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

Cobaltabis(dicarbollide) ([o-COSAN]−) as Multifunctional Chemotherapeutics: A Prospective Application in Boron Neutron Capture Therapy (BNCT) for Glioblastoma

Purpose: The aim of our study was to assess if the sodium salt of cobaltabis(dicarbollide) and its di-iodinated derivative (Na[o-COSAN] and Na[8,8′-I2-o-COSAN]) could be promising agents for dual anti-cancer treatment (chemotherapy + BNCT) for GBM. Methods: The biological activities of the small molecules were evaluated in vitro with glioblastoma cells lines U87 and T98G in 2D and 3D cell models and in vivo in the small model animal Caenorhabditis elegans (C. elegans) at the L4-stage and using the eggs. Results: Our studies indicated that only spheroids from the U87 cell line have impaired growth after treatment with both compounds, suggesting an increased resistance from T98G spheroids, contrary to what was observed in the monolayer culture, which highlights the need to employ 3D models for future GBM studies. In vitro tests in U87 and T98G cells conclude that the amount of 10B inside the cells is enough for BNCT irradiation. BNCT becomes more effective on T98G after their incubation with Na[8,8′-I2-o-COSAN], whereas no apparent cell-killing effect was observed for untreated cells. Conclusions: These small molecules, particularly [8,8′-I2-o-COSAN]−, are serious candidates for BNCT now that the facilities of accelerator-based neutron sources are more accessible, providing an alternative treatment for resistant glioblastoma

Twin-Shaping Filter Technique Applied to CZT Detectors

CdTe/CdZnTe is an attractive and consolidated material with which to realize detectors with good efficiency and energy resolution, operating at room temperature for a large variety of applications such as astrophysics, medical imaging and security. However, this type of material suffers from the low mobility of the charge carriers (particularly the holes), which are trapped and so degrade the detector response in terms of charge collection efficiency, energy resolution and photopeak efficiency. The response of a planar CdTe/CdZnTe detector, which depends on the distance between the charge formation position and the collecting electrodes, can be improved by using two kinds of techniques, based on the optimization of the electrode geometry and/or signal compensation methods. We are studying the feasibility and the reliability of a biparametric method that uses a twin pulse shaping active filter to analyze each signal from the detector twice: one “Slow”, which is proportional to the energy of the incident photon, and one “Fast”, which depends on the position of the interaction with respect to the collecting electrode. In this paper we describe the bi-parametric technique applied to planar CdZnTe detectors grown by CNR/IMEM and to Spectrometer Grade detectors. We report the experimental results in terms of energy resolution, peak-to valley ratio and photopeak efficiency, as well as the compensated spectra obtained as a function of the bias voltage, photon energy and shaping time pairs. We also report the results obtained by using a CdZnTe drift strip detector. Furthermore, this technique could be implemented in an array of detectors, whose front-end electronics is composed of ASICs, where the shaping time can be selected for each channel, like the RENA-3 IC (NOVA R&D)

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

Recent advances in the development of high-resolution 3D cadmium zinc telluride drift strip detectors

In the last two decades, great efforts have been made in the development of 3D cadmium-zinc-Telluride (CZT) detectors operating at room temperature for gamma-ray spectroscopic imaging. This work presents the spectroscopic performance of new high-resolution CZT drift strip detectors, recently developed at IMEM-CNR of Parma (Italy) in collaboration with due2lab (Italy). The detectors (19.4 mm × 19.4 mm × 6 mm) are organized into collecting anode strips (pitch of 1.6 mm) and drift strips (pitch of 0.4 mm) which are negatively biased to optimize electron charge collection. The cathode is divided into strips orthogonal to the anode strips with a pitch of 2 mm. Dedicated pulse processing analysis was performed on a wide range of collected and induced charge pulse shapes using custom 32-channel digital readout electronics. Excellent room-Temperature energy resolution (1.3% FWHM at 662 keV) was achieved using the detectors without any spectral corrections. Further improvements (0.8% FWHM at 662 keV) were also obtained through a novel correction technique based on the analysis of collected-induced charge pulses from anode and drift strips. These activities are in the framework of two Italian research projects on the development of spectroscopic gamma-ray imagers (10-1000 keV) for astrophysical and medical applications

Development of a 3D CZT Spectrometer System with Digital Readout for Hard X/Gamma-Ray Astronomy

We report on the development and of a complete X/γ rays detection system (10-1000 keV) based on CZT spectrometers with spatial resolution in three dimensions (3D) and a digital electronics acquisition chain. The prototype is made by packing four linear modules, each composed of one 3D CZT sensors. Each sensors is realized using a single spectroscopic graded CZT crystal of about 20×20×5 mm3. An electrode structure consisting of 12 collecting anodes with a pitch of 1.6 mm and 3 drift strips between each pair of anodes for 48 strips (0.15 mm wide) on the anodic side was adopted. The cathode is made of 10 strips with a pitch of 2 mm and orthogonal to anode side strips. Since the reading of the drift strips will carried out by putting in parallel all the strips that occupy the same place with respect to a collecting anode, the channels number for each sensors is only 25. The detector readout front-is based on custom designed low noise charge sensitive pre-amplifiers (CSP) implemented in hybrid 16 channels board. The CZT module and its CSP front-end provide the signals to a multichannel Digital Pulse Processing FPGA based system able to digitize and process continuously the signals. The digital system implement an innovative firmware that allow performing fine time-tagging, online pulse shape and height analysis with good energy resolution

Design of a facility for boron measurement based on neutron activation analysis

The BNCT group in Pavia developed a boron concentration measurement technique based on α spectroscopy and neutron autoradiograpy, that allow obtaining both the concentration and the spatial distribution of 10B in biological samples. However, since α spectroscopy requires that the sample is irradiated under vacuum, it cannot be exploited for liquid samples such as urine and blood. For this reason, a prompt gamma neutron activation analysis (PGNAA) facility will be installed at the Triga Mark II reactor at Pavia University. In order to design a PGNAA facility, the Monte Carlo code MCNP4c2 was used. An input file describing the geometry and the neutron source of the Triga reactor was used, and modified to design the components necessary for the beam filtering, collimation and shielding. Given the geometry of the facility and the irradiation position quite peripheral with respect to the reactor core, different variance reduction techniques were implemented to optimize the neutron and gamma transport. Following, the best set-up among the different configurations tested is described

From radiation-induced chromosome damage to cell death: modelling basic mechanisms and applications to Boron Neutron Capture Therapy

Cell death is a crucial endpoint in radiation-induced biological damage, since any cancer therapy aims to kill tumour cells and cell death is a reference endpoint to characterize the radiation action in biological targets. Starting from Lea’s target theory, many models have been proposed to interpret radiation-induced cell killing. After discussing the main models of cell survival, in this paper we will present a theoretical approach based on the experimentally observed link between chromosome aberrations and cell death [1]. A mechanistic model and a Monte Carlo code originally developed for chromosome aberrations were extended to simulate radiation-induced cell death adopting a one-to-one relationship between the average number of “lethal aberrations” (dicentrics, rings and deletions) per cell and –lnS, being S the fraction of surviving cells. Although the observation by Cornforth and Bedford was related to normal fibroblasts exposed to X rays, in the present work the approach was applied also to intermediate- and high-LET radiation. The good agreement between simulation outcomes and literature data provided a model validation for normal cells exposed to different radiation types. The same approach was then successfully applied to simulate the survival of cells enriched with Boron and irradiated with thermal neutrons at the Triga Mark II reactor in Pavia, to mimic a typical BNCT treatment