Armin Soave

Prognostic Role and HER2 Expression of Circulating Tumor Cells in Peripheral Blood of Patients Prior to Radical Cystectomy: A Prospective Study

BACKGROUND Preliminary research has suggested the potential prognostic value of circulating tumor cells (CTC) in patients with advanced nonmetastatic urothelial carcinoma of the bladder (UCB). OBJECTIVE Prospectively analyze the clinical relevance and human epidermal growth factor receptor 2 (HER2) expression of CTC in patients with clinically nonmetastatic UCB. DESIGN, SETTING, AND PARTICIPANTS Blood samples from 100 consecutive UCB patients treated with radical cystectomy (RC) were investigated for the presence (CellSearch system) of CTC and their HER2 expression status (immunohistochemistry). HER2 expression of the corresponding primary tumors and lymph node metastasis were analyzed using fluorescence in situ hybridization. INTERVENTION Blood samples were taken preoperatively. Patients underwent RC with lymphadenectomy. MEASUREMENTS Outcomes were assessed according to CTC status. HER2 expression of CTC was compared with that of the corresponding primary tumor and lymph node metastasis. RESULTS AND LIMITATIONS CTC were detected in 23 of 100 patients (23%) with nonmetastatic UCB (median: 1; range: 1-100). Presence, number, and HER2 status of CTC were not associated with clinicopathologic features. CTC-positive patients had significantly higher risks of disease recurrence and cancer-specific and overall mortality (p values: ≤ 0.001). After adjusting for effects of standard clinicopathologic features, CTC positivity remained an independent predictor for all end points (hazard ratios: 4.6, 5.2, and 3.5, respectively; p values ≤ 0.003). HER2 was strongly positive in CTC from 3 of 22 patients (14%). There was discordance between HER2 expression on CTC and HER2 gene amplification status of the primary tumors in 23% of cases but concordance between CTC, primary tumors, and lymph node metastases in all CTC-positive cases (100%). The study was limited by its sample size. CONCLUSIONS Preoperative CTC are already detectable in almost a quarter of patients with clinically nonmetastatic UCB treated with RC and were a powerful predictor of early disease recurrence and cancer-specific and overall mortality. Thus CTC may serve as an indication for multimodal therapy. Molecular characterization of CTC may serve as a liquid biopsy to guide individual targeted therapy in future clinical trials.

MALDI imaging–based identification of prognostically relevant signals in bladder cancer using large-scale tissue microarrays

OBJECTIVE Although most patients with urinary bladder cancer present with noninvasive and low-malignant stages of the disease, about 20% eventually develop life-threatening metastatic tumors. This study was designed to evaluate the potential of matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to identify molecular markers predicting the clinical course of bladder cancer. MATERIALS AND METHODS We employed MALDI-MSI to a bladder cancer tissue microarray including paraffin-embedded tissue samples from 697 patients with clinical follow-up data to search for prognostically relevant associations. RESULTS Analysis of our MALDI imaging data revealed 40 signals in the mass spectra (m/z signals) associated with epithelial structures. The presence of numerous m/z signals was statistically related to one or several phenotypical findings including tumor aggressiveness (stage, grade, or nodal status; 30 signals), solid (5 signals) or papillary (3 signals) growth patterns, and increased (6 signals) or decreased (12 signals) cell proliferation, as determined by Ki-67 immunohistochemistry. Two signals were linked with tumor recurrence in noninvasive (pTa category) tumors, of which one was also related to progression from pTa-category to pT1-category disease. The absence of one m/z signal was linked with decreased survival in the subset of 102 muscle-invasive cancers. CONCLUSION Our data demonstrate the suitability of combining MSI and large-scale tissue microarrays to simultaneously identify and validate clinically useful molecular markers in urinary bladder cancer.

Outcomes of Ventral Onlay Buccal Mucosa Graft Urethroplasty in Patients after Radiotherapy

PURPOSE We evaluated stricture-free survival and functional outcomes of buccal mucosa graft urethroplasty in patients with urethral stricture disease after radiotherapy. MATERIALS AND METHODS We reviewed our urethroplasty database for patients with a radiotherapy history who underwent buccal mucosa graft urethroplasty between January 2009 and October 2013. We reviewed patient charts and the institutional, standardized, nonvalidated questionnaires administered to each patient postoperatively. Study end points included 1) the success rate, 2) continence status, 3) erectile function and 4) patient satisfaction postoperatively. Success was defined as stricture-free survival. RESULTS Of 38 men included in the study prostate cancer was the most common indication for radiotherapy in 35 (92.1%). External beam radiotherapy was performed in 24 cases (64.9%), brachytherapy was done in 8 (21.6%) and a combination of the 2 treatments was performed in 6 (13.5%). Strictures were in the bulbar/bulbomembranous urethra and had a median length of 3.0 cm (range 1.0 to 8.0). The overall success rate was 71.1% at a median followup of 26.5 months (range 1.0 to 50.0). Median time to stricture recurrence was 17.0 months (range 3.0 to 44.0). De novo urinary incontinence was observed in 4 patients (10.5%). Erectile function remained mostly unchanged compared to preoperative status. Study limitations include the small sample size and the lack of validated questionnaires. CONCLUSIONS At short-term to mid-term followup the success rate of ventral onlay buccal mucosa graft urethroplasty in patients with radiotherapy history seems acceptable. However, patients must be counseled about the increased risk of urinary incontinence. Longer followup is warranted to address long-term outcomes.

