A case of asynchronous development of transitional cell carcinoma in the bladder and renal pelvis after prolonged cyclophosphamide therapy

Urinary bladder cancers occurring after prolonged cyclophosphamide therapy are being increasingly reported. Cyclophosphamide-induced cancer in the upper urinary tract is not, however, generally recognized. We report a case of asynchronous development of transitional cell carcinoma in the bladder and renal pelvis, after prolonged cyclophosphamide therapy for non-Hodgkin's lymphoma. To date, at least 8 cyclophosphamide-related cancers have been reported in the upper tract. These cases are reviewed briefly.     

Intramural leiomyoma of the bladder

Mesodermal tumors of the urinary bladder are rare and the majority of them are malignant. We report a case of an intramural leiomyoma of the bladder presenting with symptoms of a mild lower urinary tract infection. The patient was managed with partial cystectomy and the outcome was excellent. Received: 31 May 1999; Revised: 21 September 1999; Accepted: 21 September 1999     

Role of the forebrain in bladder overactivity following cerebral infarction in the rat

This study was undertaken to investigate the contribution of the forebrain to bladder overactivity induced by cerebral infarction (CI). CI was induced by left middle cerebral artery (MCA) occlusion in female SD rat. Two and a half hours after CI or a sham operation (SO) decerebration was performed in some animals to eliminate forebrain influences on voiding function. Then bladder activity was monitored during continuous infusion cystometrograms in awake rats for 2.5 h. The effects of cumulative intravenous doses of MK-801 (0.1-1.4 mg/kg), an NMDA (N-methyl-D-aspartate) glutamatergic receptor antagonist, or sulpiride (0.1-41.1 mg/kg), D(2) selective dopaminergic receptor antagonists were studied over a 1.5-h period beginning 5 h after MCA occlusion. Bladder capacity was reduced by 57.5% after CI. In CI rats decerebration increased bladder capacity by 62.5% of predecerebration capacity. In SO rats bladder capacity was reduced by 25% after decerebration. MK-801 (0.4 and 1.4 mg/kg) increased bladder capacity in CI and CI-decerebrate rats, but did not change bladder capacity in SO-decerebrate rats. MK-801 decreased (60.7%) bladder capacity in SO-nondecerebrate rats. Sulpiride (11.1 and 41.1 mg/kg) significantly increased bladder capacity in CI, CI-decerebrate, and SO-decerebrate rats, but had no effect in SO-nondecerebrate rats. These results indicate that CI-induced decrease in bladder capacity is mediated by two mechanisms: (1) upregulation of an excitatory pathway from the forebrain, an effect blocked by decerebration and (2) downregulation of a tonic inhibitory pathway from the forebrain. The latter effect which can be induced by decerebration as well as CI unmasks a D(2) dopaminergic excitatory mechanism. An NMDA excitatory mechanism also contributes to the bladder overactivity after CI, but not after decerebration.     

Pressure flow analysis may aid in identifying women with outflow obstruction

PURPOSE: We refined recently developed pressure flow cutoff values for female bladder outlet obstruction and applied these values in a consecutive group of women undergoing urodynamic testing for various lower urinary tract symptoms. MATERIALS AND METHODS: A total of 87 women with clinical obstruction determined by history and presenting complaint were enrolled in our prospective evaluation of pressure flow studies. We identified 3 groups of participants according to the suspected cause of obstruction, including prolapse in 33, previous incontinence surgery in 25, and no likely source of obstruction identified from history and physical examination only in 29. An additional 124 patients presenting for evaluation of stress urinary incontinence served as controls. Optimal cutoff values for determining obstruction were developed using receiver operating characteristic curves. To determine the prevalence of bladder outlet obstruction these values were prospectively applied to 106 women undergoing urodynamics for various voiding complaints. RESULTS: In controls the average maximum flow rate was 23 cc per second and average detrusor pressure was 21.9 cm. water, whereas the corresponding values in those with clinical obstruction were 10.7 cc per second and 40.8 cm. water (p <0.001). No differences were noted in the various obstruction groups. Receiver operating characteristics analysis revealed that cutoff values of 11 cc per second or less and 21 cm. water or more optimized the selection of patients with bladder outlet obstruction. Using these values we noted a bladder outlet obstruction prevalence of 20% in a consecutive cohort of women undergoing urodynamic studies at our center. CONCLUSIONS: We propose cutoff pressure flow values for identifying women with bladder outlet obstruction although they should be used only in conjunction with the overall clinical situation. Neither pressure flow data only nor clinical symptoms alone may be sufficient for diagnosing obstruction in women.     

