Sequential intravenous and intracerebroventricular GD2-CAR T-cell therapy for H3K27M-mutated diffuse midline gliomas.

H3K27M-mutant diffuse midline gliomas (DMGs) express high levels of the GD2 disialoganglioside and chimeric antigen receptor modified T-cells targeting GD2 (GD2-CART) eradicate DMGs in preclinical models. Arm A of the Phase I trial NCT04196413 administered one IV dose of autologous GD2-CART to patients with H3K27M-mutant pontine (DIPG) or spinal (sDMG) diffuse midline glioma at two dose levels (DL1=1e6/kg; DL2=3e6/kg) following lymphodepleting (LD) chemotherapy. Patients with clinical or imaging benefit were eligible for subsequent intracerebroventricular (ICV) GD2-CART infusions (10-30e6 GD2-CART). Primary objectives were manufacturing feasibility, tolerability, and identification of a maximally tolerated dose of IV GD2-CART. Secondary objectives included preliminary assessments of benefit. Thirteen patients enrolled and 11 received IV GD2-CART on study [n=3 DL1(3 DIPG); n=8 DL2(6 DIPG/2 sDMG). GD2-CART manufacturing was successful for all patients. No dose-limiting toxicities (DLTs) occurred on DL1, but three patients experienced DLT on DL2 due to grade 4 cytokine release syndrome (CRS). Nine patients received ICV infusions, which were not associated with DLTs. All patients exhibited tumor inflammation-associated neurotoxicity (TIAN). Four patients demonstrated major volumetric tumor reductions (52%, 54%, 91% and 100%). One patient exhibited a complete response ongoing for >30 months since enrollment. Eight patients demonstrated neurological benefit based upon a protocol-directed Clinical Improvement Score. Sequential IV followed by ICV GD2-CART induced tumor regressions and neurological improvements in patients with DIPG and sDMG. DL1 was established as the maximally tolerated IV GD2-CART dose. Neurotoxicity was safely managed with intensive monitoring and close adherence to a management algorithm.

High-grade glioma in infants and young children is histologically, molecularly, and clinically diverse: Results from the SJYC07 trial and institutional experience.

BACKGROUND: High-grade gliomas (HGG) in young children pose a challenge due to favorable but unpredictable outcomes. While retrospective studies broadened our understanding of tumor biology, prospective data is lacking. METHODS: A cohort of children with histologically diagnosed HGG from the SJYC07 trial was augmented with nonprotocol patients with HGG treated at St. Jude Children's Research Hospital from November 2007 to December 2020. DNA methylome profiling and whole genome, whole exome, and RNA sequencing were performed. These data were integrated with histopathology to yield an integrated diagnosis. Clinical characteristics and preoperative imaging were analyzed. RESULTS: Fifty-six children (0.0-4.4 years) were identified. Integrated analysis split the cohort into four categories: infant-type hemispheric glioma (IHG), HGG, low-grade glioma (LGG), and other-central nervous system (CNS) tumors. IHG was the most prevalent (n = 22), occurred in the youngest patients (median age = 0.4 years), and commonly harbored receptor tyrosine kinase gene fusions (7 ALK, 2 ROS1, 3 NTRK1/2/3, 4 MET). The 5-year event-free (EFS) and overall survival (OS) for IHG was 53.13% (95%CI: 35.52-79.47) and 90.91% (95%CI: 79.66-100.00) vs. 0.0% and 16.67% (95%CI: 2.78-99.74%) for HGG (p = 0.0043, p = 0.00013). EFS and OS were not different between IHG and LGG (p = 0.95, p = 0.43). Imaging review showed IHGs are associated with circumscribed margins (p = 0.0047), hemispheric location (p = 0.0010), and intratumoral hemorrhage (p = 0.0149). CONCLUSIONS: HGG in young children is heterogeneous and best defined by integrating histopathological and molecular features. Patients with IHG have relatively good outcomes, yet they endure significant deficits, making them good candidates for therapy de-escalation and trials of molecular targeted therapy.

Arrhythmias including atrial fibrillation and congenital heart disease in Kleefstra syndrome: a possible epigenetic link.

