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16O(n, p)16N: a fast neutron detector for rapid tissue inhomogeneity correction.

We have devised a transit dose technique for fast neutron therapy treatment planning based on the 16O(n, p)16N reaction in recirculating water, and have determined the effect of simulated bone and lung inhomogeneities in phantom. An effective threshold of 10.2 MeV in the 16O(n, p) reaction is exploited to detect transmitted neutrons without the need detector collimation. This system has been demonstrated with 14 MeV (d, T) neutrons and with cyclotron produced p(42) + Be neutrons. 16N decays to the 6.13 MeV excited states of 16O in 7.14 s, allowing for easy identification by NaI(T1) and for rapid recirculation. The transmission of fast neutrons can thus be related to an effective thickness of soft tissue, providing a rapid and direct measure of the effects of inhomogeneities under actual treatment conditions, with the 10 MeV threshold providing a useful degree of insensitivity to multiply scattered neutrons. Equivalent thickness of compact bone and lung relative to water were found to be 1.4 and 0.34 respectively, closely resembling the effective thicknesses for Cobalt-60 gamma rays.

Biophysical Phenomena↗

[Effect of fast neutrons on the process of muscle cell differentiation].

A study was made of the effect of fast neutron on differentiation of myoblasts in vitro. The results obtained indicate that irradiation inhibits the differentiation of myoblasts in culture. Irradiation with fast neutrons (1.5 and 2.0 Gy) inhibits the uninucleate myoblast fusion thus preventing the formation of multinuclear tissue structures with myofibrils, myosymplasts.

Animals↗

Caffeine sensitization of cultured mammalian cells and human lymphocytes irradiated with gamma rays and fast neutrons: a study of relative biological effectiveness in relation to cellular repair.

The sensitizing effects of caffeine were studied in baby hamster kidney (BHK-21) cells and human lymphocytes following irradiation with gamma rays and fast neutrons. Caffeine sensitization occurred only when log-phase BHK cells and mitogen-stimulated lymphocytes were exposed to the two radiations. Noncycling (confluent) cells of BHK resulted in a shouldered survival curve following gamma irradiation while a biphasic curve was obtained with the log-phase cells. Survival in the case of lymphocytes was estimated by measurement of [3H]thymidine uptake. Prestimulated lymphocytes exhibited a biphasic thymidine uptake curve while the postirradiation-stimulated lymphocytes resulted in an exponential curve. Fast neutrons reduced both shoulder and tail of survival curves representing resistant fractions of cell populations. Consequently, the relative biological effectiveness (RBE) of fast neutrons was found to be greater at survival levels corresponding to the resistant portions of the survival curves (shoulder or resistant tail). In both cell types, no reduction in RBE was observed when caffeine was present, because caffeine affected both gamma and neutron survival by the same proportion.

Animals↗

Dosimetric investigations in the dose buildup using bolus techniques for fast neutron therapy.

A moulded bolus is commonly used to compensate for contour irregularities of patients treated with fast neutrons. The bolus material should have the same attenuation characteristics as tissue, should be easily mouldable and sufficiently solid for multiple applications. For fast neutron beams, the mixture of equal parts of beeswax and paraffin is a suitable bolus material. As in photon beams the bolus, when placed directly on the patient skin, removes completely the skin sparing effect. However, in neutron beams the dose buildup can mostly be recovered by lining the bolus surface in contact with the patient with a thin layer of lead. This paper presents dosimetric investigations in the dose buildup of a collimated 14-MeV DT-neutron beam underneath the surface of a solid phantom behind a 1.0-cm layer of bolus material lined with 0.03 cm of lead. It is shown that most of the dose buildup of the bolus-free neutron beam can be recovered.

Cobalt Radioisotopes↗

Chromatin damage induced by fast neutrons or UV laser radiation.

Chromatin samples from livers of Wistar rats were subjected to fast neutron irradiation in doses of 10-100 Gy or to a 248 nm excimer laser radiation, in doses of 0.5-3 MJ.m-2. The action of the radiation on chromatin was monitored by chromatin intrinsic fluorescence and fluorescence lifetimes (of bound ethidium bromide to chromatin) and by analysing fluorescence resonance energy transfer between dansyl chloride and acridine orange coupled to chromatin. For the mentioned doses of UV excimer laser radiation, the action on chromatin was more intense than in the case of fast neutrons. The same types of damage are produced by the two radiations: acidic and basic destruction of chromatin protein structure, DNA strand breaking and the increase of the distance between DNA and proteins in chromatin.

Animals↗

Change in oxygen enhancement ratio with depth in tissue-equivalent material for a collimated beam of fast neutrons.

