Alexander Buchner

Prospective Evaluation of the Functional Sling Suspension for Male Postprostatectomy Stress Urinary Incontinence: Results after 1 Year

BACKGROUND Although surgical techniques for radical prostatectomy (RP) have been refined significantly, a significant number of patients still suffer from persisting postprostatectomy stress urinary incontinence (SUI). In recent years, various minimally invasive sling systems have been investigated as treatment options for such incontinence. OBJECTIVE The aim of the study was the prospective evaluation of the efficacy of the retrourethral transobturator sling for the functional treatment of male SUI after RP. DESIGN, SETTING, AND PARTICIPANTS The study documents a single-centre prospective evaluation of the outcome of 124 patients with mild to severe SUI following RP in whom an AdVance sling was implanted between February 2006 and September 2008. MEASUREMENTS All patients were comprehensively evaluated preoperatively and after 6 mo and 1 yr regarding daily pad use, 1-h and 24-h pad tests, residual urine, uroflowmetry, Incontinence Quality of Life Scale (I-QOL) score, and Incontinence Questionnaire-Urinary Incontinence Short Form (ICIQ-UI SF) score. Data were collected prospectively. RESULTS AND LIMITATIONS After 6 mo, a cure rate (no pads or one dry security pad) of 55.8%, an improved rate (one to two pads or pad reduction≥50%) of 27.4%, and a failure rate of 16.8% were observed. After 1 yr, the cure rate was 51.4%, the improved rate was 25.7%, and the failure rate was 22.9%. Daily pad use and pad weight decreased significantly postoperatively. No significant changes were seen in residual urine and flow rate. Quality-of-life scores improved significantly. Postoperative acute urinary retention was seen in 12.9% of patients. One patient had a local wound infection that was cured with antibiotics. One patient had the sling removed due to misplacement. CONCLUSIONS The retrourethral transobturator sling is an effective and attractive treatment option for male SUI resulting from RP after 1 yr of implantation.

Lysis of Prostate Carcinoma Cells by Trifunctional Bispecific Antibodies (αEpCAM × αCD3)

Bispecific monoclonal antibodies (bsAbs) are a promising immunotherapeutic option for treatment of cancer, especially in situations of minimal residual disease. The combination of an anti-CD3 and anti-tumor-associated antigen antibody redirects cytotoxic T-lymphocytes towards malignant cells. Using a trifunctional bispecific antibody against Ep-CAM × CD3, that additionally activates FcγR+ accessory cells via its Fc region, we investigated the interaction between three EpCAM+ prostate carcinoma cell lines and peripheral blood mononuclear cells (PBMCs) of healthy donors and patients with prostate carcinoma (PC). Visualization was performed by double immunocytochemical methods and computerized sequential video microscopy. Tumor cells and PBMCs supplemented with αEpCAM × αCD3 in 16-well chamber slides resulted in lysis of tumor cells within 1–3 days without any differences between patient and healthy donor PBMCs. The characteristic necrotic way of tumor cell killing (rounding, swelling, disrupting) could be observed in computerized sequences of video frames. Simultaneously, we could not reveal any form of apoptotic signal using three different apoptotic markers (TUNEL, M30 cyto death, anti-active caspase 3). Within the first 48 hr we observed typical PBMC cluster formation with increasing cell proliferation. PBMCs surrounding the tumor cells were not dominated by CD4+, CD8+, or CD14+ cells. Lymphocytes with pore-forming perforin proteins concentrated towards the tumor target cells. Our combination of double immunocytochemical and computerized video microscopic techniques may serve as an important improvement of validity of cell–cell interaction experiments using in vitro models.

