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Biomedical subjects

E L Alpen

Publications and source records attributed to E L Alpen.

At least 37 records · Page 2Linked to original sources

A comparison of water equivalent thickness measurements: CT method vs. heavy ion beam technique.

The purpose of this study was to evaluate existing X-ray CT methods for determining water-equivalent path length from body surface to a tumour site. In the method, the CT numbers are used to obtain linear attenuation coefficients which provide a measure of the electron density. These numbers are averaged over the energy spectrum of the diagnostic X-ray beam and other parameters which have a dependence on energy. From range measurements with heavy charged particles, it is also possible to obtain an independent and direct measure of electron density along the beam path. In the results reported here, the beam path electron density or water-equivalent path length was measured with charged particle beams, using radiation sensitive diodes as target markers. To minimise error which would be introduced by motion of the target volume, a frozen dog cadaver was used. Comparison was made between the water-equivalent path length measured with high energy particle beams, and the water-equivalent path length estimated from an X-ray CT image of the same target volume by the methods presently used in charged particle therapy (Chen et al. 1979). There was good agreement between the values determined directly with neon or helium ion beams, but when these values were compared with estimated path lengths derived from X-ray CT data, it was observed that the CT range could be in error by as much as 11% for adverse conditions of marked inhomogeneity and the presence of high atomic number bone. Under the best conditions of moderate inhomogeneity and absence of bone, the derived CT range values agreed reasonably well with the direct measurements.

Animals↗

High-LET radiation carcinogenesis.

The dose-response curves for the induction of tumors by high-LET radiation are complex and are insufficiently understood. There is no model or formulation to describe the dose-response relationship over a range 0-100 rad. Evidence suggests that at doses below 20 rad the response is linear, at least for life shortening and some tumor systems. Thus limiting values of RBEs for the induction of cancer in various tissues can be determined, but it will require sufficient data obtained at low single doses or with small fractions. The results obtained from experiments with heavy ions indicate an initial linear response with a plateauing of the curve at a tumor incidence level that is dependent on the type of tissue. The RBE values for the heavy ions using 60Co gamma rays as the reference radiation increase with the estimated LET from 4 or 4H to about 27 for 56Fe and 40Ar. The dose responses and RBEs for 56Fe and 40Ar are similar to those for fission neutrons. These findings suggest the possibility that the effectiveness for tumor induction reaches a maximum.

Animals↗

The RBE for renal damage after irradiation with 3 MeV neutrons.

Mouse kidneys were locally irradiated with single doses or up to 8 fractions of 240 kV X rays or 3 MeV neutrons. Damage was assessed from measurements of urine output, isotope clearance or haematocrit levels. All three assays gave steep dose-response curves by 4-5 months after irradiation. The repair capacity of the kidney was considerable after X-irradiation but was very small after irradiation with neutrons. Thus the RBE increased sharply with increasing fractionation. After large doses, an RBE of 2.3-2.5 was measured, rising to 4.5-5.1 after 8 fractions of 4 to 5 Gy X rays. Linear-quadratic analysis of these data has allowed RBE's to be calculated outside the measured dose range. The limiting RBE predicted at very low doses per fraction is 20 to 26, whereas at extremely high doses it would be as low as 1.2 to 1.4. This indicates that high RBE values may be seen in a slow turnover tissue after low doses per fraction (within the clinically relevant range) although this may not be evident after larger doses. Such high RBE's arise because of the shape of the underlying X-ray dose-response curve rather than the shape of the neutron curve.

Animals↗

Radiation-induced renal damage: the effects of hyperfractionation.

The response of mouse kidneys to multifraction irradiation was assessed using three nondestructive functional end points. A series of schedules was investigated giving 1, 2, 4, 8, 16, 32, or 64 equal X-ray doses, using doses per fraction in the range of 0.9 to 16 Gy. The overall treatment time was kept constant at 3 weeks. Kidney function was assessed from 19 to 48 weeks after irradiation by measuring changes in isotope clearance, urine output, and hematocrit. The degree of anemia (assessed from the hematocrit measurements) is a newly developed assay which is an early indicator of the extent of renal damage after irradiation. All three assays yielded steep dose-effect curves from which the repair capacity of kidney could be estimated by comparing the isoeffective doses in different schedules. There was a marked influence of fractionation, with increasing dose being required to achieve the same level of damage for increasing fraction number, even between 32 and 64 fractions. The data are well fitted by a linear quadratic dose-response equation, and analysis of the data in this way yields low values (approximately 3.0 Gy) for the ratio alpha/beta. This would suggest that hyperfractionation , using extremely small X-ray doses per fraction, would spare kidneys relative to tumors and acutely responding tissues.

