Genomic Determinants of Outcome in Acute Lymphoblastic Leukemia.

PURPOSE: Although cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 90%, ALL remains a leading cause of cancer death in children. Half of relapses arise in children initially classified with standard-risk (SR) disease. MATERIALS AND METHODS: To identify genomic determinants of relapse in children with SR ALL, we performed genome and transcriptome sequencing of diagnostic and remission samples of children with SR (n = 1,381) or high-risk B-ALL with favorable cytogenetic features (n = 115) enrolled on Children's Oncology Group trials. We used a case-control study design analyzing 439 patients who relapsed and 1,057 who remained in complete remission for at least 5 years. RESULTS: Genomic subtype was associated with relapse, which occurred in approximately 50% of cases of PAX5-altered ALL (odds ratio [OR], 3.31 [95% CI, 2.17 to 5.03]; P = 3.18 × 10-8). Within high-hyperdiploid ALL, gain of chromosome 10 with disomy of chromosome 7 was associated with favorable outcome (OR, 0.27 [95% CI, 0.17 to 0.42]; P = 8.02 × 10-10; St Jude Children's Research Hospital validation cohort: OR, 0.22 [95% CI, 0.05 to 0.80]; P = .009), and disomy of chromosomes 10 and 17 with gain of chromosome 6 was associated with relapse (OR, 7.16 [95% CI, 2.63 to 21.51]; P = 2.19 × 10-5; validation cohort: OR, 21.32 [95% CI, 3.62 to 119.30]; P = .0004). Genomic alterations were associated with relapse in a subtype-dependent manner, including alterations of INO80 in ETV6::RUNX1 ALL, IKZF1, and CREBBP in high-hyperdiploid ALL and FHIT in BCR::ABL1-like ALL. Genomic alterations were also associated with the presence of minimal residual disease, including NRAS and CREBBP in high-hyperdiploid ALL. CONCLUSION: Genetic subtype, patterns of aneuploidy, and secondary genomic alterations determine risk of relapse in childhood ALL. Comprehensive genomic analysis is required for optimal risk stratification.

Treating severe paediatric asthma with mepolizumab or omalizumab: a protocol for the TREAT randomised non-inferiority trial.

INTRODUCTION: A minority of school-aged children with asthma have persistent poor control and experience frequent asthma attacks despite maximal prescribed maintenance therapy. These children have higher morbidity and risk of death. The first add-on biologic therapy, omalizumab, a monoclonal antibody that blocks immunoglobulin (Ig)E, was licensed for children with severe asthma in 2005. While omalizumab is an effective treatment, non-response is common. A second biologic, mepolizumab which blocks interleukin 5 and targets eosinophilic inflammation, was licensed in 2018, but the licence was granted by extrapolation of adult clinical trial data to children. This non-inferiority (NI) trial will determine whether mepolizumab is as efficacious as omalizumab in reducing asthma attacks in children with severe therapy resistant asthma (STRA) and refractory difficult asthma (DA). METHODS AND ANALYSIS: This is an ongoing multicentre 1:1 randomised NI open-label trial of mepolizumab and omalizumab. Up to 150 children and young people (CYP) aged 6-17 years with severe asthma will be recruited from specialist paediatric severe asthma centres in the UK. Prior to randomisation, children will be monitored for medication adherence for up to 16 weeks to determine STRA and refractory DA diagnoses. Current prescribing recommendations of serum IgE and blood eosinophils will not influence eligibility or enrolment. The primary outcome is the 52-week asthma attack rate. Bayesian analysis using clinician-elicited prior distributions will be used to calculate the posterior probability that mepolizumab is not inferior to omalizumab. Secondary outcomes include Composite Asthma Severity Index, Paediatric Asthma Quality of Life Questionnaire, lung function measures (forced expiratory volume in one second (FEV1), bronchodilator reversibility), fractional exhaled nitric oxide, Asthma Control Test (ACT), health outcomes EuroQol 5 Dimension (EQ-5D) and optimal serum IgE and blood eosinophil levels that may predict a response to therapy. These outcomes will be analysed in a frequentist framework using longitudinal models. ETHICS AND DISSEMINATION: The study has been approved by the South Central-Berkshire Research Ethics Committee REC Number 19/SC/0634 and had Clinical Trials Authorisation from the Medicines and Healthcare Products Regulatory Agency (MHRA) (EudraCT 2019-004085-17). All parents/legal guardians will give informed consent for their child to participate in the trial, and CYP will give assent to participate. The results will be published in peer-reviewed journals, presented at international conferences and disseminated via our patient and public involvement partners. TRIAL REGISTRATION NUMBER: ISRCTN12109108; EudraCT Number: 2019-004085-17.

