MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma
Monika E. Hegi, Ph.D., Annie-Claire Diserens, M.Sc., Thierry Gorlia, M.Sc., Marie-France Hamou, Nicolas de Tribolet, M.D., Michael Weller, M.D., Johan M. Kros, M.D., Johannes A. Hainfellner, M.D., Warren Mason, M.D., Luigi Mariani, M.D., Jacoline E.C. Bromberg, M.D., Peter Hau, M.D., René O. Mirimanoff, M.D., J. Gregory Cairncross, M.D., Robert C. Janzer, M.D., and Roger Stupp, M.D.
Background Epigenetic silencing of the MGMT (O6-methylguanine–DNAmethyltransferase) DNA-repair gene by promoter methylation compromisesDNA repair and has been associated with longer survival in patientswith glioblastoma who receive alkylating agents.
Methods We tested the relationship between MGMT silencing inthe tumor and the survival of patients who were enrolled ina randomized trial comparing radiotherapy alone with radiotherapycombined with concomitant and adjuvant treatment with temozolomide.The methylation status of the MGMT promoter was determined bymethylation-specific polymerase-chain-reaction analysis.
Results The MGMT promoter was methylated in 45 percent of 206assessable cases. Irrespective of treatment, MGMT promoter methylationwas an independent favorable prognostic factor (P<0.001 bythe log-rank test; hazard ratio, 0.45; 95 percent confidenceinterval, 0.32 to 0.61). Among patients whose tumor containeda methylated MGMT promoter, a survival benefit was observedin patients treated with temozolomide and radiotherapy; theirmedian survival was 21.7 months (95 percent confidence interval,17.4 to 30.4), as compared with 15.3 months (95 percent confidenceinterval, 13.0 to 20.9) among those who were assigned to onlyradiotherapy (P=0.007 by the log-rank test). In the absenceof methylation of the MGMT promoter, there was a smaller andstatistically insignificant difference in survival between thetreatment groups.
Conclusions Patients with glioblastoma containing a methylatedMGMT promoter benefited from temozolomide, whereas those whodid not have a methylated MGMT promoter did not have such abenefit.
Epigenetic silencing of the MGMT (O6-methylguanine–DNAmethyltransferase) gene by promoter methylation has been associatedwith longer overall survival in patients with glioblastoma who,in addition to radiotherapy, received alkylating chemotherapywith carmustine or temozolomide.1,2 The MGMT gene is locatedon chromosome 10q26 and encodes a DNA-repair protein that removesalkyl groups from the O6 position of guanine, an important siteof DNA alkylation. The restoration of the DNA consumes the MGMTprotein, which the cell must replenish. Left unrepaired, chemotherapy-inducedlesions, especially O6-methylguanine, trigger cytotoxicity andapoptosis.3,4 High levels of MGMT activity in cancer cells createa resistant phenotype by blunting the therapeutic effect ofalkylating agents and may be an important determinant of treatmentfailure.5,6,7,8,9,10 Epigenetic silencing of the MGMT gene bypromoter methylation is associated with loss of MGMT expression11,12,13and diminished DNA-repair activity. In the course of tumor development,gene silencing by DNA methylation is an early and importantmechanism by which tumor-suppressor genes are inactivated.14,15
In a phase 2 evaluation of combined radiotherapy and temozolomidefor newly diagnosed glioblastoma, we found that methylationof the MGMT promoter in the tumor was associated with longersurvival.2 In the current study, we investigated whether MGMTpromoter methylation in glioblastoma is associated with a benefitfrom temozolomide treatment. We determined the MGMT promotermethylation status in tumor tissues from patients who were enrolledin a randomized trial that showed a survival advantage amongpatients treated with temozolomide and radiotherapy as comparedwith radiotherapy alone.16
Methods
Patients and Treatment
Patients were enrolled in a randomized trial of chemoradiotherapy(temozolomide plus radiotherapy) versus radiotherapy alone (carriedout by the European Organisation for Research and Treatmentof Cancer and the National Cancer Institute of Canada [NCIC])(EORTC trial 26981/22981 and NCIC trial CE.3).16 Patients inthe experimental group received the alkylating agent temozolomide(Temodal or Temodar, Schering-Plough) at a dose of 75 mg persquare meter of body-surface area daily during standard fractionatedradiotherapy (60 Gy) for 6 to 7 weeks and at a dose of 150 to200 mg per square meter per day for 5 days of every 28-day cycleafter radiotherapy, for up to six cycles. In the case of tumorprogression, salvage or second-line therapy was administeredat the investigators' discretion; most patients received additionalchemotherapy. All patients provided written informed consentfor molecular studies of their tumor, and the protocol was approvedby the ethics committee at each center.
DNA Extraction and Methylation-Specific Polymerase Chain Reaction
Genomic DNA was isolated from one or two paraffin sections ofglioblastoma tissue (Ex-Wax DNA Extraction Kit S4530, Chemicon)(proteinase digestion lasted a maximum of six hours). DNA wasdenatured with sodium hydroxide in a volume of 35 µl andsubjected to bisulfite treatment in a volume of 360 µl(4.4 M sodium bisulfite and 20 mM hydroquinone) for five hoursat 55°C and then purified (Wizard DNA Clean-Up System A7280,Promega). Unmethylated cytosine, but not its methylated counterpart,is modified into uracil by the treatment. The methylation-specificpolymerase chain reaction (PCR) was performed in a two-stepapproach.17 The results were confirmed in an independent experiment,starting with reisolation of DNA from the tumor. The PCR productswere separated on 4 percent agarose gels. The investigatorswho selected and analyzed the glioblastoma samples were blindedto all clinical information.
Statistical Analysis
Overall and progression-free survival curves were estimatedby the Kaplan–Meier technique and compared with use ofthe two-sided log-rank test. All treatment comparisons are presentedon an intention-to-treat basis according to the randomized assignment.The Cox proportional-hazards model was fitted to assess theprognostic and predictive values of the methylation status ofthe MGMT promoter, the protocol treatment, and potential prognosticfactors18 that were found to be statistically significant inthis population on the basis of univariate testing.
Organization of the Study
This project was initiated and carried out without the involvementof a commercial sponsor. Dr. Hegi designed and supervised thetranslational study and wrote the manuscript, with input fromthe coauthors. Methylation-specific PCR was performed by Ms.Diserens. The statistical analysis was performed by Mr. Gorlia.The clinical trial was designed and directed by Dr. Stupp, incollaboration with the EORTC and the NCIC Clinical Trials Group.
Results
Methylation-specific PCR was performed on 307 of 573 glioblastomaspecimens (53.6 percent) from patients enrolled at 66 of 85participating centers (Figure 1); adequate paraffin-embeddedtumor tissue was not available from 266 patients. MGMT methylationstatus could be determined for 206 of the 307 tumors (67.1 percent),or 36.0 percent of the tumors from the overall study population.The success rate of methylation-specific PCR on paraffin-embeddedtumor samples was highly variable and center-dependent. Forcenters with four or more testable samples, the median successrate was 75.0 percent (range, 0 to 100 percent). Treatment assignmentsamong the 307 patients with evaluable tumor specimens was equallydistributed, with 152 patients (49.5 percent) randomly assignedto radiotherapy alone and 155 (50.5 percent) randomly assignedto temozolomide and radiotherapy.
Figure 1. Methylation Status of the MGMT Promoter in Glioblastoma Biopsy Specimens, as Determined by a Nested Methylation-Specific PCR Assay.
