Introduction:Kallikrein-related peptidase 7 (KLK7) is a protease implicated in metabolic disease and obesity. Patients with chronic kidney disease (CKD) exhibit several cardio-metabolic comorbidities and increased mortality. The goal of this study was to investigate the associations of KLK7 levels with renal function and clinical outcomes in patients with CKD. Methods:Baseline KLK7 serum levels were cross-sectionally related to renal and cardiometabolic markers in the Leipzig-CKD cohort (n=542). Longitudinal Cox Regression analyses (n=472) were performed to associate baseline circulating KLK7 concentrations and risk of major adverse renal (MARE) and cardiovascular (MACE) events, as well as all-cause mortality. Additionally, mRNA expression of Klk7 and related genes was examined in CKD versus control mice using bulk RNA sequencing. Results:KLK7 levels were inversely associated with markers of renal function, i.e. estimated glomerular filtration rate (eGFR), and inflammation, i.e. C-reactive protein, in multivariable regression. Longitudinal analyses associated higher baseline KLK7 with lower all-cause (adjusted HR [95% CI]: 0.65 [0.49-0.86], p=0.003) and non-cardiovascular (adjusted HR [95% CI]: 0.56 [0.40-0.78], p=0.001) mortality over a median follow-up of 7.6 years. A KLK7 threshold of 1383.6 pg/ml stratified patients into low- and high-risk groups for mortality. No associations were found for MARE or MACE. In tissues of CKD and control mice, no significant changes in Klk7 mRNA expression were found. Discussion:Circulating KLK7 associates inversely with renal function and inflammation, likely reflecting reduced renal clearance. Higher circulating KLK7 independently predicts lower all-cause mortality, whereas baseline KLK7 was not related to composite renal and CV outcomes.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Measurements of plasma metanephrines and methoxytyramine provide a sensitive test for diagnosis of pheochromocytoma/paraganglioma. False-positive results remain a problem, particularly in patients taking norepinephrine reuptake-blocking drugs. Therefore, in this retrospective observational study, we measured plasma metanephrines and methoxytyramine in 61 patients taking norepinephrine reuptake blockers (tricyclic antidepressants or serotonin-norepinephrine reuptake inhibitors) and 17 others taking selective serotonin reuptake inhibitors, all without pheochromocytoma/paraganglioma. We highlight a singular case with strongly elevated plasma normetanephrine and methoxytyramine concentrations associated with norepinephrine reuptake blockade. Data were compared to results from 252 and 1804 respective patients with and without tumors. Plasma normetanephrine was 40% higher (P < 0.0001) in patients on norepinephrine reuptake blockers and methoxytyramine was 127% higher (P = 0.0062) in patients taking tricyclic antidepressants compared to patients not taking uptake blockers and without tumors. The corresponding false-positive rates rose (P < 0.0001) from 4.8% to 23.0% for normetanephrine and from 0.9% to 28.6% for methoxytyramine. Selective serotonin reuptake inhibitors did not increase plasma concentrations of metabolites. In the highlighted case, plasma normetanephrine and methoxytyramine were elevated more than six times above upper reference limits. A pheochromocytoma/paraganglioma, however, was excluded by functional imaging. All biochemical test results normalized after discontinuation of norepinephrine reuptake blockers. These findings clarify that norepinephrine reuptake blockers usually result in mild elevations of normetanephrine and methoxytyramine that, nevertheless, significantly increase the number of false-positive results. There can, however, be exceptions where increases in normetanephrine and methoxytyramine reach pathological levels. Such exceptions may reflect failure of centrally mediated sympathoinhibition that normally occurs with the norepinephrine reuptake blockade.

While suggested, surgery is not always possible as a first-line treatment of Cushing’s Disease (CD). In such cases, patients require medical therapy in order to prevent complications resulting from hypercortisolism. Although there has been a wide expansion in pharmacological options in recent years, mitotane was the agent of choice for treating hypercortisolism decades ago. Due to the introduction of other therapies, long-term experience with mitotane remains limited. Here, we report the case of a woman with CD who was treated with mitotane for 37 years. During the treatment period, biochemical and clinical disease control was achieved and the patient had two uncomplicated pregnancies. Drug-related side effects remained moderate and could be controlled by several dose adjustments. Our case highlights the ability of mitotane to allow an effective control of hypercortisolism and to represent a safe treatment option in special situations where CD requires an alternative therapeutic approach. Furthermore, we provide a literature review of the long-term use of mitotane and reported cases of pregnancy in the context of mitotane therapy.

