Diagnosis Of Glioblastoma Multiforme Research Articles

Socioeconomic status does not affect prognosis in patients with glioblastoma multiforme.

Background:Glioblastoma multiforme (GBM) is an aggressive malignancy, but there is marked heterogeneity in survival time. Health care disparities have demonstrated significance in oncologic outcomes but have not been clearly examined in this patient population. We investigated the role of sociodemographic variables in the prognosis of adult patients diagnosed with GBM.Methods:This retrospective analysis included patients with a histologically confirmed diagnosis of GBM, who underwent resection or biopsy at a single institution from 2000 to 2014. Socioeconomic status (SES) was determined by household income according to the US Census zip code tabulation areas and the US national poverty level. Multivariate Cox proportional hazards analysis calculated effects on patient survival.Results:Thirty percent of 218 subjects were of low SES, 57% mid, and 13% high. Low SES patients tended to be male (62%), Caucasian (92%), unmarried (91%), have dependents (100%), and limited to high school education (55%). SES did not predict insurance or employment status. SES was associated with marital status and number of cohabitants (P < 0.0001) but not clinical trial enrollment. Multivariate analysis demonstrated no relationship between SES and survival. Shorter prognosis was associated with history of military service (hazard ratio [HR] 2.06, P = 0.0125), elderly patients (HR 1.70, P = 0.0158), and multifocal disease (HR 1.75, P = 0.0119). Longer prognosis was associated with gross total resection (HR 0.49, P = 0.0009), radiation therapy (HR 0.12, P < 0.0001), and temozolomide (HR 0.28, P < 0.0001).Conclusions:SES alone does not predict prognosis in patients with newly diagnosed GBM. Sociodemographic variables such as old age, military service record, and insurance type may have a prognostication role.

Glioblastoma multiforme: A pediatric case series

Introduction: Glioblastoma multiforme (GbM), the most aggressive malignant primary brain tumor, is uncommon in children accounting for only 3% of primary pediatric brain tumors. We reviewed a case series of five pediatric patients diagnosed at our institution over an 8-month period. case series: Of the five pediatric GbMs, three were supratentorial, one was infratentorial and one was in the spinal cord. the diagnosis of GbM occurred at a mean age of 9.25 years and the male to female ratio was 3:2. the main presenting symptoms included headaches (60%), nausea and vomiting (40%) and limb weakness (40%). Four of five patients were treated with maximal surgical resection and radiation therapy. the majority also received chemotherapy with temozolomide and lomustine. All patients died of tumor progression with a median survival of 9.0 months following diagnosis. conclusion: Glioblastoma multiforme remains a very challenging tumor to treat in the pediatric population. Locally, the incidence of glioblastoma multiforme is increasing and further study needs to investigate if this is a national occurrence.

PO58RE-DO SURGERY IN PATIENTS WITH GLIOBLASTOMA MULTIFORME - 8 YEARS OF EXPERIENCE FROM A SINGLE CENTRE

INTRODUCTION: There remains debate on whether patients with recurrence of glioblastoma multiforme (GBM) should undergo further debulking surgery. Here we present the outcomes for all patients that underwent re-do surgery in a single centre as part of preparations for a randomised trial to investigate the benefits of re-do surgery for GBM. METHOD: Case notes for all patients with a diagnosis of GBM that had more than one debulking operation were reviewed from the last 8 years. RESULTS: 29 patients had a total of 2 debulking procedures and 2 patients had 3 debulking procedures. Excluding 3 patients still alive at the time of this review, median duration of survival from diagnosis was 530 days, and median duration of survival after re-do surgery was 193 days. The median interval between first and second procedures was 345 days. The median age at diagnosis was 52, and the average Karnofsky Performance Status at time of first surgery was 94%, which dropped to 80% prior to re-do surgery. 3 patients (9.6%) developed wound infections after re-do surgery, and 4 patients (12.9%) developed new neurological deficits.Duration of survival after re-do surgery was increased in patients that had Gliadel® wafers placed at the time of re-do surgery from a median of 218 days compared to 165 days in patients where Gliadel® was not used. MGMT methylation status was available for 10 patients who had been operated on since 2012. Patients who were methylated had a median survival of 274 days after re-do surgery (excluding one person who was still alive), compared with 167 days for those who were un-methylated. CONCLUSION: Our single centre experience supports existing data on outcomes following re-do surgery for GBM.

