Malignant Glioma Patients Research Articles

WTAP Expression Predicts Poor Prognosis in Malignant Glioma Patients.

Wilms' tumor 1-associating protein (WTAP) interacts with the Wilms' tumor 1 gene. Although originally classified as a tumor suppressor, WTAP was later found to be over-expressed in glioblastoma which is regarded as a grade IV astrocytoma. However, the expression in other glioma grades and the relationship between WTAP expression and the prognosis of glioma patients are still unknown. In this study, we investigated WTAP expression in 169 different types of glioma cases using western blot analysis and immunohistochemistry assay. Further, we evaluated the association of WTAP expression with clinicopathological characteristics using chi-square test and Spearman's correlation test. We used univariate and multivariate Cox regression analyses to evaluate the independency of diferent WTAP expression. Then, the survival curves were calculated using the Kaplan-Meier method. Results showed that WTAP was over-expressed in glioma tissues, and the expression was closely correlated with glioma grade. Moreover, high WTAP expression was correlated with poor postoperative survival in glioma patients. WTAP may serve as a novel prognostic marker.

Challenges of rehabilitation for patients with primary malignant glioma – a review of recent literature

Primary malignant glioma is one of the greatest challenges in contemporary rehabilitation. Due to the introduction of newer and newer methods of oncological treatment the overall survival in this group of patients retrospectively increased. This article is a review of the scientific literature of recent years concerning the principles of clinical assessment of patients with primary glioblastoma and the selection of methods in rehabilitation programs based on general condition. In the last years, there has been an increase in the results of clinical studies on the implementation of rehabilitation treatment in primary malignant glioma patients after oncological treatment. Thus, identification of accurate functional performance, behavior changes, evaluation of cognitive function, and cancer markers and oncological treatment as well as quality of life outcomes in this population are of major clinical importance. Primary malignant glioma patients represent a unique patient population with distinctive functional impairments and limitations to physical exercise. Therefore, individual comprehensive rehabilitation treatment may be useful in improving the physical and cognitive functioning as well as decreasing the fatigue syndrome. Such a therapy allows this group of patients to participate in society despite the consequences of cancer treatment.

Patterns of Recurrence After Resection of Malignant Gliomas With BCNU Wafer Implants: Retrospective Review in a Single Institution

Bis-chloroethylnitrosourea (BCNU) wafers have been demonstrated to be effective for prolonging survival for patients with malignant glioma and have been approved worldwide. BCNU wafers are implantable and have a unique feature of delivering chemotherapeutic drug at high concentration at tumor margin over time after resection. BCNU wafers presumably, by this mechanistic rationale, have a beneficial effect on local tumor control and thus could change the pattern of recurrence, which is most frequently local. However, no studies have demonstrated such phenomenon after BCNU wafer implants. To investigate whether the surgeries with BCNU wafers alter the predominant tendency of local recurrence pattern, we retrospectively reviewed 8 malignant glioma patients treated with BCNU wafers (BCNU wafer group), together with 22 glioma patients who did not receive BCNU wafers (no-BCNU wafer group) for comparison. Out of 6 patients in BCNU wafer group who exhibited recurrence, 1 showed local, 2 showed diffuse, and 3 showed a distant recurrence pattern, which was away from resection cavity. On the other hand, out of 18 patients in the no-BCNU wafer group who exhibited recurrence, 10 showed a local pattern, 8 showed a diffuse pattern, and no cases showed distant pattern. Distant pattern was observed significantly more frequently in the BCNU wafer group than in the no-BCNU wafer group. These results suggest that BCNU wafers could have a beneficial effect on local tumor control and may provide BCNU wafers with a new profile that could be considered for establishing future chemotherapeutic strategy for glioma patients.

The homing and inhibiting effects of hNSCs-BMP4 on human glioma stem cells.

