RESUMEN
Small renal cell carcinoma (RCC) tumors are believed to have a negligible risk of metastasis. We report on a 77-year-old man presenting with extremity weakness who was found to have a 2.5 cm brain metastasis from a subsequently discovered 1.6 cm clear cell RCC primary tumor. We review what is known about synchronous and metachronous metastasis from small renal tumors and prognostic features informing treatment for such lesions.
Asunto(s)
Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/secundario , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/secundario , Neoplasias Renales/patología , Anciano , Neoplasias Encefálicas/terapia , Carcinoma de Células Renales/terapia , Humanos , Neoplasias Renales/cirugía , Imagen por Resonancia Magnética , Masculino , Metastasectomía , Nefrectomía , Pronóstico , Radioterapia , Tomografía Computarizada por Rayos XAsunto(s)
Carcinoma de Células Renales/cirugía , Ablación por Catéter/métodos , Neoplasias Renales/cirugía , Proyectos de Investigación , Investigación Biomédica Traslacional/métodos , Animales , Carcinoma de Células Renales/patología , Ablación por Catéter/efectos adversos , Conducta Cooperativa , Medicina Basada en la Evidencia , Humanos , Cooperación Internacional , Neoplasias Renales/patología , Procedimientos Quirúrgicos Mínimamente Invasivos , Resultado del TratamientoRESUMEN
The PD-1 pathway, comprising the immune cell co-receptor Programmed Death 1 (PD-1) and its ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC), mediates local immunosuppression in the tumor microenvironment. Drugs designed to block PD-1 or PD-L1 "release the brakes" on anti-tumor immunity and have demonstrated clinical activity in several types of advanced cancers, validating this pathway as a target for cancer therapy. Two such drugs have recently been approved to treat melanoma and lung cancers, and regulatory approvals in first- and second-line settings for additional cancer types are anticipated. The manageable safety profile of PD-1/PD-L1 blocking drugs identifies them as suitable for outpatient administration and the development of combinatorial therapies. Ongoing studies aim to identify biomarkers to guide patient selection, which would further improve the risk:benefit ratio for these drugs.
Asunto(s)
Antineoplásicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Humanos , Terapia de Inmunosupresión/métodos , Neoplasias/metabolismo , Microambiente Tumoral/efectos de los fármacosRESUMEN
PURPOSE: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and radiation is one of the main treatment modalities. However, cure rates remain low despite best available therapies. Immunotherapy is a promising modality that could work synergistically with radiation, which has been shown to increase antigen presentation and promote a proinflammatory tumor microenvironment. Programmed-death-1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs. We tested the combination of anti-PD-1 immunotherapy with stereotactic radiosurgery in a mouse orthotopic GBM model. METHODS AND MATERIALS: We performed intracranial implantation of mouse glioma cell line GL261 transfected with luciferase into C57BL/6 mice. Mice were stratified into 4 treatment groups: (1) control; (2) radiation only; (3) anti-PD-1 antibody only; and (4) radiation plus anti-PD-1 antibody. Overall survival was quantified. The mice were killed on day 21 after implantation to assess immunologic parameters in the brain/tumor, cervical lymph nodes, and spleen. RESULTS: Improved survival was demonstrated with combination anti-PD-1 therapy plus radiation compared with either modality alone: median survival was 25 days in the control arm, 27 days in the anti-PD-1 antibody arm, 28 days in the radiation arm, and 53 days in the radiation plus anti-PD-1 therapy arm (P<.05 by log-rank Mantle-Cox). Long-term survival was seen only in the combined treatment arm, with a fraction (15%-40%) of animals alive at day 180+ after treatment. Immunologic data on day 21 after implantation showed increased tumor infiltration by cytotoxic T cells (CD8+/interferon-γ+/tumor necrosis factor-α+) and decreased regulatory T cells (CD4+/FOXP3) in the combined treatment group compared with the single modality arms. CONCLUSIONS: The combination of PD-1 blockade and localized radiation therapy results in long-term survival in mice with orthotopic brain tumors. These studies provide strong preclinical evidence to support combination trials in patients with GBM.
