Chen, I‐Ming

Abstract Background The Global Bipolar Cohort (GBC) was established to identify existing bipolar disorder (BD) cohorts worldwide and foster collaborations focused on descriptive and analytic outcomes relevant to BD. A distributed analytic framework has been implemented to engage multiple sites without the need for central data pooling. This report describes the GBC endeavor and global functional impairment patterns. Cross-cohort comparisons of functional correlates are limited by heterogeneous measures and data-sharing constraints. Large, culturally diverse comparisons are needed to distinguish broadly reproducible correlates from cohort-specific effects. Participating sites completed a 28-item descriptive survey covering diagnostic methods, cognition, genetics, treatment, functioning, and follow-up strategies. We implemented a harmonized local logistic regression model of dichotomized functional outcome and shared summary statistics only. Results We identified 69 cohorts across five continents. Thirty-seven cohorts contributed functional outcome analyses from 17,130 participants. Outcome measures included clinician-rated disability scales and social indicators such as employment and marital status. The proportion classified with poor functioning ranged from 16% to 77% (mean 50%). In 32 of 37 cohorts, the overall regression model significantly explained variance in functioning. Current depressive symptoms were the most robust and reproducible correlate of poor functional outcome: they were assessed in 29 cohorts, significant in 22 (75.8%), ranked among the top three correlates in 22, and were the top-ranked correlates in 19. Associations between depressive burden and poor functioning were observed across clinician-rated disability scales and work or social indicators, and across geographically diverse cohorts. Comorbid substance use disorder and medication-related variables were associated with poorer functioning in subsets of cohorts, whereas sex, ancestry, bipolar subtype, psychosis history, and premorbid IQ showed weak or inconsistent associations. Cognitive measures, available in a minority of regression models, showed modest and non-uniform effects. Conclusions Across heterogeneous international cohorts, current depressive symptom burden emerged as the most consistent correlate of poor functioning in bipolar disorder. These findings replicate earlier multisite work at a larger scale, show that protocol-based distributed analyses can identify reproducible clinical signals without sharing individual-level data, and support prioritizing detection and treatment of depressive symptoms when aiming to improve real-world functioning. Future work should expand longitudinal harmonization and representation of under-studied populations.

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.

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.

Abstract The dic(9;12)(p12;p11.2) has been described as a rare cytogenetic abnormality in pediatric precursor B-cell ALL. Initial studies suggested that the rearrangement is associated with a favorable outcome, and recent studies demonstrated the presence of a PAX5-ETV6 fusion gene was associated with this cytogenetic abnormality. Twenty cases with a cytogenetic dic(9;12) were identified in the Children’s Oncology Group (COG) cytogenetics databases. FISH analysis with the ETV6-RUNX1 (TEL-AML1) probes was done on 12 of these samples. Five cases were positive for fusion, indicating a cryptic t(12;21)(p13;q22), and also had loss of the ETV6 probe from the chromosome 12 not involved in the t(12;21). Seven cases were negative for fusion and had loss of an ETV6 signal, although one of the latter had a diminished ETV6 signal identified. To determine whether both PAX5-ETV6 and ETV6-RUNX1 rearrangements occurred in some patients, a diagnostic sample from each patient was analyzed by RT-PCR for the PAX5-ETV6 and ETV6-RUNX1 fusion genes. Primers from exon 3 of PAX5 and exon 3 of ETV6 were used for the PAX5-ETV6 analysis and from exon 5 of ETV6 and exon 4 of RUNX1 for the ETV6-RUNX1 analysis. Of the 20 cases, only 8 were RT-PCR positive for the PAX5-ETV6 fusion with the above primers; however, an additional 2 were RT-PCR positive with alternate primers, and all 10 of these were negative for the ETV6-RUNX1 fusion by RT-PCR. Of the remaining 10 patients, 9 were RT-PCR positive for the ETV6-RUNX1 fusion, including all of the ETV6-RUNX1 cases positive by FISH. The gene rearrangement associated with the dic(9;12) in these cases is not known. One patient was negative for both fusions by RT-PCR, negative by FISH for ETV6-RUNX1 rearrangement, yet had loss of an ETV6 signal. No cytogenetic differences could be seen between the 2 groups, either in the appearance of the dic(9;12) or in the other abnormalities identified. These results demonstrate the presence of two mutually exclusive dic(9;12) rearrangements in pediatric ALL; one associated with ETV6-RUNX1 rearrangement and one resulting in PAX5-ETV6 fusion. Both PAX5-ETV6 and ETV6-RUNX1 rearrangements are associated with a favorable prognosis. However, molecular analysis of the dic(9;12) patients must be performed to determine whether the dicentric chromosome results in PAX5-ETV6 fusion or whether the case has ETV6-RUNX1 fusion.