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Background EORTC study 22033–26033 showed no difference in progression-free survival between high-risk low-grade glioma receiving either radiotherapy (RT) or temozolomide (TMZ) chemotherapy alone as primary treatment. Considering the potential long-term deleterious impact of RT on memory functioning, this study aims to determine whether TMZ is associated with less impaired memory functioning. Methods Using the Visual Verbal Learning Test (VVLT), memory functioning was evaluated at baseline and subsequently every 6 months. Minimal compliance for statistical analyses was set at 60%. Conventional indices of memory performance (VVLT Immediate Recall, Total Recall, Learning Capacity, and Delayed Recall) were used as outcome measures. Using a mixed linear model, memory functioning was compared between treatment arms and over time. Results Neuropsychological assessment was performed in 98 patients (53 RT, 46 TMZ). At 12 months, compliance had dropped to 66%, restricting analyses to baseline, 6 months, and 12 months. At baseline, patients in either treatment arm did not differ in memory functioning, sex, age, or educational level. Over time, patients in both arms showed improvement in Immediate Recall (P = 0.017) and total number of words recalled (Total Recall; P < 0.001, albeit with delayed improvement in RT patients (group by time; P = 0.011). Memory functioning was not associated with RT gross, clinical, or planned target volumes. Conclusion In patients with high-risk low-grade glioma there is no indication that in the first year after treatment, RT has a deleterious effect on memory function compared with TMZ chemotherapy.

Glioblastoma treatment protocol includes chemo-radiation (CRT) after maximal safe resection. However, the recommended time-gap between surgery and CRT is unclear, most trials protocol required an interval of less than 6 weeks. In the current study we evaluated the association of the time-gap between surgery and CRT to overall survival (OS) and progression free survival (PFS) in a tertiary center. After ethics committee approval, a retrospective study was conducted. Data was collected from the medical records of consecutive glioblastoma patients treated between 2005–2014. Parameters of interest included: background characteristics of patients, treatment dates and type of treatment, treatment interruptions and survival. Only patients who were diagnosed with WHO IV, underwent surgical resection (any type), and treated with postoperative CRT were included. For the analysis, patients were divided into 3 groups according to the time gap from surgery to CRT: 6 weeks. Overall survival and PFS were investigated using the Kaplan-Meier method and Cox proportional hazard model. Out of 465 patients, 204 were included. Median age was 60 years (range: 23–79 years) and 61.7% male vs. 38.3% female. There was a significant difference in OS (HR = 0.49, p-value = 0.002, 95% CI: 0.32–0.78) and PFS (HR = 0.51, p-value = 0.003, 95% CI: 0.33–0.79) in the group who was treated with CRT 6 weeks or more after surgery, compared with the other two groups tested. In our study, 6 weeks or more time-gap (median of 8 weeks) between surgery and CRT was associated with better OS and PFS among newly diagnosed glioblastoma patients. Our results are probably subjected to unaccounted biases of a retrospective study, and that CRT in this patient population is an effective therapy that overcomes the potential harm of initiating therapy later than 6 weeks. Our current approach is to initiate CRT within 6 weeks after surgery, similar to what is recommended in the literature, but the data from this study provide us with information that no major harms was done in patients who were delayed.

Objectives Advance care planning (ACP) allows patients to acknowledge and document their preferences regarding end-of-life care and to ensure their fulfilment. Several factors were found to be related to patients' motivation regarding this process, such as their fear of being a burden on family members; however, the completion rate of the ACP forms is partial. The current study aimed to evaluate the barriers and motives among Israeli cancer patients regarding ACP, including many older adults. Setting and measurements Advanced cancer patients participated in the study. All completed an initial questionnaire to evaluate their basic knowledge regarding the issue. Participants who agreed to talk with a social worker completed a semi open-ended questionnaire which investigated their main motives and barriers regarding the issue. Results Most of the patients who completed the ACP forms were older and had lung cancer. They mentioned information and open communication with family and staff members as the main enabling factors. Their main motives were to ensure that the best medical decisions would be made and to avoid unnecessary medical procedures. The main reasons for not completing the forms was no close relative who would agree to take the responsibility as well as timing. Most of the participants did not hear about the issue from sources outside the oncology division. Conclusions Despite several limitations, the current findings may have important implications regarding ways to establish a more suitable ACP process, adjusted to older patients' needs. This may assist in promoting patients' cooperation with ACP and its implementation in the medical system, including older adults.

