Treatment Of CNS Tumors Research Articles

Low-Basicity 5-HT6 Receptor Ligands from the Group of Cyclic Arylguanidine Derivatives and Their Antiproliferative Activity Evaluation

The serotonin 5-HT6 receptor (5-HT6R), expressed almost exclusively in the brain, affects the Cdk5 signaling as well as the mTOR pathway. Due to the association of 5-HT6R signaling with pathways involved in cancer progression, we decided to check the usefulness of 5-HT6R ligands in the treatment of CNS tumors. For this purpose, a new group of low-base 5-HT6R ligands was developed, belonging to arylsulfonamide derivatives of cyclic arylguanidines. The selected group of molecules was also tested for their antiproliferative activity on astrocytoma (1321N1) and glioblastoma (U87MG, LN-229, U-251) cell lines. Some of the molecules were subjected to ADMET tests in vitro, including lipophilicity, drug binding to plasma proteins, affinity for phospholipids, drug–drug interaction (DDI), the penetration of the membrane (PAMPA), metabolic stability, and hepatotoxicity as well as in vivo cardiotoxicity in the Danio Rerio model. Two antagonists with an affinity constant Ki < 50 nM (PR 68 Ki = 37 nM) were selected. These compounds were characterized by very high selectivity. An analysis of pharmacokinetic parameters for the lead compound PR 68 confirmed favorable properties for administration, including passive diffusion and acceptable metabolic stability (metabolized in 49%, MLMs). The compound did not exhibit the potential for drug–drug interactions.

In vitro metabolic stability and in vivo phaarmacokinetic behavior of panobinostat in mouse models for the treatment of CNS tumors

In vitro metabolic stability and in vivo phaarmacokinetic behavior of panobinostat in mouse models for the treatment of CNS tumors

Integral neuro-oncological diagnosis As the basis for personalized treatment Of brain tumors (on the example of gliomas In children)

Brain tumors are the most common group of neoplasms in children, which is in the top-3 causes of infant mortality from oncopathology. The aim of the study is to make a literature review of modern approaches to the personalization of treatment of CNS tumors in children based on the study of molecular genetics, immunohistochemical and imagingт characteristics. The article provides a description of the most common types of neoplasms of the nervous system — low grade gliomas (LGG), high grade gliomas (HGG), mixed glioneural tumors, etc. The molecular genetics, immunohistochemical, visualization characteristics of each type of gliomas are described. Modern information on prognosis and treatment of tumors is also given in the publication. The prognosis of the course of LGG/GNT in children depends more often on the patient’s age, histology, and location of the tumor, as well as its molecular profile. Older patients have a more favorable prognosis than younger children. Well-visualized tumors located superficially have a better outcome than diffuse gliomas, as well as deeply located tumors. Detection of BRAF mutations and FGFR rearrangements may indicate a better prognosis than in the presence of SNV. Local mutations of BRAF with concomitant deletion of CDKN2A, as well as mutations with H3.3 pK27 are the most dangerous.

