Morbidity and mortality after robot-assisted radical cystectomy with intracorporeal urinary diversion in octogenarians: results from the European Association of Urology Robotic Urology Section Scientific Working Group.

OBJECTIVES: To evaluate the postoperative complication and mortality rate following laparoscopic radical cystectomy (RARC) with intracorporeal urinary diversion (ICUD) in octogenarians. PATIENTS AND METHODS: We conducted a retrospective analysis comparing postoperative complication and mortality rates depending on age in a consecutive series of 1890 patients who underwent RARC with ICUD for bladder cancer between 2004 and 2018 in 10 European centres. Outcomes of patients aged <80 years and those aged ≥80 years were compared with regard to postoperative complications (Clavien-Dindo grading) and mortality rate. Cancer-specific mortality (CSM) and other-cause mortality (OCM) after surgery were calculated using the non-parametric Aalen-Johansen estimator. RESULTS: A total of 1726 patients aged <80 years and 164 aged ≥80 years were included in the analysis. The 30- and 90-day rate for high-grade (Clavien-Dindo grades III-V) complications were 15% and 21% for patients aged <80 years compared to 11% and 13% for patients aged ≥80 years (P = 0.2 and P = 0.03), respectively. In a multivariable logistic regression analysis adjusting for pre- and postoperative variables, age ≥80 years was not an independent predictor of high-grade complications (odds ratio 0.6, 95% confidence interval 0.3-1.1; P = 0.12). The non-cancer-related 90-day mortality was 2.3% for patients aged ≥80 years and 1.8% for those aged <80 years, respectively (P = 0.7). The estimated 12-month CSM and OCM rates for those aged <80 years were 8% and 3%, and for those aged ≥80 years, 15% and 8%, respectively (P = 0.009 and P < 0.001). CONCLUSIONS: The minimally invasive approach to RARC with ICUD for bladder cancer in well-selected elderly patients (aged ≥80 years) achieved a tolerable high-grade complication rate; the 90-day postoperative mortality rate was driven by cancer progression and the non-cancer-related rate was equivalent to that of patients aged <80 years. However, an increased OCM rate in this elderly group after the first year should be taken into account. These results will support clinicians and patients when balancing cancer-related vs treatment-related risks and benefits.

Early urinary continence recovery following retzius-sparing robotic-assistant radical prostatectomy with suprapubic catheter: a short-term follow-up outcome.

OBJECTIVE: To evaluate the recovery of early urinary continence in patients with prostate cancer using a suprapubic catheter during Retzius-sparing robotic-assistant laparoscopic prostatectomy. PATIENTS AND METHODS: From January 2018 to January 2019, 223 patients diagnosed with prostate cancer who underwent Retzius-sparing robotic-assistant laparoscopic prostatectomy in Diakonie Klinikum Stuttgart were involved in our study. From January 2018 to June 2018, patients (112 cases) only had an indwelling urinary catheter during Retzius-sparing robotic-assistant laparoscopic prostatectomy, while from July 2018 to January 2019, patients (111 cases) were offered an extra suprapubic catheter during operation. The recovery of early urinary continence of patients was mainly investigated one month later. RESULTS: The overall early urinary continence rate was 81.61%. Patients with suprapubic catheter had better urinary control results, compared to patients with only indwelling urinary catheter (87.39% vs 75.89%, p = 0.027). In addition, International Prostate Symptom Score and irritative subscore in patients with good urinary control were significantly lower than that in patients with urinary incontinence. Suprapubic catheter insertion (OR 0.395; 95% CI 0.190-0.821) and advanced pathological tumor stage (T3a-T4) (OR 2.061; 95% CI 1.008-4.217) were two independent influencing factors for early urinary continence recovery in patients who underwent Retzius-sparing robotic-assistant laparoscopic prostatectomy through multivariate logistic regression analysis. CONCLUSION: Suprapubic catheter insertion may be helpful for early urinary continence recovery in patients with Retzius-sparing Robotic-assistant laparoscopic prostatectomy. Advanced pathological tumor stage (T3a-T4) before Retzius-sparing robotic-assistant laparoscopic prostatectomy might be associated with poor urinary control.

