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Contains fulltext : 237666.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To contribute to the debate regarding the minimum volume of radical cystectomies (RCs) that a hospital should perform by evaluating the association between hospital volume (HV) and postoperative mortality. PATIENTS AND METHODS: Patients who underwent RC for bladder cancer between 1 January 2008 and 31 December 2018 were retrospectively identified from the Netherlands Cancer Registry. To create a calendar-year independent measure, the HV of RCs was calculated per patient by counting the RCs performed in the same hospital in the 12 months preceding surgery. The relationship of HV with 30- and 90-day mortality was assessed by logistic regression with a non-linear spline function for HV as a continuous variable, which was adjusted for age, tumour, node and metastasis (TNM) stage, and neoadjuvant treatment. RESULTS: The median (interquartile range; range) HV among the 9287 RC-treated patients was 19 (12-27; 1-75). Of all the included patients, 208 (2.2%) and 518 (5.6%) died within 30 and 90 days after RC, respectively. After adjustment for age, TNM stage and neoadjuvant therapy, postoperative mortality slightly increased between an HV of 0 and an HV of 25 RCs and steadily decreased from an HV of 30 onwards. The lowest risks of postoperative mortality were observed for the highest volumes. CONCLUSION: This paper, based on high-quality data from a large nationwide population-based cohort, suggests that increasing the RC volume criteria beyond 30 RCs annually could further decrease postoperative mortality. Based on these results, the volume criterion of 20 RCs annually, as recently recommended by the European Association of Urology Guideline Panel, might therefore be reconsidered.

Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. Background: Although guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial. Objective: To bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management. Design: A steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts before voting during a consensus conference. Setting: Online Delphi survey and consensus conference. Participants: The European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management. Outcome measurements and statistical analysis: Statements were ranked by experts according to their level of agreement: 1–3 (disagree), 4–6 (equivocal), 7–9 (agree). A priori (level 1) consensus was defined as 70% agreement and 15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus). Results and limitations: Overall, 116 statements were included in the Delphi survey. Of these, 33 (28%) statements achieved level 1 consensus and 49 (42%) statements achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease and the evolving role of checkpoint inhibitor therapy in metastatic disease. Conclusions: These consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time where further evidence is available to guide our approach, The authors would like to thank Peter E. Clark from Atrium Health, Levine Cancer Institute, Charlotte, NC, USA, for his contribution to the Delphi survey. Angela Corstorphine of Kstorfin Medical Communications Ltd provided medical writing support with the preparation of this manuscript; this support was funded jointly by EAU and ESMO.

Purpose The aim of this systematic review was to compare knee pain and function after tibial nail insertion through an infrapatellar, semi-extended and suprapatellar technique. Methods A search was carried out to identify articles with an exact description of the method used for insertion of the tibial nail and description of the outcome parameters (knee pain or function). Data on study design, population, rate and severity of anterior knee pain and function scores were extracted. Pooled rates and scores were calculated. Results 67 studies with 3,499 patients were included. The pooled rate of patients with anterior knee pain was 38% (95% CI 32–44) after nail insertion through an infrapatellar approach and 10% (95% CI 1–26) after insertion through a suprapatellar approach. Pooled analysis was not possible for the semi-extended technique. Knee pain scores as measured by visual analogue score (0–10) ranged from 0.2 (95% CI − 0.1–0.5) for general knee pain to 3.7 (95% CI 1.3–6.1) for pain during kneeling. Pooled estimates for the Lysholm score were 87 points (range 77–97) for the infrapatellar technique and 85 points (range 82–85) for the suprapatellar technique. Iowa Knee scores were 94 (range 86–96) and Anterior Knee Pain Scale scores were 76 (range 75–80) after infrapatellar nail insertion. Discussion Depending on the technique used, the proportion of patients with knee pain after tibial nailing varied between 10 and 38%. The actual measured knee pain scores were, however, surprisingly low. Knee function was good for both the infra- and suprapatellar technique.

The authors regret that a co-author was mistakenly missed from the authorship. The following co-author should have been included in the authorship: Peter-Paul M. Willemse Department of Oncological Urology, University Medical Center, Utrecht Cancer Center, Utrecht, The Netherlands

Purpose In patients with open tibial fractures, bone and wound infections are associated with an increased hospital length of stay and higher costs. The infection risk increases with the use of implants. Innovations to reduce this risk include antibiotic-coated implants. This study models whether the use of a gentamicin-coated intramedullary tibial nail is cost-effective for trauma centers managing patients with a high risk of infection. Efficacy Absolute infection risk and relative risk reduction, by fracture grade, for antibiotic-coated nails compared to standard nails for patients with open tibial fractures were estimated based on the results of a meta-analysis, which assessed the additional benefit of locally-administered prophylactic antibiotics in open tibia fractures treated with implants. The observed efficacy of antibiotic-coated nails in reducing infections was applied in an economic model. Methods The model compared infection rates, inpatient days, theatre usage and costs in high risk patients, with a Gustilo-Anderson (GA) grade III open fracture, for two patient cohorts from a trauma center perspective, with a 1-year time horizon. In one cohort all GAIII patients received a gentamicin-coated nail whilst GAI and GAII patients received a standard nail. All patients in the comparator cohort received a standard nail. Four European trauma centers provided patient-level data (n=193) on inpatient days, procedures and related costs for patients with and without infections. Results Using the gentamicin-coated nail in patients at high risk of infection (GAIII) was associated with 75% lower rate of infection and cost savings (€477 - €3.263) for all included centers; the higher cost of the implant was offset by savings from fewer infections, inpatient days (-26%) and re-operations (-10%). This result was confirmed by extensive sensitivity analyses. Conclusions Analyses demonstrated that infection rates and total costs for in-hospital treatment could be potentially reduced by 75% and up to 15% respectively, by using a gentamicin-coated nail in patients at high risk of infection. Fewer infections, reduced inpatient days and re-operations may be potentially associated with use of antibiotic-coated implants. Results are sensitive to the underlying infection risk, with greatest efficacy and cost-savings when the coated implant is used in high risk patients.

Understanding animal emotions is an important scientific and ethical question but assessing emotional valence is still considered challenging. As the observation of lateralization (hemispheric asymmetries in structure and/or function) can provide insight into the underlying processes of the cognitive, physiological and behavioural components of emotions, it is a promising approach for studying them. The emotional valence hypothesis states that positive emotions are mostly processed by the left hemisphere, while negative emotions are mostly processed by the right hemisphere. Support for this hypothesis is still not conclusive; therefore, our study tested it in the context of visual laterality for viewing positive or negative emotionally conditioned stimuli. Ninety male piglets were either positively (food-reward) or negatively (mild punishment) conditioned to an object. Afterwards, the object was presented without the reinforcer under three different treatments: patch on the left or right eye (reducing input to the contralateral hemisphere) or patch between the eyes (the control). Monocular viewing had no clear effects on the negatively conditioned subjects. In contrast, in the positively conditioned group, covering the right eye caused a longer interruption of vocalization, a longer latency to touch the object, a shorter duration of exploring the arena and an increased vagal activity compared to the control. This suggests that reduced processing in the left hemisphere leads to heightened attention that is accompanied by a general orienting response, possibly resulting from a reduced positive appraisal. These findings therefore partially support the emotional valence hypothesis and suggest an important role of the left hemisphere in the quick recognition of a positive stimulus. This study demonstrated that investigating the lateralized processing of emotions can provide insight into the mechanisms of positive appraisal in animals.

