RESUMO
This study surveyed South Australian medical oncologists to capture their perceptions, willingness to participate and perceived barriers and motivations to participation in voluntary assisted dying (VAD) activities. Approximately 70% of surveyed medical oncologists reported familiarity with VAD legislation. Less than half of physicians (39.1%) reported willingness to participate in any VAD activities, and the rate of conscientious objection was 22%. The top barriers to participation were lack of time and uncertainty given no prior experience. These results demonstrate both a low rate of conscientious objection and a low rate of willingness to participate at the point of VAD implementation in South Australia, and identify barriers to participation that are largely logistical.
Assuntos
Atitude do Pessoal de Saúde , Oncologistas , Suicídio Assistido , Humanos , Austrália do Sul , Suicídio Assistido/psicologia , Suicídio Assistido/ética , Masculino , Feminino , Oncologistas/psicologia , Pessoa de Meia-Idade , Adulto , Inquéritos e Questionários , Motivação , Idoso , OncologiaAssuntos
Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas c-abl , Humanos , Proteínas Proto-Oncogênicas c-abl/genética , Proteínas Proto-Oncogênicas c-abl/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Domínios de Homologia de src/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Niacinamida/análogos & derivados , PirazóisRESUMO
The presence of a TP53 mutation is a predictor of poor outcome in leukaemia, and efficacious targeted therapies for these patients are lacking. The curaxin CBL0137 has demonstrated promising antitumour activities in multiple cancers such as glioblastoma, acting through p53 activation, NFκB inhibition and chromatin remodelling. In the present study, it was revealed using AnnexinV/7AAD apoptosis assays that CBL0137 has efficacy across several human acute leukaemia cell lines with wildtype TP53, but sensitivity is reduced in TP53mutated subtypes. A heterozygous TP53 lossoffunction mutation in the KMT2AAFF1 human RS4;11 cell line was generated, and it was demonstrated that heterozygous TP53 lossoffunction is sufficient to cause a significant reduction in CBL0137 sensitivity. To the best of our knowledge, this is the first evidence to suggest a clinically significant role for functional p53 in the efficacy of CBL0137 in acute leukaemia. Future CBL0137 clinical trials should include TP53 mutation screening, to establish the clinical relevance of TP53 mutations in CBL0137 efficacy.
Assuntos
Glioblastoma , Leucemia Mieloide Aguda , Carbazóis/farmacologia , Glioblastoma/tratamento farmacológico , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação , Proteína Supressora de Tumor p53/genéticaRESUMO
Rearrangements of the MLLT10 gene occur in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), most commonly T-lineage ALL (T-ALL), in patients of all ages. MLLT10 rearranged (MLLT10r) acute leukemia presents a complex diagnostic and therapeutic challenge due to frequent presentation of immature or mixed phenotype, and a lack of consensus regarding optimal therapy. Cases of MLLT10r AML or T-ALL bearing immature phenotype are at high risk of poor outcome, but the underlying molecular mechanisms and sensitivity to targeted therapies remain poorly characterized. This review addresses the incidence and prognostic significance of MLLT10r in acute leukemia, and how the aberrant gene expression profile of this disease can inform potential targeted therapeutic strategies. Understanding the underlying genomics of MLLT10r acute leukemia, both clinically and molecularly, will improve prognostic stratification and accelerate the development of targeted therapeutic strategies, to improve patient outcomes.
RESUMO
KMT2A rearranged (KMT2Ar) acute lymphoblastic leukaemia (ALL) is a high-risk genomic subtype, with long-term survival rates of less than 60% across all age groups. These cases present a complex clinical challenge, with a high incidence in infants, high-risk clinical features and propensity for aggressive relapse. KMT2A rearrangements are highly pathogenic leukaemic drivers, reflected by the high incidence of KMT2Ar ALL in infants, who carry few leukaemia-associated cooperative mutations. However, transgenic murine models of KMT2Ar ALL typically exhibit long latency and mature or mixed phenotype, and fail to recapitulate the aggressive disease observed clinically. Next-generation sequencing has revealed that KMT2Ar ALL also occurs in adolescents and adults, and potentially cooperative genomic lesions such as PI3K-RAS pathway variants are present in KMT2Ar patients of all ages. This review addresses the aetiology of KMT2Ar ALL, with a focus on the cell of origin and mutational landscape, and how genomic profiling of KMT2Ar ALL patients in the era of next-generation sequencing demonstrates that KMT2Ar ALL is a complex heterogenous disease. Ultimately, understanding the underlying biology of KMT2Ar ALL will be important in improving long-term outcomes for these high-risk patients.