Influence of age on induction of mammary tumors by diethylstilbestrol in C3H/HeN mice with low murine mammary tumor virus titer.

C3H/HeN female mice with low murine mammary tumor virus titer (MTV-) were fed diets containing a targeted concentration of 640 ppb diethylstilbestrol [(DES) CAS: 56-53-1; 4,4'-(1,2-diethyl-1,2-ethenediyl)bis-phenol]. Mice were started on DES at 3, 5, 7, or 9 weeks of age. Some continued on the diet throughout the rest of their life-spans, whereas others were killed as soon as they had been fed DES for 2, 4, 6, 8, 10, or 12 weeks. Controls were also examined throughout the study. Among mice killed early, the only observation significantly influenced by age at the start of DES treatment was the presence or absence of corpora lutea (CL). DES did not prevent CL from appearing in mice started on DES at 7 or 9 weeks of age, but it did prevent their appearance in about 25% of the mice started at 5 weeks and in up to 75% of the mice started at 3 weeks of age. In the life-span-exposure groups, CL either disappeared or were never formed in 88% or more of the mice, regardless of age at the start of treatment. Neoplastic or presumptive preneoplastic lesions apparently influenced by DES in the life-span-treatment groups included ovarian tubular adenomas; granulosa cell tumors and luteomas; pituitary cystoid degeneration, hyperplasia, and adenomas; uterine adenocarcinomas and cervical adenosis; mesotheliomas; and mammary hyperplastic alveolar nodules (HANs) and adenocarcinomas. Luteoma and granulosa cell tumor incidences were reduced by DES, regardless of age at the start of treatment. Influence of age at the start of treatment was minimal or not apparent for mesotheliomas, uterine adenocarcinomas, or pituitary adenomas; however, pituitary cystoid degeneration and hyperplasia and cervical adenosis occurred in higher frequency and/or with shorter duration of DES exposure the earlier that treatment was started. A delay in the start of DES treatment was associated with a remarkable delay in HAN and mammary adenocarcinoma development. This was especially apparent in young mice (3-7 wk old) in which a 2-week delay in treatment resulted in a 20-week delay in HAN or tumor onset. Age at the start of treatment was a major factor in susceptibility of C3H/HeN-MTV- female mice to DES-induced mammary tumorigenesis.

Weekly docetaxel and estramustine in patients with hormone-refractory prostate cancer.

The combination of docetaxel and estramustine has exhibited synergistic activity both in prostate cancer cell lines and in patients with hormone-refractory prostate cancer (HRPC). Based on these promising preclinical and phase I/II data, we conducted a study of weekly docetaxel and estramustine in patients with metastatic HRPC and a poor performance status. A total of 30 patients received (1) a 3-day course of oral estramustine during weeks 1 and 2 of each 3-week cycle plus (2) docetaxel, 35 mg/m(2) intravenously on day 2 of weeks 1 and 2. The median number of cycles per patient was 5, ranging from 1 to 22. The median patient age was 74 years (range, 61 to 90 years), and the median baseline Karnofsky performance status was 60% (range, 50% to 80%). Twenty-three patients (76%) had a > or =50% decrease in serum prostate-specific antigen (PSA); 17 (56%) of these patients had a > or =75% decrease in PSA. Pain scores and performance status likewise improved in 70% of patients. Three complete responses and four partial responses were observed among 12 patients with measurable disease. Toxicities were primarily nonhematologic in nature, with the most common being grade 1 through 3 nausea, asthenia, diarrhea, and edema. Given the activity and tolerability of weekly docetaxel and estramustine in this study, this regimen appears to be more suitable than previously studied docetaxel/estramustine administration schedules for treating metastatic HRPC in elderly patients with a poor performance status.

An adverse interaction between warfarin and capecitabine: a case report and review of the literature.

