@article{RemdeKranzMorelletal.2023, author = {Remde, Hanna and Kranz, Stefanie and Morell, Sarah Maria and Altieri, Barbara and Kroiss, Matthias and Detomas, Mario and Fassnacht, Martin and Deutschbein, Timo}, title = {Clinical course of patients with adrenal incidentalomas and cortisol autonomy}, series = {Frontiers in Endocrinology}, volume = {14}, journal = {Frontiers in Endocrinology}, issn = {1664-2392}, doi = {10.3389/fendo.2023.1123132}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-316793}, year = {2023}, abstract = {Background Adrenal incidentalomas with cortisol autonomy are associated with increased cardiovascular morbidity and mortality. Specific data on the clinical and biochemical course of affected patients are lacking. Methods Retrospective study from a tertiary referral centre in Germany. After exclusion of overt hormone excess, malignancy and glucocorticoid medication, patients with adrenal incidentalomas were stratified according to serum cortisol after 1 mg dexamethasone: autonomous cortisol secretion (ACS), >5.0; possible ACS (PACS), 1.9-5.0; non-functioning adenomas (NFA), ≤1.8 µg/dl. Results A total of 260 patients were enrolled (147 women (56.5\%), median follow-up 8.8 (2.0-20.8) years). At initial diagnosis, median age was 59.5 (20-82) years, and median tumour size was 27 (10-116) mm. Bilateral tumours were more prevalent in ACS (30.0\%) and PACS (21.9\%) than in NFA (8.1\%). Over time, 40/124 (32.3\%) patients had a shift of their hormonal secretion pattern (NFA to PACS/ACS, n=15/53; PACS to ACS, n=6/47; ACS to PACS, n=11/24; PACS to NFA, n=8/47). However, none of the patients developed overt Cushing's syndrome. Sixty-one patients underwent adrenalectomy (NFA, 17.9\%; PACS, 24.0\%; ACS, 39.0\%). When non-operated patients with NFA were compared to PACS and ACS at last follow-up, arterial hypertension (65.3\% vs. 81.9\% and 92.0\%; p<0.05), diabetes (23.8\% vs. 35.6\% and 40.0\%; p<0.01), and thromboembolic events (PACS: HR 3.43, 95\%-CI 0.89-13.29; ACS: HR 5.96, 95\%-CI 1.33-26.63; p<0.05) were significantly less frequent, along with a trend towards a higher rate of cardiovascular events in case of cortisol autonomy (PACS: HR 2.23, 95\%-CI 0.94-5.32; ACS: HR 2.60, 95\%-CI 0.87-7.79; p=0.1). Twenty-five (12.6\%) of the non-operated patients died, with higher overall mortality in PACS (HR 2.6, 95\%-CI 1.0-4.7; p=0.083) and ACS (HR 4.7, 95\%-CI 1.6-13.3; p<0.005) compared to NFA. In operated patients, prevalence of arterial hypertension decreased significantly (77.0\% at diagnosis to 61.7\% at last follow-up; p<0.05). The prevalence of cardiovascular events and mortality did not differ significantly between operated and non-operated patients, whereas thromboembolic events were significantly less frequent in the surgical treatment group. Conclusion Our study confirms relevant cardiovascular morbidity in patients with adrenal incidentalomas (especially those with cortisol autonomy). These patients should therefore be monitored carefully, including adequate treatment of typical cardiovascular risk factors. Adrenalectomy was associated with a significantly decreased prevalence of hypertension. However, more than 30\% of patients required reclassification according to repeated dexamethasone suppression tests. Thus, cortisol autonomy should ideally be confirmed before making any relevant treatment decision (e.g. adrenalectomy).}, language = {en} } @article{SchreiberLohrBaltesetal.2023, author = {Schreiber, Laura M. and Lohr, David and Baltes, Steffen and Vogel, Ulrich and Elabyad, Ibrahim A. and Bille, Maya and Reiter, Theresa and Kosmala, Aleksander and Gassenmaier, Tobias and Stefanescu, Maria R. and Kollmann, Alena and Aures, Julia and Schnitter, Florian and Pali, Mihaela and Ueda, Yuichiro and Williams, Tatiana and Christa, Martin and Hofmann, Ulrich and Bauer, Wolfgang and Gerull, Brenda and Zernecke, Alma and Erg{\"u}n, S{\"u}leyman and Terekhov, Maxim}, title = {Ultra-high field cardiac MRI in large animals and humans for translational cardiovascular research}, series = {Frontiers in Cardiovascular Medicine}, volume = {10}, journal = {Frontiers in Cardiovascular Medicine}, issn = {2297-055X}, doi = {10.3389/fcvm.2023.1068390}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-317398}, year = {2023}, abstract = {A key step in translational cardiovascular research is the use of large animal models to better understand normal and abnormal physiology, to test drugs or interventions, or to perform studies which would be considered unethical in human subjects. Ultrahigh field magnetic resonance imaging (UHF-MRI) at 7 T field strength is becoming increasingly available for imaging of the heart and, when compared to clinically established field strengths, promises better image quality and image information content, more precise functional analysis, potentially new image contrasts, and as all in-vivo imaging techniques, a reduction of the number of animals per study because of the possibility to scan every animal repeatedly. We present here a solution to the dual use problem of whole-body UHF-MRI systems, which are typically installed in clinical environments, to both UHF-MRI in large animals and humans. Moreover, we provide evidence that in such a research infrastructure UHF-MRI, and ideally combined with a standard small-bore UHF-MRI system, can contribute to a variety of spatial scales in translational cardiovascular research: from cardiac organoids, Zebra fish and rodent hearts to large animal models such as pigs and humans. We present pilot data from serial CINE, late gadolinium enhancement, and susceptibility weighted UHF-MRI in a myocardial infarction model over eight weeks. In 14 pigs which were delivered from a breeding facility in a national SARS-CoV-2 hotspot, we found no infection in the incoming pigs. Human scanning using CINE and phase contrast flow measurements provided good image quality of the left and right ventricle. Agreement of functional analysis between CINE and phase contrast MRI was excellent. MRI in arrested hearts or excised vascular tissue for MRI-based histologic imaging, structural imaging of myofiber and vascular smooth muscle cell architecture using high-resolution diffusion tensor imaging, and UHF-MRI for monitoring free radicals as a surrogate for MRI of reactive oxygen species in studies of oxidative stress are demonstrated. We conclude that UHF-MRI has the potential to become an important precision imaging modality in translational cardiovascular research.}, language = {en} } @article{LisowskiLutyjAbazarietal.2023, author = {Lisowski, Dominik and Lutyj, Paul and Abazari, Arya and Weick, Stefan and Traub, Jan and Polat, B{\"u}lent and Flentje, Michael and Kraft, Johannes}, title = {Impact of Radiotherapy on Malfunctions and Battery Life of Cardiac Implantable Electronic Devices in Cancer Patients}, series = {Cancers}, volume = {15}, journal = {Cancers}, number = {19}, issn = {2072-6694}, doi = {10.3390/cancers15194830}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-358008}, year = {2023}, abstract = {Purpose: This study analyses a large number of cancer patients with CIEDs for device malfunction and premature battery depletion by device interrogation after each radiotherapy fraction and compares different guidelines in regard to patient safety. Methods: From 2007 to 2022, a cohort of 255 patients was analyzed for CIED malfunctions via immediate device interrogation after every RT fraction. Results: Out of 324 series of radiotherapy treatments, with a total number of 5742 CIED interrogations, nine device malfunctions (2.8\%) occurred. Switching into back-up/safety mode and software errors occurred four times each. Once, automatic read-out could not be performed. The median prescribed cumulative dose at planning target volume (PTV) associated with CIED malfunction was 45.0 Gy (IQR 36.0-64.0 Gy), with a median dose per fraction of 2.31 Gy (IQR 2.0-3.0 Gy). The median maximum dose at the CIED at time of malfunction was 0.3 Gy (IQR 0.0-1.3 Gy). No correlation between CIED malfunction and maximum photon energy (p = 0.07), maximum dose at the CIED (p = 0.59) nor treatment localization (p = 0.41) could be detected. After excluding the nine malfunctions, premature battery depletion was only observed three times (1.2\%). Depending on the national guidelines, 1-9 CIED malfunctions in this study would have been detected on the day of occurrence and in none of the cases would patient safety have been compromised. Conclusion: Radiation-induced malfunctions of CIEDs and premature battery depletion are rare. If recommendations of national safety guidelines are followed, only a portion of the malfunctions would be detected directly after occurrence. Nevertheless, patient safety would not be compromised.}, language = {en} } @article{WeismannMoeckelPaethetal.2023, author = {Weismann, Dirk and M{\"o}ckel, Martin and Paeth, Heiko and Slagman, Anna}, title = {Modelling variations of emergency attendances using data on community mobility, climate and air pollution}, series = {Scientific Reports}, volume = {13}, journal = {Scientific Reports}, doi = {10.1038/s41598-023-47857-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357578}, year = {2023}, abstract = {Air pollution is associated with morbidity and mortality worldwide. We investigated the impact of improved air quality during the economic lockdown during the SARS-Cov2 pandemic on emergency room (ER) admissions in Germany. Weekly aggregated clinical data from 33 hospitals were collected in 2019 and 2020. Hourly concentrations of nitrogen and sulfur dioxide (NO2, SO2), carbon and nitrogen monoxide (CO, NO), ozone (O3) and particulate matter (PM10, PM2.5) measured by ground stations and meteorological data (ERA5) were selected from a 30 km radius around the corresponding ED. Mobility was assessed using aggregated cell phone data. A linear stepwise multiple regression model was used to predict ER admissions. The average weekly emergency numbers vary from 200 to over 1600 cases (total n = 2,216,217). The mean maximum decrease in caseload was 5 standard deviations. With the enforcement of the shutdown in March, the mobility index dropped by almost 40\%. Of all air pollutants, NO2 has the strongest correlation with ER visits when averaged across all departments. Using a linear stepwise multiple regression model, 63\% of the variation in ER visits is explained by the mobility index, but still 6\% of the variation is explained by air quality and climate change.}, language = {en} } @article{WeissGruendahlDeckertetal.2023, author = {Weiß, Martin and Gr{\"u}ndahl, Marthe and Deckert, J{\"u}rgen and Eichner, Felizitas A. and Kohls, Mirjam and St{\"o}rk, Stefan and Heuschmann, Peter U. and Hein, Grit}, title = {Differential network interactions between psychosocial factors, mental health, and health-related quality of life in women and men}, series = {Scientific Reports}, volume = {13}, journal = {Scientific Reports}, organization = {STAAB-COVID Study Group}, doi = {10.1038/s41598-023-38525-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357858}, year = {2023}, abstract = {Psychosocial factors affect mental health and health-related quality of life (HRQL) in a complex manner, yet gender differences in these interactions remain poorly understood. We investigated whether psychosocial factors such as social support and personal and work-related concerns impact mental health and HRQL differentially in women and men during the first year of the COVID-19 pandemic. Between June and October 2020, the first part of a COVID-19-specific program was conducted within the "Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB)" cohort study, a representative age- and gender-stratified sample of the general population of W{\"u}rzburg, Germany. Using psychometric networks, we first established the complex relations between personal social support, personal and work-related concerns, and their interactions with anxiety, depression, and HRQL. Second, we tested for gender differences by comparing expected influence, edge weight differences, and stability of the networks. The network comparison revealed a significant difference in the overall network structure. The male (N = 1370) but not the female network (N = 1520) showed a positive link between work-related concern and anxiety. In both networks, anxiety was the most central variable. These findings provide further evidence that the complex interplay of psychosocial factors with mental health and HRQL decisively depends on gender. Our results are relevant for the development of gender-specific interventions to increase resilience in times of pandemic crisis.}, language = {en} } @article{HerrmannMuellerNotzetal.2023, author = {Herrmann, Johannes and M{\"u}ller, Kerstin and Notz, Quirin and H{\"u}bsch, Martha and Haas, Kirsten and Horn, Anna and Schmidt, Julia and Heuschmann, Peter and Maschmann, Jens and Frosch, Matthias and Deckert, J{\"u}rgen and Einsele, Hermann and Ertl, Georg and Frantz, Stefan and Meybohm, Patrick and Lotz, Christopher}, title = {Prospective single-center study of health-related quality of life after COVID-19 in ICU and non-ICU patients}, series = {Scientific Reports}, volume = {13}, journal = {Scientific Reports}, doi = {10.1038/s41598-023-33783-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357174}, year = {2023}, abstract = {Long-term sequelae in hospitalized Coronavirus Disease 2019 (COVID-19) patients may result in limited quality of life. The current study aimed to determine health-related quality of life (HRQoL) after COVID-19 hospitalization in non-intensive care unit (ICU) and ICU patients. This is a single-center study at the University Hospital of Wuerzburg, Germany. Patients eligible were hospitalized with COVID-19 between March 2020 and December 2020. Patients were interviewed 3 and 12 months after hospital discharge. Questionnaires included the European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L), patient health questionnaire-9 (PHQ-9), the generalized anxiety disorder 7 scale (GAD-7), FACIT fatigue scale, perceived stress scale (PSS-10) and posttraumatic symptom scale 10 (PTSS-10). 85 patients were included in the study. The EQ5D-5L-Index significantly differed between non-ICU (0.78 ± 0.33 and 0.84 ± 0.23) and ICU (0.71 ± 0.27; 0.74 ± 0.2) patients after 3- and 12-months. Of non-ICU 87\% and 80\% of ICU survivors lived at home without support after 12 months. One-third of ICU and half of the non-ICU patients returned to work. A higher percentage of ICU patients was limited in their activities of daily living compared to non-ICU patients. Depression and fatigue were present in one fifth of the ICU patients. Stress levels remained high with only 24\% of non-ICU and 3\% of ICU patients (p = 0.0186) having low perceived stress. Posttraumatic symptoms were present in 5\% of non-ICU and 10\% of ICU patients. HRQoL is limited in COVID-19 ICU patients 3- and 12-months post COVID-19 hospitalization, with significantly less improvement at 12-months compared to non-ICU patients. Mental disorders were common highlighting the complexity of post-COVID-19 symptoms as well as the necessity to educate patients and primary care providers about monitoring mental well-being post COVID-19.}, language = {en} } @article{RodriguezRozadaFrantzTovote2023, author = {Rodriguez-Rozada, Silvia and Frantz, Stefan and Tovote, Philip}, title = {Cardiac optogenetics: regulating brain states via the heart}, series = {Signal Transduction and Targeted Therapy}, volume = {8}, journal = {Signal Transduction and Targeted Therapy}, doi = {10.1038/s41392-023-01582-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357625}, year = {2023}, abstract = {No abstract available.}, language = {en} } @article{JanzWalzCirnuetal.2024, author = {Janz, Anna and Walz, Katharina and Cirnu, Alexandra and Surjanto, Jessica and Urlaub, Daniela and Leskien, Miriam and Kohlhaas, Michael and Nickel, Alexander and Brand, Theresa and Nose, Naoko and W{\"o}rsd{\"o}rfer, Philipp and Wagner, Nicole and Higuchi, Takahiro and Maack, Christoph and Dudek, Jan and Lorenz, Kristina and Klopocki, Eva and Erg{\"u}n, S{\"u}leyman and Duff, Henry J. and Gerull, Brenda}, title = {Mutations in DNAJC19 cause altered mitochondrial structure and increased mitochondrial respiration in human iPSC-derived cardiomyocytes}, series = {Molecular Metabolism}, volume = {79}, journal = {Molecular Metabolism}, issn = {2212-8778}, doi = {10.1016/j.molmet.2023.101859}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350393}, year = {2024}, abstract = {Highlights • Loss of DNAJC19's DnaJ domain disrupts cardiac mitochondrial structure, leading to abnormal cristae formation in iPSC-CMs. • Impaired mitochondrial structures lead to an increased mitochondrial respiration, ROS and an elevated membrane potential. • Mutant iPSC-CMs show sarcomere dysfunction and a trend to more arrhythmias, resembling DCMA-associated cardiomyopathy. Background Dilated cardiomyopathy with ataxia (DCMA) is an autosomal recessive disorder arising from truncating mutations in DNAJC19, which encodes an inner mitochondrial membrane protein. Clinical features include an early onset, often life-threatening, cardiomyopathy associated with other metabolic features. Here, we aim to understand the metabolic and pathophysiological mechanisms of mutant DNAJC19 for the development of cardiomyopathy. Methods We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two affected siblings with DCMA and a gene-edited truncation variant (tv) of DNAJC19 which all lack the conserved DnaJ interaction domain. The mutant iPSC-CMs and their respective control cells were subjected to various analyses, including assessments of morphology, metabolic function, and physiological consequences such as Ca\(^{2+}\) kinetics, contractility, and arrhythmic potential. Validation of respiration analysis was done in a gene-edited HeLa cell line (DNAJC19tv\(_{HeLa}\)). Results Structural analyses revealed mitochondrial fragmentation and abnormal cristae formation associated with an overall reduced mitochondrial protein expression in mutant iPSC-CMs. Morphological alterations were associated with higher oxygen consumption rates (OCRs) in all three mutant iPSC-CMs, indicating higher electron transport chain activity to meet cellular ATP demands. Additionally, increased extracellular acidification rates suggested an increase in overall metabolic flux, while radioactive tracer uptake studies revealed decreased fatty acid uptake and utilization of glucose. Mutant iPSC-CMs also showed increased reactive oxygen species (ROS) and an elevated mitochondrial membrane potential. Increased mitochondrial respiration with pyruvate and malate as substrates was observed in mutant DNAJC19tv HeLa cells in addition to an upregulation of respiratory chain complexes, while cellular ATP-levels remain the same. Moreover, mitochondrial alterations were associated with increased beating frequencies, elevated diastolic Ca\(^{2+}\) concentrations, reduced sarcomere shortening and an increased beat-to-beat rate variability in mutant cell lines in response to β-adrenergic stimulation. Conclusions Loss of the DnaJ domain disturbs cardiac mitochondrial structure with abnormal cristae formation and leads to mitochondrial dysfunction, suggesting that DNAJC19 plays an essential role in mitochondrial morphogenesis and biogenesis. Moreover, increased mitochondrial respiration, altered substrate utilization, increased ROS production and abnormal Ca\(^{2+}\) kinetics provide insights into the pathogenesis of DCMA-related cardiomyopathy.}, language = {en} } @article{KerwagenRiemerWachteretal.2023, author = {Kerwagen, Fabian and Riemer, Uwe and Wachter, Rolf and von Haehling, Stephan and Abdin, Amr and B{\"o}hm, Michael and Schulz, Martin and St{\"o}rk, Stefan}, title = {Impact of the COVID-19 pandemic on implementation of novel guideline-directed medical therapies for heart failure in Germany: a nationwide retrospective analysis}, series = {The Lancet Regional Health - Europe}, volume = {35}, journal = {The Lancet Regional Health - Europe}, issn = {2666-7762}, doi = {10.1016/j.lanepe.2023.100778}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-350510}, year = {2023}, abstract = {Background Guideline-directed medical therapy (GDMT) is the cornerstone in the treatment of patients with heart failure and reduced ejection fraction (HFrEF) and novel substances such as sacubitril/valsartan (S/V) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) have demonstrated marked clinical benefits. We investigated their implementation into real-world HF care in Germany before, during, and after the COVID-19 pandemic period. Methods The IQVIA LRx data set is based on ∼80\% of 73 million people covered by the German statutory health insurance. Prescriptions of S/V were used as a proxy for HFrEF. Time trends were analysed between Q1/2016 and Q2/2023 for prescriptions for S/V alone and in combination therapy with SGLT2i. Findings The number of patients treated with S/V increased from 5260 in Q1/2016 to 351,262 in Q2/2023. The share of patients with combination therapy grew from 0.6\% (29 of 5260) to 14.2\% (31,128 of 219,762) in Q2/2021, and then showed a steep surge up to 54.8\% (192,429 of 351,262) in Q2/2023, coinciding with the release of the European Society of Cardiology (ESC) guidelines for HF in Q3/2021. Women and patients aged >80 years were treated less often with combined therapy than men and younger patients. With the start of the COVID-19 pandemic, the number of patients with new S/V prescriptions dropped by 17.5\% within one quarter, i.e., from 26,855 in Q1/2020 to 22,145 in Q2/2020, and returned to pre-pandemic levels only in Q1/2021. Interpretation The COVID-19 pandemic was associated with a 12-month deceleration of S/V uptake in Germany. Following the release of the ESC HF guidelines, the combined prescription of S/V and SGLT2i was readily adopted. Further efforts are needed to fully implement GDMT and strengthen the resilience of healthcare systems during public health crises.}, language = {en} } @article{BuckSerflingLindneretal.2022, author = {Buck, Andreas K. and Serfling, Sebastian E. and Lindner, Thomas and H{\"a}nscheid, Heribert and Schirbel, Andreas and Hahner, Stefanie and Fassnacht, Martin and Einsele, Hermann and Werner, Rudolf A.}, title = {CXCR4-targeted theranostics in oncology}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {49}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {12}, doi = {10.1007/s00259-022-05849-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324545}, pages = {4133-4144}, year = {2022}, abstract = {A growing body of literature reports on the upregulation of C-X-C motif chemokine receptor 4 (CXCR4) in a variety of cancer entities, rendering this receptor as suitable target for molecular imaging and endoradiotherapy in a theranostic setting. For instance, the CXCR4-targeting positron emission tomography (PET) agent [\(^{68}\)Ga]PentixaFor has been proven useful for a comprehensive assessment of the current status quo of solid tumors, including adrenocortical carcinoma or small-cell lung cancer. In addition, [\(^{68}\)Ga]PentixaFor has also provided an excellent readout for hematological malignancies, such as multiple myeloma, marginal zone lymphoma, or mantle cell lymphoma. PET-based quantification of the CXCR4 capacities in vivo allows for selecting candidates that would be suitable for treatment using the theranostic equivalent [\(^{177}\)Lu]/[\(^{90}\)Y]PentixaTher. This CXCR4-directed theranostic concept has been used as a conditioning regimen prior to hematopoietic stem cell transplantation and to achieve sufficient anti-lymphoma/-tumor activity in particular for malignant tissues that are highly sensitive to radiation, such as the hematological system. Increasing the safety margin, pretherapeutic dosimetry is routinely performed to determine the optimal activity to enhance therapeutic efficacy and to reduce off-target adverse events. The present review will provide an overview of current applications for CXCR4-directed molecular imaging and will introduce the CXCR4-targeted theranostic concept for advanced hematological malignancies.}, language = {en} } @article{AltieriLaSalviaModicaetal.2023, author = {Altieri, Barbara and La Salvia, Anna and Modica, Roberta and Marciello, Francesca and Mercier, Olaf and Filosso, Pier Luigi and de Latour, Bertrand Richard and Giuffrida, Dario and Campione, Severo and Guggino, Gianluca and Fadel, Elie and Papotti, Mauro and Colao, Annamaria and Scoazec, Jean-Yves and Baudin, Eric and Faggiano, Antongiulio}, title = {Recurrence-free survival in early and locally advanced large cell neuroendocrine carcinoma of the lung after complete tumor resection}, series = {Journal of Personalized Medicine}, volume = {13}, journal = {Journal of Personalized Medicine}, number = {2}, issn = {2075-4426}, doi = {10.3390/jpm13020330}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304000}, year = {2023}, abstract = {Background: Large Cell Neuroendocrine Carcinoma (LCNEC) is a rare subtype of lung cancer with poor clinical outcomes. Data on recurrence-free survival (RFS) in early and locally advanced pure LCNEC after complete resection (R0) are lacking. This study aims to evaluate clinical outcomes in this subgroup of patients and to identify potential prognostic markers. Methods: Retrospective multicenter study including patients with pure LCNEC stage I-III and R0 resection. Clinicopathological characteristics, RFS, and disease-specific survival (DSS) were evaluated. Univariate and multivariate analyses were performed. Results: 39 patients (M:F = 26:13), with a median age of 64 years (44-83), were included. Lobectomy (69.2\%), bilobectomy (5.1\%), pneumonectomy (18\%), and wedge resection (7.7\%) were performed mostly associated with lymphadenectomy. Adjuvant therapy included platinum-based chemotherapy and/or radiotherapy in 58.9\% of cases. After a median follow-up of 44 (4-169) months, the median RFS was 39 months with 1-, 2- and 5-year RFS rates of 60.0\%, 54.6\%, and 44.9\%, respectively. Median DSS was 72 months with a 1-, 2- and 5-year rate of 86.8, 75.9, and 57.4\%, respectively. At multivariate analysis, age (cut-off 65 years old) and pN status were independent prognostic factors for both RFS (HR = 4.19, 95\%CI = 1.46-12.07, p = 0.008 and HR = 13.56, 95\%CI 2.45-74.89, p = 0.003, respectively) and DSS (HR = 9.30, 95\%CI 2.23-38.83, p = 0.002 and HR = 11.88, 95\%CI 2.28-61.84, p = 0.003, respectively). Conclusion: After R0 resection of LCNEC, half of the patients recurred mostly within the first two years of follow-up. Age and lymph node metastasis could help to stratify patients for adjuvant therapy.}, language = {en} } @article{ModicaAltieriD’Anielloetal.2023, author = {Modica, Roberta and Altieri, Barbara and D'Aniello, Francesco and Benevento, Elio and Cannavale, Giuseppe and Minotta, Roberto and Liccardi, Alessia and Colao, Annamaria and Faggiano, Antongiulio}, title = {Vitamin D and bone metabolism in adult patients with neurofibromatosis type 1}, series = {Metabolites}, volume = {13}, journal = {Metabolites}, number = {2}, issn = {2218-1989}, doi = {10.3390/metabo13020255}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303957}, year = {2023}, abstract = {Neurofibromatosis type 1 (NF1) is a genetic multisystemic autosomal dominant disorder determining reduced life expectancy due to higher risk of developing benign and malignant tumors. Low levels of vitamin D and reduced bone mineral density (BMD) have been reported in young patients with NF1. However, correlation between vitamin D and NF1 phenotype needs to be elucidated. Aim of this study was to assess vitamin D levels and bone metabolism in NF1 patients, analyzing potential correlations with clinical phenotype. A cross-sectional study was carried out in a monocentric series of NF1 patients, evaluating genotype, clinical phenotype, BMD, biochemical evaluation with focus on serum 25OH-vitamin D, parathyroid hormone (PTH), calcium and phosphate levels. Correlations between clinical manifestations, neurofibromas, and vitamin D status have been studied in comparison with healthy controls. 