Anatomical vs nonanatomical liver resection for solitary hepatocellular carcinoma:A systematic review and meta-analysis

BACKGROUND The long-term survival of patients with solitary hepatocellular carcinoma(HCC)following anatomical resection(AR)vs non-anatomical resection(NAR)is still controversial.It is necessary to investigate which approach is better for patients with solitary HCC.AIM To compare perioperative and long-term survival outcomes of AR and NAR for solitary HCC.METHODS We performed a comprehensive literature search of PubMed,Medline(Ovid),Embase(Ovid),and Cochrane Library.Participants of any age and sex,who underwent liver resection,were considered following the following criteria:(1)Studies reporting AR vs NAR liver resection;(2)Studies focused on primary HCC with a solitary tumor;(3)Studies reporting the long-term survival outcomes(>5 years);and(4)Studies including patients without history of preoperative treatment.The main results were overall survival(OS)and disease-free survival(DFS).Perioperative outcomes were also compared.RESULTS A total of 14 studies,published between 2001 and 2020,were included in our meta-analysis,including 9444 patients who were mainly from China,Japan,and Korea.AR was performed on 4260(44.8%)patients.The synthetic results showed that the 5-year OS[odds ratio(OR):1.19;P<0.001]and DFS(OR:1.26;P<0.001)were significantly better in the AR group than in the NAR group.AR was associated with longer operating time[mean difference(MD):47.08;P<0.001],more blood loss(MD:169.29;P=0.001),and wider surgical margin(MD=1.35;P=0.04)compared to NAR.There was no obvious difference in blood transfusion ratio(OR:1.16;P=0.65)or postoperative complications(OR:1.24,P=0.18).CONCLUSION AR is superior to NAR in terms of long-term outcomes.Thus,AR can be recommended as a reasonable surgical option in patients with solitary HCC.

New insights in the metabolic function related to gut microbiota in the process of liver regeneration

Liver disease is a prominent cause of premature mortality globally(1).Many patients with liver diseases require therapeutic liver surgery,usually through hepatectomy(2).Due to the clinical demand for such practice,the study of liver regeneration following hepatectomy holds significant value.The gut microbiota,considered as a“new organ”due to its substantial influence on various physiological functions,has gained increasing attention from the scientific community,particularly in relation to the gut-liver axis.

Exosomal MicroRNA-10a Is Associated with Liver Regeneration in Rats through Downregulation of EphA4

Background： MicroRNAs （miRNAs） have been reported to play vital roles in liver regeneration. Previous studies mainly focused on the functions of intracellular miRNAs, while the functions of circulating exosomal miRNAs in liver regeneration remain largely unknown. The aim of this study was to identify the key exosomal miRNA that played vital roles in liver regeneration. Methods： The Sprague-Dawley male rats were assigned to 70% partially hepatectomized group （n = 6） and sham surgery group （n = 6）. The peripheral blood of both groups was collected 24 h after surgery. The exosomal miRNAs were extracted, and microarray was used to find out the key miRNA implicated in liver regeneration. Adenovirus was used to overexpress the key miRNA in rats, and proliferating cell nuclear antigen （PCNA） staining was applied to study the effect of key miRNA overexpression on liver regeneration. Westenl blotting was used to validate the predicted target of the key miRNA. Results： Exosomal miR-10a was upregulated more than nine times in hepatectomized rats. The level of miR-10a was increased in tile early phase of liver regeneration, reached the top at 72 h postsurgery, and decreased to perioperative level 168 h after surgery. Moreover, enforced expression ofmiR- 10a by adenovirus facilitated the process of liver regeneration as evidenced by immunohistochemical staining of PCNA. Erythropoietin-producing hepatocellular receptor A4 （EphA4） has been predicted to be a target of miR-10a. The protein level of EpbA4 was decreased in the early phase of liver regeneration, reached the bottom at 72 h postsurgery, and rose to perioperative level 168 h after surgery, which was negatively correlated with miR-10a, confirming that EphA4 served as a downstream target of miR-10a. Moreover, inhibition of EphA4 by rhynchophylline could promote the proliferation of hepatocytes by regulating the cell cycle. Conclusion： Exosomal miR- 10a might accelerate liver regeneration through downregulation of EphA4.