Transurethral en bloc submucosal hydrodissection vs conventional resection for resection of non-muscle-invasive bladder cancer (HYBRIDBLUE): a randomised, multicentre trial.

OBJECTIVE: To determine whether transurethral en bloc submucosal hydrodissection of bladder tumours (TUEB) improves the quality of the resection compared to conventional transurethral resection of bladder tumour (TURBT) in patients with non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: A randomised, multicentre trial (HYBRIDBLUE) was conducted with a superiority design. Six German academic centres participated between September 2012 and August 2015. Based on literature analysis, a sample size for accurate histopathological assessment concerning muscle invasion was assumed to be feasible in 50% (P0 = 0.5) of TURBT and 80% of TUEB cases. After pre-screening of a total of 305 patients, participants were allocated to two study arms: Group I: hexaminolevulinate (HAL)-guided TUEB; Group II: conventional HAL-guided TURBT. The primary endpoint was the proportion of specimens that could be reliably evaluated pathologically concerning muscle invasiveness. Secondary endpoints included rates of histopathological completeness of the resection, muscularis propria content, recurrence, and complication rates. RESULTS: A total of 115 patients (TUEB 56; TURBT 59) were eligible for final analysis. Adequate histopathological assessment, which included muscularis propria content and tumour margins (R0 vs R1), was present in 48/56 (86%) TUEB patients compared to 37/59 (63%; P = 0.006) in the TURBT group. R0 was confirmed in 30/56 TUEB patients (57%) and five of 59 TURBT patients (9%; P < 0.001). No complications of Grade ≥III were observed in both arms. At 3 and 12 months, three and 19 patients recurred in the TUEB group vs seven and 11 patients in the TURBT group, respectively (P = 0.33 and P = 0.08). CONCLUSIONS: In this randomised study, TUEB was shown to be clinically safe regarding perioperative endpoints. An adequate histopathological assessment concerning muscle invasion was significantly better assessable in the TUEB arm compared to standard TURBT. This finding indicates the clinical potential for reducing the rate of early re-resections. Yet, a larger study with recurrence-free survival as the primary endpoint is needed to assess the oncological efficacy between both techniques.

The prognostic role of pre-cystectomy hemoglobin levels in patients with invasive bladder cancer.

PURPOSE: To determine whether pre-treatment hemoglobin (Hb) levels in patients with bladder cancer impact on oncological outcomes after radical cystectomy (RC). METHODS: A consecutive, contemporary series of 246 patients undergoing RC and pelvic lymph node dissection for bladder cancer. Decreased Hb level was defined as ≤12 g/dL. The Kaplan-Meier method was used to estimate recurrence-free (RFS), cancer-specific (CSS) and overall survival (OS). The Fisher exact/Chi-square test was used to investigate differences between both groups. Uni- and multivariable Cox regression analysis addressed risk factors for recurrence, cancer-specific death and overall death. The median follow-up was 30 months (2-116). RESULTS: Of the 246 patients, 182 (74 %) had normal (>12 g/dL) and 64 decreased (≤12 g/dL) preoperative Hb (26 %). In univariable analysis, decreased Hb was associated with increased age, extravesical disease, hydronephrosis (all p < 0.001), node-positive disease and positive resection margins (both p = 0.01). Subanalyzed for patients with organ-confined disease (defined as ≤pT2bN0R0; N = 109), the 3-year RFS, CSS and OS was significantly lower in patients with decreased (34.9, 35.5 and 19.8 %) compared to normal Hb level (69.7, 86.3 and 77.6 %; p = 0.01/p = 0.002/p < 0.001). In multivariable analysis, RFS, CSS and OS were significantly lower in patients with decreased Hb (p = 0.007, p = 0.001 and p = 0.002), pathologically locally advanced tumor (≥pT3a; p = 0.023, p = 0.036 and p = 0.065) and nodal stage (p < 0.001, p = 0.006 and p = 0.001) and positive soft tissue surgical margins (p = 0.040, p = 0.004 and 0.012). CONCLUSIONS: Pre-cystectomy Hb levels are associated with adverse histopathologic characteristics and provide additional prognostic information especially for patients with pathologically localized bladder cancer.

