Radiotherapy For Brain Tumors Research Articles

Abstract 4808: ONC201 decreases protein chaperone ClpX to unleash mitochondrial protease ClpP activity, intregrated stress response and tumor cell death

Abstract Brain tumors are one of the most lethal cancers in children and young adults. We previously reported that first-in-class small-molecule imipridone ONC201 can antagonize dopamine receptor D2 (DRD2), inactivate ERK/AKT, induce the integrated stress response (ISR), upregulate pro-apoptotic TRAIL receptor DR5, deplete cancer stem cells, and induce growth arrest or cell death in tumor cells. ONC201 crosses the blood-brain barrier and has induced durable tumor regressions in adult and pediatric H3K27M-mutant glioma patients. We hypothesized that ONC201 may synergize with radiotherapy and temozolomide in brain tumors. Glioblastoma (GBM: SNB19, T98G and U251), diffuse intrinsic pontine glioma (DIPG: SU-DIPG-IV and SU-DIPG-36) and atypical teratoid rhabdoid tumor (ATRT: BT-12, BT-16) cell lines were tested using cell viability or colony formation assays with ONC201 up to 20 μM alone or in combination with radiotherapy up to 8 Gy and temozolomide up to 100 μM. We observed synergy between ONC201 and radiation and temozolomide by multiple assays with the best combination index of 0.31 under the treatment of 0.625 μM ONC201, 25 μM TMZ and 4 Gy irradiation in cell viability assay. We observed induction of PKA substrate phosphorylation as a marker of DRD2 antagonism, induction of ATF4 as a marker of ISR activation, and multiple markers of cell death in treated brain tumor cells. Mitochondrial dysfunction induced by ONC201 was greatly reflected in reduction of maximal cell respiration in brain tumor cell lines. ClpXP is a proteolytic machine in mitochondria comprising of the protein chaperone ClpX and protease ClpP, a recently described binding target of ONC201. We have observed that ONC201 induced cytotoxicity depends on ClpP and knockdown of ClpP strongly protects multiple human cancer cell lines from ONC201-mediated (but not other drugs, e.g. temozolomide) cytotoxicity. The ClpX protein level decreased dramatically upon ONC201 treatment. We are exploring the potential interplay between ClpP, dopamine receptors, the ISR and TRAIL signaling pathways after single agent or combinatorial treatments. Our data suggests that ONC201 may be combined synergistically with temozolomide or radiation to address gliomas, along with potential pharmacodynamic biomarkers. The results implicate ClpX and ClpP in downstream cell death induction following ONC201 treatment of brain tumor cells. Citation Format: Lanlan Zhou, Howard P. Safran, Michael J. Glantz, Wafik S. El-Deiry. ONC201 decreases protein chaperone ClpX to unleash mitochondrial protease ClpP activity, intregrated stress response and tumor cell death [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4808.

Laser interstitial thermal therapy in neuro-oncology applications.

Background: Laser interstitial thermal therapy (LITT) is a minimally invasive surgical treatment for multiple intracranial pathologies that are of growing interest to neurosurgeons and their patients and is emerging as an effective alternative to standard of care open surgery in the neurosurgical armamentarium. This option was initially considered for those patients with medical comorbidities and lesion-specific characteristics that confer excessively high risk for resection through a standard craniotomy approach but indications are changing.Methods: The PubMed database was searched for studies in the English literature on LITT for the treatment of primary and metastatic brain tumors, meningiomas, as well as for radiation necrosis (RN) in previously irradiated brain tumors.Results: This review provides an update of the relevant literature regarding application of LITT in neurosurgical oncology for the treatment of de novo and recurrent primary gliomas and brain metastases radiographically regrowing after previous irradiation as recurrent tumor or RN. In addition, this review details the limited experience of LITT with meningiomas and symptomatic peritumoral edema after radiosurgery. The advantages and disadvantages, indications, and comparisons to standard of care treatments such as craniotomy for open surgical resection are discussed for each pathology. Finally, the literature on cost-benefit analyses for LITT are reviewed.Conclusion: The studies discussed in this review have helped define the role of LITT in neurosurgical oncology and delineate optimal patient selection and tumor characteristics most suitable to this intervention.

