Showing papers in "Journal of Neuro-oncology in 2012"
TL;DR: The survival of patients with newly diagnosed glioblastoma improved from 2000–2003 to 2005–2008, likely due to temozolomide use, but median survival time after gliOBlastoma diagnosis in the SEER population remains well under one year, largely driven by poor prognosis in elderly patients.
Abstract: The standard-of-care treatment for newly diagnosed glioblastoma changed in 2005, when radiation therapy plus temozolomide chemotherapy replaced radiation therapy alone. It is not yet clear how this change in treatment has influenced patient survival in routine clinical practice, or if a survival benefit extends to patients older than those enrolled in the trial. Data from the Surveillance, Epidemiology, and End Results (SEER) Program was analyzed to compare survival of adult glioblastoma patients diagnosed from 2000–2003 to patients diagnosed from 2005–2008, in order to evaluate pre-temozolomide and post-temozolomide periods. The Kaplan–Meier method and Cox proportional hazards models were used. 6,673 patients with glioblastoma diagnosed from 2000–2003 and 7,259 patients diagnosed from 2005–2008 were identified. Median survival times of all patients diagnosed in the 2000–2003 and 2005–2008 periods were 8.1 and 9.7 months, respectively. Amongst patients treated with surgery and a radiation-containing regimen, median survival was 12.0 months in 2000–2003 and 14.2 months in 2005–2008. In the temozolomide era, median survival times ranged from a high of 31.9 months in patients age 20–29 to a low of 5.6 months in patients age 80 and older. The survival of patients with newly diagnosed glioblastoma improved from 2000–2003 to 2005–2008, likely due to temozolomide use. However, median survival time after glioblastoma diagnosis in the SEER population remains well under one year, largely driven by poor prognosis in elderly patients.
640 citations
TL;DR: Findings and techniques of genetic, epigenetic, transcriptional, and proteomic studies of glioblastoma are summarized to provide the clinician with an up-to-date overview of current identified molecular alterations that should ultimately lead to new therapeutic targets and more individualized treatment approaches in gliOBlastoma.
Abstract: Glioblastoma is the most common and most aggressive primary brain tumor. Despite maximum treatment, patients only have a median survival time of 15 months, because of the tumor’s resistance to current therapeutic approaches. Thus far, methylation of the O6-methylguanine-DNA methyltransferase (MGMT) promoter has been the only confirmed molecular predictive factor in glioblastoma. Novel “genome-wide” techniques have identified additional important molecular alterations as mutations in isocitrate dehydrogenase 1 (IDH1) and its prognostic importance. This review summarizes findings and techniques of genetic, epigenetic, transcriptional, and proteomic studies of glioblastoma. It provides the clinician with an up-to-date overview of current identified molecular alterations that should ultimately lead to new therapeutic targets and more individualized treatment approaches in glioblastoma.
387 citations
TL;DR: Encouraging results are suggested and suggest that the current treatment of glioblastoma nationwide is now associated with an improved survival compared to previous time cohorts.
Abstract: The EORTC/NCIC 22981/26981 study demonstrated an improvement in median overall survival (OS) from 12.1 to 14.6 months in patients with glioblastoma (GBM) who received temozolomide with post-operative radiotherapy (RT). The current study was performed to determine if those results translated into a survival benefit in a population-based cohort. Patients diagnosed between 2000 and 2006 with a GBM who underwent surgery and post-operative RT were selected from the Surveillance, Epidemiology and End Results database. Patients were grouped into time periods: 2000-2001, 2002-2003, 2004 and 2005-2006 (which represented those treated after the EORTC/NCIC trial presentation in 2004). Relative survival (RS) was estimated by the Kaplan-Meier method, and Cox multivariable regression modeling was used to estimate proportional hazard ratios (HR). Over time, there was improvement in the median and 2-year RS of 12 months and 15% for 2000-2001, 13 months and 19% for 2002-2003, 14 months and 24% for 2004, and 15 months and 26% for 2005-2006 (P < 0.0001 compared to 2000-2001 and 2002-2003; P = 0.07 compared to 2004). The estimated adjusted HR showed that patients diagnosed in 2005-2006 had significantly improved survival when compared to patients diagnosed in 2000-2001 (HR = 0.648, 95% CI 0.604-0.696). The median and 2 year RS of 15 months and 26% in 2005-2006 was similar to the median and 2 year OS of 14.6 months and 26% seen in the EORTC/NCIC phase III study. These results are encouraging and suggest that the current treatment of glioblastoma nationwide is now associated with an improved survival compared to previous time cohorts.
298 citations
TL;DR: Water-suppressed proton (1H) MRS provides a non-invasive measure of 2-HG in gliomas, and may serve as a potential biomarker for patients with IDH1 mutant brain tumors.
Abstract: Mutations of the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are commonly found in primary brain cancers. We previously reported that a novel enzymatic activity of these mutations results in the production of the putative oncometabolite, R(−)-2-hydroxyglutarate (2-HG). Here we investigated the ability of magnetic resonance spectroscopy (MRS) to detect 2-HG production in order to non-invasively identify patients with IDH1 mutant brain tumors. Patients with intrinsic glial brain tumors (n = 27) underwent structural and spectroscopic magnetic resonance imaging prior to surgery. 2-HG levels from MRS data were quantified using LC-Model software, based upon a simulated spectrum obtained from a GAMMA library added to the existing prior knowledge database. The resected tumors were then analyzed for IDH1 mutational status by genomic DNA sequencing, Ki-67 proliferation index by immunohistochemistry, and concentrations of 2-HG and other metabolites by liquid chromatography–mass spectrometry (LC–MS). MRS detected elevated 2-HG levels in gliomas with IDH1 mutations compared to those with wild-type IDH1 (P = 0.003). The 2-HG levels measured in vivo with MRS were significantly correlated with those measured ex vivo from the corresponding tumor samples using LC–MS (r2 = 0.56; P = 0.0001). Compared with wild-type tumors, those with IDH1 mutations had elevated choline (P = 0.01) and decreased glutathione (P = 0.03) on MRS. Among the IDH1 mutated gliomas, quantitative 2-HG values were correlated with the Ki-67 proliferation index of the tumors (r2 = 0.59; P = 0.026). In conclusion, water-suppressed proton (1H) MRS provides a non-invasive measure of 2-HG in gliomas, and may serve as a potential biomarker for patients with IDH1 mutant brain tumors. In addition to 2-HG, alterations in several other metabolites measured by MRS correlate with IDH1 mutation status.
