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Objective We conducted a prospective clinical trial of patients receiving radiation (RT) for brain metastases to identify clinical predictors of pre-RT and post-RT health-related quality of life (hrQoL). Materials and methods Patients with brain metastases completed overall (European Organisation for Research and Treatment of Cancer QLQ C15-PAL) and brain tumor-specific (QLQ-BN20) hrQoL assessments pre-RT (n=127) and 1 (n=56) and 3 (n=45) months post-RT. Linear and proportional-odds models analyzed patient, disease, and treatment predictors of baseline, 1-, and 3-month hrQoL scores. Generalized estimating equations and repeated measures proportional-odds models assessed predictors of longitudinal hrQoL scores. Results Most patients underwent stereotactic radiosurgery (SRS) (69.3%) and had non-small-cell lung (36.0%) metastases. Compared with SRS, receipt of whole brain RT was associated with a higher odds of appetite loss (baseline P=0.04, 1 mo P=0.02) and greater motor dysfunction (baseline P=0.01, 1 mo P=0.003, 3 mo P=0.02). Receipt of systemic therapy was associated with better emotional functioning after RT (1 mo P=0.03, 3 mo P=0.01). Compared with patients with breast cancer, patients with melanoma had higher odds of better global hrQoL (P=0.01) and less pain (P=0.048), while patients with lung cancer reported lower physical function (P=0.048) 3 months post-RT. Nonmarried patients had greater odds of higher global hrQoL (1 mo P=0.01), while male patients had lower odds of reporting more hair loss (baseline P=0.03, 3 mo P=0.045). Patients 60 years and above had lower odds of more drowsiness (P=0.04) and pain (P=0.049) over time. Conclusions Patients receiving SRS versus whole brain RT and systemic therapy reported better posttreatment hrQoL. In addition, melanoma metastases, nonmarried, male, and older patients with reported better hrQoL in various as well as domains after intracranial RT.

PURPOSE: Primary brain tumor patients are vulnerable to depression and anxiety symptoms, which may affect their neurocognitive functioning. We performed a prospective longitudinal analysis to examine the association between depression and anxiety symptoms and domain-specific neurocognitive functioning in primary brain tumor patients receiving radiation therapy (RT). METHODS AND MATERIALS: On a prospective trial, 54 primary brain tumor patients receiving RT underwent comprehensive neurocognitive evaluation at baseline (pre-RT), and 3, 6, and 12 months post-RT. Neurocognitive assessments measured attention/processing speed, verbal and visuospatial memory, and executive functioning, including Delis-Kaplan Executive Function System Trail-Making Test (DKEFS-TMT), DKEFS Verbal Fluency, and Brief Visuospatial Memory Test-Revised. Depression and anxiety symptoms were also assessed at each time point with Beck Depression and Anxiety Inventories (BDI-II and BAI), respectively. Higher scores reflect more numerous or severe depression or anxiety symptoms. Univariable and multivariable linear mixed-effects models assessed associations between BDI-II and BAI scores and domain-specific neurocognitive scores over time, controlling for pre-existing depression or anxiety disorders and other patient, tumor, and treatment characteristics. RESULTS: Higher BAI scores were associated with worse attention and processing speed in univariable analyses: DKEFS-TMT visual scanning (P = .003), number sequencing (P = .011), and letter sequencing (P

