[Bulbar urethral strictures : A trivial urological disease or a surgical challenge?] / Die bulbäre Harnröhrenstriktur : Banale urologische Erkrankung oder chirurgische Herausforderung?

Urethral strictures are often located in the bulbar urethra, and bulbar strictures are commonly due to urethral trauma. Diagnosis is confirmed by radiographic imaging of the urethra. In cases of short primary bulbar strictures, a simple internal urethrotomy may be curative. In contrast, open surgery should be performed in long segment or recurrent strictures because recurrence rates are near 100% in these cases. Depending of the actual findings and comorbidities, end-to-end anastomosis, graft urethroplasty, flap urethroplasty, or perineal urethrostomy may be used. If definitive treatment using open surgery is delayed and multiple endoscopic treatments are tried, urethroplasty becomes more complex and success rates of definitive treatment decline.

Allogeneic retrovirally transduced, IL-2- and IFN-gamma-secreting cancer cell vaccine in patients with hormone refractory prostate cancer--a phase I clinical trial.

BACKGROUND: The purpose of this vaccine study was to determine the safety and feasibility of vaccination with an allogeneic prostate carcinoma cell line, LNCaP, expressing recombinant interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) and to evaluate the efficacy of inducing tumor-specific immune responses in HLA-A2-matched patients with hormone refractory prostate cancer (HRPC). METHODS: In a dose-escalating phase I study, HLA-A2-matched HRPC patients received four vaccinations of irradiated allogeneic LNCaP cells retrovirally transduced to secrete IL-2 and IFN-gamma at study day 1, 15, 29 and 92 and subsequently every 91 days unless tumor progression was evident. RESULTS: Three patients receiving the first dose level (7.5 million cells) showed no evidence of dose-limiting toxicity or vaccine-related adverse events including autoimmunity. One of three patients receiving the second dose level (15 million cells) developed a transient self-limiting grade 3 local injection site reaction (ulceration) after the eighth vaccination. Vaccine-induced immune responses against a broad array of prostate tumor associated antigens were detected in all six patients. Two of the three patients receiving the higher dose showed a decline in serum prostate-specific antigen (PSA) values of more than 50%, with one patient remaining on protocol for 3 years. CONCLUSIONS: Immunisation with the allogeneic LNCaP/IL-2/IFN-gamma vaccine is safe and feasible without any dose-limiting toxicity or autoimmunity. A 50% PSA decline was achieved in two of the six patients. This encouraging data provides the scientific rationale for further investigation of the vaccine in a phase II trial.

Improved urinary continence after radical retropubic prostatectomy with preparation of a long, partially intraprostatic portion of the membraneous urethra: an analysis of 1013 consecutive cases.

PURPOSE: To improve the rate of full continence in our patients, we performed, since June 1997, a careful preparation of the distally intraprostatic part of the membranous urethra to obtain a long urethral stump for the vesicourethral anastomosis. PATIENTS AND METHODS: In all, 610 patients without (group 1) and 403 patients with (group 2) a long intraprostatic stump of the urethra were asked by a self-administered questionnaire about their continence status. The rate of positive surgical margins were compared as a marker of local tumour control. RESULTS: Full continence (no pads) was achieved in 76.02% in group 1 and in 88.84%, of all patients in group 2. Stress incontinence (SIC) I degrees was found in 12.46% and 7.44% respectively, SIC II degrees was noted in 8.69 and 3.72% and complete incontinence was seen in 2.79% in group 1 and in two patients (0.5%) in group 2. Also the time to reach the final continence status was statistically and highly significantly (P<0.001) shortened. The rate of positive margins decreased in group 2, despite intraprostatic preparation. CONCLUSIONS: The preparation of a long, partially intraprostatic portion of the membranous urethra for vesicourethral anastomosis in radical retropubic prostatectomy leads to a statistically highly significant improvement of full continence and earlier continence in prostate cancer patients without compromising local tumour control.

[Significance of endorectal nuclear magnetic resonance tomography and transrectal ultrasound diagnosis in local staging of prostatic carcinoma]. / Bedeutung von endorektaler Kernspintomographie und transrektaler Sonographie beim lokalen Staging des Prostatakarzinoms.

