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Interlaboratory comparison of different alpha-particle and radon sources: cell survival and relative biological effectiveness.

Alpha radiation-induced cell killing was determined in four different laboratories in order to: 1) measure interlaboratory variability and 2) compare the effects of radon and radon daughter exposures with the effects of 238Pu (an often-used model for radon exposure). The results suggest that differences in handling from laboratory to laboratory can affect both low and high linear energy transfer responses and should be considered when comparing results from different laboratories.

Alpha Particles↗

Determining person-years of life lost using the BEIR V method.

A method is given that permits the calculation of the estimated person-years of life lost when groups of males or females are exposed to low linear energy transfer (LET) ionizing radiation. It is felt that this determination is informative in rating risks to populations from radiation exposures. For example, when 1,000,000 females have received an acute 10 mSv, the total number of radiation-induced fatal cancers is 835. The total number of person-years of life lost is 1.4 x 10(4) or an average of about 5 d. However, the 22 who die of leukemia suffer an average of about 34 y. Those who die of other forms of cancer lose an average of 16 y. Some examples have been reported by the U.S. National Academy of Sciences (1990) report. In those cases where the Committee presented results, the method given here is in good agreement.

Age Factors↗

The Auger electron effect in radiation dosimetry.

The Auger electron effect is of importance in radiation protection related to work in radiobiology, radiophysics, and nuclear medicine. Radionuclides that emit Auger electrons are widely used in nuclear medicine (99mTc, 123I, and 201Tl) and in biomedical research (51Cr and 125I). They are also present in the environment (40K). Therefore, calculation of the absorbed dose and equivalent dose to tissues from these incorporated radionuclides is important for risk assessment. Depending on the subcellular distribution of the radionuclide, the biological effects caused by cell-incorporated Auger emitters can be as severe as those from high-linear energy transfer (LET) alpha particles. However, the recently adopted recommendations of the International Commission on Radiological Protection in Publication No. 60 do not provide guidance on calculating the equivalent dose for these radionuclides. A better understanding of the effects of Auger electrons is required to estimate the equivalent doses, and further research in this field is appropriate. There are good reasons to consider the Auger electron effect not only in medical radiation protection of patients but also in the context of annual limits of intake for workers and the public.

Animals↗

Radiation quality of a tomotherapy photon fan beam.

Tomotherapy, a novel radiotherapy technique, uses narrow fan beams for cancer patient treatment. Photon energy spectra for a rectangular 10 x 1 cm2 photon beam were analyzed in central axis and penumbra regions at depths of 3 to 10 cm in a water phantom. A 6 MV beam of a Varian 2100C/D Linear Accelerator was modeled using BEAM99 Monte Carlo calculations to simulate energy transport in a water phantom. Arrays of 4 x 2 mm2 scoring regions were arranged to cover the central axis and penumbra areas. Radiation quality factors were calculated based on dose-mean linear energy transfer. Although there appears to be a trend towards higher quality factor values in the penumbra area, this change is fairly small, at most 3% in penumbra region. We conclude that change in radiation quality is not likely to be an issue in a tomotherapeutic approach when 6 MV x rays are used.

Dose-Response Relationship, Radiation↗

Radiation enhancement with iodinated deoxyuridine.

A technique, Photon Activation Therapy (PAT), is described in which high Linear Energy Transfer (LET) radiations in the form of Auger electron distributions are generated by a photon beam through photoactivation of stable iodine incorporated as an analog of thymidine (Tyd) in DNA. Of the several halogenated deoxyribonucleosides evaluated, iodinated deoxyuridine (IdUrd) was found to be the only viable choice as a Tyd analog for PAT. Calculations show that 5% replacement of Tyd in tumor DNA multiplies the biologic effectiveness of a given photon radiotherapy dose by a factor of approximately 3. If further therapeutic advantages accorded to high LET radiations are taken into account, as well as repair and regeneration of normal tissues during protracted irradiations, an advantage of approximately 6 is realized. Five percent replacement of Tyd has already been reported for human tumor in vivo. Higher replacements of Tyd with IdUrd would provide proportionately greater advantages. The expectation is that previous clinical results with BrdUrd and high-energy X-rays can be significantly improved upon through the use of IdUrd and suitable lower energy activating photons (35-50 keV). In particular, it is suggested that protracted irradiations with implanted sources such as 145Sm or 145Pm may provide unique advantages at selected sites such as brain or head and neck tumors.

