High-grade Brain Tumors Research Articles

Phase I trial of sargramostim/pelareorep therapy in pediatric patients with recurrent or refractory high-grade brain tumors.

BackgroundBrain tumors are the leading cause of cancer death for pediatric patients. Pelareorep, an immunomodulatory oncolytic reovirus, has intravenous efficacy in preclinical glioma models when preconditioned with GM-CSF (sargramostim). We report a phase I trial with the primary goal of evaluating the safety of sargramostim/pelareorep in pediatric patients with recurrent or refractory high-grade brain tumors and a secondary goal of characterizing immunologic responses.MethodsThe trial was open to pediatric patients with recurrent or refractory high-grade brain tumors (3 + 3 cohort design). Each cycle included 3 days of subcutaneous sargramostim followed by 2 days of intravenous pelareorep. Laboratory studies and imaging were acquired upon recruitment and periodically thereafter.ResultsSix patients participated, including three glioblastoma, two diffuse intrinsic pontine glioma, and one medulloblastoma. Two pelareorep dose levels of 3 × 108 and 5 × 108 tissue culture infectious dose 50 (TCID50) were assessed. One patient experienced a dose limiting toxicity of persistent hyponatremia. Common low-grade (1 or 2) adverse events included transient fatigue, hypocalcemia, fever, flu-like symptoms, thrombocytopenia, and leukopenia. High-grade (3 or 4) adverse events included neutropenia, lymphopenia, leukopenia, hypophosphatemia, depressed level of consciousness, and confusion. All patients progressed on therapy after a median of 32.5 days and died a median of 108 days after recruitment. Imaging at progression did not show evidence of pseudoprogression or inflammation. Correlative assays revealed transient but consistent changes in immune cells across patients.ConclusionsSargramostim/pelareorep was administered to pediatric patients with recurrent or refractory high-grade brain tumors. Hyponatremia was the only dose limiting toxicity (DLT), though maximum tolerated dose (MTD) was not determined.

Evaluation of MGMT Gene Methylation in Neuroendocrine Neoplasms.

Unresectable neuroendocrine neoplasms (NENs) often poorly respond to standard therapeutic approaches. Alkylating agents, in particular temozolomide, commonly used to treat high-grade brain tumors including glioblastomas, have recently been tested in advanced or metastatic NENs, where they showed promising response rates. In glioblastomas, prediction of response to temozolomide is based on the assessment of the methylation status of the MGMT gene, as its product, O 6-methylguanine-DNA methyltransferase, may counteract the damaging effects of the alkylating agent. However, in NENs, such a biomarker has not been validated yet. Thus, we have investigated MGMT methylation in 42 NENs of different grades and from various sites of origin by two different approaches: in contrast to methylation-specific PCR (MSP), which is commonly used in glioblastoma management, amplicon bisulfite sequencing (ABS) is based on high-resolution, next-generation sequencing and interrogates several additional CpG sites compared to those covered by MSP. Overall, we found MGMT methylation in 74% (31/42) of the NENs investigated. A higher methylation degree was observed in well-differentiated tumors and in tumors originating in the gastrointestinal tract. Comparing MSP and ABS results, we demonstrate that the region analyzed by the MSP test is sufficiently informative of the MGMT methylation status in NENs, suggesting that this predictive parameter could routinely be interrogated also in NENs.

Diffuse Intrinsic Pontine Glioma in an 11-Year- Old Female Treated with Antineoplastons: Complete Response and >25 Years Survival

Rationale: Diffuse intrinsic pontine glioma (DIPG), a lethal brain tumor, is the leading cause of brain tumor–related death in children. Over the past few decades clinical trials have shown no improvement in outcome. The purpose of this case study is to detail and discuss the use of Antineoplastons A-10 (Atengenal) and AS2-1 (Astugenal) in the treatment of an eleven-year-old female with a newly diagnosed DIPG. Objectives: The patient described here was enrolled into BT-11, a Phase II protocol utilizing Antineoplastons A-10 and AS2-1 in the treatment of brainstem gliomas. The patient’s tumor response to therapy was measured by sequential MRIs of the brain, with and without gadolinium contrast. Findings: At her presentation to the Burzynski Clinic (BC), the patient was alert, and weighed 42.1 Kg. Physical examination showed dysfunction of the 6th and 7th cranial nerves, with lateral movement of the left eye being decreased by approximately 30% and with left-sided facial weakness being present. The patient obtained a baseline MRI, with and without gadolinium. Post-gadolinium T1-weighted axial images showed a 0.80 cm2 enhancing pontine mass and a 2.70 cm2 non-enhancing left-sided brainstem mass. Following Antineoplastons (ANP), the patient achieved a complete response (CR) of the enhancing pontine mass. At that time, physical examination, especially neurologic examination, showed no abnormalities. The patient was last seen at the BC on October 15, 2004 and she was in excellent health with no evidence of new/recurrent disease. On August 10, 2021, correspondence with the patient indicated that she continued in excellent health (>25 years survival). Conclusions: ANP is an effective treatment for DIPG and for a variety of low- and high-grade brain tumors. Multiple Phase II protocols utilizing ANP have now been completed and its impact on the treatment of brain tumors has been widely published.