Assessment of a new point-of-care system for detection of prostate specific antigen.

BACKGROUND: Measurement of the prostate specific antigen (PSA) remains an important tool in prostate cancer (PC) diagnosis. Due to limited availability of laboratory devices in an outpatient setting, compact and easy-to-handle point-of-care (POC) systems are desirable. Recently, a chip for PSA measurement on the concile® Ω100 POC reader platform was introduced. To investigate the clinical applicability, we evaluated the system in a consecutive cohort of patients undergoing PSA measurement in our outpatient clinic. METHODS: Between 07/2014 and 01/2015, PSA was analyzed in a total of 198 patients by the POC reader system and in parallel by an Immulite 2000® and Centaur® standard laboratory system, respectively. By standard (Immulite®) measurement, 67 (34,2 %) had PSA > 4 ng/ml and 131 (65,8 %) had PSA ≤ 4 ng/ml. Results were correlated by linear regression analyses for all patients and within PSA subgroups. For patients with available prostate histology after PSA measurement (n = 68), receiver-operating characteristic curves were created and area under the curve (AUC), sensitivity and specificity for the prediction of PC at best cut-off value were calculated. RESULTS: The coefficients of determination (r(2)) for the POC device compared to laboratory testing were 0.72 (Immulite®) and 0.63 (Centaur®), respectively (both p < 0.0001). In the PSA range of ≤4 ng/ml, the observed correlations were 0.75 and 0.70, respectively. For the POC test system, AUC for detection of PC was calculated with 0.745 while the standard laboratory tests showed 0.778 (Immulite®) and 0.771 (Centaur®). At best cut-off of 3.64 ng/ml, PSA analysis by the POC system showed a sensitivity of 85.7 % and a specificity of 66.7 %. CONCLUSIONS: The POC system obtained good concordance to elaborate laboratory measurement. In a screening scenario, the system provides quick and reliable PSA measurement, especially in the PSA range up to 4 ng/ml.

Ten Years of Complete Remission of Pulmonary Metastasis after Post-Cystectomy Palliative Cisplatin-Gemcitabine Chemotherapy with Gefitinib for Muscle Invasive Bladder Cancer: A Case Report.

Muscle-invasive bladder cancer (MIBC) is considered one of the most lethal malignancies with high metastatic potential. Usually, metastatic bladder cancer carries worse prognosis with a median survival rate of approximately 6 months, which can be prolonged for up to 14 months with palliative systemic chemotherapy. We present the case of a 61-year-old male patient diagnosed with localized MIBC 10 years ago. He underwent nerve-sparing radical cystectomy with ileal neobladder, but developed pulmonary metastatic disease 7 months postoperatively. Six cycles of gemcitabine/cisplatin combination chemotherapy with an addition of gefitinib as daily oral medication were administered within a randomized phase II clinical trial; this resulted in complete remission of the pulmonary metastases. Until now, the patient is still on gefitinib daily without any side effects. Although, the addition of gefitinib to standard systemic chemotherapy has not been shown to improve the survival in metastatic urothelial cancer, this case represents a very pleasant albeit uncommon long-term outcome.

Return to Work and Normal Daily Life Activity after Open and Robot-Assisted Radical Prostatectomy--A Single Surgeon Analysis.

PURPOSE: To evaluate differences in health related quality of life and time to return to normal activities between patients treated with open radical prostatectomy (ORP) and robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: Three hundred and two patients treated with RARP or ORP were prospectively enrolled. One year after surgery, patients received a questionnaire to evaluate social life, duration of being limited in daily and sexual life as well as satisfaction with the treatment. RESULTS: Both cohorts showed no differences in age, prostate specific-antigen-levels, Gleason score, prostate volume or T-stage (p > 0.05). Median blood loss was significant lower and the surgical time was significant higher in the RARP group. There were no significant differences regarding the duration of being limited in social or daily life or regarding the satisfaction with the treatment. The median time patients felt affected in their work was 2 months. There were no significant differences in terms of subjective global health status and HrQoL 3 months (p = 0.60 and p = 0.40) and 6 months (p = 0.30 and p = 0.20) after surgery. CONCLUSION: The present study confirms significant perioperative benefits for patients undergoing RARP compared to ORP. However, there is no difference in HrQoL as well as in the time to return to normal activities between patients treated with RARP and ORP.