Survival of reproductive capacity of murine leukaemia P-388 cells was assayed in vivo after the cells had been irradiated in vitro under aerobic or hypoxic conditions with collimated beams of X rays or 16 MeV D-Be fast neutrons at various depths in tissue-equivalent phantom material. The response to X-irradiation was the same in the absence of the phantom and at 8-7 cm depth. The response to fast neutrons under aerobic conditions was unchanged from 0 to 23 cm depth within the phantom. However, under hypoxic conditions, the dose-response curve for fast neutrons became significantly steeper with increasing depth in the phantom. The OER decreased from 2-0 in the absence of the phantom to 1-5 at 15 cm deep.

Animals↗

Specification of radiation quality in fast neutron therapy: microdosimetric and radiobiological approach.

Specification of radiation quality is an important issue in fast neutron therapy since the biological effectiveness of the beams varies to a large extent with neutron energy. It must meet specific criteria, mainly derived from the accuracy requirement for absorbed dose delivery. A first approach to this problem consists in identifying physical parameters that can be related to Relative Biological Effectiveness (RBE) and which describe the beam production technique (e.g. neutron-producing reaction, p + Be or d + Be, energy of the incident particle). A second is based on microdosimetry, which provides a description of the secondary radiation components to which the biological consequences of irradiations are more directly correlated. A third approach consists in experimental RBE determinations in reference conditions: intestinal crypt regeneration in mice after irradiation to the whole body with single doses is proposed as a standard biological system for radiobiological calibrations of clinical fast neutron beams. Dosimetric, microdosimetric and radiobiological intercomparisons are encouraged since they provide a homogeneous set of data which facilitate the exchange of clinical information. They also constitute a basis for the clinical RBE approach and an overall check of the irradiation procedure. Therefore they should be recommended in every non-conventional radiation therapy facility.

Animals↗

Med-fly cell line: response to irradiations with fast neutrons and gamma-rays.

It has been observed that biological systems have different sensitivities to various radiation qualities. Moreover, the relative response depends on the dose level of the applied radiation. In this context the radiosensitivity of Med-fly, Ceratitis capitata Wied., cells, to gamma-rays and neutrons, has been tested by observing cell population growth and mortality. Fast neutron doses ranged between 1.5 and 25 rad, a region of particular interest in radiation protection studies; the 60Co gamma-ray dose values were between 300 and 5 000 rad. The experimental results show a much higher radiosensitivity of these cells to fast neutrons than to gamma-rays, and indicate a dependence of the RBE values on the neutron-dose levels. Furthermore, there was a certain dependence on radiation quality for the morphological damage. Dose-effect relationships are analyzed for both neutrons and gamma-rays and the results are discussed.

Animals↗

The relative biological effectiveness of fractionated doses of fast neutrons (42 MeVd----Be) for normal tissues in the pig. II. Late effects on cutaneous and subcutaneous tissues.

The late effects of irradiation with single and fractionated doses of X rays (250 kV) and fast neutrons (42 MeVd----Bc), on the cutaneous and subcutaneous tissues of the pig, have been evaluated from measurements of changes in relative field length. These were determined at intervals of 26-104 weeks after irradiation. For fractionated irradiation with X rays the average fractions exponent, N, obtained from a log-log plot of iso-effect dose (ED50) against fraction number was 0.41. This was independent of the period of assessment, with no significant indication of a time factor. However, the exponent N did vary with the level of effect and was in the range 0.33-0.51. It was greatest for a greater than or equal to 10% reduction in relative field length. Assuming the validity of the linear quadratic model of cell survival, the alpha/beta ratio was 1.95 Gy. However, this model fitted the data less well for the least severe levels of damage, and for these the alpha/beta ratios were not significantly different from zero. Irradiation with fast neutrons showed a small effect of fractionation for doses given in greater than or equal to 6 fractions compared with a single dose. There was no significant increase in iso-effect dose when the dose was given in 30 fractions compared with 6 fractions. The relative biological effectiveness for late cutaneous and subcutaneous damage for the energy of fast neutrons used did not vary with the period of assessment, i.e. 26-52 weeks compared with 65-104 weeks, and was not significantly different from that previously obtained for ischaemic dermal necrosis, seen after higher doses, at 12-20 weeks after irradiation.

Animals↗

Studies on radiation-induced chromosome aberrations in mouse spermatocytes. II. Dose-response relationships of chromosome aberrations induced at zygotene stage in mouse primary spermatocytes following fast neutron- and 60Co gamma-irradiations.

