Efficacy and safety of TACE combined with tyrosine kinase inhibitors and camrelizumab for unresectable hepatocellular carcinoma: A systematic review and meta­analysis.

Transcatheter arterial chemoembolization (TACE) combined with tyrosine kinase inhibitors (TKIs) and camrelizumab (collectively: T-T-C) is a novel treatment strategy for unresectable hepatocellular carcinoma (HCC). The present systematic review and meta-analysis aimed to evaluate the efficacy and safety of T-T-C compared with TACE combined with TKIs only (T-T) in the treatment of patients with unresectable HCC. A systematic literature search was conducted on T-T and T-T-C using PubMed, Embase and the Cochrane Library. Data regarding the clinical outcome, including overall survival (OS), progression-free survival (PFS), tumor response and adverse events (AEs), were independently extracted and analyzed by two researchers using standardized protocols. In total, 7 cohort studies, including 1,798 patients (T-T-C, 838; T-T, 960), were included in the meta-analysis. The results of the present study demonstrated that the T-T-C group had significantly prolonged OS [hazard ratio (HR), 0.38; 95% confidence interval (CI), 0.29-0.50; I2=61.5%; P=0.016)] and PFS (HR, 0.37; 95% CI, 0.30-0.46; I2=44.5%; P=0.109), and showed significantly higher objective response rates [risk ratio (RR), 0.82; 95% CI, 0.69-0.96; I2=25.1%; P=0.237)] and slightly higher disease control rates without a significant difference (RR, 0.96; 95% CI, 0.89-1.03; I2=0.0%; P=0.969). In addition, grade 3/4 AEs were more common in the T-T group, including hypertension (RR, 1.15; 95% CI, 0.85-1.56), vomiting or nausea (RR, 0.88; 95% CI, 0.44-1.76) and pain (RR, 0.74; 95% CI, 0.45-1.21); however, these results were not statistically significant. In conclusion, compared with T-T combination therapy, T-T-C demonstrated a notable advantage in terms of OS, PFS, ORR and DCR in patients with unresectable HCC. For manageable AEs, although the results were not statistically significant, the incidence of AEs in the T-T group was higher than that in the T-T-C group in terms of event probability.

Lenvatinib in combination with transarterial chemoembolization vs. sorafenib in combination with transarterial chemoembolization for unresectable hepatocellular carcinoma: A network meta­analysis.

The use of tyrosine kinase inhibitors combined with transarterial chemoembolization (TACE) is considered the standard therapy for patients with unresectable hepatocellular carcinoma (uHCC). However, information regarding the efficacy of lenvatinib or sorafenib in combination with TACE for patients with uHCC is limited. The present study involved a systematic search for randomized controlled trials on the PubMed, Embase, Web of Science and the Cochrane Library online databases to compare the use of TACE combined with either lenvatinib or sorafenib, and monotherapy using either lenvatinib or sorafenib for patients with uHCC. The network meta-analysis of the present study included eight randomized controlled trials involving 2,929 patients. The random-effects model was used, and hazard ratios and risk ratios with 95% CIs were calculated. Lenvatinib in combination with TACE provided the maximal overall survival (97.92%), progression-free survival (87.8%), objective response (96.68%) and disease control (96.27%) rates. The results of the present study indicated that, in the treatment of patients with uHCC, lenvatinib in combination with TACE showed a significantly improved efficacy when compared with sorafenib and TACE. Therefore, in the future, combination therapy of lenvatinib with TACE could be potentially prioritized over sorafenib with TACE for the treatment of patients with uHCC.

Salvage liver transplantation versus curative treatment for patients with recurrent hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND: Salvage liver transplantation (SLT) is an effective treatment option for recurrent hepatocellular carcinoma (rHCC) following primary curative treatment (CUR). However, its efficacy remains controversial compared to that of CURs, including repeat liver resection (RLR) and local ablation. This meta-analysis compared the efficacy and safety of these procedures. METHODS: A systematic literature search of the PubMed, Embase, Web of Science, and Cochrane Library databases for studies investigating SLT and CUR was performed. Outcome data, including overall and disease-free survival, tumor response, and operative and postoperative outcomes, were independently extracted and analyzed by two authors using a standardized protocol. RESULTS: Fifteen cohort studies comprising 508 and 2050 patients with rHCC, who underwent SLT or CUR, respectively, were included. SLT achieved significantly longer overall survival than both CUR (hazard ratio [HR]: 0.56, 95 % confidence interval [CI]: 0.45-0.68; I2 = 34.6 %, p = 0.105) and RLR (HR: 0.64, 95 % CI: 0.49-0.84; I2 = 0.0 %, p = 0.639). Similar significantly better survival benefits were observed compared with CUR (HR: 0.30, 95 % CI: 0.20-0.45; I2 = 51.1 %, p = 0.038) or RLR (HR: 0.31, 95 % CI: 0.18-0.56; I2 = 65.7 %, p = 0.005) regarding disease-free survival. However, SLT resulted in a longer operative duration and hospital stay, larger amount of blood loss, higher rate of transfusion and postoperative morbidity, and slightly higher postoperative mortality than CUR. CONCLUSION: SLT was associated with better long-term survival than CUR or RLR in patients with rHCC after primary curative treatment.

