TOF-PET for Proton Therapy (TPPT): In-beam Time-of-Flight (TOF) Positron Emission Tomography (PET) for proton radiation therapy

TPPT project is a collaboration between four institutions in Portugal and two institutions in Texas, USA, from Jan 2020 to Dec 2023.

• Institutions in Portugal:

            - PETsys Electronics, Medical PET Detectors S. A. (project leader);

            - LIP, Laboratório de Instrumentação e Física Experimental de Partículas;

            - ICNAS, Instituto de Ciências Nucleares Aplicadas à Saúde, University of Coimbra;

            - C2TN, Centro de Ciências e Tecnologias Nucleares, IST (University of Lisboa).

• Institutions in Texas, USA:

            - University of Texas at Austin, Department of Physics, Austin;

            - UT MD Anderson Cancer Center, Proton Therapy Center, Houston.

The aim of the project is to demonstrate the feasibility of Positron Emission Tomography (PET) with very good Time Of Flight (TOF) for range verification in proton radiation therapy. The range verification will be based on the observation of positrons from the decay of 15-O during, and immediately after, the irradiation, using in-beam PET. Proton range verification will be based on radionuclide production rate maps (PRMs). A computer simulation will predict the distribution of the positron annihilation events that should be observed. Any mismatch with the observed distribution will indicate a range error and will allow correcting for it by changing the beam energy.

With an in-beam PET in hadron radiation therapy it is very difficult to completely surround the patient with a ring of detectors as is normally required in PET, because of the geometrical constraints in this setting. As a result of the recent development of PET detectors with very good TOF resolution, it is now possible to obtain good PET images with partial angular coverage around the patient. In this project we will build a prototype TOF-PET system with partial angular coverage around the patient. The system will be suitable for radiation monitoring in case of irradiations of the head and neck cancers.

We will test the system with phantoms and animals at the proton therapy center of MD Anderson Cancer Centre in Houston, Texas, USA (University of Texas MD Anderson).

At the same time, we will develop, characterize and preclinically evaluate the use of multifunctional gold nanoparticles (AuNPs) as radiosensitizers in proton therapy of glioblastoma multiforme (GBM). The aim of these studies is to establish correlations between 15-O diffusion patterns, the tumor characteristics (e.g. vascularization) and therapeutic outcomes. There is a strong synergy and complementarity between both parts of the project. The required preparations (i.e., simulations, image reconstruction, setting up beam tests etc.), are the same for both studies. There is considerable expertise in Portugal off the synthesis and characterisation of gold nanoparticles (AuNPs) as radiosensitizers. The teams in Portugal with this expertise should take advantage of the ongoing effort to organize beam test at the proton facility at MD Anderson and test AuNPs as radiosensitizers in realistic proton irradiation conditions.  The test with animals will, at the same time, test the PET detectors as a means to monitor the proton range and validate the usefulness of AuNPs as radiosensitizers.

Patient studies are not part of the present application but will be part of a follow-up project after successful conclusion of the present project.

This is an exploratory study and future applications will benefit from better understanding of the TOF-PET interactions and constraints with the proton beam.

Summary Table of Milestones 

Collaboration partners:

1.1   PETsys Electronics S.A., PI: Stefaan Tavernier

          www.petsyselectronics.com

The technology offered today by PETsys Electronics SA stems from more than ten years of R&D development involving a number of public, private and individual partners.

The R&D PET-Mammography Consortium (involving approximately 40 people from 10 research institutions gathered in 2003) was responsible for the technological solutions (i.e. electronics, mechanics, image reconstruction) that gave birth to two ClearPEM prototypes. These systems allow unmatched image resolution and sensitivity for breast imaging using PET tracers. PETsys - Medical PET Imaging Systems SA was incorporated in 2008 to bring the ClearPEM scanner technology to the market. PETsys Electronics SA was setup by PETsys - Medical PET Imaging Systems SA in 2013, to focus on gamma ray Detectors for next generation PET and PEM scanners, builds up on this expertise to propose state-of-the art solutions for the PET detectors of the future. Currently PETsys Electronics is selling several types of electronic board for SiPM readout for Time Of Flight applications and evaluation boards.

Several Academic groups have been testing intensively PETsys Electronics’ technology confirming the announced performance of our TOF (time of flight) detectors adapted for PET applications. Around ten prototypes or small systems integrating PETsys Electronics’ products (ASIC, electronics, detector modules) are being built today by our Industrial customers in order to prepare the launch of their new generation PET scanners. Our TOF detection technology has other applications (all applications using PMT – Photomultiplier Tubes eligible to be replaced by SiPMs can use with advantage our TOF detection technology). We have been working with other partners in order to make sure they understand our technology in order to use it in their specific applications (photon detection, LIDAR, radiation detection/security, …). The present project is included in those mentioned efforts in order to make sure it can also be used in Proton Therapy.