Animals↗

Boron neutron capture therapy of a rat glioma.

The purpose of the present study was to utilize a well-established rat glioma to evaluate boron neutron capture therapy for the treatment of malignant brain tumors. Boron-10 (10B) is a stable isotope which, when irradiated with thermal neutrons, produces a capture reaction yielding high linear energy transfer particles (10B + 1nth----[11B]----4He(alpha) + 7Li + 2.79 MeV). The F98 tumor is an anaplastic glioma of CD Fischer rat origin with an aggressive biological behavior similar to that of human glioblastoma multiforme. F98 cells were implanted intracerebrally into the caudate nuclei of Fischer rats. Seven to 12 days later the boron-10-enriched polyhedral borane, Na2B12H11SH, was administered intravenously at a dose of 50 mg/kg body weight at varying time intervals ranging from 3 to 23.5 hours before neutron irradiation. Pharmacokinetic studies revealed blood 10B values ranging from 0.33 to 10.5 micrograms/ml depending upon the time after administration, a T1/2 of 6.2 hours, normal brain 10B concentrations of 0.5 microgram/g, and tumor values ranging from 1.1 to 12.8 micrograms/g. No therapeutic gain was seen if the capture agent was given at 3 or 6 hours before irradiation with 4 x 10(12) n/cm2 (10 MW-min; 429 cGy). A 13.5-hour preirradiation interval resulted in a mean survival of 37.8 days (P less than 0.01), compared to 30.5 days (P less than 0.03) for irradiated controls and 22.1 days for untreated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Importance of receptor density in alpha radioimmunotherapy in B cell malignancies: an in-vitro study.

BACKGROUND: External beam radiotherapy and beta radioimmunotherapy (RIT) are effective treatments for lymphoid malignancies. The development of RIT with alpha emitters is attractive because of the high linear energy transfer (LET) and short path length, allowing higher tumour cell kill and lower toxicity to healthy tissues. AIM: To assess the binding of rituximab to samples of B cell chronic lymphocytic leukaemia (B-CLL) and splenic lymphoma with villous lymphocytes (SLVL), and to evaluate the induction of apoptosis by conventional therapies as well as with Bi conjugated to rituximab. METHOD: 213Bi was eluted from a 225Ac generator and conjugated to CD20 antibody (rituximab) with CHX-A''-DTPA as chelator. Binding assays with 213Bi-rituximab were correlated to antibody binding capacity obtained by flow cytometry. Apoptosis was scored by flow cytometric analyses of the cells stained with annexin V-FITC and 7-amino-actinomycin D. RESULTS: Binding of 213Bi-rituximab was significantly lower for B-CLL compared to SLVL samples (12+/-3 and 42+/-10 213Bi atoms per cell, respectively, at 370 kBq.ml(-1)). The induction of apoptosis did not differ significantly between the two groups (B-CLL and SLVL) after external gamma irradiation or treatment with methylprednisolone and fludarabine (17+/-12% and 18+/-11%; 23+/-14% and 21+/-12%; 9+/-9% and 11+/-8%, respectively; all results expressed as percentages of all cells). Rituximab conjugated or not to 213Bi induced significantly more apoptosis in SLVL (42+/-19% and 42+/-17%) compared to B-CLL samples (27+/-12% and 6+/-8%). CONCLUSION: Binding assays confirm that SLVL samples present more CD20 antigens compared to B-CLL samples. Conventional therapies such as fludarabine, methylprednisolone or external gamma irradiation induce similar responses in the two populations but SLVL samples present higher sensitivity towards 213Bi-rituximab. These data are in favour of alpha-RIT in SLVL patients.

Alpha Particles↗

Local control of subcutaneous murine melanoma xenografts in nude mice by neutron capture therapy.