Purpose To determine the impact on overall survival with different salvage therapies, including no treatment, reirradiation, systemic therapy, or radiation and systemic therapy, in participants of a phase 3 clinical trial evaluating dose-dense versus standard-dose temozolomide for patients with newly diagnosed glioblastoma. Methods and Materials This analysis of patients from Trial RTOG 0525 investigated the effect of reirradiation or systemic treatment after tumor progression. Survival from first progression was compared between patients receiving no therapy, systemic therapy alone, radiation alone, and both modalities. The Cox proportional hazards model was used to compare the mortality hazard, controlling for potential confounders. Results The analysis included 637 patients who progressed and had information on their management, excluding those who died less than half a month after progression. A total of 267 patients (42%) received neither reirradiation nor systemic treatment at progression, 24 (4%) received radiation alone, 282 (44%) received systemic treatment only, and 64 (10%) received both radiation and systemic therapy. Patients who received no treatment had a median survival of 4.8 months, lower than with radiation treatment alone (8.2 months), systemic therapy alone (10.6 months), and both radiation and systemic therapy (12.2 months). In survival models controlling for potential confounders, those who received radiation alone had modestly better survival (hazard ratio HR 0.74, 95% confidence interval [CI] 0.43-1.28), whereas those who underwent systemic therapy either without (HR 0.42, 95% CI 0.34-0.53) or with radiation therapy (HR 0.44, 95% CI 0.30-0.63) had better survival. There was no significant survival difference between patients who received radiation only and those who received systemic therapy (either with radiation or alone). Conclusions Patients who received no salvage treatment had poorer survival than those who received radiation, chemotherapy, or the combination. However, patient selection for no treatment likely reflects poorer expected prognosis. There was no significant survival difference among those receiving radiation therapy, systemic therapy, or both. Ongoing clinical trials will help define the role of reirradiation after glioblastoma progression.

Advance care planning (ACP) defines end-of-life care in accordance with the patients’ preferences. It is highly important during mental and/or physical deterioration, which prevents patients from expressing their wishes. Despite various attempts worldwide to promote the issue, it is not well established, suggesting various challenges in the implementation of the process in the medical system. The current study aimed to evaluate the perception of Israeli oncology staff members regarding the process. Physicians and nurses from a division of oncology participated in the study. They completed the study’s questionnaires, which included quantitative items regarding staff and patients’ motives and barriers, as well as qualitative questions to better evaluate their understanding regarding the process. According to staff members, the optimal time to complete the forms is during the final stages of the disease. Making the right medical decisions and avoiding unnecessary medical procedures were rated as the main motives for patients in the process. The communication factor was perceived as the main barrier for patients, as well as the main motive and barrier for staff. The central role of communication was demonstrated in the qualitative section as well. Various differences were demonstrated between staff members who talked with patients about ACP and those who did not. The study demonstrated the central role of communication in the process of ACP from the staff’s perception. This highlights the need to further promote training programs for staff members to establish better interactions and communication skills when dealing with end-of-life issues.

Approximately one-half of advanced cutaneous melanomas have a V600 mutation in the BRAF gene that activates the mitogen-activated protein kinase pathway. The combination of BRAF plus MEK inhibitors is one of the most effective treatments for these patients. Severe neurological toxicities have been reported in the literature. However, these toxicities are very rare. Here, we present one patient with acute motor and sensory axonal neuropathy, which is a subtype of Guillain-Barre syndrome, secondary to treatment with MEK inhibitors. This side effect had never been described as related to these agents. However, the mitogen-activated protein kinase pathway can be involved in Guillain-Barre syndrome, and awareness of early neurological injury signs is important in patients treated with MEK inhibitors.

Summary Intracranial lesions in the presence of a known cancer are highly suspicious for brain metastases. Lung cancer is the most common solid tumor responsible for brain metastases. This case emphasizes the importance of multidisciplinary tumor boards including a dedicated neuroradiologist in the management of patients with cancer.

