Impact of trametinib on the neuropsychological profile of NF1 patients.

PURPOSE: The use of trametinib in the treatment of pediatric low-grade gliomas (PLGG) and plexiform neurofibroma (PN) is being investigated in an ongoing multicenter phase II trial (NCT03363217). Preliminary data shows potential benefits with significant response in the majority of PLGG and PN and an overall good tolerance. Moreover, possible benefits of MEK inhibitor therapy on cognitive functioning in neurofibromatosis type 1 (NF1) were recently shown which supports the need for further evaluation. METHODS: Thirty-six patients with NF1 (age range 3-19 years) enrolled in the phase II study of trametinib underwent a neurocognitive assessment at inclusion and at completion of the 72-week treatment. Age-appropriate Wechsler Intelligence Scales and the Trail Making Test (for children over 8 years old) were administered at each assessment. Paired t-tests and Reliable Change Index (RCI) analyses were performed to investigate change in neurocognitive outcomes. Regression analyses were used to investigate the contribution of age and baseline score in the prediction of change. RESULTS: Stable performance on neurocognitive tests was revealed at a group-level using paired t-tests. Clinically significant improvements were however found on specific indexes of the Wechsler intelligence scales and Trail Making Test, using RCI analyses. No significant impact of age on cognitive change was evidenced. However, lower initial cognitive performance was associated with increased odds of presenting clinically significant improvements on neurocognitive outcomes. CONCLUSION: These preliminary results show a potential positive effect of trametinib on cognition in patients with NF1. We observed significant improvements in processing speed, visuo-motor and verbal abilities. This study demonstrates the importance of including neuropsychological evaluations into clinical trial when using MEK inhibitors for patients with NF1.

Outcomes of a radiation sparing approach in medulloblastoma by subgroup in young children: an institutional review.

OBJECTIVE: To describe disease outcomes including overall survival and relapse patterns by subgroup in young pediatric patients treated for medulloblastoma with a radiation-sparing approach. METHODS: Retrospective analysis of clinical outcomes includes treatment, relapse, and salvage therapy and late effects in children treated for medulloblastoma with a radiation-sparing approach at British Columbia Children's Hospital (BCCH) between 2000 and 2020. RESULTS: There were 30 patients (median age 2.8 years, 60% male) treated for medulloblastoma with a radiation-sparing approach at BCCH. Subgroups included Sonic Hedgehog (SHH) (n = 14), group 3 (n = 7), group 4 (n = 6), and indeterminate status (n = 3). Three- and 5-year event-free survival (EFS) were 49.0% (30.2-65.4%) and 42.0% (24.2-58.9%) and overall survival (OS) 66.0% (95% CI 46.0-80.1%) and 62.5% (95% CI 42.5 and 77.2%), respectively, with a median follow-up of 9.5 years. Relapse occurred in 12/25 patients following a complete response, of whom six (group 4: n = 4; group 3: n = 1; unknown: n = 1) were successfully salvaged with craniospinal axis (CSA) RT and remain alive at a median follow-up of 7 years. Disease/treatment-related morbidity included endocrinopathies (n = 8), hearing loss n = 16), and neurocognitive abnormalities (n = 9). CONCLUSIONS: This radiation sparing treatment approach for young patients with medulloblastoma resulted in a durable cure in most patients with SHH subgroup medulloblastoma. In those patients with groups 3 and 4 medulloblastoma, relapse rates were high; however, most group 4 patients were salvaged with RT.

Outcomes of Infants and Young Children With Relapsed Medulloblastoma After Initial Craniospinal Irradiation-Sparing Approaches: An International Cohort Study.

