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Background and aims: The aim of this study was to analyze the trends, demographic differences in the type and time to initiation (TTI) of adjunct treatment AT following surgery for anaplastic astrocytoma (AA). Material and methods: The National Cancer Database (NCDB) was queried for patients diagnosed with AA from 2004 to 2016. Cox proportional hazards and modeling was used to determine factors influencing survival, including the impact of time to initiation (TTI) of adjuvant therapy. Results: Overall, 5890 patients were identified from the database. The use of combined RT + CT temporally increased from 66.3% (2004–2007) to 79% (2014–2016), p < 0001. Patients more likely to receive no treatment following surgical resection included elderly (> 60 years old), hispanic patients, those with either no or government insurance, those living > 20 miles from the cancer facility, those treated at low volume centers (< 2 cases/year). AT was received following surgical resection within 0–4 weeks, 4.1–8 weeks, and > 8 weeks in 41%, 48%, and 3%, respectively. Compared to patients who received RT + CT, patients were likely to receive RT only as AT either at 4–8 weeks or > 8 weeks after the surgical procedure. Patients who received AT within 0–4 weeks had the 3-year OS of 46% compared to 56.7% for patients who received treatment at 4.1–8 weeks. Conclusion: We found significant variation in the type and timing of adjunct treatment following surgical resection of AA in the United States. A considerable number of patients (15%) received no AT following surgery. [ABSTRACT FROM AUTHOR]

Objective. To determine the incidence and identify the clinical-morphological risk factors for the development of epileptic seizures in patients with glial and metastatic brain tumors. Materials and methods. The study included 225 patients (88.6%) with glial and 29 (11.4%) with metastatic brain tumors. Results. Statistically significant differences in the incidence of epileptic seizures depending on age and histological characteristics of tumors, level of malignancy, location, involvement of the cerebral cortex, and displacement of midline structures were found. Conclusions. Epilepsy and epileptic seizures developed in 51.11% and 24.14% cases of glial and metastatic brain tumors, respectively. Risk factors for epileptic seizures were younger age (up to 57 years), histological characteristics corresponding to diffuse astrocytoma, anaplastic astrocytoma, oligodendroglioma, and oligoastrocytoma, malignancy grades I–III, lesions to the temporal lobe, and involvement of the cerebral cortex. Factors decreasing the risk of seizures were age over 57 years, histological characteristics corresponding to glioblastoma, metastatic tumors, malignancy grade IV, subcortical location of neoplasm, lesions to the occipital cortex, involvement of the conducting tracts (commissures) in the pathological process, subtentorial tumor location, absence of lesion in the temporal and frontal lobes of the brain, involvement of both hemispheres of the brain in the pathological process, lesions of two or more lobes of the brain, and displacement of midline structures. [ABSTRACT FROM AUTHOR]

Purpose: To examine the applicability of contrast leakage information from dynamic susceptibility contrast-enhanced (DSC) MRI and dynamic contrast-enhanced (DCE) MRI to determine which one is the most valuable surrogate imaging biomarker for predicting disease progression in anaplastic astrocytoma (AA) patients.Materials and Methods: This study was approved by the institutional review board (IRB), which waived informed consent. A total of seventy-three AA patients who had undergone preoperative DCE and DSC MRI and received standard treatment, including partial resection or biopsy followed by radiation therapy, were included in this retrospective study. Based on Response Assessment in Neuro-Oncology (RANO), patients were sorted into progression (n = 21) and non-progression (n = 52) groups. Tumor boundaries were defined as high-signal intensity (SI) lesions on fluid-attenuated inversion recovery (FLAIR) imaging, where we analyzed mean pharmacokinetic parameters (Ktrans, Vp, and Ve) from DCE MRI and contrast leakage information (mean extraction fraction (EF)) from DSC MRI.Results: Mean Ve and mean EF were significantly higher in patients with progression-free survival (PFS) < 18 months than in those with PFS ≥ 18 months. For distinguishing the group with PFS < 18 months, AUC values were calculated using the mean Ve value (AUC = 0.716). The Kaplan-Meier survival analysis revealed that mean Ve value was significantly correlated with PFS. In Cox proportional-hazards regression, only the mean Ve value was found to be significantly associated with PFS.Conclusion: We found that the mean Ve value based on high-SI tumor lesions on FLAIR imaging was capable of predicting outcomes of AA patients as a potential surrogate imaging biomarker.Key Points: • Mean Ve(2.152 ± 1.857 vs. 1.173 ± 1.408) was significantly higher in anaplastic astrocytoma patients with PFS < 18 months that in those with PFS ≥ 18 months (p = 0.02). • Cox proportional-hazards regression showed that only mean Ve(p = 0.034) was significantly associated with PFS, regardless of IDH mutation status, in anaplastic astrocytoma patients. [ABSTRACT FROM AUTHOR]

The SEOM/GEINO clinical guidelines provide recommendations for radiological, and molecular diagnosis, treatment and follow-up of adult patients with anaplastic gliomas (AG). We followed the 2016 WHO classification which specifies the major diagnostic/prognostic and predictive value of IDH1/IDH2 missense mutations and 1p/19q codeletions in AG. The diagnosis of anaplastic oligoastrocytoma is discouraged. Surgery, radiotherapy and chemotherapy with PCV or TMZ are the first-line standard of care for AG with slight modifications according to molecular variables. A multidisciplinary team is highly recommended in the management of these tumors. [ABSTRACT FROM AUTHOR]

Temozolomide (TMZ) for malignant gliomas is traditionally dosed in 5 out of a 28-day cycle, however alternative regimens exist, including dose-dense. Continuous daily dosing is available, but the acceptable dose and duration of therapy is unknown. We document a 40-year-old male with recurrent anaplastic astrocytoma, IDH mutant and MGMT promotor methylation negative, who has well-tolerated continuous daily TMZ for 20 months at 100 mg per day for nearly the length of this period. A trial at 80 mg per day demonstrated disease progression with response upon return to 100 mg per day. Prior to the daily TMZ, the patient underwent three surgical resections, radiation therapy with concurrent TMZ according to the EORTC-NCIC protocol, and subsequently bevacizumab in combination with use of the Optune device. Long-term survival of patients with recurrent malignant gliomas is uncommon, and currently no standard treatment strategies exist for these patients. We present this case to demonstrate the tolerability and dose dependency of prolonged daily TMZ dosing as a therapeutic option for recurrent anaplastic astrocytomas. [ABSTRACT FROM AUTHOR]

Standard treatment for GBM is radiation (RT) and temozolomide (TMZ). Arsenic trioxide (ATO) is synergistic with RT based on several mechanisms of action previously identified, however not tested herein. The MTD of ATO, RT and TMZ was determined in a Phase I trial. We now present the combined Phase I/II data. Patients with newly diagnosed malignant gliomas were eligible for treatment. Patients were treated with RT (60 GY), TMZ (75 mg/m daily × 42 days) and ATO 0.20 mg/kg daily in week 1 then twice a week ×5 weeks, after completing RT they were treated with TMZ 5/28 for up to 12 months. MRIs were performed every 8 weeks. A total of 42 patients were enrolled in both the Phase I and II trials for this study treatment. Of the 42 enrolled patients (24 M and 18 W) the median age was 54 (24-80) and median KPS 90 (60-100). 28 patients had a GBM and 14 had anaplastic glioma (AG). All patients completed RT/TMZ/ATO and went on to maintenance TMZ. Median number of post RT cycles of TMZ was 4 (0-12). Median PFS was 7 m for GBM and 75 m for AG and median OS was 17 m for GBM and NR for AG. Best response was CR in 2, SD in 28, PR in 5 and PD in 7. There were no unexpected adverse events. Grade 3 toxicities likely attributable to ATO included prolonged Qtc (n = 1), elevated liver enzymes (n = 2 for ALT/n = 1 for AST) and elevated bilirubin (n = 1). Adding ATO to RT and TMZ is feasible with no increased side effects. The addition of arsenic did not improve overall survival in the GBM patients as compared to historic data. MGMT status was analyzed in 20 of the 42 patients where tissue was available for retrieval and MGMT testing. [ABSTRACT FROM AUTHOR]