Purpose: It is currently unknown whether increasing radiation therapy (RT) volume has a negative impact on the health-related quality of life (HRQoL) of patients with low-grade glioma in the short term. The aim was to examine whether the size of the target volume is independently associated with HRQoL.Methods and Materials: We included patients who were treated with radiation therapy in the European Organisation for Research and Treatment of Cancer (EORTC) 22033-26033 study and who completed baseline HRQoL assessment. HRQoL was measured at baseline and every 3 months thereafter until progression, using the European Organisation for Research and Treatment of Cancer quality of life and brain cancer module questionnaires (QLQ-C30 and QLQ-BN20). We investigated whether there were associations between radiation volumes and (changes in) 4 preselected HRQoL scales (global health status, cognitive and social functioning, and fatigue). Also, we determined if radiation volumes were independently associated with a change in HRQoL over time.Results: We included 195 of 240 patients (81.3%) randomized to radiation therapy in this analysis. The brain volume receiving radiation therapy was not associated with (changes in) HRQoL during the first 24 months after radiation therapy. Over time, radiation volumes were also not independently associated with HRQoL. Notably, the occurrence of tumor progression was found to be associated with worse functioning and more fatigue.Conclusions: The brain target volume receiving focal radiation therapy in fractions of 1.8 Gy to a total of 50.4 Gy did not appear to be independently associated with HRQoL in high-risk patients with low-grade glioma in the short term, as opposed to tumor progression. However, the impact of radiation volumes on long-term HRQoL, as well as neurocognitive functioning, remains to be investigated. (C) 2019 Elsevier Inc. All rights reserved.

Conventional magnetic resonance imaging (MRI) is unable to differentiate tumor/nontumor enhancing tissues. We have applied delayed-contrast MRI for calculating high resolution treatment response assessment maps (TRAMs) clearly differentiating tumor/nontumor tissues in brain tumor patients.One hundred and fifty patients with primary/metastatic tumors were recruited and scanned by delayed-contrast MRI and perfusion MRI. Of those, 47 patients underwent resection during their participation in the study. Region of interest/threshold analysis was performed on the TRAMs and on relative cerebral blood volume maps, and correlation with histology was studied. Relative cerebral blood volume was also assessed by the study neuroradiologist.Histological validation confirmed that regions of contrast agent clearance in the TRAMs1 h post contrast injection represent active tumor, while regions of contrast accumulation represent nontumor tissues with 100% sensitivity and 92% positive predictive value to active tumor. Significant correlation was found between tumor burden in the TRAMs and histology in a subgroup of lesions resected en bloc (r(2) = 0.90, P.0001). Relative cerebral blood volume yielded sensitivity/positive predictive values of 51%/96% and there was no correlation with tumor burden. The feasibility of applying the TRAMs for differentiating progression from treatment effects, depicting tumor within hemorrhages, and detecting residual tumor postsurgery is demonstrated.The TRAMs present a novel model-independent approach providing efficient separation between tumor/nontumor tissues by adding a short MRI scan1 h post contrast injection. The methodology uses robust acquisition sequences, providing high resolution and easy to interpret maps with minimal sensitivity to susceptibility artifacts. The presented results provide histological validation of the TRAMs and demonstrate their potential contribution to the management of brain tumor patients.

BACKGROUND: It is currently unknown whether increasing radiotherapy volumes have a negative impact on the health-related quality of life (HRQoL) of low-grade glioma (LGG) patients on the short-term. The aim of this study was to examine if the size of the target volume is independently associated with HRQoL. MATERIAL AND METHODS: Patients treated with radiotherapy in the European Organisation for Research and Treatment of Cancer (EORTC) 22033–26033 study, and who completed a baseline HRQoL form, were included. This phase 3 trial of radiotherapy vs. temozolomide chemotherapy in high-risk LGG requiring treatment did not show a progression free survival difference. HRQoL was measured at baseline and every 3 months thereafter until progression, using the EORTC QLQ-C30 core questionnaire and QLQ-BN20 brain module. Associations between radiation volumes and (changes in) four preselected HRQoL scales (global health status, cognitive and social functioning, and fatigue) were determined. Also, it was determined if radiation volumes were independently associated with a change in HRQoL over time. RESULTS: A total of 195 out of the 240 patients randomized to radiotherapy (81.3%) were included in this analysis. The brain volume receiving radiotherapy was not associated with (changes in) HRQoL during the first 24 months after radiotherapy. Over time, radiation volumes were also not independently associated with HRQoL. Although treatment with radiotherapy resulted in worse functioning, and more fatigue three months after treatment, pre-treatment levels were reached thereafter and maintained during further follow-up. Particularly the occurrence of tumour progression was found to be associated with clinically relevant worse social functioning (Beta: -13.7, 95% CI:-19.5 to -7.9), and more fatigue (Beta: 13.2, 95% CI:7.8–18.5) during 24 months follow-up. CONCLUSION: The volume of brain receiving focal radiotherapy does not seem to be an important determinant for the level of HRQoL in high-risk LGG patients on the short-term. From this point of view, safety margins do not need to be reconsidered. However, the impact of radiation volumes on long-term HRQoL, as well as neurocognitive functioning, remains to be investigated.

