Progression rate of radiation damage to the mouse kidney: a quantitative analysis of experimental data using a simple mathematical model of the nephron

Mouse kidneys were irradiated bilaterally with a range of single or fractionated X-ray doses. After an interval of 2 weeks or 26 weeks, the animals were reirradiated with a range of single X-ray doses. The rate of development of functional kidney damage was assessed repeatedly by the 51Cr-EDTA clearance assay. The rate at which the damage is expressed was found to depend on the primary dose, on the interval between primary treatment and retreatment, and on the retreatment dose. A subset of the data was analysed using a mathematical model of nephron function. In the model, the residual activity of 51Cr-EDTA depends on the glomerular filtration rate (GFR). The GFR is related to the cellularities of three target cell populations. The filtration capacity of the glomerulus is assumed to depend on the numbers of glomerular endothelial cells and mesangial cells. The reabsorption capacity of the tubule is related to the number of tubular epithelial cells. The impact of tubulo-glomerular feedback and the reserve capacity of the kidney on residual activity is considered. The target cell populations are assumed to be of a flexible type, i.e. to consist of cells which are all both functional and self-renewing. Free parameters of the model were optimized by minimizing the residual sum of squares. With the optimized parameter values, the measured and the model-predicted rates of progression of the functional damage correspond well for a wide range of irradiation schedules. The model analysis suggests a pronounced role of tubulo-glomerular feedback in the development of functional injury in the kidney. It is concluded that the model represents a good starting point for quantitative studies of the cellular basis of radiation nephropathy.     

Reirradiation tolerance of the rat heart

PURPOSE: To investigate the influence of reirradiation on the tolerance of the heart after a previous irradiation treatment. METHODS AND MATERIALS: Female Wistar rats were locally irradiated to the thorax. Development of cardiac function loss was studied with the ex vivo working rat heart preparation (20). To compare the retreatment experiments, initial, and reirradiation doses were expressed as the percentage of the extrapolated tolerance dose (ETD) (1). RESULTS: Local heart irradiation with a single dose led to a dose-dependent and progressive decrease in cardiac function. The progressive nature of irradiation-induced heart disease is shown to affect the outcome of the retreatment, depending on both the time interval between subsequent doses and the size of the initial dose. The present data demonstrate that hearts are capable of repairing a large part of the initial dose of 10 Gy within the first 24 h. However, once biological damage as a result of the first treatment is fixed, the heart does not show any long-term recovery. At intervals up to 6 months between an initial treatment with 10 Gy and subsequent reirradiation, the reirradiation tolerance dose slightly decreased from 74% of the ETDref (at 24-h interval) to 68% of the ETDref (at 6-month interval). Between 6 and 9 months, reirradiation tolerance dose dropped more even to 43% of the ETDref. Treatment of the heart with an initial dose of 17.5 Gy, instead of 10 Gy, 6 months prior to reirradiation, also led to a further decrease of the reirradiation tolerance dose (< 38 vs. 68% of the ETDref). CONCLUSIONS: The outcome of the present study shows a decreased tolerance of the heart to reirradiation at long time intervals (interval > 6 months). This has clinical implications for the estimation of reirradiation tolerance in patients whose mediastinum has to be reirradiated a long time after a first irradiation course.     

Fluconazole sensitivities of Candida species isolated from the mouths of terminally ill cancer patients