The classification, treatment and prognosis of high-grade gliomas has been shown to correlate with the expression of molecular markers (e.g. MGMT promotor methylation and IDH1 mutations). Acquisition of tumor samples may be obtained via stereotactic biopsy or open craniotomy. Between the years 2009 and 2013, 22 patients initially diagnosed with HGGs via stereotactic biopsy, that ultimately underwent open craniotomy for resection of their tumor were prospectively included in an institutional glioma database. MGMT promotor analysis was performed using methylation-specific (MS)-PCR and IDH1R132H mutation analysis was performed using immunohistochemistry. Three patients (13.7%) exhibited IDH1R132H mutations in samples obtained via stereotactic biopsy. Tissue derived from stereotaxic biopsy was demonstrated to have MGMT promotor methylation in ten patients (45.5%), while a non-methylated MGMT promotor was demonstrated in ten patients (45.5%); inconclusive results were obtained for the remaining two patients (9%) within our cohort. The initial histologic grading, IDH1R132H mutation and MGMT promotor methylation results were confirmed using samples obtained during open craniotomy in all but one patient; here inconclusive MGMT promotor analysis was obtained in contrast to that which was obtained via stereotactic biopsy. Tumor samples acquired via stereotactic biopsy provide accurate information with regard to clinically relevant molecular markers that have been shown to impact patient care decisions. The profile of markers analyzed in our cohort was nearly concordant between those samples obtained via stereotactic biopsy or open craniotomy thereby suggesting that clinical decisions may be based on the molecular profile of the tumor samples obtained via stereotactic biopsy. [ABSTRACT FROM AUTHOR]

To determine the impact of insurance status and income for anaplastic astrocytoma (AA). Data were extracted from the National Cancer Data Base. Chi square test, Kaplan-Meier method, and Cox regression models were employed in SPSS 22.0 (Armonk, NY: IBM Corp.) for data analyses. 4325 patients with AA diagnosed from 2004 to 2013 were identified. 2781 (64.3%) had private insurance, 925 (21.4%) Medicare, 396 (9.2%) Medicaid, and 223 (5.2%) were uninsured. Those uninsured were more likely to be Black or Hispanic versus White or Asian (p < 0.001), have lower median income (p < 0.001), less educated (p < 0.001), and not receive adjuvant chemoradiation (p < 0.001). 1651 (38.2%) had income ≥$63,000, 1204 (27.8%) $48,000-$62,999, 889 (20.5%) $38,000-$47,999, and 581 (13.4%) had income <$38,000. Those with lower income were more likely to be Black or Hispanic versus White or Asian (p < 0.001), uninsured (p < 0.001), reside in a rural area (p < 0.001), less educated (p < 0.001), and not receive adjuvant chemoradiation (p < 0.001). Those with private insurance had significantly higher overall survival (OS) than those uninsured, on Medicaid, or on Medicare (p < 0.001). Those with income ≥$63,000 had significantly higher OS than those with lower income (p < 0.001). On multivariate analysis, age, insurance status, income, and adjuvant therapy were independent prognostic factors for OS. Being uninsured and having income <$38,000 were independent prognostic factors for worse OS in AA. Further investigations are warranted to help determine ways to ensure adequate medical care for those who may be socially disadvantaged so that outcome can be maximized for all patients regardless of socioeconomic status. [ABSTRACT FROM AUTHOR]

To determine the receipt and impact of adjuvant therapy on overall survival (OS) for anaplastic astrocytoma (AA). Data were extracted from the National Cancer Data Base (NCDB). Chi square test, Kaplan-Meier method, and Cox regression models were employed in SPSS 22.0 (Armonk, NY: IBM Corp.) for data analyses. 4807 patients with AA diagnosed from 2004 to 2013 who underwent surgery were identified. 3243 (67.5 %) received adjuvant chemoRT, 525 (10.9 %) adjuvant radiotherapy (RT) alone, 176 (3.7 %) adjuvant chemotherapy alone and 863 (18.0 %) received no adjuvant therapy. Patients were more likely to receive adjuvant chemoRT if they were diagnosed in 2009-2013 (p = 0.022), were ≤ 50 years (p < 0.001), were male (p = 0.043), were Asian or White race (p < 0.001), had private insurance (p < 0.001), had income ≥$38,000 (p < 0.001), or underwent total resection (p < 0.003). Those who received adjuvant chemoRT had significantly better 5-year OS than the other adjuvant treatment types (41.8 % vs. 31.2 % vs. 29.8 % vs. 27.4 %, p < 0.001). This significant 5-year OS benefit was also observed regardless of age at diagnosis. Of those undergoing adjuvant chemoRT, those receiving ≥59.4 Gy had significantly better 5-year OS than those receiving <59.4 Gy (44.4 % vs. 25.9 %, p < 0.001). There was no significant difference in OS when comparing 59.4 Gy to higher RT doses. On multivariate analysis, receipt of adjuvant chemoRT, age at diagnosis, extent of disease, and insurance status were independent prognostic factors for OS. Adjuvant chemoRT is an independent prognostic factor for improved OS in AA and concomitant chemoRT should be considered for all clinically suitable patients who have undergone surgery for the disease. [ABSTRACT FROM AUTHOR]

Adding temozolomide (TMZ) to radiation for patients with newly-diagnosed anaplastic astrocytomas (AAs) is common clinical practice despite the lack of prospective studies demonstrating a survival advantage. Two retrospective studies, each with methodologic limitations, provide conflicting advice regarding treatment. This single-institution retrospective study was conducted to determine survival trends in patients with AA. All patients ≥18 years with newly-diagnosed AA treated at Johns Hopkins from 1995 to 2012 were included. As we incorporated TMZ into high-grade glioma treatment regimens in 2004, patients were divided into pre-2004 and post-2004 groups for analysis. Clinical, radiographic, and pathologic data were collected. Median overall survival (OS) was calculated using Kaplan-Meier estimates. A total of 196 patients were identified; 74 pre-2004 and 122 post-2004; mean age 47 ± 15 years; 57 % male; 87 % white, 69 % surgical debulking. Mean RT dose 5676 + 746 cGy; duration of concurrent chemoradiation 5.8 ± 0.8 weeks; and mean adjuvant chemotherapy 4.3 + 2.8 cycles. Baseline prognostic factors did not differ between groups. Chemotherapy was administered to 12 % of patients pre-2004 (TMZ = 1, procarbazine, lomustine and vincristine = 2, carmustine wafer = 6) and 94 % post-2004 (TMZ in all, p < 0.001). Median OS was 32 months (95 % CI 23-43). Survival was longer in the post-2004 cohort (37 mo, 24-64) than pre-2004 (27 mo, 19-40; HR 0.75, 0.53-1.06, p = 0.11). Multivariate analysis controlling for age, Karnofsky performance status, and extent of resection revealed a 36 % reduced risk of death (HR 0.64, 0.44-0.91, p = 0.015) in patients treated post-2004. This retrospective review found survival in newly diagnosed patients with AA improved with the addition of temozolomide to standard radiation. Until prospective randomized phase III data are available, these data support the practice of incorporating TMZ in the management of newly-diagnosed AA. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to report the outcome in children with high-grade astrocytoma outside the brain stem and spinal cord that were treated at a single center. Materials and methods: The study included 26 patients with anaplastic astrocytoma and 37 patients with glioblastoma; all patients were aged ≤18 years. At initial diagnosis, 18 of the patients with glioblastoma received only temozolomide (TMZ), 14 received other chemotherapies, and 5 did not receive any chemotherapy. Among the patients with anaplastic astrocytoma, 9 received TMZ, 9 received other chemotherapy regimens, and 8 patients did not receive any chemotherapy. The median radiotherapy dose in all patients was 60 Gy. Results: Median age of the patients was 12.5 years. Median overall survival was 20 months and mean progression-free survival was 4.7-11.3 months (median: 8 months) in all patients. Patients with a Karnofsky performance score (KPS) ≥70 had median overall survival of 32 months, versus 7 months in those with a KPS < 70. Patients aged <15 years had median survival of 38 months, versus 16 months in those aged 15-18 years. Patients with anaplastic astrocytoma that received TMZ, other chemotherapy regimens, and no chemotherapy had median survival of 21 months, 132 months, and 11 months, respectively. Patients with glioblastoma that received TMZ, other chemotherapy regimens, and no chemotherapy had median survival of 32 months, 12 months, and 8 months, respectively. Conclusion: In the present study, patients with anaplastic astrocytoma treated with chemotherapy protocols other than TMZ had the longest OS; however, in the glioblastoma group, OS was 32 months in those treated with standard TMZ and 12 months in those treated with other protocols ( P = 0.493). Although TMZ is less toxic than PCV, it was not shown to be superior. [ABSTRACT FROM AUTHOR]