DNA from normal peripheral blood lymphocytes (PBL) was used as a control for the unmethylated MGMT promoter (U), enzymatically methylated DNA from PBL (MPBL) served as a positive control for the methylated MGMT promoter (M), and water was used as a negative control for the PCR. A 100-bp marker ladder was loaded to estimate molecular size, as shown on the left scale; the sizes of PCR products are indicated on the right scale. Glioblastoma numbers 549 and 527 contain a methylated promoter, whereas 555, 569, and 529 harbor only an unmethylated promoter. The nested PCR approach renders the analysis highly sensitive, while allowing it to retain the specificity that results in the detection of unmethylated MGMT promoter in all specimens that may also contain DNA derived from infiltrating lymphocytes, blood vessels, or contaminating normal tissue.
The subgroup of 206 patients in whom MGMT promoter methylationstatus could be determined was representative of the overalltreatment population with respect to known prognostic factorsand outcomes. However, the proportion of patients who had onlya diagnostic biopsy specimen (and no debulking surgery) wassmaller in the subgroup tested for MGMT promoter methylationthan in the subgroup of patients in whom methylation statuscould not be determined (3.4 percent vs. 23.0 percent). Overallsurvival did not vary significantly according to whether ornot the test was attempted (P=0.27 by the log-rank test) orwhether or not the results were interpretable (P=0.23 by thelog-rank test) (Figure 1 of the Supplementary Appendix, availablewith the full text of this article at www.nejm.org). Of the206 evaluated tumors, 92 (44.7 percent) had detectable MGMTpromoter methylation, whereas 114 (55.3 percent) did not. Theproportion of methylated tumors was similar in the two treatmentgroups (Table 1).
Table 1. Effect of MGMT Promoter Methylation Status on Survival, According to Random Treatment Assignment.
For the entire population of 206 patients for whom MGMT statuscould be evaluated, there was a significant difference, irrespectiveof treatment assignment, in overall survival between patientswhose tumors had MGMT promoter methylation and those whose tumorsdid not (P<0.001 by the log-rank test) (Figure 2). The hazardratio for death was 0.45 (95 percent confidence interval, 0.32to 0.61) among those with MGMT promoter methylation, a resultthat corresponds to a 55 percent decrease in the risk of deathin this subgroup. The median overall survival among patientswith methylation was 18.2 months (95 percent confidence interval,15.5 to 22.0), as compared with 12.2 months (95 percent confidenceinterval, 11.4 to 13.5) among those without methylation.
Figure 2. Kaplan–Meier Estimates of Overall Survival, According to MGMT Promoter Methylation Status.
The difference in survival between patients with a methylated MGMT promoter (92 patients, 65 of whom died) and those with an unmethylated MGMT promoter (114 patients, 105 of whom died) was highly significant (P<0.001 by the log-rank test), indicating that the MGMT methylation status has prognostic value. In the group of patients with a methylated MGMT promoter, there was a risk reduction of 55 percent (hazard ratio for death, 0.45; 95 percent confidence interval, 0.32 to 0.61), as compared with the group with an unmethylated MGMT promoter.
When both treatment assignment and MGMT promoter methylationstatus were considered, the longest median overall survival,21.7 months, was observed among patients with promoter methylationwho were assigned to receive both temozolomide and radiotherapy(Table 1). Their two-year survival rate was 46.0 percent, ascompared with 22.7 percent among those with MGMT promoter methylationwho were assigned to radiotherapy alone. Kaplan–Meierestimates of overall survival in these two subgroups were significantlydifferent (P=0.007 by the log-rank test) (Figure 3A).
Figure 3. Kaplan–Meier Estimates of Overall and Progression-free Survival, According to MGMT Promoter Methylation Status and Random Assignment to Temozolomide plus Radiotherapy or Radiotherapy Alone.
The Kaplan–Meier estimates for overall survival indicate that the group of patients with a methylated MGMT promoter who were randomly assigned to temozolomide and radiotherapy (46 patients, 40 of whom had progression and 27 of whom died) had a 49 percent risk reduction (hazard ratio for death, 0.51; 95 percent confidence interval, 0.31 to 0.84), as compared with the group with a methylated MGMT promoter who were randomly assigned to radiotherapy only (46 patients, 45 of whom had progression and 38 of whom died) (Panel A). An unmethylated MGMT promoter and random assignment to temozolomide and radiotherapy (60 patients, 53 of whom had progression and 52 of whom died) yielded a risk reduction of 31 percent (hazard ratio for death, 0.69; 95 percent confidence interval, 0.47 to 1.02), as compared with an unmethylated MGMT promoter and random assignment to radiotherapy only (54 patients, all of whom had progression and 53 of whom died). In order to display a possible effect of salvage treatment on overall survival, in particular in the group of patients with a methylated MGMT promoter who were randomly assigned to radiotherapy alone. Kaplan–Meier curves are also shown for progression-free survival (Panel B) in a similar manner.
By contrast, among patients whose tumors were not methylatedat the MGMT promoter, the difference in overall survival favoringthe temozolomide-plus-radiotherapy group was only marginallysignificant (P=0.06 by the log-rank test) (Figure 3A); the mediansurvival was 12.7 months among those assigned to temozolomideand radiotherapy and 11.8 months among those assigned to radiotherapy,with 2-year survival rates of 13.8 percent and less than 2 percent,respectively (Table 1). The interaction between the magnitudeof the treatment effect and MGMT promoter methylation statuswith respect to overall survival was not statistically significant,according to the Cox proportional-hazards model (P=0.29) (Table 2).However, this result was not unexpected, since neither theclinical trial nor this study was powered to test the interaction.
Table 2. Results of Analyses with the Cox Proportional-Hazards Models.
In addition, a probable confounding factor in the analysis ofoverall survival was the administration of temozolomide or otheralkylating chemotherapy as salvage or second-line treatmentafter disease progression. More than 70 percent of the patientsin the radiotherapy group received salvage chemotherapy; 59.7percent received temozolomide. In the temozolomide-plus-radiotherapygroup, 57.8 percent received second-line chemotherapy; 24.6percent were retreated with temozolomide. We therefore analyzedprogression-free survival relative to MGMT promoter methylationstatus and treatment assignment (Figure 3B and Table 1).
In the group of patients whose tumors contained a methylatedMGMT promoter, those who received temozolomide and radiotherapyhad a median progression-free survival of 10.3 months, as comparedwith 5.9 months for patients who received radiotherapy alone(P=0.001). Among the patients whose tumors contained an unmethylatedMGMT promoter, those who received temozolomide and radiotherapyhad a median progression-free survival of 5.3 months, as comparedwith 4.4 months for patients who were treated with radiotherapyalone (P=0.02) (Figure 3B). The relatively long overall survivaldespite the short progression-free survival among patients witha methylated MGMT promoter who were assigned to receive onlyradiotherapy indicates that salvage therapy at the time of recurrencehas some efficacy in this subpopulation.
To analyze further the influence of the methylation status ofthe MGMT promoter, we performed a multivariate analysis withthe use of the Cox proportional-hazards model, stratified accordingto treatment group and including known clinical prognostic factors(Table 2). The methylation status of the MGMT promoter (P<0.001)and the score on the Mini–Mental State Examination (P=0.007)emerged as significant independent prognostic factors. The adjustedhazard ratio of 0.41 (95 percent confidence interval, 0.29 to0.57) for MGMT promoter methylation was consistent with theunadjusted hazard ratio of 0.45 (95 percent confidence interval,0.32 to 0.61).