31 NF1 adult patients were matched for sex, age and body mass index with 31 healthy controls. A significantly difference in vitamin D level emerged in NF1 patients compared to controls. Interestingly low vitamin D levels correlated with a more aggressive phenotype and with a bigger size of neurofibromas. These data underline that vitamin D deficiency/insufficiency may play a role in clinical severity of neurofibromas in patients with NF1, suggesting the need to check bone status and replace vitamin D in these patients.}, language = {en} } @article{SerflingLapaDreheretal.2022, author = {Serfling, Sebastian E. and Lapa, Constantin and Dreher, Niklas and Hartrampf, Philipp E. and Rowe, Steven P. and Higuchi, Takahiro and Schirbel, Andreas and Weich, Alexander and Hahner, Stefanie and Fassnacht, Martin and Buck, Andreas K. and Werner, Rudolf A.}, title = {Impact of tumor burden on normal organ distribution in patients imaged with CXCR4-targeted [\(^{68}\)Ga]Ga-PentixaFor PET/CT}, series = {Molecular Imaging and Biology}, volume = {24}, journal = {Molecular Imaging and Biology}, number = {4}, doi = {10.1007/s11307-022-01717-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324622}, pages = {659-665}, year = {2022}, abstract = {Background CXCR4-directed positron emission tomography/computed tomography (PET/CT) has been used as a diagnostic tool in patients with solid tumors. We aimed to determine a potential correlation between tumor burden and radiotracer accumulation in normal organs. Methods Ninety patients with histologically proven solid cancers underwent CXCR4-targeted [\(^{68}\)Ga]Ga-PentixaFor PET/CT. Volumes of interest (VOIs) were placed in normal organs (heart, liver, spleen, bone marrow, and kidneys) and tumor lesions. Mean standardized uptake values (SUV\(_{mean}\)) for normal organs were determined. For CXCR4-positive tumor burden, maximum SUV (SUV\(_{max}\)), tumor volume (TV), and fractional tumor activity (FTA, defined as SUV\(_{mean}\) x TV), were calculated. We used a Spearman's rank correlation coefficient (ρ) to derive correlative indices between normal organ uptake and tumor burden. Results Median SUV\(_{mean}\) in unaffected organs was 5.2 for the spleen (range, 2.44 - 10.55), 3.27 for the kidneys (range, 1.52 - 17.4), followed by bone marrow (1.76, range, 0.84 - 3.98), heart (1.66, range, 0.88 - 2.89), and liver (1.28, range, 0.73 - 2.45). No significant correlation between SUV\(_{max}\) in tumor lesions (ρ ≤ 0.189, P ≥ 0.07), TV (ρ ≥ -0.204, P ≥ 0.06) or FTA (ρ ≥ -0.142, P ≥ 0.18) with the investigated organs was found. Conclusions In patients with solid tumors imaged with [\(^{68}\)Ga]Ga-PentixaFor PET/CT, no relevant tumor sink effect was noted. This observation may be of relevance for therapies with radioactive and non-radioactive CXCR4-directed drugs, as with increasing tumor burden, the dose to normal organs may remain unchanged.}, language = {en} } @article{WernerSayehliHaenscheidetal.2023, author = {Werner, Rudolf A. and Sayehli, Cyrus and H{\"a}nscheid, Heribert and Higuchi, Takahiro and Serfling, Sebastian E. and Fassnacht, Martin and Goebeler, Maria-Elisabeth and Buck, Andreas K. and Kroiss, Matthias}, title = {Successful combination of selpercatinib and radioiodine after pretherapeutic dose estimation in RET-altered thyroid carcinoma}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {50}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {6}, doi = {10.1007/s00259-022-06061-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324435}, pages = {1833-1834}, year = {2023}, abstract = {No abstract available.}, language = {en} } @article{KimpelSchindlerSchmidtPenningtonetal.2023, author = {Kimpel, Otilia and Schindler, Paul and Schmidt-Pennington, Laura and Altieri, Barbara and Megerle, Felix and Haak, Harm and Pittaway, James and Dischinger, Ulrich and Quinkler, Marcus and Mai, Knut and Kroiss, Matthias and Polat, B{\"u}lent and Fassnacht, Martin}, title = {Efficacy and safety of radiation therapy in advanced adrenocortical carcinoma}, series = {British Journal of Cancer}, volume = {128}, journal = {British Journal of Cancer}, number = {4}, doi = {10.1038/s41416-022-02082-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324411}, pages = {586-593}, year = {2023}, abstract = {Background International guidelines emphasise the role of radiotherapy (RT) for the management of advanced adrenocortical carcinoma (ACC). However, the evidence for this recommendation is very low. Methods We retrospectively analysed all patients who received RT for advanced ACC in five European centres since 2000. Primary endpoint: time to progression of the treated lesion (tTTP). Secondary endpoints: best objective response, progression-free survival (PFS), overall survival (OS), adverse events, and the establishment of predictive factors by Cox analyses. Results In total, 132 tumoural lesions of 80 patients were treated with conventional RT (cRT) of 50-60 Gy (n = 20) or 20-49 Gy (n = 69), stereotactic body RT of 35-50 Gy (SBRT) (n = 36), or brachytherapy of 12-25 Gy (BT) (n = 7). Best objective lesional response was complete (n = 6), partial (n = 52), stable disease (n = 60), progressive disease (n = 14). Median tTTP was 7.6 months (1.0-148.6). In comparison to cRT\(_{20-49Gy}\), tTTP was significantly longer for cRT\(_{50-60Gy}\) (multivariate adjusted HR 0.10; 95\% CI 0.03-0.33; p < 0.001) and SBRT (HR 0.31; 95\% CI 0.12-0.80; p = 0.016), but not for BT (HR 0.66; 95\% CI 0.22-1.99; p = 0.46). Toxicity was generally mild and moderate with three grade 3 events. No convincing predictive factors could be established. Conclusions This largest published study on RT in advanced ACC provides clear evidence that RT is effective in ACC.}, language = {en} } @article{TamburelloAltieriSbieraetal.2022, author = {Tamburello, Mariangela and Altieri, Barbara and Sbiera, Iuliu and Sigala, Sandra and Berruti, Alfredo and Fassnacht, Martin and Sbiera, Silviu}, title = {FGF/FGFR signaling in adrenocortical development and tumorigenesis: novel potential therapeutic targets in adrenocortical carcinoma}, series = {Endocrine}, volume = {77}, journal = {Endocrine}, number = {3}, doi = {10.1007/s12020-022-03074-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324420}, pages = {411-418}, year = {2022}, abstract = {FGF/FGFR signaling regulates embryogenesis, angiogenesis, tissue homeostasis and wound repair by modulating proliferation, differentiation, survival, migration and metabolism of target cells. Understandably, compelling evidence for deregulated FGF signaling in the development and progression of different types of tumors continue to emerge and FGFR inhibitors arise as potential targeted therapeutic agents, particularly in tumors harboring aberrant FGFR signaling. There is first evidence of a dual role of the FGF/FGFR system in both organogenesis and tumorigenesis, of which this review aims to provide an overview. FGF-1 and FGF-2 are expressed in the adrenal cortex and are the most powerful mitogens for adrenocortical cells. Physiologically, they are involved in development and maintenance of the adrenal gland and bind to a family of four tyrosine kinase receptors, among which FGFR1 and FGFR4 are the most strongly expressed in the adrenal cortex. The repeatedly proven overexpression of these two FGFRs also in adrenocortical cancer is thus likely a sign of their participation in proliferation and vascularization, though the exact downstream mechanisms are not yet elucidated. Thus, FGFRs potentially offer novel therapeutic targets also for adrenocortical carcinoma, a type of cancer resistant to conventional antimitotic agents.}, language = {en} } @article{TraubFreyStoerk2023, author = {Traub, Jan and Frey, Anna and St{\"o}rk, Stefan}, title = {Chronic neuroinflammation and cognitive decline in patients with cardiac disease: evidence, relevance, and therapeutic implications}, series = {Life}, volume = {13}, journal = {Life}, number = {2}, issn = {2075-1729}, doi = {10.3390/life13020329}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304869}, year = {2023}, abstract = {Acute and chronic cardiac disorders predispose to alterations in cognitive performance, ranging from mild cognitive impairment to overt dementia. Although this association is well-established, the factors inducing and accelerating cognitive decline beyond ageing and the intricate causal pathways and multilateral interdependencies involved remain poorly understood. Dysregulated and persistent inflammatory processes have been implicated as potentially causal mediators of the adverse consequences on brain function in patients with cardiac disease. Recent advances in positron emission tomography disclosed an enhanced level of neuroinflammation of cortical and subcortical brain regions as an important correlate of altered cognition in these patients. In preclinical and clinical investigations, the thereby involved domains and cell types of the brain are gradually better characterized. Microglia, resident myeloid cells of the central nervous system, appear to be of particular importance, as they are extremely sensitive to even subtle pathological alterations affecting their complex interplay with neighboring astrocytes, oligodendrocytes, infiltrating myeloid cells, and lymphocytes. Here, we review the current evidence linking cognitive impairment and chronic neuroinflammation in patients with various selected cardiac disorders including the aspect of chronic neuroinflammation as a potentially druggable target.}, language = {en} } @article{GelbrichMorbachDeutschbeinetal.2023, author = {Gelbrich, G{\"o}tz and Morbach, Caroline and Deutschbein, Timo and Fassnacht, Martin and St{\"o}rk, Stefan and Heuschmann, Peter U.}, title = {The population comparison index: an intuitive measure to calibrate the extent of impairments in patient cohorts in relation to healthy and diseased populations}, series = {International Journal of Environmental Research and Public Health}, volume = {20}, journal = {International Journal of Environmental Research and Public Health}, number = {3}, issn = {1660-4601}, doi = {10.3390/ijerph20032168}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304933}, year = {2023}, abstract = {We assume that a specific health constraint, e.g., a certain aspect of bodily function or quality of life that is measured by a variable X, is absent (or irrelevant) in a healthy reference population (Ref0), and it is materially present and precisely measured in a diseased reference population (Ref1). We further assume that some amount of this constraint of interest is suspected to be present in a population under study (SP). In order to quantify this issue, we propose the introduction of an intuitive measure, the population comparison index (PCI), that relates the mean value of X in population SP to the mean values of X in populations Ref0 and Ref1. This measure is defined as PCI[X] = (mean[X|SP] - mean[X|Ref0])/(mean[X|Ref1] - mean[X|Ref0]) × 100[\%], where mean[X|.] is the average value of X in the respective group of individuals. For interpretation, PCI[X] ≈ 0 indicates that the values of X in the population SP are similar to those in population Ref0, and hence, the impairment measured by X is not materially present in the individuals in population SP. On the other hand, PCI[X] ≈ 100 means that the individuals in SP exhibit values of X comparable to those occurring in Ref1, i.e., the constraint of interest is equally present in populations SP and Ref1. A value of 0 < PCI[X] < 100 indicates that a certain percentage of the constraint is present in SP, and it is more than in Ref0 but less than in Ref1. A value of PCI[X] > 100 means that population SP is even more affected by the constraint than population Ref1.}, language = {en} } @article{KerwagenFuchsUllrichetal.2023, author = {Kerwagen, Fabian and Fuchs, Konrad F. and Ullrich, Melanie and Schulze, Andres and Straka, Samantha and Krop, Philipp and Latoschik, Marc E. and Gilbert, Fabian and Kunz, Andreas and Fette, Georg and St{\"o}rk, Stefan and Ertl, Maximilian}, title = {Usability of a mHealth solution using speech recognition for point-of-care diagnostic management}, series = {Journal of Medical Systems}, volume = {47}, journal = {Journal of Medical Systems}, number = {1}, doi = {10.1007/s10916-022-01896-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324002}, year = {2023}, abstract = {The administrative burden for physicians in the hospital can affect the quality of patient care. The Service Center Medical Informatics (SMI) of the University Hospital W{\"u}rzburg developed and implemented the smartphone-based mobile application (MA) ukw.mobile1 that uses speech recognition for the point-of-care ordering of radiological examinations. The aim of this study was to examine the usability of the MA workflow for the point-of-care ordering of radiological examinations. All physicians at the Department of Trauma and Plastic Surgery at the University Hospital W{\"u}rzburg, Germany, were asked to participate in a survey including the short version of the User Experience Questionnaire (UEQ-S) and the Unified Theory of Acceptance and Use of Technology (UTAUT). For the analysis of the different domains of user experience (overall attractiveness, pragmatic quality and hedonic quality), we used a two-sided dependent sample t-test. For the determinants of the acceptance model, we employed regression analysis. Twenty-one of 30 physicians (mean age 34 ± 8 years, 62\% male) completed the questionnaire. Compared to the conventional desktop application (DA) workflow, the new MA workflow showed superior overall attractiveness (mean difference 2.15 ± 1.33), pragmatic quality (mean difference 1.90 ± 1.16), and hedonic quality (mean difference 2.41 ± 1.62; all p < .001). The user acceptance measured by the UTAUT (mean 4.49 ± 0.41; min. 1, max. 5) was also high. Performance expectancy (beta = 0.57, p = .02) and effort expectancy (beta = 0.36, p = .04) were identified as predictors of acceptance, the full predictive model explained 65.4\% of its variance. Point-of-care mHealth solutions using innovative technology such as speech-recognition seem to address the users' needs and to offer higher usability in comparison to conventional technology. Implementation of user-centered mHealth innovations might therefore help to facilitate physicians' daily work.}, language = {en} } @article{GerhardtKordsmeyerSehneretal.2023, author = {Gerhardt, Louisa M. S. and Kordsmeyer, Maren and Sehner, Susanne and G{\"u}der, G{\"u}lmisal and St{\"o}rk, Stefan and Edelmann, Frank and Wachter, Rolf and Pankuweit, Sabine and Prettin, Christiane and Ertl, Georg and Wanner, Christoph and Angermann, Christiane E.}, title = {Prevalence and prognostic impact of chronic kidney disease and anaemia across ACC/AHA precursor and symptomatic heart failure stages}, series = {Clinical Research in Cardiology}, volume = {112}, journal = {Clinical Research in Cardiology}, number = {7}, doi = {10.1007/s00392-022-02027-w}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323990}, pages = {868-879}, year = {2023}, abstract = {Background The importance of chronic kidney disease (CKD) and anaemia has not been comprehensively studied in asymptomatic patients at risk for heart failure (HF) versus those with symptomatic HF. We analysed the prevalence, characteristics and prognostic impact of both conditions across American College of Cardiology/American Heart Association (ACC/AHA) precursor and HF stages A-D. Methods and results 2496 participants from three non-pharmacological German Competence Network HF studies were categorized by ACC/AHA stage; stage C patients were subdivided into C1 and C2 (corresponding to NYHA classes I/II and III, respectively). Overall, patient distribution was 8.1\%/35.3\%/32.9\% and 23.7\% in ACC/AHA stages A/B/C1 and C2/D, respectively. These subgroups were stratified by the absence ( - ) or presence ( +) of CKD (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73m2) and anaemia (haemoglobin in women/men < 12/ < 13 g/dL). The primary outcome was all-cause mortality at 5-year follow-up. Prevalence increased across stages A/B/C1 and C2/D (CKD: 22.3\%/23.6\%/31.6\%/54.7\%; anaemia: 3.0\%/7.9\%/21.7\%/33.2\%, respectively), with concordant decreases in median eGFR and haemoglobin (all p < 0.001). Across all stages, hazard ratios [95\% confidence intervals] for all-cause mortality were 2.1 [1.8-2.6] for CKD + , 1.7 [1.4-2.0] for anaemia, and 3.6 [2.9-4.6] for CKD + /anaemia + (all p < 0.001). Population attributable fractions (PAFs) for 5-year mortality related to CKD and/or anaemia were similar across stages A/B, C1 and C2/D (up to 33.4\%, 30.8\% and 34.7\%, respectively). Conclusions Prevalence and severity of CKD and anaemia increased across ACC/AHA stages. Both conditions were individually and additively associated with increased 5-year mortality risk, with similar PAFs in asymptomatic patients and those with symptomatic HF.}, language = {en} } @article{LenschowWennmannHendricksetal.2022, author = {Lenschow, Christina and Wennmann, Andreas and Hendricks, Anne and Germer, Christoph-Thomas and Fassnacht, Martin and Buck, Andreas and Werner, Rudolf A. and Plassmeier, Lars and Schlegel, Nicolas}, title = {Questionable value of [\(^{99m}\)Tc]-sestamibi scintigraphy in patients with pHPT and negative ultrasound}, series = {Langenbeck's Archives of Surgery}, volume = {407}, journal = {Langenbeck's Archives of Surgery}, number = {8}, doi = {10.1007/s00423-022-02648-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323926}, pages = {3661-3669}, year = {2022}, abstract = {Purpose A successful focused surgical approach in primary hyperparathyroidism (pHPT) relies on accurate preoperative localization of the parathyroid adenoma (PA). Most often, ultrasound is followed by [\(^{99m}\)Tc]-sestamibi scintigraphy, but the value of this approach is disputed. Here, we evaluated the diagnostic approach in patients with surgically treated pHPT in our center with the aim to further refine preoperative diagnostic procedures. Methods A single-center retrospective analysis of patients with pHPT from 01/2005 to 08/2021 was carried out followed by evaluation of the preoperative imaging modalities to localize PA. The localization of the PA had to be confirmed intraoperatively by the fresh frozen section and significant dropping of the intraoperative parathyroid hormone (PTH) levels. Results From 658 patients diagnosed with pHPT, 30 patients were excluded from the analysis because of surgery for recurrent or persistent disease. Median age of patients was 58.0 (13-93) years and 71\% were female. Neck ultrasound was carried out in 91.7\% and localized a PA in 76.6\%. In 23.4\% (135/576) of the patients, preoperative neck ultrasound did not detect a PA. In this group, [\(^{99m}\)Tc]-sestamibi correctly identified PA in only 25.4\% of patients. In contrast, in the same cohort, the use of [\(^{11}\)C]-methionine or [\(^{11}\)C]-choline PET resulted in the correct identification of PA in 79.4\% of patients (OR 13.23; 95\% CI 5.24-33.56). Conclusion [\(^{11}\)C]-Methionine or [\(^{11}\)C]-choline PET/CT are superior second-line imaging methods to select patients for a focused surgical approach when previous ultrasound failed to identify PA.}, language = {en} } @article{HeringDoerriesFlemmingetal.2022, author = {Hering, Ilona and D{\"o}rries, Luise and Flemming, Sven and Krietenstein, Laura and Koschker, Ann-Kathrin and Fassnacht, Martin and Germer, Christoph-Thomas and Hankir, Mohammed K. and Seyfried, Florian}, title = {Impact of preoperative weight loss achieved by gastric balloon on peri- and postoperative outcomes of bariatric surgery in super-obese patients: a retrospective matched-pair analysis}, series = {Langenbeck's Archives of Surgery}, volume = {407}, journal = {Langenbeck's Archives of Surgery}, number = {5}, doi = {10.1007/s00423-022-02472-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323909}, pages = {1873-1879}, year = {2022}, abstract = {Background An intragastric balloon is used to cause weight loss in super-obese patients (BMI > 60 kg/m\(^2\)) prior to bariatric surgery. Whether weight loss from intragastric balloon influences that from bariatric surgery is poorly studied. Methods In this retrospective, single-center study, the effects of intragastric balloon in 26 patients (BMI 69.26 ± 6.81) on weight loss after bariatric surgery (primary endpoint), postoperative complications within 30 days, hospital readmission, operation time, and MTL30 (secondary endpoints) were evaluated. Fifty-two matched-pair patients without intragastric balloon prior to bariatric surgery were used as controls. Results Intragastric balloon resulted in a weight loss of 17.3 ± 14.1 kg (BMI 5.75 ± 4.66 kg/m\(^2\)) with a nadir after 5 months. Surgical and postoperative outcomes including complications were comparable between both groups. Total weight loss was similar in both groups (29.0\% vs. 32.2\%, p = 0.362). Direct postoperative weight loss was more pronounced in the control group compared to the gastric balloon group (29.16 ± 7.53\% vs 23.78 ± 9.89\% after 1 year, p < 0.05 and 32.13 ± 10.5\% vs 22.21 ± 10.9\% after 2 years, p < 0.05), who experienced an earlier nadir and started to regain weight during the follow-up. Conclusion A multi-stage therapeutic approach with gastric balloon prior to bariatric surgery in super-obese patients may be effective to facilitate safe surgery. However, with the gastric balloon, pre-treated patients experienced an attenuated postoperative weight loss with an earlier nadir and earlier body weight regain. This should be considered when choosing the appropriate therapeutic regime and managing patients' expectations.}, language = {en} } @article{UngethuemWiedmannWagneretal.2023, author = {Ungeth{\"u}m, K. and Wiedmann, S. and Wagner, M. and Leyh, R. and Ertl, G. and Frantz, S. and Geisler, T. and Karmann, W. and Prondzinsky, R. and Herdeg, C. and Noutsias, M. and Ludwig, T. and K{\"a}s, J. and Klocke, B. and Krapp, J. and Wood, D. and Kotseva, K. and St{\"o}rk, S. and Heuschmann, P. U.}, title = {Secondary prevention in diabetic and nondiabetic coronary heart disease patients: insights from the German subset of the hospital arm of the EUROASPIRE IV and V surveys}, series = {Clinical Research in Cardiology}, volume = {112}, journal = {Clinical Research in Cardiology}, number = {2}, doi = {10.1007/s00392-022-02093-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324037}, pages = {285-298}, year = {2023}, abstract = {Background Patients with coronary heart disease (CHD) with and without diabetes mellitus have an increased risk of recurrent events requiring multifactorial secondary prevention of cardiovascular risk factors. We compared prevalences of cardiovascular risk factors and its determinants including lifestyle, pharmacotherapy and diabetes mellitus among patients with chronic CHD examined within the fourth and fifth EUROASPIRE surveys (EA-IV, 2012-13; and EA-V, 2016-17) in Germany. Methods The EA initiative iteratively conducts European-wide multicenter surveys investigating the quality of secondary prevention in chronic CHD patients aged 18 to 79 years. The data collection in Germany was performed during a comprehensive baseline visit at study centers in W{\"u}rzburg (EA-IV, EA-V), Halle (EA-V), and T{\"u}bingen (EA-V). Results 384 EA-V participants (median age 69.0 years, 81.3\% male) and 536 EA-IV participants (median age 68.7 years, 82.3\% male) were examined. Comparing EA-IV and EA-V, no relevant differences in risk factor prevalence and lifestyle changes were observed with the exception of lower LDL cholesterol levels in EA-V. Prevalence of unrecognized diabetes was significantly lower in EA-V as compared to EA-IV (11.8\% vs. 19.6\%) while the proportion of prediabetes was similarly high in the remaining population (62.1\% vs. 61.0\%). Conclusion Between 2012 and 2017, a modest decrease in LDL cholesterol levels was observed, while no differences in blood pressure control and body weight were apparent in chronic CHD patients in Germany. Although the prevalence of unrecognized diabetes decreased in the later study period, the proportion of normoglycemic patients was low. As pharmacotherapy appeared fairly well implemented, stronger efforts towards lifestyle interventions, mental health programs and cardiac rehabilitation might help to improve risk factor profiles in chronic CHD patients.}, language = {en} } @article{StoerkBernhardtBoehmetal.2022, author = {St{\"o}rk, Stefan and Bernhardt, Alexandra and B{\"o}hm, Michael and Brachmann, Johannes and Dagres, Nikolaos and Frantz, Stefan and Hindricks, Gerd and K{\"o}hler, Friedrich and Zeymer, Uwe and Rosenkranz, Stephan and Angermann, Christiane and Aßmus, Birgit}, title = {Pulmonary artery sensor system pressure monitoring to improve heart failure outcomes (PASSPORT-HF): rationale and design of the PASSPORT-HF multicenter randomized clinical trial}, series = {Clinical Research in Cardiology}, volume = {111}, journal = {Clinical Research in Cardiology}, number = {11}, doi = {10.1007/s00392-022-01987-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324026}, pages = {1245-1255}, year = {2022}, abstract = {Background Remote monitoring of patients with New York Heart Association (NYHA) functional class III heart failure (HF) using daily transmission of pulmonary artery (PA) pressure values has shown a reduction in HF-related hospitalizations and improved quality of life in patients. Objectives PASSPORT-HF is a prospective, randomized, open, multicenter trial evaluating the effects of a hemodynamic-guided, HF nurse-led care approach using the CardioMEMS™ HF-System on clinical end points. Methods and results The PASSPORT-HF trial has been commissioned by the German Federal Joint Committee (G-BA) to ascertain the efficacy of PA pressure-guided remote care in the German health-care system. PASSPORT-HF includes adult HF patients in NYHA functional class III, who experienced an HF-related hospitalization within the last 12 months. Patients with reduced ejection fraction must be on stable guideline-directed pharmacotherapy. Patients will be randomized centrally 1:1 to implantation of a CardioMEMS™ sensor or control. All patients will receive post-discharge support facilitated by trained HF nurses providing structured telephone-based care. The trial will enroll 554 patients at about 50 study sites. The primary end point is a composite of the number of unplanned HF-related rehospitalizations or all-cause death after 12 months of follow-up, and all events will be adjudicated centrally. Secondary end points include device/system-related complications, components of the primary end point, days alive and out of hospital, disease-specific and generic health-related quality of life including their sub-scales, and laboratory parameters of organ damage and disease progression. Conclusions PASSPORT-HF will define the efficacy of implementing hemodynamic monitoring as a novel disease management tool in routine outpatient care. Trial registration ClinicalTrials.gov; NCT04398654, 13-MAY-2020.