Malignant gliomas patients have a poor survival rate, partially due to the inability in delivering therapeutic agents to the tumors, especially to the metastasis of human glioma stem cells (hGSCs). To explore whether the human neural stem cells (hNSCs) with an over-expression of BMP4 (hNSCs-BMP4) can trace and inhibit hGSCs, in this study, we examined the migration of hNSCs to hGSCs using transwell assay in vitro and performed the fluorescent tracer experiment in vivo. We examined the proliferation, differentiation, apoptosis and migration of hGSCs after co-culturing with hNSCs-BMP4 in vitro and tested the tropism and antitumor effects of hNSCs-BMP4 in the established brain xenograft models of hGSCs. We found that hNSCs-BMP4 could secrete BMP4 and trace hGSCs both in vitro and in vivo. When compared to the normal human astrocytes (NHAs) and hNSCs, hNSCs-BMP4 could significantly inhibit the invasive growth of hGSCs, promote their differentiation and apoptosis by activating Smad1/5/8 signaling, and prolong the survival time of the tumor-bearing nude mice. Collectively, this study suggested that hNSCs-BMP4 may help in developing therapeutic approaches for the treatment of human malignant gliomas.

Morusin Induces TRAIL Sensitization by Regulating EGFR and DR5 in Human Glioblastoma Cells.

Glioblastoma is one of the most malignant primary tumors, and the prognosis for glioblastoma patients remains poor. Tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) is considered a promising anticancer agent due to its remarkable ability to selectively kill tumor cells. However, since many cancers are resistant to TRAIL, strategies to overcome resistance are required for the successful use of TRAIL in the clinic. In the present study, the potential of morusin as a TRAIL sensitizer in human glioblastoma cells was evaluated. Treatment with TRAIL or morusin alone showed weak cytotoxicity in human glioblastoma cells. However, combination treatment of TRAIL with morusin synergistically decreased cell viability and increased apoptosis compared with single treatment. Morusin induced expression of death receptor 5 (DR5), but not DR4 or decoy receptors (DcR1 and DcR2). Furthermore, morusin significantly decreased anti-apoptotic molecules survivin and XIAP. In addition, morusin reduced expression of EGFR and PDFGR as well as phosphorylation of STAT3, possibly mediating down-regulation of survivin and XIAP. Together these results suggest that morusin enhances TRAIL sensitivity in human glioblastoma cells through regulating expression of DR5 and EGFR. Therefore, the combination treatment of TRAIL and morusin may be a new therapeutic strategy for malignant glioma patients.

Tryptophan-2,3-dioxygenase is regulated by prostaglandin E2 in malignant glioma via a positive signaling loop involving prostaglandin E receptor-4.

Malignant gliomas and other types of tumors generate a local immunosuppressive microenvironment, which prohibits an effective anti-tumor immune response and promotes tumor growth. Along with others, we have recently demonstrated that catabolism of the essential amino acid tryptophan via tryptophan-2,3-dioxygenase (TDO) is an important mechanism mediating tumor-associated immunosuppression particularly in gliomas. The pathways regulating TDO in tumors, however, are poorly understood. Here, we show that prostaglandins enhance TDO expression and enzymatic activity in malignant gliomas via activation of prostaglandin E receptor-4 (EP4). Stimulation with prostaglandin E2 (PGE2 ) up-regulated TDO-mediated kynurenine release in human glioma cell lines, whereas knockdown of the PGE2 receptor EP4 inhibited TDO expression and activity. In human malignant glioma tissue expression of the PGE2 -producing enzyme cyclooxygenase-2 (COX2) and its receptor EP4 were associated with TDO expression both on transcript and protein level. High expression of EP4 correlated with poor survival in malignant glioma patients WHO III-IV. Importantly, treatment of glioma cells with an EP4 inhibitor decreased TDO expression and activity. Moreover, TDO-over-expressing murine gliomas showed increased COX2 and EP4 expression suggesting a positive feedback mechanism invivo. In summary, targeting EP4 may inhibit - in addition to immunosuppressive COX2 signaling - tryptophan degradation as another important immunosuppressive pathway and thus, could provide a dual clinically relevant immunotherapeutic avenue for the treatment of malignant gliomas. We proposed that in malignant gliomas prostaglandin E2 (PGE2 ) produced by cyclooxygenases (COX) up-regulates tryptophan-2,3-dioxygenase (TDO) expression and enzyme activity through binding to its Gs-coupled receptor EP4 and therefore may mediate tumor immune escape in part through aryl hydrocarbon receptor (AHR) activation. Moreover, TDO activity itself seems to induce intratumoral PGE2 metabolism suggesting an immunosuppressive loop involving COX/EP4/TDO.

