@article{BliziotisKluijtmansSotoetal.2022,
  author    = {Bliziotis, Nikolaos G. and Kluijtmans, Leo A. J. and Soto, Sebastian and Tinnevelt, Gerjen H. and Langton, Katharina and Robledo, Mercedes and Pamporaki, Christina and Engelke, Udo F. H. and Erlic, Zoran and Engel, Jasper and Deutschbein, Timo and N{\"o}lting, Svenja and Prejbisz, Aleksander and Richter, Susan and Prehn, Cornelia and Adamski, Jerzy and Januszewicz, Andrzej and Reincke, Martin and Fassnacht, Martin and Eisenhofer, Graeme and Beuschlein, Felix and Kroiss, Matthias and Wevers, Ron A. and Jansen, Jeroen J. and Deinum, Jaap and Timmers, Henri J. L. M.},
  title     = {Pre- versus post-operative untargeted plasma nuclear magnetic resonance spectroscopy metabolomics of pheochromocytoma and paraganglioma},
  series = {Endocrine},
  volume    = {75},
  journal   = {Endocrine},
  number    = {1},
  doi       = {10.1007/s12020-021-02858-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-326574},
  pages     = {254-265},
  year      = {2022},
  abstract  = {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.},
  language  = {en}
}
@article{RemdeKranzMorelletal.2023,
  author    = {Remde, Hanna and Kranz, Stefanie and Morell, Sarah Maria and Altieri, Barbara and Kroiss, Matthias and Detomas, Mario and Fassnacht, Martin and Deutschbein, Timo},
  title     = {Clinical course of patients with adrenal incidentalomas and cortisol autonomy},
  series = {Frontiers in Endocrinology},
  volume    = {14},
  journal   = {Frontiers in Endocrinology},
  issn      = {1664-2392},
  doi       = {10.3389/fendo.2023.1123132},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-316793},
  year      = {2023},
  abstract  = {Background Adrenal incidentalomas with cortisol autonomy are associated with increased cardiovascular morbidity and mortality. Specific data on the clinical and biochemical course of affected patients are lacking. Methods Retrospective study from a tertiary referral centre in Germany. After exclusion of overt hormone excess, malignancy and glucocorticoid medication, patients with adrenal incidentalomas were stratified according to serum cortisol after 1 mg dexamethasone: autonomous cortisol secretion (ACS), >5.0; possible ACS (PACS), 1.9-5.0; non-functioning adenomas (NFA), ≤1.8 µg/dl. Results A total of 260 patients were enrolled (147 women (56.5\%), median follow-up 8.8 (2.0-20.8) years). At initial diagnosis, median age was 59.5 (20-82) years, and median tumour size was 27 (10-116) mm. Bilateral tumours were more prevalent in ACS (30.0\%) and PACS (21.9\%) than in NFA (8.1\%). Over time, 40/124 (32.3\%) patients had a shift of their hormonal secretion pattern (NFA to PACS/ACS, n=15/53; PACS to ACS, n=6/47; ACS to PACS, n=11/24; PACS to NFA, n=8/47). However, none of the patients developed overt Cushing's syndrome. Sixty-one patients underwent adrenalectomy (NFA, 17.9\%; PACS, 24.0\%; ACS, 39.0\%). When non-operated patients with NFA were compared to PACS and ACS at last follow-up, arterial hypertension (65.3\% vs. 81.9\% and 92.0\%; p<0.05), diabetes (23.8\% vs. 35.6\% and 40.0\%; p<0.01), and thromboembolic events (PACS: HR 3.43, 95\%-CI 0.89-13.29; ACS: HR 5.96, 95\%-CI 1.33-26.63; p<0.05) were significantly less frequent, along with a trend towards a higher rate of cardiovascular events in case of cortisol autonomy (PACS: HR 2.23, 95\%-CI 0.94-5.32; ACS: HR 2.60, 95\%-CI 0.87-7.79; p=0.1). Twenty-five (12.6\%) of the non-operated patients died, with higher overall mortality in PACS (HR 2.6, 95\%-CI 1.0-4.7; p=0.083) and ACS (HR 4.7, 95\%-CI 1.6-13.3; p<0.005) compared to NFA. In operated patients, prevalence of arterial hypertension decreased significantly (77.0\% at diagnosis to 61.7\% at last follow-up; p<0.05). The prevalence of cardiovascular events and mortality did not differ significantly between operated and non-operated patients, whereas thromboembolic events were significantly less frequent in the surgical treatment group. Conclusion Our study confirms relevant cardiovascular morbidity in patients with adrenal incidentalomas (especially those with cortisol autonomy). These patients should therefore be monitored carefully, including adequate treatment of typical cardiovascular risk factors. Adrenalectomy was associated with a significantly decreased prevalence of hypertension. However, more than 30\% of patients required reclassification according to repeated dexamethasone suppression tests. Thus, cortisol autonomy should ideally be confirmed before making any relevant treatment decision (e.g. adrenalectomy).},
  language  = {en}
}
@article{WernerSayehliHaenscheidetal.2023,
  author    = {Werner, Rudolf A. and Sayehli, Cyrus and H{\"a}nscheid, Heribert and Higuchi, Takahiro and Serfling, Sebastian E. and Fassnacht, Martin and Goebeler, Maria-Elisabeth and Buck, Andreas K. and Kroiss, Matthias},
