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|Phase I/IIa Study of Cilengitide and Temozolomide With Concomitant Radiotherapy Followed by Cilengitide and Temozolomide Maintenance Therapy in Patients With Newly Diagnosed Glioblastoma.|
Stupp R, Hegi ME, Neyns B, Goldbrunner R, Schlegel U, Clement PM, Grabenbauer GG, Ochsenbein AF, Simon M, Dietrich PY, Pietsch T, Hicking C, Tonn JC, Diserens AC, Pica A, Hermisson M, Krueger S, Picard M, Weller M
J Clin Oncol 2010
PURPOSE Invasion and migration are key processes of glioblastoma and are tightly linked to tumor recurrence. Integrin inhibition using cilengitide has shown synergy with chemotherapy and radiotherapy in vitro and promising activity in recurrent glioblastoma. This multicenter, phase I/IIa study investigated the efficacy and safety of cilengitide in combination with standard chemoradiotherapy in newly diagnosed glioblastoma. PATIENTS AND METHODS Patients (age >/= 18 to </= 70 years) were treated with cilengitide (500 mg) administered twice weekly intravenously in addition to standard radiotherapy with concomitant and adjuvant temozolomide. Treatment was continued until disease progression or for up to 35 weeks. The primary end point was progression-free survival (PFS) at 6 months. Results Fifty-two patients (median age, 57 years; 62% male) were included. Six- and 12-month PFS rates were 69% (95% CI, 54% to 80%) and 33% (95% CI, 21% to 46%). Median PFS was 8 months (95% CI, 6.0 to 10.7 months). Twelve- and 24-month overall survival (OS) rates were 68% (95% CI, 53% to 79%) and 35% (95% CI, 22% to 48%). Median OS was 16.1 months (95% CI, 13.1 to 23.2 months). PFS and OS were longer in patients with tumors with O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation (13.4 and 23.2 months) versus those without MGMT promoter methylation (3.4 and 13.1 months). The combination of cilengitide with temozolomide and radiotherapy was well tolerated, with no additional toxicity. No pharmacokinetic interactions between temozolomide and cilengitide were identified. CONCLUSION Compared with historical controls, the addition of concomitant and adjuvant cilengitide to standard chemoradiotherapy demonstrated promising activity in patients with glioblastoma with MGMT promoter methylation.
|Evaluation status and prognostic significance of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in pediatric high grade gliomas.|
Francesca R Buttarelli,Maura Massimino,Manila Antonelli,Libero Lauriola,Paolo Nozza,Vittoria Donofrio,Antonella Arcella,Maria A Oliva,Concezio Di Rocco,Felice Giangaspero
Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery 26 2010
In this study, we investigated the prognostic and predictive value of MGMT promoter methylation and protein expression in 30 pediatric high grade gliomas (pHGG).
|Frequency of bcl-2 gene rearrangement in B-cell Non-Hodgkin's lymphoma.|
Adeel Arif, Shahid Jamal, Sajid Mushtaq, Suhaib Ahmed, Azhar Mubarik
Asian Pacific journal of cancer prevention : APJCP 10 237-40 2009
OBJECTIVE: The objective of the study was to determine the frequency of bcl-2 gene rearrangement in B-cell Non-Hodgkin's lymphoma (NHL) and identify different breakpoints of bcl-2 gene. METHODS: Thirty cases of B-cell lymphoma (including 8 cases of follicular lymphoma, 19 cases of diffuse large B-cell lymphoma and 3 cases of T-cell rich B-cell lymphoma) were included in the study. Good quality of DNA was extracted in 4 cases from formalin fixed paraffin embedded tissue and in 26 cases from fine needle aspirate. The polymerase chain reaction was done for major break point region (mbr), minor cluster region (mcr) and intermediate cluster region (icr) of the bcl-2 gene. RESULTS: The bcl-2 gene rearrangement was identified in 23.3% of B-cell lymphoma, 50% of follicular lymphoma, 15% of diffuse large B-cell lymphoma and no bcl-2 rearrangement was identified in any of the T-cell rich B-cell lymphomas. Further analysis showed the icr breakpoint in 16.7% of B-cell lymphoma, 37.5% of follicular lymphoma and 10.5% of diffuse large B-cell lymphoma. Involvement of the mbr breakpoint was found in 6.7% of B-cell lymphoma, 12.5% of follicular lymphoma, and 5.3% of diffuse large B-cell lymphoma. Involvement of the mcr breakpoint was not seen in any of the cases. CONCLUSION: The bcl-2 gene rearrangement is quite frequent in follicular lymphoma, followed by diffuse large B-cell lymphoma. The commonest breakpoint in present series is icr followed by mbr. This indicates that primers for bcl-2 gene must include icr primer, whenever the bcl-2 gene is being evaluated for B-cell NHL in this part of the world and this might reduce the variability of frequency of bcl-2 gene rearrangement within and between different regions.