Warfarin is one of the most commonly used oral anticoagulants in the clinic. It is well established that a wide range of antineoplastic drugs interact with warfarin, resulting in altered coagulation parameters and/or bleeding sequelae. While altered coagulation parameters have been observed in patients taking the oral 5-fluorouracil prodrug, capecitabine, in combination with warfarin, no report to date has described clinically overt evidence of bleeding. Herein, we report 2 cancer patients who presented with bleeding episodes that most likely resulted from an adverse interaction between capecitabine and warfarin after 6 weeks of concomitant therapy. In each case, there was a marked elevation in both the prothrombin time and international normalized ratio (> 10), with subsequent gastrointestinal bleeding. The exact mechanism of this interaction is yet unknown, but it is possible that capecitabine might, in some manner, reduce the hepatic metabolism of warfarin. Close monitoring of coagulation parameters is recommended for all patients receiving concomitant warfarin and capecitabine, with appropriate adjustment of warfarin dosage. The nature and extent of this interaction requires further investigation.

Squamous cell carcinoma of the colon with an elevated serum squamous cell carcinoma antigen responding to combination chemotherapy.

Primary squamous cell colorectal carcinomas are uncommon, and their characteristics are not well known. They seem to occur most commonly in the fifth decade of life with a slight predominance for men. The most commonly reported anatomic locations are the rectum and the proximal colon. Clinical features and common diagnostic methods do not easily differentiate squamous cell colorectal carcinomas from adenocarcinomas. Because of their extremely rare occurrence, it is difficult to study their natural course, clinical behavior, and response to therapy. This report presents the case of a pure squamous cell colorectal cancer and provides a brief review of the literature, which includes 60 previously published cases. The case of a patient with T3N2M0 primary squamous cell carcinoma of the rectosigmoid colon, which was initially treated with abdominoperineal resection followed by adjuvant chemotherapy and radiation, is presented. During the follow-up, an elevated squamous cell carcinoma antigen (SCC Ag) level led to restaging computed tomography scans, which confirmed recurrent metastatic disease in the liver. Response to chemotherapy with a decrease in tumor size correlated with a decrease in the serum SCC Ag level. Although SCC Ag has been used as a tumor marker for squamous cell cancers of the lung, head and neck, uterine cervix, and esophagus, this is the first reported case of a squamous cell colon carcinoma presenting with an elevated SCC Ag at the time of recurrence. In addition, this patient showed an objective partial response to combination chemotherapy, with a decrease in the serum level of this tumor marker.

Mammary tumorigenesis in C3H/HeN-MTV + mice treated with diethylstilboestrol for varying periods.

C3H/HeN-MTV+ female mice were fed diets containing 320 or 640 ppb diethylstilboestrol (DES). DES feeding was started at 3 wk of age and was either continued throughout life or discontinued after 4, 8 or 26 wk of administration. A control group consisted of mice fed the same diet without DES, for the duration of the experiment. Mice were killed when palpable body masses (presumed to be mammary adenocarcinomas) reached a diameter of 1 cm. Adenocarcinomas developed in 79% of control mice and 96% of the mice exposed to DES for 26 wk, irrespective of the dose. The frequency and rate of removal of tumour-bearing mice were not increased further with lifetime exposure at a given dose. The time at which the first tumour occurred was largely dependent on the duration of exposure, not dose. The rate of occurrence of subsequent tumours was dependent on dose and duration of exposure; the rate of removal of mice with mammary adenocarcinomas was significantly greater at 640 ppb than at 320 ppb DES. Tumour frequency was 83% in mice exposed to 320 ppb DES for 8 wk and in those exposed for 4 wk; however, tumours developed at a faster rate in mice exposed for 8 wk. Tumour frequency was 94-96% in mice exposed to 640 ppb DES for 4 wk and 8 wk, and tumours developed more rapidly in mice exposed for 8 wk than in those exposed for 4 wk. When data were plotted as log-dose v. log-t50 (time to a probability that half the mice would be removed with mammary tumours) linear extrapolation to the control log-t50 gave an estimate of the no-effect level of exposure to DES. This estimate was remarkably consistent for all data sets (40-93 ppb) and was independent of the duration of exposure.

Influence of strain and age on the induction of mammary tumours by diethylstilboestrol in C3H mice.

C3H/HeJ and C3H/HeN female mice were fed diets containing targeted concentrations of 320 or 640 ppb diethylstilboestrol (DES) starting at 7 or 11 wk of age and continuing throughout their remaining lifespan. Regardless of the DES concentration there was a faster rate of development and higher final incidence of mammary adenocarcinomas among the C3H/HeN mice than among the C3H/HeJ mice. In C3H/HeN mice started on DES when 11 wk old, mammary tumours developed more rapidly than when treatment was started at 7 wk of age. This was also true for C3H/HeJ mice given 320 ppb DES but not for those treated with 640 ppb DES. Both age at the start of treatment and strain of C3H mice are important factors to be considered in designing experiments to study the tumorigenic activity of oestrogens such as DES.

