Intracranial Germinoma in Two Caucasian American Siblings With Autism Spectrum Disorder.

Intracranial germ cell tumors (IGCTs) comprise 3% to 5% of all pediatric brain tumors in the West, with a significantly higher prevalence in Asia. Although these tumors are histologically diverse, repeated somatic variants have been demonstrated. Chromosomal aneuploidies, such as Klinefelter and Down syndromes, are associated with IGCTs, but no familial germline tumor syndromes are currently known. Here, we report the novel case of 2 American siblings with underlying autism spectrum disorder who developed intracranial germinoma within months of each other, in the absence of external risk factors. Extensive genetic testing was performed, including karyotyping, chromosomal microarray, and whole exome and whole genome sequencing, and did not identify any variants accounting for the phenotypes. Despite the absence of overlapping variants, a recent retrospective review demonstrated a threefold greater prevalence of autism spectrum disorder in patients with intracranial germinoma compared with national prevalence. This report highlights the complexity of tumor development, as well as the need for further research regarding IGCTs in a neurodivergent population.

Central Nervous System Tumor With BCL6 Corepressor Internal Tandem Duplication: Treatment Course of a Long-term Survivor.

Central nervous system (CNS) tumor with BCL6 corepressor (BCOR) internal tandem duplication (ITD) is a newly described CNS tumor, characterized by in-frame ITDs of the BCOR gene. There is no standard practice regarding the management of this tumor. We report the clinical course of a 6-year-old boy who presented to the hospital with worsening headaches. Computed tomography scan showed a large right-sided parietal supratentorial mass and brain magnetic resonance imaging confirmed a 6×8×6.7 cm lobulated, solid but heterogeneous mass in the right parieto-occipital region. While initial pathology suggested a WHO grade 3 anaplastic meningioma, additional investigation with molecular analysis confirmed the diagnosis of high-grade neuroepithelial tumor with BCOR exon 15 ITD. This diagnosis was renamed CNS tumor with BCOR ITD in the 2021 WHO CNS tumor classification. The patient received 54 Gy of focal radiation and has no evidence of disease recurrence after 48 months from the end of treatment. As this is a newly discovered entity with only a few previous reports in the scientific literature, this report presents a unique treatment for this CNS tumor compared with those previously described.

Juvenile Xanthogranuloma of the Pancreas in a Pediatric Patient Mimicking Pancreatic Neoplasm With High CA 19-9: Case Report and Literature Review.

Juvenile xanthogranuloma (JXG) is a rare, non-Langerhans cell histiocytosis. It is usually a benign and self-limiting condition. The most common sites are skin and soft tissue. Pancreatic involvement is extremely rare. We present an unusual case of a 13-month-old female child with JXG of the pancreas and elevated cancer antigen 19-9. JXG should always be considered as a differential diagnosis for pediatric patients presenting with a pancreatic mass, solid and/or cystic in nature. Therefore, avoiding unnecessary invasive diagnostic procedures.

Ongoing Response in a Multiply Relapsed Metastatic Posterior Fossa Ependymoma A After Vorinostat and Concomitant Irradiation.

Posterior fossa ependymomas A confer the worst prognosis among all subtypes. They demonstrate distinct epigenetic changes, which can be targeted with epigenetic modifiers like histone deacetylase inhibitors (Vorinostat). We describe a 3-year-old male diagnosed with a posterior fossa ependymoma who had a number of recurrences requiring multimodal therapy. Molecular analysis demonstrated a BCL-6 corepressor mutation, and methylation profiling matched with posterior fossa ependymomas A. He received craniospinal irradiation and focal boost with Vorinostat. Serial imaging after irradiation revealed a progressively decreasing tumor burden with nearly complete resolution of disease at 15 months. Histone deacetylase inhibitors demonstrate promise in treatment of carefully selected cases of ependymoma.

Pneumocephalus in a Pediatric Patient with Glioma Receiving Trametinib.

