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Introduction: H3K27M-mutated diffuse intrinsic pontine glioma (DIPG) and spinal cord diffuse midline glioma (DMG) are universally lethal central nervous system (CNS) tumors in children and young adults. We previously demonstrated safety and activity of GD2.41BB.z chimeric antigen receptor T cells (CAR-Ts) at dose level 1, 1x106 GD2 CAR-T/kg (Majzner/Ramakrishna et al. Nature 2022) and reported results of dose level 2, 3x106 GD2 CAR-T/kg (Majzner et al. AACR 2022). Here, we present in depth high-dimensional analyses to define the immune states that contribute to CAR-T activity in patients. Methods: Thirteen patients (10 DIPG/3 spinal DMG; 4-30 years old; 7F/6M) were enrolled in this GD2 CAR-T phase 1 clinical trial (NCT04196413). GD2 CAR-Ts were administered to 12/13 enrolled patients. In the first cohort, CAR-Ts were administered initially intravenously (IV), followed by serial intracerebroventricular infusions (ICV; range 0-11 infusions/patient). Patient GD2 CAR-T product, peripheral blood, and cerebrospinal fluid (CSF) samples were evaluated for CAR-T expansion (qPCR; flow cytometry), cytokine signatures (Multiplex Luminex), and immune cell profiles (single cell RNA-sequencing). Data were analyzed in the context of clinical trajectory and patient response. Results: 10/12 infused subjects demonstrated clinical and/or radiographic benefit, with less systemic toxicity following ICV compared to IV infusion. CAR-T expansion was noted in the periphery and CSF of all treated patients and following serial ICV infusions. In peripheral blood, cytokine concentrations, including IFN-gamma, IL6, and CXCL9, were higher after IV compared to ICV CAR-T infusions, correlating with increased systemic inflammation. Conversely in CSF, cytokine concentrations, such as CCL2 and CXCL9, were higher following ICV compared to IV CAR-T infusions. Transcriptomic analysis was conducted on 576,199 single cells from 91 samples, including GD2 CAR-T products and patient CSF. This is the largest CAR-T dataset in CNS tumors. Patient CSF samples were dominated by T cell and myeloid populations. After IV CAR-T infusion, patient CSF exhibited an increased fraction of regulatory T cells and suppressive myeloid populations from baseline. These immune suppressive cells reduced after ICV infusion. Ongoing analyses are underway to explore the relation of these immune populations to patient response. Conclusions: H3K27M-mutated DIPG/DMG patients demonstrate continued clinical response with serial ICV GD2 CAR-T infusions, with heterogeneity in the durability of response across patients. In-depth correlative analyses profile distinct immune populations and demonstrate population shifts depending on route of administration and over the course of treatment. Key findings from these data will allow for iterative improvement in CAR-T therapies for H3K27M+ DIPG/DMG patients, providing hope to shift the paradigm of this fatal disease. Citation Format: Sneha Ramakrishna, Zinaida Good, Moksha Desai, Daniel Zamler, Rebecca Mancusi, Jasia Mahdi, Robbie Majzner, Liora Schultz, Rebecca Richards, Jennifer Kamens, Valentin Barsan, Cynthia Campen, Sonia Partap, Zachary Ehlinger, Warren Reynolds, Yiyun Chen, Mark P. Hamilton, Jennifer Moon, Christina Baggott, Michael Kunicki, Michelle Fujimoto, Amy Li, Sneha Jariwala, Sharon Mavroukakis, Emily Egeler, Ashley Jacobs, Courtney Erickson, Karen Yamabe-Kwong, Snehit Prabhu, Kara Davis, Steve Feldman, Bita Sahaf, Crystal L. Mackall, Michelle Monje. Immune signatures of GD2 CAR T cell activity in H3K27M+ diffuse midline glioma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 959.

