1. Nuclear Physics in Medicine Chapter: Medical Imaging NuPECC liaisons 1 Alexander Murphy and 2 Faiçal Azaiez 1 The University of Edinburgh, UK 2 IPN Orsay, IN2P3-CNRS, France Conveners 3 Jose Manuel Udias and 4 David Brasse 3 Universidad Complutense Madrid, Spain 4 IPHC Strasbourg, IN2P3-CNRS, France

2. Piergiorgio Cerello, INFN Torino, Italy Christophe de La Taille,Omega/IN2P3/CNRS, France Alberto Del Guerra,University of Pisa, Italy Nicola Belcari,University of Pisa, Italy Peter Dendooven,University of Groningen, The Netherlands Wolfgang Enghardt,University Hospital TU Dresden, Germany Fine Fiedler,Helmholtz-Zentrum Dresden-Rossendorf, Germany Ian Lazarus,STFC, Daresbury Laboratory, Warrington, United Kingdom Guillaume Montemont,CEA/LETI, France Christian Morel,CPPM/IN2P3/CNRS, Aix-Marseille University, France Josep F. Oliver,IFIC, Valencia University, Spain Katia Parodi,Ludwig Maximilians University Munich, Germany Marlen Priegnitz,Helmholtz-Zentrum Dresden-Rossendorf, Germany Magdalena Rafecas,IFIC, Valencia University, Spain Christoph Scheidenberger,Justus-Liebig-University Giessen and GSI-Darmstadt, Germany Paola Solevi, IFIC,Valencia University, Spain Peter.G. Thirolf,Faculty of Physics at LMU Munich, Germany Irene Torres-Espallardo,IFIC, Valencia University, Spain List of Contributors

3. ~ 10 years ago… PET/CT is a technical evolution that has led to a medical revolution (Johannes Czernin, UCLA, 2003) Invention of the Year SNM Image of the Year

4. Anthony Stevens, Medical Options From IMV PET Clinical Procedures in US

5. …in Europe… (data from Anthony Stevens, Medical Options, EANM 2011) In 2011, Number of patient studies using PET or PET/CT: - between 2005 and 2010: 21 % increase - 2011: > 900 000 exams FDG availability, scanner technology, … - 2010: 506 providers of PET or PET/CT in western Europe 64 %: public facilities Average patient per scanner 2002 : 651 2010: 1559

6. PET Time Of Flight Improvement From 400 ps to …. From David Townsend (2008 AAPM Summer school) PET/MRI is a medical evolution based on a technical revolution (Thomas Beyer) Nowadays… Few highlights Spectral CT, K-edge imaging Courtesy of C Morel et al, CPPM, France

7. Outline From Nuclear to Molecular Imaging – Small animal imaging system New Challenges – Detector design – Photon counting: towards spectral CT –  -PET imaging – Simulation and reconstruction Interfaces – Quality Control in Hadrontherapy – Mass Spectrometry

8. From Nuclear to Molecular Imaging The necessity of understanding biochemical processes at the molecular level Advance in technological instrumentation Preclinical Imaging PET: the merging of biology and imaging into molecular imaging (M Phelps)

9. University of Pittsburgh Major efforts are devoted towards obtaining higher Sensitivity Spatial resolution Cheaper and easier to handle

10. 15 MBq to target platelet, IPHC, Strasbourg SPECT/CT PET/CT SPECT/MR PET/MR From Mediso Judenhofer et al, Nat. Med 14, 459-465, 2008 Courtesy of Dr. Piero A., Salvadori and Dr. Daniele Panetta, IFC-CNR Pisa

11. New Challenges… in Detector Design PET/CT Hybrid Imaging virtually available anywhere – Clinical routine in cancer staging, therapy assessment PET/MRI Hybrid Imaging … on its way Excellent performance Can the performances be improved? Why? Better image quality and/or Lower dose Better sensitivity & specificity in disease detection Quantitative PET analysis – that also requires protocol standardization Shorter Exam Time / Lower Cost How to improve? 4D detectors with new design – Depth of Interaction, Time Of Flight – MR compatibility – Compactness – Cost & Scalability

12. How to Improve the Design ? Scintillators Photon Detectors Front-End Electronics System Design & Integration Dorenbos et col., IEEE TNS, 57, 2010 pp1162-1167 Y (ph/keV): 9 Decay (ns): 300 R (%):10 Y (ph/keV): 30 Decay (ns): 40 R (%):10 Y (ph/keV): 60 Decay (ns): 16 R (%):3

