Roland Dahlem

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.

Impact of Preoperative Anemia on Oncologic Outcomes of Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy

PURPOSE We evaluated the impact of preoperative anemia on oncologic outcomes in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy. MATERIALS AND METHODS A total of 282 patients with upper tract urothelial carcinoma underwent radical nephroureterectomy. Preoperatively measured hemoglobin values were stratified into normal and anemia based on the WHO classification of 13 gm/dl or less and 12 or less considered anemia in males and females, respectively. We performed sensitivity analysis based on contemporary anemia classifications adjusted for the impact of age, gender and race with anemia considered a hemoglobin value of 13.7 gm/dl or less and 13.2 or less in white males younger than 60 and 60 years old or older, respectively, and 12.2 gm/dl or less in white females of all ages. Univariable and multivariable Cox regression analyses were done to assess the effects of anemia on oncologic outcomes. RESULTS Median preoperative hemoglobin was 13.2 gm/dl (IQR 11.7, 14.3). A total of 112 patients (39.7%) were anemic by the WHO classification vs 129 (45.7%) by the contemporary classification. Anemia was associated with lymph node metastasis, lymphovascular invasion, sessile tumor architecture, tumor necrosis, advanced age and a higher ECOG (Eastern Cooperative Oncology Group) performance score using the WHO and/or the contemporary definition (p ≤0.044). At a median 30-month followup anemia was associated with decreased recurrence-free (p ≤0.008) and cancer specific (p <0.001) survival on Kaplan-Meier analyses. On multivariable analysis adjusted for standard clinicopathological factors anemia remained an independent predictor of disease recurrence (HR 1.76, 95% CI 1.17-2.63 and 1.89, 95% CI 1.26-2.86) and cancer specific mortality (HR 1.88, 95% CI 1.15-3.08 and 2.04, 95% CI 1.21-3.45) by the WHO and contemporary classifications, respectively. CONCLUSIONS Preoperative anemia is an independent predictor of disease recurrence and cancer specific mortality. It is associated with aggressive tumor features in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy. Hemoglobin is a promising marker for patient counseling and risk stratification for additional treatment decision making.

Open Retropubic Reanastomosis for Highly Recurrent and Complex Bladder Neck Stenosis

PURPOSE We assessed the success rate of open reanastomosis for highly recurrent bladder neck stenosis resistant to transurethral treatment. Due to the paucity of available data the success rate of this procedure is not well defined, although it can be a last treatment option before urinary diversion. MATERIALS AND METHODS A total of 158 patients were treated for bladder neck stenosis in 1998 to 2007, of whom 20 underwent open reanastomosis for highly recurrent or complex bladder neck stenosis after radical prostatectomy and were seen for followup 3 months postoperatively. They received a standardized questionnaire at the time of data acquisition in this retrospective analysis. RESULTS The 20 patients underwent a mean of 3.7 previous surgeries. Median followup was 59.2 months. Stenosis recurred after reanastomosis in 8 patients (40%) while the remaining 60% were recurrence free. Seven recurrences were successfully treated endoscopically, resulting in an overall combined 95% success rate. Urinary diversion was performed in 1 patient with another recurrence after reanastomosis and transurethral resection. Four patients (31%) had new onset incontinence and 13 were completely incontinent, of whom 9 were successfully treated with artificial urinary sphincter implantation. In another patient artificial urinary sphincter implantation is scheduled and 3 elected no further treatment. CONCLUSIONS Open reanastomosis for recurrent bladder neck stenosis is a good therapeutic option in cases of endoscopic treatment failure. The initial success rate after reanastomosis was 60%, which increased to 95% after secondary treatment. There was a relatively high risk of new onset incontinence after reconstructive surgery but this was successfully treated with artificial urinary sphincter implantation in most patients.

Transurethral Holmium Laser Enucleation Versus Transurethral Resection of the Prostate and Simple Open Prostatectomy—Which Procedure is Faster?

