Common Central Nervous System Research Articles

Dexmedetomidine Ameliorated Cognitive Dysfunction Induced by Intestinal Ischemia Reperfusion in Mice with Possible Relation to the Anti-inflammatory Effect Through the Locus Coeruleus Norepinephrine System

Cognitive impairment is a common central nervous system complication that occurs following surgery or organs damage outside the nervous system. Neuroinflammation plays a key role in the molecular mechanisms of cognitive impairment. Dexmedetomidine alleviates neuroinflammation and reduces cognitive dysfunction incidence; however, the mechanism by which dexmedetomidine alleviates cognitive dysfunction remains unclear. This study evaluated the effect of dexmedetomidine on attenuation of early cognitive impairment induced by intestinal ischemia–reperfusion in mice and examined whether the locus coeruleus norepinephrine (LCNE) system participates in the anti-inflammatory effect of dexmedetomidine. The superior mesenteric artery was clamped for 45 min to induce intestinal ischemia reperfusion injury. Dexmedetomidine alone or combined with DSP-4, a selective locus coeruleus noradrenergic neurotoxin, was used for pretreatment. Postoperative cognition was assessed using the Morris water maze. Serum and hippocampal levels of IL-1β, TNF-α, norepinephrine (NE), and malondialdehyde (MDA) were assessed by enzyme-linked immunosorbent assay. Immunofluorescence, immunohistochemistry, and hematoxylin and eosin staining were used to evaluate the expression of tyrosine hydroxylase (TH) in the locus coeruleus, hippocampal microglia, and intestinal injury. Pretreatment with dexmedetomidine alleviated intestinal injury and decreased the serum and hippocampal levels of NE, IL-1β, TNF-α, and MDA at 24 h after intestinal ischemia reperfusion, decreased TH-positive neurons in the locus coeruleus, and ameliorated cognitive impairment. Similarly, DSP-4 pre-treatment alleviated neuroinflammation and improved cognitive function. Furthermore, α2-adrenergic receptor antagonist atipamezole or yohimbine administration diminished the neuroprotective effects and improved cognitive function with dexmedetomidine. Therefore, dexmedetomidine attenuated early cognitive dysfunction induced by intestinal ischemia–reperfusion injury in mice, which may be related to its anti-inflammatory effects through the LCNE system.

Neurological Disorders of Patients Living with HIV Hospitalized in Infectious Departments of the Specialist Hospital in Lower Silesia in Poland.

Background and Objectives: Central nervous system (CNS) disorders are estimated to occur in approximately 10–20% of people living with HIV (PLWH). They are more commonly observed in newly diagnosed patients and in previously untreated patients or those refusing to undergo antiretroviral treatment. CNS diseases can also be the first manifestation of HIV/AIDS infection. The most common HIV-related central nervous system diseases (CNS-D) are CNS toxoplasmosis, CNS cryptococcosis, progressive multifocal leukoencephalopathy (PML), and HIV-associated encephalopathy treated as a neurocognitive disorder. Materials and Methods: A retrospective analysis of available medical records was performed on 476 patients hospitalised over a period from 2016 to 2021 and diagnosed with HIV/AIDS infection at the department of infectious diseases at the Provincial Specialist Hospital in Wroclaw. An additional criterion for selecting patients for the analysis was the performance of head imaging using computed tomography or magnetic resonance imaging on prospective patients. Results: Neurotoxoplasmosis, neurocryptococcosis, progressive multifocal leukoencephalopathy (PML), and neurosyphilis were the most common CNS diseases among the analysed group of patients. Based on radiological descriptions, other abnormalities, such as vascular changes or cortical and subcortical atrophy of multifactorial origin, not exclusively related to HIV infection, were also frequently observed. The most common neurological symptoms reported in the study group were headaches, limb paresis, and gait and balance disturbance. Conclusions: The clinical picture and epidemiology of neurological manifestations in the group of HIV-infected patients under assessment were similar to the results of other authors. Given the current epidemiological situation, diagnosis for HIV infection should be considered in patients admitted to neurological departments.

Weighted Gene Co-Expression Network Analysis and Support Vector Machine Learning in the Proteomic Profiling of Cerebrospinal Fluid from Extraventricular Drainage in Child Medulloblastoma.