}, language = {en} } @article{ReibetanzKelmUttingeretal.2022, author = {Reibetanz, Joachim and Kelm, Matthias and Uttinger, Konstantin L. and Reuter, Miriam and Schlegel, Nicolas and Hankir, Mohamed and Wiegering, Verena and Germer, Christoph-Thomas and Fassnacht, Martin and Lock, Johan Friso and Wiegering, Armin}, title = {Differences in morbidity and mortality between unilateral adrenalectomy for adrenal Cushing's syndrome and bilateral adrenalectomy for therapy refractory extra-adrenal Cushing's syndrome}, series = {Langenbeck's Archives of Surgery}, volume = {407}, journal = {Langenbeck's Archives of Surgery}, number = {6}, doi = {10.1007/s00423-022-02568-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323947}, pages = {2481-2488}, year = {2022}, abstract = {Purpose In selected cases of severe Cushing's syndrome due to uncontrolled ACTH secretion, bilateral adrenalectomy appears unavoidable. Compared with unilateral adrenalectomy (for adrenal Cushing's syndrome), bilateral adrenalectomy has a perceived higher perioperative morbidity. The aim of the current study was to compare both interventions in endogenous Cushing's syndrome regarding postoperative outcomes. Methods We report a single-center, retrospective cohort study comparing patients with hypercortisolism undergoing bilateral vs. unilateral adrenalectomy during 2008-2021. Patients with adrenal Cushing's syndrome due to adenoma were compared with patients with ACTH-dependent Cushing's syndrome (Cushing's disease and ectopic ACTH production) focusing on postoperative morbidity and mortality as well as long-term survival. Results Of 83 patients with adrenalectomy for hypercortisolism (65.1\% female, median age 53 years), the indication for adrenalectomy was due to adrenal Cushing's syndrome in 60 patients (72.2\%; 59 unilateral and one bilateral), and due to hypercortisolism caused by Cushing's disease (n = 16) or non-pituitary uncontrolled ACTH secretion of unknown origin (n = 7) (27.7\% of all adrenalectomies). Compared with unilateral adrenalectomy (n = 59), patients with bilateral adrenalectomy (n = 24) had a higher rate of severe complications (0\% vs. 33\%; p < 0.001) and delayed recovery (median: 10.2\% vs. 79.2\%; p < 0.001). Using the MTL30 marker, patients with bilateral adrenalectomy fared worse than patients after unilateral surgery (MTL30 positive: 7.2\% vs. 25.0\% p < 0.001). Postoperative mortality was increased in patients with bilateral adrenalectomy (0\% vs. 8.3\%; p = 0.081). Conclusion While unilateral adrenalectomy for adrenal Cushing's syndrome represents a safe and definitive therapeutic option, bilateral adrenalectomy to control ACTH-dependent extra-adrenal Cushing's syndrome or Cushing's disease is a more complicated intervention with a mortality of nearly 10\%.}, language = {en} } @article{KippnichSkazelKlingshirnetal.2022, author = {Kippnich, Maximilian and Skazel, Tobias and Klingshirn, Hanna and Gerken, Laura and Heuschmann, Peter and Haas, Kirsten and Schutzmeier, Martha and Brandstetter, Lilly and Weismann, Dirk and Reuschenbach, Bernd and Meybohm, Patrick and Wurmb, Thomas}, title = {Analyse des Weaningprozesses bei Intensivpatienten im Hinblick auf Dokumentation und Verlegung in weiterbehandelnde Einheiten}, series = {Medizinische Klinik, Intensivmedizin und Notfallmedizin}, volume = {118}, journal = {Medizinische Klinik, Intensivmedizin und Notfallmedizin}, doi = {10.1007/s00063-022-00941-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-346742}, pages = {269-276}, year = {2022}, abstract = {Hintergrund und Fragestellung Die Entw{\"o}hnung von Beatmungsger{\"a}ten wird nicht immer auf der prim{\"a}r behandelnden Intensivstation abgeschlossen. Die Weiterverlegung in andere Behandlungseinrichtungen stellt einen sensiblen Abschnitt in der Behandlung und Rehabilitation des Weaningpatienten dar. Ziel der vorliegenden Studie war die Untersuchung des {\"U}berleitungsmanagements und des Interhospitaltransfers von Weaningpatienten unter besonderer Ber{\"u}cksichtigung der Dokumentationsqualit{\"a}t. Methodik Es erfolge eine retrospektive Datenanalyse eines Jahrs (2018) auf 2 Intensivstationen eines Universit{\"a}tsklinikums. Eingeschlossen wurden alle beatmeten Patienten mit folgenden Tracerdiagnosen: COPD, Asthma, Polytrauma, Pneumonie, Sepsis, ARDS und Reanimation (Beatmung > 24 h). Ergebnisse Insgesamt konnten 750 Patienten in die Untersuchung eingeschlossen werden (Alter 64 [52, 8-76; Median, IQR]; 32 \% weiblich). Davon waren 48 (6,4 \%) Patienten zum Zeitpunkt der Verlegung nicht entw{\"o}hnt (v. a. Sepsis und ARDS). Die Routinedokumentation war bei den Abschnitten „Spontaneous Breathing Trial", „Bewertung der Entw{\"o}hungsbereitschaft" und „vermutete Entw{\"o}hnbarkeit" ausreichend, um die Erf{\"u}llung der Parameter der S2k-Leitlinie „Prolongiertes Weaning" ad{\"a}quat zu beurteilen. Vorwiegend wurden diese Patienten mit Tracheostoma (76 \%) in Rehabilitationskliniken (44 \%) mittels spezialisierten Rettungsmitteln des arztbegleiteten Patiententransports verlegt (75 \%). Diskussion Die Verlegung nicht entw{\"o}hnter Patienten nach initialem Intensivaufenthalt ist ein relevantes Thema f{\"u}r den Interhospitaltransfer. Die Routinedokumentation eines strukturierten Weaningprozesses ist in Kernelementen ausreichend, um den Weaningprozess l{\"u}ckenlos zu beschreiben. Dies ist f{\"u}r die Kontinuit{\"a}t in der Weiterbehandlung dieser Patienten von großer Bedeutung.}, language = {de} } @article{PetruskiIvlevaKucharskaNewtonPaltaetal.2017, author = {Petruski-Ivleva, Natalia and Kucharska-Newton, Anna and Palta, Priya and Couper, David and Meyer, Katie and Graff, Misa and Haring, Bernhard and Sharrett, Richey and Heiss, Gerardo}, title = {Milk intake at midlife and cognitive decline over 20 years. The Atherosclerosis risk in communities (ARIC) study}, series = {Nutrients}, volume = {9}, journal = {Nutrients}, number = {10}, doi = {10.3390/nu9101134}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173909}, year = {2017}, abstract = {Background: Faster rates of cognitive decline are likely to result in earlier onset of cognitive impairment and dementia. d-galactose, a derivative of lactose, is used in animal studies to induce neurodegeneration. Milk is the primary source of lactose in the human diet, and its effects on cognitive decline have not been fully evaluated. Objective: Assess the association of milk intake with change in cognitive function over 20 years. Methods: A total of 13,751 participants of the Atherosclerosis Risk in Communities (ARIC) cohort completed a food frequency questionnaire and three neurocognitive evaluations from 1990 through 2013. Two single nucleotide polymorphisms (SNPs) were used to determine lactase persistence (LCT-13910 C/T for Whites and LCT-14010 G/C for Blacks). Mixed-effects models were used to study the association of milk intake with cognitive change. Multiple imputations by chained equations were used to account for attrition. Results: Milk intake greater than 1 glass/day was associated with greater decline in the global z-score over a 20-year period. The difference in decline was 0.10 (95\% CI: 0.16, 0.03) z-scores, or an additional 10\% decline, relative to the group reporting "almost never" consuming milk. Conclusions: Replication of these results is warranted in diverse populations with greater milk intake and higher variability of lactase persistence genotype.}, language = {en} } @article{BalonovKurlbaumKoschkeretal.2023, author = {Balonov, Ilja and Kurlbaum, Max and Koschker, Ann-Cathrin and Stier, Christine and Fassnacht, Martin and Dischinger, Ulrich}, title = {Changes in plasma metabolomic profile following bariatric surgery, lifestyle intervention or diet restriction — insights from human and rat studies}, series = {International Journal of Molecular Sciences}, volume = {24}, journal = {International Journal of Molecular Sciences}, number = {3}, issn = {1422-0067}, doi = {10.3390/ijms24032354}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304462}, year = {2023}, abstract = {Although bariatric surgery is known to change the metabolome, it is unclear if this is specific for the intervention or a consequence of the induced bodyweight loss. As the weight loss after Roux-en-Y Gastric Bypass (RYGB) can hardly be mimicked with an evenly effective diet in humans, translational research efforts might be helpful. A group of 188 plasma metabolites of 46 patients from the randomized controlled W{\"u}rzburg Adipositas Study (WAS) and from RYGB-treated rats (n = 6) as well as body-weight-matched controls (n = 7) were measured using liquid chromatography tandem mass spectrometry. WAS participants were randomized into intensive lifestyle modification (LS, n = 24) or RYGB (OP, n = 22). In patients in the WAS cohort, only bariatric surgery achieved a sustained weight loss (BMI -34.3\% (OP) vs. -1.2\% (LS), p ≤ 0.01). An explicit shift in the metabolomic profile was found in 57 metabolites in the human cohort and in 62 metabolites in the rodent model. Significantly higher levels of sphingolipids and lecithins were detected in both surgical groups but not in the conservatively treated human and animal groups. RYGB leads to a characteristic metabolomic profile, which differs distinctly from that following non-surgical intervention. Analysis of the human and rat data revealed that RYGB induces specific changes in the metabolome independent of weight loss.}, language = {en} } @article{GernerAghaiTrommeschlaegerKrausetal.2022, author = {Gerner, Bettina and Aghai-Trommeschlaeger, Fatemeh and Kraus, Sabrina and Grigoleit, G{\"o}tz Ulrich and Zimmermann, Sebastian and Kurlbaum, Max and Klinker, Hartwig and Isberner, Nora and Scherf-Clavel, Oliver}, title = {A physiologically-based pharmacokinetic model of ruxolitinib and posaconazole to predict CYP3A4-mediated drug-drug interaction frequently observed in graft versus host disease patients}, series = {Pharmaceutics}, volume = {14}, journal = {Pharmaceutics}, number = {12}, issn = {1999-4923}, doi = {10.3390/pharmaceutics14122556}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297261}, year = {2022}, abstract = {Ruxolitinib (RUX) is approved for the treatment of steroid-refractory acute and chronic graft versus host disease (GvHD). It is predominantly metabolized via cytochrome P450 (CYP) 3A4. As patients with GvHD have an increased risk of invasive fungal infections, RUX is frequently combined with posaconazole (POS), a strong CYP3A4 inhibitor. Knowledge of RUX exposure under concomitant POS treatment is scarce and recommendations on dose modifications are inconsistent. A physiologically based pharmacokinetic (PBPK) model was developed to investigate the drug-drug interaction (DDI) between POS and RUX. The predicted RUX exposure was compared to observed concentrations in patients with GvHD in the clinical routine. PBPK models for RUX and POS were independently set up using PK-Sim\(^®\) Version 11. Plasma concentration-time profiles were described successfully and all predicted area under the curve (AUC) values were within 2-fold of the observed values. The increase in RUX exposure was predicted with a DDI ratio of 1.21 (C\(_{max}\)) and 1.59 (AUC). Standard dosing in patients with GvHD led to higher RUX exposure than expected, suggesting further dose reduction if combined with POS. The developed model can serve as a starting point for further simulations of the implemented DDI and can be extended to further perpetrators of CYP-mediated PK-DDIs or disease-specific physiological changes.}, language = {en} } @article{BețiuNoveanuHancuetal.2022, author = {Bețiu, Alina M. and Noveanu, Lavinia and H{\^a}ncu, Iasmina M. and Lascu, Ana and Petrescu, Lucian and Maack, Christoph and Elm{\´e}r, Eskil and Muntean, Danina M.}, title = {Mitochondrial effects of common cardiovascular medications: the good, the bad and the mixed}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {21}, issn = {1422-0067}, doi = {10.3390/ijms232113653}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297384}, year = {2022}, abstract = {Mitochondria are central organelles in the homeostasis of the cardiovascular system via the integration of several physiological processes, such as ATP generation via oxidative phosphorylation, synthesis/exchange of metabolites, calcium sequestration, reactive oxygen species (ROS) production/buffering and control of cellular survival/death. Mitochondrial impairment has been widely recognized as a central pathomechanism of almost all cardiovascular diseases, rendering these organelles important therapeutic targets. Mitochondrial dysfunction has been reported to occur in the setting of drug-induced toxicity in several tissues and organs, including the heart. Members of the drug classes currently used in the therapeutics of cardiovascular pathologies have been reported to both support and undermine mitochondrial function. For the latter case, mitochondrial toxicity is the consequence of drug interference (direct or off-target effects) with mitochondrial respiration/energy conversion, DNA replication, ROS production and detoxification, cell death signaling and mitochondrial dynamics. The present narrative review aims to summarize the beneficial and deleterious mitochondrial effects of common cardiovascular medications as described in various experimental models and identify those for which evidence for both types of effects is available in the literature.}, language = {en} } @article{JarauschNeuenrothAndagetal.2022, author = {Jarausch, Johannes and Neuenroth, Lisa and Andag, Reiner and Leha, Andreas and Fischer, Andreas and Asif, Abdul R. and Lenz, Christof and Eidizadeh, Abass}, title = {Influence of shear stress, inflammation and BRD4 inhibition on human endothelial cells: a holistic proteomic approach}, series = {Cells}, volume = {11}, journal = {Cells}, number = {19}, issn = {2073-4409}, doi = {10.3390/cells11193086}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-289872}, year = {2022}, abstract = {Atherosclerosis is an important risk factor in the development of cardiovascular diseases. In addition to increased plasma lipid concentrations, irregular/oscillatory shear stress and inflammatory processes trigger atherosclerosis. Inhibitors of the transcription modulatory bromo- and extra-terminal domain (BET) protein family (BETi) could offer a possible therapeutic approach due to their epigenetic mechanism and anti-inflammatory properties. In this study, the influence of laminar shear stress, inflammation and BETi treatment on human endothelial cells was investigated using global protein expression profiling by ion mobility separation-enhanced data independent acquisition mass spectrometry (IMS-DIA-MS). For this purpose, primary human umbilical cord derived vascular endothelial cells were treated with TNFα to mimic inflammation and exposed to laminar shear stress in the presence or absence of the BRD4 inhibitor JQ1. IMS-DIA-MS detected over 4037 proteins expressed in endothelial cells. Inflammation, shear stress and BETi led to pronounced changes in protein expression patterns with JQ1 having the greatest effect. To our knowledge, this is the first proteomics study on primary endothelial cells, which provides an extensive database for the effects of shear stress, inflammation and BETi on the endothelial proteome.}, language = {en} } @article{SchmitzStormsKochetal.2023, author = {Schmitz, Sophia M. and Storms, Sebastian and Koch, Alexander and Stier, Christine and Kroh, Andreas and Rheinwalt, Karl P. and Schipper, Sandra and Hamesch, Karim and Ulmer, Tom F. and Neumann, Ulf P. and Alizai, Patrick H.}, title = {Insulin resistance is the main characteristic of metabolically unhealthy obesity (MUO) associated with NASH in patients undergoing bariatric surgery}, series = {Biomedicines}, volume = {11}, journal = {Biomedicines}, number = {6}, issn = {2227-9059}, doi = {10.3390/biomedicines11061595}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319213}, year = {2023}, abstract = {(1) Background: Metabolically healthy obesity (MHO) is a concept that applies to obese patients without any elements of metabolic syndrome (metS). In turn, metabolically unhealthy obesity (MUO) defines the presence of elements of metS in obese patients. The components of MUO can be divided into subgroups regarding the elements of inflammation, lipid and glucose metabolism and cardiovascular disease. MUO patients appear to be at greater risk of developing non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) compared to MHO patients. The aim of this study was to evaluate the influence of different MUO components on NAFLD and NASH in patients with morbid obesity undergoing bariatric surgery. (2) Methods: 141 patients undergoing bariatric surgery from September 2015 and October 2021 at RWTH Aachen university hospital (Germany) were included. Patients were evaluated pre-operatively for characteristics of metS and MUO (HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension). Intraoperatively, a liver biopsy was taken from the left liver lobe and evaluated for the presence of NAFLD or NASH. In ordinal regression analyses, different factors were evaluated for their influence on NAFLD and NASH. (3) Results: Mean BMI of the patients was 52.3 kg/m\(^2\) (36-74.8, SD 8.4). Together, the parameters HbA1c, HOMA, CRP, BMI, fasting glucose, LDL, TG, HDL and the presence of arterial hypertension accounted for a significant amount of variance in the outcome, with a likelihood ratio of χ\(^2\) (9) = 41.547, p < 0.001, for predicting the presence of NASH. Only HOMA was an independent predictor of NASH (B = 0.102, SE = 0.0373, p = 0.007). Evaluation of steatosis showed a similar trend (likelihood ratio χ\(^2\) (9) = 40.272, p < 0.001). Independent predictors of steatosis were HbA1c (B = 0.833, SE = 0.343, p = 0.015) and HOMA (B = 0.136, SE = 0.039, p < 0.001). (4) Conclusions: The above-mentioned model, including components of MUO, was significant for diagnosing NASH in patients with morbid obesity undergoing bariatric surgery. Out of the different subitems, HOMA independently predicted the presence of NASH and steatosis, while HbA1c independently predicted steatosis and fibrosis. Taken together, the parameter of glucose metabolism appears to be more accurate for the prediction of NASH than the parameters of lipid metabolism, inflammation or the presence of cardiovascular disease.}, language = {en} } @article{ReelReelErlicetal.2022, author = {Reel, Smarti and Reel, Parminder S. and Erlic, Zoran and Amar, Laurence and Pecori, Alessio and Larsen, Casper K. and Tetti, Martina and Pamporaki, Christina and Prehn, Cornelia and Adamski, Jerzy and Prejbisz, Aleksander and Ceccato, Filippo and Scaroni, Carla and Kroiss, Matthias and Dennedy, Michael C. and Deinum, Jaap and Eisenhofer, Graeme and Langton, Katharina and Mulatero, Paolo and Reincke, Martin and Rossi, Gian Paolo and Lenzini, Livia and Davies, Eleanor and Gimenez-Roqueplo, Anne-Paule and Assi{\´e}, Guillaume and Blanchard, Anne and Zennaro, Maria-Christina and Beuschlein, Felix and Jefferson, Emily R.}, title = {Predicting hypertension subtypes with machine learning using targeted metabolites and their ratios}, series = {Metabolites}, volume = {12}, journal = {Metabolites}, number = {8}, issn = {2218-1989}, doi = {10.3390/metabo12080755}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286161}, year = {2022}, abstract = {Hypertension is a major global health problem with high prevalence and complex associated health risks. Primary hypertension (PHT) is most common and the reasons behind primary hypertension are largely unknown. Endocrine hypertension (EHT) is another complex form of hypertension with an estimated prevalence varying from 3 to 20\% depending on the population studied. It occurs due to underlying conditions associated with hormonal excess mainly related to adrenal tumours and sub-categorised: primary aldosteronism (PA), Cushing's syndrome (CS), pheochromocytoma or functional paraganglioma (PPGL). Endocrine hypertension is often misdiagnosed as primary hypertension, causing delays in treatment for the underlying condition, reduced quality of life, and costly antihypertensive treatment that is often ineffective. This study systematically used targeted metabolomics and high-throughput machine learning methods to predict the key biomarkers in classifying and distinguishing the various subtypes of endocrine and primary hypertension. The trained models successfully classified CS from PHT and EHT from PHT with 92\% specificity on the test set. The most prominent targeted metabolites and metabolite ratios for hypertension identification for different disease comparisons were C18:1, C18:2, and Orn/Arg. Sex was identified as an important feature in CS vs. PHT classification.}, language = {en} } @article{BliziotisKluijtmansTinneveltetal.2022, author = {Bliziotis, Nikolaos G. and Kluijtmans, Leo A. J. and Tinnevelt, Gerjen H. and Reel, Parminder and Reel, Smarti and Langton, Katharina and Robledo, Mercedes and Pamporaki, Christina and Pecori, Alessio and Van Kralingen, Josie and Tetti, Martina and Engelke, Udo F. H. and Erlic, Zoran and Engel, Jasper and Deutschbein, Timo and N{\"o}lting, Svenja and Prejbisz, Aleksander and Richter, Susan and Adamski, Jerzy and Januszewicz, Andrzej and Ceccato, Filippo and Scaroni, Carla and Dennedy, Michael C. and Williams, Tracy A. and Lenzini, Livia and Gimenez-Roqueplo, Anne-Paule and Davies, Eleanor and Fassnacht, Martin and Remde, Hanna and Eisenhofer, Graeme and Beuschlein, Felix and Kroiss, Matthias and Jefferson, Emily and Zennaro, Maria-Christina and Wevers, Ron A. and Jansen, Jeroen J. and Deinum, Jaap and Timmers, Henri J. L. M.}, title = {Preanalytical pitfalls in untargeted plasma nuclear magnetic resonance metabolomics of endocrine hypertension}, series = {Metabolites}, volume = {12}, journal = {Metabolites}, number = {8}, issn = {2218-1989}, doi = {10.3390/metabo12080679}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-282930}, year = {2022}, abstract = {Despite considerable morbidity and mortality, numerous cases of endocrine hypertension (EHT) forms, including primary aldosteronism (PA), pheochromocytoma and functional paraganglioma (PPGL), and Cushing's syndrome (CS), remain undetected. We aimed to establish signatures for the different forms of EHT, investigate potentially confounding effects and establish unbiased disease biomarkers. Plasma samples were obtained from 13 biobanks across seven countries and analyzed using untargeted NMR metabolomics. We compared unstratified samples of 106 PHT patients to 231 EHT patients, including 104 PA, 94 PPGL and 33 CS patients. Spectra were subjected to a multivariate statistical comparison of PHT to EHT forms and the associated signatures were obtained. Three approaches were applied to investigate and correct confounding effects. Though we found signatures that could separate PHT from EHT forms, there were also key similarities with the signatures of sample center of origin and sample age. The study design restricted the applicability of the corrections employed. With the samples that were available, no biomarkers for PHT vs. EHT could be identified. The complexity of the confounding effects, evidenced by their robustness to correction approaches, highlighted the need for a consensus on how to deal with variabilities probably attributed to preanalytical factors in retrospective, multicenter metabolomics studies.}, language = {en} } @article{ReuschWagenhaeuserGabeletal.2022, author = {Reusch, Julia and Wagenh{\"a}user, Isabell and Gabel, Alexander and Eggestein, Annika and H{\"o}hn, Anna and L{\^a}m, Thi{\^e}n-Tr{\´i} and Frey, Anna and Schubert-Unkmeir, Alexandra and D{\"o}lken, Lars and Frantz, Stefan and Kurzai, Oliver and Vogel, Ulrich and Krone, Manuel and Petri, Nils}, title = {Influencing factors of anti-SARS-CoV-2-spike-IgG antibody titers in healthcare workers: A cross-section study}, series = {Journal of Medical Virology}, volume = {95}, journal = {Journal of Medical Virology}, number = {1}, doi = {10.1002/jmv.28300}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318659}, year = {2022}, abstract = {Against the background of the current COVID-19 infection dynamics with its rapid spread of SARS-CoV-2 variants of concern (VOC), the immunity and the vaccine prevention of healthcare workers (HCWs) against SARS-CoV-2 continues to be of high importance. This observational cross-section study assesses factors influencing the level of anti-SARS-CoV-2-spike IgG after SARS-CoV-2 infection or vaccination. One thousand seven hundred and fifty HCWs were recruited meeting the following inclusion criteria: age ≥18 years, PCR-confirmed SARS-CoV-2 infection convalescence and/or at least one dose of COVID-19 vaccination. anti-SARS-CoV-2-spike IgG titers were determined by SERION ELISA agile SARS-CoV-2 IgG. Mean anti-SARS-CoV-2-spike IgG levels increased significantly by number of COVID-19 vaccinations (92.2 BAU/ml for single, 140.9 BAU/ml for twice and 1144.3 BAU/ml for threefold vaccination). Hybrid COVID-19 immunized respondents (after infection and vaccination) had significantly higher antibody titers compared with convalescent only HCWs. Anti-SARS-CoV-2-spike IgG titers declined significantly with time after the second vaccination. Smoking and high age were associated with lower titers. Both recovered and vaccinated HCWs presented a predominantly good humoral immune response. Smoking and higher age limited the humoral SARS-CoV-2 immunity, adding to the risk of severe infections within this already health impaired collective.}, language = {en} } @article{KrieterRuethLemkeetal.2023, author = {Krieter, Detlef H. and R{\"u}th, Marieke and Lemke, Horst-Dieter and Wanner, Christoph}, title = {Clinical performance comparison of two medium cut-off dialyzers}, series = {Therapeutic Apheresis and Dialysis}, volume = {27}, journal = {Therapeutic Apheresis and Dialysis}, number = {2}, doi = {10.1111/1744-9987.13919}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318643}, pages = {284 -- 292}, year = {2023}, abstract = {Introduction Medium-cut-off (MCO) dialyzers may beneficially impact outcomes in patients on hemodialysis. Methods In a randomized, controlled trial in maintenance hemodialysis patients, the new Nipro ELISIO-17HX MCO dialyzer was compared to the Baxter Theranova 400 filter regarding middle molecule removal. Furthermore, the suitability of two assays for free lambda-light chain (λFLC) detection (Freelite vs. N-Latex) was verified. Results ELISIO-HX achieved slightly lower reduction ratios for β2-microglobulin (71.8 ± 6.0 vs. 75.3 ± 5.8\%; p = 0.001), myoglobin (54.7 ± 8.6 vs. 64.9 ± 8.7\%; p < 0.001), and kappa-FLC (62.1 ± 8.8 vs. 56.3 ± 7.7\%; p = 0.021). λFLC reduction ratios were more conclusive with the Freelite assay and not different between ELISIO-HX and Theranova (28.4 ± 3.9 vs. 38.7 ± 13.4\%; p = 0.069). The albumin loss of Theranova was considerably higher (2.14 ± 0.45 vs. 0.77 ± 0.25 g; p = 0.001) and the Global Removal ScoreLoss alb largely inferior (30.6 ± 7.4 vs. 82.4 ± 29.2\%/g; p = 0.006) to ELISIO-HX. Conclusions The new ELISIO-HX expands the choice of dialyzers for MCO hemodialysis.}, language = {en} } @article{MaglioccaMoneDiIorioetal.2022, author = {Magliocca, Giorgia and Mone, Pasquale and Di Iorio, Biagio Raffaele and Heidland, August and Marzocco, Stefania}, title = {Short-chain fatty acids in Chronic Kidney Disease: focus on inflammation and oxidative stress regulation}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {10}, issn = {1422-0067}, doi = {10.3390/ijms23105354}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284587}, year = {2022}, abstract = {Chronic Kidney Disease (CKD) is a debilitating disease associated with several secondary complications that increase comorbidity and mortality. In patients with CKD, there is a significant qualitative and quantitative alteration in the gut microbiota, which, consequently, also leads to reduced production of beneficial bacterial metabolites, such as short-chain fatty acids. Evidence supports the beneficial effects of short-chain fatty acids in modulating inflammation and oxidative stress, which are implicated in CKD pathogenesis and progression. Therefore, this review will provide an overview of the current knowledge, based on pre-clinical and clinical evidence, on the effect of SCFAs on CKD-associated inflammation and oxidative stress.