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1.
Cancer Res ; 76(24): 7118-7129, 2016 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-27913435

RESUMO

Solid papillary carcinoma with reverse polarity (SPCRP) is a rare breast cancer subtype with an obscure etiology. In this study, we sought to describe its unique histopathologic features and to identify the genetic alterations that underpin SPCRP using massively parallel whole-exome and targeted sequencing. The morphologic and immunohistochemical features of SPCRP support the invasive nature of this subtype. Ten of 13 (77%) SPCRPs harbored hotspot mutations at R172 of the isocitrate dehydrogenase IDH2, of which 8 of 10 displayed concurrent pathogenic mutations affecting PIK3CA or PIK3R1 One of the IDH2 wild-type SPCRPs harbored a TET2 Q548* truncating mutation coupled with a PIK3CA H1047R hotspot mutation. Functional studies demonstrated that IDH2 and PIK3CA hotspot mutations are likely drivers of SPCRP, resulting in its reversed nuclear polarization phenotype. Our results offer a molecular definition of SPCRP as a distinct breast cancer subtype. Concurrent IDH2 and PIK3CA mutations may help diagnose SPCRP and possibly direct effective treatment. Cancer Res; 76(24); 7118-29. ©2016 AACR.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Papilar/genética , Carcinoma Papilar/patologia , Isocitrato Desidrogenase/genética , Fosfatidilinositol 3-Quinases/genética , Biomarcadores Tumorais/genética , Western Blotting , Classe I de Fosfatidilinositol 3-Quinases , Análise Mutacional de DNA , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Reação em Cadeia da Polimerase
2.
Neuro Oncol ; 10(2): 190-8, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18287342

RESUMO

Cyclooxygenase-2 (COX-2) expression has been linked to the prognosis, angiogenesis, and radiation sensitivity of many malignancies. Celecoxib, a selective COX-2 inhibitor, is predominantly eliminated by hepatic metabolism. This study was conducted to determine the effects of hepatic enzyme-inducing antiseizure drugs (EIASDs) on the pharmacokinetics of celecoxib. The safety of celecoxib administered with radiation for glioblastoma and the effect of the combined treatment on survival were also evaluated. Patients were stratified based on concomitant use of EIASDs. Celecoxib (400) mg was administered orally twice a day until tumor progression or dose-limiting toxicity. Standard radiation was administered without adjuvant chemotherapy. Sampling was performed to define the plasma concentration/time profile for the initial dose of celecoxib and steady-state trough concentrations. Thirty-five patients (22 +EIASD, 13 -EIASD) were enrolled. There were no significant differences in age, performance status, extent of surgery, or Mini Mental State Exam scores between the two cohorts. The treatment was well tolerated. All patients in the +EIASD arm were taking phenytoin. There were no significant differences in any celecoxib pharmacokinetic parameters between 15 +EIASD and 12 -EIASD patients. With 31 of 35 patients deceased, estimated median survival time for all patients was 12 months (+EIASD, 11.5 months; - EIASD, 16 months; p = 0.11). The pharmacokinetics of celecoxib is not significantly affected by the concomitant administration of phenytoin. Celecoxib administered during and after radiation is well tolerated. The potential difference in survival between the +EIASD and -EIASD groups deserves further evaluation.


Assuntos
Anticonvulsivantes/uso terapêutico , Antineoplásicos/farmacocinética , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Fenitoína/uso terapêutico , Pirazóis/farmacocinética , Sulfonamidas/farmacocinética , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Área Sob a Curva , Celecoxib , Terapia Combinada , Interações Medicamentosas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirazóis/uso terapêutico , Radioterapia , Convulsões/prevenção & controle , Sulfonamidas/uso terapêutico
3.
Clin Cancer Res ; 12(17): 5174-81, 2006 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-16951236

RESUMO

PURPOSE: Procarbazine hydrochloride (PCB) is one of the few anticancer drugs with activity against high-grade gliomas. This study was conducted to determine if the maximum tolerated dose and pharmacokinetics of PCB are affected by the concurrent use of enzyme-inducing antiseizure drugs (EIASD). EXPERIMENTAL DESIGN: Adults with recurrent high-grade glioma were divided into cohorts who were (+) and were not (-) taking EIASDs. PCB was given orally for 5 consecutive days each month. Six patients were evaluated at each dose level beginning with 200 mg/m2/d and escalated using the modified continual reassessment method. Toxicity and response were assessed. Pharmacokinetic studies were done with a new electrospray ionization mass spectrometry assay. RESULTS: Forty-nine patients were evaluated. The maximum tolerated dose was 393 mg/m2/d for the +EIASD group and the highest dose evaluated in -EIASD patients was 334 mg/m2/d. Myelosuppression was the primary dose-limiting toxicity. Significant hepatic dysfunction occurred in three patients in the +EIASD cohort. Four partial responses (8%) and no complete responses were observed. PCB exhibited linear pharmacokinetics with no significant differences between the two cohorts. A marked increase in peak PCB levels was noted on day 5 relative to day 1, which was not attributable to drug accumulation. CONCLUSIONS: This study suggests that (a) EIASD use does not significantly affect the pharmacokinetics of PCB; (b) changes in the peak plasma concentration of PCB, consistent with decreased apparent oral clearance due to autoinhibition of hepatic metabolism, occur with daily dosing; and (c) severe hepatic dysfunction may accompany this administration schedule.


Assuntos
Anticonvulsivantes/farmacologia , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Glioma/tratamento farmacológico , Procarbazina/efeitos adversos , Procarbazina/farmacocinética , Administração Oral , Adulto , Idoso , Anticonvulsivantes/administração & dosagem , Antineoplásicos/administração & dosagem , Estudos de Coortes , Progressão da Doença , Relação Dose-Resposta a Droga , Esquema de Medicação , Indução Enzimática/efeitos dos fármacos , Feminino , Seguimentos , Glioma/enzimologia , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Procarbazina/administração & dosagem , Espectrometria de Massas por Ionização por Electrospray/métodos , Fatores de Tempo , Resultado do Tratamento
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