Hepatectomy is still the major curative treatment for patients with liver malignancies.However,it is still a big challenge to remove the tumors in the central posterior area,especially if their location involves the r...Hepatectomy is still the major curative treatment for patients with liver malignancies.However,it is still a big challenge to remove the tumors in the central posterior area,especially if their location involves the retrohepatic inferior vena cava and hepatic veins.Ex vivo liver resection and auto-transplantation(ELRA),a hybrid technique of the traditional liver resection and transplantation,has brought new hope to these patients and therefore becomes a valid alternative to liver transplantation.Due to its technical difficulty,ELRA is still concentrated in a few hepatobiliary centers that have experienced surgeons in both liver resection and liver transplantation.The efficacy and safety of this technique has already been demonstrated in the treatment of benign liver diseases,especially in the advanced alveolar echinococcosis.Recently,the application of ELRA for liver malignances has gained more attention.However,standardization of clinical practice norms and international consensus are still lacking.The prognostic impact in these oncologic patients also needs further evaluation.In this review,we summarized the principles and recent progresses on ELRA.展开更多
Locoregional spread of abdominopelvic malignant tumors frequently results in peritoneal carcinomatosis(PC). The prognosis of PC patients treated by conventional systemic chemotherapy is poor, with a median survival of...Locoregional spread of abdominopelvic malignant tumors frequently results in peritoneal carcinomatosis(PC). The prognosis of PC patients treated by conventional systemic chemotherapy is poor, with a median survival of < 6 mo. However, over the past three decades, an integrated treatment strategy of cytoreductive surgery(CRS) + hyperthermic intraperitoneal chemotherapy(HIPEC) has been developed by the pioneering oncologists, with proved efficacy and safety in selected patients. Supported by several lines of clinical evidence from phases Ⅰ, Ⅱ and Ⅲ clinical trials, CRS + HIPEC has been regarded as the standard treatment for selected patients with PC in many established cancer centers worldwide. In China, an expert consensus on CRS + HIPEC has been reached by the leading surgical and medical oncologists, under the framework of the China Anti-Cancer Association. This expert consensus has summarized the progress in PC clinical studies and systematically evaluated the CRS + HIPEC procedures in China as well as across the world, so as to lay the foundation for formulating PC treatment guidelines specific to the national conditions of China.展开更多
AIM: To identify the prognostic value of hepatitis B virus(HBV) and hepatitis C virus(HCV) infections in patients with intrahepatic cholangiocarcinoma.METHODS: A search was performed for relevant publications in Pub M...AIM: To identify the prognostic value of hepatitis B virus(HBV) and hepatitis C virus(HCV) infections in patients with intrahepatic cholangiocarcinoma.METHODS: A search was performed for relevant publications in Pub Med, EMBASE and Web of Science databases. The pooled effects were calculated from the available information to identify the relationship between HBV or HCV infection and the prognosis and clinicopathological features. The χ2 and I2 tests were used to evaluate heterogeneity between studies. Pooled hazard ratios(HRs) with 95% confidence intervals(CIs) were calculated by a fixed-effects model, if no heterogeneity existed. If there was heterogeneity, a random-effects model was applied.RESULTS: In total, 14 studies involving 2842 cases were enrolled in this meta-analysis. The patients with HBV infection presented better overall and diseasefree survival, and the pooled HRs were significant at 0.76(95%CI: 0.70-0.83) and 0.78(95%CI: 0.66-0.94), respectively. Additionally, our study revealed that HCV infection was correlated with shortened overall survival in comparison with the control group(HR = 2.64, 95%CI: 1.77-3.93). We also found that HBV infection occurred more frequently in male patients [odds ratio(OR) = 1.91, 95%CI: 1.06-3.44] and was correlated with higher levels of serum aspartate transaminase(AST) and alpha-fetoprotein(AFP)(OR = 1.93, 95%CI: 1.11-3.35; OR = 3.86, 95%CI: 2.58-5.78) and a lower level of serum carbohydrate antigen 19-9(CA19-9)(OR = 0.47, 95%CI: 0.34-0.65). Moreover, HBV infection was associated with cirrhosis(OR = 6.44, 95%CI: 4.33-9.56), a higher proportion of capsule formation(OR = 6.04, 95%CI: 3.56-10.26), and a lower rate of lymph node metastasis(OR = 0.39, 95%CI: 0.25-0.58). No significant publication bias was seen in any of the enrolled studies.CONCLUSION: HBV infection may indicate a favorable prognosis in patients with intrahepatic cholangiocarcinoma, while HCV infection suggests a poor prognosis.展开更多
Background:The advent of immune checkpoint inhibitors(ICIs)has revolutionized the therapeutic options of hepatobiliary malignancies.However,the clinical benefit provided by immunotherapy seems limited to a small subgr...Background:The advent of immune checkpoint inhibitors(ICIs)has revolutionized the therapeutic options of hepatobiliary malignancies.However,the clinical benefit provided by immunotherapy seems limited to a small subgroup of patients with hepatobiliary malignancies.The identification of reliable predictors of the response to immunotherapy is urgently needed.Data sources:Literature search was conducted in Pub Med for relevant articles published up to May 2022.Information of clinical trials was obtained from https://clinicaltrials.gov/.Results:Biomarkers for ICI response of hepatobiliary malignancies remain in the exploration stage and lack compelling evidence.Tumor programmed death-ligand 1(PD-L1)expression is the most widely studied biomarker in hepatocellular carcinoma(HCC)and biliary tract cancers(BTCs),but there are conflicting results on its predictive potential.Tumor mutational burden(TMB)is generally low both in HCC and BTCs,and the clinical trials of TMB are rare in hepatobiliary malignancies.Promisingly,mismatch repair deficiency(dMMR)/high microsatellite instability(MSI-H)may be a predictive biomarker of response to antiPD-1 therapy in BTCs.Furthermore,some emerging biomarkers,such as gut microbiota,show predictive potential in the preliminary studies.Radiomics and liquid-biopsy biomarkers,including circulating tumor cells,circulating tumor DNA(ct DNA)and exosomal PD-L1 provide a quick and non-invasive approach for monitoring the ICI response,showing a new promising direction.Conclusions:Multiple potential biomarkers for predicting ICI response of hepatobiliary malignancies have been explored and tried to apply in clinic.Yet there is no robust evidence to prove their clinical value in predicting immunotherapeutic response for patients with hepatobiliary malignancies.The identification of predictors for response to ICIs is an urgent need and major challenge.Further studies are warranted to validate the role of emerging biomarkers in predicting immunotherapeutic responses.展开更多