}, language = {en} } @article{ShemerMekiesBenJehudaetal.2021, author = {Shemer, Yuval and Mekies, Lucy N. and Ben Jehuda, Ronen and Baskin, Polina and Shulman, Rita and Eisen, Binyamin and Regev, Danielle and Arbustini, Eloisa and Gerull, Brenda and Gherghiceanu, Mihaela and Gottlieb, Eyal and Arad, Michael and Binah, Ofer}, title = {Investigating LMNA-related dilated cardiomyopathy using human induced Pluripotent Stem Cell-derived cardiomyocytes}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {15}, issn = {1422-0067}, doi = {10.3390/ijms22157874}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285673}, year = {2021}, abstract = {LMNA-related dilated cardiomyopathy is an inherited heart disease caused by mutations in the LMNA gene encoding for lamin A/C. The disease is characterized by left ventricular enlargement and impaired systolic function associated with conduction defects and ventricular arrhythmias. We hypothesized that LMNA-mutated patients' induced Pluripotent Stem Cell-derived cardiomyocytes (iPSC-CMs) display electrophysiological abnormalities, thus constituting a suitable tool for deciphering the arrhythmogenic mechanisms of the disease, and possibly for developing novel therapeutic modalities. iPSC-CMs were generated from two related patients (father and son) carrying the same E342K mutation in the LMNA gene. Compared to control iPSC-CMs, LMNA-mutated iPSC-CMs exhibited the following electrophysiological abnormalities: (1) decreased spontaneous action potential beat rate and decreased pacemaker current (I\(_f\)) density; (2) prolonged action potential duration and increased L-type Ca\(^{2+}\) current (I\(_{Ca,L}\)) density; (3) delayed afterdepolarizations (DADs), arrhythmias and increased beat rate variability; (4) DADs, arrhythmias and cessation of spontaneous firing in response to β-adrenergic stimulation and rapid pacing. Additionally, compared to healthy control, LMNA-mutated iPSC-CMs displayed nuclear morphological irregularities and gene expression alterations. Notably, KB-R7943, a selective inhibitor of the reverse-mode of the Na\(^+\)/Ca\(^{2+}\) exchanger, blocked the DADs in LMNA-mutated iPSC-CMs. Our findings demonstrate cellular electrophysiological mechanisms underlying the arrhythmias in LMNA-related dilated cardiomyopathy.}, language = {en} } @article{DawoodBreuerStebanietal.2023, author = {Dawood, Peter and Breuer, Felix and Stebani, Jannik and Burd, Paul and Homolya, Istv{\´a}n and Oberberger, Johannes and Jakob, Peter M. and Blaimer, Martin}, title = {Iterative training of robust k-space interpolation networks for improved image reconstruction with limited scan specific training samples}, series = {Magnetic Resonance in Medicine}, volume = {89}, journal = {Magnetic Resonance in Medicine}, number = {2}, doi = {10.1002/mrm.29482}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312306}, pages = {812 -- 827}, year = {2023}, abstract = {To evaluate an iterative learning approach for enhanced performance of robust artificial-neural-networks for k-space interpolation (RAKI), when only a limited amount of training data (auto-calibration signals [ACS]) are available for accelerated standard 2D imaging. Methods In a first step, the RAKI model was tailored for the case of limited training data amount. In the iterative learning approach (termed iterative RAKI [iRAKI]), the tailored RAKI model is initially trained using original and augmented ACS obtained from a linear parallel imaging reconstruction. Subsequently, the RAKI convolution filters are refined iteratively using original and augmented ACS extracted from the previous RAKI reconstruction. Evaluation was carried out on 200 retrospectively undersampled in vivo datasets from the fastMRI neuro database with different contrast settings. Results For limited training data (18 and 22 ACS lines for R = 4 and R = 5, respectively), iRAKI outperforms standard RAKI by reducing residual artifacts and yields better noise suppression when compared to standard parallel imaging, underlined by quantitative reconstruction quality metrics. Additionally, iRAKI shows better performance than both GRAPPA and standard RAKI in case of pre-scan calibration with varying contrast between training- and undersampled data. Conclusion RAKI benefits from the iterative learning approach, which preserves the noise suppression feature, but requires less original training data for the accurate reconstruction of standard 2D images thereby improving net acceleration.}, language = {en} } @article{BrodehlMeshkovMyasnikovetal.2021, author = {Brodehl, Andreas and Meshkov, Alexey and Myasnikov, Roman and Kiseleva, Anna and Kulikova, Olga and Klauke, B{\"a}rbel and Sotnikova, Evgeniia and Stanasiuk, Caroline and Divashuk, Mikhail and Pohl, Greta Marie and Kudryavtseva, Maria and Klingel, Karin and Gerull, Brenda and Zharikova, Anastasia and Gummert, Jan and Koretskiy, Sergey and Schubert, Stephan and Mershina, Elena and G{\"a}rtner, Anna and Pilus, Polina and Laser, Kai Thorsten and Sinitsyn, Valentin and Boytsov, Sergey and Drapkina, Oxana and Milting, Hendrik}, title = {Hemi- and homozygous loss-of-function mutations in DSG2 (desmoglein-2) cause recessive arrhythmogenic cardiomyopathy with an early onset}, series = {International Journal of Molecular Sciences}, volume = {22}, journal = {International Journal of Molecular Sciences}, number = {7}, issn = {1422-0067}, doi = {10.3390/ijms22073786}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285279}, year = {2021}, abstract = {About 50\% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2-c.378+1G>T) in the first patient and a nonsense mutation (DSG2-p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.}, language = {en} } @article{vanderVeenVlietstravanDussenetal.2020, author = {van der Veen, Sanne J. and Vlietstra, Wytze J. and van Dussen, Laura and van Kuilenburg, Andr{\´e} B.P. and Dijkgraaf, Marcel G. W. and Lenders, Malte and Brand, Eva and Wanner, Christoph and Hughes, Derralynn and Elliott, Perry M. and Hollak, Carla E. M. and Langeveld, Mirjam}, title = {Predicting the development of anti-drug antibodies against recombinant alpha-galactosidase A in male patients with classical Fabry disease}, series = {International Journal of Molecular Sciences}, volume = {21}, journal = {International Journal of Molecular Sciences}, number = {16}, issn = {1422-0067}, doi = {10.3390/ijms21165784}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285687}, year = {2020}, abstract = {Fabry Disease (FD) is a rare, X-linked, lysosomal storage disease that mainly causes renal, cardiac and cerebral complications. Enzyme replacement therapy (ERT) with recombinant alpha-galactosidase A is available, but approximately 50\% of male patients with classical FD develop inhibiting anti-drug antibodies (iADAs) that lead to reduced biochemical responses and an accelerated loss of renal function. Once immunization has occurred, iADAs tend to persist and tolerization is hard to achieve. Here we developed a pre-treatment prediction model for iADA development in FD using existing data from 120 classical male FD patients from three European centers, treated with ERT. We found that nonsense and frameshift mutations in the α-galactosidase A gene (p = 0.05), higher plasma lysoGb3 at baseline (p < 0.001) and agalsidase beta as first treatment (p = 0.006) were significantly associated with iADA development. Prediction performance of a Random Forest model, using multiple variables (AUC-ROC: 0.77) was compared to a logistic regression (LR) model using the three significantly associated variables (AUC-ROC: 0.77). The LR model can be used to determine iADA risk in individual FD patients prior to treatment initiation. This helps to determine in which patients adjusted treatment and/or immunomodulatory regimes may be considered to minimize iADA development risk.}, language = {en} } @article{RapaDiIorioCampigliaetal.2019, author = {Rapa, Shara Francesca and Di Iorio, Biagio Raffaele and Campiglia, Pietro and Heidland, August and Marzocco, Stefania}, title = {Inflammation and oxidative stress in chronic kidney disease — Potential therapeutic role of minerals, vitamins and plant-derived metabolites}, series = {International Journal of Molecular Sciences}, volume = {21}, journal = {International Journal of Molecular Sciences}, number = {1}, issn = {1422-0067}, doi = {10.3390/ijms21010263}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284998}, year = {2019}, abstract = {Chronic kidney disease (CKD) is a debilitating pathology with various causal factors, culminating in end stage renal disease (ESRD) requiring dialysis or kidney transplantation. The progression of CKD is closely associated with systemic inflammation and oxidative stress, which are responsible for the manifestation of numerous complications such as malnutrition, atherosclerosis, coronary artery calcification, heart failure, anemia and mineral and bone disorders, as well as enhanced cardiovascular mortality. In addition to conventional therapy with anti-inflammatory and antioxidative agents, growing evidence has indicated that certain minerals, vitamins and plant-derived metabolites exhibit beneficial effects in these disturbances. In the current work, we review the anti-inflammatory and antioxidant properties of various agents which could be of potential benefit in CKD/ESRD. However, the related studies were limited due to small sample sizes and short-term follow-up in many trials. Therefore, studies of several anti-inflammatory and antioxidant agents with long-term follow-ups are necessary.}, language = {en} } @article{VetrivelZhangEngeletal.2022, author = {Vetrivel, Sharmilee and Zhang, Ru and Engel, Mareen and Oßwald, Andrea and Watts, Deepika and Chen, Alon and Wielockx, Ben and Sbiera, Silviu and Reincke, Martin and Riester, Anna}, title = {Characterization of adrenal miRNA-based dysregulations in Cushing's syndrome}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {14}, issn = {1422-0067}, doi = {10.3390/ijms23147676}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284394}, year = {2022}, abstract = {MiRNAs are important epigenetic players with tissue- and disease-specific effects. In this study, our aim was to investigate the putative differential expression of miRNAs in adrenal tissues from different forms of Cushing's syndrome (CS). For this, miRNA-based next-generation sequencing was performed in adrenal tissues taken from patients with ACTH-independent cortisol-producing adrenocortical adenomas (CPA), from patients with ACTH-dependent pituitary Cushing's disease (CD) after bilateral adrenalectomy, and from control subjects. A confirmatory QPCR was also performed in adrenals from patients with other CS subtypes, such as primary bilateral macronodular hyperplasia and ectopic CS. Sequencing revealed significant differences in the miRNA profiles of CD and CPA. QPCR revealed the upregulated expression of miR-1247-5p in CPA and PBMAH (log2 fold change > 2.5, p < 0.05). MiR-379-5p was found to be upregulated in PBMAH and CD (log2 fold change > 1.8, p < 0.05). Analyses of miR-1247-5p and miR-379-5p expression in the adrenals of mice which had been exposed to short-term ACTH stimulation showed no influence on the adrenal miRNA expression profiles. For miRNA-specific target prediction, RNA-seq data from the adrenals of CPA, PBMAH, and control samples were analyzed with different bioinformatic platforms. The analyses revealed that both miR-1247-5p and miR-379-5p target specific genes in the WNT signaling pathway. In conclusion, this study identified distinct adrenal miRNAs as being associated with CS subtypes.}, language = {en} } @article{ZopfFreyKienitzetal.2017, author = {Zopf, Kathrin and Frey, Kathrin R. and Kienitz, Tina and Ventz, Manfred and Bauer, Britta and Quinkler, Marcus}, title = {\(Bcl\)I polymorphism of the glucocorticoid receptor and adrenal crisis in primary adrenal insufficiency}, series = {Endocrine Connections}, volume = {6}, journal = {Endocrine Connections}, number = {8}, doi = {10.1530/EC-17-0269}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173276}, pages = {685-691}, year = {2017}, abstract = {Context: Patients with primary adrenal insufficiency (PAI) or congenital adrenal hyperplasia (CAH) are at a high risk of adrenal crisis (AC). Glucocorticoid sensitivity is at least partially genetically determined by polymorphisms of the glucocorticoid receptor (GR). Objectives: To determine if a number of intercurrent illnesses and AC are associated with the GR gene polymorphism \(Bcl\)I in patients with PAI and CAH. Design and patients: This prospective, longitudinal study over 37.7 ± 10.1 months included 47 PAI and 25 CAH patients. During the study period, intercurrent illness episodes and AC were documented. Results: The study period covered 223 patient years in which 21 AC occurred (9.4 AC/100 pat years). There were no significant differences between \(Bcl\)I polymorphisms (CC (n=29), CG (n=34) and GG (n=9)) regarding BMI, hydrocortisone equivalent daily dose and blood pressure. We did not find a difference in the number of intercurrent illnesses/patient year among \(Bcl\)I polymorphisms (CC (1.5±1.4/pat year), CG (1.2±1.2/pat year) and GG (1.6±2.2/pat year)). The occurrence of AC was not significantly different among the homozygous (GG) genotype (32.5 AC/100 pat years), the CC genotype (6.7 AC/100 pat years) and the CG genotype (4.9 AC/100 pat years). Concomitant hypothyroidism was the highest in the GG genotype group (5/9), compared to others (CC (11/29) and CG (11/34)). Conclusions: Although sample sizes were relatively small and results should be interpreted with caution, this study suggests that the GR gene polymorphism \(Bcl\)I may not be associated with the frequencies of intercurrent illnesses and AC.}, language = {en} } @article{DischingerHeckelBischleretal.2021, author = {Dischinger, Ulrich and Heckel, Tobias and Bischler, Thorsten and Hasinger, Julia and K{\"o}nigsrainer, Malina and Schmitt-B{\"o}hrer, Angelika and Otto, Christoph and Fassnacht, Martin and Seyfried, Florian and Hankir, Mohammed Khair}, title = {Roux-en-Y gastric bypass and caloric restriction but not gut hormone-based treatments profoundly impact the hypothalamic transcriptome in obese rats}, series = {Nutrients}, volume = {14}, journal = {Nutrients}, number = {1}, issn = {2072-6643}, doi = {10.3390/nu14010116}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252392}, year = {2021}, abstract = {Background: The hypothalamus is an important brain region for the regulation of energy balance. Roux-en-Y gastric bypass (RYGB) surgery and gut hormone-based treatments are known to reduce body weight, but their effects on hypothalamic gene expression and signaling pathways are poorly studied. Methods: Diet-induced obese male Wistar rats were randomized into the following groups: RYGB, sham operation, sham + body weight-matched (BWM) to the RYGB group, osmotic minipump delivering PYY3-36 (0.1 mg/kg/day), liraglutide s.c. (0.4 mg/kg/day), PYY3-36 + liraglutide, and saline. All groups (except BWM) were kept on a free choice of high- and low-fat diets. Four weeks after interventions, hypothalami were collected for RNA sequencing. Results: While rats in the RYGB, BWM, and PYY3-36 + liraglutide groups had comparable reductions in body weight, only RYGB and BWM treatment had a major impact on hypothalamic gene expression. In these groups, hypothalamic leptin receptor expression as well as the JAK-STAT, PI3K-Akt, and AMPK signaling pathways were upregulated. No significant changes could be detected in PYY3-36 + liraglutide-, liraglutide-, and PYY-treated groups. Conclusions: Despite causing similar body weight changes compared to RYGB and BWM, PYY3-36 + liraglutide treatment does not impact hypothalamic gene expression. Whether this striking difference is favorable or unfavorable to metabolic health in the long term requires further investigation.}, language = {en} } @article{RiedmeierDecarolisHaubitzetal.2021, author = {Riedmeier, Maria and Decarolis, Boris and Haubitz, Imme and M{\"u}ller, Sophie and Uttinger, Konstantin and B{\"o}rner, Kevin and Reibetanz, Joachim and Wiegering, Armin and H{\"a}rtel, Christoph and Schlegel, Paul-Gerhardt and Fassnacht, Martin and Wiegering, Verena}, title = {Adrenocortical carcinoma in childhood: a systematic review}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {21}, issn = {2072-6694}, doi = {10.3390/cancers13215266}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248507}, year = {2021}, abstract = {Adrenocortical tumors are rare in children. This systematic review summarizes the published evidence on pediatric adrenocortical carcinoma (ACC) to provide a basis for a better understanding of the disease, investigate new molecular biomarkers and therapeutic targets, and define which patients may benefit from a more aggressive therapeutic approach. We included 137 studies with 3680 ACC patients (~65\% female) in our analysis. We found no randomized controlled trials, so this review mainly reflects retrospective data. Due to a specific mutation in the TP53 gene in ~80\% of Brazilian patients, that cohort was analyzed separately from series from other countries. Hormone analysis was described in 2569 of the 2874 patients (89\%). Most patients were diagnosed with localized disease, whereas 23\% had metastasis at primary diagnosis. Only 72\% of the patients achieved complete resection. In 334 children (23\%), recurrent disease was reported: 81\% — local recurrence, 19\% (n = 65) — distant metastases at relapse. Patients < 4 years old had a different distribution of tumor stages and hormone activity and better overall survival (p < 0.001). Although therapeutic approaches are typically multimodal, no consensus is available on effective standard treatments for advanced ACC. Thus, knowledge regarding pediatric ACC is still scarce and international prospective studies are needed to implement standardized clinical stratifications and risk-adapted therapeutic strategies.}, language = {en} } @article{MonteagudoMartinezLeandroGarciaetal.2021, author = {Monteagudo, Mar{\´i}a and Mart{\´i}nez, Paula and Leandro-Garc{\´i}a, Luis J. and Mart{\´i}nez-Montes, {\´A}ngel M. and Calsina, Bruna and Pulgar{\´i}n-Alfaro, Marta and D{\´i}az-Talavera, Alberto and Mellid, Sara and Let{\´o}n, Roc{\´i}o and Gil, Eduardo and P{\´e}rez-Mart{\´i}nez, Manuel and Meg{\´i}as, Diego and Torres-Ruiz, Ra{\´u}l and Rodriguez-Perales, Sandra and Gonz{\´a}lez, Patricia and Caleiras, Eduardo and Jim{\´e}nez-Villa, Scherezade and Roncador, Giovanna and {\´A}lvarez-Escol{\´a}, Cristina and Regojo, Rita M. and Calatayud, Mar{\´i}a and Guadalix, Sonsoles and Curr{\´a}s-Freixes, Maria and Rapizzi, Elena and Canu, Letizia and N{\"o}lting, Svenja and Remde, Hanna and Fassnacht, Martin and Bechmann, Nicole and Eisenhofer, Graeme and Mannelli, Massimo and Beuschlein, Felix and Quinkler, Marcus and Rodr{\´i}guez-Antona, Cristina and Casc{\´o}n, Alberto and Blasco, Mar{\´i}a A. and Montero-Conde, Cristina and Robledo, Mercedes}, title = {Analysis of telomere maintenance related genes reveals NOP10 as a new metastatic-risk marker in pheochromocytoma/paraganglioma}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {19}, issn = {2072-6694}, doi = {10.3390/cancers13194758}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246321}, year = {2021}, abstract = {One of the main problems we face with PPGL is the lack of molecular markers capable of predicting the development of metastases in patients. Telomere-related genes, such as TERT and ATRX, have been recently described in PPGL, supporting the association between the activation of immortalization mechanisms and disease progression. However, the contribution of other genes involving telomere preservation machinery has not been previously investigated. In this work, we aimed to analyze the prognostic value of a comprehensive set of genes involved in telomere maintenance. For this study, we collected 165 PPGL samples (97 non-metastatic/63 metastatic), genetically characterized, in which the expression of 29 genes of interest was studied by NGS. Three of the 29 genes studied, TERT, ATRX and NOP10, showed differential expression between metastatic and non-metastatic cases, and alterations in these genes were associated with a shorter time to progression, independent of SDHB-status. We studied telomere length by Q-FISH in patient samples and in an in vitro model. NOP10 overexpressing tumors displayed an intermediate-length telomere phenotype without ALT, and in vitro results suggest that NOP10 has a role in telomerase-dependent telomere maintenance. We also propose the implementation of NOP10 IHC to better stratify PPGL patients.}, language = {en} } @article{BothouSharmaOoetal.2021, author = {Bothou, Christina and Sharma, Ashish and Oo, Adrian and Kim, Baek and Perge, Pal and Igaz, Peter and Ronchi, Cristina L. and Shapiro, Igor and Hantel, Constanze}, title = {Novel insights into the molecular regulation of ribonucleotide reductase in adrenocortical carcinoma treatment}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {16}, issn = {2072-6694}, doi = {10.3390/cancers13164200}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245132}, year = {2021}, abstract = {Current systemic treatment options for patients with adrenocortical carcinomas (ACCs) are far from being satisfactory. DNA damage/repair mechanisms, which involve, e.g., ataxia-telangiectasia-mutated (ATM) and ataxia-telangiectasia/Rad3-related (ATR) protein signaling or ribonucleotide reductase subunits M1/M2 (RRM1/RRM2)-encoded ribonucleotide reductase (RNR) activation, commonly contribute to drug resistance. Moreover, the regulation of RRM2b, the p53-induced alternative to RRM2, is of unclear importance for ACC. Upon extensive drug screening, including a large panel of chemotherapies and molecular targeted inhibitors, we provide strong evidence for the anti-tumoral efficacy of combined gemcitabine (G) and cisplatin (C) treatment against the adrenocortical cell lines NCI-H295R and MUC-1. However, accompanying induction of RRM1, RRM2, and RRM2b expression also indicated developing G resistance, a frequent side effect in clinical patient care. Interestingly, this effect was partially reversed upon addition of C. We confirmed our findings for RRM2 protein, RNR-dependent dATP levels, and modulations of related ATM/ATR signaling. Finally, we screened for complementing inhibitors of the DNA damage/repair system targeting RNR, Wee1, CHK1/2, ATR, and ATM. Notably, the combination of G, C, and the dual RRM1/RRM2 inhibitor COH29 resulted in previously unreached total cell killing. In summary, we provide evidence that RNR-modulating therapies might represent a new therapeutic option for ACC.}, language = {en} } @article{SommerAmrBavendieketal.2022, author = {Sommer, Kim K. and Amr, Ali and Bavendiek, Udo and Beierle, Felix and Brunecker, Peter and Dathe, Henning and Eils, J{\"u}rgen and Ertl, Maximilian and Fette, Georg and Gietzelt, Matthias and Heidecker, Bettina and Hellenkamp, Kristian and Heuschmann, Peter and Hoos, Jennifer D. E. and Keszty{\"u}s, Tibor and Kerwagen, Fabian and Kindermann, Aljoscha and Krefting, Dagmar and Landmesser, Ulf and Marschollek, Michael and Meder, Benjamin and Merzweiler, Angela and Prasser, Fabian and Pryss, R{\"u}diger and Richter, Jendrik and Schneider, Philipp and St{\"o}rk, Stefan and Dieterich, Christoph}, title = {Structured, harmonized, and interoperable integration of clinical routine data to compute heart failure risk scores}, series = {Life}, volume = {12}, journal = {Life}, number = {5}, issn = {2075-1729}, doi = {10.3390/life12050749}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-275239}, year = {2022}, abstract = {Risk prediction in patients with heart failure (HF) is essential to improve the tailoring of preventive, diagnostic, and therapeutic strategies for the individual patient, and effectively use health care resources. Risk scores derived from controlled clinical studies can be used to calculate the risk of mortality and HF hospitalizations. However, these scores are poorly implemented into routine care, predominantly because their calculation requires considerable efforts in practice and necessary data often are not available in an interoperable format. In this work, we demonstrate the feasibility of a multi-site solution to derive and calculate two exemplary HF scores from clinical routine data (MAGGIC score with six continuous and eight categorical variables; Barcelona Bio-HF score with five continuous and six categorical variables). Within HiGHmed, a German Medical Informatics Initiative consortium, we implemented an interoperable solution, collecting a harmonized HF-phenotypic core data set (CDS) within the openEHR framework. Our approach minimizes the need for manual data entry by automatically retrieving data from primary systems. We show, across five participating medical centers, that the implemented structures to execute dedicated data queries, followed by harmonized data processing and score calculation, work well in practice. In summary, we demonstrated the feasibility of clinical routine data usage across multiple partner sites to compute HF risk scores. This solution can be extended to a large spectrum of applications in clinical care.}, language = {en} } @article{RonchiAltieri2022, author = {Ronchi, Cristina L. and Altieri, Barbara}, title = {Special issue: Present and future of personalised medicine for endocrine cancers}, series = {Journal of Personalized Medicine}, volume = {12}, journal = {Journal of Personalized Medicine}, number = {5}, issn = {2075-4426}, doi = {10.3390/jpm12050710}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270705}, year = {2022}, abstract = {No abstract available}, language = {en} } @article{WiegeringRiedmeierThompsonetal.2022, author = {Wiegering, Verena and Riedmeier, Maria and Thompson, Lester D. R. and Virgone, Calogero and Redlich, Antje and Kuhlen, Michaela and Gultekin, Melis and Yalcin, Bilgehan and Decarolis, Boris and H{\"a}rtel, Christoph and Schlegel, Paul-Gerhardt and Fassnacht, Martin and Timmermann, Beate}, title = {Radiotherapy for pediatric adrenocortical carcinoma - Review of the literature}, series = {Clinical and Translational Radiation Oncology}, volume = {35}, journal = {Clinical and Translational Radiation Oncology}, doi = {10.1016/j.ctro.2022.05.003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300472}, pages = {56-63}, year = {2022}, abstract = {Background and purpose Pediatric adrenocortical carcinoma (pACC) is a rare disease with poor prognosis. Publications on radiotherapy (RT) are scarce. This review summarizes the current data on RT for pACC and possibly provides first evidence to justify its use in this setting. Materials and methods We searched the PubMed and Embase database for manuscripts regarding RT for pACC. Results We included 17 manuscripts reporting on 76 patients treated with RT, after screening 2961 references and 269 full articles. In addition, we added data of 4 unreported pACC patients treated by co-authors. All reports based on retrospective data. Median age at first diagnosis was 11.1 years (70\% female); 78\% of patients presented with hormonal activity. RT was mostly performed for curative intent (78\%). 88\% of RT were administered during primary therapy. The site of RT was predominantly the local tumor bed (76\%). Doses of RT ranged from 15 to 62 Gy (median 50 Gy). Information on target volumes or fractionation were lacking. Median follow-up was 6,9 years and 64\% of the patients died of disease, with 33\% alive without disease. In 16 of 48 patients with available follow-up data after adjuvant RT (33\%) no recurrence was reported and in 3 of 9 patients palliative RT seemed to induce some benefit for the patient. Conclusions Our first systematic review on RT for pACC provides too few data for any general recommendation, but adjuvant RT in patients with high risk might be considered. International collaborative studies are urgently needed to establish better evidence on the role of RT in this rare malignancy.