Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03

PURPOSE: To assess the efficacy of neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy in patients with muscle-invading bladder cancer treated with selective bladder preservation. PATIENTS AND METHODS: One hundred twenty-three eligible patients with tumor, node, metastasis system clinical stage T2 to T4aNXMO bladder cancer were randomized to receive (arm 1, n=61 ) two cycles of MCV before 39.6-Gy pelvic irradiation with concurrent cisplatin 100 mg/m2 for two courses 3 weeks apart. Patients assigned to arm 2 (n=62) did not receive MCV before concurrent cisplatin and radiation therapy. Tumor response was scored as a clinical complete response (CR) when the cystoscopic tumor-site biopsy and urine cytology results were negative. The CR patients were treated with an additional 25.2 Gy to a total of 64.8 Gy and one additional dose of cisplatin. Those with less than a CR underwent cystectomy. The median follow-up of all patients who survived is 60 months. RESULTS: Seventy-four percent of the patients completed the protocol with, at most, minor deviations; 67% on arm 1 and 81% on arm 2. The actuarial 5-year overall survival rate was 49%; 48% in arm 1 and 49% in arm 2. Thirty-five percent of the patients had evidence of distant metastases at 5 years; 33% in arm 1 and 39% in arm 2. The 5-year survival rate with a functioning bladder was 38%, 36% in arm 1 and 40% in arm 2. None of these differences are statistically significant. CONCLUSION: Two cycles of MCV neoadjuvant chemotherapy were not shown to increase the rate of CR over that achieved with our standard induction therapy or to increase freedom from metastatic disease. There was no impact on 5-year overall survival.     

The role of endothelial nitric oxide synthase expression in the development of pulmonary hypertension in chronically hypoxic infant swine

OBJECTIVE: Our goal was to determine the role of pulmonary endothelial nitric oxide synthase expression in the development of pulmonary hypertension in infants with congenital cyanotic heart disease. METHODS: Two groups of 4-week-old piglets were studied. In one group, the piglets were raised in an environment of 10% oxygen from 2 days of age (cyanotic, n = 6), and in the other group the piglets were raised at room air (control, n = 5). Pulmonary hemodynamics were measured in vivo for each animal, and peripheral lung biopsy specimens were obtained for Western blot analysis with the use of antiendothelial nitric oxide synthase antibody and for activity analysis with the use of the tritiated L-arginine assay. RESULTS: The piglets in the chronically hypoxic group had significant increases in mean pulmonary arterial pressure (44.0 +/- 3.8 mm Hg vs 14.8 +/- 1.2 mm Hg in controls, p = 0.0007) and pulmonary vascular resistance (7272.0 +/- 871.1 dyne x cm x sec(-5) vs 1844.5 +/- 271.2 dyne x cm x sec(-5) in controls, p = 0.002). These changes in the pulmonary hemodynamics of the hypoxic piglets were accompanied by a twofold increase in the expression of pulmonary endothelial nitric oxide synthase (p = 0.0043) but no corresponding increase in nitric oxide synthase activity. CONCLUSIONS: Raising infant piglets in an environment of 10% oxygen for 4 weeks results in significant pulmonary arterial hypertension accompanied by increased expression of nitric oxide synthase within the lung endothelium. Furthermore, the increased levels of nitric oxide synthase within the lungs of the hypoxic swine were not accompanied by a proportional increase in enzyme activity. These findings suggest that the development of pulmonary hypertension in infants with congenital cyanotic disease is not due to decreased expression of endothelial nitric oxide synthase, but instead may be related to a decreased ability of the enzyme to produce sufficient nitric oxide.     

The language of medical case histories

A six and half-year-old nulliparous mixed breed cat which had the complaints of vomiting, abdominal distention and depression was presented to the Veterinary Teaching Hospital of Osaka Prefecture University. She was suspected of pyometra by clinical signs and tests. By laparotomy, it was clarified that both uterine horns and vagina showed distension by the accumulation of secretions, and the vagina ended blindly leaving a tough connective tissue at the border between cranial and caudal part of the vagina. Postoperative contrast-radiograph of the remaining vagina proved it had no persistence of the hymen. From these findings, the condition was diagnosed as a feline atresia vaginalis with the transverse vaginal septum which is caused by the embryonic failure of canalization of the paramesonephric duct between the end of the Müllerian duct and the urogenital sinus.     

