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1.
Medicine (Baltimore) ; 100(5): e24313, 2021 Feb 05.
Artículo en Inglés | MEDLINE | ID: mdl-33592876

RESUMEN

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.


Asunto(s)
Antineoplásicos/efectos adversos , Carcinoma de Células Renales/tratamiento farmacológico , Hiperamonemia/inducido químicamente , Neoplasias Renales/tratamiento farmacológico , Síndromes de Neurotoxicidad/etiología , Sunitinib/efectos adversos , Anciano , Carcinoma de Células Renales/virología , Hepacivirus , Hepatitis C/complicaciones , Humanos , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/terapia , Neoplasias Renales/virología , Cirrosis Hepática/virología , Masculino , Diálisis Renal
2.
Nat Commun ; 12(1): 808, 2021 02 05.
Artículo en Inglés | MEDLINE | ID: mdl-33547292

RESUMEN

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.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Renales/inmunología , Regulación Neoplásica de la Expresión Génica , /inmunología , Neoplasias Renales/inmunología , Tumor Rabdoide/inmunología , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Antígeno B7-H1/inmunología , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/inmunología , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/mortalidad , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/inmunología , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/genética , Neoplasias Renales/mortalidad , Mutación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/inmunología , Estudios Retrospectivos , Tumor Rabdoide/tratamiento farmacológico , Tumor Rabdoide/genética , Tumor Rabdoide/mortalidad , Transducción de Señal , Análisis de Supervivencia , Transcripción Genética , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/inmunología , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/inmunología
4.
Medicine (Baltimore) ; 99(42): e22634, 2020 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-33080700

RESUMEN

RATIONALE: Unilateral manifestation of lymphedema during everolimus therapy has been described only rarely, mostly in transplant recipients. PATIENT CONCERNS: We report the first case of a patient who developed unilateral abdominal lymphedema, during a short period of everolimus treatment for renal cancer. DIAGNOSIS: The abdominal asymmetry occurred only on the right side of the abdomen, neither ultrasound nor CT scan detected ascites but showed enlargement of the abdominal wall. The Naranjo Adverse Drug Reaction Probability scale was evaluated, in this case, a score of 6 indicated a probable adverse reaction to everolimus. INTERVENTIONS: Discontinuation of everolimus therapy led to immediate alleviation and reduction of the lymphedema, with worsening once again after initiating retreatment with everolimus at a reduced dose. OUTCOMES: The patient's lymphedema recovered after discontinuation of everolimus. LESSONS: This rare case demonstrates the importance of the selection of mammalian target of rapamycin inhibitors using caution, especially for patients with a high risk of developing lymphedema.


Asunto(s)
Antineoplásicos/efectos adversos , Carcinoma de Células Renales/tratamiento farmacológico , Everolimus/efectos adversos , Neoplasias Renales/tratamiento farmacológico , Linfedema/inducido químicamente , Humanos , Linfedema/diagnóstico por imagen , Masculino , Persona de Mediana Edad
5.
Urol Clin North Am ; 47(4): 419-431, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-33008493

RESUMEN

The management of metastatic renal cell carcinoma (RCC) has evolved rapidly in recent years with several immunotherapy-based combinations of strategies approved as first-line therapies. Targeted strategies, including systemic antiangiogenesis agents and immune checkpoint blockade, form the basis of a therapeutic approach. With rising rates of recurrence after first-line treatment, it is increasingly important to not only adopt a personalized treatment plan with minimal adverse events but also develop predictive biomarkers for response. This review discusses currently available first-line and second-line therapies in RCC and their pivotal data, with specific focus on ongoing clinical trials in the adjuvant setting, including those involving novel agents.


Asunto(s)
Productos Biológicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Inmunoterapia/métodos , Neoplasias Renales/tratamiento farmacológico , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/cirugía , Ensayos Clínicos Fase II como Asunto , Terapia Combinada , Quimioterapia Combinada , Femenino , Humanos , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Nefrectomía/métodos , Pronóstico , Análisis de Supervivencia , Resultado del Tratamiento , Estados Unidos
6.
Cochrane Database Syst Rev ; 10: CD012796, 2020 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-33058158