High ANO1 expression is a prognostic factor and correlated with an immunosuppressive tumor microenvironment in pancreatic cancer.

Background: Aminooctylamine (ANO1) plays an oncogenic role in various cancers. However. its role in pancreatic cancer (PC) has rarely been studied. This study investigated the prognostic value of ANO1 and its correlation with the tumor microenvironment (TME) in PC. Methods: Consecutive patients with PC (n = 119) were enrolled. The expression of ANO1 in cancer cells, the expression of fibroblast activation protein (FAP) and alpha smooth muscle actin in cancer-associated fibroblasts (CAFs), and the numbers of CD8- and FOXP3-positive tumor-infiltrating lymphocytes (TILs) were evaluated using immunohistochemistry. The prognostic value of ANO1 and its correlation with CAF subgroups and TILs were analyzed. The possible mechanism of ANO1 in the TME of PC was predicted using the the Cancer Genome Atlas (TCGA) dataset. Results: The expression of AN01 was correlated with overall survival (OS) and disease-free survival. Multi-factor analysis showed that high ANO1 expression was an independent adverse prognostic factor for OS (hazard ratio, 4.137; P = 0.001). ANO1 expression was positively correlated with the expression of FAP in CAFs (P < 0.001) and negatively correlated with the number of CD8-positive TILs (P = 0.005), which was also validated by bioinformatics analysis in the TCGA dataset. Moreover, bioinformatic analysis of the TCGA dataset revealed that ANO1 may induce an immunosuppressive tumor microenvironment in pancreatic cancer in a paracrine manner. Conclusion: ANO1 is a prognostic factor in patients with PC after radical resection. ANO1 may induce an immunosuppressive tumor microenvironment in PC in a paracrine manner, suggesting that ANO1 may be a novel therapeutic target.

Should lymphadenectomy performed routinely in patients with primary intrahepatic cholangiocarcinoma undergoing curative hepatectomy? A retrospective cohort study with propensity-score matching analysis.

BACKGROUND: The benefit of routine lymphadenectomy (LD) in improving outcomes for patients with primary intrahepatic cholangiocarcinoma (ICC) undergoing curative hepatectomy remains unclear. MATERIALS AND METHODS: This study enrolled 269 consecutive patients who underwent liver resection for primary ICC from January 2009 to July 2020 in West China Hospital. The association of the nodal status with disease-free survival (DFS) and overall survival (OS) was analyzed using the Cox proportional hazards model and 1:1 propensity score matching (PSM) analysis. RESULTS: Seventy-five (27.9%) patients underwent curative liver resection combined with LD (LD+ group), while 194 (72.1%) patients received curative liver resection without LD (LD- group and Nx group). Among the LD+ group, metastatic disease was present in 36 patients (48%, N1 group) and absent in 39 patients (N0 group). During the follow-up period, 116 patients (43.1%) experienced tumor recurrence and 101 patients (37.5%) died due to recurrence. Multivariate analysis revealed that lymph node metastasis (N1, HR 3.682, 95% CI 1.949-6.957, p < 0.001) was associated with worse OS, while LD+ status (HR 0.504, 95% CI 0.298-0.853, p = 0.011) was associated with improved OS. Adjuvant therapy was a protective factor for both DFS (HR 0.602, 95% CI, 0.447-0.810, p = 0.001) and OS (HR 0.683, 95% CI 0.484-0.963, p = 0.030). After 1:1 PSM, the LD+ patients (n = 74) displayed similar 1-, 3- and 5-year DFS rates (40.0, 7.9 and 7.9% vs. 29.0, 13.7 and 13.7%, p = 0.741) and OS rates (56.0, 26.6 and 22.2% vs. 58.9, 25.6, and 16.4%, p = 0.644) to the LD- patients (n = 74). Additionally, among the 75 LD+ patients, 48 patients underwent hepatic hilar lymphadenectomy (HHL), and 27 patients underwent extended hepatic hilar lymphadenectomy (EHL). Both DFS (p = 0.504) and OS (p = 0.215) were similar between the HHL and EHL groups. CONCLUSION: Routine LD and adjuvant therapy may contribute to improved OS according to the crude analysis. LD could provide accurate staging without excessive risk and guide adjuvant therapy based on the tumor stage, potentially resulting in better survival. These results suggest that a routine LD should be considered during curative hepatectomy for ICC.