P13.15.B ULTRA-FAST DEEP-LEARNED CNS TUMOR CLASSIFICATION DURING SURGERY

Abstract BACKGROUND Central nervous system (CNS) tumors are the most lethal category of tumors, particularly among children. Most commonly, the first line treatment of CNS tumors is neurosurgical resection of the tumor. During this procedure a delicate balance must be struck between extent of resection and risk of comorbidity. Ideally, the surgical plan is based on a detailed classification of the tumor. However this classification is often unknown at the start of the surgery. Current practice consists of preoperative imaging and intraoperative diagnosis achieved by rapid histological assessment of frozen tumor sections. However, these tests do not always result in a clear diagnosis, and are sometimes even revised based on postoperative tissue-based diagnostics. As a result, some patients require a second surgery, while others could in hindsight have been operated less radically. MATERIAL AND METHODS Nanopore sequencing enables direct detection of DNA methylation status in real time, making it ideally suited for intraoperative sequencing and molecular tumor classification. The major challenge of this approach is that the classification must be performed on very few randomly distributed sequence reads. To this end we developed Sturgeon, a neural-network training approach that delivers classification models capable of classifying 81 different CNS tumor subtypes based on sparse methylation data. Sturgeon leverages illumina 450K DNA methylation profiles to simulate millions of nanopore sequencing experiments, which are then used to train and validate classifier models. The resulting models are portable, work across patients and sequence depths and require less than a minute of computation on a laptop CPU. RESULTS We demonstrate our method to be fast enough to provide a correct diagnosis with as little as 20 to 40 minutes of sequencing in 45 out of 50 retrospective pediatric brain tumor samples. We applied Sturgeon in an intraoperative setting in 25 cases, where we consistently achieve a turnaround time of 60-90 minutes from biopsy to result with a correct molecular subclassification in 18 cases and an inconclusive result in 7 cases. CONCLUSION Sturgeon classification can be used in parallel with intraoperative frozen section histology. In cases where it agrees with the pathologist, Sturgeon offers a valuable independent confirmation, and a more detailed molecular subclassification. In the rare cases where Sturgeon disagrees with the histology diagnosis, or where the histology is inconclusive, it has the potential to prevent misdiagnoses that would result in unnecessary risk of comorbidity, or the requirement for a second surgery.

RONC-17. Feasibility of proton therapy with and without simultaneous chemotherapy in CNS malignancies of children and adolescents

Abstract BACKGROUND: Proton therapy (PT) is a valuable alternative to photon radiotherapy in treatment of CNS tumors in children and adolescents. The aim of this study was to investigate the feasibility of recent treatment strategies with a particular focus on the acute toxicity of a simultaneous radiotherapy and chemotherapy (sRCT). PATIENTS AND METHODS: We investigated 199 patients (116 male, 83 female, median age 7.4 years) who received in total 200 cycles of PT (60.5% at new diagnosis, 39.5% at relapse) from September 2013 to February 2017. Entities included ependymomas (34%), medulloblastomas (16%), low grade gliomas (13%), ATRTs (12%), craniopharyngiomas (9%), germ cell tumors (6%), and other entities (10%). SRCT was administered in 52 (26%) treatment cycles. The target tumor was predominantly localized infratentorial (53%), supratentorial (23.5%) and supra-/intrasellar (18%). 38 patients received additional CSI and 8 patients a boost to metastases. Data were collected retrospectively based on patient records. Toxicity was documented according to CTCAE version 4.03. RESULTS: Severe adverse events (SAE ≥ grade 3) occurred in 33.5% of all patients, in particular in form of hematotoxicity (64.1%) and infections (26.8%). In-patient treatment for unexpected SAEs was necessary in 33 patients (16.5%). In the group treated with sRCT 15 out of 52 (28.8%) patients couldn’t receive the recommended dose or time schedule of planned chemotherapy due to SAEs. Comparing the SAE frequency in both groups, the children who have been treated with sRCT had a significantly higher risk of SAEs than the patients who have received proton therapy only (63.5% vs. 23.0%, p=0.001). CONCLUSIONS: PT and concomitant chemotherapy are feasible, but require an interdisciplinary team with continuous out-/inpatient management of patients, as the risk of toxicity is significantly increased. Risk-adapted adjustment of simultaneous chemotherapy is necessary to reduce relevant interruptions of radiotherapy. Funded by the German Childhood Cancer Foundation

Radiation in Combination With Targeted Agents and Immunotherapies for Pediatric Central Nervous System Tumors - Progress, Opportunities, and Challenges.

