Hepatocellular carcinoma(HCC)is the global leading cause of cancer-related deaths due to the deficiency of targets for precision therapy.A new modality of epigenetic regulation has emerged involving RNA-RNA crosstalk ...Hepatocellular carcinoma(HCC)is the global leading cause of cancer-related deaths due to the deficiency of targets for precision therapy.A new modality of epigenetic regulation has emerged involving RNA-RNA crosstalk networks where two or more competing endogenous RNAs(ceRNAs)bind to the same microRNAs.However,the contribution of such mechanisms in HCC has not been well studied.Herein,potential HMGB1-driven RNA-RNA crosstalk networks were evaluated at different HCC stages,identifying the mT0RC2 component RICTOR as a potential HMGB1 ceRNA in HBV^(+)early stage HCC.Indeed,elevated HMGB1 mRNA was found to promote the expressio n of RICTOR mRNA through competitively bin ding with the miR-200 family,especially miR-429.Functio nal assays emplo ying overexpressi on or in terference strategies dem on strated that the HMGB1 and RICTOR 3zuntra nslated regions(UTR)epigenetically promoted the malignant proliferation,self-renewal,and tumorigenesis in HCC cells.Intriguingly,in terference agai nst HMGB1 and RICTOR in HCC cells promoted a stron ger an ti-PD-L1 immuno therapy resp on se,which appeared to associate with the production of PD-L1^(+)exosomes.Mechanistically,the HMGB1-driven RNA-RNA crosstalk network facilitated HCC cell glutamine metabolism via dual mechanisms,activating a positive feedback loop involving mT0RC2-AKT-C-MYC to upregulate glutamine synthetase(GS)expression,and inducing mTORCI signaling to derepress SIRT4 on glutamate dehydrogenase(GDH).Meanwhile,this crosstalk network could impede the efficacy of immunotherapy through mTORCI-P70S6K dependent PD-L1 production and PD-L1^(+)exosomes activity.In conclusion,our study highlights the non-coding regulatory role of HMGB1 with implicatio ns for RNA-based therapeutic targeting together with a predictio n of an ti-PD-L1 immuno therapy in HCC.展开更多
Background:Preoperative prediction of microvascular invasion(MVI)in hepatocellular carcinoma(HCC)may optimize individualized treatment decision-making.This study aimed to investigate the prognostic differences between...Background:Preoperative prediction of microvascular invasion(MVI)in hepatocellular carcinoma(HCC)may optimize individualized treatment decision-making.This study aimed to investigate the prognostic differences between HCC patients undergoing liver resection(LR)and liver transplantation(LT)based on predicted MVI risks.Methods:We analysed 905 patients who underwent LR,including 524 who underwent anatomical resection(AR)and 117 who underwent LT for HCC within the Milan criteria using propensity score matching.A nomogram model was used to predict preoperative MVI risk.Results:The concordance indices of the nomogram for predicting MVI were 0.809 and 0.838 in patients undergoing LR and LT,respectively.Based on an optimal cut-off value of 200 points,the nomogram defined patients as high-or low-risk MVI groups.LT resulted in a lower 5-year recurrence rate and higher 5-year overall survival(OS)rate than LR among the high-risk patients(23.6%vs 73.2%,P<0.001;87.8%vs 48.1%,P<0.001)and low-risk patients(19.0%vs 45.7%,P<0.001;86.5%vs 70.0%,P=0.002).The hazard ratios(HRs)of LT vs LR for recurrence and OS were 0.18(95%confidence interval[CI],0.09–0.37)and 0.12(95%CI,0.04–0.37)among the high-risk patients and 0.37(95%CI,0.21–0.66)and 0.36(95%CI,0.17–0.78)among the low-risk patients.LT also provided a lower 5-year recurrence rate and higher 5-year OS rate than AR among the high-risk patients(24.8%vs 63.5%,P=0.001;86.7%vs 65.7%,P=0.004),with HRs of LT vs AR for recurrence and OS being 0.24(95%CI,0.11–0.53)and 0.17(95%CI,0.06–0.52),respectively.The 5-year recurrence and OS rates between patients undergoing LT and AR were not significantly different in the low-risk patients(19.4%vs 28.3%,P=0.129;85.7%vs 77.8%,P=0.161).Conclusions:LT was superior to LR for patients with HCC within the Milan criteria with a predicted high or low risk of MVI.No significant differences in prognosis were found between LT and AR in patients with a low risk of MVI.展开更多