BACKGROUND: It has been suggested that tumors respond differently after irradiation with 10 or more fractions than with less fractionated regimens and that extrapolation from experiments with only a few fractions to "curative" regimens may be invalid. To test this hypothesis, we compared hypofractionated-accelerated treatments with "curative" fractionation schedules in human squamous cell carcinoma in nude mice. MATERIAL AND METHODS: FaDu tumors were transplanted subcutaneously into the hindleg of NMRI nu/nu mice. TCD50 values, i.e., the dose necessary to control 50% of the tumors locally, were determined after irradiation under ambient blood flow conditions with 5 and 10 fractions in 5 days, 10 fractions in 10 days, and 30 fractions in 15 days, 6 weeks or 10 weeks. RESULTS: TCD50 values of the hypofractionated regimens were not significantly different and varied from 41 to 46 Gy. The number of fractions given in the same overall time had no measurable effect on local tumor control. The TCD50 after 30 fractions in 6 weeks was 30 Gy higher than after the hypofractionated regimens. This effect was caused by a substantial increase of TCD50 with overall treatment time, the dose recovered per day was 0.82 Gy (95% CI 0.66; 0.96). alpha/beta eff determined from all data was 58 Gy (13; infinite). CONCLUSIONS: The results of the present study compare well with our previous findings after different "curative" fractionation schedules in the same tumor. Thus, our study does not support that tumors respond differently after application of 10 or more fractions compared to less fractionated regimens. The biological mechanisms that govern the radiation response of FaDu tumors appear to be the same for hypofractionated-accelerated and "curative" regimens. Since only one tumor was investigated, these results cannot be generalized at the present time.     

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.     

A quantitative assay for assessing allelic proportions by iterative gap ligation

PURPOSE: We compared gastrointestinal toxicity of single vs. fractionated total body irradiation (TBI) administered at dose rates ranging from 0.021 to 0.75 Gy/min in a canine model of marrow transplantation. METHODS AND MATERIALS: Dogs were given otherwise marrow-lethal single or fractionated TBI from dual 60Co sources at total doses ranging from 8-18 Gy and delivered at dose rates of 0.021, 0.05, 0.10, 0.20, 0.40, and 0.75 Gy/min, respectively. They were protected from marrow death by infusion of previously stored autologous marrow cells and they were given intensive supportive care posttransplant. The study endpoint was 10-day mortality from gastrointestinal toxicity. Logistic regression analyses were used to jointly evaluate the effects of dose rate, total dose, and delivery regimen on toxicity. RESULTS AND CONCLUSION: With increasing dose rates, mortality increased for either mode of delivery of TBI. With dose rates through 0.10 Gy/min, mortality among dogs given single vs. fractionated TBI appeared comparable. Beginning at 0.20 Gy/min, fractionation appeared protective for the gastrointestinal tract. Results in dogs given TBI at 0.40 and 0.75 Gy/min, respectively, were comparable, and dose fractionation permitted the administration of considerably higher total doses of TBI than were possible after single doses, an increment that was on the order of 4.00 Gy. The data indicate that the impact of fractionating the total dose at high dose rates differs from the effect of fractionation at low dose rates.     

Effects of irradiation on the biomechanics of osseointegration. An experimental in vivo study in rats

The present study reports on the late effects of increasing doses of radiation on the biomechanics of commercially pure titanium implants (fixtures) installed in the proximal tibia in 26 rats. Twelve weeks after various doses (10, 20, 30, and 35 Gy) of irradiation, the fixtures were inserted into rat tibiae, and after another eight weeks these were tested mechanically in vivo. Acute dose dependent skin reactions developed after all doses except 10 Gy, but most subsided within two to three weeks. There was a statistically significant reduction in torsion but the pull-out load was not significantly reduced for single doses up to 30 Gy. Histological analysis showed that bone remodelling was impaired. Shear stresses and shear moduli were estimated for the bone-implant interface and in the surrounding bone tissue. These estimated stresses and moduli were not found to be correlated to the dose of radiation.     

Toxicology studies with cytembena (NSC-104801), an antineoplastic agent with a multispecies nephrotoxic effect

The toxic effects of cytembena in beagle dogs and rhesus monkeys were investigated with the drug given as single or daily iv injections in doses ranging from 12.5 to 200 mg/kg/day to dogs and 6.25 to 50 mg/kg/day to monkeys. Renal tubular damage was a major drug- and dose-related finding in both species and was clinically indicated by an accompanying uremia, elevated serum creatinine, and proteinuria. In the kidney, the primary lesion was cellular necrosis and desquamation of the distal tubular epithelium in animals given the lowest toxic doses. More severe but similar histologic changes produced by this drug were further characterized by single dose studies in mice which showed renal mitochondrial swelling and disruption plus generalized cell swelling as progressive, subcellular developments which were well established 24 hours after treatment. Cellular regeneration in the renal tubular epithelium was found in dogs and monkeys retained 6 weeks for observation after treatment, although functional recovery was inconsistent. A toxic effect to lymphoid tissue was an additional finding which is described.     

