Phase 2 study of adjuvant intravesical instillations of apaziquone for high risk nonmuscle invasive bladder cancer.

PURPOSE: We studied the safety and efficacy of multiple adjuvant apaziquone instillations in patients with high risk nonmuscle invasive bladder cancer. MATERIALS AND METHODS: Patients with high risk nonmuscle invasive urothelial carcinoma of the bladder underwent transurethral resection of all bladder tumor(s), and received 6 weekly adjuvant intravesical apaziquone instillations of 4 mg in 40 ml. Patients with carcinoma in situ received 3 further maintenance instillations at months 3, 6 and 12. Followup consisted of cystoscopy, urine cytology and observation of adverse events every 3 months for 18 months. RESULTS: A total of 53 patients were enrolled in the study. Although all patients were high risk according to the definitions used when the study was initiated, according to most recent guideline criteria, 80% and 20% of these patients would now be considered intermediate and high risk for recurrence, and 50% and 44% would be considered intermediate and high risk for progression, respectively. Intent to treat analysis of 49 patients with papillary tumors showed recurrent tumors in 34.7% and 44.9% at 12 and 18 months, respectively. One patient had progression to T2 or greater urothelial carcinoma after 9 months. There were 4 patients with carcinoma in situ who had complete responses at 3 months but discontinued treatment due to cystitis, recurrent papillary disease, urinary incontinence and dysuria. Most other side effects were mild (grade 1 to 2). CONCLUSIONS: Adjuvant intravesical instillations of apaziquone are generally well tolerated. The recurrence rates of 34.7% after 12 months and 44.9% after 18 months in these patients can be considered encouraging, and warrant further study.

Benign prostatic hyperplasia as a progressive disease: a guide to the risk factors and options for medical management.

Benign prostatic hyperplasia (BPH) is a complex disease that is progressive in many men. BPH is commonly associated with bothersome lower urinary tract symptoms; progressive disease can also result in complications such as acute urinary retention (AUR) and BPH-related surgery. It is therefore important to identify men at increased risk of BPH progression to optimise therapy. Several factors are associated with progression, including age and prostate volume (PV). Serum prostate-specific antigen level is closely correlated with PV, making it useful for determining the risk of BPH progression. Medical therapy is the most frequently used treatment for BPH. 5-alpha-reductase inhibitors impact the underlying disease and decrease PV; this results in improved symptoms, urinary flow and quality of life, and a reduced risk of AUR and BPH-related surgery. Alpha-blockers achieve rapid symptom relief but do not reduce the overall risk of AUR or BPH-related surgery, presumably because they have no effect on PV. Combination therapy provides greater and more durable benefits than either monotherapy and is a recommended option in treatment guidelines. The Combination of Avodart and Tamsulosin (CombAT) study is currently evaluating the combination of dutasteride with tamsulosin over 4 years in a population of men at increased risk of BPH progression. A preplanned 2-year analysis has shown sustained symptom improvement with combination therapy, significantly greater than with either monotherapy. CombAT is also the first study to show benefit in improving BPH symptoms for combination therapy over the alpha-blocker, tamsulosin, from 9 months of treatment.

Reduce bladder cancer recurrence in patients treated for upper urinary tract urothelial carcinoma: The REBACARE-trial.

BACKGROUND: Following radical nephro-ureterectomy for urothelial carcinoma of the upper urinary tract (UUT), the reported bladder recurrence rate of urothelial carcinoma is 22-47%. A single intravesical instillation of chemotherapy within 10 days following nephro-ureterectomy has the potential to decrease the risk of a bladder recurrence significantly. Despite recommendation by the European Association of Urology guideline to administer a single instillation postoperatively, the compliance rate is low because the risk of extravasation of chemotherapy. AIM: To reduce the risk of bladder cancer recurrence by a single intravesical instillation of Mitomycin immediately (within 3 h) before radical nephro-ureterectomy or partial ureterectomy. METHODS: Adult patients (age ≥ 18 years) with a (suspicion of a) urothelial carcinoma of the UUT undergoing radical nephro-ureterectomy or partial ureterectomy will be eligible and will receive a single intravesical instillation of Mitomycin within 3 h before surgery. In total, 170 patients will be included in this prospective, observational study. Follow-up will be according to current guidelines. RESULTS: The primary endpoint is the bladder cancer recurrence rate up to two years after surgery. Secondary endpoints are: a) the compliance rate; b) oncological outcome; c) possible side-effects; d) the quality of life; e) the calculation of costs of a single neoadjuvant instillation with Mitomycin and f) molecular characterization of UUT tumors and intravesical recurrences. CONCLUSIONS: A single intravesical instillation of Mitomycin before radical nephro-ureterectomy or partial ureterectomy may reduce the risk of a bladder recurrence in patients treated for UUT urothelial carcinoma and will circumvent the disadvantages of current therapy.