The chromosome aberrations induced at zygotene stage in mouse spermatocytes following exposures to fast neutrons and 60Co gamma-rays were examined at diakinesis-metaphase I. The dose-response relationships were well fitted to linear equation for deletion-type aberrations and to linear-quadratic equation for exchange-type aberrations in 60Co gamma-irradiation group. In fast neutron-irradiation group, the dose-response relationships were well fitted to linear equations for deletion- and exchange-type aberrations. The rate of deletion-type aberrations was remarkably high for fast neutrons, about 6 times higher than that after 60Co gamma-irradiation. The main types of chromosome aberrations observed were iso-chromatid breaks or fragments and chromatid exchanges in both irradiation groups as well as X-irradiation. These results indicate that there is a possibility that two double-strand breaks are induced simultaneously at iso-locus position in sister chromatids by a single track of radiations. Production of such single-track-induced two double-strand breaks in iso-chromatids may be very frequently expressed as iso-chromatid-type deletions in the high LET fast neutron-irradiation group. On the contrary, in the low LET 60Co gamma- or X-irradiation group, the above-mentioned mechanism may not be so effective for contribution to chromosome aberration induction in mouse spermatocytes. This mechanism was discussed in detail.

Animals↗

Induction and repair of DNA strand breaks in cultured mammalian cells following fast neutron irradiation.

Induction and repair of DNA breaks following irradiation with NIRS cyclotron neutrons were studied in cultured mammalian cells (L5178Y) in comparison to those following gamma-rays. The yield of the total single-strand breaks, 3'OH terminals and sites susceptible to S1 endonuclease following fast neutrons was found to be approximately 50 per cent of that following gamma-irradiation. On the other hand, the yield of double-strand breaks was slightly higher after fast neutrons than after gamma-rays. The percentage of the total single-strand breaks remaining unrejoined at 3 hours after post-irradiation incubation was found to be distinctly higher after the fast neutrons than after gamma-rays. The neutron-induced damage appears to carry a higher proportion of alkali-labile lesions compared to gamma-rays. It was concluded that the increase in the yield of double-strand breaks and of unrejoinable breaks is responsible for a high r.b.e. of the cyclotron neutrons.

Animals↗

The clinical RBE and microdosimetric characterization of radiation quality in fast neutron therapy.

High-LET radiation therapy using fast neutrons is being applied regularly at several centres worldwide and in the future, other types of radiation qualities, such as protons and heavier ions and boron neutron capture therapy (BNCT) are likely to be used. The neutron beams used are of considerably varying energy and thus considerable variations in the relative biological effectiveness (RBE) have been found. At present, no generally accepted method exists for the quantitative specification of these differences in radiation quality for clinical purposes. This is in clear discrepancy with the accuracy requirements in clinical dosimetry. An approach is presented which is based on a single parameter radiation quality characterization determined in combined microdosimetric and radiobiological experiments. It is shown that the method can meet the accuracy requirements of clinical dosimetry and that it is applicable within a concept of formalized procedure of clinical practice and experience ('clinical RBE').

Energy Transfer↗

Measuring fast neutrons in Hiroshima at distances relevant to atomic-bomb survivors.

Data from the survivors of the atomic bombs serve as the major basis for risk calculations of radiation-induced cancer in humans. A controversy has existed for almost two decades, however, concerning the possibility that neutron doses in Hiroshima may have been much larger than estimated. This controversy was based on measurements of radioisotopes activated by thermal neutrons that suggested much higher fluences at larger distances than expected. For fast neutrons, which contributed almost all the neutron dose, clear measurement validation has so far proved impossible at the large distances (900 to 1,500 m) most relevant to survivor locations. Here, the first results are reported for the detection of 63Ni produced predominantly by fast neutrons (above about 1 MeV) in copper samples from Hiroshima. This breakthrough was made possible by the development of chemical extraction methods and major improvements in the sensitivity of accelerator mass spectrometry for detection of 63Ni atoms (refs 8-11). When results are compared with 63Ni activation predicted by neutron doses for Hiroshima survivors, good agreement is observed at the distances most relevant to survivor data. These findings provide, for the first time, clear measurement validation of the neutron doses to survivors in Hiroshima.

Copper↗

Induction of mutations in antibiotic-producing microorganisms by fast neutrons from the U-120 cyclotron.

