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Immune checkpoint blockade therapies are widely used for cancer treatment, including advanced renal cell carcinoma (RCC). This study aimed to investigate the impact of zygosity in HLA genes and individual HLA genotypes on the efficacy of an anti-PD-1 Ab, nivolumab, in treating advanced RCC. Patient enrollment was conducted across 23 institutions in Japan from August 19, 2019, to September 30, 2020, with follow-up concluding on March 31, 2021. HLA genotype imputation of HLA-A, B, and C, DQB1, and DRB1 loci was performed. Among 222 patients, the presence of at least one homozygosity of the HLA-II allele significantly improved the best objective response (hazard ratio, 0.34; 95% confidence interval, 0.21-0.96; p = 0.042). The HLA evolutionary divergence (HED) of the HLA-A and HLA-B loci was higher than the HLA-C (p < 0.0001 and p < 0.0001, respectively), with high HED of the HLA-B locus correlating to clinical benefits in nivolumab treatment (hazard ratio, 0.44; 95% confidence interval, 0.21-0.90; p = 0.024) and improving cancer-specific survival compared with the low group (p = 0.0202). Additionally, high HED of the HLA-B locus was correlated with the number of infiltrated CD8+ cells in the tumor microenvironment (correlation coefficient, 0.4042). These findings indicate that the diversity of the HLA-B locus plays a significant role in the anti-tumor effect of nivolumab treatment in advanced RCC, potentially offering insights for improved risk stratification in nivolumab treatment and leading to better medical management of advanced RCC.
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Carcinoma de Células Renales , Genotipo , Antígenos HLA , Neoplasias Renales , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/inmunología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/inmunología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Antígenos HLA/genética , Antígenos HLA/inmunología , Nivolumab/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/genética , Adulto , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Kidney transplantation (KT) leads to body composition change, particularly increasing the fat mass. However, limited researches have focused on the long-term follow-up of these changes and factors influencing body composition after KT. METHODS: This study evaluated body composition in 31 adult KT recipients, measuring body mass index (BMI), the psoas muscle mass index (PMI) representing muscle mass, visceral and subcutaneous adipose tissue (VAT and SAT) representing fat mass, and skeletal muscle radiodensity (SMR) representing muscle quality before KT and at 2, 4, and 6 years posttransplantation using computed tomography. Linear mixed models (LMM) analyzed temporal changes and contributing factors, while growth curve models assessed influence of these factors on body composition changes posttransplantation. RESULTS: Following KT, BMI, and PMI remained stable, while SAT increased significantly, revealing a 1.30-fold increase from baseline 2 years after transplantation. Similarly, a substantial increase in VAT was observed, with a 1.47-fold increase from baseline 2 years after transplantation with a further 1.75-fold increase 6 years after transplantation. In contrast, SMR decreased with a 0.86-fold decrease from baseline after 2 years. VAT increase was significantly influenced by the interaction between posttransplantation and dialysis duration. Growth curve models confirmed this interaction effect persistently influenced VAT increase posttransplantation. CONCLUSIONS: The study revealed that KT promoted significant alterations in body composition characterized by increase in the VAT and SAT and a decline in SMR. Notably, dialysis duration and its interaction with posttransplantation duration emerged as significant factors influencing VAT increase.
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BACKGROUND: Nivolumab plus ipilimumab (NIVO + IPI) is the first-line treatment for patients with metastatic renal cell carcinoma (mRCC). While approximately 40% of patients treated with NIVO + IPI achieve a durable response, 20% develop primary resistance with severe consequences. Therefore, there is a clinical need for criteria to select patients suitable for NIVO + IPI therapy to optimize its therapeutic efficacy. Accordingly, our aim was to evaluate the association between candidate biomarkers measured before treatment initiation and survival. METHODS: This was a multi-institutional, retrospective, cohort study of 183 patients with mRCC treated with systematic therapies between August 2015 and July 2023. Of these, 112 received NIVO + IPI as first-line therapy: mean age, 68 years; men, 83.0% (n = 93), and clear cell histology, 80.4% (n = 90). Univariable and multivariable analyses were used to evaluate associations between biomarkers and survival. RESULTS: On univariate analysis, high C-reactive protein and systemic index, a high neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio, and a low lymphocyte-to-monocyte ratio (LMR) were associated with shorter overall survival (OS). On multivariable analysis, a LMR ≤ 3 was retained as an independent factor associated to shorter OS with the highest accuracy (C-index, 0.656; hazard ratio, 7.042; 95% confidence interval, 2.0-25.0; p = 0.002). CONCLUSION: A low LMR may identify patients who would be candidate for NIVO + IPI therapy for mRCC.
