Radiotherapy For Brain Tumors Research Articles

The Use of Treatment Response Assessment Maps in Discriminating Between Radiation Effect and Persistent Tumoral Lesion in Metastatic Brain Tumors Treated with Gamma Knife Radiosurgery

Traditional imaging modalities are not useful in the follow-up of irradiated metastatic brain tumors, because radiation can change imaging characteristics. We aimed to assess the ability of treatment response assessment maps (TRAMs) calculated from delayed-contrast magnetic resonance imaging (MRI) in differentiation between radiation effect and persistent tumoral tissue. TRAMs were calculated by subtracting three-dimensional T1 MRIs acquired 5 minutes after contrast injection from the images acquired 60-105 minutes later. Red areas were regarded as radiation effect and blue areas as persistent tumoral lesion. Thirty-seven patients with 130 metastatic brain tumors who were treated with Gamma Knife radiosurgery and who underwent TRAMs perfusion-weighted MRI were enrolled in this retrospective study. The median age was 58 years and the most common primary diagnosis was lung cancer (n= 21). The median follow-up period of patients was 12 months. The overall local control rate was 100% at 1 year and 98.9% at 2 years. The median progression-free survival was 12 months. The mean overall survival was 27.3 months. The radiologic and clinical follow-up showed a clinicoradiologic diagnosis of a persistent tumoral lesion in 3 tumors (2.3%) and radiation effect in 127 tumors (97.7%). There was a fair agreement between clinicoradiologic diagnosis and TRAMs analysis (κ= 0.380). The sensitivity and positive predictive value of TRAMs in diagnosing radiation effect were 96.06% and 99.2%, respectively. TRAMs showed comparable results to perfusion-weighted MRI, with a diagnostic odds ratio of 27.4 versus 20.7, respectively. The presented results show the ability of TRAMs in differentiating radiation effect and persistent tumoral lesions.

NIMG-48. USE OF MOBILE LIPIDS AS METABOLIC MARKERS FOR THE ASSESSMENT OF TREATMENT-INDUCED NECROSIS IN A RECURRENT GLIOBLASTOMA PATIENT TREATED WITH A NEW OSCILLATING MAGNETIC FIELD GENERATING DEVICE

Abstract The FDA has approved tumor treating fields (Optune) to treat glioblastoma (GBM) and unresectable mesothelioma. Optune uses scalp electrodes to pass a strong alternating electric field through the head, slowing GBM growth. We have recently developed and tested a novel device that uses an oscillating magnetic field (OMF) generated by rotating magnets to treat GBM. Our first GBM patient had a recurrent GBM with leptomeningeal spread. A custom-made Oncomagnetic device consisting of a multi-sport helmet with three OMF generators called oncoscillators, was worn by the patient at home. Changes in the brain and GBM tumor metabolism were examined using in vivo1H MRS on a 7T Siemens MRI scanner. 1H MRS data of the “tumor” and “non-tumor” regions during OMF treatment was obtained using sLASER pulse sequences. Both non–tumor and tumor regions showed the most common brain metabolites – myo-inositol, creatine, choline, glutamine/glutamate, and N-acetyl aspartate (NAA). 30 days after initiation of treatment, choline, creatine and NAA levels in the shrunken tumor region had collapsed. The tumor region displayed broad proton signals centered at 1.30 ppm and 0.88 ppm. These peaks have been observed following successful brain tumor radiation therapy and have been attributed to the presence of mobile lipids due to tumor necrosis. Our in vitro experiments suggest OMF-induced damage to mitochondria and elevated levels of reactive oxygen species, leading to cancer cell death via apoptosis and necrosis. We propose that loss of choline and elevation of lipid levels may be used as a metabolite ‘fingerprint’ to noninvasively assess the Oncomagnetic treatment response. This powerful new treatment holds great promise for treatment of patients with GBM, and produces rapid changes in brain chemistry during treatment.

