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Medical Imaging Workshop Molecular Imaging

Medical Imaging Workshop Molecular Imaging. Marcelo Tatit Sapienza. INFIERI Summer School Intelligent signal processing for FrontIER Research and Industry . Molecular Imaging. Overview Imaging Modalities Clinical Applications – e.g. breast cancer. Molecular Imaging. MOLECULAR BIOLOGY.

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Medical Imaging Workshop Molecular Imaging

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  1. Medical Imaging WorkshopMolecular Imaging Marcelo Tatit Sapienza INFIERI Summer School Intelligent signal processing for FrontIER Research and Industry 

  2. Molecular Imaging • Overview • Imaging Modalities • Clinical Applications – e.g. breast cancer

  3. Molecular Imaging MOLECULAR BIOLOGY In vivo Imaging visualisation, characterization and quantification of normal / pathological biological processes at the cellular and molecular level

  4. MOLECULAR BIOLOGY Molecular paradigm of diseases  Abnormal cells with pathological phenotypes Molecular expression

  5. Hallmarks of cancer – Cell 2000 Hanahan & Weinberg

  6. Abnormal cells with pathological phenotypes Molecular expression Probes / ligandsmaybedetectedandallow Therapy with labeled compounds Diagnosis Identification of targets for drugs Therapy response Therapy planning

  7. Molecular Imaging BASIC / PRECLINICAL RESEARCH • Study of mechanisms of disease development and progression • Detection and activity of receptors and pathways • Pharmacokinetics / pharmacodynamics of target drugs CLINICAL APPLICATIONS • Understanding pathophysiological mechanisms • Diagnosis / Staging • Response to target drugs /individualized therapies

  8. Translational research

  9. Translationalresearch from BENCH to BEDSIDE topublichealth

  10. Molecular Imaging • Overview • Imaging Modalities • Clinical Applications – e.g. breast cancer

  11. ImagingModalities Differences in • Spatial resolution • Depth of evaluation • Ionizing / non-ionizing radiation • Available molecular markers or probes • Detection threshold Optical systems Nuclear Medicine: PET / SPECT MRI Ultrasonography Computed tomography

  12. Imaging modalities Willmann Nature Reviews 2008

  13. Imaging modalities Optical Imaging: lower cost  high-throughput screening for targets low depth penetration  limited clinical translation Nuclear Medicine: higher cost than optical unlimited depth penetration  clinical translation MRI: high resolution and soft tissue contrast / cost and imaging time US: high spatial and temporal resolution / low cost / limited targets CT: high spatial resolution / no target specific imaging Willmann Nature Reviews 2008

  14. Spectrum ofwavelenghts Eletromagnetic radiation Low energy High energy MRI Optical CT / NM Ultra violet Infra red

  15. Optical Imaging fluorescence and bioluminescence Reporter gene (luciferase) Green fluorescentprotein NearInfraredfluorphores (NIR) Prescher Current Opinion in Chemical Biology 2010

  16. NM Radiopharmaceuticals • radiolabeled molecules designed for in vivo application: • PHARMACEUTICAL= molecular structure determining the fate of the compound within the organism • RADIO= radioactive nuclide responsible for a signal detectable outside of the organism e.g. technetium-99m half life 6 hours gamma-ray photon 140 keV

  17. Scintillationcamara Sorenson and Phelps,27 1987 W.B.Saunders

  18. SPECTSingle Photon Emission Computed Tomography

  19. Positron emitters • Positron: • Same mass as electron • opposite electrical charge • annihilation generates a pair of gamma-ray photons – 180º Nuclideshalflife • F-18 110 min • C-11 20 min • N-13 10 min • O-15 1 2 min • Ga-68 68 min • Rb-82 1.3 min

  20. PET Zanzonico Semin Nucl Med 2004

  21. PET SPECT 140 keV 511 keV SPECT / CT 511 keV PET / CT

  22. PET SPECT PET > SPECT • Spatialresolution (humanstudies) • Temporal resolution • Sensitivity • Cost

  23. Molecular ImagingRequirements • Imaging equipment • Target selection • Development of imaging probe / tracer

  24. Developmentofin vivo probes < 5% of in vitro targets allow development of an in vivo tracer • High TARGET concentration • Affinity and specificity • Absence of biological barriers (i.e. endothelium, blood brain barrier, ...) • Stable labeling of compound