281 citations
TL;DR: Bvacizumab can be administered safely to patients with meningioma and appears to be associated with encouraging anti-tumor effect when administered as either a single agent or in combination with chemotherapy.
Abstract: Intracranial meningiomas are often indolent tumors which typically grow over years to decades. Nonetheless, meningiomas that progress after maximum safe resection and radiation therapy pose a significant therapeutic challenge and effective therapies have yet to be identified. Preclinical studies implicate angiogenesis in the pathophysiology of more aggressive meningiomas, suggesting that anti-angiogenic therapies may be of utility in this setting. We performed a retrospective review of fourteen patients with recurrent meningioma treated at Duke University Medical Center with bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, administered either alone or in combination with chemotherapy. Most patients were heavily pre-treated. Progression-free survival at 6 months was 86 % and was comparable regardless of meningioma grade and whether bevacizumab was administered as monotherapy or in combination with chemotherapy. Most toxicities were mild however single patients developed CNS hemorrhage (grade 1) and intestinal perforation (grade 4), respectively. Bevacizumab can be administered safely to patients with meningioma and appears to be associated with encouraging anti-tumor effect when administered as either a single agent or in combination with chemotherapy. Phase II trials investigating bevacizumab in patients with progressive/recurrent meningioma are warranted.
171 citations
TL;DR: A retrospective review of WHO Grade II and III meningiomas treated at four institutions, selecting only those patients who received bevacizumab and found the drug was well-tolerated in patients and may be considered in patients who have exhausted radiation and surgical options.
Abstract: Atypical and anaplastic (WHO Grades II and III) meningiomas are aggressive tumors, and patients often progress despite surgery and radiation. There is no known effective chemotherapeutic option for these patients. Meningiomas have a high expression of vascular endothelial growth factor receptor (VEGFR). We sought to retrospectively study the activity of bevacizumab, which is an anti-angiogenic agent targeting the VEGF pathway in these tumors. This is a retrospective review of WHO Grade II and III meningiomas treated at four institutions, selecting only those patients who received bevacizumab. We analyzed radiographic response according to standard RANO criteria, progression-free survival (PFS) and overall survival from the initiation of bevacizumab therapy using Kaplan–Meier statistics. We identified 15 patients across four institutions who carried a diagnosis of atypical or anaplastic meningioma and were treated with bevacizumab. Best radiographic response was stable disease. MR perfusion studies showed decreased tumor blood volume in one patient. Three patients developed non-fatal intratumoral hemorrhage. Median PFS was 26 weeks (95 % CI, 10–29 weeks). Six month PFS rate was 43.8 % (95 % CI, 15.7–69.1 %). Bevacizumab was well-tolerated in our patients, and may be considered in patients who have exhausted radiation and surgical options. Prospective studies are required to define the safety and efficacy of bevacizumab in atypical and anaplastic meningiomas.
151 citations
University of California, Los Angeles1, Virginia Commonwealth University2, University of Virginia3, University of California, San Francisco4, University of Texas MD Anderson Cancer Center5, Harvard University6, Duke University7, Memorial Sloan Kettering Cancer Center8, Henry Ford Health System9, University of Chicago10
TL;DR: The predictive value of ADC histogram analysis, in which low ADC-L was associated with poor outcome, was confirmed in bevacizumab-treated patients with recurrent GBM in a post hoc analysis from the multi-center (BRAIN) study.
Abstract: We have tested the predictive value of apparent diffusion coefficient (ADC) histogram analysis in stratifying progression-free survival (PFS) and overall survival (OS) in bevacizumab-treated patients with recurrent glioblastoma multiforme (GBM) from the multi-center BRAIN study. Available MRI's from patients enrolled in the BRAIN study (n = 97) were examined by generating ADC histograms from areas of enhancing tumor on T1 weighted post-contrast images fitted to a two normal distribution mixture curve. ADC classifiers including the mean ADC from the lower curve (ADC-L) and the mean lower curve proportion (LCP) were tested for their ability to stratify PFS and OS by using Cox proportional hazard ratios and the Kaplan-Meier method with log-rank test. Mean ADC-L was 1,209 × 10(-6)mm(2)/s ± 224 (SD), and mean LCP was 0.71 ± 0.23 (SD). Low ADC-L was associated with worse outcome. The hazard ratios for 6-month PFS, overall PFS, and OS in patients with less versus greater than mean ADC-L were 3.1 (95 % confidence interval: 1.6, 6.1; P = 0.001), 2.3 (95 % CI: 1.3, 4.0; P = 0.002), and 2.4 (95 % CI: 1.4, 4.2; P = 0.002), respectively. In patients with ADC-L 0.71 versus ADC-L >1,209 and LCP <0.71, there was a 2.28-fold reduction in the median time to progression, and a 1.42-fold decrease in the median OS. The predictive value of ADC histogram analysis, in which low ADC-L was associated with poor outcome, was confirmed in bevacizumab-treated patients with recurrent GBM in a post hoc analysis from the multi-center (BRAIN) study.
151 citations
TL;DR: The purpose of this paper is to provide an overview of cognition in patients with diffuse infiltrative gliomas and the impact of resective surgery as well as other tumor and treatment-related factors.