Medulloblastoma (MB) is the most common pediatric malignant central nervous system tumor. Overall survival in MB depends on treatment tuning. There is aneed for biomarkers of residual disease and recurrence. We analyzed the proteome of waste cerebrospinal fluid (CSF) from extraventricular drainage (EVD) from six children bearing various subtypes of MB and six controls needing EVD insertion for unrelated causes. Samples included total CSF, microvesicles, exosomes, and proteins captured by combinatorial peptide ligand library (CPLL). Liquid chromatography-coupled tandem mass spectrometry proteomics identified 3560 proteins in CSF from control and MB patients, 2412 (67.7%) of which were overlapping, and 346 (9.7%) and 805 (22.6%) were exclusive. Multidimensional scaling analysis discriminated samples. The weighted gene co-expression network analysis (WGCNA) identified those modules functionally associated with the samples. A ranked core of 192 proteins allowed distinguishing between control and MB samples. Machine learning highlighted long-chain fatty acid transport protein 4 (SLC27A4) and laminin B-type (LMNB1) as proteins that maximized the discrimination between control and MB samples. Machine learning WGCNA and support vector machine learning were able to distinguish between MB versus non-tumor/hemorrhagic controls. The two potential protein biomarkers for the discrimination between control and MB may guide therapy and predict recurrences, improving the MB patients’ quality of life.

A hidden infection: Racemose neurocysticercosis causing hydrocephalus; a case report

Introduction and importanceNeurocysticercosis (NCC) is the most common helminthic central nervous system infection (CNS) in the Western hemisphere and the most common cause of acquired epilepsy worldwide. Due to its relatively prolonged latent period and clinical similarity to other infectious diseases – including bacterial or viral meningitis and other helminthic infections – NCC may be difficult to diagnose, especially for clinicians who rarely encounter it.Case presentationThis case report discusses a patient with obstructive hydrocephalus and eosinophilic meningitis secondary to racemose NCC. The diagnosis process was initially complicated by the patient's history of pork allergy and absence of radiographic evidence of helminthic CNS infection. Further investigation showed a 4th ventricle multi-cystic lesion causing hydrocephalus which prompted a surgical intervention with a ventriculoperitoneal shunt (VPS) in conjunction with anti-helminthic medical treatment. At 1-year follow-up, the patient has reported recurrence of VPS related complications.Clinical discussionLarval cysts typically deposit within the brain parenchyma, making them easily detected on head computed tomography (CT) scans and leading to neurologic sequelae such as epilepsy. In this case, the absence of CT evidence of NCC and the patient's lifelong history of pork allergy slowed the diagnosis process.ConclusionRacemose NCC is a rare subset of the disease in which cyst clusters occupy the extra parenchymal space, thereby changing the symptomatic profile and making the cysts more difficult to visualize in imaging studies. In this case, magnetic resonance imaging (MRI) was the best imaging modality to diagnosis extra parenchymal NCC and guide its surgical management.

Monkeypox virus neurological manifestations in comparison to other orthopoxviruses

Viral infectious diseases have various neurological manifestations, whether they are epidemic or pandemic in nature. Nonspecific encephalopathy is the most common central nervous system (CNS) manifestation. The spectrum of nervous evidence varies for viral pathogens. Some infectious viruses, such as the Ebola virus, exhibit direct neurotropism. Others, such as the Rift Valley fever virus, have the potential for neurotropism. Direct neurotropism is unknown in monkeypox virus, SARS-CoV-2, MERS-CoV, and even smallpox. As seen in the COVID-19, there may be evidence of para-infectious neurological syndrome. There have only been a few reports of neurological diseases caused by monkeypox infection. Future efforts to prevent the spread of infectious disease surges can reduce mortality complications, the therapeutic burden on the health-care system, and prevent further spread. This study describes the clinical and neurological complications of monkeypox infection, particularly encephalitis, as well as the laboratory diagnosis of these cases.

Incidence, follow-up, and postnatal clinical progress of children with central nervous system anomalies on fetal MRI.

