26.8 vs. 19.2 months, P = 0.011). Adverse events were consistent with previous studies of TACE-related trials. CONCLUSIONS: TACE plus TKIs and ICIs appeared to deliver longer PFS and OS in HCC patients than TACE monotherapy. "TKIs + ICIs" co-treatment within 3 months after the first TACE procedure might be a better medication strategy.

Spleen-dedicated stiffness measurement performed well to rule out high-risk varices in HBV-related hepatocellular carcinoma: Screening for high-risk varices in HCC.

BACKGROUND: Esophagogastroduodenoscopy (EGD) is required to screen for high-risk varices (HRV) in patients with hepatocellular carcinoma (HCC), especially since overall survival rates have dramatically improved with new systemic therapies. AIM: To assess the Baveno VI and Baveno VII algorithms' ability to rule out HRV in hepatitis B virus (HBV)-related HCC METHODS: We prospectively enrolled consecutive patients with HBV related, compensated cirrhosis and newly diagnosed HCC who underwent liver stiffness measurement, spleen stiffness measurement (SSM) using a 100-Hz shear wave frequency, and EGD. RESULTS: From September 2021 to August 2023, we enrolled 219 patients with HCC, with 107 (48.9%) Barcelona Clinic Liver Cancer (BCLC) A, 28 (12.8%) BCLC B and 84 (38.3%) BCLC C, respectively. HRV prevalence was 28.8% (63/219). Baveno VI criteria safely (HRV missing rate, 3.2%) avoided 27.4% unnecessary EGDs, while the Baveno VII algorithm avoided 49.3% with HRV missing rate at 7.9% (5/63). The SSM ≤40 kPa avoided 47.5% of EGDs safely (HRV missing rate, 4.8%), significantly better than the Baveno VI criteria (p < 0.001) and comparable to the Baveno VII algorithm (p = 0.390). The SSM ≤40 kPa safely avoided EGDs in patient subgroups within Milan criteria, with portal vein tumour thrombosis or BCLC B/C or candidates for systemic therapy. CONCLUSIONS: We validated that the SSM ≤40 kPa using a 100-Hz probe could safely eliminate more unnecessary EGDs than the Baveno VI criteria in patients with HBV-related HCC. However, the efficacy of the Baveno VII algorithm in patients with HCC requires further investigation.

Tyrosine kinase inhibitors, immune checkpoint inhibitors combined with hepatic arterial infusion of oxaliplatin and raltitrexed versus oxaliplatin, 5-fluorouracil and leucovorin for intermediate and advanced hepatocellular carcinoma: A retrospective study.

BACKGROUND: Hepatic arterial infusion chemotherapy (HAIC) has demonstrated promising benefits in treating advanced hepatocellular carcinoma (HCC). In China, the most frequently used HAIC regimen is oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX). However, arterial infusion of fluorouracil over 46 h was not convenient. Raltitrexed, another antimetabolic agent with a long plasma half-life, allows for shorter infusion durations. We aimed to compare the effectiveness and toxicity of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) combined with HAIC with raltitrexed plus oxaliplatin (RALOX) or FOLFOX in patients with intermediate and advanced HCC. METHODS: This retrospective study enrolled 82 eligible patients from February 2019 to December 2021. Forty patients were treated with FOLFOX HAIC (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, 5-fluorouracil bolus 400 mg/m2 administered on day 1, and 5-fluorouracil 2400 mg/m2 infusion for 46 h, every 3 weeks) combined with TKIs and ICIs. Forty-two patients received RALOX HAIC (oxaliplatin 100 mg/m2 and raltitrexed 3 mg/m2 on day 1, every 3 weeks) combined with TKIs and ICIs. We compared the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety profile. RESULTS: ORR was similar between the FOLFOX HAIC and RALOX HAIC groups (42.5% vs 42.5%, P = 0.974). DCR also showed no significant difference between the two groups (87.5% vs 85.7%, P = 0.813). Median PFS was 10.7 months in the FOLFOX HAIC group versus 10.2 months in the RALOX HAIC group (P = 0.41). Median OS was 20.3 months in the FOLFOX HAIC group, compared to 17.7 months in the RALOX HAIC group (P = 0.50). Both groups had similar profiles of grade 3/4 treatment-related adverse events, including thrombocytopenia, increased aspartate aminotransferase, increased alanine aminotransferase, and leukocytopenia. CONCLUSION: The effectiveness and safety of HAIC with RALOX were comparable to HAIC with FOLFOX in intermediate and advanced HCC patients.

