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 - Weigand, Isabel A1 - Ronchi, Cristina L. A1 - Rizk-Rabin, Marthe A1 - Dalmazi, Guido Di A1 - Wild, Vanessa A1 - Bathon, Kerstin A1 - Rubin, Beatrice A1 - Calebiro, Davide A1 - Beuschlein, Felix A1 - Bertherat, Jérôme A1 - Fassnacht, Martin A1 - Sbiera, Silviu T1 - Differential expression of the protein kinase A subunits in normal adrenal glands and adrenocortical adenomas JF - Scientific Reports N2 - Somatic mutations in protein kinase A catalytic α subunit (PRKACA) were found to be causative for 30-40% of cortisol-producing adenomas (CPA) of the adrenal gland, rendering PKA signalling constitutively active. In its resting state, PKA is a stable and inactive heterotetramer, consisting of two catalytic and two regulatory subunits with the latter inhibiting PKA activity. The human genome encodes three different PKA catalytic subunits and four different regulatory subunits that are preferentially expressed in different organs. In normal adrenal glands all regulatory subunits are expressed, while CPA exhibit reduced protein levels of the regulatory subunit IIβ. In this study, we linked for the first time the loss of RIIβ protein levels to the PRKACA mutation status and found the down-regulation of RIIβ to arise post-transcriptionally. We further found the PKA subunit expression pattern of different tumours is also present in the zones of the normal adrenal cortex and demonstrate that the different PKA subunits have a differential expression pattern in each zone of the normal adrenal gland, indicating potential specific roles of these subunits in the regulation of different hormones secretion. KW - kinases KW - immunohistochemistry Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-157952 VL - 7 IS - 49 ER - TY - JOUR A1 - Baur, Johannes A1 - Büntemeyer, Tjark-Ole A1 - Megerle, Felix A1 - Deutschbein, Timo A1 - Spitzweg, Christine A1 - Quinkler, Marcus A1 - Nawroth, Peter A1 - Kroiss, Matthias A1 - Germer, Christoph-Thomas A1 - Fassnacht, Martin A1 - Steger, Ulrich T1 - Outcome after resection of Adrenocortical Carcinoma liver metastases: a retrospective study JF - BMC Cancer N2 - Background: Metastatic Adrenocortical Carcinoma (ACC) is a rare malignancy with a poor 5-year-survival rate (<15%). A surgical approach is recommended in selected patients if complete resection of distant metastasis can be achieved. To date there are only limited data on the outcome after surgical resection of hepatic metastases of ACC. Methods: A retrospective analysis of the German Adrenocortical Carcinoma Registry was conducted. Patients with liver metastases of ACC but without extrahepatic metastases or incomplete tumour resection were included. Results: Seventy-seven patients fulfilled these criteria. Forty-three patients underwent resection of liver metastases of ACC. Complete tumour resection (R0) could be achieved in 30 (69.8%). Median overall survival after liver resection was 76.1 months in comparison to 10.1 months in the 34 remaining patients with unresected liver metastases (p < 0.001). However, disease free survival after liver resection was only 9.1 months. Neither resection status (R0/R1) nor extent of liver resection were significant predictive factors for overall survival. Patients with a time interval to the first metastasis/recurrence (TTFR) of greater than 12 months or solitary liver metastases showed significantly prolonged survival. Conclusions: Liver resection in the case of ACC liver metastases can achieve long term survival with a median overall survival of more than 5 years, but disease free survival is short despite metastasectomy. Time to recurrence and single versus multiple metastases are predictive factors for the outcome. KW - Adrenocortical Carcinoma KW - liver resection KW - retrospective study KW - prognosis KW - survival analysis Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159409 VL - 17 IS - 522 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 - 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 - 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 - 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 - 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 - 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 - 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 -