TY - JOUR A1 - Sbiera, Iuliu A1 - Kircher, Stefan A1 - Altieri, Barbara A1 - Lenz, Kerstin A1 - Hantel, Constanze A1 - Fassnacht, Martin A1 - Sbiera, Silviu A1 - Kroiss, Matthias T1 - Role of FGF Receptors and Their Pathways in Adrenocortical Tumors and Possible Therapeutic Implications JF - Frontiers in Endocrinology N2 - Adrenocortical carcinoma (ACC) is a rare endocrine malignancy and treatment of advanced disease is challenging. Clinical trials with multi-tyrosine kinase inhibitors in the past have yielded disappointing results. Here, we investigated fibroblast growth factor (FGF) receptors and their pathways in adrenocortical tumors as potential treatment targets. We performed real-time RT-PCR of 93 FGF pathway related genes in a cohort of 39 fresh frozen benign and malignant adrenocortical, 9 non-adrenal tissues and 4 cell lines. The expression of FGF receptors was validated in 166 formalin-fixed paraffin embedded (FFPE) tissues using RNA in situ hybridization (RNAscope) and correlated with clinical data. In malignant compared to benign adrenal tumors, we found significant differences in the expression of 16/94 FGF receptor pathway related genes. Genes involved in tissue differentiation and metastatic spread through epithelial to mesechymal 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 RNAscope in FFPE samples. High expression of FGFR1 and 4 was significantly associated with worse patient prognosis in univariate analysis. After multivariate adjustment for the known prognostic factors Ki-67 and ENSAT tumor stage, FGFR1 remained significantly associated with recurrence-free survival (HR=6.10, 95%CI: 1.78 – 20.86, p=0.004) and FGFR4 with overall survival (HR=3.23, 95%CI: 1.52 – 6.88, p=0.002). Collectively, our study supports a role of FGF pathways in malignant adrenocortical tumors. Quantification of FGF receptors may enable a stratification of ACC for the use of FGFR inhibitors in future clinical trials. KW - normal adrenal glands KW - adrenocortical tumors KW - FGF-pathway KW - FGFR KW - RNA Expression KW - RNAScope KW - unsupervised clustering KW - patient survival Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-251953 SN - 1664-2392 VL - 12 ER - TY - JOUR A1 - Dischinger, Ulrich A1 - Hasinger, Julia A1 - Königsrainer, Malina A1 - Corteville, Carolin A1 - Otto, Christoph A1 - Fassnacht, Martin A1 - Hankir, Mohamed A1 - Seyfried, Florian Johannes David T1 - Toward a Medical Gastric Bypass: Chronic Feeding Studies With Liraglutide + PYY\(_{3-36}\) Combination Therapy in Diet-Induced Obese Rats JF - Frontiers in Endocrinology N2 - Background Combination therapies of anorectic gut hormones partially mimic the beneficial effects of bariatric surgery. Thus far, the effects of a combined chronic systemic administration of Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine 3-36 (PYY\(_{3-36}\)) have not been directly compared to Roux-en-Y gastric bypass (RYGB) in a standardized experimental setting. Methods High-fat diet (HFD)-induced obese male Wistar rats were randomized into six treatment groups: (1) RYGB, (2) sham-operation (shams), (3) liraglutide, (4) PYY\(_{3-36}\), (5) PYY\(_{3-36}\)+liraglutide (6), saline. Animals were kept on a free choice high- and low-fat diet. Food intake, preference, and body weight were measured daily for 4 weeks. Open field (OP) and elevated plus maze (EPM) tests were performed. Results RYGB reduced food intake and achieved sustained weight loss. Combined PYY\(_{3-36}\)+liraglutide treatment led to similar and plateaued weight loss compared to RYGB. Combined PYY\(_{3-36}\)+liraglutide treatment was superior to PYY\(_{3-36}\) (p ≤ 0.0001) and liraglutide (p ≤ 0.05 or p ≤ 0.01) mono-therapy. PYY\(_{3-36}\)+liraglutide treatment and RYGB also reduced overall food intake and (less pronounced) high-fat preference compared to controls. The animals showed no signs