A review of the literature shows that late lung fibrosis is always associated with an initial pneumonitis reaction. This reaction may appear to resolve prior to the onset of late fibrosis and/or represent a continuum, leading to the suggestion that late fibrosis is a consequence of the initial inflammatory reaction. In a novel series of experiments, the lungs of rats were locally irradiated with single doses of radiation of differing quality; x-rays versus thermal neutrons (mixed beam irradiation, predominantly from the products of neutron capture by hydrogen and nitrogen), and different dose distributions produced by administering a boron-10 capture agent,p-boronophenylalanine (BPA), to the thermal neutron exposure; approximately 50% of the total physical dose coming from the short range products, alpha-particles and lithium-ions, of the 10B capture reaction. Damage was assessed by lethality, serial measurements of breathing rate and terminal histology after 180 days. Animal deaths, related to lung damage, were only seen in the higher doses selected for use, ≥11.8 Gy, 9.7 Gy and ≥9.5 Gy for x-rays, thermal neutrons and neutrons plus BPA, respectively. Nearly all deaths occurred in the first 100 days after irradiation, the period of the pneumonitic reaction. The pneuonitic reaction (approximately 20 -100 days) was reflected in a significant increase in the breathing rate (defined as a 20% increase, relative to controls). This increase was most marked after x- and thermal neutron irradiation; the incidence in responders in these groups tended to decline around day 100, only to increase again at later times. In animals receiving thermal neutron irradiation in the presence of BPA (doses of ≤8.8 Gy), a higher incidence of late compared with early responders was seen. This was reflected in the dose-effect relationships for the early (< 100 days) versus late (> 100 days) responders for a significant increase in breathing rate. In the < 100 day period the ED50 (±SE) for the thermal neutron/thermal neutron plus BPA were comparable at 9.2 ± 0.6 Gy and 8.8 ± 0.6 Gy, respectively. For the > 100 day period the ED50 (±SE) for the neutron plus BPA group of 6.7 ± 0.4 Gy was significantly lower than for thermal neutrons alone; 9.6 ± 0.6 Gy. The animals receiving BNCT type irradiation also showed more marked changes on terminal histology, reflected in a lower ED50 for a histological score. Thus, given appropriate exposure conditions, late radiation changes in lung can develop independently of early pneumonitis.

A report of recent developments in silicon microdosimetry is presented. SOI based microdosemeters have shown promise as a viable alternative to traditional tissue-equivalent proportional counters. The application of these silicon microdosemeters to such radiation therapy modalities as boron neutron capture therapy (BNCT), boron neutron capture synovectomy (BNCS), proton therapy (PT), and fast neutron therapy (FNT) has been performed. Several shortcomings of the current silicon microdosemeter were identified and will be taken into account in the design of a second-generation device.

Journal of Labelled Compounds and RadiopharmaceuticalsVolume 44, Issue S1 p. S345-S347 Article Synthesis and pet studies of [11C]D- and [11C]L-boronophenylalanine for improving BNCT in brain tumors A. Studenov, A. Studenov Chemistry Department, Brookhaven National Laboratory, Upton, New YorkSearch for more papers by this authorY.-S. Ding, Y.-S. Ding Chemistry Department, Brookhaven National Laboratory, Upton, New YorkSearch for more papers by this authorR. Ferrieri, R. Ferrieri Chemistry Department, Brookhaven National Laboratory, Upton, New YorkSearch for more papers by this authorM. Miura, M. Miura Chemistry Department, Brookhaven National Laboratory, Upton, New YorkSearch for more papers by this authorJ. Coderre, J. Coderre Chemistry Department, Brookhaven National Laboratory, Upton, New YorkSearch for more papers by this authorJ. S. Fowler, J. S. Fowler Chemistry Department, Brookhaven National Laboratory, Upton, New YorkSearch for more papers by this author A. Studenov, A. Studenov Chemistry Department, Brookhaven National Laboratory, Upton, New YorkSearch for more papers by this authorY.-S. Ding, Y.-S. Ding Chemistry Department, Brookhaven National Laboratory, Upton, New YorkSearch for more papers by this authorR. Ferrieri, R. Ferrieri Chemistry Department, Brookhaven National Laboratory, Upton, New YorkSearch for more papers by this authorM. Miura, M. Miura Chemistry Department, Brookhaven National Laboratory, Upton, New YorkSearch for more papers by this authorJ. Coderre, J. Coderre Chemistry Department, Brookhaven National Laboratory, Upton, New YorkSearch for more papers by this authorJ. S. Fowler, J. S. Fowler Chemistry Department, Brookhaven National Laboratory, Upton, New YorkSearch for more papers by this author First published: 23 April 2012 https://doi.org/10.1002/jlcr.25804401121Citations: 4AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume44, IssueS1Supplement: Journal of Labelled Compounds and RadiopharmaceuticalsMay 2001Pages S345-S347 RelatedInformation

