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Purpose The extent of lymphadenectomy and clinical features influence the risk of occult nodes in node-negative prostate cancer. We derived a simple estimation model for the negative predictive value (npv) of histopathologically node-negative prostate cancer patients (pN0) to guide adjuvant treatment. Methods Approximations of sensitivities in detecting lymph node metastasis from current publications depending on the number of removed lymph nodes were used for a theoretical deduction of a simplified formulation of npv assuming a false node positivity of 0. Results A theoretical formula of npv = p(N0IpN0) = (100 − prevalence) / (100 − sensitivity × prevalence) was calculated (sensitivity and preoperative prevalence in %). Depending on the number of removed lymph nodes (nLN), the sensitivity of pN0-staged prostate cancer was derived for three sensitivity levels accordingly: sensitivity = f(nLN) = 9 × nLN /100 for 0 ≤ nLN ≤ 8 and f(nLN) = (nLN + 70) /100 for 9 ≤ nLN ≤ 29 and f(nLN) = 1 for nLN ≥ 30. Conclusion We developed a theoretical formula for estimation of the npv in pN0-staged prostate cancer patients. It is a sine qua non to use the formula in a clinically experienced context before deciding to electively irradiate pelvic lymph nodes or to intensify adjuvant systemic treatment.

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex (dlPFC) is currently evolving as an effective and safe therapeutic tool in the treatment of major depressive disorder (MDD). However, already established rTMS treatment paradigms are rather time-consuming. With theta burst stimulation (TBS), a patterned form of rTMS, treatment time can be substantially reduced. Pilot studies and a randomized controlled trial (RCT) demonstrate non-inferiority of TBS to 10 Hz rTMS and support a wider use in MDD. Still, data from placebo-controlled multicenter RCTs are lacking. In this placebo-controlled multicenter study, 236 patients with MDD will be randomized to either intermittent TBS (iTBS) to the left and continuous TBS (cTBS) to the right dlPFC or bilateral sham stimulation (1:1 ratio). The treatment will be performed with 80% resting motor threshold intensity over six consecutive weeks (30 sessions). The primary outcome is the treatment response rate (Montgomery-Asberg Depression Rating Scale reduction ≥ 50%). The aim of the study is to confirm the superiority of active bilateral TBS compared to placebo treatment. In two satellite studies, we intend to identify possible MRI-based and (epi-)genetic predictors of responsiveness to TBS therapy. Positive results will support the clinical use of bilateral TBS as an advantageous, efficient, and well-tolerated treatment and pave the way for further individualization of MDD therapy.Trial registration: ClinicalTrials.gov (NCT04392947).

AimsTo determine long-term safety and efficacy outcomes of a subretinal gene therapy for CNGA3-associated achromatopsia. We present data from an open-label, nonrandomised controlled trial (NCT02610582).MethodsDetails of the study design have been previously described. Briefly, nine patients were treated in three escalating dose groups with subretinal AAV8.CNGA3 gene therapy between November 2015 and October 2016. After the first year, patients were seen on a yearly basis. Safety assessment constituted the primary endpoint. On a secondary level, multiple functional tests were carried out to determine efficacy of the therapy.ResultsNo adverse or serious adverse events deemed related to the study drug occurred after year 1. Safety of the therapy, as the primary endpoint of this trial, can, therefore, be confirmed. The functional benefits that were noted in the treated eye at year 1 were persistent throughout the following visits at years 2 and 3. While functional improvement in the treated eye reached statistical significance for some secondary endpoints, for most endpoints, this was not the case when the treated eye was compared with the untreated fellow eye.ConclusionThe results demonstrate a very good safety profile of the therapy even at the highest dose administered. The small sample size limits the statistical power of efficacy analyses. However, trial results inform on the most promising design and endpoints for future clinical trials. Such trials have to determine whether treatment of younger patients results in greater functional gains by avoiding amblyopia as a potential limiting factor.

Objective Despite the need for diagnostics and research, data on fluid biomarkers in hereditary spastic paraplegia (HSP) are scarce. We, therefore, explore Neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) of patients with hereditary spastic paraplegia and provide information on the influence of demographic factors. Methods The study recruited 59 HSP cases (33 genetically confirmed) and 59 controls matched in age and sex. Neurofilament light chain levels were assessed by enzyme‐linked immunosorbent assay. The statistical analysis included the effects of age, sex, and genetic status (confirmed vs. not confirmed). Results Levels of CSF NfL were significantly increased in patients with hereditary spastic paraplegia compared to controls (median 741 pg/mL vs. 387 pg/mL, p

Objectives To evaluate the influence of audio-guided self-hypnosis on claustrophobia in a high-risk cohort undergoing magnetic resonance (MR) imaging. Methods In this prospective observational 2-group study, 55 patients (69% female, mean age 53.6 ± 13.9) used self-hypnosis directly before imaging. Claustrophobia included premature termination, sedation, and coping actions. The claustrophobia questionnaire (CLQ) was completed before self-hypnosis and after MR imaging. Results were compared to a control cohort of 89 patients examined on the same open MR scanner using logistic regression for multivariate analysis. Furthermore, patients were asked about their preferences for future imaging. Results There was significantly fewer claustrophobia in the self-hypnosis group (16%; 9/55), compared with the control group (43%; 38/89; odds ratio .14; p = .001). Self-hypnosis patients also needed less sedation (2% vs 16%; 1/55 vs 14/89; odds ratio .1; p = .008) and non-sedation coping actions (13% vs 28%; 7/55 vs 25/89; odds ratio .3; p = .02). Self-hypnosis did not influence the CLQ results measured before and after MR imaging (p = .79). Self-hypnosis reduced the frequency of claustrophobia in the subgroup of patients above an established CLQ cut-off of .33 from 47% (37/78) to 18% (9/49; p = .002). In the subgroup below the CLQ cut-off of 0.33, there were no significant differences (0% vs 9%, 0/6 vs 1/11; p = 1.0). Most patients (67%; 35/52) preferred self-hypnosis for future MR examinations. Conclusions Self-hypnosis reduced claustrophobia in high-risk patients undergoing imaging in an open MR scanner and might reduce the need for sedation and non-sedation coping actions. Key Points • Forty percent of the patients at high risk for claustrophobia may also experience a claustrophobic event in an open MR scanner. • Self-hypnosis while listening to an audio in the waiting room before the examination may reduce claustrophobic events in over 50% of patients with high risk for claustrophobia. • Self-hypnosis may also reduce the need for sedation and other time-consuming non-sedation coping actions and is preferred by high-risk patients for future examinations.

Background Accumulating evidence indicates toward an association between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and procoagulatory state in blood. Thromboelastographic investigations are useful point-of-care devices to assess coagulation and fibrinolysis.Objectives We investigated the hypothesis that the procoagulatory state in COVID-19 patients is associated with impaired fibrinolysis system.Methods Altogether, 29 COVID-19 patients admitted to normal wards or to the intensive care unit (ICU) were included in this descriptive study. Whole blood samples were investigated by thromboelastography to assess coagulation and fibrinolysis. Additionally, standard routine coagulation testing and immunoassays for factors of fibrinolysis as plasminogen activator inhibitor-1 (PAI-1), tissue plasminogen activator (tPA), plasminogen activity and α2-antiplasmin (A2AP) were performed.Results A significantly increased lysis resistance and a significantly longer time of lysis after adding tissue plasminogen activator were observed in blood samples from ICU COVID-19 patients compared with healthy controls (maximal lysis: 3.25 ± 0.56 vs. 6.20 ± 0.89%, p = 0.0127; lysis time: 365.7 ± 44.6 vs. 193.2 ± 16.3 seconds, p = 0.0014). PAI-1 activity was significantly higher in plasma samples of ICU COVID-19 patients (PAI-1: 4.92 ± 0.91 vs. 1.28 ± 0.33 U/mL, p = 0.001). A positive correlation between the activity of PAI-1 and lysis time of the formed clot (r = 0.70, p = 0.0006) was observed.Conclusion Our data suggest that severe SARS-CoV-2 infection is associated with impaired fibrinolytic activity in blood, where fibrinolytic inhibitors are elevated leading to an increased resistance to clot lysis. Thromboelastography could offer a tool to investigate the contribution of the fibrinolytic status to the procoagulatory condition in COVID-19.

Background treatment goals for blood pressure (BP) lowering in older patients with heart failure (HF) are unclear. Objective to assess whether BP control < 140/90 mmHg is associated with a decreased risk of mortality in older HF patients. Design population-based prospective cohort study. Setting/subjects participants of the Berlin Initiative Study, a prospective cohort of community-dwelling older adults launched in 2009. Clinical information was obtained in face-to-face interviews and linked to administrative healthcare data. Methods Cox proportional hazards models estimated adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of cardiovascular death and all-cause mortality associated with normalised BP (systolic BP < 140 mmHg and diastolic BP < 90 mmHg) compared with non-normalised BP (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg) in HF patients. The primary analysis considered only baseline BP (‘time-fixed’); an additional analysis updated BP during follow-up (‘time-dependent’). Results at baseline, 544 patients were diagnosed with HF and treated with antihypertensive drugs (mean age 82.8 years; 45.4% female). During a median follow-up of 7.5 years and compared with non-normalised BP, normalised BP was associated with similar risks of cardiovascular death (HR, 1.24; 95% CI, 0.84–1.85) and all-cause mortality (HR, 1.16; 95% CI, 0.89–1.51) in the time-fixed analysis but with increased risks of cardiovascular death (HR, 1.79; 95% CI, 1.23–2.61) and all-cause mortality (HR, 1.48; 95% CI, 1.15–1.90) in the time-dependent analysis. Conclusions BP control < 140/90 mmHg was not associated with a decreased risk of mortality in older HF patients. The increased risk in the time-dependent analysis requires further corroboration.