Renal expression of interleukin-2 receptor mRNA in patients with crescentic glomerulonephritis

A microcolony assay was used in conjunction with fractionated gamma irradiation to determine the number of clonogens in murine intestinal crypts with varying doses of irradiation used in the determination. The experimental design allows direct comparison between two-dose methodologies, employing one and two (or two or four) equal dose fractions, and multiple-dose methodologies involving determination of the crypt survival curves for a number of fractionation regimens using equal doses per fraction. The two-dose methodology yielded estimates of clonogen number of between 3 and 4 at low delivered dose (single and double fractions each of 6.5-7.5 Gy), rising to around 40 at high biological doses (two and four fractions each of 5.75 or 6.5 Gy). The multifraction methodology yielded estimates of clonogen number which increased from 13 after a single fraction to values of 26 and 22 after three and four fractions. However, the latter values were reduced to 11 and 9, and showed little evidence of any dependence on fraction number, when data pertaining to high biologically effective doses were excluded. Hence it is concluded that the high values for clonogen number typically deduced from such multiple-dose protocols, compared with the generally lower (but dose-dependent) values obtained from two-dose protocols, may be explained at least partially by the higher biological doses generally employed in the multiple-dose protocols.     

Effect of in utero radiation dose fractionation on rat postnatal development, behavior and brain structure: 3-hour interval

Effect of In Utero Radiation Dose Fractionation on Rat Postnatal Development, Behavior and Brain Structure: 3-Hour Interval. Neurotoxicology 15(1): 183-190, 1994. We have previously shown that exposure of the rat fetus to ionizing radiation produces dose-dependent (0.25-1.25 Gy) changes in postnatal growth and behavior, and decreases in cerebral cortex thickness. Pregnant rats were exposed to single doses of 0.5 or 1.0 Gy, or to two doses of 0.5 Gy (separated by a 3 h interval) on gestational day 15. Pups were weighed and subjected to behavioral tests (righting reflex; reflex suspension; negative geotaxis; continuous corridor; and length, width, and sine of gait) over postnatal days 7-28. The rats were then sacrificed and brains removed for histology. The fractionated doses produced responses that were generally intermediate between those produced by the single doses and which, by interpolation, could be expressed as equivalent to a single dose between 0.5 and 1.0 Gy. Overall, exposure of the fetal rat to two doses of 0.5 Gy separated by 3 h produced effects equivalent to a single dose of 0.85 Gy. We conclude that fractionation of radiation dose results in less damage to the developing rat cerebral cortex, as measured by postnatal growth, behavioral tests, and morphological assessment.     

Enhancement of fractionated-dose irradiation by retinoic acid plus interferon

PURPOSE: To evaluate the relative cytotoxicity of fractionated-dose radiation in the presence and absence of 13-cis-retinoic acid (RA) plus alpha-2a-interferon (IFN), as a function of overall treatment time. METHODS AND MATERIALS: Studies were performed with the human squamous cell carcinoma line FaDu, in vitro. Attached exponential phase cells were treated with RA + IFN for 8-10 h and then exposed to single graded doses of radiation, or 1 to 6 doses of radiation at 2 Gy per dose, or to 5 doses of radiation at 2 Gy/dose with a time interval of 4-24 h between treatments. Following irradiation, the cells were incubated with drugs present throughout colony formation, and the fraction of survivors in the presence and absence of the combined drugs was calculated. RESULTS: For single graded-dose irradiation, the surviving fraction ratio at 2 Gy in the absence vs. presence of drugs was 1.27 +/- 0.19 in 3 repeat experiments. Following administration of 6 doses of radiation at 2 Gy/fraction with a 5-h time interval between treatments and, after correcting for cell proliferation between treatments, the surviving fractions differed by a factor of 3.25, again indicating an average difference in survival of 1.26 after each of the 6 2-Gy/fractions. Treatment with 5 2-Gy doses of irradiation with 24 vs. 4 h elapsing between doses, resulted in a 3-fold greater decrease in survival in the presence of drugs vs. no drug. The relatively greater cell kill due to 24 vs. 4 h between treatments was due to drug inhibition of cell proliferation between the more prolonged treatments. CONCLUSIONS: The results of this study indicate that retinoic acid plus interferon both sensitizes and inhibits cell proliferation during treatment. These results suggest that this combination of radiation and drugs, when used concurrently, may be effective for inhibiting tumor cell proliferation or accelerated repopulation during clinical fractionated radiotherapy.     