of abnormal behavior in OF or EPM. Conclusions Liraglutide and PYY\(_{3-36}\) combination therapy vastly mimics reduced food intake, food choice and weight reducing benefits of RYGB. KW - obesity KW - rygb KW - liraglutide KW - peptide tyrosine tyrosine (PYY) KW - treatment KW - gastric bypass KW - peptide tyrosine tyrosine 3-36 (PYY3-36) Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223113 SN - 1664-2392 VL - 11 ER - TY - JOUR A1 - Adam, Pia A1 - Kircher, Stefan A1 - Sbiera, Iuliu A1 - Koehler, Viktoria Florentine A1 - Berg, Elke A1 - Knösel, Thomas A1 - Sandner, Benjamin A1 - Fenske, Wiebke Kristin A1 - Bläker, Hendrik A1 - Smaxwil, Constantin A1 - Zielke, Andreas A1 - Sipos, Bence A1 - Allelein, Stephanie A1 - Schott, Matthias A1 - Dierks, Christine A1 - Spitzweg, Christine A1 - Fassnacht, Martin A1 - Kroiss, Matthias T1 - FGF-Receptors and PD-L1 in Anaplastic and Poorly Differentiated Thyroid Cancer: Evaluation of the Preclinical Rationale JF - Frontiers in Endocrinology N2 - 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. KW - tyrosine kinase inhibitor (TKI) KW - immune checkpoint inhibitor (ICI) KW - immunohistochemistry KW - immunotherapy KW - PD-L1 KW - FGFR Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-244653 SN - 1664-2392 VL - 12 ER - TY - JOUR A1 - März, Juliane A1 - Kurlbaum, Max A1 - Roche-Lancaster, Oisin A1 - Deutschbein, Timo A1 - Peitzsch, Mirko A1 - Prehn, Cornelia A1 - Weismann, Dirk A1 - Robledo, Mercedes A1 - Adamski, Jerzy A1 - Fassnacht, Martin A1 - Kunz, Meik A1 - Kroiss, Matthias T1 - Plasma Metabolome Profiling for the Diagnosis of Catecholamine Producing Tumors JF - Frontiers in Endocrinology N2 - Context Pheochromocytomas and paragangliomas (PPGL) cause catecholamine excess leading to a characteristic clinical phenotype. Intra-individual changes at metabolome level have been described after surgical PPGL removal. The value of metabolomics for the diagnosis of PPGL has not been studied yet. Objective Evaluation of quantitative metabolomics as a diagnostic tool for PPGL. Design Targeted metabolomics by liquid chromatography-tandem mass spectrometry of plasma specimens and statistical modeling using ML-based feature selection approaches in a clinically well characterized cohort study. Patients Prospectively enrolled patients (n=36, 17 female) from the Prospective Monoamine-producing Tumor Study (PMT) with hormonally active PPGL and 36 matched controls in whom PPGL was rigorously excluded. Results Among 188 measured metabolites, only without considering false discovery rate, 4 exhibited statistically significant differences between patients with PPGL and controls (histidine p=0.004, threonine p=0.008, lyso PC a C28:0 p=0.044, sum of hexoses p=0.018). Weak, but significant correlations for histidine, threonine and lyso PC a C28:0 with total urine catecholamine levels were identified. Only the sum of hexoses (reflecting glucose) showed significant correlations with plasma metanephrines. By using ML-based feature selection approaches, we identified diagnostic signatures which all exhibited low accuracy and sensitivity. The best predictive value (sensitivity 87.5%, accuracy 67.3%) was obtained by using Gradient Boosting Machine Modelling. Conclusions The diabetogenic effect of catecholamine excess dominates the plasma metabolome in PPGL patients. While curative surgery for PPGL led to normalization of catecholamine-induced alterations of metabolomics in individual patients, plasma metabolomics are not useful for diagnostic purposes, most likely due to inter-individual variability. KW - adrenal KW - pheochromocytoma KW - paraganglioma KW - targeted metabolomics KW - mass spectronomy KW - catecholamines KW - machine learning KW - feature selection Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-245710 SN - 1664-2392 VL - 12 ER - TY - JOUR A1 - Weigand, Isabel A1 - Ronchi, Cristina L. A1 - Vanselow, Jens T. A1 - Bathon, Kerstin A1 - Lenz, Kerstin A1 - Herterich, Sabine A1 - Schlosser, Andreas A1 - Kroiss, Matthias A1 - Fassnacht, Martin A1 - Calebiro, Davide A1 - Sbiera, Silviu T1 - PKA Cα subunit mutation triggers caspase-dependent RIIβ subunit degradation via Ser\(^{114}\) phosphorylation JF - Science Advances N2 - Mutations in the PRKACA gene are the most frequent cause of cortisol-producing adrenocortical adenomas leading to Cushing’s syndrome. PRKACA encodes for the catalytic subunit α of protein kinase A (PKA). We already showed that PRKACA mutations lead to impairment of regulatory (R) subunit binding. Furthermore, PRKACA mutations are associated with reduced RIIβ protein levels; however, the mechanisms leading to reduced RIIβ levels are presently unknown. Here, we investigate the effects of the most frequent PRKACA mutation, L206R, on regulatory subunit stability. We find that Ser\(^{114}\) phosphorylation of RIIβ is required for its degradation, mediated by caspase 16. Last, we show that the resulting reduction in RIIβ protein levels leads to increased cortisol secretion in adrenocortical cells. These findings reveal the molecular mechanisms and pathophysiological relevance of the R subunit degradation caused by PRKACA mutations, adding another dimension to the deregulation of PKA signaling caused by PRKACA mutations in adrenal Cushing’s syndrome. KW - mutation triggers KW - phosphorylation Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-270445 VL - 7 IS - 8 ER - TY - JOUR A1 - Kimpel, Otilia A1 - Bedrose, Sara A1 - Megerle, Felix A1 - Berruti, Alfredo A1 - Terzolo, Massimo A1 - Kroiss, Matthias A1 - Mai, Knut A1 - Dekkers, Olaf M. A1 - Habra, Mouhammed Amir A1 - Fassnacht, Martin T1 - Adjuvant platinum-based chemotherapy in radically resected adrenocortical carcinoma: a cohort study JF - British Journal of Cancer N2 - Background After radical resection, patients with adrenocortical carcinoma (ACC) frequently experience recurrence and, therefore, effective adjuvant treatment is urgently needed. The aim of the study was to investigate the role of adjuvant platinum-based therapy. Methods In this retrospective multicentre cohort study, we identified patients treated with adjuvant platinum-based chemotherapy after radical resection and compared them with patients without adjuvant chemotherapy. Recurrence-free and overall survival (RFS/OS) were investigated in a matched group analysis and by applying a propensity score matching using the full control cohort (n = 268). For both approaches, we accounted for immortal time bias. Results Of the 31 patients in the platinum cohort (R0 n = 25, RX n = 4, R1 n = 2; ENSAT Stage II n = 11, III n = 16, IV n = 4, median Ki67 30%, mitotane n = 28), 14 experienced recurrence compared to 29 of 31 matched controls (median RFS after the landmark at 3 months 17.3 vs. 7.3 months; adjusted HR 0.19 (95% CI 0.09-0.42; P < 0.001). Using propensity score matching, the HR for RFS was 0.45 (0.29-0.89, P = 0.021) and for OS 0.25 (0.09-0.69; P = 0.007). Conclusions Our study provides the first evidence that adjuvant platinum-based chemotherapy may be associated with prolonged recurrence-free and overall survival in patients with ACC and a very high risk for recurrence. KW - adjuvant platinum-based chemotherapy KW - adrenocortical carcinoma KW - radical resection Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-273000 SN - 1532-1827 VL - 125 IS - 9 ER - TY - JOUR A1 - Lippert, Juliane A1 - Fassnacht, Martin A1 - Ronchi, Cristina L. T1 - The role of molecular profiling in adrenocortical carcinoma JF - Clinical Endocrinology N2 - 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. KW - adrenocortical cancer KW - biomarkers KW - precision medicine KW - prognosis KW - targeted treatment Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-258382 