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PubMedDate not supplied

Role of radiation in the management of adult patients with sarcoma of soft tissue.

Radiation in moderate dose levels, viz. 60-65 Gy at 2 Gy/fraction, administered in combination with conservative surgery, yields local control frequencies at least comparable to those achieved by radical resectional surgery alone. The clinical interest in this management strategy is the reduction in the scope of the resection and a consequent gain in cosmetic and functional status. This combined approach is favored for sarcomas so situated that resection with wide margin, > or = 2 cm at the most narrow, cannot be realized unless there is a clinically important loss in function. Where radical surgery is planned, there must be great care in assessment of the probability of achieving good margins. The patient is ill served if there is radical surgery and then, because of close margins, postoperative radiation is required. There appears to be clinical gain for the patient with a large sarcoma by administering the radiation preoperatively. Advantages include smaller treatment volume and higher local control rates. The management of the surgical wound in the irradiated patient is discussed. Also, brief consideration is given to current use of brachytherapy, high linear energy transfer (LET) radiation, and combination of radiation and chemotherapy.

Adult↗

PubMed1991

Atomic and molecular physics in the gas phase.

The spatial and temporal distributions of energy deposition by high-linear-energy-transfer radiation play an important role in the subsequent chemical and biological processes leading to radiation damage. Because the spatial structures of energy deposition events are of the same dimensions as molecular structures in the mammalian cell, direct measurements of energy deposition distributions appropriate to radiation biology are infeasible. This circumstance has led to the development of models of energy transport based on a knowledge of atomic and molecular interactions that enable one to simulate energy transfer on an atomic scale. Such models require a detailed understanding of the interactions of ions and electrons with biologically relevant material. During the past 20 years, there has been a great deal of progress in our understanding of these interactions, much of it coming from studies in the gas phase. These studies provide information on the systematics of interaction cross sections, and lead to knowledge of the regions of energy deposition where molecular and phase effects are important-knowledge that guides development in appropriate theory. In this report, studies of the doubly differential cross sections, which are crucial to the development of stochastic energy deposition calculations and track structure simulation, are reviewed. We discuss areas of understanding and address directions for future work. Particular attention is given to experimental and theoretical findings that have changed the traditional view of secondary electron production for charged-particle interactions with atomic and molecular targets.

Animals↗

PubMed1998

Neutron therapy in malignant salivary gland tumors: results at European centers.

Malignant salivary gland tumors are relatively rare and account for only 3%-4% of all head and neck cancers. Especially in adenoid cystic carcinoma, the incidence of local recurrence and distant metastases is influenced by the perineural spread of tumor. In advanced salivary gland tumors, surgery alone has a high incidence of local failure. The results of conventional radiotherapy are suboptimal in inoperable or not completely resected salivary gland tumors and in recurrent disease. The pooled data of some international series for low linear energy transfer radiation show a local control of only 28%. Especially in advanced salivary gland tumors, neutron therapy can improve local control. In Europe at least 570 patients with salivary gland tumors have been treated with neutrons alone or with combined modalities. The clinical data of different centers in Europe and the United States result in a similar local control rate of 67% in gross disease. An analysis of different European series shows on average a complication rate of 10.6% for severe radiation-related morbidity. Modern neutron machines and the use of three-dimensional treatment planning systems are now available in a few institutions and may further reduce side effects.

Aged↗

PubMed1998

Fast neutrons in prostatic adenocarcinomas: worldwide clinical experience.

Primary tumor control remains a major problem in the treatment of locally advanced prostate carcinoma. Clinical local failure rates approach 30-40% and may be significantly higher when results of prostatic biopsy or prostate-specific antigen (PSA) levels are considered. The low growth rate and cycling fraction of prostate adenocarcinoma suggest potential therapeutic advantage for the high linear energy transfer (LET) of neutrons. The Radiation Therapy Oncology Group (RTOG) performed a multi-institutional randomized trial (RTOG 77-04) comparing mixed beam (neutron plus photon) irradiation to conventional photon irradiation for the treatment of locally advanced prostate cancer. A subsequent trial by the Neutron Therapy Collaborative Working Group (NTCWG 85-23) compared pure neutron irradiation to standard photon irradiation. Both randomized trials demonstrate significant improvement in locoregional control with neutron irradiation compared to conventional photon irradiation in the treatment of locally advanced prostate carcinoma. To date, only the mixed beam trial has shown a significant survival benefit. Future analysis of the larger NTCWG trial at the 10-year point should confirm whether or not improved locoregional control translates into a survival advantage. These findings have significant implications for all local treatment strategies including dose-escalated conformal photon irradiation, prostate implantation, and neutron radiation. Given the large numbers of patients afflicted with this disease, a positive survival advantage for neutrons or mixed beam therapy would provide a strong incentive for the development of economically feasible clinical neutron facilities.