AIMS: Kleefstra syndrome (KS), often diagnosed in early childhood, is a rare genetic disorder due to haploinsufficiency of EHMT1 and is characterized by neuromuscular and intellectual developmental abnormalities. Although congenital heart disease (CHD) is common, the prevalence of arrhythmias and CHD subtypes in KS is unknown. METHODS AND RESULTS: Inspired by a novel case series of KS patients with atrial tachyarrhythmias in the USA, we evaluate the two largest known KS registries for arrhythmias and CHD: Radboudumc (50 patients) based on health record review at Radboud University Medical Center in the Netherlands and GenIDA (163 patients) based on worldwide surveys of patient families. Three KS patients (aged 17-25 years) presented with atrial tachyarrhythmias without manifest CHD. In the international KS registries, the median [interquartile range (IQR)] age was considerably younger: GenIDA/Radboudumc at 10/13.5 (12/13) years, respectively. Both registries had a 40% prevalence of cardiovascular abnormalities, the majority being CHD, including septal defects, vascular malformations, and valvular disease. Interestingly, 4 (8%) patients in the Radboudumc registry reported arrhythmias without CHD, including one atrial fibrillation (AF), two with supraventricular tachycardias, and one with non-sustained ventricular tachycardia. The GenIDA registry reported one patient with AF and another with chronic ectopic atrial tachycardia (AT). In total, atrial tachyarrhythmias were noted in six young KS patients (6/213 or 3%) with at least four (three AF and one AT) without structural heart disease. CONCLUSION: In addition to a high prevalence of CHD, evolving data reveal early-onset atrial tachyarrhythmias in young KS patients, including AF, even in the absence of structural heart disease.

Stereotactic radiosurgery for recurrent pediatric brain tumors: clinical outcomes and toxicity.

OBJECTIVE: Recurrence of brain tumors in children after the initial course of treatment remains a problem. This study evaluated the efficacy and safety of reirradiation using stereotactic radiosurgery (SRS) in patients with recurrent pediatric primary brain tumors. METHODS: This IRB-approved retrospective review included pediatric patients with recurrent primary brain tumors treated at Stanford University from 2000 to 2019 using frameless SRS. Time to local failure (LF) and distant intracranial failure (DIF) were measured from the date of SRS and analyzed using competing risk analysis. Overall survival (OS) and progression-free survival (PFS) were analyzed with the Kaplan-Meier method. RESULTS: In total, 37 patients aged 2-24 years (median age 11 years at recurrence) were treated for 48 intracranial tumors. Ependymoma (38%) and medulloblastoma (22%) were the most common tumor types. The median (range) single fraction equivalent dose of SRS was 16.4 (12-24) Gy. The median (range) follow-up time was 22.9 (1.5-190) months. The median OS of all patients was 36.8 months. Eight of 40 (20%) lesions with follow-up imaging locally recurred. The 2-year cumulative incidence of LF after reirradiation with SRS was 12.8% (95% CI 4.6%-25.4%). The 2-year cumulative incidence of DIF was 25.3% (95% CI 12.9%-39.8%). The median PFS was 18 months (95% CI 8.9-44). Five (10.4%) patients developed toxicities potentially attributed to SRS, including cognitive effects and necrosis. CONCLUSIONS: Reirradiation using SRS for recurrent pediatric brain tumors appears safe with good local control. Innovations that improve overall disease control should continue because survival outcomes after relapse remain poor.

Differential newborn DNA methylation among individuals with complex congenital heart defects and childhood lymphoma.

BACKGROUND: There is emerging evidence that children with complex congenital heart defects (CHDs) are at increased risk for childhood lymphoma, but the mechanisms underlying this association are unclear. Thus, we sought to evaluate the role of DNA methylation patterns on "CHD-lymphoma" associations. METHODS: From >3 million live births (1988-2004) in California registry linkages, we obtained newborn dried bloodspots from eight children with CHD-lymphoma through the California BioBank. We performed case-control epigenome-wide association analyses (EWAS) using two comparison groups with reciprocal discovery and validation to identify differential methylation associated with CHD-lymphoma. RESULTS: After correction for multiple testing at the discovery and validation stages, individuals with CHD-lymphoma had differential newborn methylation at six sites relative to two comparison groups. Our top finding was significant in both EWAS and indicates PPFIA1 cg25574765 was hypomethylated among individuals with CHD-lymphoma (mean beta = 0.04) relative to both unaffected individuals (mean beta = 0.93, p = 1.5 × 10-12 ) and individuals with complex CHD (mean beta = 0.95, p = 3.8 × 10-8 ). PPFIA1 encodes a ubiquitously expressed liprin protein in one of the most commonly amplified regions in many cancers (11q13). Further, cg25574765 is a proposed marker of pre-eclampsia, a maternal CHD risk factor that has not been fully evaluated for lymphoma risk in offspring, and the tumor microenvironment that may drive immune cell malignancies. CONCLUSIONS: We identified associations between molecular changes present in the genome at birth and risk of childhood lymphoma among those with CHD. Our findings also highlight novel perinatal exposures that may underlie methylation changes in CHD predisposing to lymphoma.