Recent advances in genomic technology and genome-wide analysis have identified key molecular alterations that are relevant to the diagnosis and prognosis of brain tumors. Molecular information such as mutations in isocitrate dehydrogenase ( IDH) genes or 1p/19q co-deletion status will be more actively incorporated into the histological classification of diffuse gliomas. BRAF V600E mutations are found frequently in circumscribed low-grade gliomas such as pleomorphic xanthoastrocytoma (PXA) and extra-cerebellar pilocytic astrocytoma, or epithelioid glioblastomas (E-GBM), a rare variant of GBM. This mutation is relatively rare in other types of diffuse gliomas, especially in adult onset cases. Here, we present an adult onset case of IDH wild-type/ BRAF V600E-mutated diffuse glioma, evolving from grade III to grade IV. The tumor displayed atypical exophytic growth and had unusual histological features not fully compatible with, but indicative of PXA and E-GBM. We discuss differential diagnosis of the tumor, and review previously described diffuse gliomas with the BRAF V600E mutation. [ABSTRACT FROM AUTHOR]

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Purpose: Malignant optic glioma of adulthood is a rare, invasive neoplasm of the anterior visual pathway with 66 cases reported in the literature. It presents as anaplastic astrocytoma (WHO grade III) or glioblastoma (WHO grade IV). The present case series covers the spectrum of disease manifestations, discusses neuroradiological findings, and reviews the current literature. Methods: Retrospective case series of five patients from three tertiary referral centers and literature review. Results: Visual loss with or without pain was the presenting symptom in all patients (two women, three men). Two patients were initially misdiagnosed as optic neuritis, and one patient as atypical non-arteritic anterior ischemic optic neuropathy (NAION). A neoplastic disease was suspected in the two remaining patients. MRI features were iso- to hypointensity on T1-weighted native images, contrast enhancement, and hyperintensity on T2-weighted images. Biopsy was generally diagnostic; however, one patient required two biopsies for diagnosis. The series includes an exceptional case of intraocular tumor extension and vitreous spread. The disease was lethal within one to two years in all patients. Conclusions: Malignant optic glioma is a diagnostic challenge and remains a devastating and lethal disease. Advances in the understanding of tumor biology have yet failed to translate into effective treatment regimens. [ABSTRACT FROM AUTHOR]

We previously reported results of a phase II non-comparative trial that randomized patients with glioblastoma following radiotherapy to one of two different temozolomide schedules, followed by 13-cis-retinoic acid (RA) maintenance. Here we report the results of an exploratory cohort of patients accrued with anaplastic astrocytic tumors. Patients with newly diagnosed anaplastic astrocytoma (AA) or anaplastic oligo-astrocytoma (AOA) were treated with concurrent radiotherapy (60 Gy over 6 weeks) and temozolomide (75 mg/m), and six adjuvant 28-day cycles of either dose-dense (150 mg/m, days 1-7, 15-21) or metronomic (50 mg/m, days 1-28) temozolomide. Subsequently, maintenance RA (100 mg/m, days 1-21/28) was administered until disease progression. All outcome measures were descriptive without intention to compare between treatment arms. Survival was measured by the Kaplan-Meier method. There were 31 patients (21 men, 10 women) with median age 48 years (range 28-74), median KPS 90 (range 60-100). Extent of resection was gross-total in 35 %, subtotal 23 %, and biopsy 42 %. Histology was AA in 90 %, and AOA in 10 %. MGMT promoter methylation was methylated in 20 %, unmethylated in 50 %, and uninformative in 30 % of 30 tested. Median progression-free survival was 2.1 years (95 % CI 0.95-Not Reached), and overall survival 2.9 years (95 % CI 2.0-Not Reached). We report outcomes among a homogeneously treated population with anaplastic astrocytic tumors. Survival was unexpectedly short compared to other reports. These data may be useful as a contemporary historic control for other ongoing or future randomized trials. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme and anaplastic astrocytoma are challenges to clinical biologists at present. The patients with glioblastoma have median survival of less than 12 months, despite advances in radiotherapeutical, chemotherapeutical and conventional surgical modalities. Retinoic acids are known to effect in vitro proliferation, differentiation, and apoptosis in colon, prostate, lung, and leukemia cancers. Retinoids are known to have anti-proliferation, anti-migration, and anti-invasive activity against human malignant gliomas, suggesting that retinoids are suitable anticancer agents to inhibit progression of tumors. Recurrent malignant cerebral gliomas have been treated with ATRA and 13-cis RA. However, the side effects associated with the use of high doses of retinoic acid demand for some more potent derivative free from such effects. The present clinical trials are undertaken to investigate the clinical safety and possible efficacy of administering retinoic acid naphthalene triazole (RANT) to patients with recurrent malignant gliomas. The toxicities observed in the patients during RANT treatment were mild. These preliminary results suggest that RANT is more potent compared to RA against recurrent malignant gliomas. [ABSTRACT FROM AUTHOR]

The utility of current response criteria has not been established in anaplastic astrocytoma (AA). We retrospectively reviewed MR images for 20 patients with AA and compared RANO-based approaches to clinician impression described as follow: (1) standard RANO-based criteria met by growth of or development of new enhancing lesion (RANO-C), (2) RANO criteria for progression based on significant FLAIR increase (RANO-F) and (3) clinical progression usually resulting in change of treatment (Clinical). Patterns of failure (POF) were analyzed utilizing all proposed progression MRIs fused with the patients' radiotherapy treatment plan. With an overall median survival of 24.3 months, development of new enhancing lesion was the most common determinant of progression (70 % of patients). Median time to RANO-C, RANO-F and Clinical progression was 9.2, 9.2 and 11.76 months respectively. RANO-C and RANO-F preceded Clinical in 70 and 55 % of patients, respectively. In six patients (30 %) Clinical was concurrent with RANO-F; four of six also met RANO-C. POF for FLAIR component differed based on time point used to determine progression. FLAIR POF was more often marginal or distant when progression was defined clinically compared to either RANO-C or RANO-F criteria. Central POF based on FLAIR at Clinical determination of progression was associated with significantly poorer OS (9.8 vs. 34.4 months). Clinical progression occurs later than progression determined by RANO-based criteria. Evaluation of POF based on FLAIR signal abnormality at the time of clinical progression suggests central recurrences are associated with worse survival. [ABSTRACT FROM AUTHOR]

Children with high-grade glioma (HGG) have a poor prognosis compared to those with low-grade glioma (LGG). Adjuvant chemotherapy may be beneficial, but its optimal use remains undetermined. Histology and extent of resection are important prognostic factors. We tested the hypothesis that patients with midline HGG treated on Children's Cancer Group Study (CCG) CCG-945 have a worse prognosis compared to the entire group. Of 172 children eligible for analysis, 60 had midline tumors primarily localized to the thalamus, hypothalamus and basal ganglia. Time-to-progression and death were determined from the date of initial diagnosis, and survival curves were calculated. Univariate analyses were undertaken for extent of resection, chemotherapy regimen, anatomic location, histology, proliferation index, MGMT status and p53 over-expression. For the entire midline tumor group, 5-year PFS and OS were 18.3 ± 4.8 and 25 ± 5.4 %, respectively. Many patients only had a biopsy (43.3 %). The sub-groups with near/total resection and hypothalamic location appeared to have better PFS and OS. However, the effect of tumor histology on OS was significant for children with discordant diagnoses on central pathology review of LGG compared to HGG. Proliferative index (MIB-1 > 36 %), MGMT and p53 over-expression correlated with poor outcomes. Children treated on CCG-945 with midline HGG have a worse prognosis when compared to the entire group. The midline location may directly influence the extent of resection. Central pathology review and entry of patients on clinical trials continue to be priorities to improve outcomes for children with HGG. [ABSTRACT FROM AUTHOR]

