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Our current data demonstrate that besides the known risk factors, including apical aneurysm, reduced left ventricular longitudinal systolic function (MAPSE) and advanced diastolic dysfunction, Right ventricular dysfunction as determined by reduced tricuspid annular plane systolic excursion (TAPSE) or right ventricular fractional area change (RV_FAC) is independently associated with left ventricular thrombus formation in acute anterior myocardial infarction patients, especially in the setting of anterior myocardial infarction without the formation of an apical aneurysm. This study suggests that besides left ventricular abnormalities, right ventricular dysfunction likewise contributes LVT formation in patients with acute anterior myocardial infarction.
Aufgrund des zunehmenden Einsatzes von Schnittbildgebungen werden immer mehr Nebennieren-Raumforderungen zufällig entdeckt. Häufig ist bei diesen Zufallsbefunden („Inzidentalome“) laborchemisch eine „autonome Cortisol-Sekretion“ auffällig, ohne dass jedoch klinische Zeichen eines Glukokortikoid-Exzesses sichtbar wären.
Ein florides Cushing-Syndrom führt bekanntermaßen zu einer erhöhten kardiovaskulären Morbidität und Mortalität. Ziel unserer Untersuchung war es, die Prävalenz kardiovaskulärer Risikofaktoren und Ereignisse bei Patienten mit einem Nebennieren-Inzidentalom zu ermitteln. Hierbei wurden die Adenome hinsichtlich ihrer sekretorischen Aktivität in drei Subgruppen eingeteilt („nicht-funktionell“, „mögliche autonome Cortisol-Sekretion“ und „autonome Cortisol-Sekretion“) und getrennt voneinander betrachtet.
Die vorliegende Einzelzenter-Studie umfasst einen Zeitraum von 20 Jahren und beinhaltet sowohl retro- als auch prospektive Elemente.
Insgesamt konnten 260 Patienten mit einem Nachsorgeintervall von durchschnittlich fast 9 Jahren inkludiert werden. Die Raten von arterieller Hypertonie, Diabetes mellitus und Dyslipidämie stiegen mit zunehmender Cortisol-Sekretion an; dies war sowohl bei der Erstdiagnose als auch bei der letzten erfassten Nachsorge zu beobachten. Patienten mit einem nicht-funktionellen Adenom wiesen nach der Erstdiagnose eine signifikant geringere Inzidenz kardiovaskulärer Ereignisse auf als Patienten mit einer autonomen Cortisol-Sekretion. Mittels einer multivariaten Cox-Regression wurden die Höhe des Serumcortisols im Dexamethason-Suppressionstest und eine positive Eigenanamnese als signifikante Einflussfaktoren für das Auftreten kardiovaskulärer Ereignisse ermittelt.
Eine klinisch unterschwellige, jedoch chronische Cortisol-Exposition im Sinne einer autonomen Cortisol-Sekretion erhöht demnach das Risiko der betroffenen Patienten für die Entwicklung von Herz-Kreislauf-Erkrankungen.
(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).
Die Bindung des Chemokinrezeptors CCR7 mit seinen Liganden CCL19 und CCL21 initiiert neben immunmodulatorischen auch antiapoptotische Effekte und beeinflusst die Geschwindigkeit der Zellmigration. Ein Zusammenhang zwischen CCR7-Expression und Lymphknotenmetastasierung sowie Gesamtüberleben ist für verschiedene Tumor-Entitäten dokumentiert. In der vorliegenden Arbeit wird erstmalig die CCR7-Expression in der Nebenniere, bei Nebennierenadenomen (ACA) und beim Nebennierenkarzinom (ACC) untersucht.
Methoden: Es wurden insgesamt 252 Nebennierengewebe (ACC n=128, ACC-Metastasen n=61, ACA n=59, normale Nebennieren n=4) mittels immunhistochemischer Färbung und 37 Gewebe (ACC n=9, ACA n=24, normale Nebennieren n=4) mittels quantitativer real-time PCR auf CCR7-Expression hin untersucht. Anschließend wurden die Beziehungen zwischen CCR7-Level (dargestellt durch einen semiquantitativen H-Score) und ACC-Metastasierung, dem Gesamt- und progressionsfreien Überleben der Patienten und verschiedenen klinischen bzw. histopathologischen Parametern wie ENSAT-Stadium, Hormonsekretion und Ki67-Index analysiert.
Ergebnisse: CCR7 konnte in allen untersuchten Nebennierengeweben in unterschiedlicher Intensität nachgewiesen werden. In der gesunden Nebenniere fand sich eine starke CCR7-Expression in den äußeren Rindenzonen und dem Nebennierenmark. In den ACA zeigten sich vor allem in endokrin-inaktiven Adenomen (EIA, H-Score 2.4) und cortisolproduzierenden Adenomen (CPA, H-Score 2.3) hohe CCR7-Werte. EIA wiesen damit signifikant höhere CCR7-Level verglichen mit ACC und aldosteronproduzierenden Adenomen (APA) auf, deren H-Score bei 1.8 bzw. 1.3 lagen. CPA hatten eine signifikante höhere CCR7-Expression als APA (p<0.005).
Bei den Nebennierenkarzinomen fand sich ein signifikanter Unterschied zwischen der CCR7-Membran-Expression von Lymphknotenmetastasen und den Primärtumoren (H-Score: 2.5 vs. 1.8; p<0.001), sowie zwischen Lymphknotenmetastasen und Lokalrezidiven (H-Score: 2.5 vs. 1.6; p<0.001) und Lymphknotenmetastasen und Lungenmetastasen (H-Score: 2.5 vs. 1.7; p=0.03). Hinweise für eine Korrelation zwischen CCR7-Expression und der Tumorgröße, der Hormonproduktion oder verschiedener Prognosefaktoren (ENSAT-Stadium, Weiss-Score, Ki67-Index) fanden sich nicht. Patienten mit Lymphknotenmetastasen bei Diagnose des ACC wiesen in ihren Primärtumoren signifikant höhere CCR7-Level auf als Patienten ohne Lymphknotenmetastasen (H-Score Mittelwert: 2.1 vs. 1.7; p=0.02). Die CCR7-Expression hatte in diesem Patientenkollektiv keinen signifikanten Einfluss auf das Gesamt- oder das progressionsfreie Überleben. In der Tendenz erlitten Patienten mit hoher CCR7-Expression einen früheren Tumorprogress.
Schlussfolgerung: CCR7 ist regelhaft in den unterschiedlichen Nebennierengeweben exprimiert. Entsprechend der Beobachtungen bei anderen Karzinomerkrankungen, war eine hohe CCR7-Expression mit tendenziell kürzerer progressionsfreier Zeit und einer frühen Lymphknotenmetastasierung assoziiert. Um zu klären, welche weitere Rolle CCR7 in der gesunden Nebenniere und den Nebennierentumoren spielt, sind weitere Untersuchungen notwendig.
Cardiovascular diseases (CVD), subsuming atherosclerosis of the coronary arteries and subsequent myocardial infarction, are the leading cause of death in the European Union (over 4 million deaths annually), with devastating individual and economic consequences.
Recent studies revealed that T cells play a crucial role in post-MI inflammation, healing and remodelling processes. Nevertheless, the specificity profile of adaptive immune responses in the infarcted myocardium has not yet been differentiated. The experiments portrayed in this thesis sought to assess whether post-MI CD4+ T cell responses in mice are triggered by heart specific antigens, and eventually identify relevant epitopes.