MRI Radiogenomics of Pediatric Medulloblastoma: A Multicenter Study.

Background Radiogenomics of pediatric medulloblastoma (MB) offers an opportunity for MB risk stratification, which may aid therapeutic decision making, family counseling, and selection of patient groups suitable for targeted genetic analysis. Purpose To develop machine learning strategies that identify the four clinically significant MB molecular subgroups. Materials and Methods In this retrospective study, consecutive pediatric patients with newly diagnosed MB at MRI at 12 international pediatric sites between July 1997 and May 2020 were identified. There were 1800 features extracted from T2- and contrast-enhanced T1-weighted preoperative MRI scans. A two-stage sequential classifier was designed-one that first identifies non-wingless (WNT) and non-sonic hedgehog (SHH) MB and then differentiates therapeutically relevant WNT from SHH. Further, a classifier that distinguishes high-risk group 3 from group 4 MB was developed. An independent, binary subgroup analysis was conducted to uncover radiomics features unique to infantile versus childhood SHH subgroups. The best-performing models from six candidate classifiers were selected, and performance was measured on holdout test sets. CIs were obtained by bootstrapping the test sets for 2000 random samples. Model accuracy score was compared with the no-information rate using the Wald test. Results The study cohort comprised 263 patients (mean age ± SD at diagnosis, 87 months ± 60; 166 boys). A two-stage classifier outperformed a single-stage multiclass classifier. The combined, sequential classifier achieved a microaveraged F1 score of 88% and a binary F1 score of 95% specifically for WNT. A group 3 versus group 4 classifier achieved an area under the receiver operating characteristic curve of 98%. Of the Image Biomarker Standardization Initiative features, texture and first-order intensity features were most contributory across the molecular subgroups. Conclusion An MRI-based machine learning decision path allowed identification of the four clinically relevant molecular pediatric medulloblastoma subgroups. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Chaudhary and Bapuraj in this issue.

GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas.

Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system1. We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells2, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 106 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly3. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.

Radiomic signatures of posterior fossa ependymoma: Molecular subgroups and risk profiles.

BACKGROUND: The risk profile for posterior fossa ependymoma (EP) depends on surgical and molecular status [Group A (PFA) versus Group B (PFB)]. While subtotal tumor resection is known to confer worse prognosis, MRI-based EP risk-profiling is unexplored. We aimed to apply machine learning strategies to link MRI-based biomarkers of high-risk EP and also to distinguish PFA from PFB. METHODS: We extracted 1800 quantitative features from presurgical T2-weighted (T2-MRI) and gadolinium-enhanced T1-weighted (T1-MRI) imaging of 157 EP patients. We implemented nested cross-validation to identify features for risk score calculations and apply a Cox model for survival analysis. We conducted additional feature selection for PFA versus PFB and examined performance across three candidate classifiers. RESULTS: For all EP patients with GTR, we identified four T2-MRI-based features and stratified patients into high- and low-risk groups, with 5-year overall survival rates of 62% and 100%, respectively (P < .0001). Among presumed PFA patients with GTR, four T1-MRI and five T2-MRI features predicted divergence of high- and low-risk groups, with 5-year overall survival rates of 62.7% and 96.7%, respectively (P = .002). T1-MRI-based features showed the best performance distinguishing PFA from PFB with an AUC of 0.86. CONCLUSIONS: We present machine learning strategies to identify MRI phenotypes that distinguish PFA from PFB, as well as high- and low-risk PFA. We also describe quantitative image predictors of aggressive EP tumors that might assist risk-profiling after surgery. Future studies could examine translating radiomics as an adjunct to EP risk assessment when considering therapy strategies or trial candidacy.

Accuracy of central neuro-imaging review of DIPG compared with histopathology in the International DIPG Registry.