Identifying optimal candidates for post-TIPS patients with HCC undergoing TACE: a multicenter observational study.

OBJECTIVE: To develop a prognostic model for post-transjugular intrahepatic portosystemic shunt (TIPS) patients with hepatocellular carcinoma (HCC) beyond the Milan criteria treated by transarterial chemoembolization (TACE). DESIGN: Between January 2013 and January 2020, 512 patients with HCC beyond the Milan criteria who underwent TACE after TIPS were retrospectively recruited from 15 tertiary centers. Patients were randomly sorted into a training set (n = 382) and a validation set (n = 130). Medical data and overall survival were assessed. A prediction model was developed using multivariate Cox regression analyses. Predictive performance and discrimination were evaluated and compared with other prognostic models. RESULTS: Vascular invasion, log10(AFP), 1/creatinine, extrahepatic spread, and log10(ALT) were the most significant prognostic factors of survival. These five parameters were included in a new VACEA score. This score was able to stratify patients in the training set into four distinct risk grades whose median overall survival were 25.2, 15.1, 8.9, and 6.2 months, respectively. The 6-month, 1-year, 2-year, and 3-year AUROC values and C-index of the VACEA model were 0.819, 0.806, 0.779, 0.825, and 0.735, respectively, and higher than those of other seven currently available models in both the training and validation sets, as well as in different subgroups. CONCLUSION: The VACEA score could stratify post-TIPS patients with HCC beyond the Milan criteria treated by TACE and help to identify candidates who benefit from this treatment. KEY POINTS: • Vascular invasion, AFP, creatinine, extrahepatic spread, and ALT were independent significant prognostic factors of survival for HCC patients who underwent TACE after TIPS. • Our new model, named VACEA score, can accurately predict prognosis at the individual level and stratify patients into four distinct risk grades. • The VACEA model showed better prognostic discrimination and calibration than other current TACE-/TIPS-specific models Graphical abstract.

Sorafenib plus drug-eluting bead transarterial chemoembolization for early intrahepatic stage-progressed advanced hepatocellular carcinoma refractory to conventional transarterial chemoembolization.

PURPOSE: To investigate the effectiveness and safety of the combination of sorafenib and drug-eluting bead transarterial chemoembolization (DEB-TACE) in the treatment of early intrahepatic stage-progressed advanced hepatocellular carcinoma (ISPA-HCC). METHODS: This study was approved by the ethics committees of six tertiary medical centers in China. Between October 2017 and October 2020, 213 patients with advanced HCC received either sorafenib combined with on-demand DEB-TACE (DTS group, n = 103) or sorafenib monotherapy (S group, n = 110). Overall survival (OS), time to progression (TTP), local tumor response, and adverse events (AEs) were compared between the two groups. RESULTS: The incidences of nause/vomiting, abdonimal pain, hyperbilirubinemia, fever and ALT/AST increasing were higher in the DTS group. The post-treatment partial response, objective response, and disease control rates were significantly higher in the DTS group than in the S group (51.5% vs. 23.6%; 56.3% vs. 25.5%; 77.7% vs. 56.4%, respectively). The median OS was significantly longer in the DTS group than in the S group [16.3 vs. 10.0 months; hazard ratio (HR) = 0.43; P < 0.001], as was the TTP (6.7 vs. 4.3 months; HR = 0.60; P = 0.001). In the DTS group, patients who received ≥ 2 sessions of DEB-TACE benefited more than those who received two sessions of DEB-TACE. Multivariate analysis revealed that the α-fetoprotein level and treatment allocation were independent predictors of OS and TTP. CONCLUSION: The combination of sorafenib and DEB-TACE is safe and effective for the treatment of early ISPA-HCC.

Interaction between baseline HBV loads and the prognosis of patients with HCC receiving anti-PD-1 in combination with antiangiogenic therapy undergoing concurrent TAF prophylaxis.

