TY - JOUR A1 - Arlt, Wiebke A1 - Biehl, Michael A1 - Taylor, Angela E. A1 - Hahner, Stefanie A1 - Libé, Rossella A1 - Hughes, Beverly A. A1 - Schneider, Petra A1 - Smith, David J. A1 - Stiekema, Han A1 - Krone, Nils A1 - Porfiri, Emilio A1 - Opocher, Giuseppe A1 - Bertherat, Jerôme A1 - Mantero, Franco A1 - Allolio, Bruno A1 - Terzolo, Massimo A1 - Nightingale, Peter A1 - Shackleton, Cedric H. L. A1 - Bertagna, Xavier A1 - Fassnacht, Martin A1 - Stewart, Paul M. T1 - Urine Steroid Metabolomics as a Biomarker Tool for Detecting Malignancy in Adrenal Tumors JF - The Journal of Clinical Endocrinology & Metabolism N2 - Context: Adrenal tumors have a prevalence of around 2% in the general population. Adrenocortical carcinoma (ACC) is rare but accounts for 2–11% of incidentally discovered adrenal masses. Differentiating ACC from adrenocortical adenoma (ACA) represents a diagnostic challenge in patients with adrenal incidentalomas, with tumor size, imaging, and even histology all providing unsatisfactory predictive values. Objective: Here we developed a novel steroid metabolomic approach, mass spectrometry-based steroid profiling followed by machine learning analysis, and examined its diagnostic value for the detection of adrenal malignancy. Design: Quantification of 32 distinct adrenal derived steroids was carried out by gas chromatography/mass spectrometry in 24-h urine samples from 102 ACA patients (age range 19–84 yr) and 45 ACC patients (20–80 yr). Underlying diagnosis was ascertained by histology and metastasis in ACC and by clinical follow-up [median duration 52 (range 26–201) months] without evidence of metastasis in ACA. Steroid excretion data were subjected to generalized matrix learning vector quantization (GMLVQ) to identify the most discriminative steroids. Results: Steroid profiling revealed a pattern of predominantly immature, early-stage steroidogenesis in ACC. GMLVQ analysis identified a subset of nine steroids that performed best in differentiating ACA from ACC. Receiver-operating characteristics analysis of GMLVQ results demonstrated sensitivity = specificity = 90% (area under the curve = 0.97) employing all 32 steroids and sensitivity = specificity = 88% (area under the curve = 0.96) when using only the nine most differentiating markers. Conclusions: Urine steroid metabolomics is a novel, highly sensitive, and specific biomarker tool for discriminating benign from malignant adrenal tumors, with obvious promise for the diagnostic work-up of patients with adrenal incidentalomas. KW - adrenal cortex hormones KW - urine KW - adrenal cortex neoplasms KW - mass spectrometry KW - metabolomics Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154682 VL - 96 IS - 12 SP - 3775 EP - 3784 ER - TY - JOUR A1 - Werner, Rudolf A1 - Schmid, Jan-Stefan A1 - Higuchi, Takahiro A1 - Javadi, Mehrbod S. A1 - Rowe, Steven P. A1 - Märkl, Bruno A1 - Aulmann, Christoph A1 - Fassnacht, Martin A1 - Kroiß, Matthias A1 - Reiners, Christoph A1 - Buck, Andreas A1 - Kreissl, Michael A1 - Lapa, Constantin T1 - Predictive value of \(^{18}\)F-FDG PET in patients with advanced medullary thyroid carcinoma treated with vandetanib JF - Journal of Nuclear Medicine N2 - Introduction: Therapeutic options in advanced medullary thyroid carcinoma (MTC) have markedly improved since the introduction of tyrosine kinase inhibitors (TKI). We aimed to assess the role of metabolic imaging using 2-deoxy-2-(\(^{18}\)F)fluoro-D-glucose (\(^{18}\)F-FDG) positron emission tomography/computed tomography (PET/CT) shortly before and 3 months after initiation of TKI treatment. Methods: Eighteen patients with advanced and progressive MTC scheduled for vandetanib treatment underwent baseline \(^{18}\)F-FDG PET/CT prior to and 3 months after TKI treatment initiation. During follow-up, CT scans were performed every 3 months and analyzed according to Response Evaluation Criteria In Solid Tumors (RECIST). The predictive value for estimating progression-free (PFS) and overall survival (OS) was examined by investigating \(^{18}\)F-FDG mean/maximum standardized uptake values (SUVmean/max) of the metabolically most active lesion as well as by analyzing clinical parameters (tumor marker doubling times {calcitonin, carcinoembryonic antigen (CEA)}, prior therapies, RET (rearranged during transfection) mutational status, and disease type). Results: Within a median follow-up of 5.2 years, 9 patients experienced disease progression after a median time interval of 2.1y whereas the remainder had ongoing disease control (n=5 partial response and n=4 stable disease). Eight of the 9 patients with progressive disease died from MTC after a median of 3.5y after TKI initiation. Pre-therapeutic SUVmean >4.0 predicted a significantly shorter PFS (PFS: 1.9y vs. 5.2y; p=0.04). Furthermore, sustained high 18F-FDG uptake at 3 months with a SUVmean>2.8 tended to portend an unfavorable prognosis with a PFS of 1.9y (vs. 3.5y; p=0.3). Prolonged CEA doubling times were significantly correlated with longer PFS (r=0.7) and OS (r=0.76, p<0.01, respectively). None of the other clinical parameters had prognostic significance. Conclusions: Pre-therapeutic \(^{18}\)F-FDG PET/CT holds prognostic information in patients with advanced MTC scheduled for treatment with the TKI vandetanib. Low tumor metabolism of SUVmean < 4.0 prior to treatment predicts longer progression-free survival. KW - positron emission tomography KW - Medullärer Schilddrüsenkrebs KW - Positronen-Emissions-Tomografie KW - medullary thyroid carcinoma KW - tyrosine kinase inhibitor KW - vandetanib KW - 2- deoxy-2-(18F)fluoro-D-glucose KW - 18F-FDG Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161256 SN - 0161-5505 N1 - This research was originally published in JNM. Rudolf A. Werner, Jan-Stefan Schmid, Takahiro Higuchi, Mehrbod S. Javadi, Steven P. Rowe, Bruno Märkl, Christoph Aulmann, Martin Fassnacht, Matthias Kroiss, Christoph Reiners, Andreas K. Buck, Michael C. Kreissl, Constantin Lapa. Predictive value of 18F-FDG PET in patients with advanced medullary thyroid carcinoma treated with vandetanib. J Nucl Med. May 1, 2018;vol. 59 no. 5: 756-761. © SNMMI. ER - TY - CHAP A1 - Werner, Rudolf A1 - Higuchi, Takahiro A1 - Muegge, Dirk A1 - Javadi, Mehrbod S. A1 - Märkl, Bruno A1 - Aulmann, Christoph A1 - Buck, Andreas K. A1 - Fassnacht, Martin A1 - Lapa, Constantin A1 - Kreissl, Michael C. T1 - Predictive value of FDG-PET in patients with advanced medullary thyroid cancer undergoing vandetanib treatment T2 - Journal of Nuclear Medicine N2 - Introduction: The prognosis of medullary thyroid carcinoma (MTC) is poor using common chemotherapeutic approaches. However, during the last years encouraging results of recently introduced tyrosine kinase inhibitors (TKI) such as vandetanib have been published. In this study we aimed to correlate the results of \(^{18}\)F-fluorodeoxyglucose ([\(^{18}\)F]FDG) positron emission tomography (PET) imaging with treatment outcome. Methods: Eighteen patients after thyroidectomy with recurrent/advanced MTC lesions receiving vandetanib (300 mg orally/day) could be analysed. A baseline \(^{18}\)F-FDG PET prior to and a follow-up \(^{18}\)F-FDG PET 3 months after TKI initiation were performed. During follow-up, tumor progression was assessed every 3 months including computed tomography according to RECIST. Progression-free survival (PFS) was correlated with the maximum standardized uptake value of \(^{18}\)F-FDG in lymph nodes (SUV(LN)max) or visceral metastases (SUV(MTS)max) as well as with clinical parameters using ROC analysis. Results: Within median 3.6 years of follow-up, 9 patients showed disease progression at median 8.5 months after TKI initiation. An elevated glucose consumption assessed by baseline \(^{18}\)F-FDG PET (SUV(LN)max > 7.25) could predict a shorter PFS (2 y) with an accuracy of 76.5% (SUV(LN)max <7.25, 4.3 y; p=0.03). Accordingly, preserved tumor metabolism in the follow-up PET (SUV(MTS)max >2.7) also demonstrated an unfavorable prognosis (accuracy, 85.7%). On the other hand, none of the clinical parameters reached significance in response prediction. Conclusions: In patients with advanced and progressive MTC, tumors with higher metabolic activity at baseline are more aggressive and more prone to progression as reflected by a shorter PFS; they should be monitored more closely. Preserved glucose consumption 3 months after treatment initiation was also related to poorer prognosis. KW - 18F-FDG KW - vandetanib KW - TKI KW - PET KW - positron emission tomography Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161147 UR - http://jnm.snmjournals.org/content/58/supplement_1/169 SN - 0161-5505 N1 - This research was originally published in JNM. Rudolf A. Werner, Takahiro Higuchi, Dirk O. Muegge, Mehrbod S. Javadi, B. Märkl, C. Aulmann, Andreas K. Buck, Martin Fassnacht, Constantin Lapa, Michael C. Kreissl. Predictive value of FDG-PET in patients with advanced medullary thyroid cancer undergoing vandetanib treatment. J Nucl Med. May 1, 2017; vol. 58 no. supplement 1:169. © SNMMI. VL - 58 IS - no. supplement 1 ER - TY - JOUR A1 - Fassnacht, Martin A1 - Johanssen, Sarah A1 - Allolio, Bruno T1 - Statements Cannot Be Substantiated : In Reply JF - Deutsches Ärzteblatt International N2 - No abstract available. KW - Medicine Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-142597 VL - 108 IS - 19 ER - TY - JOUR A1 - Sbiera, Silviu A1 - Dexneit, Thomas A1 - Reichardt, Sybille D. A1 - Michel, Kai D. A1 - van den Brandt, Jens A1 - Schmull, Sebastian A1 - Kraus, Luitgard A1 - Beyer, Melanie A1 - Mlynski, Robert A1 - Wortmann, Sebastian A1 - Allolio, Bruno A1 - Reichardt, Holger M. A1 - Fassnacht, Martin T1 - Influence of Short-Term Glucocorticoid Therapy on Regulatory T Cells \(In\) \(Vivo\) JF - PLoS One N2 - Background: Pre- and early clinical studies on patients with autoimmune diseases suggested that induction of regulatory T(T(reg)) cells may contribute to the immunosuppressive effects of glucocorticoids(GCs). Objective: We readdressed the influence of GC therapy on T(reg) cells in immunocompetent human subjects and naive mice. Methods: Mice were treated with increasing doses of intravenous dexamethasone followed by oral taper, and T(reg) cells in spleen and blood were analyzed by FACS. Sixteen patients with sudden hearing loss but without an inflammatory disease received high-dose intravenous prednisolone followed by stepwise dose reduction to low oral prednisolone. Peripheral blood T(reg) cells were analyzed prior and after a 14 day GC therapy based on different markers. Results: Repeated GC administration to mice for three days dose-dependently decreased the absolute numbers of T(reg) cells in blood (100 mg dexamethasone/kg body weight: 2.8 +/- 1.8 x 10(4) cells/ml vs. 33 +/- 11 x 10(4) in control mice) and spleen (dexamethasone: 2.8 +/- 1.9 x 10(5)/spleen vs. 95 +/- 22 x 10(5)/spleen in control mice), which slowly recovered after 14 days taper in spleen but not in blood. The relative frequency of FOXP3(+) T(reg) cells amongst the CD4(+) T cells also decreased in a dose dependent manner with the effect