BACKGROUND: H3K27M-mutated DMGs express high levels of the disialoganglioside GD2 and GD2-CAR T-cells (GD2-CART) regress DMG in preclinical models. METHODS: NCT04196413 is a 3 + 3 Phase I dose escalation trial testing GD2-CART in patients with biopsy-proved H3K27M DMG, with dose-limiting toxicities (DLT) considered independently for DIPG and spinal DMG (sDMG). Arm A tested escalating doses of IV GD2-CART (DL1=1e6 GD2-CART/kg; DL2=3e6 GD2-CART/kg) following lymphodepletion (LD). After the DLT period, patients with clinical and/or radiographic benefit were eligible for subsequent ICV GD2-CART infusions (10-30e6 GD2-CART) administered via Ommaya without LD. RESULTS: Twelve subjects were treated after standard radiotherapy, 7 of whom began treatment at the time of progression [n=4 DL1 (3 DIPG/1 sDMG); n=8 DL2 (6 DIPG/2 sDMG)]. No DLTs were observed on DL1. Three subjects experienced DLT on DL2 (2 DIPG/1 sDMG) due to grade-4 cytokine release syndrome (CRS). On both dose levels, all subjects exhibited transient symptoms related to on-tumor inflammation, termed Tumor Inflammation-Associated Neurotoxicity (TIAN); no DLT due to TIAN has occurred. Ten subjects experienced radiographic and/or clinical benefit after IV infusion and received subsequent ICV infusions (median=4 ICV infusions/pt, range=1-7). ICV infusions were not associated with high-grade CRS. Four patients continue to receive ICV infusions on study and have experienced continued clinical and radiographic benefit, currently 7-11 months following enrollment. Two patients (one sDMG, one DIPG) have experienced near-complete (>95%) tumor volume reduction. CONCLUSIONS: IV treatment of DIPG and sDMG with GD2-CART is safe at a dose of 1e6/kg, but associated with frequent high-grade CRS at 3e6/kg. ICV GD2-CART has been well tolerated and has mediated impressive sustained clinical benefit in some patients with DIPG/sDMG. Given these findings, we are launching a new arm to assess safety and activity and to define the recommended phase 2 dose for ICV delivery of GD2-CART without LD.