}, language = {en} } @article{SalingerHuLiuetal.2018, author = {Salinger, Tim and Hu, Kai and Liu, Dan and Taleh, Scharoch and Herrmann, Sebastian and Oder, Daniel and Gensler, Daniel and M{\"u}ntze, Jonas and Ertl, Georg and Lorenz, Kristina and Frantz, Stefan and Weidemann, Frank and Nordbeck, Peter}, title = {Association between Comorbidities and Progression of Transvalvular Pressure Gradients in Patients with Moderate and Severe Aortic Valve Stenosis}, series = {Cardiology Research and Practice}, journal = {Cardiology Research and Practice}, doi = {10.1155/2018/3713897}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-227291}, pages = {3713897, 1-7}, year = {2018}, abstract = {Background. Fast progression of the transaortic mean gradient (P-mean) is relevant for clinical decision making of valve replacement in patients with moderate and severe aortic stenosis (AS) patients. However, there is currently little knowledge regarding the determinants affecting progression of transvalvular gradient in AS patients. Methods. This monocentric retrospective study included consecutive patients presenting with at least two transthoracic echocardiography examinations covering a time interval of one year or more between April 2006 and February 2016 and diagnosed as moderate or severe aortic stenosis at the final echocardiographic examination. Laboratory parameters, medication, and prevalence of eight known cardiac comorbidities and risk factors (hypertension, diabetes, coronary heart disease, peripheral artery occlusive disease, cerebrovascular disease, renal dysfunction, body mass index >= 30 Kg/m(2), and history of smoking) were analyzed. Patients were divided into slow (P-mean < 5 mmHg/year) or fast (P-mean >= 5 mmHg/year) progression groups. Results. A total of 402 patients (mean age 78 +/- 9.4 years, 58\% males) were included in the study. Mean follow-up duration was 3.4 +/- 1.9 years. The average number of cardiac comorbidities and risk factors was 3.1 +/- 1.6. Average number of cardiac comorbidities and risk factors was higher in patients in slow progression group than in fast progression group (3.3 +/- 1.5 vs 2.9 +/- 1.7; P = 0.036). Patients in slow progression group had more often coronary heart disease (49.2\% vs 33.6\%; P = 0.003) compared to patients in fast progression group. LDL-cholesterol values were lower in the slow progression group (100 +/- 32.6 mg/dl vs 110.8 +/- 36.6 mg/dl; P = 0.005). Conclusion. These findings suggest that disease progression of aortic valve stenosis is faster in patients with fewer cardiac comorbidities and risk factors, especially if they do not have coronary heart disease. Further prospective studies are warranted to investigate the outcome of patients with slow versus fast progression of transvalvular gradient with regards to comorbidities and risk factors.}, language = {en} } @article{RiceEikemaMarshetal.2019, author = {Rice, Carmel and Eikema, Dirk-Jan and Marsh, Judith C. W. and Knol, Cora and Hebert, Kyle and Putter, Hein and Peterson, Eefke and Deeg, H. Joachim and Halkes, Stijn and Pidala, Joseph and Anderlini, Paolo and Tischer, Johanna and Kroger, Nicolaus and McDonald, Andrew and Antin, Joseph H. and Schaap, Nicolaas P. and Hallek, Michael and Einsele, Herman and Mathews, Vikram and Kapoor, Neena and Boelens, Jaap-Jan and Mufti, Ghulam J. and Potter, Victoria and de la Tour, R{\´e}gis Pefault and Eapen, Mary and Dufour, Carlo}, title = {Allogeneic Hematopoietic Cell Transplantation in Patients Aged 50 Years or Older with Severe Aplastic Anemia}, series = {Biology of Blood and Marrow Transplantation}, volume = {25}, journal = {Biology of Blood and Marrow Transplantation}, number = {3}, doi = {10.1016/j.bbmt.2018.08.029}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225229}, pages = {488-495}, year = {2019}, abstract = {We report on 499 patients with severe aplastic anemia aged >= 50 years who underwent hematopoietic cell transplantation (HCT) from HLA-matched sibling (n = 275, 55\%) or HLA-matched (8/8) unrelated donors (n =187, 37\%) between 2005 and 2016. The median age at HCT was 57.8 years; 16\% of patients were 65 to 77 years old. Multivariable analysis confirmed higher mortality risks for patients with performance score less than 90\% (hazard ratio HR], 1.41; 95\% confidence interval [CI], 1.03 to 1.92; P= .03) and after unrelated donor transplantation (HR, 1.47; 95\% CI,1 to 2.16; P = .05). The 3-year probabilities of survival for patients with performance scores of 90 to 100 and less than 90 after HLA-matched sibling transplant were 66\% (range, 57\% to 75\%) and 57\% (range, 47\% to 76\%), respectively. The corresponding probabilities after HLA-matched unrelated donor transplantation were 57\% (range, 48\% to 67\%) and 48\% (range, 36\% to 59\%). Age at transplantation was not associated with survival, but grades II to IV acute graft-versus-host disease (GVHD) risks were higher for patients aged 65 years or older (subdistribution HR [sHR], 1.7; 95\% confidence interval, 1.07 to 2.72; P= .026). Chronic GVHD was lower with the GVHD prophylaxis regimens calcineurin inhibitor (CNI) + methotrexate (sHR, .52; 95\% CI, .33 to .81; P= .004) and CNI alone or with other agents (sHR, .27; 95\% CI, .14 to .53; P < .001) compared with CNI + mycophenolate. Although donor availability is modifiable only to a limited extent, choice of GVHD prophylaxis and selection of patients with good performance scores are key for improved outcomes. (C) 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.}, language = {en} } @article{KoehlerAdamFussetal.2022, author = {Koehler, Viktoria Florentine and Adam, Pia and Fuss, Carmina Teresa and Jiang, Linmiao and Berg, Elke and Frank-Raue, Karin and Raue, Friedhelm and Hoster, Eva and Kn{\"o}sel, Thomas and Schildhaus, Hans-Ulrich and Negele, Thomas and Siebolts, Udo and Lorenz, Kerstin and Allelein, Stephanie and Schott, Matthias and Spitzweg, Christine and Kroiss, Matthias}, title = {Treatment of RET-positive advanced medullary thyroid cancer with multi-tyrosine kinase inhibitors — a retrospective multi-center registry analysis}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {14}, issn = {2072-6694}, doi = {10.3390/cancers14143405}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-281776}, year = {2022}, abstract = {Background: RET (rearranged during transfection) variants are the most prevalent oncogenic events in medullary thyroid cancer (MTC). In advanced disease, multi-tyrosine kinase inhibitors (MKIs) cabozantinib and vandetanib are the approved standard treatment irrespective of RET status. The actual outcome of patients with RET-positive MTC treated with MKIs is ill described. Methods: We here retrospectively determined the RET oncogene variant status with a targeted DNA Custom Panel in a prospectively collected cohort of 48 patients with advanced MTC treated with vandetanib and/or cabozantinib at four German referral centers. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method. Results: In total, 44/48 (92\%) patients had germline or somatic RET variants. The M918T variant was found in 29/44 (66\%) cases. In total, 2/32 (6\%) patients with a somatic RET variant had further somatic variants, while in 1/32 (3\%) patient with a germline RET variant, additional variants were found. Only 1/48 (2\%) patient had a pathogenic HRAS variant, and no variants were found in 3 cases. In first-line treatment, the median OS was 53 (95\% CI (95\% confidence interval), 32-NR (not reached); n = 36), and the median PFS was 21 months (12-39; n = 33) in RET-positive MTC patients. In second-line treatment, the median OS was 18 (13-79; n = 22), and the median PFS was 3.5 months (2-14; n = 22) in RET-positive cases. Conclusions: RET variants were highly prevalent in patients with advanced MTC. The treatment results in RET-positive cases were similar to those reported in unselected cohorts.}, language = {en} } @article{TraubOttoSelletal.2022, author = {Traub, Jan and Otto, Markus and Sell, Roxane and G{\"o}pfert, Dennis and Homola, Gy{\"o}rgy and Steinacker, Petra and Oeckl, Patrick and Morbach, Caroline and Frantz, Stefan and Pham, Mirko and St{\"o}rk, Stefan and Stoll, Guido and Frey, Anna}, title = {Serum phosphorylated tau protein 181 and neurofilament light chain in cognitively impaired heart failure patients}, series = {Alzheimer's Research \& Therapy}, volume = {14}, journal = {Alzheimer's Research \& Therapy}, doi = {10.1186/s13195-022-01087-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300515}, year = {2022}, abstract = {Background Chronic heart failure (HF) is known to increase the risk of developing Alzheimer's dementia significantly. Thus, detecting and preventing mild cognitive impairment, which is common in patients with HF, is of great importance. Serum biomarkers are increasingly used in neurological disorders for diagnostics, monitoring, and prognostication of disease course. It remains unclear if neuronal biomarkers may help detect cognitive impairment in this high-risk population. Also, the influence of chronic HF and concomitant renal dysfunction on these biomarkers is not well understood. Methods Within the monocentric Cognition.Matters-HF study, we quantified the serum levels of phosphorylated tau protein 181 (pTau) and neurofilament light chain (NfL) of 146 extensively phenotyped chronic heart failure patients (aged 32 to 85 years; 15.1\% women) using ultrasensitive bead-based single-molecule immunoassays. The clinical work-up included advanced cognitive testing and cerebral magnetic resonance imaging (MRI). Results Serum concentrations of NfL ranged from 5.4 to 215.0 pg/ml (median 26.4 pg/ml) and of pTau from 0.51 to 9.22 pg/ml (median 1.57 pg/ml). We detected mild cognitive impairment (i.e., T-score < 40 in at least one cognitive domain) in 60\% of heart failure patients. pTau (p = 0.014), but not NfL, was elevated in this group. Both NfL (ρ = - 0.21; p = 0.013) and pTau (ρ = - 0.25; p = 0.002) related to the cognitive domain visual/verbal memory, as well as white matter hyperintensity volume and cerebral and hippocampal atrophy. In multivariable analysis, both biomarkers were independently influenced by age (T = 4.6 for pTau; T = 5.9 for NfL) and glomerular filtration rate (T = - 2.4 for pTau; T = - 3.4 for NfL). Markers of chronic heart failure, left atrial volume index (T = 4.6) and NT-proBNP (T = 2.8), were further cardiological determinants of pTau and NfL, respectively. In addition, pTau was also strongly affected by serum creatine kinase levels (T = 6.5) and ferritin (T = - 3.1). Conclusions pTau and NfL serum levels are strongly influenced by age-dependent renal and cardiac dysfunction. These findings point towards the need for longitudinal examinations and consideration of frequent comorbidities when using neuronal serum biomarkers.}, language = {en} } @article{ReiterDemirbasSchmalzingetal.2022, author = {Reiter, Theresa and Demirbas, Senem and Schmalzing, Marc and Voelker, Wolfram and Bauer, Wolfgang R. and G{\"u}der, G{\"u}lmisal}, title = {CMR detects extensive intracavitary thrombi as solitary clinical presentation of Antiphospholipid Syndrome: A case report}, series = {Clinical Case Reports}, volume = {10}, journal = {Clinical Case Reports}, number = {11}, issn = {2050-0904}, doi = {10.1002/ccr3.6568}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312766}, year = {2022}, abstract = {Intracavitary thrombi are an important differential diagnosis of cardiac masses. Cardiac magnetic resonance imaging (CMR) allows their non-invasive characterization. This case highlights extensive cardiac thrombi detected by CMR as solitary presentation of antiphospholipid syndrome.}, language = {en} } @article{WagenhaeuserRickertSommeretal.2022, author = {Wagenh{\"a}user, Laura and Rickert, Vanessa and Sommer, Claudia and Wanner, Christoph and Nordbeck, Peter and Rost, Simone and {\"U}{\c{c}}eyler, Nurcan}, title = {X-chromosomal inactivation patterns in women with Fabry disease}, series = {Molecular Genetics \& Genomic Medicine}, volume = {10}, journal = {Molecular Genetics \& Genomic Medicine}, number = {9}, doi = {10.1002/mgg3.2029}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312795}, year = {2022}, abstract = {Background Although Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the α-galactosidase A gene (GLA), women may develop severe symptoms. We investigated X-chromosomal inactivation patterns (XCI) as a potential determinant of symptom severity in FD women. Patients and Methods We included 95 women with mutations in GLA (n = 18 with variants of unknown pathogenicity) and 50 related men, and collected mouth epithelial cells, venous blood, and skin fibroblasts for XCI analysis using the methylation status of the androgen receptor gene. The mutated X-chromosome was identified by comparison of samples from relatives. Patients underwent genotype categorization and deep clinical phenotyping of symptom severity. Results 43/95 (45\%) women carried mutations categorized as classic. The XCI pattern was skewed (i.e., ≥75:25\% distribution) in 6/87 (7\%) mouth epithelial cell samples, 31/88 (35\%) blood samples, and 9/27 (33\%) skin fibroblast samples. Clinical phenotype, α-galactosidase A (GAL) activity, and lyso-Gb3 levels did not show intergroup differences when stratified for X-chromosomal skewing and activity status of the mutated X-chromosome. Conclusions X-inactivation patterns alone do not reliably reflect the clinical phenotype of women with FD when investigated in biomaterial not directly affected by FD. However, while XCI patterns may vary between tissues, blood frequently shows skewing of XCI patterns.}, language = {en} } @article{PrietoGarciaHartmannReisslandetal.2022, author = {Prieto-Garcia, Cristian and Hartmann, Oliver and Reissland, Michaela and Braun, Fabian and Bozkurt, S{\"u}leyman and Pahor, Nikolett and Fuss, Carmina and Schirbel, Andreas and Sch{\"u}lein-V{\"o}lk, Christina and Buchberger, Alexander and Calzado Canale, Marco A. and Rosenfeldt, Mathias and Dikic, Ivan and M{\"u}nch, Christian and Diefenbacher, Markus E.}, title = {USP28 enables oncogenic transformation of respiratory cells, and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K}, series = {Molecular Oncology}, volume = {16}, journal = {Molecular Oncology}, number = {17}, doi = {10.1002/1878-0261.13217}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312777}, pages = {3082-3106}, year = {2022}, abstract = {Oncogenic transformation of lung epithelial cells is a multistep process, frequently starting with the inactivation of tumour suppressors and subsequent development of activating mutations in proto-oncogenes, such as members of the PI3K or MAPK families. Cells undergoing transformation have to adjust to changes, including altered metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors. Here, we report that the ubiquitin carboxyl-terminal hydrolase 28 (USP28) enables oncogenic reprogramming by regulating the protein abundance of proto-oncogenes such as c-JUN, c-MYC, NOTCH and ∆NP63 at early stages of malignant transformation. USP28 levels are increased in cancer compared with in normal cells due to a feed-forward loop, driven by increased amounts of oncogenic transcription factors such as c-MYC and c-JUN. Irrespective of oncogenic driver, interference with USP28 abundance or activity suppresses growth and survival of transformed lung cells. Furthermore, inhibition of USP28 via a small-molecule inhibitor resets the proteome of transformed cells towards a 'premalignant' state, and its inhibition synergizes with clinically established compounds used to target EGFR\(^{L858R}\)-, BRAF\(^{V600E}\)- or PI3K\(^{H1047R}\)-driven tumour cells. Targeting USP28 protein abundance at an early stage via inhibition of its activity is therefore a feasible strategy for the treatment of early-stage lung tumours, and the observed synergism with current standard-of-care inhibitors holds the potential for improved targeting of established tumours.}, language = {en} } @article{KoepingShehataDielerSchneideretal.2018, author = {K{\"o}ping, Maria and Shehata-Dieler, Wafaa and Schneider, Dieter and Cebulla, Mario and Oder, Daniel and M{\"u}ntze, Jonas and Nordbeck, Peter and Wanner, Christoph and Hagen, Rudolf and Schraven, Sebastian P.}, title = {Characterization of vertigo and hearing loss in patients with Fabry disease}, series = {Orphanet Journal of Rare Diseases}, volume = {13}, journal = {Orphanet Journal of Rare Diseases}, doi = {10.1186/s13023-018-0882-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222818}, year = {2018}, abstract = {Background Fabry Disease (FD) is an X-linked hereditary lysosomal storage disorder which leads to a multisystemic intralysosomal accumulation of globotriaosylceramid (Gb3). Besides prominent renal and cardiac organ involvement, patients commonly complain about vestibulocochlear symptoms like high-frequency hearing loss, tinnitus and vertigo. However, comprehensive data especially on vertigo remain scarce. The aim of this study was to examine the prevalence and characteristics of vertigo and hearing loss in patients with FD, depending on renal and cardiac parameters and get hints about the site and the pattern of the lesions. Methods Single-center study with 57 FD patients. Every patient underwent an oto-rhino-laryngological examination as well as videonystagmography and vestibular evoked myogenic potentials (VEMPs) and audiological measurements using pure tone audiometry and auditory brainstem response audiometry (ABR). Renal function was measured by eGFR, cardiac impairment was graduated by NYHA class. Results More than one out of three patients (35.1\%) complained about hearing loss, 54.4\% about vertigo and 28.1\% about both symptom. In 74\% a sensorineural hearing loss of at least 25 dB was found, ABR could exclude any retrocochlear lesion. Caloric testing showed abnormal values in 71.9\%, VEMPs were pathological in 68\%. A correlation between the side or the shape of hearing loss and pathological vestibular testing could not be revealed. Conclusions Hearing loss and vertigo show a high prevalence in FD. While hearing loss seems due to a cochlear lesion, peripheral vestibular as well as central nervous pathologies cause vertigo. Thus, both the site of lesion and the pathophysiological patterns seem to differ.}, language = {en} } @article{TraubOttoSelletal.2022, author = {Traub, Jan and Otto, Markus and Sell, Roxane and Homola, Gy{\"o}rgy A. and Steinacker, Petra and Oeckl, Patrick and Morbach, Caroline and Frantz, Stefan and Pham, Mirko and St{\"o}rk, Stefan and Stoll, Guido and Frey, Anna}, title = {Serum glial fibrillary acidic protein indicates memory impairment in patients with chronic heart failure}, series = {ESC Heart Failure}, volume = {9}, journal = {ESC Heart Failure}, number = {4}, doi = {10.1002/ehf2.13986}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312736}, pages = {2626-2634}, year = {2022}, abstract = {Aims Cognitive dysfunction occurs frequently in patients with heart failure (HF), but early detection remains challenging. Serum glial fibrillary acidic protein (GFAP) is an emerging biomarker of cognitive decline in disorders of primary neurodegeneration such as Alzheimer's disease. We evaluated the utility of serum GFAP as a biomarker for cognitive dysfunction and structural brain damage in patients with stable chronic HF. Methods and results Using bead-based single molecule immunoassays, we quantified serum levels of GFAP in patients with HF participating in the prospective Cognition.Matters-HF study. Participants were extensively phenotyped, including cognitive testing of five separate domains and magnetic resonance imaging (MRI) of the brain. Univariable and multivariable models, also accounting for multiple testing, were run. One hundred and forty-six chronic HF patients with a mean age of 63.8 ± 10.8 years were included (15.1\% women). Serum GFAP levels (median 246 pg/mL, quartiles 165, 384 pg/mL; range 66 to 1512 pg/mL) did not differ between sexes. In the multivariable adjusted model, independent predictors of GFAP levels were age (T = 5.5; P < 0.001), smoking (T = 3.2; P = 0.002), estimated glomerular filtration rate (T = -4.7; P < 0.001), alanine aminotransferase (T = -2.1; P = 0.036), and the left atrial end-systolic volume index (T = 3.4; P = 0.004). NT-proBNP but not serum GFAP explained global cerebral atrophy beyond ageing. However, serum GFAP levels were associated with the cognitive domain visual/verbal memory (T = -3.0; P = 0.003) along with focal hippocampal atrophy (T = 2.3; P = 0.025). Conclusions Serum GFAP levels are affected by age, smoking, and surrogates of the severity of HF. The association of GFAP with memory dysfunction suggests that astroglial pathologies, which evade detection by conventional MRI, may contribute to memory loss beyond ageing in patients with chronic HF.}, language = {en} } @article{LauUeceylerCairnsetal.2022, author = {Lau, Kolja and {\"U}{\c{c}}eyler, Nurcan and Cairns, Tereza and Lorenz, Lora and Sommer, Claudia and Schindeh{\"u}tte, Magnus and Amann, Kerstin and Wanner, Christoph and Nordbeck, Peter}, title = {Gene variants of unknown significance in Fabry disease: Clinical characteristics of c.376AG (p.Ser126Gly)}, series = {Molecular Genetics \& Genomic Medicine}, volume = {10}, journal = {Molecular Genetics \& Genomic Medicine}, number = {5}, doi = {10.1002/mgg3.1912}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312817}, year = {2022}, abstract = {Background Anderson-Fabry disease (FD) is an X-linked lysosomal storage disorder with varying organ involvement and symptoms, depending on the underlying mutation in the alpha-galactosidase A gene (HGNC: GLA). With genetic testing becoming more readily available, it is crucial to precisely evaluate pathogenicity of each genetic variant, in order to determine whether there is or might be not a need for FD-specific therapy in affected patients and relatives at the time point of presentation or in the future. Methods This case series investigates the clinical impact of the specific GLA gene variant c.376A>G (p.Ser126Gly) in five (one heterozygous and one homozygous female, three males) individuals from different families, who visited our center between 2009 and 2021. Comprehensive neurological, nephrological and cardiac examinations were performed in all cases. One patient received a follow-up examination after 12 years. Results Index events leading to suspicion of FD were mainly unspecific neurological symptoms. However, FD-specific biomarkers, imaging examinations (i.e., brain MRI, heart MRI), and tissue-specific diagnostics, including kidney and skin biopsies, did not reveal evidence for FD-specific symptoms or organ involvement but showed normal results in all cases. This includes findings from 12-year follow-up in one patient with renal biopsy. Conclusion These findings suggest that p.Ser126Gly represents a benign GLA gene variant which per se does not cause FD. Precise clinical evaluation in individuals diagnosed with genetic variations of unknown significance should be performed to distinguish common symptoms broadly prevalent in the general population from those secondary to FD.}, language = {en} } @article{JendretzkiHennigerSchiffmannetal.2022, author = {Jendretzki, Julia and Henniger, Dorothea and Schiffmann, Lisa and Wolz, Constanze and Kollikowski, Anne and Meining, Alexander and Einsele, Hermann and Winkler, Marcela and L{\"o}ffler, Claudia}, title = {Every fifth patient suffered a high nutritional risk — Results of a prospective patient survey in an oncological outpatient center}, series = {Frontiers in Nutrition}, volume = {9}, journal = {Frontiers in Nutrition}, issn = {2296-861X}, doi = {10.3389/fnut.2022.1033265}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-311284}, year = {2022}, abstract = {Introduction Malnutrition in cancer patients often remains undetected and underestimated in clinical practice despite studies revealing prevalences from 20 to 70\%. Therefore, this study aimed to identify patient groups exposed to an increased nutritional risk in a university oncological outpatient center. Methods Between May 2017 and January 2018 we screened oncological patients there using the malnutrition universal screening tool (MUST). Qualitative data were collected by a questionnaire to learn about patients' individual information needs and changes in patients' diets and stressful personal nutrition restrictions. Results We included 311 patients with various cancers. 20.3\% (n = 63) were found to be at high risk of malnutrition, 16.4\% (n = 51) at moderate risk despite a mean body mass index (BMI) of 26.5 ± 4.7 kg/m2. The average age was 62.7 (± 11.8) with equal gender distribution (52\% women, n = 162). In 94.8\% (n = 295) unintended weight loss led to MUST scoring. Patients with gastrointestinal tumors (25\%, n = 78) and patients >65 years (22\%, n = 68) were at higher risk. Furthermore, there was a significant association between surgery or chemotherapy within six months before survey and a MUST score ≥2 (OR = 3.6). Taste changes, dysphagia, and appetite loss were also particular risk factors (OR = 2.3-3.2). Young, female and normal-weight patients showed most interest in nutrition in cancer. However, only 38\% (n = 118) had a nutritional counseling. Conclusion This study confirms that using the MUST score is a valid screening procedure to identify outpatients at risk of developing malnutrition. Here one in five was at high risk, but only 1\% would have been detected by BMI alone. Therefore, an ongoing screening procedure with meaningful parameters should be urgently implemented into the clinical routine of cancer outpatients as recommended in international guidelines.}, language = {en} } @article{IsbernerGesierichBalakirouchenaneetal.2022, author = {Isberner, Nora and Gesierich, Anja and Balakirouchenane, David and Schilling, Bastian and Aghai-Trommeschlaeger, Fatemeh and Zimmermann, Sebastian and Kurlbaum, Max and Puszkiel, Alicja and Blanchet, Benoit and Klinker, Hartwig and Scherf-Clavel, Oliver}, title = {Monitoring of dabrafenib and trametinib in serum and self-sampled capillary blood in patients with BRAFV600-mutant melanoma}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {19}, issn = {2072-6694}, doi = {10.3390/cancers14194566}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288109}, year = {2022}, abstract = {Simple Summary In melanoma patients treated with dabrafenib and trametinib, dose reductions and treatment discontinuations related to adverse events (AE) occur frequently. However, the associations between patient characteristics, AE, and exposure are unclear. Our prospective study analyzed serum (hydroxy-)dabrafenib and trametinib exposure and investigated its association with toxicity and patient characteristics. Additionally, the feasibility of at-home sampling of capillary blood was assessed, and a model to convert capillary blood concentrations to serum concentrations was developed. (Hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or AE. Co-medication with P-glycoprotein inducers was associated with lower trough concentrations of trametinib but not (hydroxy-)dabrafenib. The applicability of the self-sampling of capillary blood was demonstrated. Our conversion model was adequate for estimating serum exposure from micro-samples. The monitoring of dabrafenib and trametinib may be useful for dose modification and can be optimized by at-home sampling and our new conversion model. Abstract Patients treated with dabrafenib and trametinib for BRAF\(^{V600}\)-mutant melanoma often experience dose reductions and treatment discontinuations. Current knowledge about the associations between patient characteristics, adverse events (AE), and exposure is inconclusive. Our study included 27 patients (including 18 patients for micro-sampling). Dabrafenib and trametinib exposure was prospectively analyzed, and the relevant patient characteristics and AE were reported. Their association with the observed concentrations and Bayesian estimates of the pharmacokinetic (PK) parameters of (hydroxy-)dabrafenib and trametinib were investigated. Further, the feasibility of at-home sampling of capillary blood was assessed. A population pharmacokinetic (popPK) model-informed conversion model was developed to derive serum PK parameters from self-sampled capillary blood. Results showed that (hydroxy-)dabrafenib or trametinib exposure was not associated with age, sex, body mass index, or toxicity. Co-medication with P-glycoprotein inducers was associated with significantly lower trough concentrations of trametinib (p = 0.027) but not (hydroxy-)dabrafenib. Self-sampling of capillary blood was feasible for use in routine care. Our conversion model was adequate for estimating serum PK parameters from micro-samples. Findings do not support a general recommendation for monitoring dabrafenib and trametinib but suggest that monitoring can facilitate making decisions about dosage adjustments. To this end, micro-sampling and the newly developed conversion model may be useful for estimating precise PK parameters.