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Background: Population-based screening for prostate cancer is currently being evaluated in randomized clinical trials in the United States and in Europe. Side effects arising from the process of screening and from the earlier treatment of screen-detected prostate cancer may be important factors in the evaluation. To examine health-related quality of life (or health status) among men screened for prostate cancer, we conducted a longitudinal study of 626 attenders to the Rotterdam (The Netherlands) prostate cancer screening program and of 500 nonparticipants.Methods: Attenders of the screening program and nonparticipants completed self-assessment questionnaires (SF-36 [i.e., Medical Outcomes Study 36-Item Short-Form Health Survey] and EQ-5D [i.e., EuroQol measure for health-related quality of life] health surveys) to measure generic health status, as well as an additional questionnaire for anxiety and items relating to prostate cancer screening.Results: Physical discomfort during digital rectal examination and during transrectal ultrasound was reported by 181 (37%) of 491 men and by 139 (29%) of 487 men, respectively; discomfort during prostate biopsy was reported by 64 (55%) of 116 men. Mean scores for health status and anxiety indicated that the participants did not experience relevant changes in physical, psychological, and social functioning during the screening procedure. However, high levels of anxiety were observed throughout the screening process among men with a high predisposition to anxiety. Similar scores for anxiety predisposition were observed among attenders and nonparticipants.Conclusions: At the group level, we did not find evidence that prostate cancer screening induced important short-term health-status effects, despite the short-lasting side effects related to the biopsy procedure. However, subgroups may experience high levels of anxiety. The implication is that unfavorable health-status effects of prostate cancer screening occur mainly in the treatment phase. [ABSTRACT FROM AUTHOR]

Introduction: Surgery for locally advanced rectal cancer (LARC) or locally recurrent rectal cancer (LRRC) may require total pelvic exenteration with the need for urinary diversion. The aim of this study was to describe outcomes for ileal and colon conduits after surgery for LARC and LRRC., Methods: All consecutive patients from two tertiary referral centers who underwent total pelvic exenteration for LARC or LRRC between 2000 and 2018 with cystectomy and urinary reconstruction using an ileal or colon conduit were retrospectively analyzed. Short- (≤30 days) and long-term (>30 days) complications were described for an ileal and colon conduit., Results: 259 patients with LARC (n = 131) and LRRC (n = 128) were included, of whom 214 patients received an ileal conduit and 45 patients a colon conduit. Anastomotic leakage of the ileo-ileal anastomosis occurred in 9 patients (4%) after performing an ileal conduit. Ileal conduit was associated with a higher rate of postoperative ileus (21% vs 7%, p = 0.024), but a lower proportion of wound infections than a colon conduit (14% vs 31%, p = 0.006). The latter did not remain significant in multivariate analysis. No difference was observed in the rate of uretero-enteric anastomotic leakage, urological complications, mortality rates, major complications (Clavien-Dindo≥3), or hospital stay between both groups., Conclusion: Performing a colon conduit in patients undergoing total pelvic exenteration for LARC or LRRC avoids the risks of ileo-ileal anastomotic leakage and may reduce the risk of a post-operative ileus. Besides, there are no other differences in outcome for ileal and colon conduits., Competing Interests: Declaration of competing interest None., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Total pelvic exenteration (TPE) is a radical approach for locally advanced rectal cancer (LARC) and locally recurrent rectal cancer (LRRC) in case of tumour invasion into the urogenitary tract. The aim of this study is to assess surgical and oncological outcomes of TPE for LARC and LRRC in elderly patients compared to younger patients., Methods: All patients who underwent TPE for LARC and LRRC between January 1990 and March 2017 were retrospectively analyzed. Patients aged <70 years were classified as younger and ≥70 years as elderly patients., Results: In total 126 patients underwent TPE, of whom 88 younger and 38 elderly patients. Elderly patients had a significantly higher number of ASA > II patients (p = 0.01). Indication for surgery LARC (n = 73) and LRRC (n = 53) did not differ significantly. The 30-day mortality rate was significantly higher (p = 0.01) in elderly (13%) compared to younger patients (3%). Elderly patients experienced more anastomotic leakage (p = 0.02). Median overall survival (OS) was 75 months [95%CI 37.1; 112.9] for elderly and 45 months [95%CI 22.4; 67.8] for younger patients (p = 0.77). The 5-year OS rate was 44% in both groups. Median disease specific survival (DSS) was 78 months [95%CI 69.1; 86.9] for elderly and 60 months [95%CI 36.6; 83.4] for younger patients (p = 0.34). The 5-year DSS rate was 57% and 49%, respectively., Conclusion: TPE is an invasive treatment for rectal cancer with high 30-day mortality in elderly patients. Oncological outcomes are similar in elderly and younger patients. Therefore, TPE should not be withheld because of high age only, but careful patient selection is needed., (Copyright © 2018. Published by Elsevier Ltd.)

Objective: To determine the relationship of age to side-effects leading to discontinuation of treatment in patients with stage Ta-T1 non-muscle-invasive bladder cancer (NMIBC) treated with maintenance bacille Calmette-Guérin (BCG)., Patients and Methods: We evaluated toxicity for 487 eligible patients with intermediate- or high-risk Ta-T1 (without carcinoma in situ) NMIBC randomised to receive 3 years of maintenance BCG therapy (247 BCG alone and 240 BCG + isoniazid) in European Organisation for Research and Treatment of Cancer Genito-Urinary Group trial 30911. The percentage of patients who stopped for toxicity and the number of treatment cycles that they received were compared in four age groups, ≤60, 61-70, 71-75 and >75 years, using the Mantel-Haenszel chi-square test for trend., Results: The percentage of patients stopping BCG for toxicity was 17.9% in patients aged ≤60 years, 21.9% in patients aged 61-70 years, 22.9% in patients aged 71-75 years, and 16.4% in patients aged >75 years (P = 0.90). For both systemic and local side-effects, there was likewise no significant difference., Conclusion: In patients with intermediate- and high-risk Ta-T1 NMIBC treated with BCG, no differences in toxicity as a reason for stopping treatment were detected based on patient age., (© 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.)

Background: There are no prognostic factor publications on stage Ta-T1 non-muscle-invasive bladder cancer (NMIBC) treated with 1-3 yr of maintenance bacillus Calmette-Guérin (BCG)., Objective: To determine prognostic factors in NMIBC patients treated with 1-3 yr of BCG after transurethral resection of the bladder (TURB), to derive nomograms and risk groups, and to identify high-risk patients who should be considered for early cystectomy., Design, Setting, and Participants: Data for 1812 patients were merged from two European Organization for Research and Treatment of Cancer randomized phase 3 trials in intermediate- and high-risk NMIBC., Intervention: Patients received 1-3 yr of maintenance BCG after TURB and induction BCG., Outcome Measurements and Statistical Analysis: Prognostic factors for risk of early recurrence and times to late recurrence, progression, and death were identified in a training data set using multivariable models and applied to a validation data set., Results and Limitations: With a median follow-up of 7.4 yr, 762 patients recurred; 173 progressed; and 520 died, 83 due to bladder cancer (BCa). Statistically significant prognostic factors identified by multivariable analyses were prior recurrence rate and number of tumors for recurrence, and tumor stage and grade for progression and death due to BCa. T1G3 patients do poorly, with 1- and 5-yr disease-progression rates of 11.4% and 19.8%, respectively, and 1- and 5-yr disease-specific death rates of 4.8% and 11.3%. Limitations include lack of repeat transurethral resection in high-risk patients and exclusion of patients with carcinoma in situ., Conclusions: NMIBC patients treated with 1-3 yr of maintenance BCG have a heterogeneous prognosis. Patients at high risk of recurrence and/or progression do poorly on currently recommended maintenance schedules. Alternative treatments are urgently required., Patient Summary: Non-muscle-invasive bladder cancer patients at high risk of recurrence and/or progression do poorly on currently recommended bacillus Calmette-Guérin maintenance schedules, and alternative treatments are urgently required., Trial Registration: Study 30911 was registered with the US National Cancer Institute clinical trials database (protocol ID: EORTC 30911). Study 30962 was registered at ClinicalTrials.gov, number NCT00002990; http://clinicaltrials.gov/ct2/show/record/NCT00002990., (Copyright © 2015 European Association of Urology. All rights reserved.)

