A high-resolution large-area detector for quality assurance in radiotherapy.

Hadron therapy is an advanced radiation modality for treating cancer, which currently uses protons and carbon ions. Hadrons allow for a highly conformal dose distribution to the tumour, minimising the detrimental side-effects due to radiation received by healthy tissues. Treatment with hadrons requires sub-millimetre spatial resolution and high dosimetric accuracy. This paper discusses the design, fabrication and performance tests of a detector based on Gas Electron Multipliers (GEM) coupled to a matrix of thin-film transistors (TFT), with an active area of 60 × 80 mm2 and 200 ppi resolution. The experimental results show that this novel detector is able to detect low-energy (40 kVp X-rays), high-energy (6 MeV) photons used in conventional radiation therapy and protons and carbon ions of clinical energies used in hadron therapy. The GEM-TFT is a compact, fully scalable, radiation-hard detector that measures secondary electrons produced by the GEMs with sub-millimetre spatial resolution and a linear response for proton currents from 18 pA to 0.7 nA. Correcting known detector defects may aid in future studies on dose uniformity, LET dependence, and different gas mixture evaluation, improving the accuracy of QA in radiotherapy.

44Sc production from enriched 47TiO2 targets with a medical cyclotron.

44Sc is a ß+-emitter which has been extensively studied for nuclear medicine applications. Its promising decay characteristics [t1/2 = 3.97 h, E [Formula: see text] = 632 keV (94.3%), Eγ = 1157 keV (99.9%); 1499 keV (0.91%)] make it highly attractive for clinical PET imaging, offering an alternative to the widely used 68Ga [t1/2 = 67.7 min, E [Formula: see text] = 836 keV (87.7%)]. Notably, its nearly fourfold longer half-life opens avenues for applications with biomolecules having extended biological half-lives and enables the centralized distribution of 44Sc radiopharmaceuticals. An additional advantage of employing 44Sc as a diagnostic radioisotope lies in its counterpart, the ß--emitter 47Sc, which is currently under investigation for targeted radiotherapy. Together, they form an ideal theranostic pair, providing a comprehensive solution for both diagnostic imaging and therapeutic applications in nuclear medicine. At the Bern medical cyclotron, a study to optimize the production of scandium radioisotopes is currently ongoing. In this context, proton irradiation of titanium targets has been investigated, exploiting the reactions 47Ti(p,α)44Sc and 50Ti(p,α)47Sc. This approach enables the production of Sc radioisotopes within a single PET medical cyclotron facility, employing identical chemical procedures for target preparation and post-irradiation processing. In this paper, we report on cross-section measurements of the 47Ti(p,α)44Sc nuclear reaction using 95.7% enriched 47TiO2 targets. On the basis of the obtained results, the production yield and purity were calculated to assess the optimal irradiation conditions. Production tests were performed to confirm these findings.

Study of thulium-167 cyclotron production: a potential medically-relevant radionuclide.

Introduction: Targeted Radionuclide Therapy is used for the treatment of tumors in nuclear medicine, while sparing healthy tissues. Its application to cancer treatment is expanding. In particular, Auger-electron emitters potentially exhibit high efficacy in treating either small metastases or single tumor cells due to their short range in tissue. The aim of this paper is to study the feasibility of a large-scale production of thulium-167, an Auger-electron emitter radionuclide, in view of eventual systematic preclinical studies. Methods: Proton-irradiated enriched erbium-167 and erbium-168 oxides were used to measure the production cross sections of thulium-165, thulium-166, thulium-167, and thulium-168 utilizing an 18-MeV medical cyclotron equipped with a Beam Transport Line (BTL) at the Bern medical cyclotron laboratory. The comparison between the experimental and the TENDL 2021 theoretical cross-section results were in good agreement. Additional experiments were performed to assess the production yields of thulium radioisotopes in the BTL. Thulium-167 production yield was also measured irradiating five different target materials (167 Er 2 O 3, 168 Er 2 O 3, nat Tm 2 O 3, nat Yb 2 O 3, 171 Yb 2 O 3) with proton beams up to 63 MeV at the Injector II cyclotron of Paul Scherrer Institute. Results and Discussion: Our experiments showed that an 8-h irradiation of enriched ytterbium-171 oxide produced about 420 MBq of thulium-167 with a radionuclidic purity of 99.95% after 5 days of cooling time with a proton beam of about 53 MeV. Larger activities of thulium-167 can be achieved using enriched erbium-168 oxide with a 23-MeV proton beam, obtaining about 1 GBq after 8-h irradiation with a radionuclidic purity of <99.5% 5 days post end of bombardment.