Background: H3K27M-mutated DMGs are universally lethal central nervous system tumors that express high levels of the disialoganglioside GD2. IV administered GD2-CAR T cells (GD2-CART) regress DMG in preclinical models, and locoregionally delivered CARs demonstrate enhanced activity in xenograft models of brain tumors. Methods: NCT04196413 is a 3+3 Phase I dose escalation trial testing GD2-CART in patients with H3K27M DMG, with dose-limiting toxicities (DLT) considered independently for DIPG and spinal DMG (sDMG). Arm A tested escalating doses of IV GD2-CART (DL1: 1e6 GD2-CART/kg; DL2=3e6 GD2-CART/kg) following lymphodepletion (LD). After the DLT period, patients with clinical and/or radiographic benefit were eligible for subsequent ICV GD2-CART (10-30e6 GD2-CART) administered via Ommaya catheter without LD every 4-8 weeks for a maximum of 12 doses. We previously reported early results from 4 patients treated on DL1, which demonstrated clinical activity and manageable toxicity. Here we provide updated results for DL1 and DL2. Results: Thirteen subjects were enrolled and 11 treated [n=4 DL1 (3 DIPG/1 sDMG); n=9 DL2 (7 DIPG/2 sDMG)]. Two subjects were removed prior to treatment due to rapid progression. No DLTs were observed on DL1. Three subjects experienced DLT on DL2 (2 DIPG/1 sDMG) due to grade 4 cytokine release syndrome (CRS), successfully managed with tocilizumab, anakinra, and corticosteroids. CRS occurred earlier on DL2 vs. DL1 (Day 3 vs 7). On both dose levels, all subjects exhibited transient symptoms related to on-tumor inflammation, termed Tumor Inflammation-Associated Neurotoxicity (TIAN), which was successfully managed with anakinra and, in some cases, CSF drainage and dexamethasone. No DLT due to TIAN has occurred. Ten patients have had adequate follow-up to assess benefit. Nine experienced radiographic and/or clinical benefit after IV infusion, and they received subsequent ICV GD2-CART infusions (median= 4 ICV infusions/pt, range 1-6). ICV infusions were not associated with high-grade CRS, although some subjects developed transient fever, headache, meningismus, nausea, and/or vomiting, and several subjects developed TIAN. Four patients continue to receive ICV infusions on study and have experienced continued clinical and radiographic benefit at 11+, 9.5+, 8+ and 7+ months following enrollment. A 31-year-old with sDMG has experienced a near-complete (>95%) reduction in tumor volume and a 17-year-old with DIPG experienced a near-complete (>98%) reduction in volume of a pontine tumor. Conclusions: IV treatment of DIPG and sDMG with GD2-CART is safe at a dose of 1e6/kg, but associated with unacceptable rates of high-grade CRS at 3e6/kg. ICV GD2-CART without LD, administered following a previous course of IV GD2-CART with LD, has been well tolerated and has mediated impressive sustained clinical benefit in some patients with DIPG/sDMG. Given these findings, we are launching a new arm to assess safety and activity and to define the recommended phase 2 dose for ICV delivery of GD2-CART without LD. Patients are eligible for up to 12 ICV infusions of GD2-CART administered every 4-6 weeks. Clinical benefit will be formally assessed using patient-reported outcomes. GD2-CART has the potential to transform therapy for patients with H3K27M+ DIPG/sDMG. Citation Format: Robbie G. Majzner, Jasia Mahdi, Sneha Ramakrishna, Shabnum Patel, Harshini Chinnasamy, Kristen Yeom, Liora Schultz, Valentin Barsan, Rebecca Richards, Cynthia Campen, Agnes Reschke, Angus Martin Shaw Toland, Christina Baggott, Sharon Mavroukakis, Emily Egeler, Jennifer Moon, Ashley Jacobs, Karen Yamabe-Kwong, Lindsey Rasmussen, Esther Nie, Sean Green, Michael Kunicki, Michelle Fujimoto, Zach Ehlinger, Warren Reynolds, Snehit Prabhu, Katherine E. Warren, Tim Cornell, Sonia Partap, Paul Fisher, Gerald Grant, Hannes Vogel, Bita Sahaf, Kara Davis, Steven Feldman, Michelle Monje, Crystal L. Mackall. Major tumor regressions in H3K27M-mutated diffuse midline glioma (DMG) following sequential intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT001.

Background We previously discovered high expression of the disialoganglioside GD2 on H3K27M+ gliomas and demonstrated preclinical efficacy of intravenous (IV) GD2-targeted chimeric antigen receptor (CAR) T-cells in preclinical models of H3K27M-mutated diffuse intrinsic pontine glioma (DIPG) and diffuse midline gliomas (DMGs). We are now conducting a Phase I clinical trial (NCT04196413) of autologous GD2-targeting CAR T-cells for H3K27M+ DIPG and spinal cord DMG. Here we present the results of subjects treated at dose level 1 (DL1; 1 million GD2-CAR T-cells/kg IV). Methods Four patients (3 DIPG, 1 spinal DMG; ages 4–25; 1M/3F) were enrolled at DL1. Three subjects with H3K27M+ DIPG received 1e6 GD2-CAR T-cells/kg IV on study. One patient with spinal DMG enrolled but became ineligible after manufacturing and was treated on an eIND at DL1. An Ommaya reservoir was placed in all subjects for therapeutic monitoring of intracranial pressure. Subjects underwent lymphodepletion with fludarabine/cyclophosphamide and remained inpatient for at least two weeks post-infusion. Results All subjects developed cytokine release syndrome (Grade 1–3) manifested by fever, tachycardia and hypotension. Other toxicities included ICANS (Grade 1–2) and neurological symptoms/signs mediated by intratumoral inflammation which we have termed Tumor Inflammation-Associated Neurotoxicity (TIAN). No evidence of on-target, off-tumor toxicity was observed in any patients. No dose-limiting toxicities occurred. CAR T cells trafficked to the CNS and were detected in CSF and blood. 3/4 patients exhibited marked improvement or resolution of neurological deficits and radiographic improvement. The patient treated on an eIND exhibited >90% reduction in spinal DMG volume but progressed by month 3. Re-treatment of this subject via intracerebroventricular administration resulted in a second reduction in spinal DMG volume by ~80%. Conclusions GD2-CAR T-cells at DL1 demonstrate a tolerable safety profile in patients with H3K27M+ DIPG/DMG with clear signs of T-cell expansion and activity including clinical responses.

