Experimental investigation at CATANA facility of n-10B and p-11B reactions for the enhancement of proton therapy

The aim of the NEPTUNE (Nuclear process-driven Enhancement of Proton Therapy UNravEled) project is to investigate in detail both the physical and radiobiological phenomena that could justify an increase of the proton-induced cytogenetic effects in cells irradiated in presence of an agent containing natural boron.In this work, a double-stage silicon telescope coupled to different boron converters was irradiated at the CATANA proton therapy facility (INFN-LNS) for studying the proton boron fusion and the neutron boron capture reactions by discriminating secondary particles from primary protons.Different boron targets were developed by depositing boric acid, enriched with a higher than 99% content of ¹⁰B or ¹¹B, on a 50 µm thick PolyMethilMetacrylate (PMMA) substrate. The ¹⁰B target allows to evaluate the contribution of lithium and alpha particles produced by the boron neutron capture reaction triggered by secondary thermal neutrons, while the ¹¹B target is exploited for studying the effect of the p + ¹¹B → 3α nuclear reaction directly triggered by primary protons.Experimental results clearly show the presence of alpha particles from both the reactions. The silicon telescope is capable of discriminating, by means of the so-called “scatter plots”, the contribution of alpha particles originated by thermal neutrons on ¹⁰B with respect to the ones produced by protons impinging on ¹¹B. Although a reliable quantitative study of the alpha production rate has not been achieved yet, this work demonstrates that low energy and, therefore, high-LET particles from both the reactions can be measured.     

Mathematical Modeling of the Role of Mitochondrial Fusion and Fission in Mitochondrial DNA Maintenance

Accumulation of mitochondrial DNA (mtDNA) mutations has been implicated in a wide range of human pathologies, including neurodegenerative diseases, sarcopenia, and the aging process itself. In cells, mtDNA molecules are constantly turned over (i.e. replicated and degraded) and are also exchanged among mitochondria during the fusion and fission of these organelles. While the expansion of a mutant mtDNA population is believed to occur by random segregation of these molecules during turnover, the role of mitochondrial fusion-fission in this context is currently not well understood. In this study, an in silico modeling approach is taken to investigate the effects of mitochondrial fusion and fission dynamics on mutant mtDNA accumulation. Here we report model simulations suggesting that when mitochondrial fusion-fission rate is low, the slow mtDNA mixing can lead to an uneven distribution of mutant mtDNA among mitochondria in between two mitochondrial autophagic events leading to more stochasticity in the outcomes from a single random autophagic event. Consequently, slower mitochondrial fusion-fission results in higher variability in the mtDNA mutation burden among cells in a tissue over time, and mtDNA mutations have a higher propensity to clonally expand due to the increased stochasticity. When these mutations affect cellular energetics, nuclear retrograde signalling can upregulate mtDNA replication, which is expected to slow clonal expansion of these mutant mtDNA. However, our simulations suggest that the protective ability of retrograde signalling depends on the efficiency of fusion-fission process. Our results thus shed light on the interplay between mitochondrial fusion-fission and mtDNA turnover and may explain the mechanism underlying the experimentally observed increase in the accumulation of mtDNA mutations when either mitochondrial fusion or fission is inhibited.     

Aspects in practical neutron dosimetry with ionization chambers

Summary The calibration procedure to determine the absorbed dose within a phantom irradiated with fast neutrons is described for ionization chambers. A comparison between values of the neutron dose determined with paired ionization chambers and values of the neutron fluence measured with a fission chamber (²³⁸U) is given. The comparison indicates the energy variation of the fast neutrons within a phantom irradiated with 14 MeV neutrons.Dedicated to Prof. Dr. Dr. h. c. mult. B. Rajewsky on the occasion of his 80th birthday.     

