Boron Neutron Capture Therapy for glioblastoma multiforme: advantage of prolonged infusion of BPA-f.

OBJECTIVES: To assess possible improved efficacy of Boron Neutron Capture Therapy (BNCT) for glioblastoma multiforme (GBM) using prolonged infusion and a correspondingly higher dose of l-boronophenylalanine, as the fructose complex (BPA-f). MATERIALS AND METHODS: The benefit of prolonged infusion was analyzed by comparing the results from a Phase II study using 6 h infusion of BPA-f with those obtained from a Phase I/II study using 2 h of infusion. Median survival time (MST) from diagnosis, patient baseline characteristics, salvage treatment and severe adverse events were considered in the comparison. RESULTS: MST increased significantly, from 12.8 (95% confidence interval or CI: 10.3-14.0) months with 2 h infusion to 17.7 (95% CI: 13.6-19.9) months with 6 h of infusion. The fraction of patients with WHO grade 3-4 adverse events was similar in the two studies at 13% and 14%, respectively. CONCLUSION: Prolonged infusion was found to be beneficial for the efficacy of BNCT and it is suggested that 6 h infusion of BPA-f should be used in future trials of BNCT for GBM. BNCT, which is a single-day treatment with mild side effects, should be assessed in a controlled trial, as an alternative to 30 daily fractions of conventional fractionated photon therapy over a period of 6 weeks.

Spinal cord re-treatments using photon and proton based radiotherapy: LQ-derived tolerance doses.

Re-treatment, using megavoltage photon radiotherapy, can benefit carefully selected patients with new or recurrent tumours. Such re-treatments may involve the further exposure of tissues such as the brain or spinal cord. A time-dependent model has been developed, which incorporates data from all published radiobiological experiments concerned with the in vivo re-irradiation of the spinal cord using photons. It allows an estimation of the increasing recovery in tissue tolerance with elapsed time after the initial treatment course. In accordance with the experimental evidence, the recovery rate depends on the biological effective dose (BED) of the initial treatment. Various degrees of conservatism have been introduced in the model to allow for potential changes in CNS tissue tolerance due to patient age, chemotherapy, surgery etc. An estimation of the re-treatment dose-fractionation schedule is made easier by the use of a downloadable Graphical User Interface (GUI). Worked examples of its use are given forconventional photon (X-ray) based treatments, and also for protons, where relative biological effectiveness (RBE) considerations must be respected within the BED estimates. The model provides boundary conditions for clinical practice. The responsible clinician can choose to usemore 'forgiving' BED values and from this to calculate the re-irradiation dose-fractionation schedule. For protons, greater care is required sincethe inter-relationship between linear energy transfer (LET) and RBE can lead to significant over-dosage relative to accepted CNS tolerance doses, especially with the use of scanned proton beams. LET and RBE factors are important in order to deliver safe and effective re-treatment doses.

Effects of very low dose-rate (90)Sr/(90)Y exposure on the acute moist desquamation response of pig skin.