EPID-13CONCOMITANT GLIOBLASTOMA MULTIFORME IN PATIENTS DIAGNOSED WITH MULTIPLE SCLEROSIS: A REPORT OF TWO CASES

Multiple sclerosis (MS) and glioblastoma multiforme (GBM) are two neuropathologies at the opposite ends of the immune spectrum. The incidence of MS with concomitant GBM is rare and only a number of case reports have been described in the literature. MS is an immune-mediated disease characterized by inflammation, demyelination, gliosis and neuronal loss while GBM is a primary malignant brain neoplasm that arises either from cancer stem cells or dysregulated astrocytes that result in uncontrolled tumor growth that escaped immune surveillance. We describe two cases that illustrate the challenges of timely diagnosis and management of GBM in patients with pre-existing MS. The first case is a 59-year-old female with an 18-year history of MS, who is JC virus positive and previously received Rebif and Tysabri. She presented to the emergency department with headache and altered mental status; MRI revealed a hemorrhagic left temporal lesion. She underwent hematoma evacuation and a second craniotomy for tumor debulking and received a diagnosis of anaplastic oligodendroglioma. She received standard of care Temozolomide and radiation therapy. Six months later, the patient had tumor recurrence which required a third resection, pathology was read as GBM. Second-line therapy with Bevacizumab and Irinotecan were added due to temozolomide intolerance and clinical progression. The second case is a 48-year-old female with a 24-year history of mild MS on Copaxone, who presented with improving left sided numbness and tingling of 2 months duration. She was treated with oral steroids and an MRI of the brain was done to evaluate disease activity and showed a large, acute ring-enhancing lesion atypical for MS. She underwent a biopsy that was consistent with GBM and proceeded with oncologic treatment at another facility. Although rare, these two cases illustrate the diagnostic and treatment challenges of primary brain tumors in patients with pre-existing neurological disease.

TMOD-10EVALUATION OF GROWTH DYNAMICS OF UNTREATED GLIOBLASTOMA MULTIFORME AND CORRELATION WITH EPIDEMIOLOGICAL AND TUMOR RELATED PARAMETERS

TMOD-10. EVALUATION OF GROWTH DYNAMICS OF UNTREATED GLIOBLASTOMA MULTIFORME AND CORRELATION WITH EPIDEMIOLOGICAL AND TUMOR RELATED PARAMETERS Daniel Ruess1, Lea Flitsch1, Tobias Blau2, Chistoph Wipplinger1, Alexandra Hellerbach1, Harald Treuer1, and Maximilian I. Ruge1; Departement of Stereotaxie and functional Neurosurgery, University of Cologne, Cologne, Germany; Institute of Neuropathology, University of Cologne, Cologne, Germany BACKGROUND: To conduct stereotactic biopsy with highest precision and safetya MRI for planning is routinelyobtained close before the procedure, especially in fast growing tumours. Thus, usually two MR series are available (one leading to suspected diagnosis followed by one serving stereotactic planning). Aim of the presented study was to evaluate the growth dynamic in patients with glioblastoma multiforme (GBM) and to correlate with epidemiological and tumor related features. METHODS: For this single-centre retrospective evaluation (2010-2013) all patients with histologically confirmed diagnosis of GBM by stereotactic biopsy and with two pre-operative MR series were identified. Contrast enhancing tumour was outlined on T1w MR using Osirix Dicom Viewerw independently by two investigators and tumor volume was calculated by integrating area-thickness products. Tumor growth rate (TGR) was assessed as the percentage of volume change per day (Dvol%/d) and correlated with age, volume of contrast enhancing tumor and O6-Methylguanin-DNA-Methyltransferase (MGMT) status by using Mann-Whitney-U test. RESULTS: 52 patients (f:m 1⁄4 22:30, median age 62 (range 37-82) were included. Median time span between MR imaging was 7 days (range 1-42). Median tumor growth rate was 3.4 Dvol%/d (range 0.1-17.6). There was no significant correlation between tumor growth rate and initial tumor size, gender and age. However there was a trend to slower growth in patients .70 years (p 1⁄4 0.066) and tumors .20 ml (p 1⁄4 0.058). Furthermore, MGMT status did not correlate with TGR. CONCLUSION: These data show heterogeneous but substantial TGR in untreated GBM. There might be an influence of older age and larger tumour size while molecular features (MGMT/IDH) do not show any influence in this cohort. In how far these influences sustain in a larger patient population is still under investigation. Neuro-Oncology 17:v226–v229, 2015. doi:10.1093/neuonc/nov237.10 Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2015.

