Arnulf Stenzl

Treatment of Muscle-Invasive and Metastatic Bladder Cancer: Update of the EAU Guidelines.

CONTEXT New data regarding treatment of muscle-invasive and metastatic bladder cancer (MiM-BC) has emerged and led to an update of the European Association of Urology (EAU) guidelines for MiM-BC. OBJECTIVE To review the new EAU guidelines for MiM-BC with a specific focus on treatment. EVIDENCE ACQUISITION New literature published since the last update of the EAU guidelines in 2008 was obtained from Medline, the Cochrane Database of Systematic Reviews, and reference lists in publications and review articles and comprehensively screened by a group of urologists, oncologists, and a radiologist appointed by the EAU Guidelines Office. Previous recommendations based on the older literature on this subject were also taken into account. Levels of evidence (LEs) and grades of recommendations (GRs) were added based on a system modified from the Oxford Centre for Evidence-based Medicine Levels of Evidence. EVIDENCE SYNTHESIS Current data demonstrate that neoadjuvant chemotherapy in conjunction with radical cystectomy (RC) is recommended in certain constellations of MiM-BC. RC remains the basic treatment of choice in localised invasive disease for both sexes. An attempt has been made to define the extent of surgery under standard conditions in both sexes. An orthotopic bladder substitute should be offered to both male and female patients lacking any contraindications, such as no tumour at the level of urethral dissection. In contrast to neoadjuvant chemotherapy, current advice recommends the use of adjuvant chemotherapy only within clinical trials. Multimodality bladder-preserving treatment in localised disease is currently regarded only as an alternative in selected, well-informed, and compliant patients for whom cystectomy is not considered for medical or personal reasons. In metastatic disease, the first-line treatment for patients fit enough to sustain cisplatin remains cisplatin-containing combination chemotherapy. With the advent of vinflunine, second-line chemotherapy has become available. CONCLUSIONS In the treatment of localised invasive bladder cancer (BCa), the standard treatment remains radical surgical removal of the bladder within standard limits, including as-yet-unspecified regional lymph nodes. However, the addition of neoadjuvant chemotherapy must be considered for certain specific patient groups. A new drug for second-line chemotherapy (vinflunine) in metastatic disease has been approved and is recommended.

Generation of pluripotent stem cells from adult human testis

Human primordial germ cells and mouse neonatal and adult germline stem cells are pluripotent and show similar properties to embryonic stem cells. Here we report the successful establishment of human adult germline stem cells derived from spermatogonial cells of adult human testis. Cellular and molecular characterization of these cells revealed many similarities to human embryonic stem cells, and the germline stem cells produced teratomas after transplantation into immunodeficient mice. The human adult germline stem cells differentiated into various types of somatic cells of all three germ layers when grown under conditions used to induce the differentiation of human embryonic stem cells. We conclude that the generation of human adult germline stem cells from testicular biopsies may provide simple and non-controversial access to individual cell-based therapy without the ethical and immunological problems associated with human embryonic stem cells.

The updated EAU guidelines on muscle-invasive and metastatic bladder cancer.

CONTEXT New data regarding diagnosis and treatment of muscle-invasive and metastatic bladder cancer (MiM-BC) has emerged and led to an update of the European Association of Urology (EAU) guidelines for MiM-BC. OBJECTIVE To review the new EAU guidelines for MiM-BC. EVIDENCE ACQUISITION A comprehensive workup of the literature obtained from Medline, the Cochrane central register of systematic reviews, and reference lists in publications and review articles was developed and screened by a group of urologists, oncologists, and radiologist appointed by the EAU Guideline Committee. Previous recommendations based on the older literature on this subject were taken into account. Levels of evidence and grade of guideline recommendations were added, modified from the Oxford Centre for Evidence-based Medicine Levels of Evidence. EVIDENCE SYNTHESIS The diagnosis of muscle-invasive bladder cancer (BCa) is made by transurethral resection (TUR) and following histopathologic evaluation. Patients with confirmed muscle-invasive BCa should be staged by computed tomography (CT) scans of the chest, abdomen, and pelvis, if available. Adjuvant chemotherapy is currently only advised within clinical trials. Radical cystectomy (RC) is the treatment of choice for both sexes, and lymph node dissection should be an integral part of cystectomy. An orthotopic bladder substitute should be offered to both male and female patients lacking any contraindications, such as no tumour at the level of urethral dissection. Multimodality bladder-preserving treatment in localised disease is currently regarded only as an alternative in selected, well-informed, and compliant patients for whom cystectomy is not considered for clinical or personal reasons. An appropriate schedule for disease monitoring should be based on (1) natural timing of recurrence, (2) probability of disease recurrence, (3) functional deterioration at particular sites, and (4) consideration of treatment of a recurrence. In metastatic disease, the first-line treatment for patients fit enough to sustain cisplatin is cisplatin-containing combination chemotherapy. Presently, there is no standard second-line chemotherapy. CONCLUSIONS These EAU guidelines are a short, comprehensive overview of the updated guidelines of (MiM-BC) as recently published in the EAU guidelines and also available in the National Guideline Clearinghouse.

