Dual white matter pathology in fetal holoprosencephaly featuring concurrent malformative and destructive features: A case series.

Holoprosencephaly (HPE) is a classic brain malformation involving defective forebrain induction and patterning. Cases of HPE bearing white matter abnormalities have not been well documented, with only rare cases exhibiting hypoxic-ischemic damage. However, neuroradiologic studies of HPE using diffusion tensor imaging have suggested the presence of white matter architectural disarray. Described in this case series are the clinicopathologic features of 8 fetuses with HPE who underwent autopsy at BC Children's Hospital. All 8 cases exhibited subacute to chronic, periventricular leukomalacia (PVL)-like white matter pathology, with 7 of 8 cases also demonstrating aberrant white matter tracts, one of which manifested as a discreet bundle crossing the midline within the ventral aspects of the fused deep gray nuclei. In 6 of these 7 cases, the PVL-like pathology resided within this aberrant white matter tract. Original workup, alongside an additional HPE-focused next-generation sequencing panel identified a likely etiologic cause for the HPE in 4 cases, with an additional 2 cases exhibiting a variant of unknown significance in genes previously suggested to be involved in HPE. Despite our in-depth clinicopathologic and molecular review, no unifying etiology was definitively identified among our series of fetal HPE bearing this unusual pattern of white matter pathology.

Are CUL3 variants an underreported cause of congenital heart disease?

Complex heart defects (CHD) are a common malformation associated with disruption of developmental pathways. The Cullin-RING ligases (CRLs) are multi-subunit E3 ubiquitin ligases in which Cullin 3 (CUL3) serves as a scaffolding subunit. Heterozygous CUL3 variants have been associated with neurodevelopmental disorders and pseudohypoaldosteronism type IIE. We report a fetus with CHD and a de novo CUL3 variant (NM_003590.4:c.[1549_1552del];[=], p.(Ser517Profs*23)) and review CUL3 variants reported with CHD. We postulate that CUL3 variants predispose to CHD and hypothesize mechanisms of pathogenesis.

Establishing a Statewide Wastewater Surveillance System in Response to the COVID-19 Pandemic: A Reliable Model for Continuous and Emerging Public Health Threats.

CONTEXT: The COVID-19 pandemic sparked efforts across the globe to implement wastewater surveillance for SARS-CoV-2. PROGRAM: New York State (NYS) established the NYS Wastewater Surveillance Network to estimate the levels of COVID-19 community risk and to provide an early indication of SARS-CoV-2 transmission trends. The network is designed to provide a better understanding of public health burdens and to assist health departments to respond effectively to public health threats. IMPLEMENTATION: Wastewater surveillance across NYS increased from sporadic and geographically spare in 2020 to routine and widespread in 2022, reaching all 62 counties in the state and covering 74% of New Yorkers. The network team focused on engaging local health departments and wastewater treatment plants to provide wastewater samples, which are then analyzed through a network-affiliated laboratory. Both participating local health departments and wastewater treatment plants receive weekly memos on current SARS-CoV-2 trends and levels. The data are also made publicly available at the state dashboard. EVALUATION: Using standard indicators to evaluate infectious disease surveillance systems, the NYS Wastewater Surveillance Network was assessed for accuracy, timeliness, and completeness during the first year of operations. We observed 96.5% sensitivity of wastewater to identify substantial/high COVID-19 transmission and 99% specificity to identify low COVID-19 transmission. In total, 80% of results were reported within 1 day of sample collection and were published on the public dashboard within 2 days of sample collection. Among participating wastewater treatment plants, 32.5% provided weekly samples with zero missing data, 31% missed 1 or 2 weeks, and 36.5% missed 3 or more weeks. DISCUSSION: The NYS Wastewater Surveillance Network continues to be a key component of the state and local health departments' pandemic response. The network fosters prompt public health actions through real-time data, enhancing the preparedness capability for both existing and emerging public health threats.

Operationalizing an open-source dashboard for communicating results of wastewater-based surveillance.

