Objective:To determine the safety and the role of modulating cytokines and proteases in the immune response to intravesical Bacillus Calmette-Guérin(BCG)when primed with systemic intradermal BCG.Methods:Phase 1 a...Objective:To determine the safety and the role of modulating cytokines and proteases in the immune response to intravesical Bacillus Calmette-Guérin(BCG)when primed with systemic intradermal BCG.Methods:Phase 1 and mechanistic longitudinal,prospective,single-blind randomized study(NCT04806178).Twenty-one non-muscle invasive urothelial bladder cancer patients undergoing intravesical adjuvant BCG after transurethral resection of bladder tumor(TURBT)in a teaching hospital between September 2021 and April 2023 were randomized to 0.1 mL of intradermal BCG vaccine or placebo(0.9%saline)administered 15 days before the start of intravesical BCG therapy.Blood samples were evaluated mechanistically regarding eight cytokines serum levels interferon-induced transmembrane protein 3 Gene(IFITM3),Interleukin 1 beta(IL1-BETA),interleukin-2 receptor alpha chain(IL2 RA),Interleukin 6(IL 6),Interleukin 10(IL 10),Tumor necrosis factor alpha(TNF-α),Interferon-β,AXL,and one protease CASPASE 8.Results:After 1 exclusion,twenty patients were randomized to intradermal BCG(n=11)and intradermal placebo(n=9).There was no difference in adverse effects emerging from the intravesical Onco-BCG therapy,and no difference in the expression of the cytokines and proteases analyzed between control and intervention,and over time.Conclusions:Intradermal BCG administration before intravesical application was safe,with no increase in adverse effects.It also does not seem to change the analyzed targets during the intravesical induction-phase BCG.Other immune targets should be explored in the future.The Brazilian tuberculosis-endemic status,where BCG vaccination is mandatory,might have affected the results.展开更多
Objective:The tumor microenvironment plays a pivotal role in prostate cancer progression and may differ across metastatic sites.This study aimed to evaluate and compare the primary and metastatic prostate adenocarcino...Objective:The tumor microenvironment plays a pivotal role in prostate cancer progression and may differ across metastatic sites.This study aimed to evaluate and compare the primary and metastatic prostate adenocarcinoma tumor microenvironment.Methods:A total of 27 formalin-fixed paraffin-embedded tissue samples derived from 17 patients diagnosed with prostate adenocarcinoma,including the primary tumors,and the corresponding metastatic lymphatic and hematogenous lesions from various anatomical sites.Immunohistochemical labeling was performed using antibodies against Cluster of Differentiation 3 epsilon chain(CD3e),CD8 alpha chain(CD8a),Cluster of Differentiation 68(CD68),Cluster of Differentiation 163(CD163),Forkhead box P3(FOXP3),Cytotoxic T-Lymphocyte–Associated protein 4(CTLA-4),B7 homolog 3(B7-H3),Programmed cell death protein 1(PD-1),and Marker of proliferation Ki-67(Ki-67).Comparisons were made between primary and metastatic tumors to assess differences in immune cell infiltration,checkpoint expression,and proliferative indices.Results:Sampleswere classified into three groups:Primary Tumor n=12,Lymphatic Metastasis n=7,and Hematogenous Metastasis n=10.FOXP3(p=0.0017)and CD163(p=0.0316)expression levels were significantly higher in the Hematogenous Metastasis compared to both the Primary Tumor and Lymphatic Metastasis.PD-1 showed a clear trend(p=0.0577)toward higher levels in the Primary Tumor compared to both the HematogenousMetastasis and LymphaticMetastasis groups,suggesting distinct immunological landscapes depending on tumor location and progression.Conclusion:Diverse PD-1,CD163,and FOXP3 profiles were observed in primary and metastatic microenvironments of prostate cancer.These findings may contribute to the development of personalized therapeutic strategies and novel prognostic tools beyond conventional histological and TNM staging.展开更多
基金National Council for Scientific and Technological Development,CNPq,Research Productivity,grant numbers:304747/2018-1/310135/2022-2(Reis LO).
