Skip to main content
Top
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

Structural and advanced imaging in predicting MGMT promoter methylation of primary glioblastoma: a region of interest based analysis

Authors: Yu Han, Lin-Feng Yan, Xi-Bin Wang, Ying-Zhi Sun, Xin Zhang, Zhi-Cheng Liu, Hai-Yan Nan, Yu-Chuan Hu, Yang Yang, Jin Zhang, Ying Yu, Qian Sun, Qiang Tian, Bo Hu, Gang Xiao, Wen Wang, Guang-Bin Cui

Published in: BMC Cancer | Issue 1/2018

Login to get access

Abstract

Background

The methylation status of oxygen 6-methylguanine-DNA methyltransferase (MGMT) promoter has been associated with treatment response in glioblastoma(GBM). Using pre-operative MRI techniques to predict MGMT promoter methylation status remains inconclusive. In this study, we investigated the value of features from structural and advanced imagings in predicting the methylation of MGMT promoter in primary glioblastoma patients.

Methods

Ninety-two pathologically confirmed primary glioblastoma patients underwent preoperative structural MR imagings and the efficacy of structural image features were qualitatively analyzed using Fisher’s exact test. In addition, 77 of the 92 patients underwent additional advanced MRI scans including diffusion-weighted (DWI) and 3-diminsional pseudo-continuous arterial spin labeling (3D pCASL) imaging. Apparent diffusion coefficient (ADC) and relative cerebral blood flow (rCBF) values within the manually drawn region-of-interest (ROI) were calculated and compared using independent sample t test for their efficacies in predicting MGMT promoter methylation. Receiver operating characteristic curve (ROC) analysis was used to investigate the predicting efficacy with the area under the curve (AUC) and cross validations. Multiple-variable logistic regression model was employed to evaluate the predicting performance of multiple variables.

Results

MGMT promoter methylation was associated with tumor location and necrosis (P <  0.05). Significantly increased ADC value (P <  0.001) and decreased rCBF (P <  0.001) were associated with MGMT promoter methylation in primary glioblastoma. The ADC achieved the better predicting efficacy than rCBF (ADC: AUC, 0.860; sensitivity, 81.1%; specificity, 82.5%; vs rCBF: AUC, 0.835; sensitivity, 75.0%; specificity, 78.4%; P = 0.032). The combination of tumor location, necrosis, ADC and rCBF resulted in the highest AUC of 0.914.