After a start-up period supported by a VC investment of over 1m€, the company achieved self-sustainability in 2018 showing a profit in the accounts. Ramp-up is now expected with the adoption of this technology by the Industry organizations that are building the above mentioned prototypes.

PETsys is based in Taguspark - Lisboa Science and Technology Park, where they have the infrastructures and instrument for electronic testing and procedures (oscilloscopes, probes, multimeters).

1.2 LIP, Laboratório de Instrumentação e Física Experimental de Partículas, PI: Paulo Crespo

        www.lip.pt

LIP is a scientific and technical association that has for goal the research in the fields of Experimental High Energy Physics and Associated Instrumentation. LIP ́s research domains have grown to encompass Experimental High Energy Physics and Astroparticles, radiation detection instrumentation, data acquisition and data processing, advanced computing and applications to other fields, in particular Medical Physics. The main research activities of the lab are developed in the framework of large collaborations at CERN and at other international organizations and large facilities in Europe and elsewhere, such as ESA, SNOLAB, GSI, NASA and AUGER. LIP is an "associated laboratory" assessed as "Excellent" in three successive evaluations by international panels. In its three laboratories in Coimbra, Lisbon, and Minho LIP has about 170 people, out of which over 70 hold a PhD degree, and many are professors at the local universities.

LIP’s expertise in planning, building and operating detectors for particle physics finds natural application in the fields of radiation therapy instrumentation, medical imaging and dosimetry. These areas are covered in multidisciplinary projects developed in collaboration with partners such as the ICNAS institute for nuclear health applications, the CTN/IST centre for nuclear technology, and several hospitals and medical research centres. 

Orthogonal ray imaging is LIP’s core project in instrumentation for radiation therapy, and is developed in partnership with two Portuguese oncology institutes, the Hospital of the University of Coimbra (CHUC) and several medical research centers. The aim is to improve radiotherapy by optimizing the treatment in near real time, so that the irradiation can better accommodate the tumor and spare surrounding healthy tissue. To do this, we make use of x- or gamma-rays emitted orthogonally to the treatment beam. The OR Imaging technique may be divided into two main branches: OrthoCT (orthogonal computer tomography) for monitoring radiotherapy (high-energy x-rays); and O-PGI (orthogonal prompt-gamma imaging) for monitoring proton therapy. In 2018, the LIP team pursued these two lines of research. In OrthoCT, we have managed in the past year to complete data processing regarding the analysis of a cavity irradiated inside an acrylic, cylindrical phantom, with data taken by means of a small-scale OrthoCT system. The results proved for the first time that it is possible to obtain images of the interior of an object without rotating the x-ray source.

One of the main LIP research infrastructure is the TagusLIP Laboratory installed in 2004 at the Lisbon Science and Technology Park (Taguspark). The campus is home to a University (IST), several research centres as well as a large spectrum of startups and PMEs.

TagusLIP was conceived as a generic infrastructure for the development of radiation detectors in the areas of PET imaging and experimental particle physics. TagusLIP includes detector and electronics laboratories, electronics workshop, a hot laboratory for work with radioactive sources, offices space, and meeting rooms.

The TagusLIP laboratory is equipped with the necessary instrumentation for R&D on radiation detectors and associated electronics and data acquisition, including electronics lab equipment, computing and networking systems. The laboratory offers software tools for developing analog and digital electronic integrated circuits, for firmware development, and for the design of printed circuit boards. The TagusLIP has a computing and data storage infrastructure, suitable to software projects in various areas, such as data acquisition, equipment control, data analysis and image processing. The TagusLIP is licensed for the use of radiation sources needed to develop and test new instruments in nuclear medicine.

1.3   ICNAS, Instituto de Ciências Nucleares Aplicadas à Saúde, PI: Antero Abrunhosa    

          www.uc.pt/icnas

ICNAS is a Research Unit of the University of Coimbra dedicated to pre-clinical and clinical Molecular Imaging in the fields of Neuroscience, Oncology and Cardiology. Particular technological strengths include GMP radiopharmaceutical production (2 cyclotrons with associated production labs for 18F, 11C, 13N, 68Ga, 64/61Cu), pre-clinical imaging (9.4T MR, 0.3 mm PET, optical imaging and photoacoustic tomography) and human studies (2 PET/CT, 3T MRI, OCT, neurophysiology). The group has also a strong background in image reconstruction and quantification and data analysis.