being more pronounced in blood than in spleen. The suppressive capacity of T(reg) cells was unaltered by GC treatment in vitro. In immunocompetent humans, GCs induced mild T cell lymphocytosis. However, it did not change the relative frequency of circulating T(reg) cells in a relevant manner, although there was some variation depending on the definition of the T(reg) cells (FOXP3(+): 4.0 +/- 1.5% vs 3.4 +/- 1.5%*; AITR(+): 0.660.4 vs 0.5 +/- 0.3%, CD127(low): 4.0 +/- 1.3 vs 5.0 +/- 3.0%* and CTLA4+: 13.8 +/- 11.5 vs 15.6 +/- 12.5%; * p < 0.05). Conclusion: Short-term GC therapy does not induce the hitherto supposed increase in circulating T(reg) cell frequency, neither in immunocompetent humans nor in mice. Thus, it is questionable that the clinical efficacy of GCs is achieved by modulating T(reg) cell numbers. KW - Systemic-Lupus-Erythematosus KW - Immunological Self-Tolerance KW - Multiple-Sclerosis KW - Suppressive Function KW - Autoimmune-Diseases KW - FoxP3 Expression KW - Dendritic Cells KW - Immune-System KW - Sex-Hormones KW - Antigen 4 Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-140822 VL - 6 IS - 9 ER - TY - JOUR A1 - Dinnes, Jacqueline A1 - Bancos, Irina A1 - di Ruffano, Lavinia Ferrante A1 - Chortis, Vasileios A1 - Davenport, Clare A1 - Bayliss, Susan A1 - Sahdev, Anju A1 - Guest, Peter A1 - Fassnacht, Martin A1 - Deeks, Jonathan J A1 - Arlt, Wiebke T1 - Imaging for the diagnosis of malignancy in incidentally discovered adrenal masses: a systematic review and meta-analysis JF - European Journal of Endocrinology N2 - Objective: Adrenal masses are incidentally discovered in 5% of CT scans. In 2013/2014, 81 million CT examinations were undertaken in the USA and 5 million in the UK. However, uncertainty remains around the optimal imaging approach for diagnosing malignancy. We aimed to review the evidence on the accuracy of imaging tests for differentiating malignant from benign adrenal masses. Design: A systematic review and meta-analysis was conducted. Methods: We searched MEDLINE, EMBASE, Cochrane CENTRAL Register of Controlled Trials, Science Citation Index, Conference Proceedings Citation Index, and ZETOC (January 1990 to August 2015). We included studies evaluating the accuracy of CT, MRI, or F-18-fluoro-deoxyglucose (FDG)-PET compared with an adequate histological or imaging-based follow-up reference standard. Results: We identified 37 studies suitable for inclusion, after screening 5469 references and 525 full-text articles. Studies evaluated the accuracy of CT (n = 16), MRI (n = 15), and FDG-PET (n = 9) and were generally small and at high or unclear risk of bias. Only 19 studies were eligible for meta-analysis. Limited data suggest that CT density >10 HU has high sensitivity for detection of adrenal malignancy in participants with no prior indication for adrenal imaging, that is, masses with <= 10 HU are unlikely to be malignant. All other estimates of test performance are based on too small numbers. Conclusions: Despite their widespread use in routine assessment, there is insufficient evidence for the diagnostic value of individual imaging tests in distinguishing benign from malignant adrenal masses. Future research is urgently needed and should include prospective test validation studies for imaging and novel diagnostic approaches alongside detailed health economics analysis. KW - Positron-emission-tomography KW - Cell lung canger KW - Adrenocortial carcinomas KW - Disease prevalence KW - Spin echo KW - Contrast-enhanced CT KW - Test accuracy KW - Methodological quality KW - F-18-FDG PET/CT KW - MR Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-188086 VL - 175 IS - 2 ER - TY - JOUR A1 - Paschke, Ralf A1 - Lincke, Thomas A1 - Müller, Stefan P. A1 - Kreissl, Michael C. A1 - Dralle, Henning A1 - Fassnacht, Martin T1 - The Treatment of Well-Differentiated Thyroid Carcinoma JF - Deutsches Ärzteblatt International N2 - Background: Recent decades have seen a rise in the incidence of well-differentiated (mainly papillary) thyroid carcinoma around the world. In Germany, the age-adjusted incidence of well-differentiated thyroid carcinoma in 2010 was 3.5 per 100 000 men and 8.7 per 100 000 women per year. Method: This review is based on randomized, controlled trials and multicenter trials on the treatment of well-differentiated thyroid carcinoma that were retrieved by a selective literature search, as well as on three updated guidelines issued in the past two years. Results: The recommended extent of surgical resection depends on whether the tumor is classified as low-risk or high-risk, so that papillary microcar cinomas, which carry a highly favorable prognosis, will not be overtreated. More than 90% of localized, well-differentiated thyroid carcinomas can be cured with a combination of surgery and radioactive iodine therapy. Radio active iodine therapy is also effective in the treatment of well-differentiated thyroid carcinomas with distant metastases, yielding a 10-year survival rate of 90%, as long as there is good iodine uptake and the tumor goes into remission after treatment; otherwise, the 10-year survival rate is only 10%. In the past two years, better treatment options have become available for radioactive-iodine-resistant thyroid carcinoma. Phase 3 studies of two different tyrosine kinase inhibitors have shown that either one can markedly prolong progression-free survival, but not overall survival. Their more common clinically significant side effects are hand-foot syndrome, hypertension, diarrhea, proteinuria, and weight