Conclusion

ADC and rCBF are promising imaging biomarkers in clinical routine to predict the MGMT promoter methylation in primary glioblastoma patients.
Literature
1.
go back to reference Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review. JAMA. 2013;310(17):1842–50.CrossRefPubMed Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review. JAMA. 2013;310(17):1842–50.CrossRefPubMed
2.
go back to reference Karsy M, Huang T, Kleinman G, Karpel-Massler G. Molecular, histopathological, and genomic variants of glioblastoma. Front Biosci (Landmark Ed). 2014;19:1065–87.CrossRef Karsy M, Huang T, Kleinman G, Karpel-Massler G. Molecular, histopathological, and genomic variants of glioblastoma. Front Biosci (Landmark Ed). 2014;19:1065–87.CrossRef
3.
go back to reference Oh J, Henry RG, Pirzkall A, Lu Y, Li X, Catalaa I, Chang S, Dillon WP, Nelson SJ. Survival analysis in patients with glioblastoma multiforme: predictive value of choline-to-N-acetylaspartate index, apparent diffusion coefficient, and relative cerebral blood volume. J Magn Reson Imaging. 2004;19(5):546–54.CrossRefPubMed Oh J, Henry RG, Pirzkall A, Lu Y, Li X, Catalaa I, Chang S, Dillon WP, Nelson SJ. Survival analysis in patients with glioblastoma multiforme: predictive value of choline-to-N-acetylaspartate index, apparent diffusion coefficient, and relative cerebral blood volume. J Magn Reson Imaging. 2004;19(5):546–54.CrossRefPubMed
4.
go back to reference Marijnen CA, van den Berg SM, van Duinen SG, Voormolen JH, Noordijk EM. Radiotherapy is effective in patients with glioblastoma multiforme with a limited prognosis and in patients above 70 years of age: a retrospective single institution analysis. Radiother Oncol. 2005;75(2):210–6.CrossRefPubMed Marijnen CA, van den Berg SM, van Duinen SG, Voormolen JH, Noordijk EM. Radiotherapy is effective in patients with glioblastoma multiforme with a limited prognosis and in patients above 70 years of age: a retrospective single institution analysis. Radiother Oncol. 2005;75(2):210–6.CrossRefPubMed
5.
go back to reference Roszkowski K, Furtak J, Zurawski B, Szylberg T, Lewandowska MA. Potential role of methylation marker in glioma supporting clinical decisions. Int J Mol Sci. 2016;17(11). Roszkowski K, Furtak J, Zurawski B, Szylberg T, Lewandowska MA. Potential role of methylation marker in glioma supporting clinical decisions. Int J Mol Sci. 2016;17(11).
6.
go back to reference Dunn J, Baborie A, Alam F, Joyce K, Moxham M, Sibson R, Crooks D, Husband D, Shenoy A, Brodbelt A, et al. Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy. Br J Cancer. 2009;101(1):124–31.CrossRefPubMedPubMedCentral Dunn J, Baborie A, Alam F, Joyce K, Moxham M, Sibson R, Crooks D, Husband D, Shenoy A, Brodbelt A, et al. Extent of MGMT promoter methylation correlates with outcome in glioblastomas given temozolomide and radiotherapy. Br J Cancer. 2009;101(1):124–31.CrossRefPubMedPubMedCentral
7.
go back to reference Jiang T, Mao Y, Ma W, Mao Q, You Y, Yang X, Jiang C, Kang C, Li X, Chen L, et al. CGCG clinical practice guidelines for the management of adult diffuse gliomas. Cancer Lett. 2016;375(2):263–73.CrossRefPubMed Jiang T, Mao Y, Ma W, Mao Q, You Y, Yang X, Jiang C, Kang C, Li X, Chen L, et al. CGCG clinical practice guidelines for the management of adult diffuse gliomas. Cancer Lett. 2016;375(2):263–73.CrossRefPubMed
8.
go back to reference Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997–1003.CrossRefPubMed Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997–1003.CrossRefPubMed
9.