Objective: The expression of B-cell lymphoma 2(Bcl-2) seems to be influenced by the endocrine environment. Numerous reports demonstrate the diverse expression of Bcl-2 family members under sex steroid regulation. With...Objective: The expression of B-cell lymphoma 2(Bcl-2) seems to be influenced by the endocrine environment. Numerous reports demonstrate the diverse expression of Bcl-2 family members under sex steroid regulation. With the exception of estrogen-related tumors, androgen-related tumors have shown their characteristics in Bcl-2 expression. In this study, the status of Bcl-2 expression in male hepatocellular carcinoma(HCC) patients was examined to verify the high incidence of HCC in males.Methods: Tumor tissue microarray was used to examine Bcl-2 expression levels in 374 HCC cases including 306 males and 68 females. Kaplan-Meier method, log-rank test, and Cox proportional hazards model were applied to investigate the predictive value of Bcl-2 in HCC patients.Results: Immunohistochemistry analysis showed that male patients with higher Bcl-2 levels had significantly longer median survival time and recurrence time than those with lower levels. However, no significant differences in outcomes were found between different Bcl-2 levels in female patients. When the male patients were stratified into several age points, the level of Bcl-2expression showed poorer predictive efficiency in the 45–49 and 55–60 age groups in andropause-age patients compared with other age groups. Bcl-2 was an independent prognostic factor for both overall survival(P < 0.0001) and recurrence time(P =0.0001) in male patients. After excluding male patients in the 45–60 age group, the predictive efficiency was enhanced(n = 147,OS, P = 0.0002, TTR, P < 0.0001).Conclusions: Bcl-2 expression is an independent predictor of survival and recurrence in male HCC. Bcl-2 levels may also be regulated by androgens or androgen receptors in male HCC patients. Bcl-2 levels change and exhibit poor predictive efficiency when androgen levels vary dramatically(andropause age).展开更多
Primary liver cancer,mainly hepatocellular carcinoma(HCC),is the sixth most diagnosed cancer and third leading cause of cancer-related death globally.Recently,immunotherapies such as immune checkpoint inhibitors(ICIs)...Primary liver cancer,mainly hepatocellular carcinoma(HCC),is the sixth most diagnosed cancer and third leading cause of cancer-related death globally.Recently,immunotherapies such as immune checkpoint inhibitors(ICIs)have made great progress in the systemic treatment of HCC.However,anti-PD-1 therapy with pembrolizumab or nivolumab as a single agent did not meet their predefined end points of overall survival in the KEYNOTE-240 and Check Mate 459 trials.It is urgent to understand the immunological rationale and explore novel ways to improve the efflcacy of immunotherapy.The combination of ICIs with other therapies,such as tyrosine kinase inhibitors(TKIs),monoclonal antibodies,or local therapy,has been demonstrated to improve overall response rate and survival.In addition,modulating tumor microenvironment is a potential way to overcome the primary and secondary resistance to immunotherapies.In this review,we summarized the latest findings in the immune microenvironment,the mechanisms of their synergistic effects when combined with anti-VEGF agents or TKIs,as well as other kinds of immune treatment.展开更多
Cancer treatment failure, drug resistance, or metastatic recurrence are thought to be caused mainly by the existence of a very small number of cancer stem cells(CSCs). The characteristics of this subgroup of cells inc...Cancer treatment failure, drug resistance, or metastatic recurrence are thought to be caused mainly by the existence of a very small number of cancer stem cells(CSCs). The characteristics of this subgroup of cells include self-renewal, tumorigenesis, multiple differentiation and high invasiveness, metastasis, and drug resistance potential. Many studies have demonstrated that CSCs play important roles in tumor growth, spread and metastatic relapse after treatment, and are closely related to the prognosis of patients.From a therapeutic viewpoint, deep insights into the CSCs biology, development of specific therapeutic strategies for targeting CSCs, and characterization of their microenvironment could be an ideal way to combat cancer.展开更多
Hepatobiliary malignancies include hepatocellular carcinoma(HCC)and biliary tract cancers(BTCs).They are characterized by high heterozygosity,rapid progression,and difflcult to treat[1,2].Recent rapid progress in targ...Hepatobiliary malignancies include hepatocellular carcinoma(HCC)and biliary tract cancers(BTCs).They are characterized by high heterozygosity,rapid progression,and difflcult to treat[1,2].Recent rapid progress in targeted therapeutic agents has brought new hope for those with advanced HCC[3-5].But there are problems such as lower response rate,or drug resistance(primary or acquired),as well as poor tolerance due to their side-effects,which make this treatment alone still face great challenges.展开更多