A retrospective study of transarterial chemoembolization (TACE) combined with lenvatinib compared with TACE monotherapy for BCLC B2 stage hepatocellular carcinoma.

The present study aimed to compare the efficacy and safety of combination therapy with lenvatinib (Len) plus transarterial chemoembolization (TACE) and TACE alone in patients with Barcelona Clinic Liver Cancer (BCLC) B2 stage hepatocellular carcinoma (HCC). A total of 66 patients with BCLC B2 stage HCC were retrospectively reviewed in the present study, of which 34 patients received Len + TACE, while 32 patients received TACE alone between May 2018 and May 2020. Survival outcome, tumor response and adverse events (AEs) were compared between the two treatment groups. The 6-month, 1- and 2-year overall survival (OS) rates were significantly higher in the Len + TACE group (97.1, 85.3 and 76.3%, respectively) compared with those in the TACE group [(93.8, 81.1 and 45.4%, respectively); hazard ratio (HR), 0.395; 95% confidence interval (CI), 0.180-0.867; P=0.023], but no significant difference in progression-free survival rate was observed between the two groups (HR, 0.815; 95% CI, 0.437-1.520; P=0.510). Patients receiving Len + TACE demonstrated a higher objective response rate compared with those receiving TACE alone (64.7 vs. 34.4%; P=0.014). Therefore, Len + TACE combination therapy was associated with increased OS and tumor response compared with that of TACE monotherapy in patients with BCLC B2 stage HCC. However, large-scale, multicenter, prospective studies are needed to further confirm these results.

circPSD3 is a promising inhibitor of uPA system to inhibit vascular invasion and metastasis in hepatocellular carcinoma.

BACKGROUND: Vascular invasion is a major route for intrahepatic and distant metastasis in hepatocellular carcinoma (HCC) and is a strong negative prognostic factor. Circular RNAs (circRNAs) play important roles in tumorigenesis and metastasis. However, the regulatory functions and underlying mechanisms of circRNAs in the development of vascular invasion in HCC are largely unknown. METHODS: High throughput sequencing was used to screen dysregulated circRNAs in portal vein tumor thrombosis (PVTT) tissues. The biological functions of candidate circRNAs in the migration, vascular invasion, and metastasis of HCC cells were examined in vitro and in vivo. To explore the underlying mechanisms, RNA sequencing, MS2-tagged RNA affinity purification, mass spectrometry, and RNA immunoprecipitation assays were performed. RESULTS: circRNA sequencing followed by quantitative real-time PCR (qRT-PCR) revealed that circRNA pleckstrin and Sect. 7 domain containing 3 (circPSD3) was significantly downregulated in PVTT tissues. Decreased circPSD3 expression in HCC tissues was associated with unfavourable characteristics and predicted poor prognosis in HCC. TAR DNA-binding protein 43 (TDP43) inhibited the biogenesis of circPSD3 by interacting with the downstream intron of pre-PSD3. circPSD3 inhibited the intrahepatic vascular invasion and metastasis of HCC cells in vitro and in vivo. Serpin family B member 2 (SERPINB2), an endogenous bona fide inhibitor of the urokinase-type plasminogen activator (uPA) system, is the downstream target of circPSD3. Mechanistically, circPSD3 interacts with histone deacetylase 1 (HDAC1) to sequester it in the cytoplasm, attenuating the inhibitory effect of HDAC1 on the transcription of SERPINB2. In vitro and in vivo studies demonstrated that circPSD3 is a promising inhibitor of the uPA system. CONCLUSIONS: circPSD3 is an essential regulator of vascular invasion and metastasis in HCC and may serve as a prognostic biomarker and therapeutic target.

