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Biomedical subjects

R J Winn

Publications and source records attributed to R J Winn.

At least 55 records · Page 3Linked to original sources
PubMed1994

Individual and combined effects of relaxin, estrogen, and progesterone in ovariectomized gilts. II. Effects on mammary development.

Marked development of the mammary parenchyma (ducts, lobules, and alveoli) occurs during the last third of the 115-day gestation period in the gilt. These changes in the mammary gland are temporally correlated with elevated blood levels of relaxin, estrogen, and progesterone. We recently demonstrated that relaxin plays a major role in promoting the development of the mammary parenchyma that occurs in pregnant gilts. The roles of estrogen and progesterone in the mammary gland in gilts remain poorly understood. Accordingly, this study determined the influence of relaxin, estrogen, and progesterone, individually and in combination, on mammary development. Fifteen days after ovariectomy, six to eight nonpregnant sexually mature gilts were assigned to one of the following eight treatment groups: ovariectomized controls, relaxin treated, estrogen treated, progesterone-treated, estrogen plus relaxin treated, progesterone plus relaxin treated, estrogen plus progesterone treated and progesterone plus estrogen plus relaxin treated. Treatment was given for 10 days, with doses of relaxin (0.5 mg, four times daily), estradiol benzoate (1 mg, twice daily), and progesterone (50 mg, twice daily) selected to provide blood levels similar to those occurring between days 100-110 of gestation. The fourth mammary gland from the anterior end was collected. The cross-sectional area of the parenchymal tissue was used to measure the extent of parenchymal development. To examine mammary parenchymal development in more detail, the effect of hormone treatment on lobulo-alveolar development was conducted using morphometric analysis. Relaxin alone had little effect on mammary development, and estrogen alone stimulated mammary development only modestly. In contrast, combined treatment with estrogen and relaxin stimulated mammary development markedly. Progesterone alone had no effect on lobulo-alveolar development, but, surprisingly, when administered in combination with relaxin, progesterone reduced the organization of the collagen fibrils of the mammary stroma. In conclusion, this study is consistent with recent reports that relaxin plays an important role in the development of the mammary gland in gilts. Moreover, it demonstrates that relaxin acts in concert with estrogen to stimulate development of the mammary parenchyma. Finally, this study demonstrates that relaxin in concert with progesterone decreases the organization of the collagen matrix surrounding the growing mammary gland. This study is consistent with the view that relaxin, estrogen, and progesterone all very likely play roles in the development of the mammary gland in gilts.

Animals↗
PubMed1994

Obstacles to the accrual of patients to clinical trials in the community setting.

Data indicate that substantial pool of candidates exists, especially in the community setting, for enrollment in clinical oncologic trials. However, only a small proportion of cancer patients are actually enrolled. Obstacles to accrual include physician determinants, patient determinants, organizational issues, and health care system factors. Physicians can influence patient enlistment in their capacity as either referring physician or study investigator. A practitioner's medical orientation may impact the likelihood of referral. Physicians reluctant to enroll patients cite logistic and practical problems and the potential for disrupting patient relationships; a trial's protocol also may be questioned. Patient refusals to participate in clinical trials may stem from practical concerns, psychosocial issues, or a wariness of toxic treatment effects. Organizational issues affecting patient accrual have not been extensively studied; an institutional review board's view of research may be a major factor. Health care system factors such as escalating costs and prohibitive reimbursement policies of third-party payers also adversely affect accrual, and will require a new commitment to minimizing protocol costs. Continued evaluation of physician and patient barriers to accrual is warranted. Once these barriers are recognized, randomized intervention trials will be required to identify ways to overcome them.

Clinical Trials as Topic↗
PubMed1993

Phase II study of taxol in patients with untreated advanced non-small-cell lung cancer.

