Neuroradiology Department Bellaria Hospital Bologna University of Bologna Prof. Marco Leonardi Neuroradiology Department Bellaria Hospital Bologna 1 1

Considerations on Advanced MRI Techniques in studying brain gliomas. A.Bacci, F. Menetti, P. Agati, R. Agati, M. Messia, S. Ascanio, M. Leonardi 2 2

Bellaria Hospital 3T Installation - February 2004

Advanced MR Techniques Since 2004 we have used our 3T equipment and the advanced MR Techniques (DWI, PWI, SV Spectroscopy) in studying brain tumours Our 3T experience: a careful selection, setting up and optimization of the sequences used in order to avoid unsatisfactory results is mandatory Could advanced MR Techniques increase the proportion of correctly diagnosed cases?

3T 1.5T Higher S/N ratio Longer T1, shorter T2* and T2; Reduction of r1 relaxivity (contrast media) Increase of magnetic susceptibility Increase of geometric distortion “Chemical Shift” increase More flow artifacts More SAR More acoustic noise Increase of dieletric effect 5

3T  1.5T Higher spatial resolution Higher temporal resolution “Complex” studies Different approach to the sequences Pathologic Enhancement (SE, Flair or SPGR?): T1 Morphology: T2 (no gap) Careful selection, setting up and optimization of the sequences used in order to avoid unsatisfactory results

3T  1.5T Higher spatial resolution Higher temporal resolution “Complex” studies Different approach to the sequences Pathologic Enhancement (SE, Flair or SPGR?): T1 Morphology: T2 (no gap) Careful selection, setting up and optimization of the sequences used in order to avoid unsatisfactory results

3T  1.5T Higher spatial resolution Higher temporal resolution “Complex” studies Different approach to the sequences Pathologic Enhancement (SE, Flair or SPGR?): T1 Morphology: T2 (no gap) Careful selection, setting up and optimization of the sequences used, in order to avoid unsatisfying results

When 3T? Intraaxial Tumours Microadenomas Epilepsy White matter diseases Angio-MR (Tricks, Spine..) fMRI

Tumour Protocol 8 channels phased array coil Sag SE T1-w Ax Flair T2-w Ax FRFSE T2-w Ax SE T1-w DWI 1H-MRS SV (TR 2000, TE 35) PWI (SE-EPI) Sag SE T1-w CE Ax SE T1-w CE Cor SE T1-w CE

Tumour Protocol 8 channels phased array coil Sag SE T1-w Ax Flair T2-w Ax FRFSE T2-w Ax SE T1-w DWI 1H-MRS SV (TR 2000, TE 35) PWI (SE-EPI) Sag SE T1-w CE Ax SE T1-w CE Cor SE T1-w CE

SE T1-w on 3T? (Pathologic enhancement) On 3T, Flair or SPGR T1-w sequences allow a better grey-white matter contrast than SE However we have decided to use SE (as 1.5T) because of the improved sensitivity at: pathologic enhancement after contrast media administration haemoglobin degradation products

SPGR e/o Flair T1-w vs SE Flair SE SPGR

SE SPGR

FSE T2-w at 3T (Morphology)

FSE T2-w on 3T (Morphology)

PWI It is well known that a GE-EPI sequence is more sensitive to the first pass of gadolinium than a SE sequence However we decided to use a SE-EPI sequence because of: Less sensitivity to magnetic susceptibility artifacts along the cranial theca Improved sensitivity only to contrast agent within the capillaries (i.e. neoangiogenesis) (S.Cha et coll. Radiology 2002; 223:11-29)

Magnetic susceptibility artifacts GE-EPI SE-EPI

The first pass of gadolinium (Signal decreases) SE-EPI GE-EPI

Spectroscopy Single voxel, TR 2000, TE 35 better S/N ratio and spectral resolution quantification of variation of the metabolites more than spatial distribution of metabolites (as in CSI) Relatively long acquisition time (5 min.)