BackgroundWe sought to define the radiologic features that differentiate neoplastic from non-neoplastic T2 hyperintensities (T2Hs) in neurofibromatosis type 1 (NF1) and identify those lesions most likely to require oncologic surveillance.MethodsWe conducted a single-center retrospective review of all available brain MRIs from 68 children with NF1 (n = 190) and 46 healthy pediatric controls (n = 104). All T2Hs identified on MRI were characterized based on location, border, shape, degree of T1 hypointensity, and presence of mass effect or contrast enhancement, and subsequently classified using newly established radiologic criteria as either unidentified bright objects (UBOs) or probable tumors. Lesion classification was pathologically confirmed in 10 NF1 cases.ResultsT2Hs were a highly sensitive (94.4%; 95% confidence interval [CI] 86.4%–98.5%) and specific (100.0%; 95% CI 92.3%–100.0%) marker for the diagnosis of NF1. UBOs constituted the majority of T2Hs (82%) and were most frequently located in cerebellar white matter, medial temporal lobe, and thalamus, where they were more likely than probable tumors to be bilateral (p < 0.001) and have nondiscrete borders (p < 0.001). Surprisingly, 57% of children with T2Hs harbored lesions classified as probable tumors, and 28% of children with probable tumors received treatment. In contrast to UBOs, probable tumors were most frequently located within the globus pallidus and medulla, and rarely occurred prior to 3 years of age.ConclusionsWith the implementation of standardized radiologic criteria, a high prevalence of brain tumors was identified in this at-risk population of children, of which nearly one-third required treatment, emphasizing the need for appropriate oncologic surveillance for patients with NF1 harboring nonoptic pathway brain tumors.