Aim:To evaluate the perioperative outcomes and postoperative survival of applying staging laparoscopy(SL)in intrahepatic cholangiocarcinoma(ICC)patients undergoing surgical resection.Methods:A retrospective analysis w...Aim:To evaluate the perioperative outcomes and postoperative survival of applying staging laparoscopy(SL)in intrahepatic cholangiocarcinoma(ICC)patients undergoing surgical resection.Methods:A retrospective analysis was performed on all selected ICC patients who underwent curative-intent resection with/without applying staging laparoscopy from January 2010 to August December 2021.Perioperative outcomes and postoperative survival were analyzed.Propensity score matching(PSM)and inverse probability of treatment weighting(IPTW)were performed to reduce the bias due to confounding variables in the SL group and the non-SL group.Multivariate Cox analysis was used to ascertain the independent predictor of survival for ICC patients.Results:A total of 279 patients(24.1%)were included in the SL group,while 881 patients(75.9%)were included in the non-SL group.Compared with the non-SL group,the SL group had lower blood loss,smaller tumor size,higher R0 resection rate,and shorter hospital stay,but a higher incidence of postoperative complications.The OS of the SL group was better than that of the non-SL group(Median OS:31 months vs.20 months).The 1-,3-,and 5-year overall survival rates of the SL group were 77.9%,45.1%,and 32.9%,respectively,while the non-SL group had rates of 63.9%,31.3%,and 18.4%.SL was confirmed as an independent predictor of survival by multivariate Cox analysis.Conclusion:ICC patients receiving SL had better perioperative outcomes and significantly prolonged overall survival after resection surgery.The subgroup analysis results support the use of routine SL.展开更多
基金We gratefully acknowledge the support from the National Key R&D Program of China(2017YFA0504503)State Key Project on Infectious Diseases of China(2018ZX10723204-002-002)+2 种基金National Natural Science Foundation of China(91859205,81988101,81830054,81630070,81672777,81502416,and 82172896)Shanghai Rising-Star Program(17QA1405700)Shanghai Top Young Talents Program,Foundation of Shanghai Shenkang Hospital Development Center(SHDC2020CR2011A and SHDC12016127).
文摘Hepatocellular carcinoma(HCC)is the global leading cause of cancer-related deaths due to the deficiency of targets for precision therapy.A new modality of epigenetic regulation has emerged involving RNA-RNA crosstalk networks where two or more competing endogenous RNAs(ceRNAs)bind to the same microRNAs.However,the contribution of such mechanisms in HCC has not been well studied.Herein,potential HMGB1-driven RNA-RNA crosstalk networks were evaluated at different HCC stages,identifying the mT0RC2 component RICTOR as a potential HMGB1 ceRNA in HBV^(+)early stage HCC.Indeed,elevated HMGB1 mRNA was found to promote the expressio n of RICTOR mRNA through competitively bin ding with the miR-200 family,especially miR-429.Functio nal assays emplo ying overexpressi on or in terference strategies dem on strated that the HMGB1 and RICTOR 3zuntra nslated regions(UTR)epigenetically promoted the malignant proliferation,self-renewal,and tumorigenesis in HCC cells.Intriguingly,in terference agai nst HMGB1 and RICTOR in HCC cells promoted a stron ger an ti-PD-L1 immuno therapy resp on se,which appeared to associate with the production of PD-L1^(+)exosomes.Mechanistically,the HMGB1-driven RNA-RNA crosstalk network facilitated HCC cell glutamine metabolism via dual mechanisms,activating a positive feedback loop involving mT0RC2-AKT-C-MYC to upregulate glutamine synthetase(GS)expression,and inducing mTORCI signaling to derepress SIRT4 on glutamate dehydrogenase(GDH).Meanwhile,this crosstalk network could impede the efficacy of immunotherapy through mTORCI-P70S6K dependent PD-L1 production and PD-L1^(+)exosomes activity.In conclusion,our study highlights the non-coding regulatory role of HMGB1 with implicatio ns for RNA-based therapeutic targeting together with a predictio n of an ti-PD-L1 immuno therapy in HCC.