Interaction of a novel GDP exchange inhibitor with the Ras protein

Mutated, tumorigenic Ras is present in a variety of human tumors. Compounds that inhibit tumorigenic Ras function may be useful in the treatment of Ras-related tumors. The interaction of a novel GDP exchange inhibitor (SCH-54292) with the Ras-GDP protein was studied by NMR spectroscopy. The binding of the inhibitor to the Ras protein was enhanced at low Mg2+ concentrations, which enabled the preparation of a stable complex for NMR study. To understand the enhanced inhibitor binding and the increased GDP dissociation rates of the Ras protein, the conformational changes of the Ras protein at low Mg2+ concentrations was investigated using two-dimensional 1H-15N HSQC experiments. The Ras protein existed in two conformations in slow exchange on the NMR time scale under such conditions. The conformational changes mainly occurred in the GDP binding pocket, in the switch I and the switch II regions, and were reversible. The Ras protein resumed its regular conformation after an excess amount of Mg2+ was added. A model of the inhibitor in complex with the Ras-GDP protein was derived from intra- and intermolecular NOE distance constraints, and revealed that the inhibitor bound to the critical switch II region of the Ras protein.     

Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women

BACKGROUND: A positive relationship has generally been observed between plasma estrogen levels and breast cancer risk in postmenopausal women, but most of these studies have been small and few have evaluated specific estrogen fractions (such as percent bioavailable estradiol). In addition, few studies have evaluated plasma androgen levels in relation to breast cancer risk, and their results have been inconsistent. We prospectively evaluated relationships between sex steroid hormone levels in plasma and risk of breast cancer in postmenopausal women by use of a case-control study nested within the Nurses' Health Study. METHODS: Blood samples were collected during the period from 1989 through 1990. Among postmenopausal women not using hormone replacement therapy at blood collection (n = 11,169 women), 156 women were diagnosed with breast cancer after blood collection but before June 1, 1994. Two control subjects were selected per case subject and matched with respect to age, menopausal status, month and time of day of blood collection, and fasting status at the time of blood collection. RESULTS: From comparisons of highest and lowest (reference) quartiles, we observed statistically significant positive associations with risk of breast cancer for circulating levels of estradiol (multivariate relative risk [RR] = 1.91; 95% confidence interval [CI] = 1.06-3.46), estrone (multivariate RR = 1.96; 95% CI = 1.05-3.65), estrone sulfate (multivariate RR = 2.25; 95% CI = 1.23-4.12), and dehydroepiandrosterone sulfate (multivariate RR = 2.15; 95% CI = 1.11-4.17). We found no substantial associations with percent free or percent bioavailable estradiol, androstenedione, testosterone, or dehydroepiandrosterone. The positive relationships were substantially stronger among women with no previous hormone replacement therapy. CONCLUSION: Our data, in conjunction with past epidemiologic and animal studies, provide strong evidence for a causal relationship between postmenopausal estrogen levels and the risk of breast cancer.     

Tuberculin skin test screening practices among US colleges and universities

CONTEXT: Concern about transmission of Mycobacterium tuberculosis on college campuses has prompted some schools to institute tuberculin skin test screening of students, but this screening has never been evaluated. OBJECTIVE: To describe tuberculin skin test screening practices and results of screening in colleges and universities in the United States. DESIGN AND SETTING: Self-administered mail and telephone questionnaire in November and December 1995 to a stratified random sample of US 2-year and 4-year colleges and universities. MAIN OUTCOME MEASURES: Type of tuberculin screening required; types of schools requiring screening; number and rate of students with positive skin test results and/or diagnosed as having tuberculosis. RESULTS: Of the 3148 US colleges and universities, 624 (78%) of 796 schools surveyed responded. Overall, 378 schools (61%) required tuberculin screening; it was required for all new students (US residents and international students) in 161 (26%) of 624 schools, all new international students but not new US residents in 53 (8%), and students in specific academic programs in 294 (47%). Required screening was more likely in 4-year vs 2-year schools, schools that belonged to the American College Health Association vs nonmember schools, schools with immunization requirements vs schools without, and schools with a student health clinic vs those without (P<.001 for all). Public and private schools were equally likely to require screening (64% vs 62%; P=.21). In the 378 schools with screening requirements, tine or multiple puncture tests were accepted in 95 (25%); test results were recorded in millimeters of induration in 95 (25%); and 100 (27%) reported collecting results in a centralized registry or database. Of the 168 (27%) of 624 schools accepting only Mantoux skin tests and reporting results for school years 1992-1993 through 1995-1996, 3.1% of the 348 368 students screened had positive skin test results (median percentage positive, 0.8%). International students had a significantly higher case rate for active tuberculosis than US residents (35.2 vs 1.1 per 100000 students screened). CONCLUSIONS: Widespread tuberculin screening of students yielded a low prevalence of skin test reactors and few tuberculosis cases. To optimize the use of limited public health resources, tuberculin screening should target students at high risk for infection.