Background and Purpose: The use of HDR brachytherapy (HDR-BT) as monotherapy for prostate cancer (PC) is increasing worldwide with good tumour control rates and acceptable toxicity. We report our results on toxicity and quality of life (QoL) after HDR-BT monotherapy for PC patients., Materials and Methods: 166 low- and intermediate-risk localized PC patients were treated with HDR-BT to a total dose of 38Gy in four fractions. Genitourinary (GU) and gastrointestinal (GI) toxicities were prospectively assessed using EORTC-RTOG questionnaires and physicians charts. QoL was evaluated using EORTC QLQ-PR25 questionnaires., Results: Three months after treatment, acute GU and GI toxicities were reported in 10.8% and 7.2%. Acute toxicity resolved within two months in the majority of patients (61%). Late grade ⩾ 2 GU and GI toxicity were reported in 19.7% and 3.3% of patients 12 months after HDR-BT. Mean QLQ-PR25 scores showed clinically relevant changes from baseline for urinary symptoms and sexual functioning. With a mean follow-up of 35 months, biochemical failure was observed in 2.4%. Overall survival at 60 months was 93.6% and cancer-specific survival was 100%., Conclusions: HDR-BT monotherapy for localized PC showed excellent clinical outcome and acceptable acute and late toxicity. Urinary symptoms and sexual function QoL decreased after treatment., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Currently, the use of two classification systems for bladder cancer grade is advocated in clinical guidelines because the WHO2004 classification has not been sufficiently validated with biological markers and follow-up. The slides of 325 primary non-muscle invasive bladder cancers from three hospitals were reviewed by one uro-pathologist in two separate sessions for the WHO1973 (G1, G2 and G3) and 2004 (papillary urothelial neoplasm of low malignant potential (LMP), low-grade (LG) and high-grade (HG)) classifications. FGFR3 status was examined with PCR-SNaPshot analysis. Expression of Ki-67, P53 and P27 was analyzed by immuno-histochemistry. Clinical recurrence and progression were determined. We performed validation and cross-validation of the two systems for grade with molecular markers and clinical outcome. Multivariable analyses were done to predict prognosis and pT1 bladder cancer. Grade review resulted in 88 G1, 149 G2 and 88 G3 lesions (WHO1973) and 79 LMP, 101 LG and 145 HG lesions (WHO2004). Molecular validation of both grading systems showed that FGFR3 mutations were associated with lower grades whereas altered expression (Ki-67, P53 and P27) was found in higher grades. Clinical validation showed that the two classification systems were both significant predictors for progression but not for recurrence. Cross-validation of both WHO systems showed a significant stepwise increase in biological (molecular markers) and clinical (progression) potential along the line: G1-LG-G2-HG-G3. The LMP and G1 categories had a similar clinical and molecular profile. On the basis of molecular biology and multivariable clinical data, our results support a four-tiered grading system using the 1973 and 2004 WHO classifications with one low-grade (LMP/LG/G1) category that includes LMP, two intermediate grade (LG/G2 and HG/G2) categories and one high-grade (HG/G3) category.

Background: Although maintenance bacillus Calmette-Guérin (BCG) is the recommended treatment in high-risk non-muscle-invasive bladder cancer (NMIBC), its efficacy in older patients is controversial., Objective: To determine the effect of age on prognosis and treatment outcome in patients with stage Ta T1 NMIBC treated with maintenance BCG., Design, Setting, and Participants: A total of 957 patients with intermediate- or high-risk Ta T1 (without carcinoma in situ) NMIBC were randomized in European Organization for Research and Treatment of Cancer (EORTC) trial 30911 comparing six weekly instillations of epirubicin, BCG, and BCG plus isoniazid followed by three weekly maintenance instillations over 3 yr., Outcome Measurements and Statistical Analysis: Cox multivariate proportional hazards regression models were used to assess the relative importance of age for recurrence, progression, overall survival, and NMIBC-specific survival with adjustment for EORTC risk scores., Results and Limitations: Overall, 822 eligible patients were included: 546 patients in the BCG with or without INH arms and 276 in the epirubicin arm. In patients treated with BCG with or without INH, 34.1% were >70 yr of age and 3.7% were >80 yr. With a median follow-up of 9.2 yr, patients >70 yr had a shorter time to progression (p=0.028), overall survival (p<0.001), and NMIBC-specific survival (p=0.049) after adjustment for EORTC risk scores in the multivariate analysis. The time to recurrence was similar compared with the younger patients. BCG was more effective than epirubicin for all four end points considered, and there was no evidence that BCG was any less effective compared with epirubicin in patients >70 yr., Conclusions: In intermediate- and high-risk Ta T1 urothelial bladder cancer patients treated with BCG, patients >70 yr of age have a worse long-term prognosis; however, BCG is more effective than epirubicin independent of patient age., Patient Summary: Intravesical bacillus Calmette-Guérin for non-muscle-invasive bladder cancer is less effective in patients >70 yr of age, but it is still more effective than epirubicin., Trial Registration: This study was registered with the US National Cancer Institute clinical trials database (protocol ID: EORTC 30911; http://www.cancer.gov/clinicaltrials/search/view?cdrid=77075&version=HealthProfessional&protocolsearchid=12442243#StudyIdInfo&#95;CDR0000077075)., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: To report long-term results of a bladder preservation strategy for muscle-invasive bladder cancer (MIBC) using external beam radiation therapy and brachytherapy/interstitial radiation therapy (IRT)., Methods and Materials: Between May 1989 and October 2011, 192 selected patients with MIBC were treated with a combined regimen of preoperative external beam radiation therapy and subsequent surgical exploration with or without partial cystectomy and insertion of source carrier tubes for afterloading IRT using low dose rate and pulsed dose rate. Data for oncologic and functional outcomes were prospectively collected. The primary endpoints were local recurrence-free survival (LRFS), bladder function preservation survival, and salvage cystectomy-free survival. The endpoints were constructed according to the Kaplan-Meier method., Results: The mean follow-up period was 105.5 months. The LRFS rate was 80% and 73% at 5 and 10 years, respectively. Salvage cystectomy-free survival at 5 and 10 years was 93% and 85%. The 5- and 10-year overall survival rates were 65% and 46%, whereas cancer-specific survival at 5 and 10 years was 75% and 67%. The distant metastases-free survival rate was 76% and 69% at 5 and 10 years. Multivariate analysis revealed no independent predictors of LRFS. Radiation Therapy Oncology Group grade ≥3 late bladder and rectum toxicity were recorded in 11 patients (5.7%) and 2 patients (1%), respectively., Conclusions: A multimodality bladder-sparing regimen using IRT offers excellent long-term oncologic outcome in selected patients with MIBC. The late toxicity rate is low, and the majority of patients preserve their functional bladder., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Evidence from randomized trials on the effects of screening for prostate cancer (PCa) on disease-specific mortality accumulates slowly with increasing follow-up., Objective: To assess data on PCa-specific mortality in the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) trial., Design, Setting, and Participants: A randomized controlled trial with randomization after signed, written informed consent (efficacy trial). In the period 1993-1999, a total of 42 376 men aged 54-74 yr were randomized to a screening arm (S-arm) (n = 21 210 with screening every 4 yr, applying a total prostate-specific antigen [PSA] level cut-off ≥ 3.0 ng/ml as biopsy indication) or a control arm (C-arm) (n = 21 166; no intervention)., Outcome Measurements and Statistical Analysis: Number of PCas detected per arm depicted by predefined time periods and prognostic groups. PCa-specific mortality analyses using Poisson regression in age group 55-74 yr at randomization and separately in the predefined age group of 55-69 yr., Results and Limitations: After a median follow-up of 12.8 yr, 19 765 men (94.2%) were screened at least once and 2674 PCas were detected (of which 561 [21.0%] were interval PCas). In the C-arm, 1430 PCas were detected, resulting in an excess incidence of 59 PCas per 1000 men randomized (61 PCas per 1000 in age group 55-69 yr). Thirty-two percent of all men randomized have died. PCa-specific mortality relative-risk (RR) reductions of 20.0% overall (age: 55-74 yr; p = 0.042) and 31.6% (age: 55-69 yr; p = 0.004) were found. A 14.1% increase was found in men aged 70-74 yr (not statistically significant). Absolute PCa mortality was 1.8 per 1000 men randomized (2.6 per 1000 men randomized in age group 55-69 yr). The number needed to invite and number needed to manage were 565 and 33, respectively, for age group 55-74 yr, and 392 and 24, respectively, for age group 65-69 yr. Given the slow natural history of the disease, follow-up might be too short., Conclusions: Systematic PSA-based screening reduced PCa-specific mortality by 32% in the age range of 55-69 yr. The roughly twofold higher incidence in the S-arm underlines the importance of tools to better identify those men who would benefit from screening., (Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Various definitions are used to calculate postoperative mortality. As variation hampers comparability between reports, a study was performed to evaluate the impact of using different definitions for several types of cancer surgery., Methods: Population-based data for the period 1997-2008 were retrieved from the Rotterdam Cancer Registry for resectional surgery of oesophageal, gastric, colonic, rectal, breast, lung, renal and bladder cancer. Postoperative deaths were tabulated as 30-day, in-hospital or 90-day mortality. Postdischarge deaths were defined as those occurring after discharge from hospital but within 30 days., Results: This study included 40,474 patients. Thirty-day mortality rates were highest after gastric (8·8 per cent) and colonic (6·0 per cent) surgery, and lowest after breast (0·2 per cent) and renal (2·0 per cent) procedures. For most tumour types, the difference between 30-day and in-hospital rates was less than 1 per cent. For bladder and oesophageal cancer, however, the in-hospital mortality rate was considerably higher at 5·1 per cent (+1·3 per cent) and 7·3 per cent (+2·8 per cent) respectively. For gastric, colonic and lung cancer, 1·0 per cent of patients died after discharge. For gastric, lung and bladder cancer, more than 3 per cent of patients died between discharge and 90 days., Conclusion: The 30-day definition is recommended as an international standard because it includes the great majority of surgery-related deaths and is not subject to discharge procedures. The 90-day definition, however, captures mortality from multiple causes; although this may be of less interest to surgeons, the data may be valuable when providing information to patients before surgery., (Copyright © 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.)

