High-dose AraC is essential for the treatment of ML-DS independent of postinduction MRD: results of the COG AAML1531 trial.

Myeloid leukemia in children with Down syndrome (ML-DS) is associated with young age and somatic GATA1 mutations. Because of high event-free survival (EFS) and hypersensitivity of the leukemic blasts to chemotherapy, the prior Children's Oncology Group protocol ML-DS protocol (AAML0431) reduced overall treatment intensity but lacking risk stratification, retained the high-dose cytarabine course (HD-AraC), which was highly associated with infectious morbidity. Despite high EFS of ML-DS, survival for those who relapse is rare. AAML1531 introduced therapeutic risk stratification based on the previously identified prognostic factor, measurable residual disease (MRD) at the end of the first induction course. Standard risk (SR) patients were identified by negative MRD using flow cytometry (<0.05%) and did not receive the historically administered HD-AraC course. Interim analysis of 114 SR patients revealed a 2-year EFS of 85.6% (95% confidence interval [CI], 75.7-95.5), which was significantly lower than for MRD- patients treated with HD-AraC on AAML0431 (P = .0002). Overall survival at 2 years was 91.0% (95% CI, 83.8-95.0). Twelve SR patients relapsed, mostly within 1 year from study entry and had a 1-year OS of 16.7% (95% CI, 2.7-41.3). Complex karyotypes were more frequent in SR patients who relapsed compared with those who did not (36% vs 9%; P = .0248). MRD by error-corrected sequencing of GATA1 mutations was piloted in 18 SR patients and detectable in 60% who relapsed vs 23% who did not (P = .2682). Patients with SR ML-DS had worse outcomes without HD-AraC after risk classification based on flow cytometric MRD.

Affirming Hormone Treatment for a Transgender Adolescent After a Venous Thromboembolic Event.

BACKGROUND: Medical affirmation, including gender-affirming hormones, is an essential component in the treatment of many transgender and gender-diverse youth. The risk of venous thromboembolism (VTE) during testosterone therapy for gender-affirming care is not fully elucidated. OBSERVATION: The case describes a 17-year-old transgender male treated with testosterone therapy who presented with an occlusive deep vein thrombosis of right axillary and subclavian veins. Testosterone level was 920 ng/dL at the time of the deep vein thrombosis, and he had no risk factors for VTE. A complete hypercoagulable workup was negative. CONCLUSIONS: The possibility of testosterone therapy as a risk factor for VTE may suggest the need to include this information during informed consent discussions. Long-term anticoagulation may be considered for those restarting testosterone therapy.

Discarded portions of bone marrow aspirates are a new resource for patient-derived mesenchymal stem and stromal cells.

Bone marrow-derived mesenchymal stem and stromal cells (BM-MSCs) protect malignant cells from chemotherapy and are important potential therapeutic targets. Isolating primary BM-MSCs for research traditionally requires the sacrifice of valuable cell populations from within the same sample. To avoid this, we report here a resource for isolating patient-derived BM-MSCs from the red blood cell layer of ficoll gradients of bone marrow aspirates, a resource that has until now been universally discarded. This resource yields BM-MSCs nearly identical to those obtained conventionally and includes cells with a more stem-cell like nature. Obtaining primary BM-MSCs in this way will likely expand opportunities to study this important cell population.

FGF2-FGFR1 signaling regulates release of Leukemia-Protective exosomes from bone marrow stromal cells.

Protective signaling from the leukemia microenvironment leads to leukemia cell persistence, development of resistance, and disease relapse. Here, we demonstrate that fibroblast growth factor 2 (FGF2) from bone marrow stromal cells is secreted in exosomes, which are subsequently endocytosed by leukemia cells, and protect leukemia cells from tyrosine kinase inhibitors (TKIs). Expression of FGF2 and its receptor, FGFR1, are both increased in a subset of stromal cell lines and primary AML stroma; and increased FGF2/FGFR1 signaling is associated with increased exosome secretion. FGFR inhibition (or gene silencing) interrupts stromal autocrine growth and significantly decreases secretion of FGF2-containing exosomes, resulting in less stromal protection of leukemia cells. Likewise, Fgf2 -/- mice transplanted with retroviral BCR-ABL leukemia survive significantly longer than their +/+ counterparts when treated with TKI. Thus, inhibition of FGFR can modulate stromal function, reduce exosome secretion, and may be a therapeutic option to overcome resistance to TKIs. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Streptococcus pyogenes subdural empyema not detected by computed tomography.

A previously healthy 5-year-old boy presented with a non-specific febrile illness and seizures. Streptococcus pyogenes was identified in his blood culture. The spinal fluid revealed minimal pleocytosis and an axial computed tomography (CT) scan of the head was normal. Ongoing symptoms prompted a magnetic resonance imaging, which revealed a subdural empyema. Our patient diverges from the few previously reported S. pyogenes intracranial infections in that there was neither an adjacent infection nor a bacterial meningitis. In addition, we discuss the few studies addressing the sensitivity of CT for the diagnosis of bacterial intracranial infections.