METHODS: We assessed the staging accuracy of endorectal magnetic resonance imaging (eMRI) and transrectal ultrasonography (TRUS) for localized prostate cancer. 54 patients with biopsy proven prostate cancer underwent TRUS and eMRI prior to radical retropubic prostatectomy. The MR images were prospectively interpreted by two radiologists. These findings were compared with the histopathological results. RESULTS: Overall accuracy of eMRI in defining local tumor stage was 93% by radiologist A and 56% by radiologist B. Overall accuracy by TRUS was 63%. Analysis of interobserver agreement showed a poor correlation regarding MRI studies. Endorectal MRI was more sensitive than TRUS for detecting capsular penetration and seminal vesicle involvement. TRUS revealed a relatively high specificity and was superior to eMRI in this regard. CONCLUSION: This series shows the current limited value of TRUS and eMRI for planning treatment in patients with clinically localized prostate cancer.

Diagnosis and monitoring of urological tumors using positron emission tomography.

The purpose of this article was to critically review the diagnostic value of positron emission tomography (PET) in urological oncology. Urinary tract tumor assessment is hampered by the renal elimination of (18)F-fluorodeoxyglucose (FDG), the most commonly used PET radiopharmaceutical. PET imaging offers no significant benefits over conventional imaging modalities for renal cell and bladder carcinomas. As a result of the low metabolic activity of prostate cancer, PET does not differentiate adequately between adenoma and carcinoma, nor detect local recurrence after radical prostatectomy with sufficient sensitivity. However, lymph node staging with FDG-PET, specifically in bladder cancer, has been shown to have a potential clinical benefit. Further studies are required to determine the clinical value of retroperitoneal lymph node staging and recurrent disease detection in germ cell tumors. Finally, encouraging early results exist for the use of serial PET measurements to predict and assess therapy response to chemotherapy which may also be valuable in urological oncology.

Limited value of endorectal magnetic resonance imaging and transrectal ultrasonography in the staging of clinically localized prostate cancer.

OBJECTIVE: To examine the role of endorectal magnetic resonance imaging (eMRI) and transrectal ultrasonography (TRUS) for clinically localized prostate cancer and to assess interobserver agreement in interpreting MRI studies. PATIENTS AND METHODS: Fifty-four patients with biopsy-confirmed prostate cancer underwent TRUS and eMRI before radical retropubic prostatectomy. The MR images were prospectively interpreted by two radiologists with special expertise in this field. The criteria evaluated prospectively in each patient were extracapsular extension (ECE) and seminal vesicle invasion (SVI). The results were correlated with the histopathological findings after radical prostatectomy. RESULTS: At pathology, 27 patients had stage pT2, 15 had stage pT3a and 12 had stage pT3b lesions. The overall accuracy of eMRI in defining local tumour stage was 93% by radiologist A and 56% by radiologist B; the overall accuracy by TRUS was 63%. There was a poor correlation for the MRI studies between observers. The eMRI was more sensitive than TRUS for detecting ECE and SVI in organ-confined prostate cancer. TRUS had a relatively high specificity for ECE and SVI, and was better than eMRI in this regard. CONCLUSION: Whereas MRI tended to over-stage, TRUS under-staged prostate cancer. This series shows the current limited value of TRUS and eMRI for planning treatment in patients with clinically localized prostate cancer. Treatment decisions should not be altered based on TRUS or eMRI findings alone.

The ability of the American Joint Committee on Cancer Staging system to predict progression-free survival after radical prostatectomy.

OBJECTIVE: To examine, in a retrospective analysis of outcome based on prostate-specific antigen (PSA) levels, whether the 1992 and revised 1997 staging criteria for prostate cancer can be used to predict progression-free survival for patients after radical prostatectomy for pT2 and pT3 prostate cancer. PATIENTS AND METHODS: In all, 291 patients with a PSA determination during a 6-month interval after radical prostatectomy were analysed (mean follow-up 5.2 years). In the absence of a uniform system of pathological staging, the histopathological stage was defined according to the 1992 and 1997 American Joint Cancer Committee/Union Internationale Contre le Cancer (AJCC/UICC) tumour-nodes-metastases (TNM) staging classification. Findings were correlated with the PSA value after surgery. The subgroups of pT2 and pT3 disease were compared for the time to PSA progression, using Kaplan-Meier data analysis and the log-rank test. RESULTS: The biochemical progression-free 5-year survival rates for stage pT2 were 83% (pT2a), 81% (pT2b) and 62% (pT2c); there were no significant differences in the pT2 subgroups. The recurrence-free rates for pT3 were 79% (pT3a), 65% (pT3b) and 50% (pT3c); the actuarial recurrence-free rate was significantly different for patients with 1997 AJCC pT3a vs pT3b disease (P=0.0132). There was no significant difference in the 1992 AJCC stages pT2a vs pT2b (P=0.1232) and the recurrence-free rate was not significantly different for patients with 1992 AJCC pT3a vs pT3b disease (P=0.9). There was a significant difference in the likelihood of a PSA relapse between patients with positive and negative surgical margins (P=0.131). CONCLUSION: These results support the current revised 1997 AJCC/UICC staging system for prostate cancer. There is an urgent need to develop a pathological equivalent to the AJCC/UIC TNM clinical staging system. Greater clinical input and evaluation from different institutions are essential to reach consensus on pathological staging categories that maximize the predictability of outcome after definitive therapy. Crucial issues are the definition and quantification of extraprostatic extension and definition of surgical margin categories.