Significance of apoptotic and non-apoptotic disseminated tumor cells in the bone marrow of patients with clinically localized prostate cancer.

BACKGROUND: Disseminated tumor cells (DTC) can be detected in a high proportion of patients with localized solid malignancies. In prostate cancer (PC), determination of DTCs is critically discussed as there are conflicting results on their prognostic value. The aim of the present study was to evaluate the presence and prognostic role of DTCs in PC patients with a high risk of disease recurrence. METHODS: 248 patients with clinically localized PC undergoing radical prostatectomy with features of increased risk of recurrence (PSA ≥10 ng/ml or Gleason score ≥ 4 + 3 = 7 or pT ≥3) were included. All patients underwent intraoperative bone marrow (BM) aspiration biopsy. BM cells were evaluated by immunocytochemistry for cytokeratines and the apoptosis marker caspase-cleaved cytokeratin 18 (M30). Results of immunocytochemistry were correlated with clinical and pathological parameters and clinical outcome of the patients. RESULTS: Of 248 patients, 47 (19.0%) had evidence of DTCs at time of radical prostatectomy. In 17 of these 47 patients (36.2%), DTCs expressed the apoptosis marker M30. We observed no correlation between the presence of DTCs and tumor stage, nodal stage, prostate-specific antigen, or Gleason score. After a median-follow-up of 58 months (23-76), no differences in rates of biochemical recurrence, development of metastases and cancer-specific death were observed between patients with and without DTCs while apoptosis markers had no role. CONCLUSIONS: In a single-centre cohort of patients with increased risk for disease recurrence, the presence of DTCs at the time of prostatectomy does not influence clinical outcome. For the first time in patients with PC, DTCs were evaluated for immunocytological features indicating apoptosis. Due to conflicting results of studies on DTCs, BM biopsies at time of radical prostatectomy cannot be recommended as a standard procedure in patients with clinically localized PC.

Prognostic relevance of positive urine markers in patients with negative cystoscopy during surveillance of bladder cancer.

BACKGROUND: The role of urine markers in the surveillance of patients with non-muscle invasive bladder cancer (NMIBC) is discussed extensively. In case of negative cystoscopy the additional prognostic value of these markers has not been clearly defined yet. The present study is the first systematic approach to directly compare the ability of a urine marker panel to predict the risk of recurrence and progression in bladder cancer (BC) patients with no evidence of relapse during surveillance for NMIBC. METHODS: One hundred fourteen patients who underwent urine marker testing during surveillance for NMIBC and who had no evidence of BC recurrence were included. For all patients cytology, Fluorescence-in-situ-hybridization (FISH), immunocytology (uCyt+) and Nuclear matrix protein 22 enzyme-linked immunosorbent assay (NMP22) were performed. All patients completed at least 24 months of endoscopic and clinical follow-up of after inclusion. RESULTS: Within 24 months of follow-up, 38 (33.0%) patients experienced disease recurrence and 11 (9.8%) progression. Recurrence rates in patients with positive vs. negative cytology, FISH, uCyt+ and NMP22 were 52.6% vs. 21.9% (HR = 3.9; 95% CI 1.75-9.2; p < 0.001), 47.6% vs. 25.0% (HR 2.7; 1.2-6.2; p = 0.01), 43.8% vs. 22.4% (HR 3.3; 1.5-7.6; p = 0.003) and 43.8% vs. 16.7% (HR 4.2; 1.7-10.8; p = 0.001). In patients with negative cytology, a positive NMP22 test was associated with a shorter time to recurrence (p = 0.01), whereas FISH or uCyt+ were not predictive of recurrence in these patients. In the group of patients with negative cytology and negative NMP22, only 13.5% and 5.4% developed recurrence and progression after 24 months. CONCLUSIONS: Patients with positive urine markers at time of negative cystoscopy are at increased risk of recurrence and progression. In patients with negative cytology, only NMP22 is predictive for recurrence. Patients with negative marker combinations including NMP22 harbour a low risk of recurrence. Therefore, the endoscopic follow-up regimen may be attenuated in this group of patients.