Irradiation-Induced Upregulation of miR-711 Inhibits DNA Repair and Promotes Neurodegeneration Pathways.

Radiotherapy for brain tumors induces neuronal DNA damage and may lead to neurodegeneration and cognitive deficits. We investigated the mechanisms of radiation-induced neuronal cell death and the role of miR-711 in the regulation of these pathways. We used in vitro and in vivo models of radiation-induced neuronal cell death. We showed that X-ray exposure in primary cortical neurons induced activation of p53-mediated mechanisms including intrinsic apoptotic pathways with sequential upregulation of BH3-only molecules, mitochondrial release of cytochrome c and AIF-1, as well as senescence pathways including upregulation of p21WAF1/Cip1. These pathways of irradiation-induced neuronal apoptosis may involve miR-711-dependent downregulation of pro-survival genes Akt and Ang-1. Accordingly, we demonstrated that inhibition of miR-711 attenuated degradation of Akt and Ang-1 mRNAs and reduced intrinsic apoptosis after neuronal irradiation; likewise, administration of Ang-1 was neuroprotective. Importantly, irradiation also downregulated two novel miR-711 targets, DNA-repair genes Rad50 and Rad54l2, which may impair DNA damage responses, amplifying the stimulation of apoptotic and senescence pathways and contributing to neurodegeneration. Inhibition of miR-711 rescued Rad50 and Rad54l2 expression after neuronal irradiation, enhancing DNA repair and reducing p53-dependent apoptotic and senescence pathways. Significantly, we showed that brain irradiation in vivo persistently elevated miR-711, downregulated its targets, including pro-survival and DNA-repair molecules, and is associated with markers of neurodegeneration, not only across the cortex and hippocampus but also specifically in neurons isolated from the irradiated brain. Our data suggest that irradiation-induced miR-711 negatively modulates multiple pro-survival and DNA-repair mechanisms that converge to activate neuronal intrinsic apoptosis and senescence. Using miR-711 inhibitors to block the development of these regulated neurodegenerative pathways, thus increasing neuronal survival, may be an effective neuroprotective strategy.

Application of Diffusion Tensor Imaging-Based on Magnetic Resonance in Radiation Therapy of Brain Tumors

Diffusion Tensor Imaging (DTI) is a new Magnetic Resonance Imaging (MRI) method that is newly used in clinical practice with no traumatic advantages, which can quantitatively analyze the microstructure of the brain, such as quantitative analysis of the dispersion characteristics of lesions and normal tissues, thus providing more information for the diagnosis and differential diagnosis of diseases. At the same time, DTI has a unique advantage in the imaging of white matter fibers in the brain, can visually show the relationship between intracranial lesions, especially tumors and autologous fibers, more conducive to guiding the operation, in order to maximize the removal of tumors and protect functional areas. In order to make the dispersal volume better applied to clinical, this topic mainly hopes to provide a new basis for the benign-malignant classification of brain tumors and the diagnosis of different brain tumors, FA (fractional anisotropy) value. It can provide a stronger basis for the diagnosis of brain tumors, which is rarely done in previous research institutes. Previous studies have rarely dealt with the signal strength of FA diagrams, and extensive research in this area is needed. It is hoped that the signal strength of FA graphs will help diagnose different tumors and grade the malignant degree of brain tumors. Through this experiment, it can be proved that this purpose can be achieved by magnetic resonance dispersion volume imaging. In this study, a comparative analysis method was used to determine the ADC and FA values on the magnetic resonance dispersion weighted image and dispersal volume image of glioma and benign malignant meningioma, thus revealing the important role of this method in the diagnosis and differential diagnosis of tumors in the brain and its application value.

Cytomegalovirus Encephalopathy during Brain Tumor Irradiation.

Some patients with brain cancer show extremely short survival postradiochemotherapy treatment for unknown reasons. Recent work shows that this is closely linked to encephalopathy associated with reactivation of latent cytomegalovirus in the host. Importantly, survival can be enhanced by treatment with antiviral drugs.See related article by Goerig et al., p. 3259.

Targeted Brain Tumor Radiotherapy Using an Auger Emitter.