Abstract: Compared to classical oncological outcome measures such as time to progression and survival, the importance of cognitive functioning in patients with diffuse infiltrative brain tumors has only recently been recognized. Apart from the relatively low incidence and the invariably fatal outcome of gliomas, the general assumption that cognitive assessment is time-consuming and burdensome contributes to this notion. Our understanding of the effects of brain surgery on cognition, for instance, is largely based on studies in surgical patients with refractory epilepsy, with only a limited number of studies in surgical patients with gliomas. The impact of other factors affecting cognition in glioma patients such as direct tumor effects, radiotherapy and chemotherapy, and medical treatment, including anti-epileptic drugs and steroids, have been studied more extensively. The purpose of this paper is to provide an overview of cognition in patients with diffuse infiltrative gliomas and the impact of resective surgery as well as other tumor and treatment-related factors.
135 citations
TL;DR: The sensitivity (SN) and specificity) of an MRI-based parameter, the “lesion quotient” (LQ), in characterizing tumor progression from RN is assessed and standard MRI techniques do not reliably discriminate between tumor progression and RN after treatment with SRS for brain metastases.
Abstract: Distinguishing radiation necrosis (RN) from tumor recurrence after stereotactic radiosurgery (SRS) for brain metastases is challenging. This study assesses the sensitivity (SN) and specificity (SP) of an MRI-based parameter, the “lesion quotient” (LQ), in characterizing tumor progression from RN. Records of patients treated with SRS for brain metastases between 01/01/1999 and 12/31/2009 and with histopathologic analysis of a subsequent contrast enhancing enlarging lesion at the treated site at a single institution were examined. The LQ, the ratio of maximal nodular cross sectional area on T2-weighted imaging to the corresponding maximal cross sectional area of T1-contrast enhancement, was calculated by a neuroradiologist blinded to the histopathological outcome. Cutoffs of 0.6 have been previously suggested to have correlated with RN, mixed findings and tumor recurrence, respectively. These cutoff values were evaluated for SN, SP, positive predictive value (PPV) and negative predictive value (NPV). Logistic regression analysis evaluated for associated clinical factors. For the 51 patients evaluated, the SN, SP, PPV and NPV for identifying RN (LQ 0.6) were 59, 41, 62 and 39 %, respectively. Standard MRI techniques do not reliably discriminate between tumor progression and RN after treatment with SRS for brain metastases. Additional imaging modalities are warranted to aid in distinguishing between these diagnoses.
130 citations
TL;DR: Evidence is provided that with established dosing, cilengitide is adequately delivered to the tumor, although as a single agent, efficacy in recurrent glioblastoma is modest, however, these results demonstrating drug delivery to tumor do support continued investigation of this agent as preliminary results from recent studies combining cilENGitide with cytotoxic therapies are promising.
Abstract: Cilengitide is a cyclic pentapeptide that is a specific inhibitor of the αvβ3 and αvβ5 integrins. Preclinical studies demonstrate antiangiogenic activity and anti-invasive activity in a number of glioma models. This study was designed to evaluate the efficacy and tumor delivery of cilengitide in patients with recurrent glioblastoma. Patients with recurrent glioblastoma who require a surgical resection for optimal clinical care received 3 intravenous doses of cilengitide at either 500 or 2000 mg (day -8, -4, -1) prior to undergoing tumor resection with corresponding blood samples for plasma to tumor comparisons. After recovery from surgery, patients were treated with cilengitide (2000 mg i.v. twice weekly, maximum of 2 years of treatment). The study accrued 30 patients with recurrent glioblastoma, 26 were evaluable for efficacy. The 6-month progression free survival rate was 12%. Cilengitide was detected in all tumor specimens with higher levels in the group receiving 2000 mg dosing while corresponding plasma concentrations were low, often below the lower limit of detection. These results confirm drug delivery and possibly retention in tumor. This study provides evidence that with established dosing, cilengitide is adequately delivered to the tumor, although as a single agent, efficacy in recurrent glioblastoma is modest. However, these results demonstrating drug delivery to tumor do support continued investigation of this agent as preliminary results from recent studies combining cilengitide with cytotoxic therapies are promising.
129 citations
TL;DR: The addition of carboplatin and irinotecan to bevacizumab significantly increases toxicity but does not improve anti-tumor activity to that achieved historically with single-agent bevacsumab amongBevaczumab-naïve, recurrent GBM patients.
Abstract: We evaluated the efficacy of carboplatin, irinotecan, and bevacizumab among bevacizumab-naive, recurrent glioblastoma (GBM) patients in a phase 2, open-label, single arm trial. Forty eligible patients received carboplatin (area under the plasma curve [AUC] 4 mg/ml-min) on day one, while bevacizumab (10 mg/kg) and irinotecan (340 mg/m2 for patients on CYP3A-enzyme-inducing anti-epileptics [EIAEDs] and 125 mg/m2 for patients not on EIAEDs) were administered on days 1 and 14 of every 28-day cycle. Patients were evaluated after each of the first two cycles and then after every other cycle. Treatment continued until progressive disease, unacceptable toxicity, non-compliance, or voluntary withdrawal. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary endpoints included safety and median overall survival (OS). All patients had progression after standard therapy. The median age was 51 years. Sixteen patients (40%) had a KPS of 90–100, while 27 (68%) were at first progression. The median time from original diagnosis was 11.4 months. The PFS-6 rate was 46.5% (95% CI: 30.4, 61.0%) and the median OS was 8.3 months [95% confidence interval (CI): 5.9, and 10.7 months]. Grade 4 events were primarily hematologic and included neutropenia and thrombocytopenia in 20 and 10%, respectively. The most common grade 3 events were neutropenia, thrombocytopenia, fatigue, and infection in 25, 20, 13, and 10%, respectively. Eleven patients (28%) discontinued study therapy due to toxicity and 17 patients (43%) required dose modification. One patient died due to treatment-related intestinal perforation. The addition of carboplatin and irinotecan to bevacizumab significantly increases toxicity but does not improve anti-tumor activity to that achieved historically with single-agent bevacizumab among bevacizumab-naive, recurrent GBM patients. (ClinicalTrials.gov number NCT00953121).
TL;DR: The results from this small pilot study should be interpreted with caution, but appear to warrant additional research, in larger study samples, targeting fatigue, processing speed and executive function, and exploring different doses of stimulants.
