Periodic Reporting for period 1 - GNVISION (Gamma-Neutron Vision aimed at improved cancer treatments in Hadron Therapy)
Período documentado: 2024-01-01 hasta 2025-12-31
Hadron therapy offers superior dose localization compared to conventional radiotherapy, with over 140 facilities operational worldwide and exponential growth projected. However, two limitations constrain its clinical effectiveness. First, treatment planning based on X-ray CT introduces range uncertainties of 1–3%, necessitating conservative safety margins (up to 3.5% + 3 mm) that limit the precision advantage of proton beams. Second, secondary neutrons from beam-tissue interactions deliver unwanted dose outside the target volume, increasing secondary cancer risk, yet can only be estimated through modeling rather than directly measured.
The GNVISION project addresses both challenges through a dual neutron-gamma imaging system combining gamma-ray imaging for real-time proton range verification with thermal neutron imaging for secondary dose monitoring. The technology builds on the i-TED Compton camera platform developed during the PI's ERC Consolidator Grant (HYMNS) , whose stringent detection requirements—high efficiency, excellent energy and spatial resolution, fast timing, and neutron background suppression—translate directly to hadron therapy applications. The core innovation upgrades i-TED with neutron-gamma discriminating scintillators combined with a ⁶Li-enriched polyethylene collimator that enables neutron imaging while remaining transparent to gamma rays.
Preclinical validation of the ion-range assessement capabilities was conducted at major hadron therapy facilities covering both main cyclotron technologies, successfully imaging 100–125 MeV proton beams in polyethylene phantoms and achieving TRL6. Regarding neutron imaging, proof-of-concept tests were carried out at Institut Laue-Langevin achieving ~4° angular resolution with peak-to-background ratios of ~15. Neutron imaging reached TRL5, with dual imaging field tests completed at the LENA research reactor (Pavia, November 2025). Four peer-reviewed open-access publications document the results, with patent protection established (WO2021229132A1).
Commercialization prospects are being explored with industry and clinical partners. The rapidly expanding hadron therapy infrastructure provides immediate market opportunity, and GNVISION's unique dual imaging capability, cost-effective design, and demonstrated clinical compatibility position it competitively for adoption.
The GNVISION project addresses both challenges through a dual neutron-gamma imaging system combining gamma-ray imaging for real-time proton range verification with thermal neutron imaging for secondary dose monitoring. The technology builds on the i-TED Compton camera platform developed during the PI's ERC Consolidator Grant (HYMNS) , whose stringent detection requirements—high efficiency, excellent energy and spatial resolution, fast timing, and neutron background suppression—translate directly to hadron therapy applications. The core innovation upgrades i-TED with neutron-gamma discriminating scintillators combined with a ⁶Li-enriched polyethylene collimator that enables neutron imaging while remaining transparent to gamma rays.
Preclinical validation of the ion-range assessement capabilities was conducted at major hadron therapy facilities covering both main cyclotron technologies, successfully imaging 100–125 MeV proton beams in polyethylene phantoms and achieving TRL6. Regarding neutron imaging, proof-of-concept tests were carried out at Institut Laue-Langevin achieving ~4° angular resolution with peak-to-background ratios of ~15. Neutron imaging reached TRL5, with dual imaging field tests completed at the LENA research reactor (Pavia, November 2025). Four peer-reviewed open-access publications document the results, with patent protection established (WO2021229132A1).
Commercialization prospects are being explored with industry and clinical partners. The rapidly expanding hadron therapy infrastructure provides immediate market opportunity, and GNVISION's unique dual imaging capability, cost-effective design, and demonstrated clinical compatibility position it competitively for adoption.
The GNVISION project developed and validated a dual neutron-gamma imaging system for real-time ion-range verification and secondary neutron dose monitoring in hadron therapy, advancing the technology from TRL3 to TRL6 for gamma-ray imaging and TRL5 for neutron imaging.
System design and optimization (WP1). Monte Carlo simulation studies optimized the detector architecture for clinical conditions. Collimator material studies established that natural LiPE (20–30 mm) provides acceptable contrast for thermal neutrons at reduced cost, while 6LiPE is essential for epithermal imaging. A MURA Rank-5 coded-aperture mask yielded a 15.6× efficiency improvement over the baseline pinhole and extended the field of view from 32° to 60°. These studies, combined with preliminary experimental tests, identified CLLBC (Cs2LiLaBr2Cl2:Ce) scintillators as the preferred detection material due to their fast response (~50 ns) and dual neutron-gamma discrimination capability.
Detector development and laboratory characterization (WP2). Both CLYC- and CLLBC-based detection systems were characterized. The CLYC system achieved 6.2% energy resolution at 662 keV and neutron-gamma discrimination Figure of Merit 3.8 with the first simultaneous 2D position reconstruction and pulse shape discrimination demonstrated for this crystal type (~5 mm FWHM spatial resolution). The CLLBC system showed superior energy resolution (6.5%) and was successfully integrated with PETsys electronics for practical dual imaging within clinical timeframes. Proof-of-concept neutron imaging at the Institut Laue-Langevin (Grenoble) achieved ~4° angular resolution and peak-to-background ratios of ~15, resolving two targets separated by only 2 cm along the beam axis, confirming simulation predictions and establishing TRL5.
