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[Mechanisms of the radiation-induced disorder of DNA synthesis. The correlation of biosynthesis, DNA repair and DNA polymerase alpha and beta activity in the bone marrow of rats exposed to gamma quanta and fast neutrons].

A study was made of DNA biosynthesis and repair and alpha- and beta-DNA-polymerase activity in rat bone marrow during the first 24 hours following whole-body irradiation with gamma-quanta and fast neutrons (up to 6 Gy). There was a correlation between the post-irradiation inhibition of DNA biosynthesis, a decrease in DNA-polymerase activity and template reparability. The data obtained permitted to consider the radiation-induced disturbance of DNA biosynthesis and the change in beta-polymerase activity as one of the possible mechanisms of formation of high relative biological effectiveness of neutrons.

Animals↗

Radiation response in 10 high-grade human soft tissue sarcoma xenografts to photons and fast neutrons.

From a panel of 48 human soft tissue sarcomas growing as permanent xenografts, 10 tumor lines (five leiomyosarcomas, three malignant fibrous histiocytomas, two neurofibrosarcomas) have been selected to determine the radiation response to photons and fast neutrons. Using the specific growth delay (SGD) as an end-point, considerable variability of inherent radiosensitivity was observed. Isoeffective radiation doses varied by a factor of 27 for photons and of 9.4 for neutrons at a specific growth delay level of 0.5. The heterogeneity of the relative biological effectiveness (RBE) at this specific growth delay-level differed by a factor of 8. Relative biological effectiveness values for clamped tumors exceeded those of the normal tissues (RBE approximately 3) in 6 out of 10 tumor lines. Assuming a ratio of 0.5 for oxygen enhancement ratio-values of neutrons and photons, a therapeutic gain for neutrons existed in 4 out of 10 tumor lines under oxic conditions. No correlation between volume doubling times and relative biological effectiveness was seen.

Animals↗

Microdosimetric measurements of radiation quality variations in homogeneous phantoms irradiated by fast neutron beams.

The Dual Radiation Action Theory of Kellerer and Rossi (DRA), along with presently available microdosimetric techniques, is applied to the determination of radiation quality variation within tissue equivalent phantoms irradiated by collimated fast neutron beams. The neutron beams investigated were produced by the bombardment of 22.5 and 16 MeV d + on beryllium and by the T(d,n)4He reaction (15-MeV neutrons). Microdosimetric spectra were obtained at points of varying depth and lateral distance from the central axis within a tissue equivalent phantom, including points within the penumbra. From the microdosimetric spectra the parameter RQ, a first approximation to RBE derived from DRA theory, is calculated for each point. All RQ values are calculated for the same level of effect. For these three different beams the results show that the RQ values for the total radiation spectrum of neutron and gamma radiation remain fairly constant with depth and with lateral distance from the beam axis at 2 and 10 cm depths. The largest central axis variation in RQ is 8% for the d(16) + Be beam. The largest variation between a penumbra and an on-axis RQ value is 4% at 2 cm depth in the d(22.5) + Be beam. The results for the d (22.5) + Be beam disagree with previously reported radiological results while the 15 McV beam results are in good agreement.

Fast Neutrons↗

Fast neutron and mixed beam radiotherapy for inoperable non-small cell carcinoma of the lung. Results of an RTOG randomized study.

From July 1979 through March 1984 the Radiation Therapy Oncology Group conducted a randomized study comparing fast neutron radiotherapy versus mixed beam (neutron/photon) radiotherapy versus conventional radiotherapy for patients with non-small cell carcinoma of the lung. Patients were either medically or technically inoperable. One hundred two evaluable patients were placed on the study. The radiation doses were approximately 60 Gy-equivalent on each arm. Patients were stratified according to size of primary, histology, Karnofsky performance status, and age distribution. Overall local response rates as measured by serial radiographs were the same on the three arms, and an actuarial analysis showed no significant differences in either median or long-term survival. However, for the subgroup of patients exhibiting a complete or partial tumor response at 6 months there was a suggestion of improved 3-year survival on the two experimental arms (mixed beam, 37%; neutrons, 25%; photons, 12%). The p value for the difference between the mixed beam and photon curves is 0.14 (two-sided test). The incidence of major complications was higher on the neutron and mixed beam arms. These complications included four cases of myelitis which are analyzed in detail. The results are placed in the context of other published work on the use of neutrons in the treatment of lung cancer.

Fast Neutrons↗

Treatment experience: locally advanced sarcomas with 15 MeV fast neutrons.