Cyclophosphamide-induced cystitis in freely-moving conscious rats: behavioral approach to a new model of visceral pain

PURPOSE: To develop a model of visceral pain in rats using a behavioral approach. Cyclophosphamide (CP), an antitumoral agent known to produce toxic effects on the bladder wall through its main toxic metabolite acrolein, was used to induce cystitis. MATERIALS AND METHODS: CP was administered at doses of 50, 100 and 200 mg./kg. i.p. to male rats, and their behavior observed and scored. The effects of morphine (0.5 to 4 mg./kg. i.v.) on CP-induced behavioral modifications were tested administered alone and after naloxone (1 mg./kg. s.c.). In addition, 90 minutes after CP injection, that is, at the time of administration of morphine, the bladder was removed in some rats for histological examination. Finally, to show that the bladder is essential for the CP-induced behavioral modifications, female rats also received CP at doses of 200 mg./kg. i.p. and of 20 mg. by the intravesical route, and acrolein at doses of 0.5 mg. by the intravesical route and of 5 mg./kg. i.v. RESULTS: CP dose-relatedly induced marked behavioral modifications in male rats: breathing rate decrease, closing of the eyes and occurrence of specific postures. Morphine dose-dependently reversed these behavioral disorders. A dose of 0.5 mg./kg. produced a reduction of almost 50% of the behavioral score induced by CP 200 mg./kg. This effect was completely prevented by pretreatment with naloxone. At the time of administration of morphine, histological modifications of the bladder wall, such as chorionic and muscle layer edema, were observed. In female rats, CP 200 mg./kg. i.p. produced the same marked behavioral modifications as those observed in male rats. Administered at the dose of 20 mg. intravesically, CP did not produce any behavioral effects, whereas acrolein at 0.5 mg. intravesically induced behavioral modifications identical to those under CP 200 mg./kg. i.p., with the same maximal levels. Conversely, acrolein 5 mg./kg. i.v. did not produce any behavioral effects at all. CONCLUSIONS: Overall, these results indicate that this experimental model of CP-induced cystitis may be an interesting new behavioral model of inflammatory visceral pain, allowing a better understanding of these painful syndromes and thus a better therapeutic approach to them.     

Electromotive administration of intravesical bethanechol and the clinical impact on acontractile detrusor management: introduction of a new test

PURPOSE: It is often difficult to determine the functional status of the detrusor muscle in patients with detrusor areflexia. We performed a clinical study to establish a test defining residual detrusor capacity in such patients. MATERIALS AND METHODS: In phase 1, 5 controls with detrusor areflexia were tested with an intravesical instillation of 20 mg. bethanechol in 150 cc of sodium chloride 0.3% with and without 20 mA. of pulsed current applied via an electrode catheter through the saline. Cystometry simultaneously recorded intravesical pressure changes. In phase 2, 45 patients with detrusor areflexia were tested with electromotive administration of intravesical bethanechol. In phase 3, 25 mg. bethanechol given orally once daily were prescribed for 15 patients and voiding control was assessed after 6 weeks of therapy. RESULTS: Neither bethanechol without current nor current through saline only led to increased intravesical pressure. However, we noted a mean pressure increase of 34 cm. water during the electromotive administration of bethanechol in 24 of 26 patients with areflexia and neurological disease compared to only 3 cm. water in 3 of 11 with a history of chronic bladder dilatation. Oral bethanechol restored spontaneous voiding in 9 of 11 patients who had had a positive response to the electromotive administration of bethanechol, whereas all 4 without a pressure increase during the electromotive administration of bethanechol did not void spontaneously. CONCLUSIONS: Electromotive administration of intravesical bethanechol identifies patients with an atonic bladder and adequate residual detrusor muscle function who are candidates for restorative measures, such as oral bethanechol and intravesical electrostimulation. Those who do not respond to the electromotive administration of bethanechol do not benefit from oral bethanechol and are candidates for catheterization.     

