Exposure of Patient-Derived Mesenchymal Stromal Cells to TGFB1 Supports Fibrosis Induction in a Pediatric Acute Megakaryoblastic Leukemia Model.

Bone marrow fibrosis (BMF) is a rare complication in acute leukemia. In pediatrics, it predominantly occurs in acute megakaryoblastic leukemia (AMKL) and especially in patients with trisomy 21, called myeloid leukemia in Down syndrome (ML-DS). Defects in mesenchymal stromal cells (MSC) and cytokines specifically released by the myeloid blasts are thought to be the main drivers of fibrosis in the bone marrow niche (BMN). To model the BMN of pediatric patients with AMKL in mice, we first established MSCs from pediatric patients with AMKL (n = 5) and ML-DS (n = 9). Healthy donor control MSCs (n = 6) were generated from unaffected children and adolescents ≤18 years of age. Steady-state analyses of the MSCs revealed that patient-derived MSCs exhibited decreased adipogenic differentiation potential and enrichment of proliferation-associated genes. Importantly, TGFB1 exposure in vitro promoted early profibrotic changes in all three MSC entities. To study BMF induction for longer periods of time, we created an in vivo humanized artificial BMN subcutaneously in immunodeficient NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice, using a mixture of MSCs, human umbilical vein endothelial cell, and Matrigel. Injection of AMKL blasts as producers of TGFB1 into this BMN after 8 weeks induced fibrosis grade I/II in a dose-dependent fashion over a time period of 4 weeks. Thus, our study developed a humanized mouse model that will be instrumental to specifically examine leukemogenesis and therapeutic targets for AMKL blasts in future. IMPLICATIONS: TGFB1 supports fibrosis induction in a pediatric AMKL model generated with patient-derived MSCs. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/molcanres/18/10/1603/F1.large.jpg.

Is More than One Hour of Selective Antegrade Cerebral Perfusion in Moderate-to-Mild Systemic Hypothermic Circulatory Arrest for Surgery of Acute Type A Aortic Dissection Safe?

OBJECTIVES: Surgery for acute type A aortic dissection (AAD) remains a surgical challenge with considerable risk of morbidity and mortality. Antegrade cerebral perfusion (ACP) has been popularized, offering a more physiologic method of brain perfusion during complex aortic arch repair, often necessary in setting of AAD. The safe limits of this approach under moderate-to-mild systemic hypothermic circulatory arrest (≥ 28°C) are yet to be defined. Thus, the current study investigates our clinical results after surgical treatment for AAD in patients with a selective ACP and systemic circulatory arrest time of ≥ 60 minutes in moderate-to-mild hypothermia (≥ 28°C). METHODS: Between January 2000 and April 2016, 63 consecutive patients underwent surgical treatment for AAD employing selective ACP during moderate-to-mild systemic hypothermia (≥ 28°C) with prolonged ACP and circulatory arrest times. Patients' mean age was 59 ± 15 years, and 39 patients (62%) were men. Hemiarch replacement and total arch replacement were performed in 13 (21%) and 50 (79%) patients, respectively. Frozen elephant trunk, arch light, and elephant trunk technique were performed in nine (14%), six (10%), and three patients (5%), respectively. Clinical data were prospectively entered into our institutional database. Mean late follow-up was 6 ± 4 years and was 98% complete. RESULTS: Cardiopulmonary bypass time accounted for 245 ± 81 minutes and the myocardial ischemic time accounted for 140 ± 43 minutes. Mean duration of ACP was 74 ± 12 minutes. The mean lowest core temperature accounted for 28.9 ± 0.8°C. Unilateral ACP was performed in 44 patients (70%); bilateral ACP was used in the remaining 19 patients (30%). Intensive care unit stay reached 6 ± 5 days. New onset of acute renal failure requiring hemofiltration was observed in 8% of patients (n = 5). New postoperative permanent neurologic deficits were found in five patients (8%) and transient neurologic deficits in six patients (10%). There was one case of paraplegia. Thirty-day mortality and in-hospital mortality were 8 (n = 5) and 11% (n = 7), respectively. Overall survival at 5 years was 76 ± 9%. CONCLUSION: Our preliminary data suggest that selective ACP during moderate-to-mild systemic hypothermic circulatory arrest (≥ 28°C) can safely be applied for more than 1 hour even in the setting of AAD.