The influence of high-energy shock waves on the development of metastases.

The hypothesis that exposure of a solid tumor to high-energy shock waves (HESW) could lead to an increase of metastases was investigated in an animal model. The highly metastatic AT-6 Dunning R3327 rat prostate cancer subline was implanted in the hind limb of a Fisher-Copenhagen rat and was exposed to 6000 shock waves delivered by an experimental lithotripter, or sham-treated, as soon as the tumor had reached a volume of 175-225 mm3. The tumor-bearing leg was amputated 24 h later and the number of metastases was examined 12 weeks thereafter at autopsy. Metastases were seen in 82% of the animals exposed to HESW and in 25% of the sham-treated animals. There was no significant difference in weight of the lungs that contained metastases, between sham and treated animals. These results were confirmed in a second experiment. We conclude that the metastatic spread of tumors with a high metastatic potential may be enhanced by shock-wave exposure.

The effects of successive high-energy shock-wave tumor administration on tumor blood flow.

The effects of repeated high-energy shock wave (HESW) tumor administration on tumor blood flow (TBF) were studied in NU-1 human kidney cancer xenografts. Deuteriated water was used as a magnetic resonance spectroscopic detectable tracer for measuring tumor blood flow. Tumors were exposed twice to 800 electromagnetically generated HESW, with a 24-h interval or sham exposed. No changes in TBF occurred after sham exposure to HESW. TBF levels 2 h after the first and second HESW application were, respectively, 46% and 37% lower than the mean preexposure TBF value and returned to normal levels within 16 h. There was statistically no difference found between the effects on tumor blood flow after the first and second HESW exposure. These observations are in agreement with earlier studies and provide a rationale to shorten the time interval between HESW monotreatments to 2 to 3 h.

Removal of a missed polypropylene tape by a combined transurethral and transabdominal endoscopic approach.

Surgical intervention for bladder perforation caused by application of a transvaginally placed polypropylene tape is rare. Open as well as endoscopic procedures for removal from the bladder have been described earlier. In this case report we describe the removal of an intravesical polypropylene tape by a combined transurethral and transabdominal endoscopic approach 3 months after the initial surgical procedure.

Evaluation of early pelvic floor physiotherapy on the duration and degree of urinary incontinence after radical retropubic prostatectomy in a non-teaching hospital.

The objective of this study was to study the effect of early pelvic floor re-education on the degree and duration of incontinence and to evaluate the results of radical retropubic prostatectomy (RRP) performed in a non-teaching hospital. This is a non-randomised study. From March 2000 to November 2003, 57 consecutive men, who underwent RRP for localized prostate cancer, participated in a pelvic floor re-educating program. Continence was defined as a loss of no more than 2-g urine on the 24-h pad test and no use of pads. The 24-h pad test was performed once in every 4 weeks until the patient indicated that he was continent. Diurnal and nocturnal continence was achieved after 1, 2, 3, 6 and 12 months post catheter removal in 40, 49, 70, 86 and 88% of all men, respectively. Comparison of our results with current literature suggest that the time period towards continence after a RRP can be shortened relevantly if pelvic floor re-education is started directly after catheter removal.

Manual derotation of the twisted spermatic cord.

OBJECTIVE: To re-emphasize the safety and efficacy of manual derotation in the management of the twisted spermatic cord. PATIENTS AND METHODS: Seventeen patients (mean age 15 years, range 13-28) with acute unilateral torsion of the spermatic cord, initially treated by manual detorsion, were reviewed; all 17 patients were seen by one consulting urologist (H.F.M.K.). RESULTS: In 14 of the 17 patients the attempt resulted in successful manual derotation, i. e. the immediate relief of all symptoms and normal findings at physical examination. No testicular atrophy was detected during the follow-up (mean 22 months, range 9-72). CONCLUSIONS: These results reinforce the efficacy and safety of manual derotation with subsequent elective bilateral orchidopexy as the primary treatment for the twisted spermatic cord.