}, language = {en} } @article{TraubGrondeyGassenmaieretal.2022, author = {Traub, Jan and Grondey, Katja and Gassenmaier, Tobias and Schmitt, Dominik and Fette, Georg and Frantz, Stefan and Boivin-Jahns, Val{\´e}rie and Jahns, Roland and St{\"o}rk, Stefan and Stoll, Guido and Reiter, Theresa and Hofmann, Ulrich and Weber, Martin S. and Frey, Anna}, title = {Sustained increase in serum glial fibrillary acidic protein after first ST-elevation myocardial infarction}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {18}, issn = {1422-0067}, doi = {10.3390/ijms231810304}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288261}, year = {2022}, abstract = {Acute ischemic cardiac injury predisposes one to cognitive impairment, dementia, and depression. Pathophysiologically, recent positron emission tomography data suggest astroglial activation after experimental myocardial infarction (MI). We analyzed peripheral surrogate markers of glial (and neuronal) damage serially within 12 months after the first ST-elevation MI (STEMI). Serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were quantified using ultra-sensitive molecular immunoassays. Sufficient biomaterial was available from 45 STEMI patients (aged 28 to 78 years, median 56 years, 11\% female). The median (quartiles) of GFAP was 63.8 (47.0, 89.9) pg/mL and of NfL 10.6 (7.2, 14.8) pg/mL at study entry 0-4 days after STEMI. GFAP after STEMI increased in the first 3 months, with a median change of +7.8 (0.4, 19.4) pg/mL (p = 0.007). It remained elevated without further relevant increases after 6 months (+11.7 (0.6, 23.5) pg/mL; p = 0.015), and 12 months (+10.3 (1.5, 22.7) pg/mL; p = 0.010) compared to the baseline. Larger relative infarction size was associated with a higher increase in GFAP (ρ = 0.41; p = 0.009). In contrast, NfL remained unaltered in the course of one year. Our findings support the idea of central nervous system involvement after MI, with GFAP as a potential peripheral biomarker of chronic glial damage as one pathophysiologic pathway.}, language = {en} } @article{DetomasRitzelNasiKordhishtietal.2022, author = {Detomas, Mario and Ritzel, Katrin and Nasi-Kordhishti, Isabella and Wolfsberger, Stefan and Quinkler, Marcus and Losa, Marco and Tr{\"o}ger, Viola and Kroiss, Matthias and Fassnacht, Martin and Vila, Greisa and Honegger, J{\"u}rgen Bernd and Reincke, Martin and Deutschbein, Timo}, title = {Outcome of CRH stimulation test and overnight 8 mg dexamethasone suppression test in 469 patients with ACTH-dependent Cushing's syndrome}, series = {Frontiers in Endocrinology}, volume = {13}, journal = {Frontiers in Endocrinology}, issn = {1664-2392}, doi = {10.3389/fendo.2022.955945}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-289450}, year = {2022}, abstract = {Objective To evaluate diagnostic accuracy of the corticotropin-releasing hormone (CRH) stimulation test and the overnight 8 mg dexamethasone suppression test (DST) for the differentiation of Cushing's disease (CD) and ectopic Cushing's syndrome (ECS). Methods Retrospective study in 6 European centers. Inclusion criteria: patients with a) overt adrenocorticotropin (ACTH)-dependent Cushing's syndrome at the time of dynamic testing, b) histopathological confirmed tumors and/or c) postoperative biochemical remission and/or adrenal insufficiency. Optimal cut-offs were calculated via receiver operating characteristic (ROC) analysis using CD as reference. Results 469 patients were analyzed [78\% females; median age 43 years (IQR 19)]. CRH test and overnight 8 mg DST were performed in 420 [CD, n=394 (94\%); ECS, n=26 (6\%)] and 237 patients [228 CD (96\%), 9 ECS (4\%)]. Both tests were performed in 205 patients (44\%). The post-CRH \%-increase at 30 minutes of both ACTH (cut-off ≥31\%, sensitivity 83\%, specificity 85\%, AUC 0.81) and cortisol (cut-off ≥12\%, sensitivity 82\%, specificity 89\%, AUC 0.86) discriminated best between CD and ECS. A test duration of >60 minutes did not improve diagnostic performance of the CRH test. The optimal cortisol cut-off for the \%-suppression during the 8 mg DST was ≥55\% (sensitivity 80\%, specificity 78\%, AUC 0.75). Conclusion The CRH test has equivalent sensitivity but higher specificity than the 8 mg DST and is therefore the test of first choice. The diagnostic outcome of ACTH and cortisol is well comparable, however, sampling beyond 60 minutes post-CRH does not provide diagnostic benefits.}, language = {en} } @article{TolstikAliGuoetal.2022, author = {Tolstik, Elen and Ali, Nairveen and Guo, Shuxia and Ebersbach, Paul and M{\"o}llmann, Dorothe and Arias-Loza, Paula and Dierks, Johann and Schuler, Irina and Freier, Erik and Debus, J{\"o}rg and Baba, Hideo A. and Nordbeck, Peter and Bocklitz, Thomas and Lorenz, Kristina}, title = {CARS imaging advances early diagnosis of cardiac manifestation of Fabry disease}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {10}, issn = {1422-0067}, doi = {10.3390/ijms23105345}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284427}, year = {2022}, abstract = {Vibrational spectroscopy can detect characteristic biomolecular signatures and thus has the potential to support diagnostics. Fabry disease (FD) is a lipid disorder disease that leads to accumulations of globotriaosylceramide in different organs, including the heart, which is particularly critical for the patient's prognosis. Effective treatment options are available if initiated at early disease stages, but many patients are late- or under-diagnosed. Since Coherent anti-Stokes Raman (CARS) imaging has a high sensitivity for lipid/protein shifts, we applied CARS as a diagnostic tool to assess cardiac FD manifestation in an FD mouse model. CARS measurements combined with multivariate data analysis, including image preprocessing followed by image clustering and data-driven modeling, allowed for differentiation between FD and control groups. Indeed, CARS identified shifts of lipid/protein content between the two groups in cardiac tissue visually and by subsequent automated bioinformatic discrimination with a mean sensitivity of 90-96\%. Of note, this genotype differentiation was successful at a very early time point during disease development when only kidneys are visibly affected by globotriaosylceramide depositions. Altogether, the sensitivity of CARS combined with multivariate analysis allows reliable diagnostic support of early FD organ manifestation and may thus improve diagnosis, prognosis, and possibly therapeutic monitoring of FD.}, language = {en} } @article{WeissRamosDelgobo2022, author = {Weiß, Emil and Ramos, Gustavo Campos and Delgobo, Murilo}, title = {Myocardial-Treg crosstalk: How to tame a wolf}, series = {Frontiers in Immunology}, volume = {13}, journal = {Frontiers in Immunology}, issn = {1664-3224}, doi = {10.3389/fimmu.2022.914033}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-275591}, year = {2022}, abstract = {The immune system plays a vital role in maintaining tissue integrity and organismal homeostasis. The sudden stress caused by myocardial infarction (MI) poses a significant challenge for the immune system: it must quickly substitute dead myocardial with fibrotic tissue while controlling overt inflammatory responses. In this review, we will discuss the central role of myocardial regulatory T-cells (Tregs) in orchestrating tissue repair processes and controlling local inflammation in the context of MI. We herein compile recent advances enabled by the use of transgenic mouse models with defined cardiac antigen specificity, explore whole-heart imaging techniques, outline clinical studies and summarize deep-phenotyping conducted by independent labs using single-cell transcriptomics and T-cell repertoire analysis. Furthermore, we point to multiple mechanisms and cell types targeted by Tregs in the infarcted heart, ranging from pro-fibrotic responses in mesenchymal cells to local immune modulation in myeloid and lymphoid lineages. We also discuss how both cardiac-specific and polyclonal Tregs participate in MI repair. In addition, we consider intriguing novel evidence on how the myocardial milieu takes control of potentially auto-aggressive local immune reactions by shaping myosin-specific T-cell development towards a regulatory phenotype. Finally, we examine the potential use of Treg manipulating drugs in the clinic after MI.}, language = {en} } @article{UttingerRiedmeierReibetanzetal.2022, author = {Uttinger, Konstantin L. and Riedmeier, Maria and Reibetanz, Joachim and Meyer, Thomas and Germer, Christoph Thomas and Fassnacht, Martin and Wiegering, Armin and Wiegering, Verena}, title = {Adrenalectomies in children and adolescents in Germany - a diagnose related groups based analysis from 2009-2017}, series = {Frontiers in Endocrinology}, volume = {13}, journal = {Frontiers in Endocrinology}, issn = {1664-2392}, doi = {10.3389/fendo.2022.914449}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-282280}, year = {2022}, abstract = {Background Adrenalectomies are rare procedures especially in childhood. So far, no large cohort study on this topic has been published with data on to age distribution, operative procedures, hospital volume and operative outcome. Methods This is a retrospective analysis of anonymized nationwide hospital billing data (DRG data, 2009-2017). All adrenal surgeries (defined by OPS codes) of patients between the age 0 and 21 years in Germany were included. Results A total of 523 patient records were identified. The mean age was 8.6 ± 7.7 years and 262 patients were female (50.1\%). The majority of patients were between 0 and 5 years old (52\% overall), while 11.1\% were between 6 and 11 and 38.8\% older than 12 years. The most common diagnoses were malignant neoplasms of the adrenal gland (56\%, mostly neuroblastoma) with the majority being younger than 5 years. Benign neoplasms in the adrenal gland (D350) account for 29\% of all cases with the majority of affected patients being 12 years or older. 15\% were not defined regarding tumor behavior. Overall complication rate was 27\% with a clear higher complication rate in resection for malignant neoplasia of the adrenal gland. Bleeding occurrence and transfusions are the main complications, followed by the necessary of relaparotomy. There was an uneven patient distribution between hospital tertiles (low volume, medium and high volume tertile). While 164 patients received surgery in 85 different "low volume" hospitals (0.2 cases per hospital per year), 205 patients received surgery in 8 different "high volume" hospitals (2.8 cases per hospital per year; p<0.001). Patients in high volume centers were significant younger, had more extended resections and more often malignant neoplasia. In multivariable analysis younger age, extended resections and open procedures were independent predictors for occurrence of postoperative complications. Conclusion Overall complication rate of adrenalectomies in the pediatric population in Germany is low, demonstrating good therapeutic quality. Our analysis revealed a very uneven distribution of patient volume among hospitals.}, language = {en} } @article{WendlingerWohlfarthKreftetal.2022, author = {Wendlinger, Simone and Wohlfarth, Jonas and Kreft, Sophia and Siedel, Claudia and Kilian, Teresa and Dischinger, Ulrich and Heppt, Markus V. and Wistuba-Hamprecht, Kilian and Meier, Friedegund and Goebeler, Matthias and Schadendorf, Dirk and Gesierich, Anja and Kosnopfel, Corinna and Schilling, Bastian}, title = {Blood eosinophils are associated with efficacy of targeted therapy in patients with advanced melanoma}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {9}, issn = {2072-6694}, doi = {10.3390/cancers14092294}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-275137}, year = {2022}, abstract = {Background: Eosinophils appear to contribute to the efficacy of immunotherapy and their frequency was suggested as a predictive biomarker. Whether this observation could be transferred to patients treated with targeted therapy remains unknown. Methods: Blood and serum samples of healthy controls and 216 patients with advanced melanoma were prospectively and retrospectively collected. Freshly isolated eosinophils were phenotypically characterized by flow cytometry and co-cultured in vitro with melanoma cells to assess cytotoxicity. Soluble serum markers and peripheral blood counts were used for correlative studies. Results: Eosinophil-mediated cytotoxicity towards melanoma cells, as well as phenotypic characteristics, were similar when comparing healthy donors and patients. However, high relative pre-treatment eosinophil counts were significantly associated with response to MAPKi (p = 0.013). Eosinophil-mediated cytotoxicity towards melanoma cells is dose-dependent and requires proximity of eosinophils and their target in vitro. Treatment with targeted therapy in the presence of eosinophils results in an additive tumoricidal effect. Additionally, melanoma cells affected eosinophil phenotype upon co-culture. Conclusion: High pre-treatment eosinophil counts in advanced melanoma patients were associated with a significantly improved response to MAPKi. Functionally, eosinophils show potent cytotoxicity towards melanoma cells, which can be reinforced by MAPKi. Further studies are needed to unravel the molecular mechanisms of our observations.}, language = {en} } @article{DetomasAltieriDeutschbeinetal.2022, author = {Detomas, Mario and Altieri, Barbara and Deutschbein, Timo and Fassnacht, Martin and Dischinger, Ulrich}, title = {Metyrapone versus osilodrostat in the short-term therapy of endogenous Cushing's syndrome: results from a single center cohort study}, series = {Frontiers in Endocrinology}, volume = {13}, journal = {Frontiers in Endocrinology}, issn = {1664-2392}, doi = {10.3389/fendo.2022.903545}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-277477}, year = {2022}, abstract = {Background Although surgery is considered the first-line treatment for patients with endogenous Cushing's syndrome (CS), medical therapy is often required to control severe hypercortisolism. Metyrapone and osilodrostat are both steroidogenic inhibitors targeting the 11β-hydroxylase, however, their therapeutic effectiveness has not yet been directly compared. This study aimed to evaluate metyrapone and osilodrostat in the short-term therapy of CS. Methods Retrospective analysis of patients with endogenous CS treated with metyrapone or osilodrostat as monotherapy for at least 4 weeks. Main outcome measures were serum cortisol and 24h urinary free cortisol (UFC) at baseline (T0) and after 2 (T1), 4 (T2), and 12 weeks (T3) of therapy. Results 16 patients with endogenous CS were identified (pituitary n=7, adrenal n=4, ectopic CS n=5). Each 8 patients were treated with metyrapone and osilodrostat. Despite heterogeneity, both groups showed comparable mean UFC levels at T0 (metyrapone: 758 µg/24h vs osilodrostat: 817 µg/24h; p=0.93). From T0 to T1, the decrease of UFC was less pronounced under metyrapone than osilodrostat (-21.3\% vs -68.4\%; median daily drug dose: 1000 mg vs 4 mg). This tendency persisted at T2 (-37.3\% vs -50.1\%; median drug dose: 1250 mg vs 6 mg) while at T3 a decrease in UFC from T0 was more pronounced in the metyrapone group (-71.5\% vs -51.5\%; median dose 1250 mg vs 7 mg). Under osilodrostat, a QTc-interval prolongation was identified at T3 (mean 432 ms vs 455 ms). From T0 to T2, the number of antihypertensive drugs remained comparable under metyrapone and decreased under osilodrostat (n= -0.3 vs n= -1.0). Conclusion Although both drugs show comparable therapeutic efficacy, osilodrostat seems to reduce cortisol levels and to control blood pressure faster.}, language = {en} } @article{LoehrHaertigSchulzeetal.2022, author = {L{\"o}hr, Mario and H{\"a}rtig, Wolfgang and Schulze, Almut and Kroiß, Matthias and Sbiera, Silviu and Lapa, Constantin and Mages, Bianca and Strobel, Sabrina and Hundt, Jennifer Elisabeth and Bohnert, Simone and Kircher, Stefan and Janaki-Raman, Sudha and Monoranu, Camelia-Maria}, title = {SOAT1: A suitable target for therapy in high-grade astrocytic glioma?}, series = {International Journal of Molecular Sciences}, volume = {23}, journal = {International Journal of Molecular Sciences}, number = {7}, issn = {1422-0067}, doi = {10.3390/ijms23073726}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284178}, year = {2022}, abstract = {Targeting molecular alterations as an effective treatment for isocitrate dehydrogenase-wildtype glioblastoma (GBM) patients has not yet been established. Sterol-O-Acyl Transferase 1 (SOAT1), a key enzyme in the conversion of endoplasmic reticulum cholesterol to esters for storage in lipid droplets (LD), serves as a target for the orphan drug mitotane to treat adrenocortical carcinoma. Inhibition of SOAT1 also suppresses GBM growth. Here, we refined SOAT1-expression in GBM and IDH-mutant astrocytoma, CNS WHO grade 4 (HGA), and assessed the distribution of LD in these tumors. Twenty-seven GBM and three HGA specimens were evaluated by multiple GFAP, Iba1, IDH1 R132H, and SOAT1 immunofluorescence labeling as well as Oil Red O staining. To a small extent SOAT1 was expressed by tumor cells in both tumor entities. In contrast, strong expression was observed in glioma-associated macrophages. Triple immunofluorescence labeling revealed, for the first time, evidence for SOAT1 colocalization with Iba1 and IDH1 R132H, respectively. Furthermore, a notable difference in the amount of LD between GBM and HGA was observed. Therefore, SOAT1 suppression might be a therapeutic option to target GBM and HGA growth and invasiveness. In addition, the high expression in cells related to neuroinflammation could be beneficial for a concomitant suppression of protumoral microglia/macrophages.}, language = {en} } @article{ReiterWeissWeberetal.2022, author = {Reiter, Theresa and Weiss, Ingo and Weber, Oliver M. and Bauer, Wolfgang R.}, title = {Signal voids of active cardiac implants at 3.0 T CMR}, series = {Scientific Reports}, volume = {12}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-022-09690-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300502}, year = {2022}, abstract = {Recent technical advancements allow cardiac MRI (CMR) examinations in the presence of so-called MRI conditional active cardiac implants at 3.0 T. However, the artifact burden caused by susceptibility effects remain an obstacle. All measurements were obtained at a clinical 3.0 T scanner using an in-house designed cubic phantom and optimized sequences for artifact evaluation (3D gradient echo sequence, multi-slice 2D turbo spin echo sequence). Reference sequences according to the American Society for Testing and Materials (ASTM) were additionally applied. Four representative active cardiac devices and a generic setup were analyzed regarding volume and shape of the signal void. For analysis, a threshold operation was applied to the grey value profile of each data set. The presented approach allows the evaluation of the signal void and shape even for larger implants such as ICDs. The void shape is influenced by the orientation of the B0-field and by the chosen sequence type. The distribution of ferromagnetic material within the implants also matters. The void volume depends both on the device itself, and on the sequence type. Disturbances in the B0 and B1 fields exceed the visual signal void. This work presents a reproducible and highly defined approach to characterize both signal void artifacts at 3.0 T and their influencing factors.}, language = {en} } @article{MontellanoKluterRueckeretal.2022, author = {Montellano, Felipe A. and Kluter, Elisabeth J. and R{\"u}cker, Viktoria and Ungeth{\"u}m, Kathrin and Mackenrodt, Daniel and Wiedmann, Silke and Dege, Tassilo and Quilitzsch, Anika and Morbach, Caroline and Frantz, Stefan and St{\"o}rk, Stefan and Haeusler, Karl Georg and Kleinschnitz, Christoph and Heuschmann, Peter U.}, title = {Cardiac dysfunction and high-sensitive C-reactive protein are associated with troponin T elevation in ischemic stroke: insights from the SICFAIL study}, series = {BMC Neurology}, volume = {22}, journal = {BMC Neurology}, number = {1}, doi = {10.1186/s12883-022-03017-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300119}, year = {2022}, abstract = {Background Troponin elevation is common in ischemic stroke (IS) patients. The pathomechanisms involved are incompletely understood and comprise coronary and non-coronary causes, e.g. autonomic dysfunction. We investigated determinants of troponin elevation in acute IS patients including markers of autonomic dysfunction, assessed by heart rate variability (HRV) time domain variables. Methods Data were collected within the Stroke Induced Cardiac FAILure (SICFAIL) cohort study. IS patients admitted to the Department of Neurology, W{\"u}rzburg University Hospital, underwent baseline investigation including cardiac history, physical examination, echocardiography, and blood sampling. Four HRV time domain variables were calculated in patients undergoing electrocardiographic Holter monitoring. Multivariable logistic regression with corresponding odds ratios (OR) and 95\% confidence intervals (CI) was used to investigate the determinants of high-sensitive troponin T (hs-TnT) levels ≥14 ng/L. Results We report results from 543 IS patients recruited between 01/2014-02/2017. Of those, 203 (37\%) had hs-TnT ≥14 ng/L, which was independently associated with older age (OR per year 1.05; 95\% CI 1.02-1.08), male sex (OR 2.65; 95\% CI 1.54-4.58), decreasing estimated glomerular filtration rate (OR per 10 mL/min/1.73 m2 0.71; 95\% CI 0.61-0.84), systolic dysfunction (OR 2.79; 95\% CI 1.22-6.37), diastolic dysfunction (OR 2.29; 95\% CI 1.29-4.02), atrial fibrillation (OR 2.30; 95\% CI 1.25-4.23), and increasing levels of C-reactive protein (OR 1.48 per log unit; 95\% CI 1.22-1.79). We did not identify an independent association of troponin elevation with the investigated HRV variables. Conclusion Cardiac dysfunction and elevated C-reactive protein, but not a reduced HRV as surrogate of autonomic dysfunction, were associated with increased hs-TnT levels in IS patients independent of established cardiovascular risk factors.}, language = {en} } @article{GramGenslerAlbertovaetal.2022, author = {Gram, Maximilian and Gensler, Daniel and Albertova, Petra and Gutjahr, Fabian Tobias and Lau, Kolja and Arias-Loza, Paula-Anahi and Jakob, Peter Michael and Nordbeck, Peter}, title = {Quantification correction for free-breathing myocardial T1ρ mapping in mice using a recursively derived description of a T\(_{1p}\)\(^{*}\) relaxation pathway}, series = {Journal of Cardiovascular Magnetic Resonance}, volume = {24}, journal = {Journal of Cardiovascular Magnetic Resonance}, number = {1}, doi = {10.1186/s12968-022-00864-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300491}, year = {2022}, abstract = {Background Fast and accurate T1ρ mapping in myocardium is still a major challenge, particularly in small animal models. The complex sequence design owing to electrocardiogram and respiratory gating leads to quantification errors in in vivo experiments, due to variations of the T\(_{1p}\) relaxation pathway. In this study, we present an improved quantification method for T\(_{1p}\) using a newly derived formalism of a T\(_{1p}\)\(^{*}\) relaxation pathway. Methods The new signal equation was derived by solving a recursion problem for spin-lock prepared fast gradient echo readouts. Based on Bloch simulations, we compared quantification errors using the common monoexponential model and our corrected model. The method was validated in phantom experiments and tested in vivo for myocardial T\(_{1p}\) mapping in mice. Here, the impact of the breath dependent spin recovery time T\(_{rec}\) on the quantification results was examined in detail. Results Simulations indicate that a correction is necessary, since systematically underestimated values are measured under in vivo conditions. In the phantom study, the mean quantification error could be reduced from - 7.4\% to - 0.97\%. In vivo, a correlation of uncorrected T\(_{1p}\) with the respiratory cycle was observed. Using the newly derived correction method, this correlation was significantly reduced from r = 0.708 (p < 0.001) to r = 0.204 and the standard deviation of left ventricular T\(_{1p}\) values in different animals was reduced by at least 39\%. Conclusion The suggested quantification formalism enables fast and precise myocardial T\(_{1p}\) quantification for small animals during free breathing and can improve the comparability of study results. Our new technique offers a reasonable tool for assessing myocardial diseases, since pathologies that cause a change in heart or breathing rates do not lead to systematic misinterpretations. Besides, the derived signal equation can be used for sequence optimization or for subsequent correction of prior study results.}, language = {en} } @article{GramAlbertovaSchirmeretal.2022, author = {Gram, Maximilian and Albertova, P. and Schirmer, V. and Blaimer, M. and Gamer, M. and Herrmann, M. J. and Nordbeck, P. and Jakob, P. M.}, title = {Towards robust in vivo quantification of oscillating biomagnetic fields using Rotary Excitation based MRI}, series = {Scientific Reports}, volume = {12}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-022-19275-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300862}, year = {2022}, abstract = {Spin-lock based functional magnetic resonance imaging (fMRI) has the potential for direct spatially-resolved detection of neuronal activity and thus may represent an important step for basic research in neuroscience. In this work, the corresponding fundamental effect of Rotary EXcitation (REX) is investigated both in simulations as well as in phantom and in vivo experiments. An empirical law for predicting optimal spin-lock pulse durations for maximum magnetic field sensitivity was found. Experimental conditions were established that allow robust detection of ultra-weak magnetic field oscillations with simultaneous compensation of static field inhomogeneities. Furthermore, this work presents a novel concept for the emulation of brain activity utilizing the built-in MRI gradient system, which allows REX sequences to be validated in vivo under controlled and reproducible conditions. Via transmission of Rotary EXcitation (tREX), we successfully detected magnetic field oscillations in the lower nano-Tesla range in brain tissue. Moreover, tREX paves the way for the quantification of biomagnetic fields.