Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.294
Filtrar
1.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799514

RESUMO

Treatment of patients with urothelial carcinoma (UC) of the bladder or renal cancer has changed significantly during recent years and efforts towards biomarker-directed therapy are being investigated. Immune checkpoint inhibition (ICI) or fibroblast growth factor receptor (FGFR) directed therapy are being evaluated for non-muscle invasive bladder cancer (NMIBC) patients, as well as muscle-invasive bladder cancer (MIBC) patients. Meanwhile, efforts to predict tumor response to neoadjuvant chemotherapy (NAC) are still ongoing, and genomic biomarkers are being evaluated in prospective clinical trials. Currently, patients with metastatic UC (mUC) are usually treated with second-line ICI, while cisplatin-ineligible patients with programmed death-ligand 1 (PD-L1) positive tumors can benefit from first-line ICI. Platinum-relapsed UC patients harboring FGFR2/3 mutations can be treated with erdafitinib, while enfortumab vedotin has emerged as a novel third-line treatment option for mUC. In metastatic (clear cell) renal cell carcinoma (RCC), ICI was first introduced as second-line treatment after vascular endothelial growth factor receptor-tyrosine kinase inhibition (VEGFR-TKI). Currently, ICIs have also been introduced as first-line treatment in metastatic RCC. Although there is no evidence up to now for beneficial adjuvant treatment after surgery with VEGFR-TKIs in high-risk non-metastatic RCC, several trials are underway investigating the potential beneficial effect of ICIs in this setting.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Cisplatino/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Metástase Linfática , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Quinoxalinas/uso terapêutico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/imunologia , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/genética , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/imunologia , Recidiva , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/imunologia , Neoplasias da Bexiga Urinária/patologia
3.
Int J Mol Sci ; 22(6)2021 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-33799686

RESUMO

Von Hippel Lindau (VHL) inactivation, which is common in clear cell renal cell carcinoma (ccRCC), leads directly to the disruption of oxygen homoeostasis. VHL works through hypoxia-inducible factors (HIFs). Within this VHL-HIF system, prolyl hydroxylases (PHDs) are the intermediary proteins that initiate the degradation of HIFs. PHD isoform 3's (PHD3) role in ccRCC growth in vivo is poorly understood. Using viral transduction, we knocked down the expression of PHD3 in the human ccRCC cell line UMRC3. Compared with control cells transduced with scrambled vector (UMRC3-SC cells), PHD3-knockdown cells (UMRC3-PHD3KD cells) showed increased cell invasion, tumor growth, and response to sunitinib. PHD3 knockdown reduced HIF2α expression and increased phosphorylated epidermal growth factor (EGFR) expression in untreated tumor models. However, following sunitinib treatment, expression of HIF2α and phosphorylated EGFR were equivalent in both PHD3 knockdown and control tumors. PHD3 knockdown changed the overall redox state of the cell as seen by the increased concentration of glutathione in PHD3 knockdown tumors relative to control tumors. UMRC3-PHD3KD cells had increased proliferation in cell culture when grown in the presence of hydrogen peroxide compared to UMRC3-SC control cells. Our findings illustrate (1) the variable effect of PHD3 on HIF2α expression, (2) an inverse relationship between PHD3 expression and tumor growth in ccRCC animal models, and (3) the role of PHD3 in maintaining the redox state of UMRC3 cells and their proliferative rate under oxidative stress.