Fusion modes of an axially symmetrical mirror trap with the high power injection of fast particles

We analyzed the energy balance of a fusion system based on an axially symmetrical open trap. In the considered system, the injection of high-energy (fast) particles is the main source of plasma external heating. Simulation of physical kinetics of the injected particles is based on the numerical solution of the Fokker-Planck equation taking into account scattering into the domain of losses and participation in the fusion reactions. Despite the considerable energy losses of the injected particles when leaving the trap due to the angular scattering, the considered system is sufficiently effective to be used as a source of neutrals for the hybrid (fusion-fission) reactor. The principle possibility of achieving a power amplification of Q _pl ≈ 1 in plasma was demonstrated in operation modes with high neutron yield.     

A comparison of radioprotection from three neutron sources and 60Co by WR-2721 and WR-151327

Two thiophosphoroate radiation protectors (WR-2721 and WR-151327) were assessed for their ability to modify the effects of neutron or gamma irradiation on the gastrointestinal tract. Three neutron sources (DOSAR, JANUS, and FERMILAB) were compared to the response obtained after 60Co irradiation. The end points studied were intestinal stem cell survival and LD50(6). DOSAR and JANUS, both fission-spectrum neutrons, showed somewhat different gut sensitivities [LD50(6)] of about 240 and 400 cGy respectively. The intestinal LD50 obtained with FERMILAB neutrons (25 meV) was closer (875 cGy) to that obtained after 60Co (1068 cGy) irradiation. WR-151327 protected against the lethal effects of fission neutron (DOSAR and JANUS) to a greater degree (DMF = 2.2) than with lower LET sources such as FERMILAB neutrons (DMF = 1.7) or 60Co (DMF = 1.7). The results did not correlate with the intestinal stem cell assays where WR-2721 when compared to WR-151327 showed either similar (DOSAR; fission spectrum neutrons) or somewhat better (60Co and FERMILAB neutrons) protection. Possible explanations for the differing results are discussed.     

New horizons for therapy based on the boron neutron capture reaction

Boron neutron capture therapy (BNCT) is currently undergoing clinical trials in the USA, Japan and The Netherlands with patients afflicted with deadly brain cancer (glioblastoma multiforme) or melanoma. This therapy relies on a binary process in which the capture of a slow neutron by a ¹⁰B nucleus leads to an energetic nuclear fission reaction, with the formation of ⁷Li³⁺ and ⁴He²⁺ and accompanied by about 2.4 MeV of energy. The fleeting ⁷Li³⁺ and ⁴He²⁺ travel a distance of only about the diameter of one cell, and they are deadly to any cell in which they have been produced. Research in progress is concerned with the development of advanced boron agents and neutron sources, other than nuclear reactors, for the treatment of a variety of cancer types using novel ¹⁰B delivery methods. Non-malignant diseases such as rheumatoid arthritis offer additional opportunities for BNCT. The entire BNCT area awaits commercialization.     

Research of the small plasma focus with an auxiliary electrode at deuterium filling

The research was provided on the small plasma focus device with the Mather-type electrodes in configuration with an auxiliary electrode placed in front of the anode. It works at the current maximum of 200 kA. The total neutron yield from D-D reaction reaches 10⁵–10⁷ per one shot. The hard X-rays and neutrons were detected with scintillation detectors and the soft X-rays with a PIN detector and four MCP frames. We present preliminary results obtained from different configurations of the anode (inner electrode) and auxiliary electrode and we compare these results with that obtained in configuration without auxiliary electrode. The auxiliary electrode decreased both the neutron yield and the time of hard X-ray and neutron production. Different electrode faces has influence on the energy distribution of generated neutrons.     