BACKGROUND: Taxol, a complex plant product (a diterpene) extracted from the bark of Taxus brevifolia, has demonstrated substantial anticancer activity in ovarian and breast cancers, malignant melanoma, and acute myelogenous leukemia. Due to allergic reactions in phase I and early phase II studies, use of a 24-hour infusion of taxol with prophylactic dexamethasone, diphenhydramine, and cimetidine has been recommended. PURPOSE: In this phase II study, we attempted to determine the efficacy and toxicity of taxol in patients with advanced (stage IIIB or IV) non-small-cell lung cancer who had never received chemotherapy. METHODS: Patients were not excluded because of prior surgery or because of radiotherapy administered more than 4 weeks before study entry. Taxol was administered in the hospital at a dose of 200 mg/m2 as an intravenous infusion over 24 hours and repeated every 3 weeks, provided that patients had recovered from any toxic effects. Dexamethasone, cimetidine, and diphenhydramine were given before chemotherapy to prevent hypersensitivity reactions. Therapy was continued for at least two courses unless there was rapid disease progression and for at least three courses if no change was observed and no grade 3 or 4 toxic effects occurred. Treatment was continued for six more courses after maximum response or for two more courses after complete remission but was discontinued if disease progressed. RESULTS: Of the 27 patients entered in the study, 25 were assessable for toxic effects and response. One patient had an allergic reaction that was not life threatening. The overall response rate was 24% (one complete response and five partial responses). An additional seven patients (28%) had minor response. Granulocytopenia was the dose-limiting toxic effect, and neutropenic fever occurred in eight of 118 courses. One additional patient developed neutropenic sepsis with hypotension but recovered with intensive treatment. CONCLUSIONS: Taxol appears to have activity against non-small-cell carcinoma of the lung. IMPLICATIONS: A phase II study combining taxol, etoposide, and cisplatin and using hematopoietic stimulating factors is now proposed. The optimal dose for combination chemotherapy has yet to be determined. An important consideration is potential cardiac effects of taxol with other drugs.

Carcinoma, Non-Small-Cell Lung↗
PubMed1993

Regression of oral leukoplakia with alpha-tocopherol: a community clinical oncology program chemoprevention study.

BACKGROUND: Oral leukoplakia is an important model for developing chemoprevention approaches for lesions in the upper aerodigestive tract. These lesions most often result from exposure to carcinogens such as tobacco and alcohol and may precede development of invasive cancer. The potent antioxidant alpha-tocopherol (vitamin E) has prevented the development of cancers of the oral cavities in animal models. PURPOSE: The objectives of this study were to evaluate the toxicity and efficacy of alpha-tocopherol in patients with oral leukoplakia and to assess the feasibility of performing chemoprevention trials through the network of the Community Clinical Oncology Program (CCOP). METHODS: A single-arm phase II study using the nontoxic agent alpha-tocopherol to treat oral premalignant leukoplakia was performed at seven institutions affiliated with the CCOP through The University of Texas M. D. Anderson Cancer Center. Patients with symptomatic leukoplakia or dysplasia were treated orally with alpha-tocopherol (400 IU) twice daily for 24 weeks. Follow-up was performed at 6, 12, and 24 weeks after the start of treatment to assess toxicity and response, and serum alpha-tocopherol levels were determined at baseline and at 6 and 24 weeks. RESULTS: Of the 43 patients who have completed 24 weeks of treatment, 20 (46%) had clinical responses and nine (21%) had histologic responses. Mean serum alpha-tocopherol levels were 16.1 micrograms/mL at baseline and increased to 34.29 micrograms/mL after 24 weeks of treatment. Patient-recorded drug calendars, as well as serum drug levels, indicated excellent patient compliance; an average of 95% of the prescribed pills were taken. Treatment was extremely well tolerated; no grade 3 or 4 toxic effects were reported. CONCLUSIONS: Administration of alpha-tocopherol resulted in both clinical and histologic responses in premalignant leukoplakia lesions. The study also demonstrated that chemoprevention trials can be performed through the CCOP. The major problems were that a high percentage of patients were not assessable for response, some patients withdrew because expenses were not reimbursable, and there was limited participation within the CCOP network. These problems may reflect difficulties inherent in the implementation of multi-institutional chemoprevention trials. IMPLICATIONS: The efficacy of alpha-tocopherol alone and in combination with other chemopreventive agents for carcinogenesis in the upper aerodigestive tract should be explored in future trials.

Alcohol Drinking↗
PubMed1993

Hormonal control of the cervix in pregnant gilts. IV. Relaxin promotes changes in the histological characteristics of the cervix that are associated with cervical softening during late pregnancy in gilts.

