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J W Hopewell

Publications and source records attributed to J W Hopewell.

At least 37 records · Page 2Linked to original sources

Boron neutron capture therapy of the rat 9L gliosarcoma: evaluation of the effects of shark cartilage.

A number of anti-angiogenic substances are now under evaluation, both experimentally and clinically, as potential agents for the treatment of cancer. It has recently been demonstrated that anti-angiogenic agents can increase the therapeutic potential of photon irradiation in a range of tumour models. In the present communication a preliminary assessment is made of the effects of shark cartilage on the response of the rat 9L gliosarcoma to boron neutron capture therapy (BNCT). Shark cartilage was administered orally as an aqueous suspension at a daily dose of approximately 2000 mg kg-1 body weight. The mean survival time of rats receiving no treatment was 20.7 +/- 0.5 days post intracranial tumour implantation. Administration of shark cartilage alone extended the survival time. Two of the rats treated with shark cartilage were healthy and fully active at the end of the evaluation period (43 days post implantation). At autopsy the brain tumours of these animals were a factor of approximately 4 smaller than controls. In a repeat study with shark cartilage alone the survival time was extended by approximately 30%. After boronophenylalanine-mediated BNCT, with or without shark cartilage, the survival time of rats that eventually became moribund was increased by a factor of approximately 2 relative to controls. In both treatment groups approximately 20% of rats were healthy at 1 year after BNCT. There was no evidence of residual tumour at post-mortem. It was concluded that shark cartilage, when given alone, significantly increased the survival time of tumour-bearing rats, presumably owing to an anti-angiogenic effect. However, the survival data suggested that boronophenylalanine-mediated BNCT did not appear to be enhanced by the administration of shark cartilage.

Angiogenesis Inhibitors↗

Effects of Lipochromin and Levosinum in the modulation of radiation-induced injury to pig skin.

Pig skin was used as a model to study the effectiveness of two topically applied creams, Lipochromin and Levosinum, in modifying the development of both early and late radiation damage to pig skin. Irradiated skin sites that received daily topical application of Levosinum or Lipochromin after exposure were compared with sites on the contralateral flank of the same animal that received irradiation only. Irradiation was with graded doses of 90Sr/90Y beta-rays. Incidence of moist desquamation (acute) and ischaemic dermal necrosis (late) were used as end-points. The latency period for the development of moist desquamation and its healing time was also assessed. The latency period for the development of moist desquamation in this model ranged from 4.00-6.75 weeks. There was no significant difference between the cream treatment and control sites. Application of Levosinum shortened the healing time of moist desquamation at each dose level by 5-10 days. In three out of four dose levels used, this shortening of the healing time was statistically significant (p < 0.03). Treatment with these topical applications also reduced the incidence of late dermal necrosis and increased the ED50 values for the incidence of dermal necrosis. This increase in ED50 values was equivalent to a dose modification factor of 1.11-1.13.

Administration, Cutaneous↗

Time- and dose-related changes in the thickness of skin in the pig after irradiation with single doses of thulium-170 beta particles.

Time-related changes in skin thickness have been evaluated in the pig using a noninvasive ultrasound technique after exposure to a range of single doses of 0.97 MeV beta particles from (170)Tm plaques. The reduction in relative skin thickness developed in two phases; the separation into two phases was statistically justified only after 120 Gy (P = 0.04). The first phase was between 12 weeks and 24 weeks after irradiation. No further changes were seen until 48-60 weeks after irradiation, when a second phase of skin thinning was observed. No further changes in relative skin thickness were seen in the follow-up period of 104 weeks. The timing of these phases of relative skin thinning was totally independent of the radiation dose; however, the severity of each phase of radiation-induced skin thinning was related to the dose. The pattern of changes was similar to that reported previously after irradiation with 2.27 MeV beta particles from (90)Sr/(90)Y, but the degree of dermal thinning was less for a similar skin surface dose. From a comparison of the depth-dose distribution of the beta particles from the two radionuclides, it was concluded that the target cell population responsible for both the first and second phase of skin thinning in pig skin after irradiation may be located at approximately 800 microm depth. This corresponds to an area in the reticular dermis in pig skin and may be the appropriate site at which to measure the average dose to the dermal tissue.