Does the extent of variant histology affect oncological outcomes in patients with urothelial carcinoma of the bladder treated with radical cystectomy

BACKGROUND To evaluate the effect of variant histology and its extent on oncological outcomes in patients with urothelial carcinoma of the bladder (UCB) who are treated with radical cystectomy. MATERIAL AND METHODS Data from 485 patients with UCB who were treated with radical cystectomy without neoadjuvant chemotherapy at a single academic center between 1996 and 2011 were collected retrospectively. All pathologic specimens were meticulously re-reviewed for the presence and extent of variant UCB histologies. Cox regression models were used to evaluate the association with disease recurrence and cancer-specific survival. RESULTS Variant histology was present in 96 patients (19.8%), with squamous cell differentiation (12.6%) being most common. In patients with variant histology, the median and mean extent was 70% and 60%, respectively. Variant histology was associated with female sex, advanced tumor stage, less presence of concomitant carcinoma in situ, and administration of adjuvant chemotherapy (P ≤ 0.001). The presence of variant histology and non-squamous cell differentiation was associated with cancer-specific mortality (pairwise P ≤ 0.02). Moreover, non-squamous cell differentiation was associated with disease recurrence (P = 0.002). The presence of variant histology, non-squamous cell differentiation, and the extent of variant histology were associated with cancer-specific mortality in univariable but not in multivariable analyses. CONCLUSIONS The presence of variant histology, particularly non-squamous cell differentiation, and its extent are associated with inferior survival. However, they are not independent predictors of outcomes. The association of variant histology with established predictors of aggressive tumor biology is likely impairing oncological outcomes and thus has to be considered in clinical decision making.

Gender-specific outcomes of bladder cancer patients: A stage-specific analysis in a contemporary, homogenous radical cystectomy cohort

INTRODUCTION Controversial findings regarding gender-specific oncological outcomes of urothelial carcinoma of the bladder (UCB) have recently been reported. The aim of this study was to analyze gender-specific outcomes using a stage-adjusted approach in a homogenous, contemporary radical cystectomy (RC) cohort. MATERIAL AND METHODS We prospectively collected data of 517 UCB patients treated with RC and pelvic lymphadenectomy without neoadjuvant chemotherapy at our institution between 1996 and 2010. Stage-adjusted uni- and multivariable Cox regression models analyzed the association of gender with disease recurrence, cancer-specific mortality and overall survival. RESULTS In total, 398 (77%) patients were male and 119 (23%) were female. Compared to men, women were more likely to have advanced tumor stages (p = 0.017), nodal metastasis (p = 0.047) and received more frequently adjuvant chemotherapy (p = 0.009). At a median follow-up of 44 months, there was no statistical difference in disease recurrence, cancer-specific mortality and overall survival between both genders when analyzed as a group. In stage-adjusted analyses, only women with non-invasive UCB were more likely to die of UCB compared to the male counterparts (p = 0.013). In gender-specific multivariable analyses that adjusted for standard clinico-pathologic features, pathologic tumor stage was an independent predictor for disease recurrence (p-values ≤0.047) and cancer-specific mortality (p-values ≤0.049), respectively. CONCLUSION Women present with more aggressive tumor biologic features at RC, however this did not translate into inferior outcomes compared to men in stage-specific analyses in our cohort. Tumor stage is the most important factor influencing the course of disease in both genders. Validation of our findings is warranted in a larger cohort.

The Impact of Tumor Diameter and Tumor Necrosis on Oncologic Outcomes in Patients With Urothelial Carcinoma of the Bladder Treated With Radical Cystectomy.