Ectopic pituitary neuroendocrine tumors (PitNET)/adenomas are rare and diagnostically challenging extra-sellar tumors. Previous studies have demonstrated the impact of epigenomic analyses in the diagnostics of sellar neoplasms and characterized the close relationship of epigenomic signatures and cellular origins of PitNET/adenomas. As of today, little is known about the pathogenesis of ectopic PitNET/adenomas, and epigenomic analyses have not been performed in these rare tumors. We report on the clinical course of an 81-year-old patient with sphenoid ectopic sparsely granulated corticotroph PitNET/adenoma and deploy genome-wide DNA methylation analysis to compare its methylation profile to a reference cohort of sellar neoplasms. Genome-wide methylation analysis revealed an epigenomic profile analogous to reference sellar corticotroph PitNET/adenomas, and the copy number variation profile showed loss of chromosomes 18 and 22. The methylation profile shows concordance with sellar corticotroph PitNET/adenomas suggesting a common cellular origin and confirming the reliability of methylation analyses as a diagnostic method in these rare tumors. This is the first data suggesting that epigenetic profiles of ectopic PitNET/adenoma do not differ from their sellar counterparts.

ObjectiveAcyl-CoA-binding protein (ACBP)/diazepam-binding inhibitor has lately been described as an endocrine factor affecting food intake and lipid metabolism. ACBP is dysregulated in catabolic/malnutrition states like sepsis or systemic inflammation. However, regulation of ACBP has not been investigated in conditions with impaired kidney function, so far.Design/methodsSerum ACBP concentrations were investigated by enzyme-linked immunosorbent assay i) in a cohort of 60 individuals with kidney failure (KF) on chronic haemodialysis and compared to 60 individuals with a preserved kidney function; and ii) in a human model of acute kidney dysfunction (AKD). In addition, mACBP mRNA expression was assessed in two CKD mouse models and in two distinct groups of non-CKD mice. Further, mRNA expression of mACBP was measured in vitro in isolated, differentiated mouse adipocytes - brown and white - after exposure to the uremic agent indoxyl sulfate.ResultsMedian [interquartile range] serum ACBP was almost 20-fold increased in KF (514.0 [339.3] µg/l) compared to subjects without KF (26.1 [39.1] µg/l) (p<0.001). eGFR was the most important, inverse predictor of circulating ACBP in multivariate analysis (standardized β=-0.839; p<0.001). Furthermore, AKD increased ACBP concentrations almost 3-fold (p<0.001). Increased ACBP levels were not caused by augmented mACBP mRNA expression in different tissues of CKD mice in vivo or in indoxyl sulfate-treated adipocytes in vitro.ConclusionsCirculating ACBP inversely associates with renal function, most likely through renal retention of the cytokine. Future studies need to investigate ACBP physiology in malnutrition-related disease states, such as CKD, and to adjust for markers of renal function.

Background:Treatment options for poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinoma are unsatisfactory and prognosis is generally poor. Lenvatinib (LEN), a multi-tyrosine kinase inhibitor targeting fibroblast growth factor receptors (FGFR) 1-4 is approved for advanced radioiodine refractory thyroid carcinoma, but response to single agent is poor in ATC. Recent reports of combining LEN with PD-1 inhibitor pembrolizumab (PEM) are promising.Materials and Methods:Primary ATC (n=93) and PDTC (n=47) tissue samples diagnosed 1997-2019 at five German tertiary care centers were assessed for PD-L1 expression by immunohistochemistry using Tumor Proportion Score (TPS). FGFR 1-4 mRNA was quantified in 31 ATC and 14 PDTC with RNAscope in-situ hybridization. Normal thyroid tissue (NT) and papillary thyroid carcinoma (PTC) served as controls. Disease specific survival (DSS) was the primary outcome variable.Results:PD-L1 TPS≥50% was observed in 42% of ATC and 26% of PDTC specimens. Mean PD-L1 expression was significantly higher in ATC (TPS 30%) than in PDTC (5%; p<0.01) and NT (0%, p<0.001). 53% of PDTC samples had PD-L1 expression ≤5%. FGFR mRNA expression was generally low in all samples but combined FGFR1-4 expression was significantly higher in PDTC and ATC compared to NT (each p<0.001). No impact of PD-L1 and FGFR 1-4 expression was observed on DSS.Conclusion:High tumoral expression of PD-L1 in a large proportion of ATCs and a subgroup of PDTCs provides a rationale for immune checkpoint inhibition. FGFR expression is low thyroid tumor cells. The clinically observed synergism of PEM with LEN may be caused by immune modulation.