Background: Five-aminolevulinic acid (Gliolan, medac, Wedel, Germany, 5-ALA) is approved for fluorescence-guided resections of adult malignant gliomas. Case reports indicate that 5-ALA can be used for children, yet no prospective study has been conducted as of yet. As a basis for a study, we conducted a survey among certified European Gliolan users to collect data on their experiences with children. Methods: Information on patient characteristics, MRI characteristics of tumors, histology, fluorescence qualities, and outcomes were requested. Surgeons were further asked to indicate whether fluorescence was 'useful', i.e., leading to changes in surgical strategy or identification of residual tumor. Recursive partitioning analysis (RPA) was used for defining cohorts with high or low likelihoods for useful fluorescence. Results: Data on 78 patients <18 years of age were submitted by 20 centers. Fluorescence was found useful in 12 of 14 glioblastomas (85 %), four of five anaplastic astrocytomas (60 %), and eight of ten ependymomas grades II and III (80 %). Fluorescence was found inconsistently useful in PNETs (three of seven; 43 %), gangliogliomas (two of five; 40 %), medulloblastomas (two of eight, 25 %) and pilocytic astrocytomas (two of 13; 15 %). RPA of pre-operative factors showed tumors with supratentorial location, strong contrast enhancement and first operation to have a likelihood of useful fluorescence of 64.3 %, as opposed to infratentorial tumors with first surgery (23.1 %). Conclusions: Our survey demonstrates 5-ALA as being used in pediatric brain tumors. 5-ALA may be especially useful for contrast-enhancing supratentorial tumors. These data indicate controlled studies to be necessary and also provide a basis for planning such a study. [ABSTRACT FROM AUTHOR]

This study assesses the controversial role of temozolomide (TMZ) concurrent with adjuvant radiation (RT) in patients with anaplastic astrocytoma (AA). The impact of isocitrate dehydrogenase (IDH) status on therapy and outcomes is also examined. All adult patients diagnosed with AA from 2001 to 2011 and treated with standard doses of adjuvant RT were identified retrospectively for clinical data extraction. IDH status was determined by IDH1-R132H immunostain and sequencing for other mutations in IDH1/IDH2. Cumulative survival probabilities were estimated using the Kaplan-Meier method. Cox proportional hazards regression models were fit for univariable/multivariable analyses. 136 patients had received concurrent TMZ while 29 had not. Of these, IDH status was determined on 114 and 27 patients, respectively. On univariable analysis, improved five-year survival was independently associated with concurrent TMZ (46.2 vs. 29.3 %, p = 0.02) and IDH mutation (78.9 vs. 22.0 %, p < 0.001). IDH mutation was additionally associated with a greater likelihood of extensive resection possibly secondary to a more favorable tumor location. Gross total/subtotal resections also led to improved survival when compared to biopsy alone on univariable analysis. On multivariable analysis, the association with five-year survival persisted for both concurrent TMZ and IDH mutation, but not with extent of surgery. Both IDH mutation and concurrent TMZ are associated with improved five-year survival in patients with AA who are receiving adjuvant RT. Secondarily, the association between five-year survival and extent of resection is lost on multivariable analysis. This suggests a possible association between IDH mutation, tumor location and consequent resectability. [ABSTRACT FROM AUTHOR]

The accurate grading of malignant astrocytomas has significant prognostic and therapeutic implications. Traditional histopathological grading can be challenging due to regional tumor heterogeneity, especially in scenarios where small amounts of tissue are available for pathologic review. Here, we hypothesized that a critical tumor resection volume is needed for correct grading of astrocytomas by histopathology. For insufficient tissue sampling, IDH1 molecular testing can act as a complementary marker to improve diagnostic accuracy. Volumetric analyses were obtained using preoperative and postoperative MRI images. Histological specimens were gathered from 403 patients with malignant astrocytoma who underwent craniotomy. IDH1 status was assessed by immunohistochemistry and sequencing. Patients with >20 cubic centimeters (cc) of the total tumor volume resected on MRI have higher rate of GBM diagnosis compared to <20 cc [odds ratio (OR) 2.57, 95 % confidence interval (CI) 1.6-4.06, P < 0.0001]. The rate of IDH1 status remained constant regardless of the tumor volume resected (OR 0.81, 95 % CI 0.48-1.36, P < 0.43). The rate of GBM diagnosis is twofold greater for individual surgical specimen >10 cc than those of lower volume (OR 2.48, 95 % CI 1.88-3.28, P < 0.0001). Overall survival for AA patients with >20 cc tumor resection on MRI is significantly better than those with <20 cc tumor resected ( P < 0.05). No volume-dependent differences were observed in patients with GBM ( P < 0.4), IDH1 wild type ( P < 0.1) or IDH1 mutation ( P < 0.88). IDH1 status should be considered when total resection volume is <20 cc based on MRI analysis and for surgical specimen <10 cc to complement histopathologic diagnosis of malignant astrocytomas. In these specimens, under-diagnosis of GBM may occur when analysis is restricted to histopathology alone. [ABSTRACT FROM AUTHOR]

Background: To study patient characteristics, prognostic factors and overall survival (OS) in a consecutive, surgical series of WHO grade III anaplastic astrocytomas (AA). Methods: Patients were identified from a prospective tumor database at Oslo University Hospital, Norway, and patients undergoing surgery for an AA from 2005-2012 were included. Patients' medical charts were retrospectively reviewed for data collection. Results: A total of 99 adult patients with histologically verified AA were included. Median age was 52 years (20-81). Biopsy was conducted in 33 % and resection in 67 %. Adjuvant treatment with radiation therapy + temozolomide or radiation therapy only was given in 63 % and 26 %, respectively. The thirty-day mortality rate was 3 %. Median OS was 19 months (95 % CI 11-27 months). Age ≥ 65 years, KPS < 70, biopsy as opposed to resection, and no adjuvant treatment were confirmed negative prognostic factors in multivariate analysis. For patients undergoing resection, presence of postoperative contrast-enhanced tumor, not volume of residual tumor, had significant impact on OS in adjusted analysis. Conclusions: Median OS following surgery was 19 months, though much variable outcome was observed among subgroups of AA (95 % CI 11-27 months). Age ≥65 years, KPS < 70, biopsy as opposed to resection, and no adjuvant treatment were confirmed negative prognostic factors for OS. [ABSTRACT FROM AUTHOR]

Protein arginine methyltransferase 5 (PRMT5) catalyzes the formation of ω-NG,N′G-symmetric dimethylarginine residues on histones as well as other proteins. These modifications play an important role in cell differentiation and tumor cell growth. However, the role of PRMT5 in human glioma cells has not been characterized. In this study, we assessed protein expression profiles of PRMT5 in control brain, WHO grade II astrocytomas, anaplastic astrocytomas, and glioblastoma multiforme (GBM) by immunohistochemistry. PRMT5 was low in glial cells in control brain tissues and low grade astrocytomas. Its expression increased in parallel with malignant progression, and was highly expressed in GBM. Knockdown of PRMT5 by small hairpin RNA caused alterations of p-ERK1/2 and significantly repressed the clonogenic potential and viability of glioma cells. These findings indicate that PRMT5 is a marker of malignant progression in glioma tumors and plays a pivotal role in tumor growth. [ABSTRACT FROM AUTHOR]

The treatment of anaplastic astrocytoma (AA) is controversial. New chemotherapeutic approaches are needed for AA treatment. Temozolomide (TMZ) is one of the chemotherapeutic drugs for the treatment of AA. The cytotoxic effects of TMZ can be removed by the MGMT (O(6)-methylguanine-DNA methyltransferase) enzyme. Then, chemotherapeutic resistance to TMZ occurs. MGMT inhibition by MGMT inactivators (such as lomeguatrib) is an important anticancer therapeutic approach to circumvent TMZ resistance. We aim to investigate the effect of TMZ-lomeguatrib combination on MGMT expression and TMZ sensitivity of SW1783 and GOS-3 AA cell lines. The sensitivity of SW1783 and GOS-3 cell lines to TMZ and to the combination of TMZ and lomeguatrib was determined by a cytotoxicity assay. MGMT methylation was detected by MS-PCR. MGMT and p53 expression were investigated by real-time PCR after drug treatment, and the proportion of apoptotic cells was analyzed by flow cytometry. When the combination of TMZ-lomeguatrib (50 μM) was used in AA cell lines, IC values were reduced compared to only using TMZ. MGMT expression was decreased, p53 expression was increased, and the proportion of apoptotic cells was induced in both cell lines. The lomeguatrib-TMZ combination did not have any effect on the cell cycle and caused apoptosis by increasing p53 expression and decreasing MGMT expression. Our study is a pilot study investigating a new therapeutic approach for AA treatment, but further research is needed. [ABSTRACT FROM AUTHOR]