Socio-economic characteristics of patients with glioblastoma multiforme.

The incidence of glioblastoma multiforme (GBM) varies across the world and also within subpopulations within each nation. Many cancers show correlation with socioeconomic status and we hypothesised that incidence of GBM also does the same. We performed a retrospective analysis of all patients treated with brain tumours at a single hospital over a 6-year period. For these patients we examined markers of socioeconomic status and reviewed their histopathological diagnosis. A total of 2859 patients had surgery between April 2006 and April 2012. Of these 880 had histological diagnosis of GBM. Records for all patients were reviewed. Based on postcodes, socioeconomic data was obtained at ward level from government sources. Markers were: average weekly household income, percentage unemployed, population density, indices of deprivation and percentage of households with no car. Data was analysed for trends between incidence per ward and socio-economic markers. Increasing incidence of GBM was associated with increasing wage (p = 0.044), less unemployment (p = 0.0002), Indices of Multiple Deprivation (p = 0.05), lower population density (p = 0.0015) and greater ownership of cars (p = 0.0005). There are unique socioeconomic characteristics for patients with GBM. Although a link to aetiology cannot be established from this limited epidemiological study, these results identify issues that these patients are more likely to face. These should be taken into account when planning support services and patient care following surgery.

Abstract 4306: A prognostic model for clinical response to bevacizumab in recurrent glioblastoma multiforme

Abstract Background: Recurrent glioblastoma multiforme (GBM) is an aggressive and deadly disease with limited treatment options. In responding patients bevacizumab-containing therapy prolongs survival and improves quality of life, although the beneficial effect varies greatly. The impact of prognostic factors in recurrent GBM patients has not been studied in detail and results are inconsistent. More importantly, no validated predictive baseline markers associated with a clinical response to bevacizumab therapy have been identified. Furthermore, GBM is a very heterogenic tumor and has been shown to change molecular pattern with time and as a result of treatment. The primary goal of this study was to describe molecular characteristics in GBM tumors at initial diagnosis and at recurrence and relate these data, including clinical baseline factors, to clinical outcome with the aim of identifying predictive factors for clinical bevacizumab response. Based on these data we will also elucidate to what extent molecular markers change expression from initial GBM diagnosis to time of relapse. Materials and Methods: For generation of prognostic models 219 recurrent GBM patients treated with bevacizumab plus irinotecan according to a previous published clinical protocol were included. For biomarker analysis, routine molecular analyses were available for 147 of the included patients at time of initial diagnosis and 81 patients at time of relapse prior to bevacizumab therapy. The candidate biomarkers constituted an immunohistochemistry (IHC) panel of EGFR, P53, MGMT and IDH1 and polymerase chain reaction analysis of 1p19q-status. Tumor samples from initial diagnosis and from time of relapse were analyzed by the χ2 test and the Wilcoxon test in order to evaluate changes in IHC expression patterns. Multiple candidate prognostic factors were screened by univariate logistic regression and Cox regression analysis modeling response and survival endpoints and variables with P-values of less than 0.10 were considered for multivariate analysis. Factors with a P-value of less than 0.05 in multivariate analysis were included in the prognostic models for response, progression-free survival (PFS) and overall survival (OS). Results: In multivariate analysis, corticosteroid use had a negative predictive impact on response at first evaluation (OR = 0.45; 95% CI: 0.22-0.93; P = 0.030) and at best response (OR = 0.51; 95% CI: 0.26-1.02; P = 0.056). Independent prognostic factors (P&amp;lt;0.05) negatively associated with PFS and OS were corticosteroid use, neurocognitive deficit and multifocal disease. Based on the three identified factors a prognostic model for overall survival at 6 and 12 months was developed. Significant prognostic and potentially predictive molecular biomarkers will be added to the models and results will be presented. Citation Format: Thomas Urup, Signe Regner Michaelsen, Camilla Bjørnbak Holst, Anders Toft, Ib Jarle Christensen, Kirsten Grunnet, Michael Kosteljanetz, Helle Broholm, Ulrik Lassen, Hans Skovgaard Poulsen. A prognostic model for clinical response to bevacizumab in recurrent glioblastoma multiforme. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4306. doi:10.1158/1538-7445.AM2015-4306

Screening of differentially expressed genes associated with human glioblastoma and functional analysis using a DNA microarray.