BACKGROUND AND OBJECTIVES: Previous data, predominantly involving high dose-rate fractionated irradiation with incomplete repair intervals, had indicated that the kinetics of repair of sublethal damage for acute radiation reactions in pig skin could best be defined by a biphasic repair model with half-times for repair of 0.2 and 5.4 h, partition coefficient 0.5. To further test the validity of this finding and obtain a better estimate of the repair rate of the slow component of repair, the acute response of pig skin to very low dose-rates (VLDR), originally estimated to be 0.0067-0.0244 Gy/min, was investigated as part of a 4 fraction irradiation protocol involving an overall treatment time of <9 days to avoid confounding factors such as induced repopulation and enhanced radio-sensitivity in this animal tissue. MATERIALS AND METHODS: The flank skin of female Large White pigs, 3-4 months of age, was locally irradiated (8 sites/flank) with 22.5 mm diameter (90)Sr/(90)Y plaques. Irradiation with a 4 fraction protocol included 3 equal, high dose-rate, fractions with full repair, followed by a fourth VLDR fraction. The total doses administered were originally planned to represent the dose associated with the predicted ED(20), ED(50) and ED(80) (75% of total biological dose given at high dose-rate and 25% at VLDR) calculated on the basis of the repair kinetic parameters obtained from earlier studies. However, during the analysis a revision to the physical dosimetry was identified; this had been overlooked prior to the start of the study. Following completion of irradiation the irradiated sites were examined weekly and the presence or absence of moist desquamation recorded. RESULTS: The incidence of moist desquamation was slightly higher than expected on the basis of the parameters used to calculate iso-effective doses, at least in part as a consequence of the change to the dosimetry. Using likelihood methods and the original dose estimates, the best model based estimate of the dose-rate correction factor for the LDR and VLDR plaques was 1.29. This was comparable with the physical calibration factor, median value 1.23. The VLDR fraction associated with a 50% incidence of moist desquamation, based on experimental observation, was 23.2+/-0.84, 27+/-2.6 and 30.1+/-3.2 Gy, for corrected VLDRs of 0.0247, 0.0093 and 0.0068 Gy/min, respectively. A biphasic model, which incorporated a dose-rate correction factor, provided a better fit than a monophasic repair model to the total data set, which now included the new VLDR data. Moreover, the monophasic repair model suggested a dose-rate correction factor of 1.63, well outside the range derived from the re-evaluation of the physical dosimetry. CONCLUSION: Using the total data (with model based corrected dose-rates), the analysis revealed two components of repair with half-times of 0.103 (0.0594-0.177) and 2.97 (1.96-4.50) h; partition coefficient 0.375 (0.225-0.526). These are comparable with the estimates for other tissues (the CNS in particular) and suggest that the kinetics of repair may be relatively species and tissue independent with variation observed being more related to experimental design rather than any true differences.

The European Radiobiology Archives (ERA)--content, structure and use illustrated by an example.

The European Radiobiology Archives (ERA), supported by the European Commission and the European Late Effect Project Group (EULEP), together with the US National Radiobiology Archives (NRA) and the Japanese Radiobiology Archives (JRA) have collected all information still available on long-term animal experiments, including some selected human studies. The archives consist of a database in Microsoft Access, a website, databases of references and information on the use of the database. At present, the archives contain a description of the exposure conditions, animal strains, etc. from approximately 350,000 individuals; data on survival and pathology are available from approximately 200,000 individuals. Care has been taken to render pathological diagnoses compatible among different studies and to allow the lumping of pathological diagnoses into more general classes. 'Forms' in Access with an underlying computer code facilitate the use of the database. This paper describes the structure and content of the archives and illustrates an example for a possible analysis of such data.

Radiological protection in ion beam radiotherapy: practical guidance for clinical use of new technology.

Recently introduced technologies in radiotherapy have significantly improved the clinical outcome for patients. Ion beam radiotherapy, involving proton and carbon ion beams, provides excellent dose distributions in targeted tumours, with reduced doses to the surrounding normal tissues. However, careful treatment planning is required in order to maximise the treatment efficiency and minimise the dose to normal tissues. Radiation exposure from secondary neutrons and photons, particle fragments, and photons from activated materials should also be considered for radiological protection of the patient and medical staff. Appropriate maintenance is needed for the equipment and air in the treatment room, which may be activated by the particle beam and its secondary radiation. This new treatment requires complex procedures and careful adjustment of parameters for each patient. Therefore, education and training for the personnel involved in the procedure are essential for both effective treatment and patient protection. The International Commission on Radiological Protection (ICRP) has provided recommendations for radiological protection in ion beam radiotherapy in Publication 127 Medical staff should be aware of the possible risks resulting from inappropriate use and control of the equipment. They should also consider the necessary procedures for patient protection when new technologies are introduced into clinical practice.

Porphyrin-mediated boron neutron capture therapy: a preclinical evaluation of the response of the oral mucosa.