OBJECTIVE To evaluate the influence of tumor diameter and tumor necrosis on oncologic outcomes in patients with urothelial carcinoma of the bladder treated with radical cystectomy (RC). MATERIALS AND METHODS We treated 517 consecutive patients with urothelial carcinoma of the bladder treated with RC without neoadjuvant chemotherapy at our institution between 1996 and 2011. All RC specimens were meticulously re-reviewed for the largest residual tumor diameter and for the presence and extent of tumor necrosis. Cox regression models evaluated the association with disease recurrence and cancer-specific survival. RESULTS At RC, 155 patients (30.0%) had a residual tumor diameter ≥3 cm and tumor necrosis was present in 156 patients (30.2%). Tumor diameter and necrosis were significantly correlated (P <.001). Both a tumor diameter ≥3 cm and the presence of tumor necrosis were associated with an older age, advanced tumor stage, higher tumor grade, lymph node metastasis, positive surgical margin status, lymphovascular invasion, and administration of adjuvant chemotherapy (P values ≤.009). A tumor diameter ≥3 cm and the presence of tumor necrosis were associated with disease recurrence and cancer-specific mortality in Kaplan-Meier analyses, respectively (pairwise P values <.001). In addition, a tumor diameter ≥3 cm was an independent predictor of cancer-specific mortality in multivariate analysis that adjusted for standard clinicopathologic features. CONCLUSION Tumor diameter and necrosis are closely correlated and associated with aggressive tumor features and inferior oncologic outcomes. A residual tumor diameter ≥3 cm is an independent predictor of cancer-specific mortality. This additional information should be considered to be reported in every pathology report for consideration in patient counseling and treatment decision making. In addition, these results underscore the importance of a thorough transurethral resection of the bladder tumor before RC.

Lymph node dissection during radical cystectomy for bladder cancer treatment: considerations on relevance and extent

Despite advances in the surgical and medical treatment for urothelial carcinoma of the bladder (UCB), there have only been limited improvements in disease-specific mortality rates over the past decades. Lymph node dissection (LND) during radical cystectomy is an integral part of the treatment for muscle-invasive and high-risk UCB. LND may detect and remove lymph node (LN) metastasis and thus guide patient counseling and decision making regarding additional treatment decisions. In addition, LND may improve survival in patients both with and without LN metastasis. In this non-systematic review article, we discuss benefits and risks of LND, the role of limited versus extended LND and the dilemma of preoperative LN staging.

Outcomes of single- vs double-cuff artificial urinary sphincter insertion in low- and high-risk profile male patients with severe stress urinary incontinence

To evaluate continence and complication rates of bulbar single‐cuff (SC) and distal bulbar double‐cuff (DC) insertion in male patients with severe stress urinary incontinence (SUI) according to whether the men were considered low or high risk for unfavourable artificial urinary sphincter (AUS) outcomes.

A non-randomized, prospective, clinical study on the impact of circulating tumor cells on outcomes of urothelial carcinoma of the bladder patients treated with radical cystectomy with or without adjuvant chemotherapy.

To investigate outcomes of urothelial carcinoma of the bladder (UCB) patients treated with radical cystectomy (RC) according to the presence of circulating tumor cells (CTC) and the administration of adjuvant chemotherapy (AC). We prospectively enrolled 226 UCB patients treated with RC without neoadjuvant chemotherapy at our institution between 2007 and 2013. Blood samples were obtained from all patients preoperatively and analyzed for CTC using the CellSearch® system. Platinum‐based AC was administered in 50 patients (27.0%). Cox regression models evaluated the association of CTC with disease recurrence, cancer‐specific and overall mortality according to AC administration. 185 patients were available for analyses. CTC were present in 41 patients (22.2%). Patients with presence of CTC received AC more frequently, compared to patients without CTC (p = 0.027). At a median follow‐up of 31 months, the presence of CTC was associated with disease recurrence, cancer‐specific and overall mortality (p‐values < 0.001) in patients without AC administration. In patients who received AC, there was no difference in either endpoint between patients with or without presence of CTC. In multivariable analysis of patients without AC administration, the presence of CTC was an independent predictor for disease recurrence (HR: 4.9; p < 0.001), cancer‐specific (HR: 4.2; p = 0.003) and overall mortality (HR: 4.2; p = 0.001). The CTC status may be implemented in decision‐making regarding AC administration in UCB patients following RC. CTC measurement should be implemented in future UCB studies on systemic chemotherapy to validate our findings.

Female with bladder cancer: what and why is there a difference?

While men are at a considerable higher risk of developing urothelial carcinoma of the bladder (UCB), women present with more advanced disease stages and seem to experience unfavorable outcomes. Evaluating specific differences in the UCB incidence and outcomes between both genders in the non-muscle invasive, muscle-invasive or locally advanced and metastatic setting, as well as determining the underlying causes of disease, may allow optimizing treatment and improving the quality of urological care among both genders. In this review we summarize the best evidence and most recent findings on gender-specific differences in UCB incidence and outcomes. In addition, we present a comprehensive overview on established and potential reasons for differences in gender-specific UCB outcomes, including disparities in the pelvic anatomy, the diagnostic work-up, the modality and quality of treatment, the exposure to risk factors, the degradation of carcinogens as well as the sex-hormone signaling.