Objective:Sarcomas are a group of rare malignancies with various subtypes.Patients with metastatic sarcoma who have failed traditional treatments can possibly achieve better prognoses from using novel therapies,includ...Objective:Sarcomas are a group of rare malignancies with various subtypes.Patients with metastatic sarcoma who have failed traditional treatments can possibly achieve better prognoses from using novel therapies,including anti-programmed death-1(PD-1)-based therapies.Methods:We retrospectively analyzed clinical data of 24 metastatic sarcoma patients from June 15,2016 to December 30,2019.These patients mainly received angiogenesis inhibitors combined with anti-PD-1 therapy after they became resistant to traditional treatments.Furthermore,8 patients underwent panel DNA and whole transcript sequencing.Results:Six patients received 2 cycles of anti-PD-1 therapy and were included in the safety evaluation only group.The median follow-up time was 5.77 months.The median progression-free survival was 7.59 months,the overall response rate was 16.7%and the disease control rate was 55.6%.Based on whole exome and transcript sequencing data,there was no association between TMB,TNB,MSI,HLA-LOH,and PD-L1 expressions and sarcoma types with clinical responses.Immunotherapy efficacy and bioinformatics analyses indicated higher intratumoral heterogeneity(ITH)in progressive disease(PD)patients and lower ITH in partial response(PR)and stable disease patients.A higher percentage of immune cell infiltration,especially monocytes,was observed in PR patients.Active stromal gene expression was increased in PD patients but decreased in PR patients.Enrichment analysis revealed that an increased TGF-βsignaling pathway was reversely correlated with anti-PD-1 efficacy,while a decreased inflammatory response signaling pathway was positively correlated with anti-PD-1 efficacy.Conclusions:Our study showed PD-1 inhibitors combined with anti-angiogenesis agents were effective and well-tolerated.ITH,monocyte ratio,stroma subtypes,and the status of immune-associated signaling pathways may be related with anti-PD-1 based therapy.展开更多
The publisher regrets that some of the authors’affiliations were mistakenly annotated in the manuscript.Hence,the authors of the below article were contacted after publication to request a correction of the author af...The publisher regrets that some of the authors’affiliations were mistakenly annotated in the manuscript.Hence,the authors of the below article were contacted after publication to request a correction of the author affliction and responded with the correct by the time this erratum is being published.展开更多
Background:Small cell lung cancer(SCLC)transformation had previously been reported mainly in epidermal growth factor receptor(EGFR)mutant adenocarcinoma.However,the underlying genomic profile remains un-clear.Our stud...Background:Small cell lung cancer(SCLC)transformation had previously been reported mainly in epidermal growth factor receptor(EGFR)mutant adenocarcinoma.However,the underlying genomic profile remains un-clear.Our study aimed to find the evolution and genotypic characteristic of SCLC transformation.Methods:Thirty-one SCLC transformation patients who were initially diagnosed as non-small cell lung cancer(NSCLC)patients were included.Whole exome sequencing(WES)of both primary and transformed re-biopsy lesions was conducted on 12 patients.Clinical characteristics were analyzed using R software(v.3.6.1).Results:Our study included 31 patients,of whom,three had lung squamous cell carcinoma,6 patients did not carry EGFR mutations,and 30 patients received chemotherapy for SCLCs.The disease control rate(DCR)was 96.7%,and the median progression-free survival(PFS)was 4.03 months.The median time to transformation was 33.07 months,and the median overall survival(OS)was 62.08 months.Somatic mutation analysis showed that besides TP53,RB1,and EGFR,there was a high occurrence of mutations to CSMD3 and ADAMTS19,espe-cially in the EGFR-wild type(EGFR-wt)group.Concerning mutational signature,the EGFR-mutant(EGFR-mut)transformed group favored an apolipoprotein B(APOBEC)mRNA editing catalytic polypeptide-like-associated mutation pattern(P=0.16).DNA damage repair(DDR)-related signatures were significantly enriched in the EGFR-wt transformed group(P=0.034).Additionally,clonal evolution analysis revealed that all patients had the same main trunk genes in the phylogenetic tree.Transformed SCLCs are not sensitive to immunotherapy,possibly due to increased tumor heterogeneity.Conclusions:Our results indicate that the EGFR-wt patients could also transform to SCLCs,but they have different genetic features with EGFR-mut patients.SCLC-transformed patients respond to classical chemotherapy and have a better prognosis than those with classical SCLCs.展开更多