PURPOSE: Infant and young childhood medulloblastoma (iMB) is usually treated without craniospinal irradiation (CSI) to avoid neurocognitive late effects. Unfortunately, many children relapse. The purpose of this study was to assess salvage strategies and prognostic features of patients with iMB who relapse after CSI-sparing therapy. METHODS: We assembled a large international cohort of 380 patients with relapsed iMB, age younger than 6 years, and initially treated without CSI. Univariable and multivariable Cox models of postrelapse survival (PRS) were conducted for those treated with curative intent using propensity score analyses to account for confounding factors. RESULTS: The 3-year PRS, for 294 patients treated with curative intent, was 52.4% (95% CI, 46.4 to 58.3) with a median time to relapse from diagnosis of 11 months. Molecular subgrouping was available for 150 patients treated with curative intent, and 3-year PRS for sonic hedgehog (SHH), group 4, and group 3 were 60%, 84%, and 18% (P = .0187), respectively. In multivariable analysis, localized relapse (P = .0073), SHH molecular subgroup (P = .0103), CSI use after relapse (P = .0161), and age ≥ 36 months at initial diagnosis (P = .0494) were associated with improved survival. Most patients (73%) received salvage CSI, and although salvage chemotherapy was not significant in multivariable analysis, its use might be beneficial for a subset of children receiving salvage CSI < 35 Gy (P = .007). CONCLUSION: A substantial proportion of patients with relapsed iMB are salvaged after initial CSI-sparing approaches. Patients with SHH subgroup, localized relapse, older age at initial diagnosis, and those receiving salvage CSI show improved PRS. Future prospective studies should investigate optimal CSI doses and the role of salvage chemotherapy in this population.

Treatment-responsive Holmes tremor in a child with low-pressure hydrocephalus: video case report and systematic review of the literature.

OBJECTIVE: Holmes tremor (HT) is a rare and debilitating movement disorder comprising both rest and action tremor, and it is known for its resistance to treatment. Its most common causes include ischemic or hemorrhagic insults and trauma. Mechanistically, the combined rest and action tremor is thought to require a double lesion of both the dopaminergic nigrostriatal system and the dentatorubrothalamic pathways, often near the midbrain where both pathways converge. The aim of this study was to characterize HT as a presenting sign in cases of hydrocephalus and to discuss potential pathomechanisms, clinical presentations, and treatment options. METHODS: MEDLINE and Web of Science were searched for cases of HT with hydrocephalus from database inception to August 2021, and these were compiled along with the authors' own unique case of treatment-responsive HT in a child with low-pressure obstructive hydrocephalus secondary to a tectal tumor. Patient characteristics, presenting signs/symptoms, potential precipitating factors, interventions, and patient outcomes were recorded. RESULTS: Nine patients were identified including the authors' video case report. All patients had a triventriculomegaly pattern with at least a component of obstructive hydrocephalus, and 4 patients were identified as having low-pressure hydrocephalus. Parinaud's syndrome and bradykinesia were the most commonly associated signs. Levodopa and CSF diversion were the most commonly used and effective treatments for HT in this population. This review was not registered and did not receive any funding. CONCLUSIONS: HT is a poorly understood and probably underrecognized presentation of hydrocephalus that is difficult to treat, limiting the strength of the evidence in this review. Treatment options include CSF diversion, antiparkinsonian agents, antiepileptic agents, deep brain stimulation, and MR-guided focused ultrasound, and aim toward the nigrostriatal and dentatorubrothalamic pathways hypothesized to be involved in its pathophysiology.

Low-grade diffusely infiltrative tumour (LGDIT), SMARCB1-mutant: A clinical and histopathological distinct entity showing epigenetic similarity with ATRT-MYC.

Low-grade diffusely infiltrative tumour (LGDIT), SMARCB1-mutant, is a histopathological distinct low-grade lesion encountered in older children and young adults that shows epigenetic similarity with ATRT-MYC and has the potential for malignant progression.

Targeting integrated epigenetic and metabolic pathways in lethal childhood PFA ependymomas.

Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cycle­related genes including hexokinase-2 and pyruvate dehydrogenase. Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at hexokinase-2 and pyruvate dehydrogenase, accompanied by enhanced glycolysis and TCA cycle metabolism. AMPKα-2, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT­expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.

Multi-institutional analysis of treatment modalities in basal ganglia and thalamic germinoma.