  25. Developmentofin vivo probes < 5% of in vitro targets allow development of an in vivo tracer • High TARGET activity / concentration • Affinity and specificity • Absence of biological barriers (i.e. endothelium, blood brain barrier, ...) • Stable labeling of compound • Low BACKGROUND activity • Non-specific accumulation, • Circulating or interstitial activity • Renal or hepatic elimination

  26. Developmentofin vivo probes < 5% of in vitro targets allow development of an in vivo tracer • High TARGET activity / concentration • Affinity and specificity • Absence of biological barriers (i.e. endothelium, blood brain barrier, ...) • Stable labeling of compound • Low BACKGROUND activity • Non-specific accumulation, • Circulating or interstitial activity • Renal or hepatic elimination • Signalamplification • Celltrapping • Enzymaticconversion • "Reporter" molecules: fluorescence, radiation, magnetic

  27. EXAMPLE: 18FDG fluorodeoxyglucose = glucose analogue • Transport (Glut) • Phosphorylation (hexokinase) • Metabolism

  28. MOST TUMORS: Increased Aerobic glycolysis (Warburg effect ) • Phenotype common to most tumors • Lower production of energy / mol • X • NADPH Production - Synthesis • Hypoxiaandacidosisselectcellsresistanttoapoptosis • Acid pH associatedwithinvasion Vander Heiden Understanding the Warburg Effect Science 2009

  29. Hanahan & Weinberg Cell 2011

  30. Molecular Imaging • Overview • Imaging Modalities • Clinical Applications – e.g. breast cancer

  31. Breastcancer • Brazil • Most incident in women • ~ 50 /100,000 • 57.120 new cases ( 2014 – INCA ) deaths: 13.345 ( 2011 – SIM ) 5 y survival ~ 60 % LOBULAR DUCTAL

  32. Breastcancer Therapy choices considers also : • Clinical conditions, Age , Menopause, Histology of the tumor • Hormone Receptors and HER2 Staging - T 1 < 2 cm T2 2-5 cm T3 > 5 cm T4 thoracic wall / skin - N0, 1axillary I-II mobile, N2axillary fixed or int.thoracic, N3infra (III) / supraclavicular / axillary+int. thoracic - Metastases M0, M1 AJCC Cancer Staging Manual. 7th ed. 2010, PROGNOSIS and CONDUCT

  33. Hormone and Growth Factor Receptors expression variation PREDICTIVE biomarker = susceptibility of the tumor before indicating the therapy

  34. BIOPSY: TU hormone receptor ++  susceptible to treatment with drugs that blocks either the estrogen receptors or hormonal synthesis Biomarker-driven personalized cancer therapy Precision medicine  BUT…

  35. Establishing genetic and molecular profile by biopsy may not be sufficient: Tumor heterogeneity Gerlinger, Intratumor heterogeneity NEJM 2012

  36. 18FES – FLUOROESTRADIOL  target = hormone receptor FDG post-therapy FES FDG PREDICTIVE biomarker in breast cancer ( indicates susceptibility to treatment ) Linden JCO 2006

  37. 18FES – FLUORO ESTRADIOL FDG post-therapy FES FDG Linden JCO 2006

  38. EARLY RESPONSE biomarker = post-therapy prognosis PET- FDG in the metabolic evaluation after lymphoma chemotherapy • Reduce or increase # chemotherapy cycles • Change / add therapy Kasamon JNM 2007

  39. 18F-FES – FLUOROTHYMIDINE  target = DNA synthesis uptake after 1st cycle identifies responders ( p 0.001 ) - ( n= 15 ) EARLY RESPONSE biomarker in breast cancer Crippa F Eur J Nucl Med Mol Imaging 2015

  40. 18F-FES – FLUORO THYMIDINE EARLY RESPONSE biomarker in breast cancer uptake after 1st cycle identifies responders ( p 0.001 ) - ( n= 15 ) Crippa F Eur J Nucl Med Mol Imaging 2015

  41. Conclusion • Molecular imagingis a multidiciplinaryfield in theintersectionof molecular biologyandin vivo imaging • Mainpillarsof MI are : • Use ofimagingmodalitieswithdifferent performances • Developmentofprobes/ligandsdetectablein vivo • MI ispartoftranslationalresearchandmaybeapplied for biomarker-driven personalized therapy ( precision medicine )

  42. Thankyou ! marcelo.sapienza@hc.fm.usp.br

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