Assuntos
Carcinoma de Células Renais/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Neoplasias Renais/genética , Mutação , Interferência de RNA , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Receptores ErbB/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/metabolismo , Camundongos Endogâmicos NOD , Camundongos SCID , Fosforilação/efeitos dos fármacos , Sunitinibe/farmacologia , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
4.
N Engl J Med ; 384(9): 829-841, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33657295

RESUMO

BACKGROUND: The efficacy and safety of nivolumab plus cabozantinib as compared with those of sunitinib in the treatment of previously untreated advanced renal-cell carcinoma are not known. METHODS: In this phase 3, randomized, open-label trial, we randomly assigned adults with previously untreated clear-cell, advanced renal-cell carcinoma to receive either nivolumab (240 mg every 2 weeks) plus cabozantinib (40 mg once daily) or sunitinib (50 mg once daily for 4 weeks of each 6-week cycle). The primary end point was progression-free survival, as determined by blinded independent central review. Secondary end points included overall survival, objective response as determined by independent review, and safety. Health-related quality of life was an exploratory end point. RESULTS: Overall, 651 patients were assigned to receive nivolumab plus cabozantinib (323 patients) or sunitinib (328 patients). At a median follow-up of 18.1 months for overall survival, the median progression-free survival was 16.6 months (95% confidence interval [CI], 12.5 to 24.9) with nivolumab plus cabozantinib and 8.3 months (95% CI, 7.0 to 9.7) with sunitinib (hazard ratio for disease progression or death, 0.51; 95% CI, 0.41 to 0.64; P<0.001). The probability of overall survival at 12 months was 85.7% (95% CI, 81.3 to 89.1) with nivolumab plus cabozantinib and 75.6% (95% CI, 70.5 to 80.0) with sunitinib (hazard ratio for death, 0.60; 98.89% CI, 0.40 to 0.89; P = 0.001). An objective response occurred in 55.7% of the patients receiving nivolumab plus cabozantinib and in 27.1% of those receiving sunitinib (P<0.001). Efficacy benefits with nivolumab plus cabozantinib were consistent across subgroups. Adverse events of any cause of grade 3 or higher occurred in 75.3% of the 320 patients receiving nivolumab plus cabozantinib and in 70.6% of the 320 patients receiving sunitinib. Overall, 19.7% of the patients in the combination group discontinued at least one of the trial drugs owing to adverse events, and 5.6% discontinued both. Patients reported better health-related quality of life with nivolumab plus cabozantinib than with sunitinib. CONCLUSIONS: Nivolumab plus cabozantinib had significant benefits over sunitinib with respect to progression-free survival, overall survival, and likelihood of response in patients with previously untreated advanced renal-cell carcinoma. (Funded by Bristol Myers Squibb and others; CheckMate 9ER ClinicalTrials.gov number, NCT03141177.).


Assuntos
Anilidas/administração & dosagem , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Nivolumabe/administração & dosagem , Piridinas/administração & dosagem , Sunitinibe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anilidas/efeitos adversos , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Carcinoma de Células Renais/mortalidade , Feminino , Humanos , Análise de Intenção de Tratamento , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Piridinas/efeitos adversos , Qualidade de Vida , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Sunitinibe/efeitos adversos , Análise de Sobrevida
5.
Crit Rev Oncol Hematol ; 160: 103293, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33667661

RESUMO

BACKGROUND: The role of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC) in the era of targeted- (TT) and immuno- (IT) therapy remains controversial. DESIGN: The primary objective of the present systematic, performed according to PRISMA guidelines review, was to assess the prevalence of nephrectomy in mRCC patients enrolled in TT/IT randomized phase II/III clinical trials (RCTs) or expanded access programs (EAPs). Medline database was searched from 2003 to 2019 for studies with available nephrectomy data. RESULTS: We identified 609 studies, subsequently restricted to 57 randomized phase II/III clinical trials and 6 EAPs. Overall, 33,196 patients with mRCC were included, among whom 28,700 (86.4 %) underwent nephrectomy. The trends over time of nephrectomy occurrence remained substantially stable from 2003 to 2019. CONCLUSIONS: Our analysis highlighted that data from RCTs and EAPs driving the clinical practice originate from nephrectomized patient populations. This evidence supports the clinical relevance of CN also in mRCC patients candidate to receive TT/IT.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/cirurgia , Ensaios Clínicos Fase II como Assunto , Procedimentos Cirúrgicos de Citorredução , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/cirurgia , Terapia de Alvo Molecular , Nefrectomia , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
Life Sci ; 275: 119377, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33757771

