Particle migration after transurethral injection of carbon coated beads for stress urinary incontinence.

PURPOSE: Despite 20 years of experience with injectable bulking agents for stress urinary incontinence results are rather disappointing. The satisfying initial results of collagen injection are rapidly decreasing with time, whereas synthetic bulking agents have shown problems with migration and biocompatibility. The ideal bulking agent would be permanent with a good clinical long-term success rate. We report our experience with Durasphere (Carbon Medical Technologies, Inc., St. Paul, Minnesota), a new injectable bulking agent containing carbon coated beads. MATERIALS AND METHODS: Seven men and 13 women with a mean age of 62.5 years underwent transurethral submucosal injection. The 13 female patients had been diagnosed with type III stress urinary incontinence and each had undergone at least 1 unsuccessful previous operation for urinary incontinence. There were iatrogenic and traumatic sphincter lesions in 6 and 1 of the male patients, respectively. Mean volume injected per treatment was 6.0 cc. Mean followup was 10 months. RESULTS: After 6 months 76.9% of the female patients were improved but after 12 months the success rate decreased to 33%. In the male patients after 6 months the success rate was 66%, which decreased to 33% after 12 months. At the 6-month followup we observed significant migration of the carbon coated beads into the local and distant lymph nodes as well as into the urethral mucosa. CONCLUSIONS: Due to limited success and proved particle migration, carbon coated beads do not show any improvement over existing bulking materials. The clinical effect of bead migration must be determined before extended use of this substance.

Her-2/neu expression in prostate cancer: high level of expression associated with exposure to hormone therapy and androgen independent disease.

PURPOSE: HER-2/neu is a proto-oncogene that encodes a transmembrane receptor belonging to the family of epidermal growth factor receptors. Increasing evidences indicates that HER-2/neu may contribute to hormone resistance in prostate cancer. We investigated HER-2/neu expression in primary, androgen dependent and advanced androgen independent prostate cancer, and its potential value as a marker of disease progression. MATERIALS AND METHODS: Immunohistochemical testing was performed to investigate HER-2/neu expression in 81 patients with prostate cancer, including 31 with pathological stage C disease treated with radical prostatectomy without preoperative androgen ablation therapy (untreated group), 30 with pathological stage C disease treated before surgery with androgen ablation therapy (treated group) and 20 with advanced androgen independent prostate cancer (androgen independent group). Tumors were classified based on the percent of tumor cells showing HER-2/neu membrane immunoreactivity as low (50% or less) and high (50% or greater) expression. RESULTS: Of the 31 prostate tumors in the untreated group 9 (29%) showed high HER-2/neu expression versus 15 of 30 (50%) in the treated and 17 of 20 (85%) in the androgen independent groups. The difference in HER-2/neu expression was significant in the untreated and androgen independent (p <0.001) and in the treated and androgen independent (p = 0.016) groups. There was a significant association of Gleason score with HER-2/neu expression in the untreated group (p = 0.038) but not in the treated group. No association was found of tumor substage with HER-2/neu expression. In the untreated group patients with tumors showing high HER-2/neu expression had a decreased survival rate (p = 0.044). CONCLUSIONS: High HER-2/neu expression is highly associated with exposure to hormone therapy and androgen independence. It may contribute to androgen independence in prostate cancer and identify patients with prostate cancer more likely to have disease progression, particularly those not exposed to previous hormone therapy.

Glutathione transferase activities in renal carcinomas and adjacent normal renal tissues: factors influencing renal carcinogenesis induced by xenobiotics.

