Single dose irradiation response of pig skin: a comparison of brachytherapy using a single, high dose rate iridium-192 stepping source with 200 kV X-rays

An experimental brachytherapy model has been developed to study acute and late normal tissue reactions as a tool to examine the effects of clinically relevant multifractionation schedules. Pig skin was used as a model since its morphology, structure, cell kinetics and radiation-induced responses are similar to human skin. Brachytherapy was performed using a microSelectron high dose rate (HDR) afterloading machine with a single stepping source and a custom-made template. In this study the acute epidermal reactions of erythema and moist desquamation and the late dermal reactions of dusky mauve erythema and necrosis were evaluated after single doses of irradiation over a follow-up period of 16 weeks. The major aims of this work were: (a) to compare the effects of iridium-192 (192Ir) irradiation with effects after X-irradiation; (b) to compare the skin reactions in Yorkshire and Large White pigs; and (c) to standardize the methodology. For 192Ir irradiation with 100% isodose at the skin surface, the 95% isodose was estimated at the basal membrane, while the 80% isodose covered the dermal fat layers. After HDR 192Ir irradiation of Yorkshire pig skin the ED50 values (95% isodose) for moderate/severe erythema and moist desquamation were 24.8 Gy and 31.9 Gy, respectively. The associated mean latent period (+/- SD) was 39 +/- 7 days for both skin reactions. Late skin responses of dusky mauve erythema and dermal necrosis were characterized by ED50 values (80% isodose) of 16.3 Gy and 19.5 Gy, with latent periods of 58 +/- 7 days and 76 +/- 12 days, respectively. After X-irradiation, the incidence of the various skin reactions and their latent periods were similar. Acute and late reactions were well separated in time. The occurrence of skin reactions and the incidence of effects were comparable in Yorkshire and Large White pigs for both X-irradiation and HDR 192Ir brachytherapy. This pig skin model is feasible for future studies on clinically relevant multifractionation schedules in a brachytherapy setting.     

Residual radiation-induced injury in dermal tissue: implications for retreatment

The evidence for residual radiation-induced injury has been investigated in the dermal vascular/connective tissue of pig skin at intervals of 17-52 weeks after irradiation. The primary irradiation was a single dose of 18 Gy, which represents the upper limit of "tolerance" to X irradiation of pig dermal tissue. Re-irradiation was with graded single doses of X rays in order to establish dose-effect relationships for the incidence of late ischaemic dermal necrosis of the skin; dose-effect curves obtained for previously irradiated skin were compared with those obtained using previously unirradiated skin in the same group of animals. At intervals of 17, 35 and 52 weeks after the primary treatment the resulting ED50 values for dermal necrosis were not significantly different from those obtained for previously unirradiated skin. This suggests little or no effective residual injury at these time intervals after a primary full "tolerance" dose. This conclusion was supported by the findings for the latency time for the development of dermal necrosis, which were similar in re-irradiated and previously unirradiated skin. Epithelial desquamation was not induced by the doses used in these studies, either after the primary treatment or after re-irradiation; however, the early erythema reactions seen in re-irradiated skin were markedly reduced, particularly when this was carried out after 35 and 52 weeks, when compared with skin that had not previously been irradiated. This suggests that the early erythema reaction may be a particularly poor predictor of late effects after the re-irradiation of the skin. Although the present results suggest that dermal and subcutaneous tissues may safely be retreated with a full tolerance dose at relatively early times after an initial radical treatment, caution is recommended in extrapolating these results to other late-responding normal tissues. In other tissues some persistent injury may be present even at very long time intervals after the primary treatment.     

Manipulation of the radiosensitivity of pig epidermis by changing the concentration of oxygen and halothane in the anaesthetic gas mixture