loss. Conclusion: Slow tumor growth, good resectability, and susceptibility to radioactive iodine therapy lend a favorable prognosis to most cases of well-differentiated thyroid carcinoma. The treatment should be risk-adjusted and interdisciplinary, in accordance with the current treatment guidelines. Even metastatic thyroid carcinoma has a favorable prognosis as long as there is good iodine uptake. The newly available medical treatment options for radioactive-iodine-resistant disease need to be further studied. KW - BRAF(V600E) mutation KW - distant metastases KW - papillary KW - guidelines KW - surgery KW - dissection KW - management KW - association KW - cancer KW - radioiodine therapy Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151636 VL - 112 SP - 452 EP - 458 ER - TY - JOUR A1 - Sbiera, Silviu A1 - Tryfonidou, Marianna A. A1 - Weigand, Isabel A1 - Grinwis, Guy C. M. A1 - Broeckx, Bart A1 - Herterich, Sabine A1 - Allolio, Bruno A1 - Deutschbein, Timo A1 - Fassnacht, Martin A1 - Meij, Björn P. T1 - Lack of Ubiquitin Specific Protease 8 (USP8) Mutations in Canine Corticotroph Pituitary Adenomas JF - Plos One N2 - Purpose Cushing’s disease (CD), also known as pituitary-dependent hyperadrenocorticism, is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary tumours. Affected humans and dogs have similar clinical manifestations, however, the incidence of the canine disease is thousand-fold higher. This makes the dog an obvious model for studying the pathogenesis of pituitary-dependent hyperadrenocorticism. Despite certain similarities identified at the molecular level, the question still remains whether the two species have a shared oncogenetic background. Recently, hotspot recurrent mutations in the gene encoding for ubiquitin specific protease 8 (USP8) have been identified as the main driver behind the formation of ACTH-secreting pituitary adenomas in humans. In this study, we aimed to verify whether USP8 mutations also play a role in the development of such tumours in dogs. Methods Presence of USP8 mutations was analysed by Sanger and PCR-cloning sequencing in 38 canine ACTH-secreting adenomas. Furthermore, the role of USP8 and EGFR protein expression was assessed by immunohistochemistry in a subset of 25 adenomas. Results None of the analysed canine ACTH-secreting adenomas presented mutations in the USP8 gene. In a subset of these adenomas, however, we observed an increased nuclear expression of USP8, a phenotype characteristic for the USP8 mutated human tumours, that correlated with smaller tumour size but elevated ACTH production in those tumours. Conclusions Canine ACTH-secreting pituitary adenomas lack mutations in the USP8 gene suggesting a different genetic background of pituitary tumourigenesis in dogs. However, elevated nuclear USP8 protein expression in a subset of tumours was associated with a similar phenotype as in their human counterparts, indicating a possible end-point convergence of the different genetic backgrounds in the two species. In order to establish the dog as a useful animal model for the study of CD, further comprehensive studies are needed. KW - cytoplasmic staining KW - dogs KW - adenomas KW - pituitary gland KW - pituitary adenomas KW - nuclear staining KW - mutation KW - protein expression Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148020 VL - 11 IS - 12 ER - TY - JOUR A1 - Altieri, Barbara A1 - Sbiera, Silviu A1 - Della Casa, Silvia A1 - Weigand, Isabel A1 - Wild, Vanessa A1 - Steinhauer, Sonja A1 - Fadda, Guido A1 - Kocot, Arkadius A1 - Bekteshi, Michaela A1 - Mambretti, Egle M. A1 - Rosenwald, Andreas A1 - Pontecorvi, Alfredo A1 - Fassnacht, Martin A1 - Ronchi, Cristina L. T1 - Livin/BIRC7 expression as malignancy marker in adrenocortical tumors JF - Oncotarget N2 - Livin/BIRC7 is a member of the inhibitors of apoptosis proteins family, which are involved in tumor development through the inhibition of caspases. Aim was to investigate the expression of livin and other members of its pathway in adrenocortical tumors and in the adrenocortical carcinoma (ACC) cell line NCI-H295R. The mRNA expression of livin, its isoforms α and β, XIAP, CASP3 and DIABLO was evaluated by qRT-PCR in 82 fresh-frozen adrenal tissues (34 ACC, 25 adenomas = ACA, 23 normal adrenal glands = NAG). Livin protein expression was assessed by immunohistochemistry in 270 paraffin-embedded tissues (192 ACC, 58 ACA, 20 NAG). Livin, CASP3 and cleaved caspase-3 were evaluated in NCI-H295R after induction of livin overexpression. Relative livin mRNA expression was significantly higher in ACC than in ACA and NAG (0.060 ± 0.116 vs 0.004 ± 0.014 and 0.002 ± 0.009, respectively, p < 0.01), being consistently higher in tumors than in adjacent NAG and isoform β more expressed than α. No significant differences in CASP3, XIAP and DIABLO levels were found among these groups. In immunohistochemistry, livin was localized in both cytoplasm and nuclei. The ratio between cytoplasmic and nuclear staining was significantly higher in ACC (1.51 ± 0.66) than in ACA (0.80 ± 0.35) and NAG (0.88 ± 0.27; p < 0.0001). No significant correlations were observed between livin expression and histopathological parameters or clinical outcome. In NCI-H295R cells, the livin overexpression slightly reduced the activation of CASP3, but did not correlate with cell viability. In conclusion, livin is specifically over-expressed in ACC, suggesting that it might be involved in adrenocortical tumorigenesis and represent a new molecular marker of malignancy. KW - cancer KW - livin KW - BIRC7 