We recently described relaxin-induced changes that occur in both the physical properties and the biochemical composition of the uterine and vaginal portions of the cervix during the last third of gestation in the gilt. This study employed morphometric analysis to examine both the changes that occur in the histological characteristics of the uterine and vaginal portions of the cervix between days 80 and 110 of pregnancy in intact gilts and the effects of relaxin on these changes in ovariectomized gilts given progesterone to maintain pregnancy. There were four treatment groups: intact day 80 control gilts, sham-ovariectomized day 110 control gilts, ovariectomized progesterone-treated day 110 gilts, and ovariectomized progesterone- plus relaxin-treated day 110 gilts. The histological characteristics of the uterine portion of cervices obtained from intact controls on day 110 differed markedly from those of intact controls on day 80; there was a reduction in the density and organization of collagen fiber bundles, a reduction in the density of smooth muscle fiber bundles, and an increase in amorphous ground substance. The histological characteristics of cervices removed on day 110 from ovariectomized gilts given progesterone only did not differ from those of day 80 controls. After replacement therapy with progesterone plus relaxin, however, the histological characteristics of the cervix on day 110 did not differ from those in intact day 110 controls. Additionally, this study demonstrates that the relaxin-dependent changes are more dramatic in the uterine than in the vaginal portion of the cervix. These findings are consistent with and extend our earlier findings that relaxin-dependent changes in the physical properties and biochemical composition of the uterine portion of the cervix far exceed those in the vaginal portion of the cervix during late pregnancy in the gilt. We conclude that the relaxin-dependent changes in the histological characteristics of the cervix described in this report may contribute at least in part to the cervical softening that occurs during late pregnancy in gilts.

Animals↗
PubMed1993

A phase II study of merbarone in patients with adenocarcinoma of the pancreas.

Merbarone, a nonsedating derivative of thiobarbituric acid that has demonstrated antineoplastic activity against a variety of murine tumors, was evaluated in a phase II trial in patients with advanced, measurable adenocarcinoma of the pancreas. Seventeen patients were treated at a starting dose of 1000 mg/m2/day for 5 days by continuous intravenous infusion; the dose was escalated in accordance with the toxicity experienced, and no dosage reductions owing to toxicity were required. No complete or partial responses were observed, and only one minor response was documented, suggesting that merbarone is ineffective against pancreatic cancer at the doses and schedule in which it was administered in this trial.

Adenocarcinoma↗
PubMed1992

Phase II trial of trimetrexate for unresectable or metastatic non-small cell bronchogenic carcinoma.

We treated 34 chemotherapy-naive patients with stage IIIb or IV non-small cell lung cancer with trimetrexate 150-200 mg/m2 intravenously over 30 minutes every two weeks. Six of 31 evaluable patients (19%) achieved a partial response. The major toxic effects from this regimen were myelosuppression, nausea/vomiting, and skin rash. We conclude that this well-tolerated schedule of trimetrexate has significant activity as a single agent against non-small cell lung cancer.

Adult↗
PubMed1991

Phase II study of intravenous 6-thioguanine in patients with advanced gastric carcinoma.

In a phase II study, 18 patients with advanced gastric carcinoma were treated with intravenous 6-thioguanine. A 30-minute infusion of 55 mg/m2 (starting dose) was administered once a day for 5 consecutive days, the courses being repeated every 5 weeks. A median of 2 courses (range, 1-4) was administered. Among the 18 patients, 17 having measurable cancer and optimum follow-up were fully assessable for response. None of the patients achieved a complete or partial response. One patient achieved a transient minor response (15 weeks) of the primary gastric carcinoma but the metastatic carcinoma was unchanged. One patient had no change in his measurable carcinoma, and the other 15 patients had progressive disease while receiving intravenous-6-thioguanine. Myelosuppression, although frequent, was mild to moderate at these doses and did not result in significant morbidity. Nonhematologic toxicities were also mild. Our data suggest that intravenous 6-thioguanine given at this schedule is ineffective in previously untreated patients with advanced gastric carcinoma.

Adult↗
PubMed1991

Phase II study of intravenous 6-thioguanine in patients with advanced carcinoma of the pancreas.