MRI is increasingly employed to assess intrauterine fetal anomalies. Central nervous system (CNS) anomalies are common structural conditions that warrant evaluation with fetal MRI and subsequent prenatal consultation with a pediatric neurosurgeon. As the use of fetal MRI increases, there is greater impetus to understand the most common CNS structural anomalies diagnosed in utero, as well as their natural histories. The authors performed a single-center retrospective review of fetal MRI evaluations performed between January 2012 and December 2020. Children who underwent both prenatal and postnatal neurosurgical evaluations of CNS anomalies were included. Specific CNS anomalies on fetal MRI, associated extra-CNS findings, and suspicion for genetic abnormality or syndromes were noted. Postnatal clinical status and interventions were assessed. Between January 2012 and December 2020, a total of 469 fetal MRI evaluations were performed; of these, 114 maternal-fetal pairs had CNS anomalies that warranted prenatal consultation and postnatal pediatric neurosurgical follow-up. This cohort included 67 male infants (59%), with a mean ± SD follow-up of 29.8 ± 25.0 months after birth. Fetal MRI was performed at 27.3 ± 5.8 weeks of gestational age. The most frequently reported CNS abnormalities were ventriculomegaly (57%), agenesis or thinning of the corpus callosum (33%), Dandy-Walker complex (DWC) (21%), neuronal migration disorders (18%), and abnormalities of the septum pellucidum (17%). Twenty-one children (18%) required neurosurgical intervention at a mean age of 2.4 ± 3.7 months. The most common surgical conditions included myelomeningocele, moderate to severe ventriculomegaly, encephalocele, and arachnoid cyst. Corpus callosum agenesis or thinning was associated with developmental delay (p = 0.02) and systemic anomalies (p = 0.05). The majority of prenatal patients referred for DWC had Dandy-Walker variants that did not require surgical intervention. The most common conditions for prenatal neurosurgical assessment were ventriculomegaly, corpus callosum anomaly, and DWC, whereas the most common surgical conditions were myelomeningocele, hydrocephalus, and arachnoid cyst. Only 18% of prenatal neurosurgical consultations resulted in surgical intervention during infancy. The majority of referrals for prenatal mild ventriculomegaly and DWC were not associated with developmental or surgical sequelae. Patients with corpus callosum abnormalities should be concurrently referred to a neurologist for developmental assessments.

The first-in-class ERK inhibitor ulixertinib shows promising activity in mitogen-activated protein kinase (MAPK)-driven pediatric low-grade glioma models.

Pediatric low-grade gliomas (pLGG) are the most common pediatric central nervous system tumors, with driving alterations typically occurring in the MAPK pathway. The ERK1/2 inhibitor ulixertinib (BVD-523) has shown promising responses in adult patients with mitogen-activated protein kinase (MAPK)-driven solid tumors. We investigated the antitumoral activity of ulixertinib monotherapy as well as in combination with MEK inhibitors (MEKi), BH3-mimetics, or chemotherapy in pLGG. Patient-derived pLGG models reflecting the two most common alterations in the disease, KIAA1549:BRAF-fusion and BRAFV600E mutation (DKFZ-BT66 and BT40, respectively) were used for in vitro and in vivo (zebrafish embryos and mice) efficacy testing. Ulixertinib inhibited MAPK pathway activity in both models, and reduced cell viability in BT40 with clinically achievable concentrations in the low nanomolar range. Combination treatment of ulixertinib with MEKi or BH3-mimetics showed strong evidence of antiproliferative synergy in vitro. Ulixertinib showed on-target activity in all tested combinations. In vivo, sufficient penetrance of the drug into brain tumor tissue in concentrations above the in vitro IC50 and reduction of MAPK pathway activity was achieved. In a preclinical mouse trial, ulixertinib mono- and combined therapies slowed tumor growth and increased survival. These data indicate a high clinical potential of ulixertinib for the treatment of pLGG and strongly support its first clinical evaluation in pLGG as single agent and in combination therapy in a currently planned international phase I/II umbrella trial.

Incidence and survival of benign, borderline, and malignant meningioma patients in the United States from 2004 to 2018.

Meningioma is the most common primary central nervous system tumor, and its incidence is increasing. A systematic epidemiological and clinical analysis is required to better estimate its public health impact and understand its prognostic factors. Data were obtained from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2018 for all types of meningiomas without an age restriction. Age-adjusted incidence rates (IRs) and 95% confidence intervals were estimated according to sex, age, race, ethnicity, and tumor location. Kaplan-Meier analysis and multivariate Cox proportional hazard models were used to analyze the overall survival (OS). The competing risk regression model of Fine-Gray was used to analyze cause-specific survival. Data from a total of 109 660 meningioma patients were analyzed. A majority of patients were older than 60 years, and only 0.41% of patients were 0-19 years. The meningioma IRs were higher in females, Black, and non-Hispanic patients than in males, White, and Hispanic patients, respectively, and IRs increased with age. The ratio of IRs for females to males was 2.1 and also increased with age, peaking at 3.6 in the 45-49-year-old group. Older and male patients with all types of meningiomas, Black patients with benign and borderline meningiomas, and patients with larger borderline and malignant meningiomas showed poorer prognosis. For all meningioma types, surgical resection improved survival. The reported incidence rates and survival trends covered all demographics and subtypes of meningiomas. Older age, male sex, Black race, and tumor size may be important prognostic factors for meningioma cases, and tumor resection can substantially improve survival among meningioma patients.