A gas mixture of halothane, oxygen and nitrous oxide has been used to anesthetize pigs for irradiation. The effects of various concentrations of halothane and oxygen on the radiosensitivity of the epidermis were examined after irradiation with single doses of beta-rays from strontium-90 plaques. The incidence of moist desquamation was used as an endpoint, and experiments were compared on the basis of the dose associated with a 50 per cent incidence of moist desquamation (ED50 +/- SE). For pigs inspiring an anaesthetic gas mixture of 2 per cent halothane, approximately 70 per cent oxygen and approximately 30 per cent nitrous oxide the ED50 for moist desquamation was 27.32 +/- 0.52 Gy. A similar ED50 value of 27.39 +/- 1.20 Gy was obtained when 4 per cent halothane was used in place of 2 per cent. When the pigs were breathing air (approximately 21 per cent oxygen) in place of oxygen and nitrous oxide the ED50 values were increased significantly to 31.25 +/- 0.94 Gy and 33.72 +/- 1.08 Gy for 2, and 4 per cent halothane, respectively. This change in the radiosensitivity of the epidermis was represented by dose modification factors of approximately 1.13 and approximately 1.23 for 2 and 4 per cent halothane, respectively. Irradiation with a high oxygen concentration in the inspired gas mixture did not result in any significant variation of the dose required to produce moist desquamation in 50 per cent of the fields irradiated for dorsal, lateral and ventral positioned skin fields on the flank. However, pigs breathing air and halothane during irradiation showed marked differences in the radiosensitivity of the various sites on the flank, with ED50 values for moist desquamation of approximately 37 Gy and 26-30 Gy for dorsal and ventral positioned fields, respectively. This marked difference in radiosensitivity suggests variations in the physiological compensation over the flank when pigs are breathing oxygen at low concentrations under anaesthesia.     

Evidence for humoral effects on the radiation response of rat foot skin.

The influence of perturbation of the physiologic state of the whole body on the outcome of radiation exposure has been examined in a rat foot model. Irradiation was carried out using 60Co gamma-rays. Moist desquamation was used as an endpoint. Rats were given a priming dose of 2 Gy, 4 Gy or 7 Gy to their whole body except their hind feet (partial body priming dose). After a variable time period both hind feet of these animals were irradiated with graded doses of 60Co gamma-rays. The incidence of moist desquamation in the irradiated feet of these animals was compared with the incidence of moist desquamation in animals that had not received the initial partial body priming dose. It was noticed that the incidence of moist desquamation in the rat foot skin of animals that received 7 Gy partial body priming dose 4 h prior to irradiation of their hind feet was significantly less than moist desquamation in control animals. The ED(50) value of 22.53+/-0.16 Gy for moist desquamation of the foot skin of control animals was significantly lower (p<0.01) than the value of 25.25+/-0.29 Gy obtained for animals that received a partial body priming dose of 7 Gy 4 h prior to irradiation of their hind feet. It was concluded that the response of rat foot skin to radiation was not purely the result of epidermal stem cell kill and that it can be modified by alterations in the overall physiological state of the animal's body brought about by a priming dose to the whole of the animal's body except the hind feet.     

Protection of pig epidermis against radiation-induced damage by the infusion of BW12C.

BW12C, which was developed as an agent for the treatment of sickle cell anaemia, increases the binding of oxygen to haemoglobin and hence reduces the availability of oxygen to tissues. Due to these changes in oxygen availability BW12C could act as a protector against radiation-induced injury to normal tissues. In this study the potential value of BW12C, as a radioprotector, was studied in the irradiated epidermis of the pig. The infusion of BW12C caused an instant left shift of the oxygen dissociation curve, an effect that lasted for approximately 1.5 h. This left shift in the oxygen dissociation curves increased with increasing dose of the drug. There appeared to be no long-term systemic effects produced by doses of 20-100 mg/kg of BW12C. In the first 90 min after the infusion of BW12C skin fields were irradiated with single doses of beta-rays from strontium-90 plaques. The incidence of moist desquamation was used as an endpoint for assessing the severity of the radiation response. With animals breathing approximately 70% oxygen in the anaesthetic gas mixture, the ED50 values for moist desquamation were 30-31 Gy after a dose of 30 and 50 mg/kg, and 37-38 Gy for 75 and 100 mg/kg doses of BW12C. These ED50 values were significantly higher than the value of 27.3 Gy for radiation alone. This indicated dose modification factors (DMF) with mean values of approximately 1.13 and approximately 1.40 for irradiation following the infusion of low (30-50 mg/kg) and high (75-100 mg/kg) doses of the drug, respectively. With the animals breathing air (approximately 21% of oxygen) in the 2% halothane anaesthesia gas mixture, irradiation in the presence of 30 and 50 mg/kg of BW12C resulted in ED50 values of approximately 39 Gy for moist desquamation, which was significantly higher than the value of 31.2 Gy for radiation alone. Surprisingly, a higher dose of 75 mg/kg of BW12C resulted in a lower ED50 value for moist desquamation of 34.38 Gy. Irradiation in the presence of a dose of 100 mg/kg of BW12C produced an ED50 value which was not significantly different from that for radiation alone. In the situation where animals were breathing air (approximately 21% oxygen) during irradiation a DMF of 1.14 was obtained for irradiation alone, when the results were compared with those for irradiation alone with approximately 70% oxygen in the anaesthetic gas mixture.(ABSTRACT TRUNCATED AT 400 WORDS)     