|Treatment of recurrent malignant gliomas with fotemustine monotherapy: impact of dose and correlation with MGMT promoter methylation.|
Alessandra Fabi,Giulio Metro,Michelangelo Russillo,Antonello Vidiri,Carmine Maria Carapella,Marta Maschio,Francesco Cognetti,Bruno Jandolo,Maria Alessandra Mirri,Isabella Sperduti,Stefano Telera,Mariantonia Carosi,Andrea Pace
BMC cancer 9 2009
In recurrent malignant gliomas (MGs), a high rate of haematological toxicity is observed with the use of fotemustine at the conventional schedule (100 mg/m(2) weekly for 3 consecutive weeks followed by triweekly administration after a 5-week rest period). Also, the impact of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status on fotemustine activity has never been explored in the clinical setting.Full Text Article
|Validation of real-time methylation-specific PCR to determine O6-methylguanine-DNA methyltransferase gene promoter methylation in glioma.|
Ilse Vlassenbroeck, Stéphane Califice, Annie-Claire Diserens, Eugenia Migliavacca, Josef Straub, Ivano Di Stefano, Fabrice Moreau, Marie-France Hamou, Isabelle Renard, Mauro Delorenzi, Bruno Flamion, James DiGuiseppi, Katja Bierau, Monika E Hegi
The Journal of molecular diagnostics : JMD 10 332-7 2008
Epigenetic silencing of the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) by promoter methylation predicts successful alkylating agent therapy, such as with temozolomide, in glioblastoma patients. Stratified therapy assignment of patients in prospective clinical trials according to tumor MGMT status requires a standardized diagnostic test, suitable for high-throughput analysis of small amounts of formalin-fixed, paraffin-embedded tumor tissue. A direct, real-time methylation-specific PCR (MSP) assay was developed to determine methylation status of the MGMT gene promoter. Assay specificity was obtained by selective amplification of methylated DNA sequences of sodium bisulfite-modified DNA. The copy number of the methylated MGMT promoter, normalized to the beta-actin gene, provides a quantitative test result. We analyzed 134 clinical glioma samples, comparing the new test with the previously validated nested gel-based MSP assay, which yields a binary readout. A cut-off value for the MGMT methylation status was suggested by fitting a bimodal normal mixture model to the real-time results, supporting the hypothesis that there are two distinct populations within the test samples. Comparison of the tests showed high concordance of the results (82/91 [90%]; Cohen's kappa = 0.80; 95% confidence interval, 0.82-0.95). The direct, real-time MSP assay was highly reproducible (Pearson correlation 0.996) and showed valid test results for 93% (125/134) of samples compared with 75% (94/125) for the nested, gel-based MSP assay. This high-throughput test provides an important pharmacogenomic tool for individualized management of alkylating agent chemotherapy.Full Text Article
|MGMT gene silencing and benefit from temozolomide in glioblastoma.|
Monika E Hegi, Annie-Claire Diserens, Thierry Gorlia, Marie-France Hamou, Nicolas de Tribolet, Michael Weller, Johan M Kros, Johannes A Hainfellner, Warren Mason, Luigi Mariani, Jacoline E C Bromberg, Peter Hau, René O Mirimanoff, J Gregory Cairncross, Robert C Janzer, Roger Stupp
The New England journal of medicine 352 997-1003 2005
BACKGROUND: Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. METHODS: We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. RESULTS: The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. CONCLUSIONS: Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.