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Purpose Magnetic resonance imaging (MRI)/ultrasound-fusion prostate biopsy (FB) comprises multiple steps each of which can cause alterations in targeted biopsy (TB) accuracy leading to false-negative results. The aim was to assess the inter-operator variability of software-based fusion TB by targeting the same MRI-lesions by different urologists. Methods In this prospective study, 142 patients eligible for analysis underwent software-based FB. TB of all lesions (n = 172) were carried out by two different urologists per patient (n = 31 urologists). We analyzed the number of mismatches [overall prostate cancer (PCa), clinically significant PCa (csPCa) and non-significant PCa (nsPCa)] between both performed TB per patient. In addition we evaluated factors contributing to inter-operator variability by uni- and multivariable analyses. Results In 11.6% of all MRI-lesions (10.6% of all patients) there was a mismatch between TB1 and TB2 in terms of overall prostate cancer (PCa detection. Regarding csPCa, patient-based mismatch occurred in 14.8% (n = 21). Overall PCa and csPCa detection rate of TB1 and TB2 did not differ significantly on a per-patient and per-lesion level. Analyses revealed a smaller lesion size as predictive for mismatches (OR 9.19, 95% CI 2.02–41.83, p Conclusion Reproducibility and precision of targeting particularly small lesions is still limited although using software-based FB. Further improvements in image-fusion, segmentation, needle-guidance, and automatization are necessary.

DNA damage is a constant event in every cell caused by exogenous factors such as ultraviolet and ionizing radiation (UVR/IR) and intercalating drugs, or endogenous metabolic and replicative stress. Proteins of the DNA damage response (DDR) network sense DNA lesions and induce cell cycle arrest, DNA repair, and apoptosis. Genetic defects of DDR or DNA repair proteins can be associated with immunodeficiency, bone marrow failure syndromes, and cancer susceptibility. Although various diagnostic tools are available to evaluate DNA damage, their quality to identify DNA repair deficiencies differs enormously and depends on affected pathways. In this study, we investigated the DDR biomarkers γH2AX (Ser139), p-ATM (Ser1981), and p-CHK2 (Thr68) using flow cytometry on peripheral blood cells obtained from patients with combined immunodeficiencies due to non-homologous end-joining (NHEJ) defects and ataxia telangiectasia (AT) in response to low-dose IR. Significantly reduced induction of all three markers was observed in AT patients compared to controls. However, delayed downregulation of γH2AX was found in patients with NHEJ defects. In contrast to previous reports of DDR in cellular models, these biomarkers were not sensitive enough to identify ARTEMIS deficiency with sufficient reliability. In summary, DDR biomarkers are suitable for diagnosing NHEJ defects and AT, which can be useful in neonates with abnormal TREC levels (T cell receptor excision circles) identified by newborn screening. We conclude that DDR biomarkers have benefits and some limitations depending on the underlying DNA repair deficiency., publishedVersion

Die multiparametrische Magnetresonanztomographie (mpMRT) der Prostata ist als entscheidender Bestandteil in der Fruherkennung und Ausbreitungsdiagnostik des primaren Prostatakarzinoms etabliert. Bildgestutzte Biopsieverfahren, wie die MRT-Ultraschall-Fusionsbiopsie, erlauben nicht nur die zielgerichtete Probengewinnung aus Indexlasionen zur Diagnosesicherung, sondern verbessern die Detektion klinisch signifikanter Prostatakarzinome. Minimal-invasive Therapieformen des lokalisierten Prostatakarzinoms erganzen das Behandlungsspektrum insbesondere fur Patienten mit niedrigem und mittlerem Risiko. Fur Patienten mit niedrigem bis mittlerem Risiko konnten die MRT-gestutzten, minimal-invasiven Therapieformen in Zukunft eine lokale Tumorkontrolle, verbesserte funktionelle Ergebnisse und die Moglichkeit einer spateren Therapieeskalation vereinen. Weitere Studienergebnisse in Bezug auf multimodale Ansatze sowie den Einsatz kunstlicher Intelligenz (KI) mittels Machine-Learning- und Deep-Learning-Algorithmen konnen zukunftig dabei helfen, das volle Potenzial fokaler Therapieansatze im Sinne der personalisierten Medizin auszuschopfen. Fur die einzelnen MRT-gestutzten minimal-invasiven Therapieverfahren ist der Abschluss laufender randomisierter Studien im Vergleich zur etablierten Ganzdrusentherapie erforderlich, bevor minimal-invasive Therapieformen Einzug in die klinischen Leitlinien finden. Dieser Ubersichtartikel beschaftigt sich mit minimal-invasiven Therapieverfahren des Prostatakarzinoms und der zentralen Rolle der mpMRT der Prostata in Therapieplanung und -durchfuhrung unter besonderer Berucksichtigung der Herausforderungen im klinischen Alltag.

Scientific evidence in medicine is based on data generated from research. Recently, the number of scientifically active physicians has decreased, which has led to the development of the Clinician Scientist Programs. To better structure and focus the research of young physicians, we aimed to investigate the impact of collaborations and other factors on the quality and output of scientific publications.The abstracts of three annual congresses of the German Society of Urology were systematically analysed regarding content, collaborations, and study design. Full-text publications and journals were identified through a MEDLINE® search. Impact factors (IFs) were identified using Journal Citation Reports™. To identify factors which predict publication and IFs, χ1,074 abstracts were reviewed. The publication rate of subsequent peer-reviewed full-text publications was 52.5%. Collaborations with at least one institution (odds ratio (OR) 2.02, 95% confidence interval (CI) 1.48-2.76, p0.0001), statistical analysis (OR 1.92, 95% CI 1.41-2.60, p0.0001), study design (prospective vs. retrospective: OR 1.43, 95% CI 1.06-1.93, p=0.021), and national collaborations (OR 1.43, 95% CI 1.04-1.98, p=0.029) increased the likelihood of publication in a peer-reviewed journal in a multivariable logistic regression analysis. Experimental design (OR 2.77, 95% CI 1.32-5.84, p=0.007), international collaborations (OR 2.26, 95% CI 1.23-4.15, p=0.009), oncologic topics (OR 1.94, 95% CI 1.23-3.07, p=0.005), prostate disease (OR 1.75, 95% CI 1.08-2.84, p=0.023), and statistical analysis (OR 1.68, 95% CI 1.06-2.64, p=0.026) were associated with a higher IF.Abstracts resulting from collaborative research projects had a higher likelihood of subsequent full-text publication and a higher IF. More full-text publications were reported when abstracts included a statistical analysis. Hence, intensive networking (e. g. at congresses and workshops) of researching physicians as well as statistical/biometrical classes could be key factors to improve academic success.

Die Bestimmung des prostataspezifischen Antigens (PSA) ist die Basis der Fruherkennung des Prostatakarzinoms als haufigste Tumorentitat des Mannes in Deutschland und Europa. Grose Screeningstudien zeigen, dass hierdurch die Inzidenz lokal fortgeschrittener und metastasierter Stadien reduziert werden kann. Auch ein Effekt auf die krebsspezifische Mortalitat konnte belegt werden. Da mit einer fruhzeitigen Erkennung klinisch signifikanter Karzinome aber auch eine Uberdiagnostik und Ubertherapie nicht-signifikanter Karzinome mit nachfolgenden therapieassoziierten Nebenwirkungen einhergehen kann, muss die moderne Fruherkennung individualisiert und risikoadaptiert erfolgen. Trotz der Ablehnung eines Baseline-PSA-Werts als GKV-Leistung (Gesetzliche Krankenversicherung) durch den Gemeinsamen Bundesausschuss 2020 stellt dieser einen elementaren Baustein dieses Fruherkennungskonzepts dar und sollte durch die verfugbaren validierten Instrumente zur optimierten Erkennung signifikanter Karzinome erganzt werden.