Abstract: Limited research is available regarding the efficacy of psychostimulants in treating cognitive function in primary brain tumor patients. An open-label, randomized, pilot trial examined both the general and differential efficacy of 4 weeks of methylphenidate (MPH) and modafinil (MOD) in 24 brain tumor patients. Participants completed cognitive tests and self-report measures of fatigue, sleep disturbance, mood and quality of life at baseline and after 4 weeks.
TL;DR: For patients with craniopharyngioma, STR + RT may provide superior clinical outcome, achieving better disease control than STR and limiting side effects associated with aggressive surgical resection.
Abstract: The purpose of this study is to evaluate the roles of resection extent and adjuvant radiation in the treatment of craniopharyngiomas We reviewed the records of 122 patients ages 11–52 years who received primary treatment for craniopharyngioma between 1980 and 2009 at the University of California, San Francisco (UCSF) Primary endpoints were progression free survival (PFS) and overall survival (OS) Secondary endpoints were development of panhypopituitarism, diabetes insipidus (DI), and visual field defects Of 122 patients, 30 (24%) were treated with gross total resection (GTR) without radiation therapy (RT), 3 (3%) with GTR + RT, 41 (336%) with subtotal resection (STR) without RT, and 48 (393%) with STR + RT Median age at diagnosis was 30 years, with 46 patients 18 years or younger Median follow-up for all patients was 564 months (interquartile range 189–1442 months) and 47 months (interquartile range 123–1218 months) for the 60 patients without progression Fifty six patients progressed, 10 have died, 6 without progression Median PFS was 611 months for all patients PFS rate at 2 years was 615% (95% CI: 521–709) OS rate at 10 years was 911% (95% CI 843–979) There was no significant difference in PFS and OS between patients treated with GTR vs STR + XRT (PFS; p = 0544, OS; p = 0735), but STR alone resulted in significantly shortened PFS compared to STR + RT or GTR (p < 0001 for both) STR was associated with significantly shortened OS compared to STR + RT (p = 0050) and trended to shorter OS compared to GTR (p = 0066) GTR was associated with significantly greater risk of developing DI (563 vs 133% with STR + XRT, p < 0001) and panhypopituitarism (548 vs 267% with STR + XRT, p = 0014) In conclusion, for patients with craniopharyngioma, STR + RT may provide superior clinical outcome, achieving better disease control than STR and limiting side effects associated with aggressive surgical resection
TL;DR: Completeness of resection acts synergistically with concomitant and adjuvant radiochemotherapy, especially in patients with MGMT promoter methylation, and makes the best prognosis.
Abstract: Survival of glioblastoma patients has been linked to the completeness of surgical resection. Available data, however, were generated with adjuvant radiotherapy. Data confirming that extensive cytoreduction remains beneficial to patients treated with the current standard, concomitant temozolomide radiochemotherapy, are limited. We therefore analyzed the efficacy of radiochemotherapy for patients with little or no residual tumor after surgery. In this prospective, non-interventional multicenter cohort study, entry criteria were histological diagnosis of glioblastoma, small enhancing or no residual tumor on post-operative MRI, and intended temozolomide radiochemotherapy. The primary study objective was progression-free survival; secondary study objectives were survival and toxicity. Furthermore, the prognostic value of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation was investigated in a subgroup of patients. One-hundred and eighty patients were enrolled. Fourteen were excluded by patient request or failure to initiate radiochemotherapy. Twenty-three patients had non-evaluable post-operative imaging. Thus, 143 patients qualified for analysis, with 107 patients having residual tumor diameters ≤1.5 cm. Median follow-up was 24.0 months. Median survival or patients without residual enhancing tumor exceeded the follow-up period. Median survival was 16.9 months for 32 patients with residual tumor diameters >0 to ≤1.5 cm (95% CI: 13.3–20.5, p = 0.039), and 13.9 months (10.3–17.5, overall p 1.5 cm. Patient age at diagnosis and extent of resection were independently associated with survival. Patients with MGMT promoter methylated tumors and complete resection made the best prognosis. Completeness of resection acts synergistically with concomitant and adjuvant radiochemotherapy, especially in patients with MGMT promoter methylation.
TL;DR: The data indicate that HD-MB03 is a suitable preclinical model for Group 3 medulloblastoma, and HDACis could represent a therapeutic option for this subgroup.
Abstract: Medulloblastomas are the most common malignant brain tumors in childhood. Emerging evidence suggests that medulloblastoma comprises at least four distinct diseases (WNT, SHH, Group 3 and 4) with different biology, clinical presentation, and outcome, with especially poor prognosis in Group 3. The tight connection of biology and clinical behavior in patients emphasizes the need for subgroup-specific preclinical models in order to develop treatments tailored to each subgroup. Herein we report on the novel cell line HD-MB03, isolated from tumor material of a patient with metastasized Group 3 medulloblastoma, and preclinical testing of different histone deacetylase inhibitors (HDACis) in this model. HD-MB03 cells grow long term in vitro and form metastatic tumors in vivo upon orthotopic transplantation. HD-MB03 cells reflect the original Group 3 medulloblastoma at the histological and molecular level, showing large cell morphology, similar expression patterns for markers Ki67, p53, and glial fibrillary acidic protein (GFAP), a gene expression profile most closely matching Group 3 medulloblastomas, and persistence of typical molecular alterations, i.e., isochromosome 17q [i(17q)] and MYC amplification. Protein expression analysis of HDACs 2, 5, 8, and 9 as well as the predictive marker HR23B showed intermediate to strong expression, suggesting sensitivity to HDACis. Indeed, treatment with HDACis Helminthosporium carbonum (HC)-toxin, vorinostat, and panobinostat revealed high sensitivity to this novel drug class, as well as a radiation-sensitizing effect with significantly increased cell death upon concomitant treatment. In summary, our data indicate that HD-MB03 is a suitable preclinical model for Group 3 medulloblastoma, and HDACis could represent a therapeutic option for this subgroup.
TL;DR: Functional outcome in brain tumour inpatients who underwent early rehabilitation after surgery can improve functional outcome, justifying the delivery of rehabilitation services, even during the acute phase, to BTs inpat patients, irrespective of tumour type.