Bone Marrow Mesenchymal Stem Cells (BMSCs) Expressing Netrin-1 Alleviates Spinal Cord Injury (SCI)-Induced Inflammation

Spinal cord injury (SCI) is a common central nervous system (CNS) injury. Bone marrow mesenchymal stem cells (BMSCs) transplantation is a potential treatment for traumatic SCI. However, the role and mechanism of BMSCs with high expression of Netrin-1 on the repair and inflammation of spinal cord injury cells remains unclear. Our study intends to assess the effect of BMSCs with high Netrin-1 level on the repair of SCI cells. BMSCs or Netrin-1 transfected BMSCs were co-cultured with mechanically injured nerve cells followed by analysis of the differentiation of BMSCs by light microscope, apoptosis activity, expression of TLR-4 and NF-κB, and the TNF-α and IL-1β content in cell supernatant by ELISA. BMSCs with high Netrin-1 expression promoted the proliferation of BMSCs, inhibited apoptosis, and promoted the differentiation of nerve cells along with increased ALK activity, and the expression of GFAP and BDNF. Co-culture with BMSCs or BMSCs with high Netrin-1 expression increased mechanically damaged nerve cell proliferation, decreased apoptosis, downregulated TLR-4 and NF-κB (P < 0.05) with more significant changes after co-culture with BMSCs with high Netrin-1 expression. In conclusion, Netrin-1 can promote BMSCs proliferation and differentiation, and inhibit apoptosis. By inhibiting inflammation, it can promote damaged nerve cell proliferation and repair.

Update on pathology of central nervous system inflammatory demyelinating diseases.

Multiple sclerosis (MS) is by far the most common central nervous system inflammatory demyelinating disease (CNS-IDD). It is diagnosed according to detailed criteria based on clinical definitions, magnetic resonance imaging (MRI) and cerebrospinal fluid findings. However, in rare instances, atypical syndromes associated with CNS demyelination, such as unusual MRI findings or poor response to standard treatment, may eventually necessitate a CNS biopsy with neuropathological examination. Pathology remains the gold standard in the differentiation of atypical CNS-IDDs, the recognition of which is essential for establishing the correct prognosis and optimal therapy. However, one must bear in mind that between different CNS-IDDs there are still overlapping features, even in the pathology. In this review, we compare and highlight contrasts within a spectrum of CNS-IDDs from the neuropathological perspective. We characterise pathological hallmarks of active vs chronic multiple sclerosis. Also, we define differences in the pathology of MS, acute disseminated encephalomyelitis (ADEM), aquaporin 4-IgG positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOsd), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Detailed description of the particular CNS-IDD pathology is crucial on an individual patient level (when clinically justified in atypical cases) but also from a broader perspective i.e. to advance our understanding of the complex disease mechanisms. Recent immunobiological and pathological discoveries have led to the description of novel inflammatory CNS disorders that were previously classified as rare MS variants, such as NMOsd and MOGAD. Multiple sclerosis remains an umbrella diagnosis, as there is profound heterogeneity between patients. Advances in neuropathology research are likely to disentangle and define further CNS-IDDs that used to be categorised as multiple sclerosis.

Caspase 8 Expression Patterns in Meningiomas: A Tissue Microarray Digital Image Analysis.

Background: Caspases (cysteine-aspartic proteases) represent a family of enzymes that critically influence cell homeostasis by being involved in inflammation and apoptosis mechanisms. Meningiomas demonstrate the most common intracranial primary central nervous system tumors in adults worldwide.Aim: Our purpose was to explore the role of caspase 8 expression in meningiomas’ pathological features.Materials and methods: A total of 50 meningioma cases were included in the study, comprising a broad spectrum of histopathological sub-types. An immunohistochemistry assay was applied on tissue microarray cores followed by digital image analysis.Results: Overexpression of caspase 8 protein was observed in 21/50 (42%) cases, whereas the rest of them (29/50, 58%) demonstrated moderate to low levels of the molecule. Caspase 8 overall expression was statistically significantly correlated to grade of the examined tumors and to mitotic index (p=0.001,p=0.002, respectively).Conclusions: Caspase 8 aberrant expression is observed in meningiomas associated with their differentiation grade and mitotic activity. Targeted therapeutic strategies focused on enhancing caspase 8 expression and also inducing the overall apoptotic activity should be a very promising approach in rationally handling sub-groups of meningioma patients.