Adenocarcinoma↗

PubMed1986

Cellular and tissue responses to heavy ions: basic considerations.

Responses of the S/S variant of the L5178Y murine leukemic lymphoblast, the photoreceptor cell of the rabbit retina and the lenticular epithelium of the rabbit to heavy ions (20Ne, 28Si, 40Ar and 56Fe) are described and discussed primarily from the standpoint of the need for a comprehensive theory of cellular radiosensitivity from which a general theory of tissue radiosensitivity can be constructed. The radiation responses of the very radiosensitive, repair-deficient S/S variant during the G1- and early S phases of the cell cycle were found to be unlike those of normally radioresistant cells in culture: the relative biological effectiveness (RBE) did not increase with the linear energy transfer (LET infinity) of the incident radiation. Such behavior could be anticipated for a cell which is lacking the repair system that operates in other (normal) cells when they are exposed to ionizing radiations in the G1 phase of the cell cycle. The S/S variant does exhibit a peak of radioresistance to X-photons mid-G1 + 8 h into the cell cycle, however, and as the LET infinity was increased, the repair capacity responsible for that radioresistance was reduced progressively. Sensory cells (photoreceptors) in the retina of the New Zealand white (NZW) rabbit are very radioresistant to ionizing radiations, and several years elapsed after localized exposure (e.g., 5-10 Gy) to heavy ions (20Ne, 40Ar) before photoreceptor cells were lost from the retina. During the first few weeks after such irradiations, damage to DNA in the photoreceptor cells was repaired to a point where it could not be demonstrated by reorienting gradient sedimentation under alkaline conditions, a technique that can detect DNA damage produced by less than 0.1 Gy of X-photons. Restitution of DNA structure was not permanent, however, and months or years later, but before loss of photoreceptor cells from the retina could be detected, progressive deterioration of the DNA structure began. Age dependencies of late sequelae from densely ionizing radiations are matters of concern both for the therapeutic uses of radiation and the risk/benefit considerations of environmental exposure, especially in outer space. A pilot experiment with a single acute exposure to 20Ne ions has illustrated the need for careful examination of the role of animal age at the time of irradiation in subsequent tissue responses.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1990

Induction, repair and biological relevance of radiation-induced DNA lesions in eukaryotic cells.

This report summarizes data on the induction, repair and biological relevance of five types of radiation-induced DNA lesions for which repair kinetic studies have been performed in eukaryotic cells by various laboratories. These lesions are: DNA-protein crosslinks, base damage, single-strand breaks, double-strand breaks and bulky lesions (clustered base damage in the nm-range). The influence of various factors, such as oxia/anoxia, linear energy transfer of the radiation used, incubation medium, cell cycle stage, thiol content, hyperthermia, on the induction and repair of these lesions is described. Radiation-sensitive cell lines are also included.

Animals↗

PubMed1993

Protection of DNA from high LET radiation by two OH radical scavengers, tris (hydroxymethyl) aminomethane and 2-mercaptoethanol.

The effect of high linear energy transfer (LET) radiation on DNA in vitro, both in protective and non-protective environments was investigated. Two hydroxyl radical scavengers, tris(hydroxymethyl) aminomethane and 2-mercaptoethanol, were compared for their ability to protect SV40 DNA from radiation damage over a wide LET range. At comparable OH scavenging capacities, significant differences were found between these protective agents, indicating that other, radical scavenger-dependent processes affected the extent to which the DNA was protected. In general, a decrease in single-strand breaks (SSBs) relative to double-strand breaks (DSBs) was observed as LET increased. This effect was more pronounced when a radioprotector was present. Comparison of the relative biological efficiency (RBE) of radiation damage as LET increased showed a peak of DSB production in the mid-LET range. These data agree with measurements made by Christensen et al. (1972). An explanation for this increase in DSB production efficiency has been proposed based on the particle track structure of high-LET radiation.

DNA Damage↗

PubMed1988

Qualitatively different induction of germ cell mutations by heavy ions. A dual target theory.