Glioblastoma multiforme (GBM) is the most malignant type of human glioma, and has a poor prognosis. Screening differentially expressed genes (DEGs) in brain tumor samples and normal brain samples is of importance for identifying GBM and to design specific-targeting drugs. The transcriptional profile of GSE30563, containing three genechips of brain tumor samples and three genechips of normal brain samples, was downloaded from Gene Expression Omnibus to identify the DEGs. The differences in the expression of the DEGs in the two different samples were compared through hierarchical biclustering. The co-expression coefficient of the DEGs was calculated using the information from COXPRESdb, the network of the DEGs was constructed and functional enrichment and pathway analysis were performed. Finally, the transcription factors of important DEGs were predicted. A total of 1,006 DEGs, including 368 upregulated and 638 downregulated DEGs, were identified. A close correlation was demonstrated between six important genes, associated with immune response, HLA-DQB1, HLA-DRB1, HLA-DPA1, HLA-B, HLA-DMA and HLA-DRA, and the immune response. Allograft rejection was selected as the most significant pathway. A total of 17 transcription factors, including nuclear factor (NF)-κB and NF-κB1, and their binding sites containing these six DEGs, were also identified. The DEGs, including major histocompatibility complex (MHC) class II, DQβ1, MHC class II, DRβ1, MHC class IB, MHC class II, DMα, MHC class II, DPα1, MHC class II, DRα, may provide novel targets for the diagnosis and treatment of GBM. The transcription factors of these six genes and their binding sites may also provide evidence and direction for identifying target-specific drugs.

Risk factors for seizures and antiepileptic drug-associated adverse effects in high-grade glioma patients: A multicentre, retrospective study in Hong Kong.

AimThe aim of this present study was to determine the frequency, as well as risk factors, for seizures and antiepileptic drug (AED)-associated adverse effects among high-grade glioma (HGG) patients.Patients and MethodsA multicentre, retrospective study of adult Chinese Hong Kong patients from three neurosurgical centres diagnosed with supratentorial HGG between 1 January 2001 and 31 December 2010 was performed.ResultsA total of 198 patients, with a mean age of 55 years (range: 18–88) and a mean follow up of 15 months, was recruited. Most suffered from glioblastoma multiforme (GBM) (63 per cent) followed by anaplastic astrocytoma (25 per cent). Median overall survival for patients with GBM was 8 months, and 11 months for those with grade III gliomas. Prophylactic AED was prescribed in 165 patients (83 per cent), and 64 per cent of patients were continued until end of life or last follow up. A total of 112 patients (57 per cent) experienced seizures at a mean duration of 8 months postoperatively (range: 1 day–75 months). Independent predictors for seizures were a diagnosis of GBM [adjusted odds ratio (OR): 2.33, 95 per cent confidence interval (CI): 1.21–4.52] and adjuvant radiotherapy (adjusted OR: 2.97, 95 per cent CI: 1.49–6.62). One-fifth of patients (21 per cent) experienced AED adverse effects, with idiosyncratic cutaneous reactions and hepatotoxicity most frequently observed. An independent predictor for adverse effects was exposure to aromatic AED, such as phenytoin, carbamazepine and phenobarbital (adjusted OR: 3.32, 95 per cent CI: 1.32–8.40).ConclusionsAntiepileptic drug prescription for primary seizure prophylaxis is both pervasive and prolonged for HGG patients. Seizures occur frequently, but most were delayed and none were life threatening. Judicious prescription of AED is required, especially when a significant proportion of patients experience adverse effects. Patients with a diagnosis of GBM and exposure to radiotherapy are at risk. We suggest, contrary to present practice, that primary seizure prophylaxis be given only during the perioperative period and resumed when they occur. We also recommend avoidance of aromatic AED due to their association with idiosyncratic adverse effects.

NI-33 * THIRD VENTRICULAR GLIOBLASTOMA MULTIFORME: CASE REPORT AND LITERATURE REVIEW

BACKGROUND: Glioblastoma multiforme (GBM) typically presents in the supratentorial white matter, commonly within the centrum semiovale as a ring-enhancing lesion with areas of necrosis. An atypical presentation of this lesion, both anatomically as well as radiographically is significant and must be part of the differential for a neoplasm in this location. CASE DESCRIPTION: We present a case of a sixty-two year old female with headaches, increasing somnolence and cognitive decline for several weeks. The MRI showed mild left ventricular dilatation with a well-marginated, homogenous, and non-hemorrhagic lesion located at the ceiling of the third ventricle within the junction of the septum pellucidum (SP) and fornix, without exhibiting the typical radiographic features of hemorrhage or necrosis. Final pathology reports confirmed the diagnosis of GBM. CONCLUSION: This case report describes an unusual location for the most common primary brain neoplasm. Moreover, this case identifies the origin of a GBM related to the paracentral ventricular structures infiltrating the body of the fornix and leaves of the septum pellucidum. To our knowledge this is report is the first reported case of a GBM found in this anatomical location with an entirely atypical radiographic presentation.