ObjectiveLymphadenectomy is an integral part of surgical staging and treatment for patients with gynecologic malignancies. Since its introduction, laparoscopic lymphadenectomy has proved feasible, safe, and oncologically adequate compared with open surgery while morbidity is lower and hospital stay considerably shorter. The aim of this study was to examine if surgical outcomes may be improved after the initial learning curve is complete.MethodsAn analysis of 2535 laparoscopic pelvic and/or para-aortic lymphadenectomies was performed between July 1994 and March 2018 by one team of gynecologic oncology surgeons but with the consistent supervision of a consultant surgeon. Data were collected prospectively evaluating operative time, intra-operative and post-operative complications, number of lymph nodes, and body mass index (BMI). Previously published data of 650 patients treated after introduction of the method (period 1, 1994–2003) were compared with the latter 524 patients (period 2, 2014–2018).ResultsThe median age of the 2535 patients was 43 years (IQR 34–57). The most common indication for pelvic and/or para-aortic lymphadenectomy was cervical cancer (n=1893). Operative time for para-aortic lymph node dissection was shorter in period 2 (68 vs 100 min, p2. In contrast to period 1 (n=18, 2.9%), there were no intra-operative complications in period 2 (n=0, 0.0%, pConclusionIn this large cohort of patients who underwent laparoscopic transperitoneal lymphadenectomy, lymph node count and peri-operative complications improved after the initial learning curve.

PURPOSE We aimed to investigate differences between high-intensity interval exercise (HIIE, including high-intensity interval training and sprint interval training) and moderate-intensity continuous training (MICT) on physical fitness, body composition, blood pressure, blood lipids, insulin and glucose metabolism, inflammation, and endothelial function. METHODS Differences between HIIE and MICT were summarized using a random-effects meta-analysis on the effect size (Cohen's d). A meta-regression was conducted using the following subgroups: population, age, training duration, men ratio, exercise type, baseline values (clinical relevant ranges), and type of HIIE. Studies were included if at least one of the following outcomes were reported: maximal oxygen uptake (V˙O2max), flow-mediated dilation (FMD), body mass index (BMI), body mass, percent body fat, systolic and diastolic blood pressure, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, total cholesterol, C-reactive protein (CRP), fasting glucose and insulin, glycated hemoglobin (HbA1c), and insulin resistance (HOMA-IR). A total of 55 studies were included. RESULTS Overall, HIIE was superior to MICT in improving V˙O2max (d = 0.40, P < 0.001) and FMD (d = 0.54, P < 0.05). Oppositely, MICT was superior to HIIE in improving HbA1c (d = -0.27, P < 0.05). No differences were observed in BMI (d = -0.02), body mass (d = -0.05), percent body fat (d = 0.04), systolic blood pressure (d = -0.04), diastolic blood pressure (d = 0.03), HDL (d = -0.05), LDL (d = 0.08), triglycerides (d = 0.03), total cholesterol (d = 0.14), CRP (d = -0.11), fasting insulin (d = 0.02), fasting glucose (d = 0.02), and HOMA-IR (d = -0.04). Moderator analyses indicated that the difference between HIIE and MICT was affected by different subgroups. CONCLUSION Overall, HIIE showed to be more effective in improving cardiovascular health and cardiorespiratory fitness, whereas MICT was superior in improving long-term glucose metabolism. In the process of personalized training counseling, health-enhancing effects of exercise training may be improved by considering the individual risk profiles.

PURPOSE Three new therapies have been approved recently for the adjuvant treatment of stage III melanoma, substantially reducing the risk of tumor recurrences. This study evaluates 3 independent data sets to clarify the survival probabilities of patients with stage III melanoma. PATIENTS AND METHODS The Central Malignant Melanoma Registry (CMMR) evaluated 1,553 patients with a primary diagnosis of stage III melanoma from 2000 to 2012. Studies from the European Organisation for Research and Treatment of Cancer (EORTC), of 573 patients in the observation arm of the 18991 study and 445 patients in the placebo arm of the 18071 study, were evaluated as reference cohorts. The survival outcomes were compared with the published American Joint Committee on Cancer version 8 (AJCCv8) stage III survival data. RESULTS For the CMMR stage III cohort versus the AJCCv8 cohort, the melanoma-specific survival (MSS) rates at 5 years were 67% versus 77%, and at 10 years were 56% versus 69%, respectively. For stage IIIA, the MSS rates at 5 years were 80% versus 93%, and at 10 years were 71% versus 88%; for stage IIIB, the MSS rates at 5 years were 75% versus 83%, and at 10 years were 61% versus 77%. The MSS rates of the EORTC studies either overlapped with or were lower than, the CMMR data. CONCLUSION The MSS rates in the CMMR and EORTC cohorts over the entire stage III are less favorable than those published in AJCCv8. This is particularly true for substages IIIA and IIIB.

Radiolabeled bisphosphonates such as 99mTc-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) typically show intense uptake in skeletal metastases from metastatic castration-resistant prostate cancer (mCRPC). Extensive bone involvement is regarded as a risk factor for mCRPC patients treated with 223Ra-dichloride (223Ra). The aim of this study was to quantify 99mTc-DPD uptake by means of SPECT/CT before 223Ra and compare the results with the feasibility of treatment and overall survival (OS). Methods: Sixty consecutive mCRPC patients were prospectively included in this study. SPECT/CT of the central skeleton covering the skull to the mid-femoral level was performed before the first cycle of 223Ra. The bone compartment was defined by means of low-dose CT. Emission data were corrected for scatter, attenuation, and decay supplemented by resolution recovery using dedicated software. The Kaplan-Meier estimator, U test, and Cox regression analysis were used for statistics. Results: Total 99mTc-DPD uptake of the central skeleton varied between 11% and 56% of injected dose (%ID) or between 1.8 and 10.5 %ID/1,000 mL of bone volume (%ID/L). SUVmean ranged from 1.9 to 7.4, whereas the SUVmax range was 18-248. Patients unable to complete 223Ra treatment because of progression and/or cytopenia (n = 23) showed significantly higher uptake (31.9 vs. 25.4 %ID and 6.0 vs. 4.7 %ID/L; P < 0.02). OS after 223Ra (median, 15.2 mo) was reduced to 7.3 mo in cases of skeletal uptake that was 26 %ID or higher, as compared with 30.8 mo if lower than 26 %ID (P = 0.008). Similar results were obtained for %ID/L and SUVmean SUVmax did not correlate with survival. %ID/L was identified as an independent prognostic factor for OS (hazard ratio, 1.381 per unit), along with number of previous treatment lines. Conclusion: Quantitative SPECT/CT of bone scans performed at baseline is prognostic for survival in mCRPC patients treated with 223Ra.

Purpose Active surveillance (AS) strategies for patients with low- and early intermediate-risk prostate cancer are still not consistently defined. Within a controlled randomized trial, active surveillance was compared to other treatment options for patients with prostate cancer. Aim of this analysis was to report on termination rates of patients treated with AS including different grade groups. Methods A randomized trial comparing radical prostatectomy, active surveillance, external beam radiotherapy and brachytherapy was performed from 2013 to 2016 and included 345 patients with low- and early intermediate-risk prostate cancer (ISUP grade groups 1 and 2). The trial was prematurely stopped due to slow accrual. A total of 130 patients were treated with active surveillance. Among them, 42 patients were diagnosed with intermediate-risk PCA. Reference pathology and AS quality control were performed throughout. Results After a median follow-up time of 18.8 months, 73 out of the 130 patients (56%) terminated active surveillance. Of these, 56 (77%) patients were histologically reclassified at the time of rebiopsy, including 35% and 60% of the grade group 1 and 2 patients, respectively. No patients who underwent radical prostatectomy at the time of reclassification had radical prostatectomy specimens ≥ grade group 3. Conclusion In this prospectively analyzed subcohort of patients with AS and conventional staging within a randomized trial, the 2-year histological reclassification rates were higher than those previously reported. Active surveillance may not be based on conventional staging alone, and patients with grade group 2 cancers may be recommended for active surveillance in carefully controlled trials only.

To evaluate the clinical benefit of positron emission tomography (PET)/computed tomography (CT) in patients with advanced melanoma, primarily not selected for surgery based on management changes and survival data using the linked evidence approach (LEA). A total of 201 18F-FDG PET/CT examinations (n = 33, stage III and n = 168, stage IV) in 119 melanoma patients, primarily not scheduled for surgery, were analysed regarding their impact on clinical management. Patients were selected from a prospective oncological PET/CT registry. The three PET/CT indication groups included unclear lesions in conventional imaging (n = 8), routine follow-up after multiple surgeries (n = 115) and therapy response evaluation of systemic therapy (n = 78). PET/CT-induced management changes were categorized either as major (change from follow-up to surgical or systemic treatment or vice versa, change from surgery to systemic therapy or vice versa) or minor (modifications in systemic therapy). The expected benefit of changes was determined via the linked evidence approach (LEA) connecting registry data, outcome data including overall survival and evidence of diagnostic accuracy of PET/CT based on existing literature. Related to the total study cohort, a change of management after PET/CT was observed in 48% of scans, including 10% minor and 38% major changes. Major changes involved a shift either from follow-up (33/201) or therapy pause (7/201) to systemic therapy, to surgical or other local therapy (26/201) and BSC (2/201). Nine out of 201 cases resulted in treatment pause of systemic therapy. We could confirm the prognostic value of PET/CT-based management by observing a 5-year survival rate more than roughly doubled in patients followed up after tumour exclusion or under local therapy compared with patients under systemic therapy. We could argue for a patient benefit from PET/CT-based management changes using results on accuracy and therapeutic effects from the literature. The use of PET/CT in advanced melanoma patients, primarily not considered for surgery, resulted in frequent changes of management associated with a relevant expected clinical benefit especially in patients classified by PET/CT as tumour-free or eligible for radical surgery.

