BACKGROUND Programmed death receptor-1(PD-1)inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC),but it is still worth studying whether patients can benefit from PD-1 inhibito...BACKGROUND Programmed death receptor-1(PD-1)inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC),but it is still worth studying whether patients can benefit from PD-1 inhibitors as first-line drugs combined with targeted drugs and locoregional therapy.AIM To estimate the clinical outcome of transarterial chemoembolization(TACE)and lenvatinib plus PD-1 inhibitors for patients with unresectable HCC(uHCC).METHODS We carried out retrospective research of 65 patients with uHCC who were treated at Peking Union Medical College Hospital from September 2017 to February 2022.45 patients received the PD-1 inhibitors,lenvatinib,TACE(PD-1-Lenv-T)therapy,and 20 received the lenvatinib,TACE(Lenv-T)therapy.In terms of the dose of lenvatinib,8 mg was given orally for patients weighing less than 60 kg and 12 mg for those weighing more than 60 kg.Of the patients in the PD-1 inhibitor combination group,15 received Toripalimab,14 received Toripalimab,14 received Camrelizumab,4 received Pembrolizumab,9 received Sintilimab,and 2 received Nivolumab,1 with Tislelizumab.According to the investigators’assessment,TACE was performed every 4-6 wk when the patient had good hepatic function(Child-Pugh class A or B)until disease progression occurred.We evaluated the efficacy by the modified Response Evaluation Criteria in Solid Tumors(mRECIST criteria).We accessd the safety by the National Cancer Institute Common Terminology Criteria for Adverse Events,v 5.0.The key adverse events(AEs)after the initiation of combination therapy were observed.RESULTS Patients with uHCC who received PD-1-Lenv-T therapy(n=45)had a clearly longer overall survival than those who underwent Lenv-T therapy(n=20,26.8 vs 14.0 mo;P=0.027).The median progression-free survival time between the two treatment regimens was also measured{11.7 mo[95%confidence interval(CI):7.7-15.7]in the PD-1-Lenv-T group vs 8.5 mo(95%CI:3.0-13.9)in the Lenv-T group(P=0.028)}.The objective response rates of the PD-1-Lenv-T group and Lenv-T group were 44.4%and 20%(P=0.059)according to the mRECIST criteria,meanwhile the disease control rates were 93.3%and 64.0%(P=0.003),respectively.The type and frequency of AEs showed little distinction between patients received the two treatment regimens.CONCLUSION Our results suggest that the early combination of PD-1 inhibitors has manageable toxicity and hopeful efficacy in patients with uHCC.展开更多
BACKGROUND Oral cancer(OC)is the most common malignant tumor in the oral cavity,and is mainly seen in middle-aged and elderly men.At present,OC is mainly treated clinically by surgery or combined with radiotherapy and...BACKGROUND Oral cancer(OC)is the most common malignant tumor in the oral cavity,and is mainly seen in middle-aged and elderly men.At present,OC is mainly treated clinically by surgery or combined with radiotherapy and chemotherapy;but recently,more and more studies have shown that the stress trauma caused by surgery and the side effects of radiotherapy and chemotherapy seriously affect the prognosis of patients.AIM To determine the significance of 125I radioactive seed implantation on growth differentiation factor 11(GDF11)and programmed death receptor-1(PD-1)during treatment of OC.METHODS A total of 184 OC patients admitted to The Second Affiliated Hospital of Jiamusi University from May 2015 to May 2017 were selected as the research subjects for prospective analysis.Of these patients,89 who received 125I radioactive seed implantation therapy were regarded as the research group(RG)and 95 patients who received surgical treatment were regarded as the control group(CG).The clinical efficacy,incidence of adverse reactions and changes in GDF11 and PD-1 before treatment(T0),2 wk after treatment(T1),4 wk after treatment(T2)and 6 wk after treatment(T3)were compared between the two groups.RESULTS The efficacy and recurrence rate in the RG were better than those in the CG(P<0.05),while the incidence of adverse reactions and survival rate were not different.There was no difference in GDF11 and PD-1 between the two groups at T0 and T1,but these factors were lower in the RG than in the CG at T2 and T3(P<0.05).Using receiver operating characteristic(ROC)curve analysis,GDF11 and PD-1 had good predictive value for efficacy and recurrence(P<0.001).CONCLUSION 125I radioactive seed implantation has clinical efficacy and can reduce the recurrence rate in patients with OC.This therapy has marked potential in clinical application.The detection of GDF11 and PD-1 in patients during treatment showed good predictive value for treatment efficacy and recurrence in OC patients,and may be potential targets for future OC treatment.展开更多