Discussion
We found that MGMT promoter methylation is associated with afavorable outcome after temozolomide chemotherapy in patientswith newly diagnosed glioblastoma. Our data suggest that themethylation status of the MGMT promoter may have prognosticvalue and, in addition, may be a clinically relevant predictorof benefit from temozolomide chemotherapy. Despite the survivalbenefit associated with temozolomide among patients with a methylatedMGMT promoter, the overall survival curves for temozolomideand radiotherapy and for radiotherapy alone remain similar forthe first nine months of follow-up. This suggests that MGMTmethylation, though important, is not the sole factor determiningoutcome. Lack of mismatch-repair has also been shown to rendertumors resistant to alkylating agents, even in the absence ofMGMT.4 Additional mechanisms and predictive factors are likelyto be relevant and need to be identified.
Diagnostic MGMT testing requires sufficient and optimally preservedtumor tissue. The best results with methylation-specific PCRare obtained with cryopreserved tumor specimens, thus avoidingfixation-related deterioration of the quality of tumor DNA.Other methods, such as immunohistochemistry or activity testing,may not be reliable, since MGMT expression is prone to inductionby glucocorticoids, ionizing radiation, and genotoxic agents19,20when the MGMT promoter is not methylated.
Determination of MGMT promoter methylation status by methylation-specificPCR may allow the selection of patients most likely to benefitfrom temozolomide treatment; patients whose tumors are not methylatedat the MGMT promoter appear to derive little or no benefit fromthe addition of temozolomide to radiotherapy. For these patients,alternative treatments with a different mechanism of actionor methods of inhibiting MGMT should be developed.21,22 Ourfindings may be applicable to other solid tumors commonly treatedwith alkylating agents, such as melanoma, but possibly alsoto lung and breast cancer and lymphoma. Stratification accordingto MGMT promoter methylation status may be considered in futuretrials in which temozolomide or other alkylating agents areused.
Supported by grants from the Swiss Institute of Applied CancerResearch, the Nélia and Amadeo Barletta Foundation, andthe EORTC Translational Research Fund 2002 (to Drs. Hegi andStupp); by Award 2002 from the Jacqueline Seroussi MemorialFoundation for Cancer Research (to Dr. Hegi); by a grant (3100-64050.00/1,to Dr. Hegi) from the Swiss National Science Foundation; andby a grant (1123/1124-2-2001, to Dr. Hegi) from OncoSuisse.
Drs. Hegi, Mason, Mariani, Cairncross, Mirimanoff, and Stuppreport having received consulting and lecture fees from Schering-Plough.Drs. Hegi and Stupp report having received consulting fees fromOncoMethylome Sciences, and Dr. Stupp (consulting fees fromEMD Pharmaceuticals).
We are indebted to all the patients and their families for havingagreed to participate in this trial and to donate tumor biopsyspecimens for translational research; to Solange Gros for technicalassistance; to Denis Lacombe, Anouk Allgeier, and Linda de Prijck(of the EORTC Data Center) and Elizabeth Eisenhauer and MarinaDjurfield (of the NCIC Clinical Trials Group office); and toall investigators at the clinical centers who participated inthe trial and who made the paraffin-embedded material availablefor this translational research effort.
Source Information
From the Laboratory of Tumor Biology and Genetics, Department of Neurosurgery (M.E.H., A.-C.D., M.-F.H., N.T.), the Departments of Radiotherapy (R.O.M.) and Neuropathology (R.C.J.), and the Multidisciplinary Oncology Center (R.S.), University Hospital Lausanne, Lausanne; the Department of Neurosurgery, University Hospital Geneva, Geneva (N.T.); the National Center of Competence in Research Molecular Oncology, Swiss Institute for Experimental Cancer Research, Epalinges (M.E.H.); and the Department of Neurosurgery, Inselspital, Bern (L.M.) — all in Switzerland; the Data Center, European Organisation for Research and Treatment of Cancer, Brussels (T.G.); the Department of Neurology, University of Tübingen, Tübingen (M.W.), and the Department of Neurology, University of Regensburg, Regensburg (P.H.) — both in Germany; the Division of Neuropathology, University Hospital Rotterdam, Rotterdam (J.M.K.), and University Medical Center, Utrecht (J.E.C.B.) — both in the Netherlands; the Institute of Neurology, Medical University of Vienna, Vienna, (J.A.H.); and Princess Margaret Hospital, Toronto (W.M.), and the University of Calgary, Calgary, Alta. (J.G.C.) — both in Canada.
Address reprint requests to Dr. Hegi at the Laboratory of Tumor Biology and Genetics, Department of Neurosurgery, University Hospital (CHUV), BH19-110, 1011 Lausanne, Switzerland, or at monika.hegi{at}chuv.hospvd.ch.
References
Esteller M, Garcia-Foncillas J, Andion E, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 2000;343:1350-1354. [Erratum, N Engl J Med 2000;343:1740.] [Free Full Text]
Hegi ME, Diserens A-C, Godard S, et al. Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res 2004;10:1871-1874. [Free Full Text]
Ochs K, Kaina B. Apoptosis induced by DNA damage O6-methylguanine is Bcl-2 and caspase-9/3 regulated and Fas/caspase-8 independent. Cancer Res 2000;60:5815-5824. [Free Full Text]
Liu L, Markowitz S, Gerson SL. Mismatch repair mutations override alkyltransferase in conferring resistance to temozolomide but not to 1,3-bis(2-chloro-ethyl)nitrosourea. Cancer Res 1996;56:5375-5379. [Free Full Text]
Hotta T, Saito Y, Fujita H, et al. O6-alkylguanine-DNA alkyltransferase activity of human malignant glioma and its clinical implications. J Neurooncol 1994;21:135-140. [CrossRef][Medline]
Belanich M, Pastor M, Randall T, et al. Retrospective study of the correlation between the DNA repair protein alkyltransferase and survival of brain tumor patients treated with carmustine. Cancer Res 1996;56:783-788. [Free Full Text]
Jaeckle KA, Eyre HJ, Townsend JJ, et al. Correlation of tumor O6 methylguanine-DNA methyltransferase levels with survival of malignant astrocytoma patients treated with bis-chloroethylnitrosourea: a Southwest Oncology Group study. J Clin Oncol 1998;16:3310-3315. [Abstract]
Friedman HS, McLendon RE, Kerby T, et al. DNA mismatch repair and O6-alkylguanine-DNA alkyltransferase analysis and response to Temodal in newly diagnosed malignant glioma. J Clin Oncol 1998;16:3851-3857. [Free Full Text]
Silber JR, Blank A, Bobola MS, Ghatan S, Kolstoe DD, Berger MS. O6-methylguanine-DNA methyltransferase-deficient phenotype in human gliomas: frequency and time to tumor progression after alkylating agent-based chemotherapy. Clin Cancer Res 1999;5:807-814. [Free Full Text]
Qian XC, Brent TP. Methylation hot spots in the 5' flanking region denote silencing of the O6-methylguanine-DNA methyltransferase gene. Cancer Res 1997;57:3672-3677. [Free Full Text]
Watts GS, Pieper RO, Costello JF, Peng YM, Dalton WS, Futscher BW. Methylation of discrete regions of the O6-methylguanine DNA methyltransferase (MGMT) CpG island is associated with heterochromatinization of the MGMT transcription start site and silencing of the gene. Mol Cell Biol 1997;17:5612-5619. [Abstract]
Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 1999;59:793-797. [Free Full Text]
Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 2003;349:2042-2054. [Free Full Text]
Komine C, Watanabe T, Katayama Y, Yoshino A, Yokoyama T, Fukushima T. Promoter hypermethylation of the DNA repair gene O6-methylguanine-DNA methyltransferase is an independent predictor of shortened progression free survival in patients with low-grade diffuse astrocytomas. Brain Pathol 2003;13:176-184. [Web of Science][Medline]
Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-996. [Free Full Text]
Palmisano WA, Divine KK, Saccomanno G, et al. Predicting lung cancer by detecting aberrant promoter methylation in sputum. Cancer Res 2000;60:5954-5958. [Free Full Text]
Gorlia T, Stupp R, Eisenhauer EA, et al. Clinical prognostic factors affecting survival in patients with newly diagnosed Glioblastoma Multiforme (GBM). J Clin Oncol 2004;22:Suppl:859s-859s. abstract.