We were able to create a murine antigen atlas including a list of 206 epitopes for I-Ab and 193 epitopes for I-Ad presented on MHC-II in the context of MI. We sought to consecutively test this panel by in vitro T cell proliferation and antigen recall assays ex vivo. The elispot assay was used as a readout for antigen-specific stimulation by measurement of IL-2 and IFN-γ production, currently the most sensitive approach available to detect even small counts of antigen producing cells. Splenocytes as well as lymphocytes from mediastinal lymph nodes were purified from animals 7 days or 56 days after EMI conducted by ligation of the left anterior descending artery.
We were able to provide evidence that post-MI T cell responses in Balb/c mice are triggered by heart-specific antigens and that MYHCA, especially MYHCA614-628, is relevant for that response. Moreover, a significant specific T cell response after MI in C57BL/6J mice was observed for α actin, cardiac muscle 1 [ACTC1], myosin-binding protein C3 [MYBPC3] and myosin heavy chain α [MYHCA] derived heart specific antigens.
Generally, the epitopes of interest for Balb/c as well as C57BL/6J could be further investigated and may eventually be modulated in the future.
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.
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.
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.
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.
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.
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.
Herzinsuffizienz ist eine sehr häufige Erkrankung im hohen Lebensalter mit zudem signifikant hoher Mortalität - vergleichbar mit der Mortalität häufiger Krebsarten. Biomarker wie die natriuretischen Peptide sind von großer Wichtigkeit hinsichtlich der Diagnosestellung und Prognoseabschätzung. Auch inflammatorische Marker, Copeptin sowie Mid-regionales Adrenomedullin (MR-proADM) haben eine wichtige Rolle sowohl in der Diagnosestellung der Herzinsuffizienz als auch in der Prognoseabschätzung eingenommen. Die Aussagekraft der Biomarker in einem diagnostisch naiven Kollektiv mit dem klinisch-anamnestischen Verdacht auf das Vorliegen einer Herzinsuffizienz ist jedoch bisher kaum untersucht worden.
Die Handheld-BNP-Studie schloss diagnostisch naive Patienten ein, die sich mit Symptomen passend zu einer Herzinsuffizienz beim Hausarzt vorstellten. Binnen 14 Tagen erfolgte die Referenzdiagnose durch einen niedergelassenen Kardiologen. Ziel war es, die diagnostische Aussagekraft von BNP und der miniaturisierten Echokardiographie im primärärztlichen Bereich zu überprüfen. Die vorliegenden Follow-Up-II-Untersuchung untersuchte die prognostische Aussagekraft moderner Biomarker (N-terminales B-natriuretisches Peptid (NT-proBNP), Mid-regionales atriales natriuretisches Peptid (MR-proANP), Mid-regionales Adrenomedullin (MR-proADM), Copeptin, Tumornekrosefaktor Alpha (TNF- α) und hochsensitives C-reaktives Protein (hsCRP)). Die Endpunkte waren Tod jeder Ursache sowie kardiovaskulärer Tod.
Insgesamt traten in unseren Analysen die natriuretischen Peptide mit ihrer prognostischen Aussagekraft hervor. In den univariaten Analysen zeigte sich das NT-proBNP als wichtigster Biomarker und in den multivariaten Analysen das MR-proANP.
Bei diagnostisch naiven Patienten, die sich mit Herzinsuffizienzsymptomen bei ihrem Hausarzt vorstellen, besteht ein hohes Mortalitätsrisiko. Um diese Patienten adäquat zu selektieren, eine leitliniengerechte Therapie einzuleiten und um das Fortschreiten der Erkrankung aufzuhalten, ist eine frühzeitige Diagnosestellung beim Kardiologen wichtig. Natriuretische Peptide sind prädiktiv, jedoch stellt das MR-proANP aufgrund fehlender generalisierter Verfügbarkeit keine realistische Option im primärärztlichen Bereich dar. Das NT-proBNP hat eine flächendeckende Verfügbarkeit und wird mittlerweile in den Herzinsuffizienz-Leitlinien der ESC bei der Verdachtsdiagnose Herzinsuffizienz standardmäßig empfohlen.
Hintergrund:
Eine „blinde“ Perikardiozentese ist bei hämodynamisch instabilen Patienten in akuten Notfallsituationen Standard, wenn eine bildmorphologische Darstellung nicht verfügbar ist. In diesen Fällen orientiert man sich für den Ausgangspunkt der Punktion und die Stichrichtung an bestimmten anatomischen Landmarken. In der Literatur werden verschiedene Perikardpunktions-Techniken im Hinblick auf deren Ausgangspunkt und Stichrichtung für eine „blinde“ Perikardiozentese beschrieben. Ziel dieser retrospektiven Studie ist es, die Erfolgs- und Komplikationsrate von 13 verschiedenen simulierten Stichrichtungen für eine Perikardiozentese zu vergleichen.
Methodik:
Für die Simulation der Perikardpunktionen wurden 150 CT-Bilder von Patienten mit einem Perikarderguss von > 1 cm (Distanz zwischen Epi- und Perikard) benutzt. Es wurden 13 verschiedene Perikardpunktionen simuliert, die sich in ihrem Ausgangspunkt der Punktion, der Stichrichtung und dem Winkel zur Transversalebene unterschieden. Insgesamt wurden 1.950 Simulationen durchgeführt. Eine Perikardiozentese wurde als „erfolgreich“ gewertet, wenn der Perikarderguss getroffen wurde und die Saumbreite an der Punktionsstelle > 0,5 cm war. Im Falle einer „nicht erfolgreichen“ Punktion konnte der Erguss nicht getroffen werden und/ oder die Saumbreite an der Punktionsstelle war < 0,5 cm. Sowohl eine „erfolgreiche“ als auch eine „nicht erfolgreiche“ Punktion konnte mit Komplikationen verbunden sein. Die Fehlpunktion von Leber, Lunge, A. thoracica interna, RIVA, Colon oder Magen wurde als Komplikation gewertet.
Ergebnisse:
Die besten Ergebnisse konnten mit der Perikardpunktion von subxiphoidal ausgehend Richtung linke Medioclavicularlinie in einem Winkel von 30° zur Transversalebene erzielt werden: Die Erfolgsrate betrug 87 %. Diese simulierte Perikardiozentese hatte auch die niedrigste Komplikationsrate (5 %): Leber (n = 3; 2 %), Lunge (n = 2; 1,3 %), RIVA (n = 1; 0,7 %) und Colon (n = 1; 0,7 %). Die mittlere Distanz von der Punktionsstelle bis zum Perikarderguss betrug 5,5 cm.
Schlussfolgerung:
Im Rahmen dieser CT-basierten Studie bei 150 Patienten mit einem relevanten Perikarderguss (Distanz zwischen Epi- und Perikard > 1 cm) konnte mittels Simulation gezeigt werden, dass eine von subxiphoidal ausgehende „blinde“ Perikardiozentese in Richtung auf die linke MCL in einem Winkel von 30° zur Transversalebene mit 87 % die höchste Erfolgsrate und mit 5 % die niedrigste Komplikationsrate hat. Insgesamt variierte die Komplikationsrate je nach Stichrichtung zwischen 5 % und 32 %. Dies bestätigt, dass eine Perikardiozentese wenn möglich immer mithilfe bildmorphologischer Darstellung durchgeführt werden sollte, um Komplikationen auf ein Minimum zu reduzieren. Die „blinde“ Perikardpunktion sollte ausschließlich in äußersten Notfällen zum Einsatz kommen, wenn eine Bildgebung nicht oder nicht schnell genug zur Verfügung steht.
