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1.
Ann Oncol ; 34(9): 772-782, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37399894

RESUMEN

BACKGROUND: Patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA alterations have poor outcomes. MAGNITUDE found patients with homologous recombination repair gene alterations (HRR+), particularly BRCA1/2, benefit from first-line therapy with niraparib plus abiraterone acetate and prednisone (AAP). Here we report longer follow-up from the second prespecified interim analysis (IA2). PATIENTS AND METHODS: Patients with mCRPC were prospectively identified as HRR+ with/without BRCA1/2 alterations and randomized 1 : 1 to niraparib (200 mg orally) plus AAP (1000 mg/10 mg orally) or placebo plus AAP. At IA2, secondary endpoints [time to symptomatic progression, time to initiation of cytotoxic chemotherapy, overall survival (OS)] were assessed. RESULTS: Overall, 212 HRR+ patients received niraparib plus AAP (BRCA1/2 subgroup, n = 113). At IA2 with 24.8 months of median follow-up in the BRCA1/2 subgroup, niraparib plus AAP significantly prolonged radiographic progression-free survival {rPFS; blinded independent central review; median rPFS 19.5 versus 10.9 months; hazard ratio (HR) = 0.55 [95% confidence interval (CI) 0.39-0.78]; nominal P = 0.0007} consistent with the first prespecified interim analysis. rPFS was also prolonged in the total HRR+ population [HR = 0.76 (95% CI 0.60-0.97); nominal P = 0.0280; median follow-up 26.8 months]. Improvements in time to symptomatic progression and time to initiation of cytotoxic chemotherapy were observed with niraparib plus AAP. In the BRCA1/2 subgroup, the analysis of OS with niraparib plus AAP demonstrated an HR of 0.88 (95% CI 0.58-1.34; nominal P = 0.5505); the prespecified inverse probability censoring weighting analysis of OS, accounting for imbalances in subsequent use of poly adenosine diphosphate-ribose polymerase inhibitors and other life-prolonging therapies, demonstrated an HR of 0.54 (95% CI 0.33-0.90; nominal P = 0.0181). No new safety signals were observed. CONCLUSIONS: MAGNITUDE, enrolling the largest BRCA1/2 cohort in first-line mCRPC to date, demonstrated improved rPFS and other clinically relevant outcomes with niraparib plus AAP in patients with BRCA1/2-altered mCRPC, emphasizing the importance of identifying this molecular subset of patients.


Asunto(s)
Acetato de Abiraterona , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Prednisona , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Proteína BRCA1/genética , Reparación del ADN por Recombinación , Resultado del Tratamiento , Proteína BRCA2/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
2.
Leukemia ; 26(9): 2061-8, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22627678

RESUMEN

This phase 1b trial investigated several doses and schedules of midostaurin in combination with daunorubicin and cytarabine induction and high-dose cytarabine post-remission therapy in newly diagnosed patients with acute myeloid leukemia (AML). The discontinuation rate on the 50-mg twice-daily dose schedule was lower than 100 mg twice daily, and no grade 3/4 nausea or vomiting was seen. The complete remission rate for the midostaurin 50-mg twice-daily dose schedule was 80% (FMS-like tyrosine kinase 3 receptor (FLT3)-wild-type: 20 of 27 (74%), FLT3-mutant: 12 of 13 (92%)). Overall survival (OS) probabilities of patients with FLT3-mutant AML at 1 and 2 years (0.85 and 0.62, respectively) were similar to the FLT3-wild-type population (0.78 and 0.52, respectively). Midostaurin in combination with standard chemotherapy demonstrated high complete response and OS rates in newly diagnosed younger adults with AML, and was generally well tolerated at 50 mg twice daily for 14 days. A phase III prospective trial is ongoing (CALGB 10603, NCT00651261).


Asunto(s)
Antineoplásicos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Estaurosporina/análogos & derivados , Tirosina Quinasa 3 Similar a fms/antagonistas & inhibidores , Adolescente , Adulto , Factores de Edad , Antineoplásicos/farmacocinética , Esquema de Medicación , Femenino , Humanos , Leucemia Mieloide Aguda/enzimología , Leucemia Mieloide Aguda/mortalidad , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Mutación/genética , Inducción de Remisión , Estaurosporina/farmacocinética , Estaurosporina/uso terapéutico , Tasa de Supervivencia , Distribución Tisular , Resultado del Tratamiento , Adulto Joven , Tirosina Quinasa 3 Similar a fms/genética
3.
Gastroenterology ; 98(6): 1460-6, 1990 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-2110915

RESUMEN

Patients may fail to absorb cobalamin (vitamin B12) bound to food even when they have adequate intrinsic factor to absorb free cobalamin normally. We studied cobalamin transfer from egg yolk cobalamin-binding protein to human saliva and gastric juice as a model of this important first step in cobalamin assimilation. The cobalamin-binding protein of egg yolk eluted with human R binder on Sephadex gel chromatography and bound cobalamin with a comparable affinity, but it did not cross-react with R binder immunologically. Transfer of cobalamin from egg yolk to saliva or gastric juice R binder did not occur at neutral pH. Slight transfer (8%-12% of the 57Co-cobalamin bound to egg yolk) occurred when the saliva was acidified to pH 1.5. This minor transfer by acid was not inhibited by pepstatin A, a pepsin inhibitor. Acidification caused variable transfer to gastric juice R binder (12%-40%) that appeared to be partially due to residual gastric pepsin activity. Adding 1200 U of pepsin per milliliter enhanced cobalamin transfer to saliva or gastric juice R binders (39%-58% transfer). At no time was cobalamin transferred directly to intrinsic factor; R binder-deficient gastric juice failed to accept cobalamin from egg yolk. The transfer of cobalamin from egg yolk to human R binder requires both an acid pH and pepsin activity. While as little as 30 U of pepsin added per milliliter of saliva promoted transfer of cobalamin, the requirement for an acid pH was very strict. Virtually no transfer occurred when pH exceeded 2.0, regardless of the amount of pepsin present. Acid provided an optimal pH for pepsin activity and, to a lesser extent, affected transfer by a mechanism unrelated to pepsin. Our data suggest that compromised pepsin secretion and, probably even more importantly, compromised acid secretion interfere with transfer of food cobalamin to R binder.


Asunto(s)
Yema de Huevo , Jugo Gástrico/metabolismo , Saliva/metabolismo , Transcobalaminas/farmacocinética , Vitamina B 12/farmacocinética , Anemia Perniciosa/metabolismo , Cromatografía en Gel , Yema de Huevo/análisis , Humanos , Concentración de Iones de Hidrógeno , Pepsina A/farmacología , Unión Proteica , Factores de Tiempo , Transcobalaminas/deficiencia , Transcobalaminas/aislamiento & purificación
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