![2012.10.30.
Gene Activation: hsp-80
hsp- Summary
Image guided FUS is a new modality for non-invasive
interventions deep in soft tissue
Thermal ablation clinically established
Intense research on treatment strategies based on
mechanical effects
Very promising results in animal models for targeted
drug delivery based on transient BBBD / Sonoporation
Intense research on development of nano-constructs
for imaging and therapy
Clinical studies to come soon
Slide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin
Clot Lyses for Stroke
Outlook
Thank you !
Neurological
Disorders
Targeted Drug Delivery
In-vitro T2W MRI before
[l] and after[r] sonication
Slide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin
Thank you for your attention!
Presentation credits:
Dr. András Jakab, M.D. Ph.D.
Dr. Ervin Berényi, M.D. Ph.D.
Dr. Miklós Emri (Nuclear Medicine Institute, UD)
Prof. Ernst Martin – Uni. Zürich (Focused Ultrasound)
Beat Werner – Uni. Zürich (Focused Ultrasound)
22](https://image.slidesharecdn.com/imageguidedtherapy2012engpdf-121030100554-phpapp01/85/Week-4-Image-guided-therapies-22-320.jpg)
Week 4. Image guided therapies.
- 1. 2012.10.30. Multimodal Imaging in Neurosciences Course COURSE FAQ Forthcoming lectures: 16. October – „IGT lecture” 23. October – NO LECTURE, holiday 30. October – MR Spectroscopy 6. November – PET + Final Test Test: - Basic imaging techniques, what are they - 5-10 easy, simple choice questions Image guided therapies in - If November 6. is not good for everyone, I will organize extra neurological sciences and VR time for getting the short test done Dr. András Jakab, MD, PhD Study material: Lecture material will be distributed in PDF 2 wks before the test. Diagnostic neuroimaging modalities What is multimodality? CT – Computed Tomography Structural MRI Combining images and information from multiple Brain anatomy Fine brain anatomy imaging tools, devices Stereotactic reference frame Vascular structure Anatomical alignment of images Fusion display, co-analysis of multiple Intra-operative imaging Diffusion, perfusion MRI information sources modalities, open MRI, low- Fine pathological field information What is needed for multimodality? Positron Emission multi-modal imaging for planning Using CT, PET, MRI, SPECT, EEG, … MR Spectroscopy Tomographyimage-guided neurological interventions PET Brain metabolism Brain metabolism Biochemical mapping Hybrid devices – PET-CT, PET-MRI Brain function Image processing skills to create image fusions, etc. Electro encephalography, Functional MR imaging fMRI LORETTA, Brain function Magnetoencephalography Overview of the lecture 1. Image guided therapy – basics and the modalities used 2. Stereotactic functional neurosurgery 3. Radiosurgery and planning R di d l i 1. 1 Image guided therapy - 4. Focused ultrasound basics neurosurgery 5. VR applications in surgery 1
- 2. 2012.10.30. Image guidance AMIGO – Harvard, Boston • Using preoperative images to define target volumes in a reference space Treatment planning w/ Intraoperative imaging with • Using intraoperative preoperative imaging MRI imaging to monitor Surgical robot for biopsies treatment – Intraoperative ultrasound – Intraoperative low-field MRI – Intraoperative high-field Intraoperative open MRI, Brigham open MRI and Women’s Hospital, Harvard, Boston (credits: Prof. Ferenc Jolesz) Intraoperative MR imaging • Medtronic Polestar • Low field (0.1-0.3T) • Brain shift – a real problem • Use of nonmagnetic tools 2. 2 Stereotaxy in functional neurosurgery Why use stereotaxy in What is stereotactic? neurosurgery? • Space, spatial • Coordinate frame • Very high (<1-2mm) precision needed of the brain: • Minimal invasive procedures – Intrinsic – Electrode implantation for ablation – extrinsic – Permanent electrode implantation (DBS) – Biopsy sampling from the brain • Procedures without opening the skull – Radiosurgery, LINAC, Gamma Knife, Cyberknife – Focused ultrasound surgery 2