The systemic administration of enriched [10B]D,L-p-boronophenylalanine results in the selective uptake of boron by Harding-Passey melanoma xenografts in the nude mouse model. The boron-10 located in the tumour cells acts as a radiation sensitizer for thermal neutron irradiation. The nude mouse model can be successfully used to demonstrate that regression and local control of melanoma can be achieved by neutron capture therapy. Control is a manifestation of the high linear energy transfer radiation released after neutron capture by boron-10, and does not result from an equal fluence of neutrons alone. Histological examination of remnant tumour beds 300 days after treatment shows the presence of isolated melanoma cells. However, these cells are few in number and appear incapable of division.

Animals↗

Influence of an autocrine diffusible resistance factor on cell survival after exposure to therapeutic agents.

A subclone of Cloudman mouse melanoma cells (S91/I3) produces a resistance factor (RF) that increases the survival of a different but related subclone, S91/Amel, after exposure to either ultraviolet C (UVC) radiation or to mitomycin C (MMC). The presence of RF was deduced from experiments in which heavily irradiated S91/I3 cells were plated with the target S91/Amel cells. The effect of RF was also present in cell-free conditioned tissue culture medium (CM) from S91/I3 cultures. These results extend previous findings that both subclones produce an autocrine resistance factor (RF) that alters the radiation response of target S91/Amel cells making them less sensitive to death by low linear energy transfer (LET) ionizing radiation. S91/I3 cells are radioresistant relative to S91/Amel and produce the RF more effectively than S91/Amel. S91/I3 cells do not respond to the RF, being themselves, presumably, maximally stimulated. The significant findings are (1) the RF is effective at decreasing the killing of the target cells using cytotoxic agents that operate by different mechanisms; (2) The relative sensitivities of S91/Amel and S91/I3 to the toxic agents is not a factor in the responses of these cells to the RF: S91/Amel survivals are increased by the RF, those of S91/I3 are not; (3) the RF is elaborated by the melanoma cells whether or not they have been irradiated; it is, apparently, a normal cell product; (4) the RF is effective when added after the cytotoxic insult; its presence is not required during irradiation or drug treatment. The RF appears to act by novel mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Responses of synchronous L5178Y S/S cells to heavy ions and their significance for radiobiological theory.

Synchronous suspensions of the radiosensitive S/S variant of the L5178Y murine leukaemic lymphoblast at different positions in the cell cycle were exposed aerobically to segments of heavy-ion beams (20Ne, 28Si, 40Ar, 56Fe and 93Nb) in the Bragg plateau regions of energy deposition. The incident energies of the ion beams were in the range of 460 +/- 95 MeV u-1, and the calculated values of linear energy transfer (LET infinity) for the primary nuclei in the irradiated samples were 33 +/- 3, 60 +/- 3, 95 +/- 5, 213 +/- 21 and 478 +/- 36 keV microns-1, respectively; 280 kVp X-rays were used as the baseline radiation. Generally, the maxima or inflections in relations between relative biological effectiveness (RBE) and LET infinity were dependent upon the cycle position at which the cells were irradiated. Certain of those relations were influenced by post-irradiation hypothermia. Irradiation in the cell cycle at mid-G1 to mid-G1 + 3 h, henceforth called G1 to G1 + 3 h, resulted in survival curves that were close approximations to simple exponential functions. As the LET infinity was increased, the RBE did not exceed 1.0, and by 478 keV microns-1 it had fallen to 0.39. Although similar behaviour has been reported for inactivation of proteins and certain viruses by ionizing radiations, so far the response of the S/S variant is unique for mammalian cells. The slope of the survival curve for X-photons (D0: 0.27 Gy) is reduced in G1 to G1 + 3 h by post-irradiation incubation at hypothermic temperatures and reaches a minimum (Do: 0.51 Gy) at 25 degrees C. As the LET infinity was increased, however, the extent of hypothermic recovery was reduced progressively and essentially was eliminated at 478 keV microns-1. At the cycle position where the peak of radioresistance to X-photons occurs for S/S cells, G1 + 8 h, increases in LET infinity elicited only small increases in RBE (at 10% survival), until a maximum was reached around 200 keV microns-1. At 478 keV microns-1, what little remained of the variation in response through the cell cycle could be attributed to secondary radiations (delta rays) and smaller nuclei produced by fragmentation of the primary ions.

Animals↗

Effects of neutron radiation on mouse hair matrix cell populations.

