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Competing Interests: The author declares no conflict of interest.

Introduction: Better treatments for ovarian cancer are needed to eliminate residual peritoneal disease after initial debulking surgery. The present study evaluated Trastuzumab to deliver Pb-214/Bi-214 for targeted alpha therapy (TAT) for HER2-positive ovarian cancer in mouse models of residual disease. This study is the first report of TAT using a novel Radon-222 generator to produce short-lived Lead-214 (Pb-214, t 1/2 = 26.8 min) in equilibrium with its daughter Bismuth-214 (Bi-214, t 1/2 = 19.7 min); referred to as Pb-214/Bi-214. In this study, Pb-214/Bi-214-TCMC-Trastuzumab was tested. Methods: Trastuzumab and control IgG antibody were conjugated with TCMC chelator and radiolabeled with Pb-214/Bi-214 to yield Pb-214/Bi-214-TCMC-Trastuzumab and Pb-214/Bi-214-TCMC-IgG1. The decay of Pb-214/Bi-214 yielded α-particles for TAT. SKOV3 and OVAR3 human ovarian cancer cell lines were tested for HER2 levels. The effects of Pb-214/Bi-214-TCMC-Trastuzumab and appropriate controls were compared using clonogenic assays and in mice bearing peritoneal SKOV3 or OVCAR3 tumors. Mice control groups included untreated, Pb-214/Bi-214-TCMC-IgG1, and Trastuzumab only. Results and discussion: SKOV3 cells had 590,000 ± 5,500 HER2 receptors/cell compared with OVCAR3 cells at 7,900 ± 770. In vitro clonogenic assays with SKOV3 cells showed significantly reduced colony formation after Pb-214/Bi-214-TCMC-Trastuzumab treatment compared with controls. Nude mice bearing luciferase-positive SKOV3 or OVCAR3 tumors were treated with Pb-214/Bi-214-TCMC-Trastuzumab or appropriate controls. Two 0.74 MBq doses of Pb-214/Bi-214-TCMC-Trastuzumab significantly suppressed the growth of SKOV3 tumors for 60 days, without toxicity, compared with three control groups (untreated, Pb-214/Bi-214-TCMC-IgG1, or Trastuzumab only). Mice-bearing OVCAR3 tumors had effective therapy without toxicity with two 0.74 MBq doses of Pb-214/Bi-214-TCMC-trastuzumab or Pb-214/Bi-214-TCMC-IgG1. Together, these data indicated that Pb-214/Bi-214 from a Rn-222 generator system was successfully applied for TAT. Pb-214/Bi-214-TCMC-Trastuzumab was effective to treat mouse xenograft models. Advantages of Pb-214/Bi-214 from the novel generator systems include high purity, short half-life for fractioned therapy, and hourly availability from the Rn-222 generator system. This platform technology can be applied for a variety of cancer treatment strategies., Competing Interests: Authors NJ, JD, TG, and MZ were employed by Niowave Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Metebi, Kauffman, Xu, Singh, Nayback, Fan, Johnson, Diemer, Grimm, Zamiara and Zinn.)

We aimed to characterize non-oncologic chronic drug therapy of bladder cancer (BC) patients and evaluate a possible impact on recurrence-free (RFS) and cancer-specific survival (CSS). Patients with a first diagnosis (FD) of BC or radical cystectomy (RC) were included in a prospective, monocentric, observational study. Drugs and medical data was assessed at start and three-monthly for 24 months. Drugs were classified by anatomical-therapeutic-chemical code (ATC). Endpoints for outcome analysis were RFS and CSS in univariate (Kaplan-Meier curves and log-rank test, Cox regression for Hazard Ratio (HR)) and multivariate (Cox regression models) analyses. Of 113 patients, 52 had FD and 78 RC. Median age was 74 and 72 years, 83% and 82% were male. Drugs of 114 ATC classes were taken by 48 (92%) FD patients (median number 4.5/IQR 2-7.5) and 73 (94%) of RC patients (median 5/IQR 2-9). In univariate analysis (log-rank test (p)/Cox regression (HR, 95% CI, p)), polypharmacy ( p = 0.036/HR = 2.83, 95% CI = 1.02-7.90, p = 0.047), calcium channel blockers ( p = 0.046/HR = 2.47, 95% CI = 0.97-6.27, p = 0.057) and proton pump inhibitors ( p = 0.015/HR = 3.16, 95% CI = 1.18-8.41, p = 0.022) had a significant negative impact on RFS in RC patients, statins ( p = 0.025/HR = 0.14, 95% CI = 0.02-1.06, p = 0.057) a positive effect on RFS in FD patients, angiotensin-converting enzyme inhibitors ( p = 0.008/HR = 10.74, 95% CI = 1.20-96.17, p = 0.034) and magnesium ( p = 0.042/HR = 5.28, 95% CI = 0.88-31.59, p = 0.067) a negative impact on CSS in FD patients. In multivariate analysis, the only significant drug effects were the negative impact of angiotensin-converting enzyme inhibitors (HR = 15.20, 95% CI = 1.30-177.67, p = 0.030) and magnesium (HR = 22.87, 95% CI = 1.57-333.81), p = 0.022) on CSS in FD patients, and the positive impact of statins (HR = 0.12, 95% CI = 0.01-0.97, p = 0.047) on RFS in FD patients. Impact of non-oncologic drugs on RFS and CSS was small in this prospective study. Thus, appropriate treatment of comorbidities is encouraged.

Introduction: Patients with neurological or neurosurgical disease can suffer from impaired cough, which may result in life-threatening retention of tracheobronchial secretions, atelectasis, pneumonia and finally death. Due to a lack of alternatives and pathophysiological plausibility, the application of mechanical insufflation-exsufflation (MI-E) has already become international standard care in neuromuscular disease and spinal cord injury although a lack of evidence for efficacy. High-quality studies to support the use of MI-E in neurological and neurosurgical patients during weaning from mechanical ventilation are missing. The goal of this exploratory study is to display the effect size of MI-E intervention on the duration of mechanical ventilation and additional outcomes., Methods and Analysis: One hundred adult patients with a cough deficiency or retention of secretion admitted to a neurological intensive care unit (ICU) are planned to be recruited for this randomised controlled trial. Patients are randomised 1:1 to receive either MI-E or best standard care. Observation will take place until discharge from the hospital, death or end of the study period. The primary endpoint of this trial is the duration of mechanical ventilation from randomisation until successful weaning. The outcome will be analysed with Kaplan-Meier estimation and competing risks analyses. Secondary endpoint is the proportion of patients with successful weaning. Further outcomes will include the incidence of hospital-acquired pneumonia, mortality, decannulation rate, length of stay on the ICU and the total score of the Glasgow Coma Scale., Ethics and Dissemination: The study was approved by the Medical Ethics Committee of the University of Oldenburg. The findings of this study will be submitted for publication in a peer-reviewed journal., Trial Registration Number: DRKS00020981., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Fat-containing animal by-product streams are locally available in large quantities. Depending on their quality, they can be inexpensive substrates for biotechnological processes. To accelerate industrial polyhydroxyalkanoate (PHA) bioplastic production, the development of efficient bioprocesses that are based on animal by-product streams is a promising approach to reduce overall production costs. However, the solid nature of animal by-product streams requires a tailor-made process development. In this study, a fat/protein-emulsion (FPE), which is a by-product stream from industrial-scale pharmaceutical heparin production and of which several hundred tons are available annually, was evaluated for PHA production with Ralstonia eutropha. The FPE was used as the sole source of carbon and nitrogen in shake flask and bioreactor cultivations. A tailored pneumatic feeding system was built for laboratory bioreactors to facilitate fed-batch cultivations with the solid FPE. The process yielded up to 51 g L -1 cell dry weight containing 71 wt% PHA with a space-time yield of 0.6 g PHA L -1  h -1 without using any carbon or nitrogen sources other than FPE. The presented approach highlights the potential of animal by-product stream valorization into PHA and contributes to a transition towards a circular bioeconomy., (© 2022 The Authors. Microbial Biotechnology published by Society for Applied Microbiology and John Wiley & Sons Ltd.)

