RESUMO
KEY MESSAGE: The integration of new technologies into public plant breeding programs can make a powerful step change in agricultural productivity when aligned with principles of quantitative and Mendelian genetics. The breeder's equation is the foundational application of quantitative genetics to crop improvement. Guided by the variables that describe response to selection, emerging breeding technologies can make a powerful step change in the effectiveness of public breeding programs. The most promising innovations for increasing the rate of genetic gain without greatly increasing program size appear to be related to reducing breeding cycle time, which is likely to require the implementation of parent selection on non-inbred progeny, rapid generation advance, and genomic selection. These are complex processes and will require breeding organizations to adopt a culture of continuous optimization and improvement. To enable this, research managers will need to consider and proactively manage the, accountability, strategy, and resource allocations of breeding teams. This must be combined with thoughtful management of elite genetic variation and a clear separation between the parental selection process and product development and advancement process. With an abundance of new technologies available, breeding teams need to evaluate carefully the impact of any new technology on selection intensity, selection accuracy, and breeding cycle length relative to its cost of deployment. Finally breeding data management systems need to be well designed to support selection decisions and novel approaches to accelerate breeding cycles need to be routinely evaluated and deployed.
Assuntos
Melhoramento Vegetal/métodos , Plantas/genética , Setor Público , Marcadores Genéticos , Padrões de Herança/genética , Polimorfismo de Nucleotídeo Único/genética , Seleção GenéticaRESUMO
Central nervous system primitive neuro-ectodermal tumors (CNS-PNETs), have recently been re-classified in the most recent 2016 WHO Classification into a standby catch all category, "CNS Embryonal Tumor, not otherwise specified" (CNS embryonal tumor, NOS) based on epigenetic, biologic and histopathologic criteria. CNS embryonal tumors (NOS) are a rare, histologically and molecularly heterogeneous group of tumors that predominantly affect children, and occasionally adults. Diagnosis of this entity continues to be challenging and the ramifications of misdiagnosis of this aggressive class of brain tumors are significant. We report the case of a 45-year-old woman who was diagnosed with a central nervous system embryonal tumor (NOS) based on immunohistochemical analysis of the patient's tumor at diagnosis. However, later genome-wide methylation profiling of the diagnostic tumor undertaken to guide treatment, revealed characteristics most consistent with IDH-mutant astrocytoma. DNA sequencing and immunohistochemistry confirmed the presence of IDH1 and ATRX mutations resulting in a revised diagnosis of high-grade small cell astrocytoma, and the implementation of a less aggressive treatment regime tailored more appropriately to the patient's tumor type. This case highlights the inadequacy of histology alone for the diagnosis of brain tumours and the utility of methylation profiling and integrated genomic analysis for the diagnostic verification of adults with suspected CNS embryonal tumor (NOS), and is consistent with the increasing realization in the field that a combined diagnostic approach based on clinical, histopathological and molecular data is required to more accurately distinguish brain tumor subtypes and inform more effective therapy.
