COX-2 inhibition demonstrates potent anti-proliferative effects on bladder cancer in vitro

PURPOSE: The purpose of this work was to determine the in vitro effect of Rofecoxib and specific COX 1 and COX 2 inhibitors in regards to cell growth and apoptotic and necrotic activity. INTRODUCTION AND OBJECTIVE: Rofecoxib (Vioxx) is a nonsteroidal anti-inflammatory agent (NSAID) that selectively inhibits cyclooxygenase-2 (COX-2). The inducible isoform of COX-2 is overexpressed in many gastrointestinal and genitourinary tract tumors. We hypothesized that in vitro treatment with both COX-1 and COX-2 inhibitors would significantly reduce cellular proliferation of bladder cancer cells by apoptotic pathways. MATERIALS AND METHODS: Two human bladder cancer cell lines were grown in culture using standard techniques and treated with Rofecoxib at doses ranging from 125 microg/well serially diluted down to 8.0 microg/well. Catechin (COX 1 inhibitor) and NS398 (COX 2 inhibitor) were used at doses of 50 and 100 microM. Cell viability was measured by MTT at 24 and 72 h. Apoptosis was evaluated by the Annexin V FITC Assay. Statistical analysis was performed by ANOVA. RESULTS: Rofecoxib, Catechin, and NS398 all exhibited significant inhibition of cell growth when compared to the nontreated controls. Significant changes in apoptotic activity were observed in all agents tested in both the T24 and the TCCSUP cells. CONCLUSIONS: Selective COX-2 inhibition, using the well-tolerated and commercially available Rofecoxib (VIOXX) and specific COX 1 and 2 inhibitors, reduced the growth of human bladder cancer in vitro by apoptotic mechanisms. Further in vivo and human studies are warranted to evaluate the safety and clinical utility of this agent in patients with bladder cancer.     

Urethral evoked sympathetic skin responses and viscerosensory evoked potentials as diagnostic tools to evaluate urogenital autonomic afferent innervation in spinal cord injured patients

PURPOSE: In most spinal cord injured (SCI) patients the objective assessment of afferent neuronal pathways from the lower urinary tract and the recording of a disturbed urethral sensation and/or desire to void are still difficult. Viscerosensory evoked potentials (VSEPs) might be helpful, but they remain technically difficult to obtain and interpretation is delicate. As a new approach, sympathetic skin response (SSR) of the hand and foot were recorded after electrical stimulation of the posterior urethral mucosa. This technique should allow assessment of the integrity or deterioration of the autonomic afferent pathway. MATERIALS AND METHODS: A total of 20 males and 8 females with SCI somatosensory incomplete 15, somatosensory complete 13 and 6 healthy male volunteers were prospectively examined. During urodynamic examination electrical stimulation (single square pulses of 0.2 ms, 2 to 3-fold sensory threshold, 60 mA in complete SCI patients) of the posterior urethra/bladder neck was performed using a bipolar electrode inserted into a microtip pressure catheter. SSR recordings of the right palm and sole were simultaneously taken using surface electrodes and were analyzed by an electromyography unit. Patient reports on evoked urethral sensations at individual sensory thresholds were simultaneously noted. Additionally, well-known electrophysiological measurements such as pudendal sensory evoked potential and urethral VSEP were recorded to check clinical assessed somatosensory and viscerosensory status, and to compare SSR results with these conventional methods. RESULTS: Electrical stimulation of the posterior urethra evoked clear urethral sensation and SSRs in normal subjects. In 14 of 15 sensory incomplete SCI patients with disturbed urethral sensation SSRs could be recorded as well. Electrically evoked urethral sensations resembled the subjective desire to void at full bladder reported by controls and patients. In 13 sensory complete SCI patients with loss of any urethral sensation SSRs could not be recorded even at maximal electrical stimulation strength. All subjects with electrically induced urethral sensation had positive evoked (supralesional) SSRs of the hand. However, none of the patients with absent urethral sensation presented SSRs. Simultaneously recorded VSEPs could not be recorded clearly in 5 patients and 2 control subjects, whereas SSRs delivered clear results in all controls and patients, matching their reports. CONCLUSIONS: SSR recordings above a spinal lesion level after urethral electrostimulation might provide a useful and technically simple objective diagnostic tool to assess integrity of autonomic (visceral) afferent nerves from the lower urinary tract. Somatosensory deficits are not always paralleled by viscerosensory loss and vice versa. In this study SSRs were superior to VSEPs, the latter being more difficult to record. The subjective sensations reported by subjects during stimulation could be confirmed in an objective way in 100% of cases by positive/negative SSR findings.     

