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.

Emerging role of zinc finger protein A20 as a suppressor of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), the third leading cause of cancer-associated mortality worldwide, is a major public health problem. Zinc finger protein A20 (A20), an acute phase response gene, is a potent inhibitor of NF-κB signaling. A20 serves a critical role in liver protection, including limiting inflammation following hepatic injury, stimulating hepatocyte growth, and preventing hepatic ischemia-reperfusion injury. A20 is also involved in different processes, including tumorigenesis, progression, and metastasis through multiple mechanisms. Accumulated studies have reported the clinical implications and biological relevance of A20 in the development and progression of HCC. The underlying mechanisms of A20 in HCC include inhibition of epithelial-mesenchymal transition, protein tyrosine kinase 2 activation and Rac family GTPase 1 activity. Combining liver protection with tumor inhibition is a unique advantage of A20, which has the potential to be a novel treatment for promoting liver regeneration following liver resection in patients with HCC with liver cirrhosis. This review discusses the hepato-protective effect of A20 on hepatocytes and its potential role in cancer development, particularly its suppressor effect on HCC.

Surgery combined with post-operative trancatheter arterial chemoembolization improves survival of intermediate hepatocellular carcinoma.

AIM: To investigate the efficacy of surgery combined with post-operative trancatheter arterial chemoembolization (TACE) for intermediate hepatocellular carcinoma (HCC). METHODS: A total of 102 patients were divided into two groups: Radical liver resection only (LR group, 52 patients) and radical liver resection combined with post-operative TACE (combined group, 50 patients). Survival analysis was performed using the Kaplan-Meier method. Univariate and multivariate analysis were performed using Cox proportional analysis to detect prognostic factors of survival outcomes. RESULTS: The 1-, 3- and 5-year survival rate in the LR group were significantly lower compared with those in combined group (p = .019). The 1-, 3- and 5-year progression-free survival rate in the LR group were also lower than those in the combined group (p = .048). Multivariate analysis detected that tumor number (multiple vs single), tumor distribution (both lobes vs semi-liver), treatment strategy (surgery + TACE vs surgery) were independent factors for OS (HR values were 2.307, 3.155 and 0.526, respectively) and PFS (HR values were 1.938, 3.425 and 0.633, respectively; p < .05). CONCLUSION: In conclusion, surgery combined with post-operative TACE may improve survival outcomes for patients with intermediate HCC. Tumor number, tumor distribution and treatment strategy (surgery + TACE) were significantly associated with the prognosis of patients with intermediate HCC.

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.

Alvimopan combined with enhanced recovery strategy for managing postoperative ileus after open abdominal surgery: a systematic review and meta-analysis.

BACKGROUND: To assess the efficacy and safety of alvimopan in conjunction with enhanced recovery strategy, compared with this strategy alone, in management of postoperative ileus in patients undergoing open abdominal surgery. METHODS: Electronic databases were comprehensively searched for relevant randomized controlled trials. We were interested in doses of 6 and 12 mg. The efficacy end points included the time to recovery of full gastrointestinal (GI) function (a composite end point measured by the time to first toleration of solid food [SF] and the time to first passage of stool, GI-2), the recovery of upper (SF) or the lower (the time to first bowel movement, BM) GI function, and the length of hospital stay (the time to discharge order written). Safety end points included GI-related, non-GI-related, and serious adverse events. These parameters were all analyzed by RevMan 5.3 software. RESULTS: Nine randomized controlled trials involving 4075 patients were enrolled in this study. The pooled results showed that alvimopan significantly decreased the time to GI-2 recovery (6 mg, hazard ratio [HR] = 1.45, P < 0.00001; 12 mg, HR = 1.59, P < 0.00001), BM (6 mg, HR = 1.54, P < 0.00001; 12 mg, HR = 1.74, P = 0.0002), and the time to discharge order written (6 mg, HR = 1.37, P < 0.00001; 12 mg, HR = 1.34, P < 0.00001) compared with the placebo group. However, SF was significantly reduced in 6 mg group (HR = 1.23, P = 0.008) rather than 12 mg group (HR = 1.14, 95% confidence interval 1.00, 1.30, P = 0.04). The incidence of some GI-related and serious adverse events were significantly lower in the alvimopan group than the placebo group, and the dose of 12 mg was superior to 6 mg in this regard. CONCLUSIONS: Alvimopan can accelerate recovery of GI function (especially for the lower GI tract), shorten the length of hospital stay, and reduce postoperative ileus-related morbidity without compromising opioid analgesia in an enhanced recovery setting.

Role of microRNA in liver regeneration.

BACKGROUND: Liver regeneration is a complex process. microRNAs (miRNAs) are short, single-stranded RNAs that modify gene expression at the post-transcriptional level. Recent investigations have revealed that miRNAs are closely linked to liver regeneration. DATA SOURCES: All included studies were obtained from PubMed, Embase, the ScienceDirect databases and Web of Science, with no limitation on publication year. Only studies published in English were considered. RESULTS: We grouped studies that involved miRNA and liver regeneration into two groups: miRNAs as promoters and as inhibitors of liver regeneration. We summarized the relevant miRNAs separately from the related pathways. CONCLUSIONS: Blocking or stimulating the pathways of miRNAs in liver regeneration may be novel therapeutic strategies in future regeneration-related liver managements. We may discover additional chemotherapy targets of miRNA.