Assuntos
Astrocitoma/diagnóstico , Neoplasias Encefálicas/diagnóstico , Metilação de DNA , Perfilação da Expressão Gênica , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Astrocitoma/genética , Neoplasias Encefálicas/genética , Citodiagnóstico , Erros de Diagnóstico , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-IdadeRESUMO
Drug resistance to conventional anticancer therapies is almost inevitable in patients with advanced ovarian cancer (AOC), limiting their available treatment options. Novel phase I trial therapies within a dedicated drug development unit may represent a viable alternative; however, there is currently little evidence for patient outcomes in such patients. To address this, we undertook a retrospective review of patients with AOC allocated to phase I trials in the Drug Development Unit at Royal Marsden Hospital (RMH) between June 1998 and October 2010. A total of 200 AOC patients with progressive disease were allocated to ≥1 trial each, with a total of 281 allocations. Of these, 135 (68%) patients commenced ≥1 trial (mean 1.4 [1-8]), totaling 216 allocated trials; 65 (32%) patients did not start due to deterioration resulting from rapidly progressive disease (63 patients) or patient choice (2 patients). Response Evaluation Criteria in Solid Tumours (RECIST) complete/partial responses (CR/PR) were observed in 43 (20%) of those starting trials, including those on poly(ADP-ribose) polymerase (PARP) inhibitors (18/79 [23%]), antiangiogenics (9/65 [14%]) and chemotherapy combinations (14/43 [33%]). Factors associated with CR/PR included: fewer prior treatments, platinum-sensitive disease, CR/PR with prior therapy, (the United States-based) Eastern Cooperative Oncology Group (ECOG) performance status score, fewer metastatic sites, higher albumin and haemoglobin levels, lower white cell counts and baseline CA125 levels, germline BRCA1/2 mutations and better RMH Prognostic Score. Mean survival was 32° months for patients who achieved CR/PR. Treatments were generally well tolerated. Most patients with AOC (134/200 [67%]) received ≥1 subsequent line of therapy after phase I trials. Our data suggest that phase I trial referrals should be considered earlier in the AOC treatment pathway and before the onset of rapid disease progression particularly with the emergence of promising novel agents in the era of precision medicine.
Assuntos
Adenocarcinoma de Células Claras/tratamento farmacológico , Antineoplásicos/uso terapêutico , Carcinoma Endometrioide/tratamento farmacológico , Carcinossarcoma/tratamento farmacológico , Ensaios Clínicos Fase I como Assunto , Tumor de Células da Granulosa/tratamento farmacológico , Neoplasias Císticas, Mucinosas e Serosas/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adenocarcinoma de Células Claras/genética , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/patologia , Adulto , Idoso , Antígeno Ca-125/metabolismo , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/metabolismo , Carcinoma Endometrioide/patologia , Carcinossarcoma/genética , Carcinossarcoma/metabolismo , Carcinossarcoma/patologia , Descoberta de Drogas , Inglaterra , Feminino , Genes BRCA1 , Genes BRCA2 , Tumor de Células da Granulosa/genética , Tumor de Células da Granulosa/metabolismo , Tumor de Células da Granulosa/patologia , Hemoglobinas/metabolismo , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Humanos , Contagem de Leucócitos , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Císticas, Mucinosas e Serosas/genética , Neoplasias Císticas, Mucinosas e Serosas/metabolismo , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Prognóstico , Estudos Retrospectivos , Albumina Sérica/metabolismo , Índice de Gravidade de Doença , Taxa de Sobrevida , Resultado do TratamentoRESUMO
INTRODUCTION: Confirmed doubling of CA125 value is one definition of progression in ovarian cancer patients. If asymptomatic, the management of these patients is unclear. To provide information which may assist in therapeutic decision making, we set out to determine the independent prognostic significance for the rate of rise in CA125 during surveillance in ovarian cancer patients as measured by CA125 doubling time. PATIENT AND METHODS: Clinical information was obtained through a 2-staged chart review of ovarian cancer patients treated in our department from 1994 to 2003. We searched for patients who met criteria for CA125 progression and doubling during surveillance following first-line therapy. RESULTS: A total of 296 patients were initially identified. During surveillance, the median doubling time of CA125 was 40 d and the median survival for patients with a CA125 doubling time of 40 d was 10.6 months compared to 22.1 months for those with doubling time>40 d. In a univariate analysis, age, high-grade, suboptimal cytoreduction, short CA125 doubling time, short time to progression and high CA125 at progression were significantly associated with poor survival, but in a multivariate analysis, a short CA125 doubling time of Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem
, Antígeno Ca-125/sangue
, Recidiva Local de Neoplasia/sangue
, Neoplasias Ovarianas/sangue
, Adulto
, Idoso
, Idoso de 80 Anos ou mais
, Análise de Variância
, Progressão da Doença
, Feminino
, Humanos
, Pessoa de Meia-Idade
, Recidiva Local de Neoplasia/diagnóstico
, Neoplasias Ovarianas/tratamento farmacológico
, Neoplasias Ovarianas/mortalidade
, Prognóstico
, Taxa de Sobrevida
, Fatores de Tempo