Multi-Atlas Based Adaptive Active Contour Model with Application to Organs at Risk Segmentation in Brain MR Images

BackgroundAccurate delineation of organs at risk (OARs) is critical in radiotherapy. Manual delineation is tedious and suffers from both interobserver and intraobserver variability. Automatic segmentation of brain MR images has a wide range of applications in brain tumor radiotherapy. In this paper, we propose a multi-atlas based adaptive active contour model for OAR automatic segmentation in brain MR images. MethodsThe proposed method consists of two parts: multi-atlas based OAR contour initiation and an adaptive edge and local region based active contour evolution. In the adaptive active contour model, we define an energy functional with an adaptive edge intensity fitting force which is responsible for evaluating contour inwards or outwards, and a local region intensity fitting force which guides the evolution of the contour. ResultsExperimental results show that the proposed method achieved more accurate segmentation results in brainstem, eyes and lens automatic segmentation with the Dice Similar Coefficient (DSC) value of 87.19%, 91.96%, 77.11% respectively. Besides, the dosimetric parameters also demonstrate the high consistency of the manual OAR delineations and the auto segmentation results of the proposed method in brain tumor radiotherapy. ConclusionsThe geometric and dosimetric evaluations show the desirable performance of the proposed method on the application of OARs segmentations in brain tumor radiotherapy.

A Shift from Brain Volume to Cerebrospinal Fluid Volume after Radiotherapy: Loss of Tissue after Treatment for Brain Tumors

Healthy brain tissue shows dose-dependent atrophy after radiotherapy (RT) for brain tumors. One of the most challenging consequences of this phenomenon is post-RT cognitive decline. Changes in areas associated with cognitive functions, such as the hippocampus and cerebral cortex, have already been linked to the applied dose and cognitive outcomes. In volumetric analyses in aging and degenerative brain diseases, certain regions in both gray and white matter undergo volume loss after RT. However, the total volume within the cranium is not expected to change, as previous studies have already shown that the total intracranial volume (TIV) remains the same. Instead, the total brain volume decreases, with a converse increase in cerebrospinal fluid volume (CSF). For radiotherapy, this phenomenon has not yet been researched. We therefore performed a volumetric analysis of the brain, to verify that the TIV remains the same, and to see whether there is a shift in volume ratio of tissue and CSF. We included 28 patients undergoing radiotherapy for glioma with adequate MRI scans at baseline and 1 year after start of therapy. The brain was automatically segmented into white matter (WM), gray matter (GM) and cerebrospinal fluid (CSF) using SPM12 and CAT12. Volumes of each region were computed, as well as the ratio between total brain tissue volume (GM+WM) and TIV. Differences in pre-RT and post-RT volume were examined with a paired Wilcoxon signed rank test, with p < 0.05 as the threshold of statistical significance. Mean volumes and the post-RT changes in each area are shown in the table. Significant changes are seen in all brain regions, with GM and WM showing decrease, and CSF showing increase. The total intracranial volume did not change between the two MRI scans. The ratio of total brain tissue volume and TIV changed as well, going from a median of 80.0% to 75.7% (p = 0.03). Both gray matter and white matter volumes are affected by radiotherapy, showing a decrease in volume after one year. As the total intracranial volume does not change, the cerebrospinal fluid volume increases, as the tissue volume loss is replaced by CSF. This effect is also seen in healthy ageing and degenerative brain disease, suggesting the cognitive decline after RT could have a similar link to brain volume.Abstract 3617; TableRegionMedian pre-RT volume (cc)Median volume difference (cc)95% CI of differencep-valueTotal intracranial volume1386.12.2-11.0 – 17.60.81Gray matter608.2-12.8-24.8 – -4.7< 0.01White matter520.6-30.0-42.0 – -20.1< 0.01Cerebrospinal fluid288.044.321.3 – 75.5< 0.01 Open table in a new tab

The role of VEGF receptor inhibitors in preventing cerebral radiation necrosis: a retrospective cohort study.