go back to reference Drabycz S, Roldan G, de Robles P, Adler D, McIntyre JB, Magliocco AM, Cairncross JG, Mitchell JR. An analysis of image texture, tumor location, and MGMT promoter methylation in glioblastoma using magnetic resonance imaging. NeuroImage. 2010;49(2):1398–405.CrossRefPubMed Drabycz S, Roldan G, de Robles P, Adler D, McIntyre JB, Magliocco AM, Cairncross JG, Mitchell JR. An analysis of image texture, tumor location, and MGMT promoter methylation in glioblastoma using magnetic resonance imaging. NeuroImage. 2010;49(2):1398–405.CrossRefPubMed
10.
go back to reference Ellingson BM, Cloughesy TF, Pope WB, Zaw TM, Phillips H, Lalezari S, Nghiemphu PL, Ibrahim H, Naeini KM, Harris RJ, et al. Anatomic localization of O6-methylguanine DNA methyltransferase (MGMT) promoter methylated and unmethylated tumors: a radiographic study in 358 de novo human glioblastomas. NeuroImage. 2012;59(2):908–16.CrossRefPubMed Ellingson BM, Cloughesy TF, Pope WB, Zaw TM, Phillips H, Lalezari S, Nghiemphu PL, Ibrahim H, Naeini KM, Harris RJ, et al. Anatomic localization of O6-methylguanine DNA methyltransferase (MGMT) promoter methylated and unmethylated tumors: a radiographic study in 358 de novo human glioblastomas. NeuroImage. 2012;59(2):908–16.CrossRefPubMed
11.
go back to reference Kanas VG, Zacharaki EI, Thomas GA, Zinn PO, Megalooikonomou V, Colen RR. Learning MRI-based classification models for MGMT methylation status prediction in glioblastoma. Comput Methods Prog Biomed. 2017;140:249–57.CrossRef Kanas VG, Zacharaki EI, Thomas GA, Zinn PO, Megalooikonomou V, Colen RR. Learning MRI-based classification models for MGMT methylation status prediction in glioblastoma. Comput Methods Prog Biomed. 2017;140:249–57.CrossRef
12.
go back to reference Korfiatis P, Kline TL, Coufalova L, Lachance DH, Parney IF, Carter RE, Buckner JC, Erickson BJ. MRI texture features as biomarkers to predict MGMT methylation status in glioblastomas. Med Phys. 2016;43(6):2835.CrossRefPubMedPubMedCentral Korfiatis P, Kline TL, Coufalova L, Lachance DH, Parney IF, Carter RE, Buckner JC, Erickson BJ. MRI texture features as biomarkers to predict MGMT methylation status in glioblastomas. Med Phys. 2016;43(6):2835.CrossRefPubMedPubMedCentral
13.
go back to reference Kickingereder P, Bonekamp D, Nowosielski M, Kratz A, Sill M, Burth S, Wick A, Eidel O, Schlemmer HP, Radbruch A, et al. Radiogenomics of glioblastoma: machine learning-based classification of molecular characteristics by using multiparametric and multiregional MR imaging features. Radiology. 2016;281(3):907–18.CrossRefPubMed Kickingereder P, Bonekamp D, Nowosielski M, Kratz A, Sill M, Burth S, Wick A, Eidel O, Schlemmer HP, Radbruch A, et al. Radiogenomics of glioblastoma: machine learning-based classification of molecular characteristics by using multiparametric and multiregional MR imaging features. Radiology. 2016;281(3):907–18.CrossRefPubMed
14.
go back to reference Ryoo I, Choi SH, Kim JH, Sohn CH, Kim SC, Shin HS, Yeom JA, Jung SC, Lee AL, Yun TJ, et al. Cerebral blood volume calculated by dynamic susceptibility contrast-enhanced perfusion MR imaging: preliminary correlation study with glioblastoma genetic profiles. PLoS One. 2013;8(8):e71704.CrossRefPubMedPubMedCentral Ryoo I, Choi SH, Kim JH, Sohn CH, Kim SC, Shin HS, Yeom JA, Jung SC, Lee AL, Yun TJ, et al. Cerebral blood volume calculated by dynamic susceptibility contrast-enhanced perfusion MR imaging: preliminary correlation study with glioblastoma genetic profiles. PLoS One. 2013;8(8):e71704.CrossRefPubMedPubMedCentral
15.