  title     = {Successful combination of selpercatinib and radioiodine after pretherapeutic dose estimation in RET-altered thyroid carcinoma},
  series = {European Journal of Nuclear Medicine and Molecular Imaging},
  volume    = {50},
  journal   = {European Journal of Nuclear Medicine and Molecular Imaging},
  number    = {6},
  doi       = {10.1007/s00259-022-06061-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324435},
  pages     = {1833-1834},
  year      = {2023},
  abstract  = {No abstract available.},
  language  = {en}
}
@article{KimpelSchindlerSchmidtPenningtonetal.2023,
  author    = {Kimpel, Otilia and Schindler, Paul and Schmidt-Pennington, Laura and Altieri, Barbara and Megerle, Felix and Haak, Harm and Pittaway, James and Dischinger, Ulrich and Quinkler, Marcus and Mai, Knut and Kroiss, Matthias and Polat, B{\"u}lent and Fassnacht, Martin},
  title     = {Efficacy and safety of radiation therapy in advanced adrenocortical carcinoma},
  series = {British Journal of Cancer},
  volume    = {128},
  journal   = {British Journal of Cancer},
  number    = {4},
  doi       = {10.1038/s41416-022-02082-0},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324411},
  pages     = {586-593},
  year      = {2023},
  abstract  = {Background International guidelines emphasise the role of radiotherapy (RT) for the management of advanced adrenocortical carcinoma (ACC). However, the evidence for this recommendation is very low. Methods We retrospectively analysed all patients who received RT for advanced ACC in five European centres since 2000. Primary endpoint: time to progression of the treated lesion (tTTP). Secondary endpoints: best objective response, progression-free survival (PFS), overall survival (OS), adverse events, and the establishment of predictive factors by Cox analyses. Results In total, 132 tumoural lesions of 80 patients were treated with conventional RT (cRT) of 50-60 Gy (n = 20) or 20-49 Gy (n = 69), stereotactic body RT of 35-50 Gy (SBRT) (n = 36), or brachytherapy of 12-25 Gy (BT) (n = 7). Best objective lesional response was complete (n = 6), partial (n = 52), stable disease (n = 60), progressive disease (n = 14). Median tTTP was 7.6 months (1.0-148.6). In comparison to cRT\(_{20-49Gy}\), tTTP was significantly longer for cRT\(_{50-60Gy}\) (multivariate adjusted HR 0.10; 95\% CI 0.03-0.33; p < 0.001) and SBRT (HR 0.31; 95\% CI 0.12-0.80; p = 0.016), but not for BT (HR 0.66; 95\% CI 0.22-1.99; p = 0.46). Toxicity was generally mild and moderate with three grade 3 events. No convincing predictive factors could be established. Conclusions This largest published study on RT in advanced ACC provides clear evidence that RT is effective in ACC.},
  language  = {en}
}
@article{ReelReelErlicetal.2022,
  author    = {Reel, Smarti and Reel, Parminder S. and Erlic, Zoran and Amar, Laurence and Pecori, Alessio and Larsen, Casper K. and Tetti, Martina and Pamporaki, Christina and Prehn, Cornelia and Adamski, Jerzy and Prejbisz, Aleksander and Ceccato, Filippo and Scaroni, Carla and Kroiss, Matthias and Dennedy, Michael C. and Deinum, Jaap and Eisenhofer, Graeme and Langton, Katharina and Mulatero, Paolo and Reincke, Martin and Rossi, Gian Paolo and Lenzini, Livia and Davies, Eleanor and Gimenez-Roqueplo, Anne-Paule and Assi{\´e}, Guillaume and Blanchard, Anne and Zennaro, Maria-Christina and Beuschlein, Felix and Jefferson, Emily R.},
  title     = {Predicting hypertension subtypes with machine learning using targeted metabolites and their ratios},
  series = {Metabolites},
  volume    = {12},
  journal   = {Metabolites},
  number    = {8},
  issn      = {2218-1989},
  doi       = {10.3390/metabo12080755},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286161},
  year      = {2022},
  abstract  = {Hypertension is a major global health problem with high prevalence and complex associated health risks. Primary hypertension (PHT) is most common and the reasons behind primary hypertension are largely unknown. Endocrine hypertension (EHT) is another complex form of hypertension with an estimated prevalence varying from 3 to 20\% depending on the population studied. It occurs due to underlying conditions associated with hormonal excess mainly related to adrenal tumours and sub-categorised: primary aldosteronism (PA), Cushing's syndrome (CS), pheochromocytoma or functional paraganglioma (PPGL). Endocrine hypertension is often misdiagnosed as primary hypertension, causing delays in treatment for the underlying condition, reduced quality of life, and costly antihypertensive treatment that is often ineffective. This study systematically used targeted metabolomics and high-throughput machine learning methods to predict the key biomarkers in classifying and distinguishing the various subtypes of endocrine and primary hypertension. The trained models successfully classified CS from PHT and EHT from PHT with 92\% specificity on the test set. The most prominent targeted metabolites and metabolite ratios for hypertension identification for different disease comparisons were C18:1, C18:2, and Orn/Arg. Sex was identified as an important feature in CS vs. PHT classification.},