Background and purpose — Anterior knee pain is common after tibial nailing. Its origin is poorly understood. Injury of the infrapatellar nerve is a possible cause. In this randomized controlled trial we compared changes in knee pain after an infrapatellar nerve block with lidocaine or placebo in patients with persistent knee pain after tibial nailing. Patients and methods — Patients with chronic knee pain after tibial nailing were randomized to an infrapatellar nerve block with 5 ml 2% lidocaine or placebo (sodium chloride 0.9%), after which they performed 8 daily activities. Before and after these activities, pain was recorded using a numeric rating scale (NRS; 0–10). Primary endpoint was the change in pain during kneeling after the infrapatellar nerve block. Secondary outcomes were changes in pain after the nerve block during the other activities. Results — 34 patients (age 18–62 years) were equally randomized. A significant reduction of the NRS for kneeling pain with an infrapatellar nerve block with lidocaine was found compared with placebo (–4.5 [range –10 to –1] versus –1 [–9 to 2]; p = 0.002). There were no differences between the treatments for the NRS values for pain during other activities. Interpretation — Compared with placebo, an infrapatellar nerve block with lidocaine was more effective in reducing pain during kneeling in patients with chronic knee pain after tibial nailing. Our findings support the contention that kneeling pain after tibial nailing is a peripheral nerve-related problem.

Background Endoscopic submucosal dissection (ESD) for early esophageal and stomach cancer is usually performed under general anesthesia. However, propofol sedation without endotracheal intubation has been suggested as a viable alternative. Objective The objective of this study was to evaluate the safety of propofol sedation without endotracheal intubation during ESD in the upper gastrointestinal tract. Methods We performed a retrospective cohort study of patients who underwent ESD for upper gastrointestinal tumors with propofol-remifentanil analgosedation in a tertiary referral center in the Netherlands between October 2013 and February 2018. Primary endpoints were the rates of intraprocedural endoscopy- and anesthesia-related complications. Secondary endpoints were the postprocedural complication rates within 30 days and endotracheal intubation conversion rates. Results Of 88 patients, intraprocedural ESD-related complications occurred in three patients (3.4%). Intraprocedural anesthesia-related complications occurred in two patients (2.3%), one of whom required conversion to endotracheal intubation. Postprocedural ESD-related complications occurred in 14 patients (15.9%), and minor postprocedural complications occurred in two patients (2.3%). Eighty-two (93.2%) patients were discharged within one day after ESD. No patient was readmitted for anesthesia-related complications. Conclusion Propofol-based sedation without endotracheal intubation is safe for ESD procedures in the esophagus and stomach with low anesthesia-related complication rates and short hospital stay.

In patients with prostate cancer who have a high risk of pelvic nodal disease, the use of elective whole pelvis radiotherapy is still controversial. Two large, randomised, controlled trials (RTOG 9413 and GETUG-01) did not show a benefit of elective whole pelvis radiotherapy over prostate-only radiotherapy. In 2020, the POP-RT trial established the role of elective whole pelvis radiotherapy in patients who have more than a 35% risk of lymph node invasion (known as the Roach formula). POP-RT stressed the importance of patient selection. In patients with cN1 (clinically node positive) disease or pN1 (pathologically node positive) disease, the addition of whole pelvis radiotherapy to androgen deprivation therapy significantly improved survival compared with androgen deprivation therapy alone, as shown in large, retrospective studies. This patient population might increase in the future because use of the more sensitive prostate-specific membrane antigen PET-CT will become the standard staging procedure. Additionally, the SPORTT trial suggested a benefit of whole pelvis radiotherapy in biochemical recurrence-free survival in the salvage setting. A correct definition of the upper field border, which should include the bifurcation of the abdominal aorta, is key in the use of pelvic radiotherapy. As a result of using modern radiotherapy technology, severe late urinary and intestinal toxic effects are rare and do not seem to increase compared with prostate-only radiotherapy.

Background Open radical cystectomy (ORC) is regarded as the standard treatment for muscle-invasive bladder cancer, but robot-assisted radical cystectomy (RARC) is increasingly used in practice. A recent study showed that RARC resulted in slightly fewer minor but slightly more major complications, although the difference was not statistically significant. Some differences were found in secondary outcomes favouring either RARC or ORC. RARC use is expected to increase in coming years, which fuels the debate about whether RARC provides value for money. Objective To assess the cost-effectiveness of RARC compared to ORC in bladder cancer. Design, setting, and participants This economic evaluation was performed alongside a prospective multicentre comparative effectiveness study. We included 348 bladder cancer patients (ORC, n = 168; RARC, n = 180) from 19 Dutch hospitals. Outcome measurements and statistical analysis Over 1 yr, we assessed the incremental cost per quality-adjusted life year (QALY) gained from both healthcare and societal perspectives. We used single imputation nested in the bootstrap percentile method to assess missing data and uncertainty, and inverse probability of treatment weighting to control for potential bias. Deterministic sensitivity analyses were performed to explore the impact of various parameters on the cost difference. Results and limitations The mean healthcare cost per patient was €17 141 (95% confidence interval [CI] €15 791–€18 720) for ORC and €21 266 (95% CI €19 163–€23 650) for RARC. The mean societal cost per patient was €18 926 (95% CI €17 431–€22 642) for ORC and €24 896 (95% CI €21 925–€31 888) for RARC. On average, RARC patients gained 0.79 QALYs (95% CI 0.74–0.85) compared to 0.81 QALYs (95% CI 0.77–0.85) for ORC patients, resulting in a mean QALY difference of −0.02 (95% CI −0.05 to 0.02). Using a cost-effectiveness threshold of €80 000, RARC was cost-effective in 0.6% and 0.2% of the replications for the healthcare and societal perspectives, respectively. Conclusions RARC shows no difference in terms of QALYs, but is more expensive than ORC. Hence, RARC does not seem to provide value for money in comparison to ORC. Patient summary This study assessed the relation between costs and effects of robot-assisted surgery compared to open surgery for removal of the bladder in 348 Dutch patients with bladder cancer. We found that after 1 year, the two approaches were similarly effective according to a measure called quality-adjusted life years, but robot-assisted surgery was much more expensive. This trial was prospectively registered in the Netherlands Trial Register as NTR5362 ( https://www.trialregister.nl/trial/5214 ).

Background: Radical cystectomy with pelvic lymph node dissection (PLND) and urinary diversion in patients with bladder cancer is known for its high risk of complications. Although open radical cystectomy (ORC) is regarded as the standard treatment, robot-assisted radical cystectomy (RARC) is increasingly used in practice, despite the fact that high-quality evidence comparing the effectiveness of both techniques is lacking.Objective: To study the effectiveness of RARC compared with that of ORC, in terms of 90 d complications (Clavien-Dindo), health-related quality of life (HRQOL), and clinical outcomes.Design, setting, and participants: A prospective comparative effectiveness study was conducted in 19 Dutch centres, expert in either ORC or RARC. Follow-up visits were scheduled at 30, 90, and 365 d.Intervention: Standard ORC or RARC with PLND, using a standardised perioperative protocol. Outcome measurements and statistical analysis: The primary outcome was any-grade complications after 90 d. Secondary outcomes included HRQOL, complications (minor, major, 30 d, and 365 d), and clinical outcomes. Differences were calculated as risk differences (RDs) between the groups with 95% confidence intervals (CIs), adjusted for potential baseline differences by means of propensity score–based inverse probability of treatment weighting.Results and limitations: Between March 2016 and November 2018, 348 patients were included (n = 168 for ORC, n = 180 for RARC). At 90 d, any-grade complication rates were 63% for ORC and 56% for RARC (RD –6.4%, 95% CI –17 to 4.5). Major complication rates were 15% for ORC and 16% for RARC (RD 0.9%, 95% CI –7.0 to 8.8). Total minor complication rates were 57% for ORC and 49% for RARC (RD –7.6%, 95% CI –19 to 3.6). Analyses showed no statistically significant differences in HRQOL between ORC and RARC. Some differences were found in the secondary outcomes in favour of either RARC or ORC. The major drawback inherent to the design comprises residual confounding.Conclusions: This multicentre comparative effectiveness study showed no statistically significant differences between ORC and RARC in terms of complications and HRQOL.Patient summary: This multicentre study did not show differences in overall complication rates, health-related quality of life, mortality, and clinical and oncological outcomes between open and robot-assisted radical cystectomy in bladder cancer patients.

