RESUMEN
Minichromosome maintenance complex component 6 (MCM-6) is one of the six proteins of the MCM family, which are involved in the initiation of DNA replication, represents a marker of proliferating cells. The goal of this study was to evaluate the prognostic relevance of the neoplastic cell proliferation rate in patients with Hodgkin's lymphoma (HL). We evaluated the formalin-fixed paraffin-embedded lymph node biopsy specimens from 55 patients by using monoclonal antibody against MCM-6 and compared these findings with clinical data and treatment outcome. Median of MCM-6 expression was 85% (range: 35%-99%). In multivariate analysis, MCM-6 expression, B symptoms, and age were not statistically significant predictor for relapse in contrary to response (P=.001) and stage of disease (P=.048). Patients with lower MCM-6 expression rates showed higher relapse rate and lower disease-free survival (DFS). Meanwhile, patients with MCM-6 expression less than 85% showed shorter DFS (P=.031). We hypothesize that in group of patients with lower MCM-6 expression rate, a larger proportion of proliferating malignant cells are arrested in the very early phase of mitosis, in comparison to the group of patients with higher MCM-6 expression, and this could imply a shorter and probably higher relapse rate in the former group.
Asunto(s)
Enfermedad de Hodgkin/genética , Componente 6 del Complejo de Mantenimiento de Minicromosoma/genética , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/análisis , Proliferación Celular , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Pronóstico , Adulto JovenAsunto(s)
Antígenos CD34/metabolismo , Dermatofibrosarcoma/patología , Histiocitoma Fibroso Benigno/patología , Neoplasias Cutáneas/patología , Diagnóstico Diferencial , Femenino , Histiocitoma Fibroso Benigno/metabolismo , Humanos , Pierna/patología , Traumatismos de la Pierna/complicaciones , Persona de Mediana Edad , Neoplasias Cutáneas/metabolismoRESUMEN
INTRODUCTION: Xenograft models of epithelial malignancies potentially have greater correlation with clinical end points. We implanted 153 primary non-small cell lung carcinomas into non-obese diabetic-severe combined immunodeficient mice to develop primary lung cancer xenografts. Sixty-three xenografts formed. However, in 19 implantations, tumors consisted of a lymphocyte proliferation without a carcinoma component. We further characterized these lymphomas to determine clinicopathological features associated with their formation. METHODS: Lymphomas were investigated morphologically and by silver in situ hybridization to determine their species of origin. Characterization both of the xenograft lymphomas and the primary NSCLCs from which they were derived included immunohistochemistry for lymphoma markers and Epstein Barr virus Early RNA (EBER) by in situ hybridization. DNA was profiled using the MassARRAY platform; EML4-ALK translocations and lymphocyte infiltration were assessed in the primary tumor. Lymphoma formation was correlated with patient and primary tumor characteristics and survival. RESULTS: The lymphocytic tumors were EBER positive, human diffuse large B-cell lymphomas (DLBCLs). Significantly more DLBCLs that formed in mice arose in primary lung adenocarcinomas and in epithelial growth factor receptor mutant never smokers. DLBCL formation was not associated with the degree of tumor-infiltrating lymphocytes or EBER-positive lymphocytes in the primary NSCLCs. Patients whose tumors developed DLBCL had longer disease-free survival compared with patients whose tumors formed epithelial xenografts (hazard ratio: 0.44; 95% confidence interval: 0.18 -1.06, Wald p = 0.07), regardless of genotype. CONCLUSION: We hypothesize that mechanisms involved in the active suppression of viral antigens may also be involved in the suppression of tumor antigens, and may have resulted in the observed favorable clinical outcome.