go back to reference Ahn SS, Shin NY, Chang JH, Kim SH, Kim EH, Kim DW, Lee SK. Prediction of methylguanine methyltransferase promoter methylation in glioblastoma using dynamic contrast-enhanced magnetic resonance and diffusion tensor imaging. J Neurosurg. 2014;121(2):367–73.CrossRefPubMed Ahn SS, Shin NY, Chang JH, Kim SH, Kim EH, Kim DW, Lee SK. Prediction of methylguanine methyltransferase promoter methylation in glioblastoma using dynamic contrast-enhanced magnetic resonance and diffusion tensor imaging. J Neurosurg. 2014;121(2):367–73.CrossRefPubMed
16.
go back to reference Gupta A, Omuro AM, Shah AD, Graber JJ, Shi W, Zhang Z, Young RJ. Continuing the search for MR imaging biomarkers for MGMT promoter methylation status: conventional and perfusion MRI revisited. Neuroradiology. 2012;54(6):641–3.CrossRefPubMed Gupta A, Omuro AM, Shah AD, Graber JJ, Shi W, Zhang Z, Young RJ. Continuing the search for MR imaging biomarkers for MGMT promoter methylation status: conventional and perfusion MRI revisited. Neuroradiology. 2012;54(6):641–3.CrossRefPubMed
17.
go back to reference Moon WJ, Choi JW, Roh HG, Lim SD, Koh YC. Imaging parameters of high grade gliomas in relation to the MGMT promoter methylation status: the CT, diffusion tensor imaging, and perfusion MR imaging. Neuroradiology. 2012;54(6):555–63.CrossRefPubMed Moon WJ, Choi JW, Roh HG, Lim SD, Koh YC. Imaging parameters of high grade gliomas in relation to the MGMT promoter methylation status: the CT, diffusion tensor imaging, and perfusion MR imaging. Neuroradiology. 2012;54(6):555–63.CrossRefPubMed
18.
go back to reference Romano A, Calabria LF, Tavanti F, Minniti G, Rossi-Espagnet MC, Coppola V, Pugliese S, Guida D, Francione G, Colonnese C, et al. Apparent diffusion coefficient obtained by magnetic resonance imaging as a prognostic marker in glioblastomas: correlation with MGMT promoter methylation status. Eur Radiol. 2013;23(2):513–20.CrossRefPubMed Romano A, Calabria LF, Tavanti F, Minniti G, Rossi-Espagnet MC, Coppola V, Pugliese S, Guida D, Francione G, Colonnese C, et al. Apparent diffusion coefficient obtained by magnetic resonance imaging as a prognostic marker in glioblastomas: correlation with MGMT promoter methylation status. Eur Radiol. 2013;23(2):513–20.CrossRefPubMed
19.
go back to reference Rundle-Thiele D, Day B, Stringer B, Fay M, Martin J, Jeffree RL, Thomas P, Bell C, Salvado O, Gal Y, et al. Using the apparent diffusion coefficient to identifying MGMT promoter methylation status early in glioblastoma: importance of analytical method. J Med Radiat Sci. 2015;62(2):92–8.CrossRefPubMedPubMedCentral Rundle-Thiele D, Day B, Stringer B, Fay M, Martin J, Jeffree RL, Thomas P, Bell C, Salvado O, Gal Y, et al. Using the apparent diffusion coefficient to identifying MGMT promoter methylation status early in glioblastoma: importance of analytical method. J Med Radiat Sci. 2015;62(2):92–8.CrossRefPubMedPubMedCentral
20.
go back to reference Choi YS, Ahn SS, Kim DW, Chang JH, Kang SG, Kim EH, Kim SH, Rim TH, Lee SK. Incremental prognostic value of ADC histogram analysis over MGMT promoter methylation status in patients with glioblastoma. Radiology. 2016;281(1):175–84.CrossRefPubMed Choi YS, Ahn SS, Kim DW, Chang JH, Kang SG, Kim EH, Kim SH, Rim TH, Lee SK. Incremental prognostic value of ADC histogram analysis over MGMT promoter methylation status in patients with glioblastoma. Radiology. 2016;281(1):175–84.CrossRefPubMed
21.