Pediatric brain tumors are the most common solid tumors in children and represent a heterogenous group of diagnoses. While some are treatable with current standard of care, relapsed/refractory disease is common and some high-risk diagnoses remain incurable. A growing number of therapy options are under development for treatment of CNS tumors, including targeted therapies that disrupt key tumor promoting processes and immunotherapies that promote anti-tumor immune function. While these therapies hold promise, it is likely that single agent treatments will not be sufficient for most high-risk patients and combination strategies will be necessary. Given the central role for radiotherapy for many pediatric CNS tumors, we review current strategies that combine radiation with targeted therapies or immunotherapies. To promote the ongoing development of rational combination treatments, we highlight 1) mechanistic connections between molecular drivers of tumorigenesis and radiation response, 2) ways in which molecular alterations in tumor cells shape the immune microenvironment, and 3) how radiotherapy affects the host immune system. In addition to discussing strategies to maximize efficacy, we review principles that inform safety of combination therapies.

Molecular and Circulating Biomarkers of Brain Tumors.

Brain tumors are the most common malignant primary intracranial tumors of the central nervous system. They are often recognized too late for successful therapy. Minimally invasive methods are needed to establish a diagnosis or monitor the response to treatment of CNS tumors. Brain tumors release molecular information into the circulation. Liquid biopsies collect and analyze tumor components in body fluids, and there is an increasing interest in the investigation of liquid biopsies as a substitute for tumor tissue. Tumor-derived biomarkers include nucleic acids, proteins, and tumor-derived extracellular vesicles that accumulate in blood or cerebrospinal fluid. In recent years, circulating tumor cells have also been identified in the blood of glioblastoma patients. In this review of the literature, the authors highlight the significance, regulation, and prevalence of molecular biomarkers such as O6-methylguanine-DNA methyltransferase, epidermal growth factor receptor, and isocitrate dehydrogenase. Herein, we critically review the available literature on plasma circulating tumor cells (CTCs), cell-free tumors (ctDNAs), circulating cell-free microRNAs (cfmiRNAs), and circulating extracellular vesicles (EVs) for the diagnosis and monitoring of brain tumor. Currently available markers have significant limitations. While much research has been conductedon these markers, there is still a significant amount that we do not yet understand, which may account for some conflicting reports in the literature.

Brain Tumor Radiotherapy Role and Variation

Objectives: We report our experiences of brain tumors management by surgery and radiotherapyWhether It has been used as adjuvant, radical or palliative therapy belonging to benign or malignant tumors over 2 years period at ENT, neurosurgery and radiotherapy departments royal medical services. Methods: We used a retrospective study design to review all brain tumor patients(benign, malignant or metastatic) operated in neurosurgical department and referred to radiotherapy after discussing each case in multidisciplinary clinic in 2018 and 2019. Patient files, radiological images computed tomography (CT) or magnetic resonance imaging (MRI) scans), histo-pathological reports and radiotherapy management plan were reviewed for patients. Results: In total, 137 patients with brain tumor managed byradiotherapy 64 patients were metastatic, 37 patients high grad glioma, 12 patients atypical meningioma, 7 patients medulloblastoma, rest of cases discussed in the study . Conclusions: Radiotherapy has been fulfilling crucial part in the treatment of CNS tumors, where it has been implemented as adjuvant therapy or even being the solitary resort where surgery is inapplicable or used as palliative therapy in different regimens according to histopathology, performance status and different sites.

RONC-31. ADVANCED ECHOCARDIOGRAPHY WITH MYOCARDIAL-STRAIN-ANALYSIS DESCRIBES SUBCLINICAL CARDIAC DYSFUNCTION AFTER CRANIOSPINAL IRRADIATION (CSI) IN PEDIATRIC AND YOUNG ADULT PATIENTS WITH CENTRAL NERVOUS SYSTEM (CNS) TUMORS