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Infecciones por Virus de Epstein-Barr/complicaciones , Herpesvirus Humano 4/patogenicidad , Linfocitos Infiltrantes de Tumor/inmunología , Linfoma de Células B Grandes Difuso/etiología , Linfoma de Células B Grandes Difuso/mortalidad , Adenocarcinoma/complicaciones , Adenocarcinoma/mortalidad , Adenocarcinoma/virología , Adulto , Anciano , Anciano de 80 o más Años , Animales , Antígenos Virales/inmunología , Antígenos Virales/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/virología , Carcinoma de Células Escamosas/complicaciones , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/virología , Femenino , Reordenamiento Génico , Herpesvirus Humano 4/genética , Humanos , Técnicas para Inmunoenzimas , Inmunofenotipificación , Hibridación in Situ , Neoplasias Pulmonares/complicaciones , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/virología , Linfocitos Infiltrantes de Tumor/patología , Masculino , Ratones , Ratones SCID , Persona de Mediana Edad , Mutación/genética , Estadificación de Neoplasias , Proteínas de Fusión Oncogénica/genética , Reacción en Cadena de la Polimerasa , Pronóstico , ARN Viral/genética , Tasa de Supervivencia , Trasplante HeterólogoRESUMEN
The aims of this study were to further define the safety of sorafenib and erlotinib, given at their full approved monotherapy doses, and to correlate pharmacokinetic and pharmacodynamic markers with clinical outcome. In addition, a novel pharmacodynamic marker based on the real-time measurement of RAF signal transduction capacity (STC) is described. Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously. RAF STC was assessed in peripheral blood monocytes prior to erlotinib initiation. Epidermal growth factor receptor (EGFR) expression and K-RAS mutations were measured in archival tumor samples. Changes in pERK and CD31 were determined in fresh tumor biopsies obtained pretreatment, prior to erlotinib dosing, and during the administration of both drugs. In addition, positron emission tomography-computed tomography scans and pharmacokinetic assessments were done. Eleven patients received a total of 57 cycles (median, 5; range, 1-10). Only four patients received full doses of both drugs for the entire study course, with elevation of liver enzymes being the main reason for dose reductions and delays. Among 10 patients evaluable for response, 8 experienced tumor stabilization of >or=4 cycles. Pharmacokinetic analysis revealed no significant interaction of erlotinib with sorafenib. Sorafenib-induced decrease in RAF-STC showed statistically significant correlation with time-to-progression in seven patients. Other pharmacodynamic markers did not correlate with clinical outcome. This drug combination resulted in promising clinical activity in solid tumor patients although significant toxicity warrants close monitoring. RAF-STC deserves further study as a predictive marker for sorafenib.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bencenosulfonatos/administración & dosificación , Biomarcadores Farmacológicos/análisis , Neoplasias/tratamiento farmacológico , Piridinas/administración & dosificación , Quinazolinas/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Bajo la Curva , Bencenosulfonatos/efectos adversos , Bencenosulfonatos/farmacocinética , Biomarcadores Farmacológicos/metabolismo , Estudios de Cohortes , Clorhidrato de Erlotinib , Femenino , Humanos , Masculino , Persona de Mediana Edad , Modelos Biológicos , Neoplasias/metabolismo , Niacinamida/análogos & derivados , Compuestos de Fenilurea , Piridinas/efectos adversos , Piridinas/farmacocinética , Quinazolinas/efectos adversos , Quinazolinas/farmacocinética , Sorafenib , Resultado del TratamientoRESUMEN
BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a relatively uncommon spindle cell tumor of the skin. It is locally aggressive and can be a therapeutic challenge. There are case reports of partial response of DFSP to the tyrosine kinase inhibitor STI571 (Imatinib), despite the reported negativity of the tumor cells for CD117. At least one publication reported focal CD117 positivity of DFSP cells, and we would like to clarify the issue. Cellular dermatofibroma (CDF) can mimic DFSP, but typical cases are easily differentiated from DFSP by their staining pattern for CD34 and factor 13a. We also report our experience with CD117 staining of typical CDFs. METHODS: Thirty-seven cases of clear-cut DFSP and 13 cases of clear-cut CDF were retrieved from the archives of Sunnybrook Health Sciences Center between 2000 and 2005. RESULTS: All DFSPs were CD34 (+), factor 13a (-) and CD117 (-). All CDFs were factor 13a (+), CD34 (-) and CD117 (-). CONCLUSIONS: Our study on a relatively large number of cases confirms the negativity of DFSP and CDF for CD117. Therefore, if adjuvant therapy is attempted with drugs such as STI571 (Imatinib), the eligibility of patients should not be based on immunohistochemical assessment of CD117 expression.