RESUMO

AIMS: Silibinin offers potential anticancer effect with less aqueous solubility and high permeability. The present study aimed to develop biocompatible magnetic-core-based nanopolymeric carriers of poly (D, l-lactide-co-glycolic) acid (PLGA) encapsulated silibinin for the sustained release action on renal cancerous cell. MAIN METHODS: The synthesized iron oxide nanoparticles were prepared by precipitation method via encapsulation of silibinin in PLGA network using double emulsion method. The nanoparticle formulations were characterized for morphological, physicochemical properties (HRTEM, FTIR, Raman Spectroscopy and VSM), in vitro drug release and cytotoxicity study on kidney cancer cells (A-498). The safety of magnetic-core-based silibinin nanopolymeric carriers was conducted by i.v. administration at a dose of 50 mg/kg in mice. KEY FINDINGS: The mean particle size, zeta potential and % encapsulation efficiency of magnetic-core-based silibinin nanopolymeric carriers were found to be 285.9 ± 0.28 nm, -14.71 ± 0.15 mV and 84.76 ± 1.29%, respectively. The saturation magnetization of magnetic core and optimized nanoparticles were reported as 36.35 emu/g and 12.78 emu/g, respectively. HRTEM analyses revealed the spherical shapes of the particles with uniform size distribution. The in vitro release profile of silibinin from the nanoparticles exhibited a sustained delivery for 15 days and displayed better cytotoxicity against human kidney cancer cells (A-498) than silibinin. In vivo study showed the safety of magnetic-core-based silibinin nanopolymeric carriers in mice. SIGNIFICANCE: The magnetic-core-based silibinin nanopolymeric carriers will act as a potential carrier for targeted transportation of actives in cancer therapy.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Portadores de Fármacos , Neoplasias Renais/tratamento farmacológico , Nanopartículas de Magnetita , Silibina/uso terapêutico , Antineoplásicos Fitogênicos/administração & dosagem , Linhagem Celular Tumoral , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/efeitos adversos , Humanos , Nanopartículas de Magnetita/administração & dosagem , Nanopartículas de Magnetita/efeitos adversos , Silibina/administração & dosagem , Espectroscopia de Infravermelho com Transformada de Fourier , Análise Espectral Raman
7.
Anticancer Res ; 41(3): 1539-1545, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33788747

RESUMO

BACKGROUND/AIM: Nivolumab monotherapy for advanced/metastatic renal cell carcinoma (RCC) shows a survival benefit. The purpose of this study was to evaluate tumor responses to nivolumab in various metastatic and primary sites in patients with RCC. PATIENTS AND METHODS: We retrospectively reviewed 68 patients who underwent nivolumab monotherapy after one or more regimens of targeted therapy for advanced/metastatic RCC. The site-specific response was evaluated and progression-free survival was estimated. RESULTS: The site-specific overall response rates (ORRs) were as follows: lung (36%), bone (5%), lymph node (33%), liver (50%), adrenal gland (29%), pancreas (33%), and brain (0%). The ORR of bone metastasis was significantly worse in comparison to lung and liver metastases (p=0.017, 0.008). The site-specific median progression-free survival times were as follows: lung (5.1 months), bone (not reached), lymph node (not reached), and liver (17.5 months). CONCLUSION: Responses to nivolumab may vary depending on metastasized organs.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Nivolumabe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Feminino , Humanos , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estudos Retrospectivos , Carga Tumoral
8.
Medicine (Baltimore) ; 100(13): e25402, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33787647