Physical,dosimetric and clinical aspects and delivery systems in neutron capture therapy

Neutron capture therapy (NCT) is a targeted radiotherapy for cancer treatment. In this method, neutrons with a spectra/specific energy (depending on the type of agent used for NCT) are captured with an agent that has a high cross-section with these neutrons. There are some agents that have been proposed in NCT including ¹⁰B, ¹⁵⁷Gd and ³³S. Among these agents, only ¹⁰B is used in clinical trials. Application of ¹⁵⁷Gd is limited to in-vivo and in-vitro research. In addition, ³³S has been applied in the field of Monte Carlo simulation. In BNCT, the only two delivery agents which are presently applied in clinical trials are BPA and BSH, but other delivery systems are being developed for more effective treatment in NCT. Neutron sources used in NCT are fission reactors, accelerators, and ²⁵²Cf. Among these, fission reactors have the most application in NCT. So far, BNCT has been applied to treat various cancers including glioblastoma multiforme, malignant glioma, malignant meningioma, liver, head and neck, lung, colon, melanoma, thyroid, hepatic, gastrointestinal cancer, and extra-mammary Paget's disease. This paper aims to review physical, dosimetric and clinical aspects as well as delivery systems in NCT for various agents.     

Determination of the thermal and epithermal neutron sensitivities of an LBO chamber

An LBO (Li₂B₄O₇) walled ionization chamber was designed to monitor the epithermal neutron fluence in boron neutron capture therapy clinical irradiation. The thermal and epithermal neutron sensitivities of the device were evaluated using accelerator neutrons from the ⁹Be(d, n) reaction at a deuteron energy of 4 MeV (4 MeV d-Be neutrons). The response of the chamber in terms of the electric charge induced in the LBO chamber was compared with the thermal and epithermal neutron fluences measured using the gold-foil activation method. The thermal and epithermal neutron sensitivities obtained were expressed in units of pC cm², i.e., from the chamber response divided by neutron fluence (cm^?2). The measured LBO chamber sensitivities were 2.23 × 10^?7 ± 0.34 × 10^?7 (pC cm²) for thermal neutrons and 2.00 × 10^?5 ± 0.12 × 10^?5 (pC cm²) for epithermal neutrons. This shows that the LBO chamber is sufficiently sensitive to epithermal neutrons to be useful for epithermal neutron monitoring in BNCT irradiation.     

Relative biological effectiveness and tolerance dose of fission neutrons in canine skin for a potential combination of neutron capture therapy and fast-neutron therapy

To investigate the potential efficacy of fission neutrons from a fast-neutron reactor for the treatment of radioresistant tumors, the relative biological effectiveness (RBE) and tolerance dose of fission neutrons in canine skin were determined. The forelimbs of 34 healthy mongrel dogs received a single dose of fission neutrons (5.6, 6.8, 8.2, 9.6 or 11 Gy) or 137Cs gamma rays (10, 15, 20, 25 or 30 Gy). Based on observations of radiodermatitis for each radiation, the single-fraction RBE of fission neutrons in the sixth month was calculated as approximately 3. The tolerance doses of fission neutrons and gamma rays, defined as the highest doses giving no moist desquamation on the irradiated skin in the recovery phase, were estimated as 7.6 Gy and 20 Gy, respectively. The tolerance dose of 7.6 Gy of fission neutrons included 5.0 Gy of fast neutrons possessing high anti-tumor effects and 1.4 x 10(12) n/cm2 of thermal neutrons, which could be applicable to neutron capture therapy (NCT). The combination of fast-neutron therapy and NCT using a fast-neutron reactor might be useful for the treatment of radioresistant tumors.     

On the eptihermal neutron energy limit for Accelerator-Based Boron Neutron Capture Therapy (AB-BNCT): Study and impact of new energy limits

Background and purpose: Accelerator-Based Boron Neutron Capture Therapy is a radiotherapy based on compact accelerator neutron sources requiring an epithermal neutron field for tumour irradiations. Neutrons of 10 keV are considered as the maximum optimised energy to treat deep-seated tumours. We investigated, by means of Monte Carlo simulations, the epithermal range from 10 eV to 10 keV in order to optimise the maximum epithermal neutron energy as a function of the tumour depth.Methods: A Snyder head phantom was simulated and mono-energetic neutrons with 4 different incident energies were used: 10 eV, 100 eV, 1 keV and 10 keV. ¹⁰B capture rates and absorbed dose composition on every tissue were calculated to describe and compare the effects of lowering the maximum epithermal energy. The Therapeutic Gain (TG) was estimated considering the whole brain volume.Results: For tumours seated at 4 cm depth, 10 eV, 100 eV and 1 keV neutrons provided respectively 54%, 36% and 18% increase on the TG compared to 10 keV neutrons. Neutrons with energies between 10 eV and 1 keV provided higher TG than 10 keV neutrons for tumours seated up to 6.4 cm depth inside the head. The size of the tumour does not change these results.Conclusions: Using lower epithermal energy neutrons for AB-BNCT tumour irradiation could improve treatment efficacy, delivering more therapeutic dose while reducing the dose in healthy tissues. This could lead to new Beam Shape Assembly designs in order to optimise the BNCT irradiation.     

