Functional MRI in Oncology
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1 Functional MRI in Oncology J.O. Barentsz Chair for Research Department of Radiology Radboud University Medical Center, Nijmegen, NL
2 Learning objectives to give an introduction of functional MRI in oncology to show the clinical potential of functional MRI DCE MRIDWI MR-Spectroscopy Cell Specific: USPIO MnCl
3 Functional MRI in Oncology Introduction Technique Clinical Applications New developments DCE MRIDWI MR-Spectroscopy Cell Specific: USPIO MnCl
4 Multi-modality Learning MRI: Objectives anatomy 1 mm DCE MRIDWI MR-Spectroscopy Cell Specific: USPIO MnCl
5 Functional information by: 1. DCE- MRI: I.V. Gd-contrast: tumor enhancement (neovascularity) 2. Diffusion Weighted Imaging : H 2 0 motion 3. MR-Spectroscopy: metabolic information 4. Specific contrast agents: cell specific - USPIO: macrophages - Mn, SPIO: liver (hepatocyte, Kupfercel) - SPIO: Dendritic Cel-labelling DCE MRIDWI MR-Spectroscopy Cell Specific: USPIO MnCl
6 Functional information by: 1. DCE- MRI: I.V. Gd-contrast: tumor enhancement (neovascularity) 2. Diffusion Weighted Imaging : H 2 0 motion 3. MR-Spectroscopy: metabolic information 4. Specific contrast agents: cell specific - USPIO: macrophages - Mn, SPIO: liver (hepatocyte, Kupfercel) - SPIO: Dendritic Cel-labelling DCE MRIDWI MR-Spectroscopy Cell Specific: USPIO MnCl
7 Cancer: angiogenesis Introduction: DCE MRI perfused microvessel area capillary permeability leakage into extra cellular leakage space (V e ) DCE MRIDWI MR-Spectroscopy Cell Specific: USPIO MnCl
8 Multi-modality MRI: DCE T2W MRI ADC
9 Multi-modality MRI: DCE Histology Ca 3TP Ca PIN PIN Ca Ca Ca PIN PIN Ca Ikeda DM et al. J Magn Reson T2-W Imaging 2001; 13: Ca Ca Dyn T1-W T2b Histo-Staging T2b MRI-Staging T2b Neubauer et al. Br J Radiology 2003; 76:3-12 T2-W T2b Bloch et al, Radiology. 2007; ;245(1):
10 Multi-modality MRI: DCE DCE MRI: PCa increased vascular permeability DCE MRIDWI MR-Spectroscopy Cell Specific: USPIO MnCl
11 What do we see with DCE-MRI? A A A A B B T B B pre chemotherapy post chemotherapy DCE MRIDWI MR-Spectroscopy Cell Specific: USPIO MnCl
12 What do we see with DCE-MRI? S I (a/u) S I 160 Aorta(a/u) 120 Aorta 80 Tumor 80 pre therapy Bladder wall Tumor post 2 MVAC Bladder wall Time (s) Time (s) pre chemotherapy post chemotherapy DCE MRIDWI MR-Spectroscopy Cell Specific: USPIO MnCl
13 What do we see with DCE-MRI? pre chemotherapy post chemotherapy DCE MRIDWI MR-Spectroscopy Cell Specific: USPIO MnCl
![r 1 [Gd] map 1 min after injection](/docs-images/81/84748623/images/14-3.jpg "Histology surface of perfused")
14 What do we see with DCE-MRI? Perfused microvessels (Hoechst 33342) r 1 [Gd] map 1 min after injection Histology surface of perfused microvessels Hypoxic cells (Pimonidazole) DCE MRIDWI MR-Spectroscopy Cell Specific: USPIO MnCl
15 What do we see with DCE-MRI? linear relationship between Gd-contrast uptake rate and the surface of perfused microvessels, whereas pathology only shows microvessel density therefore, dynamic MRI can provide additional information about tumor neovascularity DCE MRIDWI MR-Spectroscopy Cell Specific: USPIO MnCl
16 Technique: DCE-MRI DCE-MRI (/2 sec) B H B H T1: hematoma = white T2: hematoma, PCa, BPH/CG = dark DCE MRIDWI MR-Spectroscopy Cell Specific: USPIO MnCl
17 DCE MRI: Where aaadce-mri is the tumor? K trans DCE MRIDWI MR-Spectroscopy Cell Specific: USPIO MnCl
18 Mammography: negative DCE MRIDWI MR-Spectroscopy Cell Specific: USPIO MnCl
19 Breast Ca: DCE-MRI DCE MRIDWI MR-Spectroscopy Cell Specific: USPIO MnCl
20 Quantification: [Gd max ], late wash
21 Quantification: Ktrans, EV, Kep
22 DCE-MRI: differentiation DCE MRIDWI MR-Spectroscopy 1 image / Cell 15 Specific: sec USPIO MnCl