Movement disorders 37(2), 405-410 (2022). doi:10.1002/mds.28844, Published by Wiley, New York, NY

Plasma clearance of iohexol is a pivotal metric to quantify glomerular filtration rate (GFR), but the optimal timing and frequency of plasma sampling remain to be assessed. In this study, we evaluated the impact of a Bayesian estimation procedure on iohexol clearance estimates, and we identified an optimal sampling strategy based on data in individuals aged 70+. Assuming a varying number of random effects, we re-estimated previously developed population pharmacokinetic two- and three-compartment models in a model development group comprising 546 patients with iohexol concentration data up to 300 min post injection. Model performance and optimal sampling times were assessed in an evaluation group comprising 104 patients with reduced GFR and concentration data up to 1440 min post injection. Two- and three-compartment models with random effects for all parameters overestimated clearance values (bias 5.07 and 4.40 mL/min, respectively) and underpredicted 24-h concentrations (bias − 14.5 and − 12.0 µg/ml, respectively). Clearance estimates improved distinctly when limiting random effects of the three-compartment model to clearance and central volume of distribution. Two blood samples, one early and one 300 min post injection, were sufficient to estimate iohexol clearance. A simplified three-compartment model is optimal to estimate iohexol clearance in elderly patients with reduced GFR.

SummaryBackgroundAcute Respiratory Distress Syndrome (ARDS) results in significant hypoxia, and ARDS is the central pathology of COVID-19. Inhaled prostacyclin has been proposed as a therapy for ARDS, but data regarding its role in this syndrome are unavailable. Therefore, we investigated whether inhaled prostacyclin would affect the oxygenation and survival of patients suffering from ARDS.MethodsWe performed a prospective randomized controlled single-blind multicenter trial across Germany. The trial was conducted from March 2019 with final follow-up on 12th of August 2021. Patients with moderate to severe ARDS were included and randomized to receive either inhaled prostacyclin (3 times/day for 5 days) or sodium chloride. The primary outcome was the oxygenation index in the intervention and control groups on Day 5 of therapy. Secondary outcomes were mortality, secondary organ failure, disease severity and adverse events.FindingsOf 707 patients approached 150 patients were randomized to receive inhaled prostacyclin (n=73) or sodium chloride (n=77). Data from 144 patients were analyzed. The baseline oxygenation index did not differ between groups. The primary analysis of the study was negative, and prostacyclin improved oxygenation by 20 mmHg more than NaCl (p=0·17). Oxygenation was significantly improved in patients with ARDS who were COVID-19-positive (34 mmHg, p=0·04). Mortality did not differ between groups. Secondary organ failure and adverse events were similar in the intervention and control groups.InterpretationAlthough the primary result of our study was negative, our data suggest that inhaled prostacyclin might be a more beneficial treatment than standard care for patients with ARDS.

Introduction/Background* It has previously been demonstrated that bevacizumab may differentially improve ovarian cancer survival. TCGA classification as well as molecular targets of anti-VEGF therapy were shown to be associated with different levels of bevacizumab efficacy. Translation into individualized treatment options or improved disease outcome was yet hindered by inconsistent results across trials and tissue types. It was the aim of this project to validate retrospective analyses of GOG-0218 derived predictive value of microvessel density (CD31) and tumor VEGF-A. Methodology CD31 and VEGF-A immunohistochemistry was performed on whole section FFPE tissue samples from the AGO-OVAR11 (ICON7) trial. Patients were stratified into high and low biomarker-expressing subgroups using median cutoffs. The association between biomarker expression and bevacizumab therapy efficacy was evaluated using a proportional Cox regression model. Efficacy endpoints were progression free survival (PFS) and overall survival (OS). Result(s)* Complete CD31 and VEGF-A immunhistochemical data were available from 387 patients of the German ICON7 trial cohort. Among all biomarker subgroups, only patients with high VEGF-A expression levels had a statistically significant benefit from the addition of bevacizumab to standard chemotherapy. Median PFS and OS of VEGF-A high patients was 23.1 months (95% CI 15.9-30.2) and 64.9 months (median not reached) respectively if bevacizumab was added to standard chemotherapy but only 14.3 (95% CI an 11.2-17) and 47.3 months (95% CI 5.6-36.3) in the control arm. In multivariable analysis, adjusted for age, FIGO and postoperative residual tumor, the anti-angiogenic therapy showed improved PFS (HR: 0.62 [95%CI 0.43-0.89], p=0.011) and OS (HR 0.59 [95%CI 0.39-0.91], p=0.02) among VEGF-A high patients. Patients with low VEGF-A expression levels showed no statistically significant improvement of PFS (HR 0.96 95% CI 0.67-1.38, p=0.83) or OS (HR 1.06 95% CI 0.69-1.62, p=0.80) after addition of bevacizumab. CD31 immunohistochemistry was not predictive for bevacizumab treatment effects in our cohort. Conclusion* A potential predictive value of VEGF-A expression levels was observed in advanced stage ovarian carcinoma patients from the German ICON7 patient cohort, partly confirming GOG-0218 derived findings. Our results may help to develop biomarker stratified anti-VEGF therapy and hold potential to promote personalized treatment strategies in ovarian carcinoma patients.

Physiological effects of spreading depolarizations (SD) are only well studied in the first hours after experimental stroke. In patients with malignant hemispheric stroke (MHS), monitoring of SDs is restricted to the postoperative ICU stay, typically day 2-7 post-ictus. Therefore, we investigated the role of physiological variables (temperature, intracranial pressure, mean arterial pressure and cerebral perfusion pressure) in relationship to SD during the late phase after MHS in humans. Additionally, an experimental stroke model was used to investigate hemodynamic consequences of SD during this time window. In 60 patients with MHS, the occurrence of 1692 SDs was preceded by a decrease in mean arterial pressure (−1.04 mmHg; p = .02) and cerebral perfusion pressure (−1.04 mmHg; p = .03). Twenty-four hours after middle cerebral artery occlusion in 50 C57Bl6/J mice, hypothermia led to prolonged SD-induced hyperperfusion (+2.8 min; p

IntroductionThe actual prevalence of a SARS-CoV-2 infection and the individual assessment of being or having been infected may differ. Facing the great uncertainty—especially at the beginning of the pandemic—and the possibility of asymptomatic or mildly symptomatic, subclinical infections, we evaluate the experience of SARS-CoV-2 antibody screening at a tertiary clinical setting.Methods and analysisAll employees of a tertiary eye centre and a research institute of ophthalmology were offered antibody testing in May 2020, using a sequential combination of different validated assays/antigens and point-of-care (POC) testing for a subset (NCT04446338). Before taking blood, a systematic inquiry into past symptoms, known contacts and a subjective self-assessment was documented. The correlations between serostatus, patient contacts and demographic characteristics were analysed. Different tests were compared by Kappa statistics.ResultsAmong 318 participants, SARS-CoV-2 antibodies were detected in 9 employees. Chemiluminescence assays (chemiluminescence immunoassay and electrochemiluminescence) showed superior specificity and high reproducibility, compared with ELISA and POC results.In contrast to the low seropositivity (2.8%) of healthcare workers, higher than that of the other departments of the hospital, a large proportion mistakenly assumed that they might have already been infected. Antiviral antibody titres increased and remained on a plateau for at least 3 months.ConclusionsThe great demand and acceptance confirmed the benefit of highly sensitive testing methods in the early phase of the pandemic. The coincidence of low seroprevalence and anxious employees may have contributed to internalising the need of hygiene measures.

Patients with primary central nervous system lymphoma (PCNSL) not fulfilling inclusion criteria for clinical trials represent an underreported population. Thirty-four consecutive PCNSL patients seen at our center between 2005 and 2019 with exclusion criteria for therapeutic trials were analyzed (non-study patients) and compared with patients from the G-PCNSL-SG-1 (German PCNSL Study Group 1) study (study patients), the largest prospective multicenter trial on PCNSL, comprising 551 patients. Median follow up was 68 months (range 1–141) in non-study patients and 51 months (1–105) in study patients. Twenty-seven/34 (79.4%) non-study patients received high dose methotrexate (HDMTX), while seven/34 (20.6%) with a glomerular filtration rate (GFR) &lt, 50 mL/min did not. Median overall survival (OS) was six months (95% confidence interval [CI] 0–21 months) in those 34 non-study patients. The 27 non-study patients treated with HDMTX were compared with 526/551 G-PCNSL-SG-1 study patients who had received HDMTX as well. Median OS was 20 months (95% CI 0–45)/21 months (95% CI 18–25) in 27 non-study/526 study patients (p = 0.766). Favorable prognostic factors in non-study patients were young age, application of HDMTX and early response on magnet resonance imaging (MRI). If HDMTX-based chemotherapy can be applied, long-term disease control is possible even in patients not qualifying for clinical trials. Initial response on early MRI might be useful for decision on treatment continuation.