Purpose This phase III trial compared adjuvant whole-brain radiotherapy (WBRT) with observation after either surgery or radiosurgery of a limited number of brain metastases in patients with stable solid tumors. Here, we report the health-related quality-of-life (HRQOL) results. Patients and Methods HRQOL was a secondary end point in the trial. HRQOL was assessed at baseline, at 8 weeks, and then every 3 months for 3 years with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and Brain Cancer Module. The following six primary HRQOL scales were considered: global health status; physical, cognitive, role, and emotional functioning; and fatigue. Statistical significance required P ≤ .05, and clinical relevance required a ≥ 10-point difference. Results Compliance was 88.3% at baseline and dropped to 45.0% at 1 year; thus, only the first year was analyzed. Overall, patients in the observation only arm reported better HRQOL scores than did patients who received WBRT. The differences were statistically significant and clinically relevant mostly during the early follow-up period (for global health status at 9 months, physical functioning at 8 weeks, cognitive functioning at 12 months, and fatigue at 8 weeks). Exploratory analysis of all other HRQOL scales suggested worse scores for the WBRT group, but none was clinically relevant. Conclusion This study shows that adjuvant WBRT after surgery or radiosurgery of a limited number of brain metastases from solid tumors may negatively impact some aspects of HRQOL, even if these effects are transitory. Consequently, observation with close monitoring with magnetic resonance imaging (as done in the EORTC trial) is not detrimental for HRQOL.

Genomic research of high grade glioma (HGG) has revealed complex biology with potential for therapeutic impact. However, the utilization of this information and impact upon patient outcome has yet to be assessed. We performed capture-based next generation sequencing (NGS) genomic analysis assay of 236/315 cancer-associated genes, with average depth of over 1000 fold, to guide treatment in HGG patients. We reviewed clinical utility and response rates in correlation to NGS results. Forty-three patients were profiled: 34 glioblastomas, 8 anaplastic astrocytomas, and one patient with anaplastic oligodendroglioma. Twenty-five patients were profiled with the 315 gene panel. The median number of identified genomic alterations (GAs) per patient was 4.5 (range 1–23). In 41 patients (95 %) at least one therapeutically-actionable GA was detected, most commonly in EGFR [17 (40 %)]. Genotype-directed treatments were prescribed in 13 patients, representing a 30 % treatment decision impact. Treatment with targeted agents included everolimus as a single agent and in combination with erlotinib; erlotinib; afatinib; palbociclib; trametinib and BGJ398. Treatments targeted various genomic findings including EGFR alterations, mTOR activation, cell cycle targets and FGFR1 mutations. None of the patients showed response to respective biologic treatments. In this group of patients with HGG, NGS revealed a high frequency of GAs that lead to targeted treatment in 30 % of the patients. The lack of response suggests that further study of mechanisms of resistance in HGG is warranted before routine use of biologically-targeted agents based on NGS results.

BACKGROUND: Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors. METHODS: For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration. Eligible patients were randomly assigned (1:1) to receive either conformal radiotherapy (up to 50·4 Gy; 28 doses of 1·8 Gy once daily, 5 days per week for up to 6·5 weeks) or dose-dense oral temozolomide (75 mg/m(2) once daily for 21 days, repeated every 28 days [one cycle], for a maximum of 12 cycles). Random treatment allocation was done online by a minimisation technique with prospective stratification by institution, 1p deletion (absent vs present vs undetermined), contrast enhancement (yes vs no), age (