KW - adrenocortical cancer KW - adrenal tumor KW - caspase-3 Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-171887 VL - 8 IS - 6 ER - TY - JOUR A1 - Fassnacht, Martin A1 - Sbiera, Silviu A1 - Dexneit, Thomas A1 - Reichardt, Sybille D. A1 - Michel, Kai D. A1 - van den Brandt, Jens A1 - Schmull, Sebastian A1 - Kraus, Luitgard A1 - Beyer, Melanie A1 - Mlynski, Robert A1 - Wortmann, Sebastian A1 - Allolio, Bruno A1 - Reichardt, Holger M. T1 - Influence of Short-Term Glucocorticoid Therapy on Regulatory T Cells In Vivo N2 - Background: Pre- and early clinical studies on patients with autoimmune diseases suggested that induction of regulatory T(Treg) cells may contribute to the immunosuppressive effects of glucocorticoids(GCs). Objective: We readdressed the influence of GC therapy on Treg cells in immunocompetent human subjects and naı¨ve mice. Methods: Mice were treated with increasing doses of intravenous dexamethasone followed by oral taper, and Treg cells in spleen and blood were analyzed by FACS. Sixteen patients with sudden hearing loss but without an inflammatory disease received high-dose intravenous prednisolone followed by stepwise dose reduction to low oral prednisolone. Peripheral blood Treg cells were analyzed prior and after a 14 day GC therapy based on different markers. Results: Repeated GC administration to mice for three days dose-dependently decreased the absolute numbers of Treg cells in blood (100 mg dexamethasone/kg body weight: 2.861.86104 cells/ml vs. 336116104 in control mice) and spleen (dexamethasone: 2.861.96105/spleen vs. 956226105/spleen in control mice), which slowly recovered after 14 days taper in spleen but not in blood. The relative frequency of FOXP3+ Treg cells amongst the CD4+ T cells also decreased in a dose dependent manner with the effect being more pronounced in blood than in spleen. The suppressive capacity of Treg cells was unaltered by GC treatment in vitro. In immunocompetent humans, GCs induced mild T cell lymphocytosis. However, it did not change the relative frequency of circulating Treg cells in a relevant manner, although there was some variation depending on the definition of the Treg cells (FOXP3+: 4.061.5% vs 3.461.5%*; AITR+: 0.660.4 vs 0.560.3%, CD127low: 4.061.3 vs 5.063.0%* and CTLA4+: 13.8611.5 vs 15.6612.5%; * p,0.05). Conclusion: Short-term GC therapy does not induce the hitherto supposed increase in circulating Treg cell frequency, neither in immunocompetent humans nor in mice. Thus, it is questionable that the clinical efficacy of GCs is achieved by modulating Treg cell numbers. KW - Medizin Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-74749 ER - TY - JOUR A1 - Baur, Johannes A1 - Schedelbeck, Ulla A1 - Pulzer, Alina A1 - Bluemel, Christina A1 - Wild, Vanessa A1 - Fassnacht, Martin A1 - Steger, U. T1 - A case report of a solitary pancreatic metastasis of an adrenocortical carcinoma JF - BMC Surgery N2 - Background Solitary metastases to the pancreas are rare. Therefore the value of resection in curative intention remains unclear. In the literature there are several promising reports about resection of solitary metastasis to the pancreas mainly of renal origin. Case presentation Here we report for the first time on the surgical therapy of a 1.5 cm solitary pancreatic metastasis of an adrenocortical carcinoma. The metastasis occurred almost 6 years after resection of the primary tumor. A partial pancreatoduodenectomy was performed and postoperatively adjuvant mitotane treatment was initiated. During the follow-up of 3 years after surgery no evidence of tumor recurrence occurred. Conclusion Resection of pancreatic tumors should be considered, even if the mass is suspicious for metastatic disease including recurrence of adrenocortical cancer. KW - surgical treatment KW - adrenocortical KW - carcinoma metastases to pancreas Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-126130 VL - 15 IS - 93 ER - TY - JOUR A1 - Drechsler, Christiane A1 - Ritz, Eberhard A1 - Tomaschitz, Andreas A1 - Pilz, Stefan A1 - Schönfeld, Stephan A1 - Blouin, Katja A1 - Bidlingmaier, Martin A1 - Hammer, Fabian A1 - Krane, Vera A1 - März, Winfried A1 - Allolio, Bruno A1 - Fassnacht, Martin A1 - Wanner, Christoph T1 - Aldosterone and cortisol affect the risk of sudden cardiac death in haemodialysis patients JF - European Heart Journal N2 - Background: Sudden cardiac death is common and accounts largely for the excess mortality of patients on maintenance dialysis. It is unknown whether aldosterone and cortisol increase the incidence of sudden cardiac death in dialysis patients. Methods and results: We analysed data from 1255 diabetic haemodialysis patients participating in the German Diabetes and Dialysis Study (4D Study). Categories of aldosterone and cortisol were determined at baseline and patients were followed for a median of 4 years. By Cox regression analyses, hazard ratios (HRs) were determined for the effect of aldosterone, cortisol, and their combination on sudden death and other adjudicated cardiovascular outcomes. The mean age of the patients was 66 ± 8 years (54% male). Median aldosterone was <15 pg/mL (detection limit) and cortisol 16.8 µg/dL. Patients with aldosterone levels >200 pg/mL had a significantly higher risk of sudden death (HR: 1.69; 95% CI: 1.06–2.69) compared with those with an aldosterone <15 pg/mL. The combined presence of high aldosterone (>200 pg/mL) and high cortisol (>21.1 µg/dL) levels increased the risk of sudden death in striking contrast to patients with low aldosterone (<15 pg/mL) and