Animals↗

High-LET radiation carcinogenesis.

Recent results for neutron radiation-induced tumors are presented to illustrate the complexities of the dose-response curves for high-LET radiation. It is suggested that in order to derive an appropriate model for dose-response curves for the induction of tumors by high-LET radiation it is necessary to take into account dose distribution, cell killing and the susceptibility of the tissue under study. Preliminary results for the induction of Harderian gland tumors in mice exposed to various heavy ion beams are presented. The results suggest that the effectiveness of the heavy ion beams increases with increasing LET. The slopes of the dose-response curves for the different high-LET radiations decrease between 20 and 40 rads and therefore comparisons of the relative effectiveness should be made from data obtained at doses below about 20-30 rads.

Animals↗

Response of colony-forming units-spleen to heavy charged particles.

Survival of colony-forming units-spleen (CFU-S) was measured after single doses of photons or heavy charged particles from the BEVALAC. The purposes were to define the radiosensitivity to heavy ions used medically and to evaluate relationships between relative biological effectiveness (RBE) and dose-averaged linear energy transfer (LET infinity). In in vitro irradiation experiments. CFU-S suspensions were exposed to 220 kVp X rays or to 20Ne (372 MeV/micron) or 40Ar (447 MeV/micron) particles in the plateau portion of the Bragg curve. In in vivo irradiation experiments, donor mice from which CFU-S were harvested were exposed to 12C (400 MeV/micron). 20Ne (400 or 670 MeV/micron), or 40Ar (570 MeV/micron) particles in Bragg peaks spread to 4 or 10 cm by spiral ridge filters. Based on RBE at 10 survival, the maximum RBE of 2.1 was observed for 40Ar particles characterized by an LET infinity of approximately 100 keV/micron. Lower RBEs were determined at lower or higher estimated values of LET infinity and ranged from 1.1 for low energy 40Ar particles to 1.5-1.6 for low energy 12C and 20Ne. The responses of CFU-S are compared with responses of other model systems to heavy charged particles and with the reported sensitivity of CFU-S to neutrons of various energies. The maximum RBE reported here, 2.1 for high energy 40Ar particles, is somewhat lower than values reported for fission-spectrum neutrons, and is appreciably lower than values for monoenergetic 0.43-1.8 MeV neutrons. Low energy 12C and 20Ne particles have RBEs in the range of values reported for 14.7 MeV neutrons.

Animals↗

Molecular and cellular radiobiology of heavy ions.

Quantitative studies at the BEVALAC have demonstrated some of the physical and radiobiological factors that promise to make accelerated heavy ions important for the therapy of cancer. The measured physical dose-biological effect relationships allow the safe and effective delivery of therapeutic schedules of heavy ions. Among the charged particle beams available, carbon, neon and helium ions in the "extended Bragg peak mode" have optimal physical and biological effectiveness for delivery of therapy to deep seated tumors. The depth-dose profiles of these beams protect intervening and adjacent tissues as well as tissues beyond the range of the particles. For the treatment of hypoxic tumors, silicon and argon beams are being considered because they significantly depress the radiobiological oxygen effect in the region of the extended Bragg ionization peak. The depth-effectiveness of the argon beam is somewhat limited, however, because of primary particle fragmentation. Silicon beams have a depth-dose profile which is intermediate between that of neon and argon, and are candidates to become the particle of choice for maximizing high LET particle effects. Heavy accelerated ions depress enzymatic repair mechanisms, decrease variations of radiosensitivity during the cell division cycle, cause greater than expected delays in cell division, and decrease the protective effects of neighboring cells in organized systems. Near the Bragg peak, enhancement of heavy particle effects are observed in split dose schedules. Late and carcinogenic effects are being studied. With the newly developed Repair-Misrepair theory we can quantitatively model most observations.