New ultradeformable drug carriers for potential transdermal application of interleukin-2 and interferon-alpha: theoretic and practical aspects.

Transfersomes (TFs) are highly deformable hydrophilic lipid vesicles that are able to penetrate the skin barrier spontaneously because of their characteristics. Transfersomes are able to transport noninvasively low- and high-molecular-weight molecules into the body. We describe the formulation and several biologic characteristics of interleukin-2 (IL-2)- and interferon-alpha (IFNalpha )-containing TFs. TFs contain natural phosphatidylcholine and sodium cholate. Recombinant human IL-2 and human hybrid IFNalpha were added to TFs and incubated for 24 hours at 4 degrees C. Immunotransfersomes were isolated from free IL-2 and IFNalpha by filtration (Centrisart, Sartorius). The biologic activity of immunotransfersomes was measured by a cytotoxic lymphoid line assay for IL-2 and by an A549-encephalomyocarditis virus assay for IFN; concentrations of proteins were determined by the enzyme-linked immunosorbent assay (ELISA). It was possible to incorporate a large amount of IL-2 and IFN in TFs (75-80%), and the incorporated IL-2, and IFN were biologically active. The increased lipid/protein ratio (90.9/1.0) led to a growing probability of association. We were thus able to show that IL-2 and IFN are trapped by transfersomes in a biologically active form and in sufficient concentrations for immunotherapy. In upcoming experiments these IL-2- and IFN-containing TFs will be used for a transdermal approach in the murine RENCA cell line model.

Antiandrogen withdrawal syndrome associated with prostate cancer therapies: incidence and clinical significance.

The antiandrogen withdrawal syndrome is a well established phenomenon in prostate cancer. It is widely accepted that a subset of patients will benefit from the withdrawal of antiandrogen or steroidal hormone from hormonal therapy, exhibiting decreasing prostate-specific antigen (PSA) values and clinical improvement. The pathophysiology of antiandrogen withdrawal syndrome is not completely understood, although androgen receptor gene mutations seem to be the likely explanation. Currently, it is not possible to identify the subset of patients whose tumours will respond to antiandrogen or steroid withdrawal. Tumours that will respond may be classified as androgen-independent and hormone-sensitive tumours as opposed to androgen-independent and hormone-insensitive tumours that do not respond. Patients who respond to antiandrogen withdrawal experience approximately 6 months with improved quality of life; however, it is unknown if this translates into prolonged survival. At the very least, antiandrogen withdrawal offers a therapeutic modality that is not associated with adverse effects and improves quality of life even if only for a very limited time. Recent reports suggest that adding a secondary hormonal therapy such as amino- glutethimide, ketoconazole or steroidal hormones may enhance the response rate and prolong response time to the antiandrogen withdrawal syndrome. However, unless there is proof that this secondary hormonal manipulation prolongs survival, maintenance of quality of life is mandatory because of the possible adverse effects from these potent drugs. The fact that about 30% of patients will respond to antiandrogen or steroid withdrawal in hormone refractory prostate cancer must be taken into account in clinical trials of new cytotoxic agents which have been and will be conducted. Cessation of flutamide for at least 4 weeks and, in the case of bicalutamide, even 8 weeks, is mandatory before antiandrogen withdrawal syndrome can be excluded as the cause of decreasing PSA values. The antiandrogen withdrawal syndrome offers another piece of the puzzle of prostatic carcinoma, but at the same time it demonstrates how different advanced prostate cancer cells may react to therapeutic strategies and, therefore, hormone refractory prostate cancer remains a difficult challenge which must be solved in the future.

Value of free prostate-specific antigen (Hybritech Tandem-R) in symptomatic patients consulting the urologist.