The relative biological effectiveness of fractionated doses of fast neutrons (42 MeVd----Be) for normal tissues in the pig. I. Effects on the epidermis and dermal vascular/connective tissues

The effects of fractionated doses of fast neutrons (42 MeVd----Be) on the early epithelial and later dermal response of pig skin have been assessed and compared with those after X irradiation. For the early epithelial reaction, i.e. moist desquamation, the relative biological effectiveness (RBE) of the neutron beam increased with the decreasing size of the X-ray dose/fraction. There was an experimentally observed upper RBE value of approximately 2.75 for X-ray doses/fraction of between 2 and 5 Gy. For the late reaction of ischaemic dermal necrosis the RBE was greater than 3.0 for X-ray doses/fraction of less than 3 Gy and, based on the assumptions made in the linearquadratic model of cell survival, an upper limiting RBE of 4.32 +/- 0.39 was calculated for infinitely small doses/fraction. These findings were compared with other radiobiological data and the conclusions drawn from the results of clinical trials. It was concluded that for the sparing of late effects in skin and subcutaneous tissues, relative to acute reactions, a relatively small number of fractions in a short overall treatment time may be optimal for fast neutron therapy.     

Protection of Pig Epidermis against Radiation-induced Damage by the Infusion of BW12C

Summary

BW12C, which was developed as an agent for the treatment of sickle cell anaemia, increases the binding of oxygen to haemoglobin and hence reduces the availability of oxygen to tissues. Due to these changes in oxygen availability BW12C could act as a protector against radiation-induced injury to normal tissues. In this study the potential value of BW12C, as a radioprotector, was studied in the irradiated epidermis of the pig. The infusion of BW12C caused an instant left shift of the oxygen dissociation curve, an effect that lasted for ～1·5 h. This left shift in the oxygen dissociation curves increased with increasing dose of the drug. There appeared to be no long-term systemic effects produced by doses of 20–100 mg/kg of BW12C. In the first 90 min after the infusion of BW12C skin fields were irradiated with single doses of β-rays from strontium-90 plaques. The incidence of moist desquamation was used as an endpoint for assessing the severity of the radiation response. With animals breathing ～70% oxygen in the anaesthetic gas mixture, the ED₅₀ values for moist desquamation were 30–31 Gy after a dose of 30 and 50 mg/kg, and 37–38 Gy for 75 and 100 mg/kg doses of BW12C. These ED₅₀ values were significantly higher than the value of 27·3 Gy for radiation alone. This indicated dose modification factors (DMF) with mean values of ～1·13 and ～1·40 for irradiation following the infusion of low (30–50 mg/kg) and high (75–100 mg/kg) doses of the drug, respectively. With the animals breathing air (～21% of oxygen) in the 2% halothane anaesthesia gas mixture, irradiation in the presence of 30 and 50 mg/kg of BW12C resulted in ED₅₀ values of ～39 Gy for moist desquamation, which was significantly higher than the value of 31·2 Gy for radiation alone. Surprisingly, a higher dose of 75 mg/kg of BW12C resulted in a lower ED₅₀ value for moist desquamation of 34·38 Gy. Irradiation in the presence of a dose of 100 mg/kg of BW12C produced an ED₅₀ value which was not significantly different from that for radiation alone. In the situation where animals were breathing air (～21% oxygen) during irradiation a DMF of 1·14 was obtained for irradiation alone, when the results were compared with those for irradiation alone with ～70% oxygen in the anaesthetic gas mixture. When this ‘air component’ is taken into account DMF values of ～1·3 were obtained for 30 and 50 mg/kg of BW12C, whereas for 75 and 100 mg/kg of BW12C this was reduced to 1·11 and 1·0, respectively. These modifications in the sensitivity of the epidermis for irradiation in the presence of various doses of BW12C were not uniform over the flank skin of the pig. For all doses of BW12C used, the skin fields positioned dorsally on the flank always showed a reduced radiosensitivy when compared with the ventrally positioned skin sites. This suggested a better physiological compensation for the effect produced by the drug in the ventral area of the flank skin. A similar variation in the radiosensitivity over the flank was noted for radiation alone when pigs were breathing air (～21% oxygen) in the anaesthetic gas mixture. Only when animals were breathing ～70% oxygen in the anaesthetic gas mixture was the radiosensitivity of the skin uniform over the whole flank.     