BACKGROUND: A high baseline hepatitis B virus (HBV) load has always been listed as an exclusion criterion for programmed cell death-1 (PD-1) inhibitor-associated therapy in clinical trials, as the interaction between HBV load and anti-PD-1/PD-L1 therapy with anti HBV therapy remains controversial. METHODS: We retrospectively enrolled 70 unresectable HCC patients who were seropositive for HBsAg and accepted tenofovir alafenamide fumarate (TAF) therapy before anti-PD-1 in combination with an antiangiogenic treatment. Patients were divided into a low HBV DNA group (≤ 2000 IU/ml) and a high HBV DNA group (> 2000 IU/ml) according to the baseline HBV DNA levels. Tumour response and progression-free survival (PFS) were compared, and univariate and multivariate Cox analyses were performed to identify potential risk factors for PFS. The incidences of HBV reactivation and HBV-associated hepatitis were also recorded. RESULTS: 48 patients were assigned to the low group and the remaining 22 patients were assigned to the high group. The objective response rates (ORRs), disease control rates (DCRs), and PFS between the two groups showed no significant difference (P = 0.761, 0.552, and 0.784, respectively). The results of Cox analyses revealed that there was no relationship between baseline HBV load and PFS. Additionally, HBV reactivation occurred in only 2 patients (2.9%), and no patient experienced HBV-related hepatic impairment when given a continuous TAF treatment. CONCLUSIONS: Baseline HBV loads do not affect the prognosis of HCC patients receiving anti-PD-1 in combination with an antiangiogenic therapy, while PD-1 inhibitors do not aggravate HBV reactivation and hepatic impairment in patients simultaneously subjected to TAF prophylaxis.

Hepatic Tumor Stiffness Measured by Shear Wave Elastography Is Prognostic for HCC Progression Following Treatment With Anti-PD-1 Antibodies Plus Lenvatinib: A Retrospective Analysis of Two Independent Cohorts.

Background: The clinical significance of liver stiffness (LS) measured by shear wave elastography (SWE) in programmed cell death protein-1 (PD-1) inhibitors treated advanced hepatocellular carcinoma (HCC) patients remains unknown. This study aimed to explore the prognostic value of baseline LS by SWE prior to PD-1 inhibitor treatment in combination with lenvatinib. Methods: We retrospectively evaluated patients (n=133) with HCC who received anti-PD-1 antibodies plus lenvatinib at two high-volume medical centres, between January 2020 and June 2021. Univariate and multivariate logistic regression analysis were used to develop a novel nomogram. RNA sequencing and immunohistochemical staining were used to assess the heterogeneity of biological and immune characteristics associated with tumor stiffness. Results: The objective response rate (ORR) and disease control rate (DCR) of the whole population were 23.4% and 72.2%, respectively. A LS value of the baseline tumorous foci of 19.53 kPa had the maximum sum of sensitivity and specificity, making it the optimal cut-off value for predicting PD-1 inhibitor efficacy. The nomogram comprised baseline tumor LS and albumin-bilirubin grade (ALBI), which provided favorable calibration and discrimination in the training dataset with an AUC of 0.840 (95%CI: 0.750-0.931) and a C-index of 0.828. Further, it showed acceptable discrimination in the validation cohort, with an AUC of 0.827 (95%CI: 0.673-0.980) and C-index of 0.803. The differentially expressed genes enriched in high stiffness tumors were predominantly associated with metabolic pathways, while those enriched in low stiffness tumors were related to DNA damage repair. Furthermore, patients with high stiffness tumors had a relatively lower infiltration of immune cells and histone deacetylase pathway inhibitors were identified as candidate drugs to promote the efficacy of immunotherapy. Conclusions: Baseline LS value of tumorous foci by SWE-that is, before administration of a PD-1 inhibitor in combination with lenvatinib-is a convenient predictor of PD-1 inhibitor efficacy in patients with advanced HCC, which has potential to be used for pretreatment stratification to optimize treatment of advanced HCC.

Lenvatinib Plus Camrelizumab vs. Lenvatinib Monotherapy as First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Multicenter Retrospective Cohort Study.