Neurotransmitter-initiated signaling pathway were reported to play an important role in regulating the malignant phenotype of tumor cells.Cancer cells could exhibit a"neural addiction"property and build up l...Neurotransmitter-initiated signaling pathway were reported to play an important role in regulating the malignant phenotype of tumor cells.Cancer cells could exhibit a"neural addiction"property and build up local nerve networks to achieve an enhanced neurotransmitter-initiated signaling through nerve growth factor-mediated axonogenesis.Targeting the dysregulated nervous systems might represent a novel strategy for cancer treatment.However,whether intrahepatic cholangiocarcinoma(ICC)could build its own nerve networks and the role of neurotransmitters in the progression ICC remains largely unknown.Immunofluorescence staining and Enzyme-linked immunosorbent assay suggested that IcC cells and the infiltrated nerves could generate a tumor microenvironment rich in acetylcholine that promotes IcC metastasis by inducing epithelial-mesenchymal transition(EMT).Acetylcholine promoted iCC metastasis through interacting with its receptor,alpha 5 nicotine acetylcholine receptor subunits(CHRNA5).Furthermore,acetylcholine/CHRNA5 axis activated GSK3β/β-catenin signaling pathway partially through the influx of Ca^(2+)-mediated activation of Ca/calmodulin-dependent protein kinases(CAMKll).In addition,acetylcholine signaling activation also expanded nerve infiltration through increasing the expression of Brain-Derived Neurotrophic Factor(BDNF),which formed a feedforward acetylcholine-BDNF axis to promote ICC progression.KN93,a small-molecule inhibitor of CAMKIll,significantly inhibited the migration and enhanced the sensitivity to gemcitabine of ICC cells.Above all,Acetylcholine/CHRNA5 axis increased the expression ofβ-catenin to promote the metastasis and resistance to gemcitabine of ICC via CAMKIl/GSK3βsignaling,and the CAMKIl inhibitor KN93 may be an effective therapeutic strategy for combating ICC metastasis.展开更多
Evidence-based medicine serves as the cornerstone of modern healthcare.Based on current evidence in the field of evidence-based medicine,a team of authoritative experts in the industry engages in comprehensive discuss...Evidence-based medicine serves as the cornerstone of modern healthcare.Based on current evidence in the field of evidence-based medicine,a team of authoritative experts in the industry engages in comprehensive discussions to develop expert consensus,following standardized procedures.The consensus serves as a foundation for clinical decision-making.However,the abundance of expert consensus varies in quality,and some viewpoints even contradict each other,leading to confusion in clinical decision-making.展开更多
Background The efficacy of immune checkpoint inhibitors(ICIs),such as programmed cell death protein-1(PD-1)or its ligand 1(PD-L1)antibody,in hepatocellular carcinoma(HCC)is limited,and it is recommended that they be c...Background The efficacy of immune checkpoint inhibitors(ICIs),such as programmed cell death protein-1(PD-1)or its ligand 1(PD-L1)antibody,in hepatocellular carcinoma(HCC)is limited,and it is recommended that they be combined with other therapies.We evaluated the combination of pegylated interferon-α(Peg-IFNα)with PD-1 blockade in HCC mouse models.Methods We analyzed the effects of Peg-IFNαon tumor-infiltrating immune cells and PD-1 expression in the HCC immune microenvironment and examined the underlying mechanism of its unique effect on the PD-1 pathway.The in vivo efficacy of anti-PD-1 and Peg-IFNαwas evaluated in both subcutaneous and orthotopic mouse models of HCC.Results The combination of Peg-IFNαwith PD-1 blockade dramatically enhanced T-cell infiltration,improved the efficacy of PD-1 antibody and prolonged mouse survival compared with PD-1 antibody monotherapy.Mechanistically,Peg-IFNαcould recruit cytotoxic CD8+T cells to infiltrate the HCC microenvironment by inducing tumor cells to secrete the chemokine CCL4.Nevertheless,the HCC microenvironment quickly overcame the immune responses by upregulating PD-1 expression in CD8+T cells via the IFNα-IFNAR1-JAK1-STAT3 signaling pathway.The combination of PD-1 blockade with Peg-IFNαcould restore the cytotoxic capacity of CD8+T cells and exerted a significant synergistic effect on HCC.Conclusion These results indicate that in addition to initiating the antitumor immune response itself,Peg-IFNαcan also generate a microenvironment favoring PD-1 blockade.Thus,the combination of Peg-IFNαand PD-1 blockade can be a promising strategy for HCC.展开更多
The immunosuppressive microenvironment plays an important role in tumor progression and immunotherapy responses.Golgi membrane protein 1(GOLM1)is correlated to hepatocellular carcinoma(HCC)progression and metastasis.H...The immunosuppressive microenvironment plays an important role in tumor progression and immunotherapy responses.Golgi membrane protein 1(GOLM1)is correlated to hepatocellular carcinoma(HCC)progression and metastasis.However,little is known about the role of GOLM1 in regulating the immunosuppressive environment and its impact on immunotherapeutic efficacy in HCC.In this study,GOLM1 was positively correlated with infiltrating tumor-associated macrophages(TAMs)expressed high levels of programmed death-ligand 1(PD-L1)and CD8^(+)T cell suppression in HCC tissues.Both gain-and loss-of-function studies determined a close correlation between GOLM1 and immunosuppression.In the mechanism,GOLM1 promoted COP9 signalosome 5-mediated PD-L1 deubiquitination in HCC cells and increased the transport of PD-L1 into exosomes via suppression of Rab27b expression.Furthermore,co-culture with exosomes derived from HCC cells upregulated the expression of PD-L1 on macrophages.Zoledronic acid in combination with anti-PD-L1 therapy reduced PD-L1^(+)TAMs infiltration and alleviated CD8^(+)T cell suppression,resulting in tumor growth inhibition in the mouse HCC model.Together,our study unveils a mechanism by which GOLM1 induces CD8^(+)T cells suppression through promoting PD-L1 stabilization and transporting PD-L1 into TAMs with exosome dependent.Targeting PD-L1^(+)TAM could be a novel strategy to enhance the efficacy of anti-PD-L1 therapy in HCC.展开更多
Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence.Furthermore,it is usually diagnosed at an advanced stage with a very dismal pro...Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence.Furthermore,it is usually diagnosed at an advanced stage with a very dismal prognosis.Due to the high heterogeneity,metabolic reprogramming,and dense stromal environment associated with pancreatic cancer,patients benefit little from current conventional therapy.Recent insight into the biology and genetics of pancreatic cancer has supported its molecular classification,thus expanding clinical therapeutic options.In this review,we summarize how the biological features of pancreatic cancer and its metabolic reprogramming as well as the tumor microenvironment regulate its development and progression.We further discuss potential biomarkers for pancreatic cancer diagnosis,prediction,and surveillance based on novel liquid biopsies.We also outline recent advances in defining pancreatic cancer subtypes and subtype-specific therapeutic responses and current preclinical therapeutic models.Finally,we discuss prospects and challenges in the clinical development of pancreatic cancer therapeutics.展开更多