RESUMO

ABSTRACT: Nivolumab has shown good prognosis in renal cell carcinoma (RCC) patients previously treated with targeted therapy. We aimed to study irAE (immune-related adverse event) due to nivolumab and numbers of previous treatment lines in RCC patients. Between October 2016 and November 2019, 114 patients were treated with nivolumab as second- and later-line therapy. Among them, 110 patients with complete data were evaluated in this retrospective observational study. The primary endpoint was the relation between irAE and numbers of previous targeted therapies. Secondary endpoints were the relation of irAE with the duration of nivolumab treatment and with best overall response. For the primary analysis, proportional odds logistic regression was used to assess the effect of the number of prior therapies on the grade of any irAE as the ordinal variable. For the secondary analysis, binomial logistic regression models adjusted for the covariates were prepared to confirm the association between the incidence of irAE and the number of courses, number of nivolumab treatments and best overall response. Overall, 69, 66, 33, 13, 9 and 9 patients were treated with sunitinib, axitinib, pazopanib, sorafenib, temsirolimus and everolimus, respectively, prior to nivolumab. In total, 60 adverse events (Grade 1, 21; Grade 2, 21; Grade 3, 14; Grade 4, 2; not evaluated, 2) were identified in the patients treated with nivolumab. Ordered logistic regression analysis showed that the adjusted odds ratios of numbers of prior treatment for grade of irAE were 1.12 (numbers of prior treatment: 2 to 1) and 1.31 (3 to 1). Odds ratios of the numbers of nivolumab treatments and best overall response for the incidence of irAE were not significant. No statistically significant relations were found between grade of irAE and numbers of treatments prior to nivolumab. Patients treated with nivolumab should be closely monitored for irAE regardless number of previous therapies.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Neoplasias Renais/tratamento farmacológico , Nivolumabe/efeitos adversos , Idoso , Antineoplásicos Imunológicos/administração & dosagem , Carcinoma de Células Renais/imunologia , Relação Dose-Resposta a Droga , Esquema de Medicação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/imunologia , Feminino , Humanos , Neoplasias Renais/imunologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/administração & dosagem , Razão de Chances , Retratamento/efeitos adversos , Retratamento/estatística & dados numéricos , Estudos Retrospectivos , Medição de Risco/estatística & dados numéricos , Índice de Gravidade de Doença , Resultado do Tratamento
9.
Hinyokika Kiyo ; 67(2): 57-61, 2021 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-33657772

RESUMO

We evaluated the impact of tumor shrinkage (TS) induced by molecular targeted therapy as the first-line systemic therapy on the survival of patients with metastatic renal cell carcinoma (mRCC). A total of 67 patients with mRCC who received first-line molecular targeted therapy were included in this study. Sixty patients were evaluable by response evaluation criteria in solid tumors. Patients underwent the first evaluation at 8-12 weeks after the start of the therapy. Twenty patients had TS ≧30%, 32 from 30% to -20%, and 8 ≦-20%. The median overall survival periods of patients who achieved TS ≧30%, from 30% to -20%, and ≦-20% at first evaluation were 41.0, 35.0, and 11.5 months, respectively. Univariate and multivariate analyses showed that TS of≧0%, in addition to negative C-reactive protein and the absence of bone metastasis were good predictors of overall survival. The patients who achieved 0% or more at the initial evaluation had longer survival than those who had no tumor reduction (40.0 months vs 12.0 months, p<0. 001). These findings suggest that early TS affects overall survival in real practice. We should consider alternative therapies for patients who have not achieved tumor reduction at the initial evaluation.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Terapia de Alvo Molecular , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento
10.
Hinyokika Kiyo ; 67(2): 63-66, 2021 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-33657773