RT-14 * TIME TO RADIATION THERAPY IN GLIOBLASTOMA MULTIFORME: IS SOONER BETTER?

INTRODUCTION: Optimal post-surgical treatment of glioblastoma multiforme (GBM) includes concurrent radiation therapy and temozolomide. However, there is conflicting data regarding the ideal timing of radiation. Proponents of early therapy cite the rapid proliferation rate of WHO grade IV tumors and advocate treatment with minimal delays. Others believe extra time allows the surgical cavity to collapse and tempers the risk of infection, minimizing complications from radiation. METHODS: We retrospectively reviewed records of 97 patients with a pathologic diagnosis of GBM at our institution who underwent postoperative treatment with at least 6 weeks of radiation according to Radiation Therapy Oncology Group guidelines and concurrent temozolomide therapy. Demographic, clinical, radiographic and operative data were reviewed. Analysis of variance(ANOVA) was used to identify differences between surgical and demographic subgroups. Kaplan-Meier survival analysis was used to estimate overall(OS) and progression free survival(PFS). Cox regression analyses were performed to determine the effect of radiation timing on survival. RESULTS: 49 male and 47 female patients had a median age at surgery of 57 years (range 18-77). Sixteen patients underwent biopsy, 64 had a subtotal resection(STR) and 16 had a gross total resection(GTR). One year OS and PFS were 70% and 16%, respectively. The median time to radiation(TTR) was 26 days (range 9-51 days). TTR was significantly longer in patients with resection compared to biopsy (p < 0.001). TTR did not significantly affect OS (p = 0.732) or PFS (p = 0.699) of the entire cohort or the subgroup treated with resection (OS, p = 0.809; PFS, p = 0.812). CONCLUSIONS: The precise timing of radiation initiation does not appear to affect survival of patients with GBM who are optimally treated with radiation and temozolomide. Therefore practitioners may allow extra time within the recommended 6 week window for optimal medical stabilization and wound healing without fear that this may adversely affect patient outcomes.

Abstract CT404: Phase I/II study of VAL-083 in patients with recurrent glioblastoma multiforme

Abstract Median survival for patients with recurrent glioblastoma multiforme (GBM) is less than 6 months. Front-line systemic therapy is temozolomide, but chemo-resistance due to O6-methylguanine-DNA-methyltransferase (MGMT) activity has been implicated in poor outcomes. VAL-083 is a structurally unique bi-functional DNA alkylating small molecule drug that crosses the blood-brain barrier and accumulates in brain tumor tissue. Previous human clinical studies by several investigators have suggested that VAL-083 has anti-tumor activity against a broad range of tumor types including GBM. In preclinical in vitro studies, VAL-083 demonstrated activity in a wide range of cancer cell lines, including pediatric and adult GBM cell lines and GBM cancer stem cells. Notably, due to crosslink formation on N7 of guanine, VAL-083 overcomes chemo-resistance to MGMT in vitro. In light of extensive safety data from several clinical trials and promising efficacy signals in CNS tumors, DelMar initiated a new clinical study to determine the safety, tolerability, pharmacokinetics, anti-tumor activity in patients with recurrent GBM. This is an open-label, single-arm Phase I/II dose-escalation study in patients with histologically-confirmed initial diagnosis of malignant GBM. The study utilizes a 3+3 dose-escalation design. Patients receive VAL-083 i.v. on days 1, 2, and 3 of a 21 day cycle. GBM patients have previously been treated with surgery and/or radiation, if appropriate, and must have failed both bevacizumab and temozolomide, unless contraindicated. In the ongoing trial, cohorts 1 through 4 (10 mg/m2) have completed the trial successfully with no drug-related serious adverse events (SAEs), and maximum tolerated dose (MTD) was not yet reached. Enrollment for Cohort 5 (20 mg/m2) has been initiated. Pharmacokinetic analyses show dose-dependent increase in exposure with a short 1-2 hour plasma half-life and a Cmax of &amp;lt;200 ng/ml at 10 mg/m2. Historical data suggests a long half-life in the cerebrospinal fluid (CSF) (&amp;gt;20 hours) with preferential accumulation to brain tumor tissue. MGMT status of patients and drug concentration in the CSF are being evaluated when possible. ClinicalTrials.gov Identifier: NCT01478178 Citation Format: Kent C. Shih, Manish R. Patel, Jeffrey Bacha, Dennis M. Brown, William J. Garner, Anne Steino, Richard S. Schwartz, Sarath Kanekal, Mike Li, Lorena M. Lopez, Howard A. Burris. Phase I/II study of VAL-083 in patients with recurrent glioblastoma multiforme. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT404. doi:10.1158/1538-7445.AM2014-CT404

