1. P. Lecoq CERN 1 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 A dedicated detector for pancreas and prostate biomarkers developments FP7 project, Grant Agreement n°256984 P. Lecoq CERN, Geneva, Switzerland

2. P. Lecoq CERN 2 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 Tool Endo = endoscope –1 for pancreas –1 for prostate TOF = Time-of-Flight PET –Endoscopic head close to organ –External plate for coincidences US = Ultrasound Imaging tool for pancreas and prostate cancer biomarker development Spatial resolution Biopsy Other organs background rejection Anatomic + Molecular imaging

3. P. Lecoq CERN 3 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 Objectives Develop new biomarkers for pancreas and prostate cancer –Ex: mAb16D10 antibody for pancreas –Ex: 68 Ga – PSMA for prostate Introduce PET as an endoscopic imaging tool Develop intra-operative interventional imaging techniques Imaging tool for pancreas and prostate cancer biomarker development

4. P. Lecoq CERN 4 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 Definition and evaluation of biomarkers - Prostate 18 F-Choline and FDG used as reference 68 Ga-PSMA in evaluation in Münich with PET/CT and PET/MR –Enzyme expressed by prostate epithelial cells 68 Ga-Bombesine first trials with patients (Lausanne) – Patients with biochemical recurrence (after prostatectomy) – 68 Ga-Bombesine PET/CT followed by standard 18 F-Choline scan – Results so far comparable with both tracers

5. P. Lecoq CERN 5 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 Bone metastasis in sacrum in a patient with biochemical relapse from a prostate cancer visualized by PET/CT with a Ga-68-bombesine receptor analogue fused onto a MRI

6. P. Lecoq CERN 6 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 Definition and evaluation of biomarkers - Pancreas Metabolites targeting tumoral processes of tumoral pancreatic cells: – 18 F-FDG for glucose metabolism Peptides targeting receptor on plasma membrane of tumoral pancreatic cells: – 68 Ga-Octreotide to detect neuroendocrine tumors expressing somatostatine receptor Antibodies targeting candidate biomarkers on plasma membrane of tumoral pancreatic cells. –CarcinoEmbryonic Antigen related Cell Adhesion Molecule 5 (CEACAM5) –S100A7 (sporiasin) : detected by MALDI –Humanized form 16D10 Fab HC of the mAb16D10

7. P. Lecoq CERN 7 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 Anatomical constraints

8. P. Lecoq CERN 8 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 EndoTOFPET-US principle

9. P. Lecoq CERN 9 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 EndoTOFPET-US principle

10. P. Lecoq CERN 10 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 External PET Plate EndoTOFPET-US principle

11. P. Lecoq CERN 11 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 External PET Plate EndoTOFPET-US principle

12. P. Lecoq CERN 12 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 External PET Plate EndoTOFPET-US principle

13. P. Lecoq CERN 13 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 External PET Plate Conventional Back-Projection EndoTOFPET-US principle

14. P. Lecoq CERN 14 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 External PET Plate With TOF Constraint t1t1 t2t2 Target CTR: 200ps  30mm FWHM EndoTOFPET-US principle

15. P. Lecoq CERN 15 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 Technical challenges High level of miniaturization imposed by anatomy –Thin crystal pixels for high granularity of the endoscopic probe with ≤ 1mm spatial resolution –High level of electronics and mechanical integration (5  m precision) Electronic collimation with < 200ps timing resolution –for background rejection outside 3cm ROI Ultrafast light detection: Multi-digital SiPM –for single optical photon counting and ultimate timing resolution Tracking of all movables parts –for ≤ 1mm determination of their relative positions

16. P. Lecoq CERN 16 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 External plate design Area 23 x 23 cm 2 256 matrices of 4x4 LYSO:Ce scintillators Crystal size 3.5 x 3.5 x 15 mm 3 Crystal pitch 3.6 mm Coating: ESR reflector by 3M Discrete Silicon-through-via (TPV) MPPCs by Hamamatsu (S12643-050CN) Dedicated fast 64 channels ASIC MPPC 4x4 array 4x4 LYSO crystal matrix