Molecular mechanisms of drug resistance of glioblastoma. Part 1: ABC family proteins and inhibitors

The most common high-grade brain tumor in the adult population is glioblastoma. The life expectancy of patients with this tumor does not exceed 12-15 months, while relapses are observed in 100% of cases. One of the main reasons for the low efficiency of glioblastoma therapy is its multidrug resistance. In the development of the latter, transporter proteins of the ABC family play a key role. In this part, the emphasis is on the search for new molecular targets among growth factors, their receptors, signal transduction kinases, microRNAs, transcription factors, protooncogenes, and tumor suppressor genes involved in the regulation of proteins and genes of the ABC family and associated with the development of multidrug resistance in glioblastoma cells. The review also discusses the mechanisms of the cytotoxic action of inhibitors: ABC family proteins, tyrosine kinase receptors, non-receptor tyrosine kinases, vascular endothelial growth factor, kinases of signaling cascades, transcription factors, histone deacetylases, methyltransferases, replication and synthesis of DNA, microtubules and proteasome used in glioblastoma therapy or undergoing clinical trials.

OL92 - Radiomics features of 11[C]-MET PET/CT in primary brain tumors: preliminary results on grading discrimination using a machine learning model

1096 Background: Nowadays Artificial Intelligence (AI) algorithms have demonstrated remarkable progress in image-recognition tasks and could be useful for the new concept of precision medicine in order to help physicians in the choice of therapeutic strategies for brain tumors. Previous data suggest that, in primary brain tumor, amino acid PET may demarcate more accurately the active disease than paramagnetic enhanced MRI that is the standard method of the evaluation in brain tumors and help in the evaluation of disease grading, as a fundamental basis for the correct clinical management of these patients. The aim of this study is to propose a radiomics workflow in order to create a predictive model on 11[C]-MET PET/CT scan images capable to discriminate between low-grade and high-grade primary brain tumors. Materials and Methods: in this retrospective study we selected fifty-six patients affected by primary brain tumor who underwent 11[C]-MET PET/CT from January 2016 to December 2019 at the Nuclear Medicine department of the Cannizzaro Hospital of Catania. Histological specimen the analysis was available in all patients in order to confirm the diagnosis and grading disease. PET/CT acquisition was performed after 10 minutes from the administration of 11C-Methionine (401-610 MBq) for a time acquisition of 15 minutes. 11[C]-MET PET/CT images were acquired using two scanners (24 patients on a Siemens scan and 32 patients on a GE scan). Then, LIFEx software was used to perform the segmentation and the extraction of features in order to identify the volume of interest (VOI) and to extract features of first, second, and third-order. LIFEx calculates 44 RF reflecting the VOI shape, the VOI voxel values, the histogram of VOI values, or the VOI textural content. A novel mixed descriptive-inferential sequential approach was used to identify a subset of relevant features that correlate with the outcome. A machine learning model based on discriminant analysis was tested in the evaluation of grading prediction (low vs high-grade) of 11[C]-MET PET/CT. Results: The machine learning model applicated in this study to stratify brain tumors as “low” and “high” grade showed discriminant texture features as follow: two features in fixed ROI respectively NGLDM Busyness (p-value: 0.1615) and GLZLM LZLGE (p-value 0.3207); three features in total volume respectively SHAPE Sphericity (p-value 0.0314), SHAPE Compacity (p-value 0.0215) and HISTO Kurtosis (p-value 0.0232). The results of performances, using a semi-automatic and user-independent segmentation process and an innovative feature extraction process on fixed ROI, showed a good performance in prediction of disease grade with an accuracy of 70.31% (AUC 64.13%) in all patients, of 80.51% (AUC 65.73%) in GE tomograph, of 84.98%(AUC 78.91%) in Siemens Tomograph. Using our model of machine learning with discriminant analysis the results of the performances were suboptimal in all patients group( 24 Siemens plus 32 GE) with an accuracy of 57.25 % and AUC of 58.51%. However in subgroup analysis, despite the low number of patients and different scanner, our model demonstrated good performances in the prediction of disease grade as follow: GE Scanner Accuracy 71.64 and AUC 62.8%; Siemens Scanner Accuracy 72,88% and AUC 78.91%. Conclusions: This preliminary study on radiomics features analysis of 11[C]-MET PET/CT suggests a possible value of Artificial Intelligence to assess primary brain tumors and to predict disease outcome in terms of grading discrimination at diagnosis. Further studies are needed to improve radiomics algorithms to personalize predictive and prognostic models and potentially support the medical decision process.