RESUMEN

BACKGROUND: Several comparative randomised controlled trials (RCTs) have been performed including combinations of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors since the publication of a Cochrane Review on targeted therapy for metastatic renal cell carcinoma (mRCC) in 2008. This review represents an update of that original review. OBJECTIVES: To assess the effects of targeted therapies for clear cell mRCC in patients naïve to systemic therapy. SEARCH METHODS: We performed a comprehensive search with no restrictions on language or publication status. The date of the latest search was 18 June 2020. SELECTION CRITERIA: We included randomised controlled trials, recruiting patients with clear cell mRCC naïve to previous systemic treatment. The index intervention was any TKI-based targeted therapy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the included studies and extracted data for the primary outcomes: progression-free survival (PFS), overall survival (OS) and serious adverse events (SAEs); and the secondary outcomes: health-related quality of life (QoL), response rate and minor adverse events (AEs). We performed statistical analyses using a random-effects model and rated the certainty of evidence according to the GRADE approach. MAIN RESULTS: We included 18 RCTs reporting on 11,590 participants randomised across 18 comparisons. This abstract focuses on the primary outcomes of select comparisons. 1. Pazopanib versus sunitinib Pazopanib may result in little to no difference in PFS as compared to sunitinib (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.90 to 1.23; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 420 per 1000 in this trial at 12 months, this corresponds to 18 fewer participants experiencing PFS (95% CI 76 fewer to 38 more) per 1000 participants. Pazopanib may result in little to no difference in OS compared to sunitinib (HR 0.92, 95% CI 0.80 to 1.06; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 27 more OSs (95% CI 19 fewer to 70 more) per 1000 participants. Pazopanib may result in little to no difference in SAEs as compared to sunitinib (risk ratio (RR) 1.01, 95% CI 0.94 to 1.09; 1 study, 1102 participants; low-certainty evidence). Based on the control event risk of 734 per 1000 in this trial, this corresponds to 7 more participants experiencing SAEs (95% CI 44 fewer to 66 more) per 1000 participants. 2. Sunitinib versus avelumab and axitinib Sunitinib probably reduces PFS as compared to avelumab plus axitinib (HR 1.45, 95% CI 1.17 to 1.80; 1 study, 886 participants; moderate-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 130 fewer participants experiencing PFS (95% CI 209 fewer to 53 fewer) per 1000 participants. Sunitinib may result in little to no difference in OS (HR 1.28, 95% CI 0.92 to 1.79; 1 study, 886 participants; low-certainty evidence). Based on the control event risk of 890 per 1000 in this trial at 12 months, this would result in 29 fewer OSs (95% CI 78 fewer to 8 more) per 1000 participants. Sunitinib may result in little to no difference in SAEs (RR 1.01, 95% CI 0.93 to 1.10; 1 study, 873 participants; low-certainty evidence). Based on the control event risk of 705 per 1000 in this trial, this corresponds to 7 more SAEs (95% CI 49 fewer to 71 more) per 1000 participants.  3. Sunitinib versus pembrolizumab and axitinib Sunitinib probably reduces PFS as compared to pembrolizumab plus axitinib (HR 1.45, 95% CI 1.19 to 1.76; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 590 per 1000 in this trial at 12 months, this corresponds to 125 fewer participants experiencing PFS (95% CI 195 fewer to 56 fewer) per 1000 participants. Sunitinib probably reduces OS (HR 1.90, 95% CI 1.36 to 2.65; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 880 per 1000 in this trial at 12 months, this would result in 96 fewer OSs (95% CI 167 fewer to 40 fewer) per 1000 participants. Sunitinib may reduce SAEs as compared to pembrolizumab plus axitinib (RR 0.90, 95% CI 0.81 to 1.02; 1 study, 854 participants; low-certainty evidence) although the CI includes the possibility of no effect. Based on the control event risk of 604 per 1000 in this trial, this corresponds to 60 fewer SAEs (95% CI 115 fewer to 12 more) per 1000 participants.  4. Sunitinib versus nivolumab and ipilimumab Sunitinib may reduce PFS as compared to nivolumab plus ipilimumab (HR 1.30, 95% CI 1.11 to 1.52; 1 study, 847 participants; low-certainty evidence). Based on the control event risk of 280 per 1000 in this trial at 30 months' follow-up, this corresponds to 89 fewer PFSs (95% CI 136 fewer to 37 fewer) per 1000 participants. Sunitinib reduces OS (HR 1.52, 95% CI 1.23 to 1.89; 1 study, 847 participants; high-certainty evidence). Based on the control event risk 600 per 1000 in this trial at 30 months, this would result in 140 fewer OSs (95% CI 219 fewer to 67 fewer) per 1000 participants. Sunitinib probably increases SAEs (RR 1.37, 95% CI 1.22 to 1.53; 1 study, 1082 participants; moderate-certainty evidence). Based on the control event risk of 457 per 1000 in this trial, this corresponds to 169 more SAEs (95% CI 101 more to 242 more) per 1000 participants. AUTHORS' CONCLUSIONS: Based on the low to high certainty of evidence, several combinations of immune checkpoint inhibitors appear to be superior to single-agent targeted therapy in terms of PFS and OS, and with a favourable AE profile. Some single-agent targeted therapies demonstrated a similar or improved oncological outcome compared to others; minor differences were observed for AE within this group. The certainty of evidence was variable ranging from high to very low and all comparisons were based on single trials.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Axitinib/efectos adversos , Axitinib/uso terapéutico , Bevacizumab/efectos adversos , Bevacizumab/uso terapéutico , Sesgo , Carcinoma de Células Renales/mortalidad , Everolimus/efectos adversos , Everolimus/uso terapéutico , Humanos , Ipilimumab/efectos adversos , Ipilimumab/uso terapéutico , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Compuestos de Fenilurea/efectos adversos , Compuestos de Fenilurea/uso terapéutico , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Calidad de Vida , Quinolinas/efectos adversos , Quinolinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Sirolimus/efectos adversos , Sirolimus/análogos & derivados , Sirolimus/uso terapéutico , Sorafenib/efectos adversos , Sorafenib/uso terapéutico , Sulfonamidas/efectos adversos , Sulfonamidas/uso terapéutico , Sunitinib/efectos adversos , Sunitinib/uso terapéutico
7.
Brasília; CONITEC; out. 2020.
No convencional en Portugués | BRISA/RedTESA | ID: biblio-1141497

