PURPOSE Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. PATIENTS AND METHODS We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E–mutated glioma treated with BRAF inhibition across 29 centers from multiple countries. RESULTS Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy ( P < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively ( P = .02). CONCLUSION Use of BRAF inhibition results in robust and durable responses in BRAF V600E–mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.

SPBT seem to be an entity defined by a) one tumor in the suprasellar and another in the pineal region, b) GCT with predominance of PG, but not exclusively, and c) MRI and endoscopy without any dissemination. The presence of two tumors does not indicate dissemination; SPBT were non-disseminated but focal tumors, and spinal radiotherapy was not necessary.

BACKGROUND Only few data are available on treatment-associated behavior of distinct rare CNS-embryonal tumor entities previously treated as “CNS-primitive neuroectodermal tumors” (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumor with multi-layered rosettes (ETMR) are needed for development of differentiated treatment strategies. METHODS Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n=307). Additional cases (n=66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n=292) were descriptively analyzed. RESULTS DNA methylation profiling of “CNS-PNET” classified 58(19%) cases as ETMR, 57(19%) as HGG, 36(12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63%±7%, OS: 85%±5%, n=63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18%±6% and 22%±7%, and 5-year OS of 24%±6% and 25%±7%, respectively. CONCLUSION The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk-CSI based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments.

Atypical teratoid/rhabdoid tumor (AT/RT) is a highly aggressive and uncommon neoplasm of the central nervous system that usually occurs in children less than 2 years of age. It is characterized by deletions and/or mutations of the INI1 tumor suppressor gene located in chromosome band 22q11.2. We performed cytogenetic and molecular studies of an AT/RT on a 15-month-old boy. The tumor showed a complex karyotype with one cell line showing monosomy 22 and another near-tetraploid one with additional chromosomal abnormalities, involving chromosomes 2, 3, 5, 6, and Y, which had not been previously described. Sequence analysis of the tumor did not identify mutations of the INI1 gene. The karyotypic evolution observed in this tumor suggests that INI1 has an epigenetic role in the maintenance of genome integrity by affecting genes, which produces mitotic defects and polyploidy. Finally, this case is the first to support the theory that loss of INI1 could induce the chromosomal instability that might be responsible for the genesis of this tumor.

BackgroundMany studies have demonstrated in the last years that once medulloblastoma has recurred, the probability of regaining tumor control is poor despite salvage therapy. Although re-irradiation has an emerging role in other relapsed brain tumors, there is a lack of strong data on re-irradiation for medulloblastoma. MethodsThis is a retrospective cohort study of patients aged 18 years or under, treated at least by a second course of external beam for recurrence medulloblastoma at Garrahan Hospital between 2009 and 2020. Twenty-four patients met eligibility criteria for inclusion. All patients received upfront radiotherapy as part of the curative-intent rst radiotherapy, either craniospinal irradiation (CSI) followed by posterior fossa boost in 20 patients or focal posterior fossa radiation in 4 infants. The second course of radiation consisted of CSI in 15 and focal in 9. The 3-year post rst failure OS (50% vs. 0%; p = 0.0010) was signi cantly better for children who received re-CSI compared to children who received focal re-irradiation. Similarly, the 3-year post-re-RT PFS (31% vs. 0%; p = 0.0005) and OS (25% vs. 0%; p = 0.0003) was signi cantly improved for patients who received re-CSI compared to patients who received focal re-irradiation. No symptomatic intratumoral haemorrhagic events or symptomatic radionecrosis were observed. Survivors fell within mild to moderate intellectual disability range, with a median IQ at last assessment of 58 (range 43-69). ConclusionRe-irradiation with CSI is a safe and effective treatment for children with relapsed medulloblastoma; improves disease control and survival compared with focal re-irradiation. However this approach carries a high neurocognitive cost.All radiation treatments were given at Garrahan Hospital, Buenos Aires, Argentina. Photon external beam therapy was used for all patients. All but four patients received CSI as part of the rst radiation course (RT1), followed by a boost to the entire posterior fossa. Standard risk (SR) patients received CSI 23.4Gy followed by posterior fossa boost 30.6Gy and high-risk (HR) patients received CSI 36Gy followed by posterior fossa boost 19.8Gy. Except for one, all of them received maintenance platinum based chemotherapy; SR as per ACNS0331 (N=2) and COG 9961 (regimen A=3, regimen B= 6); HR as per ACNS0332 (Regimen A=4, Regimen B=4). Four patients received upfront posterior fossa radiotherapy (54 Gy) due to the young age at diagnosis as per standard of care treatment administered between 2002 and 2020 at Hospital Garrahan, based on a modi ed POG-9934 strategy (15). Upon recurrence, most patients with brain solitary lesions were offered surgery followed by metronomic chemotherapy and a second course of irradiation (RT2), while those with multifocal disease received chemotherapy followed by radiotherapy. CSI was administered using standard beam's eye-view treatment planning techniques. Boost treatment and focal radiotherapy was administered using 3D-conformal radiation therapy methods. Hypofractionated stereotactic radiother...