}, language = {en} } @article{FreyLeutritzBackhausetal.2022, author = {Frey, Anna and Leutritz, Tobias and Backhaus, Joy and H{\"o}rnlein, Alexander and K{\"o}nig, Sarah}, title = {Item format statistics and readability of extended matching questions as an effective tool to assess medical students}, series = {Scientific Reports}, volume = {12}, journal = {Scientific Reports}, number = {1}, doi = {10.1038/s41598-022-25481-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300485}, year = {2022}, abstract = {Testing based on multiple choice questions (MCQ) is one of the most established forms of assessment, not only in the medical field. Extended matching questions (EMQ) represent a specific type of MCQ designed to require higher levels of cognition, such as problem-solving. The purpose of this evaluation was to assess the suitability and efficiency of EMQ as an assessment method. EMQ were incorporated into the end-of-semester examination in internal medicine, in which 154 students participated, and compared with three established MCQ types. Item and examination quality were investigated, as well as readability and processing time. EMQ were slightly more difficult to score; however, both item discrimination and discrimination index were higher when compared to other item types. EMQ were found to be significantly longer and required more processing time, but readability was improved. Students judged EMQ as clearly challenging, but attributed significantly higher clinical relevance when compared to established MCQ formats. Using the Spearman-Brown prediction, only ten EMQ items would be needed to reproduce the Cronbach's alpha value of 0.75 attained for the overall examination. EMQ proved to be both efficient and suitable when assessing medical students, demonstrating powerful characteristics of reliability. Their expanded use in favor of common MCQ could save examination time without losing out on statistical quality.}, language = {en} } @article{DetomasPivonelloPellegrinietal.2022, author = {Detomas, Mario and Pivonello, Claudia and Pellegrini, Bianca and Landwehr, Laura-Sophie and Sbiera, Silviu and Pivonello, Rosario and Ronchi, Cristina L. and Colao, Annamaria and Altieri, Barbara and De Martino, Maria Cristina}, title = {MicroRNAs and long non-coding RNAs in adrenocortical carcinoma}, series = {Cells}, volume = {11}, journal = {Cells}, number = {14}, issn = {2073-4409}, doi = {10.3390/cells11142234}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-281795}, year = {2022}, abstract = {Non-coding RNAs (ncRNAs) are a type of genetic material that do not encode proteins but regulate the gene expression at an epigenetic level, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). The role played by ncRNAs in many physiological and pathological processes has gained attention during the last few decades, as they might be useful in the diagnosis, treatment and management of several human disorders, including endocrine and oncological diseases. Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine cancer, still characterized by high mortality and morbidity due to both endocrine and oncological complications. Despite the rarity of this disease, recently, the role of ncRNA has been quite extensively evaluated in ACC. In order to better explore the role of the ncRNA in human ACC, this review summarizes the current knowledge on ncRNA dysregulation in ACC and its potential role in the diagnosis, treatment, and management of this tumor.}, language = {en} } @article{BrodehlGerull2022, author = {Brodehl, Andreas and Gerull, Brenda}, title = {Genetic insights into primary restrictive cardiomyopathy}, series = {Journal of Clinical Medicine}, volume = {11}, journal = {Journal of Clinical Medicine}, number = {8}, issn = {2077-0383}, doi = {10.3390/jcm11082094}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270621}, year = {2022}, abstract = {Restrictive cardiomyopathy is a rare cardiac disease causing severe diastolic dysfunction, ventricular stiffness and dilated atria. In consequence, it induces heart failure often with preserved ejection fraction and is associated with a high mortality. Since it is a poor clinical prognosis, patients with restrictive cardiomyopathy frequently require heart transplantation. Genetic as well as non-genetic factors contribute to restrictive cardiomyopathy and a significant portion of cases are of unknown etiology. However, the genetic forms of restrictive cardiomyopathy and the involved molecular pathomechanisms are only partially understood. In this review, we summarize the current knowledge about primary genetic restrictive cardiomyopathy and describe its genetic landscape, which might be of interest for geneticists as well as for cardiologists.}, language = {en} } @article{SchraderRieseKurlbaumetal.2021, author = {Schrader, Nikolas and Riese, Thorsten and Kurlbaum, Max and Meybohm, Patrick and Kredel, Markus and Surat, G{\"u}zin and Scherf-Clavel, Oliver and Strate, Alexander and Pospiech, Andreas and Hoppe, Kerstin}, title = {Personalized antibiotic therapy for the critically ill: Implementation strategies and effects on clinical outcome of piperacillin therapeutic drug monitoring — a descriptive retrospective analysis}, series = {Antibiotics}, volume = {10}, journal = {Antibiotics}, number = {12}, issn = {2079-6382}, doi = {10.3390/antibiotics10121452}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250052}, year = {2021}, abstract = {Therapeutic drug monitoring (TDM) is increasingly relevant for an individualized antibiotic therapy and subsequently a necessary tool to reduce multidrug-resistant pathogens, especially in light of diminishing antimicrobial capabilities. Critical illness is associated with profound pharmacokinetic and pharmacodynamic alterations, which challenge dose finding and the application of particularly hydrophilic drugs such as β-lactam antibiotics. Methods: Implementation strategy, potential benefit, and practicability of the developed standard operating procedures were retrospectively analyzed from January to December 2020. Furthermore, the efficacy of the proposed dosing target of piperacillin in critically ill patients was evaluated. Results: In total, 160 patients received piperacillin/tazobactam therapy and were subsequently included in the study. Of them, 114 patients received piperacillin/tazobactam by continuous infusion and had at least one measurement of piperacillin serum level according to the standard operating procedure. In total, 271 measurements were performed with an average level of 79.0 ± 46.0 mg/L. Seventy-one piperacillin levels exceeded 100 mg/L and six levels were lower than 22.5 mg/L. The high-level and the low-level group differed significantly in infection laboratory parameters (CRP (mg/dL) 20.18 ± 11.71 vs. 5.75 ± 5.33) and renal function [glomerular filtration rate (mL/min/1.75 m2) 40.85 ± 26.74 vs. 120.50 ± 70.48]. Conclusions: Piperacillin levels are unpredictable in critically ill patients. TDM during piperacillin/tazobactam therapy is highly recommended for all patients. Although our implementation strategy was effective, further strategies implemented into the daily clinical workflow might support the health care staff and increase the clinicians' alertness.}, language = {en} } @article{ReidenbergWannerPolskyetal.2018, author = {Reidenberg, Bruce E. and Wanner, Christoph and Polsky, Bruce and Castanheira, Mariana and Shelip, Alla and Stalleicken, Dirk and Pfaffle, Antony E.}, title = {Postmarketing experience with Neutrolin® (taurolidine, heparin, calcium citrate) catheter lock solution in hemodialysis patients}, series = {European Journal of Clinical Microbiology \& Infectious Diseases}, volume = {37}, journal = {European Journal of Clinical Microbiology \& Infectious Diseases}, number = {4}, doi = {10.1007/s10096-017-3157-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225091}, pages = {661-663}, year = {2018}, abstract = {Catheter-related bloodstream infections (CRBSI) are major complications for patients with life-threatening conditions requiring chronic vascular catheterization. The wide range of etiologic microbes and the ongoing development of resistance to antimicrobials with specific mechanisms of action make this an appropriate target for applying a nonspecific antimicrobial therapeutic. Taurolidine hydrolyzes into two antimicrobial moieties, formaldehyde and methylene glycol, which react with microbial surfaces. NeutrolinA (R) (taurolidine, heparin, calcium citrate) was recently introduced in Germany as an antimicrobial catheter lock solution. This postmarketing experience collected data on 201 patients at 20 centers from January 2014 through September 2016. Likely CRBSI was observed in 13 episodes in 47,118 days (0.2759 per 1000 days [0.1468, 0.4718]). Thrombosed catheter was observed in seven catheters in 47,118 days (0.1486 per 1000 days [0.0595, 0.3061]). No adverse drug reactions that led to the discontinuation of NeutrolinA (R) use were reported. Two patients experienced occasional transient dysgeusia. NeutrolinA (R), when used in conjunction with guideline-based catheter care, showed reduction in the rate of both CRBSI and catheter thrombosis relative to recent historical controls.}, language = {en} } @article{RosenstockPerkovicAlexanderetal.2018, author = {Rosenstock, Julio and Perkovic, Vlado and Alexander, John H. and Cooper, Mark E. and Marx, Nikolaus and Pencina, Michael J. and Toto, Robert D. and Wanner, Christoph and Zinman, Bernard and Baanstra, David and Pfarr, Egon and Mattheus, Michaela and Broedl, Uli C. and Woerle, Hans-J{\"u}rgen and George, Jyothis T. and von Eynatten, Maximilian and McGuire, Darren K.}, title = {Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin - (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk}, series = {Cardiovascular Diabetology}, volume = {17}, journal = {Cardiovascular Diabetology}, doi = {10.1186/s12933-018-0682-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-226996}, pages = {39, 1-15}, year = {2018}, abstract = {Background: Cardiovascular (CV) outcome trials in type 2 diabetes (T2D) have underrepresented patients with chronic kidney disease (CKD), leading to uncertainty regarding their kidney efficacy and safety. The CARMELINA (R) trial aims to evaluate the effects of linagliptin, a DPP-4 inhibitor, on both CV and kidney outcomes in a study population enriched for cardio-renal risk. Methods: CARMELINA (R) is a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events. Participants with evidence of CKD with or without CV disease and HbA1c 6.5-10.0\% (48-86 mmol/mol) were randomized 1:1 to receive linagliptin once daily or matching placebo, added to standard of care adjusted according to local guidelines. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. The key secondary outcome is a composite of time to first sustained occurrence of end-stage kidney disease, >= 40\% decrease in estimated glomerular filtration rate (eGFR) from baseline, or renal death. CV and kidney events are prospectively adjudicated by independent, blinded clinical event committees. CARMELINA (R) was designed to continue until at least 611 participants had confirmed primary outcome events. Assuming a hazard ratio of 1.0, this provides 90\% power to demonstrate non-inferiority of linagliptin versus placebo within the pre-specified non-inferiority margin of 1.3 at a one-sided a-level of 2.5\%. If non-inferiority of linagliptin for the primary outcome is demonstrated, then its superiority for both the primary outcome and the key secondary outcome will be investigated with a sequentially rejective multiple test procedure. Results: Between July 2013 and August 2016, 6980 patients were randomized and took >= 1 dose of study drug (40.6, 33.1, 16.9, and 9.4\% from Europe, South America, North America, and Asia, respectively). At baseline, mean +/- SD age was 65.8 +/- 9.1 years, HbA1c 7.9 +/- 1.0\%, BMI 31.3 +/- 5.3 kg/m(2), and eGFR 55 +/- 25 mL/min/1.73 m(2). A total of 5148 patients (73.8\%) had prevalent kidney disease (defined as eGFR < 60 mL/min/1.73 m(2) or macroalbuminuria [albumin-to-creatinine ratio > 300 mg/g]) and 3990 patients (57.2\%) had established CV disease with increased albuminuria; these characteristics were not mutually exclusive. Microalbuminuria (n = 2896 [41.5\%]) and macroalbuminuria (n = 2691 [38.6\%]) were common. Conclusions: CARMELINA (R) will add important information regarding the CV and kidney disease clinical profile of linagliptin by including an understudied, vulnerable cohort of patients with T2D at highest cardio-renal risk.}, language = {en} } @article{HendricksMuellerFassnachtetal.2022, author = {Hendricks, Anne and M{\"u}ller, Sophie and Fassnacht, Martin and Germer, Christoph-Thomas and Wiegering, Verena A. and Wiegering, Armin and Reibetanz, Joachim}, title = {Impact of lymphadenectomy on the oncologic outcome of patients with adrenocortical carcinoma — a systematic review and meta-analysis}, series = {Cancers}, volume = {14}, journal = {Cancers}, number = {2}, issn = {2072-6694}, doi = {10.3390/cancers14020291}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-254798}, year = {2022}, abstract = {(1) Background: Locoregional lymphadenectomy (LND) in adrenocortical carcinoma (ACC) may impact oncological outcome, but the findings from individual studies are conflicting. The aim of this systematic review and meta-analysis was to determine the oncological value of LND in ACC by summarizing the available literature. (2) Methods: A systematic search on studies published until December 2020 was performed according to the PRISMA statement. The primary outcome was the impact of lymphadenectomy on overall survival (OS). Two separate meta-analyses were performed for studies including patients with localized ACC (stage I-III) and those including all tumor stages (I-IV). Secondary endpoints included postoperative mortality and length of hospital stay (LOS). (3) Results: 11 publications were identified for inclusion. All studies were retrospective studies, published between 2001-2020, and 5 were included in the meta-analysis. Three studies (N = 807 patients) reported the impact of LND on disease-specific survival in patients with stage I-III ACC and revealed a survival benefit of LND (hazard ratio (HR) = 0.42, 95\% confidence interval (95\% CI): 0.26-0.68). Based on results of studies including patients with ACC stage I-IV (2 studies, N = 3934 patients), LND was not associated with a survival benefit (HR = 1.00, 95\% CI: 0.70-1.42). None of the included studies showed an association between LND and postoperative mortality or LOS. (4) Conclusion: Locoregional lymphadenectomy seems to offer an oncologic benefit in patients undergoing curative-intended surgery for localized ACC (stage I-III).}, language = {en} } @article{CanuPuglisiBerchiallaetal.2021, author = {Canu, Letizia and Puglisi, Soraya and Berchialla, Paola and De Filpo, Giuseppina and Brignardello, Francesca and Schiavi, Francesca and Ferrara, Alfonso Massimiliano and Zovato, Stefania and Luconi, Michaela and Pia, Anna and Appetecchia, Marialuisa and Arvat, Emanuela and Letizia, Claudio and Maccario, Mauro and Parasiliti-Caprino, Mirko and Altieri, Barbara and Faggiano, Antongiulio and Modica, Roberta and Morelli, Valentina and Arosio, Maura and Verga, Uberta and Pellegrino, Micaela and Petramala, Luigi and Concistr{\`e}, Antonio and Razzore, Paola and Ercolino, Tonino and Rapizzi, Elena and Maggi, Mario and Stigliano, Antonio and Burrello, Jacopo and Terzolo, Massimo and Opocher, Giuseppe and Mannelli, Massimo and Reimondo, Giuseppe}, title = {A multicenter epidemiological study on second malignancy in non-syndromic pheochromocytoma/paraganglioma patients in Italy}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {22}, issn = {2072-6694}, doi = {10.3390/cancers13225831}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250148}, year = {2021}, abstract = {No studies have carried out an extensive analysis of the possible association between non-syndromic pheochromocytomas and paragangliomas (PPGLs) and other malignancies. To assess >the risk of additional malignancy in PPGL, we retrospectively evaluated 741 patients with PPGLs followed-up in twelve referral centers in Italy. Incidence of second malignant tumors was compared between this cohort and Italian patients with two subsequent malignancies. Among our patients, 95 (12.8\%) developed a second malignant tumor, which were mainly prostate, colorectal and lung/bronchial cancers in males, breast cancer, differentiated thyroid cancer and melanoma in females. The standardized incidence ratio was 9.59 (95\% CI 5.46-15.71) in males and 13.21 (95\% CI 7.52-21.63) in females. At multivariable analysis, the risk of developing a second malignant tumor increased with age at diagnosis (HR 2.50, 95\% CI 1.15-5.44, p = 0.021 for 50-59 vs. <50-year category; HR 3.46, 95\% CI 1.67-7.15, p < 0.001 for >60- vs. <50-year). In patients with available genetic evaluation, a positive genetic test was inversely associated with the risk of developing a second tumor (HR 0.25, 95\% CI 0.10-0.63, p = 0.003). In conclusion, PPGLs patients have higher incidence of additional malignant tumors compared to the general population who had a first malignancy, which could have an impact on the surveillance strategy.}, language = {en} } @article{FussOtherHeinzeetal.2021, author = {Fuss, Carmina Teresa and Other, Katharina and Heinze, Britta and Landwehr, Laura-Sophie and Wiegering, Armin and Kalogirou, Charis and Hahner, Stefanie and Fassnacht, Martin}, title = {Expression of the chemokine receptor CCR7 in the normal adrenal gland and adrenal tumors and its correlation with clinical outcome in adrenocortical carcinoma}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {22}, issn = {2072-6694}, doi = {10.3390/cancers13225693}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250112}, year = {2021}, abstract = {Background: The chemokine receptor CCR7 is crucial for an intact immune function, but its expression is also associated with clinical outcome in several malignancies. No data exist on the expression of CCR7 in adrenocortical tumors. Methods: CCR7 expression was investigated by qRT-PCR and immunohistochemistry in 4 normal adrenal glands, 59 adrenocortical adenomas, and 181 adrenocortical carcinoma (ACC) samples. Results: CCR7 is highly expressed in the outer adrenocortical zones and medulla. Aldosterone-producing adenomas showed lower CCR7 protein levels (H-score 1.3 ± 1.0) compared to non-functioning (2.4 ± 0.5) and cortisol-producing adenomas (2.3 ± 0.6), whereas protein expression was variable in ACC (1.8 ± 0.8). In ACC, CCR7 protein expression was significantly higher in lymph node metastases (2.5 ± 0.5) compared to primary tumors (1.8±0.8) or distant metastases (2.0 ± 0.4; p < 0.01). mRNA levels of CCR7 were not significantly different between ACCs, normal adrenals, and adrenocortical adenomas. In contrast to other tumor entities, neither CCR7 protein nor mRNA expression significantly impacted patients' survival. Conclusion: We show that CCR7 is expressed on mRNA and protein level across normal adrenals, benign adrenocortical tumors, as well as ACCs. Given that CCR7 did not influence survival in ACC, it is probably not involved in tumor progression, but it could play a role in adrenocortical homeostasis.}, language = {en} } @article{BarreaVetraniAltierietal.2021, author = {Barrea, Luigi and Vetrani, Claudia and Altieri, Barbara and Verde, Ludovica and Savastano, Silvia and Colao, Annamaria and Muscogiuri, Giovanna}, title = {The importance of being a 'lark' in post-menopausal women with obesity: a ploy to prevent type 2 diabetes mellitus?}, series = {Nutrients}, volume = {13}, journal = {Nutrients}, number = {11}, issn = {2072-6643}, doi = {10.3390/nu13113762}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248572}, year = {2021}, abstract = {Chronotype is defined as the behavioral manifestation of circadian rhythms related to the external light-dark cycle. Evening chronotype has been associated with an increased risk of developing cardiometabolic diseases in obesity. Menopause is a lifestage associated with an increased risk of developing cardiometabolic diseases and a change in circadian rhythmicity compared to pre-menopause. However, the prevalence of chronotype categories in menopause and their role in determining menopause-related cardiometabolic risk, mostly in obesity, have not been investigated. Thus, we aimed to investigate the prevalence of chronotype categories in post-menopausal women with obesity and their role in menopause-related cardiometabolic risk. In this cross-sectional study we enrolled 49 pre-menopausal and 74 post-menopausal women with obesity. Anthropometric parameters, lifestyle habits, adherence to the Mediterranean Diet (MD), sleep quality, chronotype and the presence of type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD) were studied. No significance differences were detected in terms of lifestyle and adherence to the MD between pre- and post-menopausal women. Chronotype was classified as morning in 66 (53.6\%), evening in 20 (16.3\%) and intermediate in 37 (30.1\%) women. In addition, pre-menopausal women with obesity showed a significantly higher chance to have an intermediate chronotype (OR = 2.21, 95\% CI 1.28-3.83; p = 0.004), whereas post-menopausal women with obesity showed a trend to have a higher morning chronotype (OR = 1.42, 95\% CI 0.98-2.06; p = 0.051), although this did not reach statistical significance. No significant differences were detected in terms of prevalence of evening chronotype between the two groups. However, the evening chronotype had a significantly higher risk to have T2DM compared to the morning (OR = 17.29, 95\% CI 2.40-124.27; p = 0.005) and intermediate chronotypes (OR = 30.86, 95\% CI 2.05-464.32; p = 0.013) in both pre- and post-menopausal women with obesity. In conclusion, the intermediate chronotype was significantly more prevalent in pre-menopausal women with obesity compared to post-menopausal women. Evening chronotype was associated to T2DM in both pre- and post-menopause. These results support the importance of including the assessment of chronotype in the management of women with obesity in post-menopause.}, language = {en} } @article{MetznerHerzogHeckeletal.2022, author = {Metzner, Valentin and Herzog, Gloria and Heckel, Tobias and Bischler, Thorsten and Hasinger, Julia and Otto, Christoph and Fassnacht, Martin and Geier, Andreas and Seyfried, Florian and Dischinger, Ulrich}, title = {Liraglutide + PYY\(_{3-36}\) combination therapy mimics effects of Roux-en-Y bypass on early NAFLD whilst lacking-behind in metabolic improvements}, series = {Journal of Clinical Medicine}, volume = {11}, journal = {Journal of Clinical Medicine}, number = {3}, issn = {2077-0383}, doi = {10.3390/jcm11030753}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-255244}, year = {2022}, abstract = {Background: Treatment options for NAFLD are still limited. Bariatric surgery, such as Roux-en-Y gastric bypass (RYGB), has been shown to improve metabolic and histologic markers of NAFLD. Glucagon-like-peptide-1 (GLP-1) analogues lead to improvements in phase 2 clinical trials. We directly compared the effects of RYGB with a treatment using liraglutide and/or peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) in a rat model for early NAFLD. Methods: Obese male Wistar rats (high-fat diet (HFD)-induced) were randomized into the following treatment groups: RYGB, sham-operation (sham), liraglutide (0.4 mg/kg/day), PYY\(_{3-36}\) (0.1 mg/kg/day), liraglutide+PYY\(_{3-36}\), and saline. After an observation period of 4 weeks, liver samples were histologically evaluated, ELISAs and RNA sequencing + RT-qPCRs were performed. Results: RYGB and liraglutide+PYY\(_{3-36}\) induced a similar body weight loss and, compared to sham/saline, marked histological improvements with significantly less steatosis. However, only RYGB induced significant metabolic improvements (e.g., adiponectin/leptin ratio 18.8 ± 11.8 vs. 2.4 ± 1.2 in liraglutide+PYY\(_{3-36}\)- or 1.4 ± 0.9 in sham-treated rats). Furthermore, RNA sequencing revealed a high number of differentially regulated genes in RYGB treated animals only. Conclusions: The combination therapy of liraglutide+PYY\(_{3-36}\) partly mimics the positive effects of RYGB on weight reduction and on hepatic steatosis, while its effects on metabolic function lack behind RYGB.}, language = {en} } @article{KimpelBedroseMegerleetal.2021, author = {Kimpel, Otilia and Bedrose, Sara and Megerle, Felix and Berruti, Alfredo and Terzolo, Massimo and Kroiss, Matthias and Mai, Knut and Dekkers, Olaf M. and Habra, Mouhammed Amir and Fassnacht, Martin}, title = {Adjuvant platinum-based chemotherapy in radically resected adrenocortical carcinoma: a cohort study}, series = {British Journal of Cancer}, volume = {125}, journal = {British Journal of Cancer}, number = {9}, issn = {1532-1827}, doi = {10.1038/s41416-021-01513-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-273000}, pages = {1233-1238}, year = {2021}, abstract = {Background After radical resection, patients with adrenocortical carcinoma (ACC) frequently experience recurrence and, therefore, effective adjuvant treatment is urgently needed. The aim of the study was to investigate the role of adjuvant platinum-based therapy. Methods In this retrospective multicentre cohort study, we identified patients treated with adjuvant platinum-based chemotherapy after radical resection and compared them with patients without adjuvant chemotherapy. Recurrence-free and overall survival (RFS/OS) were investigated in a matched group analysis and by applying a propensity score matching using the full control cohort (n = 268). For both approaches, we accounted for immortal time bias. Results Of the 31 patients in the platinum cohort (R0 n = 25, RX n = 4, R1 n = 2; ENSAT Stage II n = 11, III n = 16, IV n = 4, median Ki67 30\%, mitotane n = 28), 14 experienced recurrence compared to 29 of 31 matched controls (median RFS after the landmark at 3 months 17.3 vs. 7.3 months; adjusted HR 0.19 (95\% CI 0.09-0.42; P < 0.001). Using propensity score matching, the HR for RFS was 0.45 (0.29-0.89, P = 0.021) and for OS 0.25 (0.09-0.69; P = 0.007). Conclusions Our study provides the first evidence that adjuvant platinum-based chemotherapy may be associated with prolonged recurrence-free and overall survival in patients with ACC and a very high risk for recurrence.