RESUMEN

INTRODUÇÃO: O câncer renal é responsável por aproximadamente 3% dos cânceres de adultos nos países ocidentais, é o sétimo câncer mais comum em homens e o nono mais comum em mulheres. O Carcinoma de Células Renais (CCR), também conhecido como adenocarcinoma de células renais, é o tipo mais comum, com aproximadamente nove casos em cada dez cânceres renais. O prognóstico do CCR está relacionado ao estágio da doença quando o diagnóstico é realizado - os estágios do câncer renal variam de I a IV. No Brasil, no âmbito do SUS, o tratamento é direcionado pelas Diretrizes Diagnósticas e Terapêuticas (DDT) do CCR. PERGUNTA: O cabozantinibe é eficaz, efetivo e seguro como primeira linha de tratamento de pacientes com CCR avançado/metastático que apresentam risco intermediário a alto, quando comparado às demais quimioterapias paliativas disponíveis no SUS? EVIDÊNCIAS CIENTÍFICAS: Após revisão sistemática da literatura, sete estudos foram incluídos no corpo de evidências (1 Ensaio Clínico Randomizado [ECR] fase II e seu estudo de extensão, e 5 Revisões Sistemáticas [RS] com meta-análise em rede). Todos os estudos reportavam resultados exclusivamente do mesmo ECR (CHOUEIRI et al, 2017), que apresenta problemas metodológicos. Não foi identificada diferença estatisticamente significativa entre cabozantinibe, sunitinibe e pazopanibe para o desfecho de sobrevida global nas meta-análises, sendo que o ECR apresenta resultados conflitantes com sua extensão. No desfecho de sobrevida livre de progressão, o cabozantinibe demonstrou melhor desempenho em comparação ao sunitinibe, porém apenas na análise de subgrupo dos pacientes com risco intermediário. Não foi possível avaliar o pazopanibe para a população de risco intermediário/alto. A maioria dos estudos relatou não haver diferença entre as intervenções para o desfecho de incidência de eventos adversos graves, embora para esse desfecho a análise de subgrupo não tenha sido realizada. Quanto à qualidade metodológica, todas as RS apresentaram qualidade criticamente baixa, e o ECR apresentou risco de viés incerto. AVALIAÇÃO ECONÔMICA: Foi realizada uma análise econômica do tipo árvore de decisão, com o objetivo de avaliar a relação de custo-efetividade do cabozantinibe em comparação ao sunitinibe em pacientes com CCR metastático ou avançado de risco alto/intermediário. A perspectiva adotada foi a do SUS, em um horizonte temporal de 36 meses. Foram considerados como estados de transição: pré-progressão, progressão e morte. Os custos assumidos foram os de aquisição dos medicamentos e de monitoramento dos pacientes em tratamento. Os desfechos de efetividade considerados na avaliação foram: a sobrevida livre de progressão e sobrevida global. A análise realizada estimou uma razão de custo-efetividade incremental para o cabozantinibe de R$ 21.618,10 por Mês de Vida Ganho (MVG), considerando os preços assumidos pelo demandante; e de R$ 15.365,32 por MVG quando utilizado o preço de aquisição do sunitinibe em compras públicas. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: O Impacto Orçamentário (IO) apresentado pelo demandante foi recalculado por apresentar algumas limitações. O novo modelo proposto manteve a população pretendida pelo demandante, a saber, pacientes com CCR metastático de risco intermediário/alto, na perspectiva do Sistema Único de Saúde e em um horizonte temporal de cinco anos. Os custos assumidos foram restritos aos de aquisição dos medicamentos. Para o cálculo da população elegível foram propostos dois cenários, com as populações mínima e máxima estimadas de acordo com os dados encontrados na literatura, sobre a projeção da população do IBGE. Ao longo do horizonte temporal, além de aplicarmos a incidência de novos casos ano a ano, também consideramos a saída de pacientes em cada ano, aplicando os dados de sobrevida global relatados nos ECR dos medicamentos. Dessa forma, o IO estimado utilizando os preços apresentados pelo demandante variou de R$ 34,7 milhões a 102,1 milhões acumulados em cinco anos, a depender das prevalências utilizadas. Na análise de sensibilidade, aplicando os custos reais dos medicamentos em compras públicas, o custo incremental acumulado em cinco anos ficou entre R$ 10,7 milhões e R$ 99,49 milhões em cinco anos, dependendo das prevalências aplicadas. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foram detectados três medicamentos potenciais para a indicação terapêutica em questão: o belzutifan, o savolitinibe e o tivozanibe. CONSIDERAÇÕES FINAIS: As evidências disponíveis na literatura demonstram que o cabozantinibe apresenta benefício para pacientes com CCR avançado que apresentam risco intermediário no desfecho de sobrevida livre de progressão. Para os demais desfechos e subgrupos avaliados não foram identificadas diferenças entre as intervenções. A análise econômica demonstrou uma RCEI de R$ 15.365,32 a R$ 21.618,10 por MVG, a depender do preço do sunitinibe. A análise de IO estimou um custo incremental de até R$ 147,3 milhões acumulados em cinco anos, decorrente da eventual incorporação do cabozantinibe. RECOMENDAÇÃO PRELIMINAR DA CONITEC: O Plenário da Conitec, em sua 89ª Reunião Ordinária, no dia 05 de agosto de 2020, deliberou que a matéria fosse disponibilizada em Consulta Pública com recomendação preliminar desfavorável à incorporação no SUS de cabozantinibe para tratamento de primeira linha de pacientes adultos com Câncer de Células Renais avançado e risco intermediário a alto. Os membros da Conitec consideraram a ausência de evidências acerca de benefícios adicionais quanto à sobrevida nos pacientes que utilizaram cabozantinibe, quando comparado às demais terapias disponíveis no SUS. Além disso, verificou-se que as evidências disponíveis apresentam importantes incertezas, especialmente por conta dos dados de cabozantinibe serem provenientes de um único ensaio clínico de fase II. CONSULTA PÚBLICA: A Consulta Pública nº 44 foi realizada entre os dias 24/08/2020 e 14/09/2020. Foram recebidas 29 contribuições, sendo 19 pelo formulário para contribuições técnico-científicas e 10 pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. Não foram apresentadas novas evidências científicas para o cabozantinibe. O demandante apresentou uma proposta comercial de redução de preço do medicamento para R$366,67 por comprimido. Após apreciação das contribuições encaminhadas por meio da Consulta Pública e da apresentação da proposta de redução de preço pelo demandante, e considerando a ausência de evidências acerca de benefícios adicionais quanto à sobrevida nos pacientes que utilizaram cabozantinibe quando comparado às demais terapias disponíveis no SUS, o Plenário da Conitec entendeu que não houve argumentação suficiente para alterar a recomendação inicial. RECOMENDAÇÃO FINAL DA CONITEC: A Conitec, em sua 91ª reunião ordinária, no dia 08 de outubro de 2020, recomendou a não incorporação do cabozantinibe para tratamento de pacientes com carcinoma de células renais (CCR) avançado. A recomendação considerou que a ausência de evidências acerca de benefícios adicionais quanto à sobrevida dos pacientes que utilizaram cabozantinibe, quando comparado às demais terapias disponíveis no SUS. Além disso, verificou-se que as evidências disponíveis apresentam importantes incertezas, especialmente em razão dos dados de cabozantinibe serem provenientes de um único ensaio clínico de fase II. Por fim, foi assinado o Registro de Deliberação nº 564/2020. DECISÃO: Não incorporar o cabozantinibe para tratamento de primeira linha de câncer renal avançado, no âmbito do Sistema Único de Saúde - SUS, conforme Portaria nº 52, publicada no Diário Oficial da União nº 217, seção 1, página 145, em 13 de novembro de 2020.