Background: Combining an antiangiogenic agent with an anti-PD-1 agent is a promising strategy for unresectable hepatocellular carcinoma (HCC). Aims: To explore the effectiveness and tolerability of lenvatinib plus camrelizumab vs. lenvatinib monotherapy as a first-line treatment for unresectable HCC. Methods: This multicenter, retrospective cohort study included patients with unresectable HCC treated with oral lenvatinib 8 mg daily and intravenous camrelizumab 200 mg every 3 weeks (L+C group) or lenvatinib 12 mg or 8 mg daily (L group) in four Chinese centers between September 2018 and February 2020. Tumor response was evaluated according to RECIST 1.1 and mRECIST. The outcomes included objective response rate (ORR), overall survival (OS), 1-year OS rate, progression-free survival (PFS), and safety. Results: By March 31, 2021, 92 patients were finally included, with 48 and 44 in the L+C and L groups, respectively. ORR was significantly higher in the L+C group than in the L group (RECIST 1.1: 37.5% vs. 13.6%, P=0.009; mRECIST: 41.7% vs. 20.5%, P=0.029). Median OS and 95% confidence interval (CI) was 13.9 (13.3-18.3) months in the L group and not reached in the L+C group (P=0.015). The 1-year survival rate was 79.2% and 56.8% in the L+C and L groups, respectively. Median PFS was 10.3 (6.6-14.0) months and 7.5 (5.7-9.3) months in the L+C and L groups, respectively (P=0.0098). Combined therapy vs. monotherapy was independently associated with a prolonged OS (hazard ratio=0.380, 95% CI=: 0.196-0.739, P=0.004) and a prolonged PFS (hazard ratio=0.454, 95%CI=0.282-0.731, P=0.001). The safety profile was comparable between the two groups. The most common adverse event in the L+C and L groups was loss of appetite (41.7% vs. 40.9%, P=0.941). Three patients in the L+C group and two in the L group terminated treatment owing to adverse events. Conclusion: First-line lenvatinib plus camrelizumab showed better effectiveness than lenvatinib alone in patients with unresectable HCC.

Interaction between hepatitis B virus infection and the efficacy of camrelizumab in combination with apatinib therapy in patients with hepatocellular carcinoma: a multicenter retrospective cohort study.

BACKGROUND: The interaction between hepatitis B virus (HBV) load and anti-programmed cell death (PD)-1 in combination with (+) antiangiogenic therapy remains controversial, especially for hepatocellular carcinoma (HCC) patients. This study sought to explore the effects of HBV load and antiviral therapy on anti-PD-1+ antiangiogenic therapy, and the rate of HBV reactivation during anti-PD-1+ antiangiogenic treatment. METHODS: We performed a multicenter retrospective cohort study of camrelizumab combined with apatinib (C+A) therapy between January 1, 2019 and January 1, 2021 in patients with unresectable HCC who were seropositive for hepatitis B surface antigen (HBsAg) and received antiviral therapy before C+A involvement. The effects of HBV load and antiviral therapy on C+A and the rate of HBV reactivation during C+A treatment were examined. RESULTS: Eighty-six patients were included in the analysis. The patients had a mean age of 55 years, and 72 (83.7%) were male. The objective response rates (ORRs) in patients with low (<2,000 IU/mL) and high (≥2,000 IU/mL) baseline HBV deoxyribonucleic acid (DNA) levels were 34.5% and 32.2%, respectively (χ2=0.046; P=0.829), while the disease control rates (DCRs) were 67.3% and 80.6%, respectively (χ2=1.762; P=0.184). The results of the univariate and multivariate analyses showed that the baseline HBV DNA level did not affect PD. Additionally, none of the 86 patients suffered from HBV reactivation or HBV-related hepatic impairment with continuous antiviral treatment, regardless of nucleos(t)ide analogue (NA) type (F=1.473; P=0.228). CONCLUSIONS: Baseline HBV loads did not affect the tumor responses of HCC patients receiving anti-PD-1+ antiangiogenic therapy. Thus, HBV reactivation should not be a contradiction for anti-PD-1+ antiangiogenic therapy among patients undergoing continuous and effective antiviral treatment.

DEAH-box polypeptide 32 promotes hepatocellular carcinoma progression via activating the ß-catenin pathway.