RESUMO

A 67-year-old man underwent open radical left nephrectomy for left renal cell carcinoma [pT4N0M1 (right lower lobe of lung)] and thoracoscopic partial right lung resection for lung metastasis. The patient subsequently developed a solitary lung metastasis at 10 months and then at 26 months postoperatively. He underwent partial lung resection on each occasion. During the 28 months postoperatively, he was found to have a 12 mm middle mediastinal lymph node metastasis and a 30 mm splenic metastasis, which gradually increased in size. Three months after discovery, sunitinib was initiated at 37.5 mg 2 weeks on/1 week off. Twelve days later, the patient presented with complaints of fever. A gas-producing splenic abscess was diagnosed and he was admitted on the same day. His condition improved with antibiotics and splenic drainage. On day 35 of hospitalization, he underwent laparoscopic splenectomy. The patient's postoperative clinical course was uneventful and he was discharged 7 days after the surgery.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Esplenopatias , Neoplasias Esplênicas , Abscesso/diagnóstico por imagem , Abscesso/tratamento farmacológico , Abscesso/etiologia , Idoso , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/cirurgia , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/cirurgia , Masculino , Neoplasias Esplênicas/diagnóstico por imagem , Neoplasias Esplênicas/tratamento farmacológico , Neoplasias Esplênicas/cirurgia , Sunitinibe/uso terapêutico
11.
J Surg Oncol ; 123(3): 739-750, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33595892

RESUMO

Immune checkpoint blockade (ICB) is the foundation of current first-line therapies in patients with metastatic renal cell carcinoma (mRCC) with the potential for eliciting long-lasting remissions. With the expanding arsenal of ICB-based therapies, biomarkers of response are urgently needed to guide optimal therapeutic selection. We review the data behind ICB therapy in RCC, emerging biomarkers of response, and the evolving role of surgery in patients with mRCC.


Assuntos
Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Carcinoma de Células Renais/imunologia , Ensaios Clínicos como Assunto , Humanos , Neoplasias Renais/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto
12.
N Engl J Med ; 384(14): 1289-1300, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33616314

RESUMO

BACKGROUND: Lenvatinib in combination with pembrolizumab or everolimus has activity against advanced renal cell carcinoma. The efficacy of these regimens as compared with that of sunitinib is unclear. METHODS: In this phase 3 trial, we randomly assigned (in a 1:1:1 ratio) patients with advanced renal cell carcinoma and no previous systemic therapy to receive lenvatinib (20 mg orally once daily) plus pembrolizumab (200 mg intravenously once every 3 weeks), lenvatinib (18 mg orally once daily) plus everolimus (5 mg orally once daily), or sunitinib (50 mg orally once daily, alternating 4 weeks receiving treatment and 2 weeks without treatment). The primary end point was progression-free survival, as assessed by an independent review committee in accordance with Response Evaluation Criteria in Solid Tumors, version 1.1. Overall survival and safety were also evaluated. RESULTS: A total of 1069 patients were randomly assigned to receive lenvatinib plus pembrolizumab (355 patients), lenvatinib plus everolimus (357), or sunitinib (357). Progression-free survival was longer with lenvatinib plus pembrolizumab than with sunitinib (median, 23.9 vs. 9.2 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.32 to 0.49; P<0.001) and was longer with lenvatinib plus everolimus than with sunitinib (median, 14.7 vs. 9.2 months; hazard ratio, 0.65; 95% CI, 0.53 to 0.80; P<0.001). Overall survival was longer with lenvatinib plus pembrolizumab than with sunitinib (hazard ratio for death, 0.66; 95% CI, 0.49 to 0.88; P = 0.005) but was not longer with lenvatinib plus everolimus than with sunitinib (hazard ratio, 1.15; 95% CI, 0.88 to 1.50; P = 0.30). Grade 3 or higher adverse events emerged or worsened during treatment in 82.4% of the patients who received lenvatinib plus pembrolizumab, 83.1% of those who received lenvatinib plus everolimus, and 71.8% of those who received sunitinib. Grade 3 or higher adverse events occurring in at least 10% of the patients in any group included hypertension, diarrhea, and elevated lipase levels. CONCLUSIONS: Lenvatinib plus pembrolizumab was associated with significantly longer progression-free survival and overall survival than sunitinib. (Funded by Eisai and Merck Sharp and Dohme; CLEAR ClinicalTrials.gov number, NCT02811861.).