Although several series of pineal region tumors are available, the issue of pineal gliomas has been scarcely faced in the literature. Gliomas are usually included in largest series of pineal neoplasms. Therefore, whether pineal gliomas share the biological behavior of either hemispheric gliomas or other midline lesions is not yet defined. The aim of this retrospective study is to analyze long-term morbidity and mortality of these lesions. In English published literature gliomas account for about 14-22 % of all pineal region tumors. Most of these tumors are pilocytic astrocytomas, while glioblastoma multiforme is rare. We retrospectively analyzed all pineal region tumors operated on in our department in the last 28 years, and identified eight pineal astrocytomas, accounting for 14.03 % of all pineal tumors. The series includes four pilocytic astrocytomas, two grade II diffuse astrocytomas, and two anaplastic astrocytomas. A comprehensive review of the available literature data shows that the mean survival time of WHO grade II gliomas is shorter when tumor grows in the pineal region than for hemispheric locations, although the limited amount of available data prevents a rigorous statistical analysis. This difference might be due to the peculiar infiltrating behavior of pineal tumors, which often can't be satisfactorily resected from vital structures. [ABSTRACT FROM AUTHOR]

Treatment for anaplastic astrocytoma (AA) is controversial. To assess three primary treatment approaches, patients from a single institution were retrospectively evaluated. To represent modern treatment selection, patients diagnosed with AA from December 2003 to December 2009 were selected. Those with insufficient data, incomplete pathology, and transformation or reclassification to glioblastoma in fewer than 6 months were excluded. A total of 163 patients were included in the final analyses. Median follow-up time was 4.2 years (range 0.5-7.8 years). Median age and Karnofsky performance status at diagnosis were 39.2 years and 90, respectively. 23.6 % of patients underwent biopsy, and 72.2 % underwent resection. Approximately 31 % received concurrent chemoradiation (CRT), 26.1 % had radiation therapy alone (RT), 38.2 % had radiation therapy followed by chemotherapy (RT-C), and 3 % were treated only with chemotherapy. Temozolomide was used almost exclusively during CRT (94.2 %) and adjuvantly. A median of 9.5 cycles of adjuvant chemotherapy was given. The combination of radiation and chemotherapy, either concurrent or sequential trended toward a higher rate of radiation necrosis. Median progression free survival (PFS) favored RT (not reached) over CRT (1.5 years) and RT-C (3.6 years) adjusted for pairwise comparison ( p = 0.033, p = 0.050). Median overall survival (OS) was 5.7 years, and did not differ significantly by treatment group. OS for patients with AA did not vary by initial treatment selection. Although the longer PFS in those receiving RT versus CRT may be confounded by pseudoprogression, the equivalent OS among groups supports RT. [ABSTRACT FROM AUTHOR]

Immunological factors are important in pathogenesis of various malignancies, including neural cancers. The CXC chemokine CXCL12 is involved in the immune responses. Therefore, the aim of the present study was to investigate the association between tumor tissue and circulating concentrations of CXCL12 as well as its genetic variation at position +801 known as(the SDF-1 3'A), in Iranian patients suffering from malignant glial tumors. In this study, stereotactic tumor biopsy specimens in parallel with peripheral blood samples were collected from 123 patients and 189 healthy controls. The serum level of CXCL12 was measured by ELISA and tumor tissues were subjected to Western blotting for intra-tumor CXCL12 detection; we also employed PCR-RFLP to detect the SDF-1 3'A polymorphism. Demographic data were collected by a researcher-designed questionnaire. These results demonstrated a significant difference between the A/A, A/G, and G/G genotype and A and G alleles of polymorphisms at position +801 of CXCL12. We also indicated elevated levels of CXCL12 in circulation and tumor tissue obtained from in patients suffering from malignant glial tumors. Based upon the results of this investigation, we propose that CXCL12 and its SDF-1 3'A polymorphism play a fundamental part in the pathogenesis of malignant glial tumors. It is also noteworthy that CXCL12 could probably be utilized as a beneficial biological marker in the diagnosis of these tumors. [ABSTRACT FROM AUTHOR]

A multicenter, two stage phase II study, investigated irinotecan plus temozolomide in children with newly diagnosed high grade glioma. The primary endpoint was tumor response during a two-cycle treatment window, confirmed by external review committee. Patients received oral temozolomide 100 mg/(m day) (days 1-5) and intravenous irinotecan 10 mg/(m day) (days 1-5 and 8-12) for two 21-day cycles (three cycles for patients exhibiting objective tumor response). Standard treatment was then administered according to local investigator choice. In total 17 patients were enrolled and treated by local investigators. However, central pathology review found three patients did not have a diagnosis of high grade glioma and another four patients did not have evaluable disease according to independent central radiological review. The primary endpoint was based on the first ten evaluable patients as determined by the external review committee. Recruitment was stopped for futility after there were no complete or partial responses during the two-cycle treatment window in the first ten evaluable patients. Five patients had stable disease, and five progressed. Data for secondary endpoints including; time to tumor progression, time to treatment failure, and overall survival is reported. The safety profile of the treatment showed the combination was tolerable with two patients (11.8 %) having grade three nausea, and one (5.9 %) experiencing a grade four neutropenia, leading to permanent discontinuation from adjuvant treatment. Irinotecan plus temozolomide, although well tolerated did not improve outcome over historical controls in this setting. [ABSTRACT FROM AUTHOR]

Standard treatment of anaplastic astrocytoma (AA) in good performance patients consists of maximal safe surgical resection followed by focal, fractionated, external beam radiotherapy (RT) alone or in combination with concurrent and adjuvant temozolomide (TMZ). Since prospective data regarding the use of chemoradiotherapy for AA is lacking, the practice is based on the extrapolation of results from a randomized study in glioblastoma (GB). Whether the data from the GB study can and should be extrapolated is controversial, although a large multicenter, randomized, phase III study is underway to define optimal initial AA treatment. Patients should be tapered off corticosteroids completely or to the lowest dose necessary to treat neurologic dysfunction. Anti-epileptic drugs (AED) are not indicated unless there is a history of seizure; levetiracetam is the preferred AED in malignant glioma (MG). Unless there is evidence of intracranial hemorrhage, venous thromboembolism (VTE) should be treated with low-molecular-weight heparin (LMWH) therapy. At recurrence, patients with good performance status are usually treated with cytotoxic chemotherapy following, or in lieu of, repeat surgery. TMZ is the preferred chemotherapeutic agent in patients without prior exposure; lomustine is recommended for tumors resistant to TMZ. In patients with neurologic dysfunction secondary to tumor edema and mass effect who are not amenable to surgery, the use of bevacizumab is associated with improved neurologic function and better quality of life. Given the limited treatment options at tumor recurrence, consideration for enrollment on a clinical trial is encouraged. [ABSTRACT FROM AUTHOR]