P02.01 * MRI ASSESSMENT OF TUMOR SIZE IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS TREATED WITH DENDRITIC CELL IMMUNOTHERAPY

BACKGROUND AND AIM: RANO criteria are widely used for response assessment in brain tumor clinical trials based on cytotoxic and/or anti-angiogenic treatments. In cancer immunotherapy the induction of inflammatory responses may be relevant and careful evaluation of changes in tumor size may help discriminating therapy-driven changes from tumor progression. We compared volume measurements on post-contrast, three dimensional (3D) T1-weighted images (T1WI) with cross-sectional areas on two dimensional (2D) T1WI, according to RANO, in patients with first diagnosis of glioblastoma multiforme (GBM) enrolled in a phase I-II phase study based on dendritic cell (DC) immunotherapy associated to the Stupp regimen. MATERIALS AND METHODS: We reviewed 118 MRI studies from 22 adult patients with newly diagnosed GBM. The main radiological inclusion criteria was residual tumor volume 10mm) of the contrast-enhancing lesion. In 3D measurements volume was estimated by the PACS workstation software (MedStation version 4.9.902.6). Volumetric analysis was performed on isotropic high resolution 3D T1WI. the enhancing tumor was outlined in all slices excluding the cystic areas. RESULTS: 11/118 studies (9.3%) were excluded because no enhancing lesions were present. 30 of 107 remaining scans (25.4%) were evaluated for volume only because one diameter <10 mm. The median area on 2D was 547 mm2, the median volume on 3D was 577 mm3. A high correlation between the two measurements was observed in the 77 scans in which both the area and the volume were measurable (r = 0.85, p<0.0001). When looking at the difference between scans performed at two consecutive time points, no significant difference was observed in percentage variations calculated by the two methods (Wilcoxon test p = 0.49). Furthermore there was a high correlation between the percentage differences in the two measurements (r = 0.66, p<0.0001). CONCLUSIONS: Our study suggests that tumor cross-sectional areas on post contrast 2D T1WI are comparable to volumes on 3D T1WI. However approximately 25% of scans were lost to the 2D evaluation because they had at least a diameter less than the RANO cut off (10 mm). Thus, volumetric measurements can provide a more informative evaluation of tumor size, a feature that can be particularly useful in immunotherapy trials.

