Adverse prognostic value of peritumoral vascular invasion: is it abrogated by adequate endocrine adjuvant therapy? Results from two International Breast Cancer Study Group randomized trials of chemoendocrine adjuvant therapy for early breast cancer.

BACKGROUND: Peritumoral vascular invasion (PVI) may assist in assigning optimal adjuvant systemic therapy for women with early breast cancer. PATIENTS AND METHODS: Patients participated in two International Breast Cancer Study Group randomized trials testing chemoendocrine adjuvant therapies in premenopausal (trial VIII) or postmenopausal (trial IX) node-negative breast cancer. PVI was assessed by institutional pathologists and/or central review on hematoxylin-eosin-stained slides in 99% of patients (analysis cohort 2754 patients, median follow-up >9 years). RESULTS: PVI, present in 23% of the tumors, was associated with higher grade tumors and larger tumor size (trial IX only). Presence of PVI increased locoregional and distant recurrence and was significantly associated with poorer disease-free survival. The adverse prognostic impact of PVI in trial VIII was limited to premenopausal patients with endocrine-responsive tumors randomized to therapies not containing goserelin, and conversely the beneficial effect of goserelin was limited to patients whose tumors showed PVI. In trial IX, all patients received tamoxifen: the adverse prognostic impact of PVI was limited to patients with receptor-negative tumors regardless of chemotherapy. CONCLUSION: Adequate endocrine adjuvant therapy appears to abrogate the adverse impact of PVI in node-negative disease, while PVI may identify patients who will benefit particularly from adjuvant therapy.

Predictive value of tumor Ki-67 expression in two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer.

Several small studies have reported that having a high percentage of breast tumor cells that express the proliferation antigen Ki-67 (ie, a high Ki-67 labeling index) predicts better response to neoadjuvant chemotherapy. However, the predictive value of a high Ki-67 labeling index for response to adjuvant chemotherapy is unclear. To investigate whether Ki-67 labeling index predicts response to adjuvant chemoendocrine therapy, we assessed Ki-67 expression in tumor tissue from 1924 (70%) of 2732 patients who were enrolled in two randomized International Breast Cancer Study Group trials of adjuvant chemoendocrine therapy vs endocrine therapy alone for node-negative breast cancer. A high Ki-67 labeling index was associated with other factors that predict poor prognosis. Among the 1521 patients with endocrine-responsive tumors, a high Ki-67 labeling index was associated with worse disease-free survival but the Ki-67 labeling index did not predict the relative efficacy of chemoendocrine therapy compared with endocrine therapy alone. Thus, Ki-67 labeling index was an independent prognostic factor but was not predictive of better response to adjuvant chemotherapy in these studies.

Effect of immunization against the alpha N (alphaN) and alpha C (alphaC) peptides of the alpha43 subunit of inhibin on antral follicular growth and atresia and the patterns of gonadotrophin secretion in ewes.

The aims of this study were to investigate the role of inhibin in the distribution of healthy and atretic antral follicles and the secretion patterns of gonadotrophins. Ewes were actively immunized against either alphaN or alphaC of the inhibin alpha subunit with a primary injection and three booster injections. The control ewes received adjuvant only. The ovaries were removed either before or at 24 h after hCG administration in a synchronized follicular phase 48 h after removal of intravaginal progesterone pessaries. Morphological observations were made on every fifth section of the complete ovary (one per ewe) stained with haematoxylin and eosin. The mean number of corpora lutea observed per ewe with corpora lutea was not significantly different in ewes immunized against alphaN (2.4; alphaN-immunized ewes) or alphaC (2.6; alphaC-immunized ewes), and control (2.4) ewes, although some corpora lutea appeared cystic in the immunized ovaries. Compared with luteal phase concentrations, mean basal FSH concentrations in the early follicular phase were significantly increased in the alphaC-immunized ewes, similar in alphaN-immunized ewes and reduced in control ewes. No differences were observed in any of the LH parameters. Before hCG treatment, healthy antral follicles > 1 mm in diameter were not observed in any of the 52 follicles in the aC-immunized ewes and were observed in one of 37 follicles from alphaN-immunized ewes compared with 19 of 28 follicles in control ewes (P < 0.0001). For healthy antral follicles < 1 mm in diameter, there were 72 of 85 follicles in the alphaC-immunized ewes, 79 of 81 follicles in the alphaN-immunized ewes and 81 of 82 follicles in the control ewes. Similar results were obtained in healthy antral follicles < 1 mm in diameter at 24 h after hCG administration. In contrast to the control ewes, no healthy preovulatory follicles (> 6 mm in diameter) were observed in alphaN- and alphaC-immunized ewes either before or 24 h after hCG administration. Two newly formed corpora lutea from alphaC-immunized ovaries contained retained oocytes compared with none in control and alphaN-immunized ovaries. In conclusion, immunization against alphaN and alphaC may result in disruption of the normal processes of antral follicular growth and maturation independent of the concentrations of FSH and LH.

