Understanding the potentiality of accelerator based-boron neutron capture therapy for osteosarcoma: Dosimetry assessment based on the reported clinical experience

Background: Osteosarcoma is the most frequent primary malignant bone tumour, and its incidence is higher in children and adolescents, for whom it represents more than 10% of solid cancers. Despite the introduction of adjuvant and neo-adjuvant chemotherapy that markedly increased the success rate in the treatment, aggressive surgery is still needed and a considerable percentage of patients do not survive due to recurrences or early metastases. Boron Neutron Capture Therapy (BNCT), an experimental radiotherapy, was investigated as a treatment that could allow a less aggressive surgery by killing infiltrated tumour cells in the surrounding healthy tissues. BNCT requires an intense neutron beam to ensure irradiation times of the order of 1h. In Italy, a Radio Frequency Quadrupole (RFQ) proton accelerator has been designed and constructed for BNCT, and a suitable neutron spectrum was tailored by means of Monte Carlo calculations. This paper explores the feasibility of BNCT to treat osteosarcoma using this neutron source based on accelerator. Methods: The therapeutic efficacy of BNCT was analysed evaluating the dose distribution obtained in a clinical case of femur osteosarcoma. Mixed field dosimetry was assessed with two different formalisms whose parameters were specifically derived from radiobiological experiments involving in vitro UMR-106 osteosarcoma cell survival assays and boron concentration assessments in an animal model of osteosarcoma. A clinical case of skull osteosarcoma treated with BNCT in Japan was re-evaluated from the point of view of dose calculation and used as a reference for comparison. Results: The results in the case of femur osteosarcoma show that the RFQ beam would ensure a suitable tumour dose painting in a total irradiation time of less than an hour. Comparing the dosimetry between the analysed case and the treated patient in Japan it turns out that doses obtained in the femur tumour are at least as good as the ones delivered in the skull osteosarcoma. The same is concluded when the comparison is carried out taking into account osteosarcoma irradiations with photon radiation therapy. Conclusions: The possibility to apply BNCT to osteosarcoma would allow a multimodal treatment consisting in neo-adjuvant chemotherapy, high-LET selective radiation treatment and a more conservative surgery.Fil: Bortolussi, Silva. University of Pavia; ItaliaFil: Postuma, Ian. University of Pavia; ItaliaFil: Protti, Nicoletta. University of Pavia; ItaliaFil: Provenzano, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Ferrari, Cinzia. University of Pavia; ItaliaFil: Cansolino, Laura. University of Pavia; ItaliaFil: Dionigi, Paolo. University of Pavia; ItaliaFil: Galasso, Olimpio. University of Catanzaro; ItaliaFil: Gasparini, Giorgio. University of Catanzaro; ItaliaFil: Altieri, Saverio. University of Pavia; ItaliaFil: Miyatake, Shin Ichi. Osaka Medical College; JapónFil: González, Sara Josefina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; Argentin

Bioprinting for osteosarcoma model: Methodological aspects and experimental applications

The study aims at using the bioprinting technique to create an in vitro 3D construct of osteosarcoma, as an alternative model for studies related to Boron Neutron Capture Therapy (BNCT)

Extending neutron autoradiography technique for boron concentration measurements in hard tissues

