Clinical phototheranostic agents suffer from low absorption in near-infrared(NIR)region,decreasing singlet oxygen quantum yield(^(1)O_(2)QY)caused by aggregation in water,and low photothermal conversion efficiency(PCE...Clinical phototheranostic agents suffer from low absorption in near-infrared(NIR)region,decreasing singlet oxygen quantum yield(^(1)O_(2)QY)caused by aggregation in water,and low photothermal conversion efficiency(PCE),all of which are factors weakening their phototheranostic efficacy.Herein,we designed and synthesized a donor-acceptor-donor(D-A-D)structured boron-dipyrromethene derivative(B-2TPA)which exhibited NIR absorption and fluorescence.After being encapsulated in amphiphilic distearoyl phosphoethanolamine polyethyleneglycol 2000(DSPE-PEG-2000),the water-soluble B-2TPA nanoparticles(NPs)had increasing^(1)O_(2)QY(6.7%)due to the intermolecular aggregation-induced decrease in the energy gap between singlet and triplet excited states.Moreover,the quenched fluorescence and stable twisted intramolecular charge transfer in aggregates further increased the PCE of B-2TPA NPs to 60.1%.In vitro and in vivo studies confirmed that B-2TPA NPs could be used in NIR fluorescence and photoacoustic imagingguided synergistic photodynamic and photothermal therapy in tumor treatment.展开更多
Background:CDK4/6 inhibitors(CDK4/6i)have shown promising results in the treatment of hormone receptor‐positive(HR+)metastatic breast cancer(MBC)when combined with endocrine therapy(ET).It is crucial to evaluate the ...Background:CDK4/6 inhibitors(CDK4/6i)have shown promising results in the treatment of hormone receptor‐positive(HR+)metastatic breast cancer(MBC)when combined with endocrine therapy(ET).It is crucial to evaluate the actual effectiveness and safety of CDK4/6i in clinical practice,as well as to analyze the factors that can predict their outcomes.Methods:Patients with HR+MBC who received CDK4/6i‐based therapy between May 2016 and May 2023 at Hunan Cancer Hospital were evaluated for progression‐free survival(PFS).Adverse reactions were assessed based on the National Cancer Institute Common Toxicity Criteria(version 5.0).Results:This study included 344 patients,with a median PFS(mPFS)of 12.8 months(range:10.4–15.2 months).After adjustment,Cox multivariate regression analysis revealed that visceral metastasis(specifically liver and brain metastases),Eastern Cooperative Oncology Group Performance Status(ECOG PS)≥1,estrogen receptor≤80%,progesterone receptor≤10%,Ki‐67>30%,and treatment in later stages were significant factors associated with reduced PFS.Based on this,we created a prognostic nomogram and validated its performance,obtaining a C‐index of 0.714(95%confidence interval:0.640–0.787)as well as reliable calibration and clinical impact.The mPFS of CDK4/6i rechallenge was 7.7 months;for patients who initially discontinued CDK4/6i for reasons other than disease progression,CDK4/6i rechallenge still provided a mPFS of 11.4 months.The tolerability and safety of combining CDK4/6is with ET were manageable.Adverse events led to treatment discontinuation in 3.8%of patients.Neutropenia(29.1%),leukopenia(13.7%),and anemia(4.1%)were the primary grade 3/4 adverse reactions.Conclusions:This real‐world study highlights the ample efficacy and reasonable safety of combined CDK4/6i and ET in patients with HR+MBC.Individualized treatment decisions and ongoing safety monitoring are important to optimize the therapeutic benefit of CDK4/6i treatment.展开更多
Entinostat plus exemestane in hormone receptor-positive(HR+)advanced breast cancer(ABC)previously showed encouraging outcomes.This multicenter phase 3 trial evaluated the efficacy and safety of entinostat plus exemest...Entinostat plus exemestane in hormone receptor-positive(HR+)advanced breast cancer(ABC)previously showed encouraging outcomes.This multicenter phase 3 trial evaluated the efficacy and safety of entinostat plus exemestane in Chinese patients with HR+ABC that relapsed/progressed after≥1 endocrine therapy.Patients were randomized(2:1)to oral exemestane 25 mg/day plus entinostat(n=235)or placebo(n=119)5 mg/week in 28-day cycles.The primary endpoint was the independent radiographic committee(IRC)-assessed progression-free survival(PFS).The median age was 52(range,28—75)years and 222(62.7%)patients were postmenopausal.CDK4/6 inhibitors and fulvestrant were previously used in 23(6.5%)and 92(26.0%)patients,respectively.The baseline characteristics were comparable between the entinostat and placebo groups.The median PFS was 6.32(95%CI,5.30—9.11)and 3.72(95%CI,1.91—5.49)months in the entinostat and placebo groups(HR,0.76;95%CI,0.58—0.98;P=0.046),respectively.Grade≥3 adverse events(AEs)occurred in 154(65.5%)patients in the entinostat group versus 23(19.3%)in the placebo group,and the most common grade≥3 treatment-related AEs were neutropenia[103(43.8%)],thrombocytopenia[20(8.5%)],and leucopenia[15(6.4%)].Entinostat plus exemestane significantly improved PFS compared with exemestane,with generally manageable toxicities in HR+ABC(ClinicalTrials.gov#NCT03538171).展开更多