CSI is part of the treatment of CNS tumors and is associated with cardiovascular disease; data in pediatric/young-adult patients are limited. Myocardial-strain-analysis can reveal subclinical dysfunction. Retrospective, single-center study in CNS tumor patients managed with CSI from 1986–2018. Clinical details, and echocardiography including myocardial-strain-analysis were collected at T1=first echocardiogram after CSI, and T2=most recent echocardiogram. Data are mean±standard deviation. Echocardiograms were available in 44 patients (36%female, 14±8.0years) at T1 and 39 patients (38%female, 21.0±11.3years) at T2. Standard echocardiography was normal for all subjects. At T1, global longitudinal peak systolic strain (GLS) was -16.3%±3.7% in CSI vs. -21.6%±3.5% in controls (p<0.0001); global radial peak systolic strain (GRS) was 21.5%±10.1% in CSI vs. 26.5%±7.4% in controls, and global circumferential peak systolic strain (GCS) was -19.5%±6.0% in CSI vs. -21.4%±3.4% in controls (p<0.05, both comparisons). At T2, GLS was -15.8%±5.2% in CSI vs. -21.9±3.5% in controls (p<0.0001); GRS was 22.6%±10.4% in CSI vs. 27.1±8.2% in controls (p<0.05); GCS was -20.5%±6.9% in CSI vs. -21.8±3.5% in controls (p=0.10). For 17 patients with myocardial-strain-analysis available for both time points: difference in GLS was 0.06±7.2% (p>0.95); GRS was 5.5±9.5% (p<0.05); GCS was -3.4±4.9% (p<0.05). Subclinical dysfunction is present at first echocardiogram after CSI. Myocardial impairment may recover with time, however further analysis is needed to identify risk factors and trends. These results argue for inclusion of baseline cardiovascular assessment and longitudinal follow-up in CNS tumor patients post CSI.

Improving Pediatric Neuro-Oncology Survival Disparities in the United States-Mexico Border Region: A Cross-Border Initiative Between San Diego, California, and Tijuana, Mexico.

PURPOSETreatment of children with CNS tumors (CNSTs) demands a complex, interdisciplinary approach that is rarely available in low- and middle-income countries. We established the Cross-Border Neuro-Oncology Program (CBNP) between Rady Children’s Hospital, San Diego (RCHSD), and Hospital General, Tijuana (HGT), Mexico, to provide access to neuro-oncology care, including neurosurgic services, for children with CNSTs diagnosed at HGT. Our purpose was to assess the feasibility of the CBNP across the United States-Mexico border and improve survival for children with CNSTs at HGT by implementing the CBNP.PATIENTS AND METHODSWe prospectively assessed clinicopathologic profiles, the extent of resection, progression-free survival, and overall survival (OS) in children with CNSTs at HGT from 2010 to 2017.RESULTSSixty patients with CNSTs participated in the CBNP during the study period. The most common diagnoses were low-grade glioma (24.5%) and medulloblastoma (22.4%). Of patients who were eligible for surgery, 49 underwent resection at RCHSD and returned to HGT for collaborative management. Gross total resection was achieved in 78% of cases at RCHSD compared with 0% at HGT (P < .001) and was a predictor of 5-year OS (hazard ratio, 0.250; 95% CI, 0.067 to 0.934; P = .024). Five-year OS improved from 0% before 2010 to 52% in 2017.CONCLUSIONThe CBNP facilitated access to complex neuro-oncology care for underserved children in Mexico through binational exchanges of resources and expertise. Survival for patients in the CBNP dramatically improved. Gross total resection at RCHSD was associated with higher OS, highlighting the critical role of experienced neurosurgeons in the treatment of CNSTs. The CBNP model offers an attractive alternative for children with CNSTs in low- and middle-income countries who require complex neuro-oncology care, particularly those in close proximity to institutions in high-income countries with extensive neuro-oncology expertise.

Antibodies for the Treatment of Brain Metastases, a Dream or a Reality?