The neutron autoradiography technique using polycarbonate nuclear track detectors (NTD) has been extended to quantify the boron concentration in hard tissues, an application of special interest in Boron Neutron Capture Therapy (BNCT). Chemical and mechanical processing methods to prepare thin tissue sections as required by this technique have been explored. Four different decalcification methods governed by slow and fast kinetics were tested in boron-loaded bones. Due to the significant loss of the boron content, this technique was discarded. On the contrary, mechanical manipulation to obtain bone powder and tissue sections of tens of microns thick proved reproducible and suitable, ensuring a proper conservation of the boron content in the samples. A calibration curve that relates the 10B concentration of a bone sample and the track density in a Lexan NTD is presented. Bone powder embedded in boric acid solution with known boron concentrations between 0 and 100 ppm was used as a standard material. The samples, contained in slim Lexan cases, were exposed to a neutron fluence of 1012 cm−2 at the thermal column central facility of the RA-3 reactor (Argentina). The revealed tracks in the NTD were counted with an image processing software. The effect of track overlapping was studied and corresponding corrections were implemented in the presented calibration curve. Stochastic simulations of the track densities produced by the products of the 10B thermal neutron capture reaction for different boron concentrations in bone were performed and compared with the experimental results. The remarkable agreement between the two curves suggested the suitability of the obtained experimental calibration curve. This neutron autoradiography technique was finally applied to determine the boron concentration in pulverized and compact bone samples coming from a sheep experimental model. The obtained results for both type of samples agreed with boron measurements carried out by ICP-OES within experimental uncertainties. The fact that the histological structure of bone sections remains preserved allows for future boron microdistribution analysis.Fil: Provenzano, Lucas. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Olivera, María Silvina. Comisión Nacional de Energía Atómica; ArgentinaFil: Saint Martin, María Laura Gisela. Comisión Nacional de Energía Atómica; ArgentinaFil: Rodriguez, Luis Miguel. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Patagonia Norte; ArgentinaFil: Fregenal, Daniel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Comisión Nacional de Energía Atómica; ArgentinaFil: Thorp, Silvia Inés. Comisión Nacional de Energía Atómica; ArgentinaFil: Pozzi, Emiliano César Cayetano. Comisión Nacional de Energía Atómica; ArgentinaFil: Curotto, Paula. Comisión Nacional de Energía Atómica; ArgentinaFil: Postuma, Ian. Istituto Nazionale di Fisica Nucleare; ItaliaFil: Altieri, Saverio. Istituto Nazionale di Fisica Nucleare; Italia. Universita Degli Studi Di Pavia; ItaliaFil: González, Sara Josefina. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Bortolussi, Silva. Istituto Nazionale di Fisica Nucleare; Italia. Universita Degli Studi Di Pavia; ItaliaFil: Portu, Agustina Mariana. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Lithium halide filled carbon nanocapsules: Paving the way towards lithium neutron capture therapy (LiNCT)

Neutron capture therapy (NCT) is a form of radiotherapy that exploits the potential of some specific isotopes to capture thermal neutrons and subsequently yield high linear energy transfer (LET) particles, suitable for cancer treatment. Recently, relevant technological improvements have been made in terms of accelerators as suitable neutron sources for NCT at hospitals. However, low selective delivery of current drugs to cancer cells remains as the main challenge for successful clinical application of NCT. This work presents an innovative and previously unexplored approach for the design of nanotherapeutic NCT agents. Herein, a new concept based on carbon nanomaterials that seal 6Li active NCT nuclides is investigated. The 6Li active species are located in the inner cavity of the nanocarrier (carbon nanohorns or carbon nanotubes) and therefore, completely protected from the biological environment, avoiding toxicity and degradation. After encapsulation of the active cargo, the external surface of the nanocarrier is modified for improved biocompatibility. The developed 6Li-filled carbon nanohorns offered the possibility to explore 6Li compounds as active NCT agents by delivering therapeutic doses to cancer cells. We envisage that nanoencapsulation of 6Li can trigger the successful development and implementation of Lithium Neutron Cancer Therapy (LiNCT).G. T. acknowledges funding from ERC Consolidator Grant NEST (725743). G.G. gratefully acknowledges the funding by the Portuguese Science Foundation (FCT) for Programme Stimulus of Scientific Employment – Individual Support (CEECIND/01913/2017), financial support of project CARBONCT (2022.03596.PTDC), TEMA UIDB/00481/2020 and UIDP/00481/2020; and CENTRO-01-0145-FEDER-022083 - Centro Portugal Regional Operational Programme (Centro2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund. In addition, support through the project IF/00894/2015 and within the scope of the project CICECO-Aveiro Institute of Materials, UIDB/50011/2020, UIDP/50011/2020 & LA/P/0006/2020, financed by national funds through the FCT/MEC (PIDDAC) is gratefully acknowledged. We acknowledge funding by INFN (CSN5)-project ENTER_BNCT. ICMAB and ICN2 acknowledge financial support from the Spanish Ministry of Economy and Competitiveness (Spain), through the “Severo Ochoa” Programme for Centres of Excellence in R&D (CEX2019-000917-S and CEX2021-001214-S respectively). ICN2 is supported by CERCA programme. We acknowledge funding from Generalitat de Catalunya (2021-SGR-00439, 2017 SGR 327). M.Ll. has carried out this work in the framework of the Doctoral Degree Program in Materials Science of the Universitat Autònoma de Barcelona. We acknowledge fruitful discussions with Manuel Altabas and support with the XPS analysis by Guillaume Sauthier.With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S).Peer reviewe