13. How to Improve the Design ? Scintillators Photon Detectors Front-End Electronics System Design & Integration

14. How to Improve the Design ? Scintillators Photon Detectors Front-End Electronics System Design & Integration “Catch the first de-excitation photon” – Speed – Low Noise – Low (double) threshold – Low power consumption Courtesy of Christophe De La Taille, Omega

15. How to Improve the Design ? Scintillators Photon Detectors Front-End Electronics System Design & Integration Segmented / Continuous crystal Radial/ axial orientation Block structure / 1:1 coupling System Performances - Spatial & timing resolutions - Count rate capability - Overall sensitivity Cost/compactness/scalability

16. A lot of projects going on… Focus on the AX-PET collaboration It consists only of two camera modules 48 LONG LYSO crystals (6 layers x 8 crystals) 156 plastic WLS strips (6 layers x 26 strips) 7 3.5 Crystals are staggered by 2 mm. Crystals and WLS strips are read out on alternate sides to allow maximum packing density. The other side is Al-coated, i.e. mirrored. The layers are optically separated from each other. Hamamatsu MPPC 3×3 mm 2 Hamamatsu MPPC 3.22×1.19 mm 2 3×3×100 mm 3 3×0.9×40 mm 3 Courtesy of the AXPET Collaboration 511 = 11.7 % (FWHM) 1.48 mm FWHM in the axial direction

17. Photon Counting… towards spectral CT Originally developed for vertex detectors in high energy physics Hybrid pixel arrays could replace conventional « charge integration » Advantages: - absence of dark noise, - a high dynamic range - photon energy discrimination -> Can provide spectral information Pixelized sensor Si, CdTe, CZT Readout Electronics Standard CMOS process

18. Technical specification of some hybrid pixel detector circuits Photon Counting… towards spectral CT

19. K-edge imaging of iodine XPAD3 camera XPAD-S ASIC 500um thick silicon sensors 500 kpixels 130x130 um 2 pixel pitch Courtesy of F Cassol Brunner and C Morel, CPPM, France

20. Medical Imaging using  +  Coincidences  whole class of potential PET isotopes excluded from medical application: 44m Sc, 86 Y, 94 Tc, 94m Tc, 152 Tb, or 34m Cl  3 rd, higher-energy  ray emitted from excited state in daughter nucleus: - resulting extra dose delivered to the patient - expected increase of background from Compton scattering or pair creation  Perspective: turn alleged disadvantage into promising benefit:  provided the availability of customized gamma cameras  higher sensitivity for reconstruction of radioactivity distribution in PET examinations  PET imaging: so far (exclusive)  + emitters: 18 F, 11 C  All present approaches towards ‘triple-  imaging’ or ‘  -PET’ : based on Compton Camera:

21. Medical Imaging using  +  Coincidences XEMIS: Xenon Medical Imaging System (since 2004 by Subatech, Univ. Nantes) - cryogenic Time Projection Chamber (TPC) filled with liquid xenon (LXe)  acting simultaneously as scatter, absorption and scintillation medium for the additional 3 rd photon   E/E ~ 5.7% (511 keV 4.3% (1.157 MeV)    ~ 1.25 o   x = 2.3 mm (10 cm distance) TPC C. Grignon et al., Nucl. Instr. Meth. A 571 (2007) 142. T. Oger et al., Nucl. Instr. Meth. A 695 (2012) 125. J. Donnard et al., Nucl. Med. Rev. 15 (2012), C64–C67 Example: PET + TPC

22. New Challenges… in Simulation & Reconstruction Both tomographic reconstruction and Monte-Carlo methods became feasible thanks to the advances in computer technology The development of novel prototypes for emission tomography is usually supported by dedicated Monte-Carlo simulations and image reconstruction algorithms. Monte-Carlo simulations are useful to optimize the system design and understand the observed phenomena Image reconstruction is needed to determine the (expected) prototype performance at image level Common Challenge Model accuracy / Image quality LowHigh Simple models Simple simulated phantoms Few iterations of the recon Complex models Complex simulated scenarii Computational burden ShorterLonger Efforts required to optimize balance between accuracy & computing time

23. Main Challenges… in Simulation (Emission Tomography) To increase simulation speed without jeopardizing model accuracy Parallel Implementation Implementation in GPUs Implementation in FPGAs To keeping pace with novel technologies and research scenarii Further experiments and validation studies might be needed Example of Model complexity Which phenomena should be included? Light transport / Electron tracking / Voxelized phantoms Time-dependent phenomena: Radioisotope decay / Phantom motion Scanner rotation / Accidental coincidence Electronic chain: pile-up, dead-time... Moving phantoms Radiationtherapy + Imaging Scenarios

24. Main Challenges… in Reconstruction From Scanner to Image + = InstrumentationImage Reconstruction Physics Towards improving image quality