Determination of colony numbers in pig epidermis as an estimate for radiosensitivity. A rapid assay based on in vitro BrdU-labelling

A rapid assay has been developed for the quantitation of colonies arising from surviving clonogenic cells in pig epidermis after irradiation. The number of surviving clonogenic cells per unit area was related to the epidermal in vivo response of moist desquamation. After irradiation with single doses, ranging from 20 to 36 Gy, skin biopsies were taken and incubated in dispase for enzymatic separation of the epidermis and dermis. Full thickness epidermal sheets were labelled with bromodeoxyuridine (BrdU) in vitro. Proliferating cells were visualized using standard immunohistochemical procedures. Cell groups containing > or = 16 cells were counted as colonies. These colonies were first seen on day 14/15 after irradiation. The number of colonies per cm2, as a function of skin surface dose, yielded a cell survival curve with a D0 (+/- SE) of 3.87 +/- 0.57 Gy. The ED50 for the epidermal in vivo reaction of moist desquamation corresponded with a colony density of 2.7 colonies per cm2. After higher doses, abundant smaller colonies of 4-8 BrdU-positive cells were seen and these were more radioresistant, as represented by higher D0 values.     

鼻咽癌放疗后继发性皮肤晚期放射损伤

目的 通过分析皮肤早期放射反应对皮肤晚期放射反应的影响,探讨皮肤的继发性晚期放射损伤。方法 对门诊随访的放疗后生存5年以上的335例鼻咽癌患者进行调查研究,其中放疗时中位年龄41岁(12～67岁),240例伴颈部淋巴结转移。鼻咽原发灶首程放疗中位剂量为70Gy(55～86Gy),以面颈野为主野放疗71例,以耳前野为主野放疗264例。颈部根治性放疗中位剂量为64Gy(46～72Gy),预防照射中位剂量为55Gy(21～67Gy)。48例合并化疗。根据1995年SOMA标准评价皮肤晚期放射反应。结果 随访间隔中位时间为14年(5～38年)。63例无皮肤晚期反应,1、2、3、4级皮肤晚期反应发生率分别为43.9%(147例)、20.9%(70例)、13.7%(46例)、2.7%(9例)。44例放疗中出现湿性脱皮反应,其中1、2、3、4级皮肤晚期反应发生率分别为41%(18例)、23%(10例)、30%(13例)和5%(2例);无湿性脱皮患者的相应发生率分别为44.3%(129例)、20.6%(60例)、11.3%(33例)和2.4%(7例),两者差异有统计学意义(χ²=17.42,P=0.002)。分层分析结果显示初诊时是否伴颈部淋巴结转移、放疗野及颈部淋巴结放疗剂量均对皮肤晚期反应发生有关,而性别、年龄及是否联合使用化疗与皮肤晚期反应的发生无关。 结论 严重的皮肤早期放射反应可能增加皮肤晚期放射反应,可能存在继发性皮肤晚期放射损伤。     

The effect of evening primrose oil on the radiation response and blood flow of mouse normal and tumour tissue