Experience with ten evaluable osseous sarcomas and ten evaluable advanced soft tissue sarcomas treated with neutrons of a mean neutron energy of 15 MeV are described. Neutron irradiation with or without conventional megavoltage radiotherapy is an effective modality in the treatment of these patients. No correlation between response rate and grade or whether fast neutrons alone or combined with megavoltage radiotherapy was noted. Those patients receiving a neutron dose of 2195 neutron plus gamma rads or greater all had a complete response.

Bone Neoplasms↗

Dependence of mutation induction on fast-neutron energy in a human epithelial teratocarcinoma cell line (P3).

To date, few studies have evaluated the magnitude of the risks of somatic effects in humans from low-dose or protracted radiation exposure to neutrons using in vitro or in vivo techniques (A. Kronenberg, Radiat. Res. 128, S87-S93, 1991). In earlier study a strong energy dependence was shown for neutron-induced mutations at both the hprt and the tk loci in a rodent fibroblast cell line (Zhu and Hill, Radiat. Res. 139, 300-306, 1994). Using fast neutrons produced by impinging protons on a beryllium target at the UCLA/VA cyclotron, we have been examining the energy dependence of mutation induction at the HPRT locus in a human epithelial cell line derived from solid tumor tissue. In the present study, human epithelial teratocarcinoma cells were exposed to neutron beams produced from protons with 46, 30, 20 and 14 MeV energy. We found that cytotoxicity increased by 50% as the neutron beams produced from 46 MeV to 14 MeV, confirming many earlier reports. But as with the Chinese hamster cells, the mutation frequency at the HPRT locus increased 2.5-4-fold with decreasing neutron energy. Additionally, although there was a strong energy dependence for mutation induction, we noted that the shape of the induction curves was curvilinear for the human cells compared to the linearity of the curves obtained for the Chinese hamster cells and some other non-solid tissue human cell lines. Calculations of the RBE, using gamma rays as the standard reflected these differences. The RBE for mutation at the HPRT locus was dependent not only upon energy but also on dose, giving rise to RBEs that were in some cases distinctly different from those found in the Chinese hamster cell line. In the low-dose region (doses below 75 cGy) the maximum RBE of about 5 resulted from irradiation by the lowest-energy neutron beam (14 MeV protons on beryllium).

Animals↗

An evaluation of fast neutron beam teletherapy of metastatic cervical adenopathy from squamous cell carcinomas of the head and neck region.

One hundred thirteen patients with metastatic cervical adenopathy (MCA) from advanced squamous cell carcinoma of the head and neck completed fast neutron beam irradiation between September 1976 and March 1977. With a maximum follow-up time of 49.9 months (mean 14.5 months), 54% of the total group remain disease-free at the sites of their cervical adenopathy. Control of adenopathy measuring 3 cm or less in maximum dimension was 75% with neutrons only and 87.5% with mixed beams. Nodes measuring 3-6 cm were controlled 38.1% of the time with neutrons only and 59% of the time with mixed beams. Clinical control of adenopathy measuring greater than 6 cm was obtained in 12.5% with neutrons only and 29.4% with mixed beams. For patients with controlled primary tumors, the overall control rate in the neck was 72%; 100% of nodes 3 cm or less were controlled, 82% of nodes measuring from 3-6 cm were controlled, and 42% of nodes greater than 6 cm were controlled. Patients with controlled primary tumors treated with mixed beams had 100% control of nodes measuring 3 cm or less, 96% control of nodes measuring 3-6 cm, and 50% control of nodes measuring greater than 6 cm. Overall, the control rate for mixed beams was significantly better than for treatment with neutrons only. Morbidity was less (both acute and late) in the mixed beam-irradiated group.

Carcinoma, Squamous Cell↗

N-acetylcysteine and captopril protect DNA and cells against radiolysis by fast neutrons.

N-Acetylcysteine and captopril, respectively mucolytic and antihypertensive drugs, contain free sulfhydryl groups. Since in general thiols have well-established radioprotective abilities, we sought putative radioprotective effects of these drugs against therapeutic fast neutrons. We show that pBR322 plasmid DNA is indeed protected against radiolytic strand breakage by both drugs. The oxygen independent protection is consistent with a hydroxyl radical scavenging mechanism. A clonogenicity assay reveals an increase of the survival of SCL-1 cultured keratinocytes irradiated in the presence of the drugs compared with cells irradiated without drugs. Our results suggest possible interferences between treatment with drugs bearing-SH groups and radiotherapy.

Acetylcysteine↗

Fast neutron radiotherapy for locally advanced prostate cancer. Update of a past trial and future research directions.

