1. Technologic Applications in Nuclear Molecular Imaging Arif Sheikh, MD Assistant Professor Director of Targeted Radionuclide Therapy and Cardiovascular Nuclear Medicine Divisions of Nuclear and General Medicine Departments of Radiology and Internal Medicine University of North Carolina

2. What Information does an Image Convey? Importance of image information Unique information portrayed Clinical relevance of imaging Understanding of technology behind the image

3. Issues with Nuclear Imaging Nuclear Imaging »Low resolution scans »High physical sensitivity studies »Rely on observation of physiology »Creates pictures from individual photon counts »Low target to background ratio »Poisson statistics Other Radiologic Imaging »Higher resolution »Anatomic pathology readily visible »Sensitivity is lower than Nuclear Imaging »Uses ‘energy spectra’ to create images »High target to background ratio »Gaussian statistics

4. History of Radiologic Imaging Historically, much of modern diagnostic imaging was performed by Nuclear Medicine »Neuro (Stroke) Brain scan → CT, MRI »Cardiac (Functional) MUGA → Echocardiography (ultrasound) »Pulmonary (Embolic Disease) V/Q → CT Angiography »Gastrointestinal Gallbladder (HIDA) → Ultrasound, CT, MRI Liver/spleen (Metastases) → CT, MRI »Genitourinary (Torsion) Testicular Scan → Ultrasound Despite advancements, many of these procedures are still used today!

5. Important Milestones in Nuclear Imaging Imaging »Initially, monitored uptake over body »Anger Camera (image generation) »Dynamic imaging »Gating »Tomographic (SPECT) imaging »PET imaging »Attenuation Correction »CT based correction Other technologies »Processing Filtered back projection Iterative reconstruction Scatter correction Resolution recovery »Crystals Sodium Iodide (SPECT) BGO, LSO, etc. (PET) »Computer processing Film uses Digital displays

6. Applications in Nuclear Medicine Wide range of applications (most versatile as a single imaging system) Essentially, evaluates pathology based on functional imaging Use of physiologic principles to guide surgeries Identification of tissue type based on molecular and/or physiologic parameters

7. Wide Variations of Nuclear Images Image appearance depends upon radiopharmaceutical characteristics Normal image depends upon the physiologic distribution of tracer Identification of pathology depends upon deviation from base image

8. Planar vs. SPECT Anger Camera Images Planar Imaging »Better counts »Improved resolution »Improved physical sensitivity »Ability to do dynamic images »Performed much quicker than SPECT imaging SPECT Imaging »Better contrast »Improved clinical sensitivity »Tomographic (3-dimensional) views of target region

9. Bone Imaging

10. Planar vs. SPECT vs. PET

11. Frontal view of thyroid Nodules RL Field of view of image detector Thyroid Gland Pinhole Imaging

12. Copyright restrictions may apply. Mandel, S. J. JAMA 2004;292:2632-2642. 123 I Scans of Hyperfunctioning Thyroid Nodules With suppression of extranodular thyroid Without suppression of Extranodular Thyroid

13. Renal Scanning

14. Resolution vs. Sensitivity

15. Gated Slice Display

16. Surgical Mapping Theory Certain cancers (melanoma, breast, etc.) tumours may sit in lymph nodes undetected at time of initial diagnosis/surgery Tumours spread/metastasize through lymphatic channels Detection of tumours in lymph nodes will alter therapeutic approach Need to detect specific lymph nodes in entire basins which likely have disease Need to be accurate enough to minimize chance of ‘missing’ the target (sentinel) lymph node

17. Sentinel Lymph Node Mapping Sentinel Lymph Node (SLN) is the 1 st node to which the tumour will likely metastasize Detection and examination of this lymph node will decide whether disease has spread Use particles that will travel in lymphatic channels from the tumour to the local lymph nodes to the sentinel lymph node Sulfur colloid (~0.1-1  m) particle is taken up by lymph nodes

18. infraclavicular apical lateral parasternal subareolarplexus cross-drainage from thoracic wall pectoral subscapular central to abdom. wall subcutaneousplexus

19. Malignant Melanoma of the Back

20. rightgroin rightaxilla leftaxilla rightaxilla leftaxilla

21. Dual Isotope Imaging Prostascint® is a tracer to detect prostate cancer 111 In based, targets tumour sites Also large amount of blood pool activity 99m Tc-RBC distribute in blood pool, helping distinguish vessels from lymph node uptake

22. 18 F b+b+ b-b- p c c PET Principle

23. PET vs. SPECT PET »Improved spatial resolution (clinically) »Inherent attenuation correction »Can ‘quantitate’ biologic phenomenon easily »Isotopes more biologically relevant 11 C, 13 N, 15 O Newer molecular tracers »Dynamic tomographic images possible »Shorter imaging times SPECT »Better count sensitivity »Ability for simultaneous multi (dual) isotope imaging »Wider range of pharmaceutical chemistries »Isotopes (currently) more readily available »Less cost (currently)

24. Prostate Cancer TransverseCoronalSaggital DG: 57 years old with High Grade; local resection, now mass post-RT. Recurrence? Pelvic Exent. possible?