  language  = {en}
}
@article{BliziotisKluijtmansTinneveltetal.2022,
  author    = {Bliziotis, Nikolaos G. and Kluijtmans, Leo A. J. and Tinnevelt, Gerjen H. and Reel, Parminder and Reel, Smarti and Langton, Katharina and Robledo, Mercedes and Pamporaki, Christina and Pecori, Alessio and Van Kralingen, Josie and Tetti, Martina and Engelke, Udo F. H. and Erlic, Zoran and Engel, Jasper and Deutschbein, Timo and N{\"o}lting, Svenja and Prejbisz, Aleksander and Richter, Susan and Adamski, Jerzy and Januszewicz, Andrzej and Ceccato, Filippo and Scaroni, Carla and Dennedy, Michael C. and Williams, Tracy A. and Lenzini, Livia and Gimenez-Roqueplo, Anne-Paule and Davies, Eleanor and Fassnacht, Martin and Remde, Hanna and Eisenhofer, Graeme and Beuschlein, Felix and Kroiss, Matthias and Jefferson, Emily and Zennaro, Maria-Christina and Wevers, Ron A. and Jansen, Jeroen J. and Deinum, Jaap and Timmers, Henri J. L. M.},
  title     = {Preanalytical pitfalls in untargeted plasma nuclear magnetic resonance metabolomics of endocrine hypertension},
  series = {Metabolites},
  volume    = {12},
  journal   = {Metabolites},
  number    = {8},
  issn      = {2218-1989},
  doi       = {10.3390/metabo12080679},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-282930},
  year      = {2022},
  abstract  = {Despite considerable morbidity and mortality, numerous cases of endocrine hypertension (EHT) forms, including primary aldosteronism (PA), pheochromocytoma and functional paraganglioma (PPGL), and Cushing's syndrome (CS), remain undetected. We aimed to establish signatures for the different forms of EHT, investigate potentially confounding effects and establish unbiased disease biomarkers. Plasma samples were obtained from 13 biobanks across seven countries and analyzed using untargeted NMR metabolomics. We compared unstratified samples of 106 PHT patients to 231 EHT patients, including 104 PA, 94 PPGL and 33 CS patients. Spectra were subjected to a multivariate statistical comparison of PHT to EHT forms and the associated signatures were obtained. Three approaches were applied to investigate and correct confounding effects. Though we found signatures that could separate PHT from EHT forms, there were also key similarities with the signatures of sample center of origin and sample age. The study design restricted the applicability of the corrections employed. With the samples that were available, no biomarkers for PHT vs. EHT could be identified. The complexity of the confounding effects, evidenced by their robustness to correction approaches, highlighted the need for a consensus on how to deal with variabilities probably attributed to preanalytical factors in retrospective, multicenter metabolomics studies.},
  language  = {en}
}
@article{KoehlerAdamFussetal.2022,
  author    = {Koehler, Viktoria Florentine and Adam, Pia and Fuss, Carmina Teresa and Jiang, Linmiao and Berg, Elke and Frank-Raue, Karin and Raue, Friedhelm and Hoster, Eva and Kn{\"o}sel, Thomas and Schildhaus, Hans-Ulrich and Negele, Thomas and Siebolts, Udo and Lorenz, Kerstin and Allelein, Stephanie and Schott, Matthias and Spitzweg, Christine and Kroiss, Matthias},
  title     = {Treatment of RET-positive advanced medullary thyroid cancer with multi-tyrosine kinase inhibitors — a retrospective multi-center registry analysis},
  series = {Cancers},
  volume    = {14},
  journal   = {Cancers},
  number    = {14},
  issn      = {2072-6694},
  doi       = {10.3390/cancers14143405},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-281776},
  year      = {2022},
  abstract  = {Background: RET (rearranged during transfection) variants are the most prevalent oncogenic events in medullary thyroid cancer (MTC). In advanced disease, multi-tyrosine kinase inhibitors (MKIs) cabozantinib and vandetanib are the approved standard treatment irrespective of RET status. The actual outcome of patients with RET-positive MTC treated with MKIs is ill described. Methods: We here retrospectively determined the RET oncogene variant status with a targeted DNA Custom Panel in a prospectively collected cohort of 48 patients with advanced MTC treated with vandetanib and/or cabozantinib at four German referral centers. Progression-free survival (PFS) and overall survival (OS) probabilities were estimated using the Kaplan-Meier method. Results: In total, 44/48 (92\%) patients had germline or somatic RET variants. The M918T variant was found in 29/44 (66\%) cases. In total, 2/32 (6\%) patients with a somatic RET variant had further somatic variants, while in 1/32 (3\%) patient with a germline RET variant, additional variants were found. Only 1/48 (2\%) patient had a pathogenic HRAS variant, and no variants were found in 3 cases. In first-line treatment, the median OS was 53 (95\% CI (95\% confidence interval), 32-NR (not reached); n = 36), and the median PFS was 21 months (12-39; n = 33) in RET-positive MTC patients. In second-line treatment, the median OS was 18 (13-79; n = 22), and the median PFS was 3.5 months (2-14; n = 22) in RET-positive cases. Conclusions: RET variants were highly prevalent in patients with advanced MTC. The treatment results in RET-positive cases were similar to those reported in unselected cohorts.},