COVID-19 may lead to severe acute respiratory distress syndrome (ARDS) resulting in increased morbidity and mortality. Heart failure and/or pre-existing cardiovascular disease may correlate with poor outcomes and thus require special attention from treating physicians. The present study sought to investigate a possible impact of impaired myocardial function as well as myocardial distress markers on mortality or ARDS with need for mechanical ventilation in 157 consecutive patients with confirmed SARS-CoV-2 infection. All patients were admitted and treated at the University Hospital of Tübingen, Germany, during the first wave of the pandemic. Electrocardiography, echocardiography, and routine blood sampling were performed at hospital admission. Impaired left-ventricular and right-ventricular function, tricuspid regurgitation > grade 1, and elevated RV-pressure as well as thrombotic and myocardial distress markers (D-dimers, NT-pro-BNP, and troponin-I) were associated with mechanical ventilation and/or all-cause mortality. Impaired cardiac function is more frequent amidst ARDS, leading to subsequent need for mechanical ventilation, and thus denotes a poor outcome in COVID-19. Since a causal treatment for SARS-CoV-2 infection is still lacking, guideline-compliant cardiovascular evaluation and treatment remains the best approach to improve outcomes in COVID-19 patients with cardiovascular comorbidities.

Background In the absence of randomized studies, it has been controversial whether the likelihood of acute kidney injury (AKI) differs between intravenous and intra-arterial contrast agent administration. Purpose To compare intravenous versus intra-arterial contrast agent administration in relationship to AKI and analyze the association between AKI and chronic kidney disease (defined as at least mildly decreased estimated glomerular filtration rates [eGFRs]). Materials and Methods This was a prospective study (ClinicalTrials.gov: NCT00844220) that involved randomizing participants with atypical chest pain and suspected coronary artery disease (CAD) between February 2009 and August 2015 to undergo coronary CT angiography with intravenous contrast agent administration or cardiac catheterization angiography with intra-arterial contrast agent administration. This prespecified secondary analysis compared AKI (serum creatinine increase of ≥ 25% or 0.5 mg/dL after 18-24 or 46-50 hours) determined by blinded investigators using absolute differences and relative risks, including two-sided 95% confidence intervals (CIs). Results A total of 320 participants (163 [50.9%] women; mean age, 60 years ± 11) were included. Baseline eGFR did not differ between the CT angiography group (84.3 mL/min/1.73 m2 ± 17.2) and the catheterization group (87.1 mL/min/1.73 m2 ± 16.7) (P = .14). AKI occurred in nine of 161 participants in the CT angiography group (5.6%; 95% CI: 3%, 10%) and in 21 of 159 participants in the catheterization group (13.2%; 95% CI: 9%,19%) (relative risk, 2.4; 95% CI: 1.1, 5.0; P = .02). Also in the subgroup of participants without obstructive CAD, in those not requiring coronary interventions, AKI was more common in the catheterization group (11.9%; 95% CI: 8%, 19%) than in the CT angiography group (4.3% [95% CI: 2%, 9%]; difference, 7.7% [95% CI: 1.3%, 14.1%]; relative risk, 2.8 [95% CI: 1.1, 7.0]; P = .02). Obstructive CAD (odds ratio [OR]: 2.7 [95% CI: 1.1, 6.6]; P = .02), femoral catheter access (OR: 2.5 [95% CI: 1.1, 5.6]; P = .04), and cine ventriculography were associated with AKI (OR: 2.3 [95% CI: 1.0, 4.9]; P = .03). In multivariable analysis, the presence of postcontrast AKI was associated with chronic kidney disease (hazard ratio: 12.4 [95% CI: 4.5, 34.6]; P < .01). Conclusion Acute kidney injury was more common after cardiac catheterization than after CT angiography in this prospective randomized study of patients suspected of having coronary artery disease. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Einstein and Newhouse in this issue.

ObjectiveLaparoscopic/robotic radical hysterectomy has been historically considered oncologically equivalent to open radical hysterectomy for patients with early cervical cancer. However, a recent prospective randomized trial (Laparoscopic Approach to Cervical Cancer, LACC) has demonstrated significant inferiority of the minimally invasive approach. The aim of this study is to evaluate the oncologic outcomes of combined laparoscopic-vaginal radical hysterectomy.MethodsBetween August 1994 and December 2018, patients with invasive cervical cancer were treated using minimally-invasive surgery at the Universities of Jena, Charité Berlin (Campus CCM and CBF) and Cologne and Asklepios Clinic Hamburg. 389 patients with inclusion criteria identical to the LACC trial were identified. In contrast to the laparoscopic/robotic technique used in the LACC trial, all patients in our cohort underwent a combined transvaginal-laparoscopic approach without the use of any uterine manipulator.ResultsA total of 1952 consecutive patients with cervical cancer were included in the analysis. Initial International Federation of Gynecology and Obstetrics (FIGO) stage was IA1 lymphovascular space invasion (LVSI+), IA2 and IB1/IIA1 in 32 (8%), 43 (11%), and 314 (81%) patients, respectively, and histology was squamous cell in 263 (68%), adenocarcinoma in 117 (30%), and adenosquamous in 9 (2%) patients. Lymphovascular invasion was confirmed in 106 (27%) patients. The median number of lymph nodes was 24 (range 2–86). Lymph nodes were tumor-free in 379 (97%) patients. Following radical hysterectomy, 71 (18%) patients underwent adjuvant chemoradiation or radiation. After a median follow-up of 99 (range 1–288) months, the 3-, 4.5-, and 10-year disease-free survival rates were 96.8%, 95.8%, and 93.1 %, and the 3-, 4.5-, and 10-year overall survival rates were 98.5%, 97.8%, and 95.8%, respectively. Recurrence location was loco-regional in 50% of cases with recurrence (n=10). Interestingly, 9/20 recurrences occurred more than 39 months after surgery.ConclusionThe combined laparoscopic-vaginal technique for radical hysterectomy with avoidance of spillage and manipulation of tumor cells provides excellent oncologic outcome for patients with early cervical cancer. Our retrospective data suggest that laparoscopic-vaginal surgery may be oncologically safe and should be validated in further randomized trials.

Spreading depolarizations (SDs) occur in 50–60% of patients after surgical treatment of severe traumatic brain injury (TBI) and are independently associated with unfavorable outcomes. Here we performed a pilot study to examine the relationship between SDs and various types of intracranial lesions, progression of parenchymal damage, and outcomes. In a multicenter study, fifty patients (76% male; median age 40) were monitored for SD by continuous electrocorticography (ECoG; median duration 79 h) following surgical treatment of severe TBI. Volumes of hemorrhage and parenchymal damage were estimated using unbiased stereologic assessment of preoperative, postoperative, and post-ECoG serial computed tomography (CT) studies. Neurologic outcomes were assessed at 6 months by the Glasgow Outcome Scale-Extended. Preoperative volumes of subdural and subarachnoid hemorrhage, but not parenchymal damage, were significantly associated with the occurrence of SDs (P’s

Aims To assess whether blood pressure (BP) values below 140/90 mmHg during antihypertensive treatment are associated with a decreased risk of all-cause mortality in community-dwelling older adults. Methods and results Within the Berlin Initiative Study, we assembled a cohort of patients ≥70 years treated with antihypertensive drugs at baseline (November 2009–June 2011). End of prospective follow-up was December 2016. Cox proportional hazards models yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause mortality associated with normalized BP [systolic BP (SBP) Conclusion Blood pressure values below 140/90 mmHg during antihypertensive treatment may be associated with an increased risk of mortality in octogenarians or elderly patients with previous cardiovascular events.

Co-infections with Plasmodium, Ascaris and Giardia are common in sub-Saharan Africa but epidemiological and clinical data are rare. We examined factors associated with co-infections and their clinical manifestation among Rwandan schoolchildren.Schoolchildren aged 6-10 years attending 12 schools in Huye district, Rwanda, were recruited preceding routine deworming. Data on socioeconomic status (SES) and children's histories were obtained, and children were clinically and anthropometrically examined. Blood and stool samples were collected, and infections with Plasmodium, Ascaris and Giardia were determined by microscopy and PCR assays.Among 878 schoolchildren, Plasmodium, Ascaris and Giardia were present in 22%, 35% and 36%, respectively. Co-infections with two or more parasites were found in 24%; only one-third of the children did not harbour any of the parasites examined. Factors associated with parasite (co-)infections largely overlapped and reflected low SES, in addition to a few specific risk factors. Clinically, most children were asymptomatic but anaemia (38%), underweight (17%), and reported signs and symptoms in the preceding 2 weeks (46%) were common. Many of the reported and assessed signs and symptoms were associated with Plasmodium infection, and co-infection with Ascaris and/or Giardia did basically not modify the clinical picture. One exception was malnutrition, which was pronounced in Ascaris-Giardia co-infection vs. individual mono-infections.Parasitic co-infections are common in Rwandan schoolchildren, and are associated with a rather silent clinical manifestation that nevertheless may affect school performance and long-term development. School-based health interventions should target such co-infections in an integrated manner.Les coinfections par Plasmodium, Ascaris et Giardia sont courantes en Afrique subsaharienne, mais les données épidémiologiques et cliniques sont rares. Nous avons examiné les facteurs associés aux coinfections et leurs manifestations cliniques chez les écoliers rwandais. MÉTHODES: Des écoliers âgés de 6 à 10 ans fréquentant 12 écoles du district de Huye au Rwanda ont été recrutés avant le déparasitage de routine. Les données sur le statut socioéconomique (SSE) et les antécédents des enfants ont été obtenues et les enfants ont été examinés cliniquement et anthropométriquement. Des échantillons de sang et de selles ont été recueillis et les infections à Plasmodium, Ascaris et Giardia ont été déterminées par microscopie et par PCR. RÉSULTATS: sur 878 écoliers, Plasmodium, Ascaris et Giardia étaient présents chez 22%, 35% et 36%, respectivement. Des coinfections avec deux parasites ou plus ont été trouvées chez 24%; seul un tiers des enfants n'hébergeait aucun des parasites examinés. Les facteurs associés aux (co)infections parasitaires se chevauchaient largement et reflétaient un faible statut SSE, en plus de quelques facteurs de risque spécifiques. Sur le plan clinique, la plupart des enfants étaient asymptomatiques mais l'anémie (38%), l'insuffisance pondérale (17%) et les signes et symptômes rapportés au cours des deux semaines précédentes (46%) étaient fréquents. De nombreux signes et symptômes rapportés et évalués étaient associés à l'infection au Plasmodium et la coinfection par Ascaris et/ou Giardia n'a fondamentalement pas modifié le tableau clinique. Une exception était la malnutrition, qui était prononcée dans la coinfection Ascaris-Giardia par rapport aux mono-infections individuelles.Les coinfections parasitaires sont courantes chez les écoliers rwandais et sont associées à une manifestation clinique plutôt silencieuse qui peut néanmoins affecter les performances scolaires et le développement à long terme. Les interventions de santé en milieu scolaire devraient cibler ces coinfections de manière intégrée.