QOLP-37. MOOD DISTURBANCE IN PATIENTS WITH CENTRAL NERVOUS SYSTEM (CNS) TUMORS DURING THE COVID-19 PANDEMIC

BACKGROUNDPrimary CNS tumors are associated with uncertainty likely contributing to mood disturbance that is common throughout the disease trajectory. The intersection of the COVID-19 pandemic with a CNS tumor diagnosis may further impact the anxiety/depression experienced in this population. This study assessed key anxiety/depression symptoms in patients with CNS tumors prior to and during the COVID year.METHODSPatient reported outcomes (PROs), including the PROMIS Anxiety and Depression Short Forms and EQ-5D-3L, were collected at the time of clinical or telehealth evaluation from the COVID year (March 2020-February 2021) and were compared to assessments through February 2020 (a NOB-normative sample), reflecting what we would typically see in our regular clinic evaluations.RESULTSThe COVID sample (N = 178) was primarily White (82%), male (55%), median age of 45 (range 18–79), and KPS ³ 90 (50%). The majority had high grade (70%) brain (83%) tumors with ³ 1 prior recurrence (60%) and 25% were on active treatment. Visits were primarily conducted via telehealth (64%) and 20% had progression at assessment. Compared to the NOB-normative sample, patients reported significantly higher depression scores (moderate-severe, 17% vs. 12%, p < 0.05), but not anxiety (18% vs. 16%). Eleven percent reported both moderate-severe anxiety and depressive symptoms (8% pre-COVID). Overall health assessed by the EQ-5D-3L was similar to the normative sample in all dimensions, apart from impact of moderate/extreme mood disturbance, which was more prevalent in the COVID year (53% vs. 43%, p < 0.05%).CONCLUSIONPatients with CNS tumors are at risk for significant symptoms of depression and anxiety; this risk was heightened during the COVID year. Further evaluation of clinical factors associated with risk are underway. These findings highlight the need for assessments and interventions that can be administered via telehealth to address the mental health needs of this vulnerable population.Radiobiology

NCOG-23. PATIENT-REPORTED SYMPTOM BURDEN AND INTERFERENCE: A COMPARISON BETWEEN COVID-19 PANDEMIC YEAR AND NORMATIVE DATA IN PATIENTS WITH CENTRAL NERVOUS SYSTEM (CNS) TUMORS

CNS tumor patients are highly symptomatic causing interference with activity and worse quality of life. Social distancing due to the COVID-19 pandemic increased demands on the patient, caregivers, clinicians, and the health care system. The NCI’s Neuro-Oncology Branch Natural History Study (NHS) systematically collected patient-reported outcomes (PROs) provide insight into how these challenges influenced symptom burden and interference during the COVID year. METHODS: Patient and disease characteristic as well as patient-reported symptoms and interference (MDASI-BT/-SP) and general health status (EQ-5D-3L) from 3/2020-2/2021) were compared to NHS normative sample collected prior to 3/2020. RESULTS: The sample (n = 178) was primarily White (82%), male (55%), median age of 45 (range 18 – 79) and KPS ³ 90 (51%). The majority had high-grade (70%) brain (83%) tumors (BT) with ≥ 1 prior recurrence (60%) and 25% were on active treatment. Clinical visits were primarily conducted via telehealth (64%) and 20% of all patients were diagnosed with progression at the time of assessment. Most commonly reported moderate-severe symptoms among BT patients were fatigue (30%), difficulty remembering (28%), feeling drowsy (22%). Among spinal cord tumor patients, fatigue (39%), pain (35%) and numbness/tingling in arms/legs/trunk (35%) were most frequently reported. These symptoms were reported in similar frequencies by the normative sample. Nearly half of the COVID year sample (48%) reported moderate-severe activity-related interference. Reported problems with mobility (38%), self-care (19%), pain/discomfort (40%), and usual activities (50%) were similar in both groups except for increased mood disturbance (53%) was reported during the COVID year. CONCLUSION: These findings support CNS tumor patients remained highly symptomatic with significant impact on health-related quality of life during the COVID year. Clinicians should develop timely individual care plans to help BT patients navigate their disease course. Evaluation of risk associated with more severe symptoms and functional limitations are ongoing.

NCOG-42. SYMPTOM ONSET TO TIME OF DIAGNOSIS IN PRIMARY CENTRAL NERVOUS SYSTEM TUMOR PATIENTS: A REVIEW OF FINDINGS FROM THE NOB-NHS