Background: The management of patients with locally advanced or metastatic differentiated thyroid cancer (DTC) that is refractory to radioiodine (RAI) remains a therapeutic challenge. The multi-tyrosine kinase inhibitors (TKIs) sorafenib and lenvatinib have been approved based on phase 3 clinical trials. Patients and Methods: We aimed at describing the efficacy and safety of TKI treatment of RAI-refractory DTC in a real-world setting at six German referral centers. One hundred and one patients with locally advanced or metastatic RAI-refractory DTC treated with sorafenib, lenvatinib, and/or pazopanib were included. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated by using the Kaplan-Meier method. Results: Ninety-seven of 101 patients had progressive disease before TKI initiation. The median PFS for first-line treatment with sorafenib (n = 33), lenvatinib (n = 53), and pazopanib (n = 15) was 9 (95% confidence interval 5.2-12.8), 12 (4.4-19.6), and 12 months (4.4-19.6), respectively. The median OS for first-line treatment was 37 (10-64) for sorafenib, 47 (15.5-78.5) for lenvatinib, and 34 months (20.2-47.8) for pazopanib. Serious complications (e.g., hemorrhage, acute coronary syndrome, and thrombosis/venous thromboembolism) occurred in 16 out of 75 (21%) patients taking lenvatinib, in 3 out of 42 (7%) patients taking sorafenib, and in 3 out of 24 (13%) patients taking pazopanib. Conclusions: Sorafenib, lenvatinib, and pazopanib are effective treatment options in the majority of patients with RAI-refractory DTC. The PFS and six-month survival rate in patients treated with lenvatinib und pazopanib appear to compare favorably with sorafenib in the first-line treatment setting. However, a more advanced disease stage at treatment initiation in sorafenib- and pazopanib-treated patients in the era before TKI-approval and the retrospective nature of this study precludes a direct comparison of TKIs.

Objective: Liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) has become state of the art for the quantitative analysis of steroid hormones. Although method comparisons show that aldosterone measurement using LC-MS/MS yields considerably lower levels than immunoassays (IAs), method-specific cutoff values for primary aldosteronism (PA) are largely missing. Objective of this study was to analyze the diagnostic accuracy of proposed LC-MS/MS-specific cutoff values for the saline infusion test (SIT). Design and methods: From 2016 to 2019, 104 consecutive patients suspected of PA underwent the SIT and captopril challenge test in the tertiary medical center at the University Hospital of Leipzig, Germany. Patients with positive case confirmation underwent adrenal imaging and adrenal venous sampling for subtype classification. Results: Overall, proposed assay-specific PAC(LC-MS/MS) cutoff values for the SIT achieved higher diagnostic accuracy than established PAC(IA) values with a sensitivity and specificity of 87.5% (95% CI: 71.0-96.5) and 97% (95% CI: 89.6-99.6) for a cutoff of 120 pmol/L and 93.8% (95% CI: 79.2-99.2) and 92.5% (95% CI: 83.4-97.5) for a cutoff of 94 pmol/L. The most accurate post-SIT PAC(LC-Ms/MS) cutoff value in this study was 83 pmol/L, yielding a sensitivity and specificity of 96.9% (95% CI: 83.8-99.9) and 92.5% (95% CI: 83.4-97.5), respectively. Conclusions: The present data confirm the need for the implication of lower method-specific aldosterone cutoff values for the diagnosis of PA with LC-MS/MS based aldosterone measurement.