PURPOSE: To investigate the effect of the oral administration of evening primrose oil on the radiation response and the blood flow of normal tissue and a tumour in BALB/c mice. METHODS AND MATERIALS: Aliquots of evening primrose oil were fed to BALB/c mice daily and the radiation response of the skin was assessed by the determination of ED50 values for the incidence of moist desquamation, using probit analysis. Tumour radiosensitivity was investigated by determining the growth delay caused by irradiation of a transplantable rhabdomyosarcoma. The 86RbCl uptake technique was used to determine the blood flow in normal foot and tumour tissue. The fatty-acid content of red blood cells, plasma and tumour tissue was measured using gas chromatography. RESULTS: Daily evening primrose oil dietary supplementation reduced the sensitivity of skin to radiation-induced moist desquamation and prevented the radiation-associated increase in blood flow that was observed in this tissue. No modification of tumour blood flow or of tumour sensitivity to radiation resulted from evening primrose oil supplementation of mice. Evening primrose oil supplementation resulted in changes in plasma levels of linoleic acid (LA), gamma-linolenic acid (GLA), dihomo-gamma-linolenic acid (DGLA) and arachidonic acid (AA). These changes were contingent on whether the mice had been irradiated or not. In red blood cells evening primrose oil supplementation increased the GLA level of unirradiated mice and the LA level at 20 days after irradiation. There were no changes in tumour fatty-acid levels as a result of evening primrose oil treatment. CONCLUSIONS: Daily evening primrose oil supplementation reduced the sensitivity of skin to radiation-induced moist desquamation but did not alter tumour sensitivity to radiation.     

The effect of Captopril on benign and malignant reactions in irradiated rat skin

The effect of the angiotensin converting enzyme inhibitor Captopril on the severity of radiation-induced epilation and moist desquamation and the incidence of skin tumours was determined for up to 52 weeks in male rats. The irradiation consisted of a range of single doses (0, 10, 20, 30 Gy) of 60Co gamma rays to a 3.5 cm2 right hemithorax port. Half of each radiation dose group consumed control powdered chow, and half consumed chow containing Captopril (50 mg/kg/day) continuously after irradiation. There were time- and radiation-dose-dependent increases in all three skin reactions. Rats exposed to 10 Gy exhibited a mild and transient epilation, but no moist desquamation or neoplasia in the radiation port. In animals exposed to 30 Gy, however, epilation began at 2 weeks after irradiation, reached a peak at approximately 7 weeks, then persisted essentially unchanged through 52 weeks. Captopril had no significant effect on the epilation reaction. Two waves of moist desquamation were observed after 30 Gy. The first appeared at 3 weeks after irradiation, reached a peak from 6-10 weeks, then subsided partially but significantly from 12-26 weeks. The second wave of moist desquamation began at 26-28 weeks, often was ulcerative, and occasionally was accompanied by the appearance of tumours in the irradiated volume. Captopril significantly (p less than 0.05) reduced the severity of both phases of the moist desquamation reaction after 30 Gy, and reduced the percentage of animals exhibiting the most severe desquamation score (involving 50% of the radiation port). Of particular interest was the observation that Captopril also reduced the incidence of tumours. Of the 14 tumours detected, all were malignant (fibrosarcomas, squamous cell carcinomas), and only three (p less than 0.05) occurred in rats receiving Captopril. Multiple tumours (three cases), tumours induced by 20 Gy (three cases), and tumours appearing before 6 months (one case) were observed only in rats consuming control diet, never in Captopril-treated animals. Animals which developed tumours in the second 6 months post-irradiation exhibited significantly more severe moist desquamation during the first 6 months than did the tumour-free members of their treatment group. Thus Captopril, known to ameliorate acute lung damage in irradiated rats, also reduces chronic benign and malignant skin reactions in the radiation treatment field.     

Correlation of the dose-response relationships for epidermal colony-forming units, skin reactions, and healing, in the X-irradiated mouse tail

The sensitivity of epidermal colony-forming units (CFU) in the mouse tail has been compared with the sensitivity of target units responsible for healing the epidermis (EHU). The value of D0 for epidermal CFU was 3.45 +/- 0.36 Gy, much higher than most earlier reports for CFU in dorsal epidermis. The reason for the high D0 is unknown, but it is considered unlikely to be due to marked hypoxia. The value of D0 for EHU was 2.78 +/- 0.51 Gy, which was deduced from the steepness of the dose-incidence curve for the healing of tails. A comparison of the two values of D0 indicates that the inactivation rate of CFU can account for the steepness of the dose-response curve for survival of the tissue. The dose which allowed 50% of tails to heal well corresponded to 3-4 colonies per cm2 of epidermis, to a median peak skin reaction of about 2 (moist desquamation) on an arbitrary scoring scale, and to a slightly lower median skin reaction of 1.7 when the reaction scores were averaged over the period 3 to 6 weeks after irradiation.     