Clinical validation (WP3). Preclinical experiments at the West German Proton Therapy Center (WPE, Essen) validated the system with 100–125 MeV proton pencil beams. A custom pulsed beam structure enabled temporal separation of prompt gamma imaging (PGI) during the spill and PET imaging between spills. PGI heat maps localized the Bragg peak over an 80 mm range, while 3D PET reconstruction of β⁺-emitting isotopes provided independent range validation, constituting the first worldwide demonstration of hybrid PGI-PET in an operational clinical facility (TRL6). A second campaign at the Rutherford Cancer Centre (Reading, UK) extended validation to a superconducting synchrocyclotron platform; analysis is ongoing. Field tests of the neutron imaging function at the LENA research reactor (Pavia, November 2025) demonstrated dual imaging in high-intensity neutron fields, consolidating TRL5 for neutron dose monitoring. GPU-accelerated machine learning algorithms for real-time image reconstruction were developed and deployed throughout the clinical campaigns.
System design and optimization (WP1). Monte Carlo simulation studies optimized the detector architecture for clinical conditions. Collimator material studies established that natural LiPE (20–30 mm) provides acceptable contrast for thermal neutrons at reduced cost, while 6LiPE is essential for epithermal imaging. A MURA Rank-5 coded-aperture mask yielded a 15.6× efficiency improvement over the baseline pinhole and extended the field of view from 32° to 60°. These studies, combined with preliminary experimental tests, identified CLLBC (Cs2LiLaBr2Cl2:Ce) scintillators as the preferred detection material due to their fast response (~50 ns) and dual neutron-gamma discrimination capability.
Detector development and laboratory characterization (WP2). Both CLYC- and CLLBC-based detection systems were characterized. The CLYC system achieved 6.2% energy resolution at 662 keV and neutron-gamma discrimination Figure of Merit 3.8 with the first simultaneous 2D position reconstruction and pulse shape discrimination demonstrated for this crystal type (~5 mm FWHM spatial resolution). The CLLBC system showed superior energy resolution (6.5%) and was successfully integrated with PETsys electronics for practical dual imaging within clinical timeframes. Proof-of-concept neutron imaging at the Institut Laue-Langevin (Grenoble) achieved ~4° angular resolution and peak-to-background ratios of ~15, resolving two targets separated by only 2 cm along the beam axis, confirming simulation predictions and establishing TRL5.
Clinical validation (WP3). Preclinical experiments at the West German Proton Therapy Center (WPE, Essen) validated the system with 100–125 MeV proton pencil beams. A custom pulsed beam structure enabled temporal separation of prompt gamma imaging (PGI) during the spill and PET imaging between spills. PGI heat maps localized the Bragg peak over an 80 mm range, while 3D PET reconstruction of β⁺-emitting isotopes provided independent range validation, constituting the first worldwide demonstration of hybrid PGI-PET in an operational clinical facility (TRL6). A second campaign at the Rutherford Cancer Centre (Reading, UK) extended validation to a superconducting synchrocyclotron platform; analysis is ongoing. Field tests of the neutron imaging function at the LENA research reactor (Pavia, November 2025) demonstrated dual imaging in high-intensity neutron fields, consolidating TRL5 for neutron dose monitoring. GPU-accelerated machine learning algorithms for real-time image reconstruction were developed and deployed throughout the clinical campaigns.
Advances over existing technologies. The hybrid PGI-PET methodology demonstrated in an operational clinical facility represents a world first: no prior system had exploited the pulsed structure of a clinical cyclotron to simultaneously deploy Compton-mode prompt gamma imaging and PET within the same device, providing two physically independent measurements of ion range and substantially reducing systematic uncertainties. Equally novel is the combination of ion-range verification with simultaneous thermal neutron imaging on a single compact platform—existing systems are exclusively sensitive to gamma radiation—with ~4° angular resolution and peak-to-background ratios of ~15 demonstrated experimentally. The adaptation of CLLBC scintillators to a clinically deployable Compton camera also advances the state of the art in detector instrumentation beyond the hadron therapy context.
Potential impacts. Millimeter-accurate real-time range verification could allow tighter dose conformality and improved sparing of healthy tissues, reducing toxicity particularly for tumors near critical structures. The neutron dose monitoring capability addresses a complementary need, especially for pediatric patients where secondary cancer risk is a primary concern. The rapidly expanding global hadron therapy infrastructure—over 50 facilities under construction worldwide—creates immediate and growing demand for these solutions.
Key needs for further uptake. Completing clinical validation of neutron dose monitoring, optimizing performance at full clinical beam intensities, and integrating with treatment planning workflows are the immediate research priorities. Larger-scale clinical studies and early engagement with regulatory bodies under the European MDR framework will be essential for market entry. Formalizing the ongoing collaboration with a leading industry partner, strengthening the IP portfolio, and securing complementary funding through instruments such as EIC Transition will be critical to sustain progress toward clinical and commercial deployment.
Potential impacts. Millimeter-accurate real-time range verification could allow tighter dose conformality and improved sparing of healthy tissues, reducing toxicity particularly for tumors near critical structures. The neutron dose monitoring capability addresses a complementary need, especially for pediatric patients where secondary cancer risk is a primary concern. The rapidly expanding global hadron therapy infrastructure—over 50 facilities under construction worldwide—creates immediate and growing demand for these solutions.
Key needs for further uptake. Completing clinical validation of neutron dose monitoring, optimizing performance at full clinical beam intensities, and integrating with treatment planning workflows are the immediate research priorities. Larger-scale clinical studies and early engagement with regulatory bodies under the European MDR framework will be essential for market entry. Formalizing the ongoing collaboration with a leading industry partner, strengthening the IP portfolio, and securing complementary funding through instruments such as EIC Transition will be critical to sustain progress toward clinical and commercial deployment.