Asunto(s)
Humanos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Neoplasias Renales/tratamiento farmacológico , Evaluación de la Tecnología Biomédica , Sistema Único de Salud , Brasil , Análisis Costo-Beneficio/economía
8.
Am J Clin Oncol ; 43(9): 621-627, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32889831

RESUMEN

OBJECTIVES: Despite the initial clinical benefit, resistance to antiangiogenic therapies develops through the activation of alternative pathways. We measured plasma levels of circulating angiogenic factors to explore their predictive role in metastatic renal cell carcinoma (mRCC) patients treated with pazopanib. MATERIALS AND METHODS: mRCC patients receiving first-line pazopanib were prospectively enrolled. The levels of circulating interleuchine (IL)-6, IL-8, stromal derived factor-1, vascular endothelial growth factor-A, hepatocyte growth factor (HGF), osteopontin, and E-selectin were quantified at baseline and every 4 weeks until disease progression (PD). Patients were dichotomized into "low" and "high" subgroups by a cutoff point defined by the respective median circulating angiogenic factor (CAF) value at baseline. Then, association with the objective response was determined. Changes in CAF levels between baseline and PD were also compared. RESULTS: Among 25 patients included in the final data set, 6 patients were still on treatment. As best response, 12 patients presented a partial response (48%), 9 showed stable disease, and 4 showed PD. The median follow-up was 31.9 months. The median progression-free survival was 14.8 months. Low baseline levels of IL-6, IL-8, HGF, and osteopontin were found to be significantly associated with objective response. In addition, patients with low baseline levels of HGF showed longer progression-free survival and overall survival, whereas patients with low baseline levels of IL-8 showed longer overall survival. Among patients experiencing PD, the median plasma levels of stromal derived factor-1 and vascular endothelial growth factor-A were significantly higher compared with the baseline (P=0.01; P=0.011). Conversely, the median levels of E-selectin were significantly lower compared with the baseline (P=0.017). CONCLUSION: Changes in levels of selected CAFs were associated with response/resistance to pazopanib in mRCC patients.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Resistencia a Antineoplásicos , Neoplasias Renales/tratamiento farmacológico , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Anciano , Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma de Células Renales/sangre , Carcinoma de Células Renales/secundario , Quimiocina CXCL12/sangre , Progresión de la Enfermedad , Selectina E/sangre , Femenino , Factor de Crecimiento de Hepatocito/sangre , Humanos , Interleucina-6/sangre , Interleucina-8/sangre , Neoplasias Renales/sangre , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Osteopontina/sangre , Supervivencia sin Progresión , Estudios Prospectivos , Criterios de Evaluación de Respuesta en Tumores Sólidos , Tasa de Supervivencia , Investigación en Medicina Traslacional , Factor A de Crecimiento Endotelial Vascular/sangre
9.
Anticancer Res ; 40(10): 5445-5456, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32988866

RESUMEN

BACKGROUND/AIM: Dietary interventions like time-restricted feeding (TRF) show promising anti-cancer properties. We examined whether therapeutic TRF alone or combined with immunotherapy would diminish renal tumor growth in mice of varying body weights. MATERIALS AND METHODS: Young (7 week) chow-fed or older (27 week) high-fat diet (HFD)-fed BALB/c mice were orthotopically injected with renal tumor cells expressing luciferase. After tumor establishment, mice were randomized to ad libitum feeding or TRF +/- anti-CTLA-4. Body composition, tumor viability and growth, and immune responses were quantified. RESULTS: TRF alone reduced renal tumor bioluminescence in older HFD-fed, but not young chow-fed mice. In the latter, TRF mitigated tumor-induced loss of lean- and fat-mass. However, TRF did not alter excised renal tumor weights or intratumoral immune responses and failed to improve anti-CTLA-4 outcomes in any mice. CONCLUSION: Therapeutic TRF exhibits modest anti-cancer properties but fails to improve anti-CTLA-4 immune checkpoint blockade in murine renal cancer.


Asunto(s)
Ayuno , Neoplasias Renales/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Animales , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Modelos Animales de Enfermedad , Ingestión de Alimentos/fisiología , Humanos , Inmunoterapia/efectos adversos , Neoplasias Renales/complicaciones , Neoplasias Renales/genética , Neoplasias Renales/patología , Ratones , Obesidad/complicaciones , Obesidad/genética
10.
Yonsei Med J ; 61(10): 837-843, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32975057

RESUMEN

PURPOSE: The standard schedule for sunitinib treatment is 4 weeks on and 2 weeks off (4/2) in first-line treatment for metastatic renal cell carcinoma (mRCC). Schedule modifications, including 2 weeks on and 1 week off (2/1), appear to reduce the total number of treatment-related adverse events (TRAEs) without compromising efficacy. Even though TRAEs can qualitatively differ from each other, it is not clear as to what effects a 2/1 schedule has on individual TRAEs. MATERIALS AND METHODS: This meta-analysis included one randomized controlled trial (RCT) and four non-randomized controlled studies (non-RCTs) that compared the two schedules in parallel. The primary objective was to estimate risk of individual adverse events (AEs) with a sunitinib 2/1 schedule versus a 4/2 schedule. Seven representative AEs were evaluated as standard data for the RCT and as weighted pooling data of the non-RCTs. Random effects modelling with Review Manager v5.3 was used to pool study-level data using the inverse-variance of each study as the weight. RESULTS: The five selected studies included a total of 484 patients with mRCC. Risk ratios for fatigue for a 2/1 schedule were significantly lower than those for a 4/2 schedule {0.69 [95% confidence intervals (CI), 0.51, 0.95] in the RCT and 0.77 (95% CI, 0.63, 0.94) in the non-RCTs}. Other TRAEs, except diarrhea and anorexia, also tended to decrease in both sets. Efficacy outcomes were comparable between 2/1 and standard schedules. CONCLUSION: This meta-analysis suggests that a 2/1 schedule of sunitinib lowers the risk of fatigue and the occurrence other AEs without compromising efficacy.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Sunitinib/uso terapéutico , Carcinoma de Células Renales/patología , Esquema de Medicación , Femenino , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Resultado del Tratamiento
11.
PLoS One ; 15(9): e0238809, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32915890