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Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Células Renales , Ipilimumab , Neoplasias Renales , Linfocitos , Monocitos , Nivolumab , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/secundario , Ipilimumab/administración & dosificación , Ipilimumab/uso terapéutico , Nivolumab/administración & dosificación , Nivolumab/uso terapéutico , Masculino , Anciano , Femenino , Estudios Retrospectivos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Neoplasias Renales/mortalidad , Neoplasias Renales/sangre , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfocitos/patología , Biomarcadores de Tumor/sangre , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Platinum-based chemotherapy is standard-of-care first-line treatment for advanced urothelial carcinoma. However, progression-free survival and overall survival are limited by chemotherapy resistance. METHODS: In a phase 3 trial, we randomly assigned patients with unresectable locally advanced or metastatic urothelial cancer who did not have disease progression with first-line chemotherapy (four to six cycles of gemcitabine plus cisplatin or carboplatin) to receive best supportive care with or without maintenance avelumab. The primary end point was overall survival, assessed among all patients who underwent randomization (overall population) and among those with tumors positive for programmed cell death ligand 1 (PD-L1). Secondary end points included progression-free survival and safety. RESULTS: Among all 700 patients who underwent randomization, the addition of maintenance avelumab to best supportive care significantly prolonged overall survival as compared with best supportive care alone (control). Overall survival at 1 year was 71.3% in the avelumab group and 58.4% in the control group (median overall survival, 21.4 months vs. 14.3 months; hazard ratio for death, 0.69; 95% confidence interval [CI], 0.56 to 0.86; P = 0.001). Avelumab also significantly prolonged overall survival in the PD-L1-positive population; overall survival at 1 year was 79.1% in the avelumab group and 60.4% in the control group (hazard ratio, 0.56; 95% CI, 0.40 to 0.79; P<0.001). The median progression-free survival was 3.7 months in the avelumab group and 2.0 months in the control group in the overall population (hazard ratio for disease progression or death, 0.62; 95% CI, 0.52 to 0.75) and 5.7 months and 2.1 months, respectively, in the PD-L1-positive population (hazard ratio, 0.56; 95% CI, 0.43 to 0.73). The incidence of adverse events from any cause was 98.0% in the avelumab group and 77.7% in the control group; the incidence of adverse events of grade 3 or higher was 47.4% and 25.2%, respectively. CONCLUSIONS: Maintenance avelumab plus best supportive care significantly prolonged overall survival, as compared with best supportive care alone, among patients with urothelial cancer who had disease that had not progressed with first-line chemotherapy. (Funded by Pfizer and Merck [Darmstadt, Germany]; JAVELIN Bladder 100 ClinicalTrials.gov number, NCT02603432.).
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Neoplasias Urológicas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos , Carboplatino/administración & dosificación , Cisplatino/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Femenino , Humanos , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Análisis de Supervivencia , Neoplasias Urológicas/mortalidad , Urotelio , GemcitabinaRESUMEN
BACKGROUND: Anti-PD-1 antibodies are widely used for cancer treatment including advanced renal cell carcinoma (RCC). However, their therapeutic and adverse effects vary among patients. This study aimed to identify genetic markers that predict outcome after nivolumab anti-PD-1 antibody treatment for advanced RCC. METHODS: This study was registered on the website of the University Hospital Medical Information Network (protocol ID, UMIN000037739). Patient enrollment was conducted at 23 institutions in Japan between August 19, 2019, and September 30, 2020. Patient follow-up ended on March 31, 2021. Patients were treated with nivolumab for advanced clear cell RCC. A genome-wide association study was performed in the development set, while genotyping of target regions in the validation set was undertaken. Single nucleotide polymorphisms (SNPs) in genes of interest CD274, PDCD1LG2 and PDCD1 were genotyped in the combined set. The primary endpoint was the association of SNPs with objective response following nivolumab treatment. As secondary endpoints, the