First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.
Objective Patients with comorbid cancer and dementia have poorer outcomes than those without dementia. We observe oncology teams managing patients with dementia and memory loss and explore these patients' needs and experiences of out-patient cancer services.
MethodsA single site investigation of case study design to examine practices in four clinics using multi-methods of data collection; retrospective note review, observation, interviews and recorded consultations. A framework analytic approach identifies themes within and across cases.
ResultsThirty-three clinical encounters with patients with memory loss were observed. Ten consultations were audio-recorded and 16 individuals interviewed (n=6 patients-carer dyads, n=1 lone patient, n=5 staff). Medical records were reviewed for 338 cases. Cancer referrals did not document memory health, so clinicians rely on patient/carer disclosure to identify patients with memory problems. In practice the problem often remains hidden. Treating teams who do become aware of memory difficulties are unsure how to support patients, but marked memory loss can limit treatment options and preclude radical intent. Carers are key facilitators of successful cancer consultations and management. Their support needs are largely unrecognised.
ConclusionsTraining that educates cancer teams on how to identify and support individuals with memory problems before and during treatment and recognise the carer role may facilitate complex cancer care and help reduce inequalities of outcomes.
A highly enantioselective and practical synthesis of the HIV-1 reverse transcriptase inhibitor efavirenz (1) is described. The synthesis proceeds in 62% overall yield in seven steps from 4-chloroaniline (6) to give efavirenz (1) in excellent chemical and optical purity. A novel, enantioselective addition of Li-cyclopropyl acetylide (4a) to p-methoxybenzyl-protected ketoaniline 3a mediated by (1R,2S)-N-pyrrolidinylnorephedrine lithium alkoxide (5a) establishes the stereogenic center in the target with a remarkable level of stereocontrol.
A patient with marked chronic eosinophilia and episodic angioedema (Gleich's syndrome) with a concomitant clonal proliferation of helper T-lymphocytes is described. This association has not previously been documented. The symptoms and clinical course differ markedly from the idiopathic hypereosinophilic syndrome, including an absence of end organ involvement. However, the disease appears to have a similar pathogenesis, with elevated levels of the eosinophil-specific cytokine interleukin-5 (IL-5) produced by the T-cell clone.
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