Grombacher T, Mitra S, Kaina B. Induction of the alkyltransferase (MGMT) gene by DNA damaging agents and the glucocorticoid dexamethasone and comparison with the response of base excision repair genes. Carcinogenesis 1996;17:2329-2336. [Free Full Text]
Fritz G, Tano K, Mitra S, Kaina B. Inducibility of the DNA repair gene encoding O6-methylguanine-DNA methyltransferase in mammalian cells by DNA-damaging treatments. Mol Cell Biol 1991;11:4660-4668. [Free Full Text]
Friedman HS, Pluda J, Quinn JA, et al. Phase I trial of carmustine plus O6-benzylguanine for patients with recurrent or progressive malignant glioma. J Clin Oncol 2000;18:3522-3528. [Free Full Text]
Quinn JA, Weingart J, Brem H, et al. Phase I trial of temozolomide plus O6-benzylguanine in the treatment of patients with recurrent or progressive cerebral anaplastic gliomas. Prog Proc Am Soc Clin Oncol 2003;22:103. abstract.
Treatment of Brain Tumors
Paulino A. C., Teh B. S., Sadeh M., Seiter K., Ashby L., LaRocca R., Ryken T., Aiken R. D., Rutkowski S., Ottensmeier H., Pietsch T., Stupp R., Hegi M. E., DeAngelis L. M.
Extract |
Full Text |
PDF
N Engl J Med 2005;
352:2350-2353, Jun 2, 2005.
Correspondence
This article has been cited by other articles:
Gerstner, E. R., Yip, S., Wang, D. L., Louis, D. N., Iafrate, A. J., Batchelor, T. T.
(2009). MGMT METHYLATION IS A PROGNOSTIC BIOMARKER IN ELDERLY PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA. Neurology
73: 1509-1510
[Full Text]
Fangusaro, J.
(2009). Pediatric High-Grade Gliomas and Diffuse Intrinsic Pontine Gliomas. J Child Neurol
24: 1409-1417
[Abstract]
Felsberg, J., Rapp, M., Loeser, S., Fimmers, R., Stummer, W., Goeppert, M., Steiger, H.-J., Friedensdorf, B., Reifenberger, G., Sabel, M. C.
(2009). Prognostic Significance of Molecular Markers and Extent of Resection in Primary Glioblastoma Patients. Clin. Cancer Res.
15: 6683-6693
[Abstract][Full Text]
Colman, H., Zhang, L., Sulman, E. P., McDonald, J. M., Shooshtari, N. L., Rivera, A., Popoff, S., Nutt, C. L., Louis, D. N., Cairncross, J. G., Gilbert, M. R., Phillips, H. S., Mehta, M. P., Chakravarti, A., Pelloski, C. E., Bhat, K., Feuerstein, B. G., Jenkins, R. B., Aldape, K.
(2009). A multigene predictor of outcome in glioblastoma. Neuro Oncology
0: nop007v1-nop007
[Abstract][Full Text]
Spiegl-Kreinecker, S., Pirker, C., Filipits, M., Lotsch, D., Buchroithner, J., Pichler, J., Silye, R., Weis, S., Micksche, M., Fischer, J., Berger, W.
(2009). O6-Methylguanine DNA methyltransferase protein expression in tumor cells predicts outcome of temozolomide therapy in glioblastoma patients. Neuro Oncology
0: nop003v1-nop003
[Abstract][Full Text]
SHARMA, S., SALEHI, F., SCHEITHAUER, B. W., ROTONDO, F., SYRO, L. V., KOVACS, K.
(2009). Role of MGMT in Tumor Development, Progression, Diagnosis, Treatment and Prognosis. Anticancer Res
29: 3759-3768
[Abstract][Full Text]
ZUSTOVICH, F., LOMBARDI, G., DELLA PUPPA, A., ROTILIO, A., SCIENZA, R., PASTORELLI, D.
(2009). A Phase II Study of Cisplatin and Temozolomide in Heavily Pre-treated Patients with Temozolomide-refractory High-grade Malignant Glioma. Anticancer Res
29: 4275-4279
[Abstract][Full Text]
Ghulam Muhammad, A.K.M., Candolfi, M., King, G. D., Yagiz, K., Foulad, D., Mineharu, Y., Kroeger, K. M., Treuer, K. A., Nichols, W. S., Sanderson, N. S., Yang, J., Khayznikov, M., Van Rooijen, N., Lowenstein, P. R., Castro, M. G.
(2009). Antiglioma Immunological Memory in Response to Conditional Cytotoxic/Immune-Stimulatory Gene Therapy: Humoral and Cellular Immunity Lead to Tumor Regression. Clin. Cancer Res.
15: 6113-6127
[Abstract][Full Text]
Grossman, S. A., Ye, X., Chamberlain, M., Mikkelsen, T., Batchelor, T., Desideri, S., Piantadosi, S., Fisher, J., Fine, H. A.
(2009). Talampanel With Standard Radiation and Temozolomide in Patients With Newly Diagnosed Glioblastoma: A Multicenter Phase II Trial. JCO
27: 4155-4161
[Abstract][Full Text]
Hegi, M. E., Sciuscio, D., Murat, A., Levivier, M., Stupp, R.
(2009). Epigenetic Deregulation of DNA Repair and Its Potential for Therapy. Clin. Cancer Res.
15: 5026-5031
[Abstract][Full Text]
Clarke, J. L., Iwamoto, F. M., Sul, J., Panageas, K., Lassman, A. B., DeAngelis, L. M., Hormigo, A., Nolan, C. P., Gavrilovic, I., Karimi, S., Abrey, L. E.
(2009). Randomized Phase II Trial of Chemoradiotherapy Followed by Either Dose-Dense or Metronomic Temozolomide for Newly Diagnosed Glioblastoma. JCO
27: 3861-3867
[Abstract][Full Text]
Uccella, S, Cerutti, R, Placidi, C, Marchet, S, Carnevali, I, Bernasconi, B, Proserpio, I, Pinotti, G, Tibiletti, M G, Furlan, D, Capella, C
(2009). MGMT methylation in diffuse large B-cell lymphoma: validation of quantitative methylation-specific PCR and comparison with MGMT protein expression. J. Clin. Pathol.
62: 715-723
[Abstract][Full Text]
Kristensen, L. S., Hansen, L. L.
(2009). PCR-Based Methods for Detecting Single-Locus DNA Methylation Biomarkers in Cancer Diagnostics, Prognostics, and Response to Treatment. Clin. Chem.
55: 1471-1483
[Abstract][Full Text]
Dungey, F. A., Caldecott, K. W., Chalmers, A. J.