Preclinical studies are in progress to determine the potential of boron neutron capture therapy (BNCT) for the treatment of carcinomas of the head and neck. Recently, it has been demonstrated that various boronated porphyrins can target a variety of tumor types. Of the porphyrins evaluated so far, copper tetracarboranylphenyl porphyrin (CuTCPH) is potentially a strong candidate for clinical use. In the present investigation, the response of the oral mucosa to CuTCPH-mediated boron neutron capture (BNC) irradiation was assessed using the ventral surface of the tongue of adult male Fischer 344 rats, a standard rodent model. CuTCPH was administered by intravenous infusion, at a dose of 200 mg/kg body weight, over a 48-h period. Three days after the end of the administration of CuTCPH, biodistribution studies indicated very low levels of boron (<2 microg/g) in the blood. Levels of boron in tongue tissue were 39.0 +/- 3.8 microg/g at this time. This was the time selected for irradiation with single doses of thermal neutrons from the Brookhaven Medical Research Reactor. The estimated level of boron-10 in the oral mucosa was used in the calculation of the physical radiation doses from the 10B(n,alpha)7Li reaction. This differs from the approach using the present generation of clinical boron carriers, where boron levels in blood at the time of irradiation are used for this calculation. Dose-response curves for the incidence of mucosal ulceration were fitted using probit analysis, and the doses required to produce a 50% incidence of the effect (ED50 +/- SE) were calculated. Analysis of the dose-effect data for CuTCPH-mediated BNC irradiation, compared with those for X rays and thermal neutrons alone, gave a compound biological effectiveness (CBE) factor of approximately 0.04. This very low CBE factor would suggest that there was relatively low accumulation of boron in the key target epithelial stem cells of the oral mucosa. As a consequence, with low levels of boron (<2 microg/g) in the blood, the response of the oral mucosa to CuTCPH-mediated BNCT will be governed primarily by the radiation effects of the thermal neutron beam and not from the boron neutron capture reaction [10B(n,alpha)7Li].

Effects of dexpanthenol with or without Aloe vera extract on radiation-induced oral mucositis: preclinical studies.

PURPOSE: To define the effect of dexpanthenol with or without Aloe vera extract on radiation-induced oral mucositis. MATERIALS AND METHODS: Mouse tongue mucosal ulceration was analysed as the clinically relevant endpoint. Graded single or fractionated dose irradiation (10 x 3 Gy/2 weeks, graded test doses on day 14) were combined with topical administration of dexpanthenol or a base, with or without Aloe vera extract. The formulations were applied for 14 days (single dose) or 24 days after the first fraction. RESULTS: Single dose irradiation resulted in an ED50 (dose at which a positive mucosal response was expected in 50% of the animals irradiated) of 11.9+/-1.2 Gy. None of the formulations yielded a significant change in incidence or time course of ulceration. Test irradiation after 10 x 3 Gy gave an ED50 of 9.0+/-0.1 Gy. Base treatment increased the ED50-values to 10.5+/-0.8 Gy (p = 0.0095) and 9.9+/-0.7 Gy (p = 0.0445) without or with Aloe vera. Dexpanthenol resulted in ED50 values of 9.5+/-0.1 Gy without Aloe vera (p > 0.05), and of 10.9+/-0.9 Gy (p = 0.0035) with Aloe vera. The latent time to ulceration was prolonged, compared to the control (6.3 days) without Aloe vera (8.0-8.2 days, p < 0.001) and with dexpanthenol and Aloe vera (7.3 days, p = 0.0239). CONCLUSIONS: With single dose irradiation, neither dexpanthenol nor Aloe vera extract significantly changed the oral mucosal radiation response. With fractionated irradiation, drug administration significantly increased the isoeffective radiation doses, independent of dexpanthenol or Aloe vera content. Neither dexpanthenol nor Aloe vera display a prophylactic potential.

The measurement of skin lymph flow by isotope clearance--reliability, reproducibility, injection dynamics, and the effect of massage.

The measurement of skin lymph flow was investigated using an isotope clearance technique (ICT). Multiple lymph flow determinations were undertaken in the skin of anaesthetized large white pigs to test for reproducibility, ascertain the most suitable tracer, study the influence of injection dynamics, and observe the effect of massage as a stimulus to lymph flow. Blood clearance of tracer was also investigated. Results demonstrated that lymphatic clearance is a monoexponential function with good reproducibility under controlled laboratory conditions. 99mTc-colloid (TCK17 Cis) compared favorably with 131I-human serum albumin as a tracer and both performed better than colloid gold (198Au). Lymph flow was significantly faster in one pig than in the other. No difference existed between left and right sides or between caudal and rostral sites on each flank, but clearance was significantly slower in thigh than flank skin. Sub-epidermal injections cleared faster and more consistently than either deep or subcutaneous injections. Neither injection volume nor needle tract backflow of tracer influenced results, but local massage significantly enhanced clearance. Escape of 99mTc-colloid by the blood was negligible. These results indicate that skin lymph flow can be reliably measured when conditions are controlled. Extrinsic factors such as massage strongly influence lymph flow. Greater sensitivity in detecting degrees of lymphatic insufficiency may be achieved if a standardized stimulus to lymph flow is administered during isotope clearance measurement.