Background: Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal central nervous system tumors. We previously discovered that the disialoganglioside GD2 is highly and homogenously expressed on H3K27M+ gliomas and demonstrated that GD2 CAR T cells are effective in preclinical models (Mount/Majzner et al., Nat Med, 2018). Methods: Four subjects (3 DIPG, 1 spinal cord DMG; 4-25 yr; 1M/3F) were enrolled at DL1. Three subjects with H3K27M+ DIPG received 1e6 autologous GD2 CAR T cells/kg intravenously (IV) on study. One patient, a 25 y/o with spinal cord DMG, developed rapidly progressive disease after enrollment, resulting in complete paraparesis that led to removal from the study prior to cell infusion; she was treated on a single patient eIND with the same treatment regimen as DL1. We utilized a retroviral vector expressing a 14g2a.4-1BB.z CAR construct and an inducible iCasp9 safety switch. Manufacturing was performed in the Miltenyi Prodigy on CD4/CD8 enriched apheresis product. CAR T cells were cultured in the presence of dasatinib to improve T cell fitness (Weber et al., Science, 2021). An Ommaya reservoir was placed in all patients for monitoring of intracranial pressure (ICP). Results: We generated GD2 CAR T cell products meeting release criteria for all four patients. All subjects received lymphodepletion with cyclophosphamide and fludarabine and remained inpatient for 14+ days after infusion. All patients developed cytokine release syndrome (Grade 1-3) manifested by fever, tachycardia and hypotension, beginning 6-7 days after infusion. Due to concern for tumoral edema and increased ICP, patients were managed with conservative fluid resuscitation, and early intervention with tocilizumab and anakinra +/- corticosteroids. Other toxicities included ICANS (Grade 1-2) and neurotoxicity mediated by inflammation in sites of disease which we have termed Tumor Inflammation-Associated Neurotoxicity (TIAN). TIAN most often manifested as worsening of existing deficits, but one patient developed symptoms of increased ICP which quickly resolved upon removal of CSF via the Ommaya. No evidence of on-target, off-tumor toxicity was observed in any patients. No dose-limiting toxicities occurred.CAR T cells trafficked to the CNS and were detected in both the CSF and peripheral blood. Inflammatory cytokines including IL-6 were elevated in the CSF and blood. 3/4 patients exhibited marked improvement or resolution of neurological deficits and some radiographic improvement. The patient treated on a single patient eIND exhibited a >90% reduction in her spinal cord DMG tumor volume at two months post-infusion. Durability of the therapeutic benefit remains to be determined. Conclusions: This is the first report of GD2 CAR T cell therapy for DIPG and spinal cord DMG. Toxicities are similar to other CAR T cells with additional, manageable complications due to inflammation at CNS sites of tumor. Treatment at DL1 demonstrated a tolerable safety profile and clear signs of T cell expansion and activity including clinical responses. This approach has the potential to transform therapy for patients with H3K27M+ DIPG/DMG. Further correlative studies, including single-cell RNAseq, longer-term outcomes and results from patients on subsequent dose levels will also be presented. Citation Format: Robbie G. Majzner, Sneha Ramakrishna, Aaron Mochizuki, Shabnum Patel, Harshini Chinnasamy, Kristen Yeom, Liora Schultz, Rebecca Richards, Cynthia Campen, Agnes Reschke, Jasia Mahdi, Angus Martin Shaw Toland, Christina Baggott, Sharon Mavroukakis, Emily Egeler, Jennifer Moon, Kayla Landrum, Courtney Erickson, Lindsey Rasmussen, Valentin Barsan, John S. Tamaresis, Anne Cunniffe Marcy, Michael Kunicki, Michelle Fujimoto, Zach Ehlinger, Sreevidya Kurra, Timothy Cornell, Sonia Partap, Paul Fisher, Gerald Grant, Hannes Vogel, Bita Sahaf, Kara Davis, Steven Feldman, Crystal L. Mackall, Michelle Monje. GD2 CAR T cells mediate clinical activity and manageable toxicity in children and young adults with DIPG and H3K27M-mutated diffuse midline gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT031.

Introduction We are conducting a Phase I clinical trial utilizing chimeric antigen receptor (CAR) T-cells targeting GD2 (NCT04196413) for H3K27M-mutant diffuse intrinsic pontine glioma (DIPG) and spinal cord diffuse midline glioma (DMG). Cerebrospinal fluid (CSF) is collected for correlative studies at the time of routine intracranial pressure monitoring via Ommaya catheter. Here we present single cell RNA-sequencing results from the first 3 subjects. Methods Single cell RNA-sequencing was performed utilizing 10X Genomics on cells isolated from CSF at various time points before and after CAR T-cell administration and on the CAR T-cell product. Output was aligned with Cell Ranger and analyzed in R. Results As detailed in the Majzner et al. abstract presented at this meeting, three of four subjects treated at dose-level one exhibited clear radiographic and/or clinical benefit. We have to date completed single cell RNA-sequencing for three of these four subjects (two with benefit, one without). After filtering out low-quality signals and doublets, 89,604 cells across 3 subjects were analyzed. Of these, 4,122 cells represent cells isolated from CSF and 85,482 cells represent CAR T-cell product. Two subjects who demonstrated clear clinical and radiographic improvement exhibited fewer S100A8+S100A9+ myeloid suppressor-cells and CD25+FOXP3+ regulatory T-cells in the CSF pre-infusion compared to the subject who did not derive a therapeutic response. In one subject with DIPG who demonstrated improvement, polyclonal CAR T-cells detectable in CSF at Day +14 demonstrated enrichment of CD8A, GZMA, GNLY and PDCD1 compared to the pre-infusion CAR T-cells by trajectory analysis, suggesting differentiation toward a cytotoxic phenotype; the same subject exhibited increasing numbers of S100A8+S100A9+ myeloid cells and CX3CR1+P2RY12+ microglia over time. Further analyses will be presented as data become available. Conclusions The presence of immunosuppressive myeloid populations, detectable in CSF, may correlate to clinical response in CAR T cell therapy for DIPG/DMG.