Current Understanding of Epidemiology, Genetic Etiology and Treatment of Gliomas from Indian Population

Tumors of the central nervous system (CNS) consist of 1-2% of the total cancer spectrum. Gliomas are the most common tumors within the CNS. These tumors originate from glial cells or glial precursor cells. Tumors originates from astroglial cells are known as astrocytoma, oligodendroglioma originates from oligodendroglial cells, oligoastrocytoma are mixed tumor containing cellular property of both astrocytes and oligodendrocytes and ependymal cells gives rise to ependymoma. The World Health Organization (WHO) classification of central nervous system tumors separates glioma into four grades, in which grade I and II are defined as low grade whereas grade III and IV are classified as high grade (also known as malignant glioma). Malignant glioma includes anaplastic glioma (anaplastic oligodendroglioma, anaplastic astrocytoma, and anaplastic oligoastrocytoma) and glioblastoma. With current treatment modality, survival of patients with newly diagnosed glioblastoma is around 12–16 months. The treatment strategy includes surgery followed by adjuvant radiation and chemotherapy. From 2005, a secondgeneration oral alkylating agent known as Temozolomide (TMZ) became standard of care in the treatment of malignant glioma patients worldwide including India. In this current review, we focused on epidemiology, molecular biology and management of gliomas emerged from India.

The progress in molecular biomarkers of gliomas

Malignant glioma, a common form of central nervous system tumor, has a poor prognosis. The overall survival of these patients is as low as 12–14 months only. In general, the progress in personal precision medication has been gradually directed toward the molecular profiling of the tumors. Malignant glioma is one such tumor in which treatment response relies largely on its molecular characteristics, thus making the understanding of these markers essential to deliver the best treatment possible. Representative molecular markers (isocitrate dehydrogenase 1 mutation, 1p19q codeletion, epidermal growth factor receptor variant III amplification, human telomerase reverse transcriptase promoter mutations, alpha thalassemia/mental retardation syndrome X-linked mutation, and O[6]-methylguanine DNA methyltransferase promoter methylation) are described/discussed in this article. Furthermore, the research prospects of cell-free DNA, regarded as a new developing trend of molecular markers, are discussed. There is an immense hope in these promising molecular markers which are expected to improve the overall survival and quality of life of malignant glioma patients.

EGFRvIII/integrin β3 interaction in hypoxic and vitronectinenriching microenvironment promote GBM progression and metastasis.

Glioblastoma (GBM) is one of the most lethal brain tumors with a short survival time. EGFR amplification and mutation is the most significant genetic signature in GBM. About half of the GBMs with EGFR amplification express a constitutively autophosphorylated variant of EGFR, known as EGFRvIII. Our in vitro data demonstrated further enhanced EGFRvIII activity and tumor cell invasion in the tumor microenvironment of hypoxia plus extracellular matrix (ECM) vitronectin, in which EGFRvIII and integrin β3 tended to form complexes. The treatment with ITGB3 siRNA or the integrin antagonist cilengetide preferentially interrupted the EGFRvIII/integrin β3 complex, effectively reduced tumor cell invasion and activation of downstream signaling effectors. Cilengitide is recently failed in Phase III CENTRIC trial in unselected patients with GBM. However, we found that cilengitide demonstrated efficacious tumor regression via inhibition of tumor growth and angiogenesis in EGFRvIII orthotopic xenografts. Bioinformatics analysis emphasized key roles of integrin β3, hypoxia and vitronectin and their strong correlations with EGFRvIII expression in malignant glioma patient samples in vivo. In conclusion, we demonstrate that EGFRvIII/integrin β3 complexes promote GBM progression and metastasis in the environment of hypoxia and vitronectin-enrichment, and cilengitide may serve as a promising therapeutics for EGFRvIII-positive GBMs.