Cross-section measurement of thulium radioisotopes with an 18 MeV medical PET cyclotron for an optimized 165Er production.

165Er is a pure Auger-electron emitter with promising characteristics for therapeutic applications in nuclear medicine. The short penetration path and high Linear Energy Transfer (LET) of the emitted Auger electrons make 165Er particularly suitable for treating small tumor metastases. Several production methods based on the irradiation with charged particles of Er and Ho targets can be found in the literature. In this paper, we report on the study of 165Er indirect production performed via the 166Er(p,2n)165Tm →165Er reaction at the 18 MeV Bern medical cyclotron. Despite the use of highly enriched 166Er2O3 targets, several Tm radioisotopes are produced during the irradiation, making the knowledge of the cross sections involved crucial. For this reason, a precise investigation of the cross sections of the relevant nuclear reactions in the energy range of interest was performed by irradiating Er2O3 targets with different isotopic enrichment levels and using a method based on the inversion of a linear system of equations. For the reactions 164Er(p, γ)165Tm, 166Er(p,n)166Tm, 166Er(p, γ)167Tm, 167Er(p,3n)165Tm, 167Er(p, γ)168Tm, 168Er(p,2n)167Tm and 170Er(p,3n)168Tm, the nuclear cross section was measured for the first time. From the results obtained, the production yield and purity of the parent radioisotope 165Tm were calculated to assess the optimal irradiation conditions. Several production tests with solid targets were performed to confirm these findings.

Optimized production of 67Cu based on cross section measurements of 67Cu and 64Cu using an 18 MeV medical cyclotron.

RadioNuclide Therapy (RNT) in nuclear medicine is a cancer treatment based on the administration of radioactive substances that specifically target cancer cells in the patient. These radiopharmaceuticals consist of tumor-targeting vectors labeled with ß-, α, or Auger electron-emitting radionuclides. In this framework, 67Cu is receiving increasing interest as it provides ß--particles accompanied by low-energy γ radiation. The latter allows to perform Single Photon Emission Tomography (SPECT) imaging for detecting the radiotracer distribution for an optimized treatment plan and follow-up. Furthermore, 67Cu could be used as therapeutic partner of the ß+-emitters 61Cu and 64Cu, both currently under study for Positron Emission Tomography (PET) imaging, paving the way to the concept of theranostics. The major barrier to a wider use of 67Cu-based radiopharmaceutical is its lack of availability in quantities and qualities suitable for clinical applications. A possible but challenging solution is the proton irradiation of enriched 70Zn targets, using medical cyclotrons equipped with a solid target station. This route was investigated at the Bern medical cyclotron, where an 18 MeV cyclotron is in operation together with a solid target station and a 6-m-long beam transfer line. The cross section of the involved nuclear reactions were accurately measured to optimize the production yield and the radionuclidic purity. Several production tests were performed to confirm the obtained results.

Alternative routes for 64Cu production using an 18 MeV medical cyclotron in view of theranostic applications.