Clonal evolution of the 3D chromatin landscape in patients with relapsed pediatric B-cell acute lymphoblastic leukemia.

Relapsed pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains one of the leading causes of cancer mortality in children. We performed Hi-C, ATAC-seq, and RNA-seq on 12 matched diagnosis/relapse pediatric leukemia specimens to uncover dynamic structural variants (SVs) and 3D chromatin rewiring that may contribute to relapse. While translocations are assumed to occur early in leukemogenesis and be maintained throughout progression, we discovered novel, dynamic translocations and confirmed several fusion transcripts, suggesting functional and therapeutic relevance. Genome-wide chromatin remodeling was observed at all organizational levels: A/B compartments, TAD interactivity, and chromatin loops, including some loci shared by 25% of patients. Shared changes were found to drive the expression of genes/pathways previously implicated in resistance as well as novel therapeutic candidates, two of which (ATXN1 and MN1) we functionally validated. Overall, these results demonstrate chromatin reorganization under the selective pressure of therapy and offer the potential for discovery of novel therapeutic interventions.

The genomic basis of childhood T-lineage acute lymphoblastic leukaemia.

T-lineage acute lymphoblastic leukaemia (T-ALL) is a high-risk tumour1 that has eluded comprehensive genomic characterization, which is partly due to the high frequency of noncoding genomic alterations that result in oncogene deregulation2,3. Here we report an integrated analysis of genome and transcriptome sequencing of tumour and remission samples from more than 1,300 uniformly treated children with T-ALL, coupled with epigenomic and single-cell analyses of malignant and normal T cell precursors. This approach identified 15 subtypes with distinct genomic drivers, gene expression patterns, developmental states and outcomes. Analyses of chromatin topology revealed multiple mechanisms of enhancer deregulation that involve enhancers and genes in a subtype-specific manner, thereby demonstrating widespread involvement of the noncoding genome. We show that the immunophenotypically described, high-risk entity of early T cell precursor ALL is superseded by a broader category of 'early T cell precursor-like' leukaemia. This category has a variable immunophenotype and diverse genomic alterations of a core set of genes that encode regulators of hematopoietic stem cell development. Using multivariable outcome models, we show that genetic subtypes, driver and concomitant genetic alterations independently predict treatment failure and survival. These findings provide a roadmap for the classification, risk stratification and mechanistic understanding of this disease.

Interim Phase II Results Using Panitumumab-IRDye800CW During Transoral Robotic Surgery in Patients with Oropharyngeal Cancer.

PURPOSE: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has continually increased during the past several decades. Using transoral robotic surgery (TORS) significantly improves functional outcomes relative to open surgery for OPSCC. However, TORS limits tactile feedback, which is often the most important element of cancer surgery. Fluorescence guided surgery (FGS) strategies to aid surgeon assessment of malignancy for resection are in various phases of clinical research but have the greatest potential impact for improving patient care when the surgeon has limited tactile feedback, such as during TORS. Here, we assessed the feasibility of intraoperative fluorescence imaging using panitumumab-IRDye800CW (PAN800) during TORS in OPSCC patients. PATIENTS AND METHODS: 12 consecutive patients with OPSCC were enrolled as part of a non-randomized, prospective, phase II FGS clinical trial using PAN800. TORS was performed with an integrated robot camera for surgeon assessment of fluorescence. Intraoperative and ex vivo fluorescence signals in tumors and normal tissue were quantified and correlated with histopathology. RESULTS: Intraoperative robot fluorescence views delineated OPSCC from normal tissue throughout the TORS procedure (10.7 mean tumor-to-background ratio), including in tumors with low expression of the molecular target. Tumor-specific fluorescence was consistent with surgeon-defined tumor borders requiring resection. Intraoperative robot fluorescence imaging revealed an OPSCC fragment initially overlooked during TORS based on brightfield views, further substantiating the clinical benefit of this FGS approach. CONCLUSIONS: Results from this OPSCC patient cohort support further clinical assessment of FGS during TORS to aid resection of solid tumors.