Abstract Prior reports suggest the low prevalence of primary central nervous system (PCNS) tumors and the healthcare setting where patients seek care can contribute to diagnostic delays, potentially affecting prognosis. This descriptive report highlights findings from patient-reported data at presentation collected from a sample of 623 PCNS tumor patients. Participants were White (88%), males (56%), median age at diagnosis 41 (2-79) with high grade (HG) (66%) brain tumors (BT) (89%). Among BT patients, 30% reported ≥ 3 concurrent symptoms at presentation including headaches (40%), seizures (30%), and memory problems or difficulty with balance/walking (20% each). Over half (57%) had symptoms for &amp;lt; 6 months before diagnosis and 60% presented to the Emergency Room. Sixty-five percent of HG BT patients had symptoms for &amp;lt; 6 months prior to diagnosis compared to low grade (LG) tumors (40%) and had surgery in &amp;lt; 1 month from presentation (68% vs 51%, p &amp;lt; 0.01). More HG BT patients presented with weakness in the arms/legs than LG BT (14% vs 8%). Among spine tumor (ST) patients, 45% reported ≥ 3 concurrent symptoms at presentation including back pain (65%), sensory changes (45%), and weakness (40%). Almost half (46%) were symptomatic for &amp;gt; 1 year before diagnosis, presented in an outpatient clinic (64%) with 41% having surgery &amp;lt; 1 month from presentation. Younger (40% vs 16%) and HG ST patients (56% vs 21%) more often reported symptoms for &amp;lt; 6 months before diagnosis. HG ST patients more often presented to Emergency Rooms (67% vs 25%) and had surgery &amp;lt; 1 month from presentation (60% vs 36%). Further analysis of symptom presentation and clinical course is ongoing. Tumor location, grade, patient age and healthcare setting were associated with the time from clinical presentation to diagnosis. Development of aids providing guidance on diagnostic evaluation/treatment to front-line healthcare providers is warranted.

SLUG and Truncated TAL1 Reduce Glioblastoma Stem Cell Growth Downstream of Notch1 and Define Distinct Vascular Subpopulations in Glioblastoma Multiforme.

Simple SummaryGlioblastoma multiforme is the most aggressive form of brain tumor and is still incurable. These neoplasms are particularly difficult to treat efficiently because of their highly heterogeneous and resistant characteristics. Advances in genomics have highlighted the complex molecular landscape of these tumors and the need to further develop effective and targeted therapies for each patient. A specific population of cells with enriched stem cell properties within tumors, i.e., glioblastoma stem cells (GSC), drives this cellular heterogeneity and therapeutical resistance, and thus constitutes an attractive target for the design of innovative treatments. However, the signals driving the maintenance and resistance of these cells are still unclear. We provide new findings regarding the expression of two transcription factors in these cells and directly in glioblastoma patient samples. We show that these proteins downregulate GSC growth and ultimately participate in the progression of gliomas. The forthcoming results will contribute to a better understanding of gliomagenesis.Glioblastomas (GBM) are high-grade brain tumors, containing cells with distinct phenotypes and tumorigenic potentials, notably aggressive and treatment-resistant multipotent glioblastoma stem cells (GSC). The molecular mechanisms controlling GSC plasticity and growth have only partly been elucidated. Contact with endothelial cells and the Notch1 pathway control GSC proliferation and fate. We used three GSC cultures and glioma resections to examine the expression, regulation, and role of two transcription factors, SLUG (SNAI2) and TAL1 (SCL), involved in epithelial to mesenchymal transition (EMT), hematopoiesis, vascular identity, and treatment resistance in various cancers. In vitro, SLUG and a truncated isoform of TAL1 (TAL1-PP22) were strongly upregulated upon Notch1 activation in GSC, together with LMO2, a known cofactor of TAL1, which formed a complex with truncated TAL1. SLUG was also upregulated by TGF-β1 treatment and by co-culture with endothelial cells. In patient samples, the full-length isoform TAL1-PP42 was expressed in all glioma grades. In contrast, SLUG and truncated TAL1 were preferentially overexpressed in GBMs. SLUG and TAL1 are expressed in the tumor microenvironment by perivascular and endothelial cells, respectively, and to a minor extent, by a fraction of epidermal growth factor receptor (EGFR) -amplified GBM cells. Mechanistically, both SLUG and truncated TAL1 reduced GSC growth after their respective overexpression. Collectively, this study provides new evidence for the role of SLUG and TAL1 in regulating GSC plasticity and growth.

Classification of Low-Grade and High-Grade Glioma from MR Brain Images Using Multiple-Instance Learning with Combined Feature Set

Fully automatic brain image classification of MR brain images is of great importance for research and clinical studies, since the precise detection may lead to a better treatment. In this work, an efficient method based on Multiple-Instance Learning (MIL) is proposed for the automatic classification of low-grade and high-grade MR brain tumor images. The main advantage of MIL-based approach over other classification methods is that MIL considers an image as a group of instances rather than a single instance, thus facilitating an effective learning process. The mi-Graph-based MIL approach is proposed for this classification. Two different implementations of MIL-based classification, viz. Patch-based MIL (PBMIL) and Superpixel-based MIL (SPBMIL), are made in this study. The combined feature set of LBP, SIFT and FD is used for the classification. The accuracies of low-grade–high-grade tumor image classification algorithm using SPBMIL method performed on [Formula: see text], [Formula: see text] and FLAIR images read 99.2765%, 99.4195% and 99.2265%, respectively. The error rate of the proposed classification system was noted to be insignificant and hence this automated classification system could be used for the classification of images with different pathological conditions, types and disease statuses.