Background and purpose Executive function (EF) decline is common after brain radiation therapy (RT), yet the etiology is unclear. We analyzed the association between longitudinal changes in frontal lobe white matter microstructure and decline in EF following RT in brain tumor patients on a prospective clinical trial. Materials and methods Diffusion tensor imaging was obtained on 22 patients with brain tumors prior to RT, as well as 3- and 6-months post-RT, in a prospective, observational trial. Fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were calculated within the superficial white matter (SWM) of the anterior cingulate (AC) and dorsolateral prefrontal cortex. Measures of cognitive flexibility, verbal fluency, and verbal set-shifting were obtained pre- and post-RT. Reliable change indices were calculated to determine significant baseline to 6-month EF changes. Results Decreases in FA and increases in MD were observed in the caudal AC (CAC) at 3-months post-RT. CAC changes were characterized by increased RD bilaterally. From baseline to 6-months post-RT, decreased FA and increased MD and RD of the CAC was associated with decline in verbal set-shifting ability, whereas increased MD in the CAC was associated with a decline in cognitive flexibility. Conclusion White matter underlying the AC may be particularly vulnerable to radiation effects. Early microstructural loss within AC SWM represents an important biomarker for EF decline, and dose reduction in this region may represent a possibility for cognitive preservation for patients receiving radiotherapy.

Purpose Specificity protein 1 (SP1) is involved in the transcription of several genes implicated in tumor maintenance. We investigated the effects of mithramycin A (MTA), an inhibitor of SP1 DNA binding, on radiation response. Methods and Materials Clonogenic survival after irradiation was assessed in 2 tumor cell lines (A549, UM-UC-3) and 1 human fibroblast line (BJ) after SP1 knockdown or MTA treatment. DNA damage repair was evaluated using γH2AX foci formation, and mitotic catastrophe was assessed using nuclear morphology. Gene expression was evaluated using polymerase chain reaction arrays. In vivo tumor growth delay was used to evaluate the effects of MTA on radiosensitivity. Results Targeting of SP1 with small interfering RNA or MTA sensitized A549 and UM-UC-3 to irradiation, with no effect on the BJ radiation response. MTA did not alter γH2AX foci formation after irradiation in tumor cells but did enhance mitotic catastrophe. Treatment with MTA suppressed transcription of genes involved in cell death. MTA administration to mice bearing A549 and UM-UC-3 xenografts enhanced radiation-induced tumor growth delay. Conclusions These results support SP1 as a target for radiation sensitization and confirm MTA as a radiation sensitizer in human tumor models.

IntroductionWe investigated multi-domain baseline neurocognition of primary brain tumor patients prior to radiotherapy (RT), including clinical predictors of function and association between pre-RT and post-RT impairment on a prospective trial.MethodsA multi-domain neuropsychological battery (memory, executive functioning, language, attention, processing) was performed on 37 patients, pre-RT and 3-(n = 21), 6-(n = 22) and 12-(n = 14) months post-RT. Impairment rate was the proportion of patients with standardized T-scores ≤ 1.5 standard deviations below normative means. Per-patient impairment across all domains was calculated using a global deficit score (GDS; higher value indicates more impairment). Associations between baseline GDS and clinical variables were tested. Global GDS impairment rate at each time point was the fraction of patients with GDS scores > 0.5.ResultsStatistically significant baseline neurocognitive impairments were identified on 4 memory (all p ≤ 0.03) and 2 out of 3 (p = 0.01, p = 0.027) executive functioning tests. Per-patient baseline GDS was significantly associated with tumor volume (p = 0.048), tumor type (p = 0.043), seizure history (p = 0.007), and use of anti-epileptics (p = 0.009). The percentage of patients with the same impairment status at 3-, 6-, and 12-months as at baseline were 88%, 85%, and 85% respectively.ConclusionsMemory and executive functioning impairment were the most common cognitive deficits prior to RT. Patients with larger tumors, more aggressive histology, and use of anti-epileptics had higher baseline GDS values. GDS is a promising tool to encompass multi-domain neurocognitive function, and baseline GDS can identify those at risk of cognitive impairment.