Trophic effects of essential fatty acids on pig skin.

The daily oral administration of 3 ml of two oils (So-5407 and So-1129) containing essential fatty acids (EFAs) for 16 weeks resulted in a transient increase in cell proliferative activity in the skin of female Large White pigs. The So-5407 oil contained 7% gamma-linolenic acid (GLA) whereas So-1129 was an oil of similar composition, but with no GLA. Hyperplasia of the epidermis was observed after the administration of both oils, and this was characterized by an increase in the size of the rete pegs. The maximum effect occurred at 4 weeks after the start of oil administration, at which time the number of viable cell layers had increased by a factor of approximately 1.5, and mean epidermal thickness (excluding the stratum corneum) was approximately 40% greater than that of the epidermis prior to oil administration. There was a marked increase in the labelling index (LI) of the basal cell layer of the epidermis in pigs receiving So-5407. Maximum LIs were quantified at 4 weeks after the start of administration and were 18.8 +/- 1.3% and 13.1 +/- 1.7% for pigs receiving So-5407 and So-1129, respectively. After this time the LI declined progressively and had returned to values within normal limits (P > 0.1) by 8 weeks after the start of administration of both oils. A similar pattern of change in the LI was seen in the follicular epithelium, although the peak values at 4 weeks after the start of oil administration of 12.2 +/- 1.8% and 10.8 +/- 0.9 for the groups receiving So-5407 and So-1129, respectively, were lower than in the epidermis. Labelled cells were also counted in the papillary dermis and maximum values were again seen at 4 weeks after the start of oil administration. Of the two oils, So-1129 had the greatest effect, with the number of labelled cells in the papillary dermis being a factor of three to four-fold higher than in skin prior to oil administration, between 2 and 12 weeks after the start of administration.

Modulation of the cell kinetics of pig skin by the topical application of evening primrose oil or Lioxasol.

The daily topical application of two compounds, a cream containing 10% evening primrose oil (EPO) and Lioxasol (a compound used clinically to treat radiation burns), resulted in increased cell proliferative activity in the skin of female Large White pigs. The effect was most pronounced in the case of the EPO based cream, and was comparable in magnitude with that observed in a previous study on pig skin using orally administered EPO. There was an increase in the size of the rete pegs in the epidermis by 6 weeks after the start of application of the EPO cream. However, this did not translate into an increase in the total thickness of the viable epidermis (excluding the stratum corneum) due to a reduction in the density of rete pegs, from 2 weeks after treatment. Lioxasol had no overall effect on the size of the rete pegs. The labelling index (LI) of cells in the basal layer of the epidermis of pigs receiving a daily topical application of EPO increased progressively with time from the start of application. The LI was maximal (17.9 +/- 2.4%) at the end of the observation period (8 weeks) at which time it was a factor of approximately 2 higher than in the basal layer prior to treatment. A considerably less marked increase in the LI of the basal layer was seen after the application of Lioxasol. The overall increase was approximately 20%, relative to the LI in the untreated epidermis. Labelled cell nuclei were also counted in the papillary dermis. After the application of the EPO cream, no significant increase in the number of labelled cells was observed until week 8, at which time values were approximately twice those in untreated skin. In Lioxasol treated skin the effect on the numbers of labelled cells in the papillary dermis was more immediate, with a approximately 60% increase at 2 weeks. This enhanced level of labelling was maintained until the end of the observation period of 10 weeks. Studies on the cell kinetics of the skin using the alcohol component of the Lioxasol preparation suggested that alcohol rather than Lioxasol was the most significant ingredient. It was concluded that the EPO cream merited further evaluation as a potential modulator of skin response to ionizing radiation.

Modification of doxorubicin-induced cardiotoxicity: effect of essential fatty acids and ICRF-187 (dexrazoxane).