CaPaBLE: Comparing the Patient Generated Index to standard quality of life measures in patients and caregivers affected by high-grade brain tumours - Preliminary analysis

Abstract Aims High grade gliomas are rare but have the highest number of cancer deaths in the under-40s. Treatment options are limited, resulting in a clinical focus on maintaining quality of life (QoL). However standard QoL assessment tools are time consuming, may not reflect an individual’s priorities, and are rarely used in clinical practice. Moreover, the impact of caring for someone with a high grade glioma is seldom assessed. An alternative approach to assessing quality of life is to use a patient - or carer-generated index (PGI/CaGI), which asks patients &amp; carers to raise, rank and number their concerns. This may offer a route to individualised QoL assessments within clinical and research settings. The CaPaBLE study tests the feasibility and acceptability of the PGI and CaGI methodology in patients with high-grade glioma and their caregivers. This paper highlights key similarities and differences of the PGI/CaGI to standard QoL questionnaires. Method CaPABLE is an observational phase 2 non-randomised study following patients and their caregivers over 6 months starting at either first diagnosis or recurrence (https://www.isrctn.com/ISRCTN45555598). Patients and caregivers complete both standard questionnaires (EORTC QLQ C30 &amp; BN20 and CargoQOL) and PGI/CAGI at 5 timepoints over the 6 month period. Each time the patients/caregivers complete the PGI/CAGI they are asked to identify up to 5 main topics of concern for their QoL, to score these, and rank their importance. For this analysis, we grouped topics into themes, compared the stability of themes over time and to EORTC domains. Analyses of EORTC measures are conducted using standard scoring approaches. Here we present an initial analysis of occurrence of PGI/CaGI themes compared to EORTC domains, but do not consider scores or ranking. Results 6 patients (4 male) and 5 caregivers (3 female; 4 paired with patients; one unpaired) have completed both standard questionnaire and PGI/CaGI at three or more time points, with a total of 19 (patient) and 18 (caregiver) assessments. On average people reported 3 topics at each assessment. The PGI generated 59 topics (32 themes); the CaGI, 50 topics (23 themes) and themes were consistent over time. The most common domain raised by patients was “social life” (13). Caregivers raised “personal life and family” (12 and “planning ahead” (7) more commonly. Of the 32 PGI themes, 23 align with EORTC domains. 9 PGI themes were not represented in the EORTC questionnaires, and 14 EORTC domains did not appear in the PGI. Of the 23 CaGI themes, 17 align with 7 CarGOQOL domains. 6 CaGI themes were not represented in the CarGOQOL and 3 CarGOQOL domains did not appear in the CaGI. Conclusion PGI and CaGI themes coincide with the main domains of EORTC (i.e., cognitive, social, role, physical, emotional functioning, future uncertainty). However, there were significant discrepancies: PGI (e.g., intimacy, ability to drive, and COVID related restrictions) and CaGI (e.g. personal life &amp; family) highlighted themes that are not in the standard questionnaires. Both PGI/CaGI and standard questionnaires agree that symptom-related issues such as pain and seizures are not the main priority when it comes to QoL. In addition, CarGOQOL reports positive aspects of care, whereas CaGI only raised negative areas. This study is the first to show the feasibility of PGI/CaGI in a brain tumour patient &amp; caregiver population. PGI/CaGI are notably quicker to complete and provide insights not captured by standard questionnaires. We are continuing to recruit patients and caregivers, and have submitted a protocol amendment to carry out qualitative interviews with patients and caregivers, to explore their views further.

Magnetic Resonance Imaging Mapping of Brain Tumor Burden: Clinical Implications for Neurosurgical Management: Case Report.

ABSTRACTBACKGROUND AND IMPORTANCEDistinction of brain tumor progression from treatment effect on postcontrast magnetic resonance imaging (MRI) is an ongoing challenge in the management of brain tumor patients. A newly emerging MRI biomarker called fractional tumor burden (FTB) has demonstrated the ability to spatially distinguish high-grade brain tumor from treatment effect with important implications for surgical management and pathological diagnosis.CLINICAL PRESENTATIONA 58-yr-old male with glioblastoma was treated with standard concurrent chemoradiotherapy (CRT) after initial resection. Throughout follow-up imaging, the distinction of tumor progression from treatment effect was of concern. The surgical report from a redo resection indicated recurrent glioblastoma, while the tissue sent for pathological diagnosis revealed no tumor. Presurgical FTB maps confirmed the spatial variation of tumor and treatment effect within the contrast-agent enhancing lesion. Unresected lesion, shown to be an active tumor on FTB, was the site of substantial tumor growth postresection.CONCLUSIONThis case report introduces the idea that a newly developed MRI biomarker, FTB, can provide information of tremendous benefit for surgical management, pathological diagnosis as well as subsequent treatment management decisions in high-grade glioma.