We have investigated the effects of a single low dose of 42 rads neutron radiation on hair matrix cell kinetics. Anagen hair skin sites in 3-mo-old Carworth Farms no. 1 female mice were exposed to a fast neutron beam yielding a modal energy of 3.6 MeV. In contrast to low LET (linear energy transfer) radiation at a 2 1/2 fold higher dose, neutrons induced a markedly prolonged depression (greater than 60%) in the mitotic index for more than 18 hr postradiation. In addition, from 10--18 hr after neutron irradiation sharp elevations (greater than 80%) in the labeling indices apparently reflected significant impairment in cell maturation rates and/or slowed exit rates from the proliferative compartments. Postradiation reductions of up to 20% in the size of proliferating matrix cell populations were found. At the cellular level, this study confirms previous findings of a disproportionately high relative biological effectiveness for neutron radiation following low dose level exposure.

Animals↗

A status report on the management of solid tumours.

Progressive improvements in the management of certain paediatric and haematological malignancies have provided guidelines for the current approaches to the management of the more common solid tumours of adults. These include precise histopathological grading; comprehensive evaluation of extent of disease; staging classifications accurately correlated with prognosis and progressive evaluation of available therapeutic modalities for all stages of disease in an attempt to define the best combination of local and systemic forms of therapy. Breast cancer is reviewed in detail as an example of the more responsive tumours where screening programs; improvements in pathological and clinical staging and the introduction of systemic chemotherapy together with optimal use of other methods of treatment for the various stages of disease gives hope for a significant improvement in long term survival statistics. Lung cancer has also been reviewed as an example of the more resistant types of cancer where screening programmes and current therapy including the use of combination chemotherapy have given minor encouragement but not had a definite influence on long term survival. Some further gains may still be achieved with currently available techniques but major improvements will probably require the development of better therapeutic tools including radiotherapy with high linear energy transfer particles; new chemotherapeutic agents and specific forms of immunotherapy. It is also quite possible that completely different forms of therapy for these resistant tumours will be necessary to reach the desired goal of long term improvements in survival.

Aged↗

Risk estimators for radiation-induced bone marrow syndrome lethality in humans.

This manuscript provides risk estimators for acute lethality from radiation-induced injury to the bone marrow of humans after uniform total-body exposure to low linear energy transfer (LET) radiation. The risk estimators are needed for nuclear disaster risk assessment. The approach used is based on the dose X, in units of D50 (i.e., the dose required for 50% lethality). Using animal data, it is demonstrated that the use of dose in units of D50 eliminates most of the variability associated with mammalian species, type of low-LET radiation, and low-LET dose rate. Animal data are used to determine the shape of the dose-effect curve for marrow-syndrome lethality in man and to develop a functional relationship for the dependence of the D50 on dose rate. The functional relationship is used, along with the Weibull model, to develop acute lethality risk estimators for complex temporal patterns of continuous exposure to low-LET radiation. Animal data are used to test model predictions.

Bone Marrow↗

Evaluation of the resistance of Euglena gracilis to ion beam radiation.

The resistance of Euglena (E.) gracilis to ionizing radiation was investigated using seven kinds of ion beams each with different energy characteristics. The minimum effective dose of the most lethal ion beams was 40 Gy. Given its substantially high resistance to heavy ion beams, E. gracilis possesses great potential in acting as an effective support system to produce food and regenerate oxygen in a space station. The lethal effect of ionizing radiation was dependent on the linear energy transfer value of the heavy ion beams, and reached a maximum at 196 keV/micron. This value was different from those obtained by previous irradiation experiments using mammalian and plant cells, suggesting that the radiation response of E. gracilis is distinct from that of mammalian and plant cells.

Animals↗

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↗

Pathoanatomical aspects of malignant haematological disorders among Danish patients exposed to thorium dioxide.