associations of SNPs with radiographic progression-free survival (rPFS) and treatment-related grade ≥ 3 adverse events (AEs) were evaluated. RESULTS: A genome-wide association study followed by a validation study identified that SNPs in FARP1 (rs643896 and rs685736) were associated with objective response and rPFS but not AEs following nivolumab treatment. Furthermore, SNPs in PDCD1LG2 (rs822339 and rs1411262) were associated with objective response, rPFS, and AEs following nivolumab treatment. Genetic risk category determined according to the number of risk alleles in SNPs (rs643896 in FARP1 and rs4527932 in PDCD1LG2) excellently predicted objective response and rPFS in nivolumab treatment. CONCLUSION: This study revealed that SNPs in FARP1 and PDCD1LG2 were correlated with outcome in nivolumab treatment. The use of these SNPs may be beneficial in selecting appropriate treatment for individual patients and may contribute to personalized medicine.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Nivolumab/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Estudio de Asociación del Genoma Completo , Supervivencia sin Progresión , Polimorfismo de Nucleótido Simple , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genéticaRESUMEN
BACKGROUND: Several clear cell renal cell carcinoma (ccRCC) cases harbour fibroblast growth factor receptor 4 (FGFR4) gene copy number (CN) gains. In this study, we investigated the functional contribution of FGFR4 CN amplification in ccRCC. METHODS: The correlation between FGFR4 CN determined via real-time PCR and protein expression evaluated using western blotting and immunohistochemistry was assessed in ccRCC cell lines (A498, A704, and 769-P), a papillary RCC cell line (ACHN), and clinical ccRCC specimens. The effect of FGFR4 inhibition on ccRCC cell proliferation and survival was assessed via either RNA interference or using the selective FGFR4 inhibitor BLU9931, followed by MTS assays, western blotting, and flow cytometry. To investigate whether FGFR4 is a potential therapeutic target, a xenograft mouse model was administered BLU9931. RESULTS: 60% of ccRCC surgical specimens harboured an FGFR4 CN amplification. FGFR4 CN was positively correlated with its protein expression. All ccRCC cell lines harboured FGFR4 CN amplifications, whereas ACHN did not. FGFR4 silencing or inhibition attenuated intracellular signal transduction pathways, resulting in apoptosis and suppressed proliferation in ccRCC cell lines. BLU9931 suppressed tumours at a tolerable dose in the mouse model. CONCLUSION: FGFR4 contributes to ccRCC cell proliferation and survival following FGFR4 amplification, making it a potential therapeutic target for ccRCC.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Animales , Ratones , Carcinoma de Células Renales/patología , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/genética , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/metabolismo , Línea Celular Tumoral , Proliferación Celular , Neoplasias Renales/patología , Regulación Neoplásica de la Expresión GénicaRESUMEN
INTRODUCTION: In this study, we evaluated whether SARS-CoV-2 mRNA vaccines induce anti-human leukocyte antigen (HLA) antibodies and anti- ABO blood type antibodies (ABOAb) in kidney transplant recipients (KTRs). METHODS: Sixty-three adult KTRs with functioning grafts who received two doses of the SARS-CoV-2 mRNA vaccine were enrolled in this cohort. Changes in anti-ABO blood type immunoglobulin IgM and IgG antibody titers, flow panel reactive antibody (PRA), de novo donor-specific anti-human leukocyte antigen antibodies (DSA), and kidney allograft function before and after vaccination were evaluated. RESULTS: Only one patient experienced conversion from negative to positive flow PRA after vaccination. However, there was no DSA in single antigen flow-bead assays. The mean fluorescence intensity (MFI) in the eight DSA-positive recipients did not significantly change before and after vaccination (p = .383), and no additional DSA was produced after vaccination in those patients. No significant elevation of ABOAb titer was observed for either IgM (p = .438) or IgG (p = .526) after vaccination. There was no significant deterioration in estimated glomerular filtration rate (eGFR) after vaccination (p = .877) or elevation of the urine protein-to-creatinine ratio (p = .209) after vaccination. One episode of AMR was observed in addition to a preexisting acute cellular rejection. CONCLUSIONS: The SARS-CoV-2 mRNA vaccine did not induce anti-HLA antibody or ABOAb production in KTRs.