INTRODUCTION: Prostate-specific antigen (PSA) is a widely used tumor marker in the detection and follow-up of adenocarcinoma of the prostate. Selection of candidates for prostate biopsies is hampered by the lack of specificity resulting in a large number of unnecessary biopsies. The intention of our study was to compare the percent free PSA (f-PSA; Hybritech Tandem-R) with total PSA and age-specific PSA reference values to evaluate the clinical benefit in detecting patients with prostate cancer (PC) in a selected group of patients consulting the urologist. The question was whether cutoff points are influenced by this selection of patients. METHODS: A total of 188 patients, 114 with benign prostate hyperplasia (BPH) and 74 with PC were selected. It is a selected group of patients consulting the urologist. Diagnosis was confirmed in the BPH and PC groups by either ultrasound-guided biopsy or transurethral resection of the prostate or suprapubic adenomectomy or cystoprostatectomy. Total PSA (t-PSA) and f-PSA of all patients were measured before any manipulation by Tandem-R assay for f-PSA and Tandem-E assay for t-PSA (Hybritech). Mean values of age, prostate volume, t-PSA, f-PSA, percent f-PSA were compared in patients with BPH and PC by Mann-Whitney U test. The sensitivity and specificity of t-PSA and age-specific PSA were compared to the sensitivities and specificities of different cutoff points of percent f-PSA. RESULTS: The mean value of t-PSA, f-PSA and percent f-PSA in patients with BPH (n = 114) and PC (n = 74) were statistically significantly different. At PSA levels between 4 and 10 ng/ml 19% of negative biopsies could be avoided by the use of percent f-PSA (cutoff point 25%). There was no additional benefit of age-specific PSA. At a PSA of <4 ng/ml 6 of 7 PCs could be diagnosed by percent f-PSA (cutoff point 25%), whereas only 1 patient would be diagnosed by age-specific PSA. CONCLUSION: Percent f-PSA seems to decrease the biopsy rate at PSA levels from 4 to 10 ng/ml without missing a relevant number of cancers and to increase the detection rate at PSA <4 ng/ml. Our data indicate that it might be necessary to choose high cutoff points (25%; Tandem-E and R assay, Hybritech) in a selected study population consulting the urologist with large glands and a high prevalence of disease. However, this situation is not comparable to testing of screening populations. No benefit of age-specific PSA could be observed in this study.

Fluorine-18-fluorodeoxyglucose positron emission tomography is useless for the detection of local recurrence after radical prostatectomy.

OBJECTIVE: After radical retropubic prostatectomy a rise of the prostate-specific antigen (PSA) indicates a local recurrent or metastatic disease. If the bone scan shows no apparent bone metastasis, morphological imaging methods like x-ray computed tomography, magnetic resonance imaging or transrectal ultrasound often cannot distinguish between postoperative scar and local recurrence. Therefore we investigated the feasibility of fluorine-18-fluorodeoxyglucose positron emission tomography (F-18 FDG PET) for metabolic characterization of prostatic cancer, especially for differentiation of scar or recurrent prostate cancer after radical prostatectomy. METHODS: Dynamic PET with 370 MBq F-18 deoxyglucose (F-18 FDG) up to 60 min p.i. was performed in 2 patients with biopsy-proven benign prostatic hyperplasia, in 11 patients with a histologically proven prostate cancer prior to radical retropubic prostatectomy (RRP) and 7 patients with suspected local recurrence (with negative bone scan) after RRP prior to biopsy of anastomosis (3 local recurrence, 4 postoperative scar). RESULTS: Prostate cancer showed a very low F-18 FDG uptake. The placement of regions of interest was only possible by the use of other imaging methods. There was not difference between the F-18 FDG uptake of benign prostate hyperplasia, prostate carcinoma, postoperative scar or local recurrence after radical prostatectomy. CONCLUSION: F-18 FDG seems not to be useful to distinguish between postoperative scar and local recurrence after radical prostatectomy.

Formulation of interleukin-2 and interferon-alpha containing ultradeformable carriers for potential transdermal application.