COVID-19 saw the expansion of public health tools to manage the pandemic. One tool that saw extensive use was the public health dashboard, web-based visualization tools that communicate information to users in easy-to-read graphics. Dashboards were widely used prior to the pandemic, but COVID-19 saw expanded use and development. To date, dashboards have become an important part of public health surveillance programs around the world helping decisionmakers use data to evaluate different public health metrics including caseloads, hospitalizations, and environmental surveillance results from testing wastewater. Wastewater surveillance provides community-based, spatially relevant data on disease trends within communities to assess the scale of infection in a region, which makes it an excellent candidate for dashboard development to improve public health. We developed a dashboard for New York State's wastewater surveillance program using open-source, reproducible web programming. The dashboard we developed has been used for the COVID-19 response in New York, and our methods can be adapted to other programs and pathogens. We provide:•descriptions of how the dashboard was developed and maintained•specific guidance for reproducing our dashboard in other areas and for other pathogens•fully reproducible code with step-by-step instructions for researchers and professionals to make their own data dashboards.

A Case of Primary Intracranial Sarcoma, DICER1-Mutant, in a Child with a Germline DICER1 Mutation.

DICER1 syndrome is a tumor predisposition syndrome caused by abnormal micro-RNA processing which leads to a variety of benign and malignant neoplasms in many organ systems, including the central nervous system. This paper reports the case of a primary intracranial sarcoma, DICER1-mutant, in a patient with a germline DICER1 variant thought most likely to be de novo. The patient is a ten-year-old boy who presented acutely with altered level of consciousness, emesis, and left-sided weakness. Imaging revealed a large right frontal hemorrhagic lesion, which was urgently debulked. Histology demonstrated a high-grade sarcomatous lesion. Molecular studies revealed compound heterozygous DICER1 variants (a frame shift insertion and a missense mutation), and a KRAS missense mutation. The final pathologic diagnosis was rendered to be "primary intracranial sarcoma, DICER1-mutant". Germline genetic testing revealed that the patient possessed a germline DICER1 variant (parental testing was negative). A dramatic reduction in tumor size was precipitated via chemotherapy (ifosfamide, carboplatin, and etoposide) and radiotherapy (focal proton beam therapy). There was no evidence of residual disease at the primary site at the end of the therapy.

Characterization of Switch/Sucrose Nonfermenting Complex Proteins and Nestin Expression in a Cohort of Pediatric Central Nervous System Tumors.

Tumors of the central nervous system (CNS) in pediatric patients have undergone significant diagnostic refinement through the use of immunohistochemistry (IHC) and molecular techniques. The utility of these novel IHC antibodies has been demonstrated with the inactivation of the switch/sucrose nonfermenting (SWI/SNF) chromatin-remodeling complex in the diagnosis of atypical teratoid/rhabdoid tumors, predominantly through the loss of integrase interactor 1 (INI1; SMARCB1 ). Alternatively, these tumors may have inactivation of brahma-related gene 1 (BRG1; SMARCA4 ) in a subset of cases. The role of other SWI/SNF component proteins and their expression in pediatric brain tumors is not well established. Nestin, an intermediate filament, has been shown to be present in some pediatric CNS tumors, but of uncertain diagnostic and prognostic significance. We sought to explore the immunohistochemical expression profile for common SWI/SNF subunits and nestin in a pediatric CNS tumor cohort. Using a 118-sample tissue microarray, we performed IHC for INI1, BRG1, brahma (BRM), ARID1A, ARID1B, polybromo 1, and nestin. In 19 cases, INI1 was lost and BRG1 was lost in 2 cases. Interestingly, 6 cases originally diagnosed as primitive neuroectodermal tumors showed isolated loss of BRM. Other SWI/SNF proteins did not provide further diagnostic resolution. Nestin was positive in 76.2% of INI1/BRG1-deficient tumors, compared with 29.1% in INI1/BRG1-intact tumors yielding a sensitivity of 76.2%, specificity of 68.0%, and a P value of <0.001, but nestin positivity did not correlate specifically with poor outcomes. In conclusion, we confirm the utility of BRG1 IHC in the workup of pediatric CNS tumors, which may facilitate a difficult diagnosis when conventional markers are inconclusive, or as a first-line marker in cases where intraoperative smears are suggestive of atypical teratoid/rhabdoid tumor. Although nestin expression was associated with SWI/SNF inactivation, it did not yield statistically significant diagnostic or prognostic information in our study. Interestingly, we identified 6 tumors with isolated BRM IHC loss, the significance of which is uncertain but warrants further investigation.