VL - 97 IS - 4 ER - TY - JOUR A1 - Wiegering, Verena A1 - Riedmeier, Maria A1 - Thompson, Lester D. R. A1 - Virgone, Calogero A1 - Redlich, Antje A1 - Kuhlen, Michaela A1 - Gultekin, Melis A1 - Yalcin, Bilgehan A1 - Decarolis, Boris A1 - Härtel, Christoph A1 - Schlegel, Paul-Gerhardt A1 - Fassnacht, Martin A1 - Timmermann, Beate T1 - Radiotherapy for pediatric adrenocortical carcinoma - Review of the literature JF - Clinical and Translational Radiation Oncology N2 - 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. KW - pediatric adrenocortical cancer KW - pediatric adrenocortical carcinoma KW - pediatric adrenocortical tumor KW - radiotherapy KW - therapy KW - treatment Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300472 VL - 35 ER - TY - JOUR A1 - Landwehr, Laura-Sophie A1 - Altieri, Barbara A1 - Schreiner, Jochen A1 - Sbiera, Iuliu A1 - Weigand, Isabel A1 - Kroiss, Matthias A1 - Fassnacht, Martin A1 - Sbiera, Silviu T1 - Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma JF - Journal for ImmunoTherapy of Cancer N2 - Background Adrenocortical carcinoma (ACC) is a rare endocrine malignancy. Tumor-related glucocorticoid excess is present in similar to 60% of patients and associated with particularly poor prognosis. Results of first clinical trials using immune checkpoint inhibitors were heterogeneous. Here we characterize tumor-infiltrating T lymphocytes (TILs) in ACC in association with glucocorticoids as potential explanation for resistance to immunotherapy. Methods We performed immunofluorescence analysis to visualize tumor-infiltrating T cells (CD3\(^+\)), T helper cells (CD3\(^+\)CD4\(^+\)), cytotoxic T cells (CD3\(^+\)CD8\(^+\)) and regulatory T cells (Tregs; CD3\(^+\)CD4\(^+\)FoxP3\(^+\)) in 146 ACC tissue specimens (107 primary tumors, 16 local recurrences, 23 metastases). Quantitative data of immune cell infiltration were correlated with clinical data (including glucocorticoid excess). Results 86.3% of ACC specimens showed tumor infiltrating T cells (7.7 cells/high power field (HPF)), including T helper (74.0%, 6.7 cells/HPF), cytotoxic T cells (84.3%, 5.7 cells/HPF) and Tregs (49.3%, 0.8 cells/HPF). The number of TILs was associated with better overall survival (HR for death: 0.47, 95% CI 0.25 to 0.87), which was true for CD4\(^+\)- and CD8\(^+\) subpopulations as well. In localized, non-metastatic ACC, the favorable impact of TILs on overall and recurrence-free survival was manifested even independently of ENSAT (European Network for the Study of Adrenal Tumors) stage, resection status and Ki67 index. T helper cells were negatively correlated with glucocorticoid excess (Phi=-0.290, p=0.009). Patients with glucocorticoid excess and low TILs had a particularly poor overall survival (27 vs. 121 months in patients with TILs without glucocorticoid excess). Conclusion Glucocorticoid excess is associated with T cell depletion and unfavorable prognosis. To reactivate the immune system in ACC by checkpoint inhibitors, an inhibition of adrenal steroidogenesis might be pivotal and should be tested in prospective studies. KW - immunity KW - immunotherapy KW - lymphocytes KW - tumor-infiltrating KW - t-lymphocytes KW - tumor microenvironment Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229893 VL - 8 ER - TY - JOUR A1 - Detomas, Mario A1 - Altieri, Barbara A1 - Deutschbein, Timo A1 - Fassnacht, Martin A1 - Dischinger, Ulrich T1 - Metyrapone versus osilodrostat in the short-term therapy of endogenous Cushing’s syndrome: results from a single center cohort study JF - Frontiers in Endocrinology N2 - 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. KW - metyrapone KW - osilodrostat KW - Cushing’s syndrome KW - hypercortisolism KW - medical therapy KW - blood pressure KW - isturisa KW - efficacy Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-277477 SN - 1664-2392 VL - 13 ER -