Background: The occurrence of obstructive and central sleep apnea syndromes, ventilator pump failure and reduced hypercapnic ventilatory drive in myotonic dystrophy type 1 (DM1) is well established, and there are indications for an impairment of the hypoxic ventilator drive, too. Yet, it is still unknown, to which extent the respiratory rhythm is affected by DM1, thus if a central bradypnea, cluster breathing or ataxic ("Biot's") breathing can occur. Additionally, the causes of the impairment of the central respiratory drive in DM1 are not known., Case Presentation: We present the case of a tracheotomized female patient with DM1 with central bradypnea and ataxic breathing. A 57-year-old woman with DM1 was admitted to our Neurointensive Care Unit (NICU) due to refractory tracheobronchial retention of secretions resulting from aspiration of saliva. Due to a combination of chronic hypercapnic respiratory failure, severe central bradypnea with a minimal breathing frequency of 3 per minute and ataxic breathing a pressure-controlled home ventilation was initiated., Conclusions: In our patient central bradypnea and ataxic breathing possibly were respiratory sequale of DM1, that may have been caused by pontine white matter lesions affecting the pontine respiratory nuclei. From a clinical viewpoint, polygraphy is a suitable tool to objectify disorders of the respiratory rhythm in DM1 even in tracheotomized patients. Clinical studies combining respiratory diagnostics as polygraphy, transcutaneous capnometry and blood gas analysis with brain magnetic resonance imaging (MRI) are required to better understand disorders of respiratory regulation in DM1, and to identify their anatomical correlates.

Background: Various music interventions can evoke favorable behavioral responses or physiological reactions in people with disorders of consciousness (DOC), such as coma, unresponsive wakefulness syndrome (UWS), and minimally conscious state (MCS). However, it appears that no study thus far has investigated the effects of music on the endocrine system of people with DOC., Objective: This explorative study aimed to investigate the effects of biographical music and biographical language on the physiological and endocrine systems of people with UWS and MCS., Method: A cohort of 20 people with DOC (10 women, 10 men; age range 19-77) received 20 min of biographical music and biographical language. Before and afterward, they were exposed to silence. Physiological and hormonal measurements were conducted before, during, and after the interventions., Results: Paired t -tests showed a significant decrease of salivary cortisol in the condition with biographical language interventions., Conclusion: Biographical interventions can modulate reactions in the endocrine system in people with DOC. Further studies are needed to establish whether and how individuals living with DOC show psychoneuroendocrine responses to music and other arts-based interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Grimm, Groß, Nater, Summ and Kreutz.)

Background Chronic drug therapy may impact recurrence and survival of patients with bladder cancer and thus be of concern regarding drug choice and treatment decisions. Currently, data are conflicting for some drug classes and missing for others. Objective To analyze the impact of common non-oncologic chronic drug intake on survival in patients with bladder cancer and radical cystectomy. Setting. Patients with bladder cancer and radical cystectomy (2004-2018) at the University Hospital Munich. Method Data from an established internal database with patients with bladder cancer and radical cystectomy were included in a retrospective study. Drug therapy at the time of radical cystectomy and survival data were assessed and follow-up performed 3 months after radical cystectomy and yearly until death or present. Impact on survival was analyzed for antihypertensive, antidiabetic, anti-gout, antithrombotic drugs and statins, using the Kaplan-Meier method, log-rank test and Cox-regression models. Main outcome measure Recurrence free survival, cancer specific survival and overall survival for users versus non-users of predefined drug classes. Results Medication and survival data were available in 972 patients. Median follow-up time was 22 months (IQR 7-61). In the univariate analysis, a significant negative impact among users on recurrence free survival (n = 93; p = 0.038), cancer specific survival (n = 116; p < 0.001) and overall survival (n = 116; p < 0.001) was found for calcium-channel blockers, whereas angiotensin-receptor-blockers negatively influenced overall survival (n = 96; p = 0.020), but not recurrence free survival (n = 73; p = 0.696) and cancer specific survival (n = 96; p = 0.406). No effect of angiotensin-receptor-blockers and calcium-channel blockers was seen in the multivariate analysis. None of the other studied drugs had an impact on survival. Conclusion There was no impact on bladder cancer recurrence and survival for any of the analyzed drugs. Considering our results and the controverse findings in the literature, there is currently no evidence to withhold indicated drugs or choose specific drug classes among the evaluated non-oncologic chronic drug therapies. Thus, prospective studies are required for further insight. Trail registration This is part of the trial DRKS00017080, registered 11.10.2019., (© 2021. The Author(s).)

Improved risk stratification of patients suspected of prostate cancer prior to biopsy continues to be an unmet clinical need. ExoDx Prostate (IntelliScore) "EPI" is a non-invasive urine test utilizing RNA from exosomes to provide a risk score that correlates with the likelihood of finding high grade prostate cancer at biopsy. Here, we present the results from a prospective clinical validation study of EPI-CE, a CE-marked in-vitro diagnostic (IVD) assay, specifically developed for use in European clinical laboratories. The study (NCT04720599) enrolled patients with ≥ 50 years, PSA 2-10 ng/mL, prior to MRI, who were scheduled for initial biopsy. First catch urine samples were collected from participants without prior digital rectal examination or prostate massage. Exosomal RNA was isolated and expression levels of three biomarkers ERG, PCA3 and SPDEF were analyzed according to the EPI-CE Instructions For Use. In the study cohort of N = 109 patients, EPI-CE was validated to have a Negative Predictive Value of 89%, a Sensitivity of 92% and a superior performance to two commonly used multiparametric risk calculators (PCPT and ERSPC) in both Receiver Operating Characteristics with a higher Area Under the Curve for EPI-CE 0.67 (95% CI 0.56-0.77) versus PCPT 0.59 (95% CI 0.47-0.71) and ERSPC 0.60 (95% CI 0.49-0.72) and higher Net Benefits analysis across a wide range of risk acceptance levels. This is the first clinical study reporting on the performance of EPI-CE. We demonstrate that EPI-CE provides information beyond standard clinical parameters and provides a better risk assessment prior to MRI, of patients suspected of prostate cancer, than the commonly used multiparametric risk calculators., (© 2022. The Author(s).)

Introduction: Palliative radical cystectomy (pRC) may be offered to selected bladder cancer (BC) patients with grievous local symptoms. However, there is only scarce information on perioperative complications and prognosis, especially in the case of metastatic spread. We intended to analyze morbidity and oncological outcome in this patient subgroup., Materials: Patients undergoing pRC because of BC with radiologic evidence of metastases were included in this retrospective study. Perioperative adverse events (AEs) were graded by the Clavien-Dindo Classification system. All patients underwent CT-based surveillance, and questionnaires were sent for survival follow-up in predefined intervals. Oncological outcome and predictive markers were assessed in univariate and multivariate analyses, using log-rank tests and Cox-regression analyses., Results: Between 2004 and 2016, 77 patients were identified. Median age at surgery was 70 years (IQR 66-77) and the median follow-up time was 12 months (IQR 4-44). Preoperative staging revealed pulmonary, hepatic, bone, peritoneal, and various other metastasis in 46/77 (60%), 14/77 (18%), 11/77 (14%), 5/77 (7%), and 11/77 (14%) cases, respectively. Most frequently observed symptoms at the time of pRC were severe gross hematuria (n = 41) and intense pain (n = 11). Most AEs were of minor grade (83%). The median length of stay was 20 days. Median CSS was 13 months with a 5-year CSS of 34%. Intriguingly and unsuspectedly, preoperatively suspicious lung lesions were confirmed during surveillance only in 33%, respectively. In multivariate analysis, intraoperative blood transfusions (HR = 2.25, 95% CI: 1.09-4.63, p = 0.028) were significantly associated with decreased CSS. The best outcome was observed in patients with only subpleural metastases (CSS 80 months, p = 0.039) and normal CRP- and Hb values., Conclusion: pRC can be performed with acceptable perioperative morbidity and mortality. Pulmonary lesions seem to have a risk of false-positive results and should be biopsied in all uncertain cases. Localization of lung metastases together with preoperative CRP- and Hb levels seem to play a prognostic role., (© 2022 S. Karger AG, Basel.)