Objective To determine the clinical variances between strokes and stroke mimics in a pediatric immunocompromised population that consists of children with central nervous system (CNS) and non-CNS malignancies and a history of solid organ transplantation. Methods We performed a retrospective cohort analysis of stroke alert activations in patients with high-grade gliomas, low-grade gliomas, atypical teratoid rhabdoid tumors, rare CNS tumors, B-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic leukemia, osteosarcoma, and solid organ transplants at St. Louis Children’s Hospital between February 2013 and September 2019. We categorized final diagnoses as strokes or stroke mimics. We classified diagnoses as a neurologic emergency if the diagnosis necessitated changes in management. Results Out of 217 stroke alerts, 31 alerts occurred for 28 patients meeting inclusion criteria. All final diagnoses constituted neurologic emergencies, including: stroke (39%), chemotherapy-related neurotoxicity (29%), tumor progression (19%), and seizures/posterior reversible encephalopathy syndrome (13%). Patients meeting inclusion criteria with strokes and stroke mimics presented similarly, with the exception of altered mental status, which was more prevalent in patients with strokes than stroke mimics (p = 0.03). One child received hyperacute thrombectomy for stroke. Only 58% of children with stroke mimics had complete resolution of their presenting neurologic symptoms. Children with strokes and stroke mimics had similar mortality incidences of 33% and 37%, respectively. Conclusions Although all acute neurologic changes in immunocompromised children are not strokes, stroke mimics in this population are neither benign nor self-limited and carry long-term neurologic morbidity and mortality. This study highlights the utility of an acute stroke evaluation infrastructure and the need for acute and long-term neurology involvement in the care of these patients.

ObjectiveTo define the radiologic features and natural history of nonoptic pathway tumors (non-OPTs) in children with neurofibromatosis type 1 (NF1).MethodsWe performed a retrospective cross-sectional analysis of 64 children with NF1 harboring 100 probable non-OPTs. Age at diagnosis, sex, tumor location, number of tumors, symptomology, concurrent OPT, radiographic progression (defined as qualitative and quantitative increases in size), and treatment were assessed. Tumor volumes were measured from initial presentation until treatment or end of disease progression.ResultsSixty-three percent of probable non-OPTs progressed over time, where radiographic progression was concomitantly associated with clinical progression. Fifty-two percent of patients had incidentally identified probable non-OPTs. Twenty-five percent of patients were symptomatic at initial diagnosis, all of whom harbored tumors that grew on subsequent scans and required tumor-directed therapy. There were no clinical differences between probable non-OPTs localized to the brainstem vs other locations with respect to age, sex, concurrent optic pathway glioma, symptomology, and treatment. The average time from diagnosis to stabilization or decrease in tumor size was 2.34 years (SD, 2.15 years). Nineteen biopsied lesions were all histopathologically confirmed as tumor. Six children (9%) had deep extensive tumors, who presented earlier (mean age at diagnosis, 3.88 years), required multiple treatments, and had a shorter mean progression-free survival (48 months).ConclusionsOver half of children with NF1 in this study developed probable non-OPTs, the majority of which were clinically and radiographically progressive. While brainstem and nonbrainstem gliomas share similar clinical features and natural history, deep extensive tumors comprise a distinct aggressive group of tumors that warrant close attention.

Objective:To define the clinical and radiologic features of brainstem gliomas (BSGs) in children with neurofibromatosis type 1 (NF1).Methods:We performed a retrospective cross-sectional study of 133 children with NF1 and concurrent BSGs cared for at 4 NF1 referral centers. BSG was determined using radiographic criteria. Age at diagnosis, tumor location and appearance, clinical symptoms, treatment, and presence of a concurrent optic pathway glioma were assessed.Results:The average age at BSG diagnosis was 7.2 years, and tumors occurred most often in the midbrain and medulla (66%). The majority of children with NF1-BSGs were asymptomatic (54%) and were not treated (88%). Only 9 of the 72 asymptomatic children received treatment because of progressive tumor enlargement. In contrast, 61 children presented with clinical signs/symptoms attributable to their BSG; these individuals were older and more often had focal lesions. Thirty-one patients underwent treatment for their tumor, and 14 received CSF diversion only. Progression-free survival was ∼3 years shorter for children receiving tumor-directed therapy relative to those who had either no treatment or CSF diversion only. Overall survival was 85% for the tumor-directed therapy group, whereas no deaths were reported in the untreated or CSF diversion groups.Conclusions:Unlike children with sporadically occurring BSGs, most children with NF1-BSGs were asymptomatic, and few individuals died from complications of their tumor. Those requiring tumor-directed treatment tended to be older children with focal lesions, and had clinically more aggressive disease relative to those who were not treated or underwent CSF diversion only.