Cytotoxic effects and tolerability of gemcitabine and axitinib in a xenograft model for c-myc amplified medulloblastoma

Medulloblastoma is the most common high-grade brain tumor in childhood. Medulloblastomas with c-myc amplification, classified as group 3, are the most aggressive among the four disease subtypes resulting in a 5-year overall survival of just above 50%. Despite current intensive therapy regimens, patients suffering from group 3 medulloblastoma urgently require new therapeutic options. Using a recently established c-myc amplified human medulloblastoma cell line, we performed an in-vitro-drug screen with single and combinatorial drugs that are either already clinically approved or agents in the advanced stage of clinical development. Candidate drugs were identified in vitro and then evaluated in vivo. Tumor growth was closely monitored by BLI. Vessel development was assessed by 3D light-sheet-fluorescence-microscopy. We identified the combination of gemcitabine and axitinib to be highly cytotoxic, requiring only low picomolar concentrations when used in combination. In the orthotopic model, gemcitabine and axitinib showed efficacy in terms of tumor control and survival. In both models, gemcitabine and axitinib were better tolerated than the standard regimen comprising of cisplatin and etoposide phosphate. 3D light-sheet-fluorescence-microscopy of intact tumors revealed thinning and rarefication of tumor vessels, providing one explanation for reduced tumor growth. Thus, the combination of the two drugs gemcitabine and axitinib has favorable effects on preventing tumor progression in an orthotopic group 3 medulloblastoma xenograft model while exhibiting a favorable toxicity profile. The combination merits further exploration as a new approach to treat high-risk group 3 medulloblastoma.

Coagulation Activation in Brain Neoplasms

Introduction:Cancer patients are at increased risk for venous thromboembolism (VTE), and patients with brain tumors have a VTE risk of up to 30% over the course of the disease. Factors contributing to VTE risk include age ≥60 years, obesity, glioblastoma histology, large tumor size, subtotal resection, leg paresis and treatment with surgery, radiation or chemotherapy.Coagulation activation occurs in cancer patients via several mechanisms including up-regulation of tumor or microparticle-associated tissue factor (TF) and procoagulant molecules, downregulation of tissue factor pathway inhibitor (TFPI), thrombomodulin (TM), increased plasminogen activator inhibitor (PAI-1), all resulting in increased thrombin generation and a systemic prothrombotic state.We hypothesized that patients with glioblastoma multiforme (GBM), a high-grade malignant brain tumor, exhibit increased systemic coagulation activation compared to healthy individuals and patients with benign meningiomas. We tested this hypothesis by measuring thrombin generation (TG) as a surrogate marker of systemic coagulation activation in patients with GBM and meningiomas and in age and sex matched healthy controls for comparison.Methods:This study was supported by grants from the Northern New England Clinical Oncology Society and the Neuro-oncology section at Dartmouth-Hitchcock Medical Center. The primary objective was to compare the pre-surgical peak TG in the GBM and healthy control groups. Secondary objectives were to 1) compare pre-surgical peak TG in the meningioma and healthy control groups and 2) compare tumor volumes on MRI with TG in patients with GBM and meningiomas.Patients with a new GBM or meningioma (W.H.O. grade 1 or 2) for whom a debulking procedure or surgical resection was planned were eligible. Patients with an additional active malignancy, history of idiopathic VTE at any time or provoked VTE within 5 years of entry, current treatment with an anticoagulant for any reason within the last 90 days or a surgical procedure other than a skin biopsy within the previous 30 days were excluded.After informed consent, 20 mL of blood was collected from subjects in 3.2% sodium citrate tubes prior to surgery. An additional 20 ml of blood was collected from GBM subjects 3 to 6 weeks after surgery. Platelet-poor plasma was prepared by centrifugation and stored at -80°C until analysis. TG was measured in nanomoles (nm) with a calibrated automated thrombogram assay (Thrombinoscope BV, Maastricht, Netherlands) using 1 pM TF and 4 uM phospholipids to trigger coagulation reactions. Statistical analysis was performed using Student's t-test for comparisons between groups.All GBM and meningioma subjects had pre-operative MRI scans. The highest resolution available gadolinium-enhanced anatomic scan (MPRAGE, T1-FLAIR, BRAVO, etc) was manually segmented by one of two trained segmenters to label tumor areas, with results reviewed, adjusted, and confirmed by a practicing neuroradiologist. Tumor volumes were then calculated as the number of labeled voxels times voxel volume (0.39-4.64 mm^3).Results:Fifty-eight patients consented to participate in the study. There were 15 screen failures and of the 43 patients included in the study, 20 had GBM and 23 had meningiomas. Blood from one age and sex-matched healthy blood donor was obtained for each study subject. The mean peak pre-op TG was 290 +/- 53 nm in the GBM cohort and 186 +/- 41 nm in controls; 242 +/- 55 nm in the meningioma cohort and 177 +/- 57 in controls. The p-value was <0.001 for all three pairwise comparisons. Only 9 post-op GBM samples were available for analysis. In this group, the mean pre-op TG was 323 nm +/- 38 nM and 273 nm +/- 47 nM post-op (p < 0.001). Two patients in the GBM group developed VTE with a mean peak TG of 364 nm compared to 290 nm for GBM patients without VTE (P = 0.04). We found no association between tumor volumes and pre-op TG.Conclusions:Peak TG was significantly higher in patients with GBM than in either patients with meningioma or healthy controls. TG decreased after tumor debulking surgery in GBM patients. Moreover, our results suggest that TG may be a useful marker for systemic coagulation activation in patients with GBM. Though our early results showing increased TG in GBM patients with VTE are provocative, more study is required to determine whether TG can be used to reliably predict VTE risk in this population. DisclosuresNo relevant conflicts of interest to declare.