Besides deficits in memory and cognition, impaired visual processing is common for Alzheimer's disease (AD) patients and mouse models of AD but underlying mechanisms still remain unclear. Using in vivo Ca2+ imaging of the mouse primary visual cortex (V1) we tested whether such impairment is caused by neuronal hyperactivity, an emerging functional hallmark of AD. Profound neuronal hyperactivity was indeed found in V1 of APPSWE/PS1G384A and even of PS1G384A mice, presenting neither with plaque accumulation nor with neuroinflammation. This hyperactivity was accompanied by over-responsiveness to visual stimuli and impaired visual tuning properties of individual neurons, largely caused by insufficient suppression of responses to non-preferred orientation/direction stimuli. Moreover, visual stimulation robustly suppressed the ongoing spontaneous activity in WT but not in APPSWE/PS1G384A mice. Emptying intracellular Ca2+ stores significantly reduced neuronal hyperactivity and the pathological over-responsiveness to visual stimuli, but could not rescue stimulus-induced suppression of spontaneous activity and impaired tuning properties of individual cells. Thus, our data identify the AD-mediated dysfunction of intracellular Ca2+ stores as a main cause of pathologically increased visual responsiveness in APPSWE/PS1G384A mice. At the same time, the impairment of visual tuning and the stimulus-induced suppression of spontaneous activity, identified in this study, are likely caused by different mechanisms as, for example, dysfunction of local interneurons.

Objectives Cutaneous melanoma (CM) and keratinocyte cancer (KC) cause considerable morbidity and mortality. We analysed long-term trends of CM and KC in different white populations. Material and methods Age-standardised (European Standard Population 2013) incidence and mortality rates (ASIR, ASMR) of CM were extracted from cancer registries in Denmark, New Zealand and the US SEER-Database. ASIRs of KC were sourced from registries of the German federal states Saarland and Schleswig–Holstein, and from Scotland. Age-period-cohort models were used to project melanoma incidence trends. Results In Denmark between 1943 and 2016, melanoma ASIR increased from 1.1 to 46.5 in males, and from 1.0 to 48.5 in females, estimated to reach 60.0 and 73.1 in males and females by 2036. Melanoma mortality in Denmark (1951–2016) increased from 1.4 to 6.7 (males) and 1.2 to 3.7 (females). In New Zealand between 1948 and 2016, ASIR increased from 2.7 to 81.0 (males) and from 3.8 to 54.7 (females), slight declines are estimated by 2036 for both genders. Melanoma mortality increased six-fold in New Zealand males between 1950 and 2016; smaller increases were observed in females. We observed three- to four-fold increases in melanoma incidence in US whites, predicted to rise to 56.1 and 36.2 in males and females until 2036. Melanoma mortality also increased among US whites between 1970 and 2017, female melanoma mortality remained stable. Similar trends are shown for KC. Conclusions In white populations, incidence of CM and KC significantly increased. CM incidence continues to rise in the short term but is predicted to decline in future.

Background: Having recovered from the Coronavirus Disease of 2019 (COVID-19), a considerable number of patients is still experiencing long-term sequelae, referred to as Post-COVID-19. Prevalence and clinical characteristics differ widely in studies reported so far, depending on the respective study design. The present study contributes to the understanding of Post-COVID-19 by investigating prevalence, clinical characteristics and possible risk factors in a population-based cohort. Methods: We designed a total population sampling in three German counties by inviting all patients ≥18 years of age with confirmed COVID-19 between 03/2020 and 09/2020 (n= 4,632). Participants completed a self-developed questionnaire on COVID-19 related symptoms, including validated instruments for the assessment of comorbidity and health-related quality of life (HrQoL). Potential predictors for Post-COVID-19 were identified by multiple ordinal regression analysis. Findings: The response rate was 41%, and a total of 1,732 patients were included in the study, with 198 (11%) hospitalized for acute COVID-19. The prevalence for symptoms persisting ≥12 weeks was 66.7% (n=128) and 39.4% (n=598), for hospitalized and non-hospitalized patients, respectively. The most frequent long-term symptoms were fatigue (40.6%), physical exhaustion (40.5%) and difficulty concentrating (30%). HrQoL was significantly poorer in patients with persisting symptoms. The strongest risk factors for Post-COVID-19 were female sex, level of comorbidity and severity of acute COVID-19. Interpretation: This population-based survey indicates that long-term symptoms are a frequent burden following COVID-19 which will pose major challenges to health care systems. Research into effective therapies and health care structures is urgently needed. Trial Registration: This study was registered in the German Clinical Trials Register (reference DRKS00023069). Funding: Special grant COVID-19 - Ministry of Science, Research and Art of Baden-Wuerttemberg. Declaration of Interest: All authors declare no conflicts of interest. Ethical Approval: The study was approved by the ethics committee of the university hospital Tuebingen (reference 698/2020BO)

Background: Anxiety and post-traumatic stress disorder (PTSD) are known etiologic and prognostic risk factors in patients with coronary heart disease (CHD). However, few studies have assessed the prevalence of a comprehensive set of anxiety and stress related disorders in CHD. Moreover, it is unclear whether these disorders are associated with CHD symptoms, severity and cardiovascular events and procedures. Methods: We determined the 12-month prevalence of anxiety disorders and PTSD in N = 1024 hospitalized patients with CHD and examined associations with cardiac disease characteristics, cardiovascular events and procedures. Anxiety and PTSD diagnoses were determined with the Composite International Diagnostic Interview. Socio-demographic variables were assessed with a questionnaire and cardiovascular variables were extracted from medical charts. Results: 12-month prevalence for any anxiety disorder was 11.2% for men and 24.8% for women; 12-month PTSD prevalence was 1.1% and 5.2%, respectively. The most common anxiety disorders were specific phobia (men: 8.2%, women: 18.8%) and agoraphobia and/or panic disorder (combined prevalence men: 2.9%, women: 9.9%). Anxiety disorders were not associated with any cardiovascular variables. Limitations: Due to lack of follow-up data no conclusions regarding stability of diagnoses are possible. Associations of PTSD and medical variables could not be determined because of low PTSD prevalence. Conclusions: Compared to the general population, anxiety disorders were more frequent in younger (

ObjectiveRevised staging of patients with locally advanced cervical cancer is based on clinical examination, imaging, and potential surgical findings. A known limitation of imaging techniques is an appreciable rate of understaging. In contrast, surgical staging may provide more accurate information on lymph node involvement. The aim of this prospective study was to evaluate the impact of pre-treatment surgical staging, including removal of bulky lymph nodes, on disease-free survival in patients with locally advanced cervical cancer.MethodsUterus-11 was a prospective international multicenter study including patients with locally advanced cervical cancer who were randomized 1:1 to surgical staging (experimental arm) or clinical staging (control arm) followed by primary platinum-based chemoradiation. Patients with histologically proven squamous cell carcinoma, adenocarcinoma, or adenosquamous cancer International Federation of Gynecology and Obstetrics (FIGO) 2009 stage IIB–IVA underwent gynecologic examination and pre-treatment imaging including abdominal computed tomography (CT) and/or abdominal magnetic resonance imaging (MRI). Patients had chest imaging (any of the following: X-ray, CT, or PET-CT). The primary endpoint was disease-free survival and the secondary endpoint was overall survival. An ad hoc analysis was performed after trial completion for cancer-specific survival. Randomization was conducted from February 2009 to August 2013.ResultsA total of 255 patients (surgical arm, n=130; clinical arm, n=125) with locally advanced cervical cancer were randomized. Of these, 240 patients were eligible for analysis. The two groups were comparable with respect to patient characteristics. The surgical approach was transperitoneal laparoscopy in most patients (96.6%). Laparoscopic staging led to upstaging in 39 of 120 (33%) patients. After a median follow-up of 90 months (range 1–123) in both arms, there was no difference in disease-free survival between the groups (p=0.084). For patients with FIGO stage IIB, surgical staging is superior to clinical staging with respect to disease-free survival (HR 0.51, 95% CI 0.30 to 0.86, p=0.011). In the post-hoc analysis, surgical staging was associated with better cancer-specific survival (HR 0.61, 95% CI 0.40 to 0.93, p=0.020).ConclusionOur study did not show a difference in disease-free survival between surgical and clinical staging in patients with locally advanced cervical cancer. There was a significant benefit in disease-free survival for patients with FIGO stage IIB and, in a post-hoc analysis, a cancer-specific survival benefit in favor of laparoscopic staging. The high risk of distant metastases in both arms emphasizes the need for further evaluation.