JDDG: Journal der Deutschen Dermatologischen GesellschaftVolume 17, Issue 11 p. 1168-1170 Clinical Letter Hypophysitis on immunotherapy with checkpoint inhibitors Iris Marie Jäger, Iris Marie Jäger Department of Dermatology, Venereology and Allergology, Leipzig University Medical Center, Leipzig, GermanySearch for more papers by this authorJohannes Kohlmann, Johannes Kohlmann Department of Dermatology, Venereology and Allergology, Leipzig University Medical Center, Leipzig, GermanySearch for more papers by this authorJan Christoph Simon, Jan Christoph Simon Department of Dermatology, Venereology and Allergology, Leipzig University Medical Center, Leipzig, GermanySearch for more papers by this authorBenjamin Sandner, Benjamin Sandner Department of Endocrinology, Nephrology and Rheumatology, Leipzig University Medical Center, Leipzig, GermanySearch for more papers by this authorAnke Tönjes, Anke Tönjes Department of Endocrinology, Nephrology and Rheumatology, Leipzig University Medical Center, Leipzig, GermanySearch for more papers by this authorMirjana Ziemer, Corresponding Author Mirjana Ziemer mirjana.ziemer@medizin.uni-leipzig.de Department of Dermatology, Venereology and Allergology, Leipzig University Medical Center, Leipzig, Germany Correspondence to Mirjana Ziemer, MD, PhD Department of Dermatology, Venereology and Allergology Leipzig University Medical Center Philipp-Rosenthal-Straße 23 04103 Leipzig, Germany E-mail: mirjana.ziemer@medizin.uni-leipzig.deSearch for more papers by this author Iris Marie Jäger, Iris Marie Jäger Department of Dermatology, Venereology and Allergology, Leipzig University Medical Center, Leipzig, GermanySearch for more papers by this authorJohannes Kohlmann, Johannes Kohlmann Department of Dermatology, Venereology and Allergology, Leipzig University Medical Center, Leipzig, GermanySearch for more papers by this authorJan Christoph Simon, Jan Christoph Simon Department of Dermatology, Venereology and Allergology, Leipzig University Medical Center, Leipzig, GermanySearch for more papers by this authorBenjamin Sandner, Benjamin Sandner Department of Endocrinology, Nephrology and Rheumatology, Leipzig University Medical Center, Leipzig, GermanySearch for more papers by this authorAnke Tönjes, Anke Tönjes Department of Endocrinology, Nephrology and Rheumatology, Leipzig University Medical Center, Leipzig, GermanySearch for more papers by this authorMirjana Ziemer, Corresponding Author Mirjana Ziemer mirjana.ziemer@medizin.uni-leipzig.de Department of Dermatology, Venereology and Allergology, Leipzig University Medical Center, Leipzig, Germany Correspondence to Mirjana Ziemer, MD, PhD Department of Dermatology, Venereology and Allergology Leipzig University Medical Center Philipp-Rosenthal-Straße 23 04103 Leipzig, Germany E-mail: mirjana.ziemer@medizin.uni-leipzig.deSearch for more papers by this author First published: 07 November 2019 https://doi.org/10.1111/ddg.13963Citations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume17, Issue11November 2019Pages 1168-1170 RelatedInformation

JDDG: Journal der Deutschen Dermatologischen GesellschaftVolume 17, Issue 11 p. 1168-1170 Clinical Letter Hypophysitis unter Immuntherapie mit Checkpoint-Inhibitoren Iris Marie Jäger, Iris Marie Jäger Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum LeipzigSearch for more papers by this authorJohannes Kohlmann, Johannes Kohlmann Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum LeipzigSearch for more papers by this authorJan Christoph Simon, Jan Christoph Simon Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum LeipzigSearch for more papers by this authorBenjamin Sandner, Benjamin Sandner Klinik für Endokrinologie, Nephrologie und Rheumatologie, Universitätsklinikum LeipzigSearch for more papers by this authorAnke Tönjes, Anke Tönjes Klinik für Endokrinologie, Nephrologie und Rheumatologie, Universitätsklinikum LeipzigSearch for more papers by this authorMirjana Ziemer, Corresponding Author Mirjana Ziemer mirjana.ziemer@medizin.uni-leipzig.de Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Leipzig Korrespondenzanschrift Priv.-Doz. Dr. med. habil. Mirjana Ziemer Klinik für Dermatologie, Venerologie und Allergologie Universität Leipzig Philipp-Rosenthal-Straße 23 04103 Leipzig E-Mail: mirjana.ziemer@medizin.uni-leipzig.deSearch for more papers by this author Iris Marie Jäger, Iris Marie Jäger Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum LeipzigSearch for more papers by this authorJohannes Kohlmann, Johannes Kohlmann Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum LeipzigSearch for more papers by this authorJan Christoph Simon, Jan Christoph Simon Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum LeipzigSearch for more papers by this authorBenjamin Sandner, Benjamin Sandner Klinik für Endokrinologie, Nephrologie und Rheumatologie, Universitätsklinikum LeipzigSearch for more papers by this authorAnke Tönjes, Anke Tönjes Klinik für Endokrinologie, Nephrologie und Rheumatologie, Universitätsklinikum LeipzigSearch for more papers by this authorMirjana Ziemer, Corresponding Author Mirjana Ziemer mirjana.ziemer@medizin.uni-leipzig.de Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Leipzig Korrespondenzanschrift Priv.-Doz. Dr. med. habil. Mirjana Ziemer Klinik für Dermatologie, Venerologie und Allergologie Universität Leipzig Philipp-Rosenthal-Straße 23 04103 Leipzig E-Mail: mirjana.ziemer@medizin.uni-leipzig.deSearch for more papers by this author First published: 25 November 2019 https://doi.org/10.1111/ddg.13963_gAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume17, Issue11November 2019Pages 1168-1170 RelatedInformation

