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An innovative molecule, GdBLDL, for boron neutron capture therapy (BNCT) has been developed and its effectiveness as a BNCT carrier is currently under evaluation using in vivo experiments on small animal tumour models. The molecule contains both 10B (the most commonly used NCT agent) and 157Gd nuclei. 157Gd is the second most studied element to perform NCT, mainly thanks to its high cross section for the capture of low-energy neutrons. The main drawback of 157Gd neutron capture reaction is the very short range and low-energy secondary charged particles (Auger electrons), which requires 157Gd to be very close to the cellular DNA to have an appreciable biological effect. Treatment doses were calculated by Monte Carlo simulations to ensure the optimised tumour irradiation and the sparing of the healthy organs of the irradiated animals. The enhancement of the absorbed dose due to the simultaneous presence of 157GdB and 10Gd in the experimental set-up was calculated and the advantage introduced by the presence of 157Gd was discussed. [ABSTRACT FROM AUTHOR]

The role played by DNA cluster damage and chromosome aberrations in radiation-induced cell killing was investigated, assuming that certain chromosome aberrations (dicentrics, rings and large deletions,'lethal aberrations') lead to clonogenic inactivation and that chromosome aberrations are due to micrometre-scale rejoining of chromosome fragments derived from DNA cluster lesions (CLs). The CL yield and the threshold distance governing fragment rejoining were left as model parameters. The model, implemented as a Monte Carlo code called BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations), provided simulated survival curves that were compared with survival data on AG1522 and V79 cells exposed to different radiation types, including heavy ions. The agreement between simulation outcomes and experimental data suggests that lethal aberrations are likely to play an important role in cell killing not only for AG1522 cells exposed to X rays, as already reported by others, but alsofor other radiation types and other cells. Furthermore, the results are consistent with the hypothesis that the critical DNA lesions leading to cell death and chromosome aberrations are double-strand break clusters ( possibly involving the ∼1000-10 000 bp scale) and that the effects of such clusters are modulated by micrometre-scale proximity effects during DNA damage processing. [ABSTRACT FROM AUTHOR]

The role played by DNA cluster damage and chromosome aberrations in radiation-induced cell killing was investigated, assuming that certain chromosome aberrations (dicentrics, rings and large deletions, or 'lethal aberrations') lead to clonogenic inactivation and that chromosome aberrations are due to micrometre-scale rejoining of chromosome fragments derived from DNA cluster lesions (CLs). The CL yield and the threshold distance governing fragment rejoining were left as model parameters. The model, implemented as a Monte Carlo code called BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations), provided simulated survival curves that were compared with survival data on AG1522 and V79 cells exposed to different radiation types, including heavy ions. The agreement between simulation outcomes and experimental data suggests that lethal aberrations are likely to play an important role in cell killing not only for AG1522 cells exposed to X rays, as already reported by others, but also for other radiation types and other cells. Furthermore, the results are consistent with the hypothesis that the critical DNA lesions leading to cell death and chromosome aberrations are double-strand break clusters ( possibly involving the ~1000-10 000 bp scale) and that the effects of such clusters are modulated by micrometre-scale proximity effects during DNA damage processing. [ABSTRACT FROM AUTHOR]

Purpose: Many types of lung tumors have a very poor prognosis due to their spread in the whole organ volume. The fact that boron neutron capture therapy (BNCT) would allow for selective targeting of all the nodules regardless of their position, prompted a preclinical feasibility study of ex situ BNCT at the thermal neutron facility of RA-3 reactor in the province of Buenos Aires, Argentina. (?)-4p-dihydroxy-borylphenylalanine fructose complex (BPA-F) biodistribution studies in an adult sheep model and computational dosimetry for a human explanted lung were performed to evaluate the feasibility and the therapeutic potential of ex situ BNCT. Methods: Two kinds of boron biodistribution studies were carried out in the healthy sheep: a set of pharmacokinetic studies without lung excision, and a set that consisted of evaluation of boron concentration in the explanted and perfused lung. In order to assess the feasibility of the clinical application of ex situ BNCT at RA-3, a case of multiple lung metastases was analyzed. A detailed computational representation of the geometry of the lung was built based on a real collapsed human lung. Dosimetric calculations and dose limiting considerations were based on the experimental results from the adult sheep, and on the most suitable information published in the literature. In addition, a workable treatment plan was considered to assess the clinical application in a realistic scenario. Results: Concentration-time profiles for the normal sheep showed that the boron kinetics in blood, lung, and skin would adequately represent the boron behavior and absolute uptake expected in human tissues. Results strongly suggest that the distribution of the boron compound is spatially homogeneous in the lung. A constant lung-to-blood ratio of 1.3±0.1 was observed from 80 min after the end of BPA-F infusion. The fact that this ratio remains constant during time would allow the blood boron concentration to be used as a surrogate and indirect quantification of the estimated value in the explanted healthy lung. The proposed preclinical animal model allowed for the study of the explanted lung. As expected, the boron concentration values fell as a result of the application of the preservation protocol required to preserve the lung function. The distribution of the boron concentration retention factor was obtained for healthy lung, with a mean value of 0.46±0.14 consistent with that reported for metastatic colon carcinoma model in rat perfused lung. Considering the human lung model and suitable tumor control probability for lung cancer, a promising average fraction of controlled lesions higher than 85% was obtained even for a low tumor-to-normal boron concentration ratio of 2. Conclusions: This work reports for the first time data supporting the validity of the ovine model as an adequate human surrogate in terms of boron kinetics and uptake in clinically relevant tissues. Collectively, the results and analysis presented would strongly suggest that ex situ whole lung BNCT irradiation is a feasible and highly promising technique that could greatly contribute to the treatment of metastatic lung disease in those patients without extrapulmonary spread, increasing not only the expected overall survival but also the resulting quality of life. [ABSTRACT FROM AUTHOR]