23 DCE-MRI: differentiation centrifugal enhancement 1 image / 1.25 sec centripetal enhancement DCE MRIDWI MR-Spectroscopy Cell Specific: USPIO MnCl
24 Mammography: negative
25 MRI: 4.7 cm breast cancer 3D MRI dynamic MRI DCE MRIDWI MR-Spectroscopy Cell Specific: USPIO MnCl
26 UBC: follow up chemotherapy Pathology plain MRI NR R NR 5 3 R dyn MRI Pathology NR R NR 8 1* R * response after 4 MVAC
27 UBC: T3a N+ M0 pre MVAC T t = 5
28 UBC: T3a N+ M0 post 2 MVAC T t = 5
29 UBC: T3a N+ M0 post 6 MVAC T
30 Boss et al. JMR 2001; 13: Cervical Cancer: pre radiotherapy
31 CC: 6 weeks post radiotherapy sec persisting early enhancement correlates with progressive disease
32 Functional information by: 1. DCE- MRI: I.V. Gd-contrast: tumor enhancement (neovascularity) 2. Diffusion Weighted Imaging : H 2 0 motion 3. MR-Spectroscopy: metabolic information 4. Specific contrast agents: cell specific - USPIO: macrophages - Mn, SPIO: liver (hepatocyte, Kupfercel) - SPIO: Dendritic Cel-labelling DCE MRI DWI MR-Spectroscopy Cell Specific: USPIO MnCl
33 Multi-modality MRI: DWI Brownian movement of water DWI: cell density, extracellular space, tortuosity, integrity of cellular membranes & extent of glandular tissues Tightly packed cellular tissue Well organised tissue Organised glandular tissue
34 Multi-modality MRI: function DWI: PCa restricted H 2 O movement DCE MRIDWI MR-Spectroscopy Cell Specific: USPIO MnCl
35 DWI shows aggression Correlation between CNR-ADC: GS Pearson Correlation r = 0.83 p < 0.01
36 Aggression: DWI Gleason Score = 6 (madc = 1.24 x 10-3 mm 2 /s; CNR = 2.2) ADC Map Prostatectomy + Tumor Gleason Score = 7 (madc = 0.99 x 10-3 mm 2 /s; CNR = 3.3) ADC Map Prostatectomy + Tumor Gleason Score = 9 (madc = 0.66 x 10-3 mm 2 /s; CNR = 5.8) ADC Map Prostatectomy + Tumor
37 Functional information by: 1. DCE- MRI: I.V. Gd-contrast: tumor enhancement (neovascularity) 2. Diffusion Weighted Imaging : H 2 0 motion 3. MR-Spectroscopy: metabolic information 4. Specific contrast agents: cell specific - USPIO: macrophages - Mn, SPIO: liver (hepatocyte, Kupfercel) - SPIO: Dendritic Cel-labelling DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
38 Multi-modality MRI: function MRS: PCa Choline/Citrate ratio DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
39 Multi-modality MRI TSR Anatomic: 5/5 DCE: 5/5 20/20 MRS: 5/5 DWI: 5/5
40 Localization: DCE-MRI T2-w washout Ktrans DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
41 Futterer et al Radiology 2006 Localization: DCE-MRI, MRS DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
42 Localization: DCE-MRI DCE-MRI and MRSI are more accurate in localizing PCa than T2-w MR imaging Combining sensitivity of DCE-MRI and specificity of MRSI provides accurate tumor localization Fütterer, Radiology 2006 DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
43 van Lin, Int J of Radiat Oncol Med Phys 2006 More accurate IMRT-planning High dose to DIL, low dose to surrounding tissues DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
44 Breast MRS: improved specificity DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
45 PCa MRS at 3T 1.5T 3.0T citrate choline choline citrate creatine creatine Benign choline 1.5T 3.0T citrate choline creatine citrate creatine Cancer
46 Node: MRS at 3T DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
47 Node: MRS at 3T DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
48 Functional information by: 1. DCE- MRI: I.V. Gd-contrast: tumor enhancement (neovascularity) 2. Diffusion Weighted Imaging : H 2 0 motion 3. MR-Spectroscopy: metabolic information 4. Specific contrast agents: cell specific - USPIO: macrophages - Mn, SPIO: liver (hepatocyte, Kupfercel) - SPIO: Dendritic Cel-labelling DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
