Molecular ImagingThe Future of Radiology: Molecular Imaging The Future of Radiology Robert H. Wagner, MD, FACNP, MSMIS


Topics: Topics Definitions A Brief History of Imaging Mechanisms of Molecular Imaging What’s been done What’s going on What’s on the horizon


Slide3: If you want to know the past – read history If you want to know what’s going on now– read the newspaper If you want to see the future – read science fiction


Slide4: Grumbles from the Grave – Heinlein First use of radioactive material as a weapon – 1940’s Foundation Trilogy – Asimov First use of radioactive drugs to treat cancer – 1950’s


Definitions: Definitions Molecular Imaging (ACR) The spatially localized and/or temporally resolved sensing of molecular and cellular processes in vivo.


Definitions: Definitions Molecular Imaging (ACR Primer Glossary) A growing research discipline aimed at developing and testing novel tools, reagents, and methods to image specific molecular pathways in vivo, particularly those that are key targets in disease processes.


Definitions: Definitions Molecular Imaging (ACR Primer Glossary) A growing research discipline aimed at developing and testing novel tools, reagents, and methods to image specific molecular pathways in vivo, particularly those that are key targets in disease processes. Equipment: scanners, coils, hardware, etc.


Definitions: Definitions Molecular Imaging (ACR Primer Glossary) A growing research discipline aimed at developing and testing novel tools, reagents, and methods to image specific molecular pathways in vivo, particularly those that are key targets in disease processes. Imaging agents: Paramagnetic materials, radiopharmaceuticals, bubble agents, DNA or peptides.


Definitions: Definitions Molecular Imaging (ACR Primer Glossary) A growing research discipline aimed at developing and testing novel tools, reagents, and methods to image specific molecular pathways in vivo, particularly those that are key targets in disease processes. Techniques: Imaging protocols that make use of the tools and reagents to deduce cellular functions and processes in 4d


Definitions: Definitions Molecular Imaging (ACR Primer Glossary) A growing research discipline aimed at developing and testing novel tools, reagents, and methods to image specific molecular pathways in vivo, particularly those that are key targets in disease processes. Makes the assumption that we understand the normal in vivo cellular processes.


Molecular Imaging: Molecular Imaging Molecular Biology Membrane properties and activities Intra and inter cellular processes Energy production, receptors Protein formation, etc. Nuclear processes DNA and RNA formation Molecular Chemistry Human genome project-completed Enzyme identification and actions Cellular chemistry identified – exploit changes in pathologic conditions Molecular Physics Nanotechnology Isotopes and tracer molecules Paramagnetic agents Photonic imaging


Slide12: Complicated? Illustration of the ~500 metabolic processes in a typical yeast cell. From: Molecular Biology of the Cell


History of Imaging: History of Imaging 1895 – Roentgen discovers x-rays 1896 – Cannon used barium sulfate to follow an animals GI tract 1896 Edison created the fluoroscope Becquerel discovered radioactivity 1898 - Curie discovers radium, radioactivty is named


History of Imaging: History of Imaging 1911 – George de Hevesy – credited with first use of radioactive tracers 1957 – Ian Donald – ultrasound 1958 – Hal Anger – gamma camera 1973 – Hounsfield invents CT scanner 1973 – Phelps invents PET scanner 1984 – Damadian – FDA approves MRI 2000 – Time – PET/CT Invention of the year


History of Imaging: History of Imaging Anatomic Imaging Plain film – cm resolution CT + MSCT – mm resolution Functional Imaging – cellular processes MRI and MRI spectroscopy Nuclear Medicine and fusion imaging Molecular Imaging – builds on the above and adds optical imaging and nanotechnology


Types of Imaging: Types of Imaging CT US MRI Nuclear Optical Anatomy Physiology Metabolism Molecular


Mechanisms of Molecular Imaging: Mechanisms of Molecular Imaging Mechanism #2 Locate proteins Determine Structure Agent binds to target molecule Low sensitivity High background noise Mechanism #1 Locate proteins Determine Function Agent accumulated by target activity High sensitivity Significant background noise Mechanism #3 Locate proteins Determine Function Agent converted to detectable form by target High sensitivity Minimal background noise


NM vs. MIWhich are molecular agents?: NM vs. MI Which are molecular agents? Iodine 123, 131 MIBG Lung Scan F18 FDG PET GI bleeding Prostascint Octreotide HMPAO SPECT Myocardial perfusion Tc99m WBC’s NeutraSPECT Bone Scan MAG-3 Renal scan HIDA


