Phase II clinical and pharmacological study of pirarubicin in combination with 5-fluorouracil and cyclophosphamide in metastatic breast cancer

Doxorubicin containing combination chemotherapy regimens are widely used for treatment of breast and other cancers. However, these regimens are associated with significant toxicities including myocardial dysfunction and alopecia. Analogues of doxorubicin are being developed to reduce these side effects. We conducted a Phase II trial of an anthracycline analogue, pirarubicin, administered in combination with 5-fluorouracil and cyclophosphamide every 3 weeks, as front-line chemotherapy in women with metastatic breast cancer. Patients who had received prior anthracycline therapy were excluded. The chemotherapy doses were as follows: 5-fluorouracil (500 mg/m2 on days 1 and 8), pirarubicin (50 mg/m2 on day 1), and cyclophosphamide (500 mg/m2 on day 1). Among 40 evaluable patients treated on this protocol, a major response (partial or complete remission) was observed in 26 patients (response rate, 62%; 95% confidence interval, 46-77). The median response duration was 8 months, and median survival was 16 months. Grade III/IV myelosuppression occurred in 81% of the courses. The median cumulative pirarubicin dose was 410 (range, 90-870) mg/m2. A significant decrease in left ventricular ejection fraction occurred in 12 patients (at a median cumulative pirarubicin dose of 460 mg/m2) and led to congestive heart failure in 4 of these patients (cumulative pirarubicin doses of 500, 520, 590, and 730 mg/m2, respectively). Eleven patients underwent endomyocardial biopsy, either because they experienced a drop in left ventricular ejection fraction or because they had received a cumulative pirarubicin dose of 600 mg/m2 and were still responding to the treatment. Of these, only one biopsy was found to be more than grade 1.0 (in an individual who had received a cumulative dose of 705 mg/m2). Severe alopecia occurred in two-thirds of the patients. Pharmacokinetic studies revealed a triphasic elimination of pirarubicin with alpha, beta and gamma half-lives of 0.12, 1.44, and 33.9 h, respectively. Total clearance of drug was 4.2 liters.1 h/kg while the cumulative 24-h urinary excretion was less than 10% of the administered dose. The activity of the combination appears to be similar to doxorubicin-containing regimens, while the incidence of alopecia appears to be lower than the historical experience with doxorubicin. However, cardiotoxicity remains a significant problem.     

Estrogen-replacement therapy in younger women with breast cancer

Approximately 25% of breast cancers occur in premenopausal women. In addition to local therapy, surgery or surgery plus irradiation, systemic chemotherapy administration has become the standard of care for all node-positive and many node-negative patients. Systemic adjuvant chemotherapy can result in ovarian dysfunction or failure. This renders many women prematurely estrogen deficient. The consequences of menopause, genitourinary atrophy, bone loss, and increased risk of cardiovascular disease, have not been routinely assessed in clinical trials. The risks of estrogen deficiency have not been assessed in comparison to improved disease-free and overall survival benefits of adjuvantly treated premenopausal breast cancer patients. Estrogen-replacement therapy in postmenopausal women has been shown to prevent osteoporosis and reduce fracture risk. The majority of studies also show a marked reduction in cardiovascular disease and mortality. Estrogen-replacement therapy has been considered a disease-prevention strategy rather than a therapeutic intervention. The risks and benefits of estrogen-replacement therapy in women with primary breast cancer are unknown. It is unknown how the well-known benefits accrued from reduction in skeletal and cardiovascular morbidity/mortality compare with the potential risks of increased breast cancer morbidity/mortality. Carefully designed prospective clinical trials with well-defined objectives and endpoints are required to learn if more harm than good is done by the withholding of estrogen therapy in breast cancer patients.     

Sudden death in the laboratory rat: cardiac function, sensory, and experiental factors in swimming deaths

Three reported charateristics of sudden death in the wild rat, (1) bradycardia, (2) decreased survival without whiskers, and (3) increased suvival with preexposure to the stressor, are demonstrated in the domestic rat. Differences in sudden death between wild and domestic rats are discussed as well as possible interpretations of the phenomenon.     