49 Functional Information 1. DCE- MRI: I.V. Gd-contrast: tumor enhancement 2. MR-Spectroscopy: metabolic information 3. Specific contrast agents: cell specific - USPIO: macrophages - Mn, SPIO: liver (hepatocyte, Kupfercel) - SPIO: Dendritic Cel-labelling DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
50 USPIO Nanoparticles Ferumoxtran-10 (Sinerem) Size: 21 nm R1: 17 mmsec-1 R2: 48 mmsec-1 DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
51 Nodes: Ferumoxtran-10 MRI Metal in the MR machine gives distortion of the magnetic field DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
52 Hip prosthesis DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
53 20 nm Nanoparticles Ferumoxtran-10 (Combidex / Sinerem) MR Lymphography
54 Micro Macro Benign.
55 Enhanced Sensitivity
56 MRL results PCa Node-to-node (n=334) accuracy 76% 97% specificity 90% 97% sensitivity 35% 90%* NPV 80% 98% PPV 56% 95% Harisinghani & Barentsz et al NEJM 2003
57 Dutch study: 13 centres Patient-to-patient correlation (n=375) CT MRL accuracy 86% 91% specificity 97% 93% sensitivity 34% 82% 93% NPV 89% 97% Probability of correct diagnosis: MRL 91% PLND + CT 89% Heesakkers et al Lancet Oncology 2008
58 Meta-anaysis Unenhaced MRI USPIO-MRL Will O. et al. LancetOncol 2006
59 c. Saleh, Dusseldorf, Germany Nodes: Head and Neck T2 TSE/SPIR T1 TSE T2 TSE/SPIR DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
60 Nodes: Breast Cancer Normal Metastatic Sentinel node + Primary tumor DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
61 Question How do oncologists and surgeons use this information? DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
62 MRL: clinical indications preoperative nodal staging: improved patient selection response to therapy and recurrence detection better assessment of nodes allows more precise radiotherapy planning DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
63 Pre-operative nodal staging negative MRL (NPV>98%) MRL can replace PLND positive MRL with small nodes MRL can serve as a roadmap for PLND positive MRL with large nodes image guided biopsy (this saves LND) DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
64 Standard Bilateral PLND: PCa Includes: obturator nodes Excludes: - internal nodes, - pre-sacral - common iliac, - external iliac nodes Extended BPLND: Positive nodes increased to 24 % Burkhart et al 2004
65 295 patients; 44 positive 6% 11% 59% obturator 20% internal/presacral 4% 20% 11% common iliac 6% para aortal MRL detected in 41% patients Positive nodes outside routine PLND 59% 4% external (lateral) Heesakkers et al Radiology in press
66
67 pre-ferumoxtran m n post- Ferumoxtran
68 Trans-gluteal CT-biopsy DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
69 MRL: clinical indications preoperative nodal staging: improved patient selection response to therapy and recurrence detection better assessment of nodes allows more precise radiotherapy planning DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
70 Recurrence
71 Recurrence
72 Recurrence
73 Response to therapy pre ADT post ADT DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
74 MRL: clinical indications preoperative nodal staging: improved patient selection response to therapy and recurrence detection better assessment of nodes allows more precise radiotherapy planning DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
75 IMRT planning Accurate mapping of positive MRL nodes for IMRT has the potential: - to reduce toxicity in normal tissue - allows higher doses on the positive nodes DCE MRI MR-Spectroscopy Cell Specific: USPIO MnClc
76 IMRT planning: nodes
77
78 CT/MRL fusion
79 c. Dattoli Post Brachy: PSA 2 Original treatment volumes
80 DNL IMRT DCE MRI MR-Spectroscopy Cell Specific: USPIO MnClc