low cortisol (<13.2 µg/dL) levels (HR: 2.86, 95% CI: 1.32–6.21). Furthermore, all-cause mortality was significantly increased in the patients with high levels of both hormones (HR: 1.62, 95% CI: 1.01–2.62). Conclusions: The joint presence of high aldosterone and high cortisol levels is strongly associated with sudden cardiac death as well as all-cause mortality in haemodialysed type 2 diabetic patients. Whether a blockade of the mineralocorticoid receptor decreases the risk of sudden death in these patients must be examined in future trials. KW - mortality KW - kidney disease KW - cardiovascular events KW - sudden cardiac death KW - cortisol KW - aldosterone Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-132562 VL - 34 ER - TY - JOUR A1 - Montes-Cobos, Elena A1 - Li, Xiao A1 - Fischer, Henrike J. A1 - Sasse, André A1 - Kügler, Sebastian A1 - Didié, Michael A1 - Toischer, Karl A1 - Fassnacht, Martin A1 - Dressel, Ralf A1 - Reichardt, Holger M. T1 - Inducible Knock-Down of the Mineralocorticoid Receptor in Mice Disturbs Regulation of the Renin-Angiotensin-Aldosterone System and Attenuates Heart Failure Induced by Pressure Overload JF - PLoS One N2 - Mineralocorticoid receptor (MR) inactivation in mice results in early postnatal lethality. Therefore we generated mice in which MR expression can be silenced during adulthood by administration of doxycycline (Dox). Using a lentiviral approach, we obtained two lines of transgenic mice harboring a construct that allows for regulatable MR inactivation by RNAi and concomitant expression of eGFP. MR mRNA levels in heart and kidney of inducible MR knock-down mice were unaltered in the absence of Dox, confirming the tightness of the system. In contrast, two weeks after Dox administration MR expression was significantly diminished in a variety of tissues. In the kidney, this resulted in lower mRNA levels of selected target genes, which was accompanied by strongly increased serum aldosterone and plasma renin levels as well as by elevated sodium excretion. In the healthy heart, gene expression and the amount of collagen were unchanged despite MR levels being significantly reduced. After transverse aortic constriction, however, cardiac hypertrophy and progressive heart failure were attenuated by MR silencing, fibrosis was unaffected and mRNA levels of a subset of genes reduced. Taken together, we believe that this mouse model is a useful tool to investigate the role of the MR in pathophysiological processes. KW - cells KW - balance KW - polarization KW - transgenic rats Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137575 VL - 10 IS - 11 ER - TY - JOUR A1 - Ronchi, Cristina L. A1 - Leich, Ellen A1 - Sbiera, Silviu A1 - Weismann, Dirk A1 - Rosenwald, Andreas A1 - Allolio, Bruno A1 - Fassnacht, Martin T1 - Single Nucleotide Polymorphism Microarray Analysis in Cortisol-Secreting Adrenocortical Adenomas Identifies New Candidate Genes and Pathways JF - Neoplasia N2 - The genetic mechanisms underlying adrenocortical tumor development are still largely unknown. We used high-resolution single nucleotide polymorphism microarrays (Affymetrix SNP 6.0) to detect copy number alterations (CNAs) and copy-neutral losses of heterozygosity (cnLOH) in 15 cortisol-secreting adrenocortical adenomas with matched blood samples. We focused on microalterations aiming to discover new candidate genes involved in early tumorigenesis and/or autonomous cortisol secretion. We identified 962 CNAs with a median of 18 CNAs per sample. Half of them involved noncoding regions, 89% were less than 100 kb, and 28% were found in at least two samples. The most frequently gained regions were 5p15.33, 6q16.1, 7p22.3-22.2, 8q24.3, 9q34.2-34.3, 11p15.5, 11q11, 12q12, 16q24.3, 20p11.1-20q21.11, and Xq28 (>= 20% of cases), most of them being identified in the same three adenomas. These regions contained among others genes like NOTCH1, CYP11B2, HRAS, and IGF2. Recurrent losses were less common and smaller than gains, being mostly localized at 1p, 6q, and 11q. Pathway analysis revealed that Notch signaling was the most frequently altered. We identified 46 recurrent CNAs that each affected a single gene (31 gains and 15 losses), including genes involved in steroidogenesis (CYP11B1) or tumorigenesis (CTNNB1, EPHA7, SGK1, STIL, FHIT). Finally, 20 small cnLOH in four cases affecting 15 known genes were found. Our findings provide the first high-resolution genome-wide view of chromosomal changes in cortisol-secreting adenomas and identify novel candidate genes, such as HRAS, EPHA7, and SGK1. Furthermore, they implicate that the Notch1 signaling pathway might be involved in the molecular pathogenesis of adrenocortical tumors. KW - kinase KW - comparative genomic hybridization KW - high-resolution analysis KW - Cushings syndrome KW - neutral loss KW - tumors KW - serum KW - expression KW - carcinoma KW - catenin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134953 VL - 14 IS - 3 ER - TY - JOUR A1 - Ronchi, Cristina L. A1 - Sbiera, Silviu A1 - Volante, Marco A1 - Steinhauer, Sonja A1 - Scott-Wild, Vanessa A1 - Altieri, Barbara A1 - Kroiss, Matthias A1 - Bala, Margarita A1 - Papotti, Mauro A1 - Deutschbein, Timo A1 - Terzolo, Massimo A1 - Fassnacht, Martin A1 - Allolio, Bruno T1 - CYP2W1 Is Highly Expressed in Adrenal Glands and Is Positively Associated with the Response to Mitotane in Adrenocortical Carcinoma N2 - Background Adrenocortical tumors comprise frequent adenomas (ACA) and rare carcinomas (ACC). Human cytochrome P450 2W1 (CYP2W1) is highly expressed in