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.

Cardio PyMEA: A user-friendly, open-source Python application for cardiomyocyte microelectrode array analysis.

Open source analytical software for the analysis of electrophysiological cardiomyocyte data offers a variety of new functionalities to complement closed-source, proprietary tools. Here, we present the Cardio PyMEA application, a free, modifiable, and open source program for the analysis of microelectrode array (MEA) data obtained from cardiomyocyte cultures. Major software capabilities include: beat detection; pacemaker origin estimation; beat amplitude and interval; local activation time, upstroke velocity, and conduction velocity; analysis of cardiomyocyte property-distance relationships; and robust power law analysis of pacemaker spatiotemporal instability. Cardio PyMEA was written entirely in Python 3 to provide an accessible, integrated workflow that possesses a user-friendly graphical user interface (GUI) written in PyQt5 to allow for performant, cross-platform utilization. This application makes use of object-oriented programming (OOP) principles to facilitate the relatively straightforward incorporation of custom functionalities, e.g. power law analysis, that suit the needs of the user. Cardio PyMEA is available as an open source application under the terms of the GNU General Public License (GPL). The source code for Cardio PyMEA can be downloaded from Github at the following repository: https://github.com/csdunhamUC/cardio_pymea.

Pacemaker translocations and power laws in 2D stem cell-derived cardiomyocyte cultures.

Power laws are of interest to several scientific disciplines because they can provide important information about the underlying dynamics (e.g. scale invariance and self-similarity) of a given system. Because power laws are of increasing interest to the cardiac sciences as potential indicators of cardiac dysfunction, it is essential that rigorous, standardized analytical methods are employed in the evaluation of power laws. This study compares the methods currently used in the fields of condensed matter physics, geoscience, neuroscience, and cardiology in order to provide a robust analytical framework for evaluating power laws in stem cell-derived cardiomyocyte cultures. One potential power law-obeying phenomenon observed in these cultures is pacemaker translocations, or the spatial and temporal instability of the pacemaker region, in a 2D cell culture. Power law analysis of translocation data was performed using increasingly rigorous methods in order to illustrate how differences in analytical robustness can result in misleading power law interpretations. Non-robust methods concluded that pacemaker translocations adhere to a power law while robust methods convincingly demonstrated that they obey a doubly truncated power law. The results of this study highlight the importance of employing comprehensive methods during power law analysis of cardiomyocyte cultures.

Pathologic Skull Fracture in a Near-Term Neonate with Arthrochalasia Type Ehlers-Danlos Syndrome: A Case Report.

Background: Arthrochalasia type Ehlers-Danlos Syndrome (EDS) is a connective tissue disease characterized by severe generalized joint hypermobility, congenital bilateral hip dislocations, and recurrent joint subluxations and dislocations. Only one study has reported bone fragility resulting in fractures. The genetic abnormality underlying this disorder is a variant in the COL1A1 gene causing entire or partial loss of exon 6, resulting in defective type 1 collagen synthesis. Case Report: We report a female infant born at 35 weeks of gestation presenting with pathologic skull fracture following vaginal delivery. Genetic testing revealed a pathogenic variant in the COL1A1 gene (c.472-1G > C), consistent with arthrochalasia type EDS, reported previously. Conclusion: This report adds pathologic fractures to the phenotypic breadth of this type of EDS and reinforces the importance of including the condition on the differential diagnosis when early onset non-accidental injury or trauma is being considered.

Clinically Tractable Outcome Prediction of Non-WNT/Non-SHH Medulloblastoma Based on TPD52 IHC in a Multicohort Study.