Glioblastoma multiforme is a highly aggressive form of brain cancer whose location, tendency to infiltrate healthy surrounding tissue, and heterogeneity significantly limit survival, with scant progress having been made in recent decades. 123I-MAPi (Iodine-123 Meitner-Auger PARP1 inhibitor) is a precise therapeutic tool composed of a PARP1 inhibitor radiolabeled with an Auger- and gamma-emitting iodine isotope. Here, the PARP inhibitor, which binds to the DNA repair enzyme PARP1, specifically targets cancer cells, sparing healthy tissue, and carries a radioactive payload within reach of the cancer cells' DNA. The high relative biological efficacy of Auger electrons within their short range of action is leveraged to inflict DNA damage and cell death with high precision. The gamma ray emission of 123I-MAPi allows for the imaging of tumor progression and therapy response, and for patient dosimetry calculation. Here we demonstrated the efficacy and specificity of this small-molecule radiotheranostic in a complex preclinical model. In vitro and in vivo studies demonstrate high tumor uptake and a prolonged survival in mice treated with 123I-MAPi when compared with vehicle controls. Different methods of drug delivery were investigated to develop this technology for clinical applications, including convection enhanced delivery and intrathecal injection. Taken together, these results represent the first full characterization of an Auger-emitting PARP inhibitor which demonstrate a survival benefit in mouse models of GBM and confirm the high potential of 123I-MAPi for clinical translation.

Modern Radiotherapy for Pediatric Brain Tumors.

Cancer is a leading cause of death in children with tumors of the central nervous system, the most commonly encountered solid malignancies in this population. Radiotherapy (RT) is an integral part of managing brain tumors, with excellent long-term survival overall. The tumor histology will dictate the volume of tissue requiring treatment and the dose. However, radiation in developing children can yield functional deficits and/or cosmetic defects and carries a risk of second tumors. In particular, children receiving RT are at risk for neurocognitive effects, neuroendocrine dysfunction, hearing loss, vascular anomalies and events, and psychosocial dysfunction. The risk of these late effects is directly correlated with the volume of tissue irradiated and dose delivered and is inversely correlated with age. To limit the risk of developing these late effects, improved conformity of radiation to the target volume has come from adopting a volumetric planning process. Radiation beam characteristics have also evolved to achieve this end, as exemplified through development of intensity modulated photons and the use of protons. Understanding dose limits of critical at-risk structures for different RT modalities is evolving. In this review, we discuss the physical basis of the most common RT modalities used to treat pediatric brain tumors (intensity modulated radiation therapy and proton therapy), the RT planning process, survival outcomes for several common pediatric malignant brain tumor histologies, RT-associated toxicities, and steps taken to mitigate the risk of acute and late effects from treatment.

Bevacizumab for the treatment of brain radionecrosis in cancer patients.

e19352 Background: Brain radionecrosis (BRN) occurs as a result of radiation therapy for brain tumors or metastatic brain lesions. BRN is characterized by an increase in permeability and disruption of the blood-brain barrier (BBB). There are currently no standard treatment options for BRN. While the mechanism of BRN is unknown, it is hypothesized that there is an inflammatory reaction of the local tissue to radiation which results in a continuous process involving endothelial cell dysfunction. This leads to tissue hypoxia and increased vascular endothelial growth factor (VEGF) which in turn causes capillary leakage, progressive BBB dysfunction, and cerebral edema. Bevacizumab (BEV), a humanized monoclonal antibody with action against VEGF, has recently been used in some studies for the treatment BRN. BEV essentially blocks VEGF from reaching its targets on the endothelium, thus making it an ideal treatment modality for BRN. Methods: The primary purpose of this study is to assess the effectiveness and safety of BEV for the treatment of BRN. Fifteen patients (pts), 14 diagnosed with lung cancer and one with breast cancer, that had BRN and treated with BEV between January 2014 and November 2019 were identified from Memorial Cancer Institute's database. A retrospective chart review analyzing pts's age, sex, BEV dose, dosing frequency, number of treatments received, medication-related adverse effects, and clinical benefit was conducted. Brain imaging pre-treatment and after four cycles of therapy were compared to assess the efficacy of BEV. Pts who exhibited clinical benefit (complete response (CR), partial response (PR), or stable disease (SD)) received an additional four cycles of treatment. Results: The median age was 65 years (y) (49-78y) and 10/15 (67%) of pts were female. Clinical benefit was achieved in 13/15 (87%) of pts. The most frequent dosing regimen administered was 10 mg/kg every two weeks and the median number of cycles given was eight cycles (1-12). Treatment with BEV was well tolerated with eight pts (53%) experiencing BEV-related Grade 2 or less adverse effects (AE), including hypertension (27%), proteinuria (13%), thrombocytopenia (7%), and mild nose bleeds (7%). There were no Grades 3-5 AE. Conclusions: This study demonstrates that there is a clinical benefit when administering BEV for the treatment of BRN. BEV was well tolerated and has an acceptable safety profile.