Purpose: Contrast-enhanced CT scan is the standard staging modality for patients with bladder cancer undergoing radical cystectomy (RC). Involvement of lymph nodes (LN) determines prognosis of patients with bladder cancer. The detection of LN metastasis by CT scan is still insufficient. Therefore, we investigated various CT scan characteristics to predict lymph node ratio (LNR) and its impact on survival. Also, pre-operative CT scan characteristics might hold potential to risk stratify cN+ patients., Materials and Methods: We analyzed preoperative CT scans of patients undergoing RC in a tertiary high volume center. Retrospectively, local tumor stage and LN characteristics such as size, morphology (MLN) and number of loco-regional LN (NLN) were investigated and correlation to LNR and survival was analyzed. CT scan characteristics were used to develop a risk stratification using Kaplan-Maier and multivariate analysis., Results: 764 cN0 and 166 cN+ patients with complete follow-up and imaging data were included in the study. Accuracy to detect LN metastasis and locally advanced tumor stage in CT scan was 72% and 62%. LN larger than 15mm in diameter were significantly associated with higher LNR (p=0.002). Increased NLN correlated with decreased CSS and OS (p=0.001: p=0.002). Furthermore, CT scan based scoring system precisely differentiates low-risk and high-risk profiles to predict oncological outcome (p < 0.001)., Conclusion: In our study, solely LN size >15mm significantly correlated with higher LNR. Identification of increased loco-regional LN was associated with worse survival. For the first time, precise risk stratification based on computed-tomography findings was developed to predict oncological outcome for clinical lymph node-positive patients undergoing RC., Competing Interests: None declared., (Copyright® by the International Brazilian Journal of Urology.)

A new process was developed to recover high specific activity (no carrier added) 99 Mo from electron-accelerator irradiated U 3 O 8 or uranyl sulfate targets. The process leverages a novel solvent extraction scheme to recover Mo using di(2-ethylhexyl) phosphoric acid following uranium and transuranics removal with tri-n-butyl phosphate. An anion-exchange concentration column step provides a final purification, generating pure 99 Mo intended for making 99 Mo/ 99m Tc generators. The process was demonstrated with irradiated uranium targets resulting in more than 95% 99 Mo recovery and without presence of fission products or actinides in the product.

Objective: To evaluate the impact of urinary diversion on regular features of urinalysis and to screen for risk factors of infection-related complications., Methods: We conducted a retrospective, single-centre study of 429 patients who underwent open radical cystectomy. Patients were followed for 12 months and data of the complete urinalyses were analysed at three pre-defined time points., Results: Two weeks after surgery, dipstick testing with positive reactions for leukocyte esterase and haemoglobin were confirmed in 80.7% and 80% after ileal conduit (IC) and orthotopic ileal neobladder (NB), respectively. Every patient was positive for these parameters 12 months after surgery. Correspondingly, the microscopic examination detected leukocytes (84% vs. 85.4%), erythrocytes (82.8% vs. 83.8%) and bacteria (94.3% vs. 96.8%) following IC and NB reconstruction. After 12 months, all parameters were positive irrespective of the type of urinary diversion. Two weeks after surgery positive urine cultures were obtained in more than 50% of cases after IC (52.5%) and NB (60.5%) (p > 0.05). All urine cultures were positive after 12 months with significantly more poly-microbial results found after NB (81.3%) compared with IC (67.2%) (p = 0.018). In univariate and multivariate logistic regression analysis the presence of hydronephrosis was independently associated with the occurrence of infectious complications (OR 4.2; CI 95% 1.525-11.569; p = 0.006)., Conclusion: A positive urinalysis is a common finding after urinary diversion. Hydronephrosis is a serious risk factor with respect to infection-related complications. The simple fact of a positive urinalysis does not warrant antimicrobial treatment.

Purpose: While survival outcomes of locally advanced bladder cancer patients undergoing radical cystectomy are known to be poor, less is known regarding patient-reported outcomes and predictive features for survival in this patient subgroup., Methods: One hundred and eighteen consecutive patients with pT4a cM0 urothelial carcinoma of the bladder were included. Based on pathological review, patients were stratified into 3 subgroups based on existence of additional lesions and invasion depth of the respective lesions. Cancer-specific survival and overall survival (OS) was determined using Kaplan-Meier-analyses and multivariate Cox regression models (P <0.05). Health-related quality of life was assessed using the validated EORTC-QLQ-C30 questionnaire pre- and postoperatively., Results: Seventy-two (61.0%) patients were ineligible for neoadjuvant chemotherapy. Median follow-up based on censored patients was 12 months. Twelve month OS rate was 56.1%, 24 months OS rate was 21.1%. A total of 44.4% of the patients stated good general health-related quality of life. In multivariate analysis, we found significantly adverse OS outcomes for female patients (hazard ratio 2.35, 95% confidence interval 1.09-5.08, P = 0.030). Patients with at least 1 additional locally advanced tumor had significantly worse OS outcomes compared to patients who had no additional lesions in multivariate Cox regression analysis (hazard Ratio 3.37, 95% confidence interval 1.29-8.78, P = 0.013)., Conclusion: Existence of multiple locally advanced lesions and female gender is an independent predictor of worse survival outcomes in patients with pT4a urothelial carcinoma undergoing radical cystectomy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: The rapid accumulation of crude-oil based plastics in the environment is posing a fundamental threat to the future of mankind. The biodegradable and bio-based polyhydroxyalkanoates (PHAs) can replace conventional plastics, however, their current production costs are not competitive and therefore prohibiting PHAs from fulfilling their potential., Results: Different low-quality animal by-products, which were separated by thermal hydrolysis into a fat-, fat/protein-emulsion- and mineral-fat-mixture- (material with high ash content) phase, were successfully screened as carbon sources for the production of PHA. Thereby, Ralstonia eutropha Re2058/pCB113 accumulated the short- and medium-chain-length copolymer poly(hydroxybutyrate-co-hydroxyhexanoate) [P(HB-co-HHx)]. Up to 90 wt% PHA per cell dry weight with HHx-contents of 12-26 mol% were produced in shake flask cultivations., Conclusion: In future, the PHA production cost could be lowered by using the described animal by-product streams as feedstock.

Objective: Developmental dyslexia is a highly heritable specific reading and writing disability. To identify a possible new locus and candidate gene for this disability, we investigated a four-generation pedigree where transmission of dyslexia is consistent with an autosomal dominant inheritance pattern. Methods: We performed genome wide array-based SNP genotyping and parametric linkage analysis and sequencing analysis of protein-coding exons, exon-intron boundaries and conserved extragenic regions within the haplotype cosegregating with dyslexia in DNA from one affected and one unaffected family member. Cosegregation was confirmed by sequencing all available family members. Additionally, we analyzed 96 dyslexic individuals who had previously shown positive LOD scores on chromosome 4q28 as well as an even larger sample ( n = 2591). Results: We found a single prominent linkage interval on chromosome 4q, where sequence analysis revealed a nucleotide variant in the 3' UTR of brain expressed SPRY1 in the dyslexic family member that cosegregated with dyslexia. This sequence alteration might affect the binding efficiency of the IGF2BP1 RNA-binding protein and thus influence the expression level of the SPRY1 gene product. An analysis of 96 individuals from a cohort of dyslexic individuals revealed a second heterozygous variant in this gene, which was absent in the unaffected sister of the proband. An investigation of the region in a much larger sample further found a nominal p -value of 0.0016 for verbal short-term memory (digit span) in 2,591 individuals for a neighboring SNV. After correcting for the local number of analyzed SNVs, and after taking into account linkage disequilibrium, we found this corresponds to a p -value of 0.0678 for this phenotype. Conclusions: We describe a new locus for familial dyslexia and discuss the possibility that SPRY1 might play a role in the etiology of a monogenic form of dyslexia.

Recent findings suggested a benefit of anti-EGFR therapy for basal-like muscle-invasive bladder cancer (MIBC). However, the impact on bladder cancer with substantial squamous differentiation (Sq-BLCA) and especially pure squamous cell carcinoma (SCC) remains unknown. Therefore, we comprehensively characterized pure and mixed Sq-BLCA (n = 125) on genetic and protein expression level, and performed functional pathway and drug-response analyses with cell line models and isolated primary SCC (p-SCC) cells of the human urinary bladder. We identified abundant EGFR expression in 95% of Sq-BLCA without evidence for activating EGFR mutations. Both SCaBER and p-SCC cells were sensitive to EGFR tyrosine kinase inhibitors (TKIs: erlotinib and gefitinib). Combined treatment with anti-EGFR TKIs and varying chemotherapeutics led to a concentration-dependent synergism in SCC cells according to the Chou-Talalay method. In addition, the siRNA knockdown of EGFR impaired SCaBER viability suggesting a putative "Achilles heel" of Sq-BLCA. The observed effects seem Sq-BLCA-specific since non-basal urothelial cancer cells were characterized by poor TKI sensitivity associated with a short-term feedback response potentially attenuating anti-tumor activity. Hence, our findings give further insights into a crucial, Sq-BLCA-specific role of the ERBB signaling pathway proposing improved effectiveness of anti-EGFR based regimens in combination with chemotherapeutics in squamous bladder cancers with wild-type EGFR-overexpression.