Abstract: A selective uptake of boron in the tumor is the base of Boron Neutron Capture Therapy, which can destroy the tumor substantially sparing the normal tissue. In order to deliver a lethal dose to the tumor, keeping the dose absorbed by normal tissues below the tolerance level, it is mandatory to know the 10B concentration present in each kind of tissue at the moment of irradiation. This work presents the calibration procedure adopted for a boron concentration measurement method based on neutron autoradiography, where biological samples are deposited on sensitive films and irradiated in the thermal column of the TRIGA reactor (University of Pavia). The latent tracks produced in the film by the charged particles coming from the neutron capture in 10B are made visible by a proper etching, allowing the measurement of the track density. A calibration procedure with standard samples provides curves of track density as a function of boron concentration, to be used in the measurement of biological samples. In this paper, the bulk etch rate parameter and the calibration curves obtained for both liquid samples and biological tissues with known boron concentration are presented. A bulk etch rate value of (1.64±0.02)μm/h and a linear dependence with etching time were found. The plots representing the track density versus the boron concentration in a range between 5 and 50μg/g (ppm) are linear, with an angular coefficient of (1.614±0.169)·10−3 tracks/(μm2 ppm) for liquids and (1.598±0.097)·10−2 tracks/(μm2 ppm) for tissues. [Copyright &y& Elsevier]

Cell death is a crucial endpoint in radiation-induced biological damage: on one side, cell death is a reference endpoint to characterise the action of radiation in biological targets; on the other side, any cancer therapy aims to kill tumour cells. Starting from Lea's target theory, many models have been proposed to interpret radiation-induced cell killing; after briefly discussing some of these models, in this paper, a mechanistic approach based on an experimentally observed link between chromosome aberrations and cell death was presented. More specifically, a model and a Monte Carlo code originally developed for chromosome aberrations were extended to simulate radiation-induced cell death applying an experimentally observed one-to-one relationship between the average number of ‘lethal aberrations’ (dicentrics, rings and deletions) per cell and –ln S, S being the fraction of surviving cells. Although such observation was related to X rays, in the present work, the approach was also applied to protons and alpha particles. A good agreement between simulation outcomes and literature data provided a model validation for 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 treatment for boron neutron capture therapy. [ABSTRACT FROM PUBLISHER]

A monolithic silicon telescope, consisting of a thin ΔE stage (of ~2 µm in thickness) coupled to a residual-energy stage E (thickness 500 µm), was studied and tested for measuring the boron concentration in biological samples for boron neutron capture therapy (BNCT). At the Laboratorio di Energia Nucleare Applicata BNCT facility, Pavia, Italy, this information is derived by placing the tissue sample in front of a surface barrier diode and by irradiating the system with neutrons generated in the thermal column of the TRIGA Mark H reactor. The boron concentration is estimated through the measurement of the energy deposited in the detector by the products of the 10B(n,α)7Li reaction. However, the low-energy part of the measured spectra is typically distorted by secondary electrons produced by photon background and by protons generated via the 14N(n,p)14C reaction in tissue. This work discusses the possibility of using a different silicon device, namely, the monolithic silicon telescope, for improving the accuracy of the method by exploiting its particle discrimination capabilities. A device with a sensitive area of 1 mm² was irradiated (in vacuo) bare, faced both with a certified boron implanted silicon wafer and with a thin sample of rat lung loaded with boron. The preliminary results showed that (a) alpha particles and lithium ions produced by neutron capture on boron are well identified, (b) the events due to protons generated in tissue by neutron capture on nitrogen can be well discriminated, and (c) the presence of nitrogen inside the detector dead layer gives rise to an additional contribution of protons from neutron absorption. These preliminary studies gave confidence about the possibility of improving the accuracy for the assessment of the 10B concentration in biological samples for BNCT. [ABSTRACT FROM AUTHOR]