Abstract B3: Prognostic and predictive biomarkers in recurrent WHO grade 3 malignant glioma patients treated with bevacizumab and irinotecan

Abstract BACKGROUND Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor A (VEGF-A), has demonstrated activity in the treatment of recurrent malignant glioma. High response rates have been observed, but particularly in WHO grade 3 gliomas, efforts to identify predictors of clinical response have been limited. Predictive markers and prognostic models are required in order to individualize treatment for this patient population. The primary endpoint of this study was to identify predictive biomarkers associated with response to bevacizumab therapy. The secondary endpoint was to identify prognostic factors associated with progression-free survival (PFS) and overall survival (OS). METHODS A total of 62 consecutive, recurrent grade 3 glioma patients were retrospectively evaluated. Eligible patients from our center had a WHO performance status of 0-2 and were administered bevacizumab and irinotecan between December 2005 and November 2014 according to a previously published clinical protocol. Baseline factors screened for potential prognostic and predictive value included: Age, gender, PS, WHO grade 3 diagnosis, tumor size and location, multifocal disease, extent of resection, number of prior chemotherapy regiments, response to prior chemotherapy, first-line treatment, number of previous recurrences, neurological deficit, corticosteroid use, necrosis, vascular proliferation, neutrophil-to-lymphocyte ratio, and expression of p53, EGFR, MIB-1, MGMT, IDH1 and ATRX. Candidate factors with p-values below 5% were considered for multivariate analysis. Prognostic models were generated by logistic regression and Cox regression, modelling response and survival endpoints. RESULTS Twenty-two patients (35.5%) demonstrated a response according to the RANO criteria. Responders had significantly prolonged OS (p = 0.007) and trended toward longer PFS (p = 0.067) as compared to non-responders (OS: 12.4 vs 4.3 months, PFS: 5.6 vs 3.2 months). Presence of necrosis (OR: 0.17, CI: 0.04-0.68, p = 0.012) and a WHO performance status (PS) of more than 1 (OR: 0.04, CI: 0.002-0.89, p = 0.042) were more common in non-responders than responders. Female gender (HR: 0.48, CI: 0.28-0.82, p = 0.008) and a PS of 0-1 (HR: 0.20, CI: 0.10-0.41, p < 0.0001) were identified as positive prognostic factors for PFS. Immunohistochemical p53 negativity (HR: 0.47, CI: 0.26-0.87, p = 0.016) and low PS (HR: 0.17, CI: 0.07-0.39, p < 0.0001) correlated with extended OS and these factors were included in a prognostic model. CONCLUSIONS A favorable baseline PS and absence of necrosis were positively associated with response to bevacizumab treatment in recurrent grade 3 glioma patients. Low PS, female gender and p53 negativity are prognostic of improved outcome in this patient group. Citation Format: Anders Toft, Thomas Urup, Ib J. Christensen, Signe R. Michaelsen, Babloo S. Lukram, Kirsten Grunnet, Michael Kosteljanetz, Vibeke A. Larsen, Ulrik Lassen, Helle Broholm, Hans S. Poulsen. Prognostic and predictive biomarkers in recurrent WHO grade 3 malignant glioma patients treated with bevacizumab and irinotecan. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B3.

NIMG-65EVALUATION OF THE TREATMENT RESPONSE OF MALIGNANT GLIOMA ON BEVACIZUMAB THERAPY USING 11C-METHIONINE POSITRON EMISSION TOMOGRAPHY

BACKGROUND: Although anti-angiogenic therapy using bevacizumab (BEV) can induce normalization of the blood brain barrier, its effect on tumor biological activity is not well understood. We used 11C-methionine positron emission tomography (MET-PET), to evaluate biological response to BEV in patients with malignant glioma. METHODS: 8 malignant glioma patients (anaplastic oligodendroglioma 1, anaplastic astrocytoma 2, glioblastoma5) were treated with BEV (Avastin) at the time of tumor enlargement or recurrence after surgery, radiation therapy and temozolomide treatment. After initiation of BEV, they were monitored with magnetic resonance imaging (MRI) and MET-PET. MRI treatment response was evaluated according to RANO (Response Assessment in Neuro-Oncology) criteria. Methionine uptake into the tumor was expressed as a ratio to contralateral healthy brain tissue (T/N ratio). RESULTS: MRI revealed that the size of contrast-enhanced tumor was reduced and peri-tumoral edema was diminished after the initiation of BEV in all 8 cases. MRI showed a complete response according to RANO criteria in 6 of the 8 patients (75%) and a partial response in 2 patients (25%). In the contrast-enhanced tumor lesion, T/N ratio on PET decreased after initiation of BEV. In the non-enhancing tumor lesion, T/N ratio on PET after BEV was almost no difference between that before BEV. CONCLUSIONS: Our results indicate that initiation of BEV may suppress biological activity of the contrast-enhanced tumor in addition to reduce vascular permeability by restoring the blood-brain barrier. Met-PET could give us important information to understand the therapeutic mechanisms of BEV in malignant glioma patients.