PurposeAfter radiation therapy (RT) to the brain, patients often experience memory impairment, which may be partially mediated by damage to the hippocampus. Hippocampal sparing in RT planning is the subject of recent and ongoing clinical trials. Calculating appropriate hippocampal dose constraints would be improved byefficient invivo measurements of hippocampal damage. In this study we sought to determine whether brain RT was associated with dose-dependent hippocampal atrophy.Methods and materialsHippocampal volume was measured with magnetic resonance imaging (MRI) in 52 patients who underwent fractionated, partial brain RT for primary brain tumors. Study patients had high-resolution, 3-dimensional volumetric MRI before and 1year after RT. Images were processed using software with clearance from the US Food and Drug Administration and Conformité Européene marking for automated measurement of hippocampal volume. Automated results were inspected visually for accuracy. Tumor and surgical changes were censored. Mean hippocampal dose was tested for correlation with hippocampal atrophy 1year after RT. Average hippocampal volume change was also calculated for hippocampi receiving high (>40Gy) or low (

PURPOSE: Treatment of brain tumors significantly impacts health-related quality of life (hrQOL). In this prospective longitudinal study of hrQOL in patients receiving intracranial radiotherapy (RT) we sought to better understand the factors impacting patient hrQOL following brain RT. METHODS: Data was collected prospectively at our institution from 2013–2017. Prior to RT, patients completed a core overall hrQOL tool (EORTC QLQ C-15-PAL) and a brain tumor-specific module (QLQ-BN20), repeating these questionnaires one month post-treatment and every 3-months until patient death or study withdrawal. Baseline patient data collected included age, gender, KPS, tumor type (primary or metastasis), histology, and RT treatment type. Statistical analyses using R software package included linear regression modeling for continuous hrQOL outcomes and proportional odds modeling for ordinal hrQOL outcomes. RESULTS: Two hundred twenty one patients (51% male, 49% female) completed baseline surveys. The majority of patients had brain metastases (57%) while 43% had a primary brain tumor (13% WHO grade I-II, 26% WHO grade III-IV, and 4% benign/other). Global hrQOL was significantly affected by tumor type, histology, and RT treatment type one month post-RT, with metastatic patients 41% less likely to give a higher score than primary brain tumor patients (p=0.031), WHO grade I-II patients 8 times more likely to give a higher score than those with brain metastases (p=0.017), and patients receiving SRS or WBRT 75–81% less likely to give a higher score than those receiving partial brain RT (p=0.039). Other hrQOL measures impacted by various clinical and treatment factors included future uncertainty, emotional and physical functioning, fatigue, motor dysfunction, and nausea and vomiting. CONCLUSIONS: We demonstrated significant longitudinal overall and brain tumor-specific hrQOL differences due to such factors as tumor type, disease histology, and treatment type following intracranial RT. This knowledge may help better predict certain hrQOL outcomes and guide patient care following intracranial RT.

Objectives The objectives of this systematic review were to (a) identify supportive-care (psychosocial/behavioral, pharmacological, complementary, or alternative) interventions that have been evaluated via randomized controlled trials (RCTs) to improve patient-reported health-related quality of life (HRQoL) among adults with brain tumors, (b) evaluate the quality of the intervention studies, and (c) evaluate if developed interventions have been efficacious at improving HRQoL, as compared with control conditions in RCTs. Methods This systematic review was conducted using preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Four databases were searched for RCTs of supportive-care interventions for adults with brain tumors, primary or metastatic, that included a patient-reported HRQoL outcome. Quality of the included studies was assessed using the Effective Public Health Practice Project Quality Assessment Tool for Quantitative Studies. Results Ten RCTs involving 640 patients with either a primary or metastatic brain tumor investigating supportive-care interventions with a HRQoL outcome were identified. In terms of quality, three of the studies received a "strong" rating, three received a "moderate" rating, and four of the studies received a "weak" rating. Only two of the interventions (ie, a home-based psychosocial intervention and individualized acupuncture with standard rehabilitation) demonstrated improvements in HRQoL over control conditions. Conclusions HRQoL is of the utmost importance when treating patients with brain tumors. Yet there is a notable paucity of research to inform clinical decisions and evidence-based practice. More high-quality studies of interventions aimed at improving HRQoL are needed.