PURPOSE: Hepatocellular carcinoma (HCC) is refractory cancer with high morbidity and high mortality. DEAH-box polypeptide 32 (DHX32) was upregulated in several types of malignancies and predicted poor prognosis. Herein, we investigated the role of DHX32 in HCC progression. METHODS: The expression of DHX32, ß-catenin, and epithelial-mesenchymal transition (EMT)-related makers were determined by Western blot and quantitative real-time PCR assays. Cell proliferation was tested by EdU cell proliferation assay. The effect of DHX32 and ß-catenin on cell migration and invasion were detected by wound-healing and Traswell invasion assays. Tumour xenografts were performed to determine the effect of DHX32 on HCC tumour growth. RESULTS: High level of DHX32 expression was associated with reduced overall survival in HCC patients. DHX32 expression was upregulated in human HCC cells and ectopic expression of DHX32 induced EMT, promoted the mobility and proliferation of HCC cells, and enhanced tumour growth in vivo. Silencing DHX32 reversed EMT, inhibited the malignancy behaviors of HCC cells, and suppressed tumour growth. Mechanistically, silencing DHX32 decreased the expression of ß-cateninin in nucleus and ß-catenin siRNA abrogated DHX32-mediated HCC progression. CONCLUSION: DHX32 was an attractive regulator of HCC progression and indicated DHX32 canserve as a potential biomarker and therapeutic target for HCC patients.

Safety and Efficacy of Camrelizumab Combined with Apatinib for Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombus: A Multicenter Retrospective Study.

INTRODUCTION: Previous trials demonstrated that anti-angiogenesis or anti-programmed death protein 1 (PD-1) monotherapy showed unsatisfied effect in advanced hepatocellular carcinoma (HCC). No study existed that focus on the effects of camrelizumab and apatinib ("C+A") combination therapy for HCC patients with the location and extent of portal vein tumor thrombus (PVTT) as the main variable being assessed. This study was to compare the efficacy and tolerability of "C+A" for HCC patients with PVTT. METHODS: We retrospectively analyzed patients with advanced HCC and PVTT who underwent "C+A" therapy in a multicenter retrospective cohort from Jan 2019 to July 2020. Outcomes of patients who underwent "C+A" were analyzed by using the Kaplan-Meier method according to types of PVTT: PVTT in the main portal vein (type A), PVTT in the first-order portal vein branch (type B), and PVTT in second- or lower-order portal vein branches (type C). RESULTS: Sixty-three patients were finally included and the mean duration of follow-up was 12.6 ± 4.5 months. The objective response rate (ORR) and disease control rate (DCR) for the whole cohort were 44.0% and 75.0%, respectively. The median overall survival (OS), progression-free survival (PFS) and time to progression (TTP) were 14.8 months, 11.8 months and not yet reached (NR), respectively. Patients with type B (OS, 15.9 months; PFS, 14.0 months; TTP, NR) or type C (OS, 16.0 months; PFS, 14.9 months; NR) PVTT appear to have better survival benefits compared with type A (OS, 5.8 months; PFS, 5.0 months; TTP, 7.0 months). Along with AFP, the absence of main PVTT was an independent predictive factor for survival at uni- and multivariate analysis. CONCLUSION: Camrelizumab and apatinib yielded a promising outcome in patients with advanced HCC who developed a tumor thrombus in the first lower-order portal vein branches and was generally safe and had manageable side effects.

Effectiveness and safety of toripalimab, camrelizumab, and sintilimab in a real-world cohort of hepatitis B virus associated hepatocellular carcinoma patients.

BACKGROUND: The clinical significance of programmed cell death protein-1 (PD-1)-targeted immunotherapy in Chinese patients is understudied. We thus aimed to evaluate the safety and efficacy of PD-1 inhibitors with toripalimab, camrelizumab or sintilimab for Chinese hepatocellular carcinoma (HCC) patients in a real-life cohort. METHODS: We analysed hepatitis B virus (HBV)-associated HCC patients treated with toripalimab, camrelizumab, or sintilimab in a retrospective single-center cohort from November 2018 to June 2020. Efficacy was evaluated with objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), time to tumor progression (TTP), and overall survival (OS). Safety data were also recorded. RESULTS: Seventy patients were finally included in the analysis: 23 were treated with toripalimab, 33 with camrelizumab, and 14 with sintilimab. The mean duration of follow-up was 44.7 (95% CI: 39.9-49.6) weeks and the mean cycles of PD-1 at cutoff were 8.3±8.0 for all patients. The ORR and DCR for the whole cohort were 30% and 72.9%, respectively. Overall, 25 (35.7%) patients had radiological disease progression and 10 (14.3%) patients died during follow-up. Median PFS, median TTP, and median OS had not yet been reached. Most frequent drug-related adverse events (AEs) were rash (27.1%), hypertension (18.6%), fatigue (17.1%), diarrhea (17.1%), paresthesia (15.7%), and nausea (15.7%). CONCLUSIONS: Our findings suggest that (I) PD-1 targeted immunotherapy with toripalimab, camrelizumab, or sintilimab yielded a promising outcome in Chinese HBV patients with HCC and that (II) immunotherapy was well tolerated generally and had manageable side effects. This approach thus warrants further popularization and application in clinical practice.