Phäochromozytome und Paragangliome (PPGL) sind seltene, katecholaminproduzierendeTumore des chromaffinen Gewebes. Die Erkrankung ist durch die Überproduktion von Katecholaminen gekennzeichnet und kann lebensbedrohliche Folgen haben. Die dieser Arbeit zugrunde liegende Studie untersuchte die interindividuellen Unterschiede im Metabolitenprofil bei Patient*innen mit PPGL im Vergleich zu Kontrollen mittels Flüssigchromatographie-Massenspektrometrie und einem Targeted Metabolomic Ansatz. Targeted Metabolomics beschreibt die Messung und Quantifizierung von im Voraus definierten Metaboliten in einer Probe. Von den 188 gemessenen Metaboliten zeigten vier Metabolite eine signifikanten Veränderung zwischen den Gruppen (Histidin, Threonin, LysoPC a C28:0 und Summe der Hexosen). Für alle vier Metabolite wurde ein Zusammenhang mit Katecholaminen im Urin beziehungsweise Metanephrinen im Plasma nachgewiesen. Subgruppenanalysen zeigten weitere Hinweise auf geschlechts- und phänotypspezifische Unterschiede im Metabolitenprofil zwischen Patient*innen mit PPGL und Kontrollen.
Das fortgeschrittene Nebennierenkarzinom stellt Mediziner:innen im klinischen Alltag mit seinem aggressiven Verhalten vor eine große therapeutische Herausforderung. Bisher nimmt Mitotane die zentrale Rolle der medikamentösen Tumortherapie ein. Obwohl es seit über 60 Jahren im Einsatz ist, wurde die Frage der Effektivität einer Monotherapie im fortgeschrittenen Stadium in der Literatur bisher nur wenig untersucht. Daher wurden in dieser retrospektiven Studie Daten von 127 Patient:innen aus dem deutschen Nebennierenkarzinomregister untersucht, welche eine Mitotanemonotherapie bei Erst/- Rezidivdiagnose eines fortgeschrittenen ACC erhielten. Anhand dieses Datensatzes wurde die Ansprechrate, das progressionsfreie und Gesamtüberleben mithilfe der Kaplan- Meier- Methode ermittelt. Darüber hinaus wurde der Versuch einer Definition potenzieller Prädiktoren für ein verbessertes Ansprechen mittels Cox- Regressionsanalyse unternommen. Insgesamt wurde bei 26 Patient:innen (20,5%) ein objektives Ansprechen erzielt, von denen 3 Patient:innen eine komplette und 23 Patient:innen eine partielle Remission erreichten. Bei 32 weiteren Patient:innen (25,2%) wurde eine Stabilisierung der Erkrankung verzeichnet. Das progressionsfreie Überleben lag im Median bei 4,1 Monaten, das mediane Gesamtüberleben betrug 18,5 Monate. In der multivariaten Cox- Regressionsanalyse konnten zwei wesentliche, unabhängige Faktoren identifiziert werden: Patient:innen mit einer niedrigen Tumorlast (definiert als <10 Läsionen) scheinen im Vergleich zu Patient:innen mit einer höheren Tumorlast von der Therapie hinsichtlich des progressionsfreien Überlebens (HR:0,51; 95%-CI:0,33-0,79; p=0,02) und Gesamtüberlebens (HR:0,59; 95%-CI: 0,30-0,91; p=0,017) besser zu profitieren. Interessanterweise zeigen Patient:innen, die Mitotane erst zum Zeitpunkt eines Spätrezidivs (>360 Tage nach Erstdiagnose) erhalten haben, ein deutlich besseres Ansprechen im Vergleich zu Patient:innen, welche Mitotane unmittelbar nach Erstdiagnose erhielten: Es zeigte sich ein verlängertes progressionsfreies Überleben (HR: 0,35; 95%-CI: 0,23-0,55; p=0,001) und Gesamtüberleben (HR: 0,34; 95%-CI: 0,22-0,52; p=0,001). In der weiteren Analyse zeigte sich, dass sich ein Mitotanespiegel von >14mg/l günstig auf ein verbessertes Gesamtüberleben auswirkt. Zusammenfassend zeigt unsere bisher weltweit größte zu diesem Thema durchgeführte Studie, dass eine Mitotanemonotherapie unter bestimmten Voraussetzungen zu sehr guten Ergebnissen führen kann: Dabei scheinen Patient:innen mit einer niedrigen Tumorlast und dem späten Beginn einer Mitotanetherapie besonders geeignet für diese Therapiemodalität zu sein, während man Patient:innen mit Metastasen bei Erstdiagnose bzw. einer hohen Tumorlast zum Zeitpunkts des Rezidivs besser direkt mit einer Kombination aus Mitotane plus zytotoxischer Chemotherapie behandelt.
Nebennieren-Inzidentalome werden durch den zunehmenden Einsatz von bildgebenden Methoden immer häufiger zufällig entdeckt. Hierbei liegen vorrangig klinisch unauffällige Nicht-Aldosteron-produzierende adrenokortikale Adenome (NAPACA) vor, wobei Nicht-funktionelle Adenome (NFA) von Tumoren mit (möglicher) autonomen Cortisol-Sekretion (MACS und ACS) zu differenzieren sind.
Der Verlauf und die Prognose dieser Patienten werden teilweise noch kontrovers diskutiert. Die wesentlichen Fragestellungen dieser Arbeit lauteten, welche Dynamik Nebennieren-Inzidentalome (und hierbei insbesondere die NAPACA) hinsichtlich Hormonsekretion und Malignitätspotential aufweisen und welchen Einfluss sie auf das Gesamtüberleben der Betroffenen ausüben.
In dieser Studie wurde hierfür das Patientenkollektiv des Universitätsklinikums Würzburg zwischen 1998 und 2017 retrospektiv untersucht. Die Zuordnung zu Entitäten und die Interpretation der Daten erfolgte dabei anhand der Empfehlungen der aktuellen Europäischen Leitlinie zum Management von Nebennieren-Inzidentalomen.
Für diese Arbeit wurden 357 Patienten mit einem Nebennieren-Inzidentalom identifiziert, von denen 263 (73,7 %) der NAPACA-Gruppe zuzuordnen waren. Im Verlauf kam es bei 39 (10,9 %) der Patienten zu relevanten Veränderungen der endokrinen Aktivität und bei 4 (1,1 %) auch der Dignität, wodurch die Zuordnung zu einer anderen Tumorentität notwendig wurde. In den Mortalitätsanalysen stellten Hormonaktivität und Malignität relevante prognostische Einflüsse bei Patienten mit Nebennieren-Inzidentalom dar. Speziell Patienten mit MACS und ACS wiesen eine höhere Gesamtmortalität auf als solche mit NFA, wobei das Serumcortisol im Dexamethason-Suppressionstest für die multivariaten Cox-Regressionsanalysen als kontinuierliche und nicht kategoriale Variable betrachtet wurde. NAPACA-Patienten starben vorrangig an malignen, kardiovaskulären und infektiösen Ursachen.
Zusammenfassend weisen Patienten mit Nebennieren-Inzidentalom im Allgemeinen und mit NAPACA im Speziellen im Verlauf eine geringe endokrinologische und maligne Dynamik auf. Ihr Gesamtüberleben wird maßgeblich von Hormonaktivität und Dignität bzw. von der Höhe des Serumcortisols im Dexamethason-Hemmtest beeinflusst.
Ziel: Erfassung von Morbidität, hypokalzämischen Ereignissen, subjektiver Lebensqualität (QoL) und Leistungsfähigkeit im täglichen Leben bei Patienten mit chronischem Hypoparathyreoidismus (HPT).
Methoden: Kontaktierung von Patienten mit chronischem HPT und Pseudo-HPT (n=412) aus mehreren deutschen Zentren mit Antwort von 215 (Rücklaufquote 52%) und Einschluss von 205 Probanden. Die Patienten erhielten einen krankheitsspezifischen Fragebogen. Die Bewertung der subjektiven QoL erfolgte mit dem SF-36-Fragebogen. Die Daten wurden mit geschlechts- und altersangepassten Kontrollen verglichen.