25. Main Challenges… in Reconstruction Originally: A 2D image representing radioisotope distribution within one section of the body Nowadays: Reconstruction of 3D images (volume) Dynamic reconstruction (4D): time sequences Recent advances: 5D and 6D reconstruction Time evolution Heart/respiratory motions Kinetic parameters

26. Some examples… D. Wiant et al. Med. Phys. 37. 2010 Modeling of the PSF Clinical PET Analytic vs iterative Small animal PET

27. Interfaces…Quality Control in Hadrontherapy Motivation: range uncertainties Source: HZDR, DKFZ A monitoring of the dose delivery is required In order to fully profit from the advantages of ion beams The range of the particles then the maximum dose delivery is very sensitive to modifications: tissue density, inaccuracies in patient positioning Deviations in dose distribution

28. Interfaces…Quality Control in Hadrontherapy « Several methods of medical imaging in particle ion beam therapy are under investigation in order to measure the range of the particles in the tissue or even directly measure the applied dose in vivo » Positron Emission Tomography Prompt gamma ray imaging Charged particles imaging Ion radiography and tomography Three implementations are investigated In-beam PET (GSI, NIRS, Catana) In-room PET (MGH, Kashiwa) Offline PET (HIT, Hyogo) Different detector concepts Collimated gamma camera Multi slit camera Compton camera Prompt gamma timing Recent proof-of-principle simulation and experimental studies reported from research group in France, Italy and Germany Direct measurement of the residual range of high-energy low-intensity ions traversing the patient. Prototypes are under development for both protons and carbon ion beams

29. Interfaces…Quality Control in Hadrontherapy Focus on PET: « the only clinically investigated method » PET activation (right) measured after delivery of the planned carbon ion treatment dose (left) at HIT, in comparison to the corresponding PET MC prediction (middle). The arrow marks an example of good range agreement (adapted from [Bauer 2013] with permission). On going developments: - TOF PET with  T<200ps - Characterization of nuclear reaction cross sections - Feasibility of PET verification for moving targets - Extension to others ions - Solution for automated PET range evaluation in clinical routine - Application of high energy photon therapy

30. Interfaces…Mass Spectrometry « Imaging Mass Spectrometry, where high spatial resolution is combined with mass spectrometric analysis of the sample material, is a versatile and almost universal method to analyze the spatial distribution of analytes in tissue sections” Some examples: Tissue recognition Drug development Multimodal imaging Left: single-pixel mass spectrum of the outer stripe outer medulla; The green label indicates the mass peak that is characteristic for imatinib. Right: imaging mass spectrometry yields the distribution of different substances in the mouse kidney (figures reprinted from ref. [Röm13]). IMS spectra of a mouse kidney after treatment with the anti-cancer drug imatinib.

31. Outlook Medical imaging in general, and nuclear medicine in particular, has experienced and continues to exhibit evolution at exponential speeds. The work performed in nuclear physics groups such as radiation detection, simulations, electronics, and data processing, find application in nuclear medicine. This chapter provided a glimpse of how nuclear physics research has been involved in the advance of medical imaging and, more interestingly, how our current efforts are paving the way for the imaging technologies of tomorrow. This chapter reflects the fact that inside the nuclear physics community, research and development activities in medical imaging detector development coexist, at times even within the same research group. It is our duty to help and promote the translation of developments from our nuclear physics laboratories and basic nuclear science experiments into practical tools for the clinical and preclinical environments.

32. Piergiorgio Cerello, INFN Torino, Italy Christophe de La Taille,Omega/IN2P3/CNRS, France Alberto Del Guerra,University of Pisa, Italy Nicola Belcari,University of Pisa, Italy Peter Dendooven,University of Groningen, The Netherlands Wolfgang Enghardt,University Hospital TU Dresden, Germany Fine Fiedler,Helmholtz-Zentrum Dresden-Rossendorf, Germany Ian Lazarus,STFC, Daresbury Laboratory, Warrington, United Kingdom Guillaume Montemont,CEA/LETI, France Christian Morel,CPPM/IN2P3/CNRS, Aix-Marseille University, France Josep F. Oliver,IFIC, Valencia University, Spain Katia Parodi,Ludwig Maximilians University Munich, Germany Marlen Priegnitz,Helmholtz-Zentrum Dresden-Rossendorf, Germany Magdalena Rafecas,IFIC, Valencia University, Spain Christoph Scheidenberger,Justus-Liebig-University Giessen and GSI-Darmstadt, Germany Paola Solevi, IFIC,Valencia University, Spain Peter.G. Thirolf,Faculty of Physics at LMU Munich, Germany Irene Torres-Espallardo,IFIC, Valencia University, Spain List of Contributors