Purpose: Glioblastoma (GBM) is one of the worst cancers in terms of prognosis. Standard therapy consists of resection with concomitant chemoradiotherapy. Resistance to nimustine hydrochloride (ACNU), an alkylating agent, has been linked to methylguanine DNA methyltransferase (MGMT). Daily administration of procarbazine (PCZ) has been reported to decrease MGMT activity. This study investigated the efficacy of ACNU + PCZ compared to ACNU alone for GBM and anaplastic astrocytoma (AA). Methods: Patients (20-69 years) who had newly diagnosed AA and GBM were randomly assigned to receive radiotherapy with ACNU alone or with ACNU + PCZ. The primary endpoint was overall survival (OS). This was designed as a phase II/III trial with a total sample size of 310 patients and was registered as UMIN-CTR C000000108. Results: After 111 patients from 19 centers in Japan were enrolled, this study was terminated early because temozolomide was newly approved in Japan. The median OS and median progression-free survival (PFS) with ACNU alone ( n = 55) or ACNU + PCZ ( n = 56) in the intention-to-treat population were 27.4 and 22.4 months ( p = 0.75), and 8.6 and 6.9 months, respectively. The median OS and median PFS of the GBM subgroup treated with ACNU alone ( n = 40) or ACNU + PCZ ( n = 41) were 19.0 and 19.5 months, and 6.2 and 6.3 months, respectively. Grade 3/4 hematologic adverse events occurred in more than 40 % of patients in both arms, and 27 % of patients discontinued treatment because of adverse events. Conclusions: The addition of PCZ to ACNU was not beneficial, in comparison with ACNU alone, for patients with newly diagnosed AA and GBM. [ABSTRACT FROM AUTHOR]

Few studies have assessed the presentation, management, and outcome of anaplastic astrocytoma (AA) in elderly patients in the temozolomide era. We retrospectively reviewed 42 consecutive patients aged >65 years with newly-diagnosed AA who underwent surgical resection or biopsy between 2003 and 2008. Median age and KPS score were 73 years (range, 66-88) and 80 (range, 50-90), respectively. Thirty-two patients (76 %) presented with focal deficits. Twenty patients (48 %) experienced seizures before surgery. Tumor enhanced diffusely in 24 patients (57 %) and sparsely in 18 patients (43 %). Biopsy (79 %) was more common than resection. Post-operatively, new persistent neurological deficits and hemorrhage were seen in two (4.8 %) and three (7.1 %) patients, respectively. Complete follow-up data regarding adjuvant treatment was available in 31 patients. Sixteen patients (52 %) received temozolomide and radiation therapy (RT), while nine patients (29 %) received RT alone. Chemotherapy-related grade 3/4 hematologic complication rate was 17.6 %. Median overall survival (OS) was 6.5 months (12 months with resection; 3.5 months with biopsy). Resection ( P = 0.007, risk ratio = 0.21) and sparse enhancement ( P = 0.007, risk ratio = 0.13) were associated with longer OS in multivariate analysis. Similarly, chemoradiation was associated with longer survival compared to RT alone (OS: P = 0.01, progression-free survival (PFS): P = 0.02) after adjusting for age, KPS, enhancement, and surgery. Resection was associated with longer survival among elderly patients with AA, although this could reflect selection bias. Similarly, adding chemotherapy to RT was associated with prolonged survival but carried important complication risks. In appropriately selected AA patients, aggressive treatments with radical resection and chemoradiation may be appropriate even in this age group. [ABSTRACT FROM AUTHOR]

Single-agent sunitinib, an oral small molecule inhibitor of multiple tyrosine kinase receptors, was evaluated for treatment of patients with recurrent glioblastoma (GB) and anaplastic astrocytoma (AA). Fourteen AA and 16 GB patients, all previously treated with surgery, radiotherapy, and temozolomide, were enrolled in a prospective phase II study at either first or second relapse. Patients were treated with daily sunitinib for 4 consecutive weeks, followed by a 2-week break. For AA patients, the most common side effects were fatigue (86 %), diarrhea (43 %), hand-foot syndrome (36 %), neutropenia (36 %), thrombocytopenia (36 %), and nausea (29 %). In the GB cohort, the most common side effects were fatigue (56 %), diarrhea (44 %), neutropenia (31 %), and thrombocytopenia (25 %). Six of 14 (43 %) AA and 5 of 16 (31 %) GB patients experienced grade 3 or greater toxicities. Five patients discontinued study due to drug toxicities. There were no partial or complete responses in either cohort; 8/14 (57 %) AA and 5/16 (31 %) GB patients had stable disease at the first planned assessment. Progression-free survival at 6 months was 21.5 % (AA) and 16.7 % (GB). Median overall survival was 12.1 months (AA) and 12.6 months (GB). These results are comparable to those reported in the literature in patients treated with standard cytotoxic therapies. This is the largest reported trial of sunitinib in recurrent malignant astrocytic gliomas to date, as well as contains the largest AA cohort. Nonetheless, sunitinib did not demonstrate significant anti-glioma activity in patients with recurrent malignant astrocytic gliomas. [ABSTRACT FROM AUTHOR]

The treatment of anaplastic glioma (AG) varies depending on histopathology of the tumor, molecular markers, and individual patient characteristics. Maximal surgical resection is desirable for all types of AG if technically feasible, with an acceptable level of risk, and with the goal of preserving neurologic function. As opposed to the standard treatment of glioblastoma, based on a large, randomized, phase 3 trial, there is no accepted standard treatment for AG. Anaplastic astrocytoma (AA) is most often treated with radiotherapy (RT), with or without concomitant temozolomide (TMZ) and with or without adjuvant temozolomide. Rarely is AA treated with chemotherapy alone, although different treatment modalities are being evaluated in ongoing trials. The treatment of anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) is influenced by the 1p/19q status, as allelic co-deletion of chromosomes 1p and 19q predicts increased sensitivity to chemotherapy and prolonged survival. In contrast to the treatment of AA, carefully selected patients with AO and AOA may be treated with chemotherapy alone. Temozolomide has largely replaced PCV (procarbazine, CCNU, vincristine) as the chemotherapeutic agent for AO and AOA, largely due to greater tolerability and less potential for toxicity. However, whether temozolomide has similar efficacy to PCV has not been fully evaluated. Patients with AO and AOA with significant residual tumor after surgery, intractable seizures, and/or non co-deleted 1p/19q status are often treated with RT with or without concomitant chemotherapy and with or without adjuvant chemotherapy. There is no standard postoperative care for anaplastic ependymoma (AE). The efficacy of upfront versus delayed RT has not been evaluated. Surgery may be indicated for patients with recurrent AG. There may be benefit on overall survival, although this has not been clearly proven. Reoperation may also provide symptomatic relief and confirm the pathology, including differentiation of radiation necrosis from recurrent tumor. Confirmation of tumor grade is often important for enrollment in clinical trials, a reasonable treatment choice for patients with recurrent tumor. Treatment of recurrent AG often depends on prior treatments. Patients who have progressed after RT alone may be treated with temozolomide or PCV. Patients treated previously with chemotherapy alone may be treated with RT at time of progression. Dose-intense temozolomide, bevacizumab alone, or bevacizumab in combination with a cytotoxic agent are other treatment options. Focused radiation such as stereotactic radiosurgery has no proven role in treating recurrent AG. A number of other treatment modalities are currently under active investigation, including targeted molecular inhibitors, immunotherapies, convection enhanced delivery, and viral gene therapies. There is no standard treatment for recurrent AE. Most patients undergo re-resection followed by RT if RT was not previously given. Chemotherapy may be given, but there is no standard chemotherapeutic regimen. Ongoing trials are evaluating the role of bevicizumab and targeted molecular agents in the treatment of AE. [ABSTRACT FROM AUTHOR]

High-grade gliomas are an infrequent disease diagnosed usually in the fifth or sixth decade. Careful histopathological diagnosis is essential because tumour grade and type condition the treatment. Magnetic resonance with gadolinium is considered the standard radiologic exploration and should be followed by tissue sampling. Treatment of these patients should be decided in a multidisciplinary committee. Surgery, radiotherapy and chemotherapy are the basis of patients' treatment, with the best results obtained when the three of them can be used. [ABSTRACT FROM AUTHOR]

Congenital malignant gliomas are rare brain tumors about which few reports have been published. We present the clinical course and genetic alterations in an infant with a congenital malignant glioma detected incidentally by ultrasonography at 36 weeks. The tumor occupied the right temporoparietal region, extended to the posterior fossa, and significantly compressed surrounding structures. The female infant was entirely normal without macrocrania, tense fontanel, or sucking difficulties. The tumor was subtotally resected by two-stage surgery; pathological diagnosis was anaplastic astrocytoma. Immunohistochemical staining was positive for p53 and negative for epidermal growth factor receptor. There was no O-methylguanine-DNA methyltransferase ( MGMT) gene promoter methylation, no 1p/19q loss of heterozygosity, and no isocitrate dehydrogenase 1 ( IDH1) mutation. She underwent postoperative chemotherapy and is alive and well 12 months after surgery. [ABSTRACT FROM AUTHOR]

