Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): a two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment.

Viral infections remain a major risk in immunocompromised pediatric patients, and virus-specific T cell (VST) therapy has been successful for treatment of refractory viral infections in prior studies. We performed a phase II multicenter study (NCT03475212) for the treatment of pediatric patients with inborn errors of immunity and/or post allogeneic hematopoietic stem cell transplant with refractory viral infections using partially-HLA matched VSTs targeting cytomegalovirus, Epstein-Barr virus, or adenovirus. Primary endpoints were feasibility, safety, and clinical responses (>1 log reduction in viremia at 28 days). Secondary endpoints were reconstitution of antiviral immunity and persistence of the infused VSTs. Suitable VST products were identified for 75 of 77 clinical queries. Clinical responses were achieved in 29 of 47 (62%) of patients post-HSCT including 73% of patients evaluable at 1-month post-infusion, meeting the primary efficacy endpoint (>52%). Secondary graft rejection occurred in one child following VST infusion as described in a companion article. Corticosteroids, graft-versus-host disease, transplant-associated thrombotic microangiopathy, and eculizumab treatment correlated with poor response, while uptrending absolute lymphocyte and CD8 T cell counts correlated with good response. This study highlights key clinical factors that impact response to VSTs and demonstrates the feasibility and efficacy of this therapy in pediatric HSCT.

Entinostat augments NK cell functions via epigenetic upregulation of IFIT1-STING-STAT4 pathway.

Histone deacetylase inhibitors (HDACi) are an emerging cancer therapy; however, their effect on natural killer (NK) cell-mediated anti-tumor responses remain unknown. Here, we evaluated the impact of a benzamide HDACi, entinostat, on human primary NK cells as well as tumor cell lines. Entinostat significantly upregulated the expression of NKG2D, an essential NK cell activating receptor. Independently, entinostat augmented the expression of ULBP1, HLA, and MICA/B on both rhabdomyosarcoma and Ewing sarcoma cell lines. Additionally, entinostat increased both cytotoxicity and IFN-γ production in human NK cells following coculture with these tumor cells. Mechanistically, entinostat treatment resulted in increased chromatin accessibility to the promoter region for interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) gene and thereby increasing the transcript and protein levels of IFIT1 that augmented the IFIT1-mediated IRF1, STAT4, and STING pathways. Corresponding transcriptome analysis revealed enrichment of IRF1 and STAT4 and gene sets responsible for NK cell-mediated IFN-γ production and cytotoxicity, respectively. Our results show a novel mechanism by which entinostat initiates an IFIT1-STING-mediated potentiation of STAT4 via IRF1 to augment NK cell-mediated anti-tumor responses.

Errors in Clinician-Parent Communication during Neonatal Hospitalization.

Error in clinician-parent communication is not a new issue in pediatrics. It has been the impetus behind national initiatives, namely, family-centered rounds. While family-centered rounds have proven effective, their success is dependent on the family being present during rounds. This does not always occur during prolonged hospitalizations, particularly in the Neonatal Intensive Care Unit (NICU). Current communication methods with parents not present during rounds rely heavily on the provider's prerogative and ability to multitask. Thus, errors in communication are commonplace and are largely accepted as inevitable. For the sake of the parents of a patient in the NICU, a high-fidelity communication system is urgently needed. NICUs must move beyond the telephone and use modern innovations in communication technology.

Student Leadership Development Initiative: A Pilot for a Sustainable, Replicable Model for Incorporating Leadership into Medical Education.

INTRODUCTION: Today's medical students are tomorrow's leaders. As leadership training becomes incorporated into undergraduate medical education, there is a need for validated educational models that are both effective and replicable. METHODS: Between April 2017 and October 2017, groups of 15 to 20 medical students participated in sessions with an exemplary physician leader incorporating a guided interview format and discussion about her or his career. Prepared questions ensured leadership domains were covered. The program was evaluated using a post-session survey. RESULTS: One hundred percent of survey respondents (N = 58) reported that the session was a good use of time. Seventy-eight percent felt more prepared to lead a team; 93% learned specific ways to improve their leadership skills. DISCUSSION: This leadership program is a unique model to provide leadership education to medical students that is both effective and replicable.