Ergebnisse: SF-36-Werte zeigten bei HPT-Patienten im Vergleich zur Allgemeinbevölkerung eine signifikant beeinträchtigte QoL. Die Lebenszeitprävalenz von Depressionen, Angstzuständen und Niereninsuffizienz war bei HPT-Patienten höher (22% vs. 15%; 21% vs. 6%; 11% vs. 2%, alle p<0,01). Signifikant mehr Patienten erhielten Antihypertensiva oder Antiepileptika (44% vs. 34%, p=0,003; 5% vs. 2%, p=0,01). Die Prävalenz von Katarakt, Herzrhythmusstörungen, Nierensteinen und Nephrokalzinose betrug 18%, 16%, 8% bzw. 6%. 37% berichteten über Einschränkungen im Beruf und mehr HPT-Patienten waren im Alter von <65 Jahren berentet verglichen zu Kontrollen (21% vs. 10%, p<0,001). HPT-Patienten gaben häufiger Beeinträchtigungen von Alltagsaktivitäten aus gesundheitlichen Gründen an (58% vs. 32%, p<0,001). Seit der Erstdiagnose waren 36% der Patienten mind. einmal in einer Notaufnahme vorstellig oder wegen HPT ins Krankenhaus eingeliefert worden. Die Gesamthäufigkeit von hypokalzämischen Notfällen mit notwendiger i.v. Calciumgabe betrug 14,7 Ereignisse pro 100 Patientenjahre. Die Hospitalisierungsrate innerhalb der letzten 12 Monate unterschied sich nicht signifikant von der Kontrollgruppe.
Schlussfolgerung: Trotz etablierter Therapie ist ein chronischer HPT mit einer reduzierten subjektiven QoL, einer Vielzahl von Komplikationen und einer Beeinträchtigung des Alltags- und Berufslebens assoziiert.
Das Nebennierenkarzinom ist ein sehr selten auftretender Tumor. Mitotane ist derzeit das einzige zugelassene Medikament zur adjuvanten und palliativen Behandlung von betroffenen Patienten. Eine häufig beobachtete Nebenwirkung ist die Veränderung des Schilddrüsenstoffwechsels. Mithilfe des Nebennierenkarzinomregisters ENSAT konnten in die vorliegende Arbeit 129 Patienten eingeschlossen und deren Patientendaten retrospektiv ausgewertet werden. Somit konnte insbesondere die Frage des veränderten Schilddrüsenstoffwechsels in den Patientengruppen ohne Schilddrüsenmedikation und mit Medikation untersucht und ein möglicher Einfluss der Einnahme von Levothyroxin beantwortet werden. Bei der Auswertung der Patientendaten zeigte sich, dass eine isolierte fT4-Erniedrigung in beiden Patientengruppen sehr häufig auftritt (Gruppe ohne Schilddrüsen-Medikamente 60 %; Gruppe mit Schilddrüsenmedikamenten 57 %). Bei Auswertung der fT4-Werte war auffällig, dass Patienten mit einer erniedrigten fT4-Stoffwechsellage unter Mitotanetherapie, schon vor Therapiebeginn signifikant niedrigere Ausgangswerte aufwiesen (Patientengruppe mit Schilddrüsenmedikation 18,3 pmol/l vs. 15,65 pmol/l; Patientengruppe ohne Schilddrüsenmedikation 17,3 pmol/l vs. 14,75 pmol/l). Unter Mitotanetherapie konnte sowohl in den Gruppen mit erniedrigter fT4-Stoffwechsellage, als auch ohne isoliert erniedrigtes fT4 ein Absinken des fT4-Wertes beobachtet werden. Jedoch kam es nicht in jedem Fall zu einer Änderung des Schilddrüsenstoffwechsels mit der Stoffwechsellage „erniedrigtes fT4“. TSH und fT3 zeigten keine signifikante Veränderung in beiden Patientenkollektiven unter Mitotanetherapie. Da der Mitotanespiegel nur mit geringer, bzw. keiner Effektstärke mit dem fT4-Wert korrelierte, kann mithilfe der Höhe der Mitotaneplasmakonzentration keine definitive Vorhersage zur Entwicklung des fT4-Wertes gemacht werden. Mithilfe eines In-vitro-Experimentes konnte widerlegt werden, dass isoliert erniedrigtes fT4 aufgrund eines messtechnischen Fehlers im Labor entsteht. Eine durchgeführte, kontrollierte Levothyroxin-Gabe bei Patienten mit erniedrigter fT4-Stoffwechsellage zeigte, dass bei regelmäßiger Kontrolle der Schilddrüsenparameter und individueller Levothyroxin-Dosisanpassung eine Normalisierung des Schilddrüsenfunktionsstoffwechsels in 71 % erreicht werden konnte. Ein allgemeiner Behandlungsstandard konnte nicht erkannt werden, da der Bedarf an Levothyroxin sehr unterschiedlich war. Eine Anfangsdosis von 50 µg scheint empfehlenswert und sollte anschließend abhängig von den Laborwerten in den Verlaufskontrollen angepasst werden. Nach wie vor ist der Pathomechanismus, welcher zur isolierten fT4-Erniedrigung führt, nicht vollständig geklärt. Am wahrscheinlichsten erscheint eine Induktion von TBG durch Mitotane. Insgesamt zeigt diese Arbeit erstmals in einer großen Kohorte, wenn auch mit eingeschränkter Aussagekraft aufgrund der retrospektiven Erhebung, die Häufigkeit und Art und Weise der Veränderungen von Schilddrüsenfunktionstests unter einer Mitotanetherapie und ermöglicht so bei behandelnden Ärzten eine genauere Einschätzung der Relevanz dieser Nebenwirkung.
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, Würzburg 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.
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.
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.
Ziele
Diese Studie untersuchte, ob ein aktivierter R-Modus, als Surrogat für eine chronotrope Inkompetenz, bei Patienten mit kardialem Device (CIED), mit einer schlechteren Prognose während und nach einer Episode von akuter Herzinsuffizienz (AHF) verbunden ist.
Methoden und Ergebnisse
623 Patienten, die an einer laufenden prospektiven Kohortenstudie zur Phänotypisierung von Patienten mit akuter Herzinsuffizienz teilnahmen, wurden untersucht. Wir verglichen CIED-Träger mit R-Modus-Stimulation (n=37) mit CIED-Trägern ohne R-Modus (n=64) und Patienten ohne CIED (n=511). Die durchschnittliche Herzfrequenz bei Aufnahme lag bei Patienten im R-Modus signifikant niedriger als bei Patienten mit CIED, aber ohne R-Modus oder Patienten ohne CIED. Zwar war die Krankenhaussterblichkeit in allen Gruppen ähnlich, jedoch zeigte sich das für Alter und Geschlecht adjustierte 12-Monats-Mortalitätsrisiko in der R-Modus-Gruppe signifikant erhöht. Diese Effekte blieben auch nach multivariabler Adjustierung anhand der Komorbiditäten bestehen.
Schlussfolgerung
Bei Patienten, die wegen AHF aufgenommen wurden, war die Stimulation im R-Modus mit einem signifikant erhöhten 12-Monats-Mortalitätsrisiko verbunden. Unsere Ergebnisse legen nahe, dass chronotrope Inkompetenz per se mit einer erhöhten Vulnerabilität einhergeht und möglicherweise nicht angemessen durch Beschleunigungs-basierte R-Modus-Stimulation während und nach einer AHF-Episode behandelt wird.