In humans, speech perception is lateralized, with the left hemisphere of the brain dominant in processing the communicative content and the right hemisphere dominant in processing the emotional content. However, still little is known about such a division of tasks in other species. We therefore investigated lateralized processing of communicative and emotionally relevant calls in a social mammal, the pig (Sus scrofa). Based on the contralateral connection between ears and hemispheres, we compared the behavioural and cardiac responses of 36 young male pigs during binaural and monaural (left or right) playback to the same sounds. The playback stimuli were calls of social isolation and physical restraint, whose communicative and emotional relevance, respectively, were validated prior to the test by acoustic analyses and during binaural playbacks. There were indications of lateralized processing mainly in the initial detection (left head-turn bias, indicating right hemispheric dominance) of the more emotionally relevant restraint calls. Conversely, there were indications of lateralized processing only in the appraisal (increased attention during playback to the right ear) of the more communicative relevant isolation calls. This implies differential involvement of the hemispheres in the auditory processing of vocalizations in pigs and thereby hints at similarities in the auditory processing of vocal communication in non-human animals and speech in humans. Therefore, these findings provide interesting new insight in the evolution of human language and auditory lateralization.

The aim of this study was to evaluate the measurement properties of the Short Musculoskeletal Function Assessment (SMFA) and Lower Extremity Functional Scale (LEFS) in patients who sustained a tibial shaft fracture, by comparing them with the scores of a general health-related quality of life instrument scale (i.e., EuroQoL-5D). Data of 136 patients participating in a multicenter randomized controlled trial comparing incisions for intramedullary nail entry in adults with a tibial shaft fracture were used. Patients completed the SMFA, LEFS, EQ-5D and an anchor question at 2 and 6 weeks, and at 3, 6 and 12 months. Reliability (internal consistency), construct validity, responsiveness (longitudinal validity), floor and ceiling effects, minimal important change (MIC), and smallest detectable change (SDC) were determined. The SMFA and LEFS (sub)scales showed adequate internal consistency (0.84

Background: Intravesical instillation of bacillus Calmette-Guerin (BCG) is an accepted strategy to prevent recurrence of non–muscle-invasive bladder cancer (NMIBC) but associated with significant toxicity. Objective: NIMBUS assessed whether a reduced number of standard-dose BCG instillations are noninferior to the standard number and dose in patients with high-grade NMIBC. Design, setting, and participants: A total of 345 patients from 51 sites were randomised between December 2013 and July 2019. We report results after a data review and safety analysis by the Independent Data Monitoring Committee based on the cut-off date of July 1, 2019. Intervention: The standard BCG schedule was 6 wk of induction followed by 3 wk of maintenance at 3, 6, and 12 mo (15 instillations). The reduced frequency BCG schedule was induction at wks 1, 2, and 6 followed by 2 wk (wks 1 and 3) of maintenance at 3, 6, and 12 mo (nine instillations). Outcome measurements and statistical analysis: The primary endpoint was time to first recurrence. Secondary endpoints included progression to ≥ T2 and toxicity. Results and limitations: In total, 170 patients were randomised to reduced frequency and 175 to standard BCG. Prognostic factors at initial resection were as follows: Ta/T1: 46/54%; primary/recurrent: 92/8%; single/multiple: 57/43%; and concomitant carcinoma in situ: 27%. After 12 mo of median follow-up, the intention-to-treat analysis showed a safety-relevant difference in recurrences between treatment arms: 46/170 (reduced frequency) versus 21/175 patients (standard). Additional safety analyses showed a hazard ratio of 0.40 with the upper part of the one-sided 97.5% confidence interval of 0.68, meeting a predefined stopping criterion for inferiority. Conclusions: The reduced frequency schedule was inferior to the standard schedule regarding the time to first recurrence. Further recruitment of patients was stopped immediately to avoid harm in the reduced frequency BCG arm. Patient summary: After surgical removal of the tumour, patients with high-grade non–muscle-invasive bladder cancer are treated with bacillus Calmette-Guerin to prevent recurrence and progression. This is associated with significant side effects. We report the results of a clinical trial showing a reduction in the number of instillations (from 15 to nine in total) being inferior to the standard protocol. From today's perspective, complete tumour resection and a standard number of instillations remain the standard of care. In high-grade non–muscle-invasive bladder cancer, a reduced frequency of bacillus Calmette-Guerin (BCG) instillations during induction and maintenance is inferior to the standard BCG schedule regarding time to first recurrence. Repeated transurethral resection followed by the standard BCG regimen, as recommended by the European Association of Urology guideline, remains the state of the art. (Less)

Poor translation from animal studies to human clinical trials is one of the main hurdles in the development of new drugs. Here, we used precision-cut kidney slices (PCKS) as a translational model to study renal fibrosis and to investigate whether inhibition of tyrosine kinase receptors, with the selective inhibitor nintedanib, can halt fibrosis in murine and human PCKS. We used renal tissue of murine and human origins to obtain PCKS. Control slices and slices treated with nintedanib were studied to assess viability, activation of tyrosine kinase receptors, cell proliferation, collagen type I accumulation, and gene and protein regulation. During culture, PCKS spontaneously develop a fibrotic response that resembles in vivo fibrogenesis. Nintedanib blocked culture-induced phosphorylation of platelet-derived growth factor receptor and vascular endothelial growth factor receptor. Furthermore, nintedanib inhibited cell proliferation and reduced collagen type I accumulation and expression of fibrosis-related genes in healthy murine and human PCKS. Modulation of extracellular matrix homeostasis was achieved already at 0.1 μM, whereas high concentrations (1 and 5 μM) elicited possible nonselective effects. In PCKS from human diseased renal tissue, nintedanib showed limited capacity to reverse established fibrosis. In conclusion, nintedanib attenuated the onset of fibrosis in both murine and human PCKS by inhibiting the phosphorylation of tyrosine kinase receptors; however, the reversal of established fibrosis was not achieved.

Introduction Population-based knowledge on the occurrence of specific injuries is essential for the allocation of health care services, optimization of preventive measures, and research purposes. Therefore, the aim of this study was to examine long-term nation-based trends in the incidence rate, trauma mechanism, hospital length of stay (HLOS), treatment, and outcome of hospital-admitted patients with an isolated tibia shaft fracture between 1991 and 2012 in The Netherlands. Methods All hospital-admitted patients in The Netherlands between 1991 and 2012 with an isolated tibia shaft fracture were included. Age and gender-standardized incidence rates were calculated for each year. Data were extracted from the National Medical Registration. Results The incidence rate for men decreased to 13.8/100,000 person years (py). For women the incidence rate remained stable with 7.2/100,000 py. Incidence showed a peak for adolescent men (15–19 years), and increased in both genders from 65 years onwards. Since 1993 the mean HLOS for isolated tibia fractures reduced from 10.8 to 5.4 days. Mean HLOS increased with age. Mean years lived with disability (YLD) was 4.5 years, declined linearly with age, and showed no gender effect. Conclusions In 22 years, the incidence rate of hospital admitted patients with an isolated tibia shaft fracture in The Netherlands dropped with 12%, which was mainly attributable to a 15% decline among men. Incidence rate, trauma mechanism, and HLOS were age and gender related. HLOS also reduced over time. Operation rate and YLD were only age related.