Background: With the Act on Genetic Testing (GenDG), the German legislator has issued far-reaching regulations for human genetic services, including genetic counseling. This paper presents data on the use of human genetic counseling in the years before and after the entry into force of GenDG in order to provide an informed assessment of the possible effects of the law., Materials and Methods: Over a period of 13 years (2005 to 2017), the human genetic counseling services provided within the framework of the statutory health insurance and billable by EBM via the Kassenärztliche associations were recorded via a database query at the Central Institute of the National Association of Statutory Health Insurance Physicians (ZI-KBV) and via individual Kassenärztliche Vereinigungen Deutschlands. For the discussion of the observable development of using genetic counseling and possible future development, additional data on the referral behavior, the waiting times, processing time, and reasons for consultations were extracted from the GenBIn database., Results and Discussion: Demand for genetic counseling has steadily increased at an average rate of approximately 6% per year since 2009. This increase started well before the enactment of the GenDG and may be attributed to a multiplicity of factors. Change in demand for genetic counseling is characterized by increasing self-referrals and by increasing referrals by specialists other than obstetricians/gynecologists. Waiting times between 2011 and 2016/2017 have increased. While demand has been growing, the number of key service providers, the contracted medical specialists in human genetics, has remained almost constant. It is foreseeable that capacity limits will be reached if both trends continue.

Biodegradable and biocompatible polyhydroxyalkanoates (PHAs) are promising alternatives to conventional plastics. Based on the chain length of their monomers they are classified as short chain length ( scl- ) or medium chain length ( mcl- ) PHA polymers. The type of monomers, the composition and the molecular weight (MW) define the polymer properties. To accelerate the use of PHA as a bulk material, the downstream associated costs need to be minimized. This study focuses on the evaluation of non-halogenated solvents, especially acetone as a scl -PHA non-solvent, for the recovery of poly(3-hydroxybutyrate- co -3-hydroxyhexanoate) - P(HB- co -HHx) - with an mcl -HHx content >15 mol% and a MW average ( M w ) < 2 × 10 5 Da. Solvents and precipitants were chosen regarding zeotrope formation, boiling point differences, and toxicity. Non-halogenated solvent-precipitant pairs were evaluated regarding the MW characteristics (MWCs) of the extracted polymer. Acetone and 2-propanol as a low toxic and zeotropic solvent-precipitant pair was evaluated at different extraction temperatures and multiple extraction times. The extraction process was further evaluated by using impure acetone for the extraction and implementing a multi-stage extraction process. Additionally, P(HB- co -HHx) extracted with three different solvents was characterized by 1 H and 13 C-APT NMR. The screening of precipitants resulted in a negative influence on the MWCs by ethanol precipitation for extractions with acetone and ethyl acetate, respectively. It was observed, that extractions with acetone at 70°C extracted a higher fraction of PHA from the cells compared to extractions at RT, but the M w was decreased by 9% in average. Acetone with a 2-propanol fraction of up to 30% was still able to extract the polymer 95% as efficient as pure acetone. Additionally, when acetone and ethyl acetate were used in a multi-stage extraction process, a two-stage process was sufficient to extract 98-99% of the polymer from the cells. 1 H and 13 C-APT NMR analysis confirmed the monomer fraction and structure of the extracted polymers and revealed a random copolymer structure. The presented strategy can be further developed to an ecological and economically feasible PHA downstream process and thus contributes to the commercialization of low-cost PHAs., (Copyright © 2020 Bartels, Gutschmann, Widmer, Grimm, Neubauer and Riedel.)

Background: Radical cystectomy (RC) and urinary diversion affect various dimensions of patents' health-related quality of life (HRQOL). Knowledge regarding patient-reported HRQOL following RC is mainly based on retrospective findings of cross-sectional studies., Objective: To provide data from a large prospective propensity score-matched cohort with a systematic follow-up of up to 2 yr., Design, Setting, and Participants: A total of 134 consecutive patients who underwent RC and ileal conduit (IC) or orthotopic ileal neobladder (ONB) urinary diversion in a tertiary care centre were prospectively enrolled, and a propensity score matching analysis based on American Society of Anesthesiologists score, age, and tumour stage was performed. Exclusion criteria encompassed age <30 yr and RC due to benign diseases. HRQOL was addressed with the validated European Organization for Research and TREATMENT: of Cancer QLQ-C30 questionnaire. HRQOL was assessed preoperatively, and at 3, 12, and 24 mo postoperatively. Of the nondeceased patients, 85.1% (IC) and 78.2% (ONB) completed the study., Intervention: RC., Outcome Measurements and Statistical Analysis: The primary endpoint was good general HRQOL based on previously published cut-off values. Secondary endpoints encompassed the respective HRQOL domains. Univariate and multivariate analyses were performed using binary logistic regression models., Results and Limitations: In the longitudinal analysis of RC patients, functioning and symptoms scores show a similar natural HRQOL course for IC and ONB patients. After 24 mo, general HRQOL was significantly higher in the ONB subcohort (60.5 vs 73.6, p=0.013). Good general HRQOL was reached by 32.4 (IC) versus 61.1% (ONB; p=0.019). In the multivariable analysis, ONB was not an independent predictor of good HRQOL (odds ratio 2.211, 95% confidence interval 0.684-7.150, p=0.185). Limitations include the nonbladder specificity of the QLQ-C30 questionnaire and the small sample size., Conclusions: The current study provides prospective data from a unique propensity score-matched contemporary patient cohort. We display the natural history of general HRQOL and its subdomains without observing significantly higher midterm postoperative HRQOL in patients undergoing continent urinary diversion in the multivariable analysis., Patient Summary: We analyse the health-related quality of life (HRQOL) of European patients who underwent radical cystectomy due to bladder cancer and found that HRQOL was slightly better for orthotopic ileal neobladder than for ileal conduit urinary diversion after 24 mo., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Continuous-wave photoinjectors operating at high accelerating gradients promise to revolutionize many areas of science and applications. They can establish the basis for a new generation of monochromatic x-ray free electron lasers, high-brightness hadron beams, or a new generation of microchip production. In this Letter we report on the record-performing superconducting rf electron gun with CsK&#95;{2}Sb photocathode. The gun is generating high charge electron bunches (up to 10  nC/bunch) and low transverse emittances, while operating for months with a single photocathode. This achievement opens a new era in generating high-power beams with a very high average brightness.