A New Concept for Early Recovery after Surgery for Patients Undergoing Radical Cystectomy for Bladder Cancer: Results of a Prospective Randomized Study

PURPOSE Early recovery after surgery concepts have gained wide acceptance in various surgical specialties. However, limited data are available for radical cystectomy. A new early recovery after surgery concept was compared to a more conservative regimen in patients undergoing radical cystectomy for bladder cancer. MATERIALS AND METHODS A total of 101 consecutive patients were prospectively randomized to early recovery after surgery (62) or a conservative regimen (39) (intended randomization ratio was 2 early recovery after surgery-to-1 conservative regimen). Primary end points were differences in quality of life, and secondary end points included postoperative morbidity, demand for analgesics, time spent in the intermediate care unit, mobility and number of gastrointestinal events during hospital stay. RESULTS Quality of life parameters, as measured by the EORTC (European Organization for the Research and Treatment of Cancer) Quality of Life questionnaire QLQ-30 did not change significantly between postoperative days 3 and 7 and at discharge from hospital in the conservative regimen group, whereas a significant improvement was observed in the early recovery after surgery group. Postoperative morbidity was lower in the early recovery after surgery group in terms of wound healing disorders (p = 0.006), fever (p = 0.004) and thrombosis (p = 0.027). The demand for analgesics was significantly lower in the early recovery after surgery group. The amount of food consumed in relation to the amount of food offered was significantly higher for the early recovery after surgery group as early as day 3 (p = 0.02). Time spent in the intermediate care unit was significantly shorter for the early recovery after surgery group (p <0.001). There were no significant differences between the groups with respect to gastrointestinal events. The main limitations of this study were the lack of long-term data as well as the single center approach. CONCLUSIONS Early recovery after surgery of patients who underwent radical cystectomy appears to have significant benefits compared to a conservative regimen in terms of postoperative morbidity, quality of life, use of analgesics and time spent in the intermediate care unit.

Expression of Indoleamine 2,3-Dioxygenase in Tumor Endothelial Cells Correlates with Long-term Survival of Patients with Renal Cell Carcinoma

Purpose: The inflammatory enzyme indoleamine 2,3-dioxygenase (IDO) participates in immune tolerance and tumor immune escape processes by degradation of the essential amino acid tryptophan and formation of toxic catabolites. Here, we analyzed the role of IDO in tumor growth and disease progression in patients with clear cell renal cell carcinoma (RCC). Experimental Design: Expression of IDO mRNA was analyzed by quantitative reverse transcription-PCR in 55 primary and 52 metastatic RCC, along with 32 normal kidneys. Western blot and immunohistochemistry analyses were used to semiquantitatively determine IDO proteins in a subset of tumor samples, in RCC cell lines, and microvessel endothelial cells. IDO expression was correlated with expression of the proliferation marker Ki67 in tumor cells and survival of patients with tumor. Results: More than 75% of the clear cell RCC in comparison to normal kidney contained elevated levels of IDO mRNA, which correlated with their IDO protein content. Low IDO mRNA levels in primary tumors represented an unfavorable independent prognostic factor (hazard ratio, 3.8; P = 0.016). Unexpectedly, immunohistochemical analyses revealed that IDO is nearly exclusively expressed in endothelial cells of newly formed blood vessels and is virtually absent from tumor cells, although RCC cells could principally synthesize IDO as shown by in vitro stimulation with IFN-γ. A highly significant inverse correlation between the density of IDO-positive microvessels and the content of proliferating Ki67-positive tumor cells in primary and metastatic clear cell RCC was found (P = 0.004). Conclusions: IDO in endothelial cells might limit the influx of tryptophan from the blood to the tumor or generate tumor-toxic metabolites, thus restricting tumor growth and contributing to survival.

Results of the AdVance transobturator male sling after radical prostatectomy and adjuvant radiotherapy.

OBJECTIVES To prospectively evaluate the efficacy of the functional AdVance transobturator sling for the treatment of male stress urinary incontinence (SUI) in patients after radical prostatectomy and additional adjuvant radiotherapy. METHODS Between February 2007 and November 2008, 24 patients with postprostatectomy SUI (ICS grade 2-4) and additional adjuvant radiotherapy were treated consecutively with the AdVance sling. Preoperatively, intensive workup, including urodynamic assessment and flexible urethroscopy, was performed. Physical examinations (pad test, uroflowmetry, ultrasound) and questionnaires (I-QOL score, ICIQ-UI-SF score) were performed during baseline and during follow-up. Cure rate was defined as no pad use or one dry pad, and improved rate as 1-2 pads or reduction of pads by ≥50%. RESULTS After a median follow-up of 18.0 months (range 12-33 months, mean 18.8 months), the success rate was 50%. Daily pad use and pad weight in the 1-hour pad test decreased significantly. Patients with ICS grade 2 SUI exhibited a trend for a better success rate in comparison with patients with grade 3 and 4 SUI. Results were durable over time. Postoperatively, 16.7% of the patients exhibited transient acute urinary retention which resolved without further treatment after a maximum of 6 weeks. 1 sling had to be removed because of initial misplacement. CONCLUSIONS In selected patients after adjuvant radiotherapy, the AdVance sling achieved a success rate of 50% and results were stable in a median follow-up of 18 months. Complication rates were low and comparable to complication rates for patients without additional radiotherapy.