The clinical benefit of neoadjuvant immunochemotherapy in locally advanced cervical cancer(LAcC)remains unclear.This singlearm,phase Ⅱ study(Chinese Clinical Trial Registry,ChiCTR2200065392)aimed to evaluate the effi...The clinical benefit of neoadjuvant immunochemotherapy in locally advanced cervical cancer(LAcC)remains unclear.This singlearm,phase Ⅱ study(Chinese Clinical Trial Registry,ChiCTR2200065392)aimed to evaluate the efficacy and safety of neoadjuvant anti-programmed cell death protein 1(PD-1)antibody tislelizumab in combination with chemotherapy in treatment-naive patients with stage IB3/IIA2 LACC.Enrolled patients received tislelizumab(200 mg,every 3 weeks)plus chemotherapy for 3 cycles before radical surgery.The primary endpoint was the pathological complete response(pCR).Secondary endpoints were objective response rate(ORR)per Response Evaluation Criteria in Solid Tumors version 1.1,disease-free survival,overall survival,and safety.Exploratory endpoints included tissue-based and blood-based biomarkers to identify the biological drivers behind the clinical outcomes.Between November 2022 and March 2024,30 patients were enrolled.All patients completed 3 cycles of neoadjuvant immunochemotherapy and underwent radical surgery.The pCR was observed in 20(66.7%)patients,and 4(13.3%)patients achieved major pathological response(MPR),with an optimal pathological response rate(OPR)of 80.0%.The ORR was 90.0%,with 17(56.7%)complete responses.Survival data were immature at the median follow-up of 14.7 months(data cutoff,December 31,2024).Grade 3 treatment-related adverse events(TRAEs)and immune-related AEs occurred in 26.7%and 3.3%of patients,respectively.No treatment-related death occurred.Patients with pCR had significantly higher expression of PD-L1 CPS at baseline,and a strong relationship with immune-related signature(all p<0.05).Neoadjuvant tislelizumab plus chemotherapy showed promising antitumor efficacy and a well-tolerated safety profle in patients with stage IB3/IIA2 LACC,and might be a potential option in this population.展开更多
We present the case of a 59-year-old Chinese man diagnosed with stage III clear cell renal cell carcinoma who developed 2 suspicious lung lesions 5 years after follow-up.Pathological evaluation revealed 2 distinct typ...We present the case of a 59-year-old Chinese man diagnosed with stage III clear cell renal cell carcinoma who developed 2 suspicious lung lesions 5 years after follow-up.Pathological evaluation revealed 2 distinct types of cancer:lung adenocarcinoma in situ and clear cell renal carcinoma with lung metastasis.Lung tissue samples were sequenced using a panel of 1267 cancer-related genes.The analysis revealed completely different molecular profiles between the 2 lung lesions and similar clonal mutations in the superior lingular lobe and kidney.This indicates multiple metachronous primary tumors.展开更多
Neoantigens are considered to be ultimate target of tumor immunotherapy due to their high tumor specificity and immunogenicity.Dendritic cell(DCs)vaccines based on neoantigens have exciting effects in treatment of som...Neoantigens are considered to be ultimate target of tumor immunotherapy due to their high tumor specificity and immunogenicity.Dendritic cell(DCs)vaccines based on neoantigens have exciting effects in treatment of some malignant tumors and are a promising therapeutic modality.Lung cancer is a lethal disease with the highest morbidity and mortality rate in the world.Despite the rapid development of targeted therapy and immune checkpoint inhibitors for lung cancer in recent years,their efficacy is still unsatisfactory overall.Therefore,there is an urgent unmet clinical need for lung cancer treatment.Here,we attempted to treat lung cancer using a personalized neoantigen peptide-pulsed autologous DC vaccine and conducted a single-arm,2 medical centers,pilot study initiated by the investigator(ChiCTR-ONC 16009100,NCT02956551).The patients enrolled were patients with heavily treated metastatic lung cancer.Candidate neoantigens were derived from whole-exome sequencing and RNA sequencing of fresh biopsy tissues as well as bioinformatics analysis.A total of 12 patients were enrolled in this study.A total of 85 vaccine treatments were administered with a median value of 5 doses/person(range:3-14 doses/person).In total,12-30 peptide-based neoantigens were selected for each patient.AIl treatment-related adverse events were grade 1-2 and there were no delays in dosing due to toxic effects.The objective effectiveness rate was 25%;the disease control rate was 75%;the median progression-free survival was 5.5 months and the median overall survival was 7.9 months.This study provides new evidence for neoantigen vaccine therapy and new therapeutic opportunities for lung cancer treatment.展开更多