RESUMEN

Clear-cell renal cell carcinomas (ccRCC) can be divided into four transcriptomic subtypes, two of which have a favorable and two an unfavorable prognosis. To assess mechanisms driving these subtypes, we investigated their miRNA expression patterns. miRNAs are master regulators of mRNAs, that are widely deregulated in cancer. Unsupervised clustering in our dataset (n = 128) and The Cancer Genome Atlas (TCGA) validation set identified two distinct miRNA clusters that overlapped with the transcriptomic subtypes, underscoring the validity of these subtypes on a multi-omics level and suggesting a driving role for miRNAs. Discriminatory miRNAs for the favorable subtypes repressed epithelial-to-mesenchymal transition, based on gene set enrichment analysis and target-mRNA expression levels. Strikingly, throughout the entire dataset, miRNAs associated with favorable subtypes were also associated with longer overall survival after diagnosis, and miRNAs associated with unfavorable subtypes with shorter overall survival (Pearson r = -0.54, p<0.0001). These findings indicate a general shift in miRNA expression between more and less aggressive tumors. This adds to current literature, which usually suggests only a small subset of miRNAs as markers of aggressive disease. In conclusion, this study reveals distinct mRNA expression patterns underlying transcriptomic ccRCC-subtypes, whereby miRNAs associated with favorable subtypes counteract epithelial-to-mesenchymal transition. There is a general shift in miRNA expression in ccRCC, between more and less aggressive tumors.


Asunto(s)
Carcinoma de Células Renales/genética , Perfilación de la Expresión Génica , Neoplasias Renales/genética , MicroARNs/genética , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Femenino , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , ARN Mensajero/genética , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Sunitinib/farmacología , Sunitinib/uso terapéutico , Análisis de Supervivencia
12.
Life Sci ; 259: 118395, 2020 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-32905830

RESUMEN

In recent years, natural products have increasingly attracted more attention because of their potential anticancer activity and low intrinsic toxicity. Hispidulin is a natural flavonoid with a wide range of biological activities, including anti-inflammatory, antifungal, antiplatelet, anticonvulsant, anti-osteoporotic, and notably anticancer activities. Numerous in vivo and in vitro studies have shown that hispidulin, as a potential anticancer drug, affects cell proliferation, apoptosis, cell cycle, angiogenesis, and metastasis. Moreover, hispidulin exhibits synergistic anti-tumor effects when combined with some common clinical anticancer drugs (e.g., gemcitabine, 5-fluoroucil, sunitinib, temozolomide, and TRAIL). The combination of hispidulin and chemotherapeutic drugs reduces the efflux of chemotherapeutic drugs, enhances the chemosensitivity of cancer cells, and reverses drug resistance. Herein, we outlined the anticancer effects of hispidulin in various cancers and its intracellular molecular targets and related mechanisms of its anticancer activity. Based on the available literature, it can be established that hispidulin has significant potential to become an important complementary medicine for cancer prevention and treatment. However, more in-depth in vitro and in vivo studies should be conducted to support its translation from bench to bedside.


Asunto(s)
Antineoplásicos/uso terapéutico , Flavonas/uso terapéutico , Flavonoides/uso terapéutico , Neoplasias/tratamiento farmacológico , Animales , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Gástricas/tratamiento farmacológico
13.
Croat Med J ; 61(4): 326-332, 2020 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-32881430

RESUMEN

AIM: To assess diseases outcomes and tolerability of real-life second-line nivolumab in a series of metastatic renal cell carcinoma (mRCC) patients. METHODS: This retrospective chart review involved prospectively monitored patients (named patient program) treated with second-line nivolumab for mRCC at the University Hospital Centre Zagreb from February 2016 to March 2018. RESULTS: The study enrolled 30 patients, 5 of whom (16.7%) had a complete response. The mean ± standard deviation therapeutic response time to nivolumab treatment was 14.07 ± 8.92 months, with a minimum treatment duration of 2 months and a maximum of 24 months. The median duration of therapy was 17 months (mean: 15.8 months; range: 3-24 months), and 50% (n=15/30) of patients remained alive at the end of follow up. The most common adverse events associated with nivolumab were fatigue (26.67%; n=8/30), anemia (10.0%; n=3/30), adrenal insufficiency (6.67%; n=2/30: G1=1, G2=1), grade 2 pneumonitis (6.67%; n=2/30), grade 2 neuropathy (6.67%; n=2/30), rash (6.67%; n = 2/30: G1=1, G2=1), and hepatitis (3.33%; n=1/30). CONCLUSION: The present study indicates acceptable patient responses and tolerability of nivolumab in mRCC.


Asunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Nivolumab/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/efectos adversos , Carcinoma de Células Renales/patología , Femenino , Humanos , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Nivolumab/efectos adversos , Estudios Retrospectivos , Resultado del Tratamiento
14.
Cancer Treat Rev ; 89: 102061, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32738737

RESUMEN

Renal cell cancer (RCC) is the third most diagnosed genitourinary malignancy in the world. Nearly a half of the diagnoses and 60% of related deaths occur in low-middle income countries (LMs), where prognosis is generally poor. We conducted a systematic research of ClinicalTrials.gov, searching RCC ongoing studies for adult patients. We included 205 trials in the final analysis. The enrolling centers were mainly distributed in high-income settings (88.9%). We estimated 94.6% of the trial population was enrolled in only five countries and none in LMs. Clinical drug development for RCC is driven by early phase studies, mainly assessing small molecule tyrosine kinase inhibitors and immunotherapy or the combination. Sixty percent of the trials were industry sponsored. Only a minority of the trials were in the early setting of care, adjuvant or neoadjuvant therapy. Disparities in drug development in LMs mirror a common underestimation of the value of research among the national priorities in cancer health planning, resulting in poor ethnic diversity and inclusiveness. This commonly results in incomplete knowledge of activity and safety of medicines across different ethnic groups, with consequences on priorities for cancer interventions and estimates of benefit in LMs patients. The use of RCC as a case study for inclusiveness suggests poor inclusion of non- Caucasian populations in the trials, especially trials testing new immunotherapy and targeted agents where RCC drug development is more pronounced, resulting in issues of generalizability in other ethnic groups when these compounds are approved with no ethnic restrictions or specifications.


Asunto(s)
Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Ensayos Clínicos como Asunto/métodos , Ensayos Clínicos como Asunto/estadística & datos numéricos , Desarrollo de Medicamentos/métodos , Humanos , Selección de Paciente , Ensayos Clínicos Controlados Aleatorios como Asunto
15.
Am J Med Sci ; 360(3): 279-286, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32829780

RESUMEN

BACKGROUND: The essential role of 6-phosphogluconate dehydrogenase (6PGD), the enzyme catalyzing the oxidative pentose phosphate pathway, in tumor growth and metabolism has garnered attention in recent years. In this work, we are the first to demonstrate that aberrant activation of 6PGD is a feature in renal cell carcinoma (RCC) and is critically involved in renal carcinogenesis and chemo- and immuno-resistance. MATERIALS AND METHODS: 6PGD expression and activity were systematically analyzed in normal and malignant renal cells and tissues. The roles of 6PGD and its downstream mechanism were investigated using gain-of-function and loss-of-function approaches. RESULTS: 6PGD expression and enzyme activity were increased in RCC cells and patients' samples. Activation of 6PGD via gain-of-function approach promoted growth of normal kidney but not RCC cells, and alleviated the efficacy of chemotherapeutic (e.g., 5-FU) and immunotherapeutic (e.g., IFN-α) agents. In contrast, 6PGD inhibition using siRNA knockdown and pharmacological inhibitor physcion augmented the inhibitory effects of 5-FU and IFN-α in RCC. Mechanistic studies demonstrated that 6PGD inhibition activated AMPK signaling, leading to ACC1 enzyme inhibition and reduction of lipid synthesis. In addition, 6PGD inhibition disrupted NADPH and NADH homeostasis in RCC cells as shown by the decreased level of NADPH and NADH, and suppressed SIRT-1 activity. AMPK inhibition by siRNA knockdown reversed the inhibitory effects of physcion, demonstrating that the effect of 6PGD inhibition is AMPK activation dependent. CONCLUSIONS: Our work provides preclinical evidence that 6PGD inhibition may represent a potential therapeutic strategy to augment the efficacy of RCC standard of care drugs.


Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Carcinoma de Células Renales/terapia , Reprogramación Celular/fisiología , Neoplasias Renales/terapia , Fosfogluconato Deshidrogenasa/metabolismo , Transducción de Señal/fisiología , Proteínas Quinasas Activadas por AMP/genética , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Línea Celular , Línea Celular Tumoral , Resistencia a Antineoplásicos/fisiología , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Fluorouracilo/uso terapéutico , Técnicas de Silenciamiento del Gen , Humanos , Inmunoterapia , Interferón-alfa/uso terapéutico , Riñón/patología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , NADP/fisiología , Fosfogluconato Deshidrogenasa/antagonistas & inhibidores , Fosfogluconato Deshidrogenasa/genética , ARN Interferente Pequeño , Regulación hacia Arriba
16.
Asia Pac J Clin Oncol ; 16 Suppl 3: 12-17, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32852898

RESUMEN

Adjuvant treatment with VEGFR tyrosine kinase inhibitor in renal cell carcinoma after nephrectomy has been reported through four clinical trials: S-TRAC, ASSURE, PROTECT and ATLAS. Only S-TRAC has been significantly positive on primary endpoint DFS under sunitinib compared to placebo, whereas ASSURE, PROTECT and ATLAS did not show any gain under sunitinib, sorafenib, pazopanib or axitinib, respectively. Nevertheless, there are arguments for a trend for the impact of anti-angiogenic therapy on outcome of patients with high-risk renal cell carcinoma cancer following nephrectomy, allowing for a fair discussion with patients to decide for or against an adjuvant treatment.