The capacity of an oil, containing gamma-linolenic acid (GLA), to reduce the severity of doxorubicin-induced cardiotoxicity has been investigated in a rat model. Groups of 12-week-old, male, Sprague-Dawley rats were injected intravenously (i.v.) with single doses (3 mg/kg body weight) of doxorubicin (DOX). Daily for 1 week prior to DOX administration and for up to 20 weeks afterwards groups of rats received either an oil containing both GLA and linoleic acid (So-1100, Scotia Pharmaceuticals), at two dose levels, or an oil containing linoleic acid, but no GLA (So-1129) by oral gavage. Other groups of rats received water as a control. One of the groups of rats that received water also received i.v. ICRF-187 (60 mg/kg) 15 min prior to DOX. A group of animals acted as age-matched controls. The maximum reduction in body weight in the first 2 weeks after the administration of DOX. was used as a measure of acute toxicity. This was most severe in the group receiving a combination of DOX and ICRF-187 (5.6+/-0.43%). Animals receiving 2 ml of either So-1100 or So-1129 were the least affected ( approximately 2.5%). Measurements of cardiac volume output made at various intervals after DOX administration indicated a approximately 35% reduction in cardiac function in the control and So-1129 oil group after 20 weeks. The corresponding reduction in the groups receiving ICRF-187 and 2 ml of So-1100 was approximately 16%. The group receiving daily doses of 1 ml So-1100 showed an intermediate response. The death of an animal with signs of congestive cardiac failure occurred in 40% of the animals in the DOX only control (water) group. There were no deaths in the groups of rats receiving either ICRF-187 or pre- and post-administration of 2 ml of So-1100. It was concluded that an oil containing GLA (So-1100) has similar cardioprotective properties against DOX-induced cardiotoxicity as ICRF-187, but with less general toxicity in this rat model.

An investigation into the combined effects of X-irradiation and 3MHz ultrasound-induced hyperthermia on pig skin.

The thermal enhancement of radiation-induced damage in pig skin has been investigated. Heating at 43 degrees C for 60 min was produced by a scanned 3MHz ultrasound transducer, immediately after single doses of X rays. The ED50 values for the dermal reactions of dusky/mauve erythema and necrosis after irradiation alone were 18.6 +/- 0.5 Gy and 20.5 +/- 0.4 Gy, respectively. The reduction in the ED50 values to 15.3 +/- 0.4 Gy and 17.7 +/- 0.5 Gy after irradiation plus heating was significant and suggested a thermal enhancement ratio (TER) of between 1.15 and 1.22. These TER values were within the range obtained in both pig and rat skin using other 'dry' heating methods. This would suggest that the non-thermal effects of ultrasound do not influence the thermal enhancement of x-irradiation damage.

The effects of preoperative x-irradiation on the survival and blood flow of pedicle skin flaps in the pig.

Pedicle skin flaps have been raised from pre-irradiated sites on the flanks of pigs. Radiation treatment was given as a single dose, 6 fractions in 18 days or 30 fractions in 39 days. Surgery was performed at 12, 52 or 104 weeks after irradiation. Control flaps were raised from normal skin on the other flank. The length of flap remaining viable after surgery was shorter in the irradiated than the control flaps. This reduction in flap survival was the same at the three time periods at which it was assessed and for each of the radiation doses selected for the different treatment groups. Clearance rates of an isotope (99mTechnetium) injected intradermally in the distal surviving regions of irradiated and normal flaps were compared. Clearance changes were related to those recorded in normal and irradiated skin before surgery. Isotope clearance in normal flaps was impaired after surgery (days 1-3) but then became faster than in intact skin (days 5-14). A similar pattern of changes was recorded in irradiated flaps only when the pre-operative isotope clearance rates in irradiated skin were similar to that in normal skin (i.e. for all treatment groups at 52 and 104 weeks after treatment). However, when pre-operative clearance was already slower in irradiated than in normal skin (i.e. for a single dose and 6 fraction/18 days after 12 weeks), surgery in the irradiated site did not have the usual effect of slowing the clearance rate.

Studies of dose-fractionation on early and late responses in pig skin: a reappraisal of the importance of the overall treatment time and its effects on radiosensitization and incomplete repair.

