Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: results of a European multi-center phase III study.

A total of 178 patients with metastatic renal cell cancer were randomized to receive interferon alfa-2a (rIFN alfa-2a) or interferon alfa-2a+vinblastine (VLB). IFN alfa-2a was injected intramuscularly at a dose of 18 MIU 3 times a week and VLB was given intravenously at a dose of 0.1 mg/kg once every 3 weeks. The response rate was 11% for patients on monotherapy and 24% for those on combination treatment. The 5-year survival for 145 eligible patients was 9%, independently from the treatment arm. The performance status was significantly related to long-term prognosis, and 13% of the patients with performance status 0 were alive at 5 years, as compared to 6% and 0% for patients with a WHO grade of 1 and 2, respectively. The most frequent adverse events in both treatment arms were flu-like symptoms (95%), fatigue (70%) and gastrointestinal disturbances (68%). Leukopenia was observed more frequently with combination treatment (53%) than with IFN alfa-2a alone (30%). In conclusion, rIFN alfa-2a monotherapy at this dose and schedule has modest antitumor activity in metastatic renal cell cancer. The combination of rIFN alfa-2a+VLB results in a doubling of the response rate, but this does not translate into prolonged survival. Toxicity (except leukopenia) and tolerance were similar in both treatment arms.     

Expression and functional activity of P-glycoprotein in cultured cerebral capillary endothelial cells.

Analysis of a panel of endothelial cells passaged between 5 and 25 times and derived from various organs and species demonstrated that murine and porcine cerebral capillary endothelial cells actively excluded the fluorescent dye rhodamine 123, a substrate of P-glycoprotein. In addition, rhodamine 123 accumulation could be enhanced by the multidrug resistance chemosensitizer verapamil, known to reduce P-glycoprotein-mediated drug efflux. Cloned murine and porcine cerebral capillary endothelial cells were immunoreactive with the C219 monoclonal antibody to P-glycoprotein, and a C219 epitope-specific blocking peptide could abolish staining. The antiproliferative and cytotoxic effects of vincristine, but not cis-platinum(II) diamminedichloride, were increased by the addition of either verapamil or cyclosporin A to brain endothelial cell cultures in a 72-h assay, as determined by [3H]thymidine incorporation and total protein measurement. Cyclosporin A was a more effective reversal agent than verapamil. Thus, a P-glycoprotein isoform may be constitutively expressed in brain endothelial cells in vitro and supports the available data on in situ immunohistochemical staining of P-glycoprotein at the blood-brain barrier. In addition, these findings may indicate that one function of P-glycoprotein in vivo at the blood-brain barrier is the exclusion of xenobiotics from central nervous system tissues.     

Failure of polymyxin B nonapeptide to augment bactericidal activities of novobiocin, rifampin, and of defibrinated human blood against Serratia marcescens

Polymyxin B (PB) and polymyxin B nonapeptide (PBNP), when combined with rifampin or novobiocin, but not vancomycin, yielded additive inhibitory effects against test strains of Serratia marcescens of three varieties: those that produced cocarde growths around PB disks (coc+); those that grew adjacent to PB disks (coc-, 6); and those that yielded clear inhibition zones around PB disks (coc-, clear). However, time kill curve experiments disclosed that only the combination of rifampin + PB exerted a potent bactericidal effect against coc+ strains of S. marcescens; rifampin + PBNP and novobiocin + PB or PBNP merely effected transient decreases of colony counts. Assays involving 50% (v/v) of fresh defibrinated human blood + PB or PBNP revealed that only PB clearly augmented the antibacterial activity of blood against coc+, and less so against coc- test strains of S. marcescens.     

Cotrel-Dubousset (CD) instrumentation for the correction of spinal curvature. First results in special consideration of derotation

At the University of Innsbruck, Department of Orthopedics, 30 scoliosis patients were operated on using the surgical method according to Cotrel-Dubousset in the period of May 1986-December 1987. For the correction of the curvature this instrumentation uses both distractive as well as transverse forces and attains such an unusual primary stability that postoperative immobilization by brace becomes unnecessary. In addition, it permits the three-dimensional correction of scoliosis curvatures. With an average preoperative measurement of 65.4 degrees and a postoperatively measured angle of 23.8 degrees the correction achieved is 64%. Rotation of the scoliosis was reduced by 39%. Our experiences with the application of the described method of operation and the pertinent complications are described below.     