基金supported by the State Key Project on Infectious Diseases[2018ZX10723204]Project of Shanghai Key Clinical Specialties[SHSLCZDZK02402]+2 种基金Project of Shenkang Hospital Development Center[SHDC2020CR5007,SHDC12019110]Shanghai Science and Technology Innovation Action Plan[21Y11912700]The funders had no role in the study design,data collection,data analysis,interpretation,or writing of the report.
文摘Background:Preoperative prediction of microvascular invasion(MVI)in hepatocellular carcinoma(HCC)may optimize individualized treatment decision-making.This study aimed to investigate the prognostic differences between HCC patients undergoing liver resection(LR)and liver transplantation(LT)based on predicted MVI risks.Methods:We analysed 905 patients who underwent LR,including 524 who underwent anatomical resection(AR)and 117 who underwent LT for HCC within the Milan criteria using propensity score matching.A nomogram model was used to predict preoperative MVI risk.Results:The concordance indices of the nomogram for predicting MVI were 0.809 and 0.838 in patients undergoing LR and LT,respectively.Based on an optimal cut-off value of 200 points,the nomogram defined patients as high-or low-risk MVI groups.LT resulted in a lower 5-year recurrence rate and higher 5-year overall survival(OS)rate than LR among the high-risk patients(23.6%vs 73.2%,P<0.001;87.8%vs 48.1%,P<0.001)and low-risk patients(19.0%vs 45.7%,P<0.001;86.5%vs 70.0%,P=0.002).The hazard ratios(HRs)of LT vs LR for recurrence and OS were 0.18(95%confidence interval[CI],0.09–0.37)and 0.12(95%CI,0.04–0.37)among the high-risk patients and 0.37(95%CI,0.21–0.66)and 0.36(95%CI,0.17–0.78)among the low-risk patients.LT also provided a lower 5-year recurrence rate and higher 5-year OS rate than AR among the high-risk patients(24.8%vs 63.5%,P=0.001;86.7%vs 65.7%,P=0.004),with HRs of LT vs AR for recurrence and OS being 0.24(95%CI,0.11–0.53)and 0.17(95%CI,0.06–0.52),respectively.The 5-year recurrence and OS rates between patients undergoing LT and AR were not significantly different in the low-risk patients(19.4%vs 28.3%,P=0.129;85.7%vs 77.8%,P=0.161).Conclusions:LT was superior to LR for patients with HCC within the Milan criteria with a predicted high or low risk of MVI.No significant differences in prognosis were found between LT and AR in patients with a low risk of MVI.
基金supported by the National Science Foundation of China(No.81772521)Multicenter Clinical Research Project of Shanghai Jiaotong University School of Medicine(No.DLY201807)Clinical Training Program of Shanghai Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine(No.17CSK06).
文摘Aim:To evaluate the perioperative outcomes and postoperative survival of applying staging laparoscopy(SL)in intrahepatic cholangiocarcinoma(ICC)patients undergoing surgical resection.Methods:A retrospective analysis was performed on all selected ICC patients who underwent curative-intent resection with/without applying staging laparoscopy from January 2010 to August December 2021.Perioperative outcomes and postoperative survival were analyzed.Propensity score matching(PSM)and inverse probability of treatment weighting(IPTW)were performed to reduce the bias due to confounding variables in the SL group and the non-SL group.Multivariate Cox analysis was used to ascertain the independent predictor of survival for ICC patients.Results:A total of 279 patients(24.1%)were included in the SL group,while 881 patients(75.9%)were included in the non-SL group.Compared with the non-SL group,the SL group had lower blood loss,smaller tumor size,higher R0 resection rate,and shorter hospital stay,but a higher incidence of postoperative complications.The OS of the SL group was better than that of the non-SL group(Median OS:31 months vs.20 months).The 1-,3-,and 5-year overall survival rates of the SL group were 77.9%,45.1%,and 32.9%,respectively,while the non-SL group had rates of 63.9%,31.3%,and 18.4%.SL was confirmed as an independent predictor of survival by multivariate Cox analysis.Conclusion:ICC patients receiving SL had better perioperative outcomes and significantly prolonged overall survival after resection surgery.The subgroup analysis results support the use of routine SL.