(2009). Enhanced radiosensitization of human glioma cells by combining inhibition of poly(ADP-ribose) polymerase with inhibition of heat shock protein 90. Molecular Cancer Therapeutics
8: 2243-2254
[Abstract][Full Text]
Yadav, A. K., Renfrow, J. J., Scholtens, D. M., Xie, H., Duran, G. E., Bredel, C., Vogel, H., Chandler, J. P., Chakravarti, A., Robe, P. A., Das, S., Scheck, A. C., Kessler, J. A., Soares, M. B., Sikic, B. I., Harsh, G. R., Bredel, M.
(2009). Monosomy of Chromosome 10 Associated With Dysregulation of Epidermal Growth Factor Signaling in Glioblastomas. JAMA
302: 276-289
[Abstract][Full Text]
Yip, S., Miao, J., Cahill, D. P., Iafrate, A. J., Aldape, K., Nutt, C. L., Louis, D. N.
(2009). MSH6 Mutations Arise in Glioblastomas during Temozolomide Therapy and Mediate Temozolomide Resistance. Clin. Cancer Res.
15: 4622-4629
[Abstract][Full Text]
MELLAI, M., CALDERA, V., ANNOVAZZI, L., CHIO, A., LANOTTE, M., CASSONI, P., FINOCCHIARO, G., SCHIFFER, D.
(2009). MGMT Promoter Hypermethylation in a Series of 104 Glioblastomas. Cancer Genomics Proteomics
6: 219-227
[Abstract][Full Text]
Frosina, G.
(2009). DNA Repair and Resistance of Gliomas to Chemotherapy and Radiotherapy. Mol Cancer Res
7: 989-999
[Abstract][Full Text]
Sepulveda, A. R., Jones, D., Ogino, S., Samowitz, W., Gulley, M. L., Edwards, R., Levenson, V., Pratt, V. M., Yang, B., Nafa, K., Yan, L., Vitazka, P.
(2009). CpG Methylation Analysis--Current Status of Clinical Assays and Potential Applications in Molecular Diagnostics: A Report of the Association for Molecular Pathology. J. Mol. Diagn.
11: 266-278
[Abstract][Full Text]
FABI, A., RUSSILLO, M., METRO, G., VIDIRI, A., DI GIOVANNI, S., COGNETTI, F.
(2009). Pseudoprogression and MGMT Status in Glioblastoma Patients: Implications in Clinical Practice. Anticancer Res
29: 2607-2610
[Abstract][Full Text]
Candolfi, M., Yagiz, K., Foulad, D., Alzadeh, G. E., Tesarfreund, M., Muhammad, A.K.M. G., Puntel, M., Kroeger, K. M., Liu, C., Lee, S., Curtin, J. F., King, G. D., Lerner, J., Sato, K., Mineharu, Y., Xiong, W., Lowenstein, P. R., Castro, M. G.
(2009). Release of HMGB1 in Response to Proapoptotic Glioma Killing Strategies: Efficacy and Neurotoxicity. Clin. Cancer Res.
15: 4401-4414
[Abstract][Full Text]
McCabe, M. T., Brandes, J. C., Vertino, P. M.
(2009). Cancer DNA Methylation: Molecular Mechanisms and Clinical Implications. Clin. Cancer Res.
15: 3927-3937
[Abstract][Full Text]
Stupp, R., Roila, F., On behalf of the ESMO Guidelines Working Group,
(2009). Malignant glioma: ESMO Clinical Recommendations for diagnosis, treatment and follow-up. Ann Oncol
20: iv126-iv128
[Full Text]
McKean-Cowdin, R., Barnholtz-Sloan, J., Inskip, P. D., Ruder, A. M., Butler, M., Rajaraman, P., Razavi, P., Patoka, J., Wiencke, J. K., Bondy, M. L., Wrensch, M.
(2009). Associations between Polymorphisms in DNA Repair Genes and Glioblastoma. Cancer Epidemiol. Biomarkers Prev.
18: 1118-1126
[Abstract][Full Text]
Vaillant, B., Kuo, S.-H., de Groot, J.
(2009). Emerging Subspecialties in Neurology: Neuro-oncology: A developing subspecialty with many opportunities. Neurology
72: e51-e53
[Full Text]
Kadoch, C., Dinca, E. B., Voicu, R., Chen, L., Nguyen, D., Parikh, S., Karrim, J., Shuman, M. A., Lowell, C. A., Treseler, P. A., James, C. D., Rubenstein, J. L.
(2009). Pathologic Correlates of Primary Central Nervous System Lymphoma Defined in an Orthotopic Xenograft Model. Clin. Cancer Res.
15: 1989-1997
[Abstract][Full Text]
Glas, M., Happold, C., Rieger, J., Wiewrodt, D., Bahr, O., Steinbach, J. P., Wick, W., Kortmann, R.-D., Reifenberger, G., Weller, M., Herrlinger, U.
(2009). Long-Term Survival of Patients With Glioblastoma Treated With Radiotherapy and Lomustine Plus Temozolomide. JCO
27: 1257-1261
[Abstract][Full Text]
Brandes, A. A., Tosoni, A., Franceschi, E., Sotti, G., Frezza, G., Amista, P., Morandi, L., Spagnolli, F., Ermani, M.
(2009). Recurrence Pattern After Temozolomide Concomitant With and Adjuvant to Radiotherapy in Newly Diagnosed Patients With Glioblastoma: Correlation With MGMT Promoter Methylation Status. JCO
27: 1275-1279
[Abstract][Full Text]
Quinn, J. A., Jiang, S. X., Reardon, D. A., Desjardins, A., Vredenburgh, J. J., Rich, J. N., Gururangan, S., Friedman, A. H., Bigner, D. D., Sampson, J. H., McLendon, R. E., Herndon, J. E. II, Walker, A., Friedman, H. S.
(2009). Phase II Trial of Temozolomide Plus O6-Benzylguanine in Adults With Recurrent, Temozolomide-Resistant Malignant Glioma. JCO
27: 1262-1267
[Abstract][Full Text]
Chalmers, A. J.
(2009). The potential role and application of PARP inhibitors in cancer treatment. Br Med Bull
89: 23-40
[Abstract][Full Text]
OSHIRO, S., TSUGU, H., KOMATSU, F., OHMURA, T., OHTA, M., SAKAMOTO, S., FUKUSHIMA, T., INOUE, T.
(2009). Efficacy of Temozolomide Treatment in Patients with High-grade Glioma. Anticancer Res
29: 911-917
[Abstract][Full Text]
Blumenthal, D. T., Won, M., Mehta, M. P., Curran, W. J., Souhami, L., Michalski, J. M., Rogers, C. L., Corn, B. W.
(2009). Short Delay in Initiation of Radiotherapy May Not Affect Outcome of Patients With Glioblastoma: A Secondary Analysis From the Radiation Therapy Oncology Group Database. JCO
27: 733-739
[Abstract][Full Text]
Prados, M. D., Chang, S. M., Butowski, N., DeBoer, R., Parvataneni, R., Carliner, H., Kabuubi, P., Ayers-Ringler, J., Rabbitt, J., Page, M., Fedoroff, A., Sneed, P. K., Berger, M. S., McDermott, M. W., Parsa, A. T., Vandenberg, S., James, C. D., Lamborn, K. R., Stokoe, D., Haas-Kogan, D. A.