25. SPECT SestaMIBI (Rest-Stress) Str Rst Str Rst Str Rst Str Rst Mount Sinai School of Medicine

26. 82 Rb-PET Study (Rest-Stress) Stress Rest Stress Rest Stress Rest Stress Rest Mount Sinai School of Medicine

27. Thyroid Cancer Metastasis localized to the posterior vertebral body

28. Advances in Processing: FBP vs. OSEM (Iterative) A major reason for the rise in popularity of PET imaging Improved diagnostic abilities Algorithms were once not possible due to limitations in computing power Optimal algorithms need to account for many variables »The type of camera »Radioisotope »Attenuation Correction (CT vs. rod sources) »Counts/pixel

29. Quantitative Imaging Counts per pixel are a representation of a physiologic process Change in process over time allows quantitative analysis to examine physiologic phenomenon Quantitation may be imaging based, or simply on counts (eg. blood samples, urine collections, etc.) Collection based studies »Urea breath test for Helicobacter pylori »Schilling’s test for B12 deficiency »Calculation of Glomerular Filtration Rate with 125 I- iodothalamate

30. Camilleri M. N Engl J Med 2007;356:820-829 Patterns of Gastric Emptying in Healthy People and in Patients with Diabetic Gastroparesis

31. MUGA Scans

32. Image Based Dosimetry Time-activity curve Time (d) Ã vox A vox (t) radioactivity (MBq) 0 12 Day1 Day2 Day0 Cumulated activity

33. 124 I-Iodine in Thyroid Cancer 61.89 Gy/GBq 54.86 Gy/GBq 33.78 Gy/GBq

34. Technical Developments Multipinhole SPECT Procedure specific cameras Advances in OSEM algorithms Newer detector materials Radiopharmaceuticals Transition to ‘Molecular Imaging

35. The D-SPECT Difference BROADVIEW TM Technology 9 solid state detectors  10X the sensitivity  Twice the resolution Each detector can look at 100’s to 1000’s of different angles Each detector is independently addressable

36. Patient 510- Stress/Rest ConventionalD-SPECT, Spectrum Dynamics

37. Biologic vs. Technologic Challenges Ultimately, Biology trumps technology Newer focus is development of better tracers for evaluation of biology Technology is developing to better allow for newer tracer imaging Thus, the field of ‘Molecular Imaging’ is developing »Disease specific tracers »Multiple different tracers to look at the same disease

38. Papillary Thyroid Ca FDG-PET versus 131 I scans

39. FDG vs 124 I in Thyroid Cancer PET- 124 I PET-FDG

40. FDG Prognosis of Distantly Metastatic Disease (Thyroid Ca) Wang W et al: Prognostic value of [18F]fluorodeoxyglucose positron emission tomographic scanning in patients with thyroid cancer. J Clin Endo Metab 2000 85:1107-13

41. SPECT-CT ( 111 In-Octreotide) vs PET-CT (FDG) Patient with rising calcitonin, undetected source on anatomic imaging or octreoscan SPECT-CTPET-CT

42. Wilex Renal Cell Carcinoma 124 I-cG250 Clinical Imaging Trial 013-004 (CG July 7 Clear cell Fuhrman 2) Benign

43. Gene Imaging HSV1-tk Mammalian-tk 124 I-FIAU X 124 I-FIAU-PO 4 124 I-FIAU FIAU (2'-fluoro-2'-deoxy-5'-iodo-1-β-d-arabinofuranosyluracil)/ Thymidine Kinase

44. HSV1-TK TK DPK TPK [*I]-FIAU [*I]-FIAU [*I]-FIAU-(PO 4 ) Reporter Gene HSV1-tk RadiolabeledProbe Gene Delivery mRNAHSV1-tk Paradigm for Imaging the Expression of a Reporter Gene Enzyme HSV1- TK

45. Summary Nuclear Imaging relies on a vast array of technologies in the creation and evaluation of imaging Technological advancements are important, but still secondary to biological understanding of disease Important development of the field moving from physiologic processes to Molecular Imaging Molecular Imaging promises to play an important part of future Medical Imaging Paradigm shift into the development of personalized medicine