In general, the biological activation of nephrocarcinogenic chlorinated hydrocarbons proceeds via conjugation with glutathione. It has mostly been assumed that the main site of initial conjugation is the liver, followed by a mandatory transfer of intermediates to the kidney. It was therefore of interest to study the enzyme activities of subgroups of glutathione transferases (GSTs) in renal cancers and the surrounding normal renal tissues of the same individuals (n = 21). For genotyping the individuals with respect to known polymorphic GST isozymes the following substrates with differential specificity were used: 1-chloro-2,4-dinitrobenzene for overall GST activity (except GST theta); 7-chloro-4-nitrobenzo-2-oxa- 1,3-diazole for GST alpha; 1,2-dichloro-4-nitro-benzene for GST mu; ethacrynic acid and 4-vinylpyridine for GST pi; and methyl chloride for GST theta. In general, the normal tissues were able to metabolize the test substrates. A general decrease in individual GST enzyme activities was apparent in the course of cancerization, and in some (exceptional) cases individual activities, expressed in the normal renal tissue, were lost in the tumour tissue. The GST enzyme activities in tumours were independent of tumour stage, or the age and gender of the patients. There was little influence of known polymorphisms of GSTM1, GSTM3 and GSTP1 upon the activities towards the test substrates, whereas the influence of GSTT1 polymorphism on the activity towads methyl chloride was straightforward. In general, the present findings support the concept that the initial GST-dependent bioactivation step of nephrocarcinogenic chlorinated hydrocarbons may take place in the kidney itself. This should be a consideration in toxicokinetic modelling.

[Additional aids in detection of prostate carcinomas? PSA-prostatic volume quotient, PSA-doubling time, age-dependent PSA reference values and PSA in urine]. / Zusätzliche Hilfen bei der Erkennung von Prostatakarzinomen? PSA-Prostatavolumenquotient, PSA-Verdopplungszeit, altersabhängige PSA-Referenzwerte und PSA im Urin.

Different concepts to improve the clinical utility of prostatic-specific antigen (PSA) for prostate cancer detection have been developed. PSA density and transition zone PSA density are not useful screening tools due to a high variability of prostate volume measurement. PSA velocity monitors the change in PSA in a 2-year period, therefore it is not suitable for treatment decisions in men with serum PSA levels between 4 and 10 ng/ml. Measurement of urinary PSA is not helpful for prostate cancer detection. Age-specific PSA reference ranges provide greater sensitivity for cancer detection in younger men at the expense of a greater negative biopsy rate. In older men unnecessary biopsies could be spared. However, this might lead to a lower sensitivity in these patients, missing possibly clinically insignificant tumors.

Treatment and prognosis of gastric lymphoma.

To assess the developments in the prognosis and treatment of patients with primary gastric non-Hodgkin's lymphoma we reviewed 178 papers in English, German, and French on the subject that were listed on MEDLINE between January 1974 and April 1995. We analysed the results of 3157 patients, and during that period the overall survival increased from 37% to 87%. Overall survival by Ann Arbor stage was 57%. 998/1296 (77%) for stage IE, 231/330 (70%) for stage II1E, 107/290 (37%) for stage II2E, 53/172 (31%) for stage IIIE, and 122/451 (27%) for stage IV. Over half the publications recommended resection alone. Only 12 (15%) thought that radiotherapy or chemotherapy, alone or in combination, was adequate. The results of all treatments were similar in 1296 patients with stage IE disease. For stage IIE-IVE disease, however, 66 (82%) of authors suggested a treatment protocol that included resection, and of these 39 (49%) recommended a combination of resection, local radiotherapy, and systemic chemotherapy. The number of patients reported was too small for us to be able to give precise recommendations for treatment of gastric non-Hodgkin's lymphoma, and we have been able to give only an evaluation of current treatments.

Human endothelial cells bioactivate organic nitrates to nitric oxide: implications for the reinforcement of endothelial defence mechanisms.