Withdrawn: Effectiveness and safety of toripalimab, camrelizumab and sintilimab in a real-world cohort of hepatitis B virus associated hepatocellular carcinoma patients.

The above article from British Journal of Clinical Pharmacology, published online on July 5, 2020 in Wiley Online Library (http://wileyonlinelibrary.com) has been withdrawn by agreement among the authors and John Wiley & Sons Ltd on behalf of the British Pharmacology Society. The withdrawal has been agreed in accordance with the authors' decision to revise their study providing the latest data.

Development and Validation of a Contrast-Enhanced CT-Based Radiomics Nomogram for Prediction of Therapeutic Efficacy of Anti-PD-1 Antibodies in Advanced HCC Patients.

Background: There is no study accessible now assessing the prognostic aspect of radiomics for anti-PD-1 therapy for patients with HCC. Aim: The aim of this study was to develop and validate a radiomics nomogram by incorporating the pretreatment contrast-enhanced Computed tomography (CT) images and clinical risk factors to estimate the anti-PD-1 treatment efficacy in Hepatocellular Carcinoma (HCC) patients. Methods: A total of 58 patients with advanced HCC who were refractory to the standard first-line of therapy, and received PD-1 inhibitor treatment with Toripalimab, Camrelizumab, or Sintilimab from 1st January 2019 to 31 July 2020 were enrolled and divided into two sets randomly: training set (n = 40) and validation set (n = 18). Radiomics features were extracted from non-enhanced and contrast-enhanced CT scans and selected by using the least absolute shrinkage and selection operator (LASSO) method. Finally, a radiomics nomogram was developed based on by univariate and multivariate logistic regression analysis. The performance of the nomogram was evaluated by discrimination, calibration, and clinical utility. Results: Eight radiomics features from the whole tumor and peritumoral regions were selected and comprised of the Fusion Radiomics score. Together with two clinical factors (tumor embolus and ALBI grade), a radiomics nomogram was developed with an area under the curve (AUC) of 0.894 (95% CI, 0.797-0.991) and 0.883 (95% CI, 0.716-0.998) in the training and validation cohort, respectively. The calibration curve and decision curve analysis (DCA) confirmed that nomogram had good consistency and clinical usefulness. Conclusions: This study has developed and validated a radiomics nomogram by incorporating the pretreatment CECT images and clinical factors to predict the anti-PD-1 treatment efficacy in patients with advanced HCC.

[Incidence and characteristics of benign liver space-occupying mass in 17 721 patients with chronic hepatitis B: a color Doppler ultrasound-based case-control study].