}, language = {en} } @article{EckhardtSbieraKrebsetal.2022, author = {Eckhardt, Carolin and Sbiera, Iuliu and Krebs, Markus and Sbiera, Silviu and Spahn, Martin and Kneitz, Burkhard and Joniau, Steven and Fassnacht, Martin and K{\"u}bler, Hubert and Weigand, Isabel and Kroiss, Matthias}, title = {High expression of Sterol-O-Acyl transferase 1 (SOAT1), an enzyme involved in cholesterol metabolism, is associated with earlier biochemical recurrence in high risk prostate cancer}, series = {Prostate Cancer and Prostatic Diseases}, volume = {25}, journal = {Prostate Cancer and Prostatic Diseases}, number = {3}, issn = {1476-5608}, doi = {10.1038/s41391-021-00431-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-271819}, pages = {484-490}, year = {2022}, abstract = {Background Prostate cancer (PCa) is the most frequent cancer in men. The prognosis of PCa is heterogeneous with many clinically indolent tumors and rare highly aggressive cases. Reliable tissue markers of prognosis are lacking. Active cholesteryl ester synthesis has been associated with prostate cancer aggressiveness. Sterol-O-Acyl transferases (SOAT) 1 and 2 catalyze cholesterol esterification in humans. Objective To investigate the value of SOAT1 and SOAT2 tissue expression as prognostic markers in high risk PCa. Patients and Methods Formalin-fixed paraffin-embedded tissue samples from 305 high risk PCa cases treated with radical prostatectomy were analyzed for SOAT1 and SOAT2 protein expression by semi-quantitative immunohistochemistry. The Kaplan-Meier method and Cox proportional hazards modeling were used to compare outcome. Main Outcome Measure Biochemical recurrence (BCR) free survival. Results SOAT1 expression was high in 73 (25\%) and low in 219 (75\%; not evaluable: 13) tumors. SOAT2 was highly expressed in 40 (14\%) and at low levels in 249 (86\%) samples (not evaluable: 16). By Kaplan-Meier analysis, we found significantly shorter median BCR free survival of 93 months (95\% confidence interval 23.6-123.1) in patients with high SOAT1 vs. 134 months (112.6-220.2, Log-rank p < 0.001) with low SOAT1. SOAT2 expression was not significantly associated with BCR. After adjustment for age, preoperative PSA, tumor stage, Gleason score, resection status, lymph node involvement and year of surgery, high SOAT1 but not SOAT2 expression was associated with shorter BCR free survival with a hazard ratio of 2.40 (95\% CI 1.57-3.68, p < 0.001). Time to clinical recurrence and overall survival were not significantly associated with SOAT1 and SOAT2 expression CONCLUSIONS: SOAT1 expression is strongly associated with BCR free survival alone and after multivariable adjustment in high risk PCa. SOAT1 may serve as a histologic marker of prognosis and holds promise as a future treatment target.}, language = {en} } @article{LippertFassnachtRonchi2022, author = {Lippert, Juliane and Fassnacht, Martin and Ronchi, Cristina L.}, title = {The role of molecular profiling in adrenocortical carcinoma}, series = {Clinical Endocrinology}, volume = {97}, journal = {Clinical Endocrinology}, number = {4}, doi = {10.1111/cen.14629}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258382}, pages = {460-472}, year = {2022}, abstract = {Adrenocortical carcinoma (ACC) is a rare, aggressive cancer with still partially unknown pathogenesis, heterogenous clinical behaviour and no effective treatment for advanced stages. Therefore, there is an urgent clinical unmet need for better prognostication strategies, innovative therapies and significant improvement of the management of the individual patients. In this review, we summarize available studies on molecular prognostic markers and markers predictive of response to standard therapies as well as newly proposed drug targets in sporadic ACC. We include in vitro studies and available clinical trials, focusing on alterations at the DNA, RNA and epigenetic levels. We also discuss the potential of biomarkers to be implemented in a clinical routine workflow for improved ACC patient care.}, language = {en} } @article{BasilePuglisiAltierietal.2021, author = {Basile, Vittoria and Puglisi, Soraya and Altieri, Barbara and Canu, Letizia and Lib{\`e}, Rossella and Ceccato, Filippo and Beuschlein, Felix and Quinkler, Marcus and Calabrese, Anna and Perotti, Paola and Berchialla, Paola and Dischinger, Ulrich and Megerle, Felix and Baudin, Eric and Bourdeau, Isabelle and Lacroix, Andr{\´e} and Loli, Paola and Berruti, Alfredo and Kastelan, Darko and Haak, Harm R. and Fassnacht, Martin and Terzolo, Massimo}, title = {What is the optimal duration of adjuvant mitotane therapy in adrenocortical carcinoma? An unanswered question}, series = {Journal of Personalized Medicine}, volume = {11}, journal = {Journal of Personalized Medicine}, number = {4}, issn = {2075-4426}, doi = {10.3390/jpm11040269}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236507}, year = {2021}, abstract = {A relevant issue on the treatment of adrenocortical carcinoma (ACC) concerns the optimal duration of adjuvant mitotane treatment. We tried to address this question, assessing whether a correlation exists between the duration of adjuvant mitotane treatment and recurrence-free survival (RFS) of patients with ACC. We conducted a multicenter retrospective analysis on 154 ACC patients treated for ≥12 months with adjuvant mitotane after radical surgery and who were free of disease at the mitotane stop. During a median follow-up of 38 months, 19 patients (12.3\%) experienced recurrence. We calculated the RFS after mitotane (RFSAM), from the landmark time-point of mitotane discontinuation, to overcome immortal time bias. We found a wide variability in the duration of adjuvant mitotane treatment among different centers and also among patients cared for at the same center, reflecting heterogeneous practice. We did not find any survival advantage in patients treated for longer than 24 months. Moreover, the relationship between treatment duration and the frequency of ACC recurrence was not linear after stratifying our patients in tertiles of length of adjuvant treatment. In conclusion, the present findings do not support the concept that extending adjuvant mitotane treatment over two years is beneficial for ACC patients with low to moderate risk of recurrence.}, language = {en} } @article{TraubHusseiniWeber2021, author = {Traub, Jan and Husseini, Leila and Weber, Martin S.}, title = {B cells and antibodies as targets of therapeutic intervention in neuromyelitis optica spectrum disorders}, series = {Pharmaceuticals}, volume = {14}, journal = {Pharmaceuticals}, number = {1}, issn = {1424-8247}, doi = {10.3390/ph14010037}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-222957}, year = {2021}, abstract = {The first description of neuromyelitis optica by Eug{\`e}ne Devic and Fernand Gault dates back to the 19th century, but only the discovery of aquaporin-4 autoantibodies in a major subset of affected patients in 2004 led to a fundamentally revised disease concept: Neuromyelits optica spectrum disorders (NMOSD) are now considered autoantibody-mediated autoimmune diseases, bringing the pivotal pathogenetic role of B cells and plasma cells into focus. Not long ago, there was no approved medication for this deleterious disease and off-label therapies were the only treatment options for affected patients. Within the last years, there has been a tremendous development of novel therapies with diverse treatment strategies: immunosuppression, B cell depletion, complement factor antagonism and interleukin-6 receptor blockage were shown to be effective and promising therapeutic interventions. This has led to the long-expected official approval of eculizumab in 2019 and inebilizumab in 2020. In this article, we review current pathogenetic concepts in NMOSD with a focus on the role of B cells and autoantibodies as major contributors to the propagation of these diseases. Lastly, by highlighting promising experimental and future treatment options, we aim to round up the current state of knowledge on the therapeutic arsenal in NMOSD.}, language = {en} } @article{AltieriDiDatoModicaetal.2020, author = {Altieri, Barbara and Di Dato, Carla and Modica, Roberta and Bottiglieri, Filomena and Di Sarno, Antonella and Pittaway, James F.H. and Martini, Chiara and Faggiano, Antongiulio and Colao, Annamaria}, title = {Bone metabolism and vitamin D implication in gastroenteropancreatic neuroendocrine tumors}, series = {Nutrients}, volume = {12}, journal = {Nutrients}, number = {4}, issn = {2072-6643}, doi = {10.3390/nu12041021}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203823}, year = {2020}, abstract = {Patients affected by gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) have an increased risk of developing osteopenia and osteoporosis, as several factors impact on bone metabolism in these patients. In fact, besides the direct effect of bone metastasis, bone health can be affected by hormone hypersecretion (including serotonin, cortisol, and parathyroid hormone-related protein), specific microRNAs, nutritional status (which in turn could be affected by medical and surgical treatments), and vitamin D deficiency. In patients with multiple endocrine neoplasia type 1 (MEN1), a hereditary syndrome associated with NET occurrence, bone damage may carry other consequences. Osteoporosis may negatively impact on the quality of life of these patients and can increment the cost of medical care since these patients usually live with their disease for a long time. However, recommendations suggesting screening to assess bone health in GEP-NET patients are missing. The aim of this review is to critically analyze evidence on the mechanisms that could have a potential impact on bone health in patients affected by GEP-NET, focusing on vitamin D and its role in GEP-NET, as well as on factors associated with MEN1 that could have an impact on bone homeostasis.}, language = {en} } @article{HankirRotzingerNordbecketal.2021, author = {Hankir, Mohammed K. and Rotzinger, Laura and Nordbeck, Arno and Corteville, Caroline and Dischinger, Ulrich and Knop, Juna-Lisa and Hoffmann, Annett and Otto, Christoph and Seyfried, Florian}, title = {Leptin receptors are not required for Roux-en-Y gastric bypass surgery to normalize energy and glucose homeostasis in rats}, series = {Nutrients}, volume = {13}, journal = {Nutrients}, number = {5}, issn = {2072-6643}, doi = {10.3390/nu13051544}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239550}, year = {2021}, abstract = {Sensitization to the adipokine leptin is a promising therapeutic strategy against obesity and its comorbidities and has been proposed to contribute to the lasting metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. We formally tested this idea using Zucker fatty fa/fa rats as an established genetic model of obesity, glucose intolerance, and fatty liver due to leptin receptor deficiency. We show that the changes in body weight in these rats following RYGB largely overlaps with that of diet-induced obese Wistar rats with intact leptin receptors. Further, food intake and oral glucose tolerance were normalized in RYGB-treated Zucker fatty fa/fa rats to the levels of lean Zucker fatty fa/+ controls, in association with increased glucagon-like peptide 1 (GLP-1) and insulin release. In contrast, while fatty liver was also normalized in RYGB-treated Zucker fatty fa/fa rats, their circulating levels of the liver enzyme alanine aminotransferase (ALT) remained elevated at the level of obese Zucker fatty fa/fa controls. These findings suggest that the leptin system is not required for the normalization of energy and glucose homeostasis associated with RYGB, but that its potential contribution to the improvements in liver health postoperatively merits further investigation.}, language = {en} } @article{SahitiMorbachCejkaetal.2022, author = {Sahiti, Floran and Morbach, Caroline and Cejka, Vladimir and Tiffe, Theresa and Wagner, Martin and Eichner, Felizitas A. and Gelbrich, G{\"o}tz and Heuschmann, Peter U. and St{\"o}rk, Stefan}, title = {Impact of cardiovascular risk factors on myocardial work-insights from the STAAB cohort study}, series = {Journal of Human Hypertension}, volume = {36}, journal = {Journal of Human Hypertension}, number = {3}, issn = {1476-5527}, doi = {10.1038/s41371-021-00509-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-271770}, pages = {235-245}, year = {2022}, abstract = {Myocardial work is a new echocardiography-based diagnostic tool, which allows to quantify left ventricular performance based on pressure-strain loops, and has been validated against invasively derived pressure-volume measurements. Myocardial work is described by its components (global constructive work [GCW], global wasted work [GWW]) and indices (global work index [GWI], global work efficiency [GWE]). Applying this innovative concept, we characterized the prevalence and severity of subclinical left ventricular compromise in the general population and estimated its association with cardiovascular (CV) risk factors. Within the Characteristics and Course of Heart Failure STAges A/B and Determinants of Progression (STAAB) cohort study we comprehensively phenotyped a representative sample of the population of W{\"u}rzburg, Germany, aged 30-79 years. Indices of myocardial work were determined in 1929 individuals (49.3\% female, mean age 54 ± 12 years). In multivariable analysis, hypertension was associated with a mild increase in GCW, but a profound increase in GWW, resulting in higher GWI and lower GWE. All other CV risk factors were associated with lower GCW and GWI, but not with GWW. The association of hypertension and obesity with GWI was stronger in women. We conclude that traditional CV risk factors impact selectively and gender-specifically on left ventricular myocardial performance, independent of systolic blood pressure. Quantifying active systolic and diastolic compromise by derivation of myocardial work advances our understanding of pathophysiological processes in health and cardiac disease.}, language = {en} } @article{HauserDornbergerMalzahnetal.2021, author = {Hauser, T. and Dornberger, V. and Malzahn, U. and Grebe, S. J. and Liu, D. and St{\"o}rk, S. and Nauck, M. and Friedrich, N. and D{\"o}rr, M. and Wanner, C. and Krane, V. and Hammer, F.}, title = {The effect of spironolactone on diastolic function in haemodialysis patients}, series = {The International Journal of Cardiovascular Imaging}, volume = {37}, journal = {The International Journal of Cardiovascular Imaging}, number = {6}, issn = {1573-0743}, doi = {10.1007/s10554-021-02176-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-269033}, pages = {1927-1936}, year = {2021}, abstract = {Heart failure with preserved ejection fraction (HFpEF) is highly prevalent in patients on maintenance haemodialysis (HD) and lacks effective treatment. We investigated the effect of spironolactone on cardiac structure and function with a specific focus on diastolic function parameters. The MiREnDa trial examined the effect of 50 mg spironolactone once daily versus placebo on left ventricular mass index (LVMi) among 97 HD patients during 40 weeks of treatment. In this echocardiographic substudy, diastolic function was assessed using predefined structural and functional parameters including E/e'. Changes in the frequency of HFpEF were analysed using the comprehensive 'HFA-PEFF score'. Complete echocardiographic assessment was available in 65 individuals (59.5 ± 13.0 years, 21.5\% female) with preserved left ventricular ejection fraction (LVEF > 50\%). At baseline, mean E/e' was 15.2 ± 7.8 and 37 (56.9\%) patients fulfilled the criteria of HFpEF according to the HFA-PEFF score. There was no significant difference in mean change of E/e' between the spironolactone group and the placebo group (+ 0.93 ± 5.39 vs. + 1.52 ± 5.94, p = 0.68) or in mean change of left atrial volume index (LAVi) (1.9 ± 12.3 ml/m\(^{2}\) vs. 1.7 ± 14.1 ml/m\(^{2}\), p = 0.89). Furthermore, spironolactone had no significant effect on mean change in LVMi (+ 0.8 ± 14.2 g/m\(^{2}\) vs. + 2.7 ± 15.9 g/m\(^{2}\); p = 0.72) or NT-proBNP (p = 0.96). Treatment with spironolactone did not alter HFA-PEFF score class compared with placebo (p = 0.63). Treatment with 50 mg of spironolactone for 40 weeks had no significant effect on diastolic function parameters in HD patients.}, language = {en} } @article{GramGenslerWinteretal.2022, author = {Gram, Maximilian and Gensler, Daniel and Winter, Patrick and Seethaler, Michael and Arias-Loza, Paula Anahi and Oberberger, Johannes and Jakob, Peter Michael and Nordbeck, Peter}, title = {Fast myocardial T\(_{1P}\) mapping in mice using k-space weighted image contrast and a Bloch simulation-optimized radial sampling pattern}, series = {Magnetic Resonance Materials in Physics, Biology and Medicine}, volume = {35}, journal = {Magnetic Resonance Materials in Physics, Biology and Medicine}, number = {2}, issn = {1352-8661}, doi = {10.1007/s10334-021-00951-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-268903}, pages = {325-340}, year = {2022}, abstract = {Purpose T\(_{1P}\) dispersion quantification can potentially be used as a cardiac magnetic resonance index for sensitive detection of myocardial fibrosis without the need of contrast agents. However, dispersion quantification is still a major challenge, because T\(_{1P}\) mapping for different spin lock amplitudes is a very time consuming process. This study aims to develop a fast and accurate T\(_{1P}\) mapping sequence, which paves the way to cardiac T1ρ dispersion quantification within the limited measurement time of an in vivo study in small animals. Methods A radial spin lock sequence was developed using a Bloch simulation-optimized sampling pattern and a view-sharing method for image reconstruction. For validation, phantom measurements with a conventional sampling pattern and a gold standard sequence were compared to examine T\(_{1P}\) quantification accuracy. The in vivo validation of T\(_{1P}\) mapping was performed in N = 10 mice and in a reproduction study in a single animal, in which ten maps were acquired in direct succession. Finally, the feasibility of myocardial dispersion quantification was tested in one animal. Results The Bloch simulation-based sampling shows considerably higher image quality as well as improved T\(_{1P}\) quantification accuracy (+ 56\%) and precision (+ 49\%) compared to conventional sampling. Compared to the gold standard sequence, a mean deviation of - 0.46 ± 1.84\% was observed. The in vivo measurements proved high reproducibility of myocardial T\(_{1P}\) mapping. The mean T\(_{1P}\) in the left ventricle was 39.5 ± 1.2 ms for different animals and the maximum deviation was 2.1\% in the successive measurements. The myocardial T\(_{1P}\) dispersion slope, which was measured for the first time in one animal, could be determined to be 4.76 ± 0.23 ms/kHz. Conclusion This new and fast T\(_{1P}\) quantification technique enables high-resolution myocardial T\(_{1P}\) mapping and even dispersion quantification within the limited time of an in vivo study and could, therefore, be a reliable tool for improved tissue characterization.}, language = {en} } @article{GuederWilkesmannScholzetal.2022, author = {G{\"u}der, G{\"u}lmisal and Wilkesmann, Joana and Scholz, Nina and Leppich, Robert and D{\"u}king, Peter and Sperlich, Billy and Rost, Christian and Frantz, Stefan and Morbach, Caroline and Sahiti, Floran and Stefenelli, Ulrich and Breunig, Margret and St{\"o}rk, Stefan}, title = {Establishing a cardiac training group for patients with heart failure: the "HIP-in-W{\"u}rzburg" study}, series = {Clinical Research in Cardiology}, volume = {111}, journal = {Clinical Research in Cardiology}, issn = {1861-0692}, doi = {10.1007/s00392-021-01892-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-266678}, pages = {406-415}, year = {2022}, abstract = {Background Exercise training in heart failure (HF) is recommended but not routinely offered, because of logistic and safety-related reasons. In 2020, the German Society for Prevention\&Rehabilitation and the German Society for Cardiology requested establishing dedicated ""HF training groups."" Here, we aimed to implement and evaluate the feasibility and safety of one of the first HF training groups in Germany. Methods Twelve patients (three women) with symptomatic HF (NYHA class II/III) and an ejection fraction ≤ 45\% participated and were offered weekly, physician-supervised exercise training for 1 year. Patients received a wrist-worn pedometer (M430 Polar) and underwent the following assessments at baseline and after 4, 8 and 12 months: cardiopulmonary exercise test, 6-min walk test, echocardiography (blinded reading), and quality of life assessment (Kansas City Cardiomyopathy Questionnaire, KCCQ). Results All patients (median age [quartiles] 64 [49; 64] years) completed the study and participated in 76\% of the offered 36 training sessions. The pedometer was worn ≥ 1000 min per day over 86\% of the time. No cardiovascular events occurred during training. Across 12 months, NT-proBNP dropped from 986 pg/ml [455; 1937] to 483 pg/ml [247; 2322], and LVEF increased from 36\% [29;41] to 41\% [32;46]\%, (p for trend = 0.01). We observed no changes in exercise capacity except for a subtle increase in peak VO2\% predicted, from 66.5 [49; 77] to 67 [52; 78]; p for trend = 0.03. The physical function and social limitation domains of the KCCQ improved from 60 [54; 82] to 71 [58; 95, and from 63 [39; 83] to 78 [64; 92]; p for trend = 0.04 and = 0.01, respectively. Positive trends were further seen for the clinical and overall summary scores. Conclusion This pilot study showed that the implementation of a supervised HF-exercise program is feasible, safe, and has the potential to improve both quality of life and surrogate markers of HF severity. This first exercise experiment should facilitate the design of risk-adopted training programs for patients with HF.}, language = {en} } @article{DoghmanBouguerraFinettiDurandetal.2020, author = {Doghman-Bouguerra, Mabrouka and Finetti, Pascal and Durand, Nelly and Parise, Ivy Zort{\´e}a S. and Sbiera, Silviu and Cantini, Giulia and Canu, Letizia and Hescot, S{\´e}gol{\`e}ne and Figueiredo, Mirna M. O. and Komechen, Heloisa and Sbiera, Iuliu and Nesi, Gabriella and Paci, Angelo and Al Ghuzlan, Abir and Birnbaum, Daniel and Baudin, Eric and Luconi, Michaela and Fassnacht, Martin and Figueiredo, Bonald C. and Bertucci, Fran{\c{c}}ois and Lalli, Enzo}, title = {Cancer-testis antigen FATE1 expression in adrenocortical tumors is associated with a pervasive autoimmune response and is a marker of malignancy in adult, but not children, ACC}, series = {Cancers}, volume = {12}, journal = {Cancers}, number = {3}, issn = {2072-6694}, doi = {10.3390/cancers12030689}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203211}, year = {2020}, abstract = {The SF-1 transcription factor target gene FATE1 encodes a cancer-testis antigen that has an important role in regulating apoptosis and response to chemotherapy in adrenocortical carcinoma (ACC) cells. Autoantibodies directed against FATE1 were previously detected in patients with hepatocellular carcinoma. In this study, we investigated the prevalence of circulating anti-FATE1 antibodies in pediatric and adult patients with adrenocortical tumors using three different methods (immunofluorescence, ELISA and Western blot). Our results show that a pervasive anti-FATE1 immune response is present in those patients. Furthermore, FATE1 expression is a robust prognostic indicator in adult patients with ACC and is associated with increased steroidogenic and decreased immune response gene expression. These data can open perspectives for novel strategies in ACC immunotherapy.}, language = {en} } @article{OregliaSbieraFassnachtetal.2020, author = {Oreglia, Maurine and Sbiera, Silviu and Fassnacht, Martin and Guyon, Laurent and Denis, Josiane and Cristante, Justine and Chabre, Olivier and Cherradi, Nadia}, title = {Early postoperative circulating miR-483-5p is a prognosis marker for adrenocortical cancer}, series = {Cancers}, volume = {12}, journal = {Cancers}, number = {3}, issn = {2072-6694}, doi = {10.3390/cancers12030724}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-203227}, year = {2020}, abstract = {We have previously identified serum miR-483-5p as a preoperative diagnosis and prognosis biomarker for adrenocortical cancer (ACC). Here, we aimed to determine whether circulating miR-483-5p levels measured 3 months post-operatively distinguished patients with good prognosis (no recurrence for at least 3 years; NR3yrs) from patients with poor prognosis (recurrence or death within 3 years after surgery; R < 3yrs). We conducted a single-center retrospective analysis using sera from 48 patients with ACC that were initially non-metastatic and treated by surgery. Sera sampled within 3 months after surgery were available in 26 patients. MiR-483-5p absolute circulating levels were measured using quantitative PCR. Thirteen patients showed a recurrence before 3 years (=R < 3yrs). Thirteen patients showed no recurrence within 3 years, including 11 patients with a follow-up longer than 3 years (=NR3yrs). Serum miR-483-5p levels were higher in R < 3yrs than in NR3yrs: 1,541,990 ± 428,377 copies/mL vs. 388,457 ± 62,169 copies/mL (p = 0.002). Receiver operating characteristic analysis showed that a value of 752,898 copies/mL distinguished R < 3yrs from NR3yrs with 61.5\% sensitivity (CI 31.6-86.1) and 100\% specificity (CI 71.5-100) with an area under the curve of 0.853. Patients with a value below this threshold had a significantly longer recurrence-free and overall survival. In multivariate analysis, miR-483-5p provided the single best prognostic value for recurrence-free survival (RFS) (hazard ratio (HR) for recurrence 5.98, p < 0.011) but not for overall survival. Our study suggests that serum miR-483-5p is a potent early post-operative biomarker for ACC prognosis that might be a better predictor of RFS than currently used markers.}, language = {en} } @article{LacombeSoaresMarianietal.2020, author = {Lacombe, Amanda Meneses Ferreira and Soares, Iber{\^e} Cauduro and Mariani, Beatriz Marinho de Paula and Nishi, Mirian Yumie and Bezerra-Neto, Jo{\~a}o Evangelista and Charchar, Helaine da Silva and Brondani, Vania Balderrama and Tanno, Fabio and Srougi, Victor and Chambo, Jos{\´e} Luiz and Costa de Freitas, Ricardo Miguel and Mendonca, Berenice Bilharinho and Hoff, Ana O. and Almeida, Madson Q. and Weigand, Isabel and Kroiss, Matthias and Zerbini, Maria Claudia Nogueira and Fragoso, Maria Candida Barisson Villares}, title = {Sterol O-acyl transferase 1 as a prognostic marker of adrenocortical carcinoma}, series = {Cancers}, volume = {12}, journal = {Cancers}, number = {1}, issn = {2072-6694}, doi = {10.3390/cancers12010247}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200857}, year = {2020}, abstract = {Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an unfavorable prognosis. Despite the poor prognosis in the majority of patients, no improvements in treatment strategies have been achieved. Therefore, the discovery of new prognostic biomarkers is of enormous interest. Sterol-O-acyl transferase 1 (SOAT1) is involved in cholesterol esterification and lipid droplet formation. Recently, it was demonstrated that SOAT1 inhibition leads to impaired steroidogenesis and cell viability in ACC. To date, no studies have addressed the impact of SOAT1 expression on ACC prognosis and clinical outcomes. We evaluated SOAT1 expression by quantitative real-time polymerase chain reaction and immunohistochemistry in a tissue microarray of 112 ACCs (Weiss score ≥ 3) from adults treated in a single tertiary center in Brazil. Two independent pathologists evaluated the immunohistochemistry results through a semiquantitative approach (0-4). We aimed to evaluate the correlation between SOAT1 expression and clinical, biochemical and anatomopathological parameters, recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS). SOAT1 protein expression was heterogeneous in this cohort, 37.5\% of the ACCs demonstrated a strong SOAT1 protein expression (score > 2), while 62.5\% demonstrated a weak or absent protein expression (score ≤ 2). Strong SOAT1 protein expression correlated with features of high aggressiveness in ACC, such as excessive tumor cortisol secretion (p = 0.01), an advanced disease stage [European Network for the Study of Adrenal Tumors (ENSAT) staging system 3 and 4 (p = 0.011)] and a high Ki67 index (p = 0.002). In multivariate analysis, strong SOAT1 protein expression was an independent predictor of a reduced OS (hazard ratio (HR) 2.15, confidence interval (CI) 95\% 1.26-3.66; p = 0.005) in all patients (n = 112), and a reduced RFS (HR 2.1, CI 95\% 1.09-4.06; p = 0.027) in patients with localized disease at diagnosis (n = 83). Our findings demonstrated that SOAT1 protein expression has prognostic value in ACC and reinforced the importance of investigating SOAT1 as a possible therapeutic target for patients with ACC.}, language = {en} }