The incidence of multiple primary malignancies(MPMs)has been increasing rapidly in recent years,however,the genetic pathogenesis is largely unknown on account of rare cases,especially for those patients who are diagno...The incidence of multiple primary malignancies(MPMs)has been increasing rapidly in recent years,however,the genetic pathogenesis is largely unknown on account of rare cases,especially for those patients who are diagnosed with three or more tumors.Under these circumstances,whole-exome sequencing(WES)may help to provide more comprehensive genomic information and guidance to proper therapeutic strategies.Here,we presented a rare case of a 66-year-old Chinese male patient who was diagnosed with synchronous triple primary malignancies:esophageal squamous cell carcinoma(ESCC),lung adenocarcinoma(LA),and hepatocellular carcinoma(HCC).Tumors were surgically removed within 3 months.WES was performed when the patient suffered from cancer recurrence and tumor-specific neoantigens were predicted.Each tumor displayed a distinct somatic mutation profile,providing direct evidence of independent origins.No shared driver gene mutation or neoantigen was detected among the three tumors.Two germline alterations of cancer susceptibility genes—SPINK1 c.194+2T>C and JAK3 c.425G>A were identified.This case is the first report of synchronous primary triple cancers covering the esophagus,lung,and liver.Our findings highlight the complexities of MPMs that even when under identical germline genetic backgrounds,the occurrence of MPMs can be a random event and driven by distinct somatic gene mutations.Synchronous multiple primary cancers that originated from different organs may not have common therapeutic gene targets,and it can be difficult to find a treatment to cover all the tumors.展开更多
文摘Objective:Sarcomas are a group of rare malignancies with various subtypes.Patients with metastatic sarcoma who have failed traditional treatments can possibly achieve better prognoses from using novel therapies,including anti-programmed death-1(PD-1)-based therapies.Methods:We retrospectively analyzed clinical data of 24 metastatic sarcoma patients from June 15,2016 to December 30,2019.These patients mainly received angiogenesis inhibitors combined with anti-PD-1 therapy after they became resistant to traditional treatments.Furthermore,8 patients underwent panel DNA and whole transcript sequencing.Results:Six patients received 2 cycles of anti-PD-1 therapy and were included in the safety evaluation only group.The median follow-up time was 5.77 months.The median progression-free survival was 7.59 months,the overall response rate was 16.7%and the disease control rate was 55.6%.Based on whole exome and transcript sequencing data,there was no association between TMB,TNB,MSI,HLA-LOH,and PD-L1 expressions and sarcoma types with clinical responses.Immunotherapy efficacy and bioinformatics analyses indicated higher intratumoral heterogeneity(ITH)in progressive disease(PD)patients and lower ITH in partial response(PR)and stable disease patients.A higher percentage of immune cell infiltration,especially monocytes,was observed in PR patients.Active stromal gene expression was increased in PD patients but decreased in PR patients.Enrichment analysis revealed that an increased TGF-βsignaling pathway was reversely correlated with anti-PD-1 efficacy,while a decreased inflammatory response signaling pathway was positively correlated with anti-PD-1 efficacy.Conclusions:Our study showed PD-1 inhibitors combined with anti-angiogenesis agents were effective and well-tolerated.ITH,monocyte ratio,stroma subtypes,and the status of immune-associated signaling pathways may be related with anti-PD-1 based therapy.
文摘The publisher regrets that some of the authors’affiliations were mistakenly annotated in the manuscript.Hence,the authors of the below article were contacted after publication to request a correction of the author affliction and responded with the correct by the time this erratum is being published.