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) remains a clinico-radiologic diagnosis without routine tissue acquisition. Reliable imaging distinction between DIPG and other pontine tumors with potentially more favorable prognoses and treatment considerations is essential. METHODS: Cases submitted to the International DIPG registry (IDIPGR) with histopathologic and/or radiologic data were analyzed. Central imaging review was performed on diagnostic brain MRIs (if available) by two neuro-radiologists. Imaging features suggestive of alternative diagnoses included nonpontine origin, <50% pontine involvement, focally exophytic morphology, sharply defined margins, and/or marked diffusion restriction throughout. RESULTS: Among 286 patients with pathology from biopsy and/or autopsy, 23 (8%) had histologic diagnoses inconsistent with DIPG, most commonly nondiffuse low-grade gliomas and embryonal tumors. Among 569 patients with centrally-reviewed diagnostic MRIs, 40 (7%) were classified as non-DIPG, alternative diagnosis suspected. The combined analysis included 151 patients with both histopathology and centrally-reviewed MRI. Of 77 patients with imaging classified as characteristic of DIPG, 76 (99%) had histopathologic diagnoses consistent with DIPG (infiltrating grade II-IV gliomas). Of 57 patients classified as likely DIPG with some unusual imaging features, 55 (96%) had histopathologic diagnoses consistent with DIPG. Of 17 patients with imaging features suggestive of an alternative diagnosis, eight (47%) had histopathologic diagnoses inconsistent with DIPG (remaining patients were excluded due to nonpontine tumor origin). Association between central neuro-imaging review impression and histopathology was significant (p < 0.001), and central neuro-imaging impression was prognostic of overall survival. CONCLUSIONS: The accuracy and important role of central neuro-imaging review in confirming the diagnosis of DIPG is demonstrated.

Characteristics of patients ≥10 years of age with diffuse intrinsic pontine glioma: a report from the International DIPG/DMG Registry.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) generally occur in young school-age children, although can occur in adolescents and young adults. The purpose of this study was to describe clinical, radiological, pathologic, and molecular characteristics in patients ≥10 years of age with DIPG enrolled in the International DIPG Registry (IDIPGR). METHODS: Patients ≥10 years of age at diagnosis enrolled in the IDIPGR with imaging confirmed DIPG diagnosis were included. The primary outcome was overall survival (OS) categorized as long-term survivors (LTS) (≥24 months) or short-term survivors (STS) (<24 months). RESULTS: Among 1010 patients, 208 (21%) were ≥10 years of age at diagnosis; 152 were eligible with a median age of 12 years (range 10-26.8). Median OS was 13 (2-82) months. The 1-, 3-, and 5-year OS was 59.2%, 5.3%, and 3.3%, respectively. The 18/152 (11.8%) LTS were more likely to be older (P < .01) and present with longer symptom duration (P < .01). Biopsy and/or autopsy were performed in 50 (33%) patients; 77%, 61%, 33%, and 6% of patients tested had H3K27M (H3F3A or HIST1H3B), TP53, ATRX, and ACVR1 mutations/genome alterations, respectively. Two of 18 patients with IDH1 testing were IDH1-mutant and 1 was a LTS. The presence or absence of H3 alterations did not affect survival. CONCLUSION: Patients ≥10 years old with DIPG have a median survival of 13 months. LTS present with longer symptom duration and are likely to be older at presentation compared to STS. ATRX mutation rates were higher in this population than the general DIPG population.

A Pilot Study of Low-Dose Craniospinal Irradiation in Patients With Newly Diagnosed Average-Risk Medulloblastoma.

PURPOSE: Medulloblastoma is one of the most common malignant brain tumors in children. To date, the treatment of average-risk (non-metastatic, completely resected) medulloblastoma includes craniospinal radiation therapy and adjuvant chemotherapy. Modern treatment modalities and now risk stratification of subgroups have extended the survival of these patients, exposing the long-term morbidities associated with radiation therapy. Prior to advances in molecular subgrouping, we sought to reduce the late effects of radiation in patients with average-risk medulloblastoma. METHODS: We performed a single-arm, multi-institution study, reducing the dose of craniospinal irradiation by 25% to 18 Gray (Gy) with the goal of maintaining the therapeutic efficacy as described in CCG 9892 with maintenance chemotherapy. RESULTS: Twenty-eight (28) patients aged 3-30 years were enrolled across three institutions between April 2001 and December 2010. Median age at enrollment was 9 years with a median follow-up time of 11.7 years. The 3-year relapse-free (RFS) and overall survival (OS) were 79% (95% confidence interval [CI] 58% to 90%) and 93% (95% CI 74% to 98%), respectively. The 5-year RFS and OS were 71% (95% CI 50% to 85%) and 86% (95% CI 66% to 94%), respectively. Toxicities were similar to those seen in other studies; there were no grade 5 toxicities. CONCLUSIONS: Given the known neurocognitive adverse effects associated with cranial radiation therapy, studies to evaluate the feasibility of dose reduction are needed. In this study, we demonstrate that select patients with average-risk medulloblastoma may benefit from a reduced craniospinal radiation dose of 18 Gy without impacting relapse-free or overall survival. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00031590.