In a phase II study, 32 patients with advanced pancreatic carcinoma were treated with intravenous 6-thioguanine. A 30-min infusion of 55 mg/m2 (starting dose) was administered once a day for 5 consecutive days, the course being repeated every 5 weeks. A median of two courses (range, 1-10) was administered. Among the 32 patients, 30 having measurable cancer and optimum follow-up were fully assessable for response. One patient achieved a partial response of extensive liver metastases (12+ months), and another patient had a transient minor response (5 weeks). Cancer in 27 of 30 assessable patients progressed during intravenous 6-thioguanine treatment. Myelosuppression, although frequent, was mild to moderate at these doses and did not result in significant morbidity. Nonhematologic toxicities were also mild. Our data suggest that intravenous 6-thioguanine given at this schedule is ineffective in previously untreated patients with advanced carcinoma of the pancreas.

Adult↗
PubMed1991

Effect of relaxin on mammary development in ovariectomized pregnant gilts.

The role of relaxin in mammary development was studied between days 80-110 of pregnancy in ovariectomized gilts given progesterone to maintain pregnancy. To obtain an objective measurement of lobulo-alveolar (parenchymal) composition, mammary glands were cut in cross-section through the teat, and the area of parenchymal tissue on the exposed face of the gland was determined. Ovariectomy on day 80 or 100 followed by progesterone replacement therapy resulted in a dramatic reduction in the rate of growth of mammary parenchymal cross-section area on days 100 and 110 of gestation, respectively, compared to that in controls. In contrast, progesterone plus relaxin therapy, with highly purified porcine relaxin, restored the mammary parenchymal cross-section area to control values in ovariectomized gilts. Morphometric analysis of mammary tissue on day 110 of pregnancy indicated that both the absence of relaxin after ovariectomy and replacement therapy with porcine relaxin in ovariectomized gilts had little if any effect on the percentages of the lumen, stroma, or epithelial that comprised the mammary parenchyma. It is concluded that relaxin has a stimulatory effect on the growth of mammary parenchymal tissue during late gestation in the pig.

Animals↗
PubMed1991

Hormonal control of the cervix in pregnant gilts. III. Relaxin's influence on cervical biochemical properties in ovariectomized hormone-treated pregnant gilts.

The effects of relaxin on the biochemical properties of both the uterine and vaginal portions of the cervix were examined between days 80-110 of pregnancy in ovariectomized gilts given progesterone to maintain pregnancy. In the cervix of control gilts and those ovariectomized and given progesterone plus relaxin, wet and dry weights, water content, and the glycosaminoglycan/collagen ratio increased between days 80-110 of gestation. Collagen concentrations based on wet or dry weight and glycosaminoglycan concentrations based on wet weight decreased during this period. After ovariectomy, there were no changes in these cervical connective tissue components when relaxin was not given. The glycosaminoglycans hyaluronic acid, heparan sulfate, and dermatan sulfate were found in the cervices of all treatment groups, with dermatan sulfate predominating. The ratio of the individual glycosaminoglycans did not change during pregnancy or with treatment. The major dermatan sulfate proteoglycan from the pig cervix was isolated and found to be similar in size, immunoreactivity, amino acid composition, and amino acid sequence to the major dermatan sulfate proteoglycans isolated from the cervices of other mammals. It is concluded that the relaxin-induced changes in the connective tissue composition of the cervix may contribute at least in part to increased extensibility and growth of the cervix during the last third of gestation in pigs.

Animals↗
PubMed1990

Mammographic screening of women with increased risk of breast cancer.

Five hundred one women from Dallas County, Texas who participated in the American Cancer Society 1987 Texas Breast Screening Project were selected because of a self-reported family history of breast cancer (cases). They were matched with 501 randomly selected women from the same county with no family history (controls). Although there was a statistically significant trend with age for an increasing proportion of women to report having undergone mammography, there was no significant difference when comparing mammographic histories of cases with controls after controlling for age (31.5% versus 35.1%, P = 0.33). Significantly more cases (79%) perceived their risk for breast cancer to be moderate or greater compared with controls (54%, P less than 0.0001), but mammographic histories were not different when controlling for perceived risk. Both cases and controls cited lack of physician referral and cost as their reasons for not having undergone mammography. Women at increased risk for breast cancer (because of their family history) are not undergoing regular mammographic screening despite their self-awareness of the increase in their risk.