In our phase Ib trial(ClinialTrials.gov Identifier:NCT03855358),benmelstobart(TQB2450),a novel humanized IgG1 antibody against PD-L1,plus antiangiogenic multikinase inhibitor,anlotinib,demonstrated promising antitumor...In our phase Ib trial(ClinialTrials.gov Identifier:NCT03855358),benmelstobart(TQB2450),a novel humanized IgG1 antibody against PD-L1,plus antiangiogenic multikinase inhibitor,anlotinib,demonstrated promising antitumor activities in pretreated triple negative breast cancer(TNBC)patients.We conducted explorative analyses of genomic biomarkers to explore the associations with treatment response and survival outcomes.Targeted next generation sequencing(NGS)was undertaken toward circulating tumor DNA(ctDNA)collected from peripheral blood samples prior to the start of treatment and after disease progression.A total of 31 patients received targeted NGS and functional driver mutations in 29 patients were analyzed.The most frequent mutations were TP53(72%),MLL3(28%),and PIK3CA(17%).At a blood-based tumor mutational burden(bTMB)cutoff of 6.7 mutations per megabase,patients with low bTMB showed better response to anlotinib plus TQB2450(50%vs.7%,P=0.015)and gained greater PFS benefits(7.3 vs.4.1 months,P=0.012)than those with high bTMB.At a maximum somatic allele frequency(MSAF)cutoff of 10%,a low MSAF indicated a better objective response(43%vs.20%)as well as a significantly longer median PFS(7.9 vs.2.7 months,P<0.001).Patients with both low MSAF and low bTMB showed a notably better objective response to anlotinib plus TQB2450(70%vs.11%,P<0.001)and a significantly longer median PFS(11.0 vs.2.9 months,P<0.001)than patients with other scenarios.Our findings support future studes and validation of MSAF and the combined bTMB-MSAF classification as predictive biomarkers of immune checkpoint inhibitor-based regimens in advanced TNBC patients.展开更多
基金supported by National Key Research and Development Program of China(No.2022YFA1207600)National Natural Science Foundation of China(Nos.62175262,62375289)+2 种基金The Science and Technology Innovation Program of Hunan Province(No.2022RC1201)The Climb Plan of Hunan Cancer Hospital(No.ZX2021005)The Hunan Provincial Natural Science Foundation of China(No.2023JJ60464)。
文摘Clinical phototheranostic agents suffer from low absorption in near-infrared(NIR)region,decreasing singlet oxygen quantum yield(^(1)O_(2)QY)caused by aggregation in water,and low photothermal conversion efficiency(PCE),all of which are factors weakening their phototheranostic efficacy.Herein,we designed and synthesized a donor-acceptor-donor(D-A-D)structured boron-dipyrromethene derivative(B-2TPA)which exhibited NIR absorption and fluorescence.After being encapsulated in amphiphilic distearoyl phosphoethanolamine polyethyleneglycol 2000(DSPE-PEG-2000),the water-soluble B-2TPA nanoparticles(NPs)had increasing^(1)O_(2)QY(6.7%)due to the intermolecular aggregation-induced decrease in the energy gap between singlet and triplet excited states.Moreover,the quenched fluorescence and stable twisted intramolecular charge transfer in aggregates further increased the PCE of B-2TPA NPs to 60.1%.In vitro and in vivo studies confirmed that B-2TPA NPs could be used in NIR fluorescence and photoacoustic imagingguided synergistic photodynamic and photothermal therapy in tumor treatment.
基金Hunan Provincial Natural Science Foundation of China,Grant/Award Numbers:2023JJ60334,2023JJ60464,2024JJ6289Beijing Science and Technology Innovation Medical Development Foundation,Grant/Award Number:KC2023‐JX‐0082‐05The Climb Plan of Hunan Cancer Hospital,Grant/Award Numbers:QH2023006,ZX2021005。
文摘Background:CDK4/6 inhibitors(CDK4/6i)have shown promising results in the treatment of hormone receptor‐positive(HR+)metastatic breast cancer(MBC)when combined with endocrine therapy(ET).It is crucial to evaluate the actual effectiveness and safety of CDK4/6i in clinical practice,as well as to analyze the factors that can predict their outcomes.Methods:Patients with HR+MBC who received CDK4/6i‐based therapy between May 2016 and May 2023 at Hunan Cancer Hospital were evaluated for progression‐free survival(PFS).Adverse reactions were assessed based on the National Cancer Institute Common Toxicity Criteria(version 5.0).Results:This study included 344 patients,with a median PFS(mPFS)of 12.8 months(range:10.4–15.2 months).After adjustment,Cox multivariate regression analysis revealed that visceral metastasis(specifically liver and brain metastases),Eastern Cooperative Oncology Group Performance Status(ECOG PS)≥1,estrogen receptor≤80%,progesterone receptor≤10%,Ki‐67>30%,and treatment in later stages were significant factors associated with reduced PFS.Based on this,we created a prognostic nomogram and validated its performance,obtaining a C‐index of 0.714(95%confidence interval:0.640–0.787)as well as reliable calibration and clinical impact.The mPFS of CDK4/6i rechallenge was 7.7 months;for patients who initially discontinued CDK4/6i for reasons other than disease progression,CDK4/6i rechallenge still provided a mPFS of 11.4 months.The tolerability and safety of combining CDK4/6is with ET were manageable.Adverse events led to treatment discontinuation in 3.8%of patients.Neutropenia(29.1%),leukopenia(13.7%),and anemia(4.1%)were the primary grade 3/4 adverse reactions.Conclusions:This real‐world study highlights the ample efficacy and reasonable safety of combined CDK4/6i and ET in patients with HR+MBC.Individualized treatment decisions and ongoing safety monitoring are important to optimize the therapeutic benefit of CDK4/6i treatment.
