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Background: The toxicity of a given cancer therapy is an important end point in clinical trials examining the potential costs and benefits of that therapy. Treatment-related toxicity is conventionally measured with one of several toxicity criteria grading scales, even though the reliability and validity of these scales have not been established., Purpose: We determined the reliability of the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) expanded toxicity scale and the World Health Organization (WHO) standard toxicity scale by use of a clinical simulation of actual patients., Methods: Seven experienced data managers each interviewed 12 simulated patients and scored their respective acute toxic effects. Inter-rater agreement (agreement between multiple raters of the same case) was calculated using the kappa (kappa) statistic across all seven randomly assigned raters for each of 18 toxicity categories (13 NCIC-CTG and five WHO categories). Intra-rater agreement (agreement within the same rater on one case rated on separate occasions) was calculated using kappa over repeated cases (where raters were blinded to the repeated nature of the subjects). Proportions of agreement (estimate of the probability of two randomly selected raters assigning the same toxicity grade to a given case) were also calculated for inter-rater agreement. Since minor lack of agreement might have adversely affected these statistics of agreement, both kappa and proportion of agreement analyses were repeated for the following condensed grading categories: none (0) versus low-grade (1 or 2) versus high-grade (3 or 4) toxicity present., Results: Modest levels of inter-rater reliability were demonstrated in this study with kappa values that ranged from 0.50 to 1.00 in laboratory-based categories and from -0.04 to 0.82 for clinically based categories. Proportions of agreement for clinical categories ranged from 0.52 to 0.98. Condensing the toxicity grades improved statistics of agreement, but substantial lack of agreement remained (kappa range, -0.04-0.82; proportions of agreement range, 0.67-0.98)., Conclusions: Experienced data managers, when interviewing patients, draw varying conclusions regarding toxic effects experienced by such patients. Neither the NCIC-CTG expanded toxicity scale nor the WHO standard toxicity scale demonstrated a clear superiority in reliability, although the breadth of toxic effects recorded differed.

Long-Evans rats were exposed to a single dose of head X-irradiation (600 rads) at 2 days of age. Experimental and sham irradiated rats were sacrificed at 14, 20-21, 23, 41-45, and 70-71 days. Tibial epiphyseal width and the number of cells in the epiphyseal plate were determined. Histochemical and electron microscopic studies were carried out on both costal and epiphyseal cartilage. Histochemical techniques revealed a reduction in chondroitin sulfate at 14 days in both costal and epiphyseal cartilage of X-irradiated rats. Epiphyseal cartilage demonstrated recovery subsequently, and this was followed by a normal decrease of chondroitin sulfate with increasing age, but costal cartilage did not recover. Collagen synthesis was also reduced in both costal and epiphyseal cartilage, but not as dramatically as chondroitin sulfate. Except for some electron dense cells and reduced scalloping of the cell membrane, costal chondrocytes from irradiated rats did not show major ultrastructural alterations. In contrast, epiphyseal chondrocytes demonstrated radiation induced alterations in organelles, in enhanced glycogen deposition, and in retardation of chondrocyte maturation. Extracellularly in both costal and epiphyseal cartilage of irradiated rats, collagen density and matrix granules were reduced, while calcification of the matrix was enhanced. Beyond 45 days, the effects of irradiation were markedly reduced. Comparisons of the histochemical results with metabolic studies carried out previously in cartilage from the same animals indicated a more direct concordance of the histochemical results with the pattern of physical growth and supported the usefulness of morphologic and histochemical techniques in the analysis of the growth disorder in the head-irradiated rat.

Because of lack of agreement concerning the toxicity of paraquat to the pulmonary microvasculature, we have undertaken an electron microscopic study of lungs of paraquat-treated rats. Rats were injected with paraquat or sterile water (controls) intraperitoneally; the animals were then killed at 24-h intervals for 10 days post-injection. In the control animals, lung ultrastructure remained normal throughout the study. In treated animals, the initial evidence of alveolar epithelial injury occurred 24 h post-paraquat. By 48 h, severe fragmentation and desquamation of membranous pneumocytes occurred, and both alveolar and interstitial edema were present. Epithelial damage was maximal 72-96 h post-paraquat. Pulmonary capillary endothelial abnormalities were less extensive than the alveolar epithelial lesions. Endothelial damage was first observed 48 h post-paraquat. In endothelial cells on the septal (thick) side of the capillaries, the number of pinocytotic vesicles was significantly increased (P less than 0.05) from 48 to 96 h post-paraquat. In endothelium adjacent to damaged epithelium, abnormalities included hydration, fragmentation, discontinuity, and widened intercellular junctions; these were maximal 72-96 h post-paraquat. Although other mechanisms are probably important, damaged pulmonary capillary endothelium seems to be a factor favoring paraquat-induced pulmonary edema.

The effects of different doses of various steroids on growth, and on costal and epiphyseal chondrocytes, have been studied in prenatal, immature, and adult Long-Evans rats using histochemical techniques, and both light and electron microscopy. Both prenatal and postnatal treatments have been employed. The steroids used were cortisone (CA), betamethasome (BM), and, in the prenatal group only, dexamethasone (DM). Body weight is reduced in all treated rats (except the low dose of CA) by day 17 of gestation, with greater weight reductions occurring in rats receiving the higher dose level of each steroid. In rats treated prenatally or neonatally, and sacrificed postnatally on days 39-43 or days 116-127, body weights, and tibial and tail lengths, are less than in correspondingly aged controls, thus showing a persistence of the effects of treatment. Costal and epiphyseal cartilages in prenatal rats show cellular, synthetic, and ultrastructural alterations induced by treatment with glucocorticoids but the responses are not necessarily comparable. Except for the low dose of DM, the higher doses of each steroid are more effective in inhibiting, or altering, growth and cellular differentiation in the developing fetuses. Surprisingly, a low dose of DM has a more devastating effect on the cells and extracellular matrix of both costal and epiphyseal cartilage, than do higher dose-levels of the various steroids. Low doses of CA and BM are also effective in inhibiting or altering growth and cellular differentiation, but their effectiveness is largely limited to 17 days of gestation. The order of effect of the various doses of the different steroids on fetal cartilage, listed in decreasing order of severity, is as follows: 0.12 DM, 0.24 DM, 0.42 BM, 50 CA, with 25 CA and 0.18 BM being approximately equal and only slightly different from control cartilages. The effect of prenatal or neonatal glucocorticoid treatment on chondrocytes is minimal in the 30-43 days, or 116-127 day, postnatal groups. In immature and adult rats, cortisone affects the chondrocytes more deleteriously than does betamethasone, and a 5.0 mg dose of CA seems to affect chondrocytes, body weight, and tibial and tail lengths more than 0.2 or 7.5 mg doses.