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Vacunas contra la COVID-19 , COVID-19 , Trasplante de Riñón , Adulto , Humanos , Anticuerpos Antivirales , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Antígenos HLA/inmunología , Inmunoglobulina M , ARN Mensajero/genética , SARS-CoV-2 , Receptores de Trasplantes , Vacunación/efectos adversosRESUMEN
BACKGROUND: Among patients who undergo kidney transplantation, a subsequent second kidney transplantation (TX2) is often necessary. The TX2 outcomes remain controversial, however, and only limited data are available on clinical outcomes of TX2 in Japanese patients. This study aimed to assess graft and patient survival rates of TX2 and compared these rates with those of first kidney transplantation (TX1) in Japanese patients. METHODS: Of the 898 kidney transplantations performed between 2010 and 2019 at our institution, 33 were TX2. We performed survival analysis using weighted Kaplan-Meier analysis and Cox proportional hazards analysis with propensity score matching, specifically inverse probability of treatment weighting (IPTW). RESULTS: Death-censored graft survival (DCGS) rates at 1, 3, and 5 years for the TX1 versus TX2 groups were 99.3, 97.9, and 95.0% versus 100, 96.0, and 91.2%, respectively. Overall survival (OS) rates at 1, 3, and 5 years for the TX1 versus TX2 groups were 99.4, 98.9, and 97.8% versus 100, 100, and 94.4%, respectively. Using the log-rank test, IPTW-weighted Kaplan-Meier curves showed no significant differences for TX1 versus TX2 in DCGS (p = 0.535) and OS (p = 0.302). On Cox proportional hazards analysis for TX2 versus TX1, the IPTW-adjusted hazard ratio (HR) for DCGS was 1.75 (95% CI, 0.28-10.9; p = 0.550) and for OS was 2.71 (95% CI, 0.40-18.55; p = 0.311). CONCLUSIONS: For patients who require TX2, this treatment is an acceptable option based on the short-term outcomes data for DCGS and OS.
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Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , Estudios Retrospectivos , Pueblos del Este de Asia , Supervivencia de Injerto , Análisis de Supervivencia , Modelos de Riesgos Proporcionales , Estimación de Kaplan-Meier , Resultado del TratamientoRESUMEN
BACKGROUND: The Modified International Metastatic Renal Cell Carcinoma Dataset Consortium model (mIMDC) is a preoperative prognostic model for pT3cN0M0 renal cell carcinoma (RCC). This study aimed to validate the mIMDC and to construct a new model in a localized and locally advanced RCC (LLRCC). METHODS: A database was established (the Michinoku Japan Urological Cancer Study Group database) consisting of 79 patients who were clinically diagnosed with LLRCC (cT3b/c/4NanyM0) and underwent radical nephrectomy from December 2007 to May 2018. Using univariable and multivariable analyses, we retrospectively analyzed disease-free survival (DFS) and overall survival (OS) in this database, constructed a new prognostic model according to these results, and estimated the model fit using c-index on the new and mIMDC models. RESULTS: Independent poorer prognostic factors for both DFS and OS include the following: ≥ 1 Eastern Cooperative Oncology Group performance status, 2.0 mg/dL C-reactive protein, and > upper normal limit of white blood cell count. The median DFS in the favorable (no factor), intermediate (one factor), and poor-risk group (two or three factors) was 76.1, 14.3, and 4.0 months, respectively (P < 0.001). The 3-year OS in the favorable, intermediate, and poor-risk group were 92%, 44%, and 0%, respectively (P < 0.001). The c-indices of the new and mIMDC models were 0.67 and 0.60 for DFS (P = 0.060) and 0.74 and 0.63 for OS (P = 0.012), respectively. CONCLUSION: The new preoperative prognostic model in LLRCC can be used in patient care and clinical trials.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/patología , Pronóstico , Neoplasias Renales/patología , Estudios Retrospectivos , Japón , NefrectomíaRESUMEN
BACKGROUND: Immune thrombocytopenia (ITP) is an acquired disorder characterised by a low platelet count due to immune-mediated destruction and impaired platelet production. Here we report a rare case of primary cytomegalovirus (CMV) infection followed by thrombocytopenia after renal transplantation (RT). CASE PRESENTATION: A 24-year-old male patient with end-stage kidney disease secondary to hereditary focal segmental glomerulosclerosis was treated with peritoneal dialysis and received ABO-compatible living-related RT from his aunt. Nine months after the RT, the patient was diagnosed with primary CMV infection. After initiating treatment for primary CMV infection, the patient developed thrombocytopenia. After excluding other diseases or drugs that may cause thrombocytopenia, the patient was finally diagnosed with ITP, administered prednisolone (PSL), and started on Helicobacter pylori eradication therapy. Tapering the PSL dose was difficult, but thrombopoietin receptor agonists (TPO-RAs) were effective. CONCLUSIONS: In this case, the patient was diagnosed with ITP, and other causes of thrombocytopenia after RT were successfully ruled out. This case report demonstrates that RT recipients can develop ITP after CMV infection, and, in such cases, TPO-RAs may be an attractive option as a second-line therapy.