Efficacy and safety of atezolizumab plus bevacizumab versus lenvatinib for unresectable hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: Atezolizumab plus bevacizumab and lenvatinib are the current first-line systematic therapy for unresectable hepatocellular carcinoma (uHCC). However, the selection of initial treatment among the two therapies are controversial. This meta-analysis aims to compare efficacy and safety between atezolizumab plus bevacizumab and lenvatinib. METHODS: We systematically searched for studies on atezolizumab plus bevacizumab and lenvatinib in the online databases PubMed, Embase, Web of Science and Cochrane Library. The outcome data including overall survival (OS), progression free survival (PFS), tumor response and adverse events (AEs), were independently extracted by two authors in a standardized way. RESULTS: Eight retrospective cohort studies with 3690 patients (atezolizumab plus bevacizumab: 1680, lenvatinib: 2010) were included in the meta-analysis. The atezolizumab plus bevacizumab group had significant longer PFS [hazard ratio (HR) 0.76, 95% confidence intervals (CI) 0.65-0.88; I squared statistic (I2) = 0.0%, p = 0.590], compared with lenvatinib group but no significant difference in OS (HR 0.87, 95% CI 0.75-1.01; I2 = 0.0%, p = 0.597), objective response rate (ORR) [risk ratio (RR) 0.89, 95% CI 0.79-1.02; I2 = 19.3%, p = 0.283] and disease control rate (DCR) (RR 1.03, 95% CI 0.98-1.09; I2 = 0.0%, p = 0.467) among them. Moreover, patients receiving atezolizumab plus bevacizumab exhibited lower incidences of grade 3/4 AEs than those receiving lenvatinib (RR 0.65, 95% CI 0.51-0.83; I2 = 69.3%, p = 0.003). However, in non-viral patients group, lenvatinib delivered favorable outcomes in OS (HR 1.32, 95% CI 1.04-1.67; I2 = 0.0%, p = 0.380) compared with atezolizumab plus bevacizumab. CONCLUSION: Atezolizumab plus bevacizumab provides potential advantage in efficacy and better safety than lenvatinib in the treatment of uHCC. Lenvatinib is an appropriate effective alternative to atezolizumab plus bevacizumab in patients without viral infecting.

Efficacy and safety of transarterial chemoembolization plus lenvatinib with or without programmed death-1 inhibitors in the treatment of unresectable hepatocellular carcinoma: a systematic review and meta-analysis.

BACKGROUND: Programmed death-1 inhibitors plus lenvatinib and transarterial chemoembolization (TACE) (P-L-T) is a novel combination strategy. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of P-L-T compared with lenvatinib and TACE (L-T) therapy in patients with unresectable hepatocellular carcinoma. METHODS: A systematic literature search of the PubMed, Embase, Web of Science and Cochrane Library databases for studies investigating P-L-T therapy was performed. Data regarding outcome data, including overall survival (OS), progression-free survival (PFS), tumor response, and adverse events (AEs), were independently extracted by two authors using a standardized protocol. RESULTS: Eight cohort studies comprising 847 patients (P-L-T: 416, L-T: 431) were included in the meta-analysis. The P-L-T group exhibited significantly longer OS (hazard ratio (Page et al.) 0.51 [95% confidence interval (CI) 0.42-0.62]; I2 = 9.8%; p = 0.354] and PFS (HR 0.51 [95% CI 0.43-0.61]; I2 = 0%; p = 0.824), and higher objective response rate (risk ratio [RR] 1.54 [95% CI 1.33-1.78]; I2 = 0%, p = 0.858]) and disease control rate (RR 1.27 [95% CI 1.17-1.38]; I2 = 17.3%; p = 0.467). Grade 3/4 AEs were more prevalent in the P-L-T group, including hypertension (RR 1.91 [95% CI 1.16-3.15]), vomiting or nausea (RR 2.29 [95% CI 1.01-5.19]), and hypothyroidism (RR 12.21 [95% CI 1.63-91.23]). CONCLUSION: Compared with L-T combination therapy, P-L-T demonstrated a significant advantage in terms of OS, PFS, objective response rate, disease control rate, and manageable AEs.

Corrigendum: Transarterial chemoembolization combined with lenvatinib versus transarterial chemoembolization combined with sorafenib for unresectable hepatocellular carcinoma: a systematic review and meta-analysis.

[This corrects the article DOI: 10.3389/fonc.2023.1074793.].

A circular RNA produced by LRBA promotes cirrhotic mouse liver regeneration through facilitating the ubiquitination degradation of p27.