SV vs CSI

SV

Equipment (Complex studies) 2 Workstations RIS-PACS 2 Workstations ADW 2 Functool 1 Brainwave 1 Sage 1 PC Windows (BrainVoyager) 1 PC Windows (Access) 1 PC Windows Presentation/Stim 2 Hardware for activation studies 1 PC Linux (LC-Model)

Work (still) in progress… For example we are now evaluating: other software to elaborate PWI studies such as Brainstat and DPTools (correction of the T1 effect) Arterial Spin labelling High Order Shimming (Spectroscopy)

Use of advanced MR Techniques (Our experience) Individual cases More systematic way, in population studies Glioma grading Recurrent/residual tumours vs treatment related changes (e.g. radionecrosis)

Use of advanced MR Techniques (Our experience) Individual cases More sistematic way, in population studies Glioma grading Recurrent/residual tumor vs treatment related changes

Glioma (grade?)

Diffusion (High cellularity)

(High Neoangiogenesis) Perfusion (High Neoangiogenesis)

(Intralesional Necrosis) Spectroscopy (Intralesional Necrosis)

???? Cho NAA Lip 31 31

Follow-up (Lymphoma) 32 32

Radiation injury or recurrent tumour? Cho Cr NAA mI Lip 33

Recurrent tumour 17/07/08 Cho Cr NAA mI Lip 17/07/08 34

Use of advanced MR Techniques (Our experience) Single cases More systematic way, in population studies Glioma grading Recurrent/residual tumour vs treatment related changes

Glioma grading MRI is capable of providing important morphological information but it is not very accurate in tumour grading (20- 30% of gliomas are misclassified) * Could DWI, PWI and 1H-MRS studies increase the proportion of correctly diagnosed cases? Is it possible to define threshold values? *Neuroradiology 2002; 44:371-381 Radiology 1990;174:411-415 Radiology 1999:211:791-798 Neuroradiology 1992; 34:463-469 36

MRI in gliomas Li X et al. JMRI 16:229-237, 2002 37 37

MRI in gliomas Addition of 1H-MRS and perfusion information to MRI studies significantly increases the proportion of correctly diagnosed cases Sensitivity, specificity, PPV and NPV to differentiate between high and low-grade gliomas (160 patients) with: MRI: 72.5%, 65%, 86.1%, 44.1% rCBV+Cho/Cr+Cho/NAA: 93.3%, 60%, 87.5%, 75.0% Law M et al. AJNR 24:1989-98, 2003 38

Our Study Grade II (n=25) Grade III (n=21) Grade IV (n=31) : GBM 11 Astrocytomas 12 Oligodendrogliomas 2 Oligoastrocytomas Grade III (n=21) 11 Anaplastic Astrocytomas 5 Anaplastic Oligodendrogliomas 4 Anaplastic Oligoastrocytomas 1 Gliomatosis Grade IV (n=31) : GBM Il nostro studio è stato effettuato tramite l’analisi retrospettiva di 77 pz (2004 2010) con gliomi cerebrali… 39

Our experience Histopathologic evaluation All patients underwent preoperative MR examination on a 3T system: MRI DWI (ADC ratio) PWI (rCBV ratio) SV MRS Histopathologic evaluation 40 40

ROI (ADC)

ROI (rCBV)

SV Spectroscopy

LC-model Analysis SD = 20

II grade vs III+IV grade Statistical analysis (Test Brunner Dette Monk) II grade vs III+IV grade necrosis <0.001 Adc min Adc max n.s. rCBV min <0.01 rCBV max Enhancement Lac/Cre <0.05 mI/Cre (GPC+PCh)/Cre (NAA+NAAG)/Cre (Glu+Gln)/Cre (Lip13a+Lip13b)/Cre ------- (MM09+Lip09)/Cre NAA/Cho 46

Evidence of statistically significant differences between two classes (i.e. grade II and grade III+IV gliomas) is of limited practical utility due to overlapping values between different glioma grades Our aim should be to identify threshold values to define the grade of a glioma in individual cases

Cart Software It is a decision tree that automatically sifts large, complex databases, searching for and isolating significant patterns and relationships. CART can reveal important data relationships (and threshold values) that could remain hidden using other analytical tools.