Preoperative gamma-glutamyltransferase to lymphocyte ratio predicts long-term outcomes in intrahepatic cholangiocarcinoma patients following hepatic resection

BACKGROUND Intrahepatic cholangiocarcinoma(ICC)is a heterogeneous hepatobiliary cancer with limited treatment options.A number of studies have illuminated the relationship between inflammation-based prognostic scores and outcomes in patients with ICC.However,the use of reliable and personalized prognostic algorithms in ICC after resection is pending.AIM To assess the prognostic value of the gamma-glutamyltransferase to lymphocyte ratio(GLR)in ICC patients following curative resection.METHODS ICC patients following curative resection(2009-2017)were divided into two cohorts:The derivation cohort and validation cohort.The derivation cohort was used to explore an optimal cut-off value,and the validation cohort was used to further evaluate the score.Overall survival(OS)and recurrence-free survival(RFS)were analyzed,and predictors of OS and RFS were determined.RESULTS A total of 527 ICC patients were included and randomly divided into the derivation cohort(264 patients)and the validation cohort(263 patients).The two patient cohorts had comparable baseline characteristics.The optimal cut-off value for the GLR was 33.7.Kaplan-Meier curves showed worse OS and RFS in the GLR>33.7 group compared with GLR≤33.7 group in both cohorts.After univariate and multivariate analysis,the results indicated that GLR was an independent prognostic factor of OS[derivation cohort:hazard ratio(HR)=1.620,95%confidence interval(CI):1.066-2.462,P=0.024;validation cohort:HR=1.466,95%CI:1.033-2.142,P=0.048]and RFS[derivation cohort:HR=1.471,95%CI:1.029-2.103,P=0.034;validation cohort:HR=1.480,95%CI:1.057-2.070,P=0.022].CONCLUSION The preoperative GLR is an independent prognostic factor for ICC patients following hepatectomy.A high preoperative GLR is associated with worse OS and RFS.

Role of Noncoding RNAs in the Tumor Immune Microenvironment of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most preva-lent malignancies. It has high mortality and poor clinical out-comes, but the molecular mechanisms in the pathogenesis of HCC are not understood. The tumor immune microenviron-ment (TIME) is a highly intricate system with distinct popula-tions of innate and adaptive immune cells, as well as other stromal cells. They interact and evolve with tumor cells to influence tumor growth, migration, invasion, immune eva-sion, and response to therapy. Emerging evidence has shown noncoding RNAs (ncRNAs) are prominent regulators of TIME in HCC. In this review, we elaborate on the functions and molecular mechanisms of ncRNAs in remodeling TIME of HCC and discuss their diagnostic and therapeutic potential for HCC treatment.

MDIG-mediated H3K9me3 demethylation upregulates Myc by activating OTX2 and facilitates liver regeneration

The mineral dust-induced gene(MDIG)comprises a conserved JmjC domain and has the ability to demethylate histone H3 lysine 9 trimethylation(H3K9me3),Previous studies have indicated the significance of MDIG in promoting cell proliferation by modulating cell-cycle transition.However,its involvement in liver regeneration has not been extensively investigated.In this study,we generated mice with liver-specific knockout of MDIG and applied partial hepatectomy or carbon tetrachloride mouse models to investigate the biological contribution of MDIG in liver regeneration.

Epigenome-wide development and validation of a prognostic methylation score in intrahepatic cholangiocarcinoma based on machine learning strategies

Background:Clinical parameter-based nomograms and staging systems provide limited information for the prediction of survival in intrahepatic cholangiocarcinoma(ICC)patients.In this study,we developed a methylation signature that precisely predicts overall survival(OS)after surgery.Methods:An epigenome-wide study of DNA methylation based on whole-genome bisulfite sequencing(WGBS)was conducted for two independent cohorts(discovery cohort,n=164;validation cohort,n=170)from three hepatobiliary centers in China.By referring to differentially methylated regions(DMRs),we proposed the concept of prognostically methylated regions(PMRs),which were composed of consecutive prognostically methylated CpGs(PMCs).Using machine learning strategies(Random Forest and the least absolute shrinkage and selector regression),a prognostic methylation score(PMS)was constructed based on 14 PMRs in the discovery cohort and confirmed in the validation cohort.Results:The C-indices of the PMS for predicting OS in the discovery and validation cohorts were 0.79 and 0.74,respectively.In the whole cohort,the PMS was an independent predictor of OS[hazard ratio(HR)=8.12;95% confidence interval(CI):5.48-12.04;P<0.001],and the C-index(0.78)of the PMS was significantly higher than that of the Johns Hopkins University School of Medicine(JHUSM)nomogram(0.69,P<0.001),the Eastern Hepatobiliary Surgery Hospital(EHBSH)nomogram(0.67,P<0.001),American Joint Committee on Cancer(AJCC)tumor-node-metastasis(TNM)staging system(0.61,P<0.001),and MEGNA prognostic score(0.60,P<0.001).The patients in quartile 4 of PMS could benefit from adjuvant therapy(AT)(HR=0.54;95%CI:0.32-0.91;log-rank P=0.043),whereas those in the quartiles 1-3 could not.However,other nomograms and staging system failed to do so.Further analyses of potential mechanisms showed that the PMS was associated with tumor biological behaviors,pathway activation,and immune microenvironment.Conclusions:The PMS could improve the prognostic accuracy and identify patients who would benefit from AT for ICC patients,and might facilitate decisions in treatment of ICC patients.