Abstract 5392: Magnolol induces apoptosis and inhibits invasion ability via suppression of STAT3 signaling in glioblastoma multiforme cells

Abstract Magnolol is a phenolic compound extracted from magnolia officinalis, exhibited anti-tumor potential against many types of cancers. Magnolol has also recognized as an anti-inflammation agent which can downregulate several inflammation signals transduction. Glioblastoma multiforme (GBM) is the most common central nervous system (CNS) tumor and associated with poor prognosis among adults due to rapid growth and aggressive invasion. However, the treatment efficacy of current standard therapy for GBM is remaining unsatisfied. Nevertheless, whether magnolol may suppress GBM progression and its underlying mechanism has not been elucidated. Thus, the purpose of this study was to investigate the mechanism and therapeutic efficacy of magnolol on GBM.First of all, we validated the potential treatment targets of GBM with the GEPIA (Gene Expression Profiling Interactive Analysis) analysis and Western blotting assay. GEPIA data indicated the PKCδ/STAT3 signaling pathway as a potential target of GBM that may affect patient survival. In our results, magnolol can effectively suppress the phosphorylation and the nuclear translocation of STAT3 in GBM cells. Then, we used the MTT assay to investigate the cytotoxicity of GBM cells after various dose of magnolol treatment. We also detected the extrinsic/intrinsic apoptosis induction ability of magnolol on GBM cells. This study also demonstrated that magnolol may significantly trigger the loss of mitochondrial membrane potential, and the activation of cleaved caspase-3, -8 and -9. Transwell invasion and wound healing assays was used to identify the suppression of migration and invasion effects of magnolol on glioblastoma cells. Meanwhile, tumor invasion and migration ability and the associated genes, including MMP9 and uPA, were all diminished by magnolol treatment. In sum, our results demonstrated that magnolol suppressed GBM progression may be associated with the inactivation of PKCδ/STAT3 signaling transduction. Citation Format: Sin-Rong Lee, Yuan Chang, I-Tsang Chiang, Fei-Ting Hsu. Magnolol induces apoptosis and inhibits invasion ability via suppression of STAT3 signaling in glioblastoma multiforme 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 5392.

Abstract 3243: Synergistic effects of connexin 43 inhibitor and PI3K isoform-selective inhibitors in temozolomide-resistant glioblastoma

Abstract Glioblastoma is the most common central nervous system cancer and is responsible for approximately one-half of all malignant brain tumors. With a 5-year survival rate of 6.8% and a median observed survival time of only 8 months, recurrent glioblastoma is among the world’s most lethal malignancies. Temozolomide (TMZ) has become a standard chemotherapeutic for glioblastoma due to its alkylating effects and ability to cross the blood-brain barrier. Unfortunately, many patients with glioblastoma develop resistance to TMZ, severely limiting therapeutic options. Recent studies have found a link between ectopic connexin 43 (Cx43) and TMZ-resistant glioblastoma. Further studies have shown success in overcoming this resistance by combining TMZ with alpha carboxyl terminus 1 (αCT1) peptide, a clinically tested Cx43 carboxyl terminus mimetic peptide inhibitor; however, because of the short half-life of αCT1, therapeutic potential is limited, and new approaches are needed. In this study, we hypothesized that simultaneously targeting Cx43 with αCT1 and phosphoinositide 3-kinase (PI3K) using PI3K isoform-selective inhibitors would synergistically sensitize glioblastoma to TMZ treatment because p110β, one of the four PI3K catalytic subunits, is a prime survival factor for TMZ-resistant glioblastoma. We cultured newly dissected primary glioblastoma cells, glioblastoma cell lines, and glioblastoma stem cells and dosed them with various combinations of αCT1, TMZ, and one of two clinically tested p110β inhibitors (TGX-221 or GSK2636771). Cell viability was measured using an MTS viability assay. Glioblastoma cells that expressed high levels of Cx43 and p110β experienced a significant decrease in viability when dosed with a triple combination. The additive properties of these combinations were measured using an excess over Bliss (EOB) score derived from Bliss independence modeling, which showed synergistic effects as high as 81% for triple therapy combinations in TMZ-resistant cell lines. The EOB was significantly higher in triple therapies than the double or single therapies. To support our findings, we used the same combinations in primary glioblastoma cells and measured the activity of cleaved caspase 3/7 using a luminescence assay. There was a synergistic increase in caspase 3/7 activity in the triple therapy that was not seen in any of the other combinations. Identical treatment in non-pathological human astrocytes suggests that our drug combinations do not exacerbate non-selective TMZ toxicity in the brain. Collectively, our data demonstrate that simultaneous inhibition of Cx43 and PI3K is an effective approach for overcoming TMZ resistance in glioblastoma. Citation Format: Kasen R. Hutchings, Kevin J. Pridham, Min Liu, Joseph Owens, Zhi Sheng. Synergistic effects of connexin 43 inhibitor and PI3K isoform-selective inhibitors in temozolomide-resistant glioblastoma [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 3243.