The Danish Thorotrast Study was recently reestablished and improved. The cohort has been reidentified and followed up, and now comprises 1003 Thorotrast-exposed patients. For all suspected haematological cases, cytological and histological material has been revised and malignant diseases have been reclassified. The numbers of cases of leukemia and other related haematological disorders were as follows: 16 acute myeloid leukemia (AML); 8 myelodysplastic syndrome (MDS); 1 acute lymphatic leukemia (ALL); 3 chronic myeloid leukemia (CML); 4 non-Hodgkin's lymphoma (NHL); 2 multiple myeloma (MM); 2 myelofibrosis (MF); 2 chronic lymphatic leukemia (CLL). Except for CLL, all cases might be Thorotrast-induced. (Expected number of leukemias: < 2.5.) The findings in the German, Japanese, Portuguese and Danish studies are very similar. Some of the characteristic features include a high incidence of AML with several erythroleukemias, many cases of MDS, and a relatively low incidence of CML. In several studies of leukemia induced by alkylating agents, erythroleukemia is also described as a prominent feature. The possibility exists that a phase of relative predominance of erythroid elements in the bone marrow may be a common and not an unusual feature in the pathogenesis of these secondary leukemias. The findings are also compared with histopathological data from a Danish control group of de novo leukemia patients and from atomic bomb survivors with radiation-induced leukemia. The relative frequency of AML is higher among the Thorotrast-exposed patients than among the Danish control group and the A-bomb survivors. In contrast, low relative frequencies are seen for ALL and CML in Thorotrast cases in comparison with de novo leukemia cases and A-bomb survivors. It can be concluded that differences in relative and absolute frequency of leukemias and myelodysplastic syndrome exist not only between the irradiated populations and the unexposed control group, but even between groups exposed to low-LET (linear energy transfer) and high-LET radiation.

Acute Disease↗

Relative effectiveness of polyacrylamide gel dosimeters applied to proton beams: Fourier transform Raman observations and track structure calculations.

The feasibility of using polyacrylamide gel (PAG) to characterize a clinically relevant 74 MeV proton beam has been considered. Fourier transform Raman spectroscopy has been used to measure the response (i.e., consumption of monomer) of PAG exposed to the central and end portions of a spread out Bragg peak (SOBP), i.e., in two regions with measurable difference in proton linear energy transfer (LET). The response curve in each region was compared with a typical 6 MV x-ray irradiated gel response curve, thus arriving at a gel "relative effectiveness" (RE) in each of the two regions. In addition, the theory of track structure, which is typically used to calculate a detector RE, is shown to give reasonable agreement when compared with the experimental results. Both experimental and track structure results indicate a decrease in gel response when irradiated with protons, as compared with the x-ray response. In addition, both sets of results indicate a variation in gel response between the mid and end SOBP regions, thus illuminating the dependence of gel response to proton LET. The physical phenomenon causing a lower proton versus x-ray gel response may be understood by considering the track structure calculations, which indicate that gel radiosensitive elements close to the track of a proton (i.e., within 1.5 x 10(-6) cm) are saturated. This saturation is due to the high delta-ray doses deposited in these regions. The track calculations are extended to other situations (e.g., raw BP, different gel compositions) where experimental determination of RE is difficult or time consuming. Results again indicate a gel response dependent on position in the depth dose curve (i.e., LET). Overall, this study illuminates the difficulty in using polyacrylamide gel to extract quantitative dose maps when exposed to proton radiation.

Acrylic Resins↗

Extension of x-ray imaging linear systems analysis to detectors with energy discrimination capability.

A figure of merit, the broad-spectrum generalized detective quantum efficiency, which describes the performance of digital detectors designed for broad-spectrum x-ray imaging is derived from linear response theory. This measure of the imaging efficacy of an x-ray sensor is obtained when detector contrast modulation in the domain of x-ray energy is introduced in the Fourier-based analysis of digital systems. A method is proposed to scale existing figures of merit according to the energy-dependent response of the detector and the spectral shape of the x-ray beam. The new figure of merit obtained with this method provides an extended description of system performance when comparing energy-integrating, single-photon counting, and future energy-sensitive x-ray imaging sensors. The applicability of this linear system analysis is restricted to the tasks of low-contrast object detection in radiography. The method for scaling the figure of merit to take into consideration broad-spectrum conditions is applied to mammography for future energy-dependent detectors. An approximation valid in the typical mammographic x-ray energy range is used to calculate the broad-spectrum generalized detective quantum efficiency at zero spatial frequency, for several mammographic x-ray spectra. X-ray energy weighting in mammography is investigated in the context of simulated tumors and microcalcifications detection by comparing this figure of merit, calculated for different detector technologies, under ideal imaging conditions, at zero spatial frequency.

Algorithms↗