基金sponsored by EOC Pharmaceutical CO,and CAMS Innovation Fund for Medical Sciences(CIFMS,2021I2M-1-014,China)Taizhou EOC Pharma Co.,Ltd.for supporting,developing and sponsoring this trial。
文摘Entinostat plus exemestane in hormone receptor-positive(HR+)advanced breast cancer(ABC)previously showed encouraging outcomes.This multicenter phase 3 trial evaluated the efficacy and safety of entinostat plus exemestane in Chinese patients with HR+ABC that relapsed/progressed after≥1 endocrine therapy.Patients were randomized(2:1)to oral exemestane 25 mg/day plus entinostat(n=235)or placebo(n=119)5 mg/week in 28-day cycles.The primary endpoint was the independent radiographic committee(IRC)-assessed progression-free survival(PFS).The median age was 52(range,28—75)years and 222(62.7%)patients were postmenopausal.CDK4/6 inhibitors and fulvestrant were previously used in 23(6.5%)and 92(26.0%)patients,respectively.The baseline characteristics were comparable between the entinostat and placebo groups.The median PFS was 6.32(95%CI,5.30—9.11)and 3.72(95%CI,1.91—5.49)months in the entinostat and placebo groups(HR,0.76;95%CI,0.58—0.98;P=0.046),respectively.Grade≥3 adverse events(AEs)occurred in 154(65.5%)patients in the entinostat group versus 23(19.3%)in the placebo group,and the most common grade≥3 treatment-related AEs were neutropenia[103(43.8%)],thrombocytopenia[20(8.5%)],and leucopenia[15(6.4%)].Entinostat plus exemestane significantly improved PFS compared with exemestane,with generally manageable toxicities in HR+ABC(ClinicalTrials.gov#NCT03538171).
基金supported by CAMS Innovation Fund for Medical Sciences(CIFMS,2022-I2M-2-002)CAMS Innovation Fund for Medical Sciences(CIFMS,2021-I2M-1-014)+1 种基金Beijing Hope Run Special Fund of Cancer Foundation of China(LC2022A18)CHIA TAI TIANQING PHARMACEUTICAL GROUP.
文摘In our phase Ib trial(ClinialTrials.gov Identifier:NCT03855358),benmelstobart(TQB2450),a novel humanized IgG1 antibody against PD-L1,plus antiangiogenic multikinase inhibitor,anlotinib,demonstrated promising antitumor activities in pretreated triple negative breast cancer(TNBC)patients.We conducted explorative analyses of genomic biomarkers to explore the associations with treatment response and survival outcomes.Targeted next generation sequencing(NGS)was undertaken toward circulating tumor DNA(ctDNA)collected from peripheral blood samples prior to the start of treatment and after disease progression.A total of 31 patients received targeted NGS and functional driver mutations in 29 patients were analyzed.The most frequent mutations were TP53(72%),MLL3(28%),and PIK3CA(17%).At a blood-based tumor mutational burden(bTMB)cutoff of 6.7 mutations per megabase,patients with low bTMB showed better response to anlotinib plus TQB2450(50%vs.7%,P=0.015)and gained greater PFS benefits(7.3 vs.4.1 months,P=0.012)than those with high bTMB.At a maximum somatic allele frequency(MSAF)cutoff of 10%,a low MSAF indicated a better objective response(43%vs.20%)as well as a significantly longer median PFS(7.9 vs.2.7 months,P<0.001).Patients with both low MSAF and low bTMB showed a notably better objective response to anlotinib plus TQB2450(70%vs.11%,P<0.001)and a significantly longer median PFS(11.0 vs.2.9 months,P<0.001)than patients with other scenarios.Our findings support future studes and validation of MSAF and the combined bTMB-MSAF classification as predictive biomarkers of immune checkpoint inhibitor-based regimens in advanced TNBC patients.
