Pediatric High-Grade Gliomas (pHGG) are among the deadliest childhood brain tumors and can be associated with an underlying cancer predisposing syndrome. The thorough understanding of these syndromes can aid the clinician in their prompt recognition, leading to an informed genetic counselling for the family and to a wider understanding of the specific genetic landscape of the tumor when choosing specific therapies. In this review, we summarize the main pHGG-associated cancer predisposing conditions, providing a guide for suspecting these syndromes and referring for genetic counseling.
Abstract Tridimensional (3D) rendering of volumetric neuroimaging is increasingly been used to assist surgical management of brain tumors. New technologies allowing immersive virtual reality (VR) visualization of obtained models offer the opportunity to appreciate neuroanatomical details and spatial relationship between the tumor and normal neuroanatomical structures to a level never seen before. We present our preliminary experience with the Surgical Theatre, a commercially available 3D VR system, in 60 consecutive neurosurgical oncology cases. 3D models were developed from volumetric CT scans and MR standard and advanced sequences. The system allows the loading of 6 different layers at the same time, with the possibility to modulate opacity and threshold in real time. Use of the 3D VR was used during preoperative planning allowing a better definition of surgical strategy. A tailored craniotomy and brain dissection can be simulated in advanced and precisely performed in the OR, connecting the system to intraoperative neuronavigation. Smaller blood vessels are generally not included in the 3D rendering, however, real-time intraoperative threshold modulation of the 3D model assisted in their identification improving surgical confidence and safety during the procedure. VR was also used offline, both before and after surgery, in the setting of case discussion within the neurosurgical team and during MDT discussion. Finally, 3D VR was used during informed consent, improving communication with families and young patients. 3D VR allows to tailor surgical strategies to the single patient, contributing to procedural safety and efficacy and to the global improvement of neurosurgical oncology care.
Abstract BACKGROUND Neurofibromatosis type 1 (NF1) is autosomal dominant neurogenetic disorder characterized by progressive cutaneous, neurologic, skeletal, and neoplastic manifestations. Plexiform neurofibromas (PN) are one of the different types of neurofibromas that occur in these patients. Complete surgical resection is difficult due to the tumor infiltrative behavior. We evaluated pegylated interferon- α-2b (PI) in patients with unresectable progressive or symptomatic PN. METHODS Pediatric patients (1–21 years old) affected by unresectable PN, followed at Bambino Gesù Hospital, were treated with PI. We administered PI as a weekly subcutaneous injection at a beginning dose of 1.0 mcg/kg/wk, increased to 3.0 mcg/kg/wk if well tolerated. Paracetamol (15mg/kg) was given 30 minutes prior the dose of PI and then every 4–6 hours as needed. Patients were evaluated with Magnetic Resonance Imaging (MRI) every 12 months after treatment start in case of stable disease. RESULTS 10 patients (3 females, 7 males) were enrolled. Median age was 12 years old. The median duration of treatment was 12,6 months. Grade 3 neutropenia (30%) and increased liver transaminases level (20%) were the most common toxicity. 6/10 patients experienced an improvement about pain. 7/10 patients showed clinical response. 1/10 patient had a radiological response at MRI, 1/10 experienced progression disease and 8/10 showed a stable disease at MRI evaluation. CONCLUSIONS Our study demonstrated that PI could be a suitable treatment for unresectable PN in terms of stabilization of the tumour size due to its antitumor activity although clinical response does not correlate with radiographic changes.
Abstract Purpose: Medulloblastoma (MB), the most common childhood malignant brain tumor, has a poor prognosis in about 30% of patients. The current standard of care, which includes surgery, radiation, and chemotherapy, is often responsible for cognitive, neurologic, and endocrine side effects. We investigated whether chimeric antigen receptor (CAR) T cells directed toward the disialoganglioside GD2 can represent a potentially more effective treatment with reduced long-term side effects. Experimental Design: GD2 expression was evaluated on primary tumor biopsies of MB children by flow cytometry. GD2 expression in MB cells was also evaluated in response to an EZH2 inhibitor (tazemetostat). In in vitro and in vivo models, GD2+ MB cells were targeted by a CAR-GD2.CD28.4-1BBζ (CAR.GD2)-T construct, including the suicide gene inducible caspase-9. Results: GD2 was expressed in 82.68% of MB tumors. The SHH and G3–G4 subtypes expressed the highest levels of GD2, whereas the WNT subtype expressed the lowest. In in vitro coculture assays, CAR.GD2 T cells were able to kill GD2+ MB cells. Pretreatment with tazemetostat upregulated GD2 expression, sensitizing GD2dimMB cells to CAR.GD2 T cells cytotoxic activity. In orthotopic mouse models of MB, intravenously injected CAR.GD2 T cells significantly controlled tumor growth, prolonging the overall survival of treated mice. Moreover, the dimerizing drug AP1903 was able to cross the murine blood–brain barrier and to eliminate both blood-circulating and tumor-infiltrating CAR.GD2 T cells. Conclusions: Our experimental data indicate the potential efficacy of CAR.GD2 T-cell therapy. A phase I/II clinical trial is ongoing in our center (NCT05298995) to evaluate the safety and therapeutic efficacy of CAR.GD2 therapy in high-risk MB patients.
