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Advanced systemic mastocytosis (AdvSM) is a rare myeloid neoplasm, driven by the KIT D816V mutation in >90% of patients. Avapritinib, a potent, highly selective D816V-mutant KIT inhibitor, is approved for treatment of adults with AdvSM by the US Food and Drug Administration, regardless of prior therapy, and the European Medicines Agency for patients with prior systemic therapy, based on EXPLORER (#NCT02561988; clinicaltrials.gov) and PATHFINDER (#NCT03580655; clinicaltrials.gov) clinical studies. We present latest pooled efficacy and safety analyses from patients who received ≥1 systemic therapy prior to avapritinib in EXPLORER/PATHFINDER. Overall response rate in response-evaluable patients (n = 31) was 71% (95% confidence interval: 52% to 86%; 22/31), including 19% (6/31) with complete remission (CR)/CR with partial recovery of peripheral blood counts (CRh). Median time to response was 2.3 months, median time to CR/CRh was 7.4 months, and median duration of response (DOR) was not reached. Reductions ≥50% in bone marrow mast cell infiltration (89%), KIT D816V variant allele fraction (66%), serum tryptase (89%), and reductions ≥35% in spleen size (70%) occurred in most patients. Median OS was not reached (median follow-up 17.7 months). Avapritinib was effective in all AdvSM subtypes, regardless of number/type of prior therapies or poor prognostic somatic mutations. Treatment-related adverse events (TRAEs) were observed in 94% of patients, most commonly grade 1/2; 57% had TRAEs of at least grade 3; 81% remained on treatment at 6 months. Avapritinib in adults with AdvSM who received prior systemic therapy was generally well tolerated, with high response rates regardless of prior systemic therapy.

Made available in DSpace on 2016-08-29T15:36:37Z (GMT). No. of bitstreams: 1 tese_7176_Rafael Fonseca Zanotti.pdf: 3157606 bytes, checksum: dfee1d183b6d161da963b1a9f35e3303 (MD5) Previous issue date: 2015-08-28 O feijoeiro (Phaseolus vulgaris L.) é uma cultura agrícola muito importante economicamente e nutricionalmente para a população brasileira e necessita de metodologias simples e eficazes que auxiliem o processo de melhoramento genético. As técnicas empregadas devem minimizar os efeitos indesejáveis da multicolinearidade entre as características estudadas durante o processo de seleção. A produção de sementes de feijão, normalmente, é limitada pela escassez hídrica e solos salinos. No entanto, devido a grande variabilidade genética, característica da espécie, é possível encontrar materiais genéticos mais tolerantes a esses estresses osmóticos. A germinação e o desenvolvimento inicial da plântula são fases críticas e desta maneira é importante selecionar os matérias genéticos mais tolerantes nestas fases. Além de selecionar genótipos tolerantes é necessário selecionar materiais genéticos que sejam ricos nutricionalmente, principalmente, em relação à composição mineralógica. Os principais objetivos almejados com este trabalho foram reduzir a multicolinearidade e selecionar genótipos para a tolerância ao estresse osmótico e a biofortificação dos grãos do feijoeiro, com base nos valores genéticos. Desta maneira, foram utilizadas duas técnicas para reduzir a influência da multicolinearidade: o descarte de variáveis redundantes pelas variáveis canônicas, e o uso das análises de fatores para reduzir o número de variáveis. As variáveis analisadas foram: porcentagem de germinação e de plântulas normais, tempo médio de germinação, índice de velocidade de germinação, comprimentos de raiz e de hipocótilo, massas seca de raiz e da parte aérea, razão raiz/parte aérea e o produto da porcentagem de plântulas normais pelo comprimento das plântulas. Avaliou-se também a composição mineralógica dos grãos em relação à concentração de cálcio, ferro, zinco, potássio, magnésio, manganês e fósforo. Adicionalmente, para estimar os parâmetros e os valores genéticos realizou-se análise via modelos mistos, utilizando-se a técnica de REML/BLUP. Os genótipos foram selecionados com base da média genética, estabilidade e adaptabilidade, utilizando-se a técnica da média harmônica da performance relativa dos valores genéticos. Os genótipos que apresentaram as maiores tolerâncias, adaptabilidade e estabilidade quanto aos estresses osmóticos foram: CNFC 15466, CNFC 15462, CNFC 15630, BRS Valente, Capixaba Precoce, CNFP 15290, CNFP 15292 e CNFP 15302. Enquanto os genótipos mais ricos e divergentes geneticamente do grupo comercial carioca foram: CNFC 15475 e CNFC 15625, e do grupo comercial preto foram: CNFP 15310 e CNFP 15304. Conclui-se que a utilização de técnicas multivariadas facilita a seleção de genótipos promissores como parentais na formação de linhagens tolerantes ao estresse osmótico e biofortificados. Palavras-chave: feijoeiro comum; seleção de genótipos; estresse hídrico e salino; multicolinearidade; composição mineral.

PURPOSE: The combination of bendamustine (B) and rituximab (R) is efficacious, with favorable toxicity in mantle-cell lymphoma (MCL). In this phase II study, we combined cytarabine with R and B (R-BAC) in patients with MCL age ≥ 65 years who were previously untreated or relapsed or refractory (R/R) after one prior immunochemotherapy treatment. PATIENTS AND METHODS: In stage one, we established the maximum-tolerated dose (MTD) of cytarabine in R-BAC. In stage two, patients received R (375 mg/m(2) intravenously [IV] on day 1), B (70 mg/m(2) IV on days 2 and 3), and cytarabine (MTD IV on days 2 to 4) every 28 days for four to six cycles. The primary end point (overall response rate [ORR]) was evaluated by positron emission tomography. Secondary end points included safety, progression-free survival (PFS), response duration, and overall survival. RESULTS: Forty patients (median age, 70 years; 20 previously untreated patients) were enrolled; 93% had Ann Arbor stage III/IV disease; 49% had high Mantle Cell International Prognostic Index scores, with 15% blastoid histology. All R/R patients (35% refractory) had previously received R-containing regimens. The cytarabine MTD used in stage two was 800 mg/m(2), and R-BAC was well tolerated, with an 85% treatment completion rate. The major toxicity was transient grades 3 to 4 thrombocytopenia (87% of patients); febrile neutropenia occurred in 12%. The ORR was 100% (95% complete response [CR]) for previously untreated and 80% (70% CR) for R/R patients. The 2-year PFS rate (± standard deviation) was 95% ± 5% for untreated and 70% ± 10% for R/R patients. CONCLUSION: R-BAC is well tolerated and active against MCL.

Diagnostic frameworks are essential to many scientific and technological activities and clinical practice. This study examines the main fundamental aspects of such frameworks. The three components required for all diagnoses are identified and examined, i.e. their normative dimension, temporal nature and structure, and teleological perspective. The normative dimension of a diagnosis is based on (1) epistemic values when associated with Hempel's inductive risk concerning the balance between false-positive and false-negative outcomes, leading to probabilistic judgements; and (2) non-epistemic values when related to ideas such as well-being, normality, illness, etc, as idealized norms or ideal points of reference. It should be noted that medical diagnoses match the three necessary components, while some essential diagnostic frameworks - the taxonomies of Gordon and NANDA - in nursing lack some components. The main lack is normative as the most popular frameworks in nursing diagnosis seem to be descriptions of observed reality rather than normative and value-based judgements in which both epistemic and non-epistemic values may coexist.