Radiometals play a fundamental role in the development of personalized nuclear medicine. In particular, copper radioisotopes are attracting increasing interest since they offer a varying range of decay modes and half-lives and can be used for imaging (60Cu, 61Cu, 62Cu and 64Cu) and targeted radionuclide therapy (64Cu and 67Cu), providing two of the most promising true theranostic pairs, namely 61Cu/67Cu and 64Cu/67Cu. Currently, the most widely used in clinical applications is 64Cu, which has a unique decay scheme featuring ß+-, ß--decay and electron capture. These characteristics allow its exploitation in both diagnostic and therapeutic fields. However, although 64Cu has extensively been investigated in academic research and preclinical settings, it is still scarcely used in routine clinical practice due to its insufficient availability at an affordable price. In fact, the most commonly used production method involves proton irradiation of enriched 64Ni, which has a very low isotopic abundance and is therefore extremely expensive. In this paper, we report on the study of two alternative production routes, namely the 65Cu(p,pn)64Cu and 67Zn(p, α)64Cu reactions, which enable low and high 64Cu specific activities, respectively. To optimize the 64Cu production, while minimizing the mass of copper used as a target in the first case, or the co-production of other copper radioisotopes in the second case, an accurate knowledge of the production cross sections is of paramount importance. For this reason, the involved nuclear reaction cross sections were measured at the Bern medical cyclotron laboratory by irradiating enriched 65CuO and enriched 67ZnO targets. On the basis of the obtained results, the production yield and purity were calculated to assess the optimal irradiation conditions. Several production tests were performed to confirm these findings.

47Sc and 46Sc cross-section measurement for an optimized 47Sc production with an 18 MeV medical PET cyclotron.

The availability of novel radionuclides plays a fundamental role in the development of personalized nuclear medicine. In particular, there is growing interest in pairs formed by two radioisotopes of the same element, the so-called true theranostic pairs, such as 61,64Cu/67Cu, 43,44Sc/47Sc and 155Tb/149,161Tb. In this case, the two radionuclides have identical kinetics and chemical reactivity, allowing to predict whether the patient will benefit from a therapeutic treatment on the basis of nuclear imaging data. 47Sc [t1/2 = 3.349 d, E [Formula: see text] = 440.9 keV (68.4%); 600.3 keV (31.6%), Eγ = 159.4 keV (68.3%)] is a promising radionuclide for theranostic applications in nuclear medicine. Its physical characteristics make it suitable for radionuclide therapy and allow SPECT imaging during treatment. Moreover, 47Sc is foreseen as the therapeutic partner of the ß+-emitters 43Sc and 44Sc, both under study for PET imaging, opening new avenues towards the true theranostics concept. 47Sc can be produced by proton irradiation of an enriched 50Ti oxide target with a medical cyclotron equipped with a solid target station. To optimize the production yield and the radionuclidic purity, an accurate knowledge of the production cross sections is necessary. In this paper, we report on measurements of the production cross section of 47Sc and 46Sc using enriched 50Ti titanium oxide targets, performed at the Bern University Hospital cyclotron laboratory. On the basis of the obtained results, a study of the production yield and purity was performed to assess the optimal irradiation conditions. A production test was also carried out to confirm these findings.

Cyclotron Production and Separation of Scandium Radionuclides from Natural Titanium Metal and Titanium Dioxide Targets.

Theranostic strategies involve select radionuclides that allow diagnostic imaging and tailored radionuclide therapy in the same patient. An example of a Food and Drug Administration-approved theranostic pair is the 68Ga- and 177Lu-labeled DOTATATE peptides, which are used to image neuroendocrine tumors, predict treatment response, and treat disease. However, when using radionuclides of 2 different elements, differences in the pharmacokinetic and pharmacodynamic profile of the agent can occur. Theranostic agents that incorporate the matched-pair radionuclides of scandium-43Sc/47Sc or 44Sc/47Sc-would guarantee identical chemistries and pharmacologic profiles. The aim of this study was to investigate production of 43,44,47Sc via proton-induced nuclear reactions on titanium nuclei using a 24-MeV cyclotron. Methods: Aluminum, niobium, and tantalum target holders were used with titanium foils and pressed TiO2 to produce scandium radionuclides with proton energies of up to 24 MeV. Irradiated targets were digested using NH4HF2 and HCl in a closed perfluoroalkoxy alkane vessel in 90 min. Scandium radionuclides were purified via ion-exchange chromatography using branched N,N,N',N'-tetra-2-ethylhexyldiglycolamide. The titanium target material was recovered via alkali precipitation with ammonia solution. Results: Titanium foil and TiO2 were digested with an average efficiency of 98% ± 3% and 95% ± 1%, respectively. The typical digestion time was 45 min for titanium foil and 75 min for TiO2 The average scandium recovery was 94% ± 3%, and the average titanium recoveries from digested titanium foil and TiO2 after precipitation as TiO2 were 108% ± 8% and 104% ± 5% of initial mass, respectively. Conclusion: This work demonstrated a robust method for the cyclotron production of scandium radionuclides that could be used with natural or enriched TiO2 target material.