Studies in pig skin have examined the effects of dose fractionation on the acute radiation response. The variation in ED50 values for moist desquamation for doses given as 1-48 fractions over less than or equal to 16 days were best fitted by a log-log plot of iso-effect dose against the number of fractions; the slope of this plot indicated a fraction number exponent (N) of 0.42 +/- 0.007. Based on the assumptions made in applying the linear-quadratic (LQ) model, the alpha/beta ratio was found to decrease with decreasing per fraction: for doses given as 6-27 Gy per fractions the alpha/beta ratio was 8.74 +/- 0.48 Gy, whereas for doses of 2.55-6 Gy per fraction it was only 0.85 +/- 0.29 Gy. A simple approach to a time factor could not be used to calculate iso-effect doses for acute reactions in pig skin when treatment time was increased from less than or equal to 16 days to 28-39 days. This was due to the opposing effects of radiosensitization and repopulation when the cell cycle time of epidermal basal cells was shortened. For late dermal necrosis in pig skin, repair of sublethal damage was not completed in 24 hr. This finding has a significant effect on the interpretation of the results of fractionation studies using this late endpoint. Expressed in terms of a simple power-law function, there was a significant change in the fraction number exponent "N" from 0.43 +/- 0.007 to 0.37 +/- 0.006 for the complete and incomplete repair data, respectively. Many of the fractionation effects reported for acute and late damage to pig skin would appear to be in excellent agreement with those for human skin.

The radiation response of the cervical spinal cord of the pig: effects of changing the irradiated volume.

PURPOSE: An investigation of the field size effect for the cervical spinal cord of the pig after single doses of gamma-rays. In this study, clinically relevant volumes of the spinal cord were irradiated. METHODS AND MATERIALS: The effects of the local irradiation of different lengths of the spinal cord (2.5 cm, 5.0 cm, and 10.0 cm) have been evaluated in mature pigs (37-43 weeks). Single doses of 25-31 Gy were given using a 60Co gamma-source, at a dose rate of 0.21-0.30 Gy/min. The incidence of radiation-induced paralysis was used as the endpoint. The data were analyzed using probit analysis and a normal tissue complication probability (NTCP)-model. RESULTS: Twenty-five animals out of a total of 53 developed paralysis, with histological evidence of parenchymal and vascular changes in their white matter. The slope of the dose-response curves decreased with the decrease in field size; however, there was no significant difference at the radiation dose associated with a 50% incidence of paralysis (ED50) irrespective of the method of analysis. The ED50 values +/- standard errors (+/- SE) were 27.02 +/- 0.36 Gy, 27.68 +/- 0.57 Gy, and 28.28 +/- 0.78 Gy for field lengths of 10, 5, and 2.5 cm, respectively. Analysis of the data with a normal tissue complication probability (NCTP) model gave similar results. The latent period for paralysis was 7.5-16.5 weeks with no significant differences between dose and field size. CONCLUSION: No significant field size-related differences in response were detectable in the cervical spinal cord of mature pigs after single dose irradiations, specifically at a clinically relevant level of effect (< ED10).

A new model of radiation-induced myelopathy: a comparison of the response of mature and immature pigs.

PURPOSE: The development of an experimental model of radiation-induced myelopathy in the pig which would facilitate the study of the effects of clinically relevant treatment volumes. METHODS AND MATERIALS: The effects of local spinal cord irradiation, to a standard 10 x 5 cm field, have been evaluated in mature (37-42.5 weeks) and immature (15.5-23 weeks) pigs. Irradiation was with single doses of 60Co gamma-rays at a dose-rate of 0.21-0.65 Gy/min. The incidence of paralysis was used as an endpoint. RESULTS: Irradiation of mature animals resulted in the development of frank paralysis with animals showing combined parenchymal and vascular pathologic changes in their white matter. These lesions, in common with those seen in patients, had a clear evidence of an inflammatory component. The latency for paralysis was short, 7.5-16.5 weeks, but within the wide range reported for patients. However, it was shorter than that reported in other large animal models. The ED50 value (+/- SE) for paralysis was 27.02 +/- 0.36 Gy, similar to that in rats taking into account dose-rate factors. The irradiation of immature pigs only resulted in transient neurological changes after doses comparable to those used in the mature animals, ED50 value (+/- SE) 26.09 +/- 0.37 Gy. The reasons for these transient neurological symptoms are uncertain. CONCLUSION: A reliable experimental model of radiation-induced myelopathy has been developed for mature pigs. This model is suitable for the study of clinically relevant volume effects.

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.

Development of blood vessel-related radiation damage in the fimbria of the central nervous system.