Constitutional mismatch repair deficiency is a childhood cancer predisposition syndrome associated with an increased risk of high grade paediatric brain tumours: report of 3 cases and review of the literature

Background: Constitutional mismatch repair deficiency syndrome (CMMRD) represents a biallelic (homozygous or compound heterozygous) mutation in one of the mismatch repair genes (MLH1, MSH2, MSH6 or PMS2), resulting in a recessively inherited childhood cancer predisposition syndrome. A broad range of tumours in infants and children have been described in the CMMRD spectrum, most commonly brain tumours, intestinal tumours, and haematological malignancies. This contrasts with the monoallelic mismatch repair defects (MMR) of Lynch syndrome, in which there is an increased risk of development of malignancies in particular involving the gastrointestinal and genitourinary tract, with onset in adulthood. Phenotypic features of CMMRD overlap with neurofibromatosis, with café-au-lait macules a common finding in this cohort. Aims: To highlight an increasingly recognised childhood cancer predisposition syndrome, and the importance of identification of these cases given significant implications for family counselling. There is an increased cancer risk in siblings, as well as for the parents, who may not yet be aware of their own associated monoallelic MMR defect (Lynch syndrome). Methods: We present three cases of childhood primary brain tumours that were subsequently confirmed in the setting of CMMRD. The histological, immunohistochemical and genetic findings of these cases are discussed, with focus on diagnostic pathologic features that suggest an underlying CMMRD. Results and conclusions: Three high grade brain tumours described include two high grade gliomas (a glioblastoma multiforme and a high grade diffuse intrinsic pontine glioma, H3K27M negative), and a medulloblastoma. These examples all showed complete absence of PMS2 staining on immunohistochemistry in both tumour cells and normal ‘internal control’ tissues of the patient, correlating with biallelic loss of gene function. Review of the literature shows brain tumours as the most frequent presentation in children with CMMRD, with an increased risk of gastrointestinal tumours (including colonic carcinoma) and haematological malignancies also reported.

The Current Landscape of Oncolytic Herpes Simplex Viruses as Novel Therapies for Brain Malignancies.

Despite advances in surgical resection and chemoradiation, high-grade brain tumors continue to be associated with significant morbidity/mortality. Novel therapeutic strategies and approaches are, therefore, desperately needed for patients and their families. Given the success experienced in treating multiple other forms of cancer, immunotherapy and, in particular, immunovirotherapy are at the forefront amongst novel therapeutic strategies that are currently under investigation for incurable brain tumors. Accordingly, herein, we provide a focused mini review of pertinent oncolytic herpes viruses (oHSV) that are being investigated in clinical trials.

Functional Connectivity Networks and Their Recruitment During Working Memory Tasks in Adult Survivors of Childhood Brain Tumors.

Background: Assessments of functional connectivity of default mode network (DMN) and positive task-related networks (TRNs) using independent component analysis (ICA) may help describe long-term effects of childhood brain tumors and adjuvant treatments. Methods: Aiming to identify potential neuronal markers that may aid in prognosis and inform interventions to optimize outcomes, this study used ICA to evaluate the presence of functional connectivity networks and their recruitment during a letter n-back task in 23 adult survivors of childhood posterior fossa tumors (9 low grade, 14 high grade) at least 5 years past diagnosis compared with 40 age- and sex-matched healthy peers. Results: DMN components generally demonstrated increasing disengagement as task difficulty increased, and relationships between effective DMN disengagement and improved performance were observed in healthy controls (HCs). Low-grade brain tumor survivors (LGS) demonstrated unique patterns in DMN recruitment that suggested increased involvement of the medial prefrontal cortex in LGS during tasks. TRN components generally demonstrated increasing engagement, which was related to improved task performance in HCs for one executive control network (ECN) component. High-grade brain tumor survivors (HGS) demonstrated distinct challenges recruiting an ECN component at more difficult task levels and showed a relationship between recruitment of another ECN component and task performance, indicating a potential compensatory mechanism for some HGS. Conclusions: Findings suggest the importance of cognitive intervention in both survivor groups and the necessity to track LGS despite their cognitive abilities often resembling those of their healthy peers. Impact statement Distinct functional connectivity patterns were identified between both adult survivor of childhood brain tumor groups and peers during attention and working memory tasks, reflecting different damage and recovery from treatment. Survivors of low-grade tumors demonstrated unique patterns of recruitment of default mode network components in the context of similar cognitive abilities, whereas survivors of high-grade tumors demonstrated poorer cognitive abilities and may be utilizing compensatory executive control network components in the face of challenging tasks. Long-term clinical follow-up and cognitive remediation is warranted for both groups, including low grade cerebellar tumor patients who have traditionally not been monitored as closely.