Animals↗

Quantitative assessment of protein content in irradiated human skin.

PURPOSE: Radiation-induced fibrosis is a common late reaction of radiation therapy. Due to a lack of feasible noninvasive techniques to assess this reaction, the long-term development of radiation fibrosis is not well described. In order to develop quantitative means for the purpose, subcutaneous fibrosis of breast cancer patients after postmastectomy radiotherapy was evaluated by clinical scoring and a new technique based on dielectric properties of the skin. METHODS AND MATERIALS: Dielectric properties of biological tissues at radiofrequencies are principally determined by tissue water content. The major skin components are proteins, proteoglycans, and water either free or bound to the surface of proteins and proteoglycans. Since the MR studies have shown that bound water is tightly attached onto the surface of collagen, a dielectric measurement sensitive to bound water could be related to the protein content. Therefore, the dielectric constant of human skin was measured in vivo with an open-ended coaxial probe at electromagnetic (EM) frequencies in the range of delta-dispersion. Since the in vitro experiments with protein-water solutions have indicated that the slope of the dielectric constant vs. the EM frequency is a measure of the protein concentration, a respective slope was determined with irradiated skin of 14 breast cancer patients 2 years after postmastectomy radiotherapy at 63, 100, 300, and 500 MHz. Irradiated skin sites were clinically scored for subcutaneous fibrosis using a scale: none, slight, moderate, or severe fibrosis. RESULTS: A statistically significant correlation was found between the slope and the clinical score of subcutaneous fibrosis at 63, 100, and 300 MHz but not at 500 MHz. The correlation was best at 100 and 300 MHz. CONCLUSIONS: Considerable changes in the dielectric constant of the irradiated skin were found. The correlation between the dielectric constant and clinical score suggests that this novel technique is a potential tool for the follow-up and quantitative assessment of radiation-induced subcutaneous fibrosis.

Adult↗

How valid is the assumption of equal effect per fraction?

BACKGROUND AND PURPOSE: The validity of the assumption of equal biological effect with dose per fraction in fractionated radiotherapy has been examined for the acute skin reaction in a rat foot model using a variable number of 2-Gy daily fractions followed by graded top-up doses. MATERIAL AND METHODS: Mature female rats were used. Both hind feet of each rat were irradiated with a range of fractionated and top-up doses of 60Co gamma-rays. The dose-related incidence of moist desquamation was used as an end-point. Quantal data for the incidence of moist desquamation were analysed using probit analysis and ED50 (+/-SE) values were obtained. The results were also compared with predicted values obtained from the application LQ-model. RESULTS: After a single 2-Gy fraction followed by top-up doses 24 h later, the dose effect curve for the top-up doses used was shifted to lower doses as expected and the ED50 for moist desquamation of 19.78 +/- 0.13 Gy was 1.16 Gy less than the ED50 of 20.94 +/- 0.15 Gy for large single dose exposure alone. This implied that only approximately 58% of the initial 2-Gy fraction was effective, and the rest was repaired within a 24-h interval between the 2 Gy and top-up doses. However, after two or three 2-Gy daily fractions the dose effect curves for the subsequent top-up doses moved to the higher doses again and the ED50 for top-up dose increased to 20.33 +/- 0.21 and 20.75 +/- 0.11 Gy, respectively. A further increase in the number of 2-Gy daily fractions shifted the dose effect curves for the top-up doses to lower doses and ED50 values for the top-up doses decreased progressively. CONCLUSIONS: The findings were not in keeping with values predicted based on the assumption of equal effect per fraction and could not be explained by the use of a single alpha/beta ratio in the LQ-model.

Animals↗

A morphometric analysis of glomerular and tubular alterations following fast-neutron irradiation of the pig and monkey kidney.