BACKGROUND: Central nervous system (CNS) germinomas are treatment-sensitive tumors with excellent survival outcomes. Current treatment strategies combine chemotherapy with radiotherapy (RT) in order to reduce the field and dose of RT. Germinomas originating in the basal ganglia/thalamus (BGTGs) have proven challenging to treat given their rarity and poorly defined imaging characteristics. Craniospinal (CSI), whole brain (WBI), whole ventricle (WVI), and focal RT have all been utilized; however, the best treatment strategy remains unclear. METHODS: Retrospective multi-institutional analysis has been conducted across 18 institutions in four countries. RESULTS: For 43 cases of nonmetastatic BGTGs, the 5- and 10-year event-free survivals (EFS) were 85.8% and 81.0%, respectively, while the 5- and 10-year overall survivals (OS) were 100% and 95.5%, respectively (one patient fatality from unrelated cause). Median RT doses were as follows: CSI: 2250 cGy/cGy(RBE) (1980-2400); WBI: 2340 cGy/cGy(RBE) (1800-3000); WVI: 2340 cGy/cGy(RBE) (1800-2550); focal: 3600 cGy (3060-5400). Thirty-eight patients (90.5%) received chemotherapy. There was no statistically significant difference in the EFS based on initial field extent (p = .84). Nevertheless, no relapses were reported in patients who received CSI or WBI. Chemotherapy alone had significantly inferior EFS compared to combined therapy (p = .0092), but patients were salvageable with RT. CONCLUSION: Patients with BGTGs have excellent outcomes and RT proved to be an integral component of the treatment plan. This group of patients should be included in future prospective clinical trials and the best RT field should be investigated further.

Trametinib therapy for children with neurofibromatosis type 1 and life-threatening plexiform neurofibroma or treatment-refractory low-grade glioma.

PURPOSE: To describe a series of children with extensive PNF or treatment refractory PLGG treated on a compassionate basis with trametinib. METHODS: We report on six patients with NF-1 treated with trametinib on a compassionate basis at British Columbia Children's Hospital since 2017. Data were collected retrospectively from the patient record. RAPNO and volumetric criteria were used to evaluate the response of intracranial and extracranial lesions, respectively. RESULTS: Subjects were 21 months to 14 years old at the time of initiation of trametinib therapy and 3/6 subjects are male. Duration of therapy was 4-28 months at the time of this report. All patients had partial response or were stable on analysis. Two patients with life-threatening PNF had a partial radiographic response in tandem with significant clinical improvement and developmental catch up. One subject discontinued therapy after 6 months due to paronychia and inadequate response. The most common adverse effect (AE) was grade 1-2 paronychia or dermatitis in 5/6 patients. There were no grade 3 or 4 AEs. At the time of this report, five patients remain on therapy. CONCLUSION: Trametinib is an effective therapy for advanced PNF and refractory PLGG in patients with NF-1 and is well tolerated in children. Further data and clinical trials are required to assess tolerance, efficacy and durability of response, and length of treatment required in such patients.

Histologic Correlates of Molecular Group 4 Pediatric Medulloblastoma: A Retrospective Canadian Review.

INTRODUCTION: The World Health Organization currently classifies medulloblastoma (MB) into four molecular groups (WNT, SHH, Group 3 and Group 4) and four histologic subtypes (classic, desmoplastic nodular, MB with extensive nodularity, and large cell/anaplastic). "Classic" MB is the most frequent histology, but unfortunately it does not predict molecular group or patient outcome. While MB may exhibit additional histologic features outside of the traditional WHO subtypes, the clinical significance of such features, in a molecular context, is unclear. METHODS: The clinicopathologic features of 120 pediatric MB were reviewed in the context of NanoString molecular grouping. Each case was evaluated for five ancillary histologic features, including: nodularity without desmoplasia (i.e., "biphasic", B-MB), rhythmic palisades, and focal anaplasia. Molecular and histological features were statistically correlated to clinical outcome using Chi-square, log-rank, and multivariate Cox regression analysis. RESULTS: While B-MB (N = 32) and rhythmic palisades (N = 12) were enriched amongst non-WNT/SHH MB (especially Group 4), they were not statistically associated with outcome. In contrast, focal anaplasia (N = 12) was not associated with any molecular group, but did predict unfavorable outcome. CONCLUSION: These data nominate B-MB as a surrogate marker of Groups 3 and particularly 4 MB, which may earmark a clinically significant subset of cases.