- 3. 2012.10.30. Brain biopsy Imaging for brain biopsy • Indications • CT – Tumor suspect (enhancing CT, MRI, lesion) • MRI (T1/T2+Contrast) – Inflammation, Neurodegeneration, unknown • Pathology+Radiological • Procedure (1-2 hours): consultation – where to take – St Stereo f frame attachment tt h t the sample f h l from?? – Computed tomography – Planning – General anaesthesia – Small craniotomy – Dexamethasone – Control scan(s) Functional neurosurgery Thalamotomy / pallidotomy • Parkinson disease – associated tremor • Alleviating symptoms by modifying alleviation functional areas of the brain, subcortical • Essential tremor (unkown ethiology) areas • Two main approaches: – Permanently cutting fiber pathways, destroying specific nuclei Thermoablation Targets: – Retuning / stimulating fiber pathways, specific VIM nucleus nuclei in the brain Subthalamic Deep brain stimulation nucleus, PTT Ventral Pallidum Thalamotomy • Fantom pain (after amputation) • Intractable tumor / stroke pain in limbs etc. • CL / CM nucleus – central lateralis / centré median 3
- 4. 2012.10.30. Deep brain stimulation (DBS) • FDA approval: 1997 • Implant in brain + subcutaneous stimulator (~pacemaker) • Retuning functional pathways („arrhythmia”) Deep brain stimulation Procedure • Indications: • Localization, stereotaxy – Chronic pain, PD tremor, ET, dystonia • Electrode trajectory: – Tourette, OCD, Major • Trials and depression d i monitoring • Pre/postop imaging – Parkinsons • Subthalamic nucleus • Globus pallidus interna • Zona incerta • Pallidothalamic fibers Targeting scheme Targeting scheme • 2. Defining targets on the patient’s coordinate frame (using CT+MRI) • 1. Target definition using stereotactic atlas Manually finding AC, of the human thalamus and basal ganglia PC points on scans (histology) Finding landmarks of the reference frame (stereotactic frame attached to the head) Getting x,y,z coordinates for your target Reference: AC-PC coordinate system 4
- 5. 2012.10.30. 3. Radiosurgery Gamma ART 6000N Rotating Gamma System American Radiosurgery Inc., San Diego, CA, USA Challenges • Morphological imaging by MRI – 3D isotrop voxel acquisitio • Good tissue contrast • Good signal-to-noise •only 30 Co60 sources • Minimal image distortion •Rotating sources •Collimator size: 4, 8, 14, 18 mm • Optimal image resolution •Stereotactic frame required •0,3 mm accuracy – MRI as reference system? •Source half-life approx. 5 yrs • Robust CT method is necessary Challenges of multimodality – fMRI – DTI, fibertracking – MRS, MRSI • Postprocessing – Registration, image fusion (need fast) • PET, SPECT 5
- 6. 2012.10.30. 3D T1 weighted images 3D T2 weighted images • 1,2x1,2x1,2 mm • 140 slices • 0,7x0,7x0,7 mm • 6 minutes • 40-60 slices • Gd contrast agent • 4 minutes Our imaging protocolls 3D TOF acquisition • 1,2x1,2x1,2 mm (+indications) • 190 slices • Metastasis, meningeoma • 6 minutes • AVM • g Gd contrast agent • Cavernoma • Acustic neurinoma • Hypophysis microadenoma AVM MRA Automatic radiologic image processing Automated CT/MRI registration CT/T1/T2 (gammaknife, neurosurgery automated T1 standardization, segmentation (neurosurgery, neurology) ImageSorter DICOM server automated Tensor space calculations and DWI, T1 regularization (neurosurgery, neurology) automated automated fMRI, T1, T2 SPM analysis SPM analízis (neurosurgery, neurology) automated Pet & Mri PET-MR registration and roi analysis 6
- 7. 2012.10.30. T1-CT registration for radiosurgery (gamma-knife) Image registration, alignment gamma knife - Automatic (maximalisation relative entropy) - Manual correction (with internal „landmarks”) To this time, manual correction was necessary in 60% of the cases - Optimalised automatic registration T1-CT Fiesta-CT TOF-CT Extracranial metastasis Acoustic neurinoma treatment plan (epipharynx) • 1 kezelési tervet betenni Acustic neurinoma Pre-treatment 6 months post 12 months post 7
- 8. 2012.10.30. Trigeminal neuralgia Treating trigeminal neuralgia CT and FIESTA imaging Validation of the T1-CT optimized Dataflow Service available via a DICOM-server registration method REFERENCE IMAGES AUTOMATICALLY REGISTERED IMAGES MNI and M3I tools: S01 BrainCAD: •Dicom-minc conversion • 2D fusion •Segmentation Comparison using normalized S02 •Automatic registration SPM-analysis • 3D fusion relative entropy • Fiber visualization •Spatial standardization •Automatic region analysis S03 AUTOMATIC INTERACTIVE Sn PRESENTATION MRI data revision by experts IMAGE PROCESSING IMAGE PROCESSING (neuronavigation) (occassionaly manual registrations) Further fancy options CT-DTI registration PET/SPECT images T2, PD etc. SPM images Precise T1-CT registration Structures defined in the space of a brain atlas DTI parametric images 8