Background and Aims:Wound healing and tumor progression share some common biological features;however,how variations in wound healing patterns affect hepatocellular carcinoma(HCC)prognosis remains unclear.Methods:We a...Background and Aims:Wound healing and tumor progression share some common biological features;however,how variations in wound healing patterns affect hepatocellular carcinoma(HCC)prognosis remains unclear.Methods:We analyzed the wound healing patterns of 594 HCC samples from The Cancer Genome Atlas(TCGA)and the International Cancer Genome Consortium(ICGC)and correlated them with immune infiltration and the expression levels of immune checkpoint genes.A risk score,which we named the“heal.immune”score,was established via stepwise Cox estimation.We constructed a nomogram based on age,sex,TNM stage,and heal.immune score and explored its predictive value for HCC prognosis.Seventy-four clinical patients were enrolled in this study,and all were from Huashan Hospital of Fudan University between 2015 and 2017 to serve as an independent validation group.Results:We identified two distinct wound healing patterns in HCC.The biological processes of healing cluster 1(C1)are related to metabolism,while those of healing cluster 2(C2)are related to the inflammatory response and immune cell accumulation.A total of 565 wound healing-related genes(based on Gene Ontology)and 25 immune checkpoint genes were considered.By analyzing differentially expressed genes and implementing a stepwise Cox estimation analysis,six genes with p values less than 0.02 in a multivariate Cox estimation were chosen as the“heal.immune”gene set(FCER1G,PLAT,ITGA5,CCNB1,CD86 and CD40).The“heal.immune”gene set,as an OS risk factor,was further validated in Fudan cohort.We constructed a nomogram to predict the 1-,3-and 5-year overall survival(OS)in the TCGA cohort.The area under curve vales of the receiver characteristic operator curves were 0.82,0.76 and 0.73 in the training group and 0.84,0.76 and 0.72 in the test group.Conclusions:We established a prognostic nomogram based on the heal.immune gene signature,which includes six wound healing-and immunity-related genes.This nomogram accurately predicts the OS of HCC patients.展开更多
Metastasis and metabolism reprogramming are two major hallmarks of cancer.In the initiation and progression of cancer,tumor cells are known to undergo fundamental metabolic changes to sustain their development and pro...Metastasis and metabolism reprogramming are two major hallmarks of cancer.In the initiation and progression of cancer,tumor cells are known to undergo fundamental metabolic changes to sustain their development and progression.In recent years,much more attentions have been drawn to their important roles in facilitating cancer metastasis through regulating the biological properties.In this review,we summarized the recent progresses in the studies of metabolism reprogramming of cancer metastasis,particularly of primary liver cancer,and highlight their potential applications.展开更多
Background:The judgment of the division point of the bile duct has always been one of the difficulties of laparoscopic left lateral sectionectomy(LLLS).The purpose of this study was to assess the effects of indocyanin...Background:The judgment of the division point of the bile duct has always been one of the difficulties of laparoscopic left lateral sectionectomy(LLLS).The purpose of this study was to assess the effects of indocyanine green(ICG)fluorescence cholangiography during LLLS on the occurrence of biliary complications in both donors and recipients.The optimal dose and injection time of ICG were also investigated.Methods:This is a retrospective cohort study.From October 2016 to December 2022,the clinical data of 103 donors who underwent LLLS and relevant recipients were retrospectively analyzed.According to whether ICG fluorescence cholangiography was used,they were divided into a non-ICG group(n=46)and an ICG group(n=57).Biliary complications were observed and the optimal dose and injection time of ICG were explored.Results:Three donors in the non-ICG group suffered from bile leakage.Four grafts had multiple bile duct openings and biliary complications were observed in the relevant recipients who received these grafts in the non-ICG group.Two recipients had bile leakage,and the other two had biliary stenosis.There was no biliary complications both in donors and recipients in the ICG group.The fluorescence intensity of the liver was 108.1±17.6 at a dose of 0.004 mg/kg 90 minutes after injection,significantly weaker than that at 0.05 mg/kg 30 minutes(200.3±17.6,P=0.001)and 90 minutes after injection(140.2±15.4,P=0.001).The fluorescence intensity contrast value at a dose of 0.004 mg/kg was stronger than that at 0.05 mg/kg,both measured 90 minutes after injection(0.098±0.032 vs.0.078±0.022,P=0.021).Conclusions:ICG fluorescence cholangiography is safe and feasible in LLLS.It reduces biliary complications in both donors and recipients.The optimal ICG dose was 0.004 mg/kg,and 90 minutes after injection was the best observation time.ICG fluorescence cholangiography is recommended for routine use in LLLS.展开更多
文摘Hepatectomy is still the major curative treatment for patients with liver malignancies.However,it is still a big challenge to remove the tumors in the central posterior area,especially if their location involves the retrohepatic inferior vena cava and hepatic veins.Ex vivo liver resection and auto-transplantation(ELRA),a hybrid technique of the traditional liver resection and transplantation,has brought new hope to these patients and therefore becomes a valid alternative to liver transplantation.Due to its technical difficulty,ELRA is still concentrated in a few hepatobiliary centers that have experienced surgeons in both liver resection and liver transplantation.The efficacy and safety of this technique has already been demonstrated in the treatment of benign liver diseases,especially in the advanced alveolar echinococcosis.Recently,the application of ELRA for liver malignances has gained more attention.However,standardization of clinical practice norms and international consensus are still lacking.The prognostic impact in these oncologic patients also needs further evaluation.In this review,we summarized the principles and recent progresses on ELRA.