  language  = {en}
}
@article{DetomasRitzelNasiKordhishtietal.2022,
  author    = {Detomas, Mario and Ritzel, Katrin and Nasi-Kordhishti, Isabella and Wolfsberger, Stefan and Quinkler, Marcus and Losa, Marco and Tr{\"o}ger, Viola and Kroiss, Matthias and Fassnacht, Martin and Vila, Greisa and Honegger, J{\"u}rgen Bernd and Reincke, Martin and Deutschbein, Timo},
  title     = {Outcome of CRH stimulation test and overnight 8 mg dexamethasone suppression test in 469 patients with ACTH-dependent Cushing's syndrome},
  series = {Frontiers in Endocrinology},
  volume    = {13},
  journal   = {Frontiers in Endocrinology},
  issn      = {1664-2392},
  doi       = {10.3389/fendo.2022.955945},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-289450},
  year      = {2022},
  abstract  = {Objective To evaluate diagnostic accuracy of the corticotropin-releasing hormone (CRH) stimulation test and the overnight 8 mg dexamethasone suppression test (DST) for the differentiation of Cushing's disease (CD) and ectopic Cushing's syndrome (ECS). Methods Retrospective study in 6 European centers. Inclusion criteria: patients with a) overt adrenocorticotropin (ACTH)-dependent Cushing's syndrome at the time of dynamic testing, b) histopathological confirmed tumors and/or c) postoperative biochemical remission and/or adrenal insufficiency. Optimal cut-offs were calculated via receiver operating characteristic (ROC) analysis using CD as reference. Results 469 patients were analyzed [78\% females; median age 43 years (IQR 19)]. CRH test and overnight 8 mg DST were performed in 420 [CD, n=394 (94\%); ECS, n=26 (6\%)] and 237 patients [228 CD (96\%), 9 ECS (4\%)]. Both tests were performed in 205 patients (44\%). The post-CRH \%-increase at 30 minutes of both ACTH (cut-off ≥31\%, sensitivity 83\%, specificity 85\%, AUC 0.81) and cortisol (cut-off ≥12\%, sensitivity 82\%, specificity 89\%, AUC 0.86) discriminated best between CD and ECS. A test duration of >60 minutes did not improve diagnostic performance of the CRH test. The optimal cortisol cut-off for the \%-suppression during the 8 mg DST was ≥55\% (sensitivity 80\%, specificity 78\%, AUC 0.75). Conclusion The CRH test has equivalent sensitivity but higher specificity than the 8 mg DST and is therefore the test of first choice. The diagnostic outcome of ACTH and cortisol is well comparable, however, sampling beyond 60 minutes post-CRH does not provide diagnostic benefits.},
  language  = {en}
}
@article{KimpelBedroseMegerleetal.2021,
  author    = {Kimpel, Otilia and Bedrose, Sara and Megerle, Felix and Berruti, Alfredo and Terzolo, Massimo and Kroiss, Matthias and Mai, Knut and Dekkers, Olaf M. and Habra, Mouhammed Amir and Fassnacht, Martin},
  title     = {Adjuvant platinum-based chemotherapy in radically resected adrenocortical carcinoma: a cohort study},
  series = {British Journal of Cancer},
  volume    = {125},
  journal   = {British Journal of Cancer},
  number    = {9},
  issn      = {1532-1827},
  doi       = {10.1038/s41416-021-01513-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-273000},
  pages     = {1233-1238},
  year      = {2021},
  abstract  = {Background After radical resection, patients with adrenocortical carcinoma (ACC) frequently experience recurrence and, therefore, effective adjuvant treatment is urgently needed. The aim of the study was to investigate the role of adjuvant platinum-based therapy. Methods In this retrospective multicentre cohort study, we identified patients treated with adjuvant platinum-based chemotherapy after radical resection and compared them with patients without adjuvant chemotherapy. Recurrence-free and overall survival (RFS/OS) were investigated in a matched group analysis and by applying a propensity score matching using the full control cohort (n = 268). For both approaches, we accounted for immortal time bias. Results Of the 31 patients in the platinum cohort (R0 n = 25, RX n = 4, R1 n = 2; ENSAT Stage II n = 11, III n = 16, IV n = 4, median Ki67 30\%, mitotane n = 28), 14 experienced recurrence compared to 29 of 31 matched controls (median RFS after the landmark at 3 months 17.3 vs. 7.3 months; adjusted HR 0.19 (95\% CI 0.09-0.42; P < 0.001). Using propensity score matching, the HR for RFS was 0.45 (0.29-0.89, P = 0.021) and for OS 0.25 (0.09-0.69; P = 0.007). Conclusions Our study provides the first evidence that adjuvant platinum-based chemotherapy may be associated with prolonged recurrence-free and overall survival in patients with ACC and a very high risk for recurrence.},