The incidence of brain metastases (BM) in cancer patients is increasing. After diagnosis, overall survival (OS) is poor, elicited by the lack of an effective treatment. Monoclonal antibody (mAb)-based therapy has achieved remarkable success in treating both hematologic and non-central-nervous system (CNS) tumors due to their inherent targeting specificity. However, the use of mAbs in the treatment of CNS tumors is restricted by the blood–brain barrier (BBB) that hinders the delivery of either small-molecules drugs (sMDs) or therapeutic proteins (TPs). To overcome this limitation, active research is focused on the development of strategies to deliver TPs and increase their concentration in the brain. Yet, their molecular weight and hydrophilic nature turn this task into a challenge. The use of BBB peptide shuttles is an elegant strategy. They explore either receptor-mediated transcytosis (RMT) or adsorptive-mediated transcytosis (AMT) to cross the BBB. The latter is preferable since it avoids enzymatic degradation, receptor saturation, and competition with natural receptor substrates, which reduces adverse events. Therefore, the combination of mAbs properties (e.g., selectivity and long half-life) with BBB peptide shuttles (e.g., BBB translocation and delivery into the brain) turns the therapeutic conjugate in a valid approach to safely overcome the BBB and efficiently eliminate metastatic brain cells.

THE INFLUENCE OF NUTRITIONAL CHANGES ON THE MOTOR SKILLS IN CHILDREN WITH TUMORS OF CENTRAL NERVOUS SYSTEM AND ACUTE LYMPHOBLASTIC LEUKEMIA IN REMISSION

The paper presents the results of the analysis of associations between motor skills (MS) and nutritional status (NS) in 102 children who have received treatment of CNS tumors (n=53) and ALL (n=49). Median of remission interval was 2 years (from 3 month to 10 years). MS was evaluated by Bruininks-Oseretsky Test of Motor Proficiency. NS was assessed using anthropometry and bioimpedance analysis. As a result, it was found that children after cancer treatment have motor and nutritional deficiencies. Low values of NS indicators (lean body mass, cell mass, mid-arm muscle circumference (MAMC)) are associated with a decrease in MS parameters. There was no dependence between the value, dynamics of body fat mass and MS. In those children who had a positive dynamics (+3%) of the phase angle and MAMC for 3 weeks of the observation changes in MS were also significantly positive - in contrast to the overall sample, where any reliable dynamics of MS parameters was not revealed.

Use of hyperbaric oxygen therapy in pediatric neuro-oncology: a single institutional experience.

Hyperbaric oxygen therapy (HBOT) has been utilized as adjunctive treatment of CNS tumors and for radiation necrosis (RN) with reported success. The safety and efficacy in pediatric patients is less understood. Seven patients (ages 10-23 years, six females) were treated with HBOT (3-60 sessions) for either RN (n = 5) or tumor-associated edema (n = 2). Tumor diagnosis included low-grade glioma (n = 4, two with neurofibromatosis type 1), meningioma (n = 1), medulloblastoma (n = 1) and secondary high grade glioma (n = 1). Prior therapies included: surgery (n = 4), chemotherapy (n = 4) and radiation (N = 5: four focal, one craniospinal). Three underwent biopsy: one confirming RN, one high-grade glioma, and one low-grade glioma. Patients were assessed for clinical and radiographic changes post HBOT. Median time to clinical and radiographic presentation was 8.5months (range 6 months-11years) in those who had prior radiation. Clinical improvement after HBOT (median: 40 sessions) was observed in four of seven patients. Symptoms were stable in two and worsened in one patient. Radiographic improvement was seen in four patients; three had radiographic disease progression. In the subgroup treated for presumed and biopsy-confirmed RN (n = 5), four of five (80%) had clinical and radiographic improvement. There were no long-term adverse events due to HBOT. HBOT is safe and well-tolerated in pediatric and young adult patients with CNS tumors. Clinical and radiographic improvements were observed in over half of patients. Clinical trials are needed to establish safety and efficacy of HBOT as adjunct therapy in pediatric CNS tumors.

Complications of Radiotherapy and Radiosurgery in the Brain and Spine.

To recognize the main complications of radiation therapy and stereotactic radiosurgery in the brain and spine, and to highlight the imaging findings to improve the diagnostic process and treatment planning.