The selective uptake of boron by tumors compared to that by healthy tissue makes boron neutron capture therapy (BNCT) an extremely advantageous technique for the treatment of tumors that affect a whole vital organ. An example is represented by colon adenocarcinoma metastases invading the liver, often resulting in a fatal outcome, even if surgical resection of the primary tumor is successful. BNCT can be performed by irradiating the explanted organ in a suitable neutron field. In the thermal column of the Triga Mark II reactor at Pavia University, a facility was created for this purpose and used for the irradiation of explanted human livers. The neutron field distribution inside the organ was studied both experimentally and by means of the Monte Carlo N-particle transport code (MCNP). The liver was modeled as a spherical segment in MCNP and a hepatic-equivalent solution was used as an experimental phantom. In the as-built facility, the ratio between maximum and minimum flux values inside the phantom ([uppercase_phi_synonym]max/[uppercase_phi_synonym]min) was 3.8; this value can be lowered to 2.3 by rotating the liver during the irradiation. In this study, the authors proposed a new facility configuration to achieve a uniform thermal neutron flux distribution in the liver. They showed that a [uppercase_phi_synonym]max/[uppercase_phi_synonym]min ratio of 1.4 could be obtained without the need for organ rotation. Flux distributions and dose volume histograms were reported for different graphite configurations. [ABSTRACT FROM AUTHOR]

In-phantom dosimetry studies have been carried out at the thermal columns of a thermal- and a fast-nuclear reactor for investigating: (a) the spatial distribution of the gamma dose and the thermal neutron fluence and (b) the accuracy at which the boron concentration should be estimated in an explanted organ of a boron neutron capture therapy patient. The phantom was a cylinder (11 cm in diameter and 12 cm in height) of tissue-equivalent gel. Dose images were acquired with gel dosemeters across the axial section of the phantom. The thermal neutron fluence rate was measured with activation foils in a few positions of this phantom. Dose and fluence rate profiles were also calculated with Monte Carlo simulations. The trend of these profiles do not show significant differences for the thermal columns considered in this work. [ABSTRACT FROM PUBLISHER]

We report the investigation of new organic complexes containing a magnetic moment (Gd-based molecular nanomagnets), which can serve the double purpose of acting as boron neutron capture therapy (BNCT) agents, and at the same time act as contrast agents to detect the molecule in the tissue by a proton magnetic resonance imaging (MRI). We also explore the possibility of monitoring the concentration of the BNCT agent directly via proton and boron NMR relaxation. The absorption of 10B-enriched molecules inside tumoral liver tissues has been shown by NMR measurements and confirmed by α spectroscopy. A new molecular Gd-tagged nanomagnet and BNCT agent (GdBPA) has been synthesized and characterized measuring its relaxivity R1 between 10 kHz and 66 MHz, and its use as a contrast agent in MRI has been demonstrated. The NMR-based evidence of the absorption of GdBPA into living tumoral cells is also shown. [ABSTRACT FROM AUTHOR]

Boron Neutron Capture Therapy (BNCT) is an experimental radiotherapy that uses the combination of neutron irradiation and 10 B to treat neoplasms. By means of this technique, many clinical trials were performed worldwide with promising results [1] using research nuclear reactors as neutron sources. Anyhow, these machines have several problems that hinder the development of dedicated BNCT hospitals. This issue can now be overcome by using intense-current proton accelerators, which coupled with beryllium or lithium targets yield more than 10 14 neutron per second. This can be a boost to BNCT because accelerators are more compact and can be installed within hospitals. The Italian National Institute of Nuclear Physics (INFN) designed and manufactured a Radiofrequency Quadrupole proton accelerator (RFQ) [2] , which delivers 5 MeV protons with 30 mA current in a Continuous Wave (CW) mode and it is coupled to a beryllium target. This accelerator could be installed at Centro Nazionale di Adroterapia Oncologica (CNAO) in Pavia. In this work we present the MC calculations for the tailoring of a BNCT neutron beam obtained by the described RFQ. Firstly, we show that MC transport codes such as MCNP and PHITS are not able to simulate the correct neutron spectra from 5 MeV protons interacting on beryllium. Therefore, the neutron double differential source implemented in MCNP was extracted from the measurements performed by Agosteo et al. [3] . As the energy range goes up to 3.5 MeV, neutrons need to be moderated and collimated by a Beam Shaping Assembly (BSA), because BNCT requires a spectrum peaked between 1 and 10 keV. Differently from the past, where the optimal configuration was chosen according to physical characteristics of the beam, in this case the results were evaluated on the basis of the dosimetry obtained in a real clinical case by treatment planning simulation. What emerges, is that the classical figures of merit employed for the tailoring of a clinical BNCT [4] should be taken as a first guideline, while the dosimetric assessment on realistic clinical scenarios is the most appropriate criterion for beam evaluations. [ABSTRACT FROM AUTHOR]

Abstract: 10B molecular compounds suitable for Boron Neutron Capture Therapy (BNCT) are tagged with a Gd(III) paramagnetic ion. The newly synthesized molecule, Gd-BPA, is investigated as contrast agent in Magnetic Resonance Imaging (MRI) with the final aim of mapping the boron distribution in tissues. Preliminary Nuclear Magnetic Resonance (NMR) measurements, which include 1H and 10B relaxometry in animal tissues, proton relaxivity of the paramagnetic Gd-BPA molecule in water and its absorption in tumoral living cells, are reported. [Copyright &y& Elsevier]