BACKGROUND: The treatment of metastatic castration-resistant prostate cancer has changed with the introduction of radium-223, cabazitaxel, abiraterone and enzalutamide. To assess value for money, their cost effectiveness in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel from the Dutch societal perspective was investigated.METHODS: A cost-effectiveness analysis was conducted using efficacy, symptomatic skeletal-related event and safety data obtained from indirect treatment comparisons. Missing skeletal-related event data for cabazitaxel were conservatively assumed to be identical to radium-223. A Markov model combined these clinical inputs with Dutch-specific resource use and costs for metastatic castration-resistant prostate cancer treatment from a societal perspective. Total quality-adjusted life-years and costs in 2017 euros were calculated over a 5-year (lifetime) time horizon.RESULTS: Radium-223 resulted in €6092 and €4465 lower costs and 0.02 and 0.01 higher quality-adjusted life-years compared with abiraterone and cabazitaxel, respectively, demonstrating dominance of radium-223. Sensitivity analyses reveal a 64% (54%) chance of radium-223 being cost effective compared with abiraterone (cabazitaxel) at the informal €80,000 willingness-to-pay threshold. Compared with enzalutamide, radium-223 resulted in slightly lower quality-adjusted life-years (-0.06) and €7390 lower costs, revealing a 61% chance of radium-223 being cost effective compared with enzalutamide. The lower costs of radium-223 compared with abiraterone and enzalutamide are driven by lower drug costs and prevention of expensive skeletal-related events. Compared with cabazitaxel, the lower costs of radium-223 are driven by lower costs of the drug, administration and adverse events.CONCLUSION: Radium-223 may be a less costly treatment strategy offering similar gains in health benefits compared with abiraterone, cabazitaxel and enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel from the Dutch societal perspective.

Tolvaptan, a vasopressin V2 receptor antagonist, has been shown to reduce the rates of growth in total kidney volume (TKV) and renal function loss in ADPKD patients, but also leads to polyuria because of its aquaretic effect. Prolonged polyuria can result in ureter dilatation with consequently renal function loss. Therefore, we aimed to investigate the effect of tolvaptan-induced polyuria on ureter diameter in ADPKD patients.70 ADPKD patients were included (51 were randomized to tolvaptan and 19 to placebo). At baseline and after 3 years of treatment renal function was measured (mGFR) and MRI was performed to measure TKV and ureter diameter at the levels of renal pelvis and fifth lumbar vertebral body (L5).In these patients [65.7 % male, age 41 +/- 9 years, mGFR 74 +/- 27 mL/min/1.73 m(2) and TKV 1.92 (1.27-2.67) L], no differences were found between tolvaptan and placebo-treated patients in 24-h urine volume at baseline (2.5 vs. 2.5 L, p = 0.8), nor in ureter diameter at renal pelvis and L5 (4.0 vs. 4.2 mm, p = 0.4 and 3.0 vs. 3.1 mm, p = 0.3). After 3 years of treatment 24-h urine volume was higher in tolvaptan-treated patients when compared to placebo (4.7 vs. 2.3 L, p Tolvaptan-induced polyuria did not lead to an increase in ureter diameter, suggesting that tolvaptan is a safe therapy from a urological point of view.

Item does not contain fulltext Autosomal dominant polycystic kidney disease (ADPKD) patients can suffer from chronic pain that can be refractory to conventional treatment, resulting in a wish for nephrectomy. This study aimed to evaluate the effect of a multidisciplinary treatment protocol with sequential nerve blocks on pain relief in ADPKD patients with refractory chronic pain. As a first step a diagnostic, temporary celiac plexus block with local anesthetics was performed. If substantial pain relief was obtained, the assumption was that pain was relayed via the celiac plexus and major splanchnic nerves. When pain recurred, patients were then scheduled for a major splanchnic nerve block with radiofrequency ablation. In cases with no pain relief, it was assumed that pain was relayed via the aortico-renal plexus, and catheter-based renal denervation was performed. Sixty patients were referred, of which 44 were eligible. In 36 patients the diagnostic celiac plexus block resulted in substantial pain relief with a change in the median visual analogue scale (VAS) score pre-post intervention of 50/100. Of these patients, 23 received a major splanchnic nerve block because pain recurred, with a change in median VAS pre-post block of 53/100. In 8 patients without pain relief after the diagnostic block, renal denervation was performed in 5, with a borderline significant change in the median VAS pre-post intervention of 20/100. After a median follow-up of 12 months, 81.8% of the patients experienced a sustained improvement in pain intensity, indicating that our treatment protocol is effective in obtaining pain relief in ADPKD patients with refractory chronic pain.

Een 68-jarige patient presenteerde zich met flankpijn ten gevolge van een grote renale massa. Onder verdenking van een renaalcelcarcinoom werd een nefrectomie verricht. Pathologisch onderzoek toonde een diffuus grootcellig B‑cellymfoom. Primair renale manifestatie van een lymfoom komt weinig voor. De diagnose wordt vaak gemist of pas gesteld na het verrichten van een nefrectomie. Een primair renaal lymfoom moet overwogen worden als er radiologisch sprake is van een hypovasculair, diffuus groeiend proces, waarbij de voor renaalcelcarcinoom kenmerkende calcificaties en vasculaire tumorinvasie ontbreken. Indien histologisch bewezen, kan curatieve behandeling middels chemo-immunotherapie gestart worden. In dit artikel worden de diagnostische overwegingen en kenmerken van een renaal lymfoom besproken.

Objective During implantation of a neuromodulative system, high patient satisfaction is closely associated with the equilibrium between an effective analgesia and sedation regimen, and the possibility for the patient to be awake and cooperative during procedure. This study assessed the efficacy of the sedative dexmedetomidine to achieve this balance, with patient satisfaction as the primary outcome. Methods Ten patients undergoing implantation of a dorsal column and dorsal root ganglion stimulator received dexmedetomidine (1 mcg/kg over 10 minutes, followed by 0.6 mcg/kg/hour) in combination with remifentanil at a set dose (3 mcg/kg/hour). Sedation was titrated to a Ramsay Sedation Score of 3. Recorded were as follows: patient satisfaction score, patient comfort score, operator comfort score, pain score, rescue medication and number of adjustments of dexmedetomidine intra-operatively, as well as sedation level, hemodynamic (blood pressure and heart rate), and respiratory characteristics (SpO2). Results Scores were high on patient satisfaction (median 8.5; IQR 2.0), patient comfort (3.0; IQR 1.25), and operator comfort (4.0; IQR 1.0). In all patients, intra-operative heart rate and mean arterial pressure were lower compared with baseline values. No respiratory depression or other complications related to anesthesia were reported. Moments of incident pain were effectively treated in 6 patients requiring an extra bolus of remifentanil. Conclusion In this study group, dexmedetomidine combined with remifentanil provided a high level of patient satisfaction and comfort, as well as operator comfort, without any clinically relevant adverse events. All patients were highly cooperative and instructable; incident pain needs to be closely monitored.