Grade II vs III+IV MRI (enhancement and necrosis) Actual Class Total Cases Percent Correct 2 N=31 34 N=46 2 25 84,00 21 4 34 52 80,77 10 42 Total: 77,00   Average: 82,38 Overall % Correct: 81.82 49

Grade II vs III+IV MRI and Advanced Techniques Lac/Cre 3.45 Actual Class Total Cases Percent Correct 2 N=29 34 N=48 2 25 96,00 24 1 34 52 90,38 5 47 Total: 77,00   Average: 93,19 Overall % Correct: 92.21 ADC min 1.09 rCBV max 2.02 mI/Cre 1.36 50

Grade II vs III+IV Advanced Techniques Lac/Cre 3.45 Actual Class Total Cases Percent Correct 2 N=29 34 N=48 2 25 96,00 24 1 34 52 90,38 5 47 Total: 77,00   Average: 93,19 Overall % Correct: 92.21 ADC min 1.09 rCBV max 2.02 mI/Cre 1.36 51

Grade II vs III+IV MRI + DWI, PWI, 1H-MRS DWI, PWI, MRI 1H-MRS Accuracy 0.82 0.92 Sensitivity 0.81 0.90 Specificity 0.84 0.96 PPV 0.91 0.98 NPV 0.68 0.83

WARNING The sample (77 patients) analyzed is too small to be representative of the entire population (all patients affected by glioma) For this reason these results cannot be generalized As previously discussed we made precise choices about technical parameters

Conclusion I It is not possible to definitively predict the histological grade of a glioma even if we use DWI, PWI and Spectroscopic parameters However, our experience shows that the use of these parameters can be useful not only from a statistical point of view but also in the evaluation of individual patients, through identification of threshold values

Conclusion II It is necessary to: examine more patients homogenize acquisition and analysis techniques The aim is not to state the superiority of one technique above the other, but to improve the “overall diagnostic and therapeutic performance”

Thank you for your kind attention… I would like to thank my colleagues of: Neuroradiology, Neurosurgery and Neurooncology and in particular , Prof. Patrizia Agati of Statstical Department, Bologna University Thank you for your kind attention…

Statistical analysis Accuracy: quantity of correct diagnosis Sensitivity: proportion of lesions determined to be high-grade on MRI of all high-grade lesions at histological evaluation Specificity: proportion of lesions determined to be low- grade on MRI of all low-grade lesions at histological evaluation PPV (positive predictive value): proportion of lesions correctly classified as high-grade of all classified as high-grade NPV (negative predictive value): proportion of lesions correctly classified as low-grade of all classified as low-grade

Grade III vs IV MRI (enhancement and necrosis) Actual Class Total Cases Percent Correct 3 N=19 4 N=33 3 21 76,19 16 5 4 31 90,32 28 Total: 52,00   Average: 83,26 Overall % Correct: 84,62 Accuracy 0,85 Sensitivity 0,90 Specificity 0,76 PPV VPN 0,84 58

Grade III vs IV MRI and Advanced Techniques Lip13/Cre 20.66 Enh. 0,1 Actual Class Total Cases Percent Correct 3 N=19 4 N=33 3 21 80,95 17 4 31 93,55 2 29 Total: 52,00   Average: 87,25 Overall % Correct: 88,46 Enh. 0,1 Accuracy 0,88 Sensitivity 0,94 Specificity 0,81 PPV VPN 0,89 ADC min 1.12 59

Grade III vs IV Advanced Techniques Actual Class Total Cases Percent Correct 3 N=27 4 N=25 3 21 90,48 19 2 4 31 74,19 8 23 Total: 52,00   Average: 82,33 Overall % Correct: 80,77 Accuracy 0,81 Sensitivity 0,74 Specificity 0,90 PPV 0,92 VPN 0,70 60