Abstract: Clinical experience suggests that application of the fundamental principles of rehabilitation medicine can improve the care of patients with cancer. Despite the high incidence of neurological and functional deficits in patients affected by brain tumours (BTs), rehabilitation treatment of this population is not as well established as it is for patients with other neurological conditions. To assess functional outcome in brain tumour inpatients who underwent early rehabilitation after surgery. 75 patients who had undergone neurosurgery for primary BTs and 75 patients affected by stroke were enrolled in a case-control study. All patients were evaluated by means of a core set of clinical scales (Functional Independence Measure, Sitting Balance score, Standing Balance score, Hauser Index, Massachusetts General Hospital Functional Ambulation Classification). Patients were evaluated before the beginning (T0) and at the end (T1) of rehabilitation treatment. The neurorehabilitation programme consisted of individual 60-min sessions of treatment, administered once a day, six days a week, for four consecutive weeks. Speech therapy was included when aphasia was diagnosed. All the measures of outcome were indicative of substantial improvements for neuro-oncological and for stroke patients (P = 0.000). Analysis of subgroups showed that patients affected by meningioma achieved better results (in efficiency terms) as regards independence in activities of daily living (P = 0.02) and mobility (P = 0.04) compared with patients affected by glioblastoma or stroke. Rehabilitation after surgery can improve functional outcome, justifying the delivery of rehabilitation services, even during the acute phase, to BTs inpatients, irrespective of tumour type.
TL;DR: In this paper, the authors evaluated the efficacy and toxicity of radiation therapy with concurrent temozolomide (TMZ) chemotherapy followed by adjuvant TMZ in children with diffuse intrinsic pontine glioma (DIPG).
Abstract: The purpose of this study is to evaluate the efficacy and toxicity of radiation therapy (RT) with concurrent temozolomide (TMZ) chemotherapy followed by adjuvant TMZ in children with diffuse intrinsic pontine glioma (DIPG). Newly diagnosed patients younger than 18 years with histologically proven DIPG were treated with focal radiotherapy to a dose of 54 Gy in 30 fractions along with concurrent daily TMZ (75 mg/m2/day). Four weeks after completing the initial RT–TMZ schedule, adjuvant TMZ (200 mg/m2/day, days 1–5) was given every 28 days up to six cycles. Responses/progressions were assessed by clinical and 2-monthly MRI follow-up studies. Between September 2005 and September 2009, 21 patients with newly diagnosed histologically confirmed DIPG were eligible for this study. Median age at diagnosis was 6.4 years (range 4–16 years). At last update in August 2010, 17 children have died, 1 child was alive with progressive disease and 3 with stable disease. Metastatic relapse was documented in the cerebral site in two patients and in spinal cord in two cases. The median time to progression was 7.5 months (range 28 days–14.5 months) and the median survival was 11.7 months (range 26 days–17.5 months). The 1-year PFS and the 1-year OS were 33 and 50%, respectively. Five patients presented radiological findings compatible with pseudoprogression during the treatment. Haematological toxicity (Grade III/IV thrombocytopenia and leucopenia) was the most commonly found and led to dose reductions of TMZ in 58% of the patients. TMZ with radiation therapy has not yielded any significant improvement in outcome of children with DIPG and is associated with higher toxicity compared with radiotherapy alone. Novel treatment modalities are needed to improve the outcome of these patients.
TL;DR: It is shown that IDH mutation status is stable during the progression course of LGA to sHGG, and the presence of IDH mutations fails to demonstrate a significant influence on survival in the multivariate analysis of L GA patients.
Abstract: This study investigated the prognostic and predictive significance of IDH1 and IDH2 mutations in low-grade astrocytomas (LGA). The presence and consistency of IDH mutations during the progression of LGA to secondary high-grade gliomas (sHGG) were detected. Samples of patients with LGA and sHGG were investigated. The genomic regions around IDH1 codon 132 and IDH2 codon 172 were PCR amplified and directly sequenced. Furthermore, the MGMT promoter status was provided using the methylation-specific PCR. Our population comprised 71 patients with a total of 45 pairs of LGA and their consecutive sHGG. Median follow-up was 9.6 years. IDH mutations were found in 36/45 LGA (80%) and their sHGG without changes in the mutation status. A total of 71 patients with LGA were analyzed according to clinical and molecular tumor-related factors: 56/71 patients (78.8%) had an IDH mutation without significant influence on the progression-free or overall survival (OS), and 22/71 (31%) of the patients received postoperative radiotherapy (RT) after diagnosis of LGA. Patients with early RT but without IDH mutations had the shortest survival. Our study shows that IDH mutation status is stable during the progression course of LGA to sHGG. The presence of IDH mutations fails to demonstrate a significant influence on survival in the multivariate analysis of LGA patients. Early RT appears to be beneficial only LGA patients with IDH-mutations.
TL;DR: The morbidity of pilocytic astrocytoma in adults provides rationale for future trials of adjuvant treatment in high-risk patients, and survival decreases with increasing age in adults.
Abstract: Pilocytic astrocytoma is a WHO grade 1 brain tumor common in children. Relatively little is known about the behavior of pilocytic astrocytomas in adult patients, largely due to the rarity of pilocytic astrocytoma in this population. Some data suggest that adults share the excellent prognosis seen in children, while other reports suggest more aggressive tumor behavior in adult patients. Patients diagnosed with pilocytic astrocytoma between 1973 and 2008 were identified in the National Cancer Institute Surveillance, Epidemiology, and End Results Program database. Age-group specific survival was analyzed with overall, expected, and cancer-specific survival rates. Further survival analyses were performed with the Kaplan–Meier method and Cox Proportional Hazards models. 3,066 patients with pilocytic astrocytoma were identified, including 865 patients aged 20 years and older. Survival rates declined significantly with age, from 96.5% 60-month survival in patients 5–19 years (95% CI 95.3–97.4) to 52.9% 60-month survival in adult patients 60+ years of age (95% CI 38.4–65.5), with a corresponding decrease in relative and cancer-specific survival rates. Gross total resection was a positive prognostic indicator in adults, while patients receiving radiation had shorter survival regardless of extent of resection. Pilocytic astrocytoma is associated with higher mortality in adult patients than in children and teens, and survival decreases with increasing age in adults. The morbidity of pilocytic astrocytoma in adults provides rationale for future trials of adjuvant treatment in high-risk patients.