Abstract B125: A novel BBB-permeable chemotherapeutic agent for the treatment of CNS tumors

Abstract Standard of care for glioblastoma multiforme (GBM) patients is surgical tumor resection, followed by radiation and chemotherapy with temozolomide. Unfortunately, 60% of newly diagnosed GBM patients express high levels of the DNA repair enzyme MGMT and are temozolomide-insensitive, and all patients eventually become refractory to treatment. The blood-brain barrier (BBB) remains an obstacle to adequate delivery of chemotherapeutic agents to brain tumors. Lipophilic drugs such as temozolomide and lomustine are able to cross the BBB based on passive diffusion; however, their tissue distribution also causes toxicity to critical systemic organs, such as the bone marrow, leading to dose-limiting toxicity. Therefore, BBB-permeable chemotherapeutic agents that are efficacious in temozolomide-insensitive and refractory patients are needed. The large amino acid transporter 1 (LAT1) is highly expressed on the BBB and in GBM and other malignant brain tumors such as diffuse intrinsic pontine glioma (DIPG), where it is associated with poor prognosis, but is undetectable in normal brain tissue. Targeting LAT1 transport, while avoiding interaction with other closely related transporters expressed on normal tissue such as LAT2, will target brain tumors and avoid uptake into healthy tissue. We report the generation of a novel molecule (QBS10072S) that combines a potent cytotoxic domain with the structural features of a selective LAT1 substrate. QBS10072S is 50-fold more selective for LAT1 vs. LAT2 in transport assays, and demonstrates significant in vitro cytotoxicity to LAT1-expressing GBM cell lines and minimal cytotoxicity to normal human astrocytes (LAT1-negative). Unlike temozolomide, QBS10072S is cytotoxic to cells with both high and low levels of MGMT expression. In orthotopic glioblastoma xenografts, QBS10072S causes significant delay in tumor growth and increase in mouse survival compared to vehicle. QBS10072S is well tolerated, with no toxicity seen in normal brain or the BBB. In summary, QBS10072S is a novel BBB-permeable chemotherapeutic agent with the potential to treat temozolomide-insensitive and recurrent GBM. Citation Format: Theodore P. Nicolaides, Tomoko Ozawa, Tsun Wen Yao, Michael Prados, Wolf-Nicolas Fischer, Bernd Jandeleit, Kerry Koller. A novel BBB-permeable chemotherapeutic agent for the treatment of CNS tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B125.

Enhanced radiation efficiency by gold nanoparticles after proton beam irradiation in medulloblastoma cell lines

Introduction: In pediatric oncology, one quarter of patients is diagnosed with a tumor of the CNS. Although outcome did improve significantly during the last decade, prognosis of malignant CNS-tumors in childhood is still lagging behind and needs further improvement. Especially for relapse patients, prognosis is worse and curative therapy approaches are missed. Besides radical resection and chemotherapy, radiotherapy is standard of care. However, secondary malignancy after treatment of CNS-tumors in childhood occurs in 5.5% of cases, thus accounting for 19% of all secondary cancers in childhood tumors. Although proton beam irradiation allows to cover target volumes comparable to those achieved by photons, the main advantage of proton beams is sparing of healthy tissues. Recent in vitro and in vivo studies demonstrated an enhanced biological effect of proton therapy in the presence of gold nanoparticles. This held true both for irradiated cancer cells in vitro and in vivo. In this study we wanted to extend these findings to preclinical medulloblastoma models using proton beams and well-defined gold nanoparticles. Materials and methods: Three different medulloblastoma cell lines (DAOY, ONS76 and UW228) were cultured and treated with proton beam irradiation after incubation with gold nanoparticles or without. Three different doses of irradiation (6, 10 and 20 Gy) were evaluated. Stock solutions of gold nanoparticles were used in serial dilutions. Viability of medulloblastoma cells was evaluated by using MTT assays 72 hours after irradiation. Results: As expected, proton beam irradiation had the main effect on medulloblastoma cell viability. However, in our study gold nanoparticles had a cytotoxic effect at high concentrations (> 400 µg/ml). Proton beam irradiation in the presence of gold nanoparticles decreased the IC50 that was observed when cells were irradiated only. Conclusion: Confirming published data we could show enhanced biological effectiveness of proton beam irradiation in medulloblastoma cell lines in the presence of gold nanoparticles. Sensitization was directly correlated with radiation dose and the amount of gold nanoparticles per cell. Further investigation on the impact of particle size on toxicity as well as on enhanced radiation efficiency is needed.