A case series of pediatric survivors of anaplastic pleomorphic xanthoastrocytoma.

BACKGROUND: Anaplastic pleomorphic xanthoastrocytoma (APXA) is a rare subtype of CNS astrocytoma. They are generally treated as high-grade gliomas; however, uncertainty exists regarding the optimal therapy. Here, we report on 3 pediatric cases of APXA. METHODS: Our institutional database was queried for cases of APXA and 3 cases were identified. Surgical samples were processed for methylation profiling and chromosomal microarray analysis. Methylation data were uploaded to the online CNS tumor classifier to determine methylation-based diagnoses to determine copy number variations (CNVs). RESULTS: Two patients were male, 1 female, and all were aged 12 years at diagnosis. All underwent a gross total resection (GTR) and were diagnosed with an APXA. Immunohistochemical analysis demonstrated that 2 cases were BRAF V600E positive. Methylation-based tumor classification supported the APXA diagnosis in all cases. CNV analyses revealed homozygous CKDN2A deletions in all and chromosome 9p loss in 2 cases. All patients received radiation therapy (54 Gy in 30 fractions) with concurrent temozolomide. Two patients received maintenance chemotherapy with temozolomide and lomustine for 6 cycles as per the Children's Oncology Group ACNS0423. The third patient recurred and went on to receive a second GTR and 6 cycles of lomustine, vincristine, and procarbazine. All are alive with no evidence of disease >4 years post-treatment completion (overall survival = 100%, event free survival = 67%). CONCLUSIONS: The natural history and optimal treatment of this rare pediatric tumor are not well understood. This case series supports the use of adjuvant chemoradiotherapy in the treatment of APXA. The genetic landscape may be informative for optimizing treatment and prognosis.

Clinical Outcomes and Patient-Matched Molecular Composition of Relapsed Medulloblastoma.

PURPOSE: We sought to investigate clinical outcomes of relapsed medulloblastoma and to compare molecular features between patient-matched diagnostic and relapsed tumors. METHODS: Children and infants enrolled on either SJMB03 (NCT00085202) or SJYC07 (NCT00602667) trials who experienced medulloblastoma relapse were analyzed for clinical outcomes, including anatomic and temporal patterns of relapse and postrelapse survival. A largely independent, paired molecular cohort was analyzed by DNA methylation array and next-generation sequencing. RESULTS: A total of 72 of 329 (22%) SJMB03 and 52 of 79 (66%) SJYC07 patients experienced relapse with significant representation of Group 3 and wingless tumors. Although most patients exhibited some distal disease (79%), 38% of patients with sonic hedgehog tumors experienced isolated local relapse. Time to relapse and postrelapse survival varied by molecular subgroup with longer latencies for patients with Group 4 tumors. Postrelapse radiation therapy among previously nonirradiated SJYC07 patients was associated with long-term survival. Reirradiation was only temporizing for SJMB03 patients. Among 127 patients with patient-matched tumor pairs, 9 (7%) experienced subsequent nonmedulloblastoma CNS malignancies. Subgroup (96%) and subtype (80%) stabilities were largely maintained among the remainder. Rare subgroup divergence was observed from Group 4 to Group 3 tumors, which is coincident with genetic alterations involving MYC, MYCN, and FBXW7. Subgroup-specific patterns of alteration were identified for driver genes and chromosome arms. CONCLUSION: Clinical behavior of relapsed medulloblastoma must be contextualized in terms of up-front therapies and molecular classifications. Group 4 tumors exhibit slower biological progression. Utility of radiation at relapse is dependent on patient age and prior treatments. Degree and patterns of molecular conservation at relapse vary by subgroup. Relapse tissue enables verification of molecular targets and identification of occult secondary malignancies.