(2009). Phase II Study of Erlotinib Plus Temozolomide During and After Radiation Therapy in Patients With Newly Diagnosed Glioblastoma Multiforme or Gliosarcoma. JCO
27: 579-584
[Abstract][Full Text]
Miyashita, K., Kawakami, K., Nakada, M., Mai, W., Shakoori, A., Fujisawa, H., Hayashi, Y., Hamada, J.-i., Minamoto, T.
(2009). Potential Therapeutic Effect of Glycogen Synthase Kinase 3{beta} Inhibition against Human Glioblastoma. Clin. Cancer Res.
15: 887-897
[Abstract][Full Text]
Clarke, M. J., Mulligan, E. A., Grogan, P. T., Mladek, A. C., Carlson, B. L., Schroeder, M. A., Curtin, N. J., Lou, Z., Decker, P. A., Wu, W., Plummer, E. R., Sarkaria, J. N.
(2009). Effective sensitization of temozolomide by ABT-888 is lost with development of temozolomide resistance in glioblastoma xenograft lines. Molecular Cancer Therapeutics
8: 407-414
[Abstract][Full Text]
Bromberg, J. E. C., van den Bent, M. J.
(2009). Oligodendrogliomas: Molecular Biology and Treatment. The Oncologist
14: 155-163
[Abstract][Full Text]
Augustine, C. K., Yoo, J. S., Potti, A., Yoshimoto, Y., Zipfel, P. A., Friedman, H. S., Nevins, J. R., Ali-Osman, F., Tyler, D. S.
(2009). Genomic and Molecular Profiling Predicts Response to Temozolomide in Melanoma. Clin. Cancer Res.
15: 502-510
[Abstract][Full Text]
Wick, W., Platten, M., Weller, M.
(2009). New (alternative) temozolomide regimens for the treatment of glioma. Neuro Oncol Duke
11: 69-79
[Abstract][Full Text]
Vredenburgh, J. J., Desjardins, A., Reardon, D. A., Friedman, H. S.
(2009). Experience with irinotecan for the treatment of malignant glioma. Neuro Oncol Duke
11: 80-91
[Abstract][Full Text]
Remington, M., Chtchetinin, J., Ancheta, K., Nghiemphu, P. L., Cloughesy, T., Lai, A.
(2009). The L84F polymorphic variant of human O6-methylguanine-DNA methyltransferase alters stability in U87MG glioma cells but not temozolomide sensitivity. Neuro Oncol Duke
11: 22-32
[Abstract][Full Text]
Sauvageot, C. M.-E., Weatherbee, J. L., Kesari, S., Winters, S. E., Barnes, J., Dellagatta, J., Ramakrishna, N. R., Stiles, C. D., Kung, A. L.-J., Kieran, M. W., Wen, P. Y. C.
(2009). Efficacy of the HSP90 inhibitor 17-AAG in human glioma cell lines and tumorigenic glioma stem cells. Neuro Oncol Duke
11: 109-121
[Abstract][Full Text]
Hoffmann, J., Fichtner, I., Lemm, M., Lienau, P., Hess-Stumpp, H., Rotgeri, A., Hofmann, B., Klar, U.
(2009). Sagopilone crosses the blood-brain barrier in vivo to inhibit brain tumor growth and metastases. Neuro Oncol Duke
11: 158-166
[Abstract][Full Text]
Kitange, G. J., Carlson, B. L., Schroeder, M. A., Grogan, P. T., Lamont, J. D., Decker, P. A., Wu, W., James, C. D., Sarkaria, J. N.
(2009). Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts. Neuro Oncol Duke
11: 281-291
[Abstract][Full Text]
Moyes, V J, Alusi, G, Sabin, H I, Evanson, J, Berney, D M, Kovacs, K, Monson, J P, Plowman, P N, Drake, W M
(2009). Treatment of Nelson's syndrome with temozolomide. Eur J Endocrinol
160: 115-119
[Abstract][Full Text]
Lin, Y., Jiang, T., Zhou, K., Xu, L., Chen, B., Li, G., Qiu, X., Jiang, T., Zhang, W., Song, S. W.
(2009). Plasma IGFBP-2 levels predict clinical outcomes of patients with high-grade gliomas. Neuro Oncol Duke
11: 468-476
[Abstract][Full Text]
Everhard, S., Tost, J., El Abdalaoui, H., Criniere, E., Busato, F., Marie, Y., Gut, I. G., Sanson, M., Mokhtari, K., Laigle-Donadey, F., Hoang-Xuan, K., Delattre, J.-Y., Thillet, J.
(2009). Identification of regions correlating MGMT promoter methylation and gene expression in glioblastomas. Neuro Oncol Duke
11: 348-356
[Abstract][Full Text]
Schaich, M., Kestel, L., Pfirrmann, M., Robel, K., Illmer, T., Kramer, M., Dill, C., Ehninger, G., Schackert, G., Krex, D.
(2009). A MDR1 (ABCB1) gene single nucleotide polymorphism predicts outcome of temozolomide treatment in glioblastoma patients. Ann Oncol
20: 175-181
[Abstract][Full Text]
Sigmond, J., Honeywell, R. J., Postma, T. J., Dirven, C. M. F., de Lange, S. M., van der Born, K., Laan, A. C., Baayen, J. C. A., Van Groeningen, C. J., Bergman, A. M., Giaccone, G., Peters, G. J.
(2009). Gemcitabine uptake in glioblastoma multiforme: potential as a radiosensitizer. Ann Oncol
20: 182-187
[Abstract][Full Text]
Kesari, S., Schiff, D., Drappatz, J., LaFrankie, D., Doherty, L., Macklin, E. A., Muzikansky, A., Santagata, S., Ligon, K. L., Norden, A. D., Ciampa, A., Bradshaw, J., Levy, B., Radakovic, G., Ramakrishna, N., Black, P. M., Wen, P. Y.
(2009). Phase II Study of Protracted Daily Temozolomide for Low-Grade Gliomas in Adults. Clin. Cancer Res.
15: 330-337
[Abstract][Full Text]
Kulke, M. H., Hornick, J. L., Frauenhoffer, C., Hooshmand, S., Ryan, D. P., Enzinger, P. C., Meyerhardt, J. A., Clark, J. W., Stuart, K., Fuchs, C. S., Redston, M. S.
(2009). O6-Methylguanine DNA Methyltransferase Deficiency and Response to Temozolomide-Based Therapy in Patients with Neuroendocrine Tumors. Clin. Cancer Res.
15: 338-345
[Abstract][Full Text]
Lassman, A. B.
(2009). Management of Newly Diagnosed Anaplastic Oligodendrogliomas. Am Soc Clin Oncol Ed Book
2009: 85-89
[Abstract][Full Text]
Krug, L. M., Pietanza, M. C.
(2009). Emerging Therapies in Small Cell Lung Cancer. Am Soc Clin Oncol Ed Book
2009: 455-460
[Abstract][Full Text]
Pallini, R., Ricci-Vitiani, L., Banna, G. L., Signore, M., Lombardi, D., Todaro, M., Stassi, G., Martini, M., Maira, G., Larocca, L. M., De Maria, R.
(2008). Cancer Stem Cell Analysis and Clinical Outcome in Patients with Glioblastoma Multiforme. Clin. Cancer Res.
14: 8205-8212
[Abstract][Full Text]
Brown, P. D., Krishnan, S., Sarkaria, J. N., Wu, W., Jaeckle, K. A., Uhm, J. H., Geoffroy, F. J., Arusell, R., Kitange, G., Jenkins, R. B., Kugler, J. W., Morton, R. F., Rowland, K. M. Jr, Mischel, P., Yong, W. H., Scheithauer, B. W., Schiff, D., Giannini, C., Buckner, J. C.