NM vs. MIWhich are molecular agents?: NM vs. MI Which are molecular agents? Iodine 123, 131 MIBG Lung Scan F18 FDG PET GI bleeding Prostascint Octreotide HMPAO SPECT Myocardial perfusion Tc99m WBC’s NeutraSPECT Bone Scan MAG-3 Renal scan HIDA


Thyroid Imaging/Therapy: Thyroid Imaging/Therapy Mechanism #1 – Concentrated by cell Iodine is normally concentrated by thyroid cells using an active transport mechanism The NaI symporter mechanism – well identified in cell membrane Gene sequence is known. Isotopes can be used for diagnosis or therapy


Slide24: Patient with symptoms of hyperthyroidsim Why so little uptake?


Slide25: Hot nodule - suppression


Slide26: Pre-therapy Post-therapy


Therapy with Iodine: Therapy with Iodine I-123 Imaging I-131 Imaging and Therapy 8 – 15 mCi for hyperthyroidism 25 – 29.9 mCi for Toxic nodules 100 – 200 mCi for ablation and therapy of Ca Delivers 1000 – 1500 R/mCi absorbed


Slide29: Thyroid cancer – treated with 150 mCi of I-131.


Slide30: Thyroid cancer – 6 months post treatment with I-131.


Enter PET and F18 FDG: Enter PET and F18 FDG Accumulated actively by cell (mechanism #1) Stops after hexokinase due to abnormal structure Uptake is related to time (4 D imaging) Uptake can be quantified (SUV)


Approved uses for F18 FDG PET: Approved uses for F18 FDG PET Breast cancer Esophageal Lung cancer Lymphoma Colorectal Melanoma Thyroid Brain Head and Neck NOPR – Medicare Pts Seizure Foci Hibernating cardiac


Normal Areas of Accumulation: Normal Areas of Accumulation Brain Liver Colon Kidney/Bladder Bone Cardiac +/-


SUV (Standardized Uptake Value): SUV (Standardized Uptake Value) A measurement that attempts to quantify the uptake of FDG – relates to metabolism. The higher the SUV, the higher the metabolism. Ranges 0.1 – 2.5 = Normal 2.6 – 3.5 = Suspicious >3.5 = Malignant


Clinical Case: Clinical Case 61-year-old female with left-sided posterior nodule about 1.2 cm in size on CT No mediastinal or hilar abnormalities seen on CT scan PET performed to assess nodule potential for malignancy SUV 6.7 consistent with malignancy


PET Results: PET Results In addition to the known malignant nodule, there are two other lesions seen only on PET One lesion in the right hilum One lesion in the mediastinum above the hilum Case restaged on the basis of PET


Slide37: Lymphoma


Solitary pulmonary nodule: Solitary pulmonary nodule Patient presents with left sided chest pain Comes to ER Abnormal chest x-ray shows a lung mass


Solitary pulmonary nodule: Solitary pulmonary nodule Patient now gets CT Characterizes the lung mass – looks like CA


Solitary pulmonary nodule: Solitary pulmonary nodule Now gets PET SUV is high – 6.5 – more suggestion of CA


Slide43: SUV – 6.1 … Result?


Solitary pulmonary nodule: Solitary pulmonary nodule Surgery Answer - Blastomycosis Teaching point: Just because it’s metabolically active, it does NOT mean that it’s cancer.


Prostascint: Prostascint Mechanism #2 – Receptor binding Murine antibody to PSMA (NOT PSA) Take images at 4-5 days post injection Very poor anatomical definition SPECT/CT fusion is key HAMA is possible


Distant Spread: Distant Spread Age 57 Prostatectomy Gleason 3+2, T3aN0M0 Postop PSA 0.0, NED PSA now rising to 1.0 Imaging: CT-? Left iliac bone MRI - ? Left iliac marrow Bone Scan - ? SI joint, metastasis vs. DJD


Distant Spread: Distant Spread Day 4 Day 5 Result: Metastatic disease to mesenteric and supraclavicular nodes. Residual disease in prostate bed.


Distant Spread: Distant Spread Day 0 Day 4 Day 5


Slide49: 9 year old with thyroid cancer and metastasis to lungs and lymph nodes Best therapy for metastatic disease is surgical followed by radioiodine CT scan is unremarkable Problem: How do we find the anatomic abnormality so that the surgeon can remove it?