The identification problem of the dose-limiting tissue component was investigated in the CNS of rats. Moderate single doses of radiation, ranging from 20 to 25 Gy were applied to the brain of adult female rats. The sequence of events was analyzed by scoring a series of morphological changes in one of the white matter structures that appears to represent a sensitive location, that is the fimbria hippocampi. The previously defined "Tissue Injury Unit", characterized by a dilation of the blood vessel lumen, a thickening of the blood vessel wall, an enlargement of endothelial cell nuclei, and a hypertrophy of the adjacent astrocytes which represents a combined score of four different, but related histological changes, proved to be slightly more sensitive and responsive than the earliest recognizable changes in the neurological structures, that is demyelination. In addition, the incidence of demyelination could be expressed as a function of the intensity of the "Tissue Injury Unit". These findings can be interpreted as an additional indication that blood vessel changes and the hypertrophy of the perivascular astrocytes precede degenerative changes in the white matter of the CNS after moderate doses of X rays.

Nephropathy in the mature pig after the irradiation of a single kidney: a comparison with the immature pig.

The right kidney of 11 mature 10-month-old Large White female pigs was irradiated with single doses of 9.8-14.0 Gy of 60Co gamma rays. Individual kidney glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured using 99mTc-DTPA and 131I-hippuran renography for periods up to 24 weeks after irradiation. Renal function was assessed either as a functional index, FI (FI = irradiated/unirradiated kidney function), or as the individual kidney GFR and ERPF. The radiation-induced changes after the irradiation of a single kidney (unilaterally irradiated--UI) of mature pigs were compared with those previously observed in 14-week-old immature pigs. Irradiation resulted in a dose-dependent reduction in the FI for both GFR and ERPF. However, these reductions were significantly less than those previously seen in immature pigs. Within 2 weeks of irradiation GFR increased in both the irradiated and the unirradiated kidneys in each animal, compared with unirradiated age-matched control kidneys. No marked changes in renal hemodynamics were seen in mature animals after a single dose of 9.8 Gy. This was in marked contrast to the pronounced reduction in the GFR and ERPF in the irradiated kidney previously observed in immature animals irradiated with an equivalent single dose of X rays. After higher doses, the irradiated kidney in mature pigs showed a dose-dependent reduction in GFR and ERPF. However, the extent of this reduction was significantly less than that seen in immature animals. There was no apparent difference in the response of the unirradiated kidneys in mature or immature pigs. The ED50 values, based on a probit fit to the data for the proportion of functional tests in which the irradiated kidney showed a greater than or equal to 50% reduction in GFR or ERPF, were higher in the mature animals; for example for ERPF the ED50 values were 11.76 +/- 0.28 Gy and 7.67 +/- 0.34 Gy for mature and immature animals, respectively. Thus, the UI kidney in mature pigs appears to be less radiosensitive than the UI kidney in immature animals.

Boron neutron capture therapy: a guide to the understanding of the pathogenesis of late radiation damage to the rat spinal cord.

PURPOSE: Before the commencement of new boron neutron capture therapy (BNCT) clinical trials in Europe and North America, detailed information on normal tissue tolerance is required. In this study, the pathologic effects of BNCT on the central nervous system (CNS) have been investigated using a rat spinal cord model. METHODS AND MATERIALS: The neutron capture agent used was 10B enriched sodium mercaptoundecahydro-closododecaborate (BSH), at a dosage of 100 mg/kg body weight. Rats were irradiated on the thermal beam at the Brookhaven Medical Research Reactor. The large spine of vertebra T2 was used as the lower marker of the irradiation field. Rats were irradiated with thermal neutrons alone to a maximum physical absorbed dose of 11.4 Gy, or with thermal neutrons in combination with BSH, to maximum absorbed physical doses of 5.7 Gy to the CNS parenchyma and 33.7 Gy to the blood in the vasculature of the spinal cord. An additional group of rats was irradiated with 250 kVp X rays to a single dose of 35 Gy. Spinal cord pathology was examined between 5 and 12 months after irradiation. RESULTS: The physical dose of radiation delivered to the CNS parenchyma, using thermal neutron irradiation in the presence of BSH, was a factor of two to three lower than that delivered to the vascular endothelium, and could not account for the level of damage observed in the parenchyma. CONCLUSION: The histopathological observations of the present study support the hypothesis that the blood vessels, and the endothelial cells in particular, are the critical target population responsible for the lesions seen in the spinal cord after BNCT type irradiation and by inference, after more conventional irradiation modalities such as photons or fast neutrons.