The role of sulfation and/or acetylation in the metabolism of the cooked-food mutagen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in Salmonella typhimurium and isolated rat hepatocytes

The efficacy of repopulation during treatment splits in conventional radiotherapy (5 fractions/week, 2.5, 3.5, 4.5 Gy/fraction) was studied by delayed top-up treatment of mouse tongue epithelium. Splits of 6 h to 13 days were introduced after 1 or 2 weeks of fractionated irradiation. Following 5 fractions, compensation of about 3 dose fractions was assessed after the first weekend and original tissue tolerance was restored after a split of 4-10 days. About 4.6 dose fractions were repopulated during the second treatment week, followed by a further 1.5 fractions during the first 3 split days; restoration of the initial tolerance required 3-8 days. These results indicate that repopulation was more efficient during fractionated radiotherapy than during a subsequent treatment split. Latent times to complete denudation after the top-up treatment decreased to a dose-dependent minimum after 5 fractions and remained at the decreased level when a second treatment week was added. Original values were restored within 5-8 days after 5 fractions and 6 days after 10 fractions. Epithelial cell density during treatment with 3 or 4 Gy/fraction decreased to a dose-dependent nadir of 63% and 52% of the original number after 5 fractions, and original cell counts were then restored after 5 days. Cellularity remained at 60-70% during the second treatment week and subsequently reached normal values within 4 days. In conclusion, reconstitution of epithelial cellularity precedes restoration of radiation tolerance during treatment splits.     

Efficacy of amphipathic dithiocarbamates in intracellular cadmium mobilization and in modulation of hepatic and renal metallothionein in cadmium pre-exposed rat

Forty-eight hours after an intraperitoneal injection of cadmium chloride (1.5 mg Cd/kg) to female albino rats, Cd was mainly localized in the hepatic and renal supernatant cytosolic fraction (SCF). Seventy-two hours later, the total hepatic burden remained unchanged but the total renal burden was enhanced, showing its tendency to accumulate in the kidney. A single dose (0.4 mmol/kg, i.p.) of sodium N-benzyl-D-glucamine dithiocarbamate (BG.DTC) or sodium N-(4-methoxybenzyl)-D-glucamine dithiocarbamate (MeO.BG.DTC), 24 h after Cd injection, efficiently mobilized Cd from hepatic SCF, apparently from cadmium-metallothionein (Cd-MT); MeO.BG.DTC also removed Cd from hepatic nuclear mitochondrial fraction. This treatment, however, increased the renal burden of Cd, indicating that the chelating agents, at least partly, transport Cd from the liver and possibly from other sites into the kidney. Three doses of the chelators further enhanced mobilization of Cd from hepatic as well as renal SCF, as corroborated by its enhanced urinary and, to a greater extent, fecal excretion. Hepatic and renal MT were induced several-fold above normal after a single dose of Cd as well as single or repeated doses of BG.DTC or MeO.BG.DTC. Seventy-two hours after a Cd injection, the hepatic MT declined to half of the induced level while the renal MT remained elevated. Administration of BG.DTC or MeO.BG.DTC in Cd pre-treated rats produced an additive response in hepatic MT, but the response in renal MT was less than additive at one dose and slightly declined after three doses. Hepatic Zn and Cu and renal Zn increased on treatment with Cd but were depleted after a single or repeated injection of BG.DTC or MeO.BG.DTC in normal as well as in Cd pre-exposed animals. The results indicate that intracellular access of amphipathic dithiocarbamates effectively mobilizes MT-bound Cd, which is preferentially excreted in the feces, and helps avoid further burden on the kidney and consequent nephrotoxicity. Additionally, MeO.BG.DTC was a better inducer of hepatic MT to help increased capture of toxic metal from the initial circulation and consequent toxicity.     