Boron Neutron Capture Therapy beam shaping assembly prototype MCNP and PHITS input files

BNCT BSA prototype This release contains the simulation files of a BNCT BSA prototype which can be used to evaluate bulk moderating material at the CN accelerator facility at the INFN Legnaro National Laboratories. There are two simulation source files, MCNP contains the most updated version of the prototype, we recommend using this simulation geometry as an input also for PHITS. On the other hand PHITH source file contains a tetrahedral geometry which can be more easily manipulated for shielding evaluations, keep in mind that this source file misses the shielding polyethylene shielding around the lead reflector. Updated versions of the simulations files will be provided in future releases. BSA prototype design The goal was to design and build a prototype that embodied the key elements of the BSA created for clinical BNCT[1] in order to experimentally verify how well the BSA materials work together to moderate neutrons. As mentioned above, this structure is not intended to be a replica of the clinical BSA. Instead, it was intended to build a model of the BSA enabling the collection of data regarding the impact of various materials on the neutron spectrum and Monte Carlo validation. Two configurations have been constructed, on the basis of their effectiveness in collimation and of the spectral modulation obtained by changing the moderator thickness. The first configuration (PHITS input files) consist of a 5 cm thick lead cylinder (reflector) with a cylindrical housing for the insertion of 5 cm diameter Alliflu elements. The length of the reflector is 25 cm. The reflector is surrounded by a 1 cm thick absorber of borated polyethylene. A collimator of borated polyethylene, 25 cm thick leaving a 5 cm diameter beam port ends the structure. The collimator is 25 cm long. The Alliflu elements can be housed in the core of the BSA prototype, inside the cylindrical reflector, allowing measurements with variable moderator thickness from 0 to 25 cm. The second configuration (MCNP input files) consists in adding a shell made of polyethylene to configuration 1, with the aim of improving the moderation as well as the absorption of ambient radiation. The polyethylene additional shell in the second configuration was extended towards the target to better shield the neutrons emerging in all directions. This strategy plus the extra thickness of the absorber made it possible to reach a proton current of 6 μA in some of the measurements. References 1. Postuma, Ian, et al. "A novel approach to design and evaluate BNCT neutron beams combining physical, radiobiological, and dosimetric figures of merit." Biology 10.3 (2021): 174

Modeling radiation-induced cell death: role of different levels of DNA damage clustering

Some open questions on the mechanisms underlying radiation-induced cell death were addressed by a biophysical model, focusing on DNA damage clustering and its consequences. DNA "cluster lesions" (CLs) were assumed to produce independent chromosome fragments that, if created within a micrometer-scale threshold distance (d), can lead to chromosome aberrations following mis-rejoining; in turn, certain aberrations (dicentrics, rings and large deletions) were assumed to lead to clonogenic cell death. The CL yield and d were the only adjustable parameters. The model, implemented as a Monte Carlo code called BIophysical ANalysis of Cell death and chromosome Aberrations (BIANCA), provided simulated survival curves that were directly compared with experimental data on human and hamster cells exposed to photons, protons, α-particles and heavier ions including carbon and iron. d = 5 μm, independent of radiation quality, and CL yields in the range ~2-20 CLs Gy(-1) cell(-1), depending on particle type and energy, led to good agreement between simulations and data. This supports the hypothesis of a pivotal role of DNA cluster damage at sub-micrometric scale, modulated by chromosome fragment mis-rejoining at micrometric scale. To investigate the features of such critical damage, the CL yields were compared with experimental or theoretical yields of DNA fragments of different sizes, focusing on the base-pair scale (related to the so-called local clustering), the kbp scale ("regional clustering") and the Mbp scale, corresponding to chromatin loops. Interestingly, the CL yields showed better agreement with kbp fragments rather than bp fragments or Mbp fragments; this suggests that also regional clustering, in addition to other clustering levels, may play an important role, possibly due to its relationship with nucleosome organization in the chromatin fiber

Rational design of gold nanoparticles functionalized with carboranes for application in Boron Neutron Capture Therapy