Lymph Node Density Affects Cancer-Specific Survival in Patients with Lymph Node–Positive Urothelial Bladder Cancer Following Radical Cystectomy

BACKGROUND The prognosis for patients with lymph node (LN)-positive bladder cancer (BCa) is likely affected by the extent of lymphadenectomy in radical cystectomy (RC) cases. Specifically, the prognostic significance of the LN density (ratio of positive LNs to the total number removed) has been demonstrated. OBJECTIVE To evaluate the prognostic signature of lymphadenectomy variables, including the LN density, for a large, multicentre cohort of RC patients with LN-positive BCa. DESIGN, SETTING, AND PARTICIPANTS The clinical and histopathologic data from 477 patients with LN-positive urothelial BCa (pN1-2) were analysed. The median follow-up period for all living patients was 28 mo. MEASUREMENTS Multivariable Cox regression analysis was used to test the effect of various pelvic lymph node dissection (PLND) variables on cancer-specific survival (CSS) based on colinearity in various models. RESULTS AND LIMITATIONS The median number of LNs removed was 12 (range: 1-66), and the median number of positive LNs was 2 (range: 1-25). Two hundred ninety (60.8%) of the patients presented with stage pN2 disease. The median and mean LN density was 17.6% and 29% (range: 2.3-100), respectively, where 268 (56.2%) and 209 (43.8%) patients exhibited am LN density of ≤20% and >20%, respectively. In separate multivariable Cox regression models adjusted for age, sex, pTN stage, grade, associated Tis, and adjuvant chemotherapy, the interval-scaled LN density (hazard ratio [HR]: 1.01; p=0.002) and the LN density, ordinal-scaled by 20% (HR: 1.65; p<0.001) exhibit independent effects on CSS. In addition, an independent contribution appears from the pT but not the pN stage. Limitations include surgeon selection bias when determining the extent of lymphadenectomy. CONCLUSIONS Our results support the prognostic relevance of LN density in patients with LN-positive BCa, where a threshold value of 20% stratifies the population into two prognostically distinct groups. Before LN density is integrated into the clinical decision-making process, these results should be validated by prospective studies with defined LN templates and standardised histopathologic methods.

Transcript signature predicts tissue NK cell content and defines renal cell carcinoma subgroups independent of TNM staging.

Clear cell renal cell carcinoma (ccRCC) is an aggressive and difficult to manage cancer. Immunotherapy has the potential to induce long-lasting regression in a small group of patients. However, severe side effects limit broad application which highlights the need for a marker to distinguish responder from nonresponder. TNMG staging, referring to tumor size, lymph node involvement, presence of metastasis, and grade of tumor differentiation, represents an important prognostic system but is not useful for predicting responders to immunotherapy. NK cells are potent antitumor effector cells, and a role as prognostic marker in some solid tumors has been suggested. As NK cells are responsive to various immune modifiers, they may be important mediators of patient response to immunotherapies, in particular those including IL-2. We report that the NK cell percentage within RCC-infiltrating lymphocytes, as determined by flow cytometry, allows ccRCC subgrouping in NKhigh/NKlow tissues independent of TNMG classification. Quantitative reverse transcriptase polymerase chain reaction using whole-tissue RNA identified four markers (NKp46, perforin, CX3CL1, and CX3CR1) whose transcript levels reproduced the NKhigh/NKlow tissue distinction identified by flow cytometry with high selectivity and specificity. Combined in a multiplex profile and analyzed using neural network, the accuracy of predicting the NKhigh/NKlow groups was 87.8%, surpassing that of each single marker. The tissue transcript signature, based on a robust high-throughput methodology, is easily amenable to archive material and clinical translation. This now allows the analysis of large patient cohorts to substantiate a role of NK cells in cancer progression or response to immunotherapy.