Surgical outcomes and revision rates for velopharyngeal insufficiency (VPI) in syndromic and non-syndromic children: A systematic review and meta-analysis.

PURPOSE: To evaluate pre- and post-operative resonance, surgical technique, revision rate, and revision indication among syndromic and non-syndromic children with velopharyngeal insufficiency (VPI). MATERIALS AND METHODS: A systematic review was conducted through July 2022. Children surgically treated for VPI were included. A meta-analysis of single means, proportions, comparison of proportions, and mean differences with 95 % confidence interval [CI] was conducted. RESULTS: Twenty-three articles (n = 1437) were included in the analysis. The most common surgery was Sphincter Pharyngoplasty (SP), 62.6 % [31.3-88.9] for syndromic and 76.3 % [37.5-98.9] for non-syndromic children. Among all surgical techniques, for syndromic and non-syndromic children, 54.8 % [30.9-77.5] and 73.9 % [61.3-84.6] obtained normal resonance post-operatively, respectively. Syndromic patients obtained normal resonance post-operatively in 83.3 % [57.7-96.6] of Combined Furlow Palatoplasty and Sphincter Pharyngoplasty (CPSP), 72.6 % [54.5-87.5] of Pharyngeal Flap (PF), and 45.1 % [13.2-79.8] of Sphincter Pharyngoplasty (SP) surgeries. Non-syndromic patients obtained normal resonance post-operatively in 79.2 % [66.4-88.8] of PF and 75.2 % [61.8-86.5] of SP surgeries. The revision rate for syndromic and non-syndromic patients was 19.9 % [15.0-25.6] and 11.3 % [5.8-18.3], respectively. The difference was statistically significant, 8.6 % [2.9-15.0, p = 0.003]. Syndromic patients who underwent PF were least likely to undergo revision surgery as compared to SP and CPSP, 7.7 % [2.3-17.9] vs. 23.7 % [15.5-33.1] and 15.3 % [2.8-40.7], respectively. CONCLUSIONS: Syndromic children had higher revision rates and were significantly less likely to obtain normal resonance following primary surgery than non-syndromic patients. Among syndromic children, PF and CPSP have been shown to improve resonance and reduce revision rates more so than SP alone.

Clinical Validation of a Machine-Learned, Point-of-Care System to IDENTIFY Functionally Significant Coronary Artery Disease.

Many clinical studies have shown wide performance variation in tests to identify coronary artery disease (CAD). Coronary computed tomography angiography (CCTA) has been identified as an effective rule-out test but is not widely available in the USA, particularly so in rural areas. Patients in rural areas are underserved in the healthcare system as compared to urban areas, rendering it a priority population to target with highly accessible diagnostics. We previously developed a machine-learned algorithm to identify the presence of CAD (defined by functional significance) in patients with symptoms without the use of radiation or stress. The algorithm requires 215 s temporally synchronized photoplethysmographic and orthogonal voltage gradient signals acquired at rest. The purpose of the present work is to validate the performance of the algorithm in a frozen state (i.e., no retraining) in a large, blinded dataset from the IDENTIFY trial. IDENTIFY is a multicenter, selectively blinded, non-randomized, prospective, repository study to acquire signals with paired metadata from subjects with symptoms indicative of CAD within seven days prior to either left heart catheterization or CCTA. The algorithm's sensitivity and specificity were validated using a set of unseen patient signals (n = 1816). Pre-specified endpoints were chosen to demonstrate a rule-out performance comparable to CCTA. The ROC-AUC in the validation set was 0.80 (95% CI: 0.78-0.82). This performance was maintained in both male and female subgroups. At the pre-specified cut point, the sensitivity was 0.85 (95% CI: 0.82-0.88), and the specificity was 0.58 (95% CI: 0.54-0.62), passing the pre-specified endpoints. Assuming a 4% disease prevalence, the NPV was 0.99. Algorithm performance is comparable to tertiary center testing using CCTA. Selection of a suitable cut-point results in the same sensitivity and specificity performance in females as in males. Therefore, a medical device embedding this algorithm may address an unmet need for a non-invasive, front-line point-of-care test for CAD (without any radiation or stress), thus offering significant benefits to the patient, physician, and healthcare system.