Adult↗
PubMed1990

Breast screening compliance following a statewide low-cost mammography project.

Public health educational campaigns can attract large numbers of one-time participants, but the impact on subsequent behavior remains unstudied. The American Cancer Society Texas Division, Inc. sponsored a statewide $50.00 mammography screening project in early 1987. More than 64,000 mammograms were completed at 306 centers; 37,000 screenees answered a 31-item questionnaire. Attitudes toward screening were assessed, and screening history was recorded. Eighteen months after the project, a follow-up questionnaire was sent to 1000 screenees; 411 women returned the questionnaires. In the year following the project, 51% of the women 50 years and older reported having a subsequent mammogram. Among the women in this group who had never had a mammogram prior to 1987, 42% had screening mammography repeated in the following year. These data show that media-based public education projects can be effective mechanisms for improving and maintaining compliance with mammography screening recommendations.

Adult↗
PubMed1989

Sensitivity to genotoxic effects of bleomycin in humans: possible relationship to environmental carcinogenesis.

Responses to the genotoxic effect of bleomycin in lymphocytes of blood cultures, expressed as the average number of chromatid breaks per cell (b/c), varied from less than 0.20 to more than 2.00 in 335 normal individuals. More than 11% of the subjects tested showed a b/c rate above 1.00 and more than 22% showed a b/c rate above 0.80. These individuals are considered sensitive to this radiomimetic drug. The distributional profile of bleomycin responses of the control individuals appears to be representative of the normal human population. In patients with cancers of the colon (83), upper aerodigestive tract (head/neck) (77), and lung (71), the frequencies of subjects in the hypersensitive class were found to be between 40 and 50%, and the response profiles were distinctly different from those of the control population. On the other hand, in a group of elderly cigarette smokers, who exhibited no symptoms of lung cancer, the bleomycin sensitivity profile was significantly skewed toward the more resistant stratum, with only one hypersensitive case among 56 individuals tested (1.78%). The sensitivity profile of patients with breast cancer (82) was similar to that of the control population. Our data suggest that: (1) mutagen sensitivity may play an important role in carcinogenesis of organs and tissues that have direct contact with the external environment (respiratory, digestive, and integumentary systems); (2) it appears to have no significant influence on carcinogenesis of tissues that are not directly exposed to the environment (e.g., breast, brain); and (3) it also has little impact on carcinogenesis in individuals with a hereditary predisposition to cancer (e.g., retinoblastoma, Gardner's syndrome). Development of more effective and precise test systems for carcinogen sensitivity is highly desirable for identification of persons at risk.

Adult↗
PubMed1989

Hormonal control of the cervix in pregnant gilts. II. Relaxin promotes changes in the physical properties of the cervix in ovariectomized hormone-treated pregnant gilts.

The effects of relaxin on the physical properties of both the uterine and vaginal portions of the cervix were studied between days 80 and 110 of pregnancy in ovariectomized gilts given progesterone to maintain pregnancy. In controls gilts the extensibility, lumen diameter, and wet weight of the uterine portion of the cervix were less than those of the vaginal portion of the cervix on day 80, but increased thereafter, and by day 110 did not differ (extensibility and wet weight) or approached (lumen diameter) those values of the vaginal portion of the cervix. When gilts were ovariectomized on either days 80 or 100 and given progesterone only (groups OP-100 and OP-110) extensibility, lumen diameter, and wet weight failed to increase in both the uterine and vaginal portions of the cervix. After replacement therapy with progesterone plus relaxin (groups OPR-100 and OPR-110), extensibility, lumen diameter, and wet weight increased to values as least as large as those in control groups in both portions of the cervix. In all groups the uterine portion of the cervix changed more dramatically than the vaginal portion. After hormone replacement therapy, blood levels of relaxin were moderately higher, and blood levels of progesterone were somewhat lower than those in control gilts. There was little or no difference in estrogen levels between ovariectomized and control gilts. We conclude that relaxin plays an important role in promoting increased growth and extensibility in both the uterine and vaginal portions of the cervix after day 80 of gestation in the gilt.

Animals↗