Enter – Fusion Imaging: Enter – Fusion Imaging PET/CT – Revolutionized cancer imaging SPECT/CT – Essential to NM molecular imaging


MRI - Nanotechnology: MRI - Nanotechnology MRI has greater spatial resolution than NM but is less sensitive Paramagnetic nanoparticles are in development – clinical trials in a few years Perfluorocarbon nanoparticle emulsion with high concentrations of gadolinium May allow imaging at the cellular level! Uses mechanism #1 or #2


MRI - Nanotechnology: MRI - Nanotechnology Fibrin targeted nanoparticles Imaging of thrombi Imaging of plaque avB3 Integrin Detects and quantifies angiogenesis


Slide53: Fibrin targeted fluorocarbon emulsion Scanning EM photo of emulsion attached to fibrin


Slide54: Gradient Echo (GRASE) image. Intense T1-weighted contrast enhancement (arrow) shows targeting with fibrin-specific paramagnetic nanoparticles. Flow deficit (arrow) of thrombus in the phase contrast image (3-D phase contrast angiogram) corresponding to image a.


Slide55: Angiogenesis in a 3 mm Vx-2 tumor implanted in the hind limb of a rabbit, imaged in vivo using dynamic T1-weighted MRI with nanoparticles targeted for 3-integrin. http://www.medical.philips.com


What About Mechanism #3?: What About Mechanism #3? Won’t work with nuclear medicine Might work with MRI Theoretically the most sensitive mechanism Question: How do you produce an imaging agent in vivo?


Get the cell to do it for you!: Get the cell to do it for you! Potential uses Transgenic animals Pharming Drug development Drug testing Bacterial therapy Gene therapy and splicing


Transgenic Animals: Transgenic Animals Pharming – process of using live animals to produce pharmaceuticals Bioengineered to produce the pharmaceutical in the milk. Value/animal/year Goat – tPA - $75K Sheep Factor VIII - $37K Pig – Protein C - $1M


Green Fluorescent Protein: Green Fluorescent Protein Whole-body external images of murine melanoma metastasis in brain. The metastasis were imaged by GFP expression under fluorescence microscopy. Clear images of metastatic lesions in the brain can be seen through the scalp and skull. (a) 14 days after injection of GFP-expressing tumor cells. Bar=1280 m. (b) 20 days after injection. Bar=1280 m. (c) 25 days after injection. Bar=1280 m.


How Sensitive is GFP?: How Sensitive is GFP?


Tumor Sensitivity Testing: Tumor Sensitivity Testing www.metamouse.com Control Treated Day 0 Day 2 Day 4 Day 6 Day 8


Bacteriolytic Tumor Therapy: Bacteriolytic Tumor Therapy Tumors have anaerobic centers Difficult to treat with chemotherapy or radiation Clostridium Novyi Anaerobic bacteria Produces toxins Now – genetically engineered to remove toxins! Image bacteria with GFP In vivo image of a brain tumor in a mouse – treat necrotic parts with bacteria?


Genetic/Radionuclide Therapy: In vivo sodium iodide symporter gene therapy of prostate cancer Gene Therapy (2001) 8, 1524-1531 Enhancement of sodium/iodide symporter expression in thyroid and breast cancer Endocr. Relat. Cancer, September 1, 2006; 13(3): 797 - 826. Effective Cancer Therapy with the {alpha}-Particle Emitter [211At]Astatine in a Mouse Model of Genetically Modified Sodium/Iodide Symporter-Expressing Tumors Clin. Cancer Res., February 15, 2006; 12(4): 1342 - 1348. Long-Term Radioiodine Retention and Regression of Liver Cancer after Sodium Iodide Symporter Gene Transfer in Wistar Rats Cancer Res., November 1, 2004; 64(21): 8045 - 8051 Genetic/Radionuclide Therapy


Who Will Do It?: Who Will Do It? Private offices? Small hospitals? Dedicated facilities? University Medical Centers? Obstacles Space Staffing Funding


Who Will Pay For It?: Who Will Pay For It? Gene sequencing Currently thousands of dollars per sequence and lots of time New automated sequencers – may allow for individual sequencing for only hundreds in a shorter time period Individuals? Insurance companies? Medicare? Current targeted therapies in NM can cost up to $30,000 per treatment!


Incidental Findings: Incidental Findings Incidentaloma A mass or abnormal finding found on an imaging study Incidentalome An abnormal gene sequence found in the process of DNA analysis If you look hard enough, you will find something!


What’s Ahead: What’s Ahead I DON’T KNOW! I need to read more science fiction!