Background: Survival data for recurrent or treatment refractory pediatric atypical teratoid rhabdoid tumor (AT/RT), and its association to molecular groups is extremely limited. Methods: Single-institution retrospective study of sixty-four children <21 years old with AT/RT that was recurrent or refractory to frontline therapies (PD) treated at St. Jude Children’s Research Hospital from January 2000 to December 2020. Demographic, clinicopathologic, treatment, molecular grouping (SHH, TYR and MYC) and germline SMARCB1/SMARCA4 mutational data were collected. Progression-free survival (PFS2: time from initial PD to subsequent first progression) and overall survival (OSpostPD: time from PD to death/last follow up) were estimated by Kaplan–Meier analysis. Results: Median age at and time from initial diagnosis to PD were 2.1 years (range: 0.5-17.9 years) and 5.4 months (range: 0.5-125.6 months), respectively. Only 5/64 children (7.8%) are alive at median follow-up of 10.9 (range: 4.2-18.1) years from PD. The 2/5-year PFS2 and OSpostPD were 3.1% (±1.8%)/1.6% (±1.1%) and 20.3% (±4.8%)/7.3% (±3.5%), respectively. Children with TYR group (n=10) had a better OSpostPD compared to those with MYC (n=11) (2-year survival estimates: 60.0% ±14.3% vs. 18.2% ±9.5%; p=0.019), or those with SHH (n=21; 4.8% ±3.3%; p=0.014). In univariate analyses, OSpostPD was better with older age at diagnosis (p=0.037), female gender (p=0.008), and metastatic site of PD compared to local or combined sites of PD (p<0.001). Conclusions: Children with recurrent/refractory AT/RT have dismal outcomes. Older age at diagnosis, female gender, TYR group, and metastatic site of PD were associated with relatively longer survival in our study.

Medulloblastoma (MB) is the most common malignant brain tumor of childhood and is reported to have a low mutational burden. However, in this study, we identified nine MBs with high mutational burden by next generation sequencing. Of them, two had canonical mutations in the POLE proof-reading domain, where a large proportion of mutations in these tumor genomes contributed to signature 10. We report very rare incidences of hypermutation in MB and mechanisms driving mutagenesis. Strikingly, of the four known molecular subgroups in MB—-SHH, WNT, Group 3, and Group 4—both the POLE-mutated MBs belonged to the SHH subgroup.

Background Disruption of critical cell cycle regulators is a potential therapeutic target for brain tumors in children and adolescents. The aim of this study was to determine the maximum tolerated dose (MTD) and describe toxicities related to palbociclib, a selective cyclin dependent kinase 4/6 (CDK4/6) inhibitor in pediatric patients with progressive/refractory brain tumors with intact retinoblastoma protein. Methods Palbociclib was administered orally starting at 50 mg/m2 daily for the first 21 days of a 28 day course. Dose escalation was according to the Rolling-6 statistical design in less heavily (Stratum I) and heavily pretreated (Stratum II) patients, and MTD was determined separately for each group. Pharmacokinetic studies were performed during the first course, and pharmacodynamic studies were conducted to evaluate relationships between drug levels and toxicities. Pharmacogenetic analyses were based on pre-treatment samples. Results A total of 21 patients were enrolled on Stratum I and 14 patients on Stratum II. The MTD for both strata was 75 mg/m2. Palbociclib absorption (mean Tmax between 4.9 and 6.6 h) and elimination (mean half-life between 11.3 and 19.5 h) were assessed. The most common toxicity was myelosuppression. Higher palbociclib exposure was associated with grade 3/4 neutropenia and leukopenia. No patients had an objective response to palbociclib therapy. Conclusions Palbociclib was safely administered to children and adolescents at a dosage of 75 mg/m2 for 21 consecutive days followed by 7 days of rest in both strata. Future studies will be required to establish its optimal utilization in pediatric patients with brain tumors.