- 10. 2012.10.30. Proton therapy DTI + MRI data in the CT frame. Metastatic disease, 55/M ( Gamma Radiosurgery Centre, Debrecen ) The proton advantage: Medulloblastoma PHOTONS “dose bath” Nasopharynx Photons (IMRT) Protons Dose bath 100% 60% PROTONS 10% The proton advantage: Paraspinal Photons Protons Dose bath 4. 4 Focused ultrasound neurosurgery 10
- 11. 2012.10.30. Energy Conversion and Transport in Biosystems (09.12.10) Welcome Non-invasive Beat Werner MR-Center Interventions University Children’s Hospital Zurich with www.kispi.uzh.ch/mr beat.werner@kispi.uzh.ch beat werner@kispi uzh ch Focused dipl. phys. ETH Ultrasound MR-Physics Beat Werner HIFU surgery since 2005, MR-Center research project as part of NCCR Co-Me University Children‘s Hospital Zurich Slide credits: Beat Werner, Ernst Martin Intro: Image guided interventions Intro: Image guided interventions Image Guided Interventions Improve accuracy Decrease intervention risks Minimally invasive / Non-invasive Interventions Slide credits: Beat Werner, Ernst Martin Planning and navigation Complex interventions in cranio-maxillo-facial surgery. Slide credits: Beat Werner, Ernst Martin Intro: Image guided interventions Intro: Image guided interventions "Multimodal" Imaging Enabling technologies used here: Multimodal: US, CT, MR, ... MR Multidomain: Anatomical, physiological, statistical Closed-loop intervention control information US field calibration Multi-Timescales: Static (Pre-/intra-intervention), Focused Ultrasound Realtime Mechanical / Thermal therapy Augmented reality: condition, fuse, model (Targeted) drug delivery Enhanced visualization: 2D, 3D, ..., force feedback (Targeted) drug activation Nano-Particles Molecular markers Contrast agents Drug carriers Computer-assisted support in ORL surgery Werner, Ernst Martin Slide credits: Beat Therapeutic devices Beat Werner, Ernst Martin Slide credits: 11
- 12. 2012.10.30. Motivation: Non-invasive HIFU Surgery Non- Motivation: Clinical value of MR guided Focused US Surgery Excellent soft tissue contrast for target localization Local therapy Non invasive Non-invasive No dose accumulation effects No long term toxicity Immediate result – no radiation necrosis Treatments can be repeated Closed-loop image guidance Real time monitoring Slide credits: Beat Werner, Ernst Martin Imaging <-> Focused Ultrasound <- Phased- Phased-Array Transducers Imaging (Diagnostics): want wide field of view with Phased-Array Transducer = Array of Transducers uniform low acoustic intensity Each transducer element controlled individually Transducer phases define superposition pattern of waves -> Electronic steering HIFU (Intervention / Therapy): Constructive Destructive Shift want small focal spot with Slide credits: Beat intensity high acoustic Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin Beam Forming / Focusing Phased- Phased-Array Transducers Linear Array -> Plane Wave Geometric focusing Lens focusing Electronic beam forming Electronic steering Spherical Array -> Focus Slide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin 12
- 13. 2012.10.30. Phased- Phased-Array Transducers Phased- Phased-Array Transducers Spherical Array Spherical Array Pressure Distribution Temperature Distribution Electronic Steering Slide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin Biological Effects Medical applications The effects of Ultrasound on biological tissue Lithotrypsy are a field of active research Physiotherapy Many effects are not well understood HIFU Surgery (Tissue ablation) Effects include: Blood-Brain-Barrier-Opening thermal th l non-thermal non thermal Cell sonoporation Targeted g mechanisms ultrasound mechanisms drug delivery Local drug activation energy non-cavitation mechanisms cavitation mechanisms Vessel occlusion absorption Thrombolysis temperature increase radiation force non-inertial cavitation inertial cavitation Nerve activation / blockage ablation enhanced Delivery lithothripsy Slide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin Development of HIFU Technology Development of HIFU Technology 1880 Piezoelectric effect (P. & J. Curie) 1918 Sonar (Langevin) W.Fry, circa 1960, with 4-beam HIFU system for neuro- 4- neuro- 1927 Effects on biological tissues (Looms, Wood) surgery in his 1942 First HIFU lesions in animal brains (J.Lynn, T.Putnam) bioacoustics 1950– 1950–2000 Pioneer work on (a) HIFU effects on tissue (brain laboratory. tumors) and (b) LIU for soft tissue visualization (W Fry (W.Fry & F.Fry). 1951– 1951–1960 Technical development at MGH (Cosman) 1951– 1951–1967 HIFU stereotactic neurosurgery against pain, psycho- psycho- neuroses, anxiety, depression and epilepsy (Lindstrom) and Radiosurgery (Leksell) gamma knife Mid 1970s 1970s First stereotactic HIFU brain surgery with open cranium (F.Fry & R.Heimburger). Slide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin 13