Transurethral deroofing of midline prostatic cyst for subfertile men.

We evaluated the efficacy of transurethral deroofing of a midline prostatic cyst in subfertile men with one or more of the following semen abnormalities: decreased ejaculatory volume, decreased sperm motility and oligo- or azoospermia. Results from treatment of a series of 11 subfertile men with a midline prostatic cyst by transurethral deroofing of the cyst are presented. Five patients showed an improvement of seminal volume. Only one patient demonstrated an improvement of sperm count. Sperm motility was not influenced. No relationship was found between positive outcome following operation and either size of the cyst or dilatation of the seminal vesicles. Spontaneous pregnancies did not occur after transurethral deroofing of the midline prostatic cyst. In conclusion, our study suggests a poor efficacy of transurethral deroofing of a midline prostatic cyst in subfertile men with the above mentioned semen abnormalities.

Testicular simple cyst and teratoma: asynchronous bilateral occurrence within the first year of life.

Benign and malignant testicular tumors are rare in infancy. Moreover, only a few cases of bilateral testicular tumors in children have been reported to date. To our knowledge, we report the first case of an asynchronous bilateral simple testicular cyst and testicular teratoma in an infant. This case demonstrates that although both lesions are benign in the prepubertal child, treatment decisions should be made carefully.

Influence of high-intensity focused ultrasound on the development of metastases.

OBJECTIVE: The hypothesis that exposure of a solid tumor to high-intensity focused ultrasound (HIFU) could lead to an increase of metastases was investigated in an animal model. METHODS: The highly metastatic AT-6 Dunning R3327 rat prostate cancer subline was implanted into the hind limb of Fisher-Copenhagen rats and was exposed to 1 pulse/mm2 tumor (acoustical power 1,000 W/cm2) delivered by an experimental machine (Ablatherm, Technomed, France), or the animals were sham treated, as soon as the tumor had reached a volume of 175-225 mm3. The tumor-bearing leg was amputated 24 h later and the number of metastases examined 12 weeks thereafter at autopsy. RESULTS: Metastases were seen in 3 (23%) of the 13 animals exposed to HIFU and in 4 (25%) of the 16 sham-treated animals; this is not significantly different. There was also no significant difference in weight of the lungs that contained metastases between sham-treated and HIFU-treated animals. CONCLUSION: Metastatic spread of animal tumors with a high metastatic potential is not enhanced by HIFU exposure.

Magnetic resonance spectroscopy detects metabolic differences between seven Dunning rat prostate tumor sublines with different biological behavior.

In this study, it was investigated whether prostate tumor biological parameters correlate with metabolic profiles. 1H and 31P magnetic resonance spectra were acquired from perchloric acid extracts of seven Dunning R-3327 prostate tumor sublines. Several metabolic ratios, for example, phosphocholine/total phosphate, choline/total creatine, and inositol/total creatine, did not correlate specifically with one biological characteristics but, based on each of these ratios, the well-differentiated, nonmetastatic, and hormone-dependent sublines could be discriminated from the poorly differentiated or anaplastic, metastatic, and hormone-independent sublines. The glycerophosphoethanolamine/total phosphate, glycerophosphocholine/total phosphate, and phosphocreatine/total phosphate ratios correlated with differentiation grade, and the differences in glycerophosphorylglycerol/total phosphate ratio between metastatic and nonmetastatic sublines was highly significant. No correlation for hormonal sensitivity with any of the metabolites measured could be found, neither by 31P nor by 1H MRS.

Antitumor effects of bacillus Calmette-Guerin in a syngeneic rat bladder tumor model system, RBT323.