Efficacy and Safety of Second-line Treatments in Patients with Advanced Hepatocellular Carcinoma after Sorafenib Failure:A Meta-analysis

Background and Aims:In the last decade,several second-line therapies followed by sorafenib in patients with advanced hepatocellular carcinoma(HCC)have been reported.But the outcomes were different from each other.This meta-analysis aimed to evaluate the efficacy and safety of the second-line therapies followed by sorafenib in patients with advanced HCC.Methods:Embase(1974 to October 2019)and Ovid MEDLINE(1946 to October 2019)were searched for randomized clinical trials on second-line therapies followed by sorafenib in patients with advanced HCC.The quality of each study was assessed by the modified Jadad scale.Statistical analysis was carried out by RevMan5.3 software.Efficacy and safety were analyzed.Efficacy included overall survival(OS),disease control rate,time to progression,and progression-free survival.Results:Eight studies involving 3,173 patients were eligible.No difference in OS was found between the second-line treatment group and the control group(HR=0.87,95%CI:0.74-1.01,p=0.06).Disease control rate(relative risk(RR)=1.36,95%CI:1.16-1.60,p=0.0002),time to progression(HR=0.64,95%CI:0.51-0.81,p=0.0002)and progression-free survival(HR=0.60,95%CI:0.46-0.77,p<0.0001)were significantly improved by the second-line therapies.There was a slight difference in adverse events of any grade(RR=1.07,95%CI:1.00-1.14,p=0.03)between the two groups.Conclusions:These second-line therapies followed by sorafenib may potentially improve the prognosis in patients with advanced HCC.Compared with other second-line therapies,regorafenib seemed to be more effective.

Neoadjuvant and Adjuvant Therapy in Intrahepatic Cholangiocarcinoma

Intrahepatic cholangiocarcinoma(ICC)is the second most common primary liver cancer and causes major economic and health burdens throughout the world.Although the incidence of ICC is relatively low,an upward trend has been seen over the past few decades.Owing to the lack of specific manifestations and tools for early diagnosis,most ICC patients have relatively advanced disease at diagnosis.Thus,neoadjuvant therapy is necessary to evaluate tumor biology and downstage these patients so that appropriate candidates can be selected for radical liver resection.However,even after radical resection,the recurrence rate is relatively high and is a main cause leading to death after surgery,which makes adjuvant therapy necessary.Because of its low incidence,studies in both neoadjuvant and adjuvant settings of ICC are lagging compared with other types of malignancy.While standard neoadjuvant and adjuvant regimens are not available in the current guidelines due to a lack of high-level evidence,some progress has been achieved in recent years.In this review,the available literature on advances in neoadjuvant and adjuvant strategies in ICC are evaluated,and possible challenges and opportunities for clinical and translational investigations in the near future are discussed.

Interleukin-37 promotes colitis-associated carcinogenesis via SIGIRR-mediated cytotoxic T cells dysfunction

Interleukin-37b(hereafter called IL-37)was identified as fundamental inhibitor of natural and acquired immunity.The molecular mechanism and function of IL-37 in colorectal cancer(CRC)has been elusive.Here,we found that IL-37 transgenic(IL-37tg)mice were highly susceptible to colitis-associated colorectal cancer(CAC)and suffered from dramatically increased tumor burdens in colon.Nevertheless,IL-37 is dispensable for intestinal mutagenesis,and CRC cell proliferation,apoptosis,and migration.Notably,IL-37 dampened protective cytotoxic T cell-mediated immunity in CAC and B16-OVA models.CD8^(+)T cell dysfunction is defined by reduced retention and activation as well as failure to proliferate and produce cytotoxic cytokines in IL-37tg mice,enabling tumor evasion of immune surveillance.The dysfunction led by IL-37 antagonizes IL-18–induced proliferation and effector function of CD8+T cells,which was dependent on SIGIRR(single immunoglobulin interleukin-1 receptor-related protein).Finally,we observed that IL-37 levels were significantly increased in CRC patients,and positively correlated with serum CRC biomarker CEA levels,but negatively correlated with the CD8+T cell infiltration in CRC patients.Our findings highlight the role of IL-37 in harnessing antitumor immunity by inactivation of cytotoxic T cells and establish a new defined inhibitory factor IL-37/SIGIRR in cancerimmunity cycle as therapeutic targets in CRC.