Between June, 1977, and April, 1983, the Radiation Therapy Oncology Group (RTOG) sponsored a phase III study comparing fast neutron radiotherapy as part of a mixed beam (neutron/photon) regimen with conventional photon (x-ray) radiotherapy for patients with locally advanced (Stages C and D1) adenocarcinoma of the prostate. A total of 91 analyzable patients were entered into the study with the two treatment groups balanced in regard to all major prognostic variables. The current analysis is for a median follow-up of 6.7 years (range 3.4-9.0 yrs.). The results are statistically significant in favor of the mixed-beam group of all parameters mentioned. At five years the freedom from local/regional relapse rate is 81 percent on the mixed-beam arm compared with 60 percent on the photon arm. The actuarial overall survival rate at five years is 70 percent on the mixed beam compared with 56 percent on the conventional photon arm. The determinantal survival at five years (which excluded death due to intercurrent disease in patients clinically free of cancer) was 82 percent on the mixed-beam arm compared with 61 percent on the photon arm. The type of therapy appeared to be the most important predictor of both local tumor control and patient survival in a step-wise Cox analysis. There was no difference in the treatment-related morbidity for the two patient groups. Mixed-beam therapy may be superior to standard photon radiotherapy for treatment of locally advanced prostate cancer.

Adenocarcinoma↗

Fast neutron radiation therapy for unresectable squamous cell carcinomas of the head and neck: the results of a randomized RTOG study.

Forty patients with advanced, unresectable squamous cell carcinomas of the head and neck were entered on a prospective, randomized study comparing fast neutron radiation therapy with conventional photon radiation therapy. Twenty-six patients were randomized to neutrons, and 14 patients were randomized to photons. The randomization was purposefully unbalanced in favor of the experimental treatment. The complete response rate for the neutron-treated group of patients was 52%. The complete response rate for the photon-treated group of patients was 17%. The difference is statistically significant at the p = .04 level. The two-year survival rates for the neutron-treated group and the photon-treated group were 25 and 0%, respectively. The major complication rates were not statistically significantly different for the two groups (18% for neutrons, and 33% for photons).

Aged↗

Fast neutron irradiation of metastatic cervical adenopathy: the results of a randomized RTOG study.

Between 1977 and 1982, 199 evaluable patients with measurable cervical adenopathy were entered on a prospective, randomized RTOG study evaluating the use of fast neutrons in treatment of advanced, inoperable squamous cell carcinomas of the head and neck region. One hundred-eleven patients were randomized to receive mixed beam radiation therapy, and 88 were randomized to the photon control treatment. The complete response rates were 86% for mixed beam vs 75% for photons for Stage N1 nodes, 62% for mixed beam vs 48% for photons for Stage N2 nodes, and 63% for mixed beam vs 53% for photons for N3 nodes. The percents of patients remaining free of their adenopathy for two years were 78% for mixed beam vs 55% for photons for Stage N1 nodes, 39% for both mixed beam and photons for N2 nodes and 24% for mixed beam vs 13% for photons for N3 nodes. The median disease-free status was 20.3 months for mixed beam treated patients and 6.4 months for photon-treated patients. Patients who had clearance of cervical adenopathy survived significantly longer than those who did not.

Carcinoma, Squamous Cell↗

[The reoxygenation of superficial tumors in fast-neutron therapy].

The paper is concerned with the data on reoxygenation of superficial tumors in 38 patients exposed to densely and scarcely ionizing radiation. Tumor reoxygenation curves are presented. A tumor regression rate and reoxygenation of a tumor with respect to its original size showed correlation during fast-neutron therapy at 6.3 MeV.

Adult↗

Preliminary results of fast neutron teletherapy of metastatic cervical adenopathy.

Between September 21, 1973 and May 9, 1975, 36 patients with metastatic cervical adenopathy from cancers primarily arising in the pharynx or oral cavity, including six with bilateral cervical involvement, received fast neutron teletherapy at the University of Washington. At the conclusion of treatment, the masses were no longer palpable in nine of 42 (21%) heminecks and were reduced more than 50% in 23 (55%). In 12 patients with partial regression, the masses eventually disappeared, so that in all, 21 heminecks (50%) or 20 patients (56%) were controlled for periods up to 66 weeks. Fixed cervical masses were controlled in 11 of 23 (48%) patients. These results, which must be sustained for longer observation periods, are comparable to results reported in the literature. Treatment was well tolerated; therefore, doses can be raised to study the influence on tumor control.

Fast Neutrons↗

Fast neutrons produced by nuclear fragmentation in treatment irradiations with 12C beam.