PURPOSE The longer operative time of holmium laser enucleation of the prostate compared to transurethral resection of the prostate or simple open prostatectomy reported in the literature might have been biased by the unavailability of a soft tissue morcellator, limited surgical experience with holmium laser prostate enucleation or the fact that significantly more tissue was removed by enucleation than by resection. We objectively compared the resection speed of contemporary holmium laser enucleation vs transurethral resection of the prostate and of holmium laser enucleation vs simple open prostatectomy. MATERIALS AND METHODS The study cohort consisted of 100 cases of transurethral prostate resection and 60 of simple open prostatectomy from our previous randomized, controlled trials. These cases were subjected to matched pair analysis with greater than 1,000 from our prospective contemporary database on holmium laser prostate enucleation. Exact matches were made for the same amount of resected tissue. In all contemporary holmium laser enucleation cases a mechanical soft tissue morcellator was used. We calculated and compared the specific resection speed in gm per minute and operative time for the same amount of resected tissue. RESULTS In groups 1 and 2 we matched 99 exact laser enucleation-transurethral resection pairs and 53 exact laser enucleation-simple open prostatectomy pairs, respectively. Resection speed and operative time for laser enucleation were statistically significantly faster than for resection (0.61 vs 0.51 gm per minute and 62 vs 73 minutes, p <0.01) and similar to those of simple open prostatectomy (0.92 vs 1.0 gm per minute and 101 vs 90 minutes, respectively, p ≥0.21). CONCLUSIONS Resection speed seems to be an objective criterion for comparing the efficacy of prostatic tissue removal. Based on resection speed holmium laser enucleation of the prostate is faster than transurethral resection of the prostate and similar to simple open prostatectomy.

Outcomes and prognostic factors in patients with a single lymph node metastasis at time of radical cystectomy

Lymph node (LN) metastasis is a critical predictor for disease recurrence and cancer‐specific survival in patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy. Patients with a low LN disease burden (pN1) might be cured by surgery alone, while patients with a high LN disease burden (stage ≥ pN2) might benefit most from adjuvant chemotherapy. We found that outcomes of patients with pN1 UCB are significantly affected by pathological stage and soft tissue surgical margin status. Our nomogram may help to improve outcomes prediction in patients with pN1 UCB. An accurate prediction of the individual risk of outcomes may help risk stratifying patients with pN1 UCB to help improve clinical decision‐making.

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.

Smoking Reduces the Efficacy of Intravesical Bacillus Calmette-Guérin Immunotherapy in Non–muscle-invasive Bladder Cancer

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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.

Epithelial cell adhesion molecule is an independent prognostic marker in clear cell renal carcinoma.

Epithelial cell adhesion molecule (EPCAM) has recently attained a renewed interest as a candidate protein in diagnosis, prognostication and therapy of various tumor entities. The molecular epidemiology and prognostic relevance of EPCAM in renal cell carcinoma (RCC) and amongst the histological subtypes of RCC are unclear. We analyzed the prevalence and prognostic significance of EPCAM in a tumor tissue microarray composed of 1,088 independent RCCs samples by immunohistochemistry (IHC). We found significant variations of EPCAM IHC staining intensities in between the RCC subtypes: in papillary and chromophobe RCC, the majority of tumors (89–93%) showed an at least weak EPCAM protein expression. In the largest subgroup, the clear cell (cc)RCC (n = 767), a negative EPCAM IHC was found in 1/3 of the patients and was associated with high‐grade disease and nodal metastases. Kaplan–Meier analyses demonstrated a significant association between positive EPCAM IHC and prolonged overall survival, even in a subset of low‐risk ccRCC. In multivariable analyses, EPCAM represented an independent risk factor of survival throughout all subgroups. For localized, low‐grade ccRCC, information of EPCAM IHC raised predictive accuracy of a multivariate model by ∼5%, compared to T‐stage and grade alone. Our findings indicate that EPCAM is an independent prognostic molecular marker in ccRCC and, especially in localized ccRCC, might be able to provide auxiliary information for a better prognostication.

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.