Context: Currently, bacillus Calmette-Guérin (BCG) intravesical instillations are standard treatment for patients with high-grade non-muscle-invasive bladder cancer; however, no markers are available to predict BCG response., Objective: To review the contemporary literature on markers predicting BCG response, to discuss the key issues concerning the identification of predictive markers, and to provide recommendations for further research studies., Evidence Acquisition: We performed a systematic review of the literature using PubMed and Embase databases in the period 1996-2010. The free-text search was extended by adding the following keywords: recurrence, progression, survival, molecular marker, prognosis, TP53, Ki-67, RB, fibronectin, immunotherapy, cytokine, interleukin, natural killer, macrophage, PMN, polymorphism, SNP, single nucleotide polymorphism, and gene signature., Evidence Synthesis: If thresholds for the detection of urinary interleukin (IL)-8, IL-18, and tumour necrosis factor apoptosis-inducing ligand levels are standardised, measurement of these cytokines holds promise in the assessment of BCG therapy outcome. Studies on immunohistochemical markers (ie, TP53, Ki-67, and retinoblastoma) display contradictory results, probably because of the small patient groups that were used and seem unsuitable to predict BCG response. Exploring combinations of protein levels might prove to be more helpful to establish the effect of BCG therapy. Single nucleotide polymorphisms, either in cytokines or in genes involved in DNA repair, need to be investigated in different ethnicities before their clinical relevance can be determined. Measurement of urinary IL-2 levels seems to be the most potent marker of all the clinical parameters reviewed., Conclusions: IL-2 levels are currently the most promising predictive markers of BCG response. For future studies focusing on new biomarkers, it is essential to make more use of new biomedical techniques such as microRNA profiling and genomewide sequencing., (Copyright © 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The European Organization for Research and Treatment of Cancer (EORTC) risk scores are not validated in an independent patient population. Molecular grade (mG) based on fibroblast growth factor receptor 3 (FGFR3) gene mutation status and MIB-1 expression was proposed as an alternative to pathologic grade in bladder cancer (BCa) [1]., Objective: To validate the EORTC risk score and to determine its relation to mG in a series with long-term follow-up as well as to determine reproducibility of pathologic grade and mG., Design, Setting, and Participants: In this multicenter study, we included 230 patients with primary non-muscle-invasive BCa (NMIBC)., Measurements: Four uropathologists reviewed the slides. FGFR3 mutation status was examined by two assays. MIB-1 was assessed by immunohistochemistry. The EORTC risk scores for recurrence and progression were determined. Multivariable analyses were used to find prognostic factors., Results and Limitations: Median follow-up was 8.62 yr (interquartile range: 6.6-11.8). FGFR3 mutations were significantly related to favorable disease parameters, whereas altered MIB-1 was frequently seen with pT1, high grade, and high EORTC risk scores. EORTC risk scores were significant in multivariable analyses for recurrence and progression. In multivariable analyses for progression and disease-specific survival, the mG had independent significance. The addition of mG to the multivariable model for progression increased the predictive accuracy from 74.9% to 81.7% (p<0.001; Mantel-Haenszel test). The mG (89%) was more reproducible than the pathologic grade (41-74%)., Conclusions: We validated the EORTC risk scores for primary NMIBC in a clinical and biomarker setting. Next to EORTC risk score, mG proved highly reproducible and predictive. Our long-term results justify an independent prospective analysis of mG and EORTC risk scores., ((c) 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: Despite high response rates to systemic chemotherapy, 30% of patients with advanced stage testicular carcinoma will have extra-retroperitoneal residual masses that require resection. Most often, these are located in the lungs and mediastinum and neck. Limited data are available concerning the incidence, surgical management, and follow-up of neck metastasis arising from a testicular primary tumor., Methods: We retrospectively reviewed all 665 patients who were referred to a tertiary referral center with the diagnosis of testicular cancer from January 1997 to June 2009 for the presence of cervical metastases. Patients who underwent concomitant surgical therapy were identified and analyzed. Clinical and pathological data were collected from patient records, including radiology and pathology reports. Furthermore, data on primary treatment strategy, chemotherapeutic regimens, timing of surgical procedures, complications, disease recurrence, and follow-up were collected., Results: Twenty-six patients (4%) had cervical lymph node metastasis. The majority (n = 19) had multiple ERP sites. Nine patients (35%) underwent selective neck dissection: in six patients, this was indicated because of residual masses after chemotherapy, and in three patients, cervical masses represented a late and distant relapse of previously treated disease. Viable cancer cells were present in the resected specimen only in these three patients. Seven patients are currently without evidence of disease. Two patients died of disseminated disease., Conclusions: Cervical lymph node metastases originating from testicular cancer are rare but are more commonly observed in patients with advanced stage disease. Selective neck dissection can be safely performed both after chemotherapy and in the case of recurrent disease.