In the framework of the heavy-ion tumour therapy project at GSI we investigated the nuclear fragmentation of 200 AMeV carbon ions stopping in a 12.78-cm thick water absorber. Fast neutrons and charged particles emerging from the target were registered at forward angles between 0 degrees and 30 degrees with a DeltaE-E-telescope consisting of an NE102 and a BaF2 scintillator. We obtained neutron energy spectra and angular distributions and derived the neutron yield in the energy range from 10 to 500 MeV in the forward hemisphere. In addition, we performed fragmentation measurements in actual patient treatment irradiations. The resulting angular distributions of neutrons and charged particles as well as their yields are similar to those obtained with the water absorber.

Body Burden↗

Thermoluminescence centres created selectively in MgO crystals by fast neutrons.

A possibility of using the thermoluminescent detection of collision-created interstitial centres in MgO by the TL peak at 700 K, arising at the radiative recombination of anion interstitials with F+ centres, for the selective detection of fast neutrons in mixed neutron-gamma fields, is examined. Selectivity and sensitivity of such a detector are discussed. For the present time, the sensitivity of the thermoluminescent detection of anion interstitials created by neutron irradiation is comparable to that of the EPR detection of F+ centres, the main limitations of the thermoluminescence method being connected with the background thermoluminescence and absence of suitable luminescence centres in this temperature region, when undoped and untreated MgO crystals are used. Possible ways to overcome these shortcomings are discussed.

Fast Neutrons↗

Fast-neutron irradiation of mouse embryos in the pronuclear zygote stage: mortality curves and neoplastic diseases in 30-day postnatal survivors.

Mouse embryos in the pronuclear zygote stage were either irradiated in utero with a dose of 15 rad of fast neutrons or were sham-irradiated. Those animals that survived at least 30 days after birth were observed until their natural death. We investigated the percentage incidence and mean age at death for each of the principal neoplastic diseases seen on postmortem examination and also cumulative mortality distributions. No statistically significant differences were found between irradiated and sham-irradiated mice of the same sex.

Animals↗

Study on the repair of the radioinduced lesions involved in the formation of chromosomal aberrations in G0 human lymphocytes after exposure to gamma-rays and fast neutrons.

Cytosine arabinoside (ara-C), an inhibitor of DNA synthesis and repair, has been used to study the mechanisms of formation of chromosomal aberrations after exposure to low- and high-LET radiation. When G0 human lymphocytes were exposed either to gamma-rays or to d(50 MeV)-Be neutrons and immediately treated with ara-C for increasing periods of time, the frequency of aberrations (dicentrics) increased sharply. For gamma-rays, the enhancement increased with the duration of the treatment up to 5 h, whereas for neutrons, an ara-C treatment lasting for 5 h was no more effective than treatment for 3 h. These results were confirmed by the second experiment in which ara-C was administered for 3 h with an increasing time delay following irradiation. Since no increase in the dicentric frequency was observed when ara-C was administered 5 h after gamma-irradiation, it is suggested that the induced breaks rejoined within that time. For neutrons, the data were conflicting since the repair was completed within 3 h after a dose of 0.5 Gy, and in approximately 5 h after a dose of 2.0 Gy. From both experiments, it appears that gamma-rays and fast neutrons produce similar types of lesions, as ara-C increased the frequencies of aberrations induced by both types of radiation. However, the ara-C treatment resulted in a smaller increase in aberrations following neutron irradiation. According to the enzymatic nature of break formation and the mode of action of ara-C on the polymerase activity, it is suggested that, in addition to double-strand breaks, single-strand breaks could be the lesions involved in the repair processes inhibited by ara-C. Single-strand breaks formed directly or by secondary reactions would, therefore, be one of the major lesions responsible for the aberrations produced by gamma and neutron radiations.

Cell Cycle↗

Fast-neutron irradiation of glioblastoma multiforme. Neuropathological analysis.

Various modes of therapy, alone or in combination, have had little effect in improving the survival of patients with glioblastoma multiforme. Recently, in a pilot study, 34 patients with glioblastoma were treated by fast-neutron-beam irradiation of the whole brain. Following treatment, the patients became steroid-dependent and pursued a gradual downhill course with increasing obtundation. Although there was no improvement in the length or quality of survival of these patients, neuropathological studies in the 13 patients who came to autopsy showed the following: 1) extensive coagulative necrosis of much of the tumor mass; 2) dense infiltration by collagenous connective tissue; 3) minimal phagocytic reaction; 4) marked reduction in the amount of viable tumor; 5) abnormal astrocytic proliferation, which may represent either astrocytoma or a radiation-induced bizarre gliosis, and 6) areas of gliosis and white matter degeneration in the brain stem, remote form the tumor site. These observations suggest that continued efforts to further refine this mode of therapy for glioblastoma are warranted.

Adult↗