The problem of the dependence of the biological efficiency of ionizing radiation on the Linear Energy Transfer (LET) is still unsolved. Unexpected reactions of heavy ion irradiated cellular systems such as an increasing Relative Biological Effectiveness (RBE) up to a LET of about 100 keV/micron and then a decrease below 1 oblige to dismiss some conventional interpretations. Several years ago we suggested that, especially by higher ionization density in addition to the DNA, repair systems and (or) membraneous systems could also be injured (dual target theory). Our experiments with heavy ions at the Lawrence Berkeley Laboratory with LET's between 102-970 keV/micron on different types of mutations show a strict distinction between events connected with fusion modalities (repair or misrepair) and those associated with nonfusion. With very high LET misrepair reactions such as translocations disappear, suggesting the direct damage of the repair systems and confirming our previous experiments with peak pions and ions of LET's between 1100-4800 keV/micron.

Animals↗

PubMed1993

Model of mammalian cell reproductive death. I. Basic assumptions and general equations.

A systemic model describing the major radiobiological effects of various types of radiation is proposed. The model base lines were substantiated, and general mathematical equations for cell survival developed. The model takes into consideration such physical and biological factors as linear energy transfer, ion track structure, and structural and functional organization of interphase chromatin. This paper presents the basic assumptions made and general equations for the cell killing.

Animals↗

PubMed1993

Model of mammalian cell reproductive death. II. Comparison with experimental data and discussion.

A general equation for mammalian cell survival has been derived in the previous paper. This paper presents the results of comparison of theoretical evaluations with survival data available from the literature, including different cell lines, variations in linear energy transfer, dose rate and dose fractionation effects and the effects of ultrasoft X-rays and superheavy ions. Merits and demerits of the model are considered in comparison with other models of radiation-induced killing of mammalian cells published in the literature.

Animals↗

PubMed1995

Micronucleus induction and reproductive death in a human cell line exposed to low-energy argon beam.

Little is known about the action of charged particles of very high linear energy transfer (LET) on human cells and, in particular, the relationship between DNA damage and reproductive death. The aim of this study was to measure the biological efficiency of a low-energy argon beam (E = 7.1 MeV/nucleon, LET = 1590 keV/micron) produced at GSI, Darmstadt, on a human melanoma cell line (CAL4) established in our Institute. Two different methods were used: the micronucleus (MN) test and the colony-forming assay. The MN test, using the cytochalasin-block method, is a measure of genotoxic damage. MN are scored in binucleate cells (BNC) and are formed from acentric fragments or whole chromosomes that have not been incorporated into daughter nuclei at mitosis. The colony-forming assay quantifies reproductive death. Parallel experiments were run with cobalt gamma-rays for comparison. After Co irradiation, the MN-free BNC dose-response curve coincided with that of the loss of colony-forming ability, suggesting the potential of the former as a predictive test of cell killing. After Ar irradiation, there was a dissociation between the two effects, especially at high doses: cell death was greater than the frequency of BNC with MN. The inactivation cross-section was 74 microns2; it was 39 microns2 for MN yield. Therefore, the relative biological effectiveness (RBE) was higher for cell killing than for MN yield (0.8 and 0.5, respectively at a Co dose of 3 Gy). The total MN count in BNC followed the same pattern of response as the fraction of BNC with MN.(ABSTRACT TRUNCATED AT 250 WORDS)

Argon↗

PubMed1982

Energy deposition spectra of pi- calculated from pion nucleus interaction data.

Distributions of absorbed dose in linear energy transfer (LET) and in lineal energy (y) are calculated for beams of negatively charged pions in a water phantom. The calculation is based on a comprehensive set of experimental data. The production of delta-ray electrons by fast particles is taken into account semiempirically. The results are compared with experimentally obtained spectra of ionization yields. The equivalence of data derived from pion nucleus interaction and taken from microdosimetry is clearly revealed. The distribution of absorbed dose is given in a sequence of contributions from the various secondary particles, i.e., the so-called 'star' particles emitted following a nuclear capture process or the recoil nuclei from pion scatterings. This unique feature of calculated spectra will be useful for a characterization of the beam quality in view of the existing dependence of biological effects on track structure properties.

Animals↗

PubMed1977

Mechanistic state vector model for cell killing by ionizing radiation.