Quality of life outcomes after radical cystectomy: long-term standardized assessment of Studer Pouch versus I-Pouch.

PURPOSE: To investigate whether the ileal length used for the formation of two different orthotopic bladder substitutes [Studer (S)-Pouch vs. I-Pouch; 60 vs. 40 cm] impacts quality of life (QoL). MATERIALS AND METHODS: In this cross-sectional study, a total of 56 patients underwent radical cystectomy with ileal neobladder for bladder cancer [S-Pouch: 23 pat, 19 men, 4 women); I-Pouch: 33 pat (26 men, 7 women)]. They completed general (SF-36), cancer-specific (QLQ-C30) and bladder cancer-specific questionnaires (QLQ-BLM30) as well as a novel neobladder-specific questionnaire (TNQ). The questionnaire-based follow-up was 66 months (IQR 41-104; total range 9-161). RESULTS: I-Pouch patients reported better SF-36 physical health status (p = 0.026), QLQ-BLM30 continence scores (p < 0.001) and a more favorable QLQ-C30 total score compared to S-Pouch patients (p = 0.044). S-Pouch patients reported better QLQ-BLM30 general health status (p = 0.001). For the TNQ, no significant difference was found between both groups (p = 0.09). S-Pouch patients reported use of condom urinals more frequently (p = 0.026). S-Pouch patients tended to be on vitamin B12 substitution (p = 0.06). I-Pouch patients reported significantly higher micturition volumes (≥300 ml) compared to S-Pouch patients (30/33 vs. 16/23; p = 0.040). No differences were found with regard to bicarbonate supplementation and recurrent urinary tract infections. CONCLUSION: Non-neobladder-specific questionnaires show controversial results for QoL outcomes of patients with Studer and I-Pouch. The TNQ suggests that none of these two types of neobladder is superior to the other in terms of QoL. Hence, general questionnaires are not valid enough to adequately address QoL aspects in patients with different neobladders. Development and validation of neobladder-specific questionnaires are needed.

Expression patterns and prognostic role of transketolase-like 1 in muscle-invasive bladder cancer.

PURPOSE: The pentose phosphate pathway (PPP) has been shown to play an important role in the metabolism of cancer cells. The transketolase-like 1 gene (TKTL1) encodes an enzyme representing an essential component of this pathway. Its expression has been demonstrated to correlate with stage and outcome in various tumors. The aim of the present study was to assess expression patterns and the prognostic role of TKTL1 in muscle-invasive bladder cancer (MIBC). PATIENTS AND METHODS: The expression of TKTL1 was assessed in a tissue microarray consisting of histopathologically benign and malign tissue of 112 patients who underwent radical cystectomy due to MIBC. Cytoplasmatic and nuclear expression were assessed by immunohistochemistry and compared separately with clinicopathologic parameters and outcome. RESULTS: Cytoplasmatic expression of TKTL1 was exclusively present in tumor tissue. In contrast, the proportion of nuclei positive for TKTL1 was higher in histopathologically benign tissue compared with malign tissue. No correlation was observed between cytoplasmatic or nuclear TKTL1 expression and tumor stage, grade or the presence of metastases. Patients with lymph node involvement showed a decreased frequency of cytoplasmatic expression compared with node-negative patients (p = 0.01). However, no further correlation was observed between the expression of TKTL1 and clinical outcome of patients. CONCLUSIONS: The present study shows that the cytoplasmatic expression of TKTL1 is specific for MIBC tissue compared with histopathologically benign urothelium. This specific expression is present in a subgroup of MIBC potentially identifying patients with activated PPP suitable for a targeted inhibition of sugar metabolism. In contrast to other malignancies, TKTL1 shows no prognostic significance in MIBC.

Fluorescence-guided bladder tumour resection: impact on survival after radical cystectomy.