Histological and morphometric characteristics of supratentorial meningiomas of the brain

The development of modern methods of clinical diagnosis and surgical treatment of CNS tumors necessitates reliable morphological verification of the tumor lesion with the definition of its histogenesis, morphological variant and degree of malignancy. Works on computer analysis of morphometric data of CNS tumors are rare. Meanwhile, histomorphometric studies have potential value for diagnostic purposes in the study of brain tumors.Goal: to conduct histological and morphometric analysis of the cellular composition of meningiomas, needed to improve their differential diagnosis.Material and methods. We studied surgically removed meningiomas in 39 patients aged from 40 to 66 years. 7 meningothelial meningiomas, 4 angiomatous, 6 fibrous, 7 transitional, 6 psammomatous, 2 atypical and 7 anaplastic meningiomas were included in the study.Histomorphometric analysis was performed on hematoxylin and eosin (H&amp;E)-stained histological sections. Calculation of quantitative indices was conducted using a computer system for digital image analysis KS 200 (Kontron Elektronik,Germany, lic. № 0200299). Studied objects (cell nuclei) were examined using morphometric measurements: cross-sectional area (AREA), the diameter of the object (the diameter of irregularly shaped objects was calculated through their equivalent area – parameter DCIRCLE). Coefficients (indices) of the form (FC) and elongation (EC) were used as additional morphometric characteristics of the studied objects.Results. Meningothelial meningiomas were represented by large cells with light nuclei with diffusely located fine chromatin. Most cells had a polygonal shape and did not have clear boundaries. The cell density in the field of vision averaged 55±5, cross-sectional area of the nuclei 45,24±4,77 µm2, FC and EC respectively 0,87±0,02 and 0,71±0,1.Transitional meningiomas were characterized by combined areas of meningothelial, syncytial type and areas with typical fibroblastic differentiation of cells. Two groups of cells were identified which differed in morphometric parameters: a cross-sectional area of nuclei, respectively 49,78±5,93 and 30,59± 4,16 µm2 and FC 0,87±0,05 and 0,67±0,10. EC were respectively 0,54±0,13 and 0,43±0,11.The predominant cell type in fibrous meningiomas were fibroblast-like arachnoendotheliocytes with oval, elongated nuclei containing fine chromatin, hyperchromic nuclei were frequent. Cells formed bundles going in different directions, concentric structures and psammoma bodies were often met. Tumor cell density was 46,6±13,22. In areas with fibrous extracellular matrix cells with cross-sectional area of the nuclei 37,13±4,47 µm2 dominated.Atypical meningiomas were characterized by increased cellularity – 82 cells in the field of view, more pronounced nuclear polymorphism, mitosis and the presence of small areas of necrosis. The cross sectional area of the nuclei of tumor cells was 65,78±16,97 µm2.The cross sectional area of the nuclei is significantly increased in atypical and anaplastic meningiomas, which reflects the increase in the degree of atypia (linear relationship between the degree of increasing area of the nuclei and Grade - strong positive correlation, Pearson coefficient r=0,89, p&lt;0.05).Conclusions. Conducted investigation indicates the feasibility of using a morphometric method for improving the diagnosis of various meningiomas. Prospects for further research in this area suggest the selection of reliable morphometric criteria for estimation of the recurrence rate and aggressiveness of meningiomas growth.