Purpose: Focal therapy (FT) became a frequently discussed treatment strategy of localized prostate cancer (PCa), but the acceptance and evaluation of FT by practicing urologists are still unclear. ...

Purpose Due to the tissue preserving approach of focal therapy (FT), local cancer relapse can occur. Uncertainty exists regarding triggers and outcome of salvage strategies. Methods Patients with biopsy-proven prostate cancer (PCa) after FT for localized PCa from 2011 to 2020 at eight tertiary referral hospitals in Germany that underwent salvage radical prostatectomy (S-RP), salvage radiotherapy (S-RT) or active surveillance (AS) were reported. Prostate specific antigen (PSA) changes, suspicious lesions on mpMRI and histopathological findings on biopsy were analyzed. A multivariable regression model was created for adverse pathological findings (APF) at S-RP specimen. Kaplan–Meier curves were generated to determine oncological outcomes. Results A total of 90 men were included. Cancer relapse after FT was detected at a median of 12 months (IQR 9–16). Of 50 men initially under AS 13 received S-RP or S-RT. In total, 44 men underwent S-RP and 13 S-RT. At cancer relapse 17 men (38.6%) in the S-RP group [S-RT n = 4 (30.8%); AS n = 3 (6%)] had ISUP > 2. APF (pT ≥ 3, ISUP ≥ 3, pN + or R1) were observed in 23 men (52.3%). A higher ISUP on biopsy was associated with APF [p = 0.006 (HR 2.32, 97.5% CI 1.35–4.59)] on univariable analysis. Progression-free survival was 80.4% after S-RP and 100% after S-RT at 3 years. Secondary therapy-free survival was 41.7% at 3 years in men undergoing AS. Metastasis-free survival was 80% at 5 years for the whole cohort. Conclusion With early detection of cancer relapse after FT S-RP and S-RT provide sufficient oncologic control at short to intermediate follow-up. After AS, a high secondary-therapy rate was observed.

Prostate cancer (PCa) is the second most frequent cancer diagnosis in men and the sixth leading cause of cancer death worldwide with increasing numbers globally. Therefore, differentiated diagnostic imaging and risk-adapted therapeutic approaches are warranted. Multiparametric magnetic resonance imaging (mpMRI) of the prostate supports the diagnosis of PCa and is currently the leading imaging modality for PCa detection, characterization, local staging and image-based therapy planning. Due to the combination of different MRI sequences including functional MRI methods such as diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE-MRI), mpMRI enables a high sensitivity and specificity for the detection of PCa. The rising demand for individualized treatment strategies requires methods to ensure reproducibility, completeness, and quality of prostate MRI report data. The PI-RADS (Prostate Imaging Reporting and Data System) 2.1 classification represents the classification system that is internationally recommended for MRI-based evaluation of clinically significant prostate cancer. PI-RADS facilitates clinical decision-making by providing clear reporting parameters based on clinical evidence and expert consensus. Combined with software-based solutions, structured radiology reports form the backbone to integrate results from radiomics analyses or AI-applications into radiological reports and vice versa. This review provides an overview of imaging methods for PCa detection and local staging while placing special emphasis on mpMRI of the prostate. Furthermore, the article highlights the benefits of software-based structured PCa reporting solutions implementing PI-RADS 2.1 for the integration of structured data into decision support systems, thereby paving the way for workflow automation in radiology.

The Clavien-Dindo Classification (CDC) lacks a combined score of multiple complications in one patient. The comprehensive complication index (CCI) circumvents this problem making it a valuable instrument to optimize quality control. We aimed to introduce and validate CCI in the treatment of urolithiasis. 60 day postoperative complications of 327 consecutive patients undergoing percutaneous nephrolitholapaxy (PNL) and ureterorenoscopy (URS) between 2017 and 2019 were retrospectively assessed and graded according to CDC. CCI was calculated for each patient. Overall morbidity scores of CCI and CDC were compared. Correlation analyses between the two scores and length of hospital stay (LOS) were performed. A multivariate analysis was performed to identify predictive factors for complications. Sample size calculation for an imaginary clinical trial was compared between CCI and CDC. A significant difference in overall morbidity between CCI and CDC was revealed for PNL (p 0.001) and URS (p = 0.001). There was no statistically significant difference in comparing correlations between cumulative CCI and LOS versus non-cumulative CDC and LOS for both cohorts. Operating time 90 min, maximum stone size, positive preoperative urine culture and PNL type (p 0.001) were predictive factors for postoperative complications in PNL, while urine culture (p = 0.02) was for URS. Sample size calculation based on CCI resulted in a significant reduction of required patients for PNL (- 48%) and URS (- 84%) compared to CDC. CCI could successfully be validated in endourological stone treatment with the advantage of assessing complications in their entirety compared to CDC. CCI can significantly reduce the required sample size in future clinical trials.

Purpose Focal therapies (FTs) are investigated within prospective studies on selected patients treated for localized prostate cancer (PCa). Benefits are preservation of genitourinary function and reduced complications, but follow-up is elaborate and is associated with uncertainty as cancer-free survival appears to be lower compared to standard radical treatments. The aim of this study was to analyse patient-reported acceptance of FT and evaluate factors associated with treatment decision regret. Methods 52 patients who received focal high-intensity focused ultrasound for low- to intermediate-risk PCa between 2014 and 2019 within two prospective trials were eligible for a survey regarding PCa-related treatment regret and quality-of-life (Clark’s scale) and the following potential predictors: sociodemographic variables, Charlson Comorbidity Index, subjective aging (AARC-10 SF), and general health-related quality-of-life (SF-12). Cancer persistence/recurrence (multiparametric MRI and fusion biopsy after 12 months) and functional outcomes (EPIC-26 UI/UIO/S) data were also included in this study. Results The overall survey response rate was 92.3% (48/52 patients). Median follow-up was 38 months (interquartile range = 25–50 months). In total, ten patients (20.8%) reported treatment decision regret. In univariable analyses, a clinically meaningful increase in urinary incontinence showed a significant association (OR 4.43; 95% CI 0.99–20.53; p = 0.049) with regret. Cancer recurrence (OR 12.31; 95% CI 1.78–159.26; p = 0.023) and general health worry as a domain of Clark’s scale (OR 1.07; 95% CI 1.03–1.14; p Conclusion Acceptance of FT is comparable to standard treatments. Extensive follow-up including regular PSA testing does not cause additional regret but careful patient selection and information before FT is crucial.