基金supported by the Beijing Municipal Administration of Hospitals Incubating Program(PX2019038,PX2020044)Beijing Youth Program for Outstanding Talents(2018000021469G262)+3 种基金National Key Research and Development Project(2019YFC1315700)NSFC Key Program(81630071)NSFC General Program(81871889,81972905)CAMS Key Lab of Translational Research on Lung Cancer(2018PT31035)and Aiyou Foundation(KY201701).
文摘Background:Small cell lung cancer(SCLC)transformation had previously been reported mainly in epidermal growth factor receptor(EGFR)mutant adenocarcinoma.However,the underlying genomic profile remains un-clear.Our study aimed to find the evolution and genotypic characteristic of SCLC transformation.Methods:Thirty-one SCLC transformation patients who were initially diagnosed as non-small cell lung cancer(NSCLC)patients were included.Whole exome sequencing(WES)of both primary and transformed re-biopsy lesions was conducted on 12 patients.Clinical characteristics were analyzed using R software(v.3.6.1).Results:Our study included 31 patients,of whom,three had lung squamous cell carcinoma,6 patients did not carry EGFR mutations,and 30 patients received chemotherapy for SCLCs.The disease control rate(DCR)was 96.7%,and the median progression-free survival(PFS)was 4.03 months.The median time to transformation was 33.07 months,and the median overall survival(OS)was 62.08 months.Somatic mutation analysis showed that besides TP53,RB1,and EGFR,there was a high occurrence of mutations to CSMD3 and ADAMTS19,espe-cially in the EGFR-wild type(EGFR-wt)group.Concerning mutational signature,the EGFR-mutant(EGFR-mut)transformed group favored an apolipoprotein B(APOBEC)mRNA editing catalytic polypeptide-like-associated mutation pattern(P=0.16).DNA damage repair(DDR)-related signatures were significantly enriched in the EGFR-wt transformed group(P=0.034).Additionally,clonal evolution analysis revealed that all patients had the same main trunk genes in the phylogenetic tree.Transformed SCLCs are not sensitive to immunotherapy,possibly due to increased tumor heterogeneity.Conclusions:Our results indicate that the EGFR-wt patients could also transform to SCLCs,but they have different genetic features with EGFR-mut patients.SCLC-transformed patients respond to classical chemotherapy and have a better prognosis than those with classical SCLCs.
基金supported by the 358 program Clinical Trial Fund of Tianjin Cancer Hospital(Grant No.TZ3582023-010)the National Natural Science Foundation of China(Grant No.82202863)。
文摘The clinical benefit of neoadjuvant immunochemotherapy in locally advanced cervical cancer(LAcC)remains unclear.This singlearm,phase Ⅱ study(Chinese Clinical Trial Registry,ChiCTR2200065392)aimed to evaluate the efficacy and safety of neoadjuvant anti-programmed cell death protein 1(PD-1)antibody tislelizumab in combination with chemotherapy in treatment-naive patients with stage IB3/IIA2 LACC.Enrolled patients received tislelizumab(200 mg,every 3 weeks)plus chemotherapy for 3 cycles before radical surgery.The primary endpoint was the pathological complete response(pCR).Secondary endpoints were objective response rate(ORR)per Response Evaluation Criteria in Solid Tumors version 1.1,disease-free survival,overall survival,and safety.Exploratory endpoints included tissue-based and blood-based biomarkers to identify the biological drivers behind the clinical outcomes.Between November 2022 and March 2024,30 patients were enrolled.All patients completed 3 cycles of neoadjuvant immunochemotherapy and underwent radical surgery.The pCR was observed in 20(66.7%)patients,and 4(13.3%)patients achieved major pathological response(MPR),with an optimal pathological response rate(OPR)of 80.0%.The ORR was 90.0%,with 17(56.7%)complete responses.Survival data were immature at the median follow-up of 14.7 months(data cutoff,December 31,2024).Grade 3 treatment-related adverse events(TRAEs)and immune-related AEs occurred in 26.7%and 3.3%of patients,respectively.No treatment-related death occurred.Patients with pCR had significantly higher expression of PD-L1 CPS at baseline,and a strong relationship with immune-related signature(all p<0.05).Neoadjuvant tislelizumab plus chemotherapy showed promising antitumor efficacy and a well-tolerated safety profle in patients with stage IB3/IIA2 LACC,and might be a potential option in this population.