BACKGROUND Nucleus accumbens-1(NAC-1)is highly expressed in a variety of tumors,including colon cancer,and is closely associated with tumor recurrence,metastasis,and invasion.AIM To determine whether and how NAC-1 aff...BACKGROUND Nucleus accumbens-1(NAC-1)is highly expressed in a variety of tumors,including colon cancer,and is closely associated with tumor recurrence,metastasis,and invasion.AIM To determine whether and how NAC-1 affects antitumor immunity in colon cancer.METHODS NAC-1-siRNA was transfected into RKO colon cancer cells to knock down NAC expression;tumor cells with or without knockdown of NAC-1 were treated with CD8+T cells to test their cytocidal effect.The level of the immune checkpoint programmed death receptor-1 ligand(PD-L1)in colon cancer cells with or without knockdown of NAC-1 was analyzed using Quantitative real-time polymerase chain reaction and Western blotting.A double luciferase reporter assay was used to examine the effects of NAC-1 on the transcription of PD-L1.Mice bearing MC-38-OVA colon cancer cells expressing NAC-shRNA or controlshRNA were treated with OT-I mouse CD8+T cells to determine the tumor response to immunotherapy.Immune cells in the tumor tissues were analyzed using flow cytometry.NAC-1,PD-L1 and CD8+T cells in colon cancer specimens from patients were examined using immunohistochemistry staining.RESULTS Knockdown of NAC-1 expression in colon cancer cells significantly enhanced the cytocidal effect of CD8+T cells in cell culture experiments.The sensitizing effect of NAC-1 knockdown on the antitumor action of cytotoxic CD8+T cells was recapitulated in a colon cancer xenograft animal model.Furthermore,knockdown of NAC-1 in colon cancer cells decreased the expression of PD-L1 at both the mRNA and protein levels,and this effect could be rescued by transfection of an RNAi-resistant NAC-1 expression plasmid.In a reporter gene assay,transient expression of NAC-1 in colon cancer cells increased the promoter activity of PD-L1,indicating that NAC-1 regulates PD-L1 expression at the transcriptional level.In addition,depletion of tumoral NAC-1 increased the number of CD8+T cells but decreased the number of suppressive myeloid-derived suppressor cells and regulatory T cells.CONCLUSION Tumor expression of NAC-1 is a negative determinant of immunotherapy.展开更多
In recent years,immune checkpoint blockade(ICB)therapy has become an important treatment strategy for gastrointestinal tumors,however,it only benefits about 1/3 of patients.Since the microbiome has been shown to play ...In recent years,immune checkpoint blockade(ICB)therapy has become an important treatment strategy for gastrointestinal tumors,however,it only benefits about 1/3 of patients.Since the microbiome has been shown to play an important role in the human body for a long time,a growing number of studies are focusing on its relationship to ICB therapy in cancer,specifically how intestinal microbes affect the efficacy of immune checkpoint inhibitors(ICIs)therapy in patients.On this basis,probiotic interventions,fecal microbiota transplantation(FMT),dietary interventions,and other methods which improve or maintain the structure of the intestinal flora have attracted widespread attention.This article discusses the four aspects of the microbiome,ICB,combined treatment of gastrointestinal tumors,and regulation of gut microbiome.Particularly,the discussion focuses on the contribution of probiotic intervention in improving the therapeutic effect of ICIs to prolong the survival time of patients and reduce the severity of immune-related adverse effects(irAEs).展开更多
Recent advances in pharmacological immune modulation against tumor cells has dramatically changed the paradigm of cancer treatment.Checkpoint inhibitor therapy is a form of cancer immunotherapy already in clinical set...Recent advances in pharmacological immune modulation against tumor cells has dramatically changed the paradigm of cancer treatment.Checkpoint inhibitor therapy is a form of cancer immunotherapy already in clinical setting but also under active basic and clinical investigation.Nevertheless,some patients are primary unresponsive or develop ulterior resistance to these family of drugs.This review aims to update the basic molecular mechanism of resistance as well as the current strategies for checkpoint inhibitor selection in order to propose new approaches to individualize the use of these novel therapies.展开更多
基金Supported by Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences,No.2021-I2M-1-061 and 2021-I2M-1-003Chinese Society of Clinical Oncology-Hengrui Cancer Research Fund,No.Y-HR2019-0239+1 种基金Chinese Society of Clinical Oncology-MSD Cancer Research Fund,No.Y-MSDZD2021-0213National Ten-thousand Talent Program.