Multi-institutional analysis of central nervous system germ cell tumors in patients with Down syndrome.

Primary germ cell tumors (GCTs) are the most common central nervous system (CNS) neoplasm in patients with Down syndrome (DS). However, a standard of care has not been established due to paucity of data. A retrospective multi-institutional analysis was conducted, in addition to a comprehensive review of the literature. Ten patients from six institutions (five USA, one Brazil) were identified, in addition to 31 patients in the literature from 1975 to 2021. Of the 41 total patients (mean age 9.9years; 61% male), 16 (39%) had non-germinomatous germ cell tumors (NGGCTs), 16 (39%) had pure germinomas, and eight (19.5%) had teratomas. Basal ganglia was the most common tumor location (n=13; 31.7%), followed by posterior fossa (n=7; 17%). Nine patients (22%) experienced disease relapse or progression, of which four died from tumor progression (one germinoma, three teratomas). Sixteen patients (39%) experienced treatment-related complications, of which eight (50%) died (five germinomas, three NGGCTs). Of the germinoma patients, two died from chemotherapy-related sepsis, one from postsurgery cardiopulmonary failure, one from pneumonia, and one from moyamoya following radiation therapy (RT). Of the NGGCT patients, one died from chemotherapy-related sepsis, one from postsurgical infection, and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival was 66% for all histological types: 62% germinomas, 79% for NGGCTs, and 53% for teratomas. Patients with DS treated for CNS GCTs are at an increased risk of treatment-related adverse events. A different therapeutic approach may need to be considered to mitigate treatment-related complications and long-term neurocognitive sequelae.

LINC-21. PROGNOSTIC FACTORS AND SURVIVAL OF LOW-GRADE GLIOMAS IN CHILDREN AND ADOLESCENTS – A MULTICENTER STUDY IN PERU

BACKGROUND: Low-grade gliomas (LGG) are the most common central nervous system (CNS) tumors in children. Peru is an index country for the Global Initiative for Childhood Cancer (GICC). As part of the Initiative, a multidisciplinary brain tumor team was formed in 2020 that includes five national reference centers: National Institute of Neoplastic Diseases, National Children’s Health Institute-San Borja, National Children’s Health Institute-Breña, Edgardo Rebagliati Martins National Hospital and Guillermo Almenara Irigoyen National Hospital. This multicenter study sought to evaluate the survival and prognostic factors of patients younger than 18 years diagnosed with LGG, an index cancer for the GICC. METHODS: A retrospective study included all patients diagnosed with LGG in the five centers between 2014 and 2018. We analyzed clinical characteristics, histology, and treatment modalities. We used the Kaplan-Meier method for survival. RESULTS: 194 patients were registered; 136 patients were included. M/F ratio was 1.2, mean age 7 years old. The most frequent location was infratentorial (42.2%), supratentorial (34.9%), optic/chiasm/sellar (11%) and brainstem (11.9%). The most frequent histological types were pilocytic astrocytoma (61%), diffuse astrocytoma (10.3%), oligodendroglioma (5.2%), and other low-grade neoplasms (23.5%). Surgery was performed in 109 patients (83.2%). Chemotherapy alone was used in 17 (12.5%), while radiotherapy in 20 (14.7%). Overall survival at 5 years was 82.9% (95% CI 73.3 - 89.4). Age younger than 3 years (p=0.002), diffuse histological type (p=0.04), and location in the brainstem (p=0.001) were factors associated with a worse prognosis. CONCLUSIONS: Within the framework of the GICC, this work is one of the first steps to understand the current context of pediatric CNS tumor care in Peru. Although the reported survival rate is about the GICC goal of 60%, further improvements in care are needed to increase survival to level closer to high-resource setting and decrease long term morbidity.