Predicting realistic RBE values for clinically relevant radiotherapy schedules

To consider the therapeutic potential of radiation effect modifiers it is necessary to balance the modification of the injury in tumours with that in different types of normal tissue. It is especially important to ensure that the effects that have been demonstrated in preclinical experiments are both qualitatively and quantitatively relevant for the radiation doses that will be used in clinical schedules. Most radiobiology studies are initially performed with large single doses or a few large fractions, and from those results predictions have sometimes been made of the potential clinical benefit from a radiation modifier. In the clinic they will be used with many repeated small fractions of about 2 Gy over a period of several weeks. The effects will be quantitatively different in these two dose ranges for a variety of reasons. No modifiers of radiation effect are truly dose-modifying over the whole dose spectrum. They all have a differential effect on the type of damage inflicted at high and low dose levels, i.e. those described by the linear and quadratic terms in the LQ model. This means that every modifier has a dose or dose per fraction dependence on the magnitude of the sensitization or protection. The details of that dose dependence will vary with the alpha/beta ratio of the tissue under consideration. Furthermore all tissues and tumours contain a mixture of cells, with different proliferative, redox and other characteristics that influence their sensitivity to radiation and their susceptibility to the radiomodifier. The influence of different subsets of cells changes as a fractionated treatment progresses and the sensitive cells are eradicated, leaving more resistant survivors. The overall response to a fractionated schedule then depends critically on whether there is re-assortment of cells from the resistant phase into more sensitive or modifiable phases before the next fraction in the series. In addition, the magnitude of dose modification depends totally on the standard curve against which the comparison is made. The reference standard is different in preclinical laboratory studies and in conventional clinical experience. Those differences must be considered when moving from the laboratory to the clinic and back again. The effect of these different factors is considered using the linear quadratic model to dissect the components. Examples are provided to demonstrate the clinical relevance.     

Induction thermochemotherapy increases therapeutic gain factor for the fractionated radiotherapy given to a mouse fibrosarcoma

PURPOSE: It has been shown that thermochemotherapy (TC) given prior to radiation reduces the number of clonogens, with a resultant decrease in the tumor control radiation dose. The purpose of this article was to investigate using an animal tumor model how this clonogen reduction affects subsequent fractionated radiotherapy, including repopulation of surviving clonogens, and whether the induction TC can increase the therapeutic gain factor (TGF). METHODS AND MATERIALS: The single-cell suspensions prepared from the fourth-generation isotransplants of a spontaneous fibrosarcoma, FSa-II, were transplanted into the C3Hf/Sed mouse foot. TC was given by heating tumors at 41.5 degrees C for 30 min immediately after an intraperitoneal injection of cyclophosphamide (200 mg/kg) when tumors reached an average diameter of 4 mm. Fractionated radiotherapy (R) with equally graded daily doses was initiated 24 h after TC either in air (A) or under hypoxic conditions (H). The 50% tumor control dose (TCD50) and the radiation dose to induce a score 2.0 reaction (complete epilation with fibrosis) in one-half of irradiated animals, RD50(2.0), were obtained, and the TGF was calculated. Our previous results on the fractionated radiotherapy using the same tumor system served as controls. RESULTS: The TCD50(A, single dose) and TCD50(H, single dose) following TC+R were 52.2 and 57.3 Gy, respectively, which were 14.0 and 20.4 Gy lower than those following radiation alone. The TCD50(A, TC+R) increased only slightly when the number of fractions was increased from one to 10 doses, and all TCD50s were significantly lower than the TCD50(A, R alone). Both TCD50(H, TC+R) and TCD50(H, R alone) increased consistently from a single dose to 20 doses, but all TCD50(H, TC+R) were significantly lower than the TCD50(H, R alone). Regarding the normal tissue reaction, the RD50 values both following TC+R and R alone increased consistently from a single dose to 20 daily doses. However, the RD50(TC+R) and RD50(R alone) for each corresponding number of fractions was not significantly different, resulting in the TGFs significantly > 1.0 for combined TC+R treatments, with the exception of 20 daily doses given in air. CONCLUSION: The induction TC decreased the TCD50 values substantially without altering the RD50 for a late reaction, resulting in an significant increase in the TGF. These results encourage the use of TC as an induction treatment prior to fractionated radiotherapy.     