PURPOSE: To investigate whether photodynamic diagnosis (PDD)-guided bladder tumour resection (TUR-BT) is of prognostic value in patients undergoing subsequent radical cystectomy (RC) for bladder cancer (BC). METHODS: In 224 consecutive patients who underwent RC and bilateral pelvic lymphadenectomy for BC between 2002 and 2010 (median follow-up 29 months [IQR 8-59]), we retrospectively investigated whether patients had previously undergone PDD-guided (hexaminolevulinate [HAL] vs. 5-aminolevulinate [ALA]) versus white light (WL)-TUR-BT. Kaplan-Meier analysis was used to estimate recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS) using log-rank and Cox regression model for uni- and multivariable analysis. RESULTS: Of the 224 patients, 66 (29.5 %) underwent HAL-, 23 (10.3 %) ALA- and 135 (60.2 %) WL-TUR-BT before RC. The 3-year RFS/CSS/OS was 77.8/83.9/74.0 % for HAL-, 53.6/74.5/60.9 % for ALA- and 52.4/59.7/56.5 % for WL-TUR-BT (p = 0.002/0.023/0.037 for HAL vs. WL/ALA). PDD-TUR-BT was associated with a higher number of TUR-BTs before RC (p < 0.001) and re-resections (p = 0.015), a longer time between the first TUR-BT and RC (p = 0.044) and a lower rate of post-operative systemic chemotherapy (p = 0.001). In multivariable analysis, performance of HAL-TUR-BT, pathologic tumour and nodal stage as well as soft tissue surgical margin status were independent predictors for RFS, CSS and OS. CONCLUSIONS: This series indicates for the first time that HAL-guided TUR-BT is an independent predictor for improved survival after RC.

Current status of robotic assisted radical cystectomy with intracorporeal ileal neobladder for bladder cancer.

To investigate the current status and feasibility of robotic neobladder diversion after robotic assisted radical cystectomy. A Medline search was conducted resulting in identification of 423 articles. After exclusion of ineligible studies, 3 case series and 5 case reports were considered with a total number of reported cases of 203. Although robotic intracorporeal neobladder reconstruction is in its starting phase, initial perioperative results seem to be comparable to open series. However, randomized studies are needed to confirm non-inferiority.

Inflammation and Cancer: What Can We Therapeutically Expect from Checkpoint Inhibitors?

Programmed death-ligand 1 (PD-L1) is a cell surface protein which is mainly expressed on immune cells as well as on cancer cells and functions as a co-stimulatory molecule for T lymphocytes. It is capable of inducing apoptosis in T-cells via PD-1 which leads to impaired cytokine production and loss of cytotoxicity of activated T-cells. This represents a possible escape mechanism for cancer cells. Tumor infiltration by mononuclear cells and tumor aggressiveness was found to be associated with PD-L1 expression. In light of possible autoimmunological side effects, it remains currently unclear which patient will benefit most from this novel therapeutic approach. Furthermore, immunohistochemistry for PD-L1 has not been well standardized until now. In addition, the combination of chemotherapy with checkpoint inhibitors in different clinical settings needs to be established for the near future in order to avoid overtreatment and also unnecessary cost expenditures for the health care system.

Robot-assisted radical cystectomy and intracorporeal neobladder formation: on the way to a standardized procedure.

BACKGROUND: Robot-assisted radical cystectomy (RARC) with intracorporeal diversion has been shown to be feasible in a few centers of excellence worldwide, with promising functional and oncologic outcomes. However, it remains unknown whether the complexity of the procedure allows its duplication in other non-pioneer centers. We attempt to address this issue by presenting our cumulative experience with RARC and intracorporeal neobladder formation. METHODS: We retrospectively identified 62 RARCs in 50 men and 12 women (mean age 63.6 years) in two tertiary centers. Intracorporeal Studer neobladders were created, duplicating the steps of standard open surgery. Perioperative and postoperative variables and complications were analyzed using standardized tools. Functional and oncological results were assessed. RESULTS: The mean operative time was 476.9 min (range, 310 to 690) and blood loss was 385 ml (200 to 800). The mean hospital stay was 16.7 (12 to 62) days with no open conversion. Perioperative complications were grade II in 15, grade III in 11, and grade IV in 5 patients. The mean nodal yield was 22.9 (8 to 46). Positive margins were found in in 6.4%. The 90- and 180-day mortality rates were 0% and 3.3%. The average follow-up was 37.3 months (3 to 52). Continence was achieved in 88% of patients. The cancer-specific survival rate and overall survival rate were 84% and 71%, respectively. CONCLUSIONS: A RARC with intracorporeal neobladder creation is safe and reproducible in 'non-pioneer' tertiary centers with robotic expertise with acceptable operative time and complications. Further standardization of RARC with intracorporeal diversion is a prerequisite for its widespread use.