ENSEMBLE PLUS: final results of shorter ocrelizumab infusion from a randomized controlled trial.

INTRODUCTION: Ocrelizumab is an approved intravenously administered anti-CD20 antibody for multiple sclerosis (MS). The safety profile and patient preference for conventional versus shorter ocrelizumab infusions were investigated in the ENSEMBLE PLUS study. METHODS: ENSEMBLE PLUS was a randomized, double-blind substudy to the single-arm ENSEMBLE study (NCT03085810), comparing outcomes in patients with early-stage relapsing-remitting MS receiving ocrelizumab 600 mg over the approved 3.5-h (conventional) versus 2-h (shorter) infusion. The primary endpoint was the proportion of patients with infusion-related reactions (IRRs) following the first randomized dose (RD); the secondary endpoint included IRR frequency at subsequent RDs. RESULTS: At first RD, the number of patients with an IRR in the conventional (101/373; 27.1%) versus shorter (107/372; 28.8%) infusion group was similar (difference, stratified estimates [95% CI]: 1.9% [- 4.4, 8.2]). Most IRRs (conventional: 99.4%; shorter: 97.7%) were mild/moderate. IRR frequency decreased over the course of RDs; three patients discontinued from the shorter infusion arm but continued with conventional infusion. Overall, > 98% of IRRs resolved without sequelae in both groups. Pre-randomization throat irritation was predictive of future throat irritation as an IRR symptom. Adverse events (AEs) and serious AEs were consistent with the known ocrelizumab safety profile. On completion of ENSEMBLE PLUS, most patients chose to remain on (95%) or switch to (80%) shorter infusion. CONCLUSION: ENSEMBLE PLUS demonstrates the safety and tolerability of shorter ocrelizumab infusions. Most patients remained on/switched to shorter infusion after unblinding; IRRs did not strongly influence patient decisions. CLINICAL TRIALS REGISTRATION: Substudy of ENSEMBLE (NCT03085810). REGISTRATION: March 21, 2017.

Characteristics and outcomes of interventions for pediatric laryngomalacia: A systematic review with meta-analysis.

OBJECTIVES: To analyze characteristics of children treated for laryngomalacia to determine predictive factors and provide an updated meta-analysis on outcomes. METHODS: A systematic review was conducted according to PRISMA guidelines from inception to May 2, 2023, using CINAHL, PubMed, and Scopus databases. Study screening, data extraction, quality rating, and risk of bias assessment were performed by 2 independent reviewers. Data were meta-analyzed using fixed-/random-effects model to derive continuous measures (mean), proportions (%), and mean difference (Δ) with 95% confidence interval (CI). RESULTS: 100 articles were identified with information on outcomes of pediatric patients with laryngomalacia (N = 18,317). The mean age was 10.6 months (range: 0 to 252, 95%CI: 9.6 to 11.6, p = 0.00) with a 1.4:1 male to female ratio. Many patients presented with stridor (87.9%, 95% CI: 69.8 to 98.4), and the most common comorbidity at time of diagnosis was gastroesophageal reflux disease (48.8%, 95%CI: 40.9 to 56.8). Based on the patient population included in our analysis, 86.1% received supraglottoplasty (95% CI: 78.7 to 92.1). A total of 73.6% (95% CI: 65.5 to 81.0) had reported complete resolution of symptoms. For patients with a concurrent diagnosis of sleep disordered breathing receiving supraglottoplasty, the apnea-hypopnea index improved with a mean difference of -10.0 (95%CI: 15.6 to -4.5) events per hour post-treatment. CONCLUSIONS: Laryngomalacia continues to be a common problem in the pediatric population. Supraglottoplasty remains an effective treatment option leading to symptomatic improvement in many cases. For those with concurrent sleep disordered breathing, supraglottoplasty lowers the apnea-hypopnea index.