Bacterial adherence in a rat bladder augmentation model: ileocystoplasty versus colocystoplasty

PURPOSE: Various intestinal segments are used to reconstruct the urinary tract. For unclear reasons asymptomatic chronic bacteriuria is common in patients treated with reconstruction. We compared bacterial adherence in ileum, colon and bladder in rats with ileal and colonic bladder augmentation. MATERIALS AND METHODS: Bladder augmentation using ileum or colon was performed in 8-week-old rats. After 3 months urinary pH was measured and urine was cultured. Urovirulence factors of Escherichia coli aspirated from the augmented bladders were detected by polymerase chain reaction. In rats with negative urine culture after augmentation experimental cystitis was induced by the transurethral inoculation of E. coli C5, with type I pili and aerobactin or E. coli C92 with type I pili, P fimbriae and aerobactin at a concentration of 10(5) colony forming units per 0.3 ml. After 14 days we counted the colony forming units per cm.(2) of bladder and cm.(2) of intestinal augmentation tissue. RESULTS: When cultures were negative, mean urinary pH plus or minus standard deviation for ileocystoplasty (7.35 +/- 0.33) was significantly higher than that for colocystoplasty (6.80 +/- 0.45) or in controls (6.67 +/- 0.30). Bacterial colonization occurred in 60 of 96 ileocystoplasties (62.5%) and 36 of 68 colocystoplasties (52.9%). All 32 E. coli strains aspirated from ileocystoplasties had type I pili. In colocystoplasties 14 strains had type I pili, 4 had P fimbriae and type I pili, and 1 had no virulence factor. In experimental cystitis in the ileal patch and bladder there were 10(3.2) to 10(6.2) (log mean 4.9) and 10(1.1) to 10(5.1) (log mean 3.5) colony forming units of E. coli C5, respectively. In the colonic patch and bladder there were 10(2.2) to 10(6.2) (log mean 3.9) and 10(2.1) to 10(5.1) (log mean 3.7) colony forming units of E. coli C5, respectively. In the ileal patch and bladder versus the colonic patch and bladder there were 10(3.2) to 10(6.2) (log mean 5.0) and 10(3.1) to 10(6.1) (log mean 4.5) versus 10(3.2) to 10(6.2) (log mean 4.3) and 10(2.1) to 10(6.1) (log mean 3.8) colony forming units of E. coli C92, respectively. E. coli C5 adhered to more ileum than bladder, while bacterial adherence did not differ for colon and bladder. Adherence of E. coli C92 did not differ significantly in bladder and implanted ileum or colon. CONCLUSIONS: The colonic segment offers more resistance to E. coli than the ileal segment in urinary diversion.     

Inhibition of pressure induced bladder smooth muscle cell hyperplasia using CRM197

PURPOSE: In vivo the effects of sustained hydrostatic pressure on the bladder wall and its components are evident under physiological and pathological conditions. We previously reported that exposure of bladder smooth muscle cells to 20 and 40 cm. H2O hydrostatic pressure for as little as 1 hour resulted in the up-regulation of heparin binding epidermal growth factor messenger RNA in a time dependent fashion as well as in activation of the heparin binding epidermal growth factor growth factor gene. In our current study we investigated the use of CRM197 as an agent for blocking undesirable cellular level events, such as smooth muscle cell hyperplasia, eliminating the irreversible alterations in bladder and kidney function that result from chronic and/or severe bladder outlet obstruction. MATERIALS AND METHODS: Control and experimental neonatal ovine smooth muscle cells were exposed to 0.3 pressure and 8.5 cm. H2O, respectively, for 7 days. We evaluated the mitogenic activity of the supernatant medium from bladder smooth muscle cells exposed to 8.5 cm. H2O for 5 days (conditioned medium) before and after the addition of 0.1 mg./ml. CRM197. Bladder smooth muscle cell apoptosis was also assessed after CRM197 exposure. Statistical analysis was performed using the Student t test with p <0.05 considered significant. RESULTS: Exposing bladder smooth muscle cells to sustained 8.5 cm. H2O hydrostatic pressure for 7 days resulted in increased cell proliferation. Conditioned medium contained mitogenic activity, which was ablated after CRM197 was added. No direct toxic effect of CRM197 on bladder smooth muscle cell growth was appreciated (no apoptosis). CONCLUSIONS: We demonstrated a proliferative response of neonatal bladder smooth muscle cells after exposure to sustained hydrostatic pressure. This response was partially due to the release of heparin binding epidermal growth factor and was blocked by adding CRM197. These data support the potential use of CRM197 in drug targeted therapy for diseases involving bladder outlet obstruction.