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Everolimo/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Quinolinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/mortalidade , Everolimo/efeitos adversos , Feminino , Humanos , Neoplasias Renais/mortalidade , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/efeitos adversos , Sunitinibe/efeitos adversos , Sunitinibe/uso terapêutico , Análise de Sobrevida
13.
Int Braz J Urol ; 47(3): 566-573, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33621005

RESUMO

BACKGROUND: Tyrosine kinase inhibitors (TKI) and immunotherapy improved survival in metastatic renal cell carcinoma (mRCC). Disparities in treatment access are present in healthcare systems globally. The aim of this study was to analyze survival outcomes of mRCC patients treated with first-line TKIs in the public (PHS) and private (PrS) health system in a Brazilian Cancer Center. MATERIALS AND METHODS: Records from all mRCC patients treated with first-line TKIs from 2007-2018 were reviewed retrospectively. Categorial variables were compared by Fisher's exact test. Survival was estimated by Kaplan-Maier method and survival curves were compared using the log-rank test. Prognostic factors were adjusted by Cox regression model. RESULTS: Of the 171 eligible patients, 37 (21.6%) were PHS patients and 134 (78.4%) were PrS patients. There were no difference in age, gender, or sites of metastasis. PHS patients had worse performance status (ECOG ≥2, 35.1% vs. 13.5%, p=0.007), poorer risk score (IMDC poor risk, 32.4% vs. 16.4%, p=0.09), and less nephrectomies (73% vs. 92.5%, p=0.003) than PrS patients. Median lines of therapy was one for PHS versus two for PrS patients (p=0.03). Median overall survival (OS) was 16.5 versus 26.5 months (p=0.002) and progression-free survival (PFS), 8.4 versus 11 months (p=0.01) for PHS and PrS patients, respectively. After adjusting for known prognostic factors on multivariate analysis, PHS patients still had a higher risk of death (HR: 1.61, 95% CI: 1.01-2.56, p=0.047). CONCLUSION: Patients with mRCC treated via the PHS had worse overall survival, possibly due to poorer prognosis at presentation and less drug access.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Brasil , Carcinoma de Células Renais/tratamento farmacológico , Intervalo Livre de Doença , Humanos , Neoplasias Renais/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Sunitinibe , Resultado do Tratamento
14.
Nat Commun ; 12(1): 808, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547292

RESUMO

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Renais/imunologia , Regulação Neoplásica da Expressão Gênica , /imunologia , Neoplasias Renais/imunologia , Tumor Rabdoide/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/imunologia , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , Mutação , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/imunologia , Estudos Retrospectivos , Tumor Rabdoide/tratamento farmacológico , Tumor Rabdoide/genética , Tumor Rabdoide/mortalidade , Transdução de Sinais , Análise de Sobrevida , Transcrição Genética , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/imunologia , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/imunologia
15.
Cancer Treat Rev ; 94: 102157, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33607461

RESUMO

A major breakthrough in cancer immunotherapy was the development of monoclonal antibodies targeting inhibitory immune checkpoint proteins. This approach demonstrated significant antitumor activity and efficacy in different cancer types, including metastatic renal cell carcinoma (mRCC). In the majority of patients, this drug is able to restore the patient's tumour-specific T-cell-mediated response thus improving both overall survival and objective response rate. However, a lack of clinical response occurs in a number of patients, raising questions about how to predict and increase the number of patients who receive long-term clinical benefit from immune checkpoint therapy or not. The aim of this review is to summarize available data about immune biomarkers in patients with mRCC treated with immunotherapy.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Animais , Antígeno B7-H1/biossíntese , Antígeno B7-H1/imunologia , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Ensaios Clínicos Fase III como Assunto , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Valor Preditivo dos Testes , Ensaios Clínicos Controlados Aleatórios como Assunto , Transcriptoma , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Am J Clin Oncol ; 44(3): 121-125, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33617179