  language  = {en}
}
@article{EckhardtSbieraKrebsetal.2022,
  author    = {Eckhardt, Carolin and Sbiera, Iuliu and Krebs, Markus and Sbiera, Silviu and Spahn, Martin and Kneitz, Burkhard and Joniau, Steven and Fassnacht, Martin and K{\"u}bler, Hubert and Weigand, Isabel and Kroiss, Matthias},
  title     = {High expression of Sterol-O-Acyl transferase 1 (SOAT1), an enzyme involved in cholesterol metabolism, is associated with earlier biochemical recurrence in high risk prostate cancer},
  series = {Prostate Cancer and Prostatic Diseases},
  volume    = {25},
  journal   = {Prostate Cancer and Prostatic Diseases},
  number    = {3},
  issn      = {1476-5608},
  doi       = {10.1038/s41391-021-00431-3},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-271819},
  pages     = {484-490},
  year      = {2022},
  abstract  = {Background Prostate cancer (PCa) is the most frequent cancer in men. The prognosis of PCa is heterogeneous with many clinically indolent tumors and rare highly aggressive cases. Reliable tissue markers of prognosis are lacking. Active cholesteryl ester synthesis has been associated with prostate cancer aggressiveness. Sterol-O-Acyl transferases (SOAT) 1 and 2 catalyze cholesterol esterification in humans. Objective To investigate the value of SOAT1 and SOAT2 tissue expression as prognostic markers in high risk PCa. Patients and Methods Formalin-fixed paraffin-embedded tissue samples from 305 high risk PCa cases treated with radical prostatectomy were analyzed for SOAT1 and SOAT2 protein expression by semi-quantitative immunohistochemistry. The Kaplan-Meier method and Cox proportional hazards modeling were used to compare outcome. Main Outcome Measure Biochemical recurrence (BCR) free survival. Results SOAT1 expression was high in 73 (25\%) and low in 219 (75\%; not evaluable: 13) tumors. SOAT2 was highly expressed in 40 (14\%) and at low levels in 249 (86\%) samples (not evaluable: 16). By Kaplan-Meier analysis, we found significantly shorter median BCR free survival of 93 months (95\% confidence interval 23.6-123.1) in patients with high SOAT1 vs. 134 months (112.6-220.2, Log-rank p < 0.001) with low SOAT1. SOAT2 expression was not significantly associated with BCR. After adjustment for age, preoperative PSA, tumor stage, Gleason score, resection status, lymph node involvement and year of surgery, high SOAT1 but not SOAT2 expression was associated with shorter BCR free survival with a hazard ratio of 2.40 (95\% CI 1.57-3.68, p < 0.001). Time to clinical recurrence and overall survival were not significantly associated with SOAT1 and SOAT2 expression CONCLUSIONS: SOAT1 expression is strongly associated with BCR free survival alone and after multivariable adjustment in high risk PCa. SOAT1 may serve as a histologic marker of prognosis and holds promise as a future treatment target.},
  language  = {en}
}
@article{LacombeSoaresMarianietal.2020,
  author    = {Lacombe, Amanda Meneses Ferreira and Soares, Iber{\^e} Cauduro and Mariani, Beatriz Marinho de Paula and Nishi, Mirian Yumie and Bezerra-Neto, Jo{\~a}o Evangelista and Charchar, Helaine da Silva and Brondani, Vania Balderrama and Tanno, Fabio and Srougi, Victor and Chambo, Jos{\´e} Luiz and Costa de Freitas, Ricardo Miguel and Mendonca, Berenice Bilharinho and Hoff, Ana O. and Almeida, Madson Q. and Weigand, Isabel and Kroiss, Matthias and Zerbini, Maria Claudia Nogueira and Fragoso, Maria Candida Barisson Villares},
  title     = {Sterol O-acyl transferase 1 as a prognostic marker of adrenocortical carcinoma},
  series = {Cancers},
  volume    = {12},
  journal   = {Cancers},
  number    = {1},
  issn      = {2072-6694},
  doi       = {10.3390/cancers12010247},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200857},
  year      = {2020},