BackgroundAlthough guidelines exist for advanced and variant bladder cancer management, evidence is limited/conflicting in some areas and the optimal approach remains controversial.ObjectiveTo bring together a large multidisciplinary group of experts to develop consensus statements on controversial topics in bladder cancer management.DesignA steering committee compiled proposed statements regarding advanced and variant bladder cancer management which were assessed by 113 experts in a Delphi survey. Statements not reaching consensus were reviewed; those prioritised were revised by a panel of 45 experts prior to voting during a consensus conference.SettingOnline Delphi survey and consensus conference.ParticipantsThe European Association of Urology (EAU), the European Society for Medical Oncology (ESMO), experts in bladder cancer management.Outcome measurements and statistical analysisStatements were ranked by experts according to their level of agreement: 1–3 (disagree), 4–6 (equivocal), and 7–9 (agree). A priori (level 1) consensus was defined as ≥70% agreement and ≤15% disagreement, or vice versa. In the Delphi survey, a second analysis was restricted to stakeholder group(s) considered to have adequate expertise relating to each statement (to achieve level 2 consensus).Results and limitationsOverall, 116 statements were included in the Delphi survey. Of these statements, 33 (28%) achieved level 1 consensus and 49 (42%) achieved level 1 or 2 consensus. At the consensus conference, 22 of 27 (81%) statements achieved consensus. These consensus statements provide further guidance across a broad range of topics, including the management of variant histologies, the role/limitations of prognostic biomarkers in clinical decision making, bladder preservation strategies, modern radiotherapy techniques, the management of oligometastatic disease, and the evolving role of checkpoint inhibitor therapy in metastatic disease.ConclusionsThese consensus statements provide further guidance on controversial topics in advanced and variant bladder cancer management until a time when further evidence is available to guide our approach.Patient summaryThis report summarises findings from an international, multistakeholder project organised by the EAU and ESMO. In this project, a steering committee identified areas of bladder cancer management where there is currently no good-quality evidence to guide treatment decisions. From this, they developed a series of proposed statements, 71 of which achieved consensus by a large group of experts in the field of bladder cancer. It is anticipated that these statements will provide further guidance to health care professionals and could help improve patient outcomes until a time when good-quality evidence is available.

While intratumour genetic heterogeneity of primary clear cell renal cell carcinoma (ccRCC) is well characterized, the genomic profiles of metastatic ccRCCs are seldom studied. We profiled the genomes and transcriptomes of a primary tumour and matched metastases to better understand the evolutionary processes that lead to metastasis. In one ccRCC patient, four regions of the primary tumour, one region of the thrombus in the inferior vena cava, and four lung metastases (including one taken after pegylated (PEG)-interferon therapy) were analysed separately. Each sample was analysed for copy number alterations and somatic mutations by whole exome sequencing. We also evaluated gene expression profiles for this patient and 15 primary tumour and 15 metastasis samples from four additional patients. Copy number profiles of the index patient showed two distinct subgroups: one consisted of three primary tumours with relatively minor copy number changes, the other of a primary tumour, the thrombus, and the lung metastases, all with a similar copy number pattern and tetraploid-like characteristics. Somatic mutation profiles indicated parallel clonal evolution with similar numbers of private mutations in each primary tumour and metastatic sample. Expression profiling of the five patients revealed significantly changed expression levels of 57 genes between primary tumours and metastases, with enrichment in the extracellular matrix cluster. The copy number profiles suggest a punctuated evolution from a subregion of the primary tumour. This process, which differentiated the metastases from the primary tumours, most likely occurred rapidly, possibly even before metastasis formation. The evolutionary patterns we deduced from the genomic alterations were also reflected in the gene expression profiles.

Background: During the lead implantation of most spinal cord neurostimulators, the patient has to be comfortable and without pain. However, the patient is expected to provide feedback during electrical mapping. Titrating sedatives and analgesics for this double goal can be challenging. In comparison with our standard sedative agent propofol, the pharmacological profile of dexmedetomidine is more conducive to produce arousable sedation. The latter, however, is associated with hemodynamic side effects. We investigated whether dexmedetomidine is preferable over propofol during neurostimulator implantation. Methods: This single-center single-blinded randomized controlled trial included 72 patients with an indication for a neurostimulator, randomized to sedation with either propofol (0.5 mg/kg for 10 minutes, followed by 2.0 mg/kg/h) or dexmedetomidine (1 μg/kg for 10 minutes, followed by 0.6 μg/kg/h). The primary outcome was patient satisfaction with the sedation. The secondary outcomes were patient's and operator's comfort, number of titration adjustments, standard intraoperative hemodynamic and respiratory parameters and side effects. Results: Data of 69 patients (dexmedetomidine n = 35; propofol n = 34) were analyzed. Those receiving dexmedetomidine were more satisfied with the sedation than those receiving propofol; i.e. with sedation delivery (median 100.0 vs 83.3, P

The number of elderly patients with renal cell carcinoma is rising. Elderly patients differ from their younger counterparts in, among others, higher incidence of comorbidity and reduced organ function. Age influences outcome of surgery, and therefore has to be taken into account in elderly patients eligible for cytoreductive nephrectomy. Over the last decade several novel effective drugs have become available for the metastatic setting targeting angiogenesis and mammalian target of rapamycin. Immune checkpoint blockade with a programmed death 1 antibody has recently been shown to increase survival and further studies with immune checkpoint inhibitors are ongoing. In this review we summarize the available data on efficacy and toxicity of existing and emerging therapies for metastatic renal cell carcinoma in the elderly. Where possible, we provide evidence-based recommendations for treatment choices in elderly. (C) 2016 The Authors. Published by Elsevier Ltd.

Chronic kidney disease is a major health concern, and experimental models bridging the gap between animal studies and clinical research are currently lacking. Here, we evaluated precision-cut kidney slices (PCKSs) as a potential model for renal disease. PCKSs were prepared from human cortical tissue obtained from tumor nephrectomies and cultured up to 96 hours. Morphology, cell viability, and metabolic functionality (ie, uridine 5'-diphospho-glucuronosyltransferase and transporter activity) were determined to assess the integrity of PCKSs. Furthermore, inflammatory and fibrosis-related gene expressions were characterized. Finally, to validate the model, renal fibrogenesis was induced using transforming growth factor beta 1 (TGF-beta 1). Preparation of PCKSs induced an inflammatory tissue response, whereas long-term incubation (96 hours) induced fibrogenesis as shown by an increased expression of collagen type 1A1 (COL1A1) and fibronectin 1 (FN1). Importantly, PCKSs remained functional for more than 48 hours as evidenced by active glucuronidation and phenolsulfonphthalein uptake. In addition, cellular diversity appeared to be maintained, yet we observed a clear loss of nephrin messenger RNA levels suggesting that our model might not be suitable to study the role of podocytes in renal pathology. Moreover, TGF-beta 1 exposure augmented fibrosis, as illustrated by an increased expression of multiple fibrosis markers including COL1A1, FN1, and alpha-smooth muscle actin. In conclusion, PCKSs maintain their renal phenotype during culture and appear to be a promising model to investigate renal diseases, for example, renal fibrosis. Moreover, the human origin of PCKSs makes this model very suitable for translational research.

Imaging modalities using tumor-directed monoclonal antibodies may be of value to improve the pre- and intraoperative detection and resection of lymph node (LN) metastatic disease in penile squamous cell carcinoma (PSCC). We investigated the expression of prostate-specific membrane antigen (PSMA), vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and epithelial cell adhesion molecule (EpCAM) to analyze their potency for diagnostic applications. Antigen expression was determined in primary tumors and LNs with and without metastases of 22 patients with PSCC. The total immunostaining score (TIS, 0–12) was determined as the product of a proportion score (PS, 0–4) and an intensity score (IS, 0–3). EGFR and VEGF expression were high in primary tumor (median TIS 8) and LN metastases (median TIS 6 and 8, respectively). No EGFR expression was seen in LNs without metastases. However, LNs without metastases did show VEGF expression (median TIS 6). No EpCAM or PSMA expression was seen in PSCC. This study shows that VEGF and EGFR expression is moderate to high in LN metastases of PSCC. Both VEGF and EGFR warrant further clinical evaluation to determine their value as a target for pre- and intraoperative imaging modalities in the detection of LN metastases in PSCC.

