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Purpose: This study was designed to compare tumor hypoxia assessed by invasive O2 sensitive electrodes and pimonidazole labeling in primary human cervix carcinomas., Methods and Materials: Twenty-eight patients with primary cervix carcinomas (FIGO Stage Ib-IVa) were investigated. Both invasive pO2 measurements and pimonidazole labeling were obtained in all patients. Before treatment, patients were given pimonidazole as a single injection (0.5 g/m2 i.v.). Ten to 24 h later, oxygenation measurements were done by Eppendorf histography, and after this procedure biopsies were taken for pimonidazole-binding analysis. Tumor oxygen partial pressure (pO2) was evaluated as the median tumor pO2 and the fraction of pO2 values < or = 10 mmHg (HF10). Biopsies were formalin fixed and paraffin embedded, and hypoxia was detected by immunohistochemistry using monoclonal antibodies directed against reductively activated pimonidazole. Pimonidazole binding was evaluated by a semiquantitative scoring system., Results: Both Eppendorf measurements and pimonidazole binding showed large intra-and intertumor variability. A comparison between pimonidazole binding expressed as the fraction of fields at the highest score and HF10 showed a trend for the most well-oxygenated tumors having a low fraction of fields; however, the correlation did not reach statistical significance (p = 0.43, r = 0.165; Spearman's rank correlation test)., Conclusion: Hypoxia measured in human uterine cervix carcinomas is heterogeneously expressed both within and between tumors when assessed by either invasive pO2 measurements or pimonidazole binding. Despite a trend that tumors with high pO2 values expressed less pimonidazole binding, no correlation was seen between the two assays in this preliminary report.

The effect of step-down heating was investigated in the skin of the CDF1 mouse foot. Step-down heating was induced with a 44.7 degrees C/10 min pretreatment followed by a test treatment at a lower temperature for variable time. Step-up heating, that is, a test treatment followed by a 44.7 degrees C/10 min treatment, and single heating were used as controls. The normal tissue reaction was scored at five levels of damage (from slight redness and oedema to loss of a toe or greater reaction), and the heating time to induce each level in 50% of the animals, RD50, was used as the endpoint. The effect of step-down heating was quantified by the step-down ratio, calculated as the ratio of test heating times to obtain the endpoint. A significant reduction of the RD50 was seen at all score levels when the 44.7 degrees C/10 min was given in a step-down heating schedule, and the effect increased with decreasing test treatment temperature. In contrast, the heat sensitivity was only marginally influenced by step-up heating. An analysis of the time-temperature relationship demonstrated a log-linear relationship between temperature and RD50 for single heating in the range 42.2-44.7 degrees C and for step-down heating in the range 41.7-44.7 degrees C. The curve for step-down heating showed a lesser slope indicating a decrease of the activation energy. The kinetics of the SDH effect were investigated by inserting an interval between a primary 44.7 degrees C/10 min treatment and a test treatment performed at 42.2 degrees C. The effect of step-down heating was maximal with no interval between the priming treatment and the test treatment. As the interval was increased to 1.5 hr the step-down sensitization disappeared, and with even longer intervals thermotolerance developed. From a clinical point of view, the present data indicate that step-down heating may increase the extent of both reversible and irreversible heat damage in the normal tissue.

The effect of fractionated 43.7 degrees C water bath heating on the skin of CDF1 mice was investigated. The normal tissue damage was scored at five levels (from slight redness and oedema to loss of a toe or greater damage) according to an arbitrary score system. The heating time to induce a given level of damage in half of the treated animals (RD50) was used as an end point. The feet were exposed either to a single treatment at 43.7 degrees C for different time periods or to a priming treatment of 30 min. at 43.7 degrees C followed at different intervals by a second graded heat treatment at 43.7 degrees C. In all treatment schedules, the score level increased proportionally with heating time, and the score system offered a good description of the acute skin damage following hyperthermia. The priming heat treatment induced thermotolerance with a time course independent of the score level chosen to estimate the heat response. The thermotolerance developed rapidly, reached a maximum within a 24 hr. interval, and then decayed slowly. The degree of thermotolerance was calculated by means of two previously described formulas for the thermotolerance ratio (TTR). The kinetics of thermotolerance in the skin of mice was independent of the TTR formula, whereas the degree of thermotolerance depended on both the score level and the TTR formula used.