Background: The purpose of this study was to analyze trends of bladder cancer (BC) stages and incidence in Europe and the United States (US)., Materials and Methods: Tumor stages after radical cystectomy were assessed in a monocentric cohort from 2006 to 2016. BC incidence was assessed between 2004 and 2014 based on the German Center for Cancer Registry Data dataset at the Robert Koch Institute (n = 111,002), the Netherland Cancer Registry (n = 64,226), cancer registration statistics of England (n = 179,883), and the pooled data from the Scandinavian cancer registries, NORDCAN (n = 77,585) and the SEER (Surveillance, Epidemiology, and End Results) database (n = 184,519) for the complete populations and gender-specific subgroups. The average annual percent changes (AAPC) were used for statistical evaluation., Results: Non-muscle-invasive BC (NMIBC) and muscle-invasive BC (MIBC) did not change in the institutional cohort at the point of radical cystectomy. The incidence of total BC (AAPC, -0.3), NMIBC (AAPC, -0.1), and non-metastasized MIBC (AAPC, 0.1) did not change in Germany during the time period under survey. BC total incidence in the Netherlands did not change significantly. In England and the Nordic countries, the incidence of total BC increased (AAPC, 0.8 and 0.5, respectively). In contrast, both the incidence of total BC (AAPC, -1.4), NMIBC (AAPC, -1.6), and non-metastasized MIBC (AAPC, -1.6) significantly decreased in the US., Conclusions: Between 2004 and 2014 the incidence of BC was significantly sinking in the US, was stable in Germany and the Netherlands, and increased in England and the Nordic countries. Predominantly, differences in the smoking prevalence within the last decades but also gender-specific factors might be responsible for this discrepancy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Profound endourological skills are required for optimal postoperative outcome parameters after transurethral resection of the prostate (TURP). We investigated the Karl Storz (Tuttlingen, Germany) UroTrainer for virtual simulation training of the TURP., Materials and Methods: Twenty urologists underwent a virtual reality (VR) TURP training. After a needs analysis, performance scores and self-rated surgical skills were compared before and after the curriculum, the realism of the simulator was assessed, and the optimal level of experience for VR training was evaluated. Statistical testing was done with SPSS 25., Results: Forty percent of participants indicated frequent intraoperative overload during real-life TURP and 80% indicated that VR training might be beneficial for endourological skills development, underlining the need to advance classical endourological training. For the complete cohort, overall VR performance scores (P = 0.022) and completeness of resection (P < 0.001) significantly improved. Self-rated parameters including identification of anatomical structures (P = 0.046), sparing the sphincter (P = 0.002), and handling of the resectoscope (P = 0.033) became significantly better during the VR curriculum. Participants indicated progress regarding handling of the resectoscope (70%), bleeding control (55%), and finding the correct resection depth (50%). Although overall realism and handling of the resectoscope was good, virtual bleeding control and correct tissue feedback should be improved in future VR simulators. Seventy percent of participants indicated 10 to 50 virtual TURP cases to be optimal and 80% junior residents to be the key target group for VR TURP training., Conclusions: There is a need to improve training the TURP and VR simulators might be a valuable supplement, especially for urologists beginning with the endourological desobstruction of the prostate.

Two pentadentate N3,P2 ligands coordinate zinc(ii) by their N3 pocket. Four free phosphine donors allow the coordination of four AuCl moieties leading to a pentanuclear ZnAu4 complex. In contrast, the attempt to use the phosphines for chelating coordination of two Rh(CO)Cl units results in a well-organized rearrangement that ends up with the formation of a metallomacrocycle in high yields.

Purpose: The evaluation of the potential clinical benefit of four-dimensional ultrasound (4D-US) in the assessment of bladder cancer (BC)., Material and Methods: 20 patients with indication for cystoscopy for suspicion of bladder cancer were prospectively included in this study. All patients underwent two-dimensional ultrasound (2D-US), contrast enhanced ultrasound (CEUS) and real-time four-dimensional ultrasound (4D-US). All acquisitions were compared to each other in regard to image quality. This assessment was done using a 6 point scale (1 = best). All patients underwent subsequently cystoscopy with resection of the tumor (TURB), due a histopathological analysis was possible., Results: All examinations were performed successfully and no patient had to be excluded from the study. Patients acceptance of 4D-US was consistently good. No adverse events occurred. Image quality of real time 4D-US (score: 1.27±0.46) was significantly superior (p < 0.001) to both, conventional 2D-US (score: 2.33±0.62) and also to 2D-CEUS (score: 2.00±0.53). In terms of tumor detection no superiority was evident for 4D-US compared to 2D-US or in utilization of CEUS (sensitivity = 0.89; specificity = 1.00; positive predictive value = 1.00; negative predictive value = 0.50; AUC = 0.944; (95% CI: 07.43-0.998))., Conclusion: The assessment of bladder cancer using real time 4D-US is feasible and improves the image quality and therefore also the precise anatomical consistency of intravesical tumor masses.

Background: Preoperative thrombocytosis (PTC) is frequently observed in various solid malignancies and often associated with an unfavourable oncological outcome., Objectives: The aim of this study was to investigate the influence of PTC in patients undergoing radical cystectomy (RC) for urothelial carcinoma (UC) of the bladder on the oncological prognosis and additionally on perioperative blood transfusions (PBT)., Method: A retrospective analysis of 866 patients undergoing RC in a tertiary care centre was performed. PTC was defined as a platelet count >400 G/L. A chi-square test and Mann-Whitney test were used to investigate the association of PTC with categorical clinicopathological variables. A logrank test and multivariable Cox regression analyses were used to assess the association of PTC with cancer-specific survival., Results: PTC was detected in 8% (n = 67) of the patients and was significantly associated with muscle invasion (p = 0.004), advanced tumour stages (p = 0.003) and nodal metastases (p < 0.001) and with a higher rate of PBT (p< 0.001). In the multivariate analysis, PTC was significantly related to poor oncological survival (hazard ratio 2.23, 95% CI 1.51-3.30, p < 0.001)., Conclusion: PTC is significantly associated with an impaired oncological outcome in patients undergoing RC for UC. PTC therefore represents an independent and easy to determine prognostic parameter for patients' oncological outcome. Intriguingly, PTC is significantly associated with an increased rate of PBT., (© 2019 S. Karger AG, Basel.)

Purpose: With a median age at diagnosis of 73 years, bladder cancer has the highest median age of all cancers. Age alone seems to be an independent risk factor for developing the disease with peak age advancing into the range of 85 years. As demographic changes will lead to an ever more aging population in western countries, incidence of advanced age malignancies will rise. We, therefore, analyzed a contemporary radical cystectomy (RC) series at a single high-volume center on patients undergoing RC for urothelial carcinoma of the bladder (UCB). We aim to evaluate the feasibility of RC in the oldest-old patient cohort by assessing perioperative complications and long-term outcome., Materials and Methods: We retrospectively analyzed data of 1,278 consecutive patients who underwent RC for UCB at our tertiary referral center between 2004 and 2019. A total of 408 patients were aged 75-97 years at the time of RC and were further divided into 2 groups: 75-84 years of age (group 1) and ≥85 years of age (group 2). Median follow-up was 23 months. Outcome was analyzed using the χ2 test, Mann-Whitney U test, Kaplan-Meier method, and log-rank test., Results: Perioperative Clavien-Dindo grade ≥III complications were seen in 25.1% (92/366) of group 1 patients and 35.7% (15/42) of group 2 patients (p = 0.073). Thirty- and 90-day mortality was 3.3 and 8.7% in group 1 and 4.8 and 14.3% in group 2 (p = 0.617 and p = 0.242, respectively). Three-year overall survival was 54.6% in group 1 and 31.3% in group 2 (p = 0.03). Three-year cancer-specific survival was 64.8% in group 1 and 38.8% in group 2 (p = 0.037). Recurrence-free survival was 105 months in group 1 and 12 months in group 2 (p = 0.039)., Conclusion: In light of increasing life expectancy in western nations, we sought to evaluate the impact of age in a large series of elderly patients undergoing RC for UCB. We found that RC offers acceptable perioperative complication rates in the oldest-old patient cohort (≥85 years). Therefore, RC for UCB can be offered as a viable treatment option even in the oldest patients., (© 2020 S. Karger AG, Basel.)

Objectives: Patients' oncological outcome after radical cystectomy (RC) due to urothelial carcinoma of the urinary bladder (UCB) is always up for debate. There is accumulating evidence on the influence of routine blood parameters. We aimed to identify reasonable and easy-to-detect biomarkers, such as preoperative C-reactive protein (CRP) and hemoglobin (Hb) levels, as predictors of overall survival (OS) and cancer-specific survival (CSS) in patients undergoing RC for UCB., Materials and Methods: This is a large single-center study in which both preoperative CRP and Hb levels were available in 1,043 patients undergoing RC for UCB from 2004 to 2018 with a median follow-up time of 22 months (mean 38, max. 170). We used the Kaplan-Meier method, log-rank test, and Cox regression models for assessment of OS and CSS. Using our data, we validated an existing outcome prediction score (TNR-C)., Results: Median CRP level was 0.5 mg/dL (IQR 0.2-1.4), and median Hb level was 13.4 g/dL (IQR 11.9-14.7). We found that patients with CRP values above the median reached a significantly lower median survival than those with CRP values below the median (23 vs. 83 months, p < 0.001). The TNR-C score was successfully validated, and we discriminated between 3 risk groups (5-year CSS: 76, 40, and 16% for low, intermediate, and high risk, respectively). We observed a similar outcome for patients with a Hb level below the median: CSS was significantly poorer than with Hb levels above the median (median CSS 27 vs. 91 months, p < 0.001). Multivariant analysis showed CRP and Hb levels to be independent prognostic parameters for CSS and OS., Conclusions: We found elevated preoperative CRP levels and decreased Hb levels to be independent prognostic factors indicating an unfavorable outcome in patients undergoing RC for UCB and were able to validate the TNR-C score in a large patient cohort. We propose using these routine biomarkers for individual risk stratification and optimization of therapeutic strategies in patients undergoing RC for UCB., (© 2020 S. Karger AG, Basel.)