基金Supported by Key Project of the National Natural Science Foundation of China,No.81230031
文摘Locoregional spread of abdominopelvic malignant tumors frequently results in peritoneal carcinomatosis(PC). The prognosis of PC patients treated by conventional systemic chemotherapy is poor, with a median survival of < 6 mo. However, over the past three decades, an integrated treatment strategy of cytoreductive surgery(CRS) + hyperthermic intraperitoneal chemotherapy(HIPEC) has been developed by the pioneering oncologists, with proved efficacy and safety in selected patients. Supported by several lines of clinical evidence from phases Ⅰ, Ⅱ and Ⅲ clinical trials, CRS + HIPEC has been regarded as the standard treatment for selected patients with PC in many established cancer centers worldwide. In China, an expert consensus on CRS + HIPEC has been reached by the leading surgical and medical oncologists, under the framework of the China Anti-Cancer Association. This expert consensus has summarized the progress in PC clinical studies and systematically evaluated the CRS + HIPEC procedures in China as well as across the world, so as to lay the foundation for formulating PC treatment guidelines specific to the national conditions of China.
基金Supported by National Key Projects for Infectious Diseases of ChinaNo.2012ZX10002-012+3 种基金National Key Basic Research Program of ChinaNo.2013CB910500NSFC Program of International Cooperation and ExchangesNo.81120108016
文摘AIM: To identify the prognostic value of hepatitis B virus(HBV) and hepatitis C virus(HCV) infections in patients with intrahepatic cholangiocarcinoma.METHODS: A search was performed for relevant publications in Pub Med, EMBASE and Web of Science databases. The pooled effects were calculated from the available information to identify the relationship between HBV or HCV infection and the prognosis and clinicopathological features. The χ2 and I2 tests were used to evaluate heterogeneity between studies. Pooled hazard ratios(HRs) with 95% confidence intervals(CIs) were calculated by a fixed-effects model, if no heterogeneity existed. If there was heterogeneity, a random-effects model was applied.RESULTS: In total, 14 studies involving 2842 cases were enrolled in this meta-analysis. The patients with HBV infection presented better overall and diseasefree survival, and the pooled HRs were significant at 0.76(95%CI: 0.70-0.83) and 0.78(95%CI: 0.66-0.94), respectively. Additionally, our study revealed that HCV infection was correlated with shortened overall survival in comparison with the control group(HR = 2.64, 95%CI: 1.77-3.93). We also found that HBV infection occurred more frequently in male patients [odds ratio(OR) = 1.91, 95%CI: 1.06-3.44] and was correlated with higher levels of serum aspartate transaminase(AST) and alpha-fetoprotein(AFP)(OR = 1.93, 95%CI: 1.11-3.35; OR = 3.86, 95%CI: 2.58-5.78) and a lower level of serum carbohydrate antigen 19-9(CA19-9)(OR = 0.47, 95%CI: 0.34-0.65). Moreover, HBV infection was associated with cirrhosis(OR = 6.44, 95%CI: 4.33-9.56), a higher proportion of capsule formation(OR = 6.04, 95%CI: 3.56-10.26), and a lower rate of lymph node metastasis(OR = 0.39, 95%CI: 0.25-0.58). No significant publication bias was seen in any of the enrolled studies.CONCLUSION: HBV infection may indicate a favorable prognosis in patients with intrahepatic cholangiocarcinoma, while HCV infection suggests a poor prognosis.
文摘Background:The advent of immune checkpoint inhibitors(ICIs)has revolutionized the therapeutic options of hepatobiliary malignancies.However,the clinical benefit provided by immunotherapy seems limited to a small subgroup of patients with hepatobiliary malignancies.The identification of reliable predictors of the response to immunotherapy is urgently needed.Data sources:Literature search was conducted in Pub Med for relevant articles published up to May 2022.Information of clinical trials was obtained from https://clinicaltrials.gov/.Results:Biomarkers for ICI response of hepatobiliary malignancies remain in the exploration stage and lack compelling evidence.Tumor programmed death-ligand 1(PD-L1)expression is the most widely studied biomarker in hepatocellular carcinoma(HCC)and biliary tract cancers(BTCs),but there are conflicting results on its predictive potential.Tumor mutational burden(TMB)is generally low both in HCC and BTCs,and the clinical trials of TMB are rare in hepatobiliary malignancies.Promisingly,mismatch repair deficiency(dMMR)/high microsatellite instability(MSI-H)may be a predictive biomarker of response to antiPD-1 therapy in BTCs.Furthermore,some emerging biomarkers,such as gut microbiota,show predictive potential in the preliminary studies.Radiomics and liquid-biopsy biomarkers,including circulating tumor cells,circulating tumor DNA(ct DNA)and exosomal PD-L1 provide a quick and non-invasive approach for monitoring the ICI response,showing a new promising direction.Conclusions:Multiple potential biomarkers for predicting ICI response of hepatobiliary malignancies have been explored and tried to apply in clinic.Yet there is no robust evidence to prove their clinical value in predicting immunotherapeutic response for patients with hepatobiliary malignancies.The identification of predictors for response to ICIs is an urgent need and major challenge.Further studies are warranted to validate the role of emerging biomarkers in predicting immunotherapeutic responses.