The Institute brings together researchers from the Faculties of Medicine, Pharmacy and Science and Technology, as well as clinicians and collaborators from the 3 nearby Hospitals (University Hospital, Oncology Institute and Children’s Hospital) and the pharmaceutical industry. Important achievements were made in the production of radionuclides, construction of imaging equipment and pre-clinical and clinical studies of neurodegeneration, cancer and cardiovascular diseases.

1.4 C²TN Centro de Ciências e Tecnologias Nucleares, PI: António Paulo     

        http://c2tn.tecnico.ulisboa.pt/

Instituto Superior Técnico (IST) is the largest and most reputed school of Engineering, Science and Technology in Portugal. Since its creation in 1911, IST’s mission is to contribute to the development of society by providing top quality higher education, at undergraduate and postgraduate levels, as well as developing Research, Development and Innovation (RD&I) activities to allow it to provide teaching in line with the highest international standards.

IST is involved with some of the most prestigious RD&I and technology transfer institutions in Portugal, with remarkable impact internationally in many scientific and technological domains. Internationalization has been defined as a key strategic goal over the past few years with increasing number of international students and staff as well as an increasing participation in international academic networks and establishment of several double degree programs in both MSc and PhD levels. This way, IST contributes to the development of the students’ educational level, offering them several opportunities to participate in international research networks, approaching scientific cooperation and multicultural experience, and motivating innovation and entrepreneurship.

The research unit Centro de Ciências e Tecnologias Nucleares (C2TN), is a multidisciplinary unit of Instituto Superior Técnico (IST). IST is the premium engineering, science and technology school in Portugal, integrating competences from all fields of engineering and fundamental sciences. Its mission is to provide top quality higher education and to develop RD&I that meet the highest international standards. C2TN performs basic and applied research, advanced training, and scientific and technological dissemination in Nuclear Sciences and Technologies applied to Life and Health Sciences, Cultural Heritage, Environment and Material Sciences. C2TN operates a broad range of specialized nuclear and non- nuclear techniques and facilities, most of them unique in the country, and will provide all the conditions to guarantee the success of the scientific project being proposed. The financial management is with IST-ID (Association of IST for RD&I), a private not-for-profit organization. IST is one of the founding associates of IST-ID and, through partnership agreements, makes available the majority of infrastructures and services for these RD&I activities to be carried out.

Knowledge and Expertise

At C²TN, there is extensive knowledge and expertise on the design and preclinical evaluation of radioprobes for Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) Imaging and Targeted Radionuclide Therapy (TRT). In this field, a multidisciplinary team of scientists with expertise in chemistry, radiochemistry and biological sciences, run dedicated facilities for: i) chemical synthesis, including solid phase peptide synthesis; ii) radiosynthesis; iii) biochemical, molecular biology and cellular studies; iv) animal studies. In recent years, this expertise started to be applied in the study of gold nanoparticles for image-guided drug delivery, targeted delivery of radionuclides and radiosensitization in radiation therapy. The team has in-house access to X-ray and gamma photon irradiatation facilities and has also experience on the evaluation of the biological effects of ionizing radiation (IR), encompassing (i) DNA repair systems, genotoxicity and cytotoxicity due to exposure to different IR types; (ii) computational and modelling studies in micro- and nanodosimetry.

2.1 University of Texas at Austin, PI: Karol Lang

      https://www.utexas.edu/

The group at the University of Texas at Austin has a long tradition of detector design and fabri- cation for a series of particle physics experiments at Brookhaven National Laboratory, NY, USA, Fermi National Accelerator Laboratory in Batavia, IL, USA, CERN, Geneva, Switzerland, and Laboratoire Souterrain de Modane in France. Our lab’s infrastructure allows us to launch various particle physics projects without procurement of additional equipment. Our main expertise lies in scintillators, photodetectors, drift chambers, ionization chambers, radioactive calibration systems, and light injection systems. In our common use are GEANT4 simulation package and ROOT analysis package.

Our detector engineering designer has over 20 years experience in the field and works well with undergraduate and graduate students who are routinely trained in our group. The crown jewel of the Department of Physics. Among any quality machines we have five high quality CNC mills, an EDM, and a number of manual lathes and mills.

For this project we envision that our engineer will spend an integrated 1.5 years. We will need a graduate student with majority of his/her time committed to the projects, and we will also need two undergraduates during most of lab activities and assisting in simulations.