Does REM AHI Predict Persistent OSA After Pediatric Adenotonsillectomy?

OBJECTIVE: The utility of REM AHI in managing pediatric obstructive sleep apnea (OSA) is not fully understood. This study aimed to evaluate the relationship of preoperative REM AHI to postoperative persistence of OSA in children who underwent adenotonsillectomy. METHODS: This retrospective chart review identified children under the age of 18 years that received an adenotonsillectomy for OSA and a preoperative and postoperative polysomnogram. Children with craniofacial or neuromuscular disorders or a tracheostomy were excluded. The primary outcome was the postoperative persistence of OSA, defined as a postoperative obstructive apnea-hypopnea index (oAHI) ≥ 1.5 events/hour. REM-predominant OSA was defined as a ratio of REM/NREM AHI ≥ 2. REM AHI minus NREM AHI and REM AHI minus oAHI helped to identify patients with a larger distribution of REM AHI. RESULTS: A total of 353 patients were included. Postoperative persistent OSA was seen in 232 (65.7%) children. The preoperative REM AHI, REM AHI minus NREM AHI, and REM AHI minus oAHI of children with persistent OSA did not differ significantly from children with resolution of OSA. Rates of persistence were not different between those with REM-predominant OSA and REM-independent OSA (63.8% vs 70.7%, P = .218). CONCLUSION: This study suggests that preoperative REM AHI may be a poor predictor of OSA persistence after adenotonsillectomy. Further study is needed to help characterize how pre-operative REM AHI should impact clinicians' decision making, family counseling and recommendations.

Outcomes in Children, Adolescents, and Young Adults With Down Syndrome and ALL: A Report From the Children's Oncology Group.

PURPOSE: Patients with Down syndrome (DS) and B-ALL experience increased rates of relapse, toxicity, and death. We report results for patients with DS B-ALL enrolled on Children's Oncology Group trials between 2003 and 2019. METHODS: We analyzed data for DS (n = 743) and non-DS (n = 20,067) patients age 1-30 years on four B-ALL standard-risk (SR) and high-risk trials. RESULTS: Patients with DS exhibited more frequent minimal residual disease (MRD) ≥0.01% at end induction (30.8% v 21.5%; P < .001). This difference persisted at end consolidation only in National Cancer Institute (NCI) high-risk patients (34.0% v 11.7%; P < .0001). Five-year event-free survival (EFS) and overall survival (OS) were significantly poorer for DS versus non-DS patients overall (EFS, 79.2% ± 1.6% v 87.5% ± 0.3%; P < .0001; OS, 86.8% ± 1.4% v 93.6% ± 0.2%; P < .0001), and within NCI SR and high-risk subgroups. Multivariable Cox regression analysis of the DS cohort for risk factors associated with inferior EFS identified age >10 years, white blood count >50 × 103/µL, and end-induction MRD ≥0.01%, but not cytogenetics or CRLF2 overexpression. Patients with DS demonstrated higher 5-year cumulative incidence of relapse (11.5% ± 1.2% v 9.1% ± 0.2%; P = .0008), death in remission (4.9% ± 0.8% v 1.7% ± 0.1%; P < .0001), and induction death (3.4% v 0.8%; P < .0001). Mucositis, infections, and hyperglycemia were significantly more frequent in all patients with DS, while seizures were more frequent in patients with DS on high-risk trials (4.1% v 1.8%; P = .005). CONCLUSION: Patients with DS-ALL exhibit an increased rate of relapse and particularly of treatment-related mortality. Novel, less-toxic therapeutic strategies are needed to improve outcomes.

Is there an OAHI or O2 nadir that predicts the need for preoperative echocardiogram prior to adenotonsillectomy for children with severe obstructive sleep apnea?