文摘Objective:To determine the safety and the role of modulating cytokines and proteases in the immune response to intravesical Bacillus Calmette-Guérin(BCG)when primed with systemic intradermal BCG.Methods:Phase 1 and mechanistic longitudinal,prospective,single-blind randomized study(NCT04806178).Twenty-one non-muscle invasive urothelial bladder cancer patients undergoing intravesical adjuvant BCG after transurethral resection of bladder tumor(TURBT)in a teaching hospital between September 2021 and April 2023 were randomized to 0.1 mL of intradermal BCG vaccine or placebo(0.9%saline)administered 15 days before the start of intravesical BCG therapy.Blood samples were evaluated mechanistically regarding eight cytokines serum levels interferon-induced transmembrane protein 3 Gene(IFITM3),Interleukin 1 beta(IL1-BETA),interleukin-2 receptor alpha chain(IL2 RA),Interleukin 6(IL 6),Interleukin 10(IL 10),Tumor necrosis factor alpha(TNF-α),Interferon-β,AXL,and one protease CASPASE 8.Results:After 1 exclusion,twenty patients were randomized to intradermal BCG(n=11)and intradermal placebo(n=9).There was no difference in adverse effects emerging from the intravesical Onco-BCG therapy,and no difference in the expression of the cytokines and proteases analyzed between control and intervention,and over time.Conclusions:Intradermal BCG administration before intravesical application was safe,with no increase in adverse effects.It also does not seem to change the analyzed targets during the intravesical induction-phase BCG.Other immune targets should be explored in the future.The Brazilian tuberculosis-endemic status,where BCG vaccination is mandatory,might have affected the results.
基金National Council for Scientific and Technological Development,CNPq,Research Productivity,grant numbers:304747/2018-1,310135/2022-2,INCT-UROGEN#408576/2024-3(Leonardo O.Reis)and CAPES 88887.508226/2020-00-code 001,and 88887.974845/2024-00.
文摘Objective:The tumor microenvironment plays a pivotal role in prostate cancer progression and may differ across metastatic sites.This study aimed to evaluate and compare the primary and metastatic prostate adenocarcinoma tumor microenvironment.Methods:A total of 27 formalin-fixed paraffin-embedded tissue samples derived from 17 patients diagnosed with prostate adenocarcinoma,including the primary tumors,and the corresponding metastatic lymphatic and hematogenous lesions from various anatomical sites.Immunohistochemical labeling was performed using antibodies against Cluster of Differentiation 3 epsilon chain(CD3e),CD8 alpha chain(CD8a),Cluster of Differentiation 68(CD68),Cluster of Differentiation 163(CD163),Forkhead box P3(FOXP3),Cytotoxic T-Lymphocyte–Associated protein 4(CTLA-4),B7 homolog 3(B7-H3),Programmed cell death protein 1(PD-1),and Marker of proliferation Ki-67(Ki-67).Comparisons were made between primary and metastatic tumors to assess differences in immune cell infiltration,checkpoint expression,and proliferative indices.Results:Sampleswere classified into three groups:Primary Tumor n=12,Lymphatic Metastasis n=7,and Hematogenous Metastasis n=10.FOXP3(p=0.0017)and CD163(p=0.0316)expression levels were significantly higher in the Hematogenous Metastasis compared to both the Primary Tumor and Lymphatic Metastasis.PD-1 showed a clear trend(p=0.0577)toward higher levels in the Primary Tumor compared to both the HematogenousMetastasis and LymphaticMetastasis groups,suggesting distinct immunological landscapes depending on tumor location and progression.Conclusion:Diverse PD-1,CD163,and FOXP3 profiles were observed in primary and metastatic microenvironments of prostate cancer.These findings may contribute to the development of personalized therapeutic strategies and novel prognostic tools beyond conventional histological and TNM staging.