Intravenous cholangiography,ERCP, and selective operative cholangiography in the performance of laparoscopic cholecystectomy

Between March 1990 and March 1993 some 822 consecutive patients underwent an attempt at laparoscopic cholecystectomy. Intravenous cholangiography (IVC), ERCP, and selective intraoperative cholangiography (IOC) were used in the evaluation of common bile duct (CBD) stones. Two hundred thirteen patients (26%) were identified preoperatively with either abnormal liver functions or a dilated common bile duct suggestive of CBD stones. IVC was performed in 143 patients (67%). Choledocholithiasis was identified in 14 patients (10%). Preoperative therapeutic ERCP was successful in all 14 patients (100%). Diagnostic ERCP was attempted in 61 patients and successful in 59 (97%). Choledocholithiasis was identified in 25 patients (41%). Successful extraction was accomplished in 23 patients (92%). Transcystic common bile duct exploration was used effectively in the patients with an unsuccessful ERCP. IOC was attempted in 50 patients and successful in 48 (96%). Choledocholithiasis was identified in three (6%). A retained CBD stone was present in eight patients (1%). There was one level I CBD injury (0.122%). The use of IVC, selective ERCP, and selective IOC is a reasonable approach in the performance of laparoscopic cholecystectomy.     

Pneumothorax and other lung diseases: effect of altered resolution and edge enhancement on diagnosis with digitized radiographs

Prior studies have shown that pneumothorax is one of the more difficult entities to diagnose with digitized radiography. This study was designed to test whether increasing resolution from 1.25 to 2.5 line pairs per millimeter (lp/mm) and image processing (edge enhancement from unsharp masking) would increase accuracy and confidence in the diagnosis of pneumothorax, as well as normal cases and other forms of lung disease. Conventional radiographs were digitized with use of a laser reader and then reformatted as film hard copy. Eleven observers read 35 cases reformatted in three different ways (1.25 lp/mm, 2.5 lp/mm, 1.25 lp/mm unsharp mask). The images with finer resolution (2.5 lp/mm) and unsharp mask images were superior to those with coarser resolution (1.25 lp/mm) for the diagnosis of pneumothorax. There was no difference in diagnostic accuracy for normal patients. For abnormalities other than pneumothorax, the unsharp mask images were significantly worse. Confidence in the diagnosis of pneumothorax and other abnormalities was highest with the finest resolution (2.5 lp/mm).     

Analysis of mast cell subpopulations (MCT, MCTC) in cutaneous inflammation using novel enzyme-histochemical staining techniques

Abstract In order to gain insights into the dynamics of mast cell subpopulations in normal and diseased skin, a novel enzyme-histochemical double and triple staining method was employed that allowed the detection of metachromasia (toluidine blue) and the mast cell proteases tryp-tase and chymase within the same cell. Cryostat sections were used of skin biopsies from the following specimens: normal skin (N=4), psoriasis (N=13), atopic eczema (N=7), lichen planus (N=6), interferon α2a injection sites (N=l) of a leukemic infiltrate and corresponding normal skin of the same patient before and after treatment. (i) Equal numbers of tryptase-and chymase-positive mast cells (MCTC) were obtained in all normal and diseased specimens in papillary and reticular dermis, with threefold increases around appendages, (ii) Tryptase-positive mast cells (MCT) were absent in normal skin, but were markedly increased in a disease-specific pattern within the papillary dermis, the inflammatory infiltrate and around appendages, (iii) Marked increases of MCT were also noted at interferon injection sites within the leukemic infiltrate, but not in the normal skin of the same patient. These data suggest that disease-dependent mast cell dynamics involve only MCT in cutaneous inflammation and that MCT numbers are controlled by distinct, disease-specific local tissue factors.     

Gemfibrozil reduces plasma prothrombin fragment F1 + 2 concentration, a marker of coagulability, in patients with coronary heart disease.

The effects of gemfibrozil on several indices of haemostatic activity were explored in male patients with coronary heart disease (CHD). Sixty-three of 71 patients completed a crossover study in which gemfibrozil 1,200 mg/day and matching placebo were each taken in randomised order for 2 months in a double-blind manner, separated by a 2-month washout period. Serum cholesterol decreased by an average (95% confidence interval) of 12 (9 to 15)% and non-fasting triglyceride concentration by 43 (34 to 51)% during active treatment. Plasma prothrombin fragment F1 + 2 concentration, a marker of the in vivo rate of generation of thrombin, was 25 (12 to 37)% lower on average while on gemfibrozil than during the placebo phase. Factor VII coagulant activity (VIIc) and antigen concentration, and fibrinopeptide A concentration were not influenced by gemfibrozil in the group overall. However, the VIIc response appeared to be dependent upon the untreated cholesterol level. Hypercholesterolaemic men (cholesterol greater than 6.5 mmol/l) experienced a significant reduction in VIIc averaging 6% of standard during active therapy. Other effects of gemfibrozil were a 5 (2 to 9)% increase in plasma fibrinogen by a gravimetric method, an 11 (8 to 13)% increase in platelet count, and a 6 (2 to 10)% reduction in white cell count. The reduced incidence of CHD following gemfibrozil therapy in hyperlipidaemic patients may arise in part through a reduction in procoagulant activity and thus the risk of an occlusive coronary thrombosis.