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%.
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.
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.
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.
Ziele
Diese Studie untersuchte, ob ein aktivierter R-Modus, als Surrogat für eine chronotrope Inkompetenz, bei Patienten mit kardialem Device (CIED), mit einer schlechteren Prognose während und nach einer Episode von akuter Herzinsuffizienz (AHF) verbunden ist.
Methoden und Ergebnisse
623 Patienten, die an einer laufenden prospektiven Kohortenstudie zur Phänotypisierung von Patienten mit akuter Herzinsuffizienz teilnahmen, wurden untersucht. Wir verglichen CIED-Träger mit R-Modus-Stimulation (n=37) mit CIED-Trägern ohne R-Modus (n=64) und Patienten ohne CIED (n=511). Die durchschnittliche Herzfrequenz bei Aufnahme lag bei Patienten im R-Modus signifikant niedriger als bei Patienten mit CIED, aber ohne R-Modus oder Patienten ohne CIED. Zwar war die Krankenhaussterblichkeit in allen Gruppen ähnlich, jedoch zeigte sich das für Alter und Geschlecht adjustierte 12-Monats-Mortalitätsrisiko in der R-Modus-Gruppe signifikant erhöht. Diese Effekte blieben auch nach multivariabler Adjustierung anhand der Komorbiditäten bestehen.
Schlussfolgerung
Bei Patienten, die wegen AHF aufgenommen wurden, war die Stimulation im R-Modus mit einem signifikant erhöhten 12-Monats-Mortalitätsrisiko verbunden. Unsere Ergebnisse legen nahe, dass chronotrope Inkompetenz per se mit einer erhöhten Vulnerabilität einhergeht und möglicherweise nicht angemessen durch Beschleunigungs-basierte R-Modus-Stimulation während und nach einer AHF-Episode behandelt wird.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Predicting hypertension subtypes with machine learning using targeted metabolites and their ratios
(2022)
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.
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.
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.
Hintergrund und Fragestellung
Die Entwöhnung von Beatmungsgeräten wird nicht immer auf der primär 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 Überleitungsmanagements und des Interhospitaltransfers von Weaningpatienten unter besonderer Berücksichtigung der Dokumentationsqualität.
Methodik
Es erfolge eine retrospektive Datenanalyse eines Jahrs (2018) auf 2 Intensivstationen eines Universitätsklinikums. 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 entwöhnt (v. a. Sepsis und ARDS). Die Routinedokumentation war bei den Abschnitten „Spontaneous Breathing Trial“, „Bewertung der Entwöhungsbereitschaft“ und „vermutete Entwöhnbarkeit“ ausreichend, um die Erfüllung der Parameter der S2k-Leitlinie „Prolongiertes Weaning“ adäquat zu beurteilen. Vorwiegend wurden diese Patienten mit Tracheostoma (76 %) in Rehabilitationskliniken (44 %) mittels spezialisierten Rettungsmitteln des arztbegleiteten Patiententransports verlegt (75 %).
Diskussion
Die Verlegung nicht entwöhnter Patienten nach initialem Intensivaufenthalt ist ein relevantes Thema für den Interhospitaltransfer. Die Routinedokumentation eines strukturierten Weaningprozesses ist in Kernelementen ausreichend, um den Weaningprozess lückenlos zu beschreiben. Dies ist für die Kontinuität in der Weiterbehandlung dieser Patienten von großer Bedeutung.
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.
Impact of cardiovascular risk factors on myocardial work-insights from the STAAB cohort study
(2022)
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 Würzburg, 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.
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.
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.
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.
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.
Establishing a cardiac training group for patients with heart failure: the "HIP-in-Würzburg" study
(2022)
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.
Im Rahmen des metabolischen Syndroms bei morbider Adipositas kommt es unter anderem zu Imbalancen im autonomen Nervensystem (ANS): ein Missverhältnis von Sympathikus und Parasympathikus (PS) führt zu einer Dysregulation von orexigenen und anorexigenen Hormonen und konsekutiv zu einer weiteren Gewichtszunahme.
Diese Arbeit untersucht die Auswirkung von bariatrischen Operationen auf das abdominale ANS anhand des parasympathisch regulierten PPP drei Monate nach Intervention. Die Veränderungen der Imbalance wurden mit Hilfe eines modifizierten Sham Feedings (MSF) ermittelt, bei dem nur die kephale Phase der Nahrungsaufnahme durchlaufen und die Mahlzeiten nicht geschluckt wird. Die PPP-Spiegel im Verlauf des MSF sind daher ausschließlich eine Darstellung des PS. Zusätzlich wurden die Verläufe der Insulin- und Glukosewerte bestimmt.
Die PPP-Spiegel der normalgewichtigen Kontrollgruppe sind signifikant höher als die der adipösen Patienten prä- und postoperativ. Die Kurvenverläufe des PPP sind aber zwischen den Gruppen vergleichbar. Somit ist die akute Reaktion des PS auf die Nahrungsaufnahme bei morbider Adipositas zwar unverändert, es zeigt sich aber keine Verbesserung der ANS-Dysfunktion kurz nach Intervention. Die Aufteilung der Patienten in Jüngere und Ältere (verglichen mit dem Durchschnittsalter der Studie) ergibt postoperativ absolut und relativ eine Zunahme der PPP-Spiegel bei den Älteren, während es bei den Jüngeren zu einem Abfall kommt. Bei halbierter Gruppegröße ist die Aussagekraft der Signifikanz jedoch eingeschränkt.
Auch ohne diabetische Stoffwechsellage gleichen sich die Insulin- und Glukosewerte der Patienten post-OP denen der Kontrollen an. Eine mögliche Ursache hierfür ist aber nicht nur eine primäre ANS-Verbesserung, denn vor allem in der ersten postoperativen Phase scheint die starke Nahrungsmittelrestriktion mehr Auswirkungen zu haben. Eine spätere Besserung der ANS-Imbalance durch z.B. Gewichtsverlust ist jedoch nicht ausgeschlossen.
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.
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.
Differences between immunotherapy-induced and primary hypophysitis—a multicenter retrospective study
(2022)
Objective
Immune checkpoint inhibitors can cause various immune-related adverse events including secondary hypophysitis. We compared clinical characteristics of immunotherapy-induced hypophysitis (IIH) and primary hypophysitis (PH)
Design
Retrospective multicenter cohort study including 56 patients with IIH and 60 patients with PH.
Methods
All patients underwent extensive endocrine testing. Data on age, gender, symptoms, endocrine dysfunction, MRI, immunotherapeutic agents and autoimmune diseases were collected.
Results
Median time of follow-up was 18 months in IIH and 69 months in PH. The median time from initiation of immunotherapy to IIH diagnosis was 3 months. IIH affected males more frequently than PH (p < 0.001) and led to more impaired pituitary axes in males (p < 0.001). The distribution of deficient adenohypophysial axes was comparable between both entities, however, central hypocortisolism was more frequent (p < 0.001) and diabetes insipidus considerably less frequent in IIH (p < 0.001). Symptoms were similar except that visual impairment occurred more rarely in IIH (p < 0.001). 20 % of IIH patients reported no symptoms at all. Regarding MRI, pituitary stalk thickening was less frequent in IIH (p = 0.009). Concomitant autoimmune diseases were more prevalent in PH patients before the diagnosis of hypophysitis (p = 0.003) and more frequent in IIH during follow-up (p = 0.002).
Conclusions
Clinically, IIH and PH present with similar symptoms. Diabetes insipidus very rarely occurs in IIH. Central hypocortisolism, in contrast, is a typical feature of IIH. Preexisting autoimmunity seems not to be indicative of developing IIH.
