William J. Mackillop

Non-small cell lung cancer: how oncologists want to be treated

One hundred and eighteen Canadian doctors who treat lung cancer were asked how they would wish to be managed if they had non-small cell lung cancer. Four clinical situations were described. The doctors replies to the open-ended management questions were remarkably consistent in view of their diverse backgrounds. Although opinion was divided as to the role of immediate radiotherapy in inoperable cancer, and the role of post-operative radiotherapy following incomplete surgery, there was little controversy as to the role of chemotherapy. Three per cent of doctors wanted adjuvant chemotherapy after surgery for early disease, 9% wanted chemotherapy for advanced disease confined to the chest and 15% wanted chemotherapy for symptomatic metastatic disease. The implications of these results are discussed in the light of current recommendations for treatment of non-small cell lung cancer in the standard North American textbooks of oncology.

Stage III endometrial carcinoma. A review of 90 cases

The authors present a retrospective review of 90 cases of Stage III endometrial carcinoma seen over a 10‐year period at the Princess Margaret Hospital, Toronto. Overall 5‐year survival was 45.5% and disease‐free survival was 36.0%. Prognostic factors identified within Stage III were tumor grade, geographic distribution of disease, the presence of symptoms other than vaginal bleeding or discharge, and completeness of surgery. Isolated involvement of the ovary or fallopian tube emerges as a distinct syndrome with a good prognosis (5‐year survival of 82.3%). Surgery is the treatment of choice for operable cases, but 13 of 36 patients with inoperable disease who completed radical radiotherapy were alive and free of disease at 5 years.

Thermal adaptation in CHO cells at 40°C: the influence of growth conditions and the role of heat shock proteins

The kinetics of thermal adaptation at the nonlethal temperature of 40 degrees C was studied in CHO (Chinese hamster ovary) cells in vitro. Thermal resistance, demonstrated as an increase in mean 45 degrees C killing time or as an increase in the shoulder of the 45 degrees C survival curve, was fully developed by 2 h. Control cells in early logarithmic phase were more heat sensitive than those in stationary phase. Corresponding 45 degrees C killing time frequency distributions were unimodal with an increase in mean killing time from early logarithmic to stationary phase. Cells which were thermally adapted at 40 degrees C for 6 h had biphasic 45 degrees C killing time frequency distributions, and as cells progressed from early logarithmic to stationary phase the heat-sensitive subpopulation progressively declined. Exposure to 40 degrees C produced a 30% increase in total protein synthesis. Proteins with molecular weights 72, 89, and 109 kDa which correspond to those induced by lethal heat shock were synthesized at 40 degrees C, but there was no close temporal correlation between the development of heat resistance at 40 degrees C and synthesis of the heat shock proteins. Cycloheximide (100 micrograms/ml) reduced the mean 45 degrees C killing time but did not totally prevent the development of heat resistance at 40 degrees C.

The effect of hyperthermia on the sodium-potassium pump in Chinese hamster ovary cells.

The effect of hyperthermia on the Na+-K+ pump was determined by measuring influx and efflux of 86Rb+ in Chinese hamster ovary cells from 31 to 50 degrees C. The maximum initial rate of ouabain-sensitive influx increased with temperature between 31 and 45 degrees C although Km increased significantly above 37 degrees C, implying a diminished affinity of the transport protein for its substrate. The changes in the kinetics of influx at temperatures up to 45 degrees C were rapidly reversible on return to 37 degrees C. Above 45 degrees C an irreversible decrease in 86Rb+ uptake was observed. Efflux of 86Rb+ increased from 31 to 40 degrees C but above 43 degrees C showed a small but significant decrease. The study of 86Rb+ influx after varying times of exposure to elevated temperatures showed that the Na+-K+ pump remains functional in cells which are reproductively dead. We have shown that although the kinetics of K+ transport are sensitive to temperature changes in the range used in clinical hyperthermia, the inactivation of the Na+-K+ pump is not a primary event in cell killing.

The effect of hyperthermia on the uptake and cytotoxicity of melphalan in chinese hamster ovary cells

The effect of temperature on the cytotoxicity of melphalan in CHO cells was studied in an in vitro clonogenic assay. The cytotoxicity of melphalan was significantly increased at elevated temperatures with a 4 fold increase in cytotoxicity at 42 degrees C compared to 37 degrees C. The effect of temperature on membrane permeability to melphalan was studied to determine whether the increase in cytotoxicity was due to increased intracellular drug levels. Melphalan influx and efflux rates both increase with increasing temperature. There is, however, a small net increase in steady state intracellular drug levels with increasing temperature with a 20% increase in intracellular drug levels at 42 degrees C compared to 37 degrees C. The increase in drug uptake observed in insufficient to explain the much greater increase in cytotoxicity with increasing temperature.