文摘Objective: The expression of B-cell lymphoma 2(Bcl-2) seems to be influenced by the endocrine environment. Numerous reports demonstrate the diverse expression of Bcl-2 family members under sex steroid regulation. With the exception of estrogen-related tumors, androgen-related tumors have shown their characteristics in Bcl-2 expression. In this study, the status of Bcl-2 expression in male hepatocellular carcinoma(HCC) patients was examined to verify the high incidence of HCC in males.Methods: Tumor tissue microarray was used to examine Bcl-2 expression levels in 374 HCC cases including 306 males and 68 females. Kaplan-Meier method, log-rank test, and Cox proportional hazards model were applied to investigate the predictive value of Bcl-2 in HCC patients.Results: Immunohistochemistry analysis showed that male patients with higher Bcl-2 levels had significantly longer median survival time and recurrence time than those with lower levels. However, no significant differences in outcomes were found between different Bcl-2 levels in female patients. When the male patients were stratified into several age points, the level of Bcl-2expression showed poorer predictive efficiency in the 45–49 and 55–60 age groups in andropause-age patients compared with other age groups. Bcl-2 was an independent prognostic factor for both overall survival(P < 0.0001) and recurrence time(P =0.0001) in male patients. After excluding male patients in the 45–60 age group, the predictive efficiency was enhanced(n = 147,OS, P = 0.0002, TTR, P < 0.0001).Conclusions: Bcl-2 expression is an independent predictor of survival and recurrence in male HCC. Bcl-2 levels may also be regulated by androgens or androgen receptors in male HCC patients. Bcl-2 levels change and exhibit poor predictive efficiency when androgen levels vary dramatically(andropause age).
基金supported by grants from the National Natural Science Foundation of China(81902390)the Major Program of National Natural Science Foundation of China(91959203)the Key Program of the National Natural Science Foundation of China(81930074)。
文摘Primary liver cancer,mainly hepatocellular carcinoma(HCC),is the sixth most diagnosed cancer and third leading cause of cancer-related death globally.Recently,immunotherapies such as immune checkpoint inhibitors(ICIs)have made great progress in the systemic treatment of HCC.However,anti-PD-1 therapy with pembrolizumab or nivolumab as a single agent did not meet their predefined end points of overall survival in the KEYNOTE-240 and Check Mate 459 trials.It is urgent to understand the immunological rationale and explore novel ways to improve the efflcacy of immunotherapy.The combination of ICIs with other therapies,such as tyrosine kinase inhibitors(TKIs),monoclonal antibodies,or local therapy,has been demonstrated to improve overall response rate and survival.In addition,modulating tumor microenvironment is a potential way to overcome the primary and secondary resistance to immunotherapies.In this review,we summarized the latest findings in the immune microenvironment,the mechanisms of their synergistic effects when combined with anti-VEGF agents or TKIs,as well as other kinds of immune treatment.
基金supported by the grants from the National Key Basic Research Program of China (Grant No. 2013CB910500)China National Key Projects for Infectious Disease (Grant No. 2012ZX10002-012)National Natural Science Foundation of China (Grant No. 81372647)
文摘Cancer treatment failure, drug resistance, or metastatic recurrence are thought to be caused mainly by the existence of a very small number of cancer stem cells(CSCs). The characteristics of this subgroup of cells include self-renewal, tumorigenesis, multiple differentiation and high invasiveness, metastasis, and drug resistance potential. Many studies have demonstrated that CSCs play important roles in tumor growth, spread and metastatic relapse after treatment, and are closely related to the prognosis of patients.From a therapeutic viewpoint, deep insights into the CSCs biology, development of specific therapeutic strategies for targeting CSCs, and characterization of their microenvironment could be an ideal way to combat cancer.
文摘Hepatobiliary malignancies include hepatocellular carcinoma(HCC)and biliary tract cancers(BTCs).They are characterized by high heterozygosity,rapid progression,and difflcult to treat[1,2].Recent rapid progress in targeted therapeutic agents has brought new hope for those with advanced HCC[3-5].But there are problems such as lower response rate,or drug resistance(primary or acquired),as well as poor tolerance due to their side-effects,which make this treatment alone still face great challenges.
基金supported by National Key Research and Development Program of China (2023YFC2413200/2023YFC2413201)National Nature Science Foundation of China (NSFC) (No.91959203 and No.81930074)the grant provided by National Research Center for Translational Medicine at Shanghai,Rujin Hospital,Shanghai Jiao Tong University School of Medicine (Shanghai,China) (NRCTM (SH)-2023-03).