A Relativistic Neutron Fireball from a Supernova Explosion as a Possible Source of Chiral Influence

We elaborate on a previously proposed idea that polarized electrons produced from neutrons, released in a supernova (SN) explosion, can cause chiral dissymmetry of molecules in interstellar gas-dust clouds. A specific physical mechanism of a relativistic neutron fireball with Lorentz factor of the order of 100 is assumed for propelling a great number of free neutrons outside the dense SN shell. A relativistic chiral electron–proton plasma, produced from neutron decays, is slowed down owing to collective effects in the interstellar plasma. As collective effects do not involve the particle spin, the electrons can carry their helicities to the cloud. The estimates show high chiral efficiency of such electrons. In addition to this mechanism, production of circularly polarized ultraviolet photons through polarized-electron bremsstrahlung at an early stage of the fireball evolution is considered. It is shown that these photons can escape from the fireball plasma. However, for an average density of neutrals in the interstellar medium of the order of 0.2 cm⁻³ and at distances of the order of 10 pc from the SN, these photons will be absorbed with a factor of about 10⁻⁷ due to the photoeffect. In this case, their chiral efficiency will be about five orders of magnitude less than that for polarized electrons.     

Boron Containing Pyrimidines,Nucleosides, and Oligonucleotides for Neutron Capture Therapy

Abstract

The synthesis and encouraging biological findings with boron-containing nucleosides, such as 5-dihydroxyboryl-2′-deoxyuridine, which could be used for boron neutron capture therapy (BNCT) for the treatment of various malignancies, has provided momentum to synthesize several boron containing nucleosides and oligomers. BNCT is based on the property of the non-radioactive boron-10 isotope to capture low energy neutrons, thereby producing a localized cell-destroying nuclear reaction. Thus, irradiation of tumor cells with neutrons, following incorporation of the boronated nucleoside, would result in the destruction of tumor tissue only. Intracellular phosphorylation by nucleoside kinases, and/or incorporation into the cancer cell DNA as a false nucleotide precursor, followed by irradiation by neutrons, would lead primarily to tumor cell death. The synthetic and biological approaches for boronated pyrimidines, nucleosides, and oligonucleotides for BNCT are reviewed.     

A 13C(d,n)-based epithermal neutron source for Boron Neutron Capture Therapy

PurposeBoron Neutron Capture Therapy (BNCT) requires neutron sources suitable for in-hospital siting. Low-energy particle accelerators working in conjunction with a neutron producing reaction are the most appropriate choice for this purpose. One of the possible nuclear reactions is ¹³C(d,n)¹⁴N. The aim of this work is to evaluate the therapeutic capabilities of the neutron beam produced by this reaction, through a 30 mA beam of deuterons of 1.45 MeV.MethodsA Beam Shaping Assembly design was computationally optimized. Depth dose profiles in a Snyder head phantom were simulated with the MCNP code for a number of BSA configurations. In order to optimize the treatment capabilities, the BSA configuration was determined as the one that allows maximizing both the tumor dose and the penetration depth while keeping doses to healthy tissues under the tolerance limits.ResultsSignificant doses to tumor tissues were achieved up to ∼6 cm in depth. Peak doses up to 57 Gy-Eq can be delivered in a fractionated scheme of 2 irradiations of approximately 1 h each. In a single 1 h irradiation, lower but still acceptable doses to tumor are also feasible.ConclusionsTreatment capabilities obtained here are comparable to those achieved with other accelerator-based neutron sources, making of the ¹³C(d,n)¹⁴N reaction a realistic option for producing therapeutic neutron beams through a low-energy particle accelerator.     