  abstract  = {Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with an unfavorable prognosis. Despite the poor prognosis in the majority of patients, no improvements in treatment strategies have been achieved. Therefore, the discovery of new prognostic biomarkers is of enormous interest. Sterol-O-acyl transferase 1 (SOAT1) is involved in cholesterol esterification and lipid droplet formation. Recently, it was demonstrated that SOAT1 inhibition leads to impaired steroidogenesis and cell viability in ACC. To date, no studies have addressed the impact of SOAT1 expression on ACC prognosis and clinical outcomes. We evaluated SOAT1 expression by quantitative real-time polymerase chain reaction and immunohistochemistry in a tissue microarray of 112 ACCs (Weiss score ≥ 3) from adults treated in a single tertiary center in Brazil. Two independent pathologists evaluated the immunohistochemistry results through a semiquantitative approach (0-4). We aimed to evaluate the correlation between SOAT1 expression and clinical, biochemical and anatomopathological parameters, recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS). SOAT1 protein expression was heterogeneous in this cohort, 37.5\% of the ACCs demonstrated a strong SOAT1 protein expression (score > 2), while 62.5\% demonstrated a weak or absent protein expression (score ≤ 2). Strong SOAT1 protein expression correlated with features of high aggressiveness in ACC, such as excessive tumor cortisol secretion (p = 0.01), an advanced disease stage [European Network for the Study of Adrenal Tumors (ENSAT) staging system 3 and 4 (p = 0.011)] and a high Ki67 index (p = 0.002). In multivariate analysis, strong SOAT1 protein expression was an independent predictor of a reduced OS (hazard ratio (HR) 2.15, confidence interval (CI) 95\% 1.26-3.66; p = 0.005) in all patients (n = 112), and a reduced RFS (HR 2.1, CI 95\% 1.09-4.06; p = 0.027) in patients with localized disease at diagnosis (n = 83). Our findings demonstrated that SOAT1 protein expression has prognostic value in ACC and reinforced the importance of investigating SOAT1 as a possible therapeutic target for patients with ACC.},
  language  = {en}
}
@article{WeigandRonchiVanselowetal.2021,
  author    = {Weigand, Isabel and Ronchi, Cristina L. and Vanselow, Jens T. and Bathon, Kerstin and Lenz, Kerstin and Herterich, Sabine and Schlosser, Andreas and Kroiss, Matthias and Fassnacht, Martin and Calebiro, Davide and Sbiera, Silviu},
  title     = {PKA Cα subunit mutation triggers caspase-dependent RIIβ subunit degradation via Ser\(^{114}\) phosphorylation},
  series = {Science Advances},
  volume    = {7},
  journal   = {Science Advances},
  number    = {8},
  doi       = {10.1126/sciadv.abd4176},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-270445},
  year      = {2021},
  abstract  = {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.},
  language  = {en}
}
@article{SbieraKircherAltierietal.2021,
  author    = {Sbiera, Iuliu and Kircher, Stefan and Altieri, Barbara and Lenz, Kerstin and Hantel, Constanze and Fassnacht, Martin and Sbiera, Silviu and Kroiss, Matthias},
  title     = {Role of FGF Receptors and Their Pathways in Adrenocortical Tumors and Possible Therapeutic Implications},
  series = {Frontiers in Endocrinology},
  volume    = {12},
  journal   = {Frontiers in Endocrinology},
  issn      = {1664-2392},
  doi       = {10.3389/fendo.2021.795116},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-251953},
  year      = {2021},
  abstract  = {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.},
  language  = {en}
}
@article{MaerzKurlbaumRocheLancasteretal.2021,
  author    = {M{\"a}rz, Juliane and Kurlbaum, Max and Roche-Lancaster, Oisin and Deutschbein, Timo and Peitzsch, Mirko and Prehn, Cornelia and Weismann, Dirk and Robledo, Mercedes and Adamski, Jerzy and Fassnacht, Martin and Kunz, Meik and Kroiss, Matthias},
  title     = {Plasma Metabolome Profiling for the Diagnosis of Catecholamine Producing Tumors},
  series = {Frontiers in Endocrinology},
  volume    = {12},
  journal   = {Frontiers in Endocrinology},
  issn      = {1664-2392},
  doi       = {10.3389/fendo.2021.722656},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245710},
  year      = {2021},
  abstract  = {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.},
  language  = {en}
}
@article{LenschowFussKircheretal.2021,
  author    = {Lenschow, Christina and Fuss, Carmina Teresa and Kircher, Stefan and Buck, Andreas and Kickuth, Ralph and Reibetanz, Joachim and Wiegering, Armin and Stenzinger, Albrecht and H{\"u}bschmann, Daniel and Germer, Christoph Thomas and Fassnacht, Martin and Fr{\"o}hling, Stefan and Schlegel, Nicolas and Kroiss, Matthias},
  title     = {Case Report: Abdominal Lymph Node Metastases of Parathyroid Carcinoma: Diagnostic Workup, Molecular Diagnosis, and Clinical Management},
  series = {Frontiers in Endocrinology},
  volume    = {12},
  journal   = {Frontiers in Endocrinology},
  issn      = {1664-2392},
  doi       = {10.3389/fendo.2021.643328},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233362},
  year      = {2021},