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.].

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.

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.

High expression of miR-21 is not a predictor of poor prognosis in all patients with hepatocellular carcinoma.

MicroRNA (miR)-21 has been identified as a novel biomarker of hepatocellular carcinoma (HCC). However, the prognostic value of miR-21 expression in HCC remains controversial. The aim of the present study was to investigate the value of high expression of miR-21 in predicting the prognosis of HCC. Following a search through the PubMed, Science Citation Index, EMBASE and CNKI databases, a total of 9 studies investigating the expression of miR-21 in HCC and the association between high expression of miR-21 and prognosis of HCC were identified. It was observed that high expression of miR-21 was not associated with poor overall survival of all patients with HCC (P=0.52). However, high expression of miR-21 was found to be correlated with poor prognosis of HCC patients undergoing curative resection (hazard ratio = 2.36; P<0.01). It was also demonstrated that high expression of miR-21 was correlated with tumor size >5 cm [odds ratio (OR)=1.53; P=0.04], venous invasion (OR=4.86; P=0.01), TNM stage (OR=3.44; P<0.01) and liver cirrhosis (OR=2.12; P=0.03). It was concluded that miR-21 cannot be considered as a factor complementary to α-fetoprotein, microvascular invasion and advanced tumor stage in predicting the prognosis of all HCC patients. Higher expression of miR-21 may be a promising biomarker associated with certain clinicopathological characteristics of HCC, such as tumor size, venous invasion, TNM stage and liver cirrhosis.

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.

Positive expression of ZNF689 indicates poor prognosis of hepatocellular carcinoma.

The objective of the present study was to investigate the association between zinc finger protein (ZNF) 689 expression and the clinicopathological features and prognosis of hepatocellular carcinoma (HCC). A total of 102 paired HCC and paired non-cancerous tissues, and 16 normal liver tissues were collected. ZNF689 expression was examined in HCC tissues, paired-noncancerous tissues, and normal liver tissues using RT-qPCR and immunohistochemistry analysis, and the association between ZNF689 expression and HCC prognosis was analyzed using the Kaplan-Meier method. ZNF689 expression was not significantly different between HCC tissues and paired-noncancerous tissues (P=0.61). ZNF689 expression in HCC and paired-noncancerous tissues was significantly increased compared with that in normal liver tissues (P<0.01). Positive expression of ZNF689 protein in HCC was significantly associated with a tumor size of ≥10 cm, tumor capsule infiltration, and microvascular invasion (P<0.05). Positive expression of ZNF689 was a prognostic factor for overall survival time [hazard ratio (HR):1.961; P=0.048] and progression-free survival time (HR:1.902; P=0.041). ZNF689 maybe a novel predictor for prognosis of patients with 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.

Liver resection for intermediate hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China. The Barcelona Clinic Liver Cancer (BCLC) staging system is regarded as the gold standard staging system for HCC, classifying HCC as early, intermediate, or advanced. For intermediate HCC, trans-catheter arterial chemoembolization (TACE) is recommended as the optimal strategy by the BCLC guideline. This review investigates whether liver resection is better than TACE for intermediate HCC. Based on published studies, we compare the survival benefits and complications of liver resection and TACE for intermediate HCC. We also compare the survival benefits of liver resection in early and intermediate HCC. We find that liver resection can achieve better or at least comparable survival outcomes compared with TACE for intermediate HCC; however, we do not observe a significant difference between liver resection and TACE in terms of safety and morbidity. We conclude that liver resection may improve the short- and long-term survival of carefully selected intermediate HCC patients, and the procedure may be safely performed in the management of intermediate HCC.

Management of the middle hepatic vein in right lobe living donor liver transplantation: A meta-analysis.

Living donor liver transplantation (LDLT) is a curative treatment for end stage liver disease. It is advantageous due to the shortage of deceased donors. However, in LDLT, whether the middle hepatic vein (MHV) should be preserved in donors remains controversial. We conducted searches in Pubmed, Embase, Cochrane Library, Web of Science, Ovid, and Google Scholar using the key words "living donor liver transplantation" and "middle hepatic vein". Due to ethical issues, there were no randomized control trails focusing on MHV in LDLT. The majority of reports were retrospective studies. We examined the reference lists to identify related investigations. Google Scholar was then used to obtain full texts. Nine observational studies were analyzed. There were no significant differences in liver function (WMD, -5.51; P=0.12) and complications (RR, 0.98; P=0.89) in donors with or without MHV. However, the liver function in recipients was greatly improved after LDLT with MHV (WMD, -78.32; P=0.01). No definite conclusion was obtained in terms of the liver regeneration indices between LDLT with or without MHV. It was conclude that grafts with MHV in LDLT favor recipient outcomes and do not harm the living donor if a careful preoperative evaluation is performed.