Background: A new grading system for bladder cancer (BCa) was adopted in 2004 to reduce observer variability and provide better prognostic information., Objective: We compared the World Health Organization (WHO) 1973 and 2004 systems for observer variability and prognosis., Design, Setting, and Participants: Slides of 173 primary non-muscle-invasive BCa were reviewed two times by four pathologists., Measurements: Intra- and interobserver variability were assessed using κ statistics. We determined the mean grade (eg, G1/low malignant potential is 1 grade point, G2/low grade is 2 grade points) of the pathologists per grading cycle. Kaplan-Meier analyses were applied for prediction of recurrence and progression., Results and Limitations: For WHO 2004 and 1973 grading, the agreement between the pathologists was 39-74% (κ: 0.14-0.58) and 39-64% (κ: 0.15-0.41), respectively. The intraobserver agreement varied from 71% to 88% (κ: 0.55-0.81). The mean grade of a pathologist was constant (difference below 0.1 grade point) irrespective of the grading system. Conversely, mean-grade differences among the pathologists were high, up to 0.7 grade point. The mean grades for the WHO 2004 system were 0.3-0.5 grade point higher than those of WHO 1973. Mean grade distinguished low and high graders among the pathologists and was strongly linked with risk of progression in each grade category., Conclusions: The variation in mean grade among individual pathologists exceeded the grade shift caused by WHO 2004 grading. Knowledge of the pathologist's mean grade allows a better assessment of the prognostic value of grading. Mean grade has the potential to become a tool for quality assurance in pathology., (Copyright © 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: In high-risk prostate carcinoma, there is controversy whether these patients should be treated with escalated-dose (> or =74 Gy) or conventional-dose radiotherapy (<74 Gy) combined with hormonal therapy. Furthermore, the issue of the optimal duration and timing of hormonal therapy are not well crystallized., Patients and Methods: A search for evidence from randomized- and large non-randomized studies in order to address these issues, was therefore initiated. For this purpose, MedLine, EMbase, and PubMed and the data base of the Dutch randomized dose-escalation trial, were consulted., Results and Conclusions: From this search it was concluded that the benefit of hormonal therapy in combination with conventional-dose radiotherapy (<74 Gy) in high-risk prostate cancer is evident (Level 2 evidence); Levels 2 and 3 evidence were provided by several studies supporting the use of escalated-dose radiotherapy in high-risk prostate cancer. For the combination of hormonal therapy with escalated-dose radiotherapy in these patients, there is Level 2 evidence for moderately escalated dose (74 Gy) and high escalated dose (> or =78 Gy). The optimal duration and timing of hormonal therapy are not well defined. More randomized-controlled trials and meta-analyses are therefore needed to clearly determine the independent role of dose-escalation in high-risk patients treated with hormonal therapy and the optimal duration and timing of hormonal therapy.

Purpose: The CyberKnife (CK), a linear accelerator mounted on a robotic device, enables excellent dose conformation to the target and minimizes dose to surrounding normal tissue. It is a very suitable device for performing hypofractionated stereotactic body radiotherapy as monotherapy for low- to intermediate-risk prostate cancer patients. We report our early experience using this technique., Materials and Methods: Between June 2008 and June 2009, 10 patients underwent CK monotherapy as treatment for their prostate cancer (stage

Background: Intravesical chemotherapy and bacillus Calmette-Guérin (BCG) reduce the recurrence rate in patients with stage Ta T1 urothelial bladder cancer; however, the benefit of BCG relative to chemotherapy for long-term end points is controversial, especially in intermediate-risk patients., Objective: The aim of the study was to compare the long-term efficacy of BCG and epirubicin., Design, Setting, and Participants: From January 1992 to February 1997, 957 patients with intermediate- or high-risk stage Ta T1 urothelial bladder cancer were randomized after transurethral resection to one of three treatment groups in the European Organization for Research and Treatment of Cancer Genito-Urinary Group phase 3 trial 30911., Intervention: Patients received six weekly instillations of epirubicin, BCG, or BCG plus isoniazid (INH) followed by three weekly maintenance instillations at months 3, 6, 12, 18, 24, 30, and 36., Measurements: End points were time to recurrence, progression, distant metastases, overall survival, and disease-specific survival., Results and Limitations: With 837 eligible patients and a median follow-up of 9.2 yr, time to first recurrence (p<0.001), distant metastases (p=0.046), overall survival (p=0.023), and disease-specific survival (p=0.026) were significantly longer in the two BCG arms combined as compared with epirubicin; however, there was no difference for progression. Three hundred twenty-three patients with stage T1 or grade 3 tumors were high risk, and the remaining 497 patients were intermediate risk. The observed treatment benefit was at least as large, if not larger, in the intermediate-risk patients compared with the high-risk patients., Conclusions: In patients with intermediate- and high-risk stage Ta and T1 urothelial bladder cancer, intravesical BCG with or without INH is superior to intravesical epirubicin not only for time to first recurrence but also for time to distant metastases, overall survival, and disease-specific survival. The benefit of BCG is not limited to just high-risk patients; intermediate-risk patients also benefit from BCG., Trial Registration: This study was registered with the US National Cancer Institute clinical trials database [protocol ID: EORTC-30911]. http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=77075&version=HealthProfessional&protocolsearchid=6540260., (Copyright © 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: Complete resection is the most important prognostic factor in surgery for pelvic tumors. In locally advanced and recurrent pelvic malignancies, radical margins are sometimes difficult to obtain because of close relation to or growth in adjacent organs/structures. Total pelvic exenteration (TPE) is an exenterative operation for these advanced tumors and involves en bloc resection of the rectum, bladder, and internal genital organs (prostate/seminal vesicles or uterus, ovaries and/or vagina)., Methods: Between 1994 and 2008, a TPE was performed in 69 patients with pelvic cancer; 48 with rectal cancer (32 primary and 16 recurrent), 14 with cervical cancer (1 primary and 13 recurrent), 5 with sarcoma (3 primary and 2 recurrent), 1 with primary vaginal, and 1 with recurrent endometrial carcinoma. Ten patients were treated with neoadjuvant chemotherapy and 66 patients with preoperative radiotherapy to induce down-staging. Eighteen patients received IORT because of an incomplete or marginal complete resection., Results: The median follow-up was 43 (range, 1-196) months. Median duration of surgery was 448 (range, 300-670) minutes, median blood loss was 6,300 (range, 750-21,000) ml, and hospitalization was 17 (range, 4-65) days. Overall major and minor complication rates were 34% and 57%, respectively. The in-hospital mortality rate was 1%. A complete resection was possible in 75% of all patients, a microscopically incomplete resection (R1) in 16%, and a macroscopically incomplete resection (R2) in 9%. Five-year local control for primary locally advanced rectal cancer, recurrent rectal cancer, and cervical cancer was 89%, 38%, and 64%, respectively. Overall survival after 5 years for primary locally advanced rectal cancer, recurrent rectal cancer, and cervical cancer was 66%, 8%, and 45%., Conclusions: Total pelvic exenteration is accompanied with considerable morbidity, but good local control and acceptable overall survival justifies the use of this extensive surgical technique in most patients, especially patients with primary locally advanced rectal cancer and recurrent cervical cancer.

Non-muscle invasive bladder cancers (NMI-BCs) represent 75% of bladder cancers upon presentation. After removal of the primary tumour by transurethral resection, multiple recurrences continue to develop in 70% of patients. Consequently, prolonged and costly surveillance by cystoscopy is required. Mutations in the FGFR3 oncogene are common in NMI-BCs and are associated with a lower chance of progression to muscle-invasive disease. Here we analysed the consistency of FGFR3 mutations in primary and recurrent tumours. This knowledge is of crucial importance if FGFR3 mutation analysis on urinary cells is to be used as an alternative for cystoscopical surveillance. To this end, we monitored the disease process and FGFR3 mutation status of primary and recurrent tumours in 118 patients with NMI-BC. During median follow-up of 8.8 years, these patients underwent 2133 cystoscopies and 80 patients developed 414 recurrences. FGFR3 mutations were equally prevalent in primary and recurrent tumours (63%). Patients can have different types of FGFR3 mutations in different tumours. Recurrence risk was not significantly different for patients with a mutant or wild-type primary tumour. Recurrence rates varied widely between patients but were constant for a patient and were unrelated to FGFR3 status. In the mutant patient group, in contrast to the wild-type group, recurrences continued to develop after 10 years. In 81% of the recurrences of patients with a mutant primary tumour, a mutation was found. Moreover, recurrences in this patient group were of lower stage and grade than those of patients with a wild-type primary tumour (p < 0.001). These results suggest that surveillance by FGFR3 mutation analysis on voided urine in combination with a reduced cystoscopy frequency of patients presenting with an FGFR3 mutant tumour is worth investigating.