- 14. 2012.10.30. Development of HIFU Technology Image guidance First US-image guided HIFU system to treat US-Imaging brain cancer patients. Cheap W.Fry in the 1970s Limited feedback F.Fry and R.Heimburger 1974 MR Expensive High-resolution imaging Closed loop process Slide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin Development of HIFU Technology HIFU Surgery for Uterine Fibroids Key technologies: 1. Phased array transducers 2. Acoustic field modelling 3. MR imaging for accurate real time monitoring Early 1990s l 1990s 990 Ultrasound phased arrays (Hynynen) l d h d ( ) Mid–1990s Mid–1990s MRI thermometry (Jolesz) 2001 First integrated MRgHIFU system (InSightec) 2001 Fibroadenoma of Breast and Uterine Fibroids 2004 FDA approval for Uterine Fibroid Application … 2008 Functional Neurosurgery Slide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin InSightec Exablate 2000 Treatment process for Uterine Fibroids InSightec Haifa, Israel benign (non-cancerous) tumors Technology originally GE most common pelvic tumors in women FDA approved 20-40% in women of reproductive age First & only worldwide Classical procedure: Hysterectomy GE MR-Scanners Ca. 200 systems installed Slide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin 14
- 15. 2012.10.30. Patient interface Transducer 16 element array Mechanical positioning MR-coil Patient vertical electronic steering 4 axes focal depth 12cm – 19cm Computer controlled Coupling Target Ultrasound MR-compatible Transducer Ceramic step motors Slide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin Safety checks Treatment planning Air bubbles? Delineate Metallic clips? region of Scars? treatment Bowels? System creates treatment plan p Bladder? Bl dd ? (array of Nerves? sonications to be done) Plan can be changed manually by operator Slide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin Real- Real-time temperature monitoring Treatment assessment MR-Thermometry Proton resonance frequency shift ~ Temperature Phase difference ~ Temperature difference 1.1 seconds 4.5 seconds 7.9 seconds 11.3 seconds Blue dots = Cell Treatment control by ablation as calculated contrast enhanced MR by thermal dose Very good agreement Slide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin 15
- 16. 2012.10.30. Closed loop control MRgFUS = Magnetic Resonance guided Focused UltraSound Planing Safety Real-Time Assement checks Monitoring Closed Loop Slide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin Clinical applications and research Uterine fibroids T1w contrast enhanced image before treatment Brain Tumors Brain Functional Breast Cancer T2w planning Liver Tumors image with Uterine Fibroids dose overlay Prostate Bone Tumors T1w contrast enhanced image Slide credits: Beat Werner, Ernst Martin Courtesy of Sheba Medical Center, Tel Aviv, Israel immediately post-treatment Slide credits: Beat Werner, Ernst Martin Prostate Liver tumors Treatment effects in canine prostate Thermal dose T1w contrast TTC stained estimate enhanced image tissue Sagittal, Axial and coronal post treatment dose imaging maps (in blue) and post treatment T1W+C Courtesy InSightec Courtesy of St. Mary’s Hospital, London, UK Slide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin 16
- 17. 2012.10.30. Caution-Investigational Device Limited by United States Law IDE Breast Cancer Bone tumors (Pain palliation) to Investigational Use. 10.0 Screening 9.0 Average 8.0 7 7.0 VAS score 6.0 5.0 4.0 1 Month Follow Up 3.0 1.5 3 Months 2.0 Pre treatment T1w+C 2 weeks post treatment 1.5 Follow Up 1.0 0 0 MIP image T1w+C MIP image 0.0 0 10 20 30 40 50 60 70 80 90 Days post treatment Courtesy of Breastopia Namba Hospital, Japan Courtesy InSightec Slide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin Non- Non-invasive neuro-surgery neuro- Skull: Anisotropic Aberration in the MR-suite MR- Focused waves … … are distrorted after skull Phase corrected waves … … are refocused after skull Courtesy of ESPCI, Paris, F InSightec ExAblate 4000 Patient Interface 3D-Positioner Frontend Degassed water used for acoustic coupling & Amplifier cooling InSightec ExAblate 4000 / 3.0T GE Signa HDx Stereotactic frame for patient immobillization Hemispheric 1024-element phased-array transducer Transducer Sealing membrane (650kHz) Stereotactic frame Water cooling of skull surface CT-based acoustic modeling PRS-Thermometry Transducer Installation June 2006 Water Stereotactic frame 17