Zusammenfassung Hintergrund und Ziel der Arbeit Der Jahreskongress der Deutschen Gesellschaft für Urologie (DGU) spiegelt die urologische Forschungslandschaft im deutschsprachigen Raum wider. Ziel war es, durch die longitudinale Analyse der Kongressabstracts und hervorgehenden Vollpublikationen Trends aufzudecken. Material und Methoden Es erfolgte die systematische Analyse der Kongressabstracts des Jahreskongresses 2016 auf Inhalt, Studiendesign, Kooperationen, hervorgehenden Vollpublikationen sowie der veröffentlichenden Journalen. Hiernach erfolgte der Vergleich mit den Kongressen 2002 und 2009. Statistische Berechnungen erfolgten per χ2-, Mann-Whitney-U-, Cochran-Armitage- und Kruskal-Wallis-Test. Ergebnisse Auf den Kongressen 2002, 2009 und 2016 wurden 1073 Abstracts präsentiert. Abstracts zu Prostataerkrankungen (24,2 %, 29,7 %, 34,0 %; p = 0,0043), onkologische Abstracts (50,6 %, 57,9 %, 61,7 %; p = 0,003), multizentrische Studien (18,3 %, 28,6 %, 34,3 %; p p p = 0,009) und prospektive Arbeiten (62,1 %, 42,0 %, 36,0 %; p p p p = 0,15). Schlussfolgerung Die nationale und internationale Vernetzung der urologischen Forschungsgemeinschaft nimmt zu, prospektive Studien werden weniger präsentiert. Die Rate aus DGU-Abstracts hervorgehender Vollpublikationen zeigt sich über die drei Kongresse auf hohem Niveau. Die Veröffentlichungsrate in Open-access-Journalen ist bisher gering.

1. Despite its recent successful and well-documented reintroduction history, a comprehensive and current update of the distribution and status of the Alpine ibex Capra ibex is lacking. As some concerns persist about its conservation, a status update appears essential for future conservation and management strategies on a large scale. 2. We provide an exhaustive update of the geographic range of the species, alongside estimates of its current abundance and population trends from 2004 to 2015. 3. We gathered census and distribution data for all the Alpine ibex colonies from management authorities and research groups that monitor them in different countries, and from the literature and publicly available reports. We produced a distribution map, reported the number of individuals observed in the most recent censuses, and estimated global, national, and local population trends using Bayesian hierarchical models. 4. Our model estimated that there were a total of 55297 Alpine ibex in the Alps in 2015 (lower 95% credible interval [CrI]: 51157; upper 95% CrI: 62710). The total number of individuals appears to have increased slightly over the last 10 years from the 47000-51000 estimated in previous reports. Positive population trends were observed in Switzerland and Italy, while no trend was apparent in France. For Austria, Germany, and Slovenia, there were insufficient data to estimate a trend. The slopes of the colonies’ trends were positively correlated with the year of colony foundation. 5. The geographic range of the Alpine ibex does not seem to have increased in size in recent years, although the accuracy of the spatial data varies among countries. 6. The periodic and standardised collection of census data for all colonies and a common policy of data sharing at a European level appear essential for monitoring the global trend of this species and for planning balanced conservation and management actions.

To assess if a multiparametric magnetic resonance imaging (mpMRI)-targeted biopsy (TB) strategy is precise enough to replace systematic biopsies (SB) among men with different biopsy indications since an imaging-based pathway to guide indication and targeted prostate biopsy is currently under debate.Retrospective analysis was performed of 594 patients with one or more lesions according to Prostate Imaging and Reporting Data System (PI-RADS) receiving a consecutive TB and SB for one of the 3 indications: primary cancer suspicion (51.7%), persistent cancer suspicion after prior negative biopsy (35.4%), or control of a confirmed cancer (12.9%). Detection rates for overall cancer (CaP) and clinically significant cancer (csCaP, Gleason Score ≥3+4) were compared between TB and SB and to a combined approach for all patients and within the subgroups. Characteristics of cancers missed by one biopsy strategy were analyzed.TB detected less CaP (302 vs. 366, P0.001) and csCaP (204 vs. 210 patients, P = 0.409) compared to SB except for men with prior negative biopsies (65 vs. 64 csCaP, P = 0.363). Cancer detection by TB or SB was independent of cancer localization and imaging characteristics. Combined TB and SB outperformed the single approaches for CaP and csCaP detection in each subgroup.A single mpMRI and TB approach leads to a substantial number of missed CaP and csCaP across biopsies with different indications. Ongoing improvements of imaging, reading standardization, and biopsy techniques are required before replacing SB.

Simple Summary In extensive livestock ranching, where animals are maintained at high numbers, competition between individuals is expected, but not generally assumed. To compensate for reduced food availability, herbivores modify their feeding behaviour, which can be used as an indicator of competition. We investigated behavioural changes of domestic sheep in Chilean Patagonia in response to herd size, food availability, and the presence of a wild competitor, the guanaco, considered a problem for sheep production by ranchers. Large sheep herds were associated with a decrease in sheep grazing, while food availability increased time spent feeding. Guanaco had no effect on sheep behaviours. Behavioural changes were mostly associated with competition between individual sheep and not with guanaco. We suggest that to improve sheep production, ranchers should focus on sheep management at appropriate herd sizes according to grassland capacities. Abstract In extensive livestock production, high densities may inhibit regulation processes, maintaining high levels of intraspecific competition over time. During competition, individuals typically modify their behaviours, particularly feeding and bite rates, which can therefore be used as indicators of competition. Over eight consecutive seasons, we investigated if variation in herd density, food availability, and the presence of a potential competitor, the guanaco (Lama guanicoe), was related with behavioural changes in domestic sheep in Chilean Patagonia. Focal sampling, instantaneous scan sampling, measures of bite and movement rates were used to quantify behavioural changes in domestic sheep. We found that food availability increased time spent feeding, while herd density was associated with an increase in vigilant behaviour and a decrease in bite rate, but only when food availability was low. Guanaco presence appeared to have no impact on sheep behaviour. Our results suggest that the observed behavioural changes in domestic sheep are more likely due to intraspecific competition rather than interspecific competition. Consideration of intraspecific competition where guanaco and sheep co-graze on pastures could allow management strategies to focus on herd density, according to rangeland carrying capacity.

ObjectivesTo explore men´s onset and burden of lower limb lymphedema (LLL) after radical prostatectomy (RP) with pelvic lymph node dissection.Patients and methodsA cross-sectional survey-based study was conducted nation-wide and web-based in Germany. Part 1 included 15 multidisciplinary compiled questions with three questions from Short Form 12 Health Survey (SF-12) and WHO activity recommendation, part 2 the validated German Lymph-ICF-Questionnaire (Lymph-ICF-LL). Subgroup comparisons and simple regression analyses were used to identify factors associated with therapy and burden of LLL, followed by multiple regression analyses to explain variance in impairment in the patients’ daily life.Results54 patients completed the survey. Median time of LLL-onset was reported with 2.0 (0.5-9.75) months after RP. 19 patients (35.2%) reported bilateral lymphedema, 28 (51.9%) the use of individually fitted compression stockings (CS), 25 (46.3%) of manual lymphatic drainage (LD) and 26 (48.1%) complete regression.The Lymph-ICF-LL revealed a higher total burden for patients with an active LLL compared to complete regression (total score: 25.5 vs. 11.9, p=0.01) specially for “physical function” (28.3 vs. 12.9, p=0.004) and “mental function” (26.2 vs. 6.7, pConclusionMen with LLL after RP with PLND report a significant burden in daily life. Bbasic therapy needs to be offered early. Postoperative onset of LLL is variable, which should be considered when assessing complications after RP.