CXC chemokine receptor 4 is essential for maintenance of renal cell carcinoma-initiating cells and predicts metastasis.

In many solid tumors, cancer stem cells (CSC) represent a population with tumor‐initiating, self‐renewal, and differentiation potential, which can be identified by surface protein markers. No generally applicable markers are yet known for renal cell carcinoma (RCC). Two RCC cell lines (RCC‐26, RCC‐53) were found to differ widely in their capacity to form spheres in vitro and to establish tumors in mice, potentially reflecting differences in CSC content. A subpopulation expressing the CXC chemokine receptor 4 (CXCR4) was present only in the more tumorigenic cell line RCC‐53. When grown as spheres, most of the RCC‐53 cells were CXCR4‐positive, expressed stem cell‐associated transcription factor genes at elevated levels, and were more resistant toward the tyrosine kinase inhibitors sunitinib, sorafenib, and pazopanib. Sorted CXCR4‐positive cells exhibited greater capacity for sphere formation and tumor growth‐inducing potential in vivo than CXCR4‐negative cells. Significantly, higher CXCR4 mRNA levels in primary RCC tumors from patients with localized but not disseminated disease predicted shorter survival. Downregulation of CXCR4 expression by small interfering RNA (siRNA) or pharmacological inhibition by AMD3100 compromised tumor sphere formation, viability of CXCR4‐positive cells, and increased their responsiveness toward tyrosine kinase inhibitors. In conclusion, CXCR4 identifies a subpopulation of tumor‐initiating cells in RCC cell lines and plays a role in their maintenance. The relative insensitivity of such cells to tyrosine kinase inhibitors might contribute to the development of therapy resistance in RCC patients. Future therapies therefore could combine blockade of the CXCR4 signaling pathway with standard therapies for more effective treatments of metastatic RCC. STEM Cells 2013;31:1467–1476

Lymphovascular invasion is an independent predictor of oncological outcomes in patients with lymph node-negative urothelial bladder cancer treated by radical cystectomy: a multicentre validation trial.

Study Type – Prognosis (inception cohort)
Level of Evidence 1b

External Validation of Postoperative Nomograms for Prediction of All-Cause Mortality, Cancer-Specific Mortality, and Recurrence in Patients With Urothelial Carcinoma of the Bladder

BACKGROUND The Bladder Cancer Research Consortium (BCRC) created nomograms to predict all-cause mortality (ACM), cancer-specific mortality (CSM), and recurrence after radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). OBJECTIVE To perform a formal validation of the BCRC nomograms in a large multi-institutional patient cohort from Europe. DESIGN, SETTING, AND PARTICIPANTS Records of 2501 patients who underwent RC for UCB at eight European centers were reviewed. Complete information for external validation was available in 2404 patients for the ACM and CSM nomograms and in 2243 patients for the recurrence nomogram. MEASUREMENTS For the purpose of external validation, model discrimination was measured using the receiver operating characteristics derived area under the curve. Calibration plots examined the relationship between predicted and observed probabilities at 2 yr, 5 yr, and 8 yr. Decision curve analyses were applied to assess the net benefit derived from the three models. RESULTS AND LIMITATIONS The discrimination accuracies of the BCRC nomograms for ACM and CSM at 2 yr, 5 yr, and 8 yr after RC were 71.0%, 69.1%, and 68.2%, and 74.9%, 73.1%, and 72.4%, respectively. The accuracy of discrimination for the recurrence nomogram at the same time points was 76.5%, 75.3%, and 74.9%, respectively. Calibration plots revealed slight underestimations from ideal predictions. Decision curve analyses showed an increased net benefit for the use of the BCRC nomograms in this cohort. Limitations include the retrospective study design, potential surgeon bias, and lack of a central pathologic review. CONCLUSIONS The ACM, CSM, and recurrence nomograms showed acceptable predictive accuracies and could thus be adopted into clinical practice in UCB patients treated in Europe.