PURPOSE: The morphologic responses of the pig and monkey kidney to fractionated fast-neutron irradiation were assessed. METHODS AND MATERIALS: The right kidney of approximately 14-week-old female Large White pigs was irradiated with 6.6-12.2 Gy of fast neutrons (42 MeVd-->Be) given as 12 fractions over 18 days; the left kidney served as the contralateral unirradiated kidney. Both kidneys were removed at necropsy 2 years postirradiation. In addition, the remaining hypertrophied kidney of four unilaterally nephrectomized adult rhesus monkeys was irradiated with a total dose of 11.0 Gy fast neutrons (45 MeVp-->Be) given in an identical fractionation regimen to that used in the pig studies. These kidneys were removed when the animals exhibited renal failure, between 32-94 weeks postirradiation. Glomeruli were assessed for the presence of pathologic features, including intercapillary eosinophilic material (ICE), ectatic capillaries, thrombi, hemorrhage, and sclerosis. The relative proportion of renal cortex occupied by glomeruli, interstitium, normal, or abnormal tubules was determined using a Chalkley point grid. RESULTS: The incidence of normal glomeruli, ectatic capillaries, thrombosis, and periglomerular fibrosis were significantly different in the irradiated pig kidneys compared with the unirradiated contralateral kidneys (p < or = 0.02). Linear regression analysis demonstrated a significant dose relationship in terms of normal glomeruli, ectatic capillaries, and ICE (r > or = 0.64; p < or = 0.04). Irradiation was also associated with a significant (p < 0.0001) decrease and increase in the volume of renal cortex occupied by normal and abnormal tubules, respectively. Similar morphometric changes were noted in the irradiated monkey kidneys. CONCLUSIONS: The morphologic changes seen in the pig and monkey kidney after fractionated irradiation with fast neutrons are similar to those previously noted after single-dose or fractionated-photon irradiation. These findings support the hypothesis that the development of radiation nephropathy in these various models involves common pathophysiological mechanisms.

Animals↗

Late behavioural and neuropathological effects of local brain irradiation in the rat.

The delayed consequences of radiation damage on learning and memory in rats were assessed over a period of 44 weeks, commencing 26 weeks after local irradiation of the brain with single doses of X-rays. Doses were set at levels known to produce vascular changes alone (20 Gy) or vascular changes followed by necrosis (25 Gy). Following T-maze training, 29 weeks after irradiation, irradiated and sham control groups performed equally well on the forced choice alternation task. When tested 35 weeks after irradiation, treated rats achieved a much lower percentage of correct choices than controls in T-maze alternation, with no difference between the two irradiated groups. At 38-40 weeks after irradiation, rats receiving both doses showed marked deficits in water maze place learning compared with age-matched controls; performance was more adversely affected by the higher dose. The extent of impairment was equivalent in the two groups of rats irradiated with 25 Gy, those trained or not previously trained in the T-maze, suggesting that water maze acquisition deficits were not influenced by prior experience in a different spatial task. In contrast to water maze acquisition, rats irradiated with 20 Gy showed no deficits in working memory assessed in the water maze 44 weeks after irradiation, whereas rats receiving 25 Gy showed substantial impairment. Rats receiving 25 Gy irradiation showed marked necrosis of the fimbria and degeneration of the corpus callosum, damage to the callosum occurring in animals examined histologically 46 weeks after irradiation, but in only a third of the animals examined at 41 weeks. However, there was no evidence of white matter necrosis in rats irradiated with 20 Gy, examined 46 weeks after irradiation. These findings demonstrated that local cranial irradiation with single doses of 20 and 25 Gy of X-rays produced delayed impairment of spatial learning and working memory in the rat. The extent of these deficits appears to be task- and dose-related, since rats treated with 25 Gy showed marked impairments in all measures, whereas rats treated with the lower dose showed less impairment in water maze learning and no deficits water maze working memory, despite significant disruption of working memory in the T-maze. The findings further suggest that although high dose irradiation-induced white matter necrosis is associated with substantial impairment, cognitive deficits may also be detected after a lower dose, not associated with the development of necrosis.

Animals↗

Repair, repopulation and cell cycle redistribution in rat foot skin.