By use of the mechanistic state vector model (MSV model) it is demonstrated that under circumstances where cell division during irradiation is unlikely: 1. A cell survival curve (dose-log surviving fraction curve) that is exponential can be obtained even though some of the surviving cells may have nonlethal damage. Exponential survival curves are said to have zero curvature. 2. In some cases, in the absence of a mixed population, the slope of a single-dose survival curve may decrease in magnitude, as the dose increases for a range of doses. These curves are said to show negative curvature for that range of doses. Fractionating the dose or decreasing the dose rate may result in enhanced cell killing. 3. The initial slope of a mammalian cell survival curve should be independent of the dose rate and number of dose fractions provided that the number of cells having lethal damage builds up to a steady level during the post irradiation time regime. The magnitude of the initial slope will depend on properties of the cells and on properties of the radiation. 4. A nonzero initial slope in the cell survival curve, after exposure to low linear energy transfer (LET) radiation, may be due to biology, rather than physics.

Animals↗

PubMed1976

Microdosimetric structure of heavy ion tracks in tissue.

Energy dissipation in tracks of high energy heavy ions in tissue shows a lateral spread of several to many microns depending on the energy of the primary particle. Complete dosimetric characterization, therefore, requires in addition to the Linear Energy Transfer (LET) information on the radial energy distribution. The theory of track structure distinguishes two regions: core and penumbra. The core is a narrow central zone with a radius in tissue far below 1 micron where energy deposition occurs mainly in processes of excitation and electron plasma oscillation. According to the Equipartition Principle, half of the total energy dissipation accrues in this manner. The penumbra is a peripheral zone enveloping the core where energy deposition occurs mainly in ionization events by energetic secondary electrons released by the primary particle in the center of the core traveling at rather high speed thus spreading laterally. The extension of the penumbra depends in a complex manner on the maximum transferable energy to electrons which in turn depends on the speed of the primary particle. Local energy density in the penumbra decreases with the square of increasing radius. It therefore amounts only to a very small fraction of the core density already a few microns away from the center. In general terms, track structure can be described as exhibiting a core of enormous energy density with lateral dimensions remaining entirely on the submicroscopic level surrounded by a penumbra where energy density drops precipitously to very small levels. The relationships are illustrated with micrographs of different sections of a heavy particle track in nuclear emulsion and their counterpart graphical plots.

Elementary Particles↗

PubMed1998

Biological Effects of Heavy Ion Beam on Human Breast Cancers.

BACKGROUND: Radioresistance of the extensive intraductal component (EIC) is amajor limiting factor in breast conserving therapy (BCT). The purpose of the present experiment was to elucidate the biological effects of a carbon beam on human breast cancer cell lines in order to evaluate its clinical benefits in BCT. METHODS: Human breast cancer cell lines, both grown in culture and inoculated into nude mice were subjected to X-ray (200 kV) and heavy ion beam (290 MeV/u carbon beam) irradiation. The relative biological effectiveness (RBE) of the carbon beam and X-ray irradiation was determined at the level of D10 (10% survival dose) on the dose-survival curve. By using a colony forming assay the survival curves of the three cultured cell lines (YMB-I, OUUB-M, CRL-1500) at a linear energy transfer (LET) of 80 keV/µ m were obtained. Cancer established in nude mice was exposed to single-dose and triple-fractionated irradiation at a LET of 50 keV/µm. The growth of tumorsat various doses was observed and the survival curves were determined using thetumor regrowth assay. RESULTS: The RBE of the carbon beam on each cell line ranged from 2.17 to 2.89 (2.59+/-0.37). That of the tumor in nude mice was 1.53 and 2.00 on exposure to single-dose and fractionated irradiation, respectively. CONCLUSION: Human breast cancer cell lines showed high intrinsic sensitivity to a carbon beam and its effects on the tumor were enhanced by fractionated irradiation. It is worthy using carbon beam is applied to use for clinical trials inBCT.

Journal Article↗

PubMed2005

Neutron versus photon radiotherapy for local control in inoperable breast cancer.