Animal models are a valuable tool in preclinical research. However, limited predictivity of human biological responses in the conventional models has stimulated the search for reliable preclinical tools that show translational robustness. Here, we used precision-cut kidney slices (PCKS) as a model of renal fibrosis and investigated its predictive capacity for screening the effects of anti-fibrotics. Murine and human PCKS were exposed to TGF&beta, or PDGF pathway inhibitors with established anti-fibrotic efficacy. For each treatment modality, we evaluated whether it affected: (1) culture-induced collagen type I gene expression and interstitial accumulation, (2) expression of markers of TGF&beta, and PDGF signaling, and (3) expression of inflammatory markers. We summarized the outcomes of published in vivo animal and human studies testing the three inhibitors in renal fibrosis, and drew a parallel to the PCKS data. We showed that the responses of murine PCKS to anti-fibrotics highly corresponded with the known in vivo responses observed in various animal models of renal fibrosis. Moreover, our results suggested that human PCKS can be used to predict drug efficacy in clinical trials. In conclusion, our study demonstrated that the PCKS model is a powerful predictive tool for ex vivo screening of putative drugs for renal fibrosis.

Purpose The histopathology of sepsis-associated acute kidney injury (AKI) in critically ill patients remains an understudied area. Previous studies have identified that acute tubular necrosis (ATN) is not the only driver of sepsis-AKI. The focus of this study was to identify additional candidate processes that may drive sepsis-AKI. To do this we immunohistochemically characterized the histopathological and cellular features in various compartments of human septic kidneys. Methods We studied the following histopathological features: leukocyte subsets, fibroblast activation, cellular proliferation, apoptosis, and fibrin deposition in the glomerulus and the tubulointerstitium in human post-mortem kidney biopsy tissue. Biopsy tissue samples from 27 patients with sepsis-AKI were collected 33 min (range 24–150) after death in the ICU. The unaffected part of the kidneys from 12 patients undergoing total nephrectomy as a result of renal carcinoma served as controls. Results Immunohistochemical analysis revealed the presence of more neutrophils and macrophages in the glomeruli and more neutrophils in the tubulointerstitium of renal tissue from patients with sepsis compared to control renal tissue. Type II macrophages were predominant, with some macrophages expressing both type I and type II markers. In contrast, there were almost no macrophages found in control kidneys. The number of activated (myo)fibroblasts was low in the glomeruli of sepsis-AKI kidneys, yet this was not observed in the tubulointerstitium. Cell proliferation and fibrin deposition were more pronounced in the glomeruli and tubulointerstitium of sepsis-AKI than in control kidneys. Conclusions The extensive heterogeneity of observations among and within patients emphasizes the need to thoroughly characterize patients with sepsis-AKI in a large sample of renal biopsy tissue from patients with sepsis. Electronic supplementary material The online version of this article (10.1186/s13054-018-2287-3) contains supplementary material, which is available to authorized users.

Contains fulltext : 193407.pdf (Publisher’s version ) (Open Access) Background: Following radical nephro-ureterectomy for urothelial carcinoma of the upper urinary tract (UUT), the reported bladder recurrence rate of urothelial carcinoma is 22-47%. A single intravesical instillation of chemotherapy within 10 days following nephro-ureterectomy has the potential to decrease the risk of a bladder recurrence significantly. Despite recommendation by the European Association of Urology guideline to administer a single instillation postoperatively, the compliance rate is low because the risk of extravasation of chemotherapy. Aim: To reduce the risk of bladder cancer recurrence by a single intravesical instillation of Mitomycin immediately (within 3h) before radical nephro-ureterectomy or partial ureterectomy. Methods: Adult patients (age>/=18 years) with a (suspicion of a) urothelial carcinoma of the UUT undergoing radical nephro-ureterectomy or partial ureterectomy will be eligible and will receive a single intravesical instillation of Mitomycin within 3h before surgery. In total, 170 patients will be included in this prospective, observational study. Follow-up will be according to current guidelines. Results: The primary endpoint is the bladder cancer recurrence rate up to two years after surgery. Secondary endpoints are: a) the compliance rate; b) oncological outcome; c) possible side-effects; d) the quality of life; e) the calculation of costs of a single neoadjuvant instillation with Mitomycin and f) molecular characterization of UUT tumors and intravesical recurrences. Conclusions: A single intravesical instillation of Mitomycin before radical nephro-ureterectomy or partial ureterectomy may reduce the risk of a bladder recurrence in patients treated for UUT urothelial carcinoma and will circumvent the disadvantages of current therapy.

Vocalizations have long been recognized to encode information about an individual's emotional state and, as such, have contributed to the study of emotions in animals. However, the potential of vocalizations to also encode information about an individual's emotional reactivity has received much less attention. In this study, we aimed to test whether the vocalizations of domestic pigs contain correlates of emotional reactivity that are consistent between different contexts. We recorded vocalizations of 120 young female pigs in an experimental arena in two consecutive recording contexts, social isolation and an encounter with a familiar human. Simultaneously, we measured their heart rate and behaviour to determine their emotional reactivity in the same context (within-context). In addition, we aimed to determine the subjects' emotional reactivity in other contexts (across-context) by measuring their behaviour in four common tests of emotional reactivity, the human approach test, the open door test, the open field test and the novel object test. Using a cluster analysis, we identified four different call types. Significant inter-context correlations were found for all call types, suggesting that pig vocalizations are consistent within an individual across contexts. The call rate and the proportions of the individual call types were found to correlate significantly with indices of emotional reactivity both within and across contexts. Thereby, we found more significant correlations to indices of emotional reactivity within context (behavioural and physiological response during recording) compared to across context (behavioural response in the four emotional reactivity tests). The consistency of the vocal correlates to emotional reactivity between the different contexts depended on the call type. While we found moderate evidence that the high grunt is indicative of more active, more explorative and less fearful individuals both within as well as across contexts, the other call types provided less consistent results. Thus, it seems that some call types are better suited to provide information on a caller's emotional reactivity than others, and further research is needed to clarify the underlying influential factors.

Currently, biomarkers that predict the efficacy of everolimus in metastatic renal cell carcinoma (mRCC) patients are lacking. Everolimus inhibits vascular endothelial growth factor A (VEGF-A) expression. We performed PET scans on mRCC patients with 89Zr-bevacizumab, a VEGF-A–binding antibody tracer. The aims were to determine a change in tumor tracer uptake after the start of everolimus and to explore whether 89Zr-bevacizumab PET can identify patients with early disease progression. Methods: 89Zr-bevacizumab PET was done before and 2 and 6 wk after the start of everolimus, 10 mg/d, in mRCC patients. Routine CT scans were performed at baseline and every 3 mo thereafter. Tumor tracer uptake was quantified using SUVmax. The endpoints were a change in tumor tracer uptake and treatment response on CT after 3 mo. Results:Thirteen patients participated. The median SUVmax of 94 tumor lesions was 7.3 (range, 1.6–59.5). Between patients, median tumor SUVmax varied up to 8-fold. After 2 wk, median SUVmax was 6.3 (1.7–62.3), corresponding to a mean decrease of 9.1% (P < 0.0001). Three patients discontinued everolimus early. At 6 wk, a mean decrease in SUVmax of 23.4% compared with baseline was found in 70 evaluable lesions of 10 patients, with a median SUVmax of 5.4 (1.1–49.4, P < 0.0001). All 10 patients who continued treatment had stable disease at 3 mo. Conclusion: Everolimus decreases 89Zr-bevacizumab tumor uptake. Further studies are warranted to evaluate the predictive value of 89Zr-bevacizumab PET for everolimus antitumor efficacy.