IMG-08. Response assessment for pediatric craniopharyngioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group

Abstract INTRODUCTION: Craniopharyngioma (CP) is a histologically benign tumor of the pituitary stalk that accounts for 4% of pediatric central nervous system (CNS) tumors. Given its location, CP often causes neuro-endocrine, hypothalamic, and vision dysfunction. Standard therapy consists of maximally safe resection +/- radiation therapy (RT). Medical management, including intra-cystic therapy, may have utility in certain contexts. Survival after CP is excellent, but quality of life is often poor secondary to functional deficits from the tumor and/or treatment. Few prospective CP trials have been performed, and response assessment has not been standardized. METHODS: The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee, formed of international experts in relevant subspecialties, devised consensus guidelines from published literature and/or expert opinion to assess CP response in prospective clinical trials. RESULTS: Magnetic resonance imaging (MRI) is the recommended radiological modality for baseline and follow-up CP assessment. Computed tomography can be useful for identification of calcification in the initial diagnostic work-up. The committee defined specific standard MRI-based sequences focused on comprehensive evaluation of the suprasellar space. Radiologic CP response is defined by two-dimensional measurements of both solid and cystic tumor components. Three-dimensional measurements are also encouraged in prospective trials. In certain clinical contexts, response of solid and cystic disease may be differentially considered based on their unique natural histories and responses to treatment (including transient cyst growth during or after RT). Importantly, the committee incorporated functional endpoints related to neuro-endocrine and visual assessments into CP response definitions. In most circumstances, cystic disease should be considered progressive only if growth is associated with acute, new-onset or progressive functional impairment. CONCLUSION: CP is a common pediatric CNS tumor for which standardized response parameters have not been defined. A RAPNO committee devised guidelines for baseline and longitudinal assessments of CP to uniformly define response in future prospective trials.

LGG-32. Integrated biologic, radiologic and clinical analysis of pediatric low-grade gliomas during and after targeted therapy treatment

BACKGROUND: Pediatric low grade gliomas (pLGGs) are the most common central nervous system tumor in children, characterized by driver alterations in the RAS and MAPK pathways. Genomic advances have facilitated use of molecular targeted therapies, however their long-term impact on tumor behavior remains critically unanswered. METHODS: We performed an IRB-approved, retrospective chart and imaging review of pLGGs treated with off-label targeted therapy at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center from 2010 to 2020. Volumetric analysis was performed for BRAFV600E and BRAF fusion/duplication driven pLGG subsets. RESULTS: Fifty-five patients were identified (dabrafenib n = 15, everolimus n = 26, trametinib n = 11, and vemurafenib n = 3). Targeted agent was used as first or second-line therapy for 58% (32/55). Median duration of targeted therapy was 0.79 years (0.01 – 4.87), and overall median follow-up was 2.50 years (0.01 – 7.39). The 1-year, 3-year, and 5-year EFS from targeted therapy initiation were 62.1%, 38.2%, and 31.8%, respectively. Mean volumetric change for BRAFV600E mutated pLGG on BRAF inhibitors was -54.11%, and median time to best volumetric response was 8.28 months (n = 12). Median time to largest volume post-treatment was 2.86 months. Mean volumetric change for BRAF fusion/duplication pLGG on MEK inhibitors was +7.34% with median time to best volumetric response of 6.71 months (n = 7). Median time to largest volume post-treatment was 2.38 months. CONCLUSIONS: Our integrated clinical and volumetric data suggest the majority of patients receiving BRAF inhibitors or trametinib achieve reduction in tumor volume while on therapy and that tumor stability can be achieved following targeted therapy cessation. Moreover, volumetric analysis shows promise as a tool to assess targeted therapeutic response in pLGGs.