1-[(4-Nitrophenyl)sulfonyl]-4-phenylpiperazine treatment after brain irradiation preserves cognitive function in mice.

Normal tissue toxicity is an inevitable consequence of primary or secondary brain tumor radiotherapy. Cranial irradiation commonly leads to neurocognitive deficits that manifest months or years after treatment. Mechanistically, radiation-induced loss of neural stem/progenitor cells, neuroinflammation, and demyelination are contributing factors that lead to progressive cognitive decline. The effects of 1-[(4-nitrophenyl)sulfonyl]-4-phenylpiperazine (NSPP) on irradiated murine neurospheres, microglia cells, and patient-derived gliomaspheres were assessed by sphere-formation assays, flow cytometry, and interleukin (IL)-6 enzyme-linked immunosorbent assay. Activation of the hedgehog pathway was studied by quantitative reverse transcription PCR. The in vivo effects of NSPP were analyzed using flow cytometry, sphere-formation assays, immunohistochemistry, behavioral testing, and an intracranial mouse model of glioblastoma. We report that NSPP mitigates radiation-induced normal tissue toxicity in the brains of mice. NSPP treatment significantly increased the number of neural stem/progenitor cells after brain irradiation in female animals, and inhibited radiation-induced microglia activation and expression of the pro-inflammatory cytokine IL-6. Behavioral testing revealed that treatment with NSPP after radiotherapy was able to successfully mitigate radiation-induced decline in memory function of the brain. In mouse models of glioblastoma, NSPP showed no toxicity and did not interfere with the growth-delaying effects of radiation. We conclude that NSPP has the potential to mitigate cognitive decline in patients undergoing partial or whole brain irradiation without promoting tumor growth and that the use of this compound as a radiation mitigator of radiation late effects on the central nervous system warrants further investigation.

Cerebral Morbidity After Radiation Therapy for Brain Tumors

Cerebral Morbidity After Radiation Therapy for Brain Tumors

Endothelial Autophagy: an Effective Target for Radiation-induced Cerebral Capillary Damage

Toxicity to central nervous system tissues is the common side effects for radiotherapy of brain tumor. The radiation toxicity has been thought to be related to the damage of cerebral endothelium. However, because of lacking a suitable high-resolution vivo model, cellular response of cerebral capillaries to radiation remained unclear. Here, we present the flk:eGFP transgenic zebrafish larvae as a feasible model to study the radiation toxicity to cerebral capillary. We showed that, in living zebrafish larvae, radiation could induce acute cerebral capillary shrinkage and blood-flow obstruction, resulting brain hypoxia and glycolysis retardant. Although in vivo neuron damage was also observed after the radiation exposure, further investigation found that they didn’t response to the same dosage of radiation in vitro, indicating that radiation induced neuron damage was a secondary-effect of cerebral vascular function damage. In addition, transgenic labeling and qPCR results showed that the radiation-induced acute cerebral endothelial damage was correlated with intensive endothelial autophagy. Different autophagy inhibitors could significantly alleviate the radiation-induced cerebral capillary damage and prolong the survival of zebrafish larvae. Therefore, we showed that radiation could directly damage cerebral capillary, resulting to blood flow deficiency and neuron death, which suggested endothelial autophagy as a potential target for radiation-induced brain toxicity.

Neurocognitive Decline Following Radiotherapy: Mechanisms and Therapeutic Implications.