Several chemotherapy agents induce polyneuropathy that is painful for some patients, but not for others. We assumed that these differences might be attributable to varying patterns of pain modulation.The aim of the present study was to evaluate pain modulation in such patients.Twenty-seven patients with chemotherapy-induced polyneuropathy were tested for detection thresholds (cold, warm, and mechanical) in both the forearm and foot, as well as for heat pain threshold, mechanical temporal summation (TS), and conditioned pain modulation (CPM; also known as the diffuse noxious inhibitory control-like effect), which were tested in the upper limbs.Positive correlations were found between clinical pain levels and both TS (r=0.52, P=0.005) and CPM (r=0.40, P=0.050) for all patients. In addition, higher TS was associated with less efficient CPM (r=0.56, P=0.004). The group of patients with painful polyneuropathy (n=12) showed a significantly higher warm detection threshold in the foot (P=0.03), higher TS (P0.01), and less efficient CPM (P=0.03) in comparison to the group with nonpainful polyneuropathy.The painfulness of polyneuropathy is associated with a "pronociceptive" modulation pattern, which may be primary to the development of pain. The higher warm sensory thresholds in the painful polyneuropathy group suggest that the severity of polyneuropathy may be another factor in determining its painfulness.

Purpose This European Organisation for Research and Treatment of Cancer phase III trial assesses whether adjuvant whole-brain radiotherapy (WBRT) increases the duration of functional independence after surgery or radiosurgery of brain metastases. Patients and Methods Patients with one to three brain metastases of solid tumors (small-cell lung cancer excluded) with stable systemic disease or asymptomatic primary tumors and WHO performance status (PS) of 0 to 2 were treated with complete surgery or radiosurgery and randomly assigned to adjuvant WBRT (30 Gy in 10 fractions) or observation (OBS). The primary end point was time to WHO PS deterioration to more than 2. Results Of 359 patients, 199 underwent radiosurgery, and 160 underwent surgery. In the radiosurgery group, 100 patients were allocated to OBS, and 99 were allocated to WBRT. After surgery, 79 patients were allocated to OBS, and 81 were allocated to adjuvant WBRT. The median time to WHO PS more than 2 was 10.0 months (95% CI, 8.1 to 11.7 months) after OBS and 9.5 months (95% CI, 7.8 to 11.9 months) after WBRT (P = .71). Overall survival was similar in the WBRT and OBS arms (median, 10.9 v 10.7 months, respectively; P = .89). WBRT reduced the 2-year relapse rate both at initial sites (surgery: 59% to 27%, P < .001; radiosurgery: 31% to 19%, P = .040) and at new sites (surgery: 42% to 23%, P = .008; radiosurgery: 48% to 33%, P = .023). Salvage therapies were used more frequently after OBS than after WBRT. Intracranial progression caused death in 78 (44%) of 179 patients in the OBS arm and in 50 (28%) of 180 patients in the WBRT arm. Conclusion After radiosurgery or surgery of a limited number of brain metastases, adjuvant WBRT reduces intracranial relapses and neurologic deaths but fails to improve the duration of functional independence and overall survival.

BACKGROUND: TTFields are low intensity, intermediate frequency alternating electric fields, delivered through a portable, non-invasive device (Optune, Novocure(TM)). The EF-14 phase III trial showed significant prolongation of both progression-free and overall survival in newly diagnosed glioblastoma (GBM) patients. This is the first report on clinical experience with 110 patients treated with TTFields in Israel, focusing on safety and patient acceptance in our country. METHODS: Patients received Optune-prescription in 6 neuro-oncology centers in Israel and used the device for at least one month. The cohort included both newly diagnosed (n=53) and recurrent GBM (rGBM, n=57) patients. The male/female ratio was 74/36 with a median age of 58.0 (18–82) years at start of treatment. Of patients with rGBM, 51% were treated at first progression. RESULTS: Our data shows a high acceptance, with a compliance rate (monthly usage of the device) within the first 3 months of 80% for newly diagnosed GBM and 66% for rGBM. Median treatment compliance was independent of age, sex and stage of disease. In addition, our data indicates that the compliance is not negatively correlated with time on treatment, as the median compliance for newly diagnosed GBM patients was still at 79% within the first 6 months. With regards to device-related side effects, data shows that in total 30 patients (27%) experienced mild-moderate skin irritations that were usually manageable with local steroid creams and did not cause significant treatment breaks despite the warm climate in Israel. Other side effects related to the device were heat sensation in 10 patients (9%) and electric sensation in 9 patients (8%) that did not cause significant treatment interruption. CONCLUSIONS: The accumulating clinical experience shows that TTFields are well-tolerated by patients in Israel without any major deviation from reported treatment-related side effects. Treatment compliance remains stable during a 6-month period.