PURPOSE: To investigate threshold values for obstructive apnea-hypopnea index (OAHI) and nadir oxygen saturation (NspO2) in children with severe obstructive sleep apnea (OSA) to identify children most appropriate for preoperative echocardiography. METHODS: A multi-institutional retrospective chart review was performed on children who underwent echocardiography and polysomnogram within a year. Children with severe OSA as defined by OAHI > 10 or NspO2 < 80% were included. Receiver operator curves and Youden's J index were used to assess the discriminatory ability and threshold values of OAHI and NspO2 for right heart strain (RHS) on echocardiography. RESULTS: A total of 173 prepubertal (< 10 years) children and 71 postpubertal (≥ 10 years) children of age were included. RHS was seen in 9 (5%) prepubertal children and 4 (6%) postpubertal children. In prepubertal children, OAHI and NspO2 were poor predictors of RHS (area under the curve [AUC] 0.53 [95%CI 0.45-0.61], p = 0.748; AUC 0.56 [95%CI 0.48-0.64], p = 0.609). In postpubertal children, threshold values of 55 events/hour and 69% were strong predictors for RHS (AUC 0.88 [95%CI 0.78-0.95], p < 0.001; AUC 0.92 [95%CI 0.83-0.97], p < 0.001). CONCLUSION: In children with severe OSA, evidence of RHS is low. Postpubertal children with OAHI > 55 and NspO2 < 69% appear most appropriate for echocardiography. Clinicians should weigh the risks and benefits of preoperative echocardiography for each child with these threshold values in mind.

SETD2 mutations do not contribute to clonal fitness in response to chemotherapy in childhood B cell acute lymphoblastic leukemia.

Mutations in genes encoding epigenetic regulators are commonly observed at relapse in B cell acute lymphoblastic leukemia (B-ALL). Loss-of-function mutations in SETD2, an H3K36 methyltransferase, have been observed in B-ALL and other cancers. Previous studies on mutated SETD2 in solid tumors and acute myelogenous leukemia support a role in promoting resistance to DNA damaging agents. We did not observe chemoresistance, an impaired DNA damage response, nor increased mutation frequency in response to thiopurines using CRISPR-mediated knockout in wild-type B-ALL cell lines. Likewise, restoration of SETD2 in cell lines with hemizygous mutations did not increase sensitivity. SETD2 mutations affected the chromatin landscape and transcriptional output that was unique to each cell line. Collectively our data does not support a role for SETD2 mutations in driving clonal evolution and relapse in B-ALL, which is consistent with the lack of enrichment of SETD2 mutations at relapse in most studies.

Vitamin D did not reduce multiple sclerosis disease activity after a clinically isolated syndrome.

Low serum levels of 25-hydroxyvitamin D [25(OH)D] and low sunlight exposure are known risk factors for the development of multiple sclerosis. Add-on vitamin D supplementation trials in established multiple sclerosis have been inconclusive. The effects of vitamin D supplementation to prevent multiple sclerosis is unknown. We aimed to test the hypothesis that oral vitamin D3 supplementation in high-risk clinically isolated syndrome (abnormal MRI, at least three T2 brain and/or spinal cord lesions), delays time to conversion to definite multiple sclerosis, that the therapeutic effect is dose-dependent, and that all doses are safe and well tolerated. We conducted a double-blind trial in Australia and New Zealand. Eligible participants were randomized 1:1:1:1 to placebo, 1000, 5000 or 10 000 international units (IU) of oral vitamin D3 daily within each study centre (n = 23) and followed for up to 48 weeks. Between 2013 and 2021, we enrolled 204 participants. Brain MRI scans were performed at baseline, 24 and 48 weeks. The main study outcome was conversion to clinically definite multiple sclerosis based on the 2010 McDonald criteria defined as either a clinical relapse or new brain MRI T2 lesion development. We included 199 cases in the intention-to-treat analysis based on assigned dose. Of these, 116 converted to multiple sclerosis by 48 weeks (58%). Compared to placebo, the hazard ratios (95% confidence interval) for conversion were 1000 IU 0.87 (0.50, 1.50); 5000 IU 1.37 (0.82, 2.29); and 10 000 IU 1.28 (0.76, 2.14). In an adjusted model including age, sex, latitude, study centre and baseline symptom number, clinically isolated syndrome onset site, presence of infratentorial lesions and use of steroids, the hazard ratios (versus placebo) were 1000 IU 0.80 (0.45, 1.44); 5000 IU 1.36 (0.78, 2.38); and 10 000 IU 1.07 (0.62, 1.85). Vitamin D3 supplementation was safe and well tolerated. We did not demonstrate reduction in multiple sclerosis disease activity by vitamin D3 supplementation after a high-risk clinically isolated syndrome.

