Advancing Beyond the Hippocampus to Preserve Cognition for Patients With Brain Metastases: Dosimetric Results From a Phase 2 Trial of Memory-Avoidance Whole Brain Radiation Therapy.

Purpose: Recent advances to preserve neurocognitive function in patients treated for brain metastases include stereotactic radiosurgery, hippocampal avoidance whole brain radiation therapy (WBRT), and memantine administration. The hippocampus, corpus callosum, fornix, and amygdala are key neurocognitive substructures with a low propensity for brain metastases. Herein, we report our preliminary experience using a "memory-avoidance" WBRT (MA-WBRT) approach that spares these substructures for patients with >15 brain metastases.

A Prospective Registry Study of Ga-DOTATATE PET/CT Incorporation Into Treatment Planning of Intracranial Meningiomas.

Purpose: The current standard for meningioma treatment planning involves magnetic resonance imaging-based guidance. Somatostatin receptor ligands such as Ga-DOTATATE are being explored for meningioma treatment planning due to near-universal expression of somatostatin receptors 1 and 2 in meningioma tissue. We hypothesized that Ga-DOTATATE positron emission tomography (PET)-guided treatment management for patients with meningiomas is safe and effective and can identify which patients benefit most from adjuvant radiation therapy.

Deciphering the localization and trajectory of human natural killer cell development.

Innate immune cells represent the first line of cellular immunity, comprised of both circulating and tissue-resident natural killer cells and innate lymphoid cells. These innate lymphocytes arise from a common CD34+ progenitor that differentiates into mature natural killer cells and innate lymphoid cells. The successive stages in natural killer cell maturation are characterized by increased lineage restriction and changes to phenotype and function.

Single-cell RNA sequencing identifies a population of human liver-type ILC1s.

Group 1 innate lymphoid cells (ILCs) comprise a heterogeneous family of cytotoxic natural killer (NK) cells and ILC1s. We identify a population of "liver-type" ILC1s with transcriptional, phenotypic, and functional features distinct from those of conventional and liver-resident NK cells as well as from other previously described human ILC1 subsets. LT-ILC1s are CD49aCD94CD200R1, express the transcription factor T-BET, and do not express the activating receptor NKp80 or the transcription factor EOMES.

Treatment of Brain Metastases: The Synergy of Radiotherapy and Immune Checkpoint Inhibitors.

Brain metastases are a devastating sequela of common primary cancers (e.g., lung, breast, and skin) and have limited effective therapeutic options.

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

Unlabelled: 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.

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.

Disparate Use of Chemoradiation in Elderly Patients With Localized Anal Cancer.

Background: The incidence of squamous cell carcinoma of the anus (SCCA) is increasing, particularly among the elderly (age ≥65 years). We sought to compare patterns of care for the treatment of SCCA in elderly versus nonelderly patients.

Methods: Data for patients with stages I-III SCCA diagnosed from 2004 through 2015 were obtained from the National Cancer Database.

Pediatric Family-Centered Rounds and Humanism: A Systematic Review and Qualitative Meta-analysis.

Context: Pediatric family-centered rounds (FCRs) have been shown to have benefits in staff satisfaction, teaching, and rounding efficiency, but no systematic review has been conducted to explicitly examine the humanistic impact of FCRs.

Objective: The objective with this review is to determine if FCRs promote the core values of humanism in medicine by answering the question, "Do FCRs promote humanistic pediatric care?"

Data Sources: Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we conducted a search of PubMed, Web of Science, Cumulative Index of Nursing and Allied Health Literature, and Dissertation Abstracts for peer-reviewed pediatric studies through January 1, 2020. We used search terms including FCRs, communication, humanism, and the specific descriptors in the Gold Foundation's definition of humanism.

Notch Regulates Innate Lymphoid Cell Plasticity during Human NK Cell Development.

Human NK cells develop in tonsils through discrete NK cell developmental intermediates (NKDIs), yet the mechanistic regulation of this process is unclear. We demonstrate that Notch activation in human tonsil-derived stage 3 (CD34CD117CD94NKp80) and 4A (CD34CD117CD94NKp80) NKDIs promoted non-NK innate lymphoid cell differentiation at the expense of NK cell differentiation. In contrast, stage 4B (CD34CD117CD94NKp80) NKDIs were NK cell lineage committed despite Notch activation.

EGFL7 Antagonizes NOTCH Signaling and Represents a Novel Therapeutic Target in Acute Myeloid Leukemia.