BACKGROUND: TTFields are low intensity, intermediate frequency alternating electric fields, delivered through a portable, non-invasive device (Optune, Novocure(TM)). The EF-14 phase III trial showed significant prolongation of both progression-free and overall survival in newly diagnosed glioblastoma (GBM) patients. This is the first report on clinical experience with 110 patients treated with TTFields in Israel, focusing on safety and patient acceptance in our country. MATERIAL AND METHODS: Patients received Optune-prescription in 6 neuro-oncology centers in Israel and used the device for at least one month. The cohort included both newly diagnosed (n=53) and recurrent GBM (n=57) patients. The male/female ratio was 74/36 with a median age of 58.0 (18–82) years at start of treatment. Of patients with recurrent GBM, 51% were treated at first progression. RESULTS: Our data shows a high acceptance, with a compliance rate (monthly usage of the device) within the first 3 months of 80% for newly diagnosed GBM and 66% for recurrent GBM. Median treatment compliance was independent of age, sex and stage of disease. In addition, our data indicates that the compliance is not negatively correlated with time on treatment, as the median compliance for newly diagnosed GBM patients was still at 79% within the first 6 months. With regards to device-related side effects, data shows that in total 30 patients (27%) experienced mild-moderate skin irritations that were usually manageable with local steroid creams and did not cause significant treatment breaks despite the warm climate in Israel. Other side effects related to the device were heat sensation in 10 patients (9%) and electric sensation in 9 patients (8%) that did not cause significant treatment interruption. CONCLUSION: The accumulating clinical experience shows that TTFields are well-tolerated by patients in Israel without any major deviation from reported treatment-related side effects. Treatment compliance remains stable during a 6-month period.

PURPOSE: To retrospectively analyze and assess the outcomes and prognostic factors in a large number of patients with atypical and malignant meningiomas. METHODS AND MATERIALS: Ten academic medical centers participating in this Rare Cancer Network contributed 119 cases of patients with atypical or malignant meningiomas treated with external beam radiotherapy (EBRT) after surgery or for recurrence. Eligibility criteria were histologically proven atypical or anaplastic (malignant) meningioma (World Health Organization Grade 2 and 3) treated with fractionated EBRT after initial resection or for recurrence, and age >18 years. Sex ratio (male/female) was 1.3, and mean (+/-SD) age was 57.6 +/- 12 years. Surgery was macroscopically complete (Simpson Grades 1-3) in 71% of patients; histology was atypical and malignant in 69% and 31%, respectively. Mean dose of EBRT was 54.6 +/- 5.1 Gy (range, 40-66 Gy). Median follow-up was 4.1 years. RESULTS: The 5- and 10-year actuarial overall survival rates were 65% and 51%, respectively, and were significantly influenced by age >60 years (p = 0.005), Karnofsky performance status (KPS) (p = 0.01), and high mitotic rate (p = 0.047) on univariate analysis. On multivariate analysis age >60 years (p = 0.001) and high mitotic rate (p = 0.02) remained significant adverse prognostic factors. The 5- and 10-year disease-free survival rates were 58% and 48%, respectively, and were significantly influenced by KPS (p = 0.04) and high mitotic rate (p = 0.003) on univariate analysis. On multivariate analysis only high mitotic rate (p = 0.003) remained a significant prognostic factor. CONCLUSIONS: In this multicenter retrospective study, age, KPS, and mitotic rate influenced outcome. Multicenter prospective studies are necessary to clarify the management and prognostic factors of such a rare disease.

Purpose The aim of this systematic review was to summarize the findings from the published data of frameless stereotactic radiation therapy (RT) to the resection cavity delivered with nonrobotic linear accelerator in patients with brain metastases. Methods The studies cited in this systematic review were identified through a search of the PubMed database, using the search terms: "stereotactic [Title/Abstract]" and "Brain [Title/Abstract]," and "Metas* [Title/Abstract]." The search was unlimited to language and publication year. Results A total of 9 studies were included in our review. Stereotactic RT to the resection cavity appears to provide excellent local control rates that are comparable to framed stereotactic RT. There are various factors that influence local control. Distant intracranial control rates are poor with the use of postoperative stereotactic RT compared with local treatment (surgery or stereotactic RT) plus whole-brain RT. Conclusions Stereotactic RT to the resection cavity appears to provide good local control rates and poor distant intracranial control. Postoperative treatment should be discussed by a multidisciplinary team and tailored to each case individually.