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Infecciones por Citomegalovirus , Trasplante de Riñón , Púrpura Trombocitopénica Idiopática , Trombocitopenia , Adulto , Humanos , Masculino , Adulto Joven , Citomegalovirus , Infecciones por Citomegalovirus/complicaciones , Infecciones por Citomegalovirus/tratamiento farmacológico , Trasplante de Riñón/efectos adversos , Recuento de Plaquetas , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/etiología , Receptores de Trombopoyetina/agonistas , Proteínas Recombinantes de Fusión , Trombocitopenia/etiología , Trombocitopenia/complicacionesRESUMEN
OBJECTIVE: To evaluated the trends of local intervention and their impact on oncological outcomes in metastatic hormone-naïve prostate cancer (mHNPC) in real-world practice. METHODS: This retrospective multicenter study included 760 patients treated with either androgen deprivation therapy (ADT) without local treatment (no castration-resistant prostate cancer [CRPC] progression within 12 months, control group) or ADT plus local intervention (intervention group) between January 2005 and March 2022. We evaluated the trends in the use of local intervention in patients with mHNPC and factors associated with CRPC-free survival in the intervention group. RESULTS: The use of local intervention gradually increased in combination with upfront combination treatment (docetaxel or androgen receptor axis-targeted agents) for the duration of our study. The number of patients with local intervention combined with upfront treatment was significantly higher in patients with high tumor burden disease than in those with low tumor burden disease. Of the 108 patients who received local intervention, a duration of ≤7 months of initial therapy before local intervention and a level of prostate-specific antigen ≥0.20 ng/mL at the time of local intervention were significantly associated with poor CRPC-free survival. CONCLUSIONS: The use of local intervention in combination with upfront therapy to treat mHNPC increased for the duration of our study regardless of the tumor burden. Local intervention in addition to the standard of care for mHNPC may be a feasible treatment option for selected patients, taking into consideration the duration of and response to initial treatment.
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Neoplasias de la Próstata Resistentes a la Castración , Neoplasias de la Próstata , Masculino , Humanos , Antagonistas de Andrógenos/uso terapéutico , Estudios Retrospectivos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Resultado del Tratamiento , Hormonas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
BACKGROUND: This study is part of the SNPs in Nivolumab PD-1 inhibitor for RCC (SNiP-RCC). Here we aimed to reveal clinical factors for tumor response, progression, and survival in nivolumab for advanced clear cell renal cell carcinoma (RCC) in Japanese patients. METHODS: We included patients from 23 institutions in Japan. We evaluated the objective response, radiographic progression-free survival (PFS), overall survival (OS), and treatment-related grade ≥ 3 (serious adverse events [SAEs]). RESULTS: We included 222 patients. The median age was 69 years (interquartile range 62-74 years), and 71% of the patients were male. Pancreas metastasis, lung metastases, prior cytokine therapy, and SAEs, were associated with objective response. The median PFS was 18 months. Liver metastases (hazard ratio [HR], 1.61), age ≥ 75 (HR, 0.48), previous resection of primary sites (HR, 0.47), and SAEs (HR, 0.47) were independent prognostic factors for PFS. Karnofsky Performance Status <70 (HR, 2.90), high platelets (HR, 4.48), previous resection of primary sites (HR, 0.23), and pathological grade (HR, 0.19 for grade 2 and HR, 0.12 for grade 3) were independent prognostic factors for OS. SAEs were reported in 45 (20.3%) cases. In the group of patients with prior nephrectomy, SAEs were associated with objective response, PFS, and OS. CONCLUSION: The SNiP-RCC study identified clinical parameters correlated with treatment outcomes in Japanese patients with priorly treated advanced clear cell RCC undergoing nivolumab monotherapy.
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Carcinoma de Células Renales , Neoplasias Renales , Humanos , Masculino , Persona de Mediana Edad , Anciano , Femenino , Carcinoma de Células Renales/patología , Nivolumab/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Renales/patología , Polimorfismo de Nucleótido SimpleRESUMEN
Human leukocyte antigen class I (HLA-I) genotypes are suggested to influence the cancer response to checkpoint blockade immunotherapy. This study assessed the impact of germline HLA genotypes on clinical outcomes in patients with chemoresistant advanced urothelial cancer (UC) treated with pembrolizumab. Zygosity, supertypes, evolutionary divergency, and specific alleles of germline HLA-I and -II were evaluated using the Luminex technique in 108 patients with chemoresistant metastatic or locally advanced UC treated with pembrolizumab. Among the 108 patients, 69 died and 83 showed radiographic progression during follow-up. Homozygous for at least one HLA-I locus, absence of the HLA-A03 supertype, and high HLA-I evolutionary divergence were associated with a radiographic response, but were not associated with survival outcomes. Patients with the HLA-DQB1*03:01 allele had significantly lower disease control rates than patients without the allele (17.4% vs. 53.8%, p = 0.002); its presence was also an independent risk factor for progressive disease (hazard ratio 4.35, 95% confidence interval 1.03-18.46). Furthermore, patients with the HLA-DQB1*03:01 allele had significantly worse progression-free survival than patients without the allele (median progression-free survival 3.1 vs. 4.8 months, p = 0.035). There was no significant relationship between any HLA status and the incidence of severe adverse events. Several germline HLA genotypes, especially HLA-DQB1*03:01, may be associated with radiographic progression. However, their impact on treatment response is limited, and germline HLA genotypes was not independently associated with survival outcomes. Further prospective studies are needed to confirm the relationship between germline HLA genotypes and clinical outcomes in patients with chemoresistant advanced UC treated with pembrolizumab.