The brain undergoes ionizing radiation (IR) exposure in many clinical situations, particularly during radiotherapy for malignant brain tumors. Cranial radiation therapy is related with the hazard of long-term neurocognitive decline. The detrimental ionizing radiation effects on the brain closely correlate with age at treatment, and younger age associates with harsher deficiencies. Radiation has been shown to induce damage in several cell populations of the mouse brain. Indeed, brain exposure causes a dysfunction of the neurogenic niche due to alterations in the neuronal and supporting cell progenitor signaling environment, particularly in the hippocampus—a region of the brain critical to memory and cognition. Consequent deficiencies in rates of generation of new neurons, neural differentiation and apoptotic cell death, lead to neuronal deterioration and lasting repercussions on neurocognitive functions. Besides neural stem cells, mature neural cells and glial cells are recognized IR targets. We will review the current knowledge about radiation-induced damage in stem cells of the brain and discuss potential treatment interventions and therapy methods to prevent and mitigate radiation related cognitive decline.

An examination whether KCC2, a K<sup>+</sup>-Cl<sup>-</sup> co-transporter, is efficient as a target to attenuate the neuronal dysfunction that is associated with radiation therapy for brain tumor by using oxytocin.

An examination whether KCC2, a K<sup>+</sup>-Cl<sup>-</sup> co-transporter, is efficient as a target to attenuate the neuronal dysfunction that is associated with radiation therapy for brain tumor by using oxytocin.

Case Report: Anaplastic Astrocytoma Treated with Postoperative Radiotherapy Using Flattening Filter-Free Volumetric Arc Therapy (FFF-VMAT) during Pregnancy—Acceptable Fetal Dosimetry

Background: Postoperative irradiation for brain tumor in pregnant women is a matter of concern. Aim: We aimed to assess the safety of radiotherapy for brain tumors in pregnancy. We here report a successful treatment for anaplastic astrocytoma during pregnancy: surgery + postoperative irradiation. We wish to emphasize how we devised irradiation procedure to achieve both therapeutic effectiveness and safety to the fetus/infant. Case Presentation: A 34-year-old pregnant woman suffered with brain anaplastic astrocytoma. Tumor resection under craniotomy was performed with success. We decided to conduct postoperative radiotherapy at 25 weeks of gestation to reduce the risk of recurrence. We used a flattening filter-free volumetric arc therapy (FFF-VMAT) technique, which can achieve lower out-of-field dose than VMAT with a flattening filter or helical tomotherapy. We prescribed 60 Gy over 30 fractions. During actual beam delivery, surface and rectal dose to the patient (mother) were measured. The total fetal dose was estimated at 0.006 - 0.018 Gy, which is under the threshold set by the ICRP. A male healthy infant was born vaginally at the 37th week of pregnancy. The patient (mother) and the infant are healthy at the time of writing. Conclusion: FFF-VMAT is a good choice for brain tumors during pregnancy.

Does an immobilization mask have added value during planning magnetic resonance imaging for stereotactic radiotherapy of brain tumours?

When using an immobilization mask, a magnetic resonance imaging (MRI) head receive coil cannot be used and patients may experience discomfort during the examination. We therefore wish to assess the added value of an immobilization mask during all MRI scans intended for cranial stereotactic radiotherapy (SRT) planning. An MRI was acquired with and without a thermoplastic immobilization mask in ten patients eligible for SRT. A planning computed tomography (CT) scan was also made, to which the two MRIs were independently registered. Additionally, the MRI without immobilization was registered to the MRI in mask. On each sequence, gross tumour volume (GTV), the right eye, brain stem and chiasm were delineated. The absolute differences in centre-of-gravity coordinates and Dice coefficients of the volumes of the delineated structures between the two MRIs were compared. Differences in GTV volume between the two MRIs were low, with median Dice coefficients between 0.88 and 0.91. Similarly, the median absolute differences in centre-of-gravity coordinates between the GTVs, organs at risk and landmarks delineated on the two MRIs were within 0.5mm. The 95% confidence intervals of the median absolute differences in the three GTV coordinates was within 1mm, which corresponds to the target volume safety margin used to account for possible errors during the SRT treatment chain. The effect of scanning a patient without the immobilization mask falls within acceptable bounds of error for the geometrical accuracy of the SRT treatment chain. Consequently, placing the head in treatment position during all MRI scans for patients undergoing radiotherapy of brain metastasis is deemed unnecessary.