Radiation necrosis (RN) is a potential complication after radiation therapy for brain tumors. It is hypothesized that VEGF plays an important role in the pathophysiology of RN. Bevacizumab, a monoclonal antibody against VEGF-A, is often successful in the management of RN. The objective of this study is to assess whether VEGF receptor (VEGFR) inhibitors, a group of oral tyrosine kinase inhibitors (TKIs), can prevent or reverse RN. We retrospectively studied a cohort of 102 patients with renal cell carcinoma and brain metastases seen at The Ohio State University James Cancer Center between January 1, 2011 and April 30, 2019. We identified those who developed RN and analyzed the temporal relationship between the use of VEGFR TKIs and the development of RN. The cumulative incidence of RN is 13.7% after radiation treatments that included LINAC-based stereotactic radiosurgery, fractionated stereotactic radiotherapy, or Gamma Knife radiosurgery. There was no statistically significant difference in the cumulative incidence of RN between patients taking TKIs and patients who were off TKIs (9.9% and 11.5% respectively, P = .741). The median time to development of RN was only numerically shorter in patients taking TKIs (151 vs 315 days, P = .315). One patient developed RN after stopping cabozantinib. Eight patients developed RN while on cabozantinib, pazopanib, or sunitinib. One patient was started on axitinib during active RN without significant improvement subsequently. VEGFR TKIs do not consistently prevent RN. The therapeutic effects of VEGFR TKIs against RN warrant further research.

Systematic review of the incidence and risk factors for cerebral vasculopathy and stroke after cranial proton and photon radiation for childhood brain tumors.

The aim of our study is to determine the incidence, timing, and risk factors for cerebral vasculopathy after cranial proton and photon radiation for pediatric brain tumors. We performed a single-institution retrospective review of a cohort of children treated with proton radiation for brain tumors. MRA and/or MRI were reviewed for evidence of cerebral vascular stenosis and infarcts. Twenty-one similar studies (17 photon, 4 proton) were identified by systematic literature review. For 81 patients with median follow-up of 3 years, the rates of overall and severe vasculopathy were 9.9% and 6.2% respectively, occurring a median of 2 years post radiation. Dose to optic chiasm greater than 45 Gy and suprasellar location were significant risk factors. Results were consistent with 4 prior proton studies (752 patients) that reported incidence of 5% to 6.7%, 1.5 to 3 years post radiation. With significantly longer follow-up (3.7-19 years), 9 studies (1108 patients) with traditional photon radiation reported a higher rate (6.3%-20%) and longer time to vasculopathy (2-28 years). Significant risk factors were neurofibromatosis type 1 (NF-1; rate 7.6%-60%) and suprasellar tumors (9%-20%). In 10 studies with photon radiation (1708 patients), the stroke rate was 2% to 18.8% (2.3-24 years post radiation). Childhood brain tumor survivors need screening for vasculopathy after cranial radiation, especially with higher dose to optic chiasm, NF-1, and suprasellar tumors. Prospective studies are needed to identify risk groups, and ideal modality and timing, for screening of this toxicity.

Radiotherapy for Brain Tumors: Current Practice and Future Directions

Radiotherapy is an important component of the treatment for primary and metastatic brain tumors. Due to the close proximity of critical structures and normal brain parenchyma, Central Nervous System (CNS) radiotherapy is associated with adverse effects such as neurocognitive deficits, which must be weighed against the benefit of improved tumor control. Advanced radiotherapy technology may help to mitigate toxicity risks, although there is a paucity of high-level evidence to support its use. Recent advances have been made in the treatment for gliomas, meningiomas, benign tumors, and metastases, although outcomes remain poor for many high grade tumors. This review highlights recent developments in CNS radiotherapy, discusses common treatment toxicities, critically reviews advanced radiotherapy technologies, and highlights promising treatment strategies to improve clinical outcomes in the future.

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&lt;sup&gt;+&lt;/sup&gt;-Cl&lt;sup&gt;-&lt;/sup&gt; 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&lt;sup&gt;+&lt;/sup&gt;-Cl&lt;sup&gt;-&lt;/sup&gt; co-transporter, is efficient as a target to attenuate the neuronal dysfunction that is associated with radiation therapy for brain tumor by using oxytocin.