TL;DR: FSRT appears to be an effective and safe treatment for BM not amenable to SRS and the 10 × 4 Gy fractionation scheme warrants further investigation due to its efficacy and safe toxicity profile.
Abstract: We retrospectively evaluated and compared the efficacy and the toxicity profile of stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) for the treatment of patients with brain metastases (BM). Between 2000 and 2009, 260 patients with 1–3 BM were treated using either SRS (median dose 20 Gy; n = 138) or two different FSRT dose concepts: 7 × 5 Gy (n = 61) or 10 × 4 Gy (n = 61). The median survival for SRS, 7 × 5 Gy and 10 × 4 Gy was 8, 7 and 10 months (p = 0.575), respectively, and the overall survival (OS) was 9 months. Follow-up imaging data were available in 214 of the 260 patients. The 1-year local progression-free survival (LPFS) was 73, 75 and 71 %, respectively (p = 0.191). After a mean follow-up of 28 months (range: 2.1–77 months), the rate of complete remission, partial remission, stable disease and progressive disease were 29, 40, 21 and 10 %, respectively. On multivariate analysis, RPA class I was associated with better OS and regional progression-free survival (both p < 0.001). SRS was associated with a higher toxicity rate (grade I–III) compared to the 7 × 5 Gy and 10 × 4 Gy groups (14 vs. 6 vs. 2 %, respectively; p = 0.01). Although FSRT was used for large lesions and/or lesions near critical structures, the LPFS was comparable to SRS. Importantly, FSRT presented low toxicity and appears to be an effective and safe treatment for BM not amenable to SRS. The 10 × 4 Gy fractionation scheme warrants further investigation due to its efficacy and safe toxicity profile.
TL;DR: The combination of salvage GKSR followed by bevacizumab added potential benefit and little additional risk in a small group of patients with progressive glioblastoma who experienced tumor progression despite aggressive initial multi-modality treatment.
Abstract: We evaluated the efficacy and safety of gamma knife stereotactic radiosurgery (GKSR) followed by bevacizumab combined with chemotherapy in 11 patients with recurrent glioblastoma multiforme who experienced tumor progression despite aggressive initial multi-modality treatment. Our experience included eight male and three female patients. The median patient age at GKSR was 62 years (range 46-72 years). At the time of GKSR, seven patients had a first recurrence and four had two or more recurrences. The median interval from the initial diagnosis until GKSR was 17 months (range 5-34.5 months). The median tumor volume was 13.6 cm(3) (range 1.2-45.1 cm(3)) and the median margin dose of GKSR was 16 Gy (range 13-18 Gy). Following GKSR, bevacizumab was administrated with irinotecan in nine patients and with temozolomide in one patient. One patient was treated with bevacizumab monotherapy. The treatment outcomes were compared to 44 case-matched controls who underwent GKSR without additional bevacizumab. At a median of 13.7 months (range 4.6-28.3 months) after radiosurgery, tumor progression was evident in seven patients. The median progression-free survival (PFS) was 15 months (95% confidential interval (CI), 6.5-23.3 months). Six-month and 1-year PFS rates were 73 and 55%, respectively. The median overall survival (OS) from GKSR was 18 months (95% CI, 10.1-25.7 months) and 1-year OS rate was 73%. One patient (9%) experienced grade III toxicity and one patient (9%) had major adverse radiation effects. Compared with patients who did not receive bevacizumab, the patients who received bevacizumab had significantly prolonged PFS (15 months vs. 7 months, P = 0.035) and OS (18 months vs. 12 months, P = 0.005), and were less likely to develop an adverse radiation effect (9 vs. 46%, P = 0.037). The combination of salvage GKSR followed by bevacizumab added potential benefit and little additional risk in a small group of patients with progressive glioblastoma. Further experience is needed to define the efficacy and long-term toxicity with this strategy.
TL;DR: Investigation of the interaction between VPA, TMZ, and γ-radiation finds that VPA combined with TMZ may lead to further enhancement of the radiation response, and does not antagonize the cytotoxic effects of TMZ.
Abstract: Temozolomide (TMZ) is given in addition to radiotherapy in glioma patients, but its interaction with the commonly prescribed antiepileptic drug valproic acid (VPA) is largely unknown. Induction of DNA demethylation by VPA could potentially induce expression of the O6-methylguanine-DNA-methyltransferase (MGMT) protein, causing resistance to TMZ and thereby antagonizing its effect. Therefore, this study investigates the interaction between VPA, TMZ, and γ-radiation. Two glioma cell lines were used that differ in TMZ sensitivity caused by the absence (D384) or presence (T98) of the MGMT protein. VPA was administered before (24/48 h) or after (24 h) single doses of γ-radiation; or, after 24 h, VPA treatment was accompanied by a single dose of TMZ for another 24 h. For trimodal treatment the combination of VPA and TMZ was followed by single doses of γ-radiation. In both cell lines VPA caused enhancement of the radiation response after preincubation (DMF0.2 1.4 and 1.5) but not after postirradiation (DMF0.2 1.1 and 1.0). The combination of VPA and TMZ caused enhanced cytotoxicity (DMF0.2 1.7) in both the TMZ-sensitive cell line (D384) and the TMZ-resistant cell line (T98). The combination of VPA and TMZ caused a significant radiation enhancement (DMF0.2 1.9 and 1.6) that was slightly more effective than that of VPA alone. VPA does not antagonize the cytotoxic effects of TMZ. Preincubation with VPA enhances the effect of both γ-radiation and TMZ, in both a TMZ-sensitive and a TMZ-resistant human glioma cell line. VPA combined with TMZ may lead to further enhancement of the radiation response.