Long term toxicity of intracranial germ cell tumor treatment in adolescents and young adults.

PURPOSE: The purpose of this study is to describe the long-term toxicities of intracranial germ cell tumor (IGCT) in the adolescent and young adult (AYA) population. METHODS: We report late toxicities of a multi-center cohort of AYA patients treated for IGCT between 1975 and 2015. Charts were retrospectively reviewed for hormone deficiency, ototoxicity, seizure disorder, visual deterioration, cerebrovascular events, second neoplasm, psychiatric illness, and neurocognitive impairment. Statistical analysis was performed for late toxicities to evaluate the influence of select factors. RESULTS: Our patient cohort included 112 patients with IGCTs; 84% of patients had a germinoma as opposed to a non-germinomatous germ cell tumor (NGGCT), median age at radiotherapy (RT) was 19 years, and median follow-up was 8.3 years. Of the 94 patients with germinoma, 32 (34%) received both chemotherapy and RT as part of their upfront treatment, while 62 (66%) received RT alone. All 18 patients with NGGCT received chemotherapy and RT. The most common late toxicity following IGCT treatments was physician-reported neurocognitive impairment, with a 10-year cumulative incidence (CI) of 38.5%. Ten-year CI of treatment-induced ototoxicity was 39.2% for patients who received cisplatin, compared to 3.6% for those who received carboplatin but no cisplatin (p < 0.005). Suprasellar/hypothalamic tumor location was associated with 10-year CI of treatment-induced hormone deficiency (36.1 vs 6.2%, p < 0.005). CONCLUSIONS: A significant proportion of AYAs treated for IGCTs experience late effects from treatment, including neurocognitive impairment, ototoxicity, and hormone deficiency. Suprasellar/hypothalamic tumor location and cisplatin were associated with a higher risk of treatment-induced hormone deficiency and ototoxicity, respectively.

Cancer and Tumor-Associated Childhood Stroke: Results From the International Pediatric Stroke Study.

BACKGROUND: The prevalence of cancer among children with stroke is unknown. This study sought to evaluate cancer- and tumor-associated childhood ischemic stroke in a multinational pediatric stroke registry. METHODS: Children aged 29 days to less than 19 years with arterial ischemic stroke or cerebral sinovenous thrombosis enrolled in the International Pediatric Stroke Study between January 2003 and June 2019 were included. Data including stroke treatment and recurrence were compared between subjects with and without cancer using Wilcoxon rank sum and chi-square tests. RESULTS: Cancer or tumor was present in 99 of 2968 children (3.3%) with arterial ischemic stroke and 64 of 596 children (10.7%) with cerebral sinovenous thrombosis. Among children in whom cancer type was identified, 42 of 88 arterial ischemic stroke cases (48%) had brain tumors and 35 (40%) had hematologic malignancies; 45 of 58 cerebral sinovenous thrombosis cases (78%) had hematologic malignancies and eight (14%) had brain tumors. Of 54 cancer-associated arterial ischemic stroke cases with a known cause, 34 (63%) were due to arteriopathy and nine (17%) were due to cardioembolism. Of 46 cancer-associated cerebral sinovenous thrombosis cases with a known cause, 41 (89%) were related to chemotherapy-induced or other prothrombotic states. Children with cancer were less likely than children without cancer to receive antithrombotic therapy for arterial ischemic stroke (58% vs 80%, P = 0.007) and anticoagulation for cerebral sinovenous thrombosis (71% vs 87%, P = 0.046). Recurrent arterial ischemic stroke (5% vs 2%, P = 0.04) and cerebral sinovenous thrombosis (5% vs 1%, P = 0.006) were more common among children with cancer. CONCLUSIONS: Cancer is an important risk factor for incident and recurrent childhood stroke. Stroke prevention strategies for children with cancer are needed.