Economic incentives to use fertilizer on maize under differing agro-ecological conditions in Burkina Faso

Increasing agricultural productivity while protecting natural resources depends on proper understanding of farmers’ incentives to use intensification strategies, including fertilizer. Using a large-scale household dataset collected in rural Burkina Faso, we examined how the response of maize yield to fertilizer, and thus the economic incentives for its use, varied according to agro-ecological conditions. We employed a Control Function Approach with Correlated Random Effects in order to test and control for endogeneity of fertilizer use, measuring agro-ecological conditions at several scales. We investigated the profitability of fertilizer use with value-cost ratios. We found that productivity and marginal effects of fertilizer differ significantly according to agro-ecological conditions. Micro-variation appeared to be more critical than the definition of agro-ecological zone. Burkinabe soils are severely degraded and would benefit from greater application of fertilizer. However, at full market prices, fertilizer use was unprofitable. Though it was profitable with subsidized prices, transaction costs diminish the benefits of the subsidy. Profitability of fertilizer use with maize varied across agro-ecological conditions, even for field plots located in the same agro-ecological zone. Our results confirm that policy makers need to be cautious when generalizing across regions or drawing policy recommendations from a single agro-ecological zone because crop responses and economic incentives vary widely.     

The carboxyl-terminal extension on fungal mitochondrial DNA polymerases: identification of a critical region of the enzyme from Saccharomyces cerevisiae

Fungal mitochondrial DNA (mtDNA) polymerases, in comparison to their metazoan counterparts, harbour unique carboxyl-terminal extensions (CTEs) of varying lengths and unknown function. To determine the essential regions of the 279 residue CTE of the yeast enzyme (Mip1p), several CTE-truncation variants were expressed in Saccharomyces cerevisiae. The respiratory competence of mip1delta175 cells, in which Mip1p lacks the C-terminal 175 residues, is indistinguishable from that of wild-type. In contrast, strains harbouring Mip1pdelta351 and Mip1pdelta279 rapidly lose mtDNA. Approximately one in six mip1delta216 transformants grew on glycerol, albeit poorly. Fluorescence microscopy and Southern blot analysis revealed lower levels of mtDNA in these cells, and the rapid loss of mtDNA during fermentative, but not respiratory, growth. Therefore, only the polymerase-proximal segment of the Mip1p CTE is necessary for mitochondrial function. Comparison of this essential segment with the sequences of other fungal mtDNA polymerases revealed novel features shared among the mtDNA polymerases of the Saccharomycetales.     

A numerical model of the viscosity of an epoxy prepreg resin system

The development of the viscosity of a thermoset material during processing is complicated because of the dependence of the initial material state and the kinetic rate of conversion from a liquid to a solid material. Uncured thermoset materials typically have a low enough viscosity such that the consumption of energy to generate flow is relatively low. However, as the curing process advances, the flow mechanisms become hindered by the development of a network gel during crosslinking. Once the resin has reached the appropriate degree of cure for gelation, the resin system is incapable of large fluid-like deformations. In this research, the rheological properties of an epoxy resin system used in laminate processing were measured and numerically fit with a modification to the dual Arrhenius model to predict the progression of the viscosity during cure. The numerical results were compared with the experimental measurements, and it was found that the model predicts the experimental observations quite well. It was found that the initial degree of cure of the prepreg is not as significant a factor as the temperature rate dependence on the processing time between the point of flow onset and gelation. However, the minimum viscosity during processing is strongly influenced by the initial degree of cure of the prepreg system.     

Comparison of methods to identify outliers observed in health services small area variation studies

Small area variation analysis (SAV) is an established methodology in health services and epidemiological research. The goal is to demonstrate that rates differ across areas, and to explain these differences by differences in physician practice styles or patient characteristics. While the SAV statistics provide an overall variation estimate, they do not provide a statistical means to identify significant outliers. We compared the chi-square (chi2) test with three approaches in determining significant outliers in SAV. We used data from the Canadian Institute for Health Information (CIHI) for Ontario residents discharged between 1989 and 1991. Coronary artery bypass surgery, hysterectomy and hip replacement data were used to compare four statistics in determining outliers: the chi2 test, Swift's approximate bootstrap confidence interval (ABC), Carriere's T2 (T2) with simultaneous confidence intervals (SCI), and Gentleman's normalized scores (GNS). Both the ABC and SCI correct the skewness of the distribution of the adjusted rates. With large data, confidence intervals calculated by the normal or the ABC methods are indistinguishable. The T2 can be applied to also nonbinary events. For binary events, it is asymptotically the same as the chi2. The GNS ranks the rates, but the distribution of these ranks does not differ significantly from that of the adjusted rates. We concluded that when using large data with binary events, there is little advantage in using the ABC, SCI or GNS over the commonly known chi2. The chi2 remains a useful tool in small area variation analysis to 'screen' or flag potential differences beyond chance alone.