EPCT-22 SAFETY AND EFFICACY OF INTRAVENTRICULAR IMMUNOVIROTHERAPY WITH ONCOLYTIC HSV-1 G207 FOR TREATMENT OF LEPTOMENINGEAL DISEASE

Leptomeningeal metastatic disease (LMD) occurs in 30–50% of newly diagnosed and recurrent pediatric malignant cerebellar tumors and 20–45% of malignant supratentorial tumors. Radiation and chemotherapy often cause substantial long-term neurotoxicity and outcomes remain poor for patients with LMD. At recurrence, LMD is generally minimally responsive to conventional therapies. Immunovirotherapy with engineered oncolytic HSV-1 G207 has emerged as a promising treatment for children with high-grade brain tumors. G207 infects and kills tumor cells while sparing normal cells and stimulates a robust anti-tumor immune response. Intratumoral G207 inoculation demonstrated safety and preliminary efficacy in a pediatric Phase 1 trial in recurrent/progressive high-grade glioma (NCT02457845), and a Phase 2 trial (NCT04482933) is forthcoming. Additionally, a Phase 1 trial of intratumoral G207 in recurrent/progressive malignant pediatric cerebellar tumors is ongoing (NCT03911388). While intratumoral inoculation delivers G207 directly to a primary tumor, it requires neurosurgical procedures thereby limiting repeat doses. Thus, we sought to establish the safety and efficacy of intraventricular G207. Utilizing an immunocompetent, HSV-sensitive murine strain, we determined that a standard 1x107 plaque-forming units (PFU) dose of G207 resulted in damage to the ependymal lining. However, interferon induction with an intraventricular low-dose (1x104 PFU) of G207 or polyinosinic-polycytidylic acid (poly I:C), a toll-like receptor 3 agonist, three days prior to standard treatment dose protected the ependymal lining. This approach enabled safe delivery of multiple subsequent doses. Importantly, with these protective measures, G207 significantly prolonged survival in pediatric patient-derived xenograft models and an immunocompetent murine LMD model of group 3 medulloblastoma, the most aggressive and fatal subtype. Collectively, these data indicate that toxicity from intraventricular G207 can be safely mitigated prior to a therapeutic dose, and that intraventricular G207 effectively targets group 3 medulloblastoma including LMD. These findings provide support for clinical translation of intraventricular G207.

EPCT-23 PRE-CLINICAL STUDY OF FOCUSED ULTRASOUND-MEDIATED BLOOD-BRAIN BARRIER OPENING AND PANOBINOSTAT FOR DIFFUSE INTRINSIC PONTINE GLIOMA TREATMENT

Diffuse intrinsic pontine glioma (DIPG) is the lethal high-grade brain tumor in children with no effective treatment options to date. Despite excessive clinical trials, the prognosis remains poor, with a median overall survival (mOS) of less than 1 year. Genomic studies of DIPG tissue have identified highly recurrent mutations in genes encoding histone H3 resulting in the substitution of lysine to methionine at position 27 (K27M), which is found in approximately 80% of DIPG. Recent drug screening studies identified the histone deacetylase (HDAC) inhibitors panobinostat as a highly effective drug against DIPG in vitro. However, due to the poor Blood-Brain Barrier (BBB) penetration of systemic administration, to enhance the delivery of panobinostat to improve treatment efficacy is needed. Focused ultrasound (FUS) has been shown to be able to safely and non-invasively open BBB to enhance drug delivery. Hence, in this study, we hypothesize that FUS-mediated BBBO (BBBO) can enhance the delivery of panobinostat for a therapeutic benefit in DIPG. Herein we established the syngeneic DIPG model by intracranially injecting mouse DIPG cells (PDGFB+, H3.3K27M, p53−/−) and used FUS and microbubbles to open BBB and enhance the panobinostat delivery. Magnetic resonance (MR) imaging was utilized to evaluate BBBO and tumor progression. We first demonstrated that FUS-mediated BBB-opening is safe and feasible to mice with DIPG tumors by MR imaging and passive cavitation detection. Moreover, this DIPG cell line is very sensitive to panobinostat in in vitro cytotoxicity assay. The combined treatment of FUS-mediated BBBO and panobinostat showed benefits in both local control and overall survival. The current results demonstrated FUS could increase the treatment efficacy of panobinostat to DIPG animals may be due to the increase of targeted delivery of systemic panobinostat to DIPG tumors in brainstem.

Hemodynamic and adaptive correlates of transcranial magnetotherapy in patients with high-grade malignant brain gliomas in the early postsurgery period

The results of this study have demonstrated the possibility of improving the efficiency of restoring hemodynamics and an adaptive status in patients with high-grade brain tumors by using transcranial magnetic therapy (TMT). The convenience and expediency of using the diagnostic criteria of the cardiac analyzer software CARDIOCODE consisted in obtaining complex digital data sets related to the main phase changes in the cardiac performance, energy supply and metabolism, associated with the corrective effect produced by TMT in the early postsurgery period. At the same time, it is noted that acting in concert by the cardiac performance can be provided against the background of the formation of a stable type of an integral reaction of calm activation