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Carcinoma de Células Transicionales , Genes MHC Clase II , Genes MHC Clase I , Neoplasias de la Vejiga Urinaria , Humanos , Alelos , Carcinoma de Células Transicionales/genética , Carcinoma de Células Transicionales/patología , Genotipo , Supervivencia sin Progresión , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
Early diagnosis of urological diseases is often difficult due to the lack of specific biomarkers. More powerful and less invasive biomarkers that can be used simultaneously to identify urological diseases could improve patient outcomes. The aim of this study was to evaluate a urological disease-specific scoring system established with a machine learning (ML) approach using Ig N-glycan signatures. Immunoglobulin N-glycan signatures were analyzed by capillary electrophoresis from 1312 serum subjects with hormone-sensitive prostate cancer (n = 234), castration-resistant prostate cancer (n = 94), renal cell carcinoma (n = 100), upper urinary tract urothelial cancer (n = 105), bladder cancer (n = 176), germ cell tumors (n = 73), benign prostatic hyperplasia (n = 95), urosepsis (n = 145), and urinary tract infection (n = 21) as well as healthy volunteers (n = 269). Immunoglobulin N-glycan signature data were used in a supervised-ML model to establish a scoring system that gave the probability of the presence of a urological disease. Diagnostic performance was evaluated using the area under the receiver operating characteristic curve (AUC). The supervised-ML urologic disease-specific scores clearly discriminated the urological diseases (AUC 0.78-1.00) and found a distinct N-glycan pattern that contributed to detect each disease. Limitations included the retrospective and limited pathological information regarding urological diseases. The supervised-ML urological disease-specific scoring system based on Ig N-glycan signatures showed excellent diagnostic ability for nine urological diseases using a one-time serum collection and could be a promising approach for the diagnosis of urological diseases.
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Neoplasias Renales , Neoplasias de la Próstata , Neoplasias de la Vejiga Urinaria , Biomarcadores de Tumor , Humanos , Inmunoglobulinas , Aprendizaje Automático , Masculino , Polisacáridos , Estudios Retrospectivos , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
BACKGROUND: The effect of upfront intensive therapy on the prognosis of older patients with metastatic castration-sensitive prostate cancer (mCSPC) remains unclear. Thus, we assessed the impact of older age (≥75 years) on oncological outcomes in mCSPC patients with a high tumor burden. METHODS: This multicenter retrospective study included 252 patients aged ≥75 years treated with either upfront or conventional therapy between 2014 and 2021. We compared castration-resistant prostate cancer (CRPC)-free survival (FS) and overall survival (OS) between patients with androgen deprivation therapy (ADT) plus upfront intensive therapy (docetaxel [DTX] or abiraterone acetate [ABI] plus prednisolone) and conventional therapy (ADT monotherapy or ADT combined with bicalutamide). We evaluated the effect of upfront intensive therapy on prognosis by multivariable Cox regression analysis. RESULTS: The 231 patients enrolled in our study were classified in the conventional group (n = 148) or the upfront group (n = 104; DTX = 27 and ABI = 77). The upfront group had significantly prolonged CRPC-FS and OS compared with the conventional group, and this was also the case in the background-adjusted multivariable Cox regression analysis. CONCLUSION: Patients aged ≥75 years who received upfront intensive therapy had significantly longer CRPC-FS and OS compared with similar age patients treated with conventional therapy in real-world practice. The oncological benefit may not diminish in this older population.
