1. 1 PET in the detection of breast cancer The ClearPEM Project Encontro Nacional de Ciência — Ciência 2009 Fundação Calouste Gulbenkian 29-30 de Julho de 2009 Joao Varela IST/LIP, Lisbon, Portugal

2. 2 Breast Cancer Most common type of cancer among womenMost common type of cancer among women Second deadliest cancerSecond deadliest cancer One out of 9 women develop a form of breast cancer throughout her lifeOne out of 9 women develop a form of breast cancer throughout her lifeMammographyAdvantages Low cost Low cost Good sensivity/specificity Good sensivity/specificityDisadvantages Based in structural tissue changes Based in structural tissue changes Less reliable in dense breasts Less reliable in dense breasts High false-positive rates High false-positive rates Breast Cancer

3. 3 PET Based on the decay of a positron emitting radionuclide (tracer)Based on the decay of a positron emitting radionuclide (tracer) 18 F-FDG most commonly used radiotracer 18 F-FDG most commonly used radiotracer Based on histological and metabolical changes of the tissueBased on histological and metabolical changes of the tissue PET vs. Mammography Advantages Not dependent on tissue density Not dependent on tissue density Very good sensivity Very good sensivityDisadvantages More expensive More expensive Low sensivity for small lesions (Whole Body-PET) Low sensivity for small lesions (Whole Body-PET) P.E.T. (Positron Emission Tomography)

4. 4 PET and breast cancer PET demonstrated good sensitivity to breast cancerRadiotracer FDG (fluoro-deoxyglucose): glucose labeled with the positron emitter F-18 FDG has strong affinity to cancer cells Other tracers under investigation Dedicated PEM scanners One commercial scanner (Naviscan, USA)One commercial scanner (Naviscan, USA) Two research prototypes in USATwo research prototypes in USA PET Mammography Dedicated Breast-PET Imaging Randolph Cancer Center West Virginia University X-ray mammogram

5. 5 Goal High performance scanner, to approach the limits allowed by tracer physiology Framework Project developed in the framework of the Crystal Clear Collaboration, CERNProject developed in the framework of the Crystal Clear Collaboration, CERN Funded by the Portuguese Innovation Agency (AdI) Funded by the Portuguese Innovation Agency (AdI) 6 years development 6 years development 4.5 M€ investiment 4.5 M€ investimentStatus IP licensend to PETsys, SAIP licensend to PETsys, SA Scanner in clinical trialsScanner in clinical trials The ClearPEM Project

6. 6 Requirements High counting sensitivityHigh counting sensitivity Detector capable of image resolution of 1 mmDetector capable of image resolution of 1 mm Detector capable to sustain a large flux of single photons (up to 10 MHz)Detector capable to sustain a large flux of single photons (up to 10 MHz) On-line coincidence trigger with few ns resolutionOn-line coincidence trigger with few ns resolution No data acquisition dead-time (up to 1 M coincidence events/s)No data acquisition dead-time (up to 1 M coincidence events/s) Measurement of individual hits of Compton events in the detectorMeasurement of individual hits of Compton events in the detector Movable and compact dual-head detector plates with large active areaMovable and compact dual-head detector plates with large active area No parallax effectNo parallax effect The ClearPEM Project

7. 7 The ClearPEM Scanner

8. 8 Crystals Material: LYSO:CeMaterial: LYSO:Ce Density: 7.4g.cm -3Density: 7.4g.cm -3 Emission Peak: 420nmEmission Peak: 420nm Light Yield: 27000 photons/MeVLight Yield: 27000 photons/MeV Time Constant: 40nsTime Constant: 40ns Geometry: 2x2x20 mm 3Geometry: 2x2x20 mm 3 Avalanche Photodiodes Operating Voltage: 350-450VOperating Voltage: 350-450V Dark Current: ≤10nADark Current: ≤10nA Gain uniformity (sub-array): ±15%Gain uniformity (sub-array): ±15% Detector Plates 6144 crystals6144 crystals 12288 readout channels12288 readout channels 160x180 mm 2 surface area160x180 mm 2 surface area Front-back readout for DoI measurementFront-back readout for DoI measurement Detector Technology

9. 9 Characteristics Technology: CMOS 0.35μm Area: 70mm 2 Input: 192 channels Output: 2 highest channels Max Input Charge: 90 fC Noise: ENC ~ 1300 e - Shaping: 40ns Analog Memories: 10 samples Clock Frequency: 50-100MHz Power: 3.6 mW/channel Frontend ASIC

10. 10 Frontend Board Processes 384 APD channelsProcesses 384 APD channels Contains 2 ASICs for signal selectionContains 2 ASICs for signal selection 2 High-speed ADCs (10bit, 100MHz)2 High-speed ADCs (10bit, 100MHz) 1 LVDS transmitter (600Mbps)1 LVDS transmitter (600Mbps)Supermodule Comprises 2 FE BoardsComprises 2 FE Boards Processes 768 APD channelsProcesses 768 APD channels Detector Plate Comprises 8 SupermodulesComprises 8 Supermodules Processes 6144 APD channelsProcesses 6144 APD channels Contains one Service Board to control 192 high-voltage lines as well as power supply and clock distributionContains one Service Board to control 192 high-voltage lines as well as power supply and clock distribution Frontend (FE) Electronics