OBJECTIVE: To analyze the incidence and risk factors of benign liver space-occupying mass in patients with chronic hepatitis B (CHB) and the ultrasound features that differentiate these masses from small hepatocellular carcinoma. METHODS: We retrospectively analyzed the color Doppler and clinical data of 17 721 patients with CHB treated in the Hepatology Unit of Nanfang Hospital between January, 2016 and December, 2017. The data were compared with those of 21629 healthy control subjects undergoing routine physical examination in the Center of Heath Management of Nanfang Hospital during the same period. RESULTS: Compared with the control subjects, the patients with CHB had significantly higher incidences of hepatic cysts (11.8% vs 8.7%, P < 0.05), hepatic hemangioma (8.2% vs 1.6%, P < 0.05) and hepatic cirrhosis nodules (20.6% vs 2.4%, P < 0.05). The incidences of hepatic cysts and cirrhosis nodules increased with age and was significantly higher in male than in female patients (P < 0.001). The highest incidence of hepatic hemangioma was found in CHB patients aged 30-49 years without a gender difference (P>0.05). Sonographically, the benign liver masses commonly showed homogeneous echo within the lesion with clear boundaries and regular shape. Hepatic hemangioma was distinctively hyperechoic in 83.32% (1579/1895) of the patients, while small hepatocellular carcinoma presented with weaker peripheral and internal blood flow signals with a lower flow velocity in the arteries and a higher flow velocity in the portal vein. Liver cirrhosis nodules mostly showed a mixture of strong and weak echoes (79.60%; 7637/9595) without blood flow signal within or around the nodule; an increased volume of the nodule accompanied by heterogeneous echoes within the nodule indicated an increased probability of malignant lesion. Hepatic cysts often displayed no echo within the lesion, but the echo could be enhanced posteriorly. CONCLUSIONS: The patients with CHB are at a significantly higher risk of developing hepatic cysts, hepatic hemangiomas and hepatic cirrhosis nodules than the control population, and an older age and the male gender are associated with a higher incidence of hepatic cysts or cirrhosis. The differences in the sonographic and hemodynamic features can help to differentiate hepatic benign mass from malignant lesions, and kinetic changes in sonography can be used to monitor potential malignant transformation of the cirrhotic lesions.

Apatinib Combined With Transarterial Chemoembolization in Patients With Hepatocellular Carcinoma and Portal Vein Tumor Thrombus: A Multicenter Retrospective Study.

PURPOSE: Studies focusing on the effects of combined transcatheter arterial chemoembolization (TACE) + the tyrosine kinase inhibitor apatinib in the treatment of patients with hepatocellular carcinoma (HCC), with the location and extent of portal vein tumor thrombus (PVTT) assessed as the main variable, are rare. This multicenter, retrospective, controlled study was performed to compare the efficacy and tolerability of TACE + apatinib and TACE alone in patients with HCC and PVTT. METHODS: We retrospectively analyzed data from patients with nonresectable HCC and PVTT who underwent treatment with TACE + apatinib or TACE alone between January 2015 and January 2016. Outcomes in patients who underwent TACE + apatinib were compared with the outcomes of patients who underwent TACE alone, by using the Kaplan-Meier method, according to PVTT type: PVTT in the main portal vein (type A), PVTT in the first-order portal vein branch (type B), and PVTT in second- or lower-order portal vein branches (type C). FINDINGS: One hundred eighty-eight patients were included in the analysis; 85 underwent treatment with TACE + apatinib and 103 underwent treatment with TACE. TACE + apatinib was associated with a significantly greater median survival compared with TACE alone in patients with PVTT type B (12.2 vs 7.5 months; P < 0.001) or type C (13.7 vs 7.2 months; P = 0.006). Along with treatment strategies and α-fetoprotein, the absence of main PVTT was an independent factor predictive of survival on uni- and multivariate analysis. Apatinib-related grade 3 adverse events occurred in 27 patients (31.8%). IMPLICATIONS: TACE + apatinib can be of potential benefit to patients with advanced HCC with tumor thrombus in the first- and lower-order portal vein branches. Adverse events with apatinib need to be monitored during application, despite the manageable appearance.

[Antiviral and antifibrotic therapies reduce occurrence of hepatocellular carcinoma in patients with chronic hepatitis B and liver fibrosis: a 144-week prospective cohort study].