文摘BACKGROUND Programmed death receptor-1(PD-1)inhibitors have been approved as secondline treatment regimen in hepatocellular carcinoma(HCC),but it is still worth studying whether patients can benefit from PD-1 inhibitors as first-line drugs combined with targeted drugs and locoregional therapy.AIM To estimate the clinical outcome of transarterial chemoembolization(TACE)and lenvatinib plus PD-1 inhibitors for patients with unresectable HCC(uHCC).METHODS We carried out retrospective research of 65 patients with uHCC who were treated at Peking Union Medical College Hospital from September 2017 to February 2022.45 patients received the PD-1 inhibitors,lenvatinib,TACE(PD-1-Lenv-T)therapy,and 20 received the lenvatinib,TACE(Lenv-T)therapy.In terms of the dose of lenvatinib,8 mg was given orally for patients weighing less than 60 kg and 12 mg for those weighing more than 60 kg.Of the patients in the PD-1 inhibitor combination group,15 received Toripalimab,14 received Toripalimab,14 received Camrelizumab,4 received Pembrolizumab,9 received Sintilimab,and 2 received Nivolumab,1 with Tislelizumab.According to the investigators’assessment,TACE was performed every 4-6 wk when the patient had good hepatic function(Child-Pugh class A or B)until disease progression occurred.We evaluated the efficacy by the modified Response Evaluation Criteria in Solid Tumors(mRECIST criteria).We accessd the safety by the National Cancer Institute Common Terminology Criteria for Adverse Events,v 5.0.The key adverse events(AEs)after the initiation of combination therapy were observed.RESULTS Patients with uHCC who received PD-1-Lenv-T therapy(n=45)had a clearly longer overall survival than those who underwent Lenv-T therapy(n=20,26.8 vs 14.0 mo;P=0.027).The median progression-free survival time between the two treatment regimens was also measured{11.7 mo[95%confidence interval(CI):7.7-15.7]in the PD-1-Lenv-T group vs 8.5 mo(95%CI:3.0-13.9)in the Lenv-T group(P=0.028)}.The objective response rates of the PD-1-Lenv-T group and Lenv-T group were 44.4%and 20%(P=0.059)according to the mRECIST criteria,meanwhile the disease control rates were 93.3%and 64.0%(P=0.003),respectively.The type and frequency of AEs showed little distinction between patients received the two treatment regimens.CONCLUSION Our results suggest that the early combination of PD-1 inhibitors has manageable toxicity and hopeful efficacy in patients with uHCC.
基金Supported by Heilongjiang Provincial Health and Family Planning Commission Research Project,No.2017-413
文摘BACKGROUND Oral cancer(OC)is the most common malignant tumor in the oral cavity,and is mainly seen in middle-aged and elderly men.At present,OC is mainly treated clinically by surgery or combined with radiotherapy and chemotherapy;but recently,more and more studies have shown that the stress trauma caused by surgery and the side effects of radiotherapy and chemotherapy seriously affect the prognosis of patients.AIM To determine the significance of 125I radioactive seed implantation on growth differentiation factor 11(GDF11)and programmed death receptor-1(PD-1)during treatment of OC.METHODS A total of 184 OC patients admitted to The Second Affiliated Hospital of Jiamusi University from May 2015 to May 2017 were selected as the research subjects for prospective analysis.Of these patients,89 who received 125I radioactive seed implantation therapy were regarded as the research group(RG)and 95 patients who received surgical treatment were regarded as the control group(CG).The clinical efficacy,incidence of adverse reactions and changes in GDF11 and PD-1 before treatment(T0),2 wk after treatment(T1),4 wk after treatment(T2)and 6 wk after treatment(T3)were compared between the two groups.RESULTS The efficacy and recurrence rate in the RG were better than those in the CG(P<0.05),while the incidence of adverse reactions and survival rate were not different.There was no difference in GDF11 and PD-1 between the two groups at T0 and T1,but these factors were lower in the RG than in the CG at T2 and T3(P<0.05).Using receiver operating characteristic(ROC)curve analysis,GDF11 and PD-1 had good predictive value for efficacy and recurrence(P<0.001).CONCLUSION 125I radioactive seed implantation has clinical efficacy and can reduce the recurrence rate in patients with OC.This therapy has marked potential in clinical application.The detection of GDF11 and PD-1 in patients during treatment showed good predictive value for treatment efficacy and recurrence in OC patients,and may be potential targets for future OC treatment.
