Extracorporeal shock wave lithotripsy under intravenous sedation for treatment of urolithiasis.

BACKGROUND: In contrast to treatment with oral or intramuscular analgesics, extracorporeal shock wave lithotripsy (E.S.W.L.) can be performed with patients under sedation too. Besides the advantage of increased shock energy, patients tend to have more constant breathing excursions and are more idle during treatment, potentially increasing the stone-free ratio (S.F.R.) after treatment. METHODS: This study presents the results of 310 patients who underwent 400 E.S.W.L. procedures under sedation, with a stationary lithotripter. RESULTS: After one procedure, the S.F.R. was 54.8% (170/310). A second treatment was successful in 42.1% (32/76), a third treatment in 21.4% (3/14). Therefore, 66.1% (205/310) of patients eventually became stone-free. Kidney stones were successfully treated in 65.4% (161/246), ureteral stones in 68.8% (44/64) of cases. Patients with stones ≤15 mm were successfully treated in 67.4% (194/288), patients with stones >15 mm in 50% (11/22) of cases. Considering each procedure individually, 45.3% (181/400) of procedures were successful after 3 weeks. Extending follow-up to 3 months is important, since 26.7% of stones (24/90) eventually still disappeared, increasing S.F.R. to 51.3% after one procedure. Complications occurred after 5.5% E.S.W.L.-procedures. CONCLUSIONS: E.S.W.L. is a well-tolerated, non-invasive procedure that produces reasonable stone clearance of both upper and lower urinary tract calculi. Performing the procedure whilst patients are intravenously sedated results in an acceptable S.F.R. Strong selection based on unfavourable factors could increase the chance on successful treatment and spare patients a pointless procedure. However, considering E.S.W.L.'s elegant nature, sometimes a more tolerant approach seems justifiable.

Inhibition of apoptotic proteins causes multidrug resistance in renal carcinoma cells.

Renal Cell Carcinomas (RCCs) exhibit strong resistance to the most chemotherapeutic treatments probably due to the expression of various multidrug resistance (MDR) genes. Overexpression of P-glycoprotein (Pgp) is established as one such factor, but other mechanisms such as at-MDR, characterized by attenuated DNA-topoisomerase II (topoII) activity, may be functional as well. In addition, regulating proteins involved in apoptosis can exhibit multidrug resistant features. However, prevention of apoptosis as a mechanism of MDR has not yet been assessed in RCC, nor has the cytotoxicity of a variety of chemotherapeutic agents known to trigger apoptotic or necrotic cell death been tested in RCC in a systematic fashion. Using immunohistochemistry and Western blotting, Bcl-2 and Bax expression was determined in a panel of multidrug resistant RCC lines featuring Pgp and/or at-MDR. The results were related to apoptotic activity and kind of cell death in these cell lines, demonstrated by incubation with Hoechst 33342 and propidium iodide after treatment with various cytotoxic agents and quantitated by MTT. In the drug resistant sublines, some decreased Bax and strongly increased Bcl-2 expression was seen by immunohistochemistry indicating prevention of apoptosis as a distinct feature of MDR in RCC. This was confirmed by Western blotting. Sublines revealed significant resistance for all drugs, except for CC-313 and DiMIQ. However, these drugs induced necrotic cell death, in contrast to all other drugs tested, which induced apoptotic cell death. We conclude that, in chemoselected RCC sublines, multidrug resistance appears to be functional due to inhibition of apoptosis, apart from the MDR1 and at-MDR resistance mechanisms. CC-313 and DiMIQ are very potent cytotoxic agents in RCC, probably because they do not kill by induction of apoptosis.

Decreased levels of topoisomerase II alpha in human renal cell carcinoma lines resistant to etoposide.

Renal cell carcinoma (RCC) displays strong resistance against many chemotherapeutic drugs. Overexpression of P-glycoprotein (Pgp) appears to be part of this resistance. The involvement of another resistance mechanism, involving the decreased activity of DNA topoisomerase II (topoII), remains uncertain. By culturing the human RCC lines RC2 and RC21 in the presence of increasing concentrations of etoposide, we derived the variant sublines RC2E, RC21A and RC21E, that had acquired approximately 30-, 60- and 90-fold resistance to this drug respectively. RC2E, RC21A and RC21E were approximately 50-, 5- and 400-fold cross-resistant to doxorubicin respectively. RC2E and RC21E also showed cross-resistance (approximately 200- and 3500-fold respectively) to vinblastine. Quantitative differences in MDR1 and Pgp expression (elevated in RC2E and RC21E) and topoII alpha (reduced in RC21E and RC21A) were demonstrated using Western blotting and the reverse transcriptase/polymerase chain reaction. Decreased amounts of topoII alpha were reflected in a reduced activity of RC21A and RC21E as measured by unknotting phage P4 DNA. Qualitative changes of the topoII alpha gene, such as point mutations in the motif B/DNBS and DNA-binding regions, or differences in methylation status of the promoter gene of RC21E, were not found. These cell lines represent a model of a solid tumor in which overexpression of Pgp, a combination of increased Pgp and decreased topoII alpha, and a decrease of topoII alpha are represented.