BACKGROUND AND PURPOSE: By virtue of their high linear energy transfer (LET) characteristics the biologic effectiveness of neutrons is less dependent on tissue oxygenation tension and cell cycle phase as compared to that with photons. Hence, an improved clinical benefit is to be expected predominantly in large, hypoxic and slowly growing tumors. Since a short course of radiotherapy is required for clinical reasons, it prompted the authors to initiate a randomly controlled trial on locally advanced breast cancer. PATIENTS AND METHODS: Between 1996 and 1999, 27 patients with locally advanced breast cancer were irradiated with photons (60 Gy, 30 fractions; 8 MV, (60)Co) or neutrons (18 Gy, twelve fractions; 66 MeV(p-->Be)). The mean tumor diameters were 699 +/- 399 ml for the photon group and 1,097 +/- 831 ml in the neutron group. RESULTS: After a mean follow-up period of 21.5 months tumor involution was evaluated in 22 patients. Partial and complete remissions were registered in 6/10 patients of the photon group and 5/12 patients of the neutron group. Late grade 3-4 morbidity according to RTOG definition was scored in 5/10 patients in the photon group and in 6/12 patients in the neutron group. With regard to tumor control and late radiation morbidity no differences between the two treatment arms were observed. CONCLUSION: The underlying data indicate that no benefit is to be expected from neutron therapy in breast cancer.

Adult↗

PubMed2003

In vitro evaluation of 213Bi-rituximab versus external gamma irradiation for the treatment of B-CLL patients: relative biological efficacy with respect to apoptosis induction and chromosomal damage.

External source 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. We assessed the relative biological efficacy (RBE) of alpha RIT (in vitro) compared to external gamma irradiation with respect to induction of apoptosis in B chronic lymphocytic leukaemia (B-CLL) and induction of chromosomal damage in healthy donor B and T lymphocytes. The latter was measured by a micronucleus assay. 213Bi was eluted from a 225Ac generator and conjugated to CD20 antibody (rituximab) with CHX-A"-DTPA as a chelator. B-CLL cells from five patients were cultured for 24 h in RPMI/10% FCS while exposed to 213Bi conjugated to CD20 antibody or after external 60Co gamma irradiation. Binding assays were performed in samples of all patients to calculate the total absorbed dose. Apoptosis was scored by flow cytometric analyses of the cells stained with annexin V-FITC and 7-AAD. Apoptosis was expressed as % excess over spontaneous apoptosis in control. Full dose range experiments demonstrated 213Bi-conjugated CD20 antibody to be more effective than equivalent doses of external gamma irradiation, but showed that similar plateau values were reached at 10 Gy. The RBE for induction of apoptosis in B-CLL was 2 between 1.5 and 7 Gy. The micronucleus yield in lymphocytes of healthy volunteers was measured to assess the late toxicity caused by induction of chromosomal instability. While gamma radiation induced a steady increase in micronucleus yields in B and T cells, the damage induced by 213Bi was more dramatic, with RBE ranging from 5 to 2 between 0.1 Gy and 2 Gy respectively. In contrast to gamma irradiation, 213Bi inhibited mitogen-stimulated mitosis almost completely at 2 Gy. In conclusion, high-LET targeted alpha particle exposure killed B-CLL cells more effectively than did external gamma irradiation at a low dose (RBE=2), while a plateau was reached at a high dose. Long-term toxicity on healthy B and T lymphocytes was systematically higher for the alpha emitter (RBE=5 to 2).

Aged↗

PubMed2005

Cancer radioimmunotherapy with alpha-emitting nuclides.

In lymphoid malignancies and in certain solid cancers such as medullary thyroid carcinoma, somewhat mixed success has been achieved when applying radioimmunotherapy (RIT) with beta-emitters for the treatment of refractory cases. The development of novel RIT with alpha-emitters has created new opportunities and theoretical advantages due to the high linear energy transfer (LET) and the short path length in biological tissue of alpha-particles. These physical properties offer the prospect of achieving selective tumoural cell killing. Thus, RIT with alpha-emitters appears particularly suited for the elimination of circulating single cells or cell clusters or for the treatment of micrometastases at an early stage. However, to avoid non-specific irradiation of healthy tissues, it is necessary to identify accessible tumoural targets easily and rapidly. For this purpose, a small number of alpha-emitters have been investigated, among which only a few have been used for in vivo preclinical studies. Another problem is the availability and cost of these radionuclides; for instance, the low cost and the development of a reliable actinium-225/bismuth-213 generator were probably determining elements in the choice of bismuth-213 in the only human trial of RIT with an alpha-emitter. This article reviews the literature concerning monoclonal antibodies radiolabelled with alpha-emitters that have been developed for possible RIT in cancer patients. The principal radio-immunoconjugates are considered, starting with physical and chemical properties of alpha-emitters, their mode of production, the possibilities and difficulties of labelling, in vitro studies and finally, when available, in vivo preclinical and clinical studies.

Alpha Particles↗