  abstract  = {Parathyroid carcinoma (PC) is an orphan malignancy accounting for only ~1\% of all cases with primary hyperparathyroidism. The localization of recurrent PC is of critical importance and can be exceedingly difficult to diagnose and sometimes futile when common sites of recurrence in the neck and chest cannot be confirmed. Here, we present the diagnostic workup, molecular analysis and multimodal therapy of a 46-year old woman with the extraordinary manifestation of abdominal lymph node metastases 12 years after primary diagnosis of PC. The patient was referred to our endocrine tumor center in 2016 with the aim to localize the tumor causative of symptomatic biochemical recurrence. In view of the extensive previous workup we decided to perform [18F]FDG-PET-CT. A pathological lymph node in the liver hilus showed slightly increased FDG-uptake and hence was suspected as site of recurrence. Selective venous sampling confirmed increased parathyroid hormone concentration in liver veins. Abdominal lymph node metastasis was resected and histopathological examination confirmed PC. Within four months, the patient experienced biochemical recurrence and based on high tumor mutational burden detected in the surgical specimen by whole exome sequencing the patient received immunotherapy with pembrolizumab that led to a biochemical response. Subsequent to disease progression repeated abdominal lymph node resection was performed in 10/2018, 01/2019 and in 01/2020. Up to now (12/2020) the patient is biochemically free of disease. In conclusion, a multimodal diagnostic approach and therapy in an interdisciplinary setting is needed for patients with rare endocrine tumors. Molecular analyses may inform additional treatment options including checkpoint inhibitors such as pembrolizumab.},
  language  = {en}
}
@article{SbieraKircherAltierietal.2021,
  author    = {Sbiera, Iuliu and Kircher, Stefan and Altieri, Barbara and Fassnacht, Martin and Kroiss, Matthias and Sbiera, Silviu},
  title     = {Epithelial and Mesenchymal Markers in Adrenocortical Tissues: How Mesenchymal Are Adrenocortical Tissues?},
  series = {Cancers},
  volume    = {13},
  journal   = {Cancers},
  number    = {7},
  issn      = {2072-6694},
  doi       = {10.3390/cancers13071736},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236486},
  year      = {2021},
  abstract  = {A clinically relevant proportion of adrenocortical carcinoma (ACC) cases shows a tendency to metastatic spread. The objective was to determine whether the epithelial to mesenchymal transition (EMT), a mechanism associated with metastasizing in several epithelial cancers, might play a crucial role in ACC. 138 ACC, 29 adrenocortical adenomas (ACA), three normal adrenal glands (NAG), and control tissue samples were assessed for the expression of epithelial (E-cadherin and EpCAM) and mesenchymal (N-cadherin, SLUG and SNAIL) markers by immunohistochemistry. Using real-time RT-PCR we quantified the alternative isoform splicing of FGFR 2 and 3, another known indicator of EMT. We also assessed the impact of these markers on clinical outcome. Results show that both normal and neoplastic adrenocortical tissues lacked expression of epithelial markers but strongly expressed mesenchymal markers N-cadherin and SLUG. FGFR isoform splicing confirmed higher similarity of adrenocortical tissues to mesenchymal compared to epithelial tissues. In ACC, higher SLUG expression was associated with clinical markers indicating aggressiveness, while N-cadherin expression inversely associated with these markers. In conclusion, we could not find any indication of EMT as all adrenocortical tissues lacked expression of epithelial markers and exhibited closer similarity to mesenchymal tissues. However, while N-cadherin might play a positive role in tissue structure upkeep, SLUG seems to be associated with a more aggressive phenotype.},
  language  = {en}
}
@article{DetomasAltieriSchloetelburgetal.2021,
  author    = {Detomas, Mario and Altieri, Barbara and Schl{\"o}telburg, Wiebke and Appenzeller, Silke and Schlaffer, Sven and Coras, Roland and Schirbel, Andreas and Wild, Vanessa and Kroiss, Matthias and Sbiera, Silviu and Fassnacht, Martin and Deutschbein, Timo},
  title     = {Case Report: Consecutive Adrenal Cushing's Syndrome and Cushing's Disease in a Patient With Somatic CTNNB1, USP8, and NR3C1 Mutations},
  series = {Frontiers in Endocrinology},
  volume    = {12},
  journal   = {Frontiers in Endocrinology},
  issn      = {1664-2392},
  doi       = {10.3389/fendo.2021.731579},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244596},
  year      = {2021},