Rhodamine-marked bombesin: a novel means for prostate cancer fluorescence imaging.

The gastrin releasing peptide receptor (GRPR) has been found to be strongly expressed in various types of cancers such as prostate and breast carcinomas. The GRPR ligands gastrin releasing peptide and bombesin can play a very significant role in cancer therapy and diagnostics. In this study we synthesized unlabeled bombesin BBN along with two conjugates in which the correct bombesin (BBN-Rhd) and a mutant bombesin (mBBN-Rhd) sequence was coupled to rhodamine, a fluorescent dye. These novel rhodamine fluorescent conjugates were used to study the targeting and uptake of bombesin on a cellular level. Nine different human cell lines including both tumor and healthy cells were examined using flow cytometry and confocal laser scanning microscopy. GRPR mRNA expression analysis was performed and it was found that the receptor is highly expressed in LNCaP and PC3 cells compared to the rest of other cell lines. Competition experiments were performed to verify the receptor dependence of the labeled conjugates using unmarked bombesin. The present study is a first attempt at direct fluorescence imaging of living cells using bombesin and its target, the GRPR. A rhodamine bombesin conjugate can be used as marker to differentiate between healthy cells and malignant cells such as prostate hyperplasia and prostate carcinoma in the early detection of cancer.

Chromosomal alterations in exfoliated urothelial cells from bladder cancer cases and healthy men: a prospective screening study.

BACKGROUND: Chromosomal instability in exfoliated urothelial cells has been associated with the development of bladder cancer. Here, we analyzed the accumulation of copy number variations (CNVs) using fluorescence in situ hybridization in cancer cases and explored factors associated with the detection of CNVs in tumor-free men. METHODS: The prospective UroScreen study was designed to investigate the performance of UroVysion™ and other tumor tests for the early detection of bladder cancer in chemical workers from 2003-2010. We analyzed a database compiling CNVs of chromosomes 3, 7, and 17 and at 9p21 that were detected in 191,434 exfoliated urothelial cells from 1,595 men. We assessed the accumulation of CNVs in 1,400 cells isolated from serial samples that were collected from 18 cancer cases up to the time of diagnosis. A generalized estimating equation model was applied to evaluate the influence of age, smoking, and urine status on CNVs in cells from tumor-free men. RESULTS: Tetrasomy of chromosomes 3, 7 and 17, and DNA loss at 9p21 were the most frequently observed forms of CNV. In bladder cancer cases, we observed an accumulation of CNVs that started approximately three years before diagnosis. During the year prior to diagnosis, cells from men with high-grade bladder cancer accumulated more CNVs than those obtained from cases with low-grade cancer (CNV < 2: 7.5% vs. 1.1%, CNV > 2: 16-17% vs. 9-11%). About 1% of cells from tumor-free men showed polysomy of chromosomes 3, 7, or 17 or DNA loss at 9p21. Men aged ≥50 years had 1.3-fold more cells with CNVs than younger men; however, we observed no further age-related accumulation of CNVs in tumor-free men. Significantly more cells with CNVs were detected in samples with low creatinine concentrations. CONCLUSIONS: We found an accumulation of CNVs during the development of bladder cancer starting three years before diagnosis, with more altered cells identified in high-grade tumors. Also, a small fraction of cells with CNVs were exfoliated into urine of tumor-free men, mainly exhibiting tetraploidy or DNA loss at 9p21. Whether these cells are preferentially cleared from the urothelium or are artifacts needs further exploration.