Effects of fractionated abdominal irradiation on small intestinal motility--studies in a novel in vitro animal model

Disordered small intestinal motility occurs frequently during acute radiation enteritis. However, the characteristics and time course of the motor dysfunction are poorly defined. These parameters were assessed in a novel animal model of radiation enteritis. Ileal pressures were recorded in vitro with perfused micromanometric catheter using an arterially perfused ileal loop in 22 ferrets following fractionated abdominal irradiation (9 doses 2.50 Gy thrice weekly for 3 weeks). Tissue damage was graded histologically. Studies were performed 3 to 29 days after irradiation. Tissue from 7 control animals was also studied. All treated animals developed diarrhoea. Histology showed changes consistent with mild to moderate radiation enteritis. Following irradiation, there was an initial increase in frequency followed by a non-significant reduction in the frequency, but not the amplitude of ileal pressure waves. The frequency of pressure waves showed an inverse relationship with time after radiation (r = -0.634, p < 0.002). There was no relationship between motility and histology. We conclude that abdominal irradiation is associated with a time-dependent reduction in ileal motility which does not correlate with light microscopic changes.     

Radiotherapy of glioblastoma multiforme. Feasibility of increased fraction size and shortened overall treatment

PURPOSE: With regard to the poor prognosis of patients with glioblastoma multiforme, the aspect of life quality with a minimal treatment time becomes essential. The purpose of the present study is to evaluate whether the results of a radiotherapy schedule using increased single fractions applied over a shortened treatment time is feasible without compromising treatment efficiency or providing more side effects than a conventionally fractionated treatment. PATIENTS AND METHODS: A total of 38 patients (f = 21, m = 17, mean age 58 years) with histologically proven glioblastoma multiforme were irradiated after (partial) resection (n = 29) or stereotactic surgery (n = 9) with single doses of 3.5 Gy (ICRU) 5 fractions a week up to a total dose of 42 Gy following individual treatment planning. RESULTS: Median survival was 45.7 weeks, survival rate after 6 months was 80.9% and decreased to 34.2% after 12 months. Radiotherapy was tolerated without any important acute toxicity or any late side effects during the follow-up period. CONCLUSIONS: The increase of the dose per fraction using a fraction size of 3.5 Gy enhanced neither acute nor late toxicity. The survival rate compared well to those described in the literature. Thus the shortened treatment schedule seems as efficient as conventional radiotherapy. Moreover, it seems preferable with regard to quality of life.     

The value of conventionally fractionated radiotherapy in the local treatment of HIV-related Kaposi's sarcoma

BACKGROUND: During the course of AIDS, 25 to 44% of homosexual patients infected with the human immunodeficiency virus develop Kaposi's sarcoma. Main manifestation is the skin. Response rates of 80 to 100% can be achieved with total dosage up to 50 Gy. Nevertheless, remissions can also be attained with 20 Gy of fractionated radiotherapy. As clinical data on low dose conventional fractionated radiotherapy are insufficient we analysed the response rates of an overall dose of 20 Gy in conventional fractionation. PATIENTS AND METHODS: From June 1991 to June 1993, 43 patients with 111 HIV-associated Kaposi's sarcoma of the skin or oral cavity were treated. Lesions were irradiated with 5 to 12 MeV electrons or 60Co gamma-rays. The fractionation scheme was 5 times 2 Gy/week for skin and endoral lesions with a total reference dosage of up to 20 Gy. Side effects were assessed during therapy and the therapeutic result 6 weeks after end of treatment. RESULTS: Thirty-eight out of 111 lesions were judged as complete response (CR) (34%), 61/111 as partial response (PR) (55%) and 12/111 were judged as no change (NC) (11%). Overall response (CR + PR) was 89%. Two patients with lesions of oral cavity suffered from RTOG grade-IV mucositis after 10 and 14 Gy. In 71/106 skin lesions (67%), radiation induced RTOG grade-1 reactions were observed. CONCLUSION: In patients with HIV associated Kaposi's sarcoma effective palliation can be achieved by means of radiotherapy with an overall dose of 20 Gy in conventional fractionation. Yet, the fraction of patients with complete responses is with 34 to 47% lower compared with doses above 20 Gy (66 to 100%). With reference to the reported data our results point to a dose-response relationship for Kaposi's sarcoma. Therefore higher total reference doses, e.g. 30 Gy with weekly 5 times 2 Gy or 24 Gy with 5 times 1.6 Gy for mucous lesions, respectively, are suggested as by this mean the complete response rate can be doubled.     