BACKGROUND AND AIMS: Accumulating circular RNAs (circRNAs) play important roles in tissue repair and organ regeneration. However, the biological effects of circRNAs on liver regeneration remain largely unknown. This study aims to systematically elucidate the functions and mechanisms of circRNAs derived from lipopolysaccharide-responsive beige-like anchor protein (LRBA) in regulating liver regeneration. METHODS: CircRNAs derived from mouse LRBA gene were identified using CircBase. In vivo and in vitro experiments were conducted to confirm the effects of circLRBA on liver regeneration. RNA pull-down and RNA immunoprecipitation assays were used to investigate the underlying mechanisms. Clinical samples and cirrhotic mouse models were used to evaluate the clinical significance and transitional value of circLRBA. RESULTS: Eight circRNAs derived from LRBA were registered in CircBase. The circRNA mmu_circ_0018031 (circLRBA) was significantly upregulated in the liver tissues after 2/3 partial hepatectomy (PHx). Adeno-associated virus serotype 8 (AAV8)-mediated knockdown of circLRBA markedly inhibited mouse liver regeneration after 2/3 PHx. In vitro experiments confirmed that circLRBA exerted its growth-promoting function mainly through liver parenchymal cells. Mechanistically, circLRBA acted as a scaffold for the interaction between E3 ubiquitin-protein ligase ring finger protein 123 and p27, facilitating the ubiquitination degradation of p27. Clinically, circLRBA was lowly expressed in cirrhotic liver tissues and negatively correlated with perioperative levels of total bilirubin. Furthermore, overexpression of circLRBA enhanced cirrhotic mouse liver regeneration after 2/3 PHx. CONCLUSIONS: We conclude that circLRBA is a novel growth promoter in liver regeneration and a potential therapeutic target related to deficiency of cirrhotic liver regeneration.

Transarterial chemoembolization combined with lenvatinib versus transarterial chemoembolization combined with sorafenib for unresectable hepatocellular carcinoma: A systematic review and meta-analysis.

Background: The combination of tyrosine kinase inhibitors (TKIs) and transarterial chemoembolization (TACE) fulfills an important role in the treatment of unresectable hepatocellular carcinoma (uHCC). Among the combination therapies, both lenvatinib and sorafenib combined with TACE are recommended as first-¬line treatments for uHCC. However, at present, limited data are available concerning the efficacy and safety of these two combination therapies in uHCC. Methods: A detailed systematic search for studies on lenvatinib plus TACE (LEN+TACE) and sorafenib plus TACE (SOR+TACE) was conducted in the online databases PubMed, Embase and The Cochrane Library. The outcome data including overall survival (OS), progression free survival (PFS), time to progression (TTP), tumor response and adverse events (AEs), were independently extracted by two authors in a standardized way. Results: One randomized controlled trial and five cohort studies with 598 patients (LEN+TACE: 261, SOR+TACE: 337) were included in the meta-analysis. A higher rate of odds ratio (OR) for the objective response rate (ORR) [OR: 3.63; 95% confidence intervals (95% CI): 1.89-6.95; I squared statistic (I2) = 57%, P < 0.001] and disease control rate (DCR) (OR: 3.78; 95% CI: 2.00-7.16; I2 = 52%, P = 0.0001) were observed in the LEN+SOR group compared with the SOR+TACE group. The LEN+TACE group also had significant longer OS [hazard ratio (HR): 0.67; 95% CI: 0.52-0.85; I2 = 1%, P = 0.001], PFS (HR: 0.49; 95% CI: 0.38-0.62; I2 = 0%, P? 0.001) and TTP (HR: 0.62; 95% CI: 0.45-0.84; I2 = 0%, P = 0.002) compared with the SOR+TACE group. The incidence of hypertension (OR: 3.05; 95% CI: 1.45-6.39; P = 0.003) and proteinuria (OR: 5.25; 95% CI: 1.73-15.89; P = 0.003) were significantly higher in the LEN+TACE group than SOR+TACE group, while LEN+TACE group exhibited a lower rate of hand-foot-skin reaction (HFSR) (OR: 0.51; 95% CI: 0.27-0.95; P = 0.03) compared with the SOR+TACE group. Conclusion: The combination therapy of LEN+TACE showed significant superiority compared with SOR+TACE in terms of its efficacy for patients with uHCC. SOR+TACE should be recommended as a replacement therapy when serious AEs occur during the administration of LEN+TACE as the combination therapy.

The priority of liver resection compared with transarterial chemoembolization in hepatocellular carcinoma at BCLC B1 stage: A single-center experience.

Background: This study aimed to compare the efficacy of liver resection (LR) and transarterial chemoembolization (TACE) in the treatment of Barcelona Clinic Liver Cancer B1 (BCLC B1) hepatocellular carcinoma. Methods: A total of 65 patients with BCLC B1 were divided into the radical (LR group) and TACE groups. Survival analysis was performed using the Kaplan-Meier method. Univariate and multivariate analyses were carried out, and the prognostic factors for survival outcomes were identified using Cox proportional analysis. Results: The 1-, 3-, and 5-year survival rates and the 1-, 3-, and 5-year progression-free survival (PFS) rates in the LR group (P = 0.036) were significantly higher than those in the TACE group (P = 0.027). Results of the multivariate analysis demonstrated that tumor distribution (both lobes vs. semi-liver) and treatment strategy (LR vs. TACE) were independent risk factors for the overall survival (OS) [hazard ratios (HRs): 3.926 and 0.479; P < 0.05] and PFS (HR: 3.336 and 0.465, P < 0.05). LR was associated with increased OS and PFS compared with TACE in patients with BCLC B1 hepatocellular carcinoma.