Selenium bioaccumulation and hazards in a fish community affected by coal fly ash effluent.

Bioaccumulation of selenium (Se) in the fish community of Pigeon River/Pigeon Lake, which receives inputs of Se from a coal fly ash disposal facility, was studied to assess potential hazards of Se to fish, wildlife, and humans. Se concentrations in fish from sites receiving seepage and effluents from fly ash disposal ponds were significantly greater than those in fish from upstream, where Se concentrations were near background concentrations. Se concentrations differed among fish species, and interspecific variation was greatest at the most contaminated locations. Differences in Se bioaccumulation among fish species were not consistently associated with differences in trophic status. Although Se concentrations in northern pike were consistently less than those in likely prey species, large yellow perch contained Se concentrations as great as those in spottail shiners, their likely prey. Se bioaccumulation may have been influenced by differences in habitat preferences, as limnetic species generally contained greater Se concentrations than benthic species. Se concentrations in fish from the lower Pigeon River and Pigeon Lake did not exceed lowest observable adverse effect concentrations (LOAECs) for Se in tissues of fish species, but exceeded LOAECs for dietary Se exposure of sensitive species of birds and mammals. Human consumption of moderate quantities of fish from the areas studied should not result in excessive Se intake.

Cloning and production of antisera to human placental 11 beta-hydroxysteroid dehydrogenase type 2.

By inactivating potent glucocorticoid hormones (cortisol and corticosterone), 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD2) plays an important role in the placenta by controlling fetal exposure to maternal glucocorticoids, and in aldosterone target tissues by controlling ligand access to co-localized glucocorticoid and mineralocorticoid receptors. Amino acid sequence from homogeneous human placental 11 beta-HSD2 was used to isolate a 1897 bp cDNA encoding this enzyme (predicted M(r) 44126; predicted pI 9.9). Transfection into mammalian (CHO) cells produces 11 beta-HSD2 activity which is NAD(+)-dependent, is without reductase activity, avidly metabolizes glucocorticoids (Km values for corticosterone, cortisol and dexamethasone of 12.4 +/- 1.5, 43.9 +/- 8.5 and 119 +/- 15 nM respectively) and is inhibited by glycyrrhetinic acid and carbenoxolone (IC50 values 10-20 nM). Rabbit antisera recognizing 11 beta-HSD2 have been raised to an 11 beta-HSD2-(370--383)-peptide-carrier conjugate. Recombinant 11 beta-HSD2, like native human placental 11 beta-HSD2, is detectable with affinity labelling and anti-11 beta-HSD2 antisera, and appears to require little post-translational processing for activity. 11 beta-HSD2 mRNA (approximately 1.9 kb transcript) is expressed in placenta, aldosterone target tissues (kidney, parotid, colon and skin) and pancreas. In situ hybridization and immunohistochemistry localize abundant 11 beta-HSD2 expression to the distal nephron in human adult kidney and to the trophoblast in the placenta. 11 beta-HSD2 transcripts are expressed in fetal kidney (but not lung, liver or brain) at 21-26 weeks, suggesting that an 11 beta-HSD2 distribution resembling that in the adult is established by this stage in human development.

Cytologic detection of Cryptococcus neoformans in cerebrospinal fluid. Rapid screening methods.

Yeasts of Cryptococcus neoformans in cerebrospinal fluid (CSF) were studied using polarized light and fluorescence microscopy. Ultraviolet-induced fluorescence of wet-fixed, Papanicolaou-stained smears and polarization of air-dried, Diff-Quik or Leishman-stained preparations are complementary methods that allow for rapid screening for and immediate identification of Cryptococcus in cytologic preparations of CSF.

Bacteremia and bacteriuria after transrectal prostatic biopsy.

To determine the efficacy of parenteral gentamicin versus povidone-iodine enema (P.I.E.) in preventing infectious complications, a randomized study was undertaken in 40 patients undergoing transrectal needle prostatic biopsy. In 69 per cent of patients not receiving P.I.E. bacteremia developed, and 32 per cent acquired bacteriuria; whereas only 19 per cent of patients given P.I.E. alone or in combination with gentamicin because bacteremic, and 9.5 per cent had postbiopsy bacteriuria. Thus, P.I.E. provided a safe and effective means for preventing most bacteremia and bacteriuria associated with transrectal biopsy of the prostate.

Separation from whey of three growth factors for Streptococcus agalactiae.

Wheys of milk and colostrum were treated with ethanol and the concentrated supernatant fluids were subjected to chromatographic procedures (anion exchange resin, using distilled water as eluent). The fractions were tested for capabilities to stimulate the growth of Streptococcus agalactiae in a mixture (1:32) of pasteurized milk and steamed milk. Three stimulatory factors (F), designated F-1, F-2, and F-3, were separated; F-1 was nonionic, and F-2 and F-3 were cationic. A mixture containing any 2 factors gave greater stimulation than either factor tested alone, and a mixture of all 3 gave the greatest stimulation. The F-2 activity was attributed to cystine.