Purpose
Pheochromocytomas and Paragangliomas (PPGL) result in chronic catecholamine excess and serious health complications. A recent study obtained a metabolic signature in plasma from PPGL patients; however, its targeted nature may have generated an incomplete picture and a broader approach could provide additional insights. We aimed to characterize the plasma metabolome of PPGL patients before and after surgery, using an untargeted approach, and to broaden the scope of the investigated metabolic impact of these tumors.
Design
A cohort of 36 PPGL patients was investigated. Blood plasma samples were collected before and after surgical tumor removal, in association with clinical and tumor characteristics.
Methods
Plasma samples were analyzed using untargeted nuclear magnetic resonance (NMR) spectroscopy metabolomics. The data were evaluated using a combination of uni- and multi-variate statistical methods.
Results
Before surgery, patients with a nonadrenergic tumor could be distinguished from those with an adrenergic tumor based on their metabolic profiles. Tyrosine levels were significantly higher in patients with high compared to those with low BMI. Comparing subgroups of pre-operative samples with their post-operative counterparts, we found a metabolic signature that included ketone bodies, glucose, organic acids, methanol, dimethyl sulfone and amino acids. Three signals with unclear identities were found to be affected.
Conclusions
Our study suggests that the pathways of glucose and ketone body homeostasis are affected in PPGL patients. BMI-related metabolite levels were also found to be altered, potentially linking muscle atrophy to PPGL. At baseline, patient metabolomes could be discriminated based on their catecholamine phenotype.
Chronische Nierenerkrankungen gehen mit einer erhöhten kardiovaskulären Morbidität und Mortalität einher. Charakteristisch für chronische Nierenerkrankungen, insbesondere im Stadium der Dialysepflichtigkeit, ist eine ausgeprägte Voralterung der Gefäße. Die Vorgänge, die den beschleunigten vaskulären Alterungsprozessen zugrunde liegen, umfassen ein Zusammenspiel aus einem gestörten Mineralstoffwechsel, der Akkumulation urämischer Toxine und chronischer Inflammation. Das Renin-Angiotensin-Aldosteron-System (RAAS) nimmt dabei eine zentrale Rolle ein. Eine gesteigerte Aktivität des RAAS ist ein Merkmal von kardiorenalen Syndromen und moduliert jenseits seiner Effekte auf den Blutdruck vaskuläre Entzündungs- und Remodelingprozesse. Durch das vaskuläre Altern kommt es zur Abnahme arterieller Compliance und zur Erhöhung der Pulswellengeschwindigkeit (PWV). Dadurch erhöht sich das Risiko für Endorganschäden. Die arterielle Gefäßsteifigkeit ist ein unabhängiger Prädiktor für Mortalität bei chronisch-dialysepflichtiger Niereninsuffizienz und eine Reduktion arterieller Rigidität geht mit einem verbesserten Überleben einher. Randomisierte Studien bei Dialysepatienten konnten bislang keinen eindeutigen Nutzen etablierter pharmakologischer Interventionen zur Reduktion des kardiovaskulären Risikos und vaskulärer «Stiffeningprozesse» feststellen. Als ein potentiell wirksamer Therapieansatz werden Mineralokortikoidrezeptorantagonisten (MRA) angesehen. Die vorliegende Arbeit evaluierte im Rahmen der Placebo-kontrollierten, randomisierten «Mineralocorticoid-Receptor Antagonists in End-Stage Renal Disease» (MiREnDa) Studie, ob die tägliche Einnahme von 50 mg Spironolacton über neun Monate einen Effekt auf die vaskuläre Funktion bei Patienten mit dialysepflichtiger chronischer Nierenerkrankung hat. Neben aortaler PWV, Augmentationsindex, zentralem Puls- und Blutdruck wurden zur Evaluation der vaskulären Funktion die Compliance der thorakalen Aorta und der A. carotis communis sowie die Distensibilität der A. carotis communis und die fluss-vermittelte Dilatation der A. brachialis vor Studienbeginn als sekundäre Endpunkte festgelegt. Ein weiterer Aspekt, der evaluiert wurde, war die Frage nach Korrelationen zwischen PWV und Augmentationsindex einerseits und weiteren Parametern vaskulärer Funktion, klinischen Merkmalen und Biomarkern andererseits. Die vorliegende Arbeit versuchte darüber hinaus, klinische Merkmale (Komorbiditäten, Inflammation), die ein Therapieansprechen von MRA potentiell modulieren, zu identifizieren. Das zentrale Ergebnis der Arbeit war, dass eine MRA-Therapie mit 50 mg Spironolacton täglich über neun Monate im untersuchten Kollektiv keinen Effekt auf die vaskuläre Funktion zeigte.
Recent studies have hinted to an involvement of epithelial to mesenchymal transition, a mechanism often associated with metastasis in epithelial cancers, in adrenocortical carcinoma. In addition, the knowledge about the FGF/FGFR pathway in pathogenesis of the adrenal gland, a pathway often associated with the epithelial to mesenchymal transition, is sparse and fragmented.
We assessed, in a large number of normal, benign and malignant adrenocortical tissues (a total of 181 different samples), the expression of canonical and novel epithelial and mesenchymal markers and compared it with their expression in typical epithelial and mesenchymal tissues. In addition, we also quantified the expression of most members of the FGF/FGFR pathway in adrenocortical tissues and compared it against well-studied epithelial and mesenchymal tissues as well as between malignant and not malignant adrenocortical tissues, in order to assess the possible connection to epithelial to mesenchymal transition and find possible drug targets. Surprisingly, both normal and neoplastic adrenocortical tissues lacked expression of epithelial markers (e.g. E-Cadhering or EpCAM) but strongly expressed mesenchymal markers (e.g. N-Cadherin or SLUG), suggesting a higher similarity of adrenocortical tissues to mesenchymal compared to epithelial tissues, reminiscent of the adrenocortical origin from the intermediate mesoderm. Despite their ubiquitous expression in all adrenocortical tissues, mesenchymal markers had a variable expression in adrenocortical carcinoma, associating either directly or inversely with different clinical markers of tumor aggressiveness. Lymph node infiltration was associated with high expression of SLUG (p = 0.04), and at the same time low expression of N-cadherin (p = 0.001), and the same pattern was observed for venous infiltration of tumoral tissue, Weiss score of tumor malignancy or Ki67 proliferation marker. In malignant compared to benign adrenal tumors, we found significant differences in the expression of 16 out of the 94 studied FGF receptor pathway related genes. Genes involved in tissue differentiation and metastatic spread through epithelial to mesenchymal transition were most strongly altered. The therapeutically targetable FGF receptors 1 and 4 were upregulated 4.6- and 6-fold, respectively, in malignant compared to benign adrenocortical tumors, which was confirmed by using two different quantification methods in both frozen and paraffin embedded tissue material. High expression of FGFR1 and 4 was significantly associated with worse patient prognosis (High FGFR1 expression was associated with a shorter overall patient survival of 84 vs 148 months (HR=1.8, 95% CI: 1.01-3.25) as well as a shorter resection free survival of 25 vs 75 months ((HR=2.93, 95% CI: 1.25-6.84), while high FGFR4 was associated with a much shorter overall survival of 50 vs 155 months (HR=2.44, 95% CI: 1.41-4.22).
In conclusion, epithelial to mesenchymal transition does not seem to play a role in adrenocortical carcinoma tumor progression, and the FGF/FGFR pathway, even if it is probably not related to EMT, is nonetheless associated with tumor aggressiveness. Furthermore, quantification of FGF receptors may enable a stratification of adrenocortical carcinoma for the use of FGFR inhibitors in future clinical trials.
