Association of laryngopharyngeal reflux disease and subglottic stenosis.

Laryngopharyngeal reflux (LPR) disease and extraesophageal manifestations of gastroesophageal reflux have been recognized to have dramatic effects in the upper airways. Patient-reported symptoms alone underestimate the presence of LPR, making accurate clinical diagnosis difficult. Many previous studies examine populations with only standard dual-probe pH testing that does not include a test probe in the pharynx. Therefore, documentation of acid exposure at the laryngeal inlet is lacking. In adult patients with subglottic stenosis (SGS), whether due to granulomatous disease or presumed idiopathic causes, LPR is often a contributing or causative factor. A retrospective chart review from 1991 to 1999 identified 19 patients with SGS. Ten of the 19 patients had concomitant disease states, including sarcoidosis (3), Wegener's granulomatosis (3), laryngeal trauma (3), and a history of intubation (1). Fourteen patients underwent 24-hour ambulatory pH probe testing with 3- or 4-port probes. The proximal port in either catheter was positioned by manometric guidance directly behind the laryngeal inlet. Measurements of pH of less than 4 were recorded at the level of the larynx in 12 of the 14 patients tested (86%). This finding was noted in half of the patients despite empirical therapy with proton pump inhibitors at the time of the testing. Seven of 10 patients with underlying disease were studied, and all demonstrated acid reflux in the hypopharynx. In 9 patients, the stenosis was presumed to be idiopathic. Five of the 7 patients (71%) with idiopathic SGS tested had positive pH probe studies (pH below 4 in the pharyngeal probe). Our results demonstrate a strong association of LPR and SGS. In the idiopathic group, reflux is the probable cause of their stenosis. In the group of patients with underlying disease states, reflux was involved in all tested patients and likely acts as a synergistic factor that stimulates their granulomatous disease to react and subsequently result in the development of stenosis. Evaluation for LPR with pharyngeal pH testing should be performed in all patients with SGS.

Importance of margin status in outcome of breast-conserving surgery for carcinoma.

BACKGROUND: The importance of margin status in breast-conserving therapy (BCT) for breast cancer remains unclear. We reviewed our experience with BCT to determine the risk of local recurrence as a function of margin status. METHODS: Stages I and II breast cancers treated with BCT between 1985 and 1990 were reviewed. Two hundred eleven patients were classified based on initial margin status: negative (more than 3 mm), close (3 mm or less), positive, or unknown. The incidence of reexcision and residual tumor is reported in each group. Patients with 36 months or more of follow-up (n = 183) were also stratified by final margin to examine rates of local recurrence and distant recurrence. RESULTS: Residual carcinoma was found in 0%, 24%, 44%, and 48% of the negative, close, positive, and unknown initial margin groups, respectively. The local recurrence rate was equivalent by Fisher exact test in patients with negative and close final margins (3%). The negative and close groups were not different by chi-squared analysis in terms of T stage, estrogen receptor status, and nodal status. CONCLUSIONS: Although one fourth of patients with close margins have residual tumor, recurrence rates are similar to those with negative margins. Reexcision of close margins is not necessary in patients who undergo BCT for carcinoma.

The effect of ketoconazole on steroidogenesis: I. Leydig cell enzyme activity in vitro.

The in vitro inhibition of Leydig cell microsomal steroidogenesis by ketoconazole, a potent P-450 dependent enzyme blocker, was evaluated in the human, stallion and pig. Purified Leydig cells were isolated by mechanical dispersion of teased, decapsulated whole testes and sieving through a 0.25 mm stainless steel mesh. The activity of 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta-HSD), 17-hydroxylase (17-OHase), 17,20-desmolase (17,20D), 17-ketosteroid reductase (17-KSR) and aromatase were measured using a constant amount (50 microM) of 14C-labelled substrates in the presence of varying concentrations of pure ketoconazole. Products were isolated by thin layer chromatography and verified by derivative formation. 17-OHase and 17,20D activities were significantly inhibited (p less than .001) by ketoconazole at concentrations as low as 5 microM. 3 beta-HSD, 17-KSR and aromatase activities were only significantly inhibited by ketoconazole at concentrations of 500 and 5000 microM. These data describe the specific loci of inhibition of ketoconazole on testicular steroidogenesis and confirm the observations that ketoconazole is an effective inhibitor of androgen biosynthesis in several species.

The effect of ketoconazole on steroidogenesis. II. Adrenocortical enzyme activity in vitro.

The activity of five adrenocortical steroidogenic enzymes, 3 beta-hydroxysteroid dehydrogenase/isomerase (3 beta-HSD), 17-hydroxylase (17-OHase) 17,20 desmolase (17,20D), 21-hydroxylase (21-OHase) and 11-hydroxylase (11-OHase), were measured in vitro in purified mitochondria or microsomes from rhesus monkey (Macaca mulata) and human adrenal tissue in the presence and absence of graded concentrations of ketoconazole. Rhesus 3 beta-HSD activity was unaffected by ketoconazole at concentrations up to 5000 microM. However, human adrenal 3 beta-HSD was inhibited by approximately 40% (p less than .01) at concentrations of 500 microM and by 80% at 100 microM. 17-OHase and 17,20D were significantly inhibited in the human at 5 microM (p less than .001) and in the rhesus monkey at 50 microM (p less than .001). A similar inhibitory effect was found on microsomal 21-OHase, with significant inhibition at 5 microM ketoconazole in the human and rhesus monkey (p less than 0.001). Mitochondrial 11-OHase was also significantly inhibited by ketoconazole in both the human (p less than .005) and rhesus (p less than .001) at 2.0 microM. These results represent documentation of the specific adrenal steroidogenic steps affected by ketoconazole and confirm the observations that this imidazole derivative is a powerful inhibitor of enzymes in the glucocorticoid pathway.