17. P. Lecoq CERN 17 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 CTR distribution of 266 Modules (4x4 cells each), 4256 LORs The bias voltage applied to each module is fixed to 2.5 Volt over breakdown Voltage. Same threshold and temp for all channels EndoTOFPET system performance with NINO + HPTDC 239 ps NINO ASIC @19°C 4x4 cells 3.5x3.5x15mm 3 crystals 80  m 3M ESR gap Discrete Silicon- through-via (TPV) MPPC array Hamamatsu (S12643- 050CN) 3x3mm 2, 0.6mm gap

18. P. Lecoq CERN 18 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 External plate: 2 ASIC versions Functions: ➢ Measure timing via leading-edge technique ➢ Measure energy using time-over-threshold method Challenges: ➢ Large channel density (4000 channels in 20 x 20 cm 2 ) ➢ Low noise, low timing jitter (< 30 ps) ➢ Low power consumption (10-20 mW/ch) ➢ SiPM bias tuning (500mV adjustment range) TOFPET ASIC ● Developed by LIP ● 7 x 7 mm 2 ● 128 channels single ended readout ● Analog-based integrated TDC STiC 3.0 ● Developed by KIP ● 5 x 5 mm 2 ● 64 channels single ended or differential readout ● Digital-based integrated TDC

19. P. Lecoq CERN 19 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 Preliminary results with STiC3 - 511keV and 1.27MeV peaks are seen - Selection of coincidence events within 1.5  of the 511KeV peak LYSO crystals 3.5x3.5x15mm 3 T = 18°C

20. P. Lecoq CERN 20 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 Endoscopic probe: Pancreas 1 matrix 9x18 LYSO or LSO:Ce, Ca 0.71x0.71x15mm 3 1 Multidigital-SiPM 9x18 clusters of 416 SPADs Up to 48 time stamps/event Fuji EUS probes EG530UT with biopsy needle

21. P. Lecoq CERN 21 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 Endoscopic probe: Prostate 2 matrices 9x18 LYSO or LSO:Ce, Ca 0.71x0.71x15mm 3 2 Multidigital-SiPM 9x18 clusters of 416 SPADs Up to 48 time stamps/event SPAD digital output connected to DAQ via flex-PCB

22. P. Lecoq CERN 22 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 Endoscopic probe: Prostate

23. P. Lecoq CERN 23 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 MD-SiPM: custom made chip Energy measurement: TOA of first 48 photons on 416 SPADs (1 bit/SPAD) Time measurement: 48 TDC/cluster with < 50ps time bin 9x18 clusters 16x26 = 416 SPADs/cluster 50  mx30  m SPADs 432 TDCs on chip active quenching smart reset masking high DCR channels

24. P. Lecoq CERN 24 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 DCR control: Smart Reset

25. P. Lecoq CERN 25 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 DCR control: Masking noisy channels

26. P. Lecoq CERN 26 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 EndoTOFPET-US, a benchmark for analog vs digital readout

27. P. Lecoq CERN 27 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 Conclusions EndoTOFPET-US in two versions for developping new biomarkers: –Prostate –Pancreas First time endoscopic configuration for a PET –Asymetric PET –High level of miniaturization and integration TOF performance close to 200ps within reach Opportunity to compare analog and digital aproaches in a clinical environment Other challenges not adressed in this talk: –Tracking system for all movable parts –Complex and highly integrated DAQ system –Simulation and reconstruction in a complex and unusual configuration –PET-US image fusion –Etc…

28. P. Lecoq CERN 28 September 2014 MEDAMI 2014, Alghero, 3-7 September, 2014 Acknowledgements EndoTOFPET-US collaboration PICOSEC Marie Curie TN ERC Advanced Grant