Development of osteonecrosis and improved survival in B-ALL: results of Children's Oncology Group Trial AALL0232.

Osteonecrosis is a significant toxicity of acute lymphoblastic leukemia (ALL) therapy. In retrospective analyses, superior event-free survival was noted among affected adolescents in an earlier trial. We prospectively assessed osteonecrosis incidence, characteristics, and risk factors in patients 1-30 years with newly diagnosed high-risk B-ALL on COG AALL0232. Patients were randomized to induction dexamethasone vs prednisone, and interim maintenance high-dose methotrexate vs escalating-dose Capizzi methotrexate/pegaspargase. Event-free and overall survival were compared between patients with/without imaging-confirmed osteonecrosis. Osteonecrosis developed in 322/2730 eligible, evaluable patients. The 5-year cumulative incidence was 12.2%. Risk was greater in patients ≥10 years (hazard ratio [HR], 7.23; P < 0.0001), particularly females (HR, 1.37; P = 0.0057), but lower in those with asparaginase allergy (HR, 0.60; P = 0.0077). Among rapid early responders ≥10 years, risk was greater with dexamethasone (HR, 1.84; P = 0.0003) and with prednisone/Capizzi (HR, 1.45; P = 0.044), even though neither therapy was independently associated with improved survival. Patients with osteonecrosis had higher 5-year event-free (HR, 0.51; P < 0.0001) and overall survival (HR, 0.42; P < 0.0001), and this was directly attributable to reduced relapse rates (HR, 0.57; P = 0.0014). Osteonecrosis in high-risk B-ALL patients is associated with improved survival, suggesting an important role for host factors in mediating both toxicity and enhanced efficacy of specific therapies.

Cleft Lip and/or Palate Repair in Children With Hypopituitarism: Analysis of the Kids' Inpatient Database.

OBJECTIVE: Children with hypopituitarism (CwHP) can present with orofacial clefting, frequently in the setting of multiple midline anomalies. Hypopituitarism (HP) can complicate medical and surgical care; the perioperative risk in CwHP during the traditionally lower risk cleft lip and/or palate (CL/P) repair is not well described. The objective of this study is to examine the differences in complications and mortality of CL/P repair in CwHP compared to children without hypopituitarism (CwoHP). DESIGN: A retrospective cross-sectional analysis. SETTING: The 1997 to 2019 Kids' Inpatient Databases (KID). PATIENTS: Children 3 years old and younger who underwent CL/P repair. MAIN OUTCOME MEASURE(S): Complications and mortality. RESULTS: A total of 34 106 weighted cases were analyzed, with 86 having HP. CwHP had a longer length of stay (3.0 days [IQR 2.0-10.0] vs 1.0 day [IQR 1.0-2.0], P < .001) and higher rates of complications and mortality (12.8% vs 2.9%, P < .001) compared to CwoHP. Controlling for demographic factors, CwHP had 6.61 higher odds of complications and mortality than CwoHP (95% CI 3.38-12.94, P < .001). CONCLUSIONS: CwHP can present with a CL/P and other midline defects that can increase the complexity of their care. These data show a significant increase in length of stay, complications, and mortality in CwHP undergoing CL/P repair. Increased multidisciplinary attention and monitoring may be needed for these children peri- and postoperatively, especially if additional comorbidities are present. Further studies on perioperative management in this population are warranted to reduce morbidity and mortality.

Preoperative Imaging in Patients with 22q11 Deletion Syndrome Undergoing Velopharyngeal Surgery.