Background: Perioperative cisplatin-based chemotherapy (CBC) can improve the outcome of patients with muscle-invasive bladder cancer (MIBC), but it is still to be defined which patients benefit. Mutations in DNA damage response genes (DDRG) can predict the response to CBC. The value of DDRG expression as a marker of CBC treatment effect remains unclear. Material and methods: RNA expression of the nine key DDRG (BCL2, BRCA1, BRCA2, ERCC2, ERCC6, FOXM1, RAD50, RAD51, and RAD52) was assessed by qRT-PCR in a cohort of 61 MICB patients (median age 66 y, 48 males, 13 females) who underwent radical cystectomy in a tertiary care center. The results were validated in the The Cancer Genome Atlas (TCGA) cohort of MIBC (n = 383). Gene expression was correlated with disease-free survival (DFS) and overall survival (OS). Subgroup analyses were performed in patients who received adjuvant cisplatin-based chemotherapy (ACBC) (Mannheim n = 20 and TCGA n = 75). Results: Low expression of RAD52 was associated with low DFS in both the Mannheim and the TCGA cohorts (Mannheim: p = 0.039, TCGA: p = 0.017). This was especially apparent in subgroups treated with ACBC (Mannheim: p = 0.0059, TCGA: p = 0.012). Several other genes showed an influence on DFS in the Mannheim cohort (BRCA2, ERCC2, FOXM1) where low expression was associated with poor DFS (p &lt, 0.05 for all). This finding was not fully supported by the data in the TCGA cohort, where high expression of FOXM1 and BRCA2 correlated with poor DFS. Conclusion: Low expression of RAD52 correlated with decreased DFS in the Mannheim and the TCGA cohort. This effect was especially pronounced in the subset of patients who received ACBC, making it a promising indicator for response to ACBC on the level of gene expression.

Fatty acid-binding protein 5 (FABP5), a transport protein for lipophilic molecules, has been proposed as protein marker in prostate cancer (PCa). The role of FABP5 gene expression is merely unknown. In two cohorts of PCa patients who underwent radical prostatectomy (n = 40 and n = 57) and one cohort of patients treated with palliative transurethral resection of the prostate (pTUR-P; n = 50) FABP5 mRNA expression was analyzed with qRT-PCR. Expression was correlated with clinical parameters. BPH tissue samples served as control. To independently validate findings on FABP5 expression, three microarray and sequencing datasets were reanalyzed (MSKCC 2010 n = 216; TCGA 2015 n = 333; mCRPC, Nature Medicine 2016 n = 114). FABP5 expression was correlated with ERG-fusion status, TCGA subtypes, cancer driver mutations and the expression of druggable downstream pathway components. FABP5 was overexpressed in PCa compared to BPH in the cohorts analyzed by qRT-PCR (radical prostatectomy p = 0.003, p = 0.010; pTUR-P p = 0.002). FABP5 expression was independent of T stage, Gleason Score, nodal status and PSA level. FABP5 overexpression was associated with the absence of TMPRSS2:ERG fusion (p

The aim of this study was to assess the impact of experience on the outcome of image fusion-guided prostate biopsies performed by urologists working at a high-volume medical center. The first 210 consecutive fusion biopsies were analyzed following installation of the software-based biopsy platform Artemis™ (Eigen, USA). The impact of training was measured in terms of changes in prostate cancer detection rates and biopsy duration over time. We sought to identify a threshold of experience for urologists, which predicts higher detection rates of targeted biopsies. The influence of various factors on prostate cancer detection rates was evaluated using bi- and multivariate analysis. Twenty-two urologists (n = 9 senior urologists, n = 13 urological residents) performed targeted biopsies followed by systematic 12-core biopsies. Overall, targeted biopsies yielded a positive result in 39.6% of 260 suspicious MRI lesions. A subgroup analysis of the six urologists who performed more than ten biopsies was then conducted, and their level of experience (i.e., performance of more than eight biopsies) was found to be associated with higher detection rates than those with less experience (49.0% and 23.0%, respectively; p

Background Data from interventional studies suggest that a peritoneal flap after pelvic lymph node dissection (LND) during laparoscopic, robotic-assisted radical prostatectomy (RARP) may reduce the rate of symptomatic lymphoceles in transperitoneal approach. However, most of these studies are not conducted in a randomized controlled fashion, thus limiting their scientific value. A recent prospective, randomized, controlled trial (RCT) did not show superiority of a peritoneal flap while further trials are lacking. Therefore, the aim of the presented RCT will be to show that creating a peritoneal flap decreases the rate of symptomatic lymphoceles compared to the current standard procedure without creation of a flap. Methods/design PELYCAN is a parallel-group, patient- and assessor-blinded, phase III, adaptive randomized controlled superiority trial. Men with histologically confirmed prostate cancer who undergo transperitoneal RARP with pelvic LND will be randomly assigned in a 1:1 ratio to two groups—either with creating a peritoneal flap (PELYCAN) or without creating a peritoneal flap (control). Sample size calculation yielded a sample size of 300 with a planned interim analysis after 120 patients, which will be performed by an independent statistician. This provides a possibility for early stopping or sample size recalculation. Patients will be stratified for contributing factors for the development of postoperative lymphoceles. The primary outcome measure will be the rate of symptomatic lymphoceles in both groups within 6 months postoperatively. Patients and assessors will be blinded for the intervention until the end of the follow-up period of 6 months. The surgeon will be informed about the randomization result after performance of vesicourethral anastomosis. Secondary outcome measures include asymptomatic lymphoceles at the time of discharge and within 6 months of follow-up, postoperative complications, mortality, re-admission rate, and quality of life assessed by the EORTC QLQ-C30 questionnaire. Discussion The PELYCAN study is designed to assess whether the application of a peritoneal flap during RARP reduces the rate of symptomatic lymphoceles, as compared with the standard operation technique. In case of superiority of the intervention, this peritoneal flap may be suggested as a new standard of care. Trial registration German Clinical Trials Register DRKS00016794. Registered on 14 May 2019.

The Earth System Model Evaluation Tool (ESMValTool) is a free and open-source community diagnostic and performance metrics tool for the evaluation of Earth system models such as those participating in the Coupled Model Intercomparison Project (CMIP). Version 2 of the tool (Righi et al. 2020, www.esmvaltool.org) features a brand new design composed of a core that finds and processes data according to a ‘recipe’ and an extensive collection of ready-to-use recipes and associated diagnostic codes for reproducing results from published papers. Development and discussion of the tool (mostly) takes place in public on https://github.com/esmvalgroup and anyone with an interest in climate model evaluation is welcome to join there. Since the initial release of version 2 in the summer of 2020, many improvements have been made to the tool. It is now more user friendly with extensive documentation available on docs.esmvaltool.org and a step by step online tutorial. Regular releases, currently planned three times a year, ensure that recent contributions become available quickly while still ensuring a high level of quality control. The tool can be installed from conda, but portable docker and singularity containers are also available. Recent new features include a more user-friendly command-line interface, citation information per figure including CMIP6 data citation using ES-DOC, more and faster preprocessor functions that require less memory, automatic corrections for a larger number of CMIP6 datasets, support for more observational and reanalysis datasets, and more recipes and diagnostics. The tool is now also more reliable, with improved automated testing through more unit tests for the core, as well as a recipe testing service running at DKRZ for testing the scientific recipes and diagnostics that are bundled into the tool. The community maintaining and developing the tool is growing, making the project less dependent on individual contributors. There are now technical and scientific review teams that review new contributions for technical quality and scientific correctness and relevance respectively, two new principal investigators for generating a larger support base in the community, and a newly created user engagement team that is taking care of improving the overall user experience.