Zusammenfassung Hintergrund: Der Dexamethason-Kurzzeit-Suppressionstest (DST) wird als Screeningverfahren in der Diagnostik des Cushing-Syndroms (CS) angewendet. Allerdings können Faktoren wie die variable Resorption, sowie ein gesteigerter Metabolismus von Dexamethason (DXMS) die Testergebnisse beeinflussen und zu falsch positiven Resultaten führen. Das Ziel dieser Studie war es daher den Einfluss von Geschlecht, Body-Mass-Index (BMI) und Alter auf den DXMS-Metabolismus zu untersuchen. Methoden: Bei insgesamt 183 Testpersonen wurde ein regulärer 2 mg DST durchgeführt. Nach Ausschluss von Patienten (Pat) mit CS, Depression, Störungen der Leber- und Nierenfunktion, sowie Pat unter Medikation mit Cyp3A4-modulierenden Pharmaka, erfolgte die statistische Auswertung der Daten von 72 Pat und 66 gesunden Testpersonen. Zur pharmakokinetischen Charakterisierung von DXMS und CORT wurden bei 11 Pat zusätzlich nächtliche Blutentnahmen (1, 3, 5, 7 Uhr) durchgeführt. Ergebnis: Im Rahmen des DST wurde eine ausgeprägte interindividuelle Variabilität der DXMS-Konzentration gefunden, welche invers mit dem BMI korrelierte (r=–0,24, p=0,045). Passend hierzu wiesen nicht-adipöse Pat (BMI<30 kg/m2, n=29) im Vergleich mit adipösen Pat (BMI>30 kg/m2, n=43) im Mittel signifikant höhere morgendliche DXMS-Werte auf (1,66±0,71 ng/mL vs. 1,31±0,57 ng/mL, p=0,026). Das simultan gemessene CORT korrelierte weder mit dem BMI noch mit der DXMS-Konzentration. In der Analyse der Pharmakokinetik wurde die maximale DXMS-Konzentration um 3 Uhr erreicht. Danach sank DXMS kontinuierlich auf 59,1% des medianen Spitzenwertes ab (8 Uhr). Die morgendlichen DXMS-Werte korrelierten mit der DXMS-AUC (r=0,75, p=0,013), jedoch bestand keine Korrelation zwischen den morgendlichen CORT-Spiegeln und den nächtlichen DXMS-Werten zu sämtlichen Blutentnahmezeitpunkten. Schlussfolgerung: Im Rahmen des DST besteht die Möglichkeit, dass BMI-Unterschiede Einfluss auf die Resorptionsrate und den Metabolismus von DXMS nehmen und damit die DXMS-Konzentration wesentlich verringern können. Dies scheint allerdings keinen Einfluss auf die CORT-Suppression im DST zu haben. Aufgrund dessen ist davon auszugehen, dass der DST als zuverlässiges Screeningverfahren bei adipösen Pat mit Verdacht auf CS einzustufen ist.

It has been hypothesized that insulin might mediate meal-related diurnal variation in vaspin serum concentrations. We therefore investigated whether insulin affects serum vaspin levels in humans. Vaspin serum concentrations were determined by ELISA in 10 healthy individuals, who underwent an insulin tolerance test (ITT) for the evaluation of pituitary ACTH and growth hormone reserve. The ITTs were started 08:00 am after an overnight fast with a bolus i.v. insulin dose of 0.15 IU/kg body weight (Actrapid™). Blood samples were taken at -15, 0, 15, 30, 60, 90, and 120 min after insulin administration. 15 min after insulin administration, vaspin serum concentrations decreased by 19 ± 6%, continued to decrease by 42 ± 12% at 60 min and returned to 88 ± 7% of initial values 120 min after insulin administration. Our data suggest that meal-related changes in serum vaspin concentrations might be mediated by insulin.