Ethical problems in clinical research: The need for empirical studies of the clinical trials process☆

Societys demand for progress in medicine is expressed in the form of large sums of money poured into medical research by national governments and voluntary agencies. It is widely accepted within the medical profession that society has a right to expect continuing progress in medical practice and it has been argued that the doctor must therefore sometimes weigh societys interests against those of his individual patient. This essay discusses the origin of the concept of the societal obligation of the physician and the difficult position of the clinician-scientist who attempts to meet societys demands for progress while maintaining his traditional loyalty to the individual patient. Empirical studies which describe the impact of the clinical trials process on the practice of medicine are discussed and it is shown that the large scale clinical trials of today may influence aspects of medical practice far removed from the immediate problems which they are designed to study. It is concluded that further research is needed to study the process of clinical experimentation and its societal implications and that the debate must extend beyond the medical profession to involve the general public.

Adriamycin uptake, intracellular binding and cytotoxicity in Chinese hamster ovary cells

The interaction between adriamycin influx, efflux and cytotoxicity has been studied in Chinese hamster ovary (CHO) cells. The rate of adriamycin uptake showed no evidence of saturation with increasing concentration suggesting that uptake occurred by passive diffusion. Plateau levels of adriamycin were reached within 20 min and more than 60% of this was firmly bound to the nucleus and did not efflux. Cytotoxicity studies did not correlate with uptake studies in that cell killing was an exponential function of drug exposure time well beyond the point at which intracellular concentrations had reached a maximum. This suggests that bound adriamycin is not primarily responsible for cytotoxicity.

The effect of hyperthermia on glucose transport in normal and thermal-tolerant Chinese hamster ovary cells

The effect of hyperthermia on glucose transport was studied in CHO cells to test the hypothesis that interference with membrane transport might be related to cell death at elevated temperatures. It was shown that passive diffusion of 2-deoxyglucose increases steadily over the temperature range 4-50 degrees C. Facilitated diffusion increases from 4 degrees C to 35 degrees C then exhibits a broad optimum before decreasing rapidly above 45 degrees C. The temperature dependence of glucose transport in thermally resistant cells was not however different from that of normal cells suggesting that this membrane transport process is not a critical target in cell killing by heat.

Cellular heterogeneity in normal human urothelium: Quantitative studies of lectin binding

SummaryA panel of 10 FITC-labelled lectins (MPA, PNA, ConA, DBA, SBA, RCA-120, WGA, UEA, GS-I, GS-II) was applied to cryosections of seven specimens of normal urothelium. Seven of the lectins (MPA, ConA, RCA, WGA, UEA, GS-I and GS-II) showed a pattern of increasing fluorescence intensity from basal to superficial cells of the urothelium whereas PNA, DBA and SBA showed more uniform binding throughout the urothelium. Urothelial cell suspensions labelled with FITC-lectins were studied by flow cytometry to quantify the variation in binding to different cells types. Three cellular subpopulations were identified in normal urothelium on the basis of their optical properties. Fluorescence intensity due to specific lectin binding was then measured separately for each subpopulation. Although there was some variation among individual cases, a general pattern emerged in this small series. WGA, RCA, and GS-II bind in large quantities to all urothelial cells while PNA, SBA, ConA and DBA show little binding. MPA, RCA, UEA and GS-I showed the most marked increase in fluorescence intensity from basal to superficial cells as observed microscopically and quantified by flow cytometry.

The effect of hyperthermia on intracellular K+ in Chinese hamster ovary cells.

The effect of hyperthermia on intracellular K+ concentrations was studied in Chinese hamster ovary (CHO) cells in vitro, using a flame photometer. Intracellular K+ concentrations decreased with increasing exposure time at temperatures from 40 degrees C to 45 degrees C. The decrease in K+ concentrations preceded any loss of reproductive capability at 43 degrees C and also occurred at the non-lethal temperature of 40 degrees C. Prolonged exposure to 45 degrees C resulted in an irreversible decrease in K+ concentrations. The decrease in K+ concentrations at elevated temperatures was not accounted for by changes in cell volume, loss of cells or failure of the Na+/K+ pump.