The influence of the phenomena of the repair of sublethal damage, repopulation and the role of the reassortment of surviving clonogenic target cells within the cell cycle have been examined in the foot skin of rats using a series of split dose experiments. The dose-related incidence of moist desquamation was used as an end-point. Initially the iso-effect dose for moist desquamation (ED50) increased with an increasing time interval (1-22 h) between two equal fractions. This effect was attributed to the well established phenomenon of the repair of sublethal damage. This appeared to be maximal with a 22 h gap between fractions. A further increase in the time interval, from 2-7 days, between two equal fractions resulted in a decrease in the ED50 value for moist desquamation. The phenomenon is most likely to be explained by a shortening of the cell cycle time in surviving epithelial target cells as repopulation first initiated. With intervals between two fractions of greater than 10 days the ED50 for moist desquamation again increased. This is likely to represent an increase in the number of epidermal target cells (repopulation). Further evidence for the effect of a reassortment of cells in the cell cycle has come from another study in which a half-tolerance priming dose of 16.8 Gy was followed by three daily fractions starting 48 or 125 h after the priming dose. The ED50 for moist desquamation based on the total fractionated dose (three fractions) was significantly lower (P < 0.05) after the longer time interval, i.e. fractions given on days 5, 6 and 7 after the primary dose. These findings were supported by the results of a cell proliferation kinetic study and jointly question the validity of a frequently made assumption of equal biological effect per fraction in a prolonged fractionated irradiation schedule.

Animals↗

Boron neutron capture therapy: re-irradiation response of the rat spinal cord.

PURPOSE: To evaluate the retreatment response of the CNS to BNC irradiation using a rat spinal cord model. MATERIALS AND METHODS: Fischer 344 rats were irradiated with single doses of 6 MeV X-rays which were 22, 40 or 80% of a total effect (TE). An additional group of rats was irradiated with a single exposure of thermal neutrons in the presence of the neutron capture agent boronophenylalanine (BPA) to a dose that represented 82% of the TE. After an interval of 26 weeks, animals were re-irradiated using various single doses of thermal neutrons in combination with BPA. RESULTS: The re-irradiation ED50 doses represented 77, 80 or 50% of the TE after an initial X-ray dose of 22, 40 or 80% of the TE, respectively. The re-irradiation ED50 dose was 55% of the TE after an initial BNC irradiation dose representing 82% of the TE. CONCLUSION: The level of the initial radiation damage had a direct bearing on the re-irradiation response. Recovery following initial treatment with BNC irradiation was similar to that after initial irradiation with X-rays.

Animals↗

Stenosis of the tubular neck: a possible mechanism for progressive renal failure.

Fibrosis in chronic renal failure is closely associated with declining function. Its role in affecting function is less well defined. The radiation model of chronic renal failure was used to examine the tissue distribution of fibrosis and scarring and its role in influencing the loss of function in chronic renal disease. A striking and progressive pattern of fibrosis and narrowing of the glomerulotubular neck was found in irradiated pig kidneys. These narrowed necks increased in prevalence with time after irradiation. At 20 weeks after irradiation, the average neck diameter reduction was 60%, as compared with nonirradiated controls, a percentage that is consistent with a reduction in flow and pressure at this critical point of the nephron. Glomerulotubular neck narrowing may thus directly reduce the glomerular filtration rate of an individual nephron. Fibrotic neck stenoses may be a factor in progressive chronic renal failure.

Animals↗

Central nervous system tolerance to boron neutron capture therapy with p-boronophenylalanine.