(2008). Phase I/II Trial of Erlotinib and Temozolomide With Radiation Therapy in the Treatment of Newly Diagnosed Glioblastoma Multiforme: North Central Cancer Treatment Group Study N0177. JCO
26: 5603-5609
[Abstract][Full Text]
Goldhoff, P., Warrington, N. M., Limbrick, D. D. Jr., Hope, A., Woerner, B. M., Jackson, E., Perry, A., Piwnica-Worms, D., Rubin, J. B.
(2008). Targeted Inhibition of Cyclic AMP Phosphodiesterase-4 Promotes Brain Tumor Regression. Clin. Cancer Res.
14: 7717-7725
[Abstract][Full Text]
Desjardins, A., Reardon, D. A., Herndon, J. E. II, Marcello, J., Quinn, J. A., Rich, J. N., Sathornsumetee, S., Gururangan, S., Sampson, J., Bailey, L., Bigner, D. D., Friedman, A. H., Friedman, H. S., Vredenburgh, J. J.
(2008). Bevacizumab Plus Irinotecan in Recurrent WHO Grade 3 Malignant Gliomas. Clin. Cancer Res.
14: 7068-7073
[Abstract][Full Text]
Duffy, M. J., Crown, J.
(2008). A Personalized Approach to Cancer Treatment: How Biomarkers Can Help. Clin. Chem.
54: 1770-1779
[Abstract][Full Text]
Bracht, L.-K., Wen, P., Meyerhardt, J. A., Kulke, M. H., Hornick, J. L., Redston, M., LaFrankie, D. C., Black, P. M., Kesari, S., Norden, A., Drappatz, J.
(2008). DNA Repair Enzyme Expression and Differential Response to Temozolomide in a Patient With Both Glioblastoma and Metastatic Pancreatic Neuroendocrine Tumor. JCO
26: 4843-4844
[Full Text]
Brait, M., Begum, S., Carvalho, A. L., Dasgupta, S., Vettore, A. L., Czerniak, B., Caballero, O. L., Westra, W. H., Sidransky, D., Hoque, M. O.
(2008). Aberrant Promoter Methylation of Multiple Genes during Pathogenesis of Bladder Cancer. Cancer Epidemiol. Biomarkers Prev.
17: 2786-2794
[Abstract][Full Text]
Gottardo, N. G., Gajjar, A.
(2008). Chemotherapy for Malignant Brain Tumors of Childhood. J Child Neurol
23: 1149-1159
[Abstract]
Fry, R. C., Svensson, J. P., Valiathan, C., Wang, E., Hogan, B. J., Bhattacharya, S., Bugni, J. M., Whittaker, C. A., Samson, L. D.
(2008). Genomic predictors of interindividual differences in response to DNA damaging agents. Genes Dev.
22: 2621-2626
[Abstract][Full Text]
Neyns, B., Cordera, S., Joosens, E., Nader, P.
(2008). Non-Hodgkin's Lymphoma in Patients With Glioma Treated With Temozolomide. JCO
26: 4518-4519
[Full Text]
Brandes, A. A., Franceschi, E., Tosoni, A.
(2008). In Reply. JCO
26: 4359-4360
[Full Text]
Hegi, M. E., Liu, L., Herman, J. G., Stupp, R., Wick, W., Weller, M., Mehta, M. P., Gilbert, M. R.
(2008). Correlation of O6-Methylguanine Methyltransferase (MGMT) Promoter Methylation With Clinical Outcomes in Glioblastoma and Clinical Strategies to Modulate MGMT Activity. JCO
26: 4189-4199
[Abstract][Full Text]
Linnebank, M., Semmler, A., Moskau, S., Smulders, Y., Blom, H., Simon, M.
(2008). The methylenetetrahydrofolate reductase (MTHFR) variant c.677C>T (A222V) influences overall survival of patients with glioblastoma multiforme. Neuro Oncol Duke
10: 548-552
[Abstract][Full Text]
Wen, P. Y., Kesari, S.
(2008). Malignant Gliomas in Adults. NEJM
359: 492-507
[Full Text]
Mason, W. P., Cairncross, J. G.
(2008). Invited Article: The expanding impact of molecular biology on the diagnosis and treatment of gliomas. Neurology
71: 365-373
[Abstract][Full Text]
Beier, D., Rohrl, S., Pillai, D. R., Schwarz, S., Kunz-Schughart, L. A., Leukel, P., Proescholdt, M., Brawanski, A., Bogdahn, U., Trampe-Kieslich, A., Giebel, B., Wischhusen, J., Reifenberger, G., Hau, P., Beier, C. P.
(2008). Temozolomide Preferentially Depletes Cancer Stem Cells in Glioblastoma. Cancer Res.
68: 5706-5715
[Abstract][Full Text]
Hamstra, D. A., Galban, C. J., Meyer, C. R., Johnson, T. D., Sundgren, P. C., Tsien, C., Lawrence, T. S., Junck, L., Ross, D. J., Rehemtulla, A., Ross, B. D., Chenevert, T. L.
(2008). Functional Diffusion Map As an Early Imaging Biomarker for High-Grade Glioma: Correlation With Conventional Radiologic Response and Overall Survival. JCO
26: 3387-3394
[Abstract][Full Text]
Colman, H., Aldape, K.
(2008). Molecular Predictors in Glioblastoma: Toward Personalized Therapy. Arch Neurol
65: 877-883
[Abstract][Full Text]
Liang, X.-J., Choi, Y., Sackett, D. L., Park, J. K.
(2008). Nitrosoureas Inhibit the Stathmin-Mediated Migration and Invasion of Malignant Glioma Cells. Cancer Res.
68: 5267-5272
[Abstract][Full Text]
Iafrate, A. J., Louis, D. N.
(2008). "MGMT for pt mgmt": Is Methylguanine-DNA Methyltransferase Testing Ready for Patient Management?. J. Mol. Diagn.
10: 308-310
[Abstract][Full Text]
Vlassenbroeck, I., Califice, S., Diserens, A.-C., Migliavacca, E., Straub, J., Di Stefano, I., Moreau, F., Hamou, M.-F., Renard, I., Delorenzi, M., Flamion, B., DiGuiseppi, J., Bierau, K., Hegi, M. E.
(2008). Validation of Real-Time Methylation-Specific PCR to Determine O6-Methylguanine-DNA Methyltransferase Gene Promoter Methylation in Glioma. J. Mol. Diagn.
10: 332-337
[Abstract][Full Text]
Murat, A., Migliavacca, E., Gorlia, T., Lambiv, W. L., Shay, T., Hamou, M.-F., de Tribolet, N., Regli, L., Wick, W., Kouwenhoven, M. C.M., Hainfellner, J. A., Heppner, F. L., Dietrich, P.-Y., Zimmer, Y., Cairncross, J. G., Janzer, R.-C., Domany, E., Delorenzi, M., Stupp, R., Hegi, M. E.
(2008). Stem Cell-Related "Self-Renewal" Signature and High Epidermal Growth Factor Receptor Expression Associated With Resistance to Concomitant Chemoradiotherapy in Glioblastoma. JCO
26: 3015-3024
[Abstract][Full Text]
Sarkaria, J. N., Kitange, G. J., James, C. D., Plummer, R., Calvert, H., Weller, M., Wick, W.