RESUMO

OBJECTIVES: The aim of our study was to collect data about of the outcome of metastatic renal cell carcinoma patients who progressed after immune checkpoint inhibitors in order to enhance data about efficacy and safety of treatment beyond immune-oncology (IO). MATERIALS AND METHODS: A total of 162 eligible patients, progressing to IO, were enrolled from 16 Italian referral centers adhering to the Meet-Uro association. Baseline characteristics, outcome data and toxicities were retrospectively collected. Descriptive analysis was made using median values and ranges. Kaplan-Meier method and Mantel-Haenszel log-rank test were performed to compare differences between groups. RESULTS: A total of 111 patients (68.5%) were treated after IO progression. In all, 51 patients (31.5%) did not receive further treatment for clinical deterioration. Median IO progression free survival (PFS) was 4 months (95% confidence interval [CI]: 3.1-4.8). IO-PFS tends to be longer in patients reporting adverse events (AE) of any grade (5.03 [95% CI: 3.8-6.1] vs. 2.99 [95% CI: 2.4-3.5] months P=0.004). Subsequent therapies included cabozantinib (n=79, 48%), everolimus (n=11, 6.7%), and others (n=21, 12.9%).Median PFS post-IO was 6.5 months (95% CI: 5.1-7.8). Cabozantinib showed longer PFS compared with everolimus (7.6 mo [95% CI: 5.2-10.1] vs. 3.2 mo [95% CI: 1.8-4.5]) (hazard ratio: 0.2; 95% CI: 0.1026-0.7968) and other drugs (4.3 mo [95% CI: 1.3-7.4]) (hazard ratio: 0.6; 95% CI: 0.35-1.23). All grade AE were reported in 83 patients (74%) and G3 to G4 AE in 39 patients (35%). Target therapies post-IO showed median overall survival of 14.7 months (95% CI: 0.3-21.4). CONCLUSIONS: In our real world experience after progression to IO, vascular endotelial groth factor-tyrosine kinase inhibitors, given to patients, proved to be active and safe choices. Cabozantinib was associated with a better outcome in terms of median PFS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Idoso , Anilidas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Progressão da Doença , Everolimo/administração & dosagem , Feminino , Humanos , Itália , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Nivolumabe/efeitos adversos , Nivolumabe/uso terapêutico , Receptor de Morte Celular Programada 1/metabolismo , Piridinas/administração & dosagem , Estudos Retrospectivos , Resultado do Tratamento
18.
Crit Rev Oncol Hematol ; 159: 103242, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33545356

RESUMO

OBJECTIVE: To conduct a systematic review and meta-analysis of the role of SBRTdrug combination in patients affected by mRCC and associated oncologic outcomes and toxicity profiles. EVIDENCE ACQUISITION: We performed a critical review of the Pubmed, Medline, and Embase databases from January 1, 2000 through April 30, 2020 according to the Preferred Reporting Items and Meta-Analyses statement. To assess the overall quality of the literature reviewed, we used a modified Delphi tool. EVIDENCE SYNTHESIS: A total of 6 studies were included, corresponding to a cohort of 216 patients. Tyrosine Kinases Inhibitors were the most widely used drugs in combination with SBRT, being administered in 93% patients. No study reported an increase of radiation-induced toxicity. CONCLUSIONS: SBRT resulted to be safe, without increase in terms of drugs-related adverse events in this setting. Moreover, this approach showed promising clinical outcomes in terms of LC and OS.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Preparações Farmacêuticas , Radiocirurgia , Carcinoma de Células Renais/tratamento farmacológico , Humanos , Neoplasias Renais/tratamento farmacológico , Radiocirurgia/efeitos adversos
19.
J Med Econ ; 24(1): 291-298, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33538203