Objective To examine the disease-specific survival(DSS) after checkpoint inhibitor(CPI) therapy based on FGFR alterations and FGFR mRNA expression levels in patients with metastatic urothelial cancer(mUCa) within a multi-center cohort. Methods Within a cohort of 72 patients with mUCa from five academic centers in Germany FGFR alterations, as well as FGFR1-4 mRNA expression levels in tumor samples from the primary tumor or metastatic sites. Spearman rank correlations, logistic regression, as well as Kaplan-Meier survival analyses and univariate Cox proportional hazards regression models were employed to examine the impact of different FGFR patterns on the DSS after CPI treatment. Results FGFR3 mutations or gene fusions (gene alterations) were detected in 16.9% of all samples. Patients with or without FGFR3 gene alterations did not show different oncological outcomes undergoing CPI treatment. Low expression of FGFR2 mRNA alone, as well as the combination of either low FGFR2mRNA expression and FGFR3 gene alteration or high FGFR3mRNA expression (P = 0.027), identified a subgroup of patients with unfavorable outcomes, comprising 40% of the total cohort. This trend was also observed in univariate Cox proportional hazards regression analysis(FGFR3 gene alteration: Hazard ratio(HR) 5.33, 95%Confidence interval(CI)1.76-15.0, P = 0.004; FGFR3mRNA expression:HR 3.04, 95%CI 1.40-7.13, P = 0.005). Conclusion Assessment of FGFR mRNA expression identified a high-risk subgroup of patients with mUCa. These patients showing overexpression of FGFR3 mRNA were found to have unfavorable DSS after CPI treatment. Using this approach may be suitable for identifying a patient population with poor response to CPI treatment, which may benefit from early FGFR inhibition.

BACKGROUND Recognition of viral nucleic acids is one of the primary triggers for a type I interferon-mediated antiviral immune response. Inborn errors of type I interferon immunity can be associated with increased inflammation and/or increased susceptibility to viral infections as a result of dysbalanced interferon production. NFX1-type zinc finger-containing 1 (ZNFX1) is an interferon-stimulated double-stranded RNA sensor that restricts the replication of RNA viruses in mice. The role of ZNFX1 in the human immune response is not known. OBJECTIVE We studied 15 patients from 8 families with an autosomal recessive immunodeficiency characterized by severe infections by both RNA and DNA viruses and virally triggered inflammatory episodes with hemophagocytic lymphohistiocytosis-like disease, early-onset seizures, and renal and lung disease. METHODS Whole exome sequencing was performed on 13 patients from 8 families. We investigated the transcriptome, posttranscriptional regulation of interferon-stimulated genes (ISGs) and predisposition to viral infections in primary cells from patients and controls stimulated with synthetic double-stranded nucleic acids. RESULTS Deleterious homozygous and compound heterozygous ZNFX1 variants were identified in all 13 patients. Stimulation of patient-derived primary cells with synthetic double-stranded nucleic acids was associated with a deregulated pattern of expression of ISGs and alterations in the half-life of the mRNA of ISGs and also associated with poorer clearance of viral infections by monocytes. CONCLUSION ZNFX1 is an important regulator of the response to double-stranded nucleic acids stimuli following viral infections. ZNFX1 deficiency predisposes to severe viral infections and a multisystem inflammatory disease.

Clinical Practice Points - Germline pathogenic variants in the tumor suppressor gene CYLD are associated with multiple cutaneous cylindromas. - In a subset of CYLD pathogenic variant carriers, pulmonary cylindromas may develop. - The histopathological differentiation between benign cylindroma and adenoid cystic carcinoma may be challenging, especially with small tissue samples. - At the molecular level, evidence of MYB rearrangement can support the diagnosis of adenoid cystic carcinoma. - CYLD sequencing should be initiated in patients with pulmonary nodules and a history of dermal tumors.

Objectives To report feasibility and outcome of salvage robotic-assisted laparoscopic radical prostatectomy (S-RALP) after focal therapy using high-intensity focused ultrasound (HIFU) treatment compared to primary robotic-assisted laparoscopic radical prostatectomy (pRALP). Methods In this bicentric trial patients undergoing S-RALP for detection of WHO2016/ISUP Grade Group 2 or 3 prostate cancer were previously treated in prospective focal HIFU trials. Perioperative data, complications, oncological and functional outcome were analysed. Patients who underwent pRALP were matched in a ratio 2(pRALP):1(S-RALP) according to preoperatively functional, oncological and clinical parameters. Results A total of 39 patients were included in the study (13S-RALP, 26pRALP). Median operative time in the S-RALP group was 260minutes (pRALP: 257minutes), blood loss was 230ml (pRALP: 300ml). Complications occurred in 46.2% (6/13) of S-RALP patients (pRALP: 26.9%), including four Clavien-Dindo III complications (pRALP: 2/26). In S-RALP adverse histological outcome (≥pT3a, pN+ or R1) was detected in 23.1% (3/13) (pRALP: 26.9%). There was one patient with PSA-persistence (pRALP: 2/26). Regarding functional outcomes there was no difference between the two groups observed (incontinence p=0.71, erectile function p=0.21). Conclusion S-RALP should be offered to patients with an early relapse after focal HIFU. The early oncological outcome is satisfactory and functional outcome one year postoperatively is similar to pRALP. However, S-RALP is associated with a higher rate of Clavien-Dindo III complications (mainly, placement of a drainage), of which patients should be informed beforehand.

Focal therapy (FT) with its favorable side-effect profile represents an option between active surveillance and traditional whole-gland treatment in localized prostate cancer (PCa). Consensus statements recommend eligibility criteria based on magnetic resonance imaging (MRI)-targeted and systematic combination biopsy.To estimate the future potential of FT by analyzing the number of men eligible for FT among all men with biopsy-proven PCa and to judge the potential of different energy sources.Consensus criteria on FT were analyzed. Patients with biopsy-proven PCa from six tertiary referral hospitals and one outpatient practice in Germany had received a software-based combination biopsy. Men with Prostate Imaging Reporting and Data System (PI-RADS) ≥3 lesions based on PI-RADS v2 were included.Patients were analyzed for potential treatment by FT and hemiablation. MRI lesions were mapped according to prostatic zones.In total, 2371 patients were analyzed. According to consensus criteria (biopsy-proven unifocal lesion of International Society of Urological Pathology [ISUP] grade group ≤2, prostate-specific antigen [PSA] ≤15ng/mL, and life expectancy10yr), 303 patients (12.8%; ISUP 1: n=148 [6.2%]; ISUP 2: n=155 [6.5%]) were potential candidates for FT. A maximum PSA level of10ng/mL would exclude further 60 (2.5%) of these men. The eligibility for hemiablation is slightly higher (16.2%). Unifocal lesions (n=288) were equally distributed within the prostate (anteriorly [31%], apically [29%], and dorsally [36%]).With adherence to consensus statements, only a minority of PCa patients present as potential candidates for FT. Distribution of tumor localization suggests the need for different energy modalities to warrant an optimal FT treatment.We analyzed how many men who receive a magnetic resonance imaging-targeted and systematic prostate biopsy are candidates for the experimental focal therapy of the prostate. When following expert recommendations, only a small number of men are potential candidates for this alternative treatment.