CELLULAR AND HUMORAL IMMUNE RESPONSES IN PATIENTS WITH METASTATIC RENAL CELL CARCINOMA AFTER VACCINATION WITH ANTIGEN PULSED DENDRITIC CELLS

PURPOSE Dendritic cells are the most potent stimulators of immune responses including antitumor responses. We performed a pilot study of cultured antigen loaded dendritic cells in patients with metastatic renal cell carcinoma. MATERIALS AND METHODS Dendritic cells were obtained by culturing plastic adherent mononuclear cells from peripheral blood for 5 days in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4. Day 5 dendritic cells were loaded with cell lysate from cultured autologous tumor cells and with the immunogenic protein keyhole-limpet hemocyanin (KLH) which serves as a helper antigen and as a tracer molecule. During the antigen pulse dendritic cells were activated with a combination of tumor necrosis factor-alpha and prostaglandin E2. Dendritic cells were administered by 3 intravenous infusions at monthly intervals. Cellular and humoral immune responses to KLH and cell lysate were measured in vitro before and after the vaccinations. RESULTS Preparation of 12 dendritic cell vaccines from patients with advanced renal cell carcinoma was successful. Treatment with fully activated CD83+ dendritic cells was well tolerated with moderate fever as the only side effect. Potent immunological responses to KLH and, most importantly, against cell lysate could be measured in vitro after the vaccinations. CONCLUSIONS Our data demonstrate that a dendritic cell based vaccine can induce antigen specific immunity in patients with metastatic renal cell carcinoma. Dendritic cell based immunotherapy represents a feasible, well tolerated and promising new approach for the treatment of advanced renal cell carcinoma.

Hexaminolevulinate Guided Fluorescence Cystoscopy Reduces Recurrence in Patients With Nonmuscle Invasive Bladder Cancer

PURPOSE We assessed the impact that improved detection of nonmuscle invasive bladder cancer with hexaminolevulinate fluorescence cystoscopy may have on early recurrence rates. MATERIALS AND METHODS This prospective, randomized study enrolled 814 patients suspected of having bladder cancer at increased risk for recurrence. All patients underwent white light cystoscopy and mapping of lesions, followed by transurethral resection of the bladder when indicated. Patients in the fluorescence group also received intravesical hexaminolevulinate solution at least 1 hour before cystoscopy to induce fluorescence of cancerous lesions, and underwent additional inspection with blue light before and after transurethral resection of the bladder. Adjuvant intravesical therapy was based on risk. Followup cystoscopy at 3, 6 and 9 months was conducted with white light. RESULTS Detection was performed as a within patient comparison in the fluorescence group. In this group 286 patients had at least 1 Ta or T1 tumor (intent to treat). In 47 patients (16%) at least 1 of the tumors was seen only with fluorescence (p = 0.001). During the 9-month followup (intent to treat) there was tumor recurrence in 128 of 271 patients (47%) in the fluorescence group and 157 of 280 (56%) in the white light group (p = 0.026). The relative reduction in recurrence rate was 16%. CONCLUSIONS Hexaminolevulinate fluorescence cystoscopy significantly improves the detection of Ta and T1 lesions and significantly reduces the rate of tumor recurrence at 9 months.

THE FEMALE URETHRAL SPHINCTER: A MORPHOLOGICAL AND TOPOGRAPHICAL STUDY

PURPOSE We reassess the anatomy and topography of the female urethral sphincter system and its innervation in regard to urethra sparing anterior exenteration and other surgical procedures. MATERIALS AND METHODS Anatomical and histological studies were performed on 9 fetal specimens and 4 adult cadavers. Using graphics software the anatomical structures of the true pelvis were reconstructed based on computerized tomography cross sections and digitized histological sections. On the adult cadavers anterior exenteration was performed to study the implications of the isolated urethra and its sphincter mechanism. RESULTS Strata of connective tissue were found to divide the smooth muscles of the proximal two-thirds of the female urethra into 3 layers. Computer guided 3-dimensional reconstruction of digitized histological sections showed that thin fibers of the pelvic plexus course to this part of the urethra. The majority of these fibers may be preserved by carefully dissecting the bladder neck and the proximal portion of the urethra, leaving the lateral vaginal walls intact. The striated rhabdosphincter, which is innervated by fibers of the pudendal nerve, was in the caudal third of the urethra. CONCLUSIONS A well-defined sphincteric structure or sphincter could not be anatomically recognized in the bladder neck region. The majority of rhabdosphincter fibers were found in the middle and caudal thirds of the urethra. Thus, in patients undergoing removal of the bladder neck and part of the proximal portion of the urethra continence can be maintained by the remaining urethral sphincter system, provided that innervation remains essentially intact.