文摘We present the case of a 59-year-old Chinese man diagnosed with stage III clear cell renal cell carcinoma who developed 2 suspicious lung lesions 5 years after follow-up.Pathological evaluation revealed 2 distinct types of cancer:lung adenocarcinoma in situ and clear cell renal carcinoma with lung metastasis.Lung tissue samples were sequenced using a panel of 1267 cancer-related genes.The analysis revealed completely different molecular profiles between the 2 lung lesions and similar clonal mutations in the superior lingular lobe and kidney.This indicates multiple metachronous primary tumors.
基金We gratefully acknowledge all patients who participated and their families,as well as the investigators and staff at this cdinical study for their valuable contribution to this study.This study was supported by the National key research and development program of China(Grant number 2016YFC1303502)the 1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University.
文摘Neoantigens are considered to be ultimate target of tumor immunotherapy due to their high tumor specificity and immunogenicity.Dendritic cell(DCs)vaccines based on neoantigens have exciting effects in treatment of some malignant tumors and are a promising therapeutic modality.Lung cancer is a lethal disease with the highest morbidity and mortality rate in the world.Despite the rapid development of targeted therapy and immune checkpoint inhibitors for lung cancer in recent years,their efficacy is still unsatisfactory overall.Therefore,there is an urgent unmet clinical need for lung cancer treatment.Here,we attempted to treat lung cancer using a personalized neoantigen peptide-pulsed autologous DC vaccine and conducted a single-arm,2 medical centers,pilot study initiated by the investigator(ChiCTR-ONC 16009100,NCT02956551).The patients enrolled were patients with heavily treated metastatic lung cancer.Candidate neoantigens were derived from whole-exome sequencing and RNA sequencing of fresh biopsy tissues as well as bioinformatics analysis.A total of 12 patients were enrolled in this study.A total of 85 vaccine treatments were administered with a median value of 5 doses/person(range:3-14 doses/person).In total,12-30 peptide-based neoantigens were selected for each patient.AIl treatment-related adverse events were grade 1-2 and there were no delays in dosing due to toxic effects.The objective effectiveness rate was 25%;the disease control rate was 75%;the median progression-free survival was 5.5 months and the median overall survival was 7.9 months.This study provides new evidence for neoantigen vaccine therapy and new therapeutic opportunities for lung cancer treatment.
基金This work was funded by the Sichuan Science and Technology Program(Grant No.2019YJ0022)from Sichuan Provincial Science and Technology Department.We thank Jian Bai from Berry Oncology Co.,Ltd for academic support.
文摘The incidence of multiple primary malignancies(MPMs)has been increasing rapidly in recent years,however,the genetic pathogenesis is largely unknown on account of rare cases,especially for those patients who are diagnosed with three or more tumors.Under these circumstances,whole-exome sequencing(WES)may help to provide more comprehensive genomic information and guidance to proper therapeutic strategies.Here,we presented a rare case of a 66-year-old Chinese male patient who was diagnosed with synchronous triple primary malignancies:esophageal squamous cell carcinoma(ESCC),lung adenocarcinoma(LA),and hepatocellular carcinoma(HCC).Tumors were surgically removed within 3 months.WES was performed when the patient suffered from cancer recurrence and tumor-specific neoantigens were predicted.Each tumor displayed a distinct somatic mutation profile,providing direct evidence of independent origins.No shared driver gene mutation or neoantigen was detected among the three tumors.Two germline alterations of cancer susceptibility genes—SPINK1 c.194+2T>C and JAK3 c.425G>A were identified.This case is the first report of synchronous primary triple cancers covering the esophagus,lung,and liver.Our findings highlight the complexities of MPMs that even when under identical germline genetic backgrounds,the occurrence of MPMs can be a random event and driven by distinct somatic gene mutations.Synchronous multiple primary cancers that originated from different organs may not have common therapeutic gene targets,and it can be difficult to find a treatment to cover all the tumors.