Developments toward the Implementation of 44Sc Production at a Medical Cyclotron.

44Sc has favorable properties for cancer diagnosis using Positron Emission Tomography (PET) making it a promising candidate for application in nuclear medicine. The implementation of its production with existing compact medical cyclotrons would mean the next essential milestone in the development of this radionuclide. While the production and application of 44Sc has been comprehensively investigated, the development of specific targetry and irradiation methods is of paramount importance. As a result, the target was optimized for the 44Ca(p,n)44Sc nuclear reaction using CaO instead of CaCO3, ensuring decrease in target radioactive degassing during irradiation and increased radionuclidic yield. Irradiations were performed at the research cyclotron at the Paul Scherrer Institute (~11 MeV, 50 µA, 90 min) and the medical cyclotron at the University of Bern (~13 MeV, 10 µA, 240 min), with yields varying from 200 MBq to 16 GBq. The development of targetry, chemical separation as well as the practical issues and implications of irradiations, are analyzed and discussed. As a proof-of-concept study, the 44Sc produced at the medical cyclotron was used for a preclinical study using a previously developed albumin-binding prostate-specific membrane antigen (PSMA) ligand. This work demonstrates the feasibility to produce 44Sc with high yields and radionuclidic purity using a medical cyclotron, equipped with a commercial solid target station.

165Er: A new candidate for Auger electron therapy and its possible cyclotron production from natural holmium targets.

165Er, a pure Auger-electron emitter, could be an attractive candidate for targeted radionuclide therapy. Auger electrons possess short penetration paths with high linear energy transfer. In this study, experimental cross-sections of the 165Ho(p, n)165Er nuclear reaction were measured and targets irradiated with protons using Injector II cyclotron at Paul Scherrer Institute (Switzerland) and the 18 MeV medical cyclotron laboratory at the University Hospital in Bern. A purification method was developed in order to obtain 165Er suitable for in vivo applications.

Cross-section measurement of 44mSc,47Sc, 48Sc and 47Ca for an optimized 47Sc production with an 18 MeV medical PET cyclotron.

Novel medical radioisotopes for both diagnostic and therapy are essential for the future development of personalized nuclear medicine. Among them, radiometals can be used to label both proteins and peptides and encompass promising theranostic pairs. The optimized supply of radiometals in quantity and quality for clinical applications represents a scientific and technological challenge. 47Sc is a ß- emitter that forms a theranostic pair together with one of the ß+ emitters 43Sc or 44Sc. It can be produced at a medical cyclotron by proton bombardment of an enriched calcium oxide target. The parasite production of 48Sc undermines the 47Sc purity, which strongly depends on the energy of protons impinging the target and on the thickness of the target material. For this purpose, an accurate knowledge of the production cross-sections is mandatory. In this paper, we report on the measurement of the cross-section of the reactions 44Ca(p,n)44 mSc,48Ca(p,n)48Sc, 48Ca(p,2n)47Sc and 48Ca(p,pn)47Ca using natCaCO3 targets performed at the Bern University Hospital cyclotron laboratory. On the basis of the obtained results and of the isotopic composition of commercially available enriched target materials, the thick target yields and the purity were calculated to assess the optimal irradiation conditions.