High-throughput circular RNA sequencing reveals the profiles of circular RNA in non-cirrhotic hepatocellular carcinoma.

BACKGROUND: Liver cirrhosis is a well-known risk factor for hepatocellular carcinoma (HCC). However, some HCC cases can also originate from non-cirrhotic livers. The aim of this study was to identify key circular RNAs (circRNAs) associated with the tumorigenesis of non-cirrhotic liver disease. METHODS: The differently expressed circRNAs between non-cirrhotic and cirrhotic HCCs were assessed with use of high-throughput circRNAs sequencing and validated with quantitative reverse transcription polymerase chain reaction (qRT-PCR). Potential biological functions of these dysregulated circRNAs were predicted with use of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. A circRNA-miRNA-mRNA regulation network was constructed as achieved with use of miRanda software and visualized using Cytoscape software. Biological functions of the four most prominent dysregulated circRNAs identified were confirmed by in vitro experiments. Moreover, possible translations of these dysregulated circRNAs were also predicted. RESULTS: A total of 393 dysregulated circRNAs were identified between non-cirrhotic and cirrhotic HCC, including 213 that were significantly up-regulated and 180 significantly down-regulated circRNAs. Expression levels of the six most prominent dysregulated circRNAs were further validated using qRT-PCR. Many tumor related miRNAs were involved in the circRNA-miRNA-mRNA networks, including miR-182-5p, miR-561-3p, miR-125a-5p, miR-145, miR-23b-3p and miR-30e-3p, and downstream mRNAs of dysregulated circRNAs were significantly related with biological processes involved in the progression of tumors, including proliferation, migration, differentiation, and focal adhesion. Results from the in vitro experiments demonstrated that the most prominent dysregulated circRNAs exerted notable effects upon the proliferation and migration of HCC cells. Finally, we also identified 19 dysregulated circRNAs having potential for the coding of functional peptides. CONCLUSION: The results of this present study indicate that circRNAs may play important roles in tumorigenesis of non-cirrhotic HCC. Such findings provide some novel insights and pave the way for the development of future studies directed at investigating the initiation and treatment of HCC.

Effect of statins on risk and mortality of urologic malignancies: Protocol of an umbrella review.

INTRODUCTION: Urologic malignancies are the major causes of morbidity and mortality in men over 40 years old, accounting for more than 20% of all malignant tumors. Several meta-analyses are shown that statin exposure can reduce the morbidity and mortality of various urologic cancers. The adjuvant roles of statin in tumor prevention and anti-tumor activity are now being gradually recognized and have gained attention. Nevertheless, to date, multiple clinical studies and meta-analyses found inconsistent results of their anti-cancer effects. This study aims to evaluate the credibility of the published systematic reviews and meta-analyses that assessed the effects of statin exposure for the incidence and mortality of urologic cancers through an umbrella review. METHODS AND ANALYSIS: The guidance of overviews of systematic reviews reported in the Cochrane Handbook for Systematic Reviews of interventions will be followed while performing and reporting this umbrella review. This project was registered in PROSPERO with the registration number of CRD42020208854. PubMed, Embase and Cochrane Library will be searched for systematic reviews to identify and appraise systematic reviews or meta-analyses of interventional and observational studies examining statin use and the risks of urologic cancer incidence and mortality without language restriction. The search will be carried out on 10 February 2022. Systematic reviews based on qualitative, quantitative or mixed-methods studies will be involved and critically evaluated by two authors using the Assessment of Multiple Systematic Reviews 2 (AMSTAR2, an updated version of AMSTAR) tool. We will determine the level of evidence using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) tool. The summary effect estimates will be calculated using random-effects models. Between- study heterogeneity will be assessed using the I2 statistic. Furthermore, we will also assess the evidence of excess significance bias and evidence of small study effects. ETHICS AND DISSEMINATION: Ethics approval is not required as we will search and gather data based on the published systematic reviews and meta-analyses. We plan to publish the results of this umbrella review in a peer-reviewed journal and will be presented at a urological disease conference. All the relevant additional data will also be uploaded to the online open access databases. PROSPERO REGISTRATION NUMBER: CRD42020208854.