RESUMO

BACKGROUND: Considering clinical benefits of new combination therapies for metastatic renal-cell carcinoma (mRCC), this study aims to calculate the number needed to treat (NTT) and the cost of preventing an event (COPE) for pembrolizumab plus axitinib (P + A), and nivolumab plus ipilimumab (N + I) as first-line treatments, from the Brazilian private perspective. METHODS: Overall survival (OS) and progression-free survival (PFS) data for intermediate- and poor-risk groups were obtained from KEYNOTE-426 and CHECKMATE-214 trials for P + A and N + I, respectively, versus sunitinib as mRCC first-line treatment. RESULTS: Considering a 12-month time horizon, 6 patients should be treated with P + A to prevent one death with sunitinib use, resulting in a COPE of 3,773,865 BRL. Using N + I, NNT for 12-month OS rate was 13 compared to sunitinib, with a COPE of 6,357,965 BRL. Regarding PFS data, NNT was also 6 when comparing P + A versus sunitinib, with an estimated COPE of 3,773,865 BRL. Estimated NNT was 20 comparing N + I and sunitinib, resulting in a COPE of 10,172,744 BRL. Cost differences between two treatment options, reached more than 6 million BRL for PFS, and 2 million BRL for OS. CONCLUSION: At the 12-month landmark, P + A suggests better economic scenario versus N + I as first-line mRCC treatment option for intermediate- and poor-risk groups, through an indirect comparison using sunitinib as a common comparator.


Assuntos
Antineoplásicos Imunológicos/economia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/economia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Axitinibe/economia , Axitinibe/uso terapêutico , Brasil , Carcinoma de Células Renais/patologia , Análise Custo-Benefício , Feminino , Gastos em Saúde/estatística & dados numéricos , Recursos em Saúde/economia , Recursos em Saúde/estatística & dados numéricos , Humanos , Ipilimumab/economia , Ipilimumab/uso terapêutico , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Modelos Econômicos , Nivolumabe/economia , Nivolumabe/uso terapêutico , Intervalo Livre de Progressão , Índice de Gravidade de Doença , Sunitinibe/economia , Sunitinibe/uso terapêutico , Adulto Jovem
20.
Medicine (Baltimore) ; 100(5): e24313, 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33592876

RESUMO

RATIONALE: Hyperammonemia encephalopathy is a rare but severe complication that has been reported in association with the use of sunitinib, a tyrosine kinase inhibitor. We report here a unique case of a patient with end stage renal disease that was initiated on sunitinib for metastatic renal cell carcinoma. PATIENT CONCERNS: A 65-year-old man with end stage renal disease on maintenance conventional hemodialysis and had concomitant stable Child-Pugh class B liver cirrhosis consequent of hepatitis C infection was started on sunitinib for metastatic renal cell carcinoma. He developed confusion few weeks after starting therapy with no other indication of worsening liver dysfunction otherwise. DIAGNOSIS: He was later diagnosed with hyperammonemia encephalopathy. INTERVENTIONS: His treatment was discontinued and reinitiated at a lower dose after recovery and titrated according to tolerance. As ammonia is a very low molecular weight molecule and is cleared well with diffusive clearance, we intensified his dialysis regimen by increasing intensity for each session and frequency per week. OUTCOMES: With this change in dialysis regimen, patient was able to continue treatment with sunitinib. LESSONS: Clinicians prescribing sunitinib should be vigilant to monitor for this complication in patients receiving sunitinib, apart from the more usual presentation of hepatotoxicity. We found that a more intensive hemodialysis regimen consisting of 4× a week conventional high-flux hemodialysis (HD) can permit the continuation of treatment with sunitinib in an end stage renal disease (ESRD) patient with Child-Pugh class B liver cirrhosis.


Assuntos
Antineoplásicos/efeitos adversos , Carcinoma de Células Renais/tratamento farmacológico , Hiperamonemia/induzido quimicamente , Neoplasias Renais/tratamento farmacológico , Síndromes Neurotóxicas/etiologia , Sunitinibe/efeitos adversos , Idoso , Carcinoma de Células Renais/virologia , Hepacivirus , Hepatite C/complicações , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/terapia , Neoplasias Renais/virologia , Cirrose Hepática/virologia , Masculino , Diálise Renal
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...