PURPOSE: International consensus and the 2021 WHO classification recognize eight molecular subgroups among non-WNT/non-SHH (Group 3/4) medulloblastoma, representing approximately 60% of tumors. However, very few clinical centers worldwide possess the technical capabilities to determine DNA methylation profiles or other molecular parameters of high risk for group 3/4 tumors. As a result, biomarker-driven risk stratification and therapy assignment constitutes a major challenge in medulloblastoma research. Here, we identify an IHC marker as a clinically tractable method for improved medulloblastoma risk stratification. EXPERIMENTAL DESIGN: We bioinformatically analyzed published medulloblastoma transcriptomes and proteomes identifying as a potential biomarker TPD52, whose IHC prognostic value was validated across three group 3/4 medulloblastoma clinical cohorts (n = 387) treated with conventional therapies. RESULTS: TPD52 IHC positivity represented a significant independent predictor of early relapse and death for group 3/4 medulloblastoma [HRs between 3.67 and 26.7; 95% confidence interval (CI) between 1.00 and 706.23; P = 0.05, 0.017, and 0.0058]. Cross-validated survival models incorporating TPD52 IHC with clinical features outperformed existing state-of-the-art risk stratification schemes, and reclassified approximately 50% of patients into more appropriate risk categories. Finally, TPD52 immunopositivity was a predictive indicator of poor response to chemotherapy [HR, 12.66; 95% CI, 3.53-45.40; P < 0.0001], suggesting important implication for therapeutic choices. CONCLUSIONS: This study redefines the approach to risk stratification in group 3/4 medulloblastoma in global practice. Because integration of TPD52 IHC in classification algorithms significantly improved outcome prediction, this test could be rapidly adopted for risk stratification on a global scale, independently of advanced but technically challenging molecular profiling techniques.

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.

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.

Desmoplastic myxoid tumor of pineal region, SMARCB1-mutant, in young adult.

We present a young adult woman who developed a myxoid tumor of the pineal region having a SMARCB1 mutation, which was phenotypically similar to the recently described desmoplastic myxoid, SMARCB1-mutant tumor of the pineal region (DMT-SMARCB1). The 24-year-old woman presented with headaches, nausea, and emesis. Neuroimaging identified a hypodense lesion in CT scans that was T1-hypointense, hyperintense in both T2-weighted and FLAIR MRI scans, and displayed gadolinium enhancement. The resected tumor had an abundant, Alcian-blue positive myxoid matrix with interspersed, non-neoplastic neuropil-glial-vascular elements. It immunoreacted with CD34 and individual cells for EMA. Immunohistochemistry revealed loss of nuclear INI1 expression by the myxoid component but its retention in the vascular elements. Molecular analyses identified a SMARCB1 deletion and DNA methylation studies showed that this tumor grouped together with the recently described DMT-SMARCB1. A cerebrospinal fluid cytologic preparation had several cells morphologically similar to those in routine and electron microscopy. We briefly discuss the correlation of the pathology with the radiology and how this tumor compares with other SMARCB1-mutant tumors of the nervous system.

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.

Loss of BRG1 (SMARCA4) Immunoexpression in a Pediatric Non-Central Nervous System Tumor Cohort.

Malignant rhabdoid tumors and atypical teratoid/rhabdoid tumors of the central nervous system are primitive malignancies associated with a poor prognosis. These tumors have previously been characterized by inactivation of the switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complex protein integrase interactor 1 (INI1), encoded by the SMARCB1 gene. In the last decade, sporadic publications have shown that a different SWI/SNF protein, brahma-related gene 1 (BRG1), encoded by the SMARCA4 gene, is associated with a similar rhabdoid phenotype and possible germline mutation termed rhabdoid tumor predisposition syndrome type 2. We sought to determine the presence of BRG1 expression in pediatric embryonal tumors. Using a local tissue microarray consisting of 28 tumors diagnosed as having an undifferentiated, polyphenotypic, or rhabdoid morphology, expression of BRG1 by immunohistochemistry was performed. Four cases showed loss of INI1, while 3 of the remaining 24 cases demonstrated loss of BRG1. Two cases were diagnosed as soft tissue sarcomas, and 1 case was diagnosed as a small cell carcinoma of the ovary, hypercalcemic type. Survival ranged from less than 6 months after diagnosis to more than 5 years at the time of last follow-up. In conclusion, we demonstrate that BRG1 immunohistochemistry is a useful second-line immunostain for the workup of undifferentiated, polyphenotypic or rhabdoid pediatric tumors that demonstrate retained expression of INI1.

Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.

Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.