We have studied the antitumor effects of Bacillus Calmette-Guerin (RIVM strain) in the syngeneic rat bladder tumor model RBT323. In an immunohistochemical infiltrate study we compared the antitumor effects of BCG with the immunopathological findings in order to get more insight into the possible effector mechanisms of BCG. The antitumor effects of BCG appeared not to be dose-dependent, in the dose range tested. In rechallenge experiments no difference in growth of control tumors was seen between rats pretreated- or not pretreated with BCG. There was, however, a significant increase in antitumor effect of BCG after pretreatment with BCG. Immunohistological examination of BCG treated tumors revealed infiltrates consisting of macrophages, B-cells and T-cells. These results imply that whereas no specific response against the RBT323 cells is generated by BCG treatment, possibly BCG induced antigens do serve as immunogens in this nonimmunogenic syngeneic rat bladder tumor model system.

In vitro proton magnetic resonance spectroscopy of four human prostate cancer cell lines.

There is accumulating evidence that some biochemical pathways observable by magnetic resonance spectroscopy, e.g., citrate acid and phospholipid metabolism, are altered in human prostate cancer. Four well-established human prostate cancer cell lines were therefore studied with magnetic resonance spectroscopy to compare differences in metabolic content with tumor biological behavior. Herein we demonstrate that, although each cell line has its own metabolic profile, relative creatine and citrate levels can be used to discriminate the androgen-dependent LNCaP cell line from the androgen-independent DU-145, TSU, and PC-3 cell lines.

Characterization of human prostate cancer, benign prostatic hyperplasia and normal prostate by in vitro 1H and 31P magnetic resonance spectroscopy.

In vitro 1H and 31P magnetic resonance spectra were acquired from perchloric acid extracts of human prostate tissue obtained by transurethral resection. This included tissue of patients with benign prostatic hyperplasia and prostatic adenocarcinoma; one tissue sample was obtained from a patient without any sign of BPH or malignancy. Major resonances in the magnetic resonance spectra were assigned to prostate compounds and were quantified. The citrate/lactate, citrate/total choline, phosphocholine/total creatinine, choline/total creatine, alanine/total creatine, phosphoethanolamine/total phosphate, phosphocholine/total phosphate and glycerophosphoethanolamine/total phosphate ratios were statistically different for the prostate cancer samples as compared with the BPH specimens. These observations may contribute to the understanding of in vivo magnetic resonance spectra of the prostate and indicate that magnetic resonance spectroscopy can aid in the diagnosis of prostate malignancy.

High energy shock waves induced increase in the local concentration of systemically given TNF-alpha.

The influence of high energy shock waves (HESW) on the local concentration of systemically given TNF-alpha was studied in a syngeneic rat bladder tumor model. 125I-TNF-alpha was injected intravenously and within 1 minute was followed by HESW tumor exposure. High energy shock waves were generated using an experimental shock wave emitter based on the Siemens Lithostar Plus. Administration of HESW to RBT323 tumors resulted in a 3-fold increase in uptake of 125I-TNF-alpha in the tumor compared with nontreated tumors, whereas the tissue distribution and pharmacokinetics of nontumor tissue were similar irrespective of HESW exposure. These results demonstrate that HESW administration leads to an increase in the local concentration of a systemically given drug. The capacity of HESW to increase local drug concentrations will be of importance in designing more effective combined treatment strategies.

Effects of high energy shock waves on tumor blood flow and metabolism: 31P/1H/2H nuclear magnetic resonance study.

The effects of high energy shock waves (HESW) on tumor cell metabolism and tumor blood flow were studied in the NU-1 kidney cancer xenograft by multinuclear 1H/2H/31P magnetic resonance spectroscopy. Tumor xenografts were exposed to 800 HESW using an experimental electromagnetic shock wave emitter based on the Siemens Lithostar Plus, which is used for clinical lithotripsy. Exposure of tumors to 800 HESW resulted in a temporary decrease of tumor blood flow (TBF) determined by the 2H NMR monitoring of the 2HO1H wash-out after intratumoral injection. By concomitant recording of 31P and 1H NMR spectra, tumor pH, high-energy phosphates and lactate levels were followed. Tumor treatment with HESW transiently resulted in acidification, ATP decrease, P(i) increase and lactate increase. In contrast, HESW administration adjacent to the tumor did not significantly influence TBF, tumor pH, high-energy phosphates or lactate levels, showing that the observed alterations are caused by an interaction of HESW and tumor tissue. The most likely explanation for these observations is that HESW administration causes local vascular malfunctioning followed by a reduction in oxygen and nutrient supply to the tumor which leads to a decreased aerobic energy metabolism. The results of this study may be used to aid the design of HESW-based therapies.