Asunto(s)
Antígenos de Neoplasias , Antígeno B7-H1/antagonistas & inhibidores , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Inmunoterapia/métodos , Radiocirugia/métodos , Animales , Antígenos de Neoplasias/inmunología , Encéfalo/inmunología , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/mortalidad , Línea Celular Tumoral , Terapia Combinada/métodos , Terapia Combinada/mortalidad , Femenino , Glioblastoma/inmunología , Glioblastoma/mortalidad , Inmunoterapia/mortalidad , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos C57BL , Cuello , Radiocirugia/mortalidad , Bazo/inmunología , Análisis de Supervivencia , Linfocitos T Citotóxicos/citología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Factores de Tiempo , Ensayos Antitumor por Modelo de Xenoinjerto/métodosAsunto(s)
Antígenos de Superficie/metabolismo , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/diagnóstico por imagen , Glutamato Carboxipeptidasa II/metabolismo , Neoplasias Renales/diagnóstico por imagen , Lisina/análogos & derivados , Imagen Molecular/métodos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos/administración & dosificación , Urea/análogos & derivados , Autopsia , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/secundario , Carcinoma de Células Renales/terapia , Causas de Muerte , Resultado Fatal , Humanos , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Neoplasias Renales/terapia , Lisina/administración & dosificación , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Urea/administración & dosificación , Imagen de Cuerpo EnteroRESUMEN
Dysregulation of the mammalian target of rapamycin and hypoxia-induced pathways has been consistently identified in clear cell renal cell carcinomas. However, experience with non-clear cell renal cell carcinoma subtypes is scant. In this study, we evaluated the immunohistochemical expression of upstream (PTEN and phosphorylated AKT) and downstream (phosphorylated S6 and 4EBP1) effectors of the mammalian target of rapamycin pathway, as well as related cell-cycle proteins (p27 and c-MYC), and a member of the hypoxia-induced pathway (HIF-1α) in 54 patients with papillary renal cell carcinoma treated by nephrectomy. PTEN was lower in tumor than in normal kidney, and loss of PTEN expression was found in 48% of the patients. In tumor tissues, phosphorylated S6, 4EBP1, and HIF-1α were higher than in normal kidney. Conversely, scores of p27 were lower in tumor than in normal kidney. Finally, scores of c-MYC and phosphorylated AKT were similar in tumor and in normal kidney. Overall mortality and cancer-specific mortality were 24% and 11%, respectively. Tumor progression was observed in 17% of the patients. None of the tested biomarkers predicted cancer-specific mortality or tumor progression. As expected, patients with high T-stage tumors had higher hazard ratios for cancer-specific mortality (hazard ratio, 6.9) and tumor progression (hazard ratio, 6.7). Patients with higher Fuhrman grades also had higher risks for cancer-specific mortality (hazard ratio, 11.4) and tumor progression (hazard ratio, 4.5). In summary, our study provides evidence of dysregulation of the mammalian target of rapamycin and hypoxia-induced pathways in papillary renal cell carcinoma. Immunohistochemistry for members of the mammalian target of rapamycin pathway and for HIF-1α lacked prognostic significance in our cohort.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma Papilar/metabolismo , Carcinoma de Células Renales/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Neoplasias Renales/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Papilar/patología , Carcinoma Papilar/cirugía , Carcinoma de Células Renales/patología , Carcinoma de Células Renales/cirugía , Proteínas de Ciclo Celular/metabolismo , Femenino , Humanos , Inmunohistoquímica , Neoplasias Renales/patología , Neoplasias Renales/cirugía , Masculino , Persona de Mediana Edad , Nefrectomía , Fosforilación , Pronóstico , Antígeno Nuclear de Célula en Proliferación/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Análisis de Matrices TisularesRESUMEN
The need for effective targeted therapies for renal cell carcinomas (RCCs) has fueled the interest for understanding molecular pathways involved in the oncogenesis of kidney tumors. Aiming to analyze the expression status and prognostic significance of mTOR and hypoxia-induced pathway members in patients with clear cell RCC (ccRCC), tissue microarrays were constructed from 135 primary and 41 metastatic ccRCCs. Immunoexpression levels were compared and correlated with clinicopathologic parameters and outcome. PTEN levels were significantly lower in primary and metastatic ccRCCs compared with benign tissues (P<0.001). Levels of phos-AKT, phos-S6, and 4E-binding protein-1 (4EBP1) were higher in metastatic ccRCC (P≤0.001). For phos-S6 and 4EBP1, levels were higher in primary ccRCC compared with benign tissues (P<0.001). c-MYC levels were higher in metastatic ccRCC (P<0.0001), and incremental p27 levels were observed in benign, primary ccRCC, and metastatic ccRCC (P<0.0001). HIF-1α levels were significantly higher in primary and metastatic ccRCCs compared with benign tissues (P<0.0001). In primary ccRCC, levels of all mTOR and hypoxia-induced pathway members were significantly associated with pT stage (P≤0.036), p27 levels with Fuhrman grade (P=0.031), and 4EBP1, p27, and HIF-1α levels with tumor size (P≤0.025). Tumor size, HIF-1α, and phos-S6 levels were associated with disease-specific survival (DSS) (P≤0.032) and tumor progression (P≤0.043). In conclusion, both mTOR and hypoxia-induced pathways were activated in primary and metastatic ccRCC. PTEN loss seems to be an early event during tumorigenesis. Tumor size, HIF-1α, and phos-S6 expression were found to be independent predictors of both DSS and tumor progression in primary ccRCC.