Background: To investigate outcome and toxicity of high-dose systemic methotrexate (HDMTX)-based polychemotherapy and intracerebroventricular (ICV) chemotherapy via an Ommaya reservoir in elderly patients with primary central nervous system lymphoma (PCNSL). Methods: We performed a retrospective analysis on patients ⩾65 years with first diagnosis of PCNSL admitted to our center between January 2015 and December 2019. These patients were treated with a standardized chemotherapy protocol in case of absent contraindications for HDMTX-based chemotherapy. The protocol contained induction therapy with systemic rituximab, methotrexate and ifosfamide and consolidation treatment with systemic cytarabine (AraC) and ICV methotrexate, prednisolone and AraC. Results: Of a total of 46 patients seen in this period, 3 did not qualify for HDMTX. Thus, 43 patients were included in this analysis. Median age was 74 years (range 65–86), median Karnofsky performance score was 50 (range 20–90). Of the 43 patients, 32 (74.4%) completed treatment including ICV therapy. Complete remission/complete remission unconfirmed was achieved in 26 of 43 patients (60.5%), partial response (PR) in 3 (7%); 5 (11.6%) had progressive disease, and 3 (7.0%) died due to treatment-related complications; in the remaining 6 (14.0%) therapy could not be completed. Median progression free survival was 16 months (95% confidence interval 8–24 months) and median overall survival had not been reached after a median follow up of 23 months (range 1–52 months); the 75th percentile survival time was 12 months. No Ommaya reservoir infection was observed. Complications of ICV treatment were pericatheter leucencephalopathy in two patients and surgical scar dehiscence with cerebrospinal fluid leak in one patient. Conclusion: Toxicity of HDMTX plus ICV chemotherapy for elderly patients with PCNSL was manageable and outcome was excellent for patients treated with this protocol.

Objectives The aim of this trial is to identify the effect of ambulatory treatment in early COVID-19 disease with hydroxychloroquine on the rate of hospitalization or death in older patients above the age of 64. Trial design Parallel, 2:1 randomization, double blind, placebo-controlled, multi-center trial. Participants Male and female patients above the age of 64 (i.e. ≥65 years of age) with COVID-19 diagnosis confirmed by SARS-CoV2 positive throat swab (PCR). Patients can only be included within 3 days of symptom onset in ambulatory care if they consent to the study procedure and are able to adhere to the study visit schedule and protocol requirements (including telephone visits concerning symptoms and side effects). Severity of disease at inclusion is mild to moderate defined as not requiring hospital admission: SpO2 >94%, respiratory rate Intervention and comparator Each patient will be given a first dose of 600 mg Hydroxychloroquine or the equivalent number of placebo capsules (3 capsules) at the day of inclusion. From the 2nd day on, each patient will get 200 mg or the equivalent number of placebo capsules twice a day (400mg/day) until day 7 (6 more does of 400 mg); a cumulative dose of 3 g. Main outcomes Rate of hospitalization or death at day 7 after study inclusion Randomisation All consenting adult patients having confirmed COVID-19 are randomly and blindly allocated in a 2:1 ratio to either IMP or placebo. The biostatistical center produced a randomization list (block randomization) with varying block length and stratified for the study center. This list is provided for packaging to the pharmaceutical unit which is providing encapsulated placebo and IMP. Only the pharmaceutical unit is aware of group allocation according to the randomization list. Blinding (masking) Patients and investigators, as well as treating physicians are blinded to the treatment- allocation. Numbers to be randomised (sample size) In the first stage of an adaptive design 120 patients in a 2:1 ration: 72 Verum and 36 Placebo, plus an increase for 10% drop outs. After interim analysis, the total sample size will be calculated based on the effect seen in the first stage. Total sample size is estimated approximately n = 300-400 patients. Trial Status Protocol version number: V3, 19.05.2020 Recruitment not yet started but is anticipated to begin by June 2020 and be complete by December 2020 Trial registration ClinicalTrials.gov: NCT04351516, date: 17 April 2020 EudraCT: 2020-001482-37, date: 30 March 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Purpose To assess the developments in contrast sensitivity, color vision, and subjective perception after Descemet membrane endothelial keratoplasty (DMEK) in patients with Fuchs endothelial corneal dystrophy (FECD). Methods Included in this study were pseudophakic, unilateral DMEK patients with bilateral FECD having a follow-up period of 6 months (n = 23). The mean age at surgery was 70 years (range: 52-81 years). Pseudophakic eyes without history of other ocular pathology or surgery served as a control (n = 10). Pelli-Robson contrast sensitivity and Panel-D15 color vision tests were used. Best-corrected visual acuity, modified visual functioning questionnaire-25, central corneal thickness, and endothelial cell density were assessed. We visualized the subjective impression of patients with bilateral FECD after unilateral DMEK in a subgroup using Photoshop CS6. Results Contrast sensitivity improved significantly from 1.35 ± 0.26 to 1.64 ± 0.17 (P = 0.002; control eyes: 1.92 ± 0.09). No difference in the color vision error score was observed for preoperative and postoperative eyes (P = 0.063). The best-corrected visual acuity improved significantly after surgery (P = 0.001). The average values in the Logarithm of the Minimum Angle of Resolution were 0.59 ± 0.42 preoperatively and 0.1 ± 0.10 postoperatively (control eyes: 0.01 ± 0.03). Examinations revealed a decrease of the central corneal thickness and endothelial cell density after surgery (P = 0.001; P = 0.001, respectively). Scores in the general and the driving questionnaire were significantly higher after surgery (P = 0.001; P = 0.005, respectively). Conclusions This study showed significant improvement in subjective patient satisfaction and contrast sensitivity. Spontaneous subjective color vision improvement might be explained by significantly improved contrast sensitivity. Contrast sensitivity might be considered as a parameter in preoperative decision-making and evaluation of surgical outcome.

Purpose Acute mountain sickness commonly occurs following ascent to high altitude and is aggravated following sleep. Cephalad fluid shifts have been implicated. We hypothesized that sleeping with the upper body elevated by 30o reduces the risk of acute mountain sickness. Methods In a pragmatic, randomized, observer-blinded field study at 4554 meters altitude, we investigated 134 adults aged 18-70 years with a Lake Louise score between 3 and 12 points on the evening of their arrival at the altitude. The individuals were exposed to sleeping on an inflatable cushion elevating the upper body by 30o or on a sham pillow in a horizontal position. The primary endpoint was the change in the Acute Mountain Sickness-Cerebral (AMS-C) score in the morning after sleeping at an altitude of 4554 meters compared with the evening before. Sleep efficiency was the secondary endpoint. Results Among 219 eligible mountaineers, 134 fulfilled the inclusion criteria and were randomized. The AMS-C score increased by 0.250 ± 0.575 in the control group and by 0.121 ± 0.679 in the intervention group (difference 0.105; 95% confidence interval, −0.098-0.308; P = .308). Oxygen saturation in the morning was 79% ± 6% in the intervention group and 78% ± 6% in the control group (P = .863). Sleep efficiency did not differ between groups (P = .115). Conclusions Sleeping with the upper body elevated by 30° does not lead to relevant reductions in acute mountain sickness symptoms or hypoxemia at high altitude.

Promoting patient and occupational safety are two key challenges for hospitals. When aiming to improve these two outcomes synergistically, psychosocial working conditions, leadership by hospital management and supervisors, and perceptions of patient and occupational safety climate have to be considered. Recent studies have shown that these key topics are interrelated and form a critical foundation for promoting patient and occupational safety in hospitals. So far, these topics have mainly been studied independently from each other. The present study investigated hospital staffs' perceptions of four different topics: (1) psychosocial working conditions, (2) leadership, (3) patient safety climate, and (4) occupational safety climate. We present results from a survey in two German university hospitals aiming to detect differences between nurses and physicians.We performed a cross-sectional study using a standardized paper-based questionnaire. The survey was conducted with nurses and physicians to assess the four topics. The instruments mainly consisted of scales of the German version of the COPSOQ (Copenhagen Psychosocial Questionnaire), one scale of the Copenhagen Burnout Inventory (CBI), scales to assess leadership and transformational leadership, scales to assess patient safety climate using the Hospital Survey on Patient Safety Culture (HSPSC), and analogous items to assess occupational safety climate.A total of 995 completed questionnaires out of 2512 distributed questionnaires were returned anonymously. The overall response rate was 39.6%. The sample consisted of 381 physicians and 567 nurses. We found various differences with regard to the four topics. In most of the COPSOQ and the HSPSC-scales, physicians rated psychosocial working conditions and patient safety climate more positively than nurses. With regard to occupational safety, nurses indicated higher occupational risks than physicians.The WorkSafeMed study combined the assessment of the four topics psychosocial working conditions, leadership, patient safety climate, and occupational safety climate in hospitals. Looking at the four topics provides an overview of where improvements in hospitals may be needed for nurses and physicians. Based on these results, improvements in working conditions, patient safety climate, and occupational safety climate are required for health care professionals in German university hospitals - especially for nurses.

