Acute Myeloid Leukemia Alters Group 1 Innate Lymphoid Cell Differentiation from a Common Precursor.

NK cells are known to be developmentally blocked and functionally inhibited in patients with acute myeloid leukemia (AML), resulting in poor clinical outcomes. In this study, we demonstrate that whereas NK cells are inhibited, closely related type 1 innate lymphoid cells (ILC1s) are enriched in the bone marrow of leukemic mice and in patients with AML. Because NK cells and ILC1s share a common precursor (ILCP), we asked if AML acts on the ILCP to alter developmental potential. A combination of ex vivo and in vivo studies revealed that AML skewing of the ILCP toward ILC1s and away from NK cells represented a major mechanism of ILC1 generation. This process was driven by AML-mediated activation of the aryl hydrocarbon receptor (AHR), a key transcription factor in ILCs, as inhibition of AHR led to decreased numbers of ILC1s and increased NK cells in the presence of AML. These results demonstrate a mechanism of ILC developmental skewing in AML and support further preclinical study of AHR inhibition in restoring normal NK cell development and function in the setting of AML.

Examining Trends in Implantable Arterial Doppler Usage Among North American Head and Neck Microsurgeons: A Survey Study.

BACKGROUND: There are variations in implantable arterial Doppler usage for microvascular free tissue monitoring among North American surgeons. Identifying utilization trends among the microvascular community may elucidate practice patterns that may be useful in determining protocols. Furthermore, study of this information may yield novel and unique applications in other disciplines such as vascular surgery. METHODS: Electronically disseminated survey study shared with a large database of North American head and neck microsurgeons. RESULTS: Seventy four percent of respondents use the implantable arterial Doppler; 69% report use in all cases. Ninety five percent remove the Doppler by the seventh postoperative day. All respondents felt that the Doppler did not impede care progression. Any implication of flap compromise was followed with a clinical assessment in 100% of respondents. If viable, 89% would continue monitoring after clinical examination, while 11% would take the patient for exploration regardless of clinical examination. CONCLUSIONS: The efficacy of the implantable arterial Doppler has been established in the literature and is supported by the results of this study. Further investigation is required to establish a consensus on use guidelines. The implantable Doppler is more often used in conjunction with rather than substitution for clinical examination.

Implantable arterial doppler efficacy in free flap reconstruction: A systematic review and meta-analysis.

The implantable arterial doppler (IAD) is frequently used to postoperatively monitor free flaps with high accuracy, but there are no guidelines for its use. Bedside exam is used adjunctively to determine necessary intervention. This systematic review seeks to discover why the doppler is used adjunctively despite its established record of accuracy. Criteria for inclusion and exclusion were established. In total, 280 articles were found on PubMed and Web of Science, then screened accordingly. Data from 22 articles were analyzed using a bivariate hierarchical random effects model. Twenty-two studies yielded 2996 total patients undergoing 3127 free flap procedures. The meta-analysis found a high sensitivity of 0.809 (95% CI = 0.709, 0.880) and specificity of 0.966 (95% CI = 0.947, 0.979). False-positive rate was found to be 0.034 (95% CI = 0.021, 0.053). Positive and negative predictive values were 0.711 (95% CI = 0.581, 0.817) and 0.979 (95% CI = 0.966, 0.988). Positive and negative likelihood ratios were 24.7 (95% CI = 14.5, 39.5) and 0.20 (95% CI = 0.12, 0.30). The established efficacy of the IAD is supported by this study. Clinical exams may remain as the final adjunct due to the risks of inaccurate IAD signals. Further studies are warranted to optimize its use for future practice guidelines.

Identification and Targeting of the Developmental Blockade in Extranodal Natural Killer/T-cell Lymphoma.

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with poor clinical outcomes. Here we used phenotypic and molecular profiling, including epigenetic analyses, to investigate how ENKTL ontogeny relates to normal NK-cell development. We demonstrate that neoplastic NK cells are stably, but reversibly, arrested at earlier stages of NK-cell maturation. Genes downregulated in the most epigenetic immature tumors were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involving extensive gene silencing and loss of transcription factor binding. To investigate therapeutic targeting, we treated novel patient-derived xenograft (PDX) models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reexpression of NK-cell developmental genes, phenotypic NK-cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy in ENKTL. SIGNIFICANCE: Through epigenetic and transcriptomic analyses of ENKTL, a rare, aggressive malignancy, along with normal NK-cell developmental intermediates, we identified that extreme DNA hypermethylation targets genes required for NK-cell development. Disrupting this epigenetic blockade in novel PDX models led to ENKTL differentiation and improved survival. This article is highlighted in the In This Issue feature, p. 85.