Introduction: Enhanced recovery after surgery (ERAS) concepts are implemented in various surgical disciplines. For patients undergoing radical cystectomy, prospective data are still rare. In the year 2014, our group could prove significant benefits of ERAS for these patients in a prospective randomized study compared to a conservative regimen., Objective: To evaluate long-term follow-up results of ERAS concepts in patients undergoing radical cystectomy for bladder cancer., Methods: Of the 101 patients who had initially prospectively been randomized to ERAS or a conservative regimen, 35 patients could be included in the study. Median follow-up time was 83 months. Primary end point assessed quality of life. Secondary end points were cancer-specific survival and overall survival., Results: Five to seven years after the initial inclusion to the study, no significant difference regarding quality of life parameters was detected (p values range between 0.112 and 0.970). Continence status in patients with neobladder showed no significant differences between ERAS and conservative regimens (p = 0.785). Cancer-specific survival in the ERAS group did not differ significantly from that in the conservative group (49 vs. 58%, p = 0.725)., Conclusions: While ERAS represents an excellent way to improve postoperative reconvalescence and quality of life in the short-term follow-up, our data do not support the idea that there is also a long-term effect in terms of quality of life issues., (© 2019 S. Karger AG, Basel.)

In 2016, the Department of Psychosomatic Medicine and Psychotherapy of the University Hospital of Erlangen started conducting training for professional and voluntary aid workers. In total, 149 aid workers took part in the training courses, of which 135 completed the corresponding questionnaires. Engagement motivators, perceived distress in refugee work and training needs were examined. Moreover, depressive symptoms, the prevalence of traumatic experiences and symptoms of posttraumatic stress disorder were explored. Participants named helping others as the highest motivating factor for their work with refugees and communication problems as the main burden. Thirteen aid workers (10.1%) showed clinically relevant depressive symptoms. In total, 91.4% of refugee aid workers had experienced at least one traumatic event personally or as a witness but only three (3.6%) fulfilled the psychometric requirements of a PTSD diagnosis. These three participants all belonged to the professional aid workers (6.3%). More severe symptoms of depression were significantly associated with female gender (β = 0.315, p = 0.001), higher perceived burdens of refugee work (β = 0.294, p = 0.002), and a larger number of experienced traumatic events (β = 0.357, p < 0.001). According to our results, we recommend psychological trainings and regular screenings for psychological stress in order to counteract possible mental illnesses.

Purpose: To objectively quantify continence rates and to correlate continence outcomes with health-related quality of life (HRQOL) after radical cystectomy and orthotopic ileal neobladder (ONB)., Methods: Questionnaires were sent to 244 patients who underwent radical cystectomy with ONB between 2004 and 2015, and information about the current continence status was retrieved. To objectify postoperative urine loss, daytime and nocturnal pad tests were performed. Continence was defined as need of up to one safety pad. HRQOL was assessed using EORTC QLQ-C30 scoring with global health status being the primary endpoint. Statistical analysis included Fisher's test, Mann-Whitney U test, Pearson's rank correlation, and binary regression models (p < 0.05)., Results: 178 patients (73.0%) answered the QLQ-C30 questionnaires and were included in the study. Median follow-up was 61 months. Median daytime pad use was 1 and median daily urine loss based on pad testing was 4.0 g, leading to a daytime continence rate of 48.5%. Continence had a significant impact on postoperative HRQOL (p = 0.017). ICIQ-SF score (p = 0.001, OR = 0.805) and need for condom catheter during nighttime (p = 0.015, OR = 0.123) were independent predictors for worse HRQOL outcomes based on global health status. A history of pelvic floor muscle training was an independent predictor of increased HRQOL (p = 0.009, OR = 10.459)., Conclusions: Need of condom urinals and higher ICIQ-SF scores are independent predictors for worse HRQOL outcomes. We show significant beneficial effects of pelvic floor muscle training on patients' HRQOL.

Objective: Dysregulation of the extracellular matrix molecule biglycan (BGN) predicts poor survival in several cancer entities. Our study investigated the prognostic impact of BGN in bladder cancer (BC) in 2 independent cohorts and assessed its role in epithelial-mesenchymal transition (EMT) and association with molecular BC subtypes., Methods: BGN protein expression was correlated with the oncological outcome of 162 patients with BC undergoing radical cystectomy (RC) in a single center and furthermore on gene expression level in the TCGA database. Cut-off values for BGN protein and RNA expression were tested with receiver operating characteristic (ROC) curves. BGN gene expression was correlated with established EMT and BC gene signatures in the TCGA database using gene set enrichment analysis (GSEA). Key EMT and basal/luminal molecular BC subtype markers were correlated with BGN expression and data were shown in a heat map., Results: BGN upregulation in BC cells on the protein level predicted poor oncological survival in the institutional cohort for both univariate (P = 0.007) and multivariate (P = 0.040) analyses. BGN expression was not associated with other clinicopathological parameters. The prognostic value of BGN was validated on the mRNA level in the BC TCGA database (P = 0.002). Both EMT and BC core gene signatures (P < 0.001) correlated with BGN expression in GSEA. BGN gene expression was associated with key indicators of EMT. BGN was associated positively with the molecular basal BC subtype and negatively with the BC luminal subtype., Conclusion: BGN is an independent prognosticator for poor survival in BC patients. BGN is associated with the basal molecular BC subtype. EMT might be a key player for BGN driven oncogenesis, as BGN expression correlates with EMT gene signatures., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In the prostate-specific antigen (PSA) era, most prostate cancers (PCa) are diagnosed in a localized stage and a plethora of therapeutic options are warranted in different clinical settings and disease stages of localized PCa. In the current narrative review, we give an overview of the current controversies in the therapeutic landscape of localized PCa and focus on organ-sparing approaches, percutaneous radiotherapy, brachytherapy as well as retropubic and robot-assisted prostatectomy by summarizing studies that have been published within the last two years.

Objective: The oncological outcome in patients with bladder cancer (BC) significantly correlates with the quality of transurethral resection of bladder tumors (TUR-BT). Virtual reality (VR) training simulators have been developed to improve surgical skills. We evaluated the advantages and limitations of the novel Uro Trainer (UT) (Karl Storz GmbH, Germany) with respect to training for TUR-BT., Design: Participants underwent VR training based on 4 different TUR-BT cases accompanied by self-assessment and evaluation questionnaires. Results were compared between experienced endourologists and novices, and furthermore, correlated with self-rated capabilities for content and construct validity. Student's t tests, Pearson's correlation, and chi-squared tests were performed for statistical evaluation., Setting: The study was performed at the tertiary care urological department of the Ludwig-Maximilians-University, Munich, Germany., Participants: A total of 22 urological physicians, including residents and consultants, were included in the study., Results: There is a need to improve TUR-BT training as 27.3% of the participants had already experienced overtaxing situations during TUR-BT and only a few reported of high satisfaction with the classical "see one-do one" teaching mode. Construct validity was demonstrated, as consultants achieved significantly higher overall scores (p < 0.001) and safety (p = 0.004) and visualization (p = 0.001) subscores. Interestingly, the self-assessed capability to perform a TUR-BT correlated significantly (p = 0.01) with overall UT scores. Significant progress of self-rated abilities was shown for several parameters, including inspection (p = 0.046) and resection (p = 0.026). Although participants indicated improvements in several procedural skills and overall benefit of the VR training with the UT was rated 4.6 on a 5-point scale by consultants, limitations of the UT were demonstrated predominantly for tissue feedback and authenticity of different tissue layers., Conclusions: The novel VR simulator showed a high face and construct validity, and therefore has a great potential to complement endourological training., (Copyright © 2018 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

Prostate cancer is a heterogeneous disease. In cases of low-risk prostate cancer, active surveillance represents an attractive alternative treatment. Significant complications of a definitive treatment can therefore be delayed or completely avoided. Despite strict inclusion criteria for active surveillance, the diagnosis of low-risk prostate cancer can be inaccurate and there is therefore a risk of missing the optimal point in time for definitive treatment. Multimodal diagnostics and continuous aftercare are therefore crucial.