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Neoplasias de la Próstata Resistentes a la Castración , Neoplasias de la Próstata , Anciano , Antagonistas de Andrógenos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Castración , Docetaxel/uso terapéutico , Humanos , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Estudios Retrospectivos , Carga TumoralRESUMEN
WHAT IS THIS SUMMARY ABOUT?: This is a plain language summary of an article originally published in The New England Journal of Medicine. It is about initial results (collected in October 2019) from the JAVELIN Bladder 100 study (a clinical trial), which looked at avelumab maintenance treatment in people with advanced urothelial cancer. Urothelial cancer is the most common type of bladder cancer. People with advanced urothelial cancer often receive chemotherapy. If this is the first treatment people with advanced disease are given, it is called first-line treatment. If the cancer stops growing or shrinks with first-line chemotherapy, people can be given different treatment to try to prevent the cancer from growing again. This is called maintenance treatment. It may help people live longer. WHAT HAPPENED IN THE JAVELIN BLADDER 100 STUDY?: In the JAVELIN Bladder 100 study, researchers wanted to find out if maintenance treatment with avelumab would help people with advanced urothelial cancer live longer. Avelumab is a type of medicine called immunotherapy. Immunotherapy helps the body's immune system fight cancer. 700 people took part in the study. To take part, they must have already been treated with first-line chemotherapy. Also, their cancer must have shrunk or not grown with this treatment. They were then treated with either avelumab maintenance treatment plus best supportive care or best supportive care alone. Best supportive care means treatments that help improve symptoms and quality of life. These treatments do not affect the cancer directly and can include medicines to relieve pain. WHAT WERE THE RESULTS?: Researchers found that people treated with avelumab maintenance treatment plus best supportive care lived, on average, 7 months longer than people who received best supportive care alone. People treated with avelumab had more side effects than those not treated with avelumab, but most were not severe. Common side effects with avelumab included persistent tiredness, itchy skin, urinary tract infection, and diarrhea. WHAT DO THE RESULTS OF THE STUDY MEAN?: Results from the JAVELIN Bladder 100 study support the use of avelumab as maintenance treatment for people with advanced urothelial cancer whose cancer has shrunk or not grown with first-line chemotherapy. ClinicalTrials.gov NCT number: NCT02603432.
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Carcinoma de Células Transicionales , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Neoplasias de la Vejiga Urinaria , Anticuerpos Monoclonales Humanizados , Carcinoma de Células Transicionales/tratamiento farmacológico , Humanos , Lenguaje , Calidad de Vida , Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
BACKGROUND: The phase 3 JAVELIN Bladder 100 trial showed significantly prolonged overall survival (OS) with avelumab as first-line (1L) maintenance therapy + best supportive care (BSC) vs BSC alone in patients with advanced urothelial carcinoma (UC) that had not progressed with 1L platinum-containing chemotherapy. Efficacy and safety were assessed in patients enrolled in Japan. METHODS: Patients with locally advanced or metastatic UC that had not progressed with 4-6 cycles of 1L platinum-containing chemotherapy were randomized to avelumab (10 mg/kg intravenously every 2 weeks) + BSC or BSC alone. The primary endpoint was OS, and secondary endpoints included progression-free survival (PFS) and safety. RESULTS: In Japanese patients (n = 73) randomized to avelumab + BSC (n = 36) or BSC alone (n = 37), median OS was 24.7 months (95% CI, 18.2-not estimable) vs 18.7 months (95% CI, 12.8-33.0), respectively (HR, 0.81 [95% CI, 0.41-1.58]), and median PFS was 5.6 months (95% CI, 1.9-9.4) vs 1.9 months (95% CI, 1.9-3.8), respectively (HR, 0.63 [95% CI, 0.36-1.11]). In the avelumab + BSC and BSC-alone arms, grade ≥ 3 treatment-emergent adverse events (AEs) occurred in 50.0% vs 8.1%, including grade ≥ 3 treatment-related AEs in 13.9% vs 0%, respectively. Efficacy and safety results in Japanese patients were generally consistent with findings in the overall trial population. CONCLUSION: Avelumab 1L maintenance treatment showed a favorable benefit-risk balance in Japanese patients, supporting avelumab 1L maintenance as a new standard of care in Japanese patients with advanced UC that has not progressed with 1L platinum-containing chemotherapy. TRIAL REGISTRATION: Clinicaltrials.gov NCT02603432.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Transicionales/tratamiento farmacológico , Humanos , Japón , Vejiga Urinaria , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
BACKGROUND: This retrospective multicenter study aimed to evaluate the survival benefit of upfront cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (RCC) patients stratified by International Metastatic RCC Database Consortium (IMDC) risk criteria. METHODS: We reviewed the medical records in the Michinoku Database between 2008 and 2019. Patients who received upfront CN, systemic therapy without CN (no CN) and CN after drug therapy (deferred CN) were analyzed. To exclude selection bias due to patient characteristics, baseline clinical data were adjusted by inverse probability of treatment weighting (IPTW). Overall survival (OS) was compared between upfront CN and non-upfront CN (no CN plus deferred CN). Associations between time-varying covariates including systemic therapies and OS stratified by IMDC risk criteria were analyzed by IPTW-adjusted Cox regression method. RESULTS: Of 259 patients who fulfilled the selection criteria, 107 were classified in upfront CN and 152 in non-upfront CN group. After IPTW-adjusted analysis, upfront CN showed survival benefit compared to non-upfront CN in patients with IMDC intermediate risk (median OS: 52.5 versus 31.3 months, p < 0.01) and in patients with IMDC poor risk (27.2 versus 11.4 months, p < 0.01). In IPTW-adjusted Cox regression analysis of time-varying covariates, upfront CN was independently associated with OS benefit in patients with IMDC intermediate risk (hazard ratio 0.52, 95% confidence interval 0.29-0.93, p = 0.03) and in patients with IMDC poor risk (0.26, 0.11-0.59, p < 0.01). CONCLUSIONS: Upfront CN may confer survival benefit in RCC patients with IMDC intermediate and poor risk.