81 c. Dattoli DNL IMRT DCE MRI MR-Spectroscopy Cell Specific: USPIO MnClc
82 c. Dattoli DNL IMRT DCE MRI MR-Spectroscopy Cell Specific: USPIO MnClc
83 Question What about high field strength? DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
84 3T: 11 C Choline PET/CT negative DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
85
86
87 Functional Information 1. DCE- MRI: I.V. Gd-contrast: tumor enhancement 2. MR-Spectroscopy: metabolic information 3. Specific contrast agents: cell specific - USPIO: macrophages - Mn, SPIO: liver (hepatocyte, Kupfercel) - SPIO: Dendritic Cel-labelling DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
88 Oral MnCl: hepatocyte specific Pre MnCl Post MnCl DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
89 Oral MnCl: bile ducts + bowel DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
90 Gall bladder, bile ducts, bowel T1-w GRE DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
91 MnCl MRI versus CE-CT Oral MnCl MRI CE MS-CT DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
92 Functional Information 1. DCE- MRI: I.V. Gd-contrast: tumor enhancement 2. MR-Spectroscopy: metabolic information 3. Specific contrast agents: cell specific - USPIO: macrophages - Mn, SPIO: liver (hepatocyte, Kupfercel) - SPIO: Dendritic Cel-labelling DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
93 SPIO: Kupfer cell specific Focal Nodular Hyperplasia pre SPIO post SPIO DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
94 Functional Information 1. DCE- MRI: I.V. Gd-contrast: tumor enhancement 2. MR-Spectroscopy: metabolic information 3. Specific contrast agents: cell specific - USPIO: macrophages - Mn, SPIO: liver (hepatocyte, Kupfercel) - SPIO: Dendritic Cel-labelling DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
95 Imaging of dendritic cells at 3T In vivo tracking of DCs is done by labeling with radionuclides & scintigraphy need for: - better spatial resolution - double labeling Purpose: Monitoring the application and trafficking of DCs in humans after magnetic labeling (SPIO) by MRI DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
96 Treatment & imaging schedule day Prescan MRI c Peripheral blood US Intranodal Vaccination 111 In-oxine Scintigraphy Lymph node dissection MRI Monocytes Interleukin-4 Granulocyte-monocyte stim. factor Immature DCs SPIO (200 gr Ferumoxide) Endorem Maturation medium Mature DCs Mature DCs Pulsed with melanoma peptides gp100 ; tyrosinase Ex vivo MRI Histology
97 T1-TSE insensitive, T2*-GRE sensitive for Fe T1-TSE T2*-GRE DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
98 Results: human imaging Patient right left Injection correctly in LN % Migration (scintigraphy) Scintigraphy LN + MR LN + Yes 40% 2 4 Yes 1% 1 3 Yes 4.2% 4 5 Yes 1.7% Partly 17% 2 2 * 5Seen on MRINo * 0% No * 0% No * 0% No * 0% 1 1 DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
99 Labelled DCs: correct injection in LN 1 1 Before vaccination After vaccination DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
100 Labeled DCs injection not in LN LN In peri-nodal fat LN Before vaccination After vaccination DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
101 Detection of labeled DCs migrated to draining LN: MRI>Scintigraphy Scintigraphy T2*-GRE MRI Scintigraphy 1-2% of 7.5 x 10 6 cells still visible (3T) = 10 Coronal 5 cells DCE MRI MR-Spectroscopy Cell Specific: USPIO MnCl
102 Conclusions / take home messages MRI provides both high resolution images as well as unique functional information this can be used to improve - tumor assessment / differentiation - staging - therapy response evaluation / recurrence
103 Thank you for your attention
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