Über die klinische Präsentation von Knochenmetastasen (KM) und ihre Komplikationen, sog. Skeletal-related events (SRE), beim medullären Schilddrüsenkarzinom (MTC) ist aktuell wenig bekannt. Es ist Ziel dieser multizentrischen Studie, klinische und morphologische Eigenschaften von KM beim MTC zu beschreiben und die prognostische Rolle der Morphologie der KM herauszuarbeiten. Außerdem wird die Rolle der antiresorptiven Therapie (ART) sowie der tumorspezifischen Behandlung mit Tyrosinkinase-Inhibitoren (TKI) untersucht.
Insgesamt wurden 114 Patienten mit einem MTC und KM, welche zwischen 1973 und 2016 an vier deutschen Kliniken mit Schwerpunktversorgung diagnostiziert wurden, in die Analyse eingeschlossen.
Zeit-bis-Event Analysen wurden mittels Kaplan-Meier Kurve dargestellt und Gruppen mit dem Log-Rank Test verglichen. Risikofaktoren wurden mit Cox Regression identifiziert.
KM wurden im Median 2,1 Jahre nach der Erstdiagnose MTC diagnostiziert und traten in 79 % der Fälle multifokal auf. Die häufigste Lokalisation war die Wirbelsäule (86 %), gefolgt von der Hüfte (60 %). Die Morphologie der KM war in 32 % osteolytisch, in 25 % osteoblastisch und in 22 % wurde eine gemischte Morphologie beschrieben (unbekannt: 21 %).
Innerhalb einer medianen Beobachtungszeit von 26,6 Monaten nach der Erstdiagnose KM trat in 47 % der Fälle mindestens ein SRE auf (Knochenbestrahlung 50 %, pathologische Frakturen 32 %). Davon waren 42 % bei Patienten mit osteoytischen und 17 % bei osteoblastischen KM zu finden (P = 0,047). Osteolytische Metastasen (HR 3,85, 95 % KI 1,52-9,77, P = 0,005) waren mit einem schlechterem Gesamtüberleben assoziiert. Bei Patienten, die präventiv eine ART erhielten, traten signifikant weniger SREs auf als bei unbehandelten Patienten (P = 0,04). In einer Subanalyse der 10 Patienten, die vor dem Auftreten eines SREs einen TKI erhalten hatten, waren signifikant weniger SREs zu verzeichnen (p= 0,013).
Die Studie zeigt eine Assoziation zwischen osteolytischen KM und einer schlechteren Prognose. ART sowie TKI könnten eine protektive Rolle zur Vorbeugung von knochenbezogenen Ereignissen haben. Prospektive Studien sind notwendig, um diese möglichen Zusammenhänge zu prüfen.
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.
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.
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.
In der Gruppe der Hämodialyse-PatientInnen besteht ein deutlich erhöhtes Risiko an kardiovaskulären Ereignissen zu versterben. Korrespondierend hierzu weisen Hämodia-lyse-PatientInnen eine erhöhte Prävalenz an linksventrikulärer Hypertrophie (LVH) auf. Diese gilt als starker unabhängiger Risikofaktor für kardiovaskuläre Mortalität. Auf-grund der prognostischen Aussagekraft dient die Bewertung des linksventrikulären Massenindex (LVMI) sowie die Diagnose einer LVH vor allem in prospektiven Studien als ein bedeutendes Werkzeug zur Beurteilung des kardiovaskulären Risikos. Die Be-stimmung der LVH kann anhand von bildgebenden Verfahren (u.a. Echokardiographie, CMRI) oder dem EKG erfolgen. Die CMRI-Messung wird gegenwärtig als Goldstan-dard zur Messung der LVH betrachtet.
Die 2D geführte M-mode-Methode der Echokardiographie zur Bestimmung der LVM zeichnet sich durch seine einfache und schnelle Durchführbarkeit aus und wird deshalb trotz präziserer Messverfahren wie dem 3D-Verfahren sowie diverser Einschränkungen weiterhin von der American Society of Echocardiography (ASE) als Screening-Methode und zur Untersuchung großer PatientInnenpopulationen empfohlen. Die empfohlene ASE-Formel überschätzt jedoch den LVMI nachweislich im Vergleich zum CMRI-Messverfahren. Die Überschätzung zeigte sich abhängig von der Höhe des LVMI. Es wird vermutet, dass die zunehmende Überschätzung Folge der geometrischen Grundan-nahmen ist, welche den LV vereinfachend als Ellipsoid mit konstantem L/D-Verhältnis annimmt. Dieses Verhältnis scheint sich jedoch bei zunehmender Herzgröße zu verän-dern, was wiederum zu einer Fehleinschätzung des LVMI führt. Die Teichholz (Th)-Formel korrigiert das L/D-Verhältnis mithilfe einer kurvilinearen Anpassung an den linksventrikulären Durchmesser und zeigte kürzlich in einer PatientInnengruppe mit Aor-tenstenose die geringste Tendenz der Überschätzung bei PatientInnen mit LVH. In der vorliegenden Studie wurden die echokardiographischen Formeln – ASE und Th – mit dem CMRI-Messverfahren verglichen. Beide Formeln zeigten eine deutliche Überschät-zung des LVMI. Die Th-Formel demonstrierte jedoch neben einer besseren Überein-stimmung zum CMRI, eine insgesamt geringere Überschätzung des LVMI sowie eine sukzessive Abnahme der Überschätzung mit zunehmendem LVMI. Zusammenfassend kann festgehalten werden, dass die Th-Formel der ASE-Formel in Bezug auf die Be-rechnung des LVMI bei Hämodialyse-PatientInnen insbesondere bei PatientInnen mit LVH überlegen ist. Weitere Studien sind jedoch erforderlich, um die Th-Formel in grö-ßeren Hämodialyse-PatientInnen-Kohorten mit höheren LVMI-Werten zu testen sowie um den prognostischen Wert der Th-Formel im Vergleich zur ASE-Formel zu ermitteln.
Die klassischen EKG-Indices und -Scores zur Feststellung einer LVH wiesen, wie be-reits in anderen CMRI-Vergleichsstudien gezeigt, eine schlechte Sensitivität bei guter Spezifität auf. Aufgrund dessen verlor das EKG zunehmend an Bedeutung als Scree-ning-Untersuchung. In dieser Studie wurde der Versuch unternommen die Sensitivität durch zwei Lösungsansätze zu verbessern, einerseits durch die Kombination verschiede-ner EKG-Kriterien und andrerseits durch eine Adjustierung der EKG-Kriterien an den mittels Bioimpedanz gemessenen Fettmassenanteil. Die Kombination verschiedener EKG-Kriterien erzielte eine deutlich erhöhte Sensitivität von >70 %. Auch die Anpas-sung der EKG-Kriterien an den individuellen Fettmassenanteil könnte ein hilfreicher Lösungsansatz zur Verbesserung der Sensitivität bei Adipositas darstellen.
Morbus Cushing ist die häufigste Ursache für endogenes Cushing-Syndrom und führt auf Grund eines kortikotropen Hypophysenadenoms zu einem Glucocorticoid Überschuss und wiederum zu einer hohen Morbidität und Mortalität. Die Ursache hierfür sind unter anderem somatische Mutationen in den Deubiquitinasen USP8 und USP48. Das Ziel dieser Arbeit war es mittels der CRISPR/Cas9-Methode, die Mutationen USP8 und USP48 in Zelllinien zu etablieren und diese für Cushing-Syndrom Analysen zu verwenden. Hierfür wurden in dieser Arbeit gRNAs für USP8 und USP48 designt, welche anschließend in die humane embryonale Zelllinie HEK293AD Zellen transfiziert wurden. Diese Zellen wurden zu monoklonalen Zellen vereinzelt. Ziel war einen Knock-out von USP8 bzw. USP48 zu generieren. Es konnte ein erfolgreicher Zellklon generiert werden mit einem Knock-out von USP48. Ebenfalls konnte ein Genomediting von USP8 in Exon 20 durchgeführt werden. Zusammenfassend konnte die CRISPR/Cas9 Methode für ein M. Cushing-Zellmodells etabliert und eine gute Ausgangsbasis für weitere Experimente (z.B. ein gezielter Knock-in von USP8- und USP48- Mutationen) generiert werden.