Compound heterozygous KCTD7 variants in progressive myoclonus epilepsy.

KCTD7 is a member of the potassium channel tetramerization domain-containing protein family and has been associated with progressive myoclonic epilepsy (PME), characterized by myoclonus, epilepsy, and neurological deterioration. Here we report four affected individuals from two unrelated families in which we identified KCTD7 compound heterozygous single nucleotide variants through exome sequencing. RNAseq was used to detect a non-annotated splicing junction created by a synonymous variant in the second family. Whole-cell patch-clamp analysis of neuroblastoma cells overexpressing the patients' variant alleles demonstrated aberrant potassium regulation. While all four patients experienced many of the common clinical features of PME, they also showed variable phenotypes not previously reported, including dysautonomia, brain pathology findings including a significantly reduced thalamus, and the lack of myoclonic seizures. To gain further insight into the pathogenesis of the disorder, zinc finger nucleases were used to generate kctd7 knockout zebrafish. Kctd7 homozygous mutants showed global dysregulation of gene expression and increased transcription of c-fos, which has previously been correlated with seizure activity in animal models. Together these findings expand the known phenotypic spectrum of KCTD7-associated PME, report a new animal model for future studies, and contribute valuable insights into the disease.

Functional and structural analysis of cytokine-selective IL6ST defects that cause recessive hyper-IgE syndrome.

BACKGROUND: Biallelic variants in IL6ST, encoding GP130, cause a recessive form of hyper-IgE syndrome (HIES) characterized by high IgE level, eosinophilia, defective acute phase response, susceptibility to bacterial infections, and skeletal abnormalities due to cytokine-selective loss of function in GP130, with defective IL-6 and IL-11 and variable oncostatin M (OSM) and IL-27 levels but sparing leukemia inhibitory factor (LIF) signaling. OBJECTIVE: Our aim was to understand the functional and structural impact of recessive HIES-associated IL6ST variants. METHODS: We investigated a patient with HIES by using exome, genome, and RNA sequencing. Functional assays assessed IL-6, IL-11, IL-27, OSM, LIF, CT-1, CLC, and CNTF signaling. Molecular dynamics simulations and structural modeling of GP130 cytokine receptor complexes were performed. RESULTS: We identified a patient with compound heterozygous novel missense variants in IL6ST (p.Ala517Pro and the exon-skipping null variant p.Gly484_Pro518delinsArg). The p.Ala517Pro variant resulted in a more profound IL-6- and IL-11-dominated signaling defect than did the previously identified recessive HIES IL6ST variants p.Asn404Tyr and p.Pro498Leu. Molecular dynamics simulations suggested that the p.Ala517Pro and p.Asn404Tyr variants result in increased flexibility of the extracellular membrane-proximal domains of GP130. We propose a structural model that explains the cytokine selectivity of pathogenic IL6ST variants that result in recessive HIES. The variants destabilized the conformation of the hexameric cytokine receptor complexes, whereas the trimeric LIF-GP130-LIFR complex remained stable through an additional membrane-proximal interaction. Deletion of this membrane-proximal interaction site in GP130 consequently caused additional defective LIF signaling and Stüve-Wiedemann syndrome. CONCLUSION: Our data provide a structural basis to understand clinical phenotypes in patients with IL6ST variants.

Relevance of Molecular Groups in Children with Newly Diagnosed Atypical Teratoid Rhabdoid Tumor: Results from Prospective St. Jude Multi-institutional Trials.