The mitogen-activated protein kinase (MAPK) pathway consists of the Ras/Raf/MEK/ERK signaling cascade, and its upregulation plays a major role in the pathogenesis of pediatric astrocytomas and molecular inhibitors of this pathway including trametinib and dabrafenib have been tested in early-phase clinical trials and used by pediatric oncologists in children with BRAF-mutated gliomas. We report a clinical case where a child with progressive BRAF-mutated glioma developed an uncommon and difficult to manage complication - pneumocephalus from intracranial air entry and trapping through dehisced surgical wounds and preexisting skull burr holes. The patient's wound breakdown coincided with skin toxicity from MEK inhibitor therapy. With increasing use of targeted molecular inhibitors in pediatric neuro-oncology, this case illustrates the potentially complicated course of MEK inhibitor therapy in patients with scalp surgical wounds and burr holes that were placed within few weeks from initiation of drug therapy, especially if patients have additional factors that can contribute to poor wound healing such as use of steroids and malnutrition.

Use of hyperbaric oxygen therapy in pediatric neuro-oncology: a single institutional experience.

INTRODUCTION: Hyperbaric oxygen therapy (HBOT) has been utilized as adjunctive treatment of CNS tumors and for radiation necrosis (RN) with reported success. The safety and efficacy in pediatric patients is less understood. METHODS: Seven patients (ages 10-23 years, six females) were treated with HBOT (3-60 sessions) for either RN (n = 5) or tumor-associated edema (n = 2). Tumor diagnosis included low-grade glioma (n = 4, two with neurofibromatosis type 1), meningioma (n = 1), medulloblastoma (n = 1) and secondary high grade glioma (n = 1). Prior therapies included: surgery (n = 4), chemotherapy (n = 4) and radiation (N = 5: four focal, one craniospinal). Three underwent biopsy: one confirming RN, one high-grade glioma, and one low-grade glioma. Patients were assessed for clinical and radiographic changes post HBOT. RESULTS: Median time to clinical and radiographic presentation was 8.5 months (range 6 months-11 years) in those who had prior radiation. Clinical improvement after HBOT (median: 40 sessions) was observed in four of seven patients. Symptoms were stable in two and worsened in one patient. Radiographic improvement was seen in four patients; three had radiographic disease progression. In the subgroup treated for presumed and biopsy-confirmed RN (n = 5), four of five (80%) had clinical and radiographic improvement. There were no long-term adverse events due to HBOT. CONCLUSIONS: HBOT is safe and well-tolerated in pediatric and young adult patients with CNS tumors. Clinical and radiographic improvements were observed in over half of patients. Clinical trials are needed to establish safety and efficacy of HBOT as adjunct therapy in pediatric CNS tumors.

Nivolumab in the Treatment of Recurrent or Refractory Pediatric Brain Tumors: A Single Institutional Experience.

Successful use of immune checkpoint inhibitors in a variety of cancers has generated interest in using this approach in pediatric brain tumors. We performed a retrospective review of 10 consecutive children (6 boys, 4 girls; ages, 2 to 17 y), with recurrent or refractory pediatric brain tumors (5 high-grade glioma, 1 low-grade glioma, pineoblastoma, medulloblastoma, ependymoma, and CNS embryonal tumor, NOS) treated at Rady Children's Hospital San Diego from 2015 to 2017 with the immune checkpoint inhibitor nivolumab (3 mg/kg every 2 wk). Eight of 10 patients received prior chemotherapy and 9 radiation therapy. Nine patients had radiographic disease progression (median, 2.5 doses). Median time to progression was 5.5 weeks (1.6 to 24 wk). Three patients (2 with high-grade glioma, 1 with CNS embryonal tumor NOS) showed a partial response to treatment at the primary tumor site and 2 of 3 had progression of metastatic disease. Grade 2 toxicities were observed without dose limiting side effects. Tumor mutation burden (TMB) was low to intermediate (median, 1.3; range, 0 to 6.3). Median survival for PD-L1 positive patients was 13.7 weeks versus 4.2 weeks for PD-L1 negative patients (ρ=0.08) nivolumab was well tolerated in our series of pediatric recurrent brain tumors with some transient partial responses in patients with positive PD-L1 expression and higher TMB. Our findings suggest that the use of immune checkpoint inhibitors in pediatric brain tumor patients should be limited to those with elevated PD-L1 expression and TMB.

Single-agent bevacizumab in the treatment of recurrent or refractory pediatric low-grade glioma: A single institutional experience.