Introduction. The current study evaluated the rate of ependymal enhancement and whether its presence influences survival of patients with malignant glioma (GBM). Methods. A retrospective review of all patients who were treated in our institution from 2005 to 2011 was conducted. Data extracted from the medical records included age, date of diagnosis, co-morbidities, treatment regimen, and time of death. Magnetic resonance images (MRI) were evaluated for the presence of ependymal enhancement and its extent, and the correlation to survival was investigated. Results. Between 2005 and 2011, 230 patients were treated for GBM. Eighty-nine patients were excluded from the study due to insufficient data, leaving 141 patients for analysis. Median age at diagnosis was 60 years. Sixty-seven (40.6%) patients had evidence of ependymal enhancement on MRI (group A), and 70 (42.4%) patients did not have evidence of enhancement. The assessment of ependymal enhancement was inconclusive due to mass effect and ventricular compression that precluded accurate assessment for 28 (17%) patients (group C). Median survival was 14 months for group A (range, 12–16 months), 15.9 months for group B (range, 14.28–17.65 months), and 11.7 months for group C (range, 6.47–16.92 months) (P>0.05). A multivariate analysis to predict survival indicated that male gender (P=0.039), hypertension (P=0.012), and biopsy only compared to complete gross tumor resection (P=0.001) were significant for poor survival. Conclusions. Pretreatment ependymal enhancement on MRI was not found to be associated with poorer survival. These results might be due to better treatments options compared to prior reports.

Purpose Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O6-methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM. Patients and Methods This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of ≥ 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status. Results A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio [HR], 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P < .001), PFS (8.7 v 5.7 months; HR, 1.63; P < .001), and response (P = .012). There was increased grade ≥ 3 toxicity in arm 2 (34% v 53%; P < .001), mostly lymphopenia and fatigue. Conclusion This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.

Glioblastoma multiforme (GBM) is an ultimately fatal disease that affects patients of all ages. Elderly patients (65 years and older) constitute a special subgroup of patients characterized by a worse prognosis and frequent comorbidities.To assess the efficacy of different treatment modalities in terms of survival in elderly patients with GBM.Using retrospective analysis, we extracted, anonymized and analyzed the files of 74 deceased patients (aged 65 or older) treated for GBM in a single institution.Mean survival time was 8.97 months and median survival time 7.68 months. Patients who underwent tumor resection had a mean survival of 11.83 months, as compared to patients who underwent no surgical intervention or only biopsy and had a mean survival of 5.22 months (P0.0001). Patients who underwent full radiation treatment had amean survival of 11.31 months, compared to patients who received only partial radiotherapy or none at all and had a mean survival of 4.09 months (P0.0001). Patients who underwent chemotherapy had a mean survival of 12.4 months, compared to patients who did not receive any chemotherapy andhad a mean survival of 5.89 months (P0.001).Age alone should not be a factor in the decision on which treatment should be given. Treatment should be individualized to match the patient's overall condition and his or her wishes, while taking into consideration the better overall prognosis expected with aggressive treatment.

e13007 Background: Standard chemotherapy regimens have limited efficacy for primary intracranial tumors. Many patients remain without feasible treatment options after progressing through first and ...

INTRODUCTION: Data from trials suggest that GBMs adjacent to the subventricular zone and associated with ependymal enhancement on MRI, have a more aggressive and multifocal phenotype which render the patient to a shorter overall survival (OS). The aim of the current study was to re-assess whether ependymal enhancement is associated with a worse outcome. METHODS: After institutional review board approval, a retrospective review of all patients who were treated for GBM in our institution from 2005 to 2011 was conducted. Only patients in whom the pretreatment MRI was available were included in our study. Data extracted from the medical records included age, date of diagnosis, co-morbidities, performance status at time of the first visit prior to initiating treatment, treatment regimen and time of death. All MRI imaging were blindly reviewed by one of the investigators, and were evaluated for distance from the subventricular zone, ependymal enhancement and pial enhancement. The groups were divided according to ependymal enhancement and data extracted was evaluated for association with survival. RESULTS: Between 2005 and 2011, 230 patients were treated at our center. Sixty five patients were excluded from the study due to insufficient data. Sixty seven patients (40.6%) had evidence of ependymal enhancement on MRI (group A). Seventy patients (42.4%) did not have evidence of enhancement (group B). In 28 patients (17%) the imaging was inconclusive, due to involvement of the temporal horn, therefore defined as group C. Median survival of all groups was 15.3 months (range 13.6 to 16.95). Median survival according to ependymal enhancement was 14 months for group A (range 12 to 16), 15.9 months group B (range 14.28 to 17.65) and 11.7 months for group C (range 6.47 to 16.92 ) (P > 0.05). Age

