Taxol plus recombinant human granulocyte-colony stimulating factor as initial and as salvage chemotherapy for metastatic breast cancer: a preliminary report

Twenty-eight patients received Taxol as their first chemotherapy for stage IV breast cancer. An additional 51 patients with extensive prior exposure to other chemotherapeutic agents received Taxol as salvage therapy. We found significant activity for the drug in both situations, as well as a strong clinical suggestion of non-cross-resistance with doxorubicin. An excellent response in previously irradiated skin was noted in one case. The routine use of recombinant human granulocyte-colony stimulating factor seemed to ameliorate some of the dose-limiting toxicity of neutropenia. Other toxicity was mild to moderate in most cases. With further development, Taxol should play a significant role in the systemic management of breast cancer.     

Increased apoptosis accompanies neoplastic development in the human colorectum

A disturbance in the balance between cell proliferation and cell loss, or apoptosis, may underlie neoplastic development. Therefore, we determined spontaneous apoptotic and proliferative rates in normal, hyperplastic, adenomatous, and malignant colorectal epithelia. In paired sections, DNA strand breaks were detected using the terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling assay, and apoptotic cells were also identified in H&E-stained slides by morphological criteria. Cell proliferation, bcl-2, and p53 expression were analyzed using specific monoclonal antibodies. In normal mucosa, luminal epithelial cells demonstrated higher rates of apoptosis compared to cells in the proliferative zone. Neoplastic transformation was associated with a significant increase in rates of apoptosis and proliferation. However, apoptosis, but not proliferation, decreased at the adenoma-to-carcinoma transition coincident with expression of mutant p53. In carcinomas, both mutant p53 and bcl-2 protein levels were associated with attenuated apoptotic rates. In conclusion, apoptosis is an important regulator of growth in normal and neoplastic colorectal epithelia. Increased apoptosis and proliferation accompany neoplastic transformation, suggesting that an alteration in apoptotic rates is an important event in colorectal carcinogenesis. Furthermore, the imbalance in these processes found in carcinomas may facilitate tumor growth and progression.     

The risks of licensing persons with diabetes to drive trucks

The 1990 Americans with Disabilities Act forbids employers to bar disabled persons from jobs unless employers can show the disabled person cannot perform the tasks. The Federal Highway Administration will not license persons with diabetes mellitus to drive commercial motor vehicles in interstate commerce. These individuals may experience severe hypoglycemia, greatly increasing their risk of losing control of the truck. This prohibition is currently being reexamined. We describe the disease process leading to severe hypoglycemia and its physical manifestations. To quantify the risks of licensing persons with diabetes to use insulin, we first estimate the number of potential insulin-using drivers. We estimate that 1420 insulin-using persons would seek licenses in the United States if they were permitted to do so (920 noninsulin dependent and 500 insulin dependent). Next, we estimate the annual incidence of mild and severe hypoglycemia in these populations. The third step is to estimate the number of hypoglycemic episodes while driving. Estimating the likelihood of a crash due to a mild or severe hypoglycemic episode is the fourth step. We estimate that an additional 42 crashes each year would occur if insulin using persons were licensed to drive commercial motor vehicles in interstate commerce (20 from insulin dependent and 22 from non-insulin dependent drivers).     

Mifepristone prevents the expression of long-term behavioural sensitization to amphetamine

Three weeks following intermittent amphetamine exposure (2.5 mg/kg/day for 5 days), rats showed an enhanced locomotor response to an amphetamine challenge. Mifepristone (20 mg/kg) given 45 min prior to the challenge completely prevented the expression of amphetamine hyperresponsiveness. The glucocorticoid antagonist did not affect the locomotor response to amphetamine in drug-naive rats. These data demonstrate for the first time that glucocorticoid receptor antagonist treatment may prevent long-term hyperreactivity to drugs of abuse in individuals with a drug history.     

Two pyridinium metabolites of haloperidol are present in the brain of patients at post-mortem

We have shown in patients taking the antipsychotic drug haloperidol (HP) that two pyridinium metabolites (HPP+ and RHPP+) are present in blood and urine in nM concentrations. These metabolites are structurally analogous to MPP+, the neurotoxic metabolite of the well-known parkinsonian-producing protoxin, MPTP. In this study we measured the concentrations of HPP+ and RHPP+ in seven regions of the brain (putamen, substantia nigra, globus pallidus, caudate, hippocampus, cerebellum and occipital cortex) obtained at post-mortem from three patients who were taking HP before death. Blood, urine, and bile from one patient were analysed as well. HPP+ was present in all regions (except for substantia nigra in one patient and globus pallidus in another); the amount/g ranged from 1.6-8.3 pMol but there was no preferential sequestration of the metabolite in dopaminergic regions. Similarly, RHPP+ was present relatively uniformly in all regions; the amount/g ranged from 1.1-7.6 pMol. The concentrations of HPP+ and RHPP+ in one patient were 24 and 13 nM in blood, 660 and 230 nM in urine, and 13.0 and 1.4 microM in bile, respectively. The presence of these pyridinums in brain adds another important piece of information to the case that, at least for HP, metabolite-induced neurotoxicity could contribute to the extrapyramidal side-effects in patients receiving long-term therapy.     

Regression of subcutaneous lymphoma following removal of an ovarian granulosatheca cell tumor in a horse

A 9-year-old Arabian mare was admitted for evaluation of multiple subcutaneous nodules and infertility. Fine-needle aspiration of one of the subcutaneous nodules resulted in a cytologic diagnosis of histiolymphocytic lymphoma. Palpation per rectum and transrectal ultrasonography revealed a mass associated with the left ovary. Excision of the ovarian tumor was performed, and a histopathologic diagnosis of granulosa-theca cell tumor was made. After removal of the granulosa-theca cell tumor, subcutaneous nodules regressed. The referring veterinarian reported that the nodules had also disappeared and then recurred after administration of a synthetic progestin. To further characterize the lymphoma and investigate this possible hormonal relationship, immunophenotyping and estrogen and progesterone receptor assays were performed. The subcutaneous lymphoma was classified as a T-cell rich B-cell lymphoma, results of estrogen receptor assays were negative, and results of progesterone receptor assays were positive. Clinical observations of subcutaneous lymphoma in horses indicate that the waxing and waning nature of these tumors may be associated with the estrous cycle, pregnancy, foaling, and lactation. Clinical observations and identification of progesterone receptors suggest that a relationship between serum steroid hormone concentrations, such as estrogen and progesterone, and subcutaneous lymphoma may exists.     

Joe Doupe Young Investigators Award. The Human Genome Project: tools for the identification of disease genes

In the first phase of the Human Genome Project, new and ingenious tools have made it possible to map all the individual nucleotides that make up the 23 human chromosomes. During the next 5 years, the 3 billion DNA bases and the 50,000 to 100,000 genes will be sequenced. This knowledge will have widespread applications in biology, medicine and industry. The genetic research community currently has access to abundant DNA markers, detailed chromosome maps, extensive online databases as well as rapid DNA analysis technologies, all of which can be used to identify disease-causing genetic mutations. In the next 15 to 20 years, the Human Genome Project is expected to identify defective genes causing thousands of hereditary diseases, including common diseases such as heart disease, diabetes, asthma and cancer. The hope is that these discoveries will lead to better understanding of the causes of these diseases, and to better approaches to diagnosis, prevention and treatment of human genetic disorders.