PURPOSE: Report relevance of molecular groups to clinicopathologic features, germline SMARCB1/SMARCA4 alterations (GLA), and survival of children with atypical teratoid rhabdoid tumor (ATRT) treated in two multi-institutional clinical trials. MATERIALS AND METHODS: Seventy-four participants with newly diagnosed ATRT were treated in two trials: infants (SJYC07: age < 3 years; n = 52) and children (SJMB03: age 3-21 years; n = 22), using surgery, conventional chemotherapy (infants), or dose-dense chemotherapy with autologous stem cell rescue (children), and age- and risk-adapted radiotherapy [focal (infants) and craniospinal (CSI; children)]. Molecular groups ATRT-MYC (MYC), ATRT-SHH (SHH), and ATRT-TYR (TYR) were determined from tumor DNA methylation profiles. RESULTS: Twenty-four participants (32%) were alive at time of analysis at a median follow-up of 8.4 years (range, 3.1-14.1 years). Methylation profiling classified 64 ATRTs as TYR (n = 21), SHH (n = 30), and MYC (n = 13), SHH group being associated with metastatic disease. Among infants, TYR group had the best overall survival (OS; P = 0.02). However, outcomes did not differ by molecular groups among infants with nonmetastatic (M0) disease. Children with M0 disease and <1.5 cm2 residual tumor had a 5-year progression-free survival (PFS) of 72.7 ± 12.7% and OS of 81.8 ± 11%. Infants with M0 disease had a 5-year PFS of 39.1 ± 11.5% and OS of 51.8 ± 12%. Those with metastases fared poorly [5-year OS 25 ± 12.5% (children) and 0% (infants)]. SMARCB1 GLAs were not associated with PFS. CONCLUSIONS: Among infants, those with ATRT-TYR had the best OS. ATRT-SHH was associated with metastases and consequently with inferior outcomes. Children with nonmetastatic ATRT benefit from postoperative CSI and adjuvant chemotherapy.

Outcome and molecular analysis of young children with choroid plexus carcinoma treated with non-myeloablative therapy: results from the SJYC07 trial.

BACKGROUND: Choroid plexus carcinoma (CPC) is a rare and aggressive tumor of infancy without a clear treatment strategy. This study describes the outcomes of children with CPC treated on the multi-institutional phase 2 SJYC07 trial and reports on the significance of clinical and molecular characteristics. METHODS: Eligible children <3 years-old with CPC were postoperatively stratified to intermediate-risk (IR) stratum if disease was localized or high-risk (HR) stratum, if metastatic. All received high-dose methotrexate-containing induction chemotherapy. IR-stratum patients received focal irradiation as consolidation whereas HR-stratum patients received additional chemotherapy. Consolidation was followed by oral antiangiogenic maintenance regimen. Survival rates and potential prognostic factors were analyzed. RESULTS: Thirteen patients (median age: 1.41 years, range: 0.21-2.93) were enrolled; 5 IR, 8 HR. Gross-total resection or near-total resection was achieved in ten patients and subtotal resection in 3. Seven patients had TP53-mutant tumors, including 4 who were germline carriers. Five patients experienced progression and died of disease; 8 (including 5 HR) are alive without progression. The 5-year progression-free survival (PFS) and overall survival rates were 61.5 ± 13.5% and 68.4 ± 13.1%. Patients with TP53-wild-type tumors had a 5-year PFS of 100% as compared to 28.6 ± 17.1% for TP53-mutant tumors (P = .012). Extent of resection, metastatic status, and use of radiation therapy were not significantly associated with survival. CONCLUSIONS: Non-myeloablative high-dose methotrexate-containing therapy with maximal surgical resection resulted in long-term PFS in more than half of patients with CPC. TP53-mutational status was the only significant prognostic variable and should form the basis of risk-stratification in future trials.

MR imaging features of diffuse intrinsic pontine glioma and relationship to overall survival: report from the International DIPG Registry.

BACKGROUND: This study describes imaging features of diffuse intrinsic pontine glioma (DIPG) and correlates with overall survival (OS) and histone mutation status in the International DIPG Registry (IDIPGR). METHODS: Four hundred cases submitted to the IDIPGR with a local diagnosis of DIPG and baseline MRI were evaluated by consensus review of 2 neuroradiologists; 43 cases were excluded (inadequate imaging or alternative diagnoses). Agreement between reviewers, association with histone status, and univariable and multivariable analyses relative to OS were assessed. RESULTS: On univariable analysis imaging features significantly associated with worse OS included: extrapontine extension, larger size, enhancement, necrosis, diffusion restriction, and distant disease. On central review, 9.5% of patients were considered not to have DIPG. There was moderate mean agreement of MRI features between reviewers. On multivariable analysis, chemotherapy, age, and distant disease were predictors of OS. There was no difference in OS between wild-type and H3 mutated cases. The only imaging feature associated with histone status was the presence of ill-defined signal infiltrating pontine fibers. CONCLUSIONS: Baseline imaging features are assessed in the IDIPGR. There was a 9.5% discordance in DIPG diagnosis between local and central review, demonstrating need for central imaging confirmation for prospective trials. Although several imaging features were significantly associated with OS (univariable), only age and distant disease were significant on multivariable analyses. There was limited association of imaging features with histone mutation status, although numbers are small and evaluation exploratory.