Riley Hospital for Children

ABSTRACT Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited systemic therapies and represent the leading cause of mortality for individuals with neurofibromatosis type 1 (NF1). Malignant progression can reactivate developmental precursor programs that are largely absent from normal nerve and benign tumors, creating tumor-selective vulnerabilities. Zinc finger protein 423 (ZNF423; also known as OAZ/ROAZ) is a developmentally regulated transcription factor that delays olfactory precursor differentiation and has been implicated in B-cell malignancy. Here, we asked whether ZNF423 is reactivated and functionally required in NF1-associated MPNST. In genetically defined models, Nf1 loss reduced Zfp423 in a benign tumor cell-of-origin context, whereas combined Nf1 and Cdkn2a loss induced marked Zfp423 upregulation during transformation. ZNF423 depletion impaired DNA synthesis and proliferation, induced DNA damage signaling, and activated the integrated stress response (ISR), increasing sensitivity to cytotoxic agents. In an orthotopic MPNST model, shRNA-mediated suppression of ZNF423 reduced tumor initiation in vivo; however, tumors that eventually emerged showed restoration of ZNF423 expression. ZNF423 is developmentally restricted in the peripheral nerve lineage yet elevated in MPNST, with single-cell analyses of patient nerve sheath tumors revealing localized expression restricted to malignant cells rather than SOX10-positive benign tumor cells. These data identify ZNF423 as a putative malignant biomarker, a potential dependency in NF1-MPNST, and nominate downstream stress and genome maintenance pathways as cooperative therapeutic vulnerabilities. STATEMENT OF SIGNIFICANCE ZNF423 is a developmentally restricted transcription factor selectively reactivated in NF1-associated malignant peripheral nerve sheath tumors. Targeted ablation triggers the integrated stress response, impairs DNA synthesis, sensitizes cells to chemotherapy and PARP inhibition, and restricts in vivo growth. ZNF423 represents a candidate biomarker and therapeutic vulnerability in this aggressive sarcoma.

Few approved treatments exist for children with Crohn's disease (CD). The REALITI study retrospectively assessed the effectiveness and safety of ustekinumab in real-world clinical settings for children with CD. Data were collected from the prospective ImproveCareNow (ICN) registry for pediatric patients (≥ 2 to <18 years old) and young adult patients (≥ 18 to <26 years old), regardless of baseline CD severity. Additional analyses were conducted for a subset of patients who had moderately-to-severely active CD (short pediatric CD activity index [sPCDAI] ≥30). Key Week-52 endpoints included clinical remission (sPCDAI ≤10) and corticosteroid-free (CF) clinical remission. Safety events of interest were assessed at Week 52. Overall, 479 patients with CD were treated with ustekinumab, 348 pediatric patients and 131 young adults; most were biologic-exposed (pediatric, 98.9%; young adult, 95.4%). At Week 52 (observed case; excluding patients without Week 52 data), clinical remission was achieved by 47.3% (125/264) of pediatric patients and 44.8% (39/87) of young adults, and CF clinical remission by 41.3% (109/264) and 39.1% (34/87), respectively. At Week 52 (observed case), among patients with moderately-to-severely active CD, clinical remission was achieved by 36.9% (41/111) of pediatric patients and 34.3% (12/35) of young adults, and CF clinical remission by 31.5% (35/111) and 28.6% (10/35), respectively. Ustekinumab was well tolerated, with no new safety signals identified. In the REALITI study of real-world data from the ICN registry, the effectiveness and safety of ustekinumab treatment through 52 weeks were similar in pediatric and young adult patients with CD. ClinicalTrials.gov identifier: NCT05242458; https://clinicaltrials.gov/study/NCT05242458.

Introduction: Diabetic Ketoacidosis (DKA) is a leading cause of pediatric ICU admissions. While prior studies have focused on clinical outcomes such as length of stay, morbidity, and mortality, few have investigated the association between pre-hospital sociodemographic and structural factors on illness severity at PICU presentation. We hypothesized that pre-hospital factors – including race, referral source, diabetes diagnosis status (new vs known), and neighborhood-level indices (Child Opportunity Index [COI] – are associated with worse biochemical derangements at PICU admission, including lower bicarbonate, higher anion gap, higher glucose, and elevated hemoglobin A1c (Hgb A1c). Methods: This retrospective cohort study included pediatric patients (age 0-18 years) admitted to the Riley Children’s Hospital PICU from 2018-2024 with an ICD-10 diagnosis of T1DM and DKA. Admission laboratory data – including anion gap, bicarbonate, glucose, and Hb A1c – were collected and used as markers of illness severity. These values were analyzed in relation to pre-hospital factors: age, gender, race, diagnosis status (new vs known Type 1 Diabetes Mellitus [T1DM]), referral source (direct ED vs outside hospital (OSH) transfer), and neighborhood metrics (COI) using linear regression. Results: In total, 786 encounters met study inclusion criteria. Black race (β=75; p< 0.01), OSH transfer (β=68; p< 0.01), higher COI (β=1.3; p< 0.01), and new DM1 diagnosis (β=67; p< 0.01) were all associated with increased presenting glucose levels. Increasing age (β=0.15; p< 0.01), Black race (β=0.7; p=0.01), and new DM1 diagnosis (β=1.7; p< 0.01) were associated with higher initial Hgb A1c levels. Male sex (β=1.4; p=0.01) was associated with higher presenting anion gap, while new DM1 diagnosis (β= -1.4; p=0.03) was associated with lower presenting anion gap. Conclusions: Black race, COI, older age, new onset T1DM, and OSH transfer emerged as predictors of more severe biochemical derangements. These findings underscore the need for improved early recognition, timely transfer protocols, and equitable outpatient access aimed at mitigating disparities before ICU-level care becomes necessary.

Ureteroureterostomy is a viable option for the management of duplex ureters with associated obstruction, reflux, or incontinence in upper or lower systems. Recent advancements in pediatric urology have fostered a growing interest in comparing the safety, efficacy, and outcomes of the open, laparoscopic, and robotic techniques. Herein, this systematic review and network meta-analysis (NMA) aim to evaluate the safety, efficacy, and outcomes of these three surgical approaches in pediatric patients. A systematic literature review of Medline, Embase, and Web of Science identified studies comparing these surgical approaches in children (<18 years old). NMA assessed treatment effects using log odds ratios and mean differences with random effects. Heterogeneity and inconsistency were evaluated, and the risk of bias was assessed using the ROBINS-I tool. Seven retrospective studies with 277 children (76 robotic, 124 laparoscopic, and 77 open) were included. There was no difference in age at operation across surgical techniques. No statistically significant difference in operative time was observed, but significant heterogeneity was noted (I2 = 75.2%, p = 0.0012). Overall complication rates ranged from 0% to 31.6% and were similar across all techniques. Clavien-Dindo ≥ 3 complications were low (0-11.1%) and did not significantly differ between approaches. Surgical success rates were comparable across techniques. Funnel plot demonstrated minimal likelihood of publication bias. ROBINS-I risk of bias evaluation demonstrated a serious risk of bias because of confounding from retrospective study designs. Based on our NMA, no surgical approach demonstrated clear superiority in operative time, complications, or success rates. Therefore, surgeons should choose the technique of ureteroureterostomy based on their expertise, comfort, and patient factors.