HCP-08PROGNOSTIC AWARENESS AND PROGNOSTIC COMMUNICATION IN MALIGNANT GLIOMA

BACKGROUND: For patients with incurable cancer, prognostic awareness (PA) is associated with favorable psychological states and end-of-life outcomes. Malignant glioma (MG) is a devastating cancer with uniformly poor prognosis, however prospective and systematic measurement of (1) patients' and caregivers' PA and (2) evaluation of prognostic communication (PC) has not been attempted. METHODS: Cross-sectional study of fully-oriented (Glasgow Coma Scale 15/15) MG patients and a subset of caregivers. Participants underwent a semi-structured assessment of their awareness of incurability and life expectancy and evaluated PC with Likert-scale responses. Interviews were audio-recorded and consensus-scored by two independent raters. Patients underwent multi-domain neurocognitive testing and screening for anxiety and depression. RESULTS: 34 patients with 20 matched caregivers have participated. No patients withdrew consent or refused to discuss PA. Fifteen (44%) had zero or one recurrence of disease and 19(56%) were multiply-recurrent. Fourteen (41%) patients demonstrated full PA (awareness of incurability and estimated life expectancy). Of the 20 (59%) patients with limited or no PA, 10 (50%) had multiply-recurrent MG; 8 (40%) indicated that they desired more PC and 9(45%) rated the quality of PC as satisfactory, fair, or poor. Full PA was not associated with anxiety or depression as compared to limited/no awareness (36% versus 32% and 43% versus 42%, respectively). There was no significant difference in cognitive performance between those with full versus limited/no awareness. Fourteen (70%) of caregivers had full PA. CONCLUSIONS: Candid discussion of prognostic information is feasible in MG. A significant proportion of MG patients are unaware of their life expectancy, even in the setting of multiply-recurrent disease. Absence of awareness does not appear related to lower importance attributed to PC, or to worse cognitive function, as compared to full awareness. Full awareness is not associated with psychological distress. Further study of PA and associated outcomes in MG is necessary.

Radiation Dose to Ipsilateral Subventricular Zone as a Prognostic Factor in Malignant Glioma Patients

ranging from 18-30 Gy in 1-6 fractions (54% were 24 Gy x 1). All patients were evaluated and managed by a multidisciplinary spine team including a radiation oncologist, neurosurgeon, and interventional radiologist. Twentyseven percent of lesions were surgically resected prior to SBRT and 48% of lesions had radiographic epidural disease at time of SBRT. All sites of progression within the spinal axis were mapped according to number of vertebral levels away from the treated lesion. Kaplan-Meier method was used to capture actuarial rates, and R-squared statistics were used to assess correlation. Results: The median follow-up for the cohort was 14.4 months, with 82% of patients followed until death. At the time of last follow-up, 47% (nZ56) of patients had not progressed at any site in the spinal axis. Of the remaining 53% (nZ64), only 23% (nZ15) progressed at a single vertebral level, with 59% (nZ38) progressing at 3 sites within the spine simultaneously. The 1-year actuarial local failure-free survival (LFFS), adjacent segment failure-free survival (ASFFS), and distant segment failure-free survival rates were 87%, 85%, and 66%, respectively. However, 75% of local failures and 90% of adjacent segment failures occurred in conjunction with distant spine failures. The 1-year actuarial rate for isolated LFFS and isolated ASFFS were 96% and 98%, respectively. The patterns of failure by distance from the treated lesion were 8.4% crude failure at the index lesion and 10.8%, 11.6%, 10.3%, and 6.8% for lesions 1, 2, 3, and 4 segments away. Linear regression analysis revealed a relationship of decreasing risk of failure with increasing distance from the treated index lesion (R Z 0.87), and 52% occurred 5 segments away. Conclusion: We report the first detailed spinal axis patterns of failure analysis for patients undergoing SBRT for metastatic osseous spine disease. We demonstrate that local control is excellent, and importantly, isolated local and adjacent segment failures are 5 vertebral levels away from the index lesion. Thus, total spine imaging in close interval is requisite for surveillance post-treatment. Author Disclosure: J.E. Leeman: None. M. Bilsky: None. I. Laufer: None. M.R. Folkert: None. N.K. Taunk: None. J.R. Osborne: None. J. Zatcky: None. K.M. Alektiar: None. Y. Yamada: Consultant; Varian Medical. D.E. Spratt: None.