(2008). Mechanisms of Chemoresistance to Alkylating Agents in Malignant Glioma. Clin. Cancer Res.
14: 2900-2908
[Abstract][Full Text]
Rietschel, P., Wolchok, J. D., Krown, S., Gerst, S., Jungbluth, A. A., Busam, K., Smith, K., Orlow, I., Panageas, K., Chapman, P. B.
(2008). Phase II Study of Extended-Dose Temozolomide in Patients With Melanoma. JCO
26: 2299-2304
[Abstract][Full Text]
Geiger, G. A., Fu, W., Kao, G. D.
(2008). Temozolomide-Mediated Radiosensitization of Human Glioma Cells in a Zebrafish Embryonic System. Cancer Res.
68: 3396-3404
[Abstract][Full Text]
Plummer, E. R., Calvert, H.
(2008). Targeting Poly(ADP-Ribose) Polymerase: A Two-Armed Strategy for Cancer Therapy. aacredbook
2008: 15-22
[Abstract][Full Text]
Esteller, M.
(2008). Epigenetics in Cancer. NEJM
358: 1148-1159
[Full Text]
Kaloshi, G., Everhard, S., Laigle-Donadey, F., Marie, Y., Navarro, S., Mokhtari, K., Idbaih, A., Ducray, F., Thillet, J., Hoang-Xuan, K., Delattre, J.-Y, Sanson, M.
(2008). Genetic markers predictive of chemosensitivity and outcome in gliomatosis cerebri. Neurology
70: 590-595
[Abstract][Full Text]
Heimberger, A. B., Sun, W., Hussain, S. F., Dey, M., Crutcher, L., Aldape, K., Gilbert, M., Hassenbusch, S. J., Sawaya, R., Schmittling, B., Archer, G. E., Mitchell, D. A., Bigner, D. D., Sampson, J. H.
(2008). Immunological responses in a patient with glioblastoma multiforme treated with sequential courses of temozolomide and immunotherapy: Case study. Neuro Oncol Duke
10: 98-103
[Abstract][Full Text]
Kil, W. J., Cerna, D., Burgan, W. E., Beam, K., Carter, D., Steeg, P. S., Tofilon, P. J., Camphausen, K.
(2008). In vitro and In vivo Radiosensitization Induced by the DNA Methylating Agent Temozolomide. Clin. Cancer Res.
14: 931-938
[Abstract][Full Text]
Sathornsumetee, S., Cao, Y., Marcello, J. E., Herndon, J. E. II, McLendon, R. E., Desjardins, A., Friedman, H. S., Dewhirst, M. W., Vredenburgh, J. J., Rich, J. N.
(2008). Tumor Angiogenic and Hypoxic Profiles Predict Radiographic Response and Survival in Malignant Astrocytoma Patients Treated With Bevacizumab and Irinotecan. JCO
26: 271-278
[Abstract][Full Text]
Reardon, D. A., Desjardins, A., Vredenburgh, J. J., Sathornsumetee, S., Rich, J. N., Quinn, J. A., Lagattuta, T. F., Egorin, M. J., Gururangan, S., McLendon, R., Herndon, J. E. II, Friedman, A. H., Salvado, A. J., Friedman, H. S.
(2008). Safety and pharmacokinetics of dose-intensive imatinib mesylate plus temozolomide: Phase 1 trial in adults with malignant glioma. Neuro Oncol Duke
10: 330-340
[Abstract][Full Text]
Kesari, S., Schiff, D., Henson, J. W., Muzikansky, A., Gigas, D. C., Doherty, L., Batchelor, T. T., Longtine, J. A., Ligon, K. L., Weaver, S., Laforme, A., Ramakrishna, N., Black, P. McL., Drappatz, J., Ciampa, A., Folkman, J., Kieran, M., Wen, P. Y.
(2008). Phase II study of temozolomide, thalidomide, and celecoxib for newly diagnosed glioblastoma in adults. Neuro Oncol Duke
10: 300-308
[Abstract][Full Text]
Assadian, S., Aliaga, A., Del Maestro, R. F., Evans, A. C., Bedell, B. J.
(2008). FDG-PET imaging for the evaluation of antiglioma agents in a rat model. Neuro Oncol Duke
10: 292-299
[Abstract][Full Text]
Zalutsky, M. R., Reardon, D. A., Akabani, G., Coleman, R. E., Friedman, A. H., Friedman, H. S., McLendon, R. E., Wong, T. Z., Bigner, D. D.
(2008). Clinical Experience with {alpha}-Particle Emitting 211At: Treatment of Recurrent Brain Tumor Patients with 211At-Labeled Chimeric Antitenascin Monoclonal Antibody 81C6. JNM
49: 30-38
[Abstract][Full Text]
Wick, W., Stupp, R., Beule, A.-C., Bromberg, J., Wick, A., Ernemann, U., Platten, M., Marosi, C., Mason, W. P., van den Bent, M., Weller, M., Rorden, C., Karnath, H.-O., the European Organisation for Research and Treatme,
(2008). A novel tool to analyze MRI recurrence patterns in glioblastoma. Neuro Oncol Duke
10: 1019-1024
[Abstract][Full Text]
Nagane, M., Kobayashi, K., Ohnishi, A., Shimizu, S., Shiokawa, Y.
(2007). Prognostic Significance of O6-Methylguanine-DNA Methyltransferase Protein Expression in Patients with Recurrent Glioblastoma Treated with Temozolomide. Jpn J Clin Oncol
0: hym132v1-10
[Abstract][Full Text]
Alonso, M. M., Gomez-Manzano, C., Bekele, B. N., Yung, W.K. A., Fueyo, J.
(2007). Adenovirus-Based Strategies Overcome Temozolomide Resistance by Silencing the O6-Methylguanine-DNA Methyltransferase Promoter. Cancer Res.
67: 11499-11504
[Abstract][Full Text]
Batista, L. F.Z., Roos, W. P., Christmann, M., Menck, C. F.M., Kaina, B.
(2007). Differential Sensitivity of Malignant Glioma Cells to Methylating and Chloroethylating Anticancer Drugs: p53 Determines the Switch by Regulating xpc, ddb2, and DNA Double-Strand Breaks. Cancer Res.
67: 11886-11895
[Abstract][Full Text]
Shirahata, M., Iwao-Koizumi, K., Saito, S., Ueno, N., Oda, M., Hashimoto, N., Takahashi, J. A., Kato, K.
(2007). Gene Expression-Based Molecular Diagnostic System for Malignant Gliomas Is Superior to Histological Diagnosis. Clin. Cancer Res.
13: 7341-7356
[Abstract][Full Text]
Lefranc, F., Facchini, V., Kiss, R.
(2007). Proautophagic Drugs: A Novel Means to Combat Apoptosis-Resistant Cancers, with a Special Emphasis on Glioblastomas. The Oncologist
12: 1395-1403
[Abstract][Full Text]
Broniscer, A., Gururangan, S., MacDonald, T. J., Goldman, S., Packer, R. J., Stewart, C. F., Wallace, D., Danks, M. K., Friedman, H. S., Poussaint, T. Y., Kun, L. E., Boyett, J. M., Gajjar, A., for the Pediatric Brain Tumor Consortium,
(2007). Phase I Trial of Single-Dose Temozolomide and Continuous Administration of O6-Benzylguanine in Children with Brain Tumors: a Pediatric Brain Tumor Consortium Report. Clin. Cancer Res.
13: 6712-6718
[Abstract][Full Text]
Previous