A Handbook of Radioactivity Measurement Procedures

The long-term expression of TGF beta1 in mouse skin after localized irradiation with a beta-emitting source is reported. The skin of CBA/ca mice was exposed to 50Gy superficial beta radiation from an 11 mm strontium-90 source. Such a dose produced an acute moist desquamation reaction in 100% of the animals, which was macroscopically resolved within 30 days. The acute response was followed by progressive remodelling of dermal tissues as characterized by histological means. The expression of TGF beta1 was followed for 12 months after irradiation and showed three distinct waves of expression at the RNA level. Levels of expression initially rose to 230% above controls at 6h before returning to control levels around 24-48 h. Expression then rose again to 169 and 234% above controls at 14 and 28 days postirradiation respectively. Levels then declined to those of the controls by 2 months. A progressive increase in expression was then noted after 3 months, which peaked around 9 months and was resolved by 12 months. In a parallel study the skin of 144 CBA/ca mice was exposed to 50Gy superficial beta radiation from 2 4 cm Thulium-170 source and compared with a similar group of sham-irradiated controls. The irradiated group showed a cumulative tumour incidence of 54.3% compared with 0% incidence in the sham-irradiated group. Of the 45 radiation-induced tumours a representative sample of 16 (nine malignant fibrous histiocytomas; three fibrosarcomas; two fibromas; one squamous cell carcinoma; one rhabdomyosarcoma) were selected for further study. Semiquantitative PCR on all these tumours showed elevated levels of TGFbeta1 expression ranging from 1. 8 to 87-fold above the levels found in normal skin. This study is part of ongoing investigations into the long-term effects of single accidental exposures. The 50Gy dose used is comparable with the surface doses obtained by some of the victims of the Chernobyl accident.     

Porphyrin-mediated boron neutron capture therapy: evaluation of the reactions of skin and central nervous system

Purpose: Recently, various boronated porphyrins have been shown to preferentially target a variety of tumour types. Of the different porphyrins evaluated, copper tetra-phenyl-carboranyl porphyrin (CuTCPH) is a strong candidate for future preclinical evaluation. In the present study, the responses of two critical normal tissues, skin and central nervous system (CNS), to boron neutron capture (BNC) irradiation in the presence of this porphyrin were evaluated.

Materials and methods: Standard models for the skin and spinal cord of adult male Fischer 344 rats were used. CuTCPH was administered by intravenous infusion at a dose of 200 mg kg^{m 1} body weight, over 48 h. The thermal beam at the Brookhaven Medical Research Reactor was used for the BNC irradiations. The 20-mm diameter irradiation field, for both the skin and the spinal cord, was located on the mid-dorsal line of the neck. Dose-response data were fitted using probit analysis and the doses required to produce a 50% incidence rate of early and late skin changes or myeloparesis (ED 50 - SE) were calculated from these curves.

Results: Biodistribution studies indicated very low levels of boron (<3 µ;g g^{m 1}) in the blood 3 days after the administration of CuTCPH. This was the time point selected for radiation exposure in the radiobiological studies. Levels of boron in the CNS were also low (2.8 - 0.6 µ;g g^{m 1}) after 3 days. However, the concentration of boron in the skin was considerably higher at 22.7 - 2.6 µ;g g^{m 1}. Single radiation exposures were carried out using a thermal neutron beam. The impact of CuTCPH-mediated BNC irradiation on the normal skin and CNS at therapeutically effective exposure times was minimal. This was primarily due to the very low blood boron levels (from CuTCPH) at the time of irradiation. Analysis of the relevant dose-effect data gave compound biological effectiveness factors of about 1.8 for skin (moist desquamation) and about 4.4 for spinal cord (myeloparesis) for CuTCPH. These values were based on the BNC radiation doses to tissues calculated using the blood boron levels at the time of irradiation.

Conclusions: CuTCPH-mediated BNC irradiation will not cause significant damage to skin and CNS at clinically relevant radiation doses provided that blood boron levels are low at the time of radiation exposure.     