Influence of age and environment on the induction of mammary tumours by diethylstilboestrol in C3H/HeN-MTV+ mice.

C3H/HeN-MTV+ female mice were fed diets containing targeted concentrations of 320 or 640 ppb diethylstilboestrol (DES) starting at 3, 5, 7 or 11 wk of age and continuing throughout their remaining lifespan. Mice were housed in either a single-corridor conventional animal room or in a double-corridor barrier-type animal room. Mice housed in the conventional animal room and started on DES at 7 or 11 week of age developed palpable mammary tumours somewhat sooner than the corresponding groups of mice kept in the barrier animal room. In mice housed in the barrier animal room and exposed to a given DES concentration, there was very little difference between mice started on DES at 3, 5 or 7 wk of age in the exposure time required for the development of palpable mammary tumours. There was a striking difference, however, between mice started on DES at 7 wk and those started at 11 wk of age in the exposure time needed before mammary tumours appeared. Mice started at 11 wk of age developed tumours with, on average, about 4 wk less exposure than did those started at 7 wk. This suggests that treatment between 7 and 11 wk of age had little or no effect on mammary tumour development. In conclusion, both animal-room environment and age at the start of DES treatment influenced the mammary tumour response in female C3H/HeN-MTV+ mice.

Investigation of microtrauma after sexual intercourse.

An investigation was carried out to determine whether colposcopic examination would be valuable in documenting vaginal intercourse. A prospective study was conducted on 18 volunteers, each of whom was examined after 72 hours of sexual abstinence and again within 6 hours after vaginal intercourse. Each of two examinations consisted of a colposcopic examination of the vaginal mucosa before and after staining with Lugol's solution to maximize the possibility of finding trauma. Positive colposcopic findings were found in 61.1% of patients after consensual vaginal intercourse as compared with 11.1% of patients after abstinence (p less than 0.01).

Comparison of patient-controlled analgesia and epidural morphine for postcesarean pain and recovery.

A greater awareness of the advantages and limitations of new methods of administering postcesarean analgesia would help the obstetrician care for the recovering patient. Patient-controlled analgesia and epidural morphine are two new modalities for postoperative pain relief. The purpose of this prospective investigation was to compare their effectiveness, safety, side effects, patient satisfaction and cost. During an eight-month period, 161 women undergoing cesarean delivery were assigned to receive narcotics by either epidural morphine (76 patients) or patient-controlled analgesia (85 patients) using a combined continuous infusion and demand dosing of meperidine. The demographic characteristics of the two groups were similar. Mild or no pain was reported with similar frequencies in both groups. No reduced respiration or undesired sedation was seen in either group. The postoperative times before sitting at the bedside, ambulating, tolerating clear liquids and leaving the hospital were also comparable. No complications were encountered with patient-controlled analgesia, but pruritus and alarms from apnea monitors occurred commonly in the epidural morphine group. The costs to the patient were similar for the two groups. Patient-controlled analgesia using a combined continuous infusion and demand dosing is an acceptable alternative to epidural morphine after cesarean delivery.

Development and use of an automated clinical pharmacy services documentation system.

Clinical pharmacy practice has been shown to have a positive impact on patient care in hospitals, but is still the subject of much scrutiny in light of the current status of reimbursement for health care in the institutional environment. Although a number of systems have been utilized in an attempt to document workload and the impact of clinical pharmacy services, the ideal system has yet to be developed and methods for assessing the data generated are limited. This paper describes the development of an automated clinical pharmacy services documentation system which is interactive with database management, word processing, and statistics software. The present and future utilization of this system at the University of Nebraska Hospital and Clinics is discussed.

Antibiotic streamlining: monitoring and compliance.