Exposure to ionizing radiation (IR) can result in the development of cutaneous fibrosis, for which few therapeutic options exist. We tested the hypothesis that bone marrow-derived mesenchymal stem cells (BMSC) would favorably alter the progression of IR-induced fibrosis. We found that a systemic infusion of BMSC from syngeneic or allogeneic donors reduced skin contracture, thickening, and collagen deposition in a murine model. Transcriptional profiling with a fibrosis-targeted assay demonstrated increased expression of interleukin-10 (IL-10) and decreased expression of IL-1β in the irradiated skin of mice 14 days after receiving BMSC. Similarly, immunoassay studies demonstrated durable alteration of these and several additional inflammatory mediators. Immunohistochemical studies revealed a reduction in infiltration of proinflammatory classically activated CD80+ macrophages and increased numbers of anti-inflammatory regulatory CD163+ macrophages in irradiated skin of BMSC-treated mice. In vitro coculture experiments confirmed that BMSC induce expression of IL-10 by activated macrophages, suggesting polarization toward a regulatory phenotype. Furthermore, we demonstrated that tumor necrosis factor-receptor 2 (TNF-R2) mediates IL-10 production and transition toward a regulatory phenotype during coculture with BMSC. Taken together, these data demonstrate that systemic infusion of BMSC can durably alter the progression of radiation-induced fibrosis by altering macrophage phenotype and suppressing local inflammation in a TNF-R2-dependent fashion.

The inhibition of the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway through the suppression of mutated Ras or MAPK/extracellular signal-regulated kinase 1/2 (MEK1/2) has been shown to sensitize tumor cells to ionizing radiation (IR). The molecular mechanisms of this sensitization however, are not yet fully understood. In this study, we investigated the role of transforming growth factor-α (TGF-α) in the radiosensitizing effects of selumetinib, a selective inhibitor of MEK1/2. The expression of epidermal growth factor receptor (EGFR) ligands was assessed by ELISA in both Ras wild-type and Ras mutant cells that were exposed to radiation with or without selumetinib. The effects of selumetinib on the TGF-α/EGFR signaling cascade in response to radiation were examined by western blot analysis, clonogenic assay and by determing the yield of mitotic catastrophe. The treatment of cells with selumetinib reduced the basal and IR-induced secretion of TGF-α in both Ras wild-type and Ras mutant cell lines in vitro and in vivo. The reduction of TGF-α secretion was accompanied with a reduction in phosphorylated tumor necrosis factor-α converting enzyme (TACE) in the cells treated with selumetinib with or without IR. The treatment of cells with selumetinib with or without IR inhibited the phosphorylation of EGFR and check-point kinase 2 (Chk2), and reduced the expression of survivin. Supplementation with exogenous TGF-α partially rescued the selumetinib-treated cells from IR-induced cell death, restored EGFR and Chk2 phosphorylation and increased survivin expression. These data suggest that the inhibition of MEK1/2 with selumetinib may provide a mechanism to sensitize tumor cells to IR in a fashion that prevents the activation of the TGF-α autocrine loop following IR.

Purpose and objectivesNeurologic deficits after brain radiation therapy (RT) typically involve decline in higher-order cognitive functions such as attention and memory rather than sensory defects or paralysis. We sought to determine whether areas of the cortex critical to cognition are selectively vulnerable to radiation dose-dependent atrophy.Methods and materialsWe measured change in cortical thickness in 54 primary braintumor patients who underwent fractionated, partial brain RT. The study patients underwent high-resolution, volumetric magnetic resonance imaging (T1-weighted; T2 fluid-attenuated inversion recovery, FLAIR) before RT and 1year afterward. Semiautomated software was used to segment anatomic regions of the cerebral cortex for each patient. Cortical thickness was measured for each region before RT and 1year afterward. Two higher-order cortical regions of interest (ROIs) were tested for association between radiation dose and cortical thinning: entorhinal (memory) and inferior parietal (attention/memory). For comparison, 2 primary cortex ROIs were also tested: pericalcarine (vision) and paracentral lobule (somatosensory/motor). Linear mixed-effects analyses were used to test all other cortical regions for significant radiation dose-dependent thickness change. Statistical significance was set at α=0.05 using 2-tailed tests.ResultsCortical atrophy was significantly associated with radiation dose in the entorhinal (P=.01) and inferior parietal ROIs (P=.02). By contrast, no significant radiation dose-dependent effect was found in the primary cortex ROIs (pericalcarine and paracentral lobule). In the whole-cortex analysis, 9 regions showed significant radiation dose-dependent atrophy, including areas responsible for memory, attention, and executive function (P≤.002).ConclusionsAreas of cerebral cortex important for higher-order cognition may be most vulnerable to radiation-related atrophy. This is consistent with clinical observations that brain radiation patients experience deficits in domains of memory, executive function, and attention. Correlations of regional cortical atrophy with domain-specific cognitive functioning in prospective trials are warranted.