Background: Kidney pain is a common complication in patients with autosomal dominant polycystic kidney disease (ADPKD), and data from the TEMPO 3: 4 trial suggested that tolvaptan, a vasopressin V2 receptor antagonist, may have a positive effect on kidney pain in this patient group. Because pain is difficult to measure, the incidence of kidney pain leading to objective medical interventions was used in the present study to assess pain.Study Design: Secondary analysis from a randomized controlled trial.Setting & Participants: Patients with ADPKD with preserved kidney function.Intervention: Tolvaptan or placebo.Outcomes: Kidney pain events defined by objective medical interventions.Measurements: Kidney pain events were recorded and independently adjudicated. Incidence of a first kidney pain event was assessed overall and categorized into 5 subgroups according to severity.Results: Of 1,445 participating patients (48.4% women; mean age, 39 +/- 7 [SD] years; mean estimated glomerular filtration rate, 81 +/- 22 mL/min/1.73 m(2); median total kidney volume, 1,692 [IQR, 750-7,555] mL), 50.9% reported a history of kidney pain at baseline. History of urinary tract infections, kidney stones, or hematuria (all P 0.05). The effect of tolvaptan was explained at least in part by a decrease in incidence of urinary tract infections, kidney stones, and hematuria when compared to placebo.Limitations: Trial has specific inclusion criteria for total kidney volume and kidney function.Conclusions: Tolvaptan decreased the incidence of kidney pain events independent of patient characteristics predisposing for kidney pain and possibly in part due to reductions in ADPKD-related complications. (C) 2016 The Authors. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.

Our study assessed whether rising age, socioeconomic status (SES) and the presence of serious comorbidity affected treatment choice and survival in a population-based series of patients with muscle-invasive bladder cancer (MIBC) in The Netherlands. Therefore, a consecutive series was studied, including all patients diagnosed with MIBC between 1995 and 2009 in the Eindhoven Cancer Registry, preceding centralization of cystectomy. The independent effects of age, SES and serious comorbidity on therapy choice and their effects on overall survival were estimated by multivariate logistic regression and multivariate Cox proportional hazard analyses, respectively. Out of the 2,445 patients, 38% were aged ≥ 75 years at diagnosis and 63% had at least one serious comorbid condition. Higher age and serious comorbidity were independent predictors for abstaining from cystectomy, where SES was not (61-74 vs. ≤ 60: odds ratio [OR], 0.8; 95% confidence interval [CI], 0.6-1.0; ≥ 75 vs. ≤ 60: OR, 0.1; 95% CI,0.1-0.2; one comorbid condition vs. none: OR, 0.7; 95% CI, 0.5-0.9; two vs. none: OR, 0.6; 95% CI, 0.5-0.8). Patients undergoing cystectomy, external beam radiotherapy or interstitial radiotherapy survived longer independent of age, SES and serious comorbidity (hazard ratio [HR]: 0.4; 95% CI: 0.4-0.5; HR: 0.8; 95% CI: 0.7-0.9; HR: 0.4; 95% CI: 0.3-0.5, respectively). Consequently, preceding centralization of cystectomy, higher age and serious comorbidity were independent predictors for abstaining from cystectomy owing to an expected high rate of short-term medical problems. As cystectomy is associated with a better survival, independently of age, SES and serious comorbidity, it can be questioned whether cystectomy has been underutilised in elderly and in patients with serious comorbidity. Centralization might be a solution for this suggested underutilisation.

The study and protection of animal welfare are based on the assumption that animals are sentient beings, capable of experiencing emotions. Still, our understanding of animal emotions is limited. In this review we focus on the potential of cerebral-lateralization research to provide new insights into animal emotional processing. Thereby, our aims were, first, to find a universal lateralization pattern in emotional processing across vertebrates and, second, to discuss how knowledge of emotional-lateralization patterns can be used in science and practice to contribute to improve farm-animal welfare. A literature review suggests evidence of lateralized functioning during emotional contexts across the vertebrate classes, from early vertebrates such as fish and amphibians to non-human primates. With the possible exception of fish, all vertebrate classes seem to show a similar lateralization pattern for emotional processing, with a right-hemisphere dominance for processing rather negatively connotated emotions, such as fear and aggression, and a left-hemisphere dominance for processing positively connotated emotions, such as those elicited by a food reward. Thus, both hemispheres are involved in emotional processing and hemispheric dominance may be used as an indicator of emotional valence (negative-positive). Although only a few domestic animal species (e.g. chicken, sheep, dog and horse) have been extensively studied with regard to emotional lateralization, evidence gathered so far suggests that the right-hemisphere dominance for fear and aggression and left-hemisphere dominance in responses to food rewards also applies to these species. Such patterns could be exploited in animal welfare studies to gain insight into how an animal experiences a potentially emotional situation and to improve farm-animal management. Further research should focus on rarely-studied species and on rarely-studied emotional contexts, such as sex and positive social situations, to improve our understanding of animal emotional lateralization.

PURPOSE: To evaluate the effect of total PSA (tPSA) and PSA kinetics on the detection rates of (11)C-Choline PET in patients with biochemical recurrence (BCR) after radical prostatectomy (RP) or external beam radiotherapy (EBRT).METHODS: We included 185 patients with BCR after RP (PSA >0.2 ng/ml) or after EBRT (ASTRO definition). After injection of 400 MBq 11C-Choline i.v., a scan was made using the ECAT HR + PET camera with CT fusion images or Siemens mCT PET/CT. Biopsy-proven histology, confirmative imaging (CT or bone scan) and/or clinical follow-up (PSA) were used as composite reference. Statistical analysis was performed using PASW Statistics 18.RESULTS: 11C-Choline PET was positive in 124/185 cases (65%) (in 22/61 (36%) after RP, 102/124 (82%) after EBRT). In 79 patients a local recurrence was identified, and 45 patients showed locoregional metastases on PET/CT. In 20 cases a proven false-negative PET scan was observed. Positive PET scans were confirmed by histology in 87/124 (70%) cases, by confirmatory imaging in 34/124 (28%) and by clinical follow-up after salvage treatment in 3 (2%) cases. The ROC analysis to detect a recurrence showed significant difference in area under the curve (AUC) of tPSA 0.721(p < 0.001) and PSA velocity 0.730 (p < 0.001). PSA doubling time showed no significant difference with an AUC of 0.542 (p = 0.354). Detection rates are CONCLUSIONS: Total serum PSA and PSA velocity have significant effect on the detection rates of 11C-Choline PET/CT in men with a BCR after RP or EBRT.

Two hunger-related indicators are used for tracking progress towards the first Millennium Development Goal (MDG), the eradication of extreme poverty and hunger, with one of the targets being to halve the proportion of people suffering from hunger by 2015 as compared to 1990. The prevalence of people with inadequate food intake (undernourishment) is based on national food statistics, which are not very reliable in sub-Saharan Africa. The other indicator (prevalence of underweight among under-fives, based on anthropometric surveys) appears to be more reliable. The measurement of height in addition to weight allows a more refined classification of anthropometric failure. A specially designed cross-tabulation (called 'Anthro Table') facilitates the inspection of the resulting interconnected prevalence data. An example from Kenya confirms the reliability of underweight as a sound overall indicator of child growth, while the prevalence of stunting (low height) remains a useful additional indicator that can help attribute any trends in underweight to chronic and/or acute undernutrition. App., bibliogr., notes, ref., sum. [Book abstract, edited].