Background and Purpose— Pediatric acute stroke teams are a new phenomenon. We sought to characterize the final diagnoses of children with brain attacks in the emergency department where the pediatric acute stroke protocol was activated and to describe the time to neurological evaluation and neuroimaging. Methods— Clinical and demographic information was obtained from a quality improvement database and medical records for consecutive patients (age, ≤20 years) presenting to a single institution’s pediatric emergency department where the acute stroke protocol was activated between April 2011 and October 2014. Stroke protocol activation means that a neurology resident evaluates the child within 15 minutes, and urgent magnetic resonance imaging is available. Results— There were 124 stroke alerts (age, 11.2±5.2 years; 63 boys/61 girls); 30 were confirmed strokes and 2 children had a transient ischemic attack. Forty-six of 124 (37%) cases were healthy children without any significant medical history. Nonstroke neurological emergencies were found in 17 children (14%); the majority were meningitis/encephalitis (n=5) or intracranial neoplasm (n=4). Other common final diagnoses were complex migraine (17%) and seizure (15%). All children except 1 had urgent neuroimaging. Magnetic resonance imaging was the first study in 76%. The median time from emergency department arrival to magnetic resonance imaging was 94 minutes (interquartile range, 49–151 minutes); the median time to computed tomography was 59 minutes (interquartile range, 40–112 minutes). Conclusions— Of pediatric brain attacks, 24% were stroke, 2% were transient ischemic attack, and 14% were other neurological emergencies. Together, 40% had a stroke or other neurological emergency, underscoring the need for prompt evaluation and management of children with brain attacks.

Introduction: In 2013 our institution established a multidisciplinary pediatric neurovascular conference (PNVC) for coordination of care. Here we review our initial experience. Hypothesis: Collaboration yields coordinated care for children with complex cerebrovascular disease and treatment protocols for commonly discussed conditions. Methods: Clinical and demographic data were obtained from medical records for patients presented to PNVC from April 2013 to July 2014. Survey data were collected from PNVC participants. Results: The PNVC met 26 times in the study period. Overall, 78 children were presented a total of 112 times, 41% with history of stroke. Of 64 (82%) with a diagnosed vascular lesion, AVM (30%), cavernous malformation (14%), and moyamoya (11%) were most common. Most discussions were for review of imaging (35%), need for additional imaging (27%), or treatment plan (25%) [Table]. Follow-up angiography was performed in 27%. A surgical operation was employed in 22%; 18% received neurointervention; 9% received radiosurgery. Twenty-three patients (29%) were discussed more than once. Standardized care protocols for AVM and moyamoya were developed from discussions among physicians from 7 different specialties [Figure]. Participants cited PNVC’s greatest utility as facilitation of a collaborative approach to patient care. Conclusion: A multidisciplinary conference among a diverse group of providers guides complex care decisions, helps standardize care protocols, promotes faculty collaboration, and supports continuity of care in pediatric neurovascular disease.