The principles of antibiotic streamlining are discussed. At the University of Nebraska Medical Center, antibiotic streamlining is conducted through the coordination of decentralized pharmacists and a comprehensive drug-usage evaluation program. Streamlining is focused on reducing redundant antibiotic coverages and converting from i.v. to oral therapy whenever possible. Examples include switching from i.v. to oral ciprofloxacin and reducing the number of ampicillin-sulbactam, clindamycin combinations. Benefits and drawbacks of the program are discussed.

Dietary and age influence on the pharmacokinetic parameters of 2-acetylaminofluorene in BALB/c mice.

In a chronic study conducted in our laboratories, we found dietary effects on 2-acetylaminofluorene (2-AAF) toxicity. To determine if the absorption, distribution, metabolism, or elimination of 2-AAF was altered by the age of the animals, diet, or 2-AAF treatment, pharmacokinetic studies were conducted on young (11 weeks) and old (78 weeks) BALB/c mice that had been fed one of four diets containing 4 or 24% fat and 12 or 24% protein. Blood, urine, and feces samples were obtained over a 31-hr period after dosing with 500 ppm 2-[14C]AAF (10 microCi/mouse). Total radioactivity was determined after combusting each sample in an oxygen atmosphere and counting in a scintillation counter. The data from each individual mouse was simulated on an analog-digital hybrid computer utilizing a two-compartment model with metabolism. The pharmacokinetic parameters within groups were analyzed to make statistical comparisons of the effects of diet, dose, age, and interactions among the groups. The pharmacokinetic predictions of a shorter elimination half-life, smaller area-under-the-curve value, and therefore a decreased exposure to 2-AAF and metabolites due to an increased elimination rate of the parent compound through the urine were consistent with the decreased pathological effects found from the chronic study for the low protein/low fat diet mice.

Effect of a P & T committee newsletter on anti-infective prescribing habits.

P & T newsletters are commonly employed as a way in which to educate the medical staff. However, studies suggest that a newsletter is an ineffective method of education. This study describes the effects of a newsletter and direct in-service education on altering prescribing habits of physicians in a university-based teaching hospital. The newsletter and in-service recommended that physicians switch from a commonly used anti-infective to a more cost-effective alternative that had recently been added to the formulary. Prescribing patterns were altered and sustained for at least 3 months. The newsletter was at least as effective as direct in-service education.

Pathological changes in female C3H mice continuously fed diets containing diethylstilbestrol or 17beta--estradiol.

To study the long term effects of estrogen administration in mice, virgin female C3H/HeJ mice are being fed diets containing 0, 10, 100 or 500 ppb of diethylstilbestrol (DES) or 0, 100, 1000, or 5000 pph of 17beta-estradiol (E2) from 6 to 110 weeks of age. C3HeB/FeJ mice are being fed diets containing 08 10, 100, or 500 ppb DES FROM 6 TO 136 WEEKS OF AGE. Pathologic studies were conducted on 396 such mice sacrificed at 52 weeks and on over 500 others sacrificed at various intervals. After 52 weeks on 500 ppb DES or 5000 ppb E2, the cervix of both populations often showed stromal mucoid changes and adenosis characterized by focal replacement of squamous by columnar epithelium lining the cervical canal assoicated with glandular downgrowths into the subjacent stroma. The uterine horns showed hyperplastic glands, which often penetrated the muscularis, and focal endometrial and perivascular hyalin deposits. The ovaries showed atrophy with absence of corpora lutea. Ceroid deposits were increased in the ovaries and adrenals. Sternal bony trabeculae were increased. The incidence of uterine cervical adenosis and of mammary hyperplastic alveolar nodules and tumors (mainly type B, Dunn's classification), was higher in C3H/HeJ than in C3HeB/FeJ mice. Mice on lower doses of DES or E2 had less frequent and severe similar changes. Tumors observed to date only in estrogen-treated mice included 4 endometrial adenocarcinomas and an adenoacanthoma of a uterine horn, 14 cervical adenocarcinomas often appearing to arise from areas of adenosis, a vaginal squamous cell carcinoma, a cervical granular cell myoblastoma, 1 sternal and 3 cranial osteosarcomas, and a mesothelioma. The majority of the malignancies occurred in C3H/HeJ mice. These findings indicate that the mammary tumor virus factor facilitates DES-induced mammary tumorigenesis in C3H mice and may contribute to other DES-induced malignant and premalignant lesions.

Oil gavage test-compound administration effects in NTP carcinogenesis-toxicity testing.