A rat spinal cord model was used to evaluate the effects of boron neutron capture irradiation on the central nervous system (CNS), using a range of doses of the boron delivery agent p-boronophenylalanine (BPA). Three doses of BPA 700, 1000 and 1600 mg kg(-1) were used to establish the biodistribution of boron-10 (10B) in blood, spinal cord and brain over a 3-h period after intraperitoneal (i.p.) administration. At the lowest dose of BPA used, blood 10B levels remained relatively stable over the 3-h sampling period. With the two higher doses of BPA, blood 10B concentrations were greatest at 1 h after BPA administration, and thereafter exhibited a biphasic clearance profile. The largest decline in blood 10B levels occurred between 1 and 2 h after i.p. injection and was most pronounced (approximately 45%) in the highest BPA dose group. Considered overall, 10B concentrations were marginally lower in the spinal cord than in the brain. Levels of 10B in both of these organs showed a slow but progressive increase with time after administration of BPA. The 10B concentration ratio for blood relative to CNS tissue increased with BPA dosage and reached a peak value of approximately 10:1 in the highest BPA dose group, at 1 h after i.p. injection. However, at 3 h after injection the 10B concentration ratios had decreased to approximately 3:1 in all of the BPA dose groups. After irradiation with thermal neutrons in combination with BPA at blood 10B concentrations of approximately 42 and approximately 93 microg g(-1), myelopathy developed after latent intervals of 20.0 +/- 0.6 and 20.0 +/- 1.2 weeks respectively. ED50 values (+/- s.e.) for the incidence of myelopathy were calculated from probit-fitted curves, and were 17.5 +/- 0.7 and 25.0 +/- 0.6 Gy after irradiation with thermal neutrons at blood 10B levels of approximately 42 and approximately 93 microg g(-1) respectively. The compound biological effectiveness (CBE) factor values, estimated from these data, were 0.67 +/- 0.23 and 0.48 +/- 0.18 respectively. This compared with a previous estimate of 0.88 +/- 0.14 at a blood 10B concentration of approximately 19 microg g(-1). It was concluded that the value of the CBE factor was not influenced by the level of 10B in the blood, but by the blood:CNS 10B concentration ratio. In effect, the CBE factor decreases as the concentration ratio increases. Simulations using boron neutron capture therapy (BNCT) treatment planning software indicate a significant therapeutic advantage could be obtained in moving to higher BPA doses than those in current clinical use.

Animals↗

Response of the central nervous system to fractionated boron neutron capture irradiation: studies with borocaptate sodium.

The response of the central nervous system (CNS) to fractionated doses of boron neutron capture (BNC) irradiation was assessed using a rat spinal cord model. The thermal neutron beam at the Brookhaven Medical Research Reactor (BMRR) was used for the spinal cord irradiations, with borocaptate sodium (BSH) as the neutron capture agent. Irradiations were given as a single dose or as two or four equal fractions. The ED50 for radiation-induced myeloparesis, as indicated by limb paralysis within 7 months, after a single exposure to thermal neutrons in the presence of BSH (blood boron-10 content approximately 70 micrograms/g) was 27.2 +/- 0.9 Gy. This was expressed as the total physical dose to the blood. Dividing the radiation dose into two consecutive daily fractions or four fractions given over 1 week, resulted in ED50 = 32.0 +/- 1.4 and 31.5 +/- 0.4 Gy respectively. Although there was no significant dose sparing in moving from two to four fractions, there was a dose increment of approximately 17% as compared with single-dose irradiation. The variation in the relative biological effectiveness of the thermal neutron beam, with dose per fraction, was established using data from a previous study with single and fractionated doses of thermal neutrons in the absence of a neutron capture agent. This varied from 1.40 to 3.74 for thermal neutron dose per fraction in the range 13.6-1.5 Gy. Previously published CBE factors for both BSH and BPA have been recalculated in the present report to take into account the change in the RBE of the thermal neutron beam with dose. In all cases the recalculated CBE factors were lower than those obtained previously. Values for this parameter increased with fraction number. In the case of BSH, the CBE factor increased from 0.36 +/- 0.03 after a single-dose to 0.51 +/- 0.06 after four fractions.

Animals↗

The volume effect in radiotherapy--its biological significance.

Volume-related effects are an important consideration in clinical radiotherapy. The early rationale for the need to consider treatment volume has become clouded by the lack of clarity and a misinterpretation of some early clinical findings. In particular, there is a need to separate our understanding of biologically iso-effective radiation responses from the clinical concept of normal tissue tolerance, as they relate to changes in treatment volume. Animal data, including those for large animals, are reviewed. These animal studies indicate the need for caution in extrapolating retrospective clinical data to new treatment situations, since the conclusions reached may have been dictated by dogma and not by careful consideration of different factors that may have been involved. These include anatomical and physiological factors, and variations in the dose distribution pattern to a specific organ or tissue. These biological factors could limit the general applicability of simple approaches based on mathematical models to the volume effect relationship in radiotherapy.