The influence of field size on the late tolerance of the rat spinal cord to single doses of X rays

Varying lengths of the cervical spinal cord of rats were irradiated with single doses of X rays. Dose-related changes in the latency for the development of paralysis, or for the presence of histological lesions in the spinal cord, indicated a dependency on the length of spine irradiated. The dose associated with a specified latency increased as the field size was reduced from 16 mm to 4 mm. A more precise indication of the importance of field size came from a determination of the ED50 values for rats developing paralysis in less than 30 weeks of irradiation or from those that showed neurological signs, or histological evidence, of irradiation damage, occurring after latent periods of greater than 30 weeks. These end-points were primarily related to white-matter necrosis and gross vascular damage respectively. For paralysis in greater than 30 weeks the ED50 increased markedly from 21.5 +/- 0.3 Gy for a 16 mm field to 50.98 +/- 2.28 Gy when a 4 mm length of cord was irradiated. For vascular lesions only a small change in ED50 value was found, from 20.0 +/- 0.5 Gy to 25.58 +/- 2.78 Gy for 16 mm and 4 mm fields respectively. At less than or equal to ED25 no evidence for a field-size effect was seen for this late lesion. These results were examined in the light of some old and some more recently analysed clinical data for radiation myelopathy. It is hoped that this will initiate other investigations in this important area of radiotherapy practice.     

Porphyrin-mediated boron neutron capture therapy: evaluation of the reactions of skin and central nervous system

PURPOSE: Recently, various boronated porphyrins have been shown to preferentially target a variety of tumour types. Of the different porphyrins evaluated, copper tetra-phenyl-carboranyl porphyrin (CuTCPH) is a strong candidate for future preclinical evaluation. In the present study, the responses of two critical normal tissues, skin and central nervous system (CNS), to boron neutron capture (BNC) irradiation in the presence of this porphyrin were evaluated. MATERIALS AND METHODS: Standard models for the skin and spinal cord of adult male Fischer 344 rats were used. CuTCPH was administered by intravenous infusion at a dose of 200 mg x kg(-1) body weight, over 48 h. The thermal beam at the Brookhaven Medical Research Reactor was used for the BNC irradiations. The 20-mm diameter irradiation field, for both the skin and the spinal cord, was located on the mid-dorsal line of the neck. Dose-response data were fitted using probit analysis and the doses required to produce a 50% incidence rate of early and late skin changes or myeloparesis (ED(50) +/- SE) were calculated from these curves. RESULTS: Biodistribution studies indicated very low levels of boron (<3 microg x g(-1)) in the blood 3 days after the administration of CuTCPH. This was the time point selected for radiation exposure in the radiobiological studies. Levels of boron in the CNS were also low (2.8 +/- 0.6 microg x g(-1)) after 3 days. However, the concentration of boron in the skin was considerably higher at 22.7 +/- 2.6 microg x g(-1). Single radiation exposures were carried out using a thermal neutron beam. The impact of CuTCPH-mediated BNC irradiation on the normal skin and CNS at therapeutically effective exposure times was minimal. This was primarily due to the very low blood boron levels (from CuTCPH) at the time of irradiation. Analysis of the relevant dose-effect data gave compound biological effectiveness factors of about 1.8 for skin (moist desquamation) and about 4.4 for spinal cord (myeloparesis) for CuTCPH. These values were based on the BNC radiation doses to tissues calculated using the blood boron levels at the time of irradiation. CONCLUSIONS: CuTCPH-mediated BNC irradiation will not cause significant damage to skin and CNS at clinically relevant radiation doses provided that blood boron levels are low at the time of radiation exposure.     

The effects of single doses of X rays on the mechanical properties of pig skin in vivo

