Objective:Based on the findings of the KEYNOTE-048 study,pembrolizumab in combination with platinum and fluorouracil is the standard first-line treatment for recurrent or metastatic head and neck squamous cell carcino...Objective:Based on the findings of the KEYNOTE-048 study,pembrolizumab in combination with platinum and fluorouracil is the standard first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma(R/M HNSCC).The efficacy and safety of pembrolizumab combined with nab-paclitaxel and platinum in such patients remain unexplored.Methods:This single-arm phase 2 study enrolled patients with R/M HNSCC who received pembrolizumab(200 mg),nab-paclitaxel(260 mg/m^(2)),and either cisplatin(75 mg/m^(2))or carboplatin[area under the curve(AUC)5]every 21 d for up to six cycles,followed by pembrolizumab maintenance therapy.The primary endpoint was the objective response rate(ORR).Secondary endpoints included disease control rate(DCR),progression-free survival(PFS),duration of response(Do R),overall survival(OS),and safety.Exploratory multi-omics analyses were conducted.Results:Between April 23,2021,and August 20,2023,a total of 67 patients with R/M HNSCC were enrolled and received the study treatment.By the data cut-off date of March 2,2024,62(92.5%)patients had received cisplatin,while five(7.5%)patients had received carboplatin.The median follow-up duration was 12.7(range:2.3-34.8)months.The ORR was 62.7%,and the DCR was 88.1%.The median PFS,Do R,and OS were 9.7,13.0,and 18.7 months,respectively.The most common grade 3 adverse events(AEs)were leukopenia(22.4%)and neutropenia(28.4%).Genomic alterations correlated with efficacy outcomes,and dynamic changes in 17 plasma proteins were associated with treatment response.Upregulation of serum interferon(IFN)-γand interleukin(IL)8levels was linked to treatment-related AEs.Conclusions:Pembrolizumab in combination with nab-paclitaxel and platinum demonstrated promising efficacy and a manageable safety profile in patients with R/M HNSCC.Future studies are warranted to confirm these findings.展开更多
Objective:In this study,we aimed to identify novel genetic loci and protein biomarkers associated with silicosis susceptibility in Chinese workers through integrated proteomic and genomic analyses and to develop an ea...Objective:In this study,we aimed to identify novel genetic loci and protein biomarkers associated with silicosis susceptibility in Chinese workers through integrated proteomic and genomic analyses and to develop an early diagnostic prediction model.Methods:A genome-wide association study(GWAS)was conducted on 163 patients with silicosis and 183 controls,followed by Olink proteomic profiling of 92 plasma proteins.Protein quantitative trait loci(pQTL)mapping,Mendelian randomization(MR),and Bayesian co-localization were used to infer causal relationships.A causal protein risk score(CPRS)model integrating genetic and proteomic data was developed and validated using 10-fold cross-validation.Results:GWAS identified 16 novel risk loci(P<1×10^(-5)),including rs6677666(WLS)and rs2272528(COL4A4).MR analysis revealed eight plasma proteins associated with silicosis risk,with MMP12,EGF,Gal_9,GZMA,and ICOSLG showing significant differential expression(P<0.05).The CPRS model combining these proteins demonstrated a high diagnostic accuracy(AUC=0.915),outperforming traditional clinical variables.Conclusion:This multi-omics study uncovered genetic and proteomic markers linked to silicosis susceptibility and established a robust predictive model.The integration of GWAS and proteomics offers novel insights into the pathogenesis of silicosis,and supports development of early detection and prevention policies for high-risk populations.展开更多
基金supported by the China National Major Project for New Drug Innovation(No.2017ZX09304015)the Beijing Hope Run Special Fund of the Cancer Foundation of China(No.LC2022A30)the Beijing Vlove Charity Foundation(No.JYKY2024-0200616033)。
文摘Objective:Based on the findings of the KEYNOTE-048 study,pembrolizumab in combination with platinum and fluorouracil is the standard first-line treatment for recurrent or metastatic head and neck squamous cell carcinoma(R/M HNSCC).The efficacy and safety of pembrolizumab combined with nab-paclitaxel and platinum in such patients remain unexplored.Methods:This single-arm phase 2 study enrolled patients with R/M HNSCC who received pembrolizumab(200 mg),nab-paclitaxel(260 mg/m^(2)),and either cisplatin(75 mg/m^(2))or carboplatin[area under the curve(AUC)5]every 21 d for up to six cycles,followed by pembrolizumab maintenance therapy.The primary endpoint was the objective response rate(ORR).Secondary endpoints included disease control rate(DCR),progression-free survival(PFS),duration of response(Do R),overall survival(OS),and safety.Exploratory multi-omics analyses were conducted.Results:Between April 23,2021,and August 20,2023,a total of 67 patients with R/M HNSCC were enrolled and received the study treatment.By the data cut-off date of March 2,2024,62(92.5%)patients had received cisplatin,while five(7.5%)patients had received carboplatin.The median follow-up duration was 12.7(range:2.3-34.8)months.The ORR was 62.7%,and the DCR was 88.1%.The median PFS,Do R,and OS were 9.7,13.0,and 18.7 months,respectively.The most common grade 3 adverse events(AEs)were leukopenia(22.4%)and neutropenia(28.4%).Genomic alterations correlated with efficacy outcomes,and dynamic changes in 17 plasma proteins were associated with treatment response.Upregulation of serum interferon(IFN)-γand interleukin(IL)8levels was linked to treatment-related AEs.Conclusions:Pembrolizumab in combination with nab-paclitaxel and platinum demonstrated promising efficacy and a manageable safety profile in patients with R/M HNSCC.Future studies are warranted to confirm these findings.
基金Supported by the Jiangsu Provincial Social Development Program of the Key R&D Project(BE2022803)Natural Science Foundation of Jiangsu(BK20201485)+1 种基金Jiangsu Provincial Key Medical Discipline(ZDXK202249)Scientific Research Project of Jiangsu Health Commission(M2022085).
文摘Objective:In this study,we aimed to identify novel genetic loci and protein biomarkers associated with silicosis susceptibility in Chinese workers through integrated proteomic and genomic analyses and to develop an early diagnostic prediction model.Methods:A genome-wide association study(GWAS)was conducted on 163 patients with silicosis and 183 controls,followed by Olink proteomic profiling of 92 plasma proteins.Protein quantitative trait loci(pQTL)mapping,Mendelian randomization(MR),and Bayesian co-localization were used to infer causal relationships.A causal protein risk score(CPRS)model integrating genetic and proteomic data was developed and validated using 10-fold cross-validation.Results:GWAS identified 16 novel risk loci(P<1×10^(-5)),including rs6677666(WLS)and rs2272528(COL4A4).MR analysis revealed eight plasma proteins associated with silicosis risk,with MMP12,EGF,Gal_9,GZMA,and ICOSLG showing significant differential expression(P<0.05).The CPRS model combining these proteins demonstrated a high diagnostic accuracy(AUC=0.915),outperforming traditional clinical variables.Conclusion:This multi-omics study uncovered genetic and proteomic markers linked to silicosis susceptibility and established a robust predictive model.The integration of GWAS and proteomics offers novel insights into the pathogenesis of silicosis,and supports development of early detection and prevention policies for high-risk populations.