Although in therapeutic use for more than a century, the mode of cellular action of organic nitrates remains incompletely understood. Despite ample experimental evidence from animal studies to show that nitrates are metabolized to NO in the vascular smooth muscle, direct demonstration of such an activity in human vascular cells is still lacking. Moreover, the role of the endothelium in modulating the pharmacodynamic action of nitrates is far from clear. We therefore aimed to investigate whether or not human endothelial cells are capable of bioactivating these drugs to NO and whether the amounts generated are sufficient to elicit any biological effects. Using cultured human umbilical vein endothelial cells (HUVECs) as an established model system a combination of three different methods was used to address this issue: (1) quantification of NO formation upon endothelial nitrate metabolism using the oxyhaemoglobin technique; (2) evaluation of the second messenger response using radioimmunoassay for cGMP; and (3) assessment of mechanism and extent of potentiation of the anti-aggregatory effect of nitrates in the presence of endothelial cells as a relevant bioassay. We now show that superfusion of cultured human endothelial cells on microcarrier beads with either glyceryl trinitrate (GTN) or isosorbide dinitrate (ISDN; both at 0.1-100 mumol L-1) results in a concentration-dependent formation of NO. NO generation from isosorbide 5-mononitrate (IS-5-N) was below the detection limit. The amounts of NO produced (maximally 2.97 +/- 0.98 pmoles NO min-1 x mg protein with 100 mumol L-1 GTN; n = 8) were similar to those elicited upon challenge of the cells with 100 nM bradykinin. NO formation from either organic nitrate was accompanied, in a concentration-dependent and methylene blue-inhibitable manner, by stimulation of endothelial soluble guanylyl cyclase with consequent increases in the intracellular level of cGMP (maximally 32-fold over basal levels with ISDN), a significant portion of which was released into the extracellular space. Upon continuous 30 min superfusion or repeated application of high concentrations of GTN (100 mumol L-1) nitrate bioactivation to NO was subject to partial tachyphylaxis. Co-incubation of washed human platelets with HUVECs potentiated the anti-aggregatory action of nitrates in a cell number dependent and oxyhaemoglobin-sensitive manner and this effect, too, was accompanied by increases in intraplatelet cGMP levels. The potentiating effect was largely inhibited after blockade of sulfhydryl groups by pre-incubation of HUVECs with N-ethylmaleimide and completely abrogated after pretreatment of cells with the tissue fixative glutaraldehyde. These results demonstrate that human endothelial cells are capable of bioactivating organic nitrates to NO by an enzymatic, apparently thiol-sensitive pathway, in quantities sufficient to influence endothelial and platelet function. Besides the well known vasorelaxant action of organic nitrates, which is mainly due to their metabolism in the smooth muscle compartment, these drugs may therefore be endowed with a hitherto underestimated potential to directly influence endothelial functions via the NO/cGMP pathway. Through specific bioactivation in the endothelium itself organic nitrates can thus mimic and reinforce protective functions normally served by a functional endothelium such as the modulation of blood cell/vessel wall interactions and inhibition of cell proliferation.

An autoradiographic investigation of the proliferative activity of pyloric caeca and gondas of Asterias rubens.

The proliferative activity of the pyloric caeca of Asterias rubens was investigated. Autoradiographic experiments using intracoelomically injected (methyl-3 H)-thymidine were performed throughout the year and incorporation into pyloric caeca and into gonads was studied. Tritiated thymidine was found to be incorporated mainly in the coelomic lining of both organs. Cell divisions in the coelomic lining may be necessary for the growth of these organs, for the production of coelomocytes or, in the case of the pyloric caeca, for growth of the digestive epithelium. Proliferative activity of the digestive epithelium of the pyloric caeca was only observed in the median duct. It is hypothesized that new cells, arising from mitosis, grow from the median duct to the side lobes and differentiate into storage cells, for example. The existence of a mitosis-inducing or mitosis-stimulating substance is discussed. In the ovaries follicle cells were found to incorporate (methyl-3 H)-thymidine; in the testis, proliferation of the germinal epithelium occurred simultaneously in all spermatogenic columns. First, the spermatogonia and then later the spermatocytes became labeled. Absorption of substances from the coelomic fluid is discussed.