Asunto(s)
Carcinoma de Células Renales/tratamiento farmacológico , Quimioterapia Adyuvante/métodos , Neoplasias Renales/tratamiento farmacológico , Nefrectomía/métodos , Carcinoma de Células Renales/mortalidad , Supervivencia sin Enfermedad , Humanos , Neoplasias Renales/mortalidad
17.
Oncogene ; 39(38): 6113-6128, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32814829

RESUMEN

VHL mutations are the most common tumorigenic lesions in clear cell renal cell carcinoma (ccRCC) and result in continued activation of the HIF/VEGF pathway and uncontrolled cancer progression. Receptor tyrosine kinase (RTK) inhibitors such as sunitinib have been demonstrated to target tumorigenic signaling pathways, delay tumor progression, and improve patient prognosis in metastatic renal cell carcinoma (mRCC). Although several mechanisms of sunitinib resistance have been reported, the solutions to overcome this resistance remain unclear. In our study, we found that increased expression of Y-box binding protein 1 (YB1, a multidrug resistance associated protein) and EphA2 (a member of the erythropoietin-producing hepatocellular (Eph) receptor family, belonging to the RTK family) mediated sunitinib resistance and mRCC exhibited a large phenotypic dependence on YB1 and EphA2. In addition, our findings confirm that YB1 promotes the invasion, metastasis and sunitinib resistance of ccRCC by regulating the EphA2 signaling pathway. Furthermore, pharmacological inhibition of EphA2 through the small molecule inhibitor ALW-II-41-27 reduced the proliferation of sunitinib-resistant tumor cells, suppressed tumor growth in vivo, and restored the sensitivity of sunitinib-resistant tumor cells to sunitinib in vitro and in vivo. Mechanistically, YB1 increases the protein levels of EphA2 by maintaining the protein stability of EphA2 through inhibition of the proteasomal degradation pathway. Collectively, our findings provide the theoretical rationale that ccRCC metastasis and RTK-directed therapeutic resistance could be prospectively and purposefully targeted.


Asunto(s)
Carcinoma de Células Renales/metabolismo , Resistencia a Antineoplásicos , Neoplasias Renales/metabolismo , Receptor EphA2/metabolismo , Transducción de Señal , Proteína 1 de Unión a la Caja Y/metabolismo , Adulto , Anciano , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Movimiento Celular , Biología Computacional/métodos , Transición Epitelial-Mesenquimal/genética , Femenino , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Modelos Biológicos , Metástasis de la Neoplasia , Estadificación de Neoplasias , Fenotipo , Estabilidad Proteica , Proteínas Proto-Oncogénicas c-akt/metabolismo , Factor de Transcripción STAT3/metabolismo
18.
J Cancer Res Clin Oncol ; 146(11): 3075-3078, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32816108

RESUMEN

This letter summarizes recommendations from the interdisciplinary working group of renal tumors (IAGN) of the German Cancer Society for the systemic treatment of advanced/metastatic renal cell carcinoma in the context of the current SARS-CoV-2 pandemic.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Infecciones por Coronavirus , Neoplasias Renales/tratamiento farmacológico , Pandemias , Neumonía Viral , Betacoronavirus , Humanos
20.
Anticancer Res ; 40(8): 4395-4400, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32727768

RESUMEN

BACKGROUND/AIM: The therapeutic outcomes of patients with metastatic renal cell carcinoma (mRCC) have dramatically improved with the introduction of molecular-targeted agents. The observational multicenter study was conducted to develop a novel stratification system for the intermediate risk group of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model. PATIENTS AND METHODS: The present study included 252 Japanese patients with mRCC who received first-line molecular-targeted therapy at four institutions. RESULTS: The 252 patients were classified into the favorable, intermediate, and poor risk groups by the IMDC model. For the intermediate risk group, multivariate analysis of the six factors included in the IMDC model revealed that a low performance status, anemia, and a high platelet count were independent predictors of poor overall survival (OS). The intermediate risk group was subsequently divided into the following two groups (int -group 1 and 2) by the three independent OS predictors. Significant differences in the OS were noted among the IMDC favorable risk group, int-group 1, int-group 2, and poor risk group. CONCLUSION: The novel stratification presented in this study could be a useful tool for further prognostication of patients with mRCC classified into the intermediate risk group according to the IMDC model after first-line molecular-targeted therapy.


Asunto(s)
Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Terapia Molecular Dirigida/métodos , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/mortalidad , Femenino , Humanos , Neoplasias Renales/metabolismo , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Estudios Retrospectivos , Medición de Riesgo , Análisis de Supervivencia , Resultado del Tratamiento , Adulto Joven
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