RESUMEN
Brain radiation necrosis (RN) is a subacute or late adverse event following radiotherapy, involving an exacerbated inflammatory response of the brain tissue. The risk of symptomatic RN associated with stereotactic radiosurgery (SRS) as part of the treatment of brain metastases (BMs) has been a subject of recent investigation. The activation of the signal transducer and activator of transcription 3 (STAT3) was shown in reactive astrocytes (RA) associated with BMs. Given that the pathophysiological mechanisms behind RN are not fully understood, we sought to investigate the role of STAT3 among other inflammatory markers in RN development. A mouse model of RN using clinical LINAC-based SRS was designed to induce brain necrosis with the administration of 50 Gy in a single fraction to the left hemisphere using a circular collimator of 5 mm diameter. Immunohistochemistry and multiplex staining for CD4, CD8, CD68, GFAP, and STAT3 were performed. For validation, eleven patients with BMs treated with SRS who developed symptomatic RN and required surgery were identified to perform staining for CD68, GFAP, and STAT3. In the mouse model, the RN and perinecrotic areas showed significantly higher staining for F4/80+ and GFAP+ cells, with a high infiltration of CD4 and CD8 T-lymphocytes, when compared to the non-irradiated cerebral hemisphere. A high number of GFAP+pSTAT3+ and F4/80+pSTAT3+ cells was found in the RN areas and the rest of the irradiated hemisphere. The analysis of human brain specimens showed that astrocytes and microglia were actively phosphorylating STAT3 in the areas of RN and gliosis. Phosphorylated STAT3 is highly expressed in the microglia and RA pertaining to the areas of brain RN. Targeting STAT3 via inhibition represents a promising strategy to ameliorate symptomatic RN in BM patients undergoing SRS.
RESUMEN
Sunitinib is one of the most widely used targeted therapeutics for renal cell carcinoma (RCC), but acquired resistance against targeted therapies remains a major clinical challenge. To dissect mechanisms of acquired resistance and unravel reliable predictive biomarkers for sunitinib in RCC, we sequenced the exons of 409 tumor-suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and after development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in silico prediction models, six predicted to be deleterious, located in G6PD, LRP1B, SETD2, TET2, SYNE1, and DCC. Consistently, immunoblotting analysis of lysates derived from sunitinib-desensitized RCC cells and their parental counterparts showed marked differences in the levels and expression pattern of the proteins encoded by these genes. Our further analysis demonstrates essential roles for these proteins in mediating sunitinib cytotoxicity and shows that their loss of function renders tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the six proteins was overcome by treatment with cabozantinib or a low-dose combination of lenvatinib and everolimus. Collectively, our results unravel novel markers of acquired resistance to sunitinib and clinically relevant approaches for overcoming this resistance in RCC.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma de Células Renales/genética , Resistencia a Antineoplásicos , Neoplasias Renales/genética , Mutación , Animales , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/metabolismo , Línea Celular Tumoral , Exones , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Renales/metabolismo , Ratones , Trasplante de Neoplasias , Análisis de Secuencia de ADN , SunitinibRESUMEN
BACKGROUND AND OBJECTIVES: there are few published data on the use of EUS guided fine-needle aspiration in secondary pancreatic lesions. We describe the largest series published so far in a European country. PATIENTS AND METHODS: a retrospective review of the cases identified in our institution from 2004 to 2016 has been recorded. The clinical data are described, comparing the latency period from the primary tumor diagnosis to the detection of the pancreatic metastasis and the survival of patients according to the cytological diagnosis. RESULTS: forty-four patients were diagnosed with pancreatic metastasis using EUS guided fine needle aspiration. Ancillary cytological studies were performed in 28 (63.6%). The most common primary tumor sites were kidney and lung. Thirty-four patients (77.3%) had a previous history of malignancy, with a latency period ranging from 6 months to 18.8 years. Patients diagnosed with primary renal carcinoma had a significantly longer latency period and longer survival compared to those with primary lung cancer. In 13 patients, EUS was either the only technique that detected the PM or showed a greater number of intrapancreatic lesions. These metastases were significantly smaller than those diagnosed by other imaging studies (11.9 ± 4.1 mm vs 30.7 ± 19.8 mm, p < 0.001). CONCLUSIONS: EUS guided fine-needle aspiration plays a crucial role in the diagnosis of pancreatic metastases and may have a major clinical impact. Patients with renal cell carcinoma could benefit from long-term follow-up with EUS.
Asunto(s)
Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/secundario , Anciano , Biopsia por Aspiración con Aguja Fina Guiada por Ultrasonido Endoscópico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Atezolizumab is an IgG1 isotype monoclonal antibody against the protein programmed cell death-ligand 1 (PD- L1). PD-L1 may be highly expressed in some tumors and is believed to inhibit immune cells that recognize and attack tumor cells. Inhibition of PD-L1 can remove its inhibitory effect and provoke an anti-tumor response. In October 2016, the Food and Drugs Administration (FDA) approved atezolizumab for the treatment of patients with metastatic non-small cell lung cancer after disease progression during or following platinum based chemotherapy. We present the case of a 43-year-old male with stage IV lung adenocarcinoma in progression, despite standard chemotherapy.
Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Colitis/inducido químicamente , Colitis/inmunología , Neoplasias Pulmonares/complicaciones , Adulto , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Colitis/diagnóstico por imagen , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , MasculinoRESUMEN
BACKGROUND: HLA-G in biological fluids has been proposed to be useful as a tumor marker as both a diagnostic and prognostic factor. Most HLA-G measurement procedures are based on ELISA methods using highly specific antibodies. However, results of published studies are in conflict regarding the clinical utility and even the nature of HLA-G present in circulation. METHODS: We collected 118 exudates, 94 from cancer patients and 24 from patients without tumors. We measured HLA-G concentrations by ELISA using MEM-G/9 or G233 as capture antibody. Samples were immunoprecipitated with an anti-HLA-G antibody and analyzed by Western blot using a different anti-HLA-G antibody. RESULTS: Discrepancies in HLA-G concentrations in exudates were observed depending on what capture anti-HLA-G antibody was used for ELISA (r = 0.376). These discrepancies were not observed when the ELISAs were performed using culture supernatants from HLA-G1-transfected cells (r = 0.983). Immunoprecipitation and Western blot of cell culture supernatants with 2 different anti-HLA-G antibodies produced the typical band at 39 kDa assigned to HLA-G. When the immunoprecipitation and western blot were performed with exudates, however, there were bands at 53 kDa and 70-76 kDa, higher molecular weights than those usually assigned to HLA-G. These HLA-G-like molecules were associated with ß(2)-microglobulin and could also form disulfide bridges with other HLA-G-like molecules. CONCLUSIONS: The main HLA-G antigenic molecules in exudates are HLA-G-like complexes, a factor that should be considered when analyzing HLA-G in biological fluids.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Exudados y Transudados/metabolismo , Antígenos HLA/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Neoplasias/metabolismo , Especificidad de Anticuerpos , Western Blotting , Estudios de Casos y Controles , Línea Celular , Ensayo de Inmunoadsorción Enzimática , Femenino , Antígenos HLA/genética , Antígenos HLA/inmunología , Antígenos HLA-G , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Inmunoprecipitación , Masculino , Transfección , Microglobulina beta-2/metabolismoAsunto(s)
Cirugía Bariátrica , Anomalías del Sistema Digestivo , Hepatopatías , Fallo Hepático , Trasplante de Hígado , Obesidad Mórbida , Cirugía Bariátrica/efectos adversos , Humanos , Hígado , Hepatopatías/cirugía , Fallo Hepático/cirugía , Trasplante de Hígado/efectos adversos , Necrosis/etiología , Obesidad Mórbida/cirugíaRESUMEN
No disponible
Asunto(s)
Humanos , Masculino , Adulto , Colitis/inducido químicamente , Anticuerpos Monoclonales/efectos adversos , Antineoplásicos/efectos adversos , Neoplasias Pulmonares/complicaciones , Colitis/inmunología , Hemorragia Gastrointestinal/etiología , Corticoesteroides/uso terapéuticoRESUMEN
Antecedentes y objetivos: hay pocas publicaciones sobre el papel de la ecoendoscopia con punción en lesiones pancreáticas secundarias. Describimos la serie más amplia publicada hasta ahora en un país europeo. Pacientes y métodos: revisamos retrospectivamente los casos identificados en nuestra institución de 2004 a 2016. Describimos las características clínicas de los pacientes, comparando el periodo de latencia desde el diagnóstico del tumor primario hasta la detección de la metástasis pancreática y la supervivencia de los pacientes según el diagnóstico citológico. Resultados: cuarenta y cuatro pacientes fueron diagnosticados de metástasis pancreáticas mediante ecoendoscopia con punción. Se realizaron estudios citológicos auxiliares en 28 (63,6%). Los tumores primarios más comunes fueron riñón y pulmón. Treinta y cuatro pacientes (77,3%) tenían historia previa de cáncer, con un periodo de latencia desde seis meses hasta 18,8 años. Los pacientes diagnosticados de carcinoma renal primario presentaron tiempos de latencia significativamente más largos y una supervivencia más prolongada que aquellos cuyo tumor primario fue pulmonar. En 13 pacientes, la ecoendoscopia fue la única técnica que detectó la metástasis pancreática o la que mostró un mayor número de lesiones intrapancreáticas. Las lesiones detectadas solo por ecoendoscopia fueron significativamente más pequeñas que las diagnosticadas por otros métodos de imagen (11,9 +/- 4,1 mm frente a 30,7 +/- 19,8 mm, p < 0,001). Conclusiones: la ecoendoscopia con punción juega un papel crucial en el diagnóstico de metástasis pancreáticas y puede tener un impacto clínico importante. Los pacientes con carcinoma de células renales podrían beneficiarse del seguimiento a largo plazo con ecoendoscopia
Background and objectives: there are few published data on the use of EUS guided fine-needle aspiration in secondary pancreatic lesions. We describe the largest series published so far in a European country. Patients and methods: a retrospective review of the cases identified in our institution from 2004 to 2016 has been recorded. The clinical data are described, comparing the latency period from the primary tumor diagnosis to the detection of the pancreatic metastasis and the survival of patients according to the cytological diagnosis. Results: forty-four patients were diagnosed with pancreatic metastasis using EUS guided fine needle aspiration. Ancillary cytological studies were performed in 28 (63.6%). The most common primary tumor sites were kidney and lung. Thirty-four patients (77.3%) had a previous history of malignancy, with a latency period ranging from 6 months to 18.8 years. Patients diagnosed with primary renal carcinoma had a significantly longer latency period and longer survival compared to those with primary lung cancer. In 13 patients, EUS was either the only technique that detected the PM or showed a greater number of intrapancreatic lesions. These metastases were significantly smaller than those diagnosed by other imaging studies (11.9 +/- 4.1 mm vs 30.7 +/- 19.8 mm, p < 0.001). Conclusions: EUS guided fine-needle aspiration plays a crucial role in the diagnosis of pancreatic metastases and may have a major clinical impact. Patients with renal cell carcinoma could benefit from long-term follow-up with EUS