Background: Microsatellite analysis (MA) of voided-urine samples has been promoted as an alternative for cystoscopy surveillance (UCS) of patients with low-grade non-muscle-invasive papillary urothelial carcinoma (UC)., Objective: To assess the feasibility and clinical utility of MA on voided-urine samples in a routine setting to detect or predict bladder cancer recurrences., Design, Setting, and Participants: We evaluated 228 patients monitored by MA of voided-urine samples and synchronous UCS who participated in a longitudinal prospective study in 10 hospitals. Follow-up started after diagnosis of a primary or recurrent pTa, pT1, grade 1 or grade 2 papillary UC., Measurements: Clinico-pathological parameters and fibroblast growth factor receptor 3 (FGFR3) gene mutation status of the inclusion tumour were determined. MA outcome was analysed in 1012 urine samples during a mean follow-up of 41 mo. Poor DNA quality prevented MA in 19% (197/1012) of the samples, leaving 815 visits for a cross-sectional analysis of sensitivity and specificity. We determined the predictive value (PPV) in a longitudinal analysis for 458 series with persistent MA results. Factors influencing diagnostic quality of MA were investigated. Kaplan-Meier analysis was performed to relate MA results to recurrence., Results and Limitations: Cross-sectional sensitivity and specificity of MA for detection of a recurrence were 58% (49/84) and 73% (531/731), respectively. One pT1 grade 3 UC was missed. In a longitudinal analysis, the 2-yr risk to develop a recurrence reached 83% if MA outcome was persistently positive and 22% when MA was persistently negative. PPV of MA was higher with wild-type FGFR3 gene status and smoking habits. All four upper urinary tract tumours detected were preceded by a positive MA test., Conclusions: Consecutive positive MA results are a strong predictor for future recurrences, but sensitivity needs to be improved, for example, by patient selection and testing of additional genetic markers in urine samples.

Purpose: To quantify the residual geometric uncertainties after on-line corrections with intraprostatic fiducial markers, this study analyzed the deformation of the prostate and, in particular, the seminal vesicles relative to such markers., Patients and Methods: A planning computed tomography (CT) scan and three repeat CT scans were obtained for 21 prostate cancer patients who had had three to four cylindrical gold markers placed. The prostate and whole seminal vesicles (clinical target volume [CTV]) were delineated on each scan at a slice thickness of 1.5 mm. Rigid body transformations (translation and rotation) mapping the markers onto the planning scan positions were obtained. The translation only (T(only)) or both translation and rotation were applied to the delineated CTVs. Next, the residue CTV surface displacements were determined using nonrigid registration of the delineated contours. For translation and rotation of the CTV, the residues represented deformation; for T(only), the residues stemmed from deformation and rotation. T(only) represented the residues for most currently applied on-line protocols. The patient and population statistics of the CTV surface displacements were calculated. The intraobserver delineation variation was similarly quantified using repeat delineations for all patients and corrected for., Results: The largest CTV deformations were observed at the anterior and posterior side of the seminal vesicles (population average standard deviation

Objectives: The clinical management of non-muscle-invasive urothelial cell carcinoma of the bladder (UCC) is challenging, as it has a marked tendency to recur and to progress. Aim of this study was to investigate the prognostic value of the WHO 1973 and 2004 grading systems and biomarkers FGFR3, CK20 and Ki-67., Methods: In a prospective study, tumours from 221 patients were studied for the expression of CK20 and Ki-67 by immunohistochemistry, and FGFR3 status by SNaPshot mutation detection. Staging and grading were performed according to the WHO classification systems of 1973 and 2004., Results: : Median follow-up was 35 mo. Recurrence occurred in 72 of 221 patients. None of the parameters was able to predict disease recurrence. CK20, Ki-67, FGFR3 mutation, molecular grade using FGFR3 mutation analysis and Ki-67, and histological grading and staging were significantly associated with disease progression in stage. In multivariable analyses, WHO 1973 and 2004 grading systems remained statistically significant and independent predictors of progression, with p=0.005 for WHO 1973 and p=0.004 for 2004. FGFR3 status was able to discriminate progressors from nonprogressors in a subset of patients with high-grade UCC (p=0.009)., Conclusions: This is the first prospective study comparing the WHO 1973 and 2004 grading systems. We show that both grading systems contribute valuable independent information. Therefore, it should be considered whether a better grading system could be developed that incorporates essential elements from both. The combination of WHO 2004 grading with FGFR3 status allows a better risk stratification for patients with high-grade non-muscle-invasive UCC.

Objective: To compare, in patients with non-muscle-invasive low-grade (pTa/pT1, G1/G2) urothelial cell carcinoma of the urinary bladder, the perceived burden of flexible cystoscopy or surveillance by microsatellite analysis (MA) in voided urine, as such patients are normally recommended to adhere to regular cysto-urethroscopic surveillance (CUS)., Patients and Methods: In all, 220 participants of a randomized trial comparing CUS and surveillance by MA were asked to complete questionnaires 1 week after cystoscopy or urine sample collection. We assessed the discomfort and pain reported during CUS, experiences with MA, and physical symptoms, medical consumption and general functioning in the week after CUS/urine sampling., Results: We analysed data from 732 questionnaires (197 patients) completed after CUS and 184 (67 patients) after collecting urine. The introduction of the cystoscope was reported to cause discomfort in 39% and pain in 35% of the responses to the questionnaires; the waiting time for the results of MA was reported as burdensome in 19%. Painful micturition was significantly more frequent in the week after CUS than after MA (30% and 12%, respectively). The frequency of fever (1% and 2%) and haematuria (7% and 6%) was similar in both groups. Older patients reported significantly less pain and discomfort from cystoscopy, and this was not related to having more previous cystoscopies., Conclusion: CUS caused pain and discomfort in about a third of patients. The burden of MA appeared fully attributable to the waiting time for the test result. The present results are a further motivation in the search for less invasive surveillance tests.

Objective: Analyse the outcome of pelvic exenteration for gynaecological malignancies in a tertiary referral center. Post-operative in-hospital morbidity, long-term morbidity, disease free and overall survival rates were studied., Study Design: Between 1991 and 2004, 42 patients underwent an anterior, total or posterior exenteration for gynaecological malignancies. Follow-up was obtained from patient files; disease free and overall survival were calculated and prognostic factors were studied., Results: A pelvic exenteration was performed in 14 patients for primary and 28 patients for recurrent gynaecological cancers. In-hospital complications occurred in 19 patients (45%) of whom seven patients needed a reoperation (17%). Late complications occurred in 31 patients (75%); 21 reinterventions were performed (50%). Five-year disease free and overall survival was, respectively, 48 and 52%. Age, type of surgery, histology, localisation of the tumour, lateral wall involvement, completeness of resection and primary versus recurrent cancer were not identified as prognostic factors for recurrence or survival., Conclusion: Long-term survival is possible in about 50% of patients after pelvic exenteration for gynaecological cancers, but is associated with significant post-operative morbidity.

Aims: To report the role of total pelvic exenteration in a series of locally advanced and recurrent rectal cancers., Methods: In the period 1994-2004, TPE was performed in 35 of 296 patients with primary locally advanced and recurrent rectal cancer treated in the Daniel den Hoed Cancer Center; 23 of 176 with primary locally advanced and 12 of 120 with recurrent rectal cancer. All but one patient received pre-operative External Beam Radiation Therapy (EBRT). After 1997, Intra Operative Radiotherapy (IORT) was performed in case of a resection margin less than 2 mm., Results: Overall major complication rates were not significantly different between patients with primary and recurrent rectal cancer (26% vs. 50%, p=0.94). The hospital mortality rate was 3%. The 5-year local control and overall survival of patients with primary locally advanced rectal cancer were 88% and 52%, respectively. In patients with recurrent rectal cancer 3-year local control and survival rates were 60% and 32%, respectively. An incomplete resection, preoperative pain and advanced Wanebo stage for recurrent cancer were negative prognostic factors for both local control and overall survival., Conclusion: TPE in primary locally advanced rectal cancer enables good local control and acceptable overall survival, thereby justifying the use of the procedure. Patients with recurrent rectal cancer showed a high rate of major complications, a high distant metastasis rate, and a poor overall survival.

Objectives: To evaluate the tumor characteristics and prognostic factors in screen-detected prostate cancers in two successive screening rounds with a 4-year screening interval in the European Randomized Study of Screening for Prostate Cancer, section Rotterdam., Methods: From 1993 to 2000, 42,376 men (21,210 in the screening arm and 21,166 in the control arm) were randomized and screened. Prostate-specific antigen testing, digital rectal examination, transrectal ultrasonography, and sextant biopsies were offered to the participants in the screening arm. A total of 1218 men with a biopsy indication at the first screening received an additional screening after 1 year (early recall). By 2004, all men had received their second screening. Interval carcinomas were defined as cancers detected during the screening interval and were identified by linkage with the Cancer Registry., Results: In the first round, 1014 prostate cancers were detected--24 in the men noncompliant to screening, 63 at the early recall screening, and 433 in the second round of screening. Also, 62 interval carcinomas were diagnosed. In the second screening round, the mean prostate-specific antigen value was lower (5.6 versus 11.1 ng/mL), advanced clinical stage T3-T4 was 7.1-fold less common, and 76.4% versus 61.5% of the biopsy Gleason scores were less than 7. In the first screening round, 13 regional and 9 distant metastases were detected; in the second round, 2 cases with distant metastasis were found., Conclusions: Overall, a shift toward more favorable tumor characteristics was seen for the second round of screening. These results support the screening methods used and the interscreening interval of 4 years.

Objectives: We determined the role of Digital Rectal Examination (DRE) in the follow-up of those patients treated with radical prostatectomy for clinically localised prostate cancer having an undetectable PSA. We discuss the implications of our findings., Materials and Methods: An analysis was performed of a prospectively organised data base of 1118 patients treated at our institution by radical prostatectomy after the introduction of PSA in 1987. A strict definition of PSA progression was used, that is any elevation above undetectable PSA or lowest recorded post-operative PSA (nadir), in order not to miss a single patient who may have recurrent local disease or distant metastases without PSA progression. We counted local recurrent disease as those patients having histologically proven adenocarcinoma on TRUS directed biopsies, and distant disease as those patients having detectable metastatic disease on radionuclide bone scan., Results: The median follow-up was 4.0 years (3 months to 15 years). 524 men (46.9%) had a follow-up of more than 5 years and 88 men (7.9%) of more than 10 years. A total of 397 men (35.5%) had biochemical progression according to our strict definition. 53 patients (4.7%) developed a histological local recurrence and 57 men (5.1%) developed bony metastases; none of these men had an undetectable PSA or a stable PSA at nadir level at the time of detection. They all demonstrated a rising PSA., Conclusions: DRE is no longer necessary in the routine follow-up of patients with an undetectable PSA after radical prostatectomy. Following a period of approximately 2 years of out-patient clinic follow-up post-operatively in which issues such as incontinence and erectile dysfunction are addressed and treated, it is possible to restrict follow-up to PSA determinations alone and as long as the PSA remains undetectable counselling can be carried out by a nurse practitioner.

Although with earlier detection of prostate cancer more men face the long-term consequences of primary treatment, studies on the impact of treatment on long-term health-related quality of life (HRQoL) are scarce. We followed 314 men with newly diagnosed localized prostate cancer from 1 month before until 5 years after radical prostatectomy (n = 127) or external beam radiotherapy (n = 187; median follow-up = 52 months). Questionnaires addressing disease-specific (UCLA PCI) and generic (SF-36, EQ-5D) HRQoL were sent 1 month before and 6, 12 and 52 months after treatment. Repeated-measures modeling was used to study HRQoL over time. Regular urinary leakage was reported by 12% of prostatectomy patients before treatment and by 31% at the 52-month assessment. Erectile dysfunction before treatment was reported by 31% of prostatectomy patients and by 40% of radiotherapy patients; at the 52-month assessment, these percentages were 88% and 64%, respectively. Erectile dysfunction present at 1 year posttreatment can be considered permanent. Prostatectomy patients reported better generic functioning both before and after treatment than radiotherapy patients, who were on average 5.9 years older and had more comorbid conditions. General physical functioning of prostatectomy patients slightly improved over time, but declined in radiotherapy patients. The relation between age and physical scores was found to be nonlinear. The long-term physical decline in radiotherapy patients partly resulted from aging and its nonlinear impact on health, although treatment effects cannot be excluded. Scores of both patient groups remained above those of norm populations. Innovative graphs describing disease-specific and generic functions after treatment can help patients and physicians in their treatment choices., (Copyright 2005 Wiley-Liss, Inc.)

Fibroblast growth factor receptor 3 (FGFR3) and P53 mutations are frequently observed in bladder cancer. We here describe the distribution of FGFR3 mutations and P53 overexpression in 260 primary urothelial cell carcinomas. FGFR3 mutations were observed in 59% and P53 overexpression in 25%. Interestingly, FGFR3 and P53 alterations were mutually exclusive, because they coincided in only 5.7% of tumors. Consequently, we propose that they characterize two alternative genetic pathways in urothelial cell carcinoma pathogenesis. The genetic alterations were reflected in the pathology and the clinical outcome, i.e., FGFR3 mutations were found in low-stage/-grade tumors and were associated with a favorable disease course, whereas P53 alterations were tied to adverse disease parameters.

Objectives: To describe our experience with laparoscopic donor nephrectomy (LDN) and open donor nephrectomy (ODN) regarding ureteral complications. LDN has proved to be safe and to offer significant benefits to the donor compared with ODN. Of major importance is the effect of the surgical technique on the graft. Studies have shown an increased incidence of ureteral complications in recipients of laparoscopically procured kidneys. Operative reconstruction results in additional morbidity for the recipient., Methods: Living donors and their recipients, who underwent surgery from January 1994 to April 2002, were included in this retrospective study. A total of 122 LDN and 77 ODN recipients were included., Results: Of the 122 LDN and 77 ODN recipients, 15 (12%) and 10 (13%), respectively, required percutaneous nephrostomy drainage. In total, 5 LDN (4.1%) and 5 ODN (6.5%) recipients required reconstruction of the ureter because of obstruction of the ureter or urine leakage (P value not statistically significant, excluding reconstruction required for technical errors). The operating time, warm ischemia time, and serum creatinine were comparable between recipients with or without ureter complications requiring reconstruction., Conclusions: In our experience, LDN was not associated with an increased incidence of ureteral complications in the recipient compared with ODN.

Objective: To describe the preliminary results of the Dutch section of a large multicentre study of screening for prostate cancer, the European Randomized study of Screening for Prostate Cancer (ERSPC), initiated in the Netherlands and Belgium in 1991., Materials and Methods: After a series of five pilot studies which started in 1991, full-capacity screening started in 1994 with the use of a serum prostate-specific antigen (PSA) determination, a digital rectal examination (DRE) and transrectal ultrasonography (TRUS) as screening tests. Depending on the results and the screening protocol used, men were referred for further examination by sextant biopsies (extended with a seventh biopsy if TRUS showed abnormality). The protocols used, efficiency of the different screening tests, number of cancers detected in the pilot studies, initial screening round and preliminary results of the second screening round are described., Results: After the pilot studies it became clear that a study of prostate cancer screening was feasible in the Rotterdam area. The screening protocol was workable and the recruitment rate acceptable (39.5%). An inventory of the population registries of Rotterdam and surrounding municipalities, and the known recruitment rate, made it clear that a contribution of 40000 men (aged 55-74 years) from the Dutch centre to the ERSPC was feasible. The initial screening round started in December 1993 and lasted until December 1999 (protocol 5-10). In all, 42376 men were randomized and 1014 cancers detected (5.1%). During this screening the protocol was simplified. After evaluating the different screening tests abnormal results of the DRE and TRUS were omitted as an indication for a sextant biopsy. Only a serum PSA level of > or = 3.0 ng/mL is now used as the indication. The second screening round started in December 1997 and continues. To December 2002, 9920 men were screened for the second time, 4 years after their initial screening visit. To date 446 cancers have been detected (4.5%); this round will last to December 2003. Further evaluation of the screening regimen and characteristics of the cancers detected are constantly assessed within the Dutch ERSPC. Meanwhile a third screening round has also been initiated, which will last to December 2007., Conclusions: A prostate cancer screening study of the projected magnitude is feasible in Rotterdam; the recruitment rate is acceptable and the screening tests well tolerated. The study has generated many scientific publications and will be of great value in determining whether prostate cancer screening should be part of general healthcare.

Testicular germ-cell tumors (TGCTs) of adolescents and adults originate from intratubular germ cell neoplasia (ITGCN), which is composed of the malignant counterparts of embryonal germ cells. ITGCN cells are characterized, among others, by the presence of stem cell factor receptor c-KIT. Once established, ITGCN will always progress to invasiveness. Approximately 2.5-5% of patients with a TGCT will develop bilateral disease and require complete castration, resulting in infertility, a need for lifelong androgen replacement, and psychological stress. To date, the only way to predict a contralateral tumor is surgical biopsy of the contralateral testis to demonstrate ITGCN. We did a retrospective study of 224 unilateral and 61 proven bilateral TGCTs (from 46 patients, in three independently collected series in Europe) for the presence of activating c-KIT codon 816 mutations. A c-KIT codon 816 mutation was found in three unilateral TGCT (1.3%), and in 57 bilateral TGCTs (93%; P < 0.0001). In the two wild-type bilateral tumors for which ITGCN was available, the preinvasive cells contained the mutation. The mutations were somatic in origin and identical in both tumors. We conclude that somatic activating codon 816 c-KIT mutations are associated with development of bilateral TGCT. Detection of c-KIT codon 816 mutations in unilateral TGCT identifies patients at risk for bilateral disease. These patients may undergo tailored treatment to prevent the development of bilateral disease, with retention of testicular hormonal function.

Objective: We aimed at developing and testing a Dutch health-related quality of life measure for localized prostate cancer patients., Methods: Scales on urinary and bowel function and bother from the UCLA Prostate Cancer Index (PCI) underwent formal linguistic and cultural translation. PCI sexual scales were replaced by an existing Dutch sexual activities module (SAc). After qualitative pilot testing 389 patients with localized prostate cancer (mean age 67 +/- 7 years) completed the measure before and at 2 time points after primary treatment. Psychometric properties (feasibility, score distribution, reliability, construct validity and responsiveness to change) of the new instrument were analyzed., Results: Response rates ranged from 93% at baseline to 87% after treatment. Urinary and bowel function scales showed Cronbach's alphas >0.7. Urinary function and bother, and bowel function and bother were significantly correlated. Pre- vs. post-prostatectomy effect sizes were >0.9 only for urinary scales; while pre- vs. post-radiotherapy effect sizes were >0.75 only for bowel scales. Six months after baseline erectile dysfunction was reported by 64% of respondents, either as a problem in sexual activity or as a reason for not being sexually active., Conclusion: The Dutch PCI and SAc performed well in men treated for early stage prostate cancer.

Purpose: Fibroblast growth factor receptor 3 (FGFR3) mutations were recently found at a high frequency in well-differentiated urothelial cell carcinoma (UCC). We investigated the relationship between FGFR3 status and three molecular markers (MIB-1, P53, and P27kip1) associated with worse prognosis and determined the reproducibility of pathologic grade and molecular variables., Patients and Methods: In this multicenter study, we included 286 patients with primary (first diagnosis) UCC. The histologic slides were reviewed. FGFR3 status was examined by polymerase chain reaction-single strand conformation polymorphism and sequencing. Expression levels of MIB-1, P53, and P27kip1 were determined by immunohistochemistry. Mean follow-up was 5.5 years (range, 0.4 to 18.4 years)., Results: FGFR3 mutations were detected in 172 (60%) of 286 UCCs. Grade 1 tumors had an FGFR3 mutation in 88% of patient samples and grade 3 tumors in 16% of patient samples. Conversely, aberrant expression patterns of MIB-1, P53, and P27kip1 were seen in 5%, 2%, and 3% of grade 1 tumors and in 85%, 60%, and 56% of grade 3 tumors, respectively. In multivariate analysis with recurrence rate, progression, and disease-specific survival as end points, the combination of FGFR3 and MIB-1 proved independently significant in all three cases. By using these two molecular markers, three molecular grades (mGs) could be identified: mG1 (mutation; normal expression), favorable prognosis; mG2 (two remaining combinations), intermediate prognosis; and mG3 (no mutation; high expression), poor prognosis. The molecular variables were more reproducible than pathologic grade (85% to 100% v 47% to 61%)., Conclusion: The FGFR3 mutation represents the favorable molecular pathway of UCC. Molecular grading provides a new, simple, and highly reproducible tool for clinical decision making in UCC patients.

Objectives: The interpretation of cystoscopy and cytology may be troublesome in bladder cancer patients previously treated by radiotherapy. We evaluated polymerase chain reaction (PCR)-based molecular cytology by microsatellite analysis (MA) and routine urine cytology (RUC) and expert urine cytology (EUC) as modes of surveillance for patients previously treated by radiotherapy with curative intent., Methods: Eighty-one voided urine samples were obtained from 49 patients prior to cystoscopy and subjected to MA, RUC and EUC., Results: During the follow-up period, six patients developed a recurrence. Sensitivity of MA, RUC and EUC was 83%, 50% and 33%, respectively. The specificity of MA, RUC and EUC was 93%, 85% and 97%, respectively. Cystoscopy was positive in 15 cases. Therefore, the positive predictive value of cystoscopy remained limited to 40%., Conclusions: Next to recent studies demonstrating a high accuracy for MA in non-irradiated patients, our results indicate that molecular cytology by MA may also be a useful tool to improve the surveillance of bladder cancer patients previously treated by radiotherapy.

Purpose: Fibroblast growth factor receptor 3 (FGFR3) mutations were reported recently at a high frequency in low-grade urothelial cell carcinoma (UCC). We investigated the feasibility of combining microsatellite analysis (MA) and the FGFR3 status for the detection of UCC in voided urine., Experimental Design: In a prospective setting, 59 UCC tissues and matched urine samples were obtained, and subjected to MA (23 markers) and FGFR3 mutation analysis (exons 7, 10, and 15). In each case, a clinical record with tumor and urine features was provided. Fifteen patients with a negative cystoscopy during follow-up served as controls., Results: A mutation in the FGFR3 gene was found in 26 (44%) UCCs of which 22 concerned solitary pTaG1/2 lesions. These mutations were absent in the 15 G3 tumors. For the 6 cases with leukocyturia, 46 microsatellite alterations were found in the tumor. Only 1 of these was also detected in the urine. This was 125 of 357 for the 53 cases without leukocyte contamination. The sensitivity of MA on voided urine was lower for FGFR3-positive UCC (15 of 21; 71%) as compared with FGFR3 wild-type UCC (29 of 32; 91%). By including the FGFR3 mutation, the sensitivity of molecular cytology increased to 89% and was superior to the sensitivity of morphological cytology (25%) for every clinical subdivision. The specificity was 14 of 15 (93%) for the two (molecular and morphological) cytological approaches., Conclusions: Molecular urine cytology by MA and FGFR3 mutation analysis enables a highly sensitive and specific detection of UCC. The similarity of molecular profiles in tumor and urine corroborate their clonal relation.

Objectives: To evaluate the complication rates and possible risk factors of biopsy of the prostate, with the aim of improving patient counseling and the safety of the procedure. Biopsy of the prostate has to be a relatively safe procedure and the participants have to be well informed about the possible complications., Methods: Within the biopsy protocol of the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer, we evaluated 5802 transrectal ultrasound-guided systematic sextant biopsies. All participants received prophylactic antibiotic therapy., Results: We performed 5802 biopsies. Hematuria lasting longer than 3 days and hematospermia were present after 22.6% and 50.4% of the procedures, respectively. More severe complications were far less frequent. Two hundred participants (3.5%) developed fever after biopsy. Urinary retention was seen 20 times (0.4%), and hospitalization was needed in 27 cases (0.5%). Twenty-five of these men were admitted because of signs of prostatitis and/or urosepsis. Risk factor analyses revealed that an earlier episode of prostatitis was significantly associated with hospital admission and pain after biopsy. Characteristics of prostatic hyperplasia, such as prostate volume, transition zone volume/total prostate volume ratio, and a higher International Prostate Symptom Score, were all predictors of urinary retention., Conclusions: Minor complications are frequently seen but major complications are rare after prostate biopsy. Assessment of the risk factors before biopsy can help to improve the adequacy of counseling, and precautionary measures can be taken to minimize the risk of complications after the procedure. Transrectal ultrasound-guided sextant biopsy remains a safe procedure for the diagnosis of prostate cancer within the general population.