TL;DR: This combined treatment is feasible, efficient (surgery made possible by neoadjuvant chemotherapy) and well-tolerated (preservation of quality of life, no serious cognitive disturbances).
Abstract: Diffuse WHO grade II (GIIG) may be unresectable when involving critical structures. To assess the feasibility and functional tolerance (cognition and quality of life) of an original therapeutic strategy combining neoadjuvant chemotherapy followed by surgical resection for initially inoperable GIIG. Ten patients underwent Temozolomide for unresectable GIIG, as initial treatment or at recurrence after previous partial resection, due to invasion of eloquent areas or bi-hemispheric diffusion preventing a total/subtotal removal. Functional outcome after both treatments was assessed, with evaluation of seven cognitive domains. Chemotherapy induced tumor shrinkage (median volume decrease 38.9%) in ipsilateral functional areas in six patients and in the contralateral hemisphere in four. Only four patients had a 1p19q codeletion. The tumor shrinkage made possible the resection (mean extent of resection 93.3%, 9 total or subtotal removals) of initially inoperable tumors. Postoperatively, three patients had no deficits, while verbal episodic memory and executive functions were slightly impaired in seven patients. However, global quality of life was roughly preserved on the EORTC QLQ C30 + BN 20 (median score: 66.7%). Role functioning score was relatively reduced (median score: 66.7%) whereas KPS was preserved (median score: 90, range 80-100). Seven patients became seizure-free while three improved. This combined treatment is feasible, efficient (surgery made possible by neoadjuvant chemotherapy) and well-tolerated (preservation of quality of life, no serious cognitive disturbances). Cognitive deficits seem mostly related to tumor location. Because KPS is not reliable enough, a detailed neuropsychological assessment should be systematically performed in GIIG.
TL;DR: It is described how a neuropsychological evaluation in patients with brain tumors should be performed, specifically in the case of low-grade gliomas, and underline that sensitive and wide-ranging tests are required; specific tasks based on the lesion site should be added.
Abstract: We describe how a neuropsychological evaluation in patients with brain tumors should be performed, specifically in the case of low-grade gliomas. Neuropsychological examination is crucial before starting any treatment as well as during the follow-up, since it can improve neurosurgery techniques and reveal potential cognitive effects of chemotherapy and radiotherapy, besides planning rehabilitation. We underline that sensitive and wide-ranging tests are required; specific tasks based on the lesion site should be added. Moreover, some tests can provide additional information about the evolution of the tumor. A careful, thorough examination improves quality of life.
TL;DR: Results indicate that downregulation of KIF23 decreases proliferation of glioma cells and that Kif23 may be a novel therapeutic target in malignant gliomas.
Abstract: To identify therapeutic molecular targets for glioma, we performed modified serological identification of antigens by recombinant complementary DNA (cDNA) expression cloning using sera from a mouse glioma model. Two clones, kinesin family member 23 (Kif23) and structural maintenance of chromosomes 4 (Smc4), were identified as antigens through immunological reaction with sera from mice harboring synergic GL261 mouse glioma and intratumoral inoculation with a mutant herpes simplex virus. The human Kif23 homolog KIF23 is a nuclear protein that localizes to the interzone of mitotic spindles, acting as a plus-end-directed motor enzyme that moves antiparallel microtubules in vitro. Expression analysis revealed a higher level of KIF23 expression in glioma tissues than in normal brain tissue. The introduction of small interfering RNA (siRNA) targeting KIF23 into two different glioma cell lines, U87MG and SF126, downregulated KIF23 expression, which significantly suppressed glioma cell proliferation in vitro. KIF23 siRNA-treated glioma cells exhibited larger cell bodies with two or more nuclei compared with control cells. In vivo analysis using mouse xenograft showed that KIF23 siRNA/DNA chimera-treated tumors were significantly smaller than tumors treated with control siRNA/DNA chimera. Taken together, our results indicate that downregulation of KIF23 decreases proliferation of glioma cells and that KIF23 may be a novel therapeutic target in malignant glioma.
TL;DR: HU though well tolerated and convenient appeared to have very limited activity, raise questions of what constitutes effective salvage therapy and indicates an unmet need for alternative treatments for recurrent high-grade meningiomas.
Abstract: Hydroxyurea (HU), an orally administered chemotherapy, has become the de facto standard chemotherapeutic agent in patients with surgically and radiation refractory meningiomas based on a limited literature. A retrospective case series of 35 patients with recurrent WHO Grade 2 (n = 22) or 3 (n = 13) meningioma treated with HU following progression after surgery and radiotherapy was collated with primary study objectives of overall response rate, median and progression free survival (PFS) at 6-months. Thirty-five patients (25 women; 10 men: median age 63 years, range 34–86) with recurrent high-grade meningioma were treated with HU (1,000 mg/m2 orally divided twice per day; one cycle operationally defined as 4 weeks of daily HU). Patients had progressed radiographically after prior therapy with surgery (35/35) and radiotherapy (35/35: external beam radiotherapy 35/35; stereotactic radiotherapy 35/35). No patient received prior chemotherapy or targeted therapy before instituting HU. Patients received 0.5–7 cycles (median 2.0) of HU with modest toxicity (28.5% all grades and 8.5% grade 3+ anemia or fatigue). There were no radiographic responses, 43% of patients had stable disease and 57% manifested progressive disease at first evaluation. The overall PFS was 3.0% at 6 months (median PFS 2.0 months; 95% CI 1.6–2.4). The majority of patients (80%) following progression on HU were subsequently treated on an investigational trial. In this retrospective series, HU though well tolerated and convenient appeared to have very limited activity, raise questions of what constitutes effective salvage therapy and indicates an unmet need for alternative treatments for recurrent high-grade meningiomas.
TL;DR: It is believed that cognitive assessment performed in conjunction with language testing is a necessary step in the global evaluation of brain tumor patients both before and after surgery.