Reverse-biased silicon p-n junction arrays using Silicon-On-Insulator technology have been proposed as microdosimeters. The performance of such detectors in boron neutron capture therapy (BNCT) is discussed. This work provides the first reported measurements using boron-coated silicon diode arrays as microdosimeters in BNCT. Results are in good agreement with measurements with gas proportional counters. Various boron-coating options are investigated along with device orientation effects. Finally, a 235U coating is tested to simulate the behavior of the device in a heavy-ion therapy beam.

PURPOSE:To study the uptake, toxicity and radiation effects in vitro of a diol-amino acid-carborane (DAAC-1) and make comparisons with the previously studied diol-amine-carborane (DAC-1).MATERIALS AND METHODS:Toxicity and radiation effects were studied with clonogenic survival, uptake by measuring the cellular boron content and the subcellular distribution was investigated after organelle separation with centrifugation. The studied cell line was human glioma U343.RESULTS:DAAC-1 showed an accumulation of 1-1.5 times, compared with the culture medium, and was non-toxic up to 47 microg boron/ml. The accumulation of DAC-1 was about 90 times, but toxic effects were detectable already at the concentration 5 microg boron/ml. None of the compounds was localized in the cell nucleus. Following irradiation with thermal neutrons, DAC-1 was about 2.5 times more effective than DAAC-1 and about 4.9 times more effective than neutrons alone, at the survival level 0.2. The dose modifying factors, when compared with the neutron beam alone, were for both DAAC-1 and DAC-1 about 1.5 and about 5 when compared with 60Co-gamma-radiation.CONCLUSIONS:DAAC-1 was less toxic than DAC-1 but gave less accumulation of boron. Both substances gave significant boron-dependent cell inactivation when the test cells were exposed to thermal neutrons.

The application of MOSFET dosimeters in complicated mixed radiation fields for measurement of absorbed dose distribution in tissue equivalent phantoms has been studied. The spectra of secondary charged particles have been measured simultaneously with average absorbed doses by the same MOSFET dosimeter. A good correlation has been observed between neutron depth dose distribution in a water phantom obtained using MOSFETs in integral mode and a tissue equivalent (T.E.) ionisation chamber. Such MOSFET dosimeters are a promising tool for micro-macro dosimetry in Boron Neutron Capture Therapy (BNCT) and Fast Neutron Therapy (FNT). Paired MOSFETs with one of the dosimeters covered by /sup 10/B have been applied for measuring of average boron dose distribution and microdosimetric spectra due to alpha particles and /sup 7/Li ions throughout a perspex phantom exposed in the epithermal neutron beam at the Brookhaven Medical Research Reactor (BMRR).

In boron neutron capture therapy (BNCT), 10B is delivered selectively to the tumour cells and the nuclide then forms high-LET radiation (4He2+ and 7Li3+) upon neutron capture. Today much research is focused on development of a variety of boron compounds aimed for BNCT. The compounds must be thoroughly analysed in preclinical tests regarding basic characteristics such as binding and subcellular distribution to enable accurate estimations of dose-modifying factors. DAC-1, 2-[2-(3-amino-propyl)-1,2-dicarba-closo-dodecaboran(12) -1-yl-methoxy]-1,3-propanediol was synthesized at our laboratories and the human colon carcinoma cells LS-174T were used as an in vitro model. The boron compound showed a remarkable intracellular accumulation, 20–100 times higher than the boron content in the culture medium, in cultured cells and was not removed by extensive washes. Approximately half of the boron taken up also remained within the cells for at least 4 days. The DAC-1 compound alone was not toxic at boron concentrations below 2.5 μg B/g. The intracellular distribution of the boron compound was investigated by subcellular fractionation experiments and low pH treatments. It is possible that DAC-1 binds to some intracellular molecules or to membranes connected with organelles in the cytoplasm or even to the inside of the outer cell membrane. Another possibility is that the compound, due to the somewhat lipophilic properties, is embedded in the membranes. Thermal neutron irradiations were carried out at the Brookhaven Medical Research Reactor (BMRR). At a survival level of 0.1, DAC-1 + thermal neutrons were about 10.5 times more effective in cell inactivation than the thermal neutrons alone. Monte Carlo calculations gave a mean value of the 10B-dependent specific energy, the dose, of 0.22 Gy. The total physical dose during irradiation of DAC-1-containing cells with a neutron fluence of 0.18 × 1012 n/cm2 was 0.39 Gy. The dose-modifying factor, at survival level 0.1, when comparing irradiation with thermal neutrons with and without DAC-1 was 3.4, while the dose-modifying factor when comparing neutron irradiations of cells with DAC-1 and irradiation of the cells with 60Co-γ was 7.3. The results are encouraging and in vivo tests of tissue distributions and tumour uptake should now be carried out.