  abstract  = {The occurrence of different subtypes of endogenous Cushing's syndrome (CS) in single individuals is extremely rare. We here present the case of a female patient who was successfully cured from adrenal CS 4 years before being diagnosed with Cushing's disease (CD). The patient was diagnosed at the age of 50 with ACTH-independent CS and a left-sided adrenal adenoma, in January 2015. After adrenalectomy and histopathological confirmation of a cortisol-producing adrenocortical adenoma, biochemical hypercortisolism and clinical symptoms significantly improved. However, starting from 2018, the patient again developed signs and symptoms of recurrent CS. Subsequent biochemical and radiological workup suggested the presence of ACTH-dependent CS along with a pituitary microadenoma. The patient underwent successful transsphenoidal adenomectomy, and both postoperative adrenal insufficiency and histopathological workup confirmed the diagnosis of CD. Exome sequencing excluded a causative germline mutation but showed somatic mutations of the β-catenin protein gene (CTNNB1) in the adrenal adenoma, and of both the ubiquitin specific peptidase 8 (USP8) and the glucocorticoid receptor (NR3C1) genes in the pituitary adenoma. In conclusion, our case illustrates that both ACTH-independent and ACTH-dependent CS may develop in a single individual even without evidence for a common genetic background.},
  language  = {en}
}
@article{AdamKircherSbieraetal.2021,
  author    = {Adam, Pia and Kircher, Stefan and Sbiera, Iuliu and Koehler, Viktoria Florentine and Berg, Elke and Kn{\"o}sel, Thomas and Sandner, Benjamin and Fenske, Wiebke Kristin and Bl{\"a}ker, Hendrik and Smaxwil, Constantin and Zielke, Andreas and Sipos, Bence and Allelein, Stephanie and Schott, Matthias and Dierks, Christine and Spitzweg, Christine and Fassnacht, Martin and Kroiss, Matthias},
  title     = {FGF-Receptors and PD-L1 in Anaplastic and Poorly Differentiated Thyroid Cancer: Evaluation of the Preclinical Rationale},
  series = {Frontiers in Endocrinology},
  volume    = {12},
  journal   = {Frontiers in Endocrinology},
  issn      = {1664-2392},
  doi       = {10.3389/fendo.2021.712107},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-244653},
  year      = {2021},
  abstract  = {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.},
  language  = {en}
}
@article{LandwehrAltieriSchreineretal.2020,
  author    = {Landwehr, Laura-Sophie and Altieri, Barbara and Schreiner, Jochen and Sbiera, Iuliu and Weigand, Isabel and Kroiss, Matthias and Fassnacht, Martin and Sbiera, Silviu},
  title     = {Interplay between glucocorticoids and tumor-infiltrating lymphocytes on the prognosis of adrenocortical carcinoma},
  series = {Journal for ImmunoTherapy of Cancer},
  volume    = {8},
  journal   = {Journal for ImmunoTherapy of Cancer},
  doi       = {10.1136/jitc-2019-000469},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229893},
  year      = {2020},
  abstract  = {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.},
  language  = {en}
}
@article{ChifuHeinzeFussetal.2020,
  author    = {Chifu, Irina and Heinze, Britta and Fuss, Carmina T. and Lang, Katharina and Kroiss, Matthias and Kircher, Stefan and Ronchi, Cristina L. and Altieri, Barbara and Schirbel, Andreas and Fassnacht, Martin and Hahner, Stefanie},
  title     = {Impact of the Chemokine Receptors CXCR4 and CXCR7 on Clinical Outcome in Adrenocortical Carcinoma},
  series = {Frontiers in Endocrinology},
  volume    = {11},
  journal   = {Frontiers in Endocrinology},
  issn      = {1664-2392},
  doi       = {10.3389/fendo.2020.597878},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-216494},
  year      = {2020},
  abstract  = {Chemokine receptors have a negative impact on tumor progression in several human cancers and have therefore been of interest for molecular imaging and targeted therapy. However, their clinical and prognostic significance in adrenocortical carcinoma (ACC) is unknown. The aim of this study was to evaluate the chemokine receptor profile in ACC and to analyse its association with clinicopathological characteristics and clinical outcome. A chemokine receptor profile was initially evaluated by quantitative PCR in 4 normal adrenals, 18 ACC samples and human ACC cell line NCI-H295. High expression of CXCR4 and CXCR7 in both healthy and malignant adrenal tissue and ACC cells was confirmed. In the next step, we analyzed the expression and cellular localization of CXCR4 and CXCR7 in ACC by immunohistochemistry in 187 and 84 samples, respectively. These results were correlated with clinicopathological parameters and survival outcome. We detected strong membrane expression of CXCR4 and CXCR7 in 50\% of ACC samples. Strong cytoplasmic CXCR4 staining was more frequent among samples derived from metastases compared to primaries (p=0.01) and local recurrences (p=0.04). CXCR4 membrane staining positively correlated with proliferation index Ki67 (r=0.17, p=0.028). CXCR7 membrane staining negatively correlated with Ki67 (r=-0.254, p=0.03) but positively with tumor size (r=0.3, p=0.02). No differences in progression-free or overall survival were observed between patients with strong and weak staining intensities for CXCR4 or CXCR7. Taken together, high expression of CXCR4 and CXCR7 in both local tumors and metastases suggests that some ACC patients might benefit from CXCR4/CXCR7-targeted therapy.},
  language  = {en}
}