Purpose: EGF-like domain 7 (EGFL7) is a secreted protein and recently has been shown to play an important role in acute myeloid leukemia (AML); however, the underlying mechanism by which EGFL7 promotes leukemogenesis is largely unknown.

Experimental Design: Using an antibody interaction array, we measured the ability of EGFL7 to bind directly approximately 400 proteins expressed by primary AML blasts. Primary patient samples were stimulated with recombinant EGFL7 (rEGFL7) or anti-EGFL7 blocking antibody to assess alterations in downstream signaling and the ability to effect blast differentiation and survival.

The Mechanism of Anti-PD-L1 Antibody Efficacy against PD-L1-Negative Tumors Identifies NK Cells Expressing PD-L1 as a Cytolytic Effector.

Blockade of PD-L1 expression on tumor cells via anti-PD-L1 monoclonal antibody (mAb) has shown great promise for successful cancer treatment by overcoming T-cell exhaustion; however, the function of PD-L1 on natural killer (NK) cells and the effects of anti-PD-L1 mAb on PD-L1 NK cells remain unknown. Moreover, patients with PD-L1 tumors can respond favorably to anti-PD-L1 mAb therapy for unclear reasons. Here, we show that some tumors can induce PD-L1 on NK cells via AKT signaling, resulting in enhanced NK-cell function and preventing cell exhaustion.

The IL-15-AKT-XBP1s signaling pathway contributes to effector functions and survival in human NK cells.

Interleukin 15 (IL-15) is one of the most important cytokines that regulate the biology of natural killer (NK) cells. Here we identified a signaling pathway-involving the serine-threonine kinase AKT and the transcription factor XBP1s, which regulates unfolded protein response genes-that was activated in response to IL-15 in human NK cells. IL-15 induced the phosphorylation of AKT, which led to the deubiquitination, increased stability and nuclear accumulation of XBP1s protein.

Erratum: First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia.

[This corrects the article on p. 1083 in vol. 8, PMID: 30034945.

CD56 Expression Marks Human Group 2 Innate Lymphoid Cell Divergence from a Shared NK Cell and Group 3 Innate Lymphoid Cell Developmental Pathway.

According to the established model of murine innate lymphoid cell (ILC) development, helper ILCs develop separately from natural killer (NK) cells. However, it is unclear how helper ILCs and NK cells develop in humans. Here we elucidated key steps of NK cell, ILC2, and ILC3 development within human tonsils using ex vivo molecular and functional profiling and lineage differentiation assays.

Human AML activates the aryl hydrocarbon receptor pathway to impair NK cell development and function.

Acute myeloid leukemia (AML) can evade the mouse and human innate immune system by suppressing natural killer (NK) cell development and NK cell function. This is driven in part by the overexpression of microRNA (miR)-29b in the NK cells of AML patients, but how this occurs is unknown. In the current study, we demonstrate that the transcription factor aryl hydrocarbon receptor (AHR) directly regulates miR-29b expression.

First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia.

CAR T cells have shown clinical efficacy for acute lymphoblastic leukemia, but this therapy has not been effective for acute myeloid leukemia (AML), and other treatment options are needed. Theoretically, CAR-NK cells have a more favorable toxicity profile compared to CAR T cells, especially in avoiding adverse effects such as cytokine release syndrome. However, the clinical evidence for this has not yet been reported.

The natural product chitosan enhances the anti-tumor activity of natural killer cells by activating dendritic cells.

Natural products comprise an important class of biologically active molecules. Many of these compounds derived from natural sources exhibit specific physiologic or biochemical effects. An example of a natural product is chitosan, which is enriched in the shells of certain seafood that are frequently consumed worldwide.

IL-18 Drives ILC3 Proliferation and Promotes IL-22 Production via NF-κB.

Group 3 innate lymphoid cells (ILC3s) are important regulators of the immune system, maintaining homeostasis in the presence of commensal bacteria, but activating immune defenses in response to microbial pathogens. ILC3s are a robust source of IL-22, a cytokine critical for stimulating the antimicrobial response. We sought to identify cytokines that can promote proliferation and induce or maintain IL-22 production by ILC3s and determine a molecular mechanism for this process.

Concise enantioselective synthesis of diospongins A and B.

Ether transfer methodology is capable of stereoselectively generating 1,3-diol mono- and diethers in good yield. Surprisingly, allylic and benzylic substrates provide none of the desired products when exposed to previously optimized conditions of iodine monochloride. Herein, second-generation activation conditions for ether transfer have been developed that circumvents undesired side reactions for these substrates.