OBJECTIVE: To evaluate the utility of preoperative imaging before velopharyngeal dysfunction (VPD) surgery in children with 22q11 Deletion Syndrome (22qDS) in evaluating internal carotid artery (ICA) medialization. DATA SOURCES: PubMed, Scopus, and CINAHL. REVIEW METHODS: Following PRISMA guidelines, a systematic review was performed. Studies of children with 22qDS who underwent preoperative imaging (MRA or CTA) to identify ICA anomalies were included. High-risk medialized ICAs were defined as either submucosal, retropharyngeal, Pfeiffer Grade III-IV, or <3 mm from the pharyngeal mucosa. Meta-analyses of proportions were performed. RESULTS: Eleven studies met inclusion criteria, comprising 398 patients with 22qDS (weighted mean age 7.6 years). In 372 patients with imaging, the rate of ICA medialization on imaging was 47.1% (95%CI 29.2-65.5), of which 46.3% (95%CI 27.4-65.8) were determined high risk. Operative plans were modified in 19.4% (95%CI 5.7-38.8) of 254 surgeries due to medialized ICA. In studies attempting to use nasopharyngoscopy pulsations to identify medialization for 214 patients, the true-positive rate was 53.9% (95%CI 27.5-79.2) and the false-positive rate was 16.2% (95%CI 7.9-26.8). Nine of eleven studies (81.8%) recommended universal preoperative imaging of the ICAs in children with 22qDS undergoing VPD surgery. No cases of perioperative bleeding secondary to ICA injury were identified. CONCLUSION: Although most studies endorse routine preoperative imaging to assess for ICA medialization in children with 22qDS undergoing VPD surgery, only a minority of these cases led to surgical modification. Additional studies are needed to compare outcomes in children with and without preoperative imaging given the low rates of ICA injury in the literature. LEVEL OF EVIDENCE: N/A Laryngoscope, 2023.

Identification and targeting of treatment resistant progenitor populations in T-cell Acute Lymphoblastic Leukemia.

Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to cure in T-cell Acute Lymphoblastic Leukemia (T-ALL). Biomarker guided risk stratification and targeted therapy have the potential to improve outcomes in high-risk T-ALL; however, cellular and genetic factors contributing to treatment resistance remain unknown. Previous bulk genomic studies in T-ALL have implicated tumor heterogeneity as an unexplored mechanism for treatment failure. To link tumor subpopulations with clinical outcome, we created an atlas of healthy pediatric hematopoiesis and applied single-cell multiomic (CITE-seq/snATAC-seq) analysis to a cohort of 40 cases of T-ALL treated on the Children's Oncology Group AALL0434 clinical trial. The cohort was carefully selected to capture the immunophenotypic diversity of T-ALL, with early T-cell precursor (ETP) and Near/Non-ETP subtypes represented, as well as enriched with both relapsed and treatment refractory cases. Integrated analyses of T-ALL blasts and normal T-cell precursors identified a bone-marrow progenitor-like (BMP-like) leukemia sub-population associated with treatment failure and poor overall survival. The single-cell-derived molecular signature of BMP-like blasts predicted poor outcome across multiple subtypes of T-ALL within two independent patient cohorts using bulk RNA-sequencing data from over 1300 patients. We defined the mutational landscape of BMP-like T-ALL, finding that NOTCH1 mutations additively drive T-ALL blasts away from the BMP-like state. We transcriptionally matched BMP-like blasts to early thymic seeding progenitors that have low NR3C1 expression and high stem cell gene expression, corresponding to a corticosteroid and conventional cytotoxic resistant phenotype we observed in ex vivo drug screening. To identify novel targets for BMP-like blasts, we performed in silico and in vitro drug screening against the BMP-like signature and prioritized BMP-like overexpressed cell-surface (CD44, ITGA4, LGALS1) and intracellular proteins (BCL-2, MCL-1, BTK, NF-κB) as candidates for precision targeted therapy. We established patient derived xenograft models of BMP-high and BMP-low leukemias, which revealed vulnerability of BMP-like blasts to apoptosis-inducing agents, TEC-kinase inhibitors, and proteasome inhibitors. Our study establishes the first multi-omic signatures for rapid risk-stratification and targeted treatment of high-risk T-ALL.

Brief Action Planning in Health and Health Care: A Scoping Review.

Achieving maximal health outcomes via health promotion and disease prevention requires the adoption of healthy behaviors. Brief action planning (BAP) is a method for patient self-management, health behavior change, and health coaching with potentially broad implications for and clinical applications in health and health care contexts. This scoping review presents 5 major findings about the literature on BAP: the principal geographic locations and the clinical contexts of its application, the types of research evaluations that it has undergone to date, the theoretic frameworks in which it is grounded, and the fidelity of its use in clinical practice.