文摘Neurotransmitter-initiated signaling pathway were reported to play an important role in regulating the malignant phenotype of tumor cells.Cancer cells could exhibit a"neural addiction"property and build up local nerve networks to achieve an enhanced neurotransmitter-initiated signaling through nerve growth factor-mediated axonogenesis.Targeting the dysregulated nervous systems might represent a novel strategy for cancer treatment.However,whether intrahepatic cholangiocarcinoma(ICC)could build its own nerve networks and the role of neurotransmitters in the progression ICC remains largely unknown.Immunofluorescence staining and Enzyme-linked immunosorbent assay suggested that IcC cells and the infiltrated nerves could generate a tumor microenvironment rich in acetylcholine that promotes IcC metastasis by inducing epithelial-mesenchymal transition(EMT).Acetylcholine promoted iCC metastasis through interacting with its receptor,alpha 5 nicotine acetylcholine receptor subunits(CHRNA5).Furthermore,acetylcholine/CHRNA5 axis activated GSK3β/β-catenin signaling pathway partially through the influx of Ca^(2+)-mediated activation of Ca/calmodulin-dependent protein kinases(CAMKll).In addition,acetylcholine signaling activation also expanded nerve infiltration through increasing the expression of Brain-Derived Neurotrophic Factor(BDNF),which formed a feedforward acetylcholine-BDNF axis to promote ICC progression.KN93,a small-molecule inhibitor of CAMKIll,significantly inhibited the migration and enhanced the sensitivity to gemcitabine of ICC cells.Above all,Acetylcholine/CHRNA5 axis increased the expression ofβ-catenin to promote the metastasis and resistance to gemcitabine of ICC via CAMKIl/GSK3βsignaling,and the CAMKIl inhibitor KN93 may be an effective therapeutic strategy for combating ICC metastasis.
基金funded by National Natural Science Foundation of China(No.82272836).
文摘Evidence-based medicine serves as the cornerstone of modern healthcare.Based on current evidence in the field of evidence-based medicine,a team of authoritative experts in the industry engages in comprehensive discussions to develop expert consensus,following standardized procedures.The consensus serves as a foundation for clinical decision-making.However,the abundance of expert consensus varies in quality,and some viewpoints even contradict each other,leading to confusion in clinical decision-making.
基金This work was supported by the National Natural Science Foundation of China(81902390 and 81902952)the National Key Research and Development Program of China(2017YFC1308604).
文摘Background The efficacy of immune checkpoint inhibitors(ICIs),such as programmed cell death protein-1(PD-1)or its ligand 1(PD-L1)antibody,in hepatocellular carcinoma(HCC)is limited,and it is recommended that they be combined with other therapies.We evaluated the combination of pegylated interferon-α(Peg-IFNα)with PD-1 blockade in HCC mouse models.Methods We analyzed the effects of Peg-IFNαon tumor-infiltrating immune cells and PD-1 expression in the HCC immune microenvironment and examined the underlying mechanism of its unique effect on the PD-1 pathway.The in vivo efficacy of anti-PD-1 and Peg-IFNαwas evaluated in both subcutaneous and orthotopic mouse models of HCC.Results The combination of Peg-IFNαwith PD-1 blockade dramatically enhanced T-cell infiltration,improved the efficacy of PD-1 antibody and prolonged mouse survival compared with PD-1 antibody monotherapy.Mechanistically,Peg-IFNαcould recruit cytotoxic CD8+T cells to infiltrate the HCC microenvironment by inducing tumor cells to secrete the chemokine CCL4.Nevertheless,the HCC microenvironment quickly overcame the immune responses by upregulating PD-1 expression in CD8+T cells via the IFNα-IFNAR1-JAK1-STAT3 signaling pathway.The combination of PD-1 blockade with Peg-IFNαcould restore the cytotoxic capacity of CD8+T cells and exerted a significant synergistic effect on HCC.Conclusion These results indicate that in addition to initiating the antitumor immune response itself,Peg-IFNαcan also generate a microenvironment favoring PD-1 blockade.Thus,the combination of Peg-IFNαand PD-1 blockade can be a promising strategy for HCC.
基金This work was supported by grants from the National Key Project for Infectious Diseases of China(2017ZX10203207)the National Natural Science Foundation of China(81672848,81972703,82072696).
文摘The immunosuppressive microenvironment plays an important role in tumor progression and immunotherapy responses.Golgi membrane protein 1(GOLM1)is correlated to hepatocellular carcinoma(HCC)progression and metastasis.However,little is known about the role of GOLM1 in regulating the immunosuppressive environment and its impact on immunotherapeutic efficacy in HCC.In this study,GOLM1 was positively correlated with infiltrating tumor-associated macrophages(TAMs)expressed high levels of programmed death-ligand 1(PD-L1)and CD8^(+)T cell suppression in HCC tissues.Both gain-and loss-of-function studies determined a close correlation between GOLM1 and immunosuppression.In the mechanism,GOLM1 promoted COP9 signalosome 5-mediated PD-L1 deubiquitination in HCC cells and increased the transport of PD-L1 into exosomes via suppression of Rab27b expression.Furthermore,co-culture with exosomes derived from HCC cells upregulated the expression of PD-L1 on macrophages.Zoledronic acid in combination with anti-PD-L1 therapy reduced PD-L1^(+)TAMs infiltration and alleviated CD8^(+)T cell suppression,resulting in tumor growth inhibition in the mouse HCC model.Together,our study unveils a mechanism by which GOLM1 induces CD8^(+)T cells suppression through promoting PD-L1 stabilization and transporting PD-L1 into TAMs with exosome dependent.Targeting PD-L1^(+)TAM could be a novel strategy to enhance the efficacy of anti-PD-L1 therapy in HCC.
基金This work was supported by the following:the National Key Research and Development Program of China(No.2017YFC1308604)National Natural Science Foundation of China(Nos.81802903,81672820,81940074,and 81872356)+1 种基金the Program of Shanghai Academic Research Leader(No.20XD1400900)the Shanghai International Science and Technology Collaboration Program.