INTRODUCTION: Bevacizumab-based therapy has been demonstrated to be effective in the treatment of refractory or recurrent pediatric low-grade glioma (LGG); however its efficacy as a single agent is less understood. METHODS: We report our experience with single-agent bevacizumab for the treatment of recurrent or refractory LGG treated with either standard 2 week dosing (10 mg/kg/dose every 2 weeks) or with a standard 2 week dosing followed by an increased interval dosing (10 mg/kg/dose every 4 weeks). RESULTS: From 2012 to 2017, 15 patients (five males and 10 females) with recurrent/refractory LGG (nine suprasellar, three thalamic, two brainstem, and one intramedullary spinal cord) were treated with a total of 156 doses of bevacizumab (115 every 2 week dosing, 41 every 4 week dosing, median 10 doses). Patients were refractory to a median of one nonsurgical therapy (range 0-3) prior to treatment with bevacizumab. Twelve of 15 demonstrated radiographic response (three complete, nine partial, and three stable disease). Significant clinical responses including improved visual fields (four), cranial neuropathy (three3), strength (seven), and gait (two) were observed. Bevacizumab was discontinued in 12 patients (resolution, one; disease stability, seven; progression, two; toxicity, one; and other, one) and three patients continue to receive monthly bevacizumab. Eleven patients eventually had radiographic progression (median 5 months, range 0.5-31) without clinical progression, and four of five receiving bevacizumab rechallenge had lpartial response. CONCLUSION: Single-agent bevacizumab is efficacious in the management of recurrent or refractory pediatric LGG with radiographic and clinical responses similar to those reported for bevacizumab-based therapies.

Molecular insights into malignant progression of atypical choroid plexus papilloma.

Choroid plexus tumors are rare pediatric neoplasms ranging from low-grade papillomas to overtly malignant carcinomas. They are commonly associated with Li-Fraumeni syndrome and germline TP53 mutations. Choroid plexus carcinomas associated with Li-Fraumeni syndrome are less responsive to chemotherapy, and there is a need to avoid radiation therapy leading to poorer outcomes and survival. Malignant progression from choroid plexus papillomas to carcinomas is exceedingly rare with only a handful of cases reported, and the molecular mechanisms of this progression remain elusive. We report a case of malignant transformation of choroid plexus papilloma to carcinoma in a 7-yr-old male with a germline TP53 mutation in which we present an analysis of molecular changes that might have led to the progression based on the next-generation genetic sequencing of both the original choroid plexus papilloma and the subsequent choroid plexus carcinoma. Chromosomal aneuploidy was significant in both lesions with mostly gains present in the papilloma and additional significant losses in the carcinoma. The chromosomal loss that occurred, in particular loss of Chromosome 13, resulted in the losses of two critical tumor suppressor genes, RB1 and BRCA2, which might play a possible role in the observed malignant transformation.

Clinical Impact of Next-generation Sequencing in Pediatric Neuro-Oncology Patients: A Single-institutional Experience.

The implementation of next-generation sequencing (NGS) in pediatric neuro-oncology may impact diagnosis, prognosis, therapeutic strategies, clinical trial enrollment, and germline risk. We retrospectively analyzed 58 neuro-oncology patients (31 boys, 27 girls, average age 7.4 years) who underwent NGS tumor profiling using a single commercially available platform on paraffin-embedded tissue obtained at diagnosis (20 low-grade gliomas, 12 high-grade gliomas, 11 embryonal tumors, four ependymal tumors, three meningeal tumors, and eight other CNS tumors) from May 2014 to December 2016. NGS results were analyzed for actionable mutations, variants of unknown significance and clinical impact. Seventy-four percent of patients (43 of 57) had actionable mutations; 26% had only variants of uncertain significance (VUS). NGS findings impacted treatment decisions in 55% of patients; 24% were given a targeted treatment based on NGS findings. Seven of eight patients with low-grade tumors treated with targeted therapy (everolimus, trametinib, or vemurafenib) experienced partial response or stable disease. All high-grade tumors had progressive disease on targeted therapy. Forty percent of patients had a revision or refinement of their diagnosis, and nine percent of patients were diagnosed with a previously unconfirmed cancer predisposition syndrome. Turnaround time between sample shipment and report generation averaged 13.4 ± 6.4 days. One sample failed due to insufficient DNA quantity. Our experience highlights the feasibility and clinical utility of NGS in the management of pediatric neuro-oncology patients. Future prospective clinical trials using NGS are needed to establish efficacy.