Abstract: In surgery for tumors of the dominant hemisphere, the attention devoted to quality of resection and preservation of language function has not been accompanied by comparable interest in preservation of cognitive abilities which may affect quality of life. We studied 22 patients undergoing awake surgery for glioma removal in the language areas of the brain. Besides monitoring tumor variables (size, location, histology, edema), we used a multifaceted battery of tests to investigate mood, cognition, and language in an attempt to assess the burden of disease and treatment, and the relationships between these three dimensions. Baseline assessment showed that 45% of the patients were depressed and 23% anxious; some cognitive and language impairment was noted for 59 and 50%, respectively. A general decline in postoperative cognitive performance (significant for memory and attention only) and language function (significant for picture naming) was observed, whereas depression was unchanged and anxiety decreased. Tumor histology, but not demographic variables or extent of resection, correlated with postoperative cognitive changes: patients undergoing surgery for high-grade tumors were more likely to improve. No correlation was observed between scores for mood, cognition, and language function. A subset of patients with low-grade glioma was followed up for 3–6 months; although some improvement was observed they did not always regain their preoperative performance. In conclusion, we believe that cognitive assessment performed in conjunction with language testing is a necessary step in the global evaluation of brain tumor patients both before and after surgery.
TL;DR: RNAi knockdown and immunoprecipitation experiments suggest that the p38α MAPK isoform drives inflammation in GBM cells, and p38 MAPK inhibition strongly reduced invasion of U251 glioblastoma cells in an inflammatory microenvironment, providing evidence for a p38MAPK-regulated link between inflammation and invasiveness in G BM pathophysiology.
Abstract: Increasing evidence suggests that an inflammatory microenvironment promotes invasion by glioblastoma (GBM) cells. Together with p38 mitogen-activated protein kinase (MAPK) activation being regarded as promoting inflammation, we hypothesized that elevated inflammatory cytokine secretion and p38 MAPK activity contribute to expansion of GBMs. Here we report that IL-1β, IL-6, and IL-8 levels and p38 MAPK activity are elevated in human glioblastoma specimens and that p38 MAPK inhibitors attenuate the secretion of pro-inflammatory cytokines by microglia and glioblastoma cells. RNAi knockdown and immunoprecipitation experiments suggest that the p38α MAPK isoform drives inflammation in GBM cells. Importantly, p38 MAPK inhibition strongly reduced invasion of U251 glioblastoma cells in an inflammatory microenvironment, providing evidence for a p38 MAPK-regulated link between inflammation and invasiveness in GBM pathophysiology.
TL;DR: Overexpression of cyclin D1 enhanced the proliferation and invasive potential of human glioblastoma cells, while reducing apoptosis, and may provide a new gene therapy approach for patients with malignant glioma.
Abstract: Elevated cyclin D1 (CCND1) in human glioblastoma correlates with poor clinical prognosis. In this study, the human glioblastoma cell lines SHG-44 and U251 were stably transfected with short hairpin RNA (shRNA) targeting cyclin D1 or with ectogenic cyclin D1 by lentivirus-mediated transfection. Glioblastoma cells overexpressing or underexpressing cyclin D1 were then examined by in vitro growth assays, apoptosis assays, cell cycle analysis, and invasion assays. Cyclin D1 knockdown in SHG-44 cells inhibited cell proliferation, induced apoptosis, and attenuated migration across Matrigel, a model of invasive capacity. Western blot analysis and quantitative reverse-transcription polymerase chain reaction (RT-PCR) revealed that cells underexpressing CCND1 exhibited decreased multidrug resistance protein 1 (MDR1) and B-cell lymphoma-2 (Bcl-2) expression, but enhanced apoptosis effector caspase-3 expression. In contrast, cyclin D1 overexpression promoted cell proliferation, attenuated apoptosis, and enhanced invasive capacity. Furthermore, cyclin D1 overexpression was associated with increased expression of MDR1 and Bcl-2, and decreased caspase-3 expression. Results using the U251 cell line confirmed the effects of CCND1-targeted shRNA and lentivirus-mediated overexpression on proliferation and apoptosis of glioblastoma cells. Overexpression of cyclin D1 enhanced the proliferation and invasive potential of human glioblastoma cells, while reducing apoptosis. The ability to suppress the malignant phenotype by downregulating cyclin D1 expression may provide a new gene therapy approach for patients with malignant glioma.
TL;DR: Anticoagulant use during BVZ therapy may increase the risk of hemorrhage in glioma patients, although it is generally well tolerated.
Abstract: Venous thromboembolic events (VTE) are common in glioma patients and are typically treated with anticoagulant medications. The anti-angiogenic agent bevacizumab (BVZ) increases the risks of both VTE and hemorrhagic complications. Little is known about the hemorrhagic risk of anticoagulation in glioma patients receiving BVZ. We reviewed medical records from 282 BVZ-treated patients at our center and identified 64 who received concurrent anticoagulant therapy. The risk and severity of hemorrhagic complications were assessed. Fisher’s exact test was used to compare the risk of hemorrhage between subjects who received and did not receive anticoagulants. Forty-seven patients (73%) had glioblastoma, 15 (23%) anaplastic glioma, and 2 (3%) other tumors. Thirteen (20%) and 51 (80%) patients received warfarin and low-molecular-weight heparin, respectively. The indication for anticoagulation was deep venous thrombosis in 37 patients (58%), pulmonary embolism in 22 (34%), and both in 5 (8%). Thirteen patients (20%) experienced hemorrhage, of which four hemorrhages (6%) were serious (grade ≥ 3): one patient had grade 5 intracerebral hemorrhage (ICH), one grade 4 ICH, one grade 3 epistaxis, and one grade 3 gastrointestinal hemorrhage. ICH was seen in seven patients (11%), of which five (8%) were grade 1. Among 218 patients who did not receive anticoagulants, there were two (1%) serious hemorrhages (both grade 4 ICH). Both the serious hemorrhage rate and overall ICH rate were higher in patients who received anticoagulants (P = 0.03 and 0.02, respectively). Anticoagulant use during BVZ therapy may increase the risk of hemorrhage in glioma patients, although it is generally well tolerated.