Thermal and resonance neutrons generated by various electron and X-ray therapeutic beams from medical linacs installed in polish oncological centers

BackgroundHigh-energy photon and electron therapeutic beams generated in medical linear accelerators can cause the electronuclear and photonuclear reactions in which neutrons with a broad energy spectrum are produced. A low-energy component of this neutron radiation induces simple capture reactions from which various radioisotopes originate and in which the radioactivity of a linac head and various objects in the treatment room appear.AimThe aim of this paper is to present the results of the thermal/resonance neutron fluence measurements during therapeutic beam emission and exemplary spectra of gamma radiation emitted by medical linac components activated in neutron reactions for four X-ray beams and for four electron beams generated by various manufacturers’ accelerators installed in typical concrete bunkers in Polish oncological centers.Materials and methodsThe measurements of neutron fluence were performed with the use of the induced activity method, whereas the spectra of gamma radiation from decays of the resulting radioisotopes were measured by means of a portable high-purity germanium detector set for field spectroscopy.ResultsThe fluence of thermal neutrons as well as resonance neutrons connected with the emission of a 20 MV X-ray beam is ～10⁶ neutrons/cm² per 1 Gy of a dose in water at a reference depth. It is about one order of magnitude greater than that for the 15 MV X-ray beams and about two orders of magnitude greater than for the 18–22 MeV electron beams regardless of the type of an accelerator.ConclusionThe thermal as well as resonance neutron fluence depends strongly on the type and the nominal potential of a therapeutic beam. It is greater for X-ray beams than for electrons. The accelerator accessories and other large objects should not be stored in a treatment room during high-energy therapeutic beam emission to avoid their activation caused by thermal and resonance neutrons. Half-lives of the radioisotopes originating from the simple capture reaction (n,γ) (from minutes to hours) are long enough to accumulate radioactivity of components of the accelerator head. The radiation emitted by induced radioisotopes causes the additional doses to staff operating the accelerators.     

Halogenated pyrimidines as radiosensitizers for high-LET radiation

The incorporation of iododeoxyuridine (IdUrd) into Chinese hamster cells was examined as a possible radiosensitizer for fission spectrum neutrons. Dose-response curves comparing both X rays and neutrons in the same cell line with the same IdUrd replacement showed a similar radiation enhancement for IdUrd incorporation. Enhancement ratios at the 1% survival level were 1.8 for X rays and 1.5 for fission spectrum neutrons. While the mechanism of this enhancement in the response for fission neutron radiation is unclear, these positive data should support further exploration to determine if halogenated pyrimidine incorporation results in sensitization for neutron energies employed in therapy.     

Small-size magnetically insulated plasma diodes for neutron generation

Results from experimental and theoretical studies of deuteron acceleration in small-size magnetically insulated plasma diodes are presented. The problems of creating accelerating tubes for neutron generation on the basis of magnetically insulated diodes are considered. The prospects of creating small-size neutron generators with neutron fluxes of 10¹⁰–10¹² neutrons/s into the full solid angle are estimated.     

Correlation of the neutron yield anisotropy with the electrical characteristics of a plasma focus discharge

The anisotropy of the yield and energy of neutrons generated in a small-size plasma focus chamber with a total neutron yield of about 4 × 10⁹ DD neutrons per shot was investigated experimentally. The neutrons were recorded using scintillation detectors on a 3-m-long flight base. The measurements were performed at the angles 0° and 90° with respect to the chamber axis. The maximum neutron energy measured by the time-of-flight method at the angles 0° and 90° was found to be 2.8 and 2.5 MeV, respectively. The measured anisotropy of the neutron yield was in the range 1.15–1.88. The integral DD neutron yield of the source was measured using the activation method (by activating silver isotopes). It is found that the neutron yield and the yield anisotropy depend linearly on the discharge current jump ΔI at the instant of neutron generation.     