The group at the University of Texas at Austin, has over 6,000 ft2 of laboratory space, including a cleanroom, in the Robert Lee Moore Hall on the campus of the University of Texas at Austin. This is the same building that houses the Physics, Math, and Astronomy departments. Our labs are well equipped with standard tools of HEP detector work (e.g., digital oscilloscopes, flexible NIM electronics, HV systems, etc.)and have been in use for detector work in support of HEP experiments since 1988.The Physics Department machine shop is available to us at a highly subsidized labor rate(currently $5 per hour). The machine shop is staffed by nine full-time machinists and is equipped with modern CNC machines and a full complement of standard machine tools. This facility has contributed to the fabrication of detector components for our previous experiments, and it will provide a cost-effective means to do so in the future. The Texas Advanced Computing Center is a supercomputer center operated by the University of Texas at Austin in partnership with NSF's XSEDE program. It operates a number of high-performance computing systems, including Stampede 2, a Intel Knights Landing/Xeon Skylake machine planned as an 18 petaflop system. Ten percent of the system is allocated at the discretion of the TACC director separately from XSEDE allocations, and as faculty of the University of Texas at Austin we can request discretionary allocations. This has benefited MINOS and MINOS+. Currently all MINOS+ Monte Carlo generation is performed using TACC. The 30,000 core Lonestar 5 system is primarily allocated to researchers in Texas and can also be used. Machine learning, in particular deep learning neural networks, are becoming increasingly important in HEP and training requires significant compute power typically provided by GPU coprocessors. The group owns a server with an NVidia K80 dual GPU which we use for machine learning applications. In addition, TACC's Lonestar 5 has 16 nodes with NVidia K40 GPUs which members of the group have access to.

Equipment: The labs contain a standard complement of research tools, and we were able to upgrade our equipment base using an Infrastructure grant from DOE HEP (based on ARRA funding) that was received 2009. The Infrastructure funding was also used to purchase the

2.2 UT MD Anderson Cancer Center, Proton Therapy Center, PI: Narayan Sahoo

            https://www.mdanderson.org/patients-family/diagnosis-treatment/care-centers-clinics/proton-therapy-center.html

UT MD Anderson Cancer Center is one of the largest NCI designated Cancer in the US with ample resources for research and developmental work for cancer diagnosis and treatment.  It has a synchrotron based proton therapy center, animal care facility, machine shop, computational resources and radiobiological research facilities to carry out the research and developmental activities described above. The physics group at the UT MD Anderson Cancer Center Proton Therapy Center in Houston will provide the support for the irradiation of the phantom and animals with proton beam. It will also provide support for the Monte Carlo simulation of the O-15 distribution in the phantom and animals to be used for comparison with the PET measured data. 

Project management

       Project Director: Stefaan Tavernier of PETsys Electronics S.A.

       Deputy Project Director: Karol Lang of UT Austin.

The project has a number of tasks that will be executed in two geographically distant locations, Portugal and Texas. It has a coordination to maximize synchronous progress and realization of all tasks of the project. Several key actors in this project have a long experience in participating, and managing, such geographically distributed collaborations.

Decisions are taken by Project Director in consultation with The Project Management Board (PMB). The PMB is comprised of all Activity leaders and is chaired by the Project Director (PD) or the Deputy Project Director (DPD). If there is one institution that doesn’t have an Activity leader, it will mandate a representative in the PMB. If one institution has several members in the PMB they will only have one vote.

The PMB will meet twice per year in-person, once in Portugal and once in the US. It will conduct an in-depth review and inspection of progress of all the tasks and to exchange ideas leading towards completing the project.

The active participants in the project will meet every month in project meetings, (PM), usually by teleconference. Each Activity leader will report on the situation and the progress in his activity. The teleconference will be also a forum for bringing up and discussing all variances of the execution plan.

Project Director and Deputy Project Director will frequently interact with Activity leaders to maintain the schedule, assure of progress, and monitor expenditures.

At the start of the project a kick-off meeting was organized in Portugal to Identify the main risks of the project and proposed contingency plans.

The project is very realistic, and we have foreseen adequate manpower to perform the tasks; the risk is small. It could be that there is some delay in the preparation of everything needed for the beam tests. It is one of the main tasks of the Project Management Board to identify such delays in time an propose adequate measures. What measures will be needed depends on the nature and the cause of the delay. But there are enough resources in the collaboration to cope with such a situation.

Project co-funded by: