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Pim Brandenbarg,1 Puk Rooijers,1 Martijn G Steffens,2 Michael R van Balken,3 Henk-Jan Mulder,4 Marco H Blanker1 1University of Groningen, University Medical Centre Groningen, Department of General Practice & Elderly Care Medicine, Groningen, The Netherlands; 2Isala Clinics, Department of Urology, Zwolle, The Netherlands; 3Rijnstate Hospital, Department of Urology, Arnhem, The Netherlands; 4Martini Hospital, Department of Urology, Groningen, The NetherlandsCorrespondence: Marco H BlankerUniversity of Groningen, University Medical Centre Groningen, Department of General Practice & Elderly Care Medicine, Groningen, The NetherlandsTel +31 50 361 6729Email m.h.blanker@umcg.nlPurpose: To identify the expectations of men with LUTS referred to a urologist and to study the association between those expectations and satisfaction with the care provided.Methods: In this prospective cohort study, adult men with LUTS completed a questionnaire before their first outpatient appointment, and again at 6 and 12 weeks. The questionnaires included IPSS and OABq-SF, and self-constructed questions on patient expectations, outcome of expectations and satisfaction.Results: Data from 182 participants showed positive expectations about the urologist performing examinations, providing explanations and finding the underlying cause, but mostly neutral expectations for treatment plans and outcomes. Positive treatment expectations were associated with positive expectations about outcomes after physiotherapy, drug treatment and surgery. Higher symptom scores and age were associated with higher expectations about drug treatment. Expectations were subjectively and objectively fulfilled for 66.4% and 27.3%, respectively. Symptom improvement (decrease in IPSS scores) was significantly more in men with objectively fulfilled expectations than in men with no unfulfilled expectations. No significant difference was present between men with subjectively fulfilled expectations and men with unfulfilled expectations. However, satisfaction was significantly higher for patients with subjectively fulfilled expectations at 6 and 12 weeks compared with those who had unfulfilled expectations.Conclusion: Most men referred to a urologist with LUTS do express clear expectations about treatment in secondary care. Patients with higher expectations for treatment outcomes are more likely to expect to receive that treatment. Satisfaction with the care of a urologist is also higher when patients self-report that they receive the treatment they expected.Keywords: lower urinary tract symptoms, LUTS, expectations, satisfaction, urologist

Background: In the Netherlands, parents of children with daytime urinary incontinence (UI) first consult general practitioners (GPs). However, GPs need more specific guidelines for daytime UI management, resulting in care and referral decisions being made without clear guidance., Objectives: We aimed to identify Dutch GP considerations when treating and referring a child with daytime UI., Methods: We invited GPs who referred at least one child aged 4-18 years with daytime UI to secondary care. They were asked to complete a questionnaire about the referred child and the management of daytime UI in general., Results: Of 244 distributed questionnaires, 118 (48.4%) were returned by 94 GPs. Most reported taking a history and performing basic diagnostic tests like urine tests (61.0%) and physical examinations (49.2%) before referral. Treatment mostly involved lifestyle advice, with only 17.8% starting medication. Referrals were usually at the explicit wish of the child/parent (44.9%) or because of symptom persistence despite treatment (39.0%). GPs usually referred children to a paediatrician ( n  = 99, 83.9%), only referring to a urologist in specific situations. Almost half (41.4%) of the GPs did not feel competent to treat children with daytime UI and more than half (55.7%) wanted a clinical practice guideline. In the discussion, we explore the generalisability of our findings to other countries., Conclusion: GPs usually refer children with daytime UI to a paediatrician after a basic diagnostic assessment, usually without offering treatment. Parental or child demand is the primary stimulus for referral.

Objective: To review the effect of bladder outlet procedures on urodynamic outcomes and symptom scores in males with detrusor underactivity (DU) or acontractile detrusors (AD)., Materials and Methods: We performed a systematic review and meta-analysis of research publications derived from PubMed, Embase, Web of Science, and Ovid Medline to identify clinical studies of adult men with non-neurogenic DU or AD who underwent any bladder outlet procedure. Outcomes comprised the detrusor pressure at maximum flow (P det Q max ), maximum flow rate (Q max ), international prostate symptom score (IPSS), and quality of life (QoL). This study is registered under PROSPERO CRD42020215832., Results: We included 13 studies of bladder outlet procedures, of which 6 reported decreased and 7 reported improved P det Q max after the procedure. Meta-analysis revealed an increase in the pooled mean P det Q max of 5.99 cmH 2 0 after surgery (95% CI: 0.59-11.40; p = 0.03; I 2 95%). Notably, the P det Q max improved in all subgroups with a preoperative bladder contractility index (BCI) <50 and decreased in all subgroups with a BCI ≥50. All studies reported an improved Q max after surgery, with a pooled mean difference of 5.87 mL/s (95% CI: 4.25-7.49; I 2 93%). Only three studies reported QoL, but pooling suggested significant improvements after surgery (mean, -2.41 points; 95% CI: -2.81 to -2.01; p = 0.007). All seven studies reporting IPSS demonstrated improvement (mean, -12.82; 95% CI: -14.76 to -10.88; p < 0.001)., Conclusions: This review shows that P det Q max and Q max increases after surgical bladder outlet procedures in men with DU and AD. Bladder outlet procedures should be discussed as part of the shared decision-making process for this group. The evidence was of low to very low certainty., (© 2023 The Authors. Neurourology and Urodynamics published by Wiley Periodicals LLC.)

Introduction and Hypothesis: Patients with recurrent urinary tract infection (rUTI) have limited knowledge of preventive strategies to lower the risk of UTI. We aimed to develop and test the feasibility of an eHealth system for women with rUTI, named myRUTIcoach, and explored the facilitators and barriers related to its adoption., Methods: We developed myRUTIcoach in a structured iterative process and tested its feasibility among 25 women with rUTI over 2 months. Subsequent questionnaires covered satisfaction, accessibility, and experiences with myRUTIcoach. A random selection of participants and relevant stakeholders took part in semi-structured interviews to explore adoption. Data were analyzed and elaborated using inductive and deductive approaches using the Non-adoption, Abandonment, Spread, Scale-up, and Sustainability (NASSS) framework., Results: MyRUTIcoach was not only widely accepted but also facilitated communication with health care professionals (HCPs) and contributed to greater knowledge of rUTI. Women graded the system a mean of 8.0 (±0.6) out of 10, with 89% stating that they would recommend it to others. Patients indicated that self-management skills were the major facilitators and barriers related to adoption, whereas HCPs stated that the disconnect between myRUTIcoach and electronic health care records (EHRs) was the major barrier., Conclusions: This research describes the development and testing of myRUTIcoach for women with rUTI. Patients and HCPs reported high satisfaction and compliance with myRUTIcoach. However, adoption by the intended users is complex and influenced by all examined domains of the NASSS framework. We have already improved linkage to EHRs, but further optimization to meet patient needs may improve the effectiveness of this self-management tool for rUTI., (© 2023. The Author(s).)

Background: An increase in infections after transrectal prostate biopsy (PB), related to an increasing number of patients with ciprofloxacin-resistant rectal flora, necessitates the exploration of alternatives for the traditionally used empirical prophylaxis of ciprofloxacin. We compared infectious complication rates after transrectal PB using empirical ciprofloxacin prophylaxis versus culture-based prophylaxis., Methods: In this nonblinded, randomized trial, between 4 April 2018 and 30 July 2021, we enrolled 1538 patients from 11 Dutch hospitals undergoing transrectal PB. After rectal swab collection, patients were randomized 1:1 to receive empirical prophylaxis with oral ciprofloxacin (control group [CG]) or culture-based prophylaxis (intervention group [IG]). Primary outcome was any infectious complication within 7 days after biopsy. Secondary outcomes were infectious complications within 30 days, and bacteremia and bacteriuria within 7 and 30 days postbiopsy. For primary outcome analysis, the χ2 test stratified for hospitals was used. Trial registration number: NCT03228108., Results: Data from 1288 patients (83.7%) were available for analysis (CG, 652; IG, 636). Infection rates within 7 days postbiopsy were 4.3% (n = 28) (CG) and 2.5% (n = 16) (IG) (P value = .08; reduction: -1.8%; 95% confidence interval, -.004 to .040). Ciprofloxacin-resistant bacteria were detected in 15.2% (n = 1288). In the CG, the presence of ciprofloxacin-resistant rectal flora resulted in a 6.2-fold higher risk of early postbiopsy infection., Conclusions: Our study supports the use of culture-based prophylaxis to reduce infectious complications after transrectal PB. Despite adequate prophylaxis, postbiopsy infections can still occur. Therefore, culture-based prophylaxis must be weighed against other strategies that could reduce postbiopsy infections. Clinical Trials Registration. NCT03228108., Competing Interests: Potential conflicts of interest. D. M. S. reports grants or contracts from Besins and Astellas; payment for expert testimony from Bayer, Janssen, and MSD; a leadership or fiduciary role with the Dutch Urological Association; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Samantree and Besins. The other authors reported no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Culture-based antibiotic prophylaxis is a plausible strategy to reduce infections after transrectal prostate biopsy (PB) related to fluoroquinolone-resistant pathogens., Objective: To assess the cost effectiveness of rectal culture-based prophylaxis compared with empirical ciprofloxacin prophylaxis., Design Setting and Participants: The study was performed alongside a trial in 11 Dutch hospitals investigating the effectiveness of culture-based prophylaxis in transrectal PB between April 2018 and July 2021 (trial registration number: NCT03228108)., Intervention: Patients were 1:1 randomized for empirical ciprofloxacin prophylaxis (oral) or culture-based prophylaxis. Costs for both prophylactic strategies were determined for two scenarios: (1) all infectious complications within 7 d after biopsy and (2) culture-proven Gram-negative infections within 30 d after biopsy., Outcome Measurements and Statistical Analysis: Differences in costs and effects (quality-adjusted life-years [QALYs]) were analyzed from a healthcare and societal perspective (including productivity losses, and travel and parking costs) using a bootstrap procedure presenting uncertainty surrounding the incremental cost-effectiveness ratio in a cost-effectiveness plane and acceptability curve., Results and Limitations: For the 7-d follow-up period, culture-based prophylaxis ( n  = 636) was €51.57 (95% confidence interval [CI] 6.52-96.63) more expensive from a healthcare perspective and €16.95 (95% CI -54.29 to 88.18) from a societal perspective than empirical ciprofloxacin prophylaxis ( n  = 652). Ciprofloxacin-resistant bacteria were detected in 15.4%. Extrapolating our data, from a healthcare perspective, 40% ciprofloxacin resistance would lead to equal cost for both strategies. Results were similar for the 30-d follow-up period. No significant differences in QALYs were observed., Conclusions: Our results should be interpreted in the context of local ciprofloxacin resistance rates. In our setting, from a healthcare perspective, culture-based prophylaxis was significantly more expensive than empirical ciprofloxacin prophylaxis. From a societal perspective, culture-based prophylaxis was somewhat more cost effective against the threshold value customary for the Netherlands (€80.000)., Patient Summary: Culture-based prophylaxis in transrectal prostate biopsy was not associated with reduced costs compared with empirical ciprofloxacin prophylaxis., (© 2023 The Author(s).)

Children with a solitary functioning kidney (SFK) have an increased risk of kidney injury. The exact risk of and risk factors for kidney injury remain unknown, which impedes personalized care. Here, we recruited a nationwide multicenter cohort of 944 patients with SFK to get more insight into this by consenting patients born in 1993-2020 and diagnosed with congenital or acquired SFK before adulthood. The median follow-up was 12.8 years and four indications of kidney injury were studied: urine protein-creatinine ratios, blood pressure, estimated glomerular filtration rate and use of anti-hypertensive/proteinuric medication. For each indicator except medication use, separate cut-off values for any injury and severe injury were used. Survival analyses indicated that at 18 years of age, any or severe kidney injury were present in 75% and 39% of patients with congenital SFK, respectively. Risk factors for kidney injury included kidney agenesis as cause of the SFK, anomalies in the SFK, and high body mass index at last follow-up. Kidney agenesis and being overweight were specifically associated with proteinuria and high blood pressure, whereas anomalies in the SFK were associated with reduced estimated glomerular filtration rates. The high prevalence of kidney injury in patients with SFK emphasizes the need for long-term follow-up, in which lifestyle is an important topic to address. More research into the etiological role of risk factors will help to translate our findings into individualized care strategies. Thus, our study shows that a significant proportion of children with SFK will develop kidney injury over time., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: It remains uncertain whether transrectal ultrasound (TRUS)-guided systematic biopsies can be omitted and rely solely on multiparametric magnetic resonance imaging-targeted biopsies (MRI-TBx) in biopsy-naïve men suspected of prostate cancer (PCa)., Objective: To compare PCa detection in biopsy-naïve men between systematic biopsy and MRI-TBx., Design Setting and Participants: A prospective cohort study was conducted in a Dutch teaching hospital. Consecutive patients with suspected PCa, no history of biopsy, and no clinical suspicion of metastasis underwent both TRUS-guided systematic biopsies and MRI-TBx by multiparametric magnetic resonance imaging (mpMRI)-ultrasound fusion, including sham biopsies in case of negative mpMRI., Outcome Measurements and Statistical Analysis: Clinically significant PCa (csPCa), defined as group ≥2 on the International Society of Urological Pathology grading, was detected., Results and Limitations: The overall prevalence of csPCa, irrespective of biopsy technique, was 37.4% (132/353) in our population. MRI-TBx were performed in 263/353 (74.5%) patients with suspicious mpMRI (Prostate Imaging Reporting and Data System [PI-RADS] ≥3). The detection rates for csPCa were 39.5% for MRI-TBx and 42.9% for systematic biopsies. The added values, defined as the additional percentages of patients with csPCa detected by adding one biopsy technique, were 8.7% for the systematic biopsies and 5.3% for MRI-TBx. In patients with nonsuspicious mpMRI, five cases (6%) of csPCa were found by systematic biopsies., Conclusions: This study in biopsy-naïve patients suspected for PCa showed that systematic biopsies have added value to MRI-TBx alone in patients with mpMRI PI-RADS >2., Patient Summary: We studied magnetic resonance imaging (MRI)-guided prostate biopsy for diagnosing prostate cancer and compared it with the standard method of prostate biopsy. Standard systematic biopsies cannot be omitted in patients with suspicious MRI, as they add to the detection of significant prostate cancer., (© 2022 The Authors.)

Objective: To explore the treatment options for chronic urinary retention (CUR) in men, including treatment-related complications and consequences., Methods: This retrospective cohort study included male patients diagnosed with a non-neurogenic, symptomatic and/or high-risk, CUR >150 mL in a large Dutch non-academic teaching hospital. Data for treatments, complications, and consequences (eg, diagnostics, additional treatments, and hospital contact) were recorded and incidence rate ratios (IRRs) were calculated., Results: We enrolled 177 patients (median age, 77 years; range, 44-94) with a median follow-up of 68 months (range, 1-319) during which they had a median of 8 events (range, 1-51). Most patients initially received a urethral catheter (74%) and some form of catheterization as their final treatment (87%). Compared with non-surgical cases, catheterization was more likely to be stopped after de-obstructive prostate surgery (IRR, 4.18; P < 0.001). Urinary tract infection (IRR, 3.68; P < 0.001) and macroscopic hematuria (IRR, 5.35; P < 0.001) were more common with catheterization, but post-renal problems were more likely in patients with no catheterization (IRR, 25.36; P < 0.001). The lowest chance of complication was with clean intermittent catheterization, and complications were usually managed in outpatient (77%) or emergency (6%) departments, rather than by admission (17%)., Conclusion: Most patients require catheterization for CUR, with clean intermittent catheterization preferred due to its comparatively lower complication risk. De-obstructive prostate surgery increases the chance of stopping catheterization and may be considered in suitable cases., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction and Hypothesis: To quantify and compare the outcomes of routine vs. urologist-requested diagnostic testing for recurrent urinary tract infections (rUTI)., Methods: A retrospective cohort study of patients with rUTI referred to a large non-academic teaching hospital between 2016 and 2018 (Hospital A) and a university hospital between 2014 and 2016 (Hospital B). Electronic medical records were reviewed for baseline and diagnostic data. Women underwent the following assessments routinely: urinalysis, voiding diary, flowmetry in Hospital A and urinalysis, voiding diary, flowmetry, ultrasound, abdominal x-ray and cystoscopy in Hospital B. All other diagnostics were performed by indication in each hospital., Results: We included 295 women from Hospital A and 298 from Hospital B, among whom the mean age (57.6 years) and mean UTI frequency (5.6/year) were comparable, though more were postmenopausal in Hospital A. We identified abnormalities by flowmetry or post-void residual volumes in 134 patients (Hospital A: 79; Hospital B: 55), cystoscopy in 14 patients (Hospital A: 6; Hospital B: 8) and ultrasound in 42 patients (Hospital A: 16; Hospital B: 26), but these differences were not significant. Diagnostics altered treatment in 117 patients (e.g., pelvic floor muscle training, referral to another specialist, surgical intervention), mostly due to flowmetry and post-void residual volume measurement. The retrospective design and absence of follow-up data limit these results., Conclusions: The routine use of cystoscopy and ultrasound in female patients with rUTIs should not be recommended as they yield few abnormalities and lead to additional costs., (© 2021. The Author(s).)

Introduction and Hypothesis: Recommendations for preventing and diagnosing recurrent urinary tract infection (UTI) tend to vary between clinical practice guidelines (CPGs) because of low-quality scientific evidence, potentially leading to practice variation and suboptimal care. We assessed the quality of existing CPGs for recurrent UTI., Methods: A systematic search was performed from January 2000 to June 2021 in PubMed and EMBASE for CPGs on recurrent UTI prevention or hospital diagnostics in Dutch, English, and Spanish. Each CPG was assessed by four appraisers in a multidisciplinary review team, using the Appraisal of Guidelines, Research, and Evaluation II (AGREE II) instrument., Results: We identified and assessed eight CPGs published between 2013 and 2021. The scope and purpose (mean and standard deviation: 67.3 ± 21.8) and clarity of presentation (74.8 ± 17.6) domains scored highly. However, issues with methods, patient participation, conflict of interests, and facilitators and barriers were common and resulted in lower scores for the rigour of development (56.9 ± 25.9), applicability (19.6 ± 23.4), stakeholder involvement (50.4 ± 24.6), and editorial independence (62.1 ± 23.1) domains. Overall, two CPGs were recommended, three were recommended with modifications, and three were not recommended., Conclusions: Significant room for improvement exists in the quality of CPGs for recurrent UTI, with most displaying serious limitations in the stakeholder involvement, rigour of development, and applicability domains. These aspects must be improved to decrease diagnostic and therapeutic uncertainty. Developers could benefit from using checklists and following guidelines when developing de novo CPGs., (© 2022. The Author(s).)

A 47-year-old man received a snouted cobra ( Naja annulifera ) snake bite to his genitals while on holiday in South Africa. His penis and scrotum were noted to be swollen, deep purple in color, and painful on hospital admission. Scrotal necrosis was diagnosed, and he received multiple doses of a non-specific snake venom antiserum and broad-spectrum antibiotics. Although no neurological sequelae developed, he did require hemodialysis due to acute kidney injury. After stabilizing, he was repatriated to the Netherlands for further treatment and has since made a full recovery., (© 2021 Published by Elsevier Inc.)

Introduction: Daytime urinary incontinence (UI) can have an enormous impact on a child's life, lowering both self-esteem and quality of life. Although most children start therapy after their first visit to our outpatient clinic, no studies have reported on parents' or patients' expectations of care for daytime UI in this setting., Objective: We aimed to explore the expectations of the parents of children referred to an outpatient clinic for daytime UI., Study Design: This was a qualitative study that involved performing semi-structured interviews with the parents of children who had been referred for daytime UI (with or without nocturnal enuresis). Interviews took place between July 2018 and October 2018 and continued until saturation was reached. The results were transcribed verbatim and analyzed according to Giorgi's strategy of phenomenological data analysis., Results: Nine parents of children, aged 5-12 years old, were interviewed, revealing "(Experienced) Health," Self-management," and "Social Impact" as the main themes that influenced parental expectations. All parents wanted to know if there was a medical explanation for UI, some were satisfied when diagnostics revealed no underlying condition, and others wanted treatment. Parents expressed no preferences about diagnostics or the content and duration of treatment, but they hoped that any previously attempted ineffective steps would not be repeated. Some parents defined treatment success as their child becoming completely dry, but most stated that learning coping strategies was more important., Discussion: This is the first study to explore the expectations of parents when attending outpatient care for children with daytime UI. We employed a strong theoretical framework with a clear interview guide. The main limitations are that we only interviewed parents and that this was a qualitative study, precluding the drawing of firm conclusions. Nevertheless, our results point to the need for quantitative evaluation., Conclusion: Expectations seem to be influenced by (experienced) health, efforts at self-management, and the social impact of UI, making it critical that these themes are addressed. It was interesting to note that parents do not always attend outpatient departments with the goal of completely resolving daytime UI. Instead, some only want to know if there is an underlying medical condition or want to reduce the social impact by learning coping mechanisms. Excluding underlying medical conditions may therefore stimulate acceptance of watchful waiting without the need to start treatment., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: To develop a questionnaire to facilitate the inventorying of women's expectations for the assessment and treatment of recurrent urinary tract infection (UTI) in secondary care., Methods: Semi-structured interviews were conducted among women with recurrent UTI referred to our urology department. The interviews were conducted by one interviewer, recorded, transcribed verbatim, and analyzed thematically by two researchers. We first developed 35 questions to identify potential themes, and we then tested them among women with and without recurrent UTI. Changes were made according to the feedback received., Results: Six interviews were conducted before saturation was reached. Thematic analysis identified three themes: patient pathway, personal knowledge, and social implications. All respondents had received multiple antibiotic courses but no prophylactic antibiotic therapy, and although all were aware of some preventive measures, they wanted more information about their disease. However, some women were afraid to access information for fear of what they might learn. Recurrent UTI also significantly affected the daily lives all respondents. Some women expressed fears over frequent antibiotic use, and others felt that there must be something wrong with their body to have so many UTIs. Women expected the urologist to provide an explanation and to start adequate therapy for their recurrent UTI. We created a 32-item questionnaire based on these themes CONCLUSION: This study not only developed a questionnaire for use when assessing patient expectations of recurrent UTI management in secondary care but also provided novel insights into the thoughts, opinions, and expectations of women who are referred.

Objectives: To determine the minimal important difference (MID) of the International Prostate Symptom Score (IPSS) and the Overactive Bladder Questionnaire short form (OAB-q SF) assessed in primary care among patients treated for lower urinary tract symptoms (LUTS)., Design: Single-arm, open-label observational cohort study with a 6-week follow-up., Setting: Twenty-two pharmacies in the Netherlands., Participants: We enrolled Dutch men with uncomplicated LUTS who received a new alpha-blocker prescription from their general practitioner or urologist., Primary and Secondary Outcomes: The IPSS and OAB-q SF were completed before and after 6 weeks of therapy. At 6 weeks, men also completed the Patient Global Impression of Improvement (PGI-I). The mean change scores of the IPSS and OAB-q SF were calculated for each PGI-I outcome category, with the category 'a little better' used to determine the MID. The SE of measurement (SEM) was calculated for each questionnaire., Results: In total, 165 men completed follow-up. The MID was 5.2 points (95% CI 3.9 to 6.4; SEM 3.6) for the IPSS and 11.0 points (95% CI 7.1 to 14.9; SEM 9.7) for the OAB-q SF. For both questionnaires, CIs showed an overlap with the no-change categories. However, the MID for the IPSS was higher in men with severe baseline symptoms (7.1; 95% CI 5.3 to 9.0) than in men with moderate baseline symptoms (3.2; 95% CI 1.7 to 4.8)., Conclusion: In this study, the MID for the IPSS was considerably higher than the MID of 3.1 reported in the only other study on this topic, but may be due to methodological differences. Interpretation of the MID for the OAB-q SF is hampered by the overlap with the SEM. Future studies are needed to confirm our results because correlations between the PGI-I and symptom questionnaires were suboptimal., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Objectives: We aimed to synthesise the available data for the effect of stopping alpha-blocker therapy among men with lower urinary tract symptoms. The focus was on symptom, uroflowmetry and quality of life outcomes, but we also reviewed the adverse events (AEs) and the number of patients who restarted therapy., Data Sources: We searched MEDLINE/PubMed, EMBASE/Ovid and The Cochrane Central Register of Controlled Trials from inception to May 2018., Eligibility Criteria: We selected studies regardless of study design in which men were treated with an alpha-blocker for at least 3 months and in which the effects of alpha-blocker discontinuation were subsequently studied. Only controlled trials were used for the primary objective., Data Extraction and Synthesis: Two reviewers independently extracted data and assessed the risk of bias for the controlled studies only using the Cochrane Collaboration's tool for assessing risk of bias. Data were pooled using random-effects meta-analyses., Results: We identified 10 studies (1081 participants) assessing the primary objective. Six studies (733 participants) assessed differences in AEs between continuation and discontinuation, and six studies (501 participants) reported the numbers of subjects that restarted treatment after discontinuation. No studies in primary care were identified. After discontinuing monotherapy, symptom scores increased and peak flow rates decreased at 3 and 6 months, but not at 12 months; however, neither parameter changed when alpha-blockers were stopped during combination therapy. Small differences in post-void residual volumes and quality of life scores were considered clinically irrelevant. We also found that 0%-49% of patients restarted after stopping alpha-blocker therapy and that AEs did not increase with discontinuation., Conclusions: Discontinuing alpha-blocker monotherapy leads to a worsening compared with continuing therapy. Discontinuing the alpha-blocker after combination therapy had no significant effects on outcomes in either the short or long term. Discontinuation may be appropriate for the frail, elderly or those with concomitant illness or polypharmacy. However, studies in primary care are lacking., Prospero Registration Number: CRD42016032648., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.)

Aims: To explore the effect of an online self-management program in secondary care for men with lower urinary tract symptoms (LUTS)., Methods: We performed a prospective nonrandomized double-cohort pilot study of consecutive adult men referred with uncomplicated LUTS to three urology outpatient departments. Men in both cohorts received care as usual from a urologist, but men in the intervention cohort also had access to an online self-management program. Outcomes were assessed after 6 and 12 weeks: LUTS severity was assessed with the International Prostate Symptom Score (IPSS), the Overactive Bladder Questionnaire (OABq), and the Perceived Global Impression of Improvement (PGI-I). The main outcome of interest was a clear improvement in the PGI-I scores ("much better" or "very much better")., Results: Age, symptom severity, and quality of life scores were comparable between the intervention (n = 113) and standard care (n = 54) cohorts. Clear improvement in the PGI-I scores was reported after 12 weeks in 19.4% and 26.1% of men in the intervention and standard care cohorts, respectively. However, logistic regression analysis indicated that the difference between cohorts was not significant. Multivariable linear regression analysis also indicated no significant differences between cohorts for the IPSS or the OABq score at either assessment point. Notably, the uptake of the intervention was low (53%)., Conclusions: We found no significant benefit from adding an online self-management program to standard care for men with LUTS, probably due to the low uptake of the intervention that may have resulted from the timing in the care pathway., (© 2019 The Authors. Neurourology and Urodynamics published by Wiley Periodicals, Inc.)

Purpose: α-Blockers are commonly used for the treatment of male lower urinary tract symptoms (LUTS). The Dutch GP guideline on male LUTS contains an advice to discontinue treatment after 3-6 months of successful treatment. The guideline for urologists does not support this advice. It is unclear if these differences lead to other patterns of (dis)continuation of α-blockers. We aim to study continuation rates of α-blockers, prescribed by a urologist or a general practitioner (GP), and to predict discontinuation after 1 year., Methods: We conducted a retrospective inception cohort study on prescription patterns of α-blockers among Dutch men between 2006 and 2014, using the IADB.nl pharmacy prescription database from the University of Groningen. We selected men aged 30 years or older with a first α-blocker prescription between 2006 and 2013, and analysed continuation of prescriptions., Results: The database included 12,191 individual patients with at least one α-blocker prescriptions from a urologist (44.5%) or a GP (55.5%). The median treatment period for patients who started in the GPs office was 210 days, compared to 150 days for patients with a prescription from a urologist. Of all patients, 60.3% (GP prescriptions) and 66.1% (urologists' prescriptions) had discontinued treatment (Chi-square p < 0.001). Discontinuation rates were age dependent with higher rates in the youngest age groups., Conclusion: In this study, the discontinuation rate 1 year after the initiation of treatment was high. Although Dutch GP's and urologist's guidelines differ with respect to a discontinuation advice, we could not find clinically relevant difference in (temporary) discontinuation rates.

Aims: To develop an online platform to facilitate evidence-based self-management of lower urinary tract symptoms (LUTS) in men., Methods: Using the PubMed database (search until January 2017) and relevant guidelines, we reviewed evidence for the self-management of LUTS and identified suitable components for the intervention. Next, we built an algorithm that provided individualized advice based on patient characteristics and symptoms for use on an online platform. Men with LUTS tested the usability of the intervention and provided feedback. Finally, we surveyed urologists and general practitioners to identify potential areas for improvement of the intervention., Results: We identified nine self-help interventions from 48 eligible publications. These were as follows: information and education about LUTS, pelvic floor muscle training, bladder training, urethral milking, double voiding, caffeine management, alcohol management, fluid management, and exercise advice. The level of evidence for each item was low due to the paucity of research available. Six men with LUTS reported difficulties understanding and completing the frequency-volume chart online. The 158 surveyed physicians agreed (≥50% positive ratings) on the inclusion of seven advice items, but not for double voiding and fluid management. Respondents noted that some advice should be provided to all men with LUTS, while other advice should only be presented to certain groups. Some recommendations for additions were offered., Conclusions: Despite a lack of evidence for the self-management advice, physicians agreed with most of the included advice. The online platform needs further development. Therefore, adjustments will be made and we will assess its impact in future studies., (© 2019 The Authors. Neurourology and Urodynamics Published by Wiley Periodicals, Inc.)

Objectives: Clinicians should not only know how many patients will benefit from alpha-blocker therapy but should also be able to identify who will benefit. We studied the changes in patient symptoms following alpha-blocker therapy and the predictors of symptom improvement in clinical practice., Design: This was a single-arm, open-label observational cohort study with a 6-week follow-up., Setting: Twenty-two pharmacies in the Netherlands., Participants: Patients were eligible for inclusion if they attended a pharmacy with a new prescription for an alpha-blocker from a general practitioner or urologist., Primary and Secondary Outcomes: Outcomes were assessed using the International Prostate Symptom Score (IPSS), Overactive Bladder Questionnaire Short Form (OAB-q SF), and Patient Global Impression of Improvement (PGI-I). Demographic, disease-related, and drug-related information were collected to identify predictors of symptom improvement. These predictors were then assessed by logistic and linear regression analyses of both the original data set and an imputed data set that accounted for the missing variables., Results: During the study, 37% of patients with lower urinary tract symptoms perceived clear symptomatic improvement based on the results of the PGI-I. Improvement was more likely in those who still used alpha-blockers at the end of the 6-week study period and in those who used multiple medications. Although symptom scores decreased significantly on the IPSS and OAB-q SF, the only predictor of change was the pretreatment symptom severity., Conclusions: Approximately one-third of our cohort perceived symptom improvement on alpha-blocker therapy. However, we identified no clear predictors of who might benefit from alpha-blocker treatment, indicating that alpha-blockers should still be prescribed on a trial basis., Competing Interests: The authors have declared that no competing interests exist.

A spontaneous, non-traumatic, urinary bladder rupture is a rare condition. We describe a case of a 23-year-old male with a spontaneous bladder rupture secondary to urinary retention, due to an urethral stricture. He presented to the emergency department with voiding difficulties, severe abdominal pain and renal failure. Abdominal ultrasound revealed large amounts of ascites. After an unsuccessful attempt to place a Foley catheter a cystoscopy was performed which showed an urethral stricture. On CT-cystogram an intra-peritoneal bladder rupture was diagnosed and the patient underwent laparoscopic repair of the bladder wall. The postoperative course was uneventful.

Aims: Frequency Volume Charts (FVC) are recommended for the evaluation of enuretic patients. Although this is a good instrument for the assessment of functional bladder capacity, it is known that patient compliance could introduce problems. Therefore, we assessed whether uroflowmetry and post-void residual volume could replace FVC recordings in specific cases, by comparing the bladder capacity as measured by FVC or uroflowmetry., Methods: We performed post-hoc analyses using data from a retrospective cohort study, in secondary/tertiary care. This included 907 patients between 2003 and 2013, aged ≥11 years, suffering from enuresis (≥1 wet night/fortnight). Data were collected from the medical files. Bland Altman plots were made to compare the two methods., Results: Agreement between uroflowmetry and FVC was reasonable only when uroflowmetry was between 200 and 450 ml., Conclusions: For individual clinical purposes, uroflowmetry can be used if values are in this range. For future research, we recommend to keep measuring bladder capacity with an FVC. Neurourol. Urodynam. 36:745-747, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Aims: Reference values of Frequency Volume Chart (FVC) and uroflowmetry parameters for adolescent and adult enuresis patients are lacking. In this study, we aim to describe those parameters, in order to interpret findings from FVCs and uroflowmetries in those patients., Methods: Retrospective, descriptive cohort study, concerning 907 patients aged 11 years and older, suffering from enuresis of at least one wet night per fortnight, treated in a secondary/tertiary centre, between 2003 and 2013. The main FVC parameters of interest were: maximum voided volume (MVV), 24 hr urine production and nocturnal urine volume (NUV) including first morning void (FMV). Nocturnal polyuria (NP) was defined based on both International Children's Continence Society (ICCS, 2014) and International Continence Society (ICS, 2002) definitions. Data of all patients were collected from the medical files., Results: Age had an impact on diurnal and nocturnal FVC parameters. Median MVV excluding FMV was 250 ml in the youngest, 11-year-old males and 363 ml in the eldest, ≥18-yr-old males. For females, these values were 230 ml and 310 ml. Median 24 hr urine production increased from 1,025 ml to 1,502 ml (males) and from 1,007 ml to 1,557 ml (females). Median NUV showed an increase from 387 ml to 519 ml (males) and from 393 ml to 525 (females). Forty-two percent of men and 30% of women had a small MVV (for age). Prevalence of NP differed when assessed by the ICS or the ICCS definition: following ICS guidelines, NP was present in 96% of our male and 93% of our female population, compared to 27% and 41%, respectively, following ICCS guidelines., Conclusions: Both small MVV and NP were found frequently in our adolescent and adult enuresis patients, which is in line with the current thoughts on causal factors. NP prevalence is quite different when using ICS or ICCS definitions, respectively. We would like to encourage the development of an unambiguous definition of NP to use both in pediatric and adult urology. Neurourol. Urodynam. 36:463-468, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Aims: Adapted Dry Bed Training (Adapted DBT) has been shown to be effective in therapy-resistant adolescents and adults with enuresis. Given the substantial impact of enuresis and the time-consuming nature of Adapted DBT, we investigated which patients benefited most from Adapted DBT. Therefore, we identified predictors for a successful treatment response to Adapted DBT in this population., Methods: Retrospective cohort study in 907 consecutive patients, aged 11-42 years, subjected to in-hospital Adapted DBT in our Dry Bed Center between January 2003 and July 2013. Outcome was defined as treatment success after six months (primary outcome) and six weeks. Results of logistic regression analyses are presented in odds ratios and 95% confidence intervals., Results: Predictors for a successful treatment response to Adapted DBT in adolescents and adults with enuresis after six months are: gender (female), initial degree of enuresis (mild: 0-3 nights/week), current diaper use, never used anticholinergics in the past, and degree of enuresis six weeks after training. Predictors for successful treatment response after six weeks are: gender and initial degree of enuresis only., Limitation: The low explained variance of our model, showing that many other factors, not included in our study, could be of interest in the prediction of success., Conclusions: Several factors that predicted a successful treatment response of Adapted DBT after six weeks and six months were identified. However, the low explained variance of our model suggests that other non-identified factors are also important in predicting outcome. Neurourol. Urodynam. 35:1006-1010, 2016. © 2015 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Pyoderma gangrenosum is a rare non-infectious skin disorder. It is often associated with systemic diseases, like the inflammatory bowel disease, rheumatological disease and (hematological) malignancy. The diagnosis is affirmed through a process of elimination and is principally based on clinical presentation and course. We present a 59-year-old male with T-cell large granular lymphocyte leukemia and pyoderma gangrenosum of penis and scrotum. Finally the patient was successfully treated with systemic prednisolone.

Background: PCA3 and ERG are mRNA-based prostate cancer (PCa) specific biomarkers that can be detected in urine. However, urine is a complex substrate that can be separated in several fractions. In this study we compared the levels of PCa-specific biomarkers (PCA3 and ERG) and KLK3 as prostate-specific reference gene in three urine substrates-whole urine, urinary sediment (cell pellet) and exosomes-and evaluated the influence of performing a digital rectal examination (DRE) prior to urine sampling., Methods: First-voided urine samples were prospectively obtained before and after DRE from 29 men undergoing prostate biopsies. The urine was separated in whole urine, cell pellet and exosomes and the biomarker levels were measured with RT-qPCR., Results: PCa was identified in 52% (15/29) of men. In several samples the mRNA levels were below the analytical limit of detection (BDL). The biomarker levels were highest in whole urine and significantly higher after DRE in all substrates. In PCa patients higher levels of PCA3 and ERG were found in all urine substrates after DRE compared to non-PCa patients., Conclusions: This is the first study in which urinary PCa-specific biomarker levels were compared directly in three separate urine fractions. These results suggest that whole urine could be the urine substrate of choice for PCa-diagnostics based on analytical sensitivity, which is reflected directly in the high informative rate. Moreover, the significant positive effect of performing a DRE prior to urine sampling is confirmed. These findings could be of influence in the development of PCa-diagnostic urine tests.

Objective: To systematically review and evaluate the impact of the International Continence Society (ICS)-2002 report on standardisation of terminology in nocturia, on publications reporting on nocturia and nocturnal polyuria (NP). In 2002, the ICS defined NP as a Nocturnal Polyuria Index (nocturnal urine volume/total 24-h urine volume) of >0.2-0.33, depending on age., Materials and Methods: In April 2013 the PubMed and Embase databases were searched for studies (in English, German, French or Dutch) based on original data and adult participants, investigating the relationship between nocturia and NP. A methodological quality assessment was performed, including scores on external validity, internal validity and informativeness. Quality scores of items were compared between studies published before and after the ICS-2002 report., Results: The search yielded 78 publications based on 66 studies. Quality scores of studies were generally high for internal validity (median 5, interquartile range [IQR] 4-6) but low for external validity. After publication of the ICS-2002 report, external validity showed a significant change from 1 (IQR 1-2) to 2 (IQR 1-2.5; P = 0.019). Nocturia remained undefined in 12 studies. In all, 19 different definitions were used for NP, most often being the ICS (or similar) definition: this covered 52% (n = 11) of studies before and 66% (n = 27) after the ICS-2002 report. Clear definitions of both nocturia and NP were identified in 67% and 76% before, and in 88% and 88% of the studies after the ICS-2002 report, respectively., Conclusion: The ICS-2002 report on standardisation of terminology in nocturia appears to have had a beneficial impact on reporting definitions of nocturia and NP, enabling better interpretation of results and comparisons between research projects. Because the external validity of most of the 66 studies is considered a problem, the results of these studies may not be validly extrapolated to other populations. The ICS definition of NP is used most often. However, its discriminative value seems limited due to the estimated difference of 0.6 nocturnal voids between individuals with and without NP. Refinement of current definitions based on robust research is required. Based on pathophysiological reasoning, we argue that it may be more appropriate to define NP based on nocturnal urine production or nocturnal voided volumes, rather than on a diurnal urine production pattern., (© 2014 The Authors. BJU International © 2014 BJU International.)

Purpose: We determined the relationship between nocturia and nocturnal polyuria., Materials and Methods: The PubMed® and Embase® databases were searched for studies written in English, German, French or Dutch with original data on adult participants in an investigation of the relationship between nocturia and nocturnal polyuria. A meta-analysis of the difference in mean nocturnal voiding frequencies between patients with and without nocturnal polyuria was conducted. Nocturnal polyuria risk was compared between participants with and without nocturia, and the resulting odds ratio was subsequently converted to relative risk with 95% CIs., Results: From 511 references identified we selected 78 publications of 66 studies, 15 of which met the inclusion criteria for this study. Quality scores of studies were generally high for internal validity but low for external validity. In 7 studies (1,416 participants) we estimated a standardized mean difference of 0.59 (95% CI 0.29-0.89) for nocturnal voids between nocturnal polyuria and nonnocturnal polyuria cases. In 8 other studies (with 2,320 participants) we calculated a pooled OR of 4.99 (3.92-6.37) for nocturnal polyuria in individuals with nocturia. The corresponding RR, based on a nocturnal polyuria risk in the pooled population of 63.8%, was 1.41 (1.37-1.44)., Conclusions: The association between nocturia and nocturnal polyuria is apparent and robust. However, the clinical importance of the association appears to be less obvious than previously suggested based on single studies. The observed high prevalence of nocturnal polyuria, as a result of the applied International Continence Society definition, may be responsible for this discrepancy., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Chronic scrotal pain can be a difficult clinical entity to treat. Many different treatment options have been proposed. We describe the case of a young boy with chronic scrotal and inguinal pain on the right side, following two orchidopexies. After many therapies had failed, we treated the dorsal root ganglia of thoracic 12, lumbar 1 and lumbar 2 with pulsed radiofrequency, finally resulting in alleviation of his pain., (Copyright © 2013 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Objective: To determine the reliability and internal validity of the Hypospadias Objective Penile Evaluation (HOPE)-score, a newly developed scoring system assessing the cosmetic outcome in hypospadias., Patients and Methods: The HOPE scoring system incorporates all surgically-correctable items: position of meatus, shape of meatus, shape of glans, shape of penile skin and penile axis. Objectivity was established with standardized photographs, anonymously coded patients, independent assessment by a panel, standards for a "normal" penile appearance, reference pictures and assessment of the degree of abnormality. A panel of 13 pediatric urologists completed 2 questionnaires, each consisting of 45 series of photographs, at an interval of at least 1 week. The inter-observer reliability, intra-observer reliability and internal validity were analyzed., Results: The correlation coefficients for the HOPE-score were as follows: intra-observer reliability 0.817, inter-observer reliability 0.790, "non-parametric" internal validity 0.849 and "parametric" internal validity 0.842. These values reflect good reproducibility, sufficient agreement among observers and a valid measurement of differences and similarities in cosmetic appearance., Conclusions: The HOPE-score is the first scoring system that fulfills the criteria of a valid measurement tool: objectivity, reliability and validity. These favorable properties support its use as an objective outcome measure of the cosmetic result after hypospadias surgery., (Copyright © 2013 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Objective: To determine the impact of the European Randomized Study of Screening for Prostate Cancer (ERSPC) publication in 2009 on prostate-specific antigen (PSA) level testing by Dutch general practitioners (GPs) in men aged ≥40 years., Materials and Methods: Retrospective study with a Dutch insurance company database (containing PSA test claims) and a large district hospital-laboratory database (containing PSA-test results). The difference in primary PSA-testing rate as well as follow-up testing before and after the ERSPC was tested using the chi-square test with statistical significance at P < 0.05., Results: Decline in PSA tests 4 months after ERSPC publication, especially for men aged ≥60 years. Primary testing as well as follow-up testing decreased, both for PSA levels of <4 ng/mL as well as for PSA levels of 4-10 ng/mL. Follow-up testing after a PSA level result of >10 ng/mL moderately increased (P = 0.171). Referral to a urologist after a PSA level result of >4 ng/mL decreased slightly after the ERSPC publication (P = 0.044)., Conclusions: After the ERSPC publication primary PSA testing as well as follow-up testing decreased. Follow-up testing seemed not to be adequate after an abnormal PSA result. The reasons for this remain unclear., (© 2013 BJU International.)

A 38-year-old man presented with abdominal pain, dysuria, pneumaturia and pyuria, due to an enterovesical fistula in Crohn's disease.

Background: The aim of this prospective study was to evaluate the role of fluorodeoxyglucose positron emission tomography (FDG-PET) in the staging of high-risk women with primary or recurrent breast cancer., Methods: FDG-PET was performed in 42 women with a primary breast cancer and unfavourable characteristics, or who had a suspected relapse. FDG-PET and conventional staging methods were compared. In case of abnormality on FDG-PET, confirmation was always attempted., Results: Increased uptake was found in five of 17 women with a primary cancer. In the 25 women with a suspected relapse, FDG-PET showed increased uptake in 43 areas, 22 correctly confirming the area of suspected relapse and 21 indicating other sites of metastases. Compared with conventional imaging, FDG-PET revealed additional (confirmed) lesions in two women with primary cancers and three with relapse. Patient management was changed for five women., Conclusion: FDG-PET is a sensitive diagnostic method for the detection of distant metastatic disease. Its exact role in women with breast cancer remains to be defined.

Renal cell carcinoma was diagnosed in three male patients, 45, 53 and 52 years of age. In addition, they had paraneoplastic symptoms: hypercalcaemia, hyperglycaemia and elevated hepatic enzyme levels, respectively. All three patients underwent tumour nephrectomy, after which the paraneoplastic symptoms disappeared. The first patient died 16 months postoperatively, while the other two were alive and free of symptoms after a follow-up of nine months and four years, respectively. Many patients with renal cell carcinoma remain asymptomatic for a long period of time and 30% of all patients have metastatic disease at the time of diagnosis. The classic triad of flank pain, haematuria and an abdominal mass occurs in only 10% of all cases. However, 20-40% of all patients present with signs of a paraneoplastic syndrome, of which anaemia (20-40%), fever (30%), hypertension (24%), hypercalcaemia (10-15%) and hepatic dysfunction (3-6%) are the most common.

The aims of this study were to establish the percentage of metastatic renal cell carcinoma (RCC) lesions detected by radioimmunoscintigraphy (RIS) with the chimeric monoclonal antibody 131I-cG250 versus positron emission tomography (PET) with 18F-labelled deoxyglucose ([18F]FDG), and to evaluate the use of these radionuclide imaging modalities compared with routinely used imaging techniques. Twenty patients with metastatic RCC disease were examined with [18F]FDG-PET and 131I-cG250 RIS within 1 week. Total body gamma camera images were obtained up to 120h after injection of 232MBq 131I-cG250. Total body PET scanning was performed 45-60 min after intravenous injection of 370MBq [18F]FDG. Nuclear medicine techniques were compared to routine imaging procedures. Routine imaging modalities revealed a total of 79 metastases. [18F]FDG-PET and 131I-cG250 RIS detected 33 previously unknown metastases, of which 32 were [18F]FDG positive and seven were 131I-cG250 positive. Of the 112 tumour lesions that were documented, [18F]FDG-PET detected 69% (77 out of 112), whereas 131I-cG250 RIS detected only 30% (34 out of 112). In conclusion, [18F]FDG-PET is superior to 131I-cG250 RIS in detecting metastases in patients with metastatic RCC, and therefore seems a promising tool for (re)staging patients with RCC. The usefulness of RIS with a diagnostic dose of 131I-cG250 seems to be restricted to selecting patients for radioimmunotherapy with 131I-cG250.

Clinical tumor targeting studies with chimeric monoclonal antibody G250 (cG250) in renal cell carcinoma (RCC) patients indicated the potential use of this antibody for radioimmunotherapy. Here we report on a phase I activity dose escalation study to determine the safety, the maximum tolerable dose (MTD), and the possible therapeutic potential of 131I-labeled cG250 in patients with progressive metastatic RCC. All patients (n = 12) received a diagnostic i.v. infusion of 5 mg of cG250 labeled with 222 MBq of 131I. If accumulation of the antibody in metastatic lesions was observed, patients were hospitalized and a second, therapeutic, i.v. infusion of 5 mg of cG250 labeled with a high dose of 131I was administered (n = 8). Three patients per dose level were entered, starting at 1665 MBq/m2. If no dose-limiting toxicity occurred, the study continued at the next dose level (555 MBq/m2 increase). Most patients experienced mild nausea without vomiting. No other complaints were reported during hospitalization. In two of two patients who received a dose of 2775 MBq/m2, grade IV hematological toxicity was observed, which was defined as dose limiting. Thus, the MTD was set at 2220 MBq/m2. In one patient (2220 MBq/m2), stable disease (lasting 3-6 months) was achieved, whereas another patient (2220 MBq/m2) showed a partial response that is ongoing (>9 months). The minor responses observed in this phase I trial in patients with an advanced stage of RCC are encouraging and warrant further study in a phase II setting at the MTD to determine the efficacy of radioimmunotherapy for metastatic RCC.

Unlabelled: In previous clinical studies, excellent visualization of tumor lesions has been observed with 131I-labeled monoclonal antibody (mAb) G250 in patients with renal cell carcinoma (RCC). In several cases, 131I-cG250 immunoscintigraphy disclosed tumor lesions that were not visualized by radiography or CT. To improve image quality, we aimed to develop a 99mTc-labeled mAb G250 preparation for radioimmunodetection of RCC. We studied in vitro stability, biodistribution and imaging potential of three 99mTc-labeled G250 preparations in nude mice with subcutaneous RCC xenografts.125I-G250 and the nonspecific mAb 131I-MN14 were used as control antibodies., Methods: The mAb G250 was labeled with 99mTc according to three methods using: (a) S-hydrazinonicotinamide (HYNIC), (b) S-benzoylmercaptoacetyltriglycine (MAG3) and (c) a direct labeling method (Schwarz method). The stability of all preparations was tested in serum at 37 degrees C during 48 h. In addition, diethylenetriamine pentaacetic acid, cysteine and glutathione challenge assays were performed., Results: All preparations showed good stability in serum during the 48-h incubation period. 99mTc-G250 (Schwarz) showed release of the radiolabel at a 100-fold or higher molar excess of cysteine and at a 10,000-fold or higher molar excess of glutathione. 99mTc-MAG3-G250 showed release of the radiolabel at a 10,000-fold molar excess of cysteine. 99mTc-HYNIC-G250 was stable under all conditions. Tumors were clearly visualized with all preparations. 99mTc-G250 (Schwarz) showed significantly lower blood levels (3.8 %ID/g) compared with all other preparations (11.2, 13.4 and 13.4 %ID/g for 99mTc-HYNIC-G250, 99mTc-MAG3-G250 and 125I-G250, respectively, 48 h postinjection). At 48-h postinjection, mean tumor uptake was very high with all mAb G250 preparations: 92.4 (99mTc-HYNIC-G250), 125.9 (99mTc-MAG3-G250), 29.4 (99mTc-G250 Schwarz) and 75.4 (125I-G250) %ID/g. Mean tumor uptake of the nonspecific 131I-MN14 mAb was 6.6 %ID/g., Conclusion: In this study, 99mTc-HYNIC-G250 showed excellent in vitro stability and tumor targeting. Moreover, this preparation could be labeled with high efficiency (>95%) at room temperature within 15 min. Therefore, 99mTc-HYNIC-G250 seems to be an ideal candidate for radioimmunodetection of RCC.

Tumor uptake of the chimeric G250 (cG250) monoclonal antibody (mAb) in patients with primary renal cell carcinoma (RCC) is among the highest reported in solid tumors. However, as observed in other tumor types, the intratumoral distribution of the antibody is highly heterogeneous, which may limit the efficacy of radioimmunotherapy. A number of highly dynamic physiological factors have been postulated that may contribute to heterogeneous tumor uptake of antibodies. Their impact on tumor uptake of antibodies may vary from one tumor region to another as well as from one day to the next. Here, we report on a clinical study that was designed to investigate whether the pattern of mAb cG250 uptake within RCC tumors is altered with subsequent injections. Ten patients with a clinical diagnosis of primary RCC were studied. Nine days before surgery, patients received 125I-cG250 (5 mg of cG250, 50 microCi of 125I), followed by a second injection of 131I-cG250 (5 mg of cG250, 3.5 mCi of 131I) 4 days later. Postsurgery, the tumor was cut into (1-cm) thick slices. Slices were imaged on a gamma camera, and the slice with the most pronounced heterogeneity in 131I-cG250 distribution was selected and cut into 1-cm3 cubes. Each cube was analyzed for 121I-cG250 and 131I-cG250 uptake, and the 131I/125I ratio was determined. For each tumor slice, the distribution patterns of both isotopes were reconstructed and compared with each other. All tumors analyzed showed a heterogeneous distribution of both isotopes throughout the tumor slice; focal uptake in some areas of a tumor reached very high levels (up to 0.19% injected dose/g), whereas other tumorous areas of the same slice showed much lower uptake (as low as 0.0047% injected dose/g). Remarkably, in all tumors, the distribution pattern of both injections was identical: without exception, in all samples analyzed (n = 692), the uptake of 125I-cG250 was similar to 131I-cG250 uptake. Overall, the 131I/125I ratio was 1.64+/-0.31 (mean+/-SD). The constant 131I/125I ratios, observed in all tumor samples investigated, indicate that the tumor parameters governing cG250 mAb uptake were not altered significantly within the time period studied. In addition, the results of this study suggest that multiple radiolabeled antibody injections, administered within short time periods, will target the same areas within a tumor and, thus, will not solve the problem of heterogeneous tumor uptake of antibody.

Clinical tumor targeting studies with monoclonal antibody (mAb) G250 showed excellent targeting of primary renal cell carcinomas (RCC). However, tumor uptake decreased at higher mAb G250 doses, suggesting saturation of the G250 antigenic determinants. In this immunohistochemical study we investigated the saturability of G250 antigen sites after i.v. administration of mAb G250 at various protein doses in nude mice with RCC xenografts. Five groups of mice received five different protein doses (1, 3, 10, 30 or 100 micrograms) of murine mAb G250. Three days post injection mice were killed and the tumors were removed. Free G250 antigen sites, i.e., not targeted by the i.v. injected murine mAb G250 were determined by immunohistochemical staining with chimeric mAb G250. Distinct staining of the G250 antigen was observed only at the 1 and 3 micrograms dose whereas G250 antigen staining at higher doses was virtually negative. The results of this study indicate that saturation of antigen occurs at relatively low doses of i.v. administered mAb G250. Apparently, all antigenic determinants present on the RCC tumor cells were targeted, while previous preclinical studies suggested that i.v. administration of mAb G250 only saturated the accessible antigen sites.

Unlabelled: In radioimmunotherapy of solid tumors substantial gain might be achieved by carefully selecting the radionuclide and the linker connecting it to the antibody. In contrast to 131I, radiometals such as 90Y and 111In may be retained in the tumor cell after internalization of the antibody, thereby enhancing the radiation dose to the tumor. The physical properties of 186Re with 1.08 MeV beta-emission (71%) and 137 keV gamma-emission (10%) seem ideal for radioimmunotherapy. In this study we investigated in nude mice with s.c. renal cell carcinoma xenografts the biodistribution and the retention in the tumor of 186Re-MAG3 labeled monoclonal antibody (mAb) G250 as compared to 111In-DTPA-G250, to 125I-G250 and to 131I-MN14 (non-specific control mAb). Radiolabeled antibody preparations were i.v. injected. Seventy two hours p.i. the biodistribution of the radiolabel was determined. Blood levels of all mAb G250 preparations were remarkably low (mean: 2.38, 1.40 and 1.43% ID/g for 125I, 111In and 186Re respectively) whereas blood levels of mAb MN14 were significantly higher (mean: 12.3% ID/g), indicating tumor processing of mAb G250. Retention of 111In in the tumor was significantly higher than of 186Re and 125I whereas retention in the tumor of 186Re and 125I did not differ significantly., Conclusion: In contrast to other radiometals such as 111In and 90Y, 186Re is not retained in the tumor cell. Therefore 186Re has no additional advantage for radioimmunotherapy with respect to retention in the tumor.

Purpose: Pharmacokinetics, biodistribution, immunogenicity, and imaging characteristics of iodine 131 (131I)-labeled chimeric monoclonal antibody (mAb) G250 (cG250) were studied in patients with renal cell carcinoma (RCC) to determine the therapeutic potential of this antibody., Patients and Methods: Sixteen patients with RCC received a single intravenous (IV) infusion of 6 mCi 131I-labeled cG250. Five protein dose levels were investigated (2 to 50 mg). Planar scintigraphic images were acquired, and normal tissue biopsies and tumor samples were obtained of surgery (7 days postinjection). The immunogenicity of cG250 was investigated using a sandwich enzyme-linked immunosorbent assay (ELISA) and dosimetric analysis was performed., Results: In all patients with antigen-positive tumors (n = 13), the primary tumors and all known metastases were clearly visualized. Overall uptake, expressed as the percentage of the injected dose (%ID), in the primary tumors ranged from 2.4 to 9.0. Focally, 131I-cG250 uptake as high as 0.52% ID/g was observed. However, intratumoral uptake was highly heterogeneous. 131I-cG250 uptake in nontumorous tissues remained low. Dosimetric analysis showed that up to .48 Gy/mCi was guided to the primary tumors. Selected "hot areas" within these tumors received up to .72 Gy/mCi. A bone metastasis received .23 Gy/mCi and regional lymph node metastases received .20 Gy/mCi. Minimal human antichimeric antibody (HACA) levels were detected in two of 16 patients., Conclusion: 131I-cG250 tumor uptake is among the highest reported in clinical studies with antitumor antibodies in solid tumors. Since tumor-sterilizing levels may be guided to the tumor when high doses 131I-cG250 are administered (> 100 mCi) and cG250 appears to be immunosilent, cG250 is a promising vehicle for radioimmunotherapy in RCC.