Background: It has been shown that microsatellite analysis (MA) is able to detect bladder carcinoma in urine. Relatively small groups of patients often with high stage and grade disease were investigated. However, greater than 85% of cystoscopies are performed for follow-up of superficial bladder carcinoma. The authors evaluated this DNA-based method in a group of consecutive patients in follow-up after transurethral resection of superficial disease., Methods: Matched blood and urine samples from 109 patients were obtained before cystoscopy and subjected to MA. The BTA stat test (Bard Diagnostic Sciences, Inc., Redmond, WA) and cytology were used for comparison., Results: Sixteen patients were excluded: the DNA was of insufficient quality for 7 patients and leukocyte abundance rendered the result of MA unreliable for 9 patients. For the remaining 93 patients, MA detected 18 of the 24 recurrent tumors. The six undetected tumors were small pTaG1 lesions for which immediate surgery was not necessary. Conversely, 5 of 9 patients with a positive MA and a negative cystoscopy had a tumor recurrence within 6 months after urine collection. In contrast, a recurrence occurred in only 7 of 60 patients who were negative in both MA and cystoscopy (P = 0.006). The MA (74%) appeared more sensitive than the BTA stat test (56%) or urine cytology (22%)., Conclusions: Microsatellite analysis is a DNA test in urine that reliably signals the presence of recurrent bladder carcinoma, sometimes even before cystoscopic evidence of the disease. This noninvasive diagnostic tool has the potential to replace cystoscopy in many cases. The authors' results warrant the need for randomized trials., (Copyright 2001 American Cancer Society.)

Purpose: We ascertain the incidence, management and long-term outcome of early urological complications requiring surgical exploration in kidney transplantation., Materials and Methods: Data of 695 consecutive kidney transplantations performed between January 1985 and January 1997 were assessed in regard to urological complications that occurred within 1 year after transplant. A computerized database was used to analyze graft recipient characteristics, the implantation procedure, complications and outcome in select patients and all those who underwent transplant during the same period. In the noncomplication group sufficient data for evaluation was available for 556 patients. We performed the Cox proportional hazards analysis with overall graft failure, graft failure or death as end points of observation., Results: Overall, 42 (6.0%) patients required revision of vesicoureteral anastomosis. Complications were identified after a median of 6 days (range 0 to 135). The primary reconstruction technique was extravesical in 64% and transvesical in 33% of patients, including 1 that involved ureteral Bricker anastomosis. Obstruction and/or leakage at vesicoureteral anastomosis accounted for 69% of urological complications. Revision was performed with a number of different reconstruction techniques. A second revision was required in 16.7%. Mean followup after primary transplant was 9.1 years (range 3.2 to 15). Multivariate analysis showed that surgical treatment of urological complication during year 1 after kidney transplantation did not increase the risk of overall graft failure, graft failure or death., Conclusions: Our results indicate that long-term graft survival is not affected by a surgically treated urological complication.

Purpose: The current study was undertaken within the framework of a screening trial to compare the health-related quality-of-life (HRQOL) outcomes of two primary treatment modalities for localized prostate cancer: radical prostatectomy and external-beam radiotherapy., Patients and Methods: We conducted a prospective longitudinal cohort study among 278 patients with early screen-detected (59%) or clinically diagnosed (41%) prostate cancer using both generic and disease-specific HRQOL measures (SF-36, UCLA Prostate Cancer Index [urinary and bowel modules] and items relating to sexual functioning) at three points in time: t1 (baseline), t2 (6 months later), and t3 (12 months after t1)., Results: Questionnaires were completed by 88% to 93% of all initially enrolled patients. Patients referred for primary radiotherapy were significantly older than prostatectomy patients (63 v 68 years, P <.01). Analyses (adjusted for age and pretreatment level of functioning) revealed poorer levels of generic HRQOL after radiotherapy. Prostatectomy patients reported significantly higher (P <.01) posttreatment incidences of urinary incontinence (39% to 49%) and erectile dysfunction (80% to 91%) than radiotherapy patients (respectively, 6% to 7% and 41% to 55%). Bowel problems (urgency) affected 30% to 35% of the radiotherapy group versus 6% to 7% of the prostatectomy group (P <.01). Patients with screen-detected and clinically diagnosed cancer reported similar posttreatment HRQOL., Conclusion: Prostatectomy and radiotherapy differed in the type of HRQOL impairment. Because the HRQOL effects may be valued differently at the individual level, patients should be made fully aware of the potential benefits and adverse consequences of therapies for early prostate cancer. Differences in posttreatment HRQOL were not related to the method of cancer detection.

We analyzed the possible prognostic value of the recently discovered fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer. A FGFR3 mutation was found in 34 of 53 pTaG1-2 bladder cancers, whereas none of the 19 higher-staged tumors had a mutation (P < 0.0001). In 57 patients with superficial disease followed prospectively by cystoscopy for 12 months, 14 of 23 patients in the wild-type FGFR3 group developed recurrent bladder cancer compared with only 7 of 34 patients in the mutant group (P = 0.004). The recurrence rate per year was 0.24 for the FGFR3 mutant tumors and 1.12 for tumors with a wild-type FGFR3 gene. In addition, FGFR3 mutation status was the strongest predictor of recurrence when compared with stage and grade (P = 0.008). This is the first mutation in bladder cancer that selectively identifies patients with favorable disease characteristics. Our results suggest that the frequency of cystoscopic examinations can be reduced considerably in patients with FGFR3-positive tumors.

Background: The purpose of this study was to evaluate baseline health-related quality of life (HRQOL) in patients with localized prostate cancer before primary treatment (radical prostatectomy or radiotherapy)., Methods: Two hundred patients with newly diagnosed localized (screen-detected or clinically diagnosed) prostate cancer completed HRQOL questionnaires (generic and disease-specific measures). Clinical data were collected from patients' medical records in four Rotterdam hospitals., Results: Screen-detected tumors were of more favorable stages and grades than clinically diagnosed ones. The diagnostic groups did not differ significantly in bowel and sexual functioning. Differences were found in urinary functioning, favoring patients with screen-detected tumors of T2-T3 stages. Patients with screen-detected T2 cancer reported better generic HRQOL (physical aspects) than the clinical group, but HRQOL of the latter group was similar to the population norm. Radiotherapy patients were significantly older and had more comorbidity than subjects referred to prostatectomy. Urinary, bowel, and sexual problems were uncommon. Older (> 65 years) radiotherapy patients appeared to be less sexually active. Radiotherapy patients also reported poorer levels of generic HRQOL., Conclusions: Screen-detected prostate cancer patients presented with more favorable cancer stage and grade. HRQOL was related to both the tumor stage and the detection method. Pre-treatment HRQOL differences between prostatectomy and radiotherapy patients were associated neither with tumor characteristics nor with the detection method. Baseline differences in HRQOL should be taken into account when evaluating post-treatment HRQOL., (Copyright 2001 Wiley-Liss, Inc.)

Background: The aims of this study were to investigate the motives for refusing or attending population-based screening for prostate cancer, in relation to various background characteristics., Methods: The present study is part of the European Randomized Study of Screening for Prostate Cancer (ERSPC), and took place in 1995-1996. Men aged 55-75 years were invited using the Rotterdam population registry (100 per cent coverage), of whom 42 per cent gave written informed consent. These men were randomized to receive either determination of prostate specific antigen (PSA), digital rectal examination (DRE), transrectal ultrasound (TRUS) and biopsy on indication (screening group), or no screening (control group). To 626 consecutive men of the screening group a questionnaire was sent before the screening. To 500 randomly selected refusers (no written informed consent) a similar questionnaire was sent, followed by two reminders. In both refusers and attenders we addressed motives, knowledge of prostate cancer, attitudes towards screening, background characteristics and urological complaints (American Urological Association symptom index, AUA7)., Results: Response rates for questionnaires were 48 per cent in refusers and 99 per cent in attenders. Main reported motives for refusing were absence of urological complaints (57 per cent) and anticipated pain or discomfort (18 per cent). Main reported motives for attending were personal benefit (82 per cent), contribution to science (49 per cent) and presence of urological complaints (25 per cent). Compared with attenders, refusers were slightly and significantly older, less often married and had a lower level of education; they had less knowledge about prostate cancer and a less positive attitude towards screening; they had worse general health but fewer urological complaints (AUA7 median 2 versus 4, p < 0.001)., Conclusion: In refusing or attending population-based prostate cancer screening, urological complaints but also knowledge, attitudes and sociodemographic factors seem to play a role. Therefore, the approach of the general population should be carefully considered.