Current outcome prediction markers for localized prostate cancer (PCa) are insufficient. The impact of the lipid-modifying Sphingomyelin Phosphodiesterase Acid Like 3B (SMPDL3B) in PCa is unknown. Two cohorts of patients with PCa who underwent radical prostatectomy (n = 40, n = 56) and benign prostate hyperplasia (BPH) controls (n = 8, n = 11) were profiled for SMPDL3B expression with qRT-PCR. Publicly available PCa cohorts (Memorial Sloane Kettering Cancer Centre (MSKCC, n = 131, n = 29 controls) and The Cancer Genome Atlas (TCGA, n = 497, n = 53 controls)) served for validation. SMPDL3B&rsquo, s impact on proliferation and migration was analyzed in PC3 cells by siRNA knockdown. In both cohorts, a Gleason score and T stage independent significant overexpression of SMPDL3B was seen in PCa compared to BPH (p &lt, 0.001 each). A lower expression of SMPDL3B was associated with a shorter overall survival (OS) (p = 0.005) in long term follow-up. A SMPDL3B overexpression in PCa tissue was confirmed in the validation cohorts (p &lt, 0.001 each). In the TCGA patients with low SMPDL3B expression, biochemical recurrence-free survival (p = 0.011) and progression-free interval (p &lt, 0.001) were shorter. Knockdown of SMPDL3B impaired PC3 cell migration but not proliferation (p = 0.0081). In summary, SMPLD3B is highly overexpressed in PCa tissue, is inversely associated with localized PCa prognosis, and impairs PCa cell migration.

Introduction: Urinary tract infections (UTI) represent the most frequent complications after transrectal focal ablation of prostate cancer. Single-shot antibiotic prophylaxis for prevention has not yet been described. Methods: In this cohort study of patients who received a high-intensity focused ultrasound (HIFU) ablation of prostate cancer within a registered prospective single-arm trial, we analyzed posttreatment UTI (≤30 days after HIFU) related to perioperative antibiotic management in an exploratory analysis: single-shot prophylaxis or targeted treatment for bacteriuria. Potential risk factors associated with UTI were evaluated by uni- and multivariate regression analyses. Results: In total, 55 patients were eligible for analysis. Of these, 76.4% received antibiotic single-shot prophylaxis. UTI occurred in 10.7% of all patients, 5.4% developed fever, 3.6% required hospitalization. An antibiotic single-shot prophylaxis helped to protect 90.5% of men from infectious complications. Estimated effects indicate that a longer posttreatment catheterization (OR 3.38, 95% CI 0.47–27.08) and larger ablation volume (OR 4.85, 95% CI 0.61–107.49) might be associated with the highest risk for UTI after treatment. Conclusion: Single-shot antibiotic prophylaxis compared to a targeted antibiotic treatment showed a similar effectivity to prevent patients from infectious complications and should be considered as an element of antibiotic stewardship. Further research on risk factors and antibiotic strategies is required.

Baselines are one of the most ubiquitous, yet unrecognized, components of contemporary environmental regulation. Usually understood as the ‘natural’ or ‘historical’ state of a species popul...

Cultural heritage is widely recognized to be at risk due to the impact of climate change and associated hazards, such as events of heavy rain, flooding, and drought. User-driven solutions are urgently required for sustainable management and protection of monumental complexes and related collections exposed to changes of extreme climate. With this purpose, maps of risk-prone areas in Europe and in the Mediterranean Basin have been produced by an accurate selection and analysis of climate variables (daily minimum and maximum temperature - Tn and Tx, daily cumulated precipitation - RR) and climate-extreme indices (R20mm, R95pTOT, Rx5 day, CCD, Tx90p) defined by Expert Team on Climate Change Detection Indices (ETCCDI). Maps are available to users via an interactive Web GIS (Geographic Information System) tool, which provides evaluations based on historical observations (high-resolution gridded data set of daily climate over Europe - E-OBS, 25 km) and climate projections (regional climate models - RCM, ~12 km) for the near and far future, under Representative Concentration Pathways (RCP) 4.5 and 8.5 scenarios. The tool aims to support public authorities and private organizations in the decision making process to safeguard at-risk cultural heritage. In this paper, maps of risk-prone areas of heavy rain in Central Europe (by using R20mm index) are presented and discussed as example of the outputs achievable by using the Web GIS tool. The results show that major future variations are always foreseen for the 30-year period 2071&ndash, 2100 under the pessimistic scenario (RCP 8.5). In general, the coastal area of the Adriatic Sea, the Northern Italy, and the Alps are foreseen to experience the highest variations in Central Europe.

This study was conducted in order to review randomized controlled trial (RCT) data published January 2016–March 2019 on long-acting injectable antipsychotics (LAIs) for schizophrenia. Thirty-one RCTs (primary studies = 7; post hoc analyses = 24; n = 4738) compared LAIs vs. placebo (studies = 11, n = 1875), LAIs vs. oral antipsychotics (OAPs) (studies = 7, n = 658), and LAI vs. LAI (studies = 13, n = 2205). LAIs included two new formulations, aripiprazole lauroxil nanocrystal dispersion and subcutaneously injectable risperidone Perseris, as well as aripiprazole lauroxil, aripiprazole once-monthly, paliperidone once-monthly, paliperidone 3-monthly, and risperidone-LAI. Regarding prevention of relapse and hospitalization, LAIs consistently outperformed placebo, being partly superior to OAPs, without relevant LAI–LAI differences. LAIs were comparable to OAPs regarding all-cause discontinuation, functioning, quality of life, and tolerability, being associated with higher patient satisfaction and service engagement. Recent meta-analyses yielded mixed results, but never favoring OAPs over LAIs. In RCTs, LAIs are superior to placebo, but only in some aspects, superior to OAPs. Comparative effectiveness of LAIs vs. OAPs requires further study, ideally in generalizable/real-world samples.

Prostate-specific membrane antigen (PSMA) positron emission tomography-computed tomography (PET-CT) imaging for the localization of prostate cancer is increasingly available in Germany. The advances and limitations in different disease stages are reviewed. As the clinical relevance of oligometastatic disease in primary cancer detected by PSMA PET-CT imaging is not yet completely understood, it should only be used in clinical trials. In recurrent prostate cancer after therapy with curative intent, PSMA PET-CT shows encouraging potential for the planning of salvage therapy. In metastatic castration-resistant prostate cancer evidence for its use is not available.

Background The cell surface interleukin 22 (IL-22) receptor complex is mainly expressed in epithelial and tissue cells like pancreatitis cells. Recent studies described that IL-22R was overexpressed in malignant diseases and was associated with a poor overall survival (OS). The role of IL-22RA1 gene expression in muscle invasive bladder cancer (MIBC) has not been investigated, yet. Objectives The aim of this study was to analyze the role of IL-22RA1 gene expression in patients with MIBC. Methods In a cohort of 114 patients with MIBC who underwent radical cystectomy, IL-22RA1 gene expression was analyzed with qRT-PCR and correlated with clinical parameters. Furthermore, Kaplan-Meier and Cox regression analysis were performed. For validation, an in silico dataset (TCGA 2017, n=407) was reanalyzed. Results IL-22RA1 gene expression was independent of clinicopathological parameters like age (P=0.2681), T stage (P=0.2130), nodal status (P=0.3238) and lymph vascular invasion (LVI, P=0.5860) in patients with MIBC. A high expression of IL-22RA1 was associated with a shorter OS (P=0.0040) and disease-specific survival (P=0.0385). Furthermore, a shorter disease-free survival (DFS) was also associated with a high expression of IL-22RA1 (P=0.0102). In the multivariable analysis, IL-22RA1 expression was an independent prognostic predictors regarding OS (P=0.0096, HR=0.48). In the TCGA cohort, IL-22RA1 expression was independent regarding to OS and DFS. Conclusion A high IL-22RA1 gene expression was associated with worse outcome. Furthermore, IL-22RA1 represented an independent predictor regarding OS in our cohort and therefore might be used for risk stratification in patients with MIBC.