some cancers holding the potential to activate certain drugs into tumor cytotoxins. Objective To investigate the CYP2W1 expression in adrenal samples and its relationship with clinical outcome in ACC. Material and Methods CYP2W1 expression was investigated by qRT-PCR in 13 normal adrenal glands, 32 ACA, 25 ACC, and 9 different non-adrenal normal tissue samples and by immunohistochemistry in 352 specimens (23 normal adrenal glands, 33 ACA, 239 ACC, 67 non-adrenal normal or neoplastic samples). Results CYP2W1 mRNA expression was absent/low in normal non-adrenal tissues, but high in normal and neoplastic adrenal glands (all P<0.01 vs non-adrenal normal tissues). Accordingly, CYP2W1 immunoreactivity was absent/low (H-score 0–1) in 72% of non-adrenal normal tissues, but high (H-score 2–3) in 44% of non-adrenal cancers, in 65% of normal adrenal glands, in 62% of ACAs and in 50% of ACCs (all P<0.001 vs non-adrenal normal tissues), being significantly increased in steroid-secreting compared to non-secreting tumors. In ACC patients treated with mitotane only, high CYP2W1 immunoreactivity adjusted for ENSAT stage was associated with longer overall survival and time to progression (P<0.05 and P<0.01, respectively), and with a better response to therapy both as palliative (response/stable disease in 42% vs 6%, P<0.01) or adjuvant option (absence of disease recurrence in 69% vs 45%, P<0.01). Conclusion CYP2W1 is highly expressed in both normal and neoplastic adrenal glands making it a promising tool for targeted therapy in ACC. Furthermore, CYP2W1 may represent a new predictive marker for the response to mitotane treatment. KW - CYP2W1 KW - cancer treatment KW - adrenal glands KW - carcinomas KW - drug therapy KW - hormones KW - immune response KW - immunohistochemistry techniques KW - surgical oncology Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-113096 ER - TY - JOUR A1 - Sbiera, Silviu A1 - Ronchi, Cristina L. A1 - Leich, Ellen A1 - Henzel, Katharina A1 - Rosenwald, Andreas A1 - Allolio, Bruno A1 - Fassnacht, Martin T1 - Single Nucleotide Polymorphism Array Profiling of Adrenocortical Tumors - Evidence for an Adenoma Carcinoma Sequence? JF - PLoS ONE N2 - Adrenocortical tumors consist of benign adenomas and highly malignant carcinomas with a still incompletely understood pathogenesis. A total of 46 adrenocortical tumors (24 adenomas and 22 carcinomas) were investigated aiming to identify novel genes involved in adrenocortical tumorigenesis. High-resolution single nucleotide polymorphism arrays (Affymetrix) were used to detect copy number alterations (CNAs) and copy neutral losses of heterozygosity (cnLOH). Genomic clustering showed good separation between adenomas and carcinomas, with best partition including only chromosome 5, which was highly amplified in 17/22 malignant tumors. The malignant tumors had more relevant genomic aberrations than benign tumors, such as a higher median number of recurrent CNA (2631 vs 94), CNAs >100 Kb (62.5 vs 7) and CN losses (72.5 vs 5.5), and a higher percentage of samples with cnLOH (91% vs 29%). Within the carcinoma cohort, a precise genetic pattern (i.e. large gains at chr 5, 7, 12, and 19, and losses at chr 1, 2, 13, 17, and 22) was associated with a better prognosis (overall survival: 72.2 vs 35.4 months, P=0.063). Interestingly, >70% of gains frequent in beningn were also present in malignant tumors. Notch signaling was the most frequently involved pathway in both tumor entities. Finally, a CN gain at imprinted “IGF2” locus chr 11p15.5 appeared to be an early alteration in a multi-step tumor progression, followed by the loss of one or two alleles, associated with increased IGF2 expression, only in carcinomas. Our study serves as database for the identification of genes and pathways, such as Notch signaling, which could be involved in the pathogenesis of adrenocortical tumors. Using these data, we postulate an adenoma-carcinoma sequence for these tumors. KW - adenomas KW - cancer diagnosis KW - cancer detection KW - carcinogenesis KW - carcinomas KW - chromosomes KW - genetic loci KW - malignant tumors KW - notch signaling Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97218 ER - TY - JOUR A1 - Hendricks, Anne A1 - Müller, Sophie A1 - Fassnacht, Martin A1 - Germer, Christoph-Thomas A1 - Wiegering, Verena A. A1 - Wiegering, Armin A1 - Reibetanz, Joachim T1 - Impact of lymphadenectomy on the oncologic outcome of patients with adrenocortical carcinoma — a systematic review and meta-analysis JF - Cancers N2 - (1) Background: Locoregional lymphadenectomy (LND) in adrenocortical carcinoma (ACC) may impact oncological outcome, but the findings from individual studies are conflicting. The aim of this systematic review and meta-analysis was to determine the oncological value of LND in ACC by summarizing the available literature. (2) Methods: A systematic search on studies published until December 2020 was performed according to the PRISMA statement. The primary outcome was the impact of lymphadenectomy on overall survival (OS). Two separate meta-analyses were performed for studies including patients with localized ACC (stage I–III) and those including all tumor stages (I–IV). Secondary endpoints included postoperative mortality and length of hospital stay (LOS). (3) Results: 11 publications were identified for inclusion. All studies were retrospective studies, published between 2001–2020, and 5 were included in the meta-analysis. Three studies (N = 807 patients) reported the impact of LND on disease-specific survival in patients