Paravesical abscess as an unusual late complication of inguinal hernia repair in children

PURPOSE: We analyzed pitfalls in the etiology, diagnosis and treatment of pediatric patients who had a paravesical abscess (PVA) resulting from previous inguinal hernia repair. MATERIALS AND METHODS: We retrospectively reviewed the records of 6 children undergoing operation for PVA related to previous inguinal hernia repair between 1994 and 2002. RESULTS: All patients were male and 1.5 to 8 years old. The location of PVA was the right side of the bladder in 4 patients and the left side in 2. History showed that only 2 cases were complicated by early postoperative wound infection. Four patients were hospitalized with a relapse of symptoms following antibiotic treatment for possible urinary tract infection. The interval between initial inguinal hernia repair and the diagnosis of PVA was 6 to 48 months. Five patients had from recurrent lower urinary tract symptoms, 2 had ipsilateral groin discomfort and 1 had lower abdominal discomfort. There were swelling and tenderness at palpation of the ipsilateral groin in 5 patients not present at previous examinations. Only 1 patient had fever and leukocytosis. Urinalysis showed microscopic hematuria in all patients, of whom 2 had also leukocyturia. All patients had negative urine cultures. Ultrasound and computerized tomography findings suggested features of abscess formation at the paravesical space with concomitant focal thickening of the adjacent bladder wall. At surgery when entering the abscess cavity, thick pus and granulation tissues were débrided. Transfixing silk sutures were found to be secured to the adjacent bladder wall in 2 patients and in the area of the internal ring in 4. They were removed. The adjacent bladder walls needed no additional intervention. Biopsy specimens revealed only chronic inflammatory components. Antibiotics were continued for a mean of 7 days. Weekly ultrasound was performed to evaluate bladder wall thickening, which resolved completely within 3 to 5 weeks. Followup was 5 months to 6 years and no recurrence was noted. CONCLUSIONS: In children presenting with lower urinary tract symptoms (early period) plus findings of soft tissue infection at the ipsilateral inguinal region (late period) after inguinal hernia repair clinicians should be aware of the possibility of PVA as a primary problem to avoid insufficient treatment because its definitive treatment is removal of the infected suture material.     

Rectal distention inhibits bladder activity via glycinergic and GABAergic mechanisms in rats

PURPOSE: We examined the influence of rectal distention on the spinobulbospinal micturition reflex and the mechanism underlying the inhibition of bladder contraction. MATERIALS AND METHODS: A total of 22 female Sprague-Dawley rats were used in this study. Using urethane anesthesia isovolumetric cystometry was performed before and after distention of the rectum by inflation of a rectal balloon (0 to 3 cm3), followed by the intrathecal injection of strychnine (a glycine receptor antagonist, 0.001 to 10 microg) and/or bicuculline (a gamma-aminobutyric acid(A) receptor antagonist, 0.001 to 1 microg) at the lumbosacral level of the spinal cord. RESULTS: Rectal distention (1.5 to 3.0 cm3) prolonged the interval, decreased the amplitude and shortened the duration of bladder contraction and finally almost abolished bladder activity. After intrathecal injection of strychnine or bicuculline in animals with inhibition of the bladder by rectal distention the interval and duration of bladder contraction returned to baseline but amplitude only recovered to 47% to 54% of the control level. However, simultaneous intrathecal injection of strychnine and bicuculline (0.001 microg each) restored amplitude to the control level. There were no differences between strychnine and bicuculline with respect to their effects on the interval, amplitude and duration of bladder contraction. CONCLUSIONS: An inhibitory rectovesical reflex exists in the lumbosacral cord of rats. The afferent limb of the spinobulbospinal micturition reflex pathway may be additionally and redundantly inhibited by glycinergic and GABAergic mechanisms, while the efferent limb of this pathway may be synergistically inhibited by these mechanisms.     

Spontaneous resolution of high grade infantile vesicoureteral reflux

PURPOSE: We studied the spontaneous resolution rate in a group of infants with high grade vesicoureteral reflux (VUR). The influence of gender, prenatal or postnatal diagnosis, recurrent urinary tract infections (UTIs) and bladder dysfunction on the resolution rate was also evaluated. MATERIALS AND METHODS: This prospective study comprised 115 infants (80 boys and 35 girls) with high grade VUR (grades III to V). Bilateral reflux was seen in 70% of cases. The majority of patients (71%) were diagnosed after UTI during infancy and only 26% were prenatally diagnosed. Median age at diagnosis was 2.7 months. Patients were followed according to a program of repeat video cystometry and noninvasive 4-hour voiding observations. Median followup was 39 months. RESULTS: The overall spontaneous resolution rate to grade II or less for all grades was 39% with no difference between boys and girls. However, when comparing the more severe grades IV and V, we found a significantly higher resolution rate in boys during the infant year. No difference in VUR disappearance could be detected when comparing the groups according to presentation, prenatal ultrasound or pyelonephritis. Breakthrough UTIs were seen in 47% of cases despite antibacterial prophylaxis and they significantly correlated with VUR nonresolution. Bladder dysfunction was found in 37% of patients and it also significantly correlated with nonresolution. CONCLUSIONS: The spontaneous resolution rate for high grade (grades IV and V) congenital VUR was high in boys during the infant year (29%), whereas in girls and boys after the infant year the resolution rate was 9% yearly during followup. Negative prognostic factors for resolution were recurrent UTIs and bladder dysfunction.     