Purpose: Damage to the surrounding normal brain tissue limits the amount of radiation that can be delivered to intracranial tumors. Boron neutron capture therapy (BNCT) is a binary treatment that allows selective tumor irradiation. This study evaluates the damage imparted to the normal brain during BNCT or x-irradiation. Methods and Materials: The brains of rats with implanted 9L gliosarcomas were examined 1 year after tumor-curative doses of either 250 kV X rays or BNCT. Histopathologic techniques included hematoxylin and eosin staining, horseradish peroxidase perfusion, and electron microscopy. Results: Longterm X ray survivors showed extensive cortical atrophy, loss of neurons, and widespread leakage of the blood-brain barrier (BBB), particularly around the tumor scar. In contrast, the brains and the BBB of longterm BNCT survivors appeared relatively normal under both light- and electron-microscopic examination. Intact blood vessels were observed running directly through the avascular, collagenous tumor scar. Conclusion: The selective therapeutic effect of BNCT is evident in comparison to x-irradiation. Both groups of animals showed no evidence of residual tumor at 1 year. However, with x-irradiation there is no therapeutic ratio and tumor eradication severely injures the remaining brain parenchyma. These observations indicate a substantial therapeutic gain for BNCT.

Boron neutron capture therapy (BNCT) is a form of radiation therapy that requires selective uptake of boron by the tumor and irradiation with thermal neutrons. Phenylalanine is an amino acid precursor of melanin and when boronated (p-boronophenylalanine [BPA]) was found to be selectively taken up by Greene melanoma cells in the anterior chamber of rabbits. This tumor model was irradiated 24 hr after oral administration of BPA and was used for biodistribution studies that compared BPA and sodium pentaborate. Three groups were irradiated: group 1 (11 rabbits) received BPA followed by thermal neutron irradiation, group 2 (9 rabbits) received thermal neutron irradiation only, and group 3 (9 rabbits) served as unirradiated, undrugged control animals. Eight of the 11 tumors in group 1 were treated successfully; all tumors in groups 2 and 3 grew. Histopathologic examination did not reveal vascular or retina damage in group 1. These preliminary experiments confirm that newer boronated compounds, such as BPA, used in BNCT and improved neutron beams can provide selective irradiation of ocular melanomas.

The conditions for the possible initiation of clinical trials with neutron capture therapy at a number of locations in the U.S. is reviewed. There are several new technical developments or plans at the Brookhaven Medical Research Reactor (BMRR), the Power Burst Facility (PBF) at INEL, the Massachusetts Institute of Technology Reactor (MITR) and the Georgia Institute of Technology Research Reactor (GTRR). Emphasis is on the development of epithermal beams for the treatment of deepseated tumors with neutron fluxes in between 10(9) to 10(10) n/cm2s. Therapeutic dose gains, defined as the ratio of tumour dose to maximum normal tissue dose in the treatment volume are expected to be between 2 and 4, depending on the degree of suppression of fast neutron dose. Boron concentrations considered in this case in the tumour are around 35 micrograms 10B/g and tumour/normal tissue concentrations are around 10. The compound development throughout three generations is discussed. The compound proposed nowadays, Na2B12H11SH (or BSH), employed in the treatments in Japan, will likely be replaced in the future by analogous of biomolecules being enriched in the tumour by physiological pathways. Examples are p-boronophenylalanine or boronated porphyrius. The most promising solution envisaged would be the employment of tumour cell specific brononated monoclonal antibodies. Finally the mode of therapy is discussed which will likely be based on a fractioned scheme, to achieve optimized results.