with stage I–III ACC and revealed a survival benefit of LND (hazard ratio (HR) = 0.42, 95% confidence interval (95% CI): 0.26–0.68). Based on results of studies including patients with ACC stage I–IV (2 studies, N = 3934 patients), LND was not associated with a survival benefit (HR = 1.00, 95% CI: 0.70–1.42). None of the included studies showed an association between LND and postoperative mortality or LOS. (4) Conclusion: Locoregional lymphadenectomy seems to offer an oncologic benefit in patients undergoing curative-intended surgery for localized ACC (stage I–III). KW - adrenocortical carcinoma KW - adrenal cancer KW - lymphadenectomy KW - lymph node dissection KW - LND KW - LNE KW - review KW - meta-analysis Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-254798 SN - 2072-6694 VL - 14 IS - 2 ER - TY - JOUR A1 - Fuss, Carmina Teresa A1 - Other, Katharina A1 - Heinze, Britta A1 - Landwehr, Laura-Sophie A1 - Wiegering, Armin A1 - Kalogirou, Charis A1 - Hahner, Stefanie A1 - Fassnacht, Martin T1 - Expression of the chemokine receptor CCR7 in the normal adrenal gland and adrenal tumors and its correlation with clinical outcome in adrenocortical carcinoma JF - Cancers N2 - Background: The chemokine receptor CCR7 is crucial for an intact immune function, but its expression is also associated with clinical outcome in several malignancies. No data exist on the expression of CCR7 in adrenocortical tumors. Methods: CCR7 expression was investigated by qRT-PCR and immunohistochemistry in 4 normal adrenal glands, 59 adrenocortical adenomas, and 181 adrenocortical carcinoma (ACC) samples. Results: CCR7 is highly expressed in the outer adrenocortical zones and medulla. Aldosterone-producing adenomas showed lower CCR7 protein levels (H-score 1.3 ± 1.0) compared to non-functioning (2.4 ± 0.5) and cortisol-producing adenomas (2.3 ± 0.6), whereas protein expression was variable in ACC (1.8 ± 0.8). In ACC, CCR7 protein expression was significantly higher in lymph node metastases (2.5 ± 0.5) compared to primary tumors (1.8±0.8) or distant metastases (2.0 ± 0.4; p < 0.01). mRNA levels of CCR7 were not significantly different between ACCs, normal adrenals, and adrenocortical adenomas. In contrast to other tumor entities, neither CCR7 protein nor mRNA expression significantly impacted patients' survival. Conclusion: We show that CCR7 is expressed on mRNA and protein level across normal adrenals, benign adrenocortical tumors, as well as ACCs. Given that CCR7 did not influence survival in ACC, it is probably not involved in tumor progression, but it could play a role in adrenocortical homeostasis. KW - CCR7 KW - chemokine receptor KW - adrenocortical carcinoma KW - adrenal tumors Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250112 SN - 2072-6694 VL - 13 IS - 22 ER - TY - JOUR A1 - Johanssen, Sarah A1 - Hahner, Stefanie A1 - Saeger, Wolfgang A1 - Quinkler, Marcus A1 - Beuschlein, Felix A1 - Dralle, Henning A1 - Haaf, Michaela A1 - Kroiss, Matthias A1 - Jurowich, Christian A1 - Langer, Peter A1 - Oelkers, Wolfgang A1 - Spahn, Martin A1 - Willenberg, Holger S. A1 - Maeder, Uwe A1 - Allolio, Bruno A1 - Fassnacht, Martin T1 - Deficits in the Management of Patients With Adrenocortical Carcinoma in Germany N2 - Background: Adrenocortical carcinoma (ACC) is a rare tumor with a poor prognosis. Often, the physicians who first treat patients with ACC have no prior experience with the disease. The aim of our study was to evaluate the quality of medical care for patients with ACC in Germany. Methods: Data from the German ACC registry were analyzed with regard to the patients’ preoperative diagnostic evaluation, histopathological reporting, and clinical followup. The findings were compared with the recommendations of the European Network for the Study of Adrenal Tumors (ENSAT). Results: Data were analyzed from 387 patients who had been given an initial diagnosis of ACC in the years 1998 to 2009. 21% of them underwent no hormonal evaluation before surgery, and 59% underwent an inadequate hormonal evaluation. This exposed the patients to unnecessary perioperative risks and impaired their follow-up. 48% did not undergo CT scanning of the chest, even though the lungs are the most frequent site of metastases of ACC. For 13% of the patients, the diagnosis of ACC was later revised by a reference pathologist. For 11% of the patients, the histopathology report contained no information about resection status, even though this is an important determinant of further treatment and prognosis. Optimal management requires re-staging at three-month intervals, yet some patients underwent re-staging only after a longer delay, or not at all. Conclusion: We have identified significant deficits in the care of patients with ACC in Germany. We suspect that the situation is similar for other rare diseases. The prerequisite to better care is close and early cooperation of the treating physicians with specialized centers. Y1 - 2010 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-85897 ER - TY - JOUR A1 - Sbiera, Iuliu A1 - Kircher, Stefan A1 - Altieri, Barbara A1 - Fassnacht, Martin A1 - Kroiss, Matthias A1 - Sbiera, Silviu T1 - Epithelial and Mesenchymal Markers in Adrenocortical Tissues: How Mesenchymal Are Adrenocortical Tissues? JF - Cancers N2 - 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. KW - adrenocortical tissues KW - EMT KW - epithelial markers KW - mesenchymal markers KW - recurrence-free survival Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236486 SN - 2072-6694 VL - 13 IS - 7 ER -