Although outcome following bevacizumab among recurrent grade IV malignant glioma patients is documented as poor by several analyses, outcome for recurrent grade III patients following bevacizumab therapy has not been specifically evaluated. We performed a pooled analysis of 96 recurrent grade III malignant glioma patients enrolled on three consecutive phase II bevacizumab salvage trials to evaluate overall outcome following bevacizumab trial discontinuation. Outcome on the three bevacizumab trials, which included similar eligibility, treatment and assessment criteria, was comparable. Forty-nine patients who progressed on bevacizumab trial therapy and remained alive for at least 30 days elected to receive additional therapy. These patients achieved a median PFS-6 and OS of 30.6% (95% CI: 18.4, 43.6) and 10.3 months (95% CI: 5.2, 11.7), respectively. Among patients who continued bevacizumab therapy ( n = 23) after study progression, PFS-6 and median OS were 39.1% (95% CI: 19.9, 58.0) and 9.2 months (95% CI: 5.2, 13.6), respectively, compared to 23.1% (95% CI: 9.4, 40.3; P = 0.51) and 10.3 months (95% CI: 2.5, 14.4; P = 0.91) for patients who initiated non-bevacizumab containing therapy ( n = 26). Outcome after discontinuation of bevacizumab therapy for recurrent grade III malignant glioma patients is associated with improved outcome compared to historical data for recurrent grade IV malignant glioma patients. Salvage therapies following bevacizumab failure have modest activity for grade III malignant glioma patients that is independent of further bevacizumab continuation. [ABSTRACT FROM AUTHOR]

Newcastle disease virus (NDV) is a member of genus Avulavirus within the family Paramyxoviridae. Interest of using NDV as an anticancer agent has arisen from its ability to kill tumor cells with limited toxicity to normal cells. In this investigation, the cytotolytic properties of NDV strain AF2240 were evaluated on brain tumor cell line, anaplastic astrocytoma (U-87MG), by using MTT assay. Cytological observations were studied using fluorescence microscopy and transmission electron microscopy to show the apoptogenic features of NDV on U-87MG. DNA laddering in agarose gel electrophoresis and terminal deoxyribonucleotide transferase-mediated dUTP-X nick end-labeling staining assay confirmed that the mode of cell death was by apoptosis. However, analysis of the cellular DNA content by flowcytometery showed that there was a loss of treated U-87MG cells in all cell cycle phases (G1, S and G2/M) accompanied with increasing in sub-G1 region (apoptosis peak). Early apoptosis was observed 6 h post-inoculation by annexin-V flow-cytometry method. It could be concluded that NDV strain AF2240 is a potent antitumor agent that induce apoptosis and its cytotoxicity increasing while increasing of time and virus titer. [ABSTRACT FROM AUTHOR]

Malignant gliomas have long been a therapeutic dilemma in neuro-oncology, with a poor overall prognosis. Standard treatment, consisting of primary resection, followed by radiation therapy and temozolomide, has improved prognosis. Recently, studies have looked at the addition of bevacizumab (Avastin), a humanized murine IgG1 monoclonal antibody against vascular endothelial growth factor-A, to conventional regiments. Bevacizumab gained US FDA approval for single agent use in recurrent glioblastoma in 2009. Known side effects of bevacizumab include increased risk of arterial and venous thromboembolism, as well as hemorrhage. With emerging data for the use of bevacizumab in malignant gliomas, the extent of risks such as bleeding and thrombosis in patients with primary brain tumors treated with bevacizumab remains unknown. Here, we present only the second reported case of dural venous sinus thrombosis during treatment with bevacizumab and the first reported case for a primary glioma treated with temozolomide, radiation, and bevacizumab. [ABSTRACT FROM AUTHOR]

Since the development of the Radiation Therapy Oncology Group-Recursive Partitioning Analysis (RTOG-RPA) risk classes for high-grade glioma, radiation therapy in combination with temozolomide (TMZ) has become standard care. While this combination has improved survival, the prognosis remains poor in the majority of patients. Therefore, strong interest in high-grade gliomas from basic research to clinical trials persists. We sought to evaluate whether the current RTOG-RPA retains prognostic significance in the TMZ era or alternatively, if modifications better prognosticate the optimal selection of patients with similar baseline prognosis for future clinical protocols. The records of 159 patients with newly-diagnosed glioblastoma (GBM, WHO grade IV) or anaplastic astrocytoma (AA, WHO grade III) were reviewed. Patients were treated with intensity-modulated radiation therapy (IMRT) and concurrent followed by adjuvant TMZ ( n = 154) or adjuvant TMZ only ( n = 5). The primary endpoint was overall survival. Three separate analyses were performed: (1) application of RTOG-RPA to the study cohort and calculation of subsequent survival curves, (2) fit a new tree model with the same predictors in RTOG-RPA, and (3) fit a new tree model with an expanded predictor set. All analyses used a regression tree analysis with a survival outcome fit to formulate new risk classes. Overall median survival was 14.9 months. Using the RTOG-RPA, the six classes retained their relative prognostic significance and overall ordering, with the corresponding survival distributions significantly different from each other ( P < 0.01, χ statistic = 70). New recursive partitioning limited to the predictors in RTOG-RPA defined four risk groups based on Karnofsky Performance Status (KPS), histology, age, length of neurologic symptoms, and mental status. Analysis across the expanded predictors defined six risk classes, including the same five variables plus tumor location, tobacco use, and hospitalization during radiation therapy. Patients with excellent functional status, AA, and frontal lobe tumors had the best prognosis. For patients with newly-diagnosed high-grade gliomas, RTOG-RPA classes retained prognostic significance in patients treated with TMZ and IMRT. In contrast to RTOG-RPA, in our modified RPA model, KPS rather than age represented the initial split. New recursive partitioning identified potential modifications to RTOG-RPA that should be further explored with a larger data set. [ABSTRACT FROM AUTHOR]

This prospective study was performed to determine the efficacy, safety, and tolerability of concurrent chemoradiotherapy (CCRT) followed by adjuvant chemotherapy with temozolomide (TMZ) in the treatment of patients with WHO grade III gliomas. Thirty-three adult patients with WHO grade III glioma and aged >17 years were enrolled from three institutions between 2003 and 2008. The median age was 41 years (range, 17-60 years). The pathological diagnoses were anaplastic astrocytomas in 21 patients and anaplastic oligodendrogliomas in 12 patients. The preoperative Karnofsky performance scale score was >60 for all patients. The patients received fractionated focal irradiation in daily fractions of 2 Gy administered five days per week for six weeks, for a total of 60 Gy, in combination with continuous daily TMZ, followed by six cycles of adjuvant TMZ. The median dose of radiotherapy was 59.4 Gy (range, 28.8-61.2 Gy) and the duration of CCRT was 7.0 weeks (range, 3.1-8.3 weeks). A median of 6.2 cycles (range, 2-12 cycles) of TMZ chemotherapy were performed during the period of adjuvant chemotherapy. The response rate was 61% and the tumor-control rate was 82%. Mean progression-free survival (PFS) was 48.7 months (95% CI, 36.0-61.4) and the 12, 24, and 36-month PFS was 74%, 60%, and 50%, respectively. Mean overall survival (OS) was 66.4 months (95% CI, 56.4-76.4) and the 12 and 24-month OS was 97% and 77%, respectively. The extent of surgical resection was a significant prognostic factor for PFS and OS (hazard ratio, 0.24; 95% CI, 0.02-0.73; and hazard ratio, 0.12; 95% CI, 0.01-0.88, respectively; P < 0.001). However, there was no significant difference in the PFS and OS of patients regarding loss of heterozygosity in chromosomes 1p and 19q and methylation of O-methylguanine-DNA methyltransferase promoter, because of the small number of patients available. Only five cases (15%) receiving CCRT with TMZ and three cases (9%) receiving adjuvant chemotherapy had hematological toxicity greater than grade 3. All these patients, however, tolerated the therapy well enough to continue treatment. No opportunistic infections were noted. This protocol for WHO grade III gliomas was relatively safe and tolerable. It showed the possibility of achieving favorable results compared with those of historical controls. A randomized controlled study with a long-term follow-up may be mandatory to evaluate its efficacy. [ABSTRACT FROM AUTHOR]