In this paper we propose a bottom-up approach to obtain new boron carriers built with ortho-carborane functionalized gold nanoparticles (GNPs) for applications in Boron Neutron Capture Therapy. The interaction between carboranes and the gold surface was assured by one or two SH-groups directly linked to the boron atoms of the B10C2 cage. This allowed obtaining stable, non toxic systems, though optimal biological performance was hampered by low solubility in aqueous media. To improve cell uptake, the hydrophilic character of carborane functionalized GNPs was enhanced by further coverage with an appropriately tailored diblock copolymer (PEO-b-PCL). This polymer also contained pendant carboranes to provide anchoring to the pre-functionalized GNPs. In vitro tests, carried out on osteosarcoma cells, showed that the final vectors possessed excellent biocompatibility joint to the capacity of concentrating boron atoms in the target, which is encouraging evidenced to pursue applications in vivo

LungQuant

LungQuant is a software for the quantification of lesions in CT scans of COVID-19 patients. Its functioning is based on a cascade of three Convolutional Neural Networks (CNN): 1) the first one is used to produce a bounding box enclosing the lungs; 2) the second CNN is used to segment the lungs; 3) the third CNN is devoted to lesion segmentation. The system takes in input Computed Tomography (CT) scans in nifti format. The system returns in output: the lungs and lesion masks and other information that can be useful to describe the infection

Inter-comparison of boron concentration measurements at INFN-University of Pavia (Italy) and CNEA (Argentina)

An inter-comparison of three boron determination techniques was carried out between laboratories from INFN-University of Pavia (Italy) and CNEA (Argentina): alpha spectrometry (alpha-spect), neutron capture radiography (NCR) and quantitative autoradiography (QTA). Samples of different nature were analysed: liquid standards, liver homogenates and tissue samples from different treatment protocols. The techniques showed a good agreement in a concentration range of interest in BNCT (1-100ppm), thus demonstrating their applicability as precise methods to quantify boron and determine its distribution in tissues

A Novel Approach to Design and Evaluate BNCT Neutron Beams Combining Physical, Radiobiological, and Dosimetric Figures of Merit

Simple Summary Clinical potential and safety are presented as novel criteria to evaluate neutron beams designed for boron neutron capture therapy (BNCT). The presently used figures of merit are a set of physical quantities calculated in air, related to the neutron flux, the collimation, and the spectral characteristics. However, the capability of the beam to deliver an effective and safe treatment to patients should be the most important criterion in view of the clinical application. This work presents the design of a neutron beam produced by a proton accelerator coupled to a beryllium target and the use of new figures of merit to choose the best beam among different candidates. These figures of merit use tridimensional dosimetry simulated in phantoms and patients, to calculate the probability of tumor control without affecting healthy tissues, employing proper radiobiological models. Moreover, the dose absorbed by out-of-field healthy organs is used as a criterion to establish the safest beam for clinical treatments. Results show that beams that would be rejected by physical in-air quantities demonstrate a clinical performance comparable to existing neutron beams successfully used for patients, and that the presented criteria allow a clear selection of the most adequate beam among the ones presented. (1) Background:The quality of neutron beams for Boron Neutron Capture Therapy (BNCT) is currently defined by its physical characteristics in air. Recommendations exist to define whether a designed beam is useful for clinical treatment. This work presents a new way to evaluate neutron beams based on their clinical performance and on their safety, employing radiobiological quantities. (2) Methods: The case study is a neutron beam for deep-seated tumors from a 5 MeV proton beam coupled to a beryllium target. Physical Figures of Merit were used to design five beams; however, they did not allow a clear ranking of their quality in terms of therapeutic potential. The latter was then evaluated based on in-phantom dose distributions and on the calculation of the Uncomplicated Tumor Control Probability (UTCP). The safety of the beams was also evaluated calculating the in-patient out-of-beam dosimetry. (3) Results: All the beams ensured a UTCP comparable to the one of a clinical beam in phantom; the safety criterion allowed to choose the best candidate. When this was tested in the treatment planning of a real patient treated in Finland, the UTCP was still comparable to the one of the clinical beam. (4) Conclusions: Even when standard physical recommendations are not met, radiobiological and dosimetric criteria demonstrate to be a valid tool to select an effective and safe beam for patient treatment.Peer reviewe