文摘Pancreatic cancer is an increasingly common cause of cancer mortality with a tight correspondence between disease mortality and incidence.Furthermore,it is usually diagnosed at an advanced stage with a very dismal prognosis.Due to the high heterogeneity,metabolic reprogramming,and dense stromal environment associated with pancreatic cancer,patients benefit little from current conventional therapy.Recent insight into the biology and genetics of pancreatic cancer has supported its molecular classification,thus expanding clinical therapeutic options.In this review,we summarize how the biological features of pancreatic cancer and its metabolic reprogramming as well as the tumor microenvironment regulate its development and progression.We further discuss potential biomarkers for pancreatic cancer diagnosis,prediction,and surveillance based on novel liquid biopsies.We also outline recent advances in defining pancreatic cancer subtypes and subtype-specific therapeutic responses and current preclinical therapeutic models.Finally,we discuss prospects and challenges in the clinical development of pancreatic cancer therapeutics.
基金supported by the Program of Shanghai Aca-demic Research Leader(No.20XD1400900)the National Nat-ural Science Foundation of China(Nos.81940074,81772563,and 81672820)+2 种基金the China Postdoctoral Science Founda-tion(No.2017M611459)the Project of Medical Engineering,Fudan University(No.yg2021-017)the“Fuqing Scholar”Student Scientific Research Program of Shanghai Medical Col-lege(No.FQXZ202115B).
文摘Background and Aims:Wound healing and tumor progression share some common biological features;however,how variations in wound healing patterns affect hepatocellular carcinoma(HCC)prognosis remains unclear.Methods:We analyzed the wound healing patterns of 594 HCC samples from The Cancer Genome Atlas(TCGA)and the International Cancer Genome Consortium(ICGC)and correlated them with immune infiltration and the expression levels of immune checkpoint genes.A risk score,which we named the“heal.immune”score,was established via stepwise Cox estimation.We constructed a nomogram based on age,sex,TNM stage,and heal.immune score and explored its predictive value for HCC prognosis.Seventy-four clinical patients were enrolled in this study,and all were from Huashan Hospital of Fudan University between 2015 and 2017 to serve as an independent validation group.Results:We identified two distinct wound healing patterns in HCC.The biological processes of healing cluster 1(C1)are related to metabolism,while those of healing cluster 2(C2)are related to the inflammatory response and immune cell accumulation.A total of 565 wound healing-related genes(based on Gene Ontology)and 25 immune checkpoint genes were considered.By analyzing differentially expressed genes and implementing a stepwise Cox estimation analysis,six genes with p values less than 0.02 in a multivariate Cox estimation were chosen as the“heal.immune”gene set(FCER1G,PLAT,ITGA5,CCNB1,CD86 and CD40).The“heal.immune”gene set,as an OS risk factor,was further validated in Fudan cohort.We constructed a nomogram to predict the 1-,3-and 5-year overall survival(OS)in the TCGA cohort.The area under curve vales of the receiver characteristic operator curves were 0.82,0.76 and 0.73 in the training group and 0.84,0.76 and 0.72 in the test group.Conclusions:We established a prognostic nomogram based on the heal.immune gene signature,which includes six wound healing-and immunity-related genes.This nomogram accurately predicts the OS of HCC patients.
基金This study was supported by National Major Science and Technology Projects of China(No.2017ZX10203207)National Natural Science Foundation of China(No.81472677).
文摘Metastasis and metabolism reprogramming are two major hallmarks of cancer.In the initiation and progression of cancer,tumor cells are known to undergo fundamental metabolic changes to sustain their development and progression.In recent years,much more attentions have been drawn to their important roles in facilitating cancer metastasis through regulating the biological properties.In this review,we summarized the recent progresses in the studies of metabolism reprogramming of cancer metastasis,particularly of primary liver cancer,and highlight their potential applications.
基金National Natural Science Foundation of China(No.82272836).
文摘Background:The judgment of the division point of the bile duct has always been one of the difficulties of laparoscopic left lateral sectionectomy(LLLS).The purpose of this study was to assess the effects of indocyanine green(ICG)fluorescence cholangiography during LLLS on the occurrence of biliary complications in both donors and recipients.The optimal dose and injection time of ICG were also investigated.Methods:This is a retrospective cohort study.From October 2016 to December 2022,the clinical data of 103 donors who underwent LLLS and relevant recipients were retrospectively analyzed.According to whether ICG fluorescence cholangiography was used,they were divided into a non-ICG group(n=46)and an ICG group(n=57).Biliary complications were observed and the optimal dose and injection time of ICG were explored.Results:Three donors in the non-ICG group suffered from bile leakage.Four grafts had multiple bile duct openings and biliary complications were observed in the relevant recipients who received these grafts in the non-ICG group.Two recipients had bile leakage,and the other two had biliary stenosis.There was no biliary complications both in donors and recipients in the ICG group.The fluorescence intensity of the liver was 108.1±17.6 at a dose of 0.004 mg/kg 90 minutes after injection,significantly weaker than that at 0.05 mg/kg 30 minutes(200.3±17.6,P=0.001)and 90 minutes after injection(140.2±15.4,P=0.001).The fluorescence intensity contrast value at a dose of 0.004 mg/kg was stronger than that at 0.05 mg/kg,both measured 90 minutes after injection(0.098±0.032 vs.0.078±0.022,P=0.021).Conclusions:ICG fluorescence cholangiography is safe and feasible in LLLS.It reduces biliary complications in both donors and recipients.The optimal ICG dose was 0.004 mg/kg,and 90 minutes after injection was the best observation time.ICG fluorescence cholangiography is recommended for routine use in LLLS.