Ischemia causes rapidly progressive nephropathy in the diabetic rat

We examined the influence of renal ischemia in rats with diabetes mellitus (DM). Male Wistar rats were rendered diabetic by streptozotocin treatment. Two weeks later, 30 minutes of complete ischemia was induced in the left kidney of DM and non-DM animals. Both groups were evaluated functionally and morphologically four or eight weeks post-ischemia. In non-DM animals renal function and morphology showed almost complete recovery. In the DM animals, however, this comparatively short period of ischemia caused a substantial loss of renal function. Four weeks post-ischemia inulin clearance in the DM kidneys rendered ischemic was only 20% of that in the corresponding non-DM kidneys, and after eight weeks the DM kidneys were completely anuric. Extensive inflammation and tubulointerstitial fibrosis were evident in DM kidneys four weeks after ischemia and seemed to increase over time. After eight weeks, tubular atrophy was found in the ischemic DM kidneys, resulting in a substantial loss of kidney mass. We conclude that in diabetic rats renal ischemia causes rapidly progressive kidney damage that in several respects resembles diabetic nephropathy in humans. Since advanced renal lesions similar to those seen in human diabetic nephropathy never develop in the rat solely as a result of DM, the present study may provide an experimental model for further studies on renal failure in diabetes mellitus.     

Induction of acute phase gene expression by brain irradiation

PURPOSE: To investigate the in vivo acute phase molecular response of the brain to ionizing radiation. METHODS AND MATERIALS: C3Hf/Sed/Kam mice were given midbrain or whole-body irradiation. Cerebral expression of interleukins (IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6), interferon (IFN-gamma), tumor necrosis factors (TNF-alpha and TNF-beta), intercellular adhesion molecule-1 (ICAM-1), inducible nitric oxide synthetase (iNOS), von Willebrand factor (vWF), alpha 1-antichymotrypsin (EB22/5.3), and glial fibrillary acidic protein (GFAP) was measured at various times after various radiation doses by ribonuclease (RNase) protection assay. The effects of dexamethasone or pentoxifylline treatment of mice on radiation-induced gene expression were also examined. RESULTS: Levels of TNF-alpha, IL-1 beta, ICAM-1, EB22/5.3 and to a lesser extent IL-1 alpha and GFAP, messenger RNA were increased in the brain after irradiation, whether the dose was delivered to the whole body or only to the midbrain. Responses were radiation dose dependent, but were not found below 7 Gy; the exception being ICAM-1, which was increased by doses as low as 2 Gy. Most responses were rapid, peaking within 4-8 h, but antichymotrypsin and GFAP responses were delayed and still elevated at 24 h, by which time the others had subsided. Pretreatment of mice with dexamethasone or pentoxifylline suppressed radiation-induced gene expression, either partially or completely. Dexamethasone was more inhibitory than pentoxifylline at the doses chosen. CONCLUSIONS: The initial response of the brain to irradiation involves expression of inflammatory gene products, which are probably responsible for clinically observed early symptoms of brain radiotherapy. This mechanism explains the beneficial effects of the clinical use of steroids in such circumstances.