QOL-25EVALUATION OF THE UTILITY OF THE EQ-5D AND MDASI-BT IN PRIMARY BRAIN TUMOR PATIENTS

BACKGROUND: Patients with malignant glioma are highly symptomatic and often have functional limitations beginning from the time of diagnosis. The utility of measuring general health status may have value in determining impact of disease. This study provided a description of health status and utility scores in glioma patients throughout the illness trajectory using the EQ-5D. Furthermore, it evaluated the additive information provided by MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT) in describing health-related quality of life as assessed by the EQ-5D. METHODS: Malignant glioma patients completed the EQ-5D and MDASI-BT self-reports. The MDASI-BT is a measure of symptom burden and interference whereas the EQ-5D is a functional measure of general health status. Linear regression evaluated whether MDASI-BT scores adequately predict patient health outcomes measured by the EQ-5D. RESULTS: The sample included 100 patients [65% male, 75% with a GBM, median age 52 (range 20-75), 56% in active treatment]. Thirty percent of patients reported no problems on any of the 5 areas measured by the EQ-5D. The remaining 70% reported some/moderate problems in at least 1 area. The most extreme cases reported inability to perform usual activities (8%) and significant anxiety/depression (5%). The MDASI-BT neurologic factor score and the WAW (Walking/Activity/Work) interference score explained 52% of the variability in the EQ-5D in this patient population while adjusting for the effect of tumor grade, recurrence status, and Karnofsky Performance Status (KPS). Residual diagnostics confirmed the adequacy of model fit. CONCLUSIONS: The majority of brain tumor patients reported at least one functional limitation on the EQ-5D. Over half of the variance in the EQ-5D was explained by the MDASI-BT, KPS, tumor grade, and recurrence status underscoring the benefit of using this information for planning patient care. The resultant model demonstrates the significant contribution symptom burden has on determining health status in this patient population.

A Simple Kinetic Model Provides an Early Prediction of Thrombocytopenia in Malignant Glioma Patients Treated With Radiation and Temozolomide

A Simple Kinetic Model Provides an Early Prediction of Thrombocytopenia in Malignant Glioma Patients Treated With Radiation and Temozolomide

Evaluation of serial changes on computed tomography and magnetic resonance imaging after implantation of carmustine wafers in patients with malignant gliomas for differential diagnosis of tumor recurrence.

Carmustine wafers are approved for localized treatment of malignant glioma. In this study, overall changes in computed tomography (CT) and magnetic resonance (MR) images of malignant glioma patients treated with carmustine wafer implantation were evaluated. The subjects were 25 patients undergoing craniotomy for malignant glioma resection and carmustine wafer implantation. Changes in the appearance of wafers, the resection cavity, and the adjacent parenchyma on CT and MR imaging were evaluated retrospectively. On CT, the wafers changed from an initially high-dense to an iso-dense appearance. All MR studies showed a low-intense wafer within 2 days. The wafers changed to a high- or iso-intense appearance on fluid attenuated inversion recovery and T1-weighted imaging, whereas they changed to an iso- to low-intense appearance on T2-weighted imaging. Gas in the cavity increased gradually after surgery, achieved a peak at 1 week postoperatively, and then disappeared in 1-3 months. Increased volume of the resection cavity was observed in 48% of patients. Regarding changes in the adjacent parenchyma, obvious contrast enhancement at the wall of the resection cavity was seen in 91% of cases at 1 month, but this disappeared gradually. Edema around the resection cavity was increased in 7 patients (28%), of whom only two experienced symptoms due to edema. We conclude that these radiological changes after carmustine wafer implantation should be carefully followed up, because these changes can easily be mistaken for infectious disease or recurrent tumors.