Changes in the mechanical properties of pig skin have been studied in vivo, using a dermal extensometer, after irradiation with a single dose of 18 Gy of X rays. There was no significant change in the stiffness of irradiated skin, when compared with unirradiated skin, until 9 weeks after irradiation when the irradiated skin was significantly stiffer. This effect was also found at 12 and 15 weeks after irradiation. When the increase in skin thickness, as a consequence of oedema, was taken into account a significant increase in the unrelaxed elastic modulus of irradiated skin was only seen at 12 and 15 weeks after irradiation. There were no significant changes in force relaxation, after extension of the skin, over this time period. After the resolution of oedema, which was associated with a significant 20% reduction in the thickness of irradiated skin relative to unirradiated skin, the mechanical properties of irradiated skin were not markedly different from those of unirradiated skin. However, between 30 and 39 weeks after irradiation there was a further wave of dermal thinning, resulting in a total reduction in the thickness of irradiated skin relative to unirradiated skin of 26%. This was associated with a rapid rise in the skin stiffness and unrelaxed elastic modulus by approximately 65 and approximately 140%, respectively. It was only at these late times after irradiation that the force relaxation of the skin was modified significantly. At 9 and 12 weeks after irradiation the reduction in skin stiffness and the unrelaxed elastic modulus were dose related. Based on the percentage of fields showing a significant reduction in these biomechanical parameters, ED50 values of between 12 and 14.5 Gy were established. This would appear to be a sensitive method for assessing radiation-induced dermal changes since few gross changes are observed in this dose range.     

湿润环境促进中厚皮片供皮区创面愈合的临床观察

目的：观察湿润环境对中厚皮供皮区创面愈合的促进作用。方法：水胶体敷料和藻酸盐敷料在中厚皮片区创面上形成密闭的湿润伤口环境,观察创面愈合时间,感染可能性及伤口疼痛程度。结果：在密闭和半密闭的湿润环境下中厚皮片供皮区创面愈合时间明显缩短,创面无感染,疼痛减轻,结论：湿润环境能促进中厚片供皮区创面愈合,是一种安全,有效的方法。     

Treatment of Bowen's disease with a specially designed radioactive skin patch

Bowen's disease can be treated by various methods, including surgical excision, cryosurgery, laser ablation, curettage, Mohs' microsurgery and ionizing radiation. Radiotherapy has been a useful therapeutic modality in the treatment of Bowen's disease and other skin cancers in areas which are difficult to excise, especially the central areas of the face, including eyelids, nose and lips. To overcome some of the disadvantages of external radiotherapy, a specially designed skin patch coated with high-energy beta-emitter holmium-166 was made for topical application at our institute. Twenty-nine sites of Bowen's disease in eight patients, confirmed by skin biopsy, were treated with 166Ho patches. The patches were applied to the surface of skin cancers for 30-60 min for a total radiation dose of 35 Gy (3500 rads). One to two weeks after application of the 166Ho patch, desquamation, erythema or erosion developed in treated sites, but these acute radiation reactions healed gradually with epithelial regeneration, and they showed good functional and cosmetic results without any complications. Follow-up biopsies were performed 1-5 months after 166Ho patch therapy, and they did not show any signs of Bowen's disease. One to two years after treatment with 166Ho skin patches, there were no recurrences of Bowen's diseases and no late complications. The 166Ho patch is an effective and convenient alternative method for the treatment of Bowen's disease that yields good cosmetic and functional results.     

Moist Skin Care Can Diminish Acute Radiation-Induced Skin Toxicity

BACKGROUND: Radiation treatment may induce acute skin reactions. There are several methods of managing them. Validity of these methods, however, is not sufficiently studied. We therefore investigated, whether moist skin care with 3% urea lotion will reduce acute radiation skin toxicity. PATIENTS AND METHODS: 88 patients with carcinomas of the head and neck undergoing radiotherapy with curative intent (mean total dose 60 Gy, range: 50-74 Gy) were evaluated weekly for acute skin reactions according to the RTOG-CTC score. In 63 patients, moist skin care with 3% urea lotion was performed. The control group consisted of 25 patients receiving conventional dry skin care. The incidence of grade I, II, and III reactions and the radiation dose at occurrence of a particular reaction were determined and statistically analyzed using the log-rank test. The dose-time relations of individual skin reactions are described. RESULTS: At some point of time during radiotherapy, all patients suffered from acute skin reactions grade I, > 90% from grade II reactions. 50% of patients receiving moist skin care experienced grade I reactions at 26 Gy as compared to 22 Gy in control patients (p = 0.03). Grade II reactions occurred at 51 Gy versus 34 Gy (p = 0.006). Further, 22% of the patients treated with moist skin care suffered from acute skin toxicity grade III as compared to 56% of the controls (p = 0.0007). CONCLUSION: Moist skin care with 3% urea lotion delays the occurrence and reduces the grade of acute skin reactions in percutaneously irradiated patients with head and neck tumors.