Serum receptor activator of nuclear factor κB ligand (RANKL) levels predict biochemical recurrence in patients undergoing radical prostatectomy.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: There is increasing evidence that the receptor activator of nuclear factor κB ligand (RANKL) pathway not only contributes to the development of bone metastases, but also influences tumour biology in earlier stages of cancer. The study shows that preoperative serum levels of RANKL and its inhibitor osteoprotegerin (OPG) have a prognostic impact in patients undergoing radical prostatectomy for clinically localized prostate cancer. Both high levels of RANKL and a higher RANKL/OPG ratio are independent predictors of early biochemical recurrence in these patients. OBJECTIVE: To assess the prognostic impact of proteins of the receptor activator of nuclear factor κB (RANKL) pathway in serum samples from patients undergoing radical prostatectomy. PATIENTS AND METHODS: We retrospectively determined soluble RANKL (sRANKL) and osteoprotegerin (OPG) by ELISA in serum samples of 178 patients undergoing radical prostatectomy between 2004 and 2006. Clinical and patient follow-up data were analysed using the Wilcoxon-Mann-Whitney test, the Kaplan-Maier method, and single variable or multifactorial Cox proportional hazards analysis. RESULTS: Higher serum sRANKL levels (P = 0.01), lower serum OPG levels (P = 0.01) and a higher sRANKL/OPG ratio (P = 0.004) were significant risk factors for biochemical recurrence (BCR). In multifactorial analysis, adjusted for the common risk factors for BCR, sRANKL and sRANKL/OPG ratio were confirmed as independent prognostic factors. Neither sRANKL nor OPG showed a clear association with histopathological factors such as pT stage, pN Gleason score or resection margin status, nor were they associated with prostate-specific antigen level. CONCLUSIONS: Greater activity of the RANKL pathway in the serum of patients with prostate cancer undergoing radical prostatectomy is a risk factor for BCR. The RANKL pathway seems to contribute to the biological behaviour of prostate cancer even at the organ-confined stage of the disease.

Is there an anti-androgen withdrawal syndrome for enzalutamide?

BACKGROUND: The anti-androgen withdrawal syndrome (AAWS) can be seen in one-third of patients after discontinuation of first-generation non-steroidal anti-androgen therapy. With the introduction of new agents for anti-androgen therapy as well as alternate mechanisms of action, new therapeutic options before and after docetaxel chemotherapy have arisen (Ohlmann et al. in World J Urol 30(4):495-503, 2012). The question regarding the occurrence of an enzalutamide withdrawal syndrome (EWS) has not been evaluated yet. In this study, we assess prostate-specific antigen (PSA) response after discontinuation of enzalutamide. METHODS: In total 31 patients with metastatic castration-resistant prostate cancer (mCRPC) underwent an enzalutamide withdrawal and were evaluated. Data were gathered from 6 centres in Germany. Patients with continuous oral administration of enzalutamide with rising serum PSA levels were evaluated, starting from enzalutamide withdrawal until subsequent therapy was initiated, follow-up ended or death of the patient occurred. Statistical evaluation was performed applying one-sided binomial testing using R-statistical software, version 3.0.1. RESULTS: Mean withdrawal follow-up was 6.5 weeks (range 1-26.1 weeks). None of the 31 patients showed a PSA decline. Mean relative PSA rise over all patients was 73.9 % (range 0.5-440.7 %) with a median of 44.9 %. CONCLUSIONS: If existent, an AAWS is at least very rare for enzalutamide in patients with mCRPC after taxane-based chemotherapy and does not play a clinical role in this setting. This may be attributed to the different pharmacodynamics of enzalutamide. Longer duration of therapy or a longer withdrawal interval may reveal a rare EWS in the future.

Surgical removal of retroperitoneal tumors after chemotherapy treated testicular tumors.

In the era of chemotherapy, patients with advanced testicular tumor often presents with residual mass after completion of chemotherapy. Post chemotherapy RPLND is an important part of the multimodality treatment in these patients. According to current guidelines and recommendations, post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) is recommended in NSGCT patients with all residual lesions and normalized tumor markers. In seminomas, surgery is considered in patients with residual tumor > 3 cm and a positive positron emission tomography (PET) scan. A conventional bilateral template should be performed for patients undergoing PC-RPLND. However, a modified template can be performed in select patients with low volume disease to reduce the long-term morbidities and peri-operative complications. Laparoscopic PC-RPLND is safe and feasible. The oncological outcome of PC-RPLND is excellent if all tumors are resected. PC-RPLND is a complex surgery and should be done in high volume tertiary centers.