go back to reference Yamashita K, Hiwatashi A, Togao O, Kikuchi K, Hatae R, Yoshimoto K, Mizoguchi M, Suzuki SO, Yoshiura T, Honda H. MR imaging-based analysis of glioblastoma Multiforme: estimation of IDH1 mutation status. AJNR Am J Neuroradiol. 2016;37(1):58–65.CrossRefPubMed Yamashita K, Hiwatashi A, Togao O, Kikuchi K, Hatae R, Yoshimoto K, Mizoguchi M, Suzuki SO, Yoshiura T, Honda H. MR imaging-based analysis of glioblastoma Multiforme: estimation of IDH1 mutation status. AJNR Am J Neuroradiol. 2016;37(1):58–65.CrossRefPubMed
22.
go back to reference Sunwoo L, Choi SH, Park CK, Kim JW, Yi KS, Lee WJ, Yoon TJ, Song SW, Kim JE, Kim JY, et al. Correlation of apparent diffusion coefficient values measured by diffusion MRI and MGMT promoter methylation semiquantitatively analyzed with MS-MLPA in patients with glioblastoma multiforme. J Magn Reson Imaging. 2013;37(2):351–8.CrossRefPubMed Sunwoo L, Choi SH, Park CK, Kim JW, Yi KS, Lee WJ, Yoon TJ, Song SW, Kim JE, Kim JY, et al. Correlation of apparent diffusion coefficient values measured by diffusion MRI and MGMT promoter methylation semiquantitatively analyzed with MS-MLPA in patients with glioblastoma multiforme. J Magn Reson Imaging. 2013;37(2):351–8.CrossRefPubMed
23.
go back to reference Eoli M, Menghi F, Bruzzone MG, De Simone T, Valletta L, Pollo B, Bissola L, Silvani A, Bianchessi D, D'Incerti L, et al. Methylation of O6-methylguanine DNA methyltransferase and loss of heterozygosity on 19q and/or 17p are overlapping features of secondary glioblastomas with prolonged survival. Clin Cancer Res. 2007;13(9):2606–13.CrossRefPubMed Eoli M, Menghi F, Bruzzone MG, De Simone T, Valletta L, Pollo B, Bissola L, Silvani A, Bianchessi D, D'Incerti L, et al. Methylation of O6-methylguanine DNA methyltransferase and loss of heterozygosity on 19q and/or 17p are overlapping features of secondary glioblastomas with prolonged survival. Clin Cancer Res. 2007;13(9):2606–13.CrossRefPubMed
24.
go back to reference Lim DA, Cha S, Mayo MC, Chen MH, Keles E, VandenBerg S, Berger MS. Relationship of glioblastoma multiforme to neural stem cell regions predicts invasive and multifocal tumor phenotype. Neuro-Oncology. 2007;9(4):424–9.CrossRefPubMedPubMedCentral Lim DA, Cha S, Mayo MC, Chen MH, Keles E, VandenBerg S, Berger MS. Relationship of glioblastoma multiforme to neural stem cell regions predicts invasive and multifocal tumor phenotype. Neuro-Oncology. 2007;9(4):424–9.CrossRefPubMedPubMedCentral
25.
go back to reference Hu YC, Yan LF, Sun Q, Liu ZC, Wang SM, Han Y, Tian Q, Sun YZ, Zheng DD, Wang W, et al. Comparison between ultra-high and conventional mono b-value DWI for preoperative glioma grading. Oncotarget. 2017;8(23):37884–895. Hu YC, Yan LF, Sun Q, Liu ZC, Wang SM, Han Y, Tian Q, Sun YZ, Zheng DD, Wang W, et al. Comparison between ultra-high and conventional mono b-value DWI for preoperative glioma grading. Oncotarget. 2017;8(23):37884–895.
26.
go back to reference Zhang L, Min Z, Tang M, Chen S, Lei X, Zhang X. The utility of diffusion MRI with quantitative ADC measurements for differentiating high-grade from low-grade cerebral gliomas: evidence from a meta-analysis. J Neurol Sci. 2017;373:9–15.CrossRefPubMed Zhang L, Min Z, Tang M, Chen S, Lei X, Zhang X. The utility of diffusion MRI with quantitative ADC measurements for differentiating high-grade from low-grade cerebral gliomas: evidence from a meta-analysis. J Neurol Sci. 2017;373:9–15.CrossRefPubMed
27.
go back to reference Pope WB, Lai A, Mehta R, Kim HJ, Qiao J, Young JR, Xue X, Goldin J, Brown MS, Nghiemphu PL, et al. Apparent diffusion coefficient histogram analysis stratifies progression-free survival in newly diagnosed bevacizumab-treated glioblastoma. AJNR Am J Neuroradiol. 2011;32(5):882–9.CrossRefPubMed Pope WB, Lai A, Mehta R, Kim HJ, Qiao J, Young JR, Xue X, Goldin J, Brown MS, Nghiemphu PL, et al. Apparent diffusion coefficient histogram analysis stratifies progression-free survival in newly diagnosed bevacizumab-treated glioblastoma. AJNR Am J Neuroradiol. 2011;32(5):882–9.CrossRefPubMed