- 18. 2012.10.30. MRI- MRI-HIFU Console Clinical phase I study Centro-Lateral Thalamotomy against chronic, therapy resistant, neuropathic pain Established procedure: RF-ablation o minimally invasive o n (pain) > 100 interventions New procedure: Non-invasive TcMRgHIFU o Minimize intervention risks (Collateral damage, infections, bleeding, tissue shift) o Enhanced efficacy (no trajectory restrictions, anatomically adapted volume ablation, image guidance) o Outpatient process Bildfolge der Behandlung (sonication procedure) Bildfolge der Behandlung (sonication procedure) X+20’: Stereotactic frame X+50: Positioning X+1h20: Imaging X+3h: Verification sonications 18
- 19. 2012.10.30. X+3h: Verification sonications X+4h: Ablation Dosemap 17 CEM 43°C 43° Dosemap 240 CEM 43°C 43° X+6h: End of treatment Patient #4 #4 Patient #2 #2 immediately after 48 h after the intervention the intervention Trigeminal neuralgia Chronic lumbar pain syndrome following disc hernia op L4/L5 L4/L5 X+7h: Happy End Slide credits: Beat Werner, Ernst Martin 19
- 20. 2012.10.30. Patient #4 #4 Patient #2 #2 Patient #4 #4 Patient #2 #2 immediately after 48 h after immediately after 48 h after the intervention the intervention the intervention the intervention T1WI + Gd T1WI + Gd DTI DTI Combined Tumor therapy: Blood Brain Barrier HIFU- HIFU-Ablation & LIFU BBBD Brain protected by BBB: Tumorvolume Structural and functional barrier in the vessel walls Controls transport and diffusion from the HIFU- HIFU-Ablation vasculature to the central nervous system Severely limits ability to deliver drugs to the brain McDannold et al. Neurosurgery 2010 BBB- BBB-Opening with Low Intensity Focused Ultrasound (LIFU) and Adjuvant Chemotherapy Slide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin Reversible BBB-Disruption using BBB- TcMRgFUS BBB-Disruption BBB- FUS and Microbubble UCA US freq. 220kHz – 1MHz Microbubbles Lipid monolayer Acc.Power < 1W Phospholipid / Hexafluorid (2-4um) Sonication 10 – 200s Commercial CE / FDA Duty cycle 1% Tail vein injection MR-contrast agent / drug Micro bubbles Inj. Drug Inj. Micro bubbles Histo MRI MRI Reversible opening of BBB by Low Intensity US Cavitation (Bursts of 10ms/1000ms) Shear stress (Acoustic streaming, radiation force, ...) Slide credits: Beat Werner, Ernst Martin 20
- 21. 2012.10.30. TcMRgFUS BBB-Disruption BBB- TcMRgFUS BBB-Disruption BBB- Duration MR-Scanner: GE 3.0T several hours Transducer: Imasonic (Aperture 8cm, f# 0.8) Application Microbubbles: Bracco Neuro- Positioner P iti MR-Coil MR C il Phamacology Tumors Alzheimer Neuron regeneration Transducer Watertank Mouse Targeted Drug Delivery Targeted Drug Delivery Targeted Drug Delivery Target specific Carries contrast agents (Dye, fluorescent, magnetic, ...) Carries drugs Remote activation Bubble constructs Add specificity Add payload Remote activation Targeted Drug Delivery Gene Delivery Releasing drug by Ultrasound Heat Cavitation 21
- 22. 2012.10.30. Gene Activation: hsp-80 hsp- Summary Image guided FUS is a new modality for non-invasive interventions deep in soft tissue Thermal ablation clinically established Intense research on treatment strategies based on mechanical effects Very promising results in animal models for targeted drug delivery based on transient BBBD / Sonoporation Intense research on development of nano-constructs for imaging and therapy Clinical studies to come soon Slide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin Clot Lyses for Stroke Outlook Thank you ! Neurological Disorders Targeted Drug Delivery In-vitro T2W MRI before [l] and after[r] sonication Slide credits: Beat Werner, Ernst Martin Slide credits: Beat Werner, Ernst Martin Thank you for your attention! Presentation credits: Dr. András Jakab, M.D. Ph.D. Dr. Ervin Berényi, M.D. Ph.D. Dr. Miklós Emri (Nuclear Medicine Institute, UD) Prof. Ernst Martin – Uni. Zürich (Focused Ultrasound) Beat Werner – Uni. Zürich (Focused Ultrasound) 22