Purpose: Early rehabilitation (ER) after radical cystectomy (RC) seems to be crucial for quality of life, education and prevention of complications after hospital discharge. We investigated an inpatient ER setting for bladder cancer (BC) patients., Methods: In total, 103 BC patients who underwent ileum neobladder reconstruction were included. The major issues from the patients' point of view, functional outcome parameters and complications during ER were analysed. A Wilcoxon signed rank test was used to compare body mass index (BMI) and diurnal as well as nocturnal use of urinary pads before and after ER., Results: At the beginning of ER, the median Karnovsky performance scale score was 70% (interquartile range [IQR] 70-90%) and the mean BMI was 25.8 kg/m2 (IQR 21.9-27.9). The 4 most common complaints were urinary incontinence (80.6%), general weakness (73.8%), urinary mucus (49.5%) and mental distress (44.7%). During the programme, 28.2% of patients had a urinary tract infection requiring antibiotics and 15.5% presented a symptomatic acidosis. Median diurnal use of urinary pads significantly decreased during ER (4 vs. 3; p < 0.001). At the end of the ER programme, 76.0, 54.8 and 30.8% of the patients indicated an improvement of their physical capacity, incontinence and psychological distress respectively., Conclusions: Our study demonstrates the need for postoperative rehabilitation after RC. Further investigations should compare outcome parameters to ambulatory and outpatient ER models., (© 2019 S. Karger AG, Basel.)

Background: The purpose of this study was to investigate major complications and risk factors for adverse clinical outcome in surgical high-risk (American Society of Anesthesiologists [ASA] 3-4) patients undergoing radical cystectomy (RC) in a high-volume setting., Patients and Methods: A total of 1206 patients underwent RC between 2004 and 2017 in our institution and were included. We assessed complications graded by the Clavien-Dindo-Classification system (CDC) in addition to the 90-day mortality rate and stratified results by the ASA classification. In a multivariate analysis, risk factors for high-grade complications (CDC ≥ 3) were tested. Additionally, outcome parameters were compared between 2004 to 2010 and 2010 to 2017., Results: Patients with ASA ≥ 3 presented with more locally advanced tumors pT ≥ 3 (52.1% vs. 42.4%; P = .002) and positive lymphatic spread N1 (27.2% vs. 23.5%; P = .001) compared with patients with ASA ≤ 2. High-grade complications were significantly (P < .001) more prevalent in patients with ASA ≥ 3 compared with patients with ASA ≤ 2: CDC3 (14.6% vs. 9.4%), CDC4 (10.2% vs. 5.4%), and CDC5 (2.5% vs. 1.0%). The 90-day mortality rate (7.6% vs. 3.2%; P = .002) and perioperative reinterventions (23.5% vs. 13.1%; P < .001) were elevated in patients with ASA ≥ 3. ASA (odds ratio [OR], 2.701, 95% confidence interval [CI], 1.089-6.703; P = .032), previous abdominal operations (OR, 1.683; 95% CI, 1.188-2.384; P = .003), and body mass index ≥ 30 (OR, 1.533; 95% CI, 1.021-2.304; P = .039) proved to function as independent predictors for major complications. CDC ≥ 3 complications (31.7% vs. 24.3%; P = .029) and 90-day mortality (10.4% vs. 5.6%; P = .018) were significantly lower in the second half of the study period., Conclusions: Mortality and morbidity in surgical high-risk patients with ASA 3 to 4 undergoing RC is about twice as high compared with patients with ASA 1 to 2. ASA, previous abdominal operations, and elevated body mass index independently predict adverse clinical outcome in patients with ASA 3 to 4. Our results may help to weigh the surgical risk of RC in multimorbid patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Prognostic/therapeutic stratification of papillary urothelial cancers is solely based upon histology, despite activated FGFR3-signaling was found to be associated with low grade tumors and favorable outcome. However, there are FGFR3-overexpressing tumors showing high proliferation-a paradox of coexisting favorable and adverse features. Therefore, our study aimed to decipher the relevance of FGFR3-overexpression/proliferation for histopathological grading and risk stratification. N = 142 ( n = 82 pTa, n = 42 pT1, n = 18 pT2-4) morphologically G1⁻G3 tumors were analyzed for immunohistochemical expression of FGFR3 and Ki67. Mutation analysis of FGFR3 and TP53 and FISH for FGFR3 amplification and rearrangement was performed. SPSS 23.0 was used for statistical analysis. Overall FGFR3 high /Ki67 high status ( n = 58) resulted in a reduced ∆mean progression-free survival (PFS) ( p < 0.01) of 63.92 months, and shorter progression-free survival ( p < 0.01; mean PFS: 55.89 months) in pTa tumors ( n = 50). FGFR3 mut / TP53 mut double mutations led to a reduced ∆mean PFS ( p < 0.01) of 80.30 months in all tumors, and FGFR3 mut / TP53 mut pTa tumors presented a dramatically reduced PFS ( p < 0.001; mean PFS: 5.00 months). Our results identified FGFR3 high /Ki67 high papillary pTa tumors as a subgroup with poor prognosis and encourage histological grading as high grade tumors. Tumor grading should possibly be augmented by immunohistochemical stainings and suitable clinical surveillance by endoscopy should be performed.

Objective: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative process affecting upper and lower motor neurons as well as non-motor systems. In this study, precentral and postcentral cortical thinning detected by structural magnetic resonance imaging (MRI) were combined with clinical (ALS-specific functional rating scale revised, ALSFRS-R) and neurophysiological (motor unit number index, MUNIX) biomarkers in both cross-sectional and longitudinal analyses. Methods: The unicenter sample included 20 limb-onset classical ALS patients compared to 30 age-related healthy controls. ALS patients were treated with standard Riluzole and additional long-term G-CSF (Filgrastim) on a named patient basis after written informed consent. Combinatory biomarker use included cortical thickness of atlas-based dorsal and ventral subdivisions of the precentral and postcentral cortex, ALSFRS-R, and MUNIX for the musculus abductor digiti minimi (ADM) bilaterally. Individual cross-sectional analysis investigated individual cortical thinning in ALS patients compared to age-related healthy controls in the context of state of disease at initial MRI scan. Beyond correlation analysis of biomarkers at cross-sectional group level ( n = 20), longitudinal monitoring in a subset of slow progressive ALS patients ( n = 4) explored within-subject temporal dynamics of repeatedly assessed biomarkers in time courses over at least 18 months. Results: Cross-sectional analysis demonstrated individually variable states of cortical thinning, which was most pronounced in the ventral section of the precentral cortex. Correlations of ALSFRS-R with cortical thickness and MUNIX were detected. Individual longitudinal biomarker monitoring in four slow progressive ALS patients revealed evident differences in individual disease courses and temporal dynamics of the biomarkers. Conclusion: A combinatory use of structural MRI, neurophysiological and clinical biomarkers allows for an appropriate and detailed assessment of clinical state and course of disease of ALS.

The stratification of bladder cancer into luminal and basal tumors has recently been introduced as a novel prognostic system in patient cohorts of muscle-invasive bladder cancer or high-grade papillary carcinomas. Using a representative immunohistochemistry panel, we analyzed luminal and basal marker expression in a large case series (n = 156) of urothelial carcinoma in situ (CIS), a precancerous lesion that frequently progresses to muscle-invasive disease. The majority of CIS cases was characterized by a positivity for luminal markers (aberrant cytokeratin (CK) 20 85% (132/156), GATA3 median Remmele score (score of staining intensity (0-3) multiplied with percentage of positive cells (0-4)): 12, estrogen receptor (ER) β Remmele score > 2: 88% (138/156), human epidermal growth factor receptor 2 (Her2) Dako score 3+ 32% (50/156), Her2 Dako score 2+ 33% (51/156)), and marginal expression of basal markers (CK5/6+ 2% (3/156), CK14+ 1% (2/156)). To further investigate phenotypic stability during disease progression, we compared 48 pairs of CIS and invasive tumors from the same biopsy. A highly significant loss of luminal marker expression (p < 0.001) was observed in the course of progression whereas an increase of basal marker expression (p < 0.01) was noted in the invasive compartment. Importantly, 91% of CIS cases demonstrated a positivity for at least one of the two predictive markers Her2 and ERβ, indicating that the analysis of Her2 and ERβ may help to identify CIS-patient subgroups prone to more efficient targeted treatment strategies. Larger prospective and biomarker-embedded clinical trials are needed to confirm and validate our preliminary findings.