OBJECTIVE: To compare the efficacy and safety of different antiviral and antifibrotic regimens in patients with chronic hepatitis B (CHB) and hepatic fibrosis and the incidence of hepatocellular carcinoma (HCC) associated with these therapies. METHODS: A total of 840 patients with CHB and concurrent hepatic fibrosis, who received antiviral therapy in Nanfang Hospital between June, 2010 and June, 2018, were enrolled in this follow-up cohort study. The patients were assigned to 3 cohorts matched for gender, age (difference≤5 years), HBeAg status and liver stiffness measurement (LSM) for treatment with one of the 3 antiviral drugs, namely entecavir, tenofovir dipivoxil and adefovir dipivoxil; each cohort was divided into 2 groups, with one of the groups having a combined treatment with Fufang Biejiaruangan tablet. The cumulative negative conversion rate of HBV DNA, normalization rate of ALT, hepatic fibrosis regression and the incidence of HCC were compared among the 3 cohorts and across the 6 groups at 144 weeks. RESULTS: A total of 749 patients were available to follow-up at 144 weeks. Compared with the baseline data, the cumulative negative conversion rate of HBV DNA increased gradually and the abnormal rate of ALT decreased significantly over time during the treatment in all the 6 groups (all P < 0.001). Compared with the any of the antiviral drugs used alone, the combined treatments all resulted in significantly better antifibrotic effects (χETV cohort2=11.345, χTDF cohort2=10.160, χADV cohort2=6.358; all P < 0.05). At 144 weeks, the incidence of HCC were 2.2%, 1.7%, 1.7% and 3.3% in enecavir group, enecavir with Biejiaruangan tablet group, adefovir group, and adefovir with Biejiaruangan tablet group, respectively, showing no significant difference between the two cohorts (4 groups; χ2=6.813, P=0.138). None of the patients in the 2 groups with tenofovir treatment had HCC by the end of the observation. CONCLUSIONS: Antiviral therapy combined with antifibrotic therapy can effectively reverse hepatic fibrosis and reduce the incidence of HCC in patients with CHB; among the 3 antiviral drugs, tenofovir dipivoxil can be a better option for reducing the incidence of HCC in these patients.

Serum­derived hepatitis C virus can infect human glioblastoma cell line SF268 and activate the PI3K­Akt pathway.

Extra­hepatic manifestations are frequently observed in hepatitis C virus (HCV)­infected patients; however the underlying mechanisms remain largely unknown. In the present study, the human glioblastoma SF268 cell line (the precise origin of the cell type is not clear) was infected with HCV using HCV­positive serum, and viral replication was assessed by immunofluorescence, reverse transcription­polymerase chain reaction (PCR), quantitative PCR and western blotting following infection. HCV core protein and HCV RNA were detected in HCV­positive serum­infected SF268 cells at day 4 post­infection, while no infection was observed in cells exposed to HCV­negative serum. The mean HCV RNA levels at day 4 post­infection were up to 5.00 IU/ml log10; however, HCV RNA and immunostaining for core protein were negative when cultured to day 6 or longer. The data suggest that human glioblastoma SF268 cells were transiently infected with HCV. AKT serine/threonine kinase phosphorylation was also detected in HCV­infected SF268 cells at day 4 post­infection. To the best of our knowledge, this is the first demonstration that a human glioblastoma cell line can be infected with serum­derived HCV. The results provide evidence that HCV infection can occur in cells of the central nervous system. Neurological disorder­associated phosphoinositide 3­kinase­AKT signaling pathway was activated in parallel with HCV infection, suggesting that SF268 may serve as an in vitro model for investigating HCV­nervous system cell interactions.

AFP specificity for HCC surveillance is increased by mitigating liver injury among treated chronic hepatitis B patients with elevated AFP.

OBJECTIVE: The aim of this study was to assess AFP response in chronic hepatitis B (CHB) patients with baseline positive AFP (≥7 ng/mL) who received antiviral therapy thereafter. METHODS: A cohort study was conducted to assess AFP response in CHB patients who had baseline positive AFP and got antiviral therapy. RESULTS: This retrospective study enrolled 302 antiviral-treatment-naïve CHB patients with positive AFP. After a 12-month antiviral treatment, 144 patients normalized AFP during follow-up while the rest remained AFP-positive. There were no significant differences in baseline characteristics and virologic and ALT responses to antiviral therapy between the two groups. During a mean follow-up of 34 ± 6 months, 16 patients (5.3%) in this cohort developed HCC, and 14 (8.9%) of them emerged in the AFP positive group. There was a significant difference (P=0.004) in HCC occurrence between AFP normalized and non-normalized groups after treatment. Univariate and multivariate analyses revealed that cirrhosis (HR=9.983, 95% CI=3.609-27.617, P<0.001), and non-AFP response to antiviral treatment (HR=6.517, 95% CI=1.475-28.784, P=0.013) were two independent factors associated with HCC occurrence. CONCLUSIONS: To our knowledge, this is the first investigator-initiated cohort study to assess the performance of on-treatment AFP in CHB patients with baseline positive AFP. In contrast to the criticism that AFP is neither sensitive nor specific, the current study has provided important evidence that on-antiviral-treatment AFP normalization is a specific protective marker for HCC in patients with HBV-related chronic liver diseases who started antiviral therapy thereafter.