P17.19 * TO TREAT OR NOT TO TREAT: IMPACT OF AGE AND COMORBIDITIES IN GLIOBLASTOMA PATIENTS

PURPOSE/OBJECTIVE: Age and comorbidities could influence compliance to adjuvant Radiochemotherapy. We evaluate compliance and outcomes in elderly patients (>65 years old) with Glioblastoma Multiforme (GBM) treated according to three prospective phase II trials using Temozolomide (TMZ) concurrently and sequential to radiotherapy. MATERIALS AND METHODS: Three prospective phase II trials were performed for patients with a histological diagnosis of GBM (≥ 18 yrs); radiotherapy was delivered on tumor bed +/- residual + margin of 1,5 cm (CTV1: 59.4 Gy) and tumor bed +/- residual + edema until March 2008 or + margin of 3 cm (CTV2: 45 Gy) subsequently. The timing of concurrent Temozolomide (TMZ) was different between the studies: TMZ was administrated in the first and the last week of RT until December 2003 and every five days for week successively excluding Saturday and Sunday; in the third study patients received concomitant or sequential Fractionated Stereotactic Conformal RT boost to increase dose (69.4 Gy). Adjuvant TMZ was administered to all patients: six cycles if disease was absent, or until disease progression or unbearable toxicity in the other cases. Overall co-morbidities were assessed using the Charlson Index of Co-morbidity (CCI). Toxicity was evaluated according to RTOG; survival analisys was calculated using Kaplan-Meier method. RESULTS: 72 patients were treated between October 2001 to December 2012. Median age was 69 yrs (range 65-80 yrs): 41 male and 31 female. 41 patients underwent a partial removal and 31 a complete surgery. A CC1≥ 1 was present in 41% of patients. 66 patients received a total dose of 60 Gy, while six 69.4 Gy. The compliance to the treatment was 98%. Acute toxicity was reversible in all patients. Neutropenia was observed in in 16.6% (G1-2 11,1% and G3-G4 5,5%); thrombocytopenia was reported in 30,6% (G1-2 15,3% and G3-G4 15,3%). Neurologic toxicity was present in 30,6% of the patients without difference between G1-2 and G3-4. With a median follow-up of 72 months (range 6-139 months), median progression-free-survival was 12 months. Median overall survival (OS) was 15 months, 2-yrs OS was 30%, no patient being alive at 5 years. A significant impact on OS was been represented from only complete surgery vs partial (p = 0.03) and a trend for radiation dose of 7000 vs 6000 cGy (p = 0.06). It was not observe any difference in OS after a stratification of elderly (two subsets ≥ and 75 yrs). In particular, at 2 years OS was: 10% for patients >75 years old, 21% for >70 and <74, 38% for < 70. CONCLUSIONS: This study suggests that radio-chemotherapy is feasible also in elderly with an improved OS for higher doses of RT. CCI ≤ 2 does not impact on compliance and outcomes. A prospective study is ongoing to confirm these findings.

Including Edema or Not in Glioblastoma?: Analysis From Sequential Prospective Phase 2 Studies

Including Edema or Not in Glioblastoma?: Analysis From Sequential Prospective Phase 2 Studies

Predicting the likelihood of an isocitrate dehydrogenase 1 or 2 mutation in diagnoses of infiltrative glioma.

Several variables are associated with the likelihood of isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation in gliomas, though no guidelines yet exist for when testing is warranted, especially when an R132H IDH1 immunostain is negative. A cohort of 89 patients was used to build IDH1/2 mutation prediction models in World Health Organization grades II-IV gliomas, and an external cohort of 100 patients was used for validation. Logistic regression and backward model selection with the Akaike information criterion were used to develop prediction models. A multivariable model, incorporating patient age, glioblastoma multiforme diagnosis, and prior history of grade II or III glioma, was developed to predict IDH1/2 mutation probability. This model generated an area under the curve (AUC) of 0.934 (95% CI: 0.878, 0.978) in the external validation cohort and 0.941 (95% CI: 0.918, 0.962) in the cohort of The Cancer Genome Atlas. When R132H IDH1 immunostain information was added, AUC increased to 0.986 (95% CI: 0.967, 0.998). This model had an AUC of 0.947 (95% CI: 0.891, 0.995) in predicting whether an R132H IDH1 immunonegative case harbored a less common IDH1 or IDH2 mutation. The models were also 94% accurate in predicting IDH1/2 mutation status in gliomas from The Cancer Genome Atlas. An interactive web-based application for calculating the probability of an IDH1/2 mutation is now available using these models. We have integrated multiple variables to generate a probability of an IDH1/2 mutation. The associated web-based application can help triage diffuse gliomas that would benefit from mutation testing in both clinical and research settings.

Association of increased progression-free survival in primary glioblastomas with lymphopenia at baseline and activation of NK and NKT cells after dendritic cell immunotherapy.

2087 Background: DENDR1 is a phase I-II phase study aimed at evaluating dendritic cell (DC) immunotherapy in patients with first diagnosis of glioblastoma multiforme (GBM). Here we provide results ...