Evolution and current status of the subclassification of intermediate hepatocellular carcinoma.

The staging and treatment of intermediate hepatocellular carcinoma (HCC) remains controversial. According to the recommendations of Barcelona Clinic Liver Cancer staging system, patients with intermediate HCC are candidates for transcatheter arterial chemoembolization. However, not all patients with intermediate HCC benefit from transcatheter arterial chemoembolization. Therefore, it is meaningful to propose a novel staging system of intermediate HCC in order to allocate different treatments for different subgroups. Bolondi et al proposed the first subclassification system of intermediate HCC. Subsequently, investigators performed studies to validate the feasibility of Bolondi' s criteria and proposed several novel staging systems. The present study reviewed the literatures and provided a general overview of the evolution and current status of the subclassification of intermediate HCC. We propose to expand the indication of liver resection and add radical treatments as the first option of the treatment for patients with intermediate HCC.

Comparison of Transarterial Chemoembolization Combined with Radiofrequency Ablation Therapy versus Surgical Resection for Early Hepatocellular Carcinoma.

Both radiofrequency ablation (RFA) and surgical resection (SR) are radical treatment recommended for early hepatocellular carcinoma (HCC). Transarterial chemoembolization (TACE) is a palliative treatment for intermediate HCC, and TACE+RFA combined therapy is considered superior to TACE or RFA alone for management of early HCC. This systematic review compared the efficacy and safety of TACE+RFA combined therapy with SR for early HCC. Web of Science, PubMed, EMBASE, and the Cochrane Library were searched for literatures related with our topic. The primary endpoint was overall survival (OS), and the secondary endpoint was the recurrence-free survival (RFS) rate; safety was measured by the rate of major complications. The effect sizes of OS, RFS, and local progression rates were expressed by odds ratio (OR), while the effect size of complications was presented using relative risk. TACE+RFA combined therapy and SR had a similar 1-year OS rate [OR: 1.84; 95% confidence interval (CI): 0.82, 4.14; P > 0.05], 3-year OS rate (OR: 0.84; 95% CI: 0.43, 1.67; P > 0.05), 1-year RFS rate (OR: 0.77; 95% CI: 0.53, 1.11; P > 0.05), and 3-year RFS rate (OR: 0.88; 95% CI: 0.48, 1.42; P > 0.05) for early HCC. However, the 5-year OS rate (OR: 0.54; 95% CI: 0.40, 0.73; P < 0.05) and 5-year RFS rate (OR: 0.49; 95% CI: 0.27, 0.90; P < 0.05) were lower in patients with TACE+RFA than in those with SR. SR is associated with better long-term survival outcomes and a lower recurrence rate than TACE+RFA for patients with early HCC and is the optimal choice for patients with early HCC.

Hepatic resection combined with radiofrequency ablation versus hepatic resection alone for multifocal hepatocellular carcinomas: A meta-analysis.

This meta-analysis aimed to comprehensively assess the efficacy and safety of hepatic resection combined with radiofrequency ablation versus hepatic resection (HR) alone for the treatment of multifocal hepatocellular carcinomas (HCC). A literature search was conducted from the database including MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL) and China Biology Medicine (CBM) disc. The primary outcomes included the 1-, 3-, 5-year overall survival (OS) and disease-free survival (DFS) rate. The secondary outcomes contained the intraoperative parameters and postoperative adverse events (AEs). These parameters were all analyzed by RevMan 5.3 software. After carefully screening relevant studies, four retrospective studies of high quality involving 466 patients (197 in the combined group and 269 in the HR group) were included in this study. The pooled results showed that the 1-, 3-, 5-year OS rate in the combined group were comparable with those in the HR group (OR=0.77, 0.96, 0.88; P=0.33, 0.88, 0.70, respectively). Similarly, there was no significant difference in 1-, 3-, 5-year DFS rate between the combined group and the HR alone group (OR=0.57, 0.83, 0.72; P=0.17, 0.37, 0.32, respectively). And the intraoperative parameters and postoperative AEs were also comparable between the above two cohorts. However, two included studies reported that tumor often recurred in the ablation site in the combined group. The present meta-analysis indicated that the HR combined with RFA could reach a long-term survival outcome similar to curative HR for multifocal HCC patients. And this therapy may be a promising alternative for these patients with marginal liver function or complicated tumor distribution. Furthermore, high quality randomized controlled trials (RCTs) are imperative to verify this conclusion.

miR-203 inhibits augmented proliferation and metastasis of hepatocellular carcinoma residual in the promoted regenerating liver.