28.
go back to reference Gupta A, Prager A, Young RJ, Shi W, Omuro AM, Graber JJ. Diffusion-weighted MR imaging and MGMT methylation status in glioblastoma: a reappraisal of the role of preoperative quantitative ADC measurements. AJNR Am J Neuroradiol. 2013;34(1):E10–1.CrossRefPubMed Gupta A, Prager A, Young RJ, Shi W, Omuro AM, Graber JJ. Diffusion-weighted MR imaging and MGMT methylation status in glioblastoma: a reappraisal of the role of preoperative quantitative ADC measurements. AJNR Am J Neuroradiol. 2013;34(1):E10–1.CrossRefPubMed
29.
go back to reference Eidel O, Burth S, Neumann JO, Kieslich PJ, Sahm F, Jungk C, Kickingereder P, Bickelhaupt S, Mundiyanapurath S, Baumer P, et al. Tumor infiltration in enhancing and non-enhancing parts of glioblastoma: a correlation with histopathology. PLoS One. 2017;12(1):e0169292.CrossRefPubMedPubMedCentral Eidel O, Burth S, Neumann JO, Kieslich PJ, Sahm F, Jungk C, Kickingereder P, Bickelhaupt S, Mundiyanapurath S, Baumer P, et al. Tumor infiltration in enhancing and non-enhancing parts of glioblastoma: a correlation with histopathology. PLoS One. 2017;12(1):e0169292.CrossRefPubMedPubMedCentral
30.
go back to reference Roy B, Awasthi R, Bindal A, Sahoo P, Kumar R, Behari S, Ojha BK, Husain N, Pandey CM, Rathore RK, et al. Comparative evaluation of 3-dimensional pseudocontinuous arterial spin labeling with dynamic contrast-enhanced perfusion magnetic resonance imaging in grading of human glioma. J Comput Assist Tomogr. 2013;37(3):321–6.CrossRefPubMed Roy B, Awasthi R, Bindal A, Sahoo P, Kumar R, Behari S, Ojha BK, Husain N, Pandey CM, Rathore RK, et al. Comparative evaluation of 3-dimensional pseudocontinuous arterial spin labeling with dynamic contrast-enhanced perfusion magnetic resonance imaging in grading of human glioma. J Comput Assist Tomogr. 2013;37(3):321–6.CrossRefPubMed
31.
go back to reference Haller S, Zaharchuk G, Thomas DL, Lovblad KO, Barkhof F, Golay X. Arterial spin labeling perfusion of the brain: emerging clinical applications. Radiology. 2016;281(2):337–56.CrossRefPubMed Haller S, Zaharchuk G, Thomas DL, Lovblad KO, Barkhof F, Golay X. Arterial spin labeling perfusion of the brain: emerging clinical applications. Radiology. 2016;281(2):337–56.CrossRefPubMed
32.
go back to reference Chahal M, Xu Y, Lesniak D, Graham K, Famulski K, Christensen JG, Aghi M, Jacques A, Murray D, Sabri S, et al. MGMT modulates glioblastoma angiogenesis and response to the tyrosine kinase inhibitor sunitinib. Neuro-Oncology. 2010;12(8):822–33.CrossRefPubMedPubMedCentral Chahal M, Xu Y, Lesniak D, Graham K, Famulski K, Christensen JG, Aghi M, Jacques A, Murray D, Sabri S, et al. MGMT modulates glioblastoma angiogenesis and response to the tyrosine kinase inhibitor sunitinib. Neuro-Oncology. 2010;12(8):822–33.CrossRefPubMedPubMedCentral
Metadata
Title
Structural and advanced imaging in predicting MGMT promoter methylation of primary glioblastoma: a region of interest based analysis
Authors
Yu Han
Lin-Feng Yan
Xi-Bin Wang
Ying-Zhi Sun
Xin Zhang
Zhi-Cheng Liu
Hai-Yan Nan
Yu-Chuan Hu
Yang Yang
Jin Zhang
Ying Yu
Qian Sun
Qiang Tian
Bo Hu
Gang Xiao
Wen Wang
Guang-Bin Cui
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-4114-2

Other articles of this Issue 1/2018

BMC Cancer 1/2018 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine