Immune checkpoint inhibitors(ICIs)combined with vascular endothelial growth factor tyrosine kinase inhibitors(VEGF-TKIs)have transformed the treatment landscape of advanced clear cell renal cell carcinoma(ccRCC).Curre...Immune checkpoint inhibitors(ICIs)combined with vascular endothelial growth factor tyrosine kinase inhibitors(VEGF-TKIs)have transformed the treatment landscape of advanced clear cell renal cell carcinoma(ccRCC).Current guidelines favour ICI plus VEGF-TKI(IO+TKI)combinations for favourable-risk disease(International Metastatic RCC Database Consortium[IMDC]score 0)based on improved objective response rates and progression-free survival.However,no IO+TKI combination has demonstrated a statistically significant overall survival(OS)benefit in this subgroup.A pooled analysis of four pivotal phase III trials(n=839 favourable-risk patients)revealed no OS advantage for IO+TKI versus sunitinib monotherapy(hazard ratio[HR]1.24;95%CI 0.86-1.78)despite higher toxicity rates(71-82%Grade≥3 adverse events vs.63-72%with sunitinib)and substantially greater cost.The IMDC favourable-risk category represents approximately 20%of metastatic ccRCC cases and is often characterised by indolent disease biology.Emerging molecular classifications reveal distinct transcriptomic subgroups,including an angiogenic subtype(ccA/CC-e.2/clusters 1-2)enriched in favourable-risk patients,characterised by high hypoxia-inducible factor(HIF)pathway gene expression,frequent PBRM1 mutations,robust VEGF-TKI responsiveness,and comparatively lower benefit from immunotherapy.Current clinical risk stratification fails to capture this molecular heterogeneity,limiting optimal treatment selection.VEGF-TKI monotherapy(median OS 47.6-79.4 months)and active surveillance remain valid,evidence-based alternatives in carefully selected favourable-risk patients,particularly those with asymptomatic,metachronous,or otherwise indolent disease.Uncritical universal use of IO+TKI in this population may therefore represent overtreatment.The development and validation of predictive biomarkers,refinement of molecular risk stratification,and exploration of novel agents with more favourable toxicity profiles(e.g.,HIF-2αinhibitors)are urgently required to personalise therapy and identify candidates for rational treatment de-escalation.展开更多
Objective To establish a stable and efficient method of culturing imDCs in vitro,and to explore the effect of GW5074,which blocks ERK1 /2 signal pathway in the process of immature dentritic cells ( imDCs) on inducing ...Objective To establish a stable and efficient method of culturing imDCs in vitro,and to explore the effect of GW5074,which blocks ERK1 /2 signal pathway in the process of immature dentritic cells ( imDCs) on inducing differentiation of the naive allogeneic CD4 + T展开更多
Metastatic Renal Cell Carcinoma(mRCC)is a highly heterogeneous disease that is notoriously difficult to treat successfully.However,the discovery of novel,targeted therapies over the last decade has revolutionized its ...Metastatic Renal Cell Carcinoma(mRCC)is a highly heterogeneous disease that is notoriously difficult to treat successfully.However,the discovery of novel,targeted therapies over the last decade has revolutionized its management.As the therapeutic options continue to evolve,developing a more individualized treatment strategy is of paramount importance.The International mRCC Database Consortium(IMDC)is a prognostic model that is commonly used in trials and clinical settings to risk stratify patients.This allows for optimal therapy selection on a more individual basis.However,the distinct lack of validated predictive biomarkers in mRCC renders it difficult to assess therapy response.An improved understanding of tumor biology and genetics has prompted a shift from cytokine therapy to the use of vascular endothelial growth factor(VEGF)inhibitors,tyrosine kinase Inhibitors,immune checkpoint inhibitors or combination strategies.Studies have identified some putative markers and genetic mutations as potential predictors of therapy response.Early results are promising,and there are many ongoing trials further assessing their suitability for clinical use.This review will evaluate the current treatment landscape and molecular biology of mRCC,with a specific focus on the prognostic and predictive markers available to guide treatment options and further improve patient outcomes.展开更多
摘要Immune checkpoint inhibitors(ICIs)combined with vascular endothelial growth factor tyrosine kinase inhibitors(VEGF-TKIs)have transformed the treatment landscape of advanced clear cell renal cell carcinoma(ccRCC).Current guidelines favour ICI plus VEGF-TKI(IO+TKI)combinations for favourable-risk disease(International Metastatic RCC Database Consortium[IMDC]score 0)based on improved objective response rates and progression-free survival.However,no IO+TKI combination has demonstrated a statistically significant overall survival(OS)benefit in this subgroup.A pooled analysis of four pivotal phase III trials(n=839 favourable-risk patients)revealed no OS advantage for IO+TKI versus sunitinib monotherapy(hazard ratio[HR]1.24;95%CI 0.86-1.78)despite higher toxicity rates(71-82%Grade≥3 adverse events vs.63-72%with sunitinib)and substantially greater cost.The IMDC favourable-risk category represents approximately 20%of metastatic ccRCC cases and is often characterised by indolent disease biology.Emerging molecular classifications reveal distinct transcriptomic subgroups,including an angiogenic subtype(ccA/CC-e.2/clusters 1-2)enriched in favourable-risk patients,characterised by high hypoxia-inducible factor(HIF)pathway gene expression,frequent PBRM1 mutations,robust VEGF-TKI responsiveness,and comparatively lower benefit from immunotherapy.Current clinical risk stratification fails to capture this molecular heterogeneity,limiting optimal treatment selection.VEGF-TKI monotherapy(median OS 47.6-79.4 months)and active surveillance remain valid,evidence-based alternatives in carefully selected favourable-risk patients,particularly those with asymptomatic,metachronous,or otherwise indolent disease.Uncritical universal use of IO+TKI in this population may therefore represent overtreatment.The development and validation of predictive biomarkers,refinement of molecular risk stratification,and exploration of novel agents with more favourable toxicity profiles(e.g.,HIF-2αinhibitors)are urgently required to personalise therapy and identify candidates for rational treatment de-escalation.
摘要Objective To establish a stable and efficient method of culturing imDCs in vitro,and to explore the effect of GW5074,which blocks ERK1 /2 signal pathway in the process of immature dentritic cells ( imDCs) on inducing differentiation of the naive allogeneic CD4 + T
摘要Metastatic Renal Cell Carcinoma(mRCC)is a highly heterogeneous disease that is notoriously difficult to treat successfully.However,the discovery of novel,targeted therapies over the last decade has revolutionized its management.As the therapeutic options continue to evolve,developing a more individualized treatment strategy is of paramount importance.The International mRCC Database Consortium(IMDC)is a prognostic model that is commonly used in trials and clinical settings to risk stratify patients.This allows for optimal therapy selection on a more individual basis.However,the distinct lack of validated predictive biomarkers in mRCC renders it difficult to assess therapy response.An improved understanding of tumor biology and genetics has prompted a shift from cytokine therapy to the use of vascular endothelial growth factor(VEGF)inhibitors,tyrosine kinase Inhibitors,immune checkpoint inhibitors or combination strategies.Studies have identified some putative markers and genetic mutations as potential predictors of therapy response.Early results are promising,and there are many ongoing trials further assessing their suitability for clinical use.This review will evaluate the current treatment landscape and molecular biology of mRCC,with a specific focus on the prognostic and predictive markers available to guide treatment options and further improve patient outcomes.