INTRODUCTION: Transfersomes (TF) are new highly deformable hydrophilic lipid vesicles, which are able to spontaneously penetrate the skin barrier because of their characteristics. Transfersomes are able to transport non-invasively low as well as high molecular weight molecules into the body. We describe the formulation and several biological characteristics of Interleukin-2 and Interferon-a containing TF. MATERIAL AND METHODS: TF contain natural phosphatidylcholine and sodium cholate. Recombinant human IL-2 and human hybrid interferon-alpha A/D were added to TF and incubated for 24 hours at 4 degrees C. Immunotransfersomes were isolated from free IL-2 and IFN by filtration (Centrisart, Sartorius). Biological activity of immunotransfersomes was measured by CTLL-cell-assay for IL-2 and by A549--EMCV-assay for IFN, concentrations of proteins by ELISA. RESULTS: It has been possible to incorporate a high amount of IL-2 and IFN in TF (75-80%). Incorporated IL-2 and IFN were biological active. The increase of the proportion of lipid to protein to 90.9/1 led to growing probability of association. CONCLUSION: We were able to show, that IL-2 as well as IFN is trapped by transfersomes in biological active form and in sufficient concentrations for immunotherapy. In upcoming experiments these IL-2 and IFN-containing TF are used for a transdermal approach in the murine RENCA cell line model.

[Probability of seminal vesicle involvement in localized prostatic carcinoma. Significance in conformal radiotherapy]. / Wahrscheinlichkeit des Samenblasenbefalls beim lokal begrenzten Prostatakarzinom. Bedeutung für die konformale Strahlentherapie.

PURPOSE: The development of objective criteria for selecting patients for seminal vesicle irradiation on radical radiotherapy for prostate cancer will be important for successful planning of 3D conformal radiotherapy. MATERIALS AND METHODS: Based on morphometric studies from radical prostatectomy specimens, new imaging modalities with potential in the investigation of patients with gross seminal vesicle involvement and clinical factors with potential in the identification of patients with subclinical disease the development of objective guidelines is possible. RESULTS: Clinical tumor stage as determined by digital rectal examination, diagnostic tumor biopsy (Gleason Score), and pretherapy serum prostate-specific antigen value were significant factors for the probability of involvement of seminal vesicles. Studies show that seminal vesicle involvement is unlikely if the PSA is < 4 ng/ml or 4 to 10 ng/ml and Gleason Score < 7 and stage < or = T2b. In contrast, involvement of seminal vesicles is highly likely with levels above 20 ng/ml. In patients with PSA levels between 10 and 20 ng/ml and Gleason Score < 7 ultrasonographic findings with regard to tumor volume and localization will be useful to determine the extent of the target volume. For treatment planning a significant reduction in the volumes of irradiation to the rectum and bladder is evident when seminal vesicles were excluded. CONCLUSION: Prospective use of the objective criteria will be useful in the selection of patients for seminal vesicle involvement and should be an integral part in 3D conformal radiotherapy of prostate cancer.

[What does the urologist expect and hope for from the pathologist in diagnosis of prostate carcinoma]. / Was erwartet und erhofft der Urologe vom Pathologen in der Diagnostik des Prostatakarzinoms?

Prostate cancer has become the most common cancer in males in Western countries. In the United States 317,000 men were newly diagnosed with this disease in 1996. Screening efforts will identify increasing numbers of men who will be scheduled for prostate biopsy. Since the progression of prostate cancer varies widely from rapid tumor growth with early distant metastases to slow growth with good prognosis, it is of utmost importance that prognostic parameters be identified which allow the course of the disease to be predicted. Thus, the correct pathohistological staging, the evaluation of different grading systems, and the biological impact of positive surgical margins after radical prostatectomy requires collaboration between urologists and pathologists.

[Treatment of progressive, locally advanced prostate carcinoma]. / Behandlung des progredienten, lokal fortgeschrittenen Prostatakarzinoms.

Due to the lack of randomized and controlled trials comparing treatment options for locally advanced prostate cancer no clear cut therapeutical advise can be given. Currently, external beam radiotherapy is the form of treatment most often applied to which other therapeutic modalities have to be compared. Radical prostatectomy alone does not improve survival at this stage. The combination of local treatment modalities with neoadjuvant androgen deprivation seems to be a promising approach which has to be a promising approach which has to be evaluated in prospective clinical trials.

[Anti-androgen withdrawal syndrome]. / Das Antiandrogenentzugssyndrom.

Since the mid-forties androgen deprivation is regarded the standard treatment of incurable prostate cancer. Antiandrogens can be given either as monotherapy or in combination with bilateral orchidectomy or gonadotropin-releasing-hormone analoga. Recently reports have been published that withdrawal of antiandrogens in patients with hormone-resistant prostate cancer caused reduction of PSA and clinical improvement. Thus, in patients who progress under maximal androgen blockade or antiandrogen-monotherapy the antiandrogen should first be withdrawn and-in case of monotherapy-be replaced by GnRH-analoga. In approximately 30-50% of the cases a reduction of serum-PSA can be expected lasting for approx. 6 months. In some patients an improvement of symptoms and objective remission is observed.