A 42-year-old woman who sought treatment for left drop foot was found to have a right frontoparietal parasagittal mass. Gross total resection of the tumor was performed and pathologic analysis revealed high grade osteoblastic osteosarcoma. The patient received adjuvant chemotherapy and continues to do well with no evidence of metastases or local recurrence 3 years after initial presentation.

✓ It was recently demonstrated that imaging of brain tumors by relative cerebral blood volume (CBV) maps reconstructed from dynamic magnetic resonance (MR) data provide similar diagnostic information compared to positron emission tomography (PET) or 201Tl single-photon emission computerized tomography (201Tl-SPECT) scans. The authors used relative CBV mapping for routine follow-up evaluation of patients with brain tumors and compared its sensitivity to diagnostic MR imaging, 201Tl-SPECT and clinical assessment. Fifty-nine patients were prospectively followed using 191 concomitant studies of dual section relative CBV maps, MR imaging, 201Tl-SPECT, and neurological evaluations. Studies were repeated every 2 to 3 months (median three evaluations/patient). The relative CBV maps were graded as relative CBV 0 to 4, where Grades 3 and 4 are indicative of proliferating tumors (four = rapid leak). There were 44 high-grade and 15 low-grade tumors followed during treatment. During the follow-up period a change in relative CBV grade was observed in 56% of the patients, revealing an increasing grade in 72% of them. The rapid leak phenomenon was detected in 35% of all studies and in 81% of those with a worsening relative CBV grade. Tumor progression was detected earlier by relative CBV maps as follows: earlier than MR imaging in 32% of the studies (earlier by a median of 4.5 months; p < 0.01); earlier than 201Tl-SPECT in 63% (median 4.5 months; p < 0.01), and earlier than clinical assessment in 55% (median 6 months; p < 0.01). In 82% of studies with positive MR imaging but negative 201Tl-SPECT, the lesions were smaller than 1.5 cm. The relative CBV maps clearly delineated the appearance of rapid leak in these lesions. Routine use of relative CBV maps that can be implemented on any high-field MR unit and added to the regular MR evaluation provides useful functional information in patients with brain tumors. When used as an adjunct follow-up evaluation it proved more sensitive than the other modalities for early prediction of tumor growth. It is very sensitive to small regional changes, unlike functional imaging such as PET or SPECT scans. Based on previous experience with 76 regional CBV studies, the authors conclude that regional CBV mapping correlates with active tumor and it may separate enhancing scar and radiation injury from infiltrative tumor. A new effect named the rapid leak phenomenon was also observed; this phenomenon, as identified on the regional CBV maps, correlates with high malignancy.

The toxicity of hyperbaric oxygen in the central nervous system is expressed by clinical and electroencephalographic (EEC) manifestations resembling those of generalized tonic-clonic seizures. In the search for drugs effective against these seizures, we tested vigabatrin, an irreversible inhibitor of GABA (γ-aminobutyric acid) transaminase. Five different doses of vigabatrin (ranging from 50 to 500 mg/kg) or vehicle were injected i.p. in rats implanted with cortical electrodes, 4 h prior to exposure to 5 ATA (0.5 MPa) oxygen. EEG and spectral analysis of the background EEG activity were monitored for the different dosages of the drug. The duration of the latent period before the appearance of electrical discharges in the EEG was used as an index of oxygen loxicity. The protective effect of vigabatrin was dose-related, and complete protection against hyperoxic-induced discharges was at 180 mg/kg. The protective effect lasted 24 h and decreased gradually disappearing completely on the third day. An increase in the low frequency bands of the EEG and a decrease in the faster activity were correlated with the vigabatrin dosage injected. Our results suggest that vigabatrin has the potential of being a useful drug in the treatment and prevention of oxygen-induced seizures during hyperbaric oxygen therapy.