Abstract 5310: Prognostic and predictive biomarkers of clinical response to Bevacizumab in recurrent WHO grade 3 malignant glioma patients

Abstract Background: Bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor A (VEGF-A), has proven activity in treatment of recurrent high-grade glioma. High response rates have been demonstrated, but particularly in WHO grade 3 malignant gliomas, efforts to identify predictors of clinical response have been limited. Predictive biomarkers and prognostic models are required in order to individualize treatment for this patient population. The primary end-point of this study was identification of prognostic and potentially predictive clinical and paraclinical factors of response. The secondary end-point was to identify prognostic factors associated with progression-free survival (PFS) and overall survival (OS). Materials and methods: A total of 64 recurrent grade 3 glioma patients treated with bevacizumab and irinotecan were retrospectively evaluated. Eligible patients from our center had a WHO performance status of 0-2 and were administered bevacizumab and irinotecan between December 2005 and November 2014 according to a previously published clinical protocol. The possibly relevant prognostic baseline factors screened for included: Age, gender, WHO grade 3 diagnosis, tumor size and location, multifocal disease, extent of resection, number of prior chemotherapy regiments, response to prior chemotherapy, first-line treatment, number of previous recurrences, neurological deficit, corticosteroid use, performance status, necrosis, vascular proliferation, neutrophil-to-lymphocyte ratio, and expression of p53, EGFR, Mib-1, MGMT, IDH-1 and ATRX. Candidate factors were subjected to univariate analysis and factors with P-values below 0.10 were considered for multivariate analysis. Prognostic models were generated by logistic regression and Cox regression, modeling response and survival end-points. P-values below 0.05 were considered statistically significant. Results will be presented. Citation Format: Anders Toft, Thomas Urup, Kirsten Grunnet, Ib J. Christensen, Signe R. Michaelsen, Helle Broholm, Vibeke A. Larsen, Michael Kosteljanetz, Ulrik Lassen, Hans S. Poulsen. Prognostic and predictive biomarkers of clinical response to Bevacizumab in recurrent WHO grade 3 malignant glioma patients. [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 5310. doi:10.1158/1538-7445.AM2015-5310

Abstract 5448: In vitro drug response (IVDR), biomarkers (BM) and clinical outcome (CO) in malignant glioma (GM) patients

Abstract Assessment of the tumor-associated (TA) response factors may serve to guide targeted salvage therapy. This is a retrospective correlative analysis of in vitro test results with clinical outcome of anonymized patients with MG. In a centralized testing facility, IVDR to at least ten chemotherapeutic drugs (Chemo) and immunohistochemistry (IHC)-derived TA BMs (including Ki67, p53, EGFR, MGMT, GSTpi, and MDR-1) were assessed in viable tumor resections from 65 previously treated (PT) and untreated (UT) patients with progressive and recurrent MGs (10 astrocytomas [A], 36 glioblastoma multiforme [GBM], and 19 gliomas of various histology), and correlated results with CO (response [RES] and time to progression [TTP]). IVDR results were generated by exposing aliquots of tumor cell suspensions to single agent Chemo at physiologic doses for 5-days, and determining the percentage of cell growth inhibition (PCI) via tritium uptake. Chemo included Camptothecin (SN-38 is active species), Carmustine (BCNU), platinum analogs Carboplatin (CARBO) and cisplatin (CP), Temozolomide (TEMO) and Dacarbazine (DTIC). For each drug tested, tumor responses were categorized into either extreme drug resistance (EDR) or Intermediate plus Low Drug Resistance [IDR/LDR]. Standard IHC tests on paraffin-embedded tumor tissue sections yielded BM expression from which frequency rates were determined. Patients’ resections and treatments were performed at a single medical center between 1994 and 1998; and included surgery alone or combined with irradiation (XRT) and single-agent or combination Chemo. Biopsies were obtained from recurrent patients prior to second-line therapy. The median time between treatment and TTP or recurrence was 10 months. For each drug, IVDR profiles were comparatively similar, with the exception of tumors from PT patients which were significantly more resistant to CARBO (N = 20; 2-tailed t test, p = 0.0433) and CPLAT (N = 22; p = 0.0076). Frequencies of BM expression between PT (N = 29) and UT patients (N = 54) were similar among tumor types, except for GBMs from patients who progressed following treatment. Their tumors generally overexpressed EGFR (1.8-fold) and MGMT (2.4-fold). Patients’ overall RES rate was 24%, while rates for A (33%), GBMs (6%) and other gliomas (58%) differed significantly (Fisher exact test, p = 0.0104). Most patients (81%) exhibited PD following therapy, and had relatively similar EDR vs. IDR/LDR response profiles for median TTP (10 months vs. 10 months), and median survival. For TEMO, CPT-11, and BCNU - common drugs used against MGs, there were no significant differences in median TTP, median survival, or overall survival (Log-rank, p<0.05, p = 0.1301 and p = 0.6123, respectively). Results suggest that a detailed assessment of molecular mechanisms related to IVDR and TA BMs may be required to identify (non)response factors that facilitate stratifying patient treatment leading to improved CO. Citation Format: Ricardo J. Parker, Michael Myers, Patric Schiltz. In vitro drug response (IVDR), biomarkers (BM) and clinical outcome (CO) in malignant glioma (GM) patients. [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 5448. doi:10.1158/1538-7445.AM2015-5448