Pontine gliomas a 10-year population-based study: a report from The Canadian Paediatric Brain Tumour Consortium (CPBTC).

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPG) are midline gliomas that arise from the pons and the majority are lethal within a few months after diagnosis. Due to the lack of histological diagnosis the epidemiology of DIPG is not completely understood. The aim of this report is to provide population-based data to characterize the descriptive epidemiology of this condition in Canadian children. PATIENTS AND METHODS: A national retrospective study of children and adolescents diagnosed with DIPG between 2000 and 2010 was undertaken. All cases underwent central review to determine clinical and radiological diagnostic characteristics. Crude incidence figures were calculated using age-adjusted (0-17 year) population data from Statistics Canada. Survival analyses were performed using the Kaplan-Meier method. RESULTS: A total of 163 patients with pontine lesions were identified. Central review determined one-hundred and forty-three patients who met clinical, radiological and/or histological criteria for diagnosis. We estimate an incidence rate of 1.9 DIPG/1,000,000 children/year in the Canadian population over a 10 years period. Median age at diagnosis was 6.8 years and 50.3% of patients were female. Most patients presented with cranial nerve palsies (76%) and ataxia (66%). Despite typical clinical and radiological characteristics, histological confirmation reported three lesions to be low-grade gliomas and three were diagnosed as CNS embryonal tumor not otherwise specified (NOS). CONCLUSIONS: Our study highlights the challenges associated with epidemiology studies on DIPG and the importance of central review for incidence rate estimations. It emphasizes that tissue biopsies are required for accurate histological and molecular diagnosis in patients presenting with pontine lesions and reinforces the limitations of radiological and clinical diagnosis in DIPG. Likewise, it underscores the urgent need to increase the availability and accessibility to clinical trials.

Excellent outcome of young children with nodular desmoplastic medulloblastoma treated on "Head Start" III: a multi-institutional, prospective clinical trial.

BACKGROUND: "Head Start" III, was a prospective clinical trial using intensive induction followed by myeloablative chemotherapy and autologous hematopoietic cell rescue (AuHCR) to either avoid or reduce the dose/volume of irradiation in young children with medulloblastoma. METHODS: Following surgery, patients received 5 cycles of induction followed by myeloablative chemotherapy using carboplatin, thiotepa, and etoposide with AuHCR. Irradiation was reserved for children >6 years old at diagnosis or with residual tumor post-induction. RESULTS: Between 2003 and 2009, 92 children <10 years old with medulloblastoma were enrolled. Five-year event-free survival (EFS) and overall survival (OS) rates (±SE) were 46 ±â€…5% and 62 ±â€…5% for all patients, 61 ±â€…8% and 77 ±â€…7% for localized medulloblastoma, and 35 ±â€…7% and 52 ±â€…7% for disseminated patients. Nodular/desmoplastic (ND) medulloblastoma patients had 5-year EFS and OS (±SE) rates of 89 ±â€…6% and 89 ±â€…6% compared with 26 ±â€…6% and 53 ±â€…7% for classic and 38 ±â€…13% and 46 ±â€…14% for large-cell/anaplastic (LCA) medulloblastoma, respectively. In multivariate Cox regression analysis, histology was the only significant independent predictor of EFS after adjusting for stage, extent of resection, regimen, age, and sex (P <0.0001). Five-year irradiation-free EFS was 78 ±â€…8% for ND and 21 ±â€…5% for classic/LCA medulloblastoma patients. Myelosuppression was the most common toxicity, with 2 toxic deaths. Twenty-four survivors completed neurocognitive evaluation at a mean of 4.9 years post-diagnosis. IQ and memory scores were within average range overall, whereas processing speed and adaptive functioning were low-average. CONCLUSION: We report excellent survival and preservation of mean IQ and memory for young children with ND medulloblastoma using high-dose chemotherapy, with most patients surviving without irradiation.

Intracranial growing teratoma syndrome (iGTS): an international case series and review of the literature.