Third Ventricular Glioblastoma Multiforme: Case Report &amp; Literature Review

Glioblastoma multiforme (GBM) typically presents in the cerebrum, localized to the frontal, temporal, or parietal lobes. The usual radiographic finding is a ring-enhanced lesion, with areas of necrosis on Magnetic Resonance Imaging (MRI). Here, we present a case of a sixty-two year old female with headaches, increasing somnolence and cognitive decline over several weeks. MRI showed mild hydrocephalus with a well marginated, homogenous, and non-hemorrhagic lesion of the posterior third ventricle. The lesion was found extending between the leaves of the septum pellucidum, and the body of the fornix, without evidence of either necrosis or ring enhancement on post-contrast T1-weighted MRI imaging (Fig. 1a). Final pathology reports confirmed the diagnosis of GBM, including GFAP by immunohistochemistry and a high Ki-67 by immunohistochemistry. There were also classic microscopic findings such as a serpentine patter of necrosis, surrounding hypercellularity, and the characteristic perinecrotic pseudo-palisading pattern of GBM (Fig. 2). This case report describes an unusual location for the most common primary brain neoplasm. Moreover, this case also identifies the origin of a GBM related to the paracentral ventricular structures, interpositioning itself between the body of the fornix and leaves of the septum pellucidum. We also review the existing literature on rare incidents of glioblastomas that were reported to be isolated to the third ventricle. A discussion of the current theories on the potential origins of glioblastoma follows, and we also propose a hypothesis for how such lesions can form in the third ventricle. Moreover, the radiographic findings in this case did not show any evidence or typical characteristic attributable to GBM. To our knowledge this is the first reported case of a GBM found in this anatomical location, with such atypical radiographic presentation.

A small noncoding RNA signature found in exosomes of GBM patient serum as a diagnostic tool

Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults, and its prognosis remains dismal despite intensive research and therapeutic advances. Diagnostic biomarkers would be clinically meaningful to allow for early detection of the tumor and for those cases in which surgery is contraindicated or biopsy results are inconclusive. Recent findings show that GBM cells release microvesicles that contain a select subset of cellular proteins and RNA. The aim of this hypothesis-generating study was to assess the diagnostic potential of miRNAs found in microvesicles isolated from the serum of GBM patients. To control disease heterogeneity, we used patients with newly diagnosed GBM. In the discovery stage, PCR-based TaqMan Low Density Arrays followed by individual quantitative reverse transcriptase polymerase chain reaction were used to test the differences in the miRNA expression levels of serum microvesicles among 25 GBM patients and healthy controls paired by age and sex. The detected noncoding RNAs were then validated in another 50 GBM patients. We found that the expression levels of 1 small noncoding RNA (RNU6-1) and 2 microRNAs (miR-320 and miR-574-3p) were significantly associated with a GBM diagnosis. In addition, RNU6-1 was consistently an independent predictor of a GBM diagnosis. Altogether our results uncovered a small noncoding RNA signature in microvesicles isolated from GBM patient serum that could be used as a fast and reliable differential diagnostic biomarker.

Case comparison and literature review of glioblastoma: A tale of two tumors.

Background:Diagnosis of glioblastoma multiforme (GBM) includes a heterogeneous group of tumors. We describe two cases with histopathologically and molecularly similar tumors, but very different outcomes. We attempt to illustrate the need for improved prognostic markers for GBM.Case Description:Two patients with similar molecular profiles were retrospectively identified. The following markers were assessed: O6-methylguanine DNA methyltransferase (MGMT) methylation, isocitrate dehydrogenase (IDH) 1 and 2 status, epidermal growth factor receptor (EGFR) amplification, phosphatase and tensin homolog (PTEN) status, Ki-67, p53, and 1p/19q status. Each patient was assigned a Karnofsky performance score at presentation. Case 1 (62-year-old male) was a right temporal lobe glioblastoma with a molecular profile of amplified EGFR, normal PTEN, no IDH1/2 mutation, 28.7% MGMT promoter methylation, 5-20% Ki-67, 1p deletion, and 19q intact. The patient underwent resection followed by radiation therapy and 2 years of chemotherapy, and was asymptomatic and tumor free 5 years post diagnosis. Tumor eventually recurred and the patient expired 72 months after initial diagnosis. Case 2 (63-year-old male) was a right frontal white matter mass consistent with glioblastoma with a molecular profile of amplified EGFR, absent PTEN, no IDH1/2 mutation, 9.9% MGMT promoter methylation, 5-10% Ki-67, and 1p/19q status inconclusive. A radical subtotal resection was performed; however, 2 weeks later symptoms had returned. Subsequent imaging revealed a tumor larger than at diagnosis. The patient expired 3 months after initial diagnosis.Conclusion:The need for formulating more robust means to classify GBM tumor subtypes is paramount. Standard histopathologic and molecular analyses are costly and did not provide either of these patients with a realistic appraisal of their prognosis. Individualized whole genome testing similar to that being reported for medulloblastoma and other tumors may be preferable to the array of tests as currently utilized.