Despite a growing body of knowledge about the morbidities and functional impairment that frequently lead to care dependency, the role of social determinants is not yet well understood. The purpose of this study was to examine the effect of social determinants on care dependency onset and progression.[for full text, please go to the a.m. URL], 65th Annual Meeting of the German Association for Medical Informatics, Biometry and Epidemiology (GMDS), Meeting of the Central European Network (CEN: German Region, Austro-Swiss Region and Polish Region) of the International Biometric Society (IBS)

6574 Background: DURTRERAD is a randomized phase II study evaluating feasibility and efficacy of durvalumab (anti-PD-L1) vs. durvalumab and tremelimumab (anti-CTLA-4) in combination with radiotherapy as primary treatment for locally advanced HPV negative HNSCC. (NCT03624231). Concurrent chemo-RT with a platinum-based regimen is considered the standard treatment, although efficacy and long-term toxicity are not satisfactory. Combining immunotherapy with RT might result in improved efficacy with limited long-term toxicity. Methods: The phase II study planned to enroll 120 pts, 60 pts (1:1) in each treatment arm. Treatment with DT (1500mg/75 mg, arm DT),or D (1500mg, arm D) both in combination with RT (70Gy) was considered to be feasible if less than 10% of the patients treated will discontinue treatment due to on-treatment toxicities. A first interim analysis for feasibility and efficacy was planned after randomisation of 20 patients. Results: So far 23 patients have been screened, 16 patients have been randomised and started their allocated treatment, 10 in arm D and 6 in arm DT. Of 10 patients in arm D 1 patient stopped infusional treatment due to immune related toxicity. Out of 6 patients in the DT arm, however, 5 patients stopped treatment due to treatment related AEs, 2 pts due to immune related toxicity with one Grade 5 AE. Three patients stopped due to non-immune related AE. The grade 5 AE prompted the interim analysis, which revealed non-feasibility as well as safety-issues of the DT+radiotherapy combination . As a result, the DT arm was prematurely terminated. Conclusions: Even though in the recurrent/metastatic setting DT was not associated with increased toxicity, DT in combination with RT was not feasible in our poor prognostic, vulnerable patient cohort of advanced HPV negative unresectable HNSCC, warranting early disclosure of these results. No increase in toxicity was observed in the D monotherapy arm, and the trial continued with D monotherapy in combination with RT. Clinical trial information: NCT03624231 .

The purpose of this study was to evaluate the impact of PET/CT on clinical management of cancer patients based on a prospective data registry. The study was developed to inform consultations with public health insurances on PET/CT coverage. We evaluated a prospective patient cohort having a clinically indicated PET/CT at a single German University Center from April 2013 to August 2016. The registry collected questionnaire data from requesting physicians on intended patient management before and after PET/CT. A total of 4,504 patients with 5,939 PET/CT examinations were enrolled in the registry, resulting in evaluable data from 3,724 patients receiving 4,754 scans. The impact of PET/CT on patient management was assessed across 22 tumor types, for different indications (diagnosis, staging, suspected recurrence) and different categories of management including treatment (curative or palliative) and non-treatment (watchful waiting, additional imaging, invasive tests). The most frequent PET/CT indication was tumor staging (59.7%). Melanoma, lung cancer, lymphoma, neuroendocrine tumor and prostate cancer accounted for 70% of cases. Overall, the use of PET/CT resulted in a 37.1% change of clinical management (95% CI, 35.7–38.5), most frequently (30.6%) from an intended non-treatment strategy before PET/CT to active treatment after PET/CT. The frequency of changes ranged from 28.3% for head and neck cancers up to 46.0% for melanomas. The impact of PET/CT was greatest in reducing demands for additional imaging which decreased from 66.1% before PET/CT to 6.1% after PET/CT. Pre-PET/CT planned invasive tests could be avoided in 72.7% of cases. The treatment goal changed after PET/CT in 21.7% of cases, in twice as many cases from curative to palliative therapy than vice versa. The data of this large prospective registry confirm that physicians often change their intended management on the basis of PET/CT by initiating treatment and reducing additional imaging as well as invasive tests. This applies to various cancer types and indications.

This study aimed to evaluate subjective and objective hearing loss in cervical cancer patients after chemoradiation with cisplatin (mono). A total of 51 cervical cancer patients with indication for chemoradiation were included. Pure tone and impedance audiometry were performed before and after chemoradiation. Hearing loss was scaled according to ASHA criteria. Subjective hearing was assessed with the Oldenburger Sentence Test. To consider age-dependent changes, hearing loss was corrected for age and the time interval between measurements. Median age at diagnosis was 46 years, 46% were active/former smokers (n = 24), 28 (54%) patients were never-smokers. Median total weekly cisplatin dose was 70 ± 14.2 mg. Cumulative doses of cisplatin during chemoradiation ranged between 115.2 and 400 mg cisplatin (mean 336.1 mg, median 342 ± 52.7 mg). The median interval between last chemotherapy and second audiometry was 320 ± 538 days (35–2262 days). Changes in hearing threshold ≥20 dB were experienced by 32/52 patients (62%) following chemoradiation, 55% of them for frequencies ≥6000 Hz. No statistically significant hearing loss remained after chemoradiation upon correction for age and time interval. Patients >40 years had a higher risk of hearing loss than younger patients. Objective data on hearing function did not correlate with subjective hearing loss and did not impair daily activity in any patient. Chemoradiation with cumulative cisplatin doses up to 400 mg did not lead to significant impairment of objective or subjective hearing. For cervical cancer patients undergoing chemoradiation, standard audiometry is not indicated.

This study investigates the role of body image self-appraisal in predicting the outcomes of outpatient psychotherapy in patients with anorexia nervosa (AN). Multiple linear regression analyses and a path-analysis model were applied to test the study hypotheses that body image at baseline predicts treatment outcomes of outpatient psychotherapy in patients with AN at follow-up measurement. The analyses were conducted as secondary analyses in a subgroup (n = 148) of the anorexia nervosa treatment of outpatient-cohort (ANTOP-study) (N = 242) of patients with AN. The results show that Negative Evaluation of the Body at baseline predicts perceived stress during psychotherapy, which in turn predicts depressive symptoms at the end of therapy which in turn predicts the outcomes body mass index and EDI-2 sum score at 12 months follow-up. The results underline the importance of body image disturbance in the course of AN and call for body image as a central target of psychotherapeutic interventions in patients with AN.

Objective To investigate non-inferiority of intermittent docetaxel compared to continuous docetaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). Patient and methods The investigator initiated randomised phase III study included 187 chemotherapy-naive patients with mCRPC who were allocated to two treatment arms: intermittent docetaxel and continuous docetaxel. Docetaxel was applied in both arms as weekly (35 mg/m2 ) or 3-weekly (75 mg/m2 ). The primary endpoint was 1-year survival, which was tested for non-inferiority (margin δ = 0.125). The secondary endpoints were: overall survival (OS), progression-free survival (PFS), median time to treatment failure (TTF), and toxicity. Results Of 156 eligible patients, 78 were allocated to each arm. The intermittent treatment met the non-inferiority criteria for 1-year survival (two-sided 95% confidence interval, -0.12, 18, P = 0.022), but not for OS, according to the result of a post hoc analysis. The differences between the study arms in PFS and TTF were not significant. The median (range) treatment holiday in the intermittent arm was 110 (13-486) days, or 38% of the overall treatment duration. Safety profiles of both study arms were comparable. The main limitation of this study was that the planned number of patients could not be recruited. Conclusion Intermittent docetaxel chemotherapy was non-inferior to continuous therapy for 1-year survival; non-inferiority in regard to OS was not reached.

Extract: Prostate cancer (PCa) and type 2 diabetes mellitus are under the most frequent diseases in men with a tremendous impact on morbidity and mortality (Giovannucci, et al. 2010). Incidence of many common types of cancer is known to be higher in diabetes (Giovannucci et al. 2010). However, studies reported that incidence of PCa is not increased in men with type 2 diabetes, some studies even found reduced prevalence (Kasper, et al. 2009). In contrast, PCa survival is markedly reduced in patients with coincident type 2 diabetes (Chen, et al. 2017). The underlying molecular mechanisms for shortened survival are still under ongoing debate and not fully understood. They might include altered insulin or IGF-1 signaling and enhanced androgen receptor activity. Of note, diabetes and PCa share numerous risk factors, most importantly the nonmodifiable risk factor age and the modifiable risk factor obesity (Giovannucci et al. 2010). Although PCa incidence is not elevated in obese men, patients with excess bodyweight are reported to display higher cancer-related mortality (Ma, et al. 2008). Carefully adjusted studies for these risk factors investigating the impact of diabetes on PCa outcomes and aggressiveness are sparse. To better understand why PCa related survival is shortened in men with concommittant diabetes, we evaluated the relation of diabetes with TNM-staging and an established PCa risk score (Mohler, et al. 2016), independent of age and body weight ...