The master circadian pacemaker located within the suprachiasmatic nuclei (SCN) controls neural and neuroendocrine rhythms in the mammalian brain. Astrocytes are abundant in the SCN, and this cell type displays circadian rhythms in clock gene expression and extracellular accumulation of ATP. Still, the intracellular signaling pathways that link the SCN clockworks to circadian rhythms in extracellular ATP accumulation remain unclear. Because ATP release from astrocytes is a calcium-dependent process, we investigated the relationship between intracellular Ca(2+) and ATP accumulation and have demonstrated that intracellular Ca(2+) levels fluctuate in an antiphase relationship with rhythmic ATP accumulation in rat SCN2.2 cell cultures. Furthermore, mitochondrial Ca(2+) levels were rhythmic and maximal in precise antiphase with the peak in cytosolic Ca(2+). In contrast, our finding that peak mitochondrial Ca(2+) occurred during maximal extracellular ATP accumulation suggests a link between these cellular rhythms. Inhibition of the mitochondrial Ca(2+) uniporter disrupted the rhythmic production and extracellular accumulation of ATP. ATP, calcium, and the biological clock affect cell division and have been implicated in cell death processes. Nonetheless, rhythmic extracellular ATP accumulation was not disrupted by cell cycle arrest and was not correlated with caspase activity in SCN2.2 cell cultures. Together, these results demonstrate that mitochondrial Ca(2+) mediates SCN2.2 rhythms in extracellular ATP accumulation and suggest a role for circadian gliotransmission in SCN clock function.

The master circadian pacemaker located within the suprachiasmatic nucleus (SCN) of the mammalian brain controls system-level rhythms in animal physiology. Specific SCN outputs synchronize circadian physiological rhythms in other brain regions. Within the SCN, communication among neural cells provides for the coordination of autonomous cellular oscillations into ensemble rhythms. ATP is a neural transmitter involved in local communication among astrocytes and between astrocytes and neurons. Using a luciferin-luciferase chemiluminescence assay, we have demonstrated that ATP levels fluctuate rhythmically within both SCN2.2 cell cultures and the rat SCN in vivo. SCN2.2 cells generated circadian oscillations in both the production and extracellular accumulation of ATP. Circadian fluctuations in ATP accumulation persisted with an average period (tau) of 23.7 h in untreated as well as vehicle-treated and forskolin-treated SCN2.2 cells, indicating that treatment with an inductive stimulus is not necessary to propagate these rhythms. ATP levels in the rat SCN in vivo were marked by rhythmic variation during exposure to 12 h of light and 12 h of dark or constant darkness, with peak accumulation occurring during the latter half of the dark phase or subjective night. Primary cultures of cortical astrocytes similarly expressed circadian oscillations in extracellular ATP accumulation that persisted for multiple cycles with periods of about 23 h. These results suggest that circadian oscillations in extracellular ATP levels represent a physiological output of the mammalian cellular clock, common to the SCN pacemaker and astrocytes from at least some brain regions, and thus may provide a mechanism for clock control of gliotransmission between astrocytes and to neurons.