Animals↗

Boron neutron capture irradiation of the rat spinal cord: effects of variable doses of borocaptate sodium.

The Fischer 344 rat spinal cord model has been used to evaluate the response of the central nervous system to boron neutron capture irradiation with variable doses of the neutron capture agent, borocaptate sodium (BSH). Three doses of BSH, 190, 140 and 80 mg/kg body weight, administered by i.p. injection, were used to establish the time course of 10B accumulation in and removal from the blood. After administration of the two lower doses of BSH, blood 10B levels peaked at 0.5 h after injection, with no significant (P > 0.1) change at 1 h after injection. Beyond this time point, levels of 10B in the blood began to decrease after a dose of 80 mg/kg BSH, but remained constant until 3 h after administration after the two higher doses of BSH. Myelopathy developed after latent intervals of 20.4 +/- 0.1, 20.8 +/- 1.4, 15.0 +/- 0.8, 15.4 +/- 0.4 and 15.6 +/- 0.4 weeks, following irradiation with thermal neutrons in combination with BSH at doses of 20, 40, 80, 140 and 190 mg/kg body weight, respectively. The radiation-induced lesion in the spinal cord was white matter necrosis. ED50 values for myelopathy were calculated from probit-fitted dose-effect curves. Expressed as total physical absorbed doses, these values were 20.7 +/- 1.9, 24.9 +/- 1.2, 27.2 +/- 0.9, 28.4 +/- 0.6 and 32.4 +/- 1.9 Gy after irradiation with thermal neutrons in the presence of 20, 40, 80, 140 and 190 mg/kg body weight of BSH, respectively. The compound biological effectiveness (CBE) factor values, estimated from this data, were in the range 0.49-0.55. There was no significant (P > 0.1) variation in the CBE factor for BSH as a function of increasing 10B concentration in the blood. It was concluded that there was no significant synergistic interaction between the low and high linear energy transfer (LET) components of the boron neutron capture (BNC) radiation field.

Animals↗

Repair kinetics in pig epidermis: an analysis based on two separate rates of repair.

Pig skin was irradiated using 90Sr/90Y plaques and the dose-related incidence of induced moist desquamation was determined. The repair of radiation-induced sublethal damage (SLD) was studied by fitting these response data to the generalized LQ equation for incomplete repair using quasilikelihood methods with binomial statistics, and either a Poisson or logistic link to relate the probability of response to the covariates. A Poisson response analysis based on the assumption that SLD was governed by two repair processes gave estimated repair half-times of 0.20 [(95% confidence limits) 0.12, 0.34] and 6.6 [4.3, 10.0] h. The estimates of the short and long repair half-times were significantly different, although there was no significant difference between the results using the Poisson and logistic modes of analyses. The partition coefficient for the longer repair process was 0.5 [0.34, 0.71] indicating that about 33% of SLD-derived lethal damage is associated with the longer repair process in the case of 'complete repair' protocols. However, this proportionation is, in general, protocol dependent for incomplete repair protocols. A chi2 test on the residual deviance showed that the assumption of two repair processes for SLD gave a superior fit to the data than a single repair process at a significance level >99%. The radiation dose to the assumed target cell population depends upon their depth from the skin surface, due to the relatively short range of the electron emission from the 90Sr/90Y plaques. However, further modelling analyses have shown that the estimated repair half-times were independent of the assumed target cell distribution in the skin. This is in contrast with the alpha/beta ratio, where different (clinically significant) estimates can be obtained depending upon the assumed target cell distribution. If the target cells were at 16 micrometer depth from the surface of the skin, the estimated value for the alpha/beta ratio using the biphasic repair model would be 4.6[3.6, 5.6] Gy(Poisson analysis). However, the estimates decrease with the assumed depth (distribution) of the target cells.

Animals↗