Animals↗

Treatment of cancer with heavy charged particles.

A clinical radiotherapeutic trial using heavy charged particles in the treatment of human cancers has accrued over 400 patients since 1975, 378 of whom were treated with particles and 28 with low LET photons as control patients. Heavy charged particle radiotherapy offers the potential advantages of improved dose localization and/or enhanced biologic effect, depending on particle selected for treatment. Target sites have included selected head and neck tumors, ocular melanomata, malignant gliomata of the brain, carcinoma of the esophagus, carcinoma of the stomach, carcinoma of the pancreas, selected juxtaspinal tumors and other locally advanced, unresectable tumors. A Phase III prospective clinical trial has been started in carcinoma of the pancreas using helium ions. Phase I-II studies are underway with heavier particles such as carbon, neon and argon ions in order to prepare for prospective Phase III trials. Silicon ions are also under consideration for clinical trial. These studies are supported by the United States Department of Energy and National Institutes of Health.

Adult↗

Current status of clinical particle radiotherapy at Lawrence Berkeley Laboratory.

Clinical experience with charged particle irradiation of human cancers has been underway at the University of California Lawrence Berkeley Laboratory. Over 150 patients have been irradiated with heavy charged particle beams including helium, carbon, neon, and argon ions. Pilot studies have included such tumor sites as glioma of the brain, carcinoma of the esophagus, carcinoma of the pancreas, carcinoma of the stomach, ocular melanoma, and carcinoma of the uterine cervix. Prospective studies are planned to investigate the improved dose localization potential (helium) and the enhanced biologic and physical dose potential (carbon, neon) in a controlled trial against the best available megavoltage irradiation techniques.

Argon↗

Regulation of red blood cell production by erythropoietin: normal mouse marrow in vitro.

The response of immediate erythroid precursors to timed exposures of erythropoietin (Ep) were investigated by examining the formation of murine erythroid colonies in vitro. At various times after the initiation of normal marrow cultures with Ep, enough anti-erythropoietin serum was added to neutralize the actions of the hormone for the rest of the 48 h culture period in plasma clots. Results show that a significant number of erythroid precursors develop to a mature colony after very short Ep exposures (as little as 18 min), but they account for only about 13% of the total colonies generated when Ep is active for 48 h. Only if Ep is active for more than 6 h do additional colonies form, in direct proportion to the length of the Ep exposure. Maximum erythroid colony production requires prolonged exposure to Ep, and the longer Ep is active, the larger the percentage of erythroid colonies that reach 17 cells or more. The mechanism(s) behind these two effects appear intimately connected. These results suggest the existence of two populations of Ep-responsive cells in the immediate erythroid precursor compartment of mice: (1) A CFUE pool, which is on the verge of commitment into the recognizable erythron, and requires very short Ep exposures for this entry; and (2) a "pre-CFUE" stage which feeds into the CFUE pool in the presence of Ep, and which produces colonies only after longer Ep exposures. It is proposed that the pre-CFUE response to Ep involves 1-2 self-replications before entering the CFUE population.

Animals↗

Erythroid colony production in vitro as a function of exposure time to erythropoietin.

The effects of timed exposure to erythropoietin of murine bone marrow cells has been studied in in vitro plasma clot cultures. Erythropoietin was added at the start of the incubation period, and at various times after initiation of the culture an anti-erythropoietin serum was added in an amount adequate to neutralize the erythropoietin. Culture methods were used which allow the transformation of the immediate progenitor stem cell of the recognized erythron, the CFU-E. The incorporation of 59Fe was used as an identity marker for hemoglobin synthesis which allowed the classification of colonies as erythroid in autoradiographs. Brief exposure to the hormone for one to two hours produced activation of about 20% of the control (continuous exposure for the 48 h of culture) value. More protracted exposure to erythropoietin caused the conversion of what appears to be a second population of CFU-E, but even 24 h of exposure was not adequate to cause the maximum activation of CFU-E seen in the control cultures.

Animals↗