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.
Aims
There is an ongoing discussion whether the categorization of patients with heart failure according to left ventricular ejection fraction (LVEF) is scientifically justified and clinically relevant. Major efforts are directed towards the identification of appropriate cut-off values to correctly allocate heart failure-specific pharmacotherapy. Alternatively, an LVEF continuum without definite subgroups is discussed. This study aimed to evaluate the natural distribution of LVEF in patients presenting with acutely decompensated heart failure and to identify potential subgroups of LVEF in male and female patients.
Methods and results
We identified 470 patients (mean age 75 ± 11 years, n = 137 female) hospitalized for acute heart failure in whom LVEF could be quantified by Simpson's method in an in-hospital echocardiogram. Non-parametric modelling revealed a bimodal shape of the LVEF distribution. Parametric modelling identified two clusters suggesting two LVEF peaks with mean (variance) of 61% (9%) and 31% (10%), respectively. Sub-differentiation by sex revealed a sex-specific bimodal clustering of LVEF. The respective threshold differentiating between ‘high’ and ‘low’ LVEF was 45% in men and 52% in women.
Conclusions
In patients presenting with acute heart failure, LVEF clustered in two subgroups and exhibited profound sex-specific distributional differences. These findings might enrich the scientific process to identify distinct subgroups of heart failure patients, which might each benefit from respectively tailored (pharmaco)therapies.
Mitotane führt zur vermehrten Expression des CHOP-Proteins. Da es ebenfalls gelang weitere Expressionsveränderungen von am ER-Stress-beteiligten Proteinen nachzuweisen, kann von einer ER-Stress-Induktion durch Mitotane ausgegangen werden. Des Weiteren ließ sich zeigen, dass die gesteigerte CHOP-Expression nicht zelltypspezifisch ist, da sie sich ebenfalls in weiteren Zelllinien nachweisen ließ. Hierzu gehörten IMR32-, HeLaz91wt-, HepG2- und HEK293T-Zellen. Zudem kam es durch die Inkubation der NCI H295R-Zellen mit Mitotane zu einer Abnahme der Expression von SREBP 1 sowohl der Vorläuferstufe als auch der aktiven Form. Dies weist auf eine Herunterregulation des Lipidstoffwechsels durch Mitotane hin.
Neben Mitotane gab es mit ATR 101 und AZD 3988 weitere Substanzen, die zu einer Zunahme der CHOP-Expression geführt haben.
Das Nebennierenrindenkarzinom (ACC) ist eine sehr seltene maligne Erkrankung, die mit einer infausten Prognose vergesellschaftet ist. In Zeiten apparativ geprägter Medizin treten suspekte Befunde der Nebenniere gehäufter auf als je zuvor. Diese Nebennierenraumforderungen, die zumeist bei Bildgebungen auffallen, die aus anderen Gründen indiziert waren, werden Nebenniereninzidentalome genannt und sind meist benigne Befunde. Dennoch wird es angesichts dieser steigenden Zahl an Inzidentalomen immer wichtiger, die Entität der gefundenen Raumforderung schnell zu sichern, um die entsprechende Therapie einleiten zu können. Somit sollen das Zeitfenster bis zur Krebstherapie verkleinert und gleichsam unnötige chirurgische Eingriffe bei Patient*innen mit benignen Nebennierentumoren vermieden werden. Um die diagnostischen Schritte weiter zu verbessern, wurde in der vorliegenden Arbeit eine bioinformatische Regressionsanalyse an Steroidhormonkonzentrationen von ACC-Patient*innen und Kontrollen durchgeführt und der diagnostische Wert der berechneten Steroidsignaturen untersucht. Dabei zeigte sich im geschlechtsspezifischen Modell jeweils eine 6-Steroid-Signatur mit bester Trennschärfe zwischen benignen und malignen NN-Befunden. So konnte mit der 6-Steroid-Signatur in der männlichen Patientengruppe mit einer Sensitivität von 80% und Spezifität von 97%, in der weiblichen Patientinnengruppe mit einer Sensitivität von 78% und Spezifität von 97% die Diagnose richtig zugewiesen werden. Im Rahmen der targeted Metabolomics Untersuchung konnten Tumor-assoziierte Stoffwechselalterationen aufgezeigt werden. Eine Plasma-Metabolit-Signatur zur Differenzierung von ACCs und Nebennierenadenomen, welche die gängige Diagnostik bei der Abklärung von unklaren Nebennierentumoren erleichtern könnte, erscheint jedoch angesichts der großen Anzahl an zu bestimmenden Metaboliten - auch unter ökonomischen Gesichtspunkten - zu diesem Zeitpunkt noch nicht mit der Routine-Patient*innenversorgung vereinbar.
Mineralocorticoid-receptor antagonism and its metabolic consequences in haemodialysis patients
(2022)
Patients on haemodialysis are highly susceptible to different forms of heart failure. To date, the benefit of Mineralocorticoid-receptor antagonist (MRA) administration in haemodialysis patients remains subject to discussion. Biomarkers play an important role in therapy guidance and pose a promising tool to detect pathological processes of heart failure in an earlier stage. The randomised-controlled Mineralocorticoid-Receptor Antagonists in End-Stage Renal Disease (MiREnDa) trial was set up to investigate the effect of 50 mg of spironolactone once daily on left ventricular mass index in haemodialysis patients and several secondary endpoints. This dissertation reports findings from the MiREnDa trial on (a) the efficacy of spironolactone to influence serum levels of biomarkers of heart failure, fibrosis and inflammation and electrolytes and (b) the ability of N-terminal pro-B-type natriuretic peptide (NT-proBNP), Galectin-3 and soluble source of tumorigenicity 2 (sST2) to reflect left ventricular hypertrophy and diastolic dysfunction assessed by imaging characteristics. Treatment of spironolactone over a 40-week period did not alter serum levels of biomarkers of heart failure, fibrosis and inflammation including NT-proBNP, Galectin-3 and sST2. A small but significant effect on serum sodium but not potassium was observed. NT-proBNP was significantly different in the presence or absence of left ventricular hypertrophy (LVH) (normal vs. LVH (median [IQR]): 2,120 [810; 5,040] vs. 6,340 [2,410; 15,360] pg/ml, p<0.01) or moderate and severe diastolic dysfunction (DD) (normal diastolic function and DD grade I vs. DD grade II and DD grade III: 2,300 [850; 6,050] vs. 12,260 [3,340; 34,830] pg/ml, p=0.02). NT-proBNP further showed a significant correlation at baseline with LVMi (Spearman’s rho=0.41, p<0.001), LAVi (Spearman’s rho=0.55, p<0.001) and septal E/e’ (Spearman’s rho=0.45, p<0.001). No correlation was observed between Galectin-3 and the investigated functional and morphological parameters. sST2 was mildly correlated to LVMi at baseline (Spearman’s rho=0.21, p=0.05) and NT-proBNP at baseline (Spearman’s rho=0.37, p<0.001). In conclusion, spironolactone did not affect the investigated parameters but NT-proBNP proved to be significantly correlated to cardiac imaging measurements.
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.
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.