Ziel der fokalen Therapie (FT) des Prostatakarzinoms (PC) ist eine Teilbehandlung der Prostata unter Schonung der angrenzenden Strukturen. Dadurch sollen typische Nebenwirkungen radikaler Therapieoptionen bei gleichzeitiger Tumorkontrolle minimiert werden. Zahlreiche etablierte und neue Technologien kommen dazu zum Einsatz. Ergebnisse zahlreicher Fallserien belegen ein geringes Nebenwirkungsspektrum bei guten funktionellen Ergebnissen. Onkologische Langzeitergebnisse liegen bislang nicht vor.

To evaluate the accuracy of a T2-weighted (T2w) - and a parallel transmit zoomed b = 2000 s/mm2 (b2000) - diffusion-weighted imaging sequence among three readers with different degrees of experience for prostate cancer (Pca) detection.Ninety-three patients with suspected Pca were enrolled. For b2000 a two-dimensional spatially-selective RF pulse using an echo-planar transmit trajectory was applied, and the field of view (FOV) was reduced to one-third. All three readers (Reader A: 7, B 4 and C1 years of experience in prostate MRI) independently evaluated b2000 with regard to the presence of suspicious lesions that displayed increased signal. The results were compared to histopathology obtained by real-time MR/ultrasound fusion and systematic biopsy.In 62 patients Pca was confirmed. One significant Pca (Gleason score (GS) 7b) was missed by Reader C. Overall, sensitivity/specificity/positive predictive value/negative predictive value were 90/71/86/79% for Reader A, 87/84/92/76% for Reader B and 85/74/87/72% for Reader C, respectively. Detection rates for significant Pca (GS7a) were 100/100/94% for Readers A/B/C, respectively. Inter-reader agreement was generally good (Kappa A/B: 0.8; A/C: 0.82; B/C: 0.74).B2000 in combination with a T2w could be useful to detect clinically significant Pca.• Significant prostate cancer using zoomed ultra-high b-value DWI was detected. • Diagnostic performance among readers with different degrees of experience was good. • mp- MRI of the prostate using a comprehensive non-contrast protocol is clinically feasible.

Background: Limited data are available for the use of agents in metastatic castration-resistant prostate cancer (mCRPC) beyond the third-line. We provide data during treatment with cabazitaxel (CAB), helping to improve the informed-consent process. Patients and Methods: We retrospectively reviewed patients treated with fourth-line or beyond CAB for mCRPC after failure of previous therapies with docetaxel, abiraterone acetate, enzalutamide and/or radium-223. The progression-free survival (PFS) and the overall survival (OS) were estimated using the Kaplan-Meier method and compared to published data based on a structured literature review. The hospitalization rate was recorded. Factors influencing 6-months OS were analyzed. Results: Fifteen patients were identified at 4 institutions and included in the analysis. The median PFS was 104 days (range 47-397 days). The median time to death was 10 months (range 2-16). PFS and OS data are in accordance with 17 published patients so far. During the therapy, eleven (73%) of the patients were hospitalized. Prostate-specific antigen (PSA, 500 units; hazards ratio [HR] 1.491, 95% CI 1.000-2.0175), white blood cell count (HR 0.425, 95% CI 0.108-0.952), hemoglobin (HR 0.6014, 95% CI 0.2942-1.0758), and alkaline phosphatase (100 units; HR 1.0964, 95% CI 1.000-1.2859) correlate with 6-months OS. Conclusions: CAB beyond the third-line is often accompanied by hospitalization. PFS is a significant proportion of the median time of OS. The baseline laboratory might be a good indicator for the decision between CAB and best-supportive care.

Es existieren zahlreiche Systeme zur MRT/TRUS-fusionierten Biopsie der Prostata. Insgesamt liegt ausreichend Literatur zur Fusionsbiopsie vor, die einen Vorteil bei der Tumordetektion und der Diagnosequalitat gegenuber der Randombiopsie belegt. Der Nutzen der Systeme im Rahmen der fokalen Therapie des Prostatakarzinoms (PC) ist unklar. Ziel war die kritische Prufung der vorhandenen Fusionssysteme fur die Planung und Verlaufskontrolle einer fokalen Therapie des PC. Es erfolgte eine systematische Literaturrecherche zu den erhaltlichen Fusionssystemen fur den Zeitraum 2013–5/2016. Durch den Arbeitskreis „Fokale und Mikrotherapie“ wurde ein Kriterienkatalog zu technischen Details, der Eignung in speziellen Situationen und der Eignung im Rahmen der fokalen Therapie des PC erstellt. Acht Fusionssysteme wurden betrachtet (Artemis™, BioJet, BiopSee®, iSR’obot™ Mona Lisa, Hitachi HI-RVS, UroNav und Urostation®). Unterschiede zwischen den Systemen bestehen u. a. in der Art der Biopsie (transrektal, perineal, beides moglich), im Fusionsmodus (starr bzw. elastisch), in der Navigationsart (bildbasiert, elektromagnetisch bzw. mechanisch) sowie im Platzbedarf. Fusionssysteme werden im Rahmen der fokalen Therapie des PC von verschiedenen Konsensusgruppen empfohlen. Wunschenswerte Eigenschaften sind neben dem „needle tracking“ die Ubertragbarkeit des Biopsiedatensatzes in ein Behandlungsgerat (Artemis™, BiopSee® und Urostation®: jeweils mit Focal One®, BiopSee®, Hitachi HI-RVS: jeweils mit Nanoknife®, BioJet und BiopSee®: Kryoablation, Brachytherapie). Studien zur Planung einer fokalen Therapie liegen nur fur vereinzelte Systeme vor und fehlen fur die Verlaufskontrolle nach fokaler Therapie.

Schizophrenia remains one of the most severe medical diseases. Current dopamine modulating first-generation and second-generation antipsychotics target mainly positive symptoms, but not/inadequately negative and cognitive symptoms. Additional challenges include non-adherence and adverse effects, especially cardiometabolic dysregulation. This review evaluates new/emerging pharmacological treatments for schizophrenia. Therapies targeting total symptoms include cannabidiol, D3antagonist/5-HT1Apartial agonist F17464, lumateperone (ITI-007), phosphodiesterase 10A (PDE10A) inhibitors MK-8189 and TAK-063, sodium nitroprusside, and trace amine-associated receptor-1 (TAAR1) agonist RO5263397 and SEP-363856. Treatments targeting negative symptoms include the PDE10A inhibitor LuAF-11167, 5-HT2A inverse agonist pimavanserin, sigma-2/5-HT2A antagonist roluperidone (MIN-101), and d-amino acid oxidase (DAAO) inhibitor TAK-831. Agents targeting primarily cognitive dysfunction are the glycine transporter-1 inhibitor BI-425809 and cannabidiol. Therapies targeting residual positive symptoms/treatment-resistant schizophrenia include pimavanserin, dopamine D1/D2antagonist LuAF-35700, and DAAO inhibitor sodium benzoate. Two new long-acting injectable antipsychotic formulations, Aripiprazole Lauroxil NanoCrystal®and the first subcutaneous injectable LAI Perseris (RBP-7000), were recently approved by U.S. Food and Drug Administration, and positive results were announced for Risperidone ISM®, each achieving therapeutic levels within 24 hours, without need for initial oral cotreatment/loading injection-strategies. Paliperidone palmitate 6-monthly intramuscularly injectable and Risperidone subcutaneously injectable TV46000 are currently under investigation. Finally, the samidorphan+olanzapine combination targets reduced weight gain liability, while maintaining olanzapine’s efficacy. Most of these trial programs are still ongoing or have yielded mixed or even negative results. Thus, additional mechanisms of action and agents require study to improve schizophrenia outcomes for total/positive symptoms with reduced adverse effects, but also cognitive symptoms, negative symptoms, and treatment resistance, the areas of greatest need in schizophrenia currently.