The dosimetry system DS86 and the neutron discrepancy in Hiroshima – historical review, present status, and future options

The historical development of the dosimetry systems for Hiroshima and Nagasaki is outlined from the time immediately after the A-bomb explosions to the publication of the dosimetry system DS86 in 1987, and the present status of the so-called Hiroshima neutron discrepancy is summarized. Several long-lived radionuclides are discussed with regard to their production by neutrons from the A-bomb explosions. With the exception of ⁶³Ni, these radionuclides have not, up to now, been measured in samples from Hiroshima and Nagasaki. Two of them, ⁶³Ni in copper samples and ³⁹Ar in granite samples, were predominantly produced by fast neutrons. ⁶³Ni can be determined by accelerator mass spectrometry with a gas-filled analyzing magnet. It should be measurable, in the near future, in copper samples up to 1500 m from the hypocenter in Hiroshima. ³⁹Ar can be measured in terms of low-level beta-counting. This should be feasible up to a distance of about 1000 m from the hypocenter. Three radionuclides, ¹⁰Be, ¹⁴C , and ⁵⁹Ni, were produced predominantly by thermal neutrons with smaller fractions due to the epithermal and fast neutrons, which contribute increasingly more at larger distances from the hypocenter. State-of-the-art accelerator mass spectrometry is likely to permit the determination of ¹⁰Be close to the hypocenter and of ¹⁴C up to a distance of about 1000 m. ⁵⁹Ni should be detectable up to a distance of about 1000 m in terms of accelerator mass spectrometry with a gas-filled magnet. The measurements of ¹⁰Be, ¹⁴C, ³⁹Ar, ⁵⁹Ni – and potentially of ¹³¹Xe – can be performed in the same granitic sample that was already analyzed for ³⁶Cl, ⁴¹Ca, ⁶⁰Co, ¹⁵²Eu, and ¹⁵⁴Eu. This will provide extensive information on the neutron spectrum at the specified location, and similarly complete analyses can conceivably be performed on granite samples at other locations. Received: 7 May 1998 / Accepted in revised form: 16 September 1998     

Do spherical tokamaks have a thermonuclear future?

This work has been initiated by the publication of a review by B.V.Kuteev et al., ??Intense Fusion Neutron Sources?? [Plasma Physics Reports 36, 281 (2010)]. It is stated that the key thesis of the above review that a spherical tokamak can be recommended for research neutron sources and for demonstration hybrid systems as an alternative to expensive ??classical?? tokamaks of the JET and ITER type is inconsistent. The analysis of the experimental material obtained during the last 10 years in the course of studies on the existing spherical tokamaks shows that the TIN-ST fusion neutron source spherical tokamak proposed by the authors of the review and intended, according to the authors?? opinion, to replace ??monsters?? in view of its table-top dimensions (2 m³) and laboratory-level energetics cannot be transformed into any noticeable stationary megawatt-power neutron source competing with the existing classical tokamaks (in particular, with JET with its quasi-steady DT fusion power at a level of 5 MW). Namely, the maximum plasma current in the proposed tokamak will be not 3 MA, as the authors suppose erroneously, but, according to the present-day practice of spherical tokamaks, within 0.6?C0.7 MA, which will lead to a reduction on the neutron flux by two to three orders of magnitude from the expected 5 MW. The possibility of the maintenance of the stationary process itself even in such a ??weakened?? spherical tokamak is very doubtful. The experience of the largest existing devices of this type (such as NSTX and MAST) has shown that they are incapable of operating even in a quasi-steady operating mode, because the discharge in them is spontaneously interrupted about 1 s after the beginning of the current pulse, although its expected duration is of up to 5 s. The nature of this phenomenon is the subject of further study of the physics of spherical tokamaks. This work deals with a critical analysis of the available experimental data concerning such tokamaks and a discussion of the potential possibility of their use in thermonuclear research.