Cochlear Sparing for Brain Tumor Radiotherapy: A Retrospective Study Comparing Intensity-Modulated Radiotherapy and Volumetric Modulated Arc Therapy

Cochlear Sparing for Brain Tumor Radiotherapy: A Retrospective Study Comparing Intensity-Modulated Radiotherapy and Volumetric Modulated Arc Therapy

Subventricular zone volumetric and dosimetric changes during postoperative brain tumor irradiation and its impact on overall survival

PurposeThe aim of this retrospective study was to investigate the relationship between the dose to the subventricular zone (SVZ) and overall survival (OS) of 41 patients with glioblastoma multiforme (GBM), who were treated with an adaptive approach involving repeated topometric CT and replanning at two-thirds (40 Gy) of their course of postoperative radiotherapy for planning of a 20 Gy boost. MethodsWe examined changes in the ipsilateral lateral ventricle (LV) and SVZ (iLV and iSVZ), as well as in the contralateral LV and SVZ (cLV and cSVZ). We evaluated the volumetric changes on both planning CT scans (primary CT1 and secondary CT2). The survival of the GBM patients was analyzed using the Kaplan–Meier method; the multivariate Cox regression was also performed. ResultsMedian follow-up and OS were 34.5 months and 17.6 months, respectively. LV and SVZ structures exhibited significant volumetric changes on CT2, resulting in an increase of dose coverage. At a cut-off point of 58 Gy, a significant correlation was detected between the iSVZ2 mean dose and OS (27.8 vs 15.6 months, p = 0.048). In a multivariate analysis, GBM patients with a shorter time to postoperative chemoradiotherapy (<3.8 weeks), with good performance status (≥70%) and higher mean dose (≥58 Gy) to the iSVZ2 had significantly better OS. ConclusionsSignificant anatomical and dose distribution changes to the brain structures were observed, which have a relevant impact on the dose-effect relationship for GBM; therefore, involving the iSVZ in the target volume should be considered and adapted to the changes.

EXTH-57. PRECLINICAL COMBINATION OF ONC201 WITH RADIOTHERAPY OR TEMOZOLOMIDE IN GBM, DIPG AND ATRT CELL LINES RESULTS IN DOPAMINE RECEPTOR ANTAGONISM, ATF4 INDUCTION AND CELL DEATH

Abstract CNS tumors are one of the most lethal cancers in children and young adults. We previously reported that first-in-class small-molecule imipridone ONC201 can antagonize dopamine receptor D2 (DRD2), inactivate ERK/AKT, induce the integrated stress response (ISR), upregulate pro-apoptotic TRAIL receptor DR5, deplete cancer stem cells, and induce growth arrest or cell death in tumor cells. ONC201 crosses the blood-brain barrier and has induced durable tumor regressions in adult and pediatric H3K27M-mutant glioma patients. We hypothesized that ONC201 may synergize with radiotherapy or temozolomide in brain tumors. Glioblastoma (GBM: SNB19, T98G and U251), diffuse intrinsic pontine glioma (DIPG: SF8628) and atypical teratoid rhabdoid tumor (ATRT: BT-12, BT-16) cell lines were tested using cell viability or colony formation assays with ONC201 up to 20 μM alone or in combination with radiotherapy up to 8 Gy or temozolomide up to 100 μM. We observed synergy between ONC201 and radiation or temozolomide by multiple assays. We observed induction of PKA substrate phosphorylation as a marker of DRD2 antagonism, induction of ATF4 as a marker of ISR activation, and multiple markers of cell death in treated brain tumor cells. We are evaluating the relevance of mitochondrial protease ClpP, a recently described binding target of ONC201, in ONC201-induced glioma cell death. We have observed that knockdown of ClpP strongly protects multiple human cancer cell lines from ONC201-mediated cytotoxicity. Thus, we are exploring the potential interplay between ClpP, dopamine receptors, the ISR and TRAIL signaling pathways after single agent or combinatorial treatments. Our data suggests that ONC201 may be combined synergistically with temozolomide or radiation to address gliomas, along with potential pharmacodynamic biomarkers.