A multicenter randomized controlled study of temozolomide in 97 patients with malignant brain glioma

To investigate the efficacy and safety of temozolomide (TMZ) and lomustine (CCNU) in malignant brain gliomas. In this multicenter, randomized, double-blind, positive-controlled study, patients with malignant glioma of a histological grade III/IV were randomly divided into two groups. In experiment group, TMZ capsule 150 mg/m2 was given orally on days 1 through 5 and CCNU placebo 130 mg/m2 while on day 1. In control group, CCNU capsule 130 mg/m2 was taken orally on day 1 and TMZ placebo 150 mg/m2 while on days 1 through 5. In both groups drugs were given on the first 5 days of 28 day therapeutic course. Every patient was administered at least 3 cycles continuously. 97 patients were enrolled in the clinical trial, 86 cases of which were evaluable for efficacy. The basic conditions of patients in both groups were comparable. After 12 weeks, the response rates in TMZ and CCNU group were 35.71% and 9.09% (P < 0.01) respectively, and the clinical benefit rates in TMZ and CCNU group were 90.48% and 75.00% (P < 0.05) respectively. No obvious improvement was showed in quality of life and neural symptoms in both groups. The common side effects of TMZ were nausea and vomiting with grade I/II. TMZ capsule can produce higher efficacy than CCNU in the treatment for refractory malignant brain glioma patients with an acceptable safety profile , indicating that TMZ could be an ideal chemotherapy selection for malignant brain glioma.

MB-06 * PROGNOSTIC IMPACT OF O6-METHYLGUANINE-DNA METHYLTRANSFERASE (MGMT) PROMOTER METHYLATION IN MEDULLOBLASTOMA

BACKGROUND: O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that plays an important role in tumor resistance to alkylating agents. Recent study revealed that MGMT promoter methylation is associated with favorable outcomes in malignant glioma patients. However, MGMT status in pediatric medulloblastoma and the prognostic impact of this methylation status and clinical outcomes of this tumor has not been fully evaluated. The objective of this study is to investigate the association between MGMT methylation status and clinical outcomes for medulloblastoma patients. MATERIALS AND METHODS: Patients with medulloblastoma treated at our institution between 1995 and 2012 were reviewed retrospectively. Tumor tissues were obtained from formalin-fixed paraffin-embedded tumor samples. Methylation statuses of 18 CpG sites of MGMT promoter region were determined by bisulfite sequencing analysis. RESULTS: Tumor material and clinical information were available for 22 patients. Median follow-up period was 48 months (13-190 months). Median age at diagnosis was 8.5 years (1-23 years). After the first line treatment, 10 had been in complete remission, 8 had relapse of disease, 1 had progressive disease, 1 had stable disease and 2 were lost follow-up. The patients in complete remission had higher accumulation of methylated CpG sites (median 5, range 2-9) than the relapsed patients (median 2, range 1-4) (p = 0.036). CONCLUSION: The results indicated that MGMT promoter methylation correlates with favorable outcome of medulloblastoma.