TU‐A‐BRA‐04: Choreographing Couch and Collimator in Volumetric Modulated Arc Therapy

Purpose: The Trilogy® MX (Varian Medical Systems) supports simultaneous motion of the couch, gantry and collimator during volumetric modulated arc therapy (VMAT). This study investigates the feasibility and potential advantages of treating CNS tumors using VMAT with such capabilities. Method and Materials: To guide the selection of couch, gantry and collimator trajectories, a score function estimates the geometric overlap between tumor and organs at risk (OAR) for each couch/gantry combination. An initial set of beam trajectory candidates includes couch and gantry combinations, that correspond to minima found in a search of the overlap score map excluding zones of collision and long beam paths through the patient. This set is clustered into multiple continuous arcs subject to mechanical limitations. Following determination of couch/gantry trajectories, a principal component analysis finds the collimator angle at each beam orientation that minimizes residual tumor‐OAR overlap. A purpose‐developed VMAT optimization algorithm determines the optimal MLC position and MU for control points within each arc. A planning study of seven CNS patients compared trajectory VMAT with dynamic gantry, leaf, couch and collimator motion (Tra‐VMAT), standard non‐coplanar VMAT (Std‐VMAT, no couch/collimator motion within subarcs), and non‐coplanar IMRT plans. Results: Tra‐VMAT yields improved tumor dose conformality, lowered maximum dose to optic nerve, brainstem and chiasm, by 6%, 1.8%, 0.9%, 1.3%, respectively, relative to Std‐VMAT. Tra‐VMAT also yields higher PTV minimum dose, reduced maximum dose to chiasm, optic nerve, and cochlea, and reduced cochlea mean dose, by 4.4%, 1.5%, 6.4%, 10.2%, 8.9%, respectively, relative to IMRT. Tra‐VMAT average beam‐on time is comparable to Std‐VMAT, but significantly (42%) less compared to IMRT. Conclusion: Optimized couch/collimator trajectories can be integrated with VMAT. Trajectory VMAT, with improved mechanical flexibility, results in better dosimetric properties and improved treatment efficiency in the treatment of CNS tumors. Conflict of Interest: Sponsered by Varian Medical System

Postural sway in children and young adults, survivors of CNS tumours

Brain tumours are the most common solid tumours in children and adolescents. The increasing survival rate of these patients makes their follow-up and quality of life assessment an important task. The evaluation of the negative influence of anti-cancer treatment on their balance is the aim of this study. The balance assessment was performed on patients who completed the treatment of CNS tumours and were disease-free at the time of the study. Eighty-eight patients aged 5 to 24 years participated in the study. Postural sway was recorded using Kistler force plate. Balance test parameters from two conditions: eyes open and eyes closed were calculated and compared with reference data. The severity of the balance disorders was scored for both conditions. The balance disorders were generally not dependent on the localisation of the tumour. Only patients treated for posterior fossa tumours had a higher score (indicating pronounced balance deficit) in eyes closed condition comparing to others. The patients treated for spinal cord tumours seemed to have increased total sway path in comparison to others. The severity of the balance deficits tended to diminish in time. These results suggest that the repair mechanisms of the CNS could overcome the problems inflicted by the illness and therapy.

Underappreciated delayed late complication of adult brain irradiation: development of cerebral cavernous malformations

Background:Cerebral cavernous malformations (CCM) are an uncommon delayed late complication of brain radiotherapy in adults. Aim: Describe an adult treated for a malignant glioma with chemotherapy and radiotherapy who subsequently presented with multiple CCM. Methods: Case report and literature review of CCM. Results:Multiple CCM were discovered in an adult following presentation with a symptomatic intracranial hemorrhage. Conclusion: The occurrence of CCM is an unusual delayed late radiation side effect following treatment of CNS tumors. Gradient echo MRI should be considered as a standard sequence in patients with previously treated brain tumors.