Genetic studies have led to identification of an increasing number of monogenic primary immunodeficiency disorders. Monoallelic pathogenic gain-of-function (GOF) variants in NFKBIA, the gene encoding IκBα, result in an immunodeficiency disorder, typically accompanied by anhidrotic ectodermal dysplasia (EDA). So far, 14 patients with immunodeficiency due to NFKBIA GOF mutations have been reported. In this study we report three patients from the same family with immunodeficiency, presenting with recurrent respiratory tract infections, bronchiectasis and viral skin conditions due to a novel pathogenic NFKBIA variant (c.106 T > G, p.Ser36Ala), which results in reduced IκBα degradation. Immunological investigations revealed inadequate antibody responses against vaccine antigens, despite hypergammaglobulinemia. Interestingly, none of the studied patients displayed features of EDA. Therefore, missense NFKBIA variants substituting serine 36 of IκBα, differ from the rest of pathogenic GOF NFKBIA variants in that they cause combined immunodeficiency, even in the absence of EDA.

To systematically analyze the impact of prophylactic abdominal or retroperitoneal drain placement or omission in uro-oncologic surgery. This systematic review follows the Cochrane recommendations and was conducted in line with the PRISMA and the AMSTAR-II criteria. A comprehensive database search including Medline, Web-of-Science, and CENTRAL was performed based on the PICO criteria. All review steps were done by two independent reviewers. Risk of bias was assessed with the Cochrane tool for randomized trials and the Newcastle–Ottawa Scale. The search identified 3427 studies of which eleven were eligible for qualitative and ten for quantitative analysis reporting on 3664 patients. Six studies addressed radical prostatectomy (RP), four studies partial nephrectomy (PN) and one study radical cystectomy. For RP a reduction in postoperative complications was found without drainage (odds ratio (OR)[95% confidence interval (CI)]: 0.62[0.44;0.87], p = 0.006), while there were no differences for re-intervention (OR[CI]: 0.72[0.39;1.33], p = 0.300), lymphocele OR[CI]: 0.60[0.22;1.60], p = 0.310), hematoma (OR[CI]: 0.68[0.18;2.53], p = 0.570) or urinary retention (OR[CI]: 0.57[0.26;1.29], p = 0.180). For partial nephrectomy no differences were found for overall complications (OR[CI]: 0.99[0.65;1.51], p = 0.960) or re-intervention (OR[CI]: 1.16[0.31;4.38], p = 0.820). For RC, there were no differences for all parameters. The overall-quality of evidence was assessed as low. The omission of drains can be recommended for standardized RP and PN cases. However, deviations from the standard can still mandate the placement of a drain and remains surgeon preference. For RC, there is little evidence to recommend the omission of drains and future research should focus on this issue. CRD42019122885

Background Abiraterone Acetate (AA) represents a highly effective androgen-receptor (AR) axis targeted agent. Treatment with AA in castration-resistant prostate cancer (CRPC) may partly mediate neuroendocrine differentiation (NED) as an escape mechanism, which may have implications for the choice of sequential therapy in CRPC. We evaluated how treatment with AA influences circulating neuromediators chromogranin A (CGA), neuron-specific enolase (NSE), and pro-gastrin-releasing peptide (Pro-GRP) in chemotherapy-naive CRPC patients. Methods We conducted an analysis in chemotherapy-naive CRPC patients with clinical or radiographic progression of disease. A total of 35 patients were included at five institutions between February 2013 and December 2014. Sixteen of them had received AA. Serum samples were obtained before a docetaxel-based chemotherapy and analyzed in a reference laboratory. Univariable and multivariable analyses were performed to test the influence of AA treatment, its duration of treatment, and other clinicopathological variables on circulating neuromediators. Results CGA and NSE levels were above the upper limit of normal (ULN) in n = 20 (57.1%) and n = 13 (37.1%), respectively. Treatment with AA and duration of treatment were not associated with levels above the ULN (CGA and NSE) or higher levels (Pro-GRP) of neuromediators. CGA levels were associated with age (P = 0.092), lymph node metastasis (P = 0.014), duration of androgen deprivation therapy (ADT; P = 0.083), and intake of proton pump inhibitors (P = 0.069). Pro-GRP levels were significantly associated with PSA levels (P = 0.002). On multivariate analysis, CGA levels above the ULN were significantly correlated with ADT (P = 0.01) and intake of proton pump inhibitors (P = 0.03). Conclusions Circulating neuromediators in chemotherapy-naive CRPC patients were elevated in a high percentage of patients. ADT was found to be a relevant NED driver in this cohort. Our results may imply that patients with CRPC after first-line treatment with AA in CRPC are not at a higher risk for developing NED. The major limitation of the study represents the one-time analysis of neuromediators. Larger studies with serial blood measurements or biopsy analysis before and after treatment are needed to confirm our results. Prostate © 2016 Wiley Periodicals, Inc.

Radiomics is an emerging field of image analysis with potential applications in patient risk stratification. This study developed and evaluated machine learning models using quantitative radiomic features extracted from multiparametric magnetic resonance imaging (mpMRI) to detect and classify prostate cancer (PCa). In total, 191 patients that underwent prostatic mpMRI and combined targeted and systematic fusion biopsy were retrospectively included. Segmentations of the whole prostate glands and index lesions were performed manually in apparent diffusion coefficient (ADC) maps and T2-weighted MRI. Radiomic features were extracted from regions corresponding to the whole prostate gland and index lesion. The best performing combination of feature setup and classifier was selected to compare its predictive ability of the radiologist’s evaluation (PI-RADS), mean ADC, prostate specific antigen density (PSAD) and digital rectal examination (DRE) using receiver operating characteristic (ROC) analysis. Models were evaluated using repeated 5-fold cross-validation and a separate independent test cohort. In the test cohort, an ensemble model combining a radiomics model, with models for PI-RADS, PSAD and DRE achieved high predictive AUCs for the differentiation of (i) malignant from benign prostatic lesions (AUC = 0.889) and of (ii) clinically significant (csPCa) from clinically insignificant PCa (cisPCa) (AUC = 0.844). Our combined model was numerically superior to PI-RADS for cancer detection (AUC = 0.779; p = 0.054) as well as for clinical significance prediction (AUC = 0.688; p = 0.209) and showed a significantly better performance compared to mADC for csPCa prediction (AUC = 0.571; p = 0.022). In our study, radiomics accurately characterizes prostatic index lesions and shows performance comparable to radiologists for PCa characterization. Quantitative image data represent a potential biomarker, which, when combined with PI-RADS, PSAD and DRE, predicts csPCa more accurately than mADC. Prognostic machine learning models could assist in csPCa detection and patient selection for MRI-guided biopsy.