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Carcinoma de Células Renales , Neoplasias Renales , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/cirugía , Procedimientos Quirúrgicos de Citorreducción/métodos , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Nefrectomía/métodos , Estudios RetrospectivosRESUMEN
Accompanied by the development of systemic therapy for metastatic renal cell carcinoma, the concept of focal treatment, including surgical treatment, has been changing. Although immediate cytoreductive nephrectomy was essentially considered for synchronous metastatic renal cell carcinoma patients, the CARMENA trial and SURTIME trial revealed the negative impact of immediate cytoreductive nephrectomy. Therefore, immediate cytoreductive nephrectomy is currently considered only for a limited number of patients. Besides, deferred cytoreductive nephrectomy seems to have efficacy for overall survival in prior retrospective studies. Two randomized controlled trials, the PROBE trial (NCT04510597) and the NORDIC-SUN trial (NCT03977571), are underway to elucidate deferred cytoreductive nephrectomy. Metastasectomy is also considered in metastatic renal cell carcinoma patients because previous studies demonstrated the overall survival benefit of metastasectomy. However, since all reports were retrospective studies, physicians could exclude the patients who were not expected to show the efficacy of metastasectomy. Therefore, an adequate patient selection for metastasectomy is important. A common factor predicting better overall survival was complete resection. Radiotherapies for metastatic lesions during systemic therapy showed approximately 90% local disease control rate at 1 year. However, no report has demonstrated that radiotherapy improves survival so far. Since surgical and focal treatments for metastatic renal cell carcinoma patients generally have minimal evidence, further investigations are needed.
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Carcinoma de Células Renales , Neoplasias Renales , Carcinoma de Células Renales/secundario , Carcinoma de Células Renales/cirugía , Procedimientos Quirúrgicos de Citorreducción , Humanos , Neoplasias Renales/cirugía , Nefrectomía , Estudios RetrospectivosRESUMEN
OBJECTIVES: We evaluated whether the treatment history of low-dose rituximab affected safety profiles, and humoral and cellular responses induced by severe acute respiratory syndrome coronavirus 2 messenger ribonucleic acid vaccine in healthy controls and kidney transplant recipients. METHODS: We enrolled 10 healthcare workers as controls, 22 kidney transplant recipients with rituximab, and 36 kidney transplant recipients without rituximab without history of coronavirus disease 2019 who received two doses of vaccine. We assessed anti-severe acute respiratory syndrome coronavirus 2 spike antibody and the antigen-specific T cells using enzyme-linked immunospot against spike protein at baseline and after two doses of vaccine. RESULTS: All controls showed anti-severe acute respiratory syndrome coronavirus 2 antibody seroconversion and enzyme-linked immunospot positivity. Only 19/58 (33%) kidney transplant recipients experienced anti-severe acute respiratory syndrome coronavirus 2 antibody seroconversion and 31/58 (53%) kidney transplant recipients developed enzyme-linked immunospot assay positivity after vaccination. The anti-severe acute respiratory syndrome coronavirus 2 antibody seroconversion rate and enzyme-linked immunospot assay positivity rate after vaccination were not significantly different between kidney transplant recipients with or without rituximab. Multivariate regression analysis demonstrated rituximab was not associated with a lack of humoral and cellular responses to the vaccine. CONCLUSIONS: Low-dose rituximab in kidney transplant recipients did not affect humoral or cellular responses to the severe acute respiratory syndrome coronavirus 2 messenger ribonucleic acid vaccine without severe systemic adverse events including the deterioration of kidney function.