基金the Changsha Municipal Natural Science Foundation,No.kq2014258.
文摘BACKGROUND Nucleus accumbens-1(NAC-1)is highly expressed in a variety of tumors,including colon cancer,and is closely associated with tumor recurrence,metastasis,and invasion.AIM To determine whether and how NAC-1 affects antitumor immunity in colon cancer.METHODS NAC-1-siRNA was transfected into RKO colon cancer cells to knock down NAC expression;tumor cells with or without knockdown of NAC-1 were treated with CD8+T cells to test their cytocidal effect.The level of the immune checkpoint programmed death receptor-1 ligand(PD-L1)in colon cancer cells with or without knockdown of NAC-1 was analyzed using Quantitative real-time polymerase chain reaction and Western blotting.A double luciferase reporter assay was used to examine the effects of NAC-1 on the transcription of PD-L1.Mice bearing MC-38-OVA colon cancer cells expressing NAC-shRNA or controlshRNA were treated with OT-I mouse CD8+T cells to determine the tumor response to immunotherapy.Immune cells in the tumor tissues were analyzed using flow cytometry.NAC-1,PD-L1 and CD8+T cells in colon cancer specimens from patients were examined using immunohistochemistry staining.RESULTS Knockdown of NAC-1 expression in colon cancer cells significantly enhanced the cytocidal effect of CD8+T cells in cell culture experiments.The sensitizing effect of NAC-1 knockdown on the antitumor action of cytotoxic CD8+T cells was recapitulated in a colon cancer xenograft animal model.Furthermore,knockdown of NAC-1 in colon cancer cells decreased the expression of PD-L1 at both the mRNA and protein levels,and this effect could be rescued by transfection of an RNAi-resistant NAC-1 expression plasmid.In a reporter gene assay,transient expression of NAC-1 in colon cancer cells increased the promoter activity of PD-L1,indicating that NAC-1 regulates PD-L1 expression at the transcriptional level.In addition,depletion of tumoral NAC-1 increased the number of CD8+T cells but decreased the number of suppressive myeloid-derived suppressor cells and regulatory T cells.CONCLUSION Tumor expression of NAC-1 is a negative determinant of immunotherapy.
基金supported by grants from the National Natural Science Foundation of China(No.82002619)Shanxi Science and Technology Project(No.202204041101042 and 202204051001031)the Key Medical Research Projects of Shanxi Province(No.2020XM55)。
文摘In recent years,immune checkpoint blockade(ICB)therapy has become an important treatment strategy for gastrointestinal tumors,however,it only benefits about 1/3 of patients.Since the microbiome has been shown to play an important role in the human body for a long time,a growing number of studies are focusing on its relationship to ICB therapy in cancer,specifically how intestinal microbes affect the efficacy of immune checkpoint inhibitors(ICIs)therapy in patients.On this basis,probiotic interventions,fecal microbiota transplantation(FMT),dietary interventions,and other methods which improve or maintain the structure of the intestinal flora have attracted widespread attention.This article discusses the four aspects of the microbiome,ICB,combined treatment of gastrointestinal tumors,and regulation of gut microbiome.Particularly,the discussion focuses on the contribution of probiotic intervention in improving the therapeutic effect of ICIs to prolong the survival time of patients and reduce the severity of immune-related adverse effects(irAEs).
基金We are grateful for the financial support from the“Fondo de Investigaciones Sanitarias”(PI17/01489)the Miguel Servet Program(CPII16/00056)del Instituto de Salud Carlos IIIthe Ministerio de Economía y Competitividad-FEDERER(RTC-2016-4990-1,RTC-2015-3846-1).
文摘Recent advances in pharmacological immune modulation against tumor cells has dramatically changed the paradigm of cancer treatment.Checkpoint inhibitor therapy is a form of cancer immunotherapy already in clinical setting but also under active basic and clinical investigation.Nevertheless,some patients are primary unresponsive or develop ulterior resistance to these family of drugs.This review aims to update the basic molecular mechanism of resistance as well as the current strategies for checkpoint inhibitor selection in order to propose new approaches to individualize the use of these novel therapies.
