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BrainChild-03 is a phase 1 clinical trial delivering repeated locoregional 2nd generation B7-H3 CAR T cells with 4-1BB co-stimulation to children with central nervous system (CNS) tumors without lymphodepleting chemotherapy. The primary endpoints are feasibility and safety, with secondary endpoints of disease response and correlatives of CAR T cell activity. There are 3 arms: (A) – weekly delivery into the tumor cavity, (B) – weekly delivery into the lateral ventricle for metastatic disease, (C) – biweekly delivery into the lateral ventricle for diffuse intrinsic pontine glioma (DIPG). In total, 23/24 (96%) enrolled patients have had successful CAR T manufacturing. 16/24 patients are evaluable and have received a total of 141 intracranial CAR T cell doses. Unevaluable patients include 5 never treated and 3 who progressed prior to receiving the minimum doses to become evaluable. The most common adverse events have been headache (16/16, 100%), nausea/vomiting (12/16, 75%), and fever (10/16, 63%). There has been 1 DLT for an intratumoral hemorrhage and no cytokine release syndrome (CRS). 7 evaluable patients with DIPG (Arm C) have received a cumulative 50 infusions. 5/7 DIPG patients enrolled after progression and have a median survival of 246.5 days post-initial CAR T cell infusion, with 4/5 still alive. The 2 DIPG patients enrolled prior to progression had radiographic improvement, including 1 with improvement of a cranial nerve 6 palsy who self-withdrew from protocol therapy after 18 infusions over 12 months and 1 still on protocol therapy after 11 infusions over 6 months. DIPG patients have had increased CSF levels of proinflammatory mediators (e.g. CXCL10, CCL2, IFNg, GM-CSF, IL-12) without systemic cytokine changes. 5/7 DIPG patients had detectable CAR T cells in their CSF post-infusion. Ultimately, the preliminary experience suggests locoregional delivery of B7-H3 CAR T cells may be feasible and tolerable in children with CNS tumors, including DIPG.

OBJECTIVE Hydrocephalus may be seen in patients with multisuture craniosynostosis and, less commonly, single-suture craniosynostosis. The optimal treatment for hydrocephalus in this population is unknown. In this study, the authors aimed to evaluate the success rate of ventriculoperitoneal shunt (VPS) treatment and endoscopic third ventriculostomy (ETV) both with and without choroid plexus cauterization (CPC) in patients with craniosynostosis. METHODS Utilizing the Hydrocephalus Clinical Research Network (HCRN) Core Data Project (Registry), the authors identified all patients who underwent treatment for hydrocephalus associated with craniosynostosis. Descriptive statistics, demographics, and surgical outcomes were evaluated. RESULTS In total, 42 patients underwent treatment for hydrocephalus associated with craniosynostosis. The median gestational age at birth was 39.0 weeks (IQR 38.0, 40.0); 55% were female and 60% were White. The median age at first craniosynostosis surgery was 0.6 years (IQR 0.3, 1.7), and at the first permanent hydrocephalus surgery it was 1.2 years (IQR 0.5, 2.5). Thirty-three patients (79%) had multiple different sutures fused, and 9 had a single suture: 3 unicoronal (7%), 3 sagittal (7%), 2 lambdoidal (5%), and 1 unknown (2%). Syndromes were identified in 38 patients (90%), with Crouzon syndrome being the most common (n = 16, 42%). Ten patients (28%) received permanent hydrocephalus surgery before the first craniosynostosis surgery. Twenty-eight patients (67%) underwent VPS treatment, with the remaining 14 (33%) undergoing ETV with or without CPC (ETV ± CPC). Within 12 months after initial hydrocephalus intervention, 14 patients (34%) required revision (8 VPS and 6 ETV ± CPC). At the most recent follow-up, 21 patients (50%) required a revision. The revision rate decreased as age increased. The overall infection rate was 5% (VPS 7%, 0% ETV ± CPC). CONCLUSIONS This is the largest prospective study reported on children with craniosynostosis and hydrocephalus. Hydrocephalus in children with craniosynostosis most commonly occurs in syndromic patients and multisuture fusion. It is treated at varying ages; however, most patients undergo surgery for craniosynostosis prior to hydrocephalus treatment. While VPS treatment is performed more frequently, VPS and ETV are both reasonable options, with decreasing revision rates with increasing age, for the treatment of hydrocephalus associated with craniosynostosis.

OBJECTIVEPrevious Hydrocephalus Clinical Research Network (HCRN) retrospective studies have shown a 15% difference in rates of conversion to permanent shunts with the use of ventriculosubgaleal shunts (VSGSs) versus ventricular reservoirs (VRs) as temporization procedures in the treatment of hydrocephalus due to high-grade intraventricular hemorrhage (IVH) of prematurity. Further research in the same study line revealed a strong influence of center-specific decision-making on shunt outcomes. The primary goal of this prospective study was to standardize decision-making across centers to determine true procedural superiority, if any, of VSGS versus VR as a temporization procedure in high-grade IVH of prematurity.METHODSThe HCRN conducted a prospective cohort study across 6 centers with an approximate 1.5- to 3-year accrual period (depending on center) followed by 6 months of follow-up. Infants with premature birth, who weighed less than 1500 g, had Grade 3 or 4 IVH of prematurity, and had more than 72 hours of life expectancy were included in the study. Based on a priori consensus, decisions were standardized regarding the timing of initial surgical treatment, upfront shunt versus temporization procedure (VR or VSGS), and when to convert a VR or VSGS to a permanent shunt. Physical examination assessment and surgical technique were also standardized. The primary outcome was the proportion of infants who underwent conversion to a permanent shunt. The major secondary outcomes of interest included infection and other complication rates.RESULTSOne hundred forty-five premature infants were enrolled and met criteria for analysis. Using the standardized decision rubrics, 28 infants never reached the threshold for treatment, 11 initially received permanent shunts, 4 were initially treated with endoscopic third ventriculostomy (ETV), and 102 underwent a temporization procedure (36 with VSGSs and 66 with VRs). The 2 temporization cohorts were similar in terms of sex, race, IVH grade, head (orbitofrontal) circumference, and ventricular size at temporization. There were statistically significant differences noted between groups in gestational age, birth weight, and bilaterality of clot burden that were controlled for in post hoc analysis. By Kaplan-Meier analysis, the 180-day rates of conversion to permanent shunts were 63.5% for VSGS and 74.0% for VR (p = 0.36, log-rank test). The infection rate for VSGS was 14% (5/36) and for VR was 17% (11/66; p = 0.71). The overall compliance rate with the standardized decision rubrics was noted to be 90% for all surgeons.CONCLUSIONSA standardized protocol was instituted across all centers of the HCRN. Compliance was high. Choice of temporization techniques in premature infants with IVH does not appear to influence rates of conversion to permanent ventricular CSF diversion. Once management decisions and surgical techniques are standardized across HCRN sites, thus minimizing center effect, the observed difference in conversion rates between VSGSs and VRs is mitigated.

Generalized enchondromatosis, of which Ollier disease is the most common type, is a rare bone dysplasia characterized by multiple intraosseous tumors near growth-plate cartilage. These cartilaginous tumors have a propensity to transform into chondrosarcomas. Enchondromas of the skull base are exceedingly rare. We present the case of a patient with generalized enchondromatosis who developed a large enchondroma of the clivus, and we discuss the clinical presentation and potential treatments for this entity.