Optimal therapeutic targeting by HDAC inhibition in biopsy-derived treatment-naïve diffuse midline glioma models.

BACKGROUND: Diffuse midline gliomas (DMGs), including diffuse intrinsic pontine gliomas (DIPGs), have a dismal prognosis, with less than 2% surviving 5 years postdiagnosis. The majority of DIPGs and all DMGs harbor mutations altering the epigenetic regulatory histone tail (H3 K27M). Investigations addressing DMG epigenetics have identified a few promising drugs, including the HDAC inhibitor (HDACi) panobinostat. Here, we use clinically relevant DMG models to identify and validate other effective HDACi and their biomarkers of response. METHODS: HDAC inhibitors were tested across biopsy-derived treatment-naïve in vitro and in vivo DMG models with biologically relevant radiation resistance. RNA sequencing was performed to define and compare drug efficacy and to map predictive biomarkers of response. RESULTS: Quisinostat and romidepsin showed efficacy with low nanomolar half-maximal inhibitory concentration (IC50) values (~50 and ~5 nM, respectively). Comparative transcriptome analyses across quisinostat, romidepsin, and panobinostat showed a greater degree of shared biological effects between quisinostat and panobinostat, and less overlap with romidepsin. However, some transcriptional changes were consistent across all 3 drugs at similar biologically effective doses, such as overexpression of troponin T1 slow skeletal type (TNNT1) and downregulation of collagen type 20 alpha 1 chain (COL20A1), identifying these as potential vulnerabilities or on-target biomarkers in DMG. Quisinostat and romidepsin significantly (P < 0.0001) inhibited in vivo tumor growth. CONCLUSIONS: Our data highlight the utility of treatment-naïve biopsy-derived models; establishes quisinostat and romidepsin as effective in vivo; illuminates potential mechanisms and/or biomarkers of DMG cell lethality due to HDAC inhibition; and emphasizes the need for brain tumor-penetrant versions of potentially efficacious agents.

Donor-specific Antibody Surveillance and Graft Outcomes in Pediatric Kidney Transplant Recipients.

BACKGROUND: The development of de novo donor-specific antibodies (dnDSA) has been associated with rejection and graft loss in kidney transplantation, and DSA screening is now recommended in all kidney transplant recipients. However, the clinical significance of dnDSA detected by screening patients with a stable creatinine remains unclear. METHODS: One hundred three patients younger than 18years receiving a first, kidney alone transplant between December 1, 2007, and December 31, 2013, underwent DSA screening every 3months for 2years posttransplant, with additional testing as clinically indicated. No treatment was given for DSAs in the absence of biopsy-proven rejection. RESULTS: Twenty (19%) patients had dnDSA first detected on a screening test, and 13 (13%) patients had dnDSA first detected on a for-cause test. Mean follow-up time posttransplant was 4.4years. Screening-detected dnDSA was associated with an increased risk of rejection within 3years, microvascular inflammation, and C4d staining on a 2-year protocol biopsy. In a Cox proportional hazards regression, screening-detected dnDSA was not associated with time to 30% decline in estimated glomerular filtration rate (adjusted hazard ratio, 0.88; 95% confidence interval [CI], 0.30-2.00; P=0.598) or graft loss. dnDSA first detected on for-cause testing was associated with a 2.8 times increased risk of decline in graft function (95% CI, 1.08-7.27; P=0.034) and a 7.34 times increased risk of graft loss (95% CI, 1.37-39.23 P=0.020) compared with those who did not develop dnDSA. CONCLUSIONS: The clinical setting in which dnDSA is first detected impacts the association between dnDSA and graft function. Further research is needed to clarify the role of dnDSA screening in pediatric kidney transplantation.

Prospective Assessment of Adenovirus Infection in Pediatric Kidney Transplant Recipients.

BACKGROUND: Adenovirus infection is associated with graft dysfunction and graft loss in pediatric cardiac, lung, and liver transplants in prior retrospective studies, but data in pediatric kidney transplant recipients is limited. METHODS: We conducted a prospective single-center cohort study of 75 consecutive pediatric kidney transplant recipients who underwent monthly screening for adenovirus viremia and symptom assessment for 2 years posttransplant. RESULTS: Adenovirus viremia was detected in 11 (14.7%) patients at a median onset of 173 days (interquartile range, 109-310 days) posttransplant, 6 (8%) had asymptomatic viremia, and 5 (6.7%) had symptomatic disease (2 with hematuria and 3 with an acute febrile respiratory illness). Viremic patients did not differ from nonviremic patients in age, immunosuppression management, or cytomegalovirus or Epstein-Barr virus serostatus, but were more likely to develop cytomegalovirus viremia during the first 2 years posttransplant. No patient had an increase in creatinine from baseline during the time of adenovirus viremia. In a Cox proportional hazards regression, subclinical adenovirus viremia was not associated with a faster time to a 30% decline in estimated glomerular filtration rate. CONCLUSIONS: Adenovirus infection is common among pediatric kidney transplant recipients and frequently causes symptomatic disease; however, symptoms are often mild and are not associated with a decline in graft function. Routine monitoring for adenovirus viremia in pediatric kidney transplant recipients may not be warranted.