Introduction: Many children’s hospitals, including ours, have instituted acute stroke protocols, with a pediatric acute stroke team that is alerted and responds urgently for children with acute brain attacks. The purpose of this study was to characterize the final diagnoses of children with brain attacks in the emergency department where the acute stroke protocol was activated. Hypothesis: We hypothesized that less than half of pediatric brain attacks would have a confirmed diagnosis of acute stroke. Methods: Clinical and demographic information were obtained from a quality improvement database and medical records for consecutive patients (age 0-20 y) presenting to a single institution’s pediatric emergency department where the acute stroke protocol was activated between April 2011 and December 2013. Activation of this protocol means that a neurology resident sees the child within 15 minutes and acute MRI is available. All values were assessed with descriptive statistics. Results: There were 100 cases of brain attack (mean age 11.3 y, SD 5.1 y, 55% male); 25 were confirmed strokes (Figure) and 3 children had a transient ischemic attack (TIA). Nine (36%) children with stroke were previously healthy. There were 17 (68%) ischemic strokes, 7 (28%) hemorrhages, and 1 (4%) sinovenous thrombosis. Non-stroke neurological emergencies were found in 13% of patients; the majority were meningitis (n=5) or neoplasm (n=3). Complex migraine was present in 17% and seizure in 12%. All children had urgent neuroimaging. MRI was the first study in 70%. Conclusion: Of pediatric brain attacks, 25% were stroke, 3% were TIA, and 13% were other neurological emergencies. Clinicians evaluating a child for possible acute stroke should consider these frequencies in their differential diagnosis. There are many stroke mimics, some life-threatening, underscoring the need for prompt evaluation and management of children with brain attacks.

Several 2-(2-chlorophenyl)-1-phenylethanones and (2-chlorophenyl)(phenyl)methanones were prepared by the Friedel–Crafts acylation reaction of 2-(2-chlorophenyl) acetic acids and 2-chlorocarboxylic acids, respectively, in the presence of cyanuric chloride, pyridine, and AlCl3 or FeCl3 using microwave heating. The yields of the ketones were significantly higher than those obtained using conventional heating. In addition, similar reactions carried out with the less inexpensive and less toxic FeCl3 gave titled ketones in comparable yields. Interestingly, the FeCl3 catalyzed reactions gave pure ketones (no chromatographic purification required), whereas the AlCl3 catalyzed reaction gave impure product that required chromatographic purification.

Introduction In 2013, our institution established a multidisciplinary pediatric neurovascular conference for coordination of care. Here, we review our initial experience. Methods Clinical and demographic data were obtained from medical records for patients presented to the pediatric neurovascular conference from April 2013 to July 2014. Patient descriptive characteristics were described by mean and standard deviation for continuous measures and by number and percent for categorical measures. Patients were secondarily stratified by lesion/disease type, and descriptive statistics were used to measure demographic and clinical variables. Results The pediatric neurovascular conference met 26 times in the study period. Overall, 75 children were presented to the conference over a 15-month period. The mean age was 9.8 (standard deviation, 6.3) years. There were 42 (56%) male patients. These 75 children were presented a total of 112 times. There were 28 (37%) patients with history of stroke. Complex vascular lesions were the most frequently discussed entity; of 62 children (83%) with a diagnosed vascular lesion, brain arteriovenous malformation (29%), cavernous malformation (15%), and moyamoya (11%) were most common. Most discussions were for review of imaging (35%), treatment plan formulation (27%), the need for additional imaging (25%), or diagnosis (13%). Standardized care protocols for arteriovenous malformation and moyamoya were developed. Conclusion A multidisciplinary conference among a diverse group of providers guides complex care decisions, helps standardize care protocols, promotes provider collaboration, and supports continuity of care in pediatric neurovascular disease.

Several 2-(2-chlorophenyl)-1-phenylethanones and (2-chlorophenyl)(phenyl)methanones were prepared by the Friedel–Crafts acylation reaction of 2-(2-chlorophenyl) acetic acids and 2-chlorocarboxylic acids, respectively, in the presence of cyanuric chloride, pyridine, and AlCl3 or FeCl3 using microwave heating. The yields of the ketones were significantly higher than those obtained using conventional heating. In addition, similar reactions carried out with the less inexpensive and less toxic FeCl3 gave titled ketones in comparable yields. Interestingly, the FeCl3 catalyzed reactions gave pure ketones (no chromatographic purification required), whereas the AlCl3 catalyzed reaction gave impure product that required chromatographic purification.