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Malignant primary spinal cord gliomas (PSCGs) are rare, and the optimal treatment for these lesions remains controversial. We report herein treatment outcomes of six malignant PSCGs managed with temozolomide (TMZ)-based multidisciplinary treatment. TMZ was administered concomitantly with fractionated radiotherapy for two newly diagnosed primary spinal cord glioblastoma multiforme (GBM), followed by adjuvant chemotherapy with TMZ. For one anaplastic astrocytoma (AA) and one anaplastic ependymoma (AEPN), TMZ was given as adjuvant therapy at first recurrence. One malignantly transformed ependymoma (EPN) and one malignantly transformed diffuse astrocytoma (DA) were treated with TMZ after radiotherapy at second recurrence. Two patients with newly diagnosed GBM died, 12 and 16 months, respectively, after being treated with TMZ, during and after radiation therapy. One patient with AA and one with malignantly transformed EPN showed good response to salvage therapy with TMZ and had stable disease 21 and 20 months, respectively, after TMZ treatment. One patient with recurrent AEPN and one with malignantly transformed DA died from uncontrolled progression of the lesions despite TMZ chemotherapy. Three patients developed grade 1 or 2 neutropenia, anemia, and infection. Nonhematologic toxicities occurred in all patients; however, they were below grade 3 in severity. TMZ treatment may have a positive effect on control of malignant PSCGs and survival for some patients. Specifically, treatment with TMZ during and after radiation therapy might provide survival benefit to patients with primary spinal cord GBM. A multicenter cooperative investigation for a large-scale study on malignant PSCGs may be required. [ABSTRACT FROM AUTHOR]

WHO grading of human brain tumors extends beyond a strictly histological grading system by providing a basis predictive for the clinical behavior of the respective neoplasm. For example, patients with glioblastoma WHO grade IV usually show a less favorable clinical course and receive more aggressive first-line treatment than patients with anaplastic astrocytoma WHO grade III. Here we provide evidence that the IDH1 status is more prognostic for overall survival than standard histological criteria that differentiate high-grade astrocytomas. We sequenced the isocitrate dehydrogenase 1 gene ( IDH1) at codon 132 in 382 patients with anaplastic astrocytoma and glioblastoma from the NOA-04 trial and from a prospective translational cohort study of the German Glioma Network. Patients with anaplastic astrocytomas carried IDH1 mutations in 60%, and patients with glioblastomas in 7.2%. IDH1 was the most prominent single prognostic factor (RR 2.7; 95% CI 1.6-4.5) followed by age, diagnosis and MGMT. The sequence from more favorable to poorer outcome was (1) anaplastic astrocytoma with IDH1 mutation, (2) glioblastoma with IDH1 mutation, (3) anaplastic astrocytoma without IDH1 mutation and (4) glioblastoma without IDH1 mutation ( p < 0.0001). In this combined set of anaplastic astrocytomas and glioblastomas both, IDH1 mutation and IDH1 expression status were of greater prognostic relevance than histological diagnosis according to the current WHO classification system. Our data indicate that much of the prognostic significance of patient age is due to the predominant occurrence of IDH1 mutations in younger patients. Immunohistochemistry using a mutation-specific antibody recognizing the R132H mutation yielded similar results. We propose to complement the current WHO classification and grading of high-grade astrocytic gliomas by the IDH1 mutation status and to use this combined histological and molecular classification in future clinical trials. [ABSTRACT FROM AUTHOR]

A case of unclassified, pediatric cerebral neuroepithelial tumor in a 10-year-old girl that showed remarkable radiosensitivity is reported. MRI revealed a brain tumor of mixed intensity with heterogeneous enhancement in the medial temporal lobe, extending to the basal ganglia. The tumor was partially removed. On pathology, the main part of the tumor showed immature features: the tumor cells had a chromatin-rich large nucleus and less cytoplasm, and mitoses and fragmentation of the nuclei were frequent. On immunohistochemistry, the tumor cells were negative for glial fibrillary acidic protein (GFAP) and synaptophysin and positive for Olig2. The maximum MIB-1 index was 70%. The part invading into the surrounding brain showed similarities in form to a highly anaplastic astrocytoma. The infiltrating tumor cells were positive for GFAP and less positive for Olig2. After 40 Gy radiation, the residual tumor was markedly reduced. Neuroepithelial tumors rarely show such high radiosensitivity, and the reason for the radiosensitivity in the present case may have been the immaturity of the tumor cells. [ABSTRACT FROM AUTHOR]

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The rationale of this study was to investigate the feasibility of three-dimensional (3D) methods to analyze 18F-fluoro-deoxy-glucose (FDG) uptake in children with anaplastic astrocytoma (AA) in a multi-institutional trial, to compare 3D and two-dimensional (2D) methods and explore data associations with progression-free survival (PFS). 3D tumor volumes from pretreatment MR images (fluid attenuation inversion recovery and postgadolinium) of children with recurrent AA on a phase I trial of imatinib mesylate were coregistered to FDG positron emission tomography (PET) images. PET data were normalized. Four metrics were defined: the maximum ratio (maximum pixel value within the 3D tumor volume, normalized), the total ratio (cumulative pixel values within the tumor volume, normalized) and tumor mean ratio (total pixel value divided by volume, normalized). 2D analysis methods were compared. Cox proportional hazards models were used to estimate the association between these methods and PFS. Strongest correlations between 2D and 3D methods were with analyses using postcontrast T1 images for volume of interest (VOI). The analyses suggest 3D maximum tumor and mean tumor ratios, whether normalized by gray matter or white matter, were associated with PFS. This study of a series of pretreatment AA patients suggests that 3D PET methods using VOIs based on postcontrast T1 correlate with 2D methods and are related to PFS. These methods yield an estimate of metabolically active tumor burden and may add prognostic information after tumor grade is determined. Future rigorous multi-institutional protocols with larger numbers of patients will be required for validation. [ABSTRACT FROM AUTHOR]

The utility of external beam radiotherapy for the treatment of malignant brain tumours is compromised by the need to avoid excessive radiation damage to normal CNS tissues. This review describes the current status of targeted radiotherapy, an alternative strategy for brain tumour treatment that offers the exciting prospect of increasing the specificity of tumour cell irradiation.British Journal of Cancer (2004) 90, 1469-1473. doi:10.1038/sj.bjc.6601771 www.bjcancer.com Published online 6 April 2004 [ABSTRACT FROM AUTHOR]

Object: Symptomatic spinal dissemination of malignant astrocytoma is rarely found except at autopsy. This study evaluated the clinical incidence and characteristics of spinal dissemination and the effect on outcome. Patients and methods: Patients treated for primary malignant astrocytoma, including 33 with anaplastic astrocytoma and 35 with glioblastoma, at our department between 1997 and 1999 were followed up until April 30, 2001. Head magnetic resonance (MR) imaging of all patients was obtained every 2–3 months. Signs and symptoms of leptomeningeal spread were checked at monthly outpatient examinations. Spinal MR imaging was performed if any symptoms indicating spinal dissemination were found. Results: Median survival times of patients with anaplastic astrocytoma and glioblastoma were 40.5 and 16.0 months, respectively. Seventeen patients (25%) developed intracranial dissemination and 15 of these died. Six patients (8.8%), one with anaplastic astrocytoma and five with glioblastoma, developed spinal dissemination. All patients with spinal dissemination also had intracranial dissemination. Five of the six patients died, despite systemic radiochemotherapy in four patients. All patients died of extensive whole brain and spinal dissemination or nodular mass enlargement at the upper cervical cord, not of local massive tumor progression. Conclusions: Symptomatic spinal dissemination of malignant astrocytoma is not so rare, and is the cause of death. The relatively high incidence of symptomatic leptomeningeal dissemination must be considered in the treatment of malignant astrocytomas. [ABSTRACT FROM AUTHOR]