LGG-04. Clinical and molecular characterization of metastatic pediatric low grade gliomas

BACKGROUND: Despite being the most common central nervous system tumor in children, ≤5% of pediatric low grade gliomas (pLGG) present with metastases. Due to their rarity, there is a paucity of clinical and molecular data in metastatic pLGGs. To address the need, we analyzed a cohort of 22 patients with pLGG followed at Texas Children’s Hospital who presented with metastatic disease. RESULTS: The predominant histology was pilocytic astrocytoma (16/22, 73%); average age at diagnosis was 4 years 11 months. The most common sites of primary disease were optic pathway/chiasm (7/22, 32%) and suprasellar (5/22, 23%). Metastatic disease was most commonly noted in the leptomeninges (12/22, 55%). 16/22 patients (73%) were treated with up-front medical therapy following tumor biopsy/resection, the majority with carboplatin-based therapy; the remaining 6 patients received only surgery up-front. Only 2/22 patients (9%) did not progress after their initial treatment with an average follow-up of 42 months. 14 patients (14/22, 64%) had continued disease progression after at least 2 therapeutic interventions; however, only 3 patients (3/22, 14%) eventually received craniospinal radiation. 10 patients (10/22, 45%) received treatment with an agent targeting the mitogen-activated protein kinase (MAPK) pathway. 20/22 patients (91%) were alive at last follow-up (average 72 months). 4/21 patients (19%) harbored a BRAF V600E mutation while 7/20 (35%) had a BRAF::KIAA1549 duplication/fusion. 8/20 patients (40%) were wildtype for both analyzed molecular alterations in BRAF. 8 patients had germline whole exome sequencing performed and all were negative for pathogenic/likely-pathogenic variants related to their clinical phenotype. Methylation analyses are pending on patients with available tumor tissue. CONCLUSION: In our cohort of patients with metastatic pLGG, most tumors progressed despite numerous therapeutic regimens, but the overall survival was >90%. 40% of patients were wild type for the 2 most common MAPK alterations seen in pLGG.

GCT-15. Multi-institutional analysis and literature review of central nervous system germ cell tumors in patients with Down syndrome

Abstract BACKGROUND: A standard-of-care has not been established for the management of patients with Down syndrome (DS) who develop primary central nervous system (CNS) germ cell tumors (GCTs) – the most common CNS neoplasm in DS – despite being more susceptible to treatment-related adverse events. METHODS: Data from large academic institutions were collected and a comprehensive review of the medical literature was conducted. RESULTS: Ten patients from six institutions (five USA, one Brazil) were reviewed. Additionally, thirty-one patients were identified in the literature from 1975-2021. Of the 41 total patients, mean age was ten years (range, birth to 35 years); males were predominant (61%). Basal ganglia were the most common tumor location (n=12; 29%), followed by posterior fossa (n=7; 17%). Sixteen patients had non-germinomatous germ cell tumors (NGGCTs) (39%), 14 had pure germinomas (34%), and eight had teratomas (20%); histology was unreported for two (5%). Nine patients (22%) experienced disease relapse, of which four died from tumor progression (one germinoma versus three teratoma). Fifteen patients (37%) experienced treatment-related complications - seven died (four germinoma versus three NGGCT). Of the germinoma patients, two died from chemotherapy-related sepsis, one from post-surgery cardiopulmonary failure, and one from Moyamoya following radiation-therapy (RT) only. Of the NGGCT patients, one died from chemotherapy-related sepsis, one from post-surgical infection, and one from pneumonia following surgery/chemotherapy/RT. Three-year overall survival (OS) was 66% for all histological types - 62% germinoma, 79% for NGGCT, and 53% for teratoma. Three-year OS for patients who received RT or chemotherapy was 71% and 75% respectively. Twenty-seven patients remain alive at latest follow-up (mean follow-up from diagnosis: 46.8 months). CONCLUSIONS: Patients with DS treated for CNS GCTs are at an increased risk of treatment-related adverse events. A different therapeutic approach may need to be considered for this patient population to mitigate treatment-related complications and long-term neurocognitive sequelae.

Pneumonia in Nervous System Injuries: An Analytic Review of Literature and Recommendations.

Pneumonia is one of the most common complications in intensive care units and is the most common nosocomial infection in this setting. Patients with neurocritical conditions who are admitted to ICUs are no exception, and in fact, are more prone to infections such as pneumonia because of factors such as swallow dysfunction, need for mechanical ventilation, longer length of stay in hospitals, etc. Common central nervous system pathologies such as ischemic stroke, traumatic brain injury, subarachnoid hemorrhage, intracerebral hemorrhage, neuromuscular disorders, status epilepticus, and demyelinating diseases can cause long in-hospital admissions and increase the risk of pneumonia each with a mechanism of its own. Brain injury-induced immunosuppression syndrome is usually considered the common mechanism through which patients with critical central nervous system conditions become susceptible to different kinds of infection including pneumonia. Evaluating the patients and assessment of the risk factors can lead our attention toward better infection control in this population and therefore decrease the risk of infections in central nervous system injuries.