Background: Vascular calcification is a common phenomenon in patients with chronic kidney disease and strongly associated with increased cardiovascular mortality. Vascular calcification is an active process mediated in part by inflammatory processes in vascular smooth muscle cells (VSMC). These could be modified by the insufficient removal of proinflammatory cytokines through conventional high-flux (HF) membranes. Recent trials demonstrated a reduction of inflammation in VSMC by use of dialysis membranes with a higher and steeper cut-off. These membranes caused significant albumin loss. Therefore, the effect of high retention Onset (HRO) dialysis membranes on vascular calcification and its implications in vitro was evaluated. Methods: In the PERCI II trial, 48 chronic dialysis patients were dialyzed using HF and HRO dialyzers and serum samples were collected. Calcifying VSMC were incubated with the serum samples. Calcification was determined using alizarin red staining (AZR) and determination of alkaline phosphatase (ALP) activity. Furthermore, apoptosis was evaluated, and release of matrix Gla protein (MGP), osteopontin (OPN) and growth differentiation factor 15 (GDF-15) were measured in cell supernatants. Results: Vascular calcification in vitro was significantly reduced by 24% (ALP) and 36% (AZR) after 4 weeks of HRO dialysis and by 33% (ALP) and 48% (AZR) after 12 weeks of dialysis using HRO membranes compared to HF dialysis. Apoptosis was significantly lower in the HRO group. The concentrations of MGP and OPN were significantly elevated after incubation with HF serum compared to HRO serum and healthy controls. Similarly, GDF-15 release in the supernatant was elevated after incubation with HF serum, an effect significantly ameliorated after treatment with HRO medium. Conclusions: Expanded haemodialysis therapy reduces the pro-calcific potential of serum from dialysis patients in vitro. With a markedly reduced albumin filtration compared to high cut-off dialysis, use of the HRO dialyzers may possibly provide a treatment option for chronic dialysis patients to reduce the progression of vascular calcification.

Auditory verbal hallucinations (AH) are core symptoms of schizophrenia. They are often severely distressing and refractory to therapy. Their perception is associated with increased activity in temporoparietal areas of the brain. Repetitive transcranial magnetic stimulation (rTMS) can reduce focal brain hyperactivity and has been shown to ameliorate AH. However, controlled multicenter clinical trials are still missing, effect sizes are moderate, and the treatment with rTMS is time consuming. Continuous theta burst stimulation (cTBS) is a quicker and potentially more effective technique to reduce cortical hyperactivity. First case and pilot studies indicate effectiveness in the treatment of AH. In this randomized, sham-controlled, double-blind multicenter clinical trial, 86 patients with schizophrenia spectrum disorder will be randomized to either cTBS or sham to the left and right temporoparietal cortex during three consecutive weeks (15 sessions totally). In each session, both hemispheres will be stimulated sequentially. The order in the first session (left-right or right-left, respectively) will be determined by randomization and alternated in all following sessions. Primary outcome is the reduction of mean PSYRATS-AH score after cTBS as compared to sham treatment. Follow-up measurements will be performed 1, 3 and 6 months after the end of the treatment. Statistical analysis will be based on the intention-to-treat population including all randomized patients using an analysis of covariance. This multicenter-controlled clinical trial will be able to provide decisive evidence for the efficacy of cTBS in the treatment of AH. The results will be suitable to clarify the role of this innovative, pathophysiology-based therapeutic approach in treatment guidelines for AH.ClinicalTrials.gov identifier: NCT02670291.

Introduction The CD19 targeting CAR-T cell constructs axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) have become an accepted standard salvage treatment of LBCL beyond the second line. Patients scheduled for approved CAR-T cell therapies usually have 4-8 weeks wait time for CAR-T cell infusion, thus often requiring bridging strategies in rapidly progressing patients to achieve disease control until start of lymphodepletion. It is still unclear, however, if the adverse impact of active progressive lymphoma can be overcome by successful bridging. We have addressed this question using registry data provided by the German Registry for Stem Cell Transplantation (DRST), the national partner of the EBMT. Methods We analyzed 356 consecutive patients who received standard of care axi-cel (n=173) or tisa-cel (n=183) treatment of LBCL between November 2018 and April 2021 at 21 German centers and were registered with the DRST/EBMT. Baseline patient, disease, and transplant data were collected from MED-A cellular therapy forms. Centers were contacted to provide additional treatment and follow-up information. Predictors of progression-free survival (PFS) were analyzed by uni- and multivariate comparisons. Results Compared to the approval trials, patients were of poor risk with 58% presenting with elevated LDH at lymphodepletion and 71% having received ≥3 pretreatment lines, resulting in ineligibility for the ZUMA-1 study in 87% of cases. Kaplan-Maier estimates of overall survival, PFS and non-relapse mortality (NRM) 12 months after dosing were 52%, 30% and 7%, respectively. Information on bridging was available for 355 patients (99%). Of these, 279 patients (78%) underwent at least one line of bridging attempt, whereas bridging was deemed unnecessary in 76 patients (22%). A wide variety of modalities were employed for bridging, with the most frequent being chemoimmunotherapy (n=188), chemotherapy (n=41), radiation (n=30), immunotherapy (n=12) and steroids (n=6). Bridging resulted in disease control (CR/PR) in 58 of 270 patients evaluable for response (21%). With a median follow-up of 11 months, 12-month PFS rates for patients without bridging, successful bridging, and bridging failure were 41%, 52%, and 20%, respectively, p= Conclusion The results of this large German GLA/DRST analysis suggest that effective bridging can overcome the adverse impact of active disease on the outcome of standard-of-case CD19 CAR-T therapy. With current treatment strategies, however, bridging is often unsuccessful, highlighting the need for exploring innovative tools for inducing temporary LBCL control for CAR-T therapy preparation. Figure 1 Figure 1. Disclosures Bethge: Novartis: Consultancy, Honoraria, Speakers Bureau; Kite-Gilead: Consultancy, Honoraria, Speakers Bureau; Miltenyi Biotec: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Schmitt: TolerogenixX: Current holder of individual stocks in a privately-held company; Novartis: Other: Travel grants, Research Funding; Kite Gilead: Other: Travel grants; Apogenix: Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Other: Travel grants; Hexal: Other: Travel grants, Research Funding. Holtick: Celgene: Honoraria; Sanofi: Honoraria. Borchmann: Gilead Sciences: Honoraria; BMS/Celgene: Honoraria; Janssen: Honoraria; Miltenyi Biotech: Honoraria; Novartis: Honoraria. Subklewe: Klinikum der Universität München: Current Employment; Pfizer: Consultancy, Speakers Bureau; Roche: Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; MorphoSys: Research Funding; Janssen: Consultancy; Seattle Genetics: Consultancy, Research Funding; Takeda: Speakers Bureau; Miltenyi: Research Funding; Gilead: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Research Funding, Speakers Bureau. von Tresckow: Roche: Consultancy, Honoraria; Kite-Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Pentixafarm: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: congress and travel support, Research Funding; MSD: Consultancy, Honoraria, Other: congress and travel support, Research Funding; BMS-Celgene: Consultancy, Honoraria, Other: congress and travel support; AstraZeneca: Honoraria, Other: congress and travel support; Amgen: Consultancy, Honoraria; AbbVie: Other: congress and travel support; Takeda: Consultancy, Honoraria, Other, Research Funding. Ayuk: Gilead: Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria; Miltenyi Biomedicine: Honoraria; Celgene/BMS: Honoraria; Novartis: Honoraria. Kroeger: Novartis: Honoraria; AOP Pharma: Honoraria; Gilead/Kite: Honoraria; Riemser: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding. Wulf: Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Clinigen: Consultancy, Honoraria. Marks: Merck: Consultancy; Kite/Gilead: Honoraria; AbbVie: Other: Meeting attendance; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees. Penack: Astellas: Honoraria; Gilead: Honoraria; Jazz: Honoraria; Omeros: Consultancy; Shionogi: Consultancy; Priothera: Consultancy; Incyte: Research Funding; Takeda: Research Funding; Therakos: Honoraria; Pfizer: Honoraria; Neovii: Honoraria; Novartis: Honoraria; MSD: Honoraria. Koenecke: Kite/Gilead: Consultancy; BMS/Celgene: Consultancy; Janssen: Consultancy; Novartis: Consultancy; EUSA Pharm: Consultancy. Von Bonin: Kite/Gilead: Other: traveling support and advisory fees; Novartis: Other: traveling support and advisory fees; Daiichi Sankyo: Other: traveling support and advisory fees. Stelljes: Amgen: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Kite/Gilead: Consultancy, Speakers Bureau. Glass: BMS: Consultancy; Helios Klinik Berlin-Buch: Current Employment; Kite: Consultancy; Novartis: Consultancy; Riemser: Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau. Baldus: Novartis: Honoraria; Amgen: Honoraria; Celgene/BMS: Honoraria; Jazz: Honoraria. Vucinic: Janssen: Honoraria, Other: Travel Sponsoring; Novartis: Honoraria; Abbvie: Honoraria, Other: Travel Sponsoring; Gilead: Honoraria, Other: Travel Sponsoring; MSD: Honoraria. Topp: Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy; Amgen: Consultancy, Research Funding; Gilead: Research Funding; Regeneron: Consultancy, Research Funding; Macrogeniecs: Research Funding; Universitatklinikum Wurzburg: Current Employment. Schroers: BMS/Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Takeda: Honoraria. Thomas: Abbvie: Honoraria, Speakers Bureau; Art tempi: Honoraria, Speakers Bureau; BMS-Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: travel support; Kite-Gilead: Honoraria, Other: travel support, Research Funding, Speakers Bureau; Medigene: Consultancy, Honoraria, Other: Travel support; Novartis: Consultancy, Honoraria, Other: travel support, Speakers Bureau; Pfizer: Consultancy, Honoraria, Other: Travel support, Speakers Bureau. Dreger: Bluebird Bio: Consultancy; BMS: Consultancy; AbbVie: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Speakers Bureau; Janssen: Consultancy; AstraZeneca: Consultancy, Speakers Bureau.