Prostate Cancer Gene 3 (PCA3): Development and Internal Validation of a Novel Biopsy Nomogram

BACKGROUND Urinary prostate cancer gene 3 (PCA3) represents a promising novel marker of prostate cancer detection. OBJECTIVE To test whether urinary PCA3 assay improves prostate cancer (PCa) risk assessment and to construct a decision-making aid in a multi-institutional cohort with pre-prostate biopsy data. DESIGN, SETTING, AND PARTICIPANTS PCA3 assay cut-off threshold analyses were followed by logistic regression models which used established predictors to assess PCa-risk at biopsy in a large multi-institutional data set of 809 men at risk of harboring PCa. MEASUREMENTS Regression coefficients were used to construct four sets of nomograms. Predictive accuracy (PA) estimates of biopsy outcome predictions were quantified using the area under the curve of the receiver operator characteristic analysis in models with and without PCA3. Bootstrap resamples were used for internal validation and to reduce overfit bias. The extent of overestimation or underestimation of the observed PCa rate at biopsy was explored graphically using nonparametric loss-calibration plots. Differences in PA were tested using the Mantel-Haenszel test. Finally, nomogram-derived probability cut-offs were tested to assess the ability to identify patients with or without PCa. RESULTS AND LIMITATIONS PCA3 was identified as a statistically independent risk factor of PCa at biopsy. Addition of a PCA3 assay improved bootstrap-corrected multivariate PA of the base model between 2% and 5%. The highest increment in PA resulted from a PCA3 assay cut-off threshold of 17, where a 5% gain in PA (from 0.68 to 0.73, p=0.04) was recorded. Nomogram probability-derived risk cut-off analyses further corroborate the superiority of the PCA3 nomogram over the base model. CONCLUSIONS PCA3 fulfills the criteria for a novel marker capable of increasing PA of multivariate biopsy models. This novel PCA3-based nomogram better identifies men at risk of harboring PCa and assists in deciding whether further evaluation is necessary.

Original Articles: Bladder Cancer: The Risk of Urethral Tumors in Female Bladder Cancer: Can the Urethra be Used for Orthotopic Reconstruction of the Lower Urinary Tract?

ABSTRACTWe studied the risk of synchronous or secondary urethral tumors after long-term followup in women with bladder cancer. The charts of women treated for various stages of bladder cancer between 1973 and 1992 were reviewed. Of 356 evaluable patients 268 presented initially with primary and 78 with multilocular tumor involvement. There were 498 episodes of recurrent tumors in 127 patients, and a total 1,210 tumor locations in 854 primary and recurrent episodes of bladder cancer. Mean followup for these patients was 5.5 years (range 0.05 to 33.1). Overall 7 of 356 patients (2%) had urethral tumor involvement, all at initial presentation. Statistical comparison of various defined tumor localizations in the bladder revealed that the bladder neck (p <0.000) and trigone (p <0.035) were significantly more often the region of primary tumor occurrence in the urethral tumor group. All patients with secondary urethral tumors had tumor involvement of the bladder neck at the same time. A 1% urethral tumor involve...

Rationale and Technique of Nerve Sparing Radical Cystectomy Before an Orthotopic Neobladder Procedure in Women

PURPOSE We developed refinements in the technique of cystectomy and subsequent intestine to urethra anastomosis to improve postoperative results in women undergoing anterior exenteration and creation of an orthotopic neobladder to the urethra. MATERIALS AND METHODS Anatomical dissection and microdissection studies were performed on formalin-carbol fixed adult cadavers and correlated with previous anatomical and clinical findings. The resulting surgical variations were performed in 5 carefully selected women undergoing lower urinary tract reconstruction. RESULTS Optimal postoperative results in regard to continence and voiding without compromising oncological outcome may be obtained by preserving the entire lateral vaginal walls, performing nerve sparing dissection of the bladder neck and proximal urethra, removing 1 cm. proximal urethra en bloc with the cystectomy specimen and using additional attachments of the anastomosed intestinal pouch to surrounding pelvic structures. Patients achieved day and night continence after 6 months, mean pouch volume was 580 cc (range 450 to 750) and residual volumes ranged from 0 to 150 cc. No tumor recurred after 6 to 17 months. CONCLUSIONS Refinements in the technique of radical cystectomy and orthotopic neobladder to the urethra in women may improve continence and spontaneous voiding without compromising surgical oncological outcome, and they further justify orthotopic diversion in select women with bladder cancer.

Prevention and early detection of prostate cancer

Prostate cancer is a common malignancy in men and the worldwide burden of this disease is rising. Lifestyle modifications such as smoking cessation, exercise, and weight control offer opportunities to reduce the risk of developing prostate cancer. Early detection of prostate cancer by prostate-specific antigen (PSA) screening is controversial, but changes in the PSA threshold, frequency of screening, and the use of other biomarkers have the potential to minimise the overdiagnosis associated with PSA screening. Several new biomarkers for individuals with raised PSA concentrations or those diagnosed with prostate cancer are likely to identify individuals who can be spared aggressive treatment. Several pharmacological agents such as 5α-reductase inhibitors and aspirin could prevent development of prostate cancer. In this Review, we discuss the present evidence and research questions regarding prevention, early detection of prostate cancer, and management of men either at high risk of prostate cancer or diagnosed with low-grade prostate cancer.