The aim of this study was to evaluate in small cervical biopsies (non-cone, non-large loop excision of the transformation zone, LLETZ) the prognostic value of both routinely assessed and reviewed cervical intraepithelial neoplasia (CIN) grades 1 and 2, oncogenic human papillomavirus (onco-HPV) DNA (HPV status) and Ki-67 immuno-quantitative features for the prediction of progression. In biopsies from 44 CIN patients (the learning set), subjective CIN grade, onco-HPV by PCR, and Ki-67 immuno-quantitative features were assessed. We followed development of the lesions by colposcopy and cytology, but the final endpoint was the histological grade (again in small biopsies). The outcome was defined as progression (histological (CIN 1 to (CIN 2 or 3)) or CIN 2 to CIN 3) or not (all other cases). Single and multivariate (Cox regression) and survival analyses were applied. The resulting predictive combination of quantitative features was then applied to a new test set of 35 consecutive CIN 2 (small) biopsies followed by large (cone or LLETZ) biopsies. In the learning set, mean follow-up of non-progression cases was 18.8 months (range 4.7-35.9), and of progression cases 13.1 months (range 6.4-32.9) (p = 0.18). Five cases progressed (11%). Of the 16 CIN 1 and 28 CIN 2 lesions, 31 cases (70%) were onco-HPV positive (5 of the CIN 1 and 26 of the CIN 2). The age of women with progression or not did not differ (p = 0.68). All 5 progression cases were CIN 2 (on review, one of these was reclassified as CIN 1), and positive for onco-HPV. Cox regression analysis showed that the percentage of Ki-67-positive cells located in the middle third layer of the epithelium (MIDTHIRD) and the 90th percentile of the stratification index (SI90) was the best combination to predict progression (log rank = 5.1, p = 0.02). Furthermore, sensitivity (100%), specificity (56%), positive predictive value (23%), negative predictive value (100%), and overall percentage correctly classified cases (61%) of this Ki-67 combination were higher than that of subjective CIN grade or HPV status, either single or combined (both for routine and review CIN grades). Adding CIN grade or HPV status did not improve the Ki-67 prognostic results. Application of the prognostic Ki-67 combination to the test set of 35 small biopsies followed by large (cone or LLETZ biopsies) gave comparable results. Analyses on homogeneous subgroups (CIN 2 only, onco-HPV+ only, or CIN2/onco-HPV+ only) gave similar results. In conclusion, Ki-67 immuno-quantitation of small biopsies showing CIN 1 or CIN 2 has strong independent prognostic value for progression.
A group of 41 patients, all admitted to hospital because of acute purulent exacerbations of chronic respiratory disease, were treated with either doxycycline or minocycline in a double-blind randomized study. Drug dosage was one 100 mg capsule twice daily for seven days. Bacteriological and clinical assessment before and immediately after treatment showed no significant differences between the doxycycline and the minocycline groups, nor did further evaluation after seven days follow-up. Pharmacokinetic studies showed that the Cmax and 0-11 h AUC values in blood were higher for doxycycline, whereas the sputum Cmax was, on average, higher for minocycline because of the greater penetration of the latter. The MIC values for the two antibiotics differed slightly, usually, but not always, in favour of minocycline. Problems were experienced with both agents in the eradication of Haemophilus influenzae. The net clinical results with the two drugs were identical.
In a double-blind prospective study, 180 patients admitted to hospital with acute purulent exacerbations of chronic bronchitis were treated for seven days with twice daily 1 g intramuscular injections of either cefodizime or cefotaxime. Sputum cultures performed before, during and immediately after treatment showed complete eradication of the infection in 89/90 given cefodizime and 86/90 receiving cefotaxime. Some symptomatic Pseudomonas aeruginosa superinfections occurred with each agent. During the follow-up week, recurrences or reinfections after apparent clearance occurred in 15 patients given cefodizime and in 21 receiving cefotaxime. Pharmacokinetic studies in blood showed mean Cmax values of 50.8 mg/l for cefodizime and 36.5 mg/l for cefotaxime, corresponding values in the sputum being 1.61 and 0.62 mg/l. Mean AUC values in both blood and sputum were 2 1/2- to 3-fold higher for cefodizime. Some features suggested better performance by cefodizime than by cefotaxime, but the clinical results were not statistically significantly different.
1 or 2 g doses of cefodizime i.m. were studied in 287 patients admitted to hospital with acute purulent exacerbations of chronic bronchitis, mostly associated with Haemophilus influenzae, Streptococcus pneumoniae or Moraxella catarrhalis. Pharmacokinetic studies in serum and sputum on the first treatment day yielded mean peak serum concentrations of 50 to 100 mg/l, with corresponding sputum concentrations of 1.4 and 2.7 mg/l, after the two respective doses. No great differences were found between the clinical and microbiological results in the various dosage groups, and no corresponding improvement was noted with the highest dosages studied. In general, infection was eliminated in 90 to 95% of patients at the end of treatment, and in approximately 70 to 80% after a follow-up week. Some infections associated with beta-lactamase producing M. catarrhalis persisted or relapsed after treatment. Unwanted drug effects were recorded in five patients, leading to discontinuation in two. It is concluded that a single daily intramuscular dose of 1 g cefodizime for seven days produces satisfactory results in most patients.
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