Liver resection is still the most commonly used therapeutic treatment for hepatocellular carcinoma (HCC), and liver regeneration promotes HCC growth in the regenerating liver. The high recurrence/metastasis of HCC is the main cause of death for HCC patients after liver resection. However, how the augmented growth and metastasis of residual HCC induced by the promoted liver regeneration following liver resection can be abolished remains unclear. In this study, a rat model with liver cirrhosis and diffused HCC was established by administration of diethylnitrosamine. Recombinant miR-203 adenovirus was administered to induce hepatic miR-203 overexpression and 30% partial hepatectomy (PH) followed. The effect of miR-203 on the proliferation, invasion and metastasis of the residual HCC in the remnant cirrhotic liver with promoted regeneration was investigated. We found that the basic spontaneous regeneration of the non-tumorous liver by 30% PH promoted proliferation, invasion and lung metastasis of the hepatic residual HCC. miR-203 overexpression further promoted the regeneration of the non-tumorous liver by upregulating Ki67 expression and enhancing IL-6/SOCS3/STAT3 pro-proliferative signals. Importantly, miR-203 overexpression markedly inhibited the proliferation, invasion and metastasis of hepatic residual HCC through suppressing expression of Ki67, CAPNS1 and lung metastasis. Moreover, it was found that miR-203 overexpression reversed the epithelial-mesenchymal transition induced by hepatectomy through targeting IL-1ß, Snail1 and Twist1. In conclusion, our results suggested that miR-203 overexpression inhibited the augmented proliferation and lung metastasis of the residual HCC induced by the promoted liver regeneration following PH partly by regulating epithelial-mesenchymal transition.

The circular RNA ciRS-7 (Cdr1as) acts as a risk factor of hepatic microvascular invasion in hepatocellular carcinoma.

PURPOSE: Circular RNAs (circRNA) represent a novel class of widespread and diverse endogenous RNAs that regulate gene expression in mammals. microRNA-7 (miR-7) is a well-demonstrated suppressor of hepatocellular carcinoma (HCC). Recent studies have showed that one such circRNA, ciRS-7 (also termed as Cdr1as) was the inhibitor and sponge of miR-7 in the embryonic zebrafish midbrain and islet cells. However, the relationships among ciRS-7, miR-7 and clinical features of HCC remain to be clarified. METHODS: Expression levels of ciRS-7, miR-7 and three miR-7-targeted mRNAs in 108 pairs of HCC and their matched non-tumor tissues were examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). The protein production of these three miR-7-targeted mRNAs was further verified by Western blot. The relationship between ciRS-7 level and clinicopathological features as well as the recurrence of HCC patients was analyzed. The univariate and multivariate logistic regression analyses were used to detect the risk factors of hepatic microvascular invasion (MVI). The correlation among ciRS-7, miR-7 and miR-7-targeted mRNAs was evaluated using Spearman's correlation test. RESULTS: There was no significant difference of ciRS-7 expression levels between the HCC tissues and the matched non-tumor tissues (0.67 ± 1.49 vs. 0.44 ± 0.45, p = 0.13), and the ciRS-7 levels in more than half of HCC tissues (65 out of 108, 60.2 %) were down-regulated when compared with their matched non-tumor tissues. However, the expression of ciRS-7 was significantly correlated with the following three clinicopathological characteristics of HCC patients: age <40 years (p = 0.02), serum AFP ≥400 ng/µl (p < 0.01) and hepatic MVI (p = 0.03). Meanwhile, up-regulated ciRS-7 expression was not only an independent risk factor of hepatic MVI but also had a capable predictive ability for MVI (AUC = 0.68, p = 0.001) at the cut-off value of 0.135. Furthermore, the expression of ciRS-7 in HCC tissues with concurrent MVI was inversely correlated with that of miR-7 (r = -0.39, p = 0.007) and positively related with that of two miR-7-targeted genes [PIK3CD (r = 0.55, p < 0.001) and p70S6K (r = 0.34, p = 0.021)]. In addition, the median recurrent time of patients from higher ciRS-7 level group was shorter than that of lower ciRS-7 group (18 vs. 25 months), but no significant difference was observed (p = 0.38). CONCLUSIONS: The expression levels of ciRS-7 were comparable between HCC and matched non-tumor tissues. However, the highly ciRS-7 expression in HCC tissues was significantly correlated with hepatic MVI, AFP level and younger age and thus partly related with the deterioration of HCC. Especially, ciRS-7 was one of the independent factors of hepatic MVI. These data suggested that ciRS-7 may be a promising biomarker of hepatic MVI and a novel therapy target for restraining MVI.