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BACKGROUND Prognostic significance of IDH-mutation in glioma is incompletely understood in children and adolescents/young adults (YAs). We compared the clinico-genomic features, outcomes and prognostic factors observed in IDH-mutant gliomas across age groups. METHODS Clinical, histologic and molecular data of patients with IDH-mutant gliomas from 8 pediatric institutions (spanning twenty years) and adult patients from two institutions (from 2013–2019) were identified. Patients were grouped as pediatric (< 19y), YA (19y to < 40y) or older adult (≥ 40y). Genomic alterations, including somatic mutations and copy number variants, were captured with institutional next generation sequencing. Factors were compared across age categories using Fisher’s exact test or analysis-of-variance. Cox proportional-hazards regression tested factors for association with overall (OS) and progression-free survival (PFS). RESULTS Of 379 patients, 48(13%) were pediatric, 204(54%) YA and 127(33%) older adult. Histological subtype differed significantly by age group (p< 0.0001). YAs had higher rates of malignant transformation (p=0.01) and shorter time-from-diagnosis-to-malignant transformation (p=0.01) compared to other age groups. Analysis of genomic alterations revealed an age-related difference in distribution in ATRX mutations only (p=0.0018). Median PFS and OS for the entire cohort were 4.62 and 17.19 years. In univariate models, PFS differed by age group (p=0.0012), with YAs having the worst outcomes. Lack of MGMT methylation (p=0.024) predicted poorer OS. Upfront observant management was predictive of poorer PFS. Gene mutations were not associated with PFS. In multi-variable models, YAs had shorter PFS compared to pediatric (hazard ratio [HR]=2.03, p=0.01) and older adults (HR=1.59, p=0.003) after adjusting for histology, extent of resection, and initial therapy. Age at diagnosis was not associated with OS in multi-variable analysis. CONCLUSIONS Within our cohort, YA with IDH-mutant tumors progressed more quickly compared to their pediatric counterparts. Further study of YA patients with IDH-mutant glioma is critical to better define best practices for this group.

BackgroundNUT midline carcinoma, renamed NUT carcinoma (NC), is an aggressive squamous cancer defined by rearrangement of the NUTM1 gene. Although a subset of patients can be cured, for the majority of patients the prognosis is grim. We sought to classify patients into risk groups based on molecular and clinicopathologic factors at the time of diagnosis.MethodsClinicopathologic variables and survival outcomes were extracted for a total of 141 NC patients from the NUT midline carcinoma Registry using questionnaires and medical records. Translocation type was identified by molecular analyses. Survival tree regression analysis was performed to determine risk factors associated with overall survival (OS).ResultsFor 141 patients, the median age at diagnosis was 23.6 years. Fifty-one percent had thoracic origin compared with 49% nonthoracic sites (41% head and neck, 6% bone or soft tissue, 1% other). The median OS was 6.5 months (95% confidence interval [CI] = 5.8 to 9.1 months). Most patients had the BRD4-NUTM1 fusion (78%), followed by BRD3-NUTM1 (15%) and NSD3-NUTM1 (6%). Survival tree regression identified three statistically distinct risk groups among 124 patients classified by anatomical site and genetics: group A is nonthoracic primary, BRD3-, or NSD3-NUT (n = 12, median OS = 36.5 months, 95% CI = 12.5 to not reported months); group B is nonthoracic primary, BRD4-NUT (n = 45, median OS = 10 months, 95% CI = 7 to 14.6 months); and group C is thoracic primary (n = 67, median OS = 4.4 months, 95% CI = 3.5 to 5.6 months). Only groups A and B had long-term (≥3 years, n = 12) survivors.ConclusionsWe identify three risk groups defined by anatomic site and NUT fusion type. Nonthoracic primary with non-BRD4-NUT fusion confers the best prognosis, followed by nonthoracic primary with BRD4-NUT. Thoracic NC patients, regardless of the NUT fusion, have the worst survival.