Study Type – Prognosis (cohort series) Level of Evidence 2a What's known on the subject? and What does the study add? The present study is one of the first to investigate urologists' and patients' compliance with recommendations based on a risk calculator that calculates the probability of indolent prostate cancer. A threshold was set for a recommendation of active surveillance vs active treatment. Active surveillance recommendations based on a prostate cancer risk calculator were followed by most patients, but 30% with active treatment recommendations chose active surveillance instead. This indicates that the threshold may be too high for urologists and patients. OBJECTIVES • To assess urologists' and patients' compliance with treatment recommendations based on a prostate cancer risk calculator (RC) and the reasons for non-compliance. • To assess the difference between patients who were compliant and non-compliant with recommendations based on this RC. PATIENTS AND METHODS • Eight urologists from five Dutch hospitals included 240 patients with prostate cancer (PCa), aged 55–75 years, from December 2008 to February 2011. • The urologists used the European Randomized Study of Screening for Prostate Cancer RC which predicts the probability of potentially indolent PCa (P[indolent]), using serum prostate-specific antigen (PSA), prostate volume and pathological findings on biopsy. • Inclusion criteria were PSA 70%, active surveillance (AS) was recommended, and active treatment (AT) otherwise. • After the treatment decision, patients completed a questionnaire about their treatment choice, related (dis)advantages, and validated measurements of other factors, e.g. anxiety. RESULTS • Most patients (45/55, 82%) were compliant with an AS recommendation. Another 54 chose AS despite an AT recommendation (54/185, 29%). • The most common reason for non-compliance with AT recommendations by urologists was the patient's preference for AS (n= 30). These patients most often reported the delay of physical side effects of AT as the main advantage (n= 19). • Those who complied with AT recommendations had higher mean PSA levels (8 vs 7 ng/mL, P= 0.02), higher mean amount of cancer tissue (7 vs 3 mm, P < 0.001), lower mean P(indolent) (36% vs 55%, P < 0.001), and higher mean generic anxiety scores (42 vs 38, P= 0.03) than those who did not comply. CONCLUSIONS • AS recommendations were followed by most patients, while 29% with AT recommendations chose AS instead. • Although further research is needed to validate the RC threshold, the current version is already useful in treatment decision-making in men with localized PCa.

Purpose: To evaluate the pattern of care in patients with high risk non muscle invasive bladder cancer (NMIBC) in the Comprehensive Cancer Center North-Netherlands (CCCN) and to assess factors associated with the choice of treatment, recurrence and progression free survival rates.Materials and Methods: Retrospective analysis of 412 patients with newly diagnosed high risk NMIBC. Clinical, demographic and follow-up data were obtained from the CCCN Cancer Registry and a detailed medical record review. Uni and multivariate analysis was performed to identify factors related to choice of treatment and 5 year recurrence and progression free survival.Results: 74/412 (18%) patients with high risk NMIBC underwent a transurethral resection (TUR) as single treatment. Adjuvant treatment after TUR was performed in 90.7% of the patients treated in teaching hospitals versus 71.8 % in non-teaching hospitals (p 80 years OR 0.1 p = 0.001) and treatment in non-teaching hospitals (OR 0.25; p Conclusion: In this pattern of care study in high risk NMIBC, 18% of the patients were treated with TUR as single treatment. Age and treatment in non-teaching hospitals were associated with less adjuvant treatment after TUR. None of the variables sex, age, comorbidity, hospital type, stage and year of treatment was associated with 5 year recurrence or progression rates.

OBJECTIVE: To assess treatments and survival of patients with muscle invasive bladder cancer (MIBC) in the Comprehensive Cancer Center Northern Netherlands (CCCN) region.STUDY DESIGN AND SETTING: Retrospective cohort analysis. Data of 548 patients with MIBC diagnosed between 1997 and 2002 were collected from the CCCN cancer registry. All had a follow-up of at least 5 years. Logistic regression analysis on treatments as well as survival analysis was performed.RESULTS: The treatments were radical cystectomy in 205/548 (37.5%) patients. TUR plus radiotherapy in 246 (44.9%) and palliation in 97 (17.7%). Multivariate analysis identified TNM stage (P < 0.0001) and age (P < 0.0001) as independent variables for cystectomy. Hospital type and year of diagnosis were not significant different between patients treated by cystectomy versus other type of treatment. TNM stage (P < 0.0001), age (P = 0.0043), and comorbidity (P = 0.0028) were independent variables for disease-specific survival (DSS) after cystectomy.CONCLUSION: In the CCCN region, only 1/3 of patients with MIBC were treated with radical cystectomy. TNM stage and age were identified as main variables for the choice for cystectomy. TNM stage, age, and comorbidity were independent variables for disease-specific survival after cystectomy.

PURPOSE: An elevated serum prostate-specific antigen (PSA) level cannot distinguish between local-regional recurrences and the presence of distant metastases after treatment with curative intent for prostate cancer. With the advent of salvage treatment such as cryotherapy, it has become important to localize the site of recurrence (local or distant). In this study, the potential of (11)C-choline positron emission tomography (PET) to identify site of recurrence was investigated in patients with rising PSA after external-beam radiotherapy (EBRT).METHODS AND MATERIALS: Seventy patients with histologically proven prostate cancer treated with EBRT and showing biochemical recurrence as defined by American Society for Therapeutic Radiology and Oncology consensus statement and 10 patients without recurrence underwent a PET scan using 400 MBq (11)C-choline intravenously. Biopsy-proven histology from the site of suspicion, findings with other imaging modalities, clinical follow-up and/or response to adjuvant therapy were used as comparative references.RESULTS: None of the 10 patients without biochemical recurrence had a positive PET scan. Fifty-seven of 70 patients with biochemical recurrence (median PSA 9.1 ng/mL; mean PSA 12.3 ng/mL) showed an abnormal uptake pattern (sensitivity 81%). The site of recurrence was only local in 41 of 57 patients (mean PSA 11.1 ng/mL at scan), locoregionally and/or distant in 16 of 57 patients (mean PSA 17.7 ng/mL). Overall the positive predictive value and negative predictive value for (11)C-choline PET scan were 1.0 and 0.44 respectively. Accuracy was 84%.CONCLUSIONS: (11)C-choline PET scan is a sensitive technique to identify the site of recurrence in patients with PSA relapse after EBRT for prostate cancer.

Background The treatment of metastatic castration-resistant prostate cancer has changed with the introduction of radium-223, cabazitaxel, abiraterone and enzalutamide. To assess value for money, their cost effectiveness in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel from the Dutch societal perspective was investigated. Methods A cost-effectiveness analysis was conducted using efficacy, symptomatic skeletal-related event and safety data obtained from indirect treatment comparisons. Missing skeletal-related event data for cabazitaxel were conservatively assumed to be identical to radium-223. A Markov model combined these clinical inputs with Dutch-specific resource use and costs for metastatic castration-resistant prostate cancer treatment from a societal perspective. Total quality-adjusted life-years and costs in 2017 euros were calculated over a 5-year (lifetime) time horizon. Results Radium-223 resulted in €6092 and €4465 lower costs and 0.02 and 0.01 higher quality-adjusted life-years compared with abiraterone and cabazitaxel, respectively, demonstrating dominance of radium-223. Sensitivity analyses reveal a 64% (54%) chance of radium-223 being cost effective compared with abiraterone (cabazitaxel) at the informal €80,000 willingness-to-pay threshold. Compared with enzalutamide, radium-223 resulted in slightly lower quality-adjusted life-years (−0.06) and €7390 lower costs, revealing a 61% chance of radium-223 being cost effective compared with enzalutamide. The lower costs of radium-223 compared with abiraterone and enzalutamide are driven by lower drug costs and prevention of expensive skeletal-related events. Compared with cabazitaxel, the lower costs of radium-223 are driven by lower costs of the drug, administration and adverse events. Conclusion Radium-223 may be a less costly treatment strategy offering similar gains in health benefits compared with abiraterone, cabazitaxel and enzalutamide in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel from the Dutch societal perspective. Electronic supplementary material The online version of this article (doi:10.1007/s40258-017-0350-x) contains supplementary material, which is available to authorized users.