The purpose of this study was to investigate the activity of fast neutrons from a U-120 cyclotron in the induction of mutations in streptomycetes, resulting in strains with enhanced antibiotic production. Three streptomycete strains producing the antibiotics: lincomycin, moenomycin, and demethylchlorotetracycline were used. Correlation between the survival rate of spores of the examined strains and neutron dose was determined. Several morphological and physiological features (particularly production of antibiotics for 1543 variants derived from the parent strains) and their distribution within the population were also studied. The survival rate of the streptomycetes spores after irradiation with fast neutrons was found to be an individual strain property. Several variants with considerably increased antibiotic yield were isolated. The results are compared with those obtained after treatment with other mutagens. Several variants of one of the strains with a strongly enhanced antibiotic yield (200--220%) were isolated. No such variants were found after UV irradiation.

Demeclocycline↗

The treatment of recurrence following fast neutron therapy for head and neck malignancy.

Twenty-eight patients received fast neutron therapy for head and neck malignancy. Of these, seven had no recurrence, 13 had a recurrence at the primary site, five had a recurrence in the neck and three had a recurrence in the neck and at the primary site. Treatment of a primary site recurrence was difficult with seven of the eight patients submitted for major surgical resection developing serious complications. Of the six patients developing a fistula four required flap repair. The tumour specific 5-year survival for the whole group of 28 patients was 29%. The surgical treatment of locoregional recurrence following fast neutron therapy is fraught with problems and some type of flap repair is usually necessary.

Adult↗

Characteristics of malignant melanoma cells in the treatment with fast neutrons.

The radioresistance of malignant melanoma cells has been explained by the wide shoulder of the dose-cell-survival curve of the cells exposed to photon beams. Fast neutrons, 30 MeV d-Be, were used to treat patients who had malignant melanoma in order to confirm the biological effects of high linear energy transfer (LET) radiation for tumor control. Seventy-two patients suffering from malignant melanoma participated in the clinical trials with fast neutrons between November 1975 and December 1986. Of 72 patients, 45 had melanoma of the skin, 20 had melanoma of the head and neck, and seven had choroidal melanoma. Five-year survival rate of the patients who had previously untreated melanoma of the skin was 61% and for patients who received postoperative irradiation, it was 35.7% whereas no patients who had recurrent tumor survived over 4 years. Of 22 patients who had melanoma of the skin, stage I, local control in four cases was achieved by irradiation alone, whereas local control was achieved in 17 of 18 patients who required salvage surgery after fast-neutron therapy. The results of pathological studies performed with specimens obtained from salvage surgery have shown that melanoma cells growing in intradermal tissue are radio-resistant, compared with cells growing in intraepidermal tissue. This might suggest that melanoma cells acquire radioresistance when the connective tissue is involved. Five-year survival rate of the patients who had locally advanced melanoma of the head and neck, previously untreated, was 15.4%. Radiation therapy with accelerated protons was suitable for patients suffering from choroidal melanoma.

Cell Survival↗

Independent effect of a mixed-beam regimen of fast neutrons and gamma rays on a murine fibrosarcoma.

Biological effectiveness of a mixed-beam regimen of fast neutrons and photons was studied in an animal tumor system. NFSa , a spontaneous fibrosarcoma in a C3H mouse, was transplanted in the right hind legs of syngeneic male mice and locally irradiated with a single dose or five daily doses. Tumor control experiments showed that five gamma-ray doses increased TCD50 values by 20 Gy and produced a shallower slope on the dose-response curve compared to that after a single fraction. Fractionated neutron doses also increased the TCD50 value by 9 Gy without changing the slope of the dose-response curve. A mixed-beam regimen of N-gamma-gamma-gamma-N resulted in an independent effect on the tumor. Second, tumor cell survival was examined by the lung colony assay. Nembutal anesthesia reduced the tumor oxic cell fraction, resulting in a single component dose-response curve after a single gamma ray. Five fractionated doses of gamma rays increased both D0 and extrapolation number while those of fast neutrons increased only extrapolation number. The D0 and extrapolation number of the mixed-beam regimen were again identical to those values assuming that the mixed-beam effect was independent. RBEs obtained from cell survival were fairly close to those from TCD50 assays except single-dose experiments.

Animals↗

[Lethal and mutagenic effect of fast neutrons of different energies on the spores of Streptomyces griseus].

A study was made of lethal and mutagenic effects of fast neutrons of different energy on spores of prototrophic and auxotrophic strains of Streptomyces griseus. Relative biological effectiveness of fast neutrons is higher than that of gamma-rays and depends on beam energy. Neutrons of 22-50 MeV induce Streptomyces griseus mutations more frequently (by one order of magnitude) than neutrons of 1.4-1.6 MeV do. The obtained mutants can be used in studying Streptomyces griseus genetics.

Dose-Response Relationship, Radiation↗