NCMP-15. BEVACIZUMAB FOR THE TREATMENT OF CEREBRAL RADIATION NECROSIS: A RETROSPECTIVE COHORT STUDY

Abstract BACKGROUND Cerebral radiation necrosis (RN) is a critical complication of radiotherapy for brain tumors. Treatment with corticosteroids provides suboptimal symptom relief, and may have considerable side effects. Small-scale studies support the use of bevacizumab, but systematic data from clinical practice on its efficacy and toxicity remain scarce. METHODS In this retrospective cohort study, we included consecutive patients with symptomatic RN that underwent treatment with bevacizumab in our academic neuro-oncology clinic. RN was diagnosed based on imaging, histology or both. The primary outcomes were reported neurological improvement during follow-up, the duration of response, the reported improvement on MRI, and radiological outcome according to RANO criteria. Other outcomes included reduction of dexamethasone dose and the occurrence of adverse events. RESULTS Of the 37 included patients (39 RN-episodes), the majority had a glioblastoma (n = 22) or other diffuse glioma (8), followed by brain metastases (4) or other (3). Clinical response was reported in 17 RN-episodes (43.6%) and lasted for a median of 13 weeks (IQR 6–32 weeks). Radiological improvement during follow-up was reported in 29 RN-episodes (80.6%). RANO-defined radiological responses included 1 complete response (3.4%), 7 partial responses (24.1%), 1 minor response (3.4%) and 17 stable disease (58.6%). In total, 36 adverse events occurred, most commonly venous thrombo-embolism, hypertension and dyspnea, with 8 grade III-IV complications and 2 deaths (grade V) which were possibly related to bevacizumab. Of 32 patients on dexamethasone, 9 (28.1%) had completely stopped its use at treatment cessation. CONCLUSION This observational study confirms that patients with cerebral RN can benefit both clinically and radiologically from bevacizumab treatment in a real-life clinical setting, although our results are more modest than previous literature suggests. The high prevalence of – sometimes severe – adverse events should be weighed against the possible clinical benefit when counselling patients about this treatment option.

NCOG-04. COGNITIVE FUNCTIONS BEFORE RADIOTHERAPY IN PEDIATRIC PATIENTS WITH BRAIN TUMORS

Abstract OBJECTIVE To assess the cognitive functions before radiotherapy in pediatric patients with brain tumors and explore the related influence factors. METHODS Before radiotherapy for brain tumors, adaptive behavior scale (adaptive quotient) and Wechsler intelligence scale for children were used to evaluate the cognitive functions in pediatric patients. Herein the assessment items of verbal IQ, performance IQ, total score and the corresponding percentile. The cognitive functions of pediatric patients with different pathological diagnoses, lesion locations, with or without epilepsy, hydrocephalus or hypopituitarism were compared. RESULTS A total of 128 pediatric patients were enrolled in this study. The mean verbal IQ score was 83.7±20.8 (range, 36–128), and the corresponding percentile mean value was 27.699±30.3. The mean performance IQ score was 82.83±20.5 (range, 30–126), and the corresponding percentile mean value was 26.6±29.1. The total score of Wechsler intelligence scale was 0–128, with a mean value of 81.4±21.7, and the corresponding percentile was 0–97, with a mean value of 25.5±28.5. Moreover, the adaptive quotient for all enrolled patients was 32–164, with a mean value of 95.1±29.4. The results of multivariate analysis on the clinical factors related to cognitive functions revealed that the mean performance IQ, the corresponding percentile and the mean of the total score of Wechsler intelligence scale in patients with lesions involving basal ganglia region were 76±16, 15.1±19.6 and 75.29±15, respectively, which were lower than 84±20.7, 28±19.1 and 82.4±22 in those with lesion without involving basal ganglia region, with statistical differences (P= 0.031, 0.018, 0.046). CONCLUSION The cognitive functions before radiotherapy in pediatric patients with brain tumors are proved to be inferior to those in normal children. The performance IQ and total score of pediatric patients with brain tumors involving basal ganglia region were lower than those of the other patients for the lesions have affected the limb movement.