Objectives: The effects of music interventions including active and receptive music therapy for people living with neurogenic disorders of consciousness (DOC) have been subject to empirical studies in the past. The aim of this systematic review was to find and analyse the current research about the effects of musical interventions on people with DOC., Methods: For this purpose, studies with music interventions and patients with DOC from the year 1900 to 2017 were searched in English, German, and French in different databases. Risk-of-bias-analyses were conducted for each study that fulfilled the inclusion criteria., Results: Twenty-two quantitative studies (three randomised controlled trials with more than 10 participants) were found eligible for review. They include a total of 329 participants living with either coma, unresponsive wakefulness syndrome, or minimally conscious state. Music interventions were associated with favourable behavioural and physiological responses in several studies, but methodological quality and outcomes were heterogeneous., Conclusions: More studies with a larger number of participants are needed as well as a consensus on key characteristics of effective short-term and long-term music interventions for DOC.

Context: There is growing interest in minimally invasive (MI) treatment options for male lower urinary tract symptoms (LUTS). Among these options, the temporary implantable nitinol device (TIND; Medi-Tate, Or Akiva, Israel) is a novel instrument used to alleviate symptoms by creating incisions in the prostate via mechanical stress., Objective: To review recent data for TIND as an MI procedure to improve LUTS., Evidence Acquisition: Medline, PubMed, the Cochrane Database, and Embase were screened for clinical trials, randomized controlled trials, and review articles on the use of TIND in patients with male LUTS., Evidence Synthesis: There are currently two studies available, one being a follow-up of the first pilot study. Both 12-mo and 36-mo results suggest at least medium-term effects of TIND in terms of symptom improvement (International Prostate Symptom Score, IPSS) and maximum urinary flow (Q max ). IPSS was improved by 41% after 12mo (p<0.001) and worsened only insignificantly after 36mo compared to baseline values. Q max increased by 4.4ml/s after 12mo (p<0.001) and did not decrease significantly after 36mo. Postoperative complications were mild and included urinary tract infection and urinary retention., Conclusions: Preliminary data suggest that TIND is a safe and effective MI technique for patients with male LUTS. Symptom relief and increase in urinary flow after 36mo are promising. However, long-term results are needed., Patient Summary: Various treatment options for male patients suffering from urinary voiding symptoms are emerging. TIND, a temporary implantable nitinol device, appears to be a safe option that improves symptoms without affecting sexuality., (Copyright © 2018 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Currently, stratification of patients with bladder cancer (BC) mainly relies on histopathologic and clinical staging. Furthermore, inflammation plays an important role in the pathogenesis of BC. With the preoperative platelet-to-leukocyte ratio (PLR), we introduce a novel prognostic marker based on routine hematologic values in patients undergoing radical cystectomy (RC)., Patients and Methods: In our cohort of 665 patients undergoing RC (2004-2015) for urothelial carcinoma of the bladder (UCB), we analyzed a variety of preoperative hematologic parameters. We investigated the effect of thrombocytosis, leukocytosis, and the PLR on the oncologic outcomes, including cancer-specific survival (CSS), progression-free survival (PFS), and overall survival (OS). Both univariate (log-rank test) and multivariate (Cox regression) analysis were performed. The prevalence of thrombocytosis and leukocytosis and differences in the PLR was assessed using the Mann-Whitney U test. The cutoff levels for leukocytosis, thrombocytosis, and the PLR were defined using receiver operating characteristic curve analysis, with the 5-year CSS as the binary classifier., Results: A PLR of ≤ 28 (CSS, P = .033; OS, P = .029) and leukocytosis (CSS, P = .01; OS, P = .001; PFS, P = .003) were significantly associated with adverse oncologic outcomes using the log-rank test. On multivariate regression analysis, the PLR (CSS, P = .022; OS, P = .025) remained a significant prognostic marker among the standard staging variables and hemoglobin level. Advanced BC disease was significantly more prevalent in the patient subgroup with a low PLR (pT2-pT4, 35%; vs. pT ≤ 1, 24%; P = .006) and leukocytosis (pT2-pT4, 46%; vs. pT ≤ 1, 30%; P < .001; pN + , 49%; vs. pN0, 39%; P < .047)., Conclusion: To the best of our knowledge, the present study is the first report of the preoperative PLR as a prognostic factor in patients undergoing RC for UCB. Compared with other inflammatory markers in BC, the PLR can be assessed without additional effort. External validation and its combination with other parameters might improve current prognostication systems for UCB., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: According to current guidelines, radical cystectomy (RC) should be combined with an extended pelvic lymphadenectomy (PLND) as therapeutic and staging instrument. Objective of this study was to analyze the influence of PLND on survival rates and complication rates in a selected group of elderly patients with a minimum age of 80 years., Materials and Methods: In this single-center retrospective analysis, we evaluated 102 patients who underwent RC due to UCB from 2004 to 2015 at our institution. In 74 patients (73%), RC was combined with PLND; in 28 cases (27%), RC was performed without PLND. Impact of PLND on cancer specific survival (CSS), overall survival (OS) and progression-free survival (PFS) was analyzed using log-rank test and COX regression model., Results: In univariate analysis of the data, we were not able to show a significant impact of PLND on CSS (p = 0.606), OS (p = 0.979) or PFS (p = 0.883). Also in multivariate analysis of the data, we were not able to identify PLND as an independent prognostic parameter on survival rates of patients undergoing RC, neither for CSS (p = 0.912) nor OS (p = 0.618) or PFS (p = 0.900)., Conclusions: Our small and single-center study was not able to demonstrate a significant independent influence of PLND on CSS, OS and PFS in octogenarians undergoing RC due to UCB. There is no doubt that RC should usually be combined with PLND, but the results of this small data set with a selected patient cohort indicate that RC without PLND might be an option in selected cases of elderly patients.

There is insufficient information available in the current literature regarding how nurses assess, intervene, and advocate for patients with indwelling gastric and enteral tube feedings. To understand ways in which nurses could be more supportive, a survey, distributed through private online social media groups, was designed to elicit preliminary data from patients who are currently, or had recently been treated, with a feeding tube. This survey examines nurse behaviors that patients identify as actually or potentially helpful with the physical, emotional, social, and logistical aspects of having a feeding tube. The results of the survey reveal that, although some patients report feeling cared for by nurses and believe that their nurses were compassionate, a greater number of respondents express that their nurses were less informed and less able to provide help with their emotional challenges. Further investigation is needed to assess how nurses can better support these patients and better identify the successful and transformative interventions that would be helpful to them.

Purpose: As the use of fluorescence endoscopy is recommended today by different guidelines during the follow-up of high-grade non-muscle-invasive bladder cancer, the aim of this study is to analyze whether the multiple use of hexylaminolevulinate (HAL) for TUR-BT can be performed safely within the same patient over a time interval., Methods: Data of patients diagnosed and treated with HAL-TUR-B at our institute between 2008 and 2013 were analyzed. Special interest was given to side effects observed during the instillation of the substance, on the whole day of the instillation and during the entire hospital stay. We focussed on side effects associated with the use of HAL, such as allergic reactions, urinary tract infections, photosensitization of the skin, and relevant changes in blood pressure., Results: In the time between 2008 and 2013, 2480 HAL-TUR-BTs were performed in total at our institute. In 80 patients, HAL-TUR-BT was used at least 2 times, and on average 4 times (2-12 times). Only patients with multiple uses were included for our final analysis. We observed no allergizations in any of the treated patients. Minor side effects were urinary tract infections (n = 4), dysuria (n = 4), pollakisuria (n = 9), and bladder spasms (n = 17)., Conclusion: In our study cohort, the multiple use of HAL-TUR-BT within the same patient caused no major side effects or an induction of allergization against the substance. We, therefore, conclude that HAL-TUR-BT can be performed safely in the same patient during the follow-up of aggressive tumors as recommended by different guidelines today., (Copyright © 2017 Elsevier Inc. All rights reserved.)