PURPOSE: Intracranial growing teratoma syndrome (iGTS) is a rare phenomenon of paradoxical growth of a germ cell tumor (GCT) during treatment despite normalization of tumor markers. We sought to evaluate the frequency, clinical characteristics and outcome of iGTS in Western countries. METHODS: Pediatric patients from 22 North American and Australian institutions diagnosed with iGTS between 2000 and 2017 were retrospectively evaluated. RESULTS: From a total of 777 cases of central nervous system (CNS) GCT, 39 cases of iGTS were identified for an overall frequency of 5%. Pineal region was a more frequent location for iGTS as compared to cases of GCT without iGTS (p < 0.00001). In patients with an initial tissue diagnosis of GCT, immature teratoma was present in 50%. Serum AFP or ßhCG was detectable in 87% of patients (median values 66 ng/mL and 44 IU/L, respectively). iGTS occurred at a median of 2 months (range 0.5-32) from diagnosis, in the majority of patients. All patients underwent surgical resection, leading to gross total resection in 79%. Following surgery, all patients resumed adjuvant therapy or post treatment follow-up for GCT. At a median follow-up of 5.3 years (range 0.2-11.8), 37 (95%) of patients are alive, including 5 with stable residual mass. CONCLUSION: iGTS occurs in 5% of patients with GCT in Western countries. Tumors of the pineal region and GCT containing immature teratoma appear to be associated with a higher risk of developing iGTS. Complete surgical resection is the mainstay of treatment. Overall survival of patients developing iGTS remains favorable.

Pontine Embryonal Tumor With Multilayered Rosettes: An Autopsy Case Exhibiting Extensive Posttreatment Glial and Neuronal Maturation.

Embryonal tumor with multilayered rosettes (ETMR) is a rare and highly aggressive embryonal central nervous system tumor that primarily affects young children. It is characterized by (1) amplification of the C19MC miRNA cluster at 19q13.42 and (2) immunohistochemical tumor cell positivity for LIN28A. We describe the case of a 3-year-old girl who presented with a 2-week history of multiple neurological deficits. Based primarily on imaging findings that revealed a large pontine tumor, biopsy was not performed and the patient was clinically diagnosed with a "diffuse intrinsic pontine glioma." She was subsequently treated with radiation and concurrent adjuvant temozolomide, but unfortunately there was minimal response and the patient died 6 months after diagnosis. Autopsy revealed an ETMR that was confirmed via C19MC fluorescence in situ hybridization and LIN28 immunohistochemistry. Although widespread central nervous system dissemination was observed, large portions of the main pontine mass exhibited evidence of extensive glial and neuronal maturation (ie, differentiation). We consider this tissue "maturation" to have been induced by chemotherapy and radiation. Herein, we discuss the importance of antemortem biopsy of intrinsic pontine tumors and the clinical significance of glial and neuronal maturation post therapy in the context of ETMR.

Locoregional delivery of CAR T cells to the cerebrospinal fluid for treatment of metastatic medulloblastoma and ependymoma.

Recurrent medulloblastoma and ependymoma are universally lethal, with no approved targeted therapies and few candidates presently under clinical evaluation. Nearly all recurrent medulloblastomas and posterior fossa group A (PFA) ependymomas are located adjacent to and bathed by the cerebrospinal fluid, presenting an opportunity for locoregional therapy, bypassing the blood-brain barrier. We identify three cell-surface targets, EPHA2, HER2 and interleukin 13 receptor α2, expressed on medulloblastomas and ependymomas, but not expressed in the normal developing brain. We validate intrathecal delivery of EPHA2, HER2 and interleukin 13 receptor α2 chimeric antigen receptor T cells as an effective treatment for primary, metastatic and recurrent group 3 medulloblastoma and PFA ependymoma xenografts in mouse models. Finally, we demonstrate that administration of these chimeric antigen receptor T cells into the cerebrospinal fluid, alone or in combination with azacytidine, is a highly effective therapy for multiple metastatic mouse models of group 3 medulloblastoma and PFA ependymoma, thereby providing a rationale for clinical trials of these approaches in humans.