Abnormal expression of molecular markers for bladder impermeability and differentiation in the urothelium of patients with interstitial cystitis

PURPOSE: Despite a lack of consensus concerning the etiology of interstitial cystitis (IC) the loss of impermeability and other abnormalities of the urothelium are features of the disease. In this study the distribution of proteins involved with epithelial adhesion, cellular differentiation and bladder impermeability in urothelial biopsies were explored by the immunohistochemical assessment of E-cadherin, ZO-1, uroplakin and chondroitin sulfate. MATERIALS AND METHODS: Biopsies obtained from 27 patients with IC and 7 controls were immediately fixed in formalin, immunohistochemically labeled for the described proteins and scored for protein expression, morphology and differentiation. RESULTS: Only 3 IC samples appeared completely normal, while 24 of the 27 showed an abnormality in at least 1 marker and in 6 all 4 markers were abnormal. In patients vs controls findings were abnormal for uroplakin in 13 of 27 vs 1 of 7 (p = 0.085), for E-cadherin (over expressed) in 18 of 27 vs 0 of 7 (p = 0.0021), for ZO-1 in 11 of 27 vs 0 of 7 (p = 0.046) and for chondroitin sulfate in 15 of 27 vs 0 of 7 (p = 0.0054). The morphology/polarity score significantly correlated with ZO-1 (Pearson r = 0.3935, p = 0.0423) and chondroitin sulfate (Pearson r = 0.7079, p <0.0001) expression. Chondroitin sulfate and ZO-1 showed a high correlation with each other (Pearson r = 0.5587, p = 0.0025). Uroplakin and E-cadherin expression were independent of all other markers. CONCLUSIONS: The findings reported strongly suggest abnormal differentiation in the IC bladder. The disruption of ZO-1 is similar to that reported in feline IC. Elevated E-cadherin may represent an adaptation to increased bladder permeability.     

Bladder contraction strength parameters poorly predict the necessity of long-term catheterization after a pubovaginal rectus fascial sling procedure

PURPOSE: We verified if the necessity of long-term catheterization after a pubovaginal rectus fascial sling procedure can be predicted by preoperatively determined bladder contraction strength. MATERIALS AND METHODS: We analyzed the files of 58 consecutive nonneurogenic women who underwent a sling procedure for severe or refractory stress urinary incontinence. Preoperative urodynamic measurements in these patients were re-analyzed using the power factor WF and the bladder contractility index as bladder contraction strength parameters. Catheterization was considered necessary if the patient self-catheterized at least once daily. RESULTS: One patient was lost to followup. Three and 6 months after surgery 24 (42%) of 57 and 18 (33%) of 54 patients were on catheterization. On average patients who were not on catheterization had a stronger bladder but the results were not consistently statistically significant. CONCLUSIONS: A trend toward higher bladder contraction strength in patients not on catheterization was found. However, preoperative urodynamic examination can only poorly predict the necessity of long-term catheterization after sling surgery.     

Partial cystectomy: a contemporary review of the Memorial Sloan-Kettering Cancer Center experience and recommendations for patient selection

PURPOSE: Partial cystectomy is a bladder sparing procedure that has been used to treat invasive bladder cancer in highly selected patients. This study analyzes the outcomes of partial cystectomy in a contemporary cohort of patients to identify appropriate selection criteria for the procedure. MATERIALS AND METHODS: Records were reviewed for 58 patients with a primary bladder tumor who had undergone partial cystectomy at Memorial Sloan-Kettering Cancer Center from 1995 to 2001. Information was collected on tumor size, histology, location, presence of carcinoma in situ (CIS), multifocality, neoadjuvant treatment, clinical stage, pathological stage and disease status. RESULTS: For the 58 patients analyzed, overall 5-year survival was 69% with a mean followup of 33 months (range 1 to 83). Of the patients 43 (74%) are alive with an intact bladder, 39 (67%) are currently disease-free with an intact bladder and 32 (55%) have been continuously disease-free with an intact bladder. Seven patients experienced a superficial recurrence and were treated successfully while 15 patients experienced an advanced recurrence. On univariate analysis CIS and multifocality were related to superficial recurrence, and lymph node involvement and positive surgical margin were related to advanced recurrence. On multivariate analysis concomitant CIS (odds ratio 7.05, p = 0.004) and lymph node involvement (odds ratio 4.38, p = 0.031) were predictors of advanced recurrence. CONCLUSIONS: In highly selected patients with invasive bladder cancer, partial cystectomy offers acceptable outcomes. Concomitant CIS and presence of metastases to regional lymph nodes predict advanced recurrence.