11. 11 Pulse Shape Amplifier response rise time: 20nsAmplifier response rise time: 20ns Variation in baseline <0.5%Variation in baseline <0.5%Noise ENC = 1300 e - r.m.s.ENC = 1300 e - r.m.s. Inter-channel dispersion ~ 8%Inter-channel dispersion ~ 8% (2.2 ADC Counts = 5keV) (Noise measurements obtained with full electronics chain) FE Electronics Performance

12. 12 DAE Crate System DAE housed in a single 19” rack crateDAE housed in a single 19” rack crate Uses two cPCI backplanesUses two cPCI backplanes 1 TGR/DCC Board1 TGR/DCC Board 4 DAQ Boards4 DAQ Boards FE - DAE bandwidth up to 19.2GbpsFE - DAE bandwidth up to 19.2Gbps Sophisticated coincidence trigger (36k calibration constants)Sophisticated coincidence trigger (36k calibration constants) DAE-Acq Server bandwidth up to 6.4GbpsDAE-Acq Server bandwidth up to 6.4Gbps Data Acquisition Electronics

13. 13 Trigger Performance Events in coincidence up to 2.5MHzEvents in coincidence up to 2.5MHz (This involves computation of energy and time and Compton grouping and transmission to the trigger processor) Acquisition rate up to 0.8MHzAcquisition rate up to 0.8MHz (This involves readout of the event dataframe after the issueing of a trigger) Disk storage > 300MBpsDisk storage > 300MBps Data Acquisition Electronics Performance

14. 14 Performance results Dispersion of channel gain 15.3%Dispersion of channel gain 15.3% Energy resolution at 511 keV 15.9% Dispersion of energy resolution 8.8% Single photon time resolution 1.5 ns (RMS) Coincidence time resolution 5.2 ns (FWHM) Resolution in DoI 2 mmResolution in DoI 2 mm Detector Performance Resolution ~12.5% 137 Cs

15. 15 Image Setup 1mm Na-22 source1mm Na-22 source Grid with 5mm pitchGrid with 5mm pitch Two acquisitions with orthogonal plate orientations for each source location (400-600 keV)Two acquisitions with orthogonal plate orientations for each source location (400-600 keV) Simultaneous reconstruction of 16 source positionsSimultaneous reconstruction of 16 source positionsResults Horizontal FWHM: 1.3mmHorizontal FWHM: 1.3mm Vertical FWHM: 1.2mmVertical FWHM: 1.2mm ClearPEM Image Resolution OSEM-2DOSEM-3D

16. 16 ClearPEM Image Resolution 5 mm 1 mm Parallax effect Measurement of 3D photon interaction coordinates eliminates parallax effectMeasurement of 3D photon interaction coordinates eliminates parallax effect ClearPEM is unique in this respect (DoI resolution of 2mm)ClearPEM is unique in this respect (DoI resolution of 2mm) Images without parallax correction show considerable blurringImages without parallax correction show considerable blurring

17. 17 ClearPEM Image Uniformity Images of uniform Ge-68 source Image artifacts due to detector effects are correctedImage artifacts due to detector effects are corrected Absorption and scatter corrections are not applied (less intensity at the center)Absorption and scatter corrections are not applied (less intensity at the center) Reconstruction with 4 orientations of the detector platesReconstruction with 4 orientations of the detector plates Very good uniformityVery good uniformity Cylinder filled with positron emitter Ge-68 2 mm slices

18. 18 Simulations Simulation Model NURBS CArdiac Torso (NCAT) PhantomNURBS CArdiac Torso (NCAT) Phantom Detector detailed descriptionDetector detailed description Standard injection of 10mCi (370MBq)Standard injection of 10mCi (370MBq)

19. 19 Scanner Installation Hospital Garcia Orta at Almada not availableHospital Garcia Orta at Almada not available Obliged fall back solution at IPO, PortoObliged fall back solution at IPO, Porto Phase 1 Tuning the image reconstruction with real casesTuning the image reconstruction with real cases Patients indicated for PET/CT (other disease)Patients indicated for PET/CT (other disease) Normally negative breast examsNormally negative breast exams Started in June 2009Started in June 2009 Phase 2 Assessment of PEM sensitivity / specificityAssessment of PEM sensitivity / specificity Comparison to mammography and MRIComparison to mammography and MRI Patients with positive indication from x-rays mammographyPatients with positive indication from x-rays mammography Clinical Trials

20. 20 Clinical Images Tuning image reconstruction Phase 1Phase 1 Normalization correctionNormalization correction Correction of the effect of background radiationCorrection of the effect of background radiation Effect of scattered radiationEffect of scattered radiation Measure detector sensitivityMeasure detector sensitivity Evaluate FDG uptake in the breastEvaluate FDG uptake in the breast Validate simulation resultsValidate simulation results

21. 21  Multimodal PET – US  CERIMED and University Hospital Marseille  Ultra-sound probe with elastography capabilities coupled to ClearPEM  Cross-reference system and PET-US image fusion  Construction of second ClearPEM machine well advanced ClearPEM and Ultrasound

22. 22 ClearPEM technological developments were successfully completedClearPEM technological developments were successfully completed The detector performance is excellentThe detector performance is excellent ClearPEM is one of the most innovative APD-based PET systems in clinicalClearPEM is one of the most innovative APD-based PET systems in clinical Scanner is presently installed at IPO, PortoScanner is presently installed at IPO, Porto Clinical Phase 1 is on-goingClinical Phase 1 is on-going Conclusions

23. 23