Consulting toxicologists began in 1982 to question the use and potential involvement of oil gavage test-compound administration in unexpected NTP carcinogenesis responses. Investigations have focused on corn oil gavage alternatives, vehicle type and volume, alteration of MTD, teratogenic effects, disposition of test compounds, and target tissues. Micoencapsulation will require considerable development research to make it a suitable alternative. Vehicle type and volume appear to have different effects on the apparent MTD, teratogenicity and disposition of very similar compounds. Only two tissue effects have been observed in the NTP oil gavage bioassay data. First, there is a sporadic and weak association with exocrine pancreatic acinar cell proliferative lesions; these lesions are highly correlated with overweight male Fischer 344/N rats. Second, leukemia is reduced about 50 percent in the male Fischer 344/N rats; this is a strong association which results in an 8-10 percent increase in survival. The protective effect of corn oil gavage is remarkable and there is no significant enhancement of tumor development. Corn oil gavage under the conditions of the NTP carcinogenesis bioassay does contribute to overnutrition and undesirable increased body weight, especially in male Fischer 344/N rats. The NTP and NCTR research programs include research plans to address critical oil gavage, diet composition feeding regimen, exercise and hormonal status questions. Results of these studies will point the way to improving long-term carcinogenesis and toxicity testing.

Neoplastic and nonneoplastic responses to chronic feeding of diethylstilbestrol in C3H mice.

Over 3000 female C3H/Hen-MTV+ mice continuously received graded dietary levels (0, 2.5, 5, 10, 20, 40, 80, 160, 320, and 640 ppb) of diethylstilbestrol (DES) beginning at weaning. Mice were scheduled to be killed after 3 or 26 wk of exposure and were palpated weekly and removed for histological evaluation when subcutaneous masses reached 1 cm diameter. Mammary tumors were more prevalent than in controls only at 320 and 640 ppb DES. However, palpable mammary tumors appeared significantly earlier than in controls in mice fed 80 ppb and above. Mice killed at 3 wk and later showed a dose-response for several nonneoplastic endpoints. At 3 wk, moderate to severe uterine glandular hyperplasia, lack of corpora lutea, and vaginal keratinization were more prevalent than in controls at 80 ppb; cervical adenosis was more prevalent than in controls at 160 ppb and above. Generally, the prevalence of other nonneoplastic responses such as uterine fibrosis, stromal mucoid changes, and bony trabecular proliferation were increased above control levels only later than 3 wk at 160 ppb and greater. This study demonstrated neoplastic and nonneoplastic responses to DES at and above 80 ppb, but gave no clear evidence of either type of response below this level. Conclusions are, (1) dietary levels of DES causing nonneoplastic effects also cause neoplastic effects when fed chronically, and (2) neoplastic levels of DES may be predicted from a 3 wk feeding study in C3H/HeN-MTV+ female mice based on nonneoplastic responses.

Nonneoplastic changes induced in female C3H mice by chronic exposure to diethylstilbestrol or 17 beta-estradiol.

The long-term nonneoplastic effects of estrogenic diets were studied in female C3H/HeJ and C3HeB/FeJ mice. C3H/HeJ mice received diets containing 0, 10, 100, or 500 ppb diethylstilbestrol (DES) or 100, 1000, or 5000 ppb 17 beta-estradiol (E2) from 6 to 110 wk of age. C3HeB/FeJ females were fed diets containing nominal concentrations of 0, 10, 100, or 500 ppb DES from 6 to 136 wk of age. Responses of both strains to DES were qualitatively identical. Histological changes in the reproductive tract induced or increased by DES in both strains and by E2 in C3H/HeJ mice included stromal mucoid changes in the vagina and cervix, epithelial keratinization in the vagina, and glandular hyperplasia in the uterine horns. Increasing doses above 10 ppb DES or 100 ppb E2 increased the prevalence and, in some cases, severity of these responses. Dose-responses to DES for these endpoints were virtually indistinguishable in the two strains. At 10 ppb DES or 100 ppb E2 there were minimal or no observable effects. When the nonneoplastic dose-response data were compared with neoplastic dose-response data previously reported, no consistent relation between doses causing neoplastic and nonneoplastic responses was seen for the two estrogens.