@article{DrechslerRitzTomaschitzetal.2013, author = {Drechsler, Christiane and Ritz, Eberhard and Tomaschitz, Andreas and Pilz, Stefan and Sch{\"o}nfeld, Stephan and Blouin, Katja and Bidlingmaier, Martin and Hammer, Fabian and Krane, Vera and M{\"a}rz, Winfried and Allolio, Bruno and Fassnacht, Martin and Wanner, Christoph}, title = {Aldosterone and cortisol affect the risk of sudden cardiac death in haemodialysis patients}, series = {European Heart Journal}, volume = {34}, journal = {European Heart Journal}, doi = {10.1093/eurheartj/ehs361}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132562}, pages = {578-585}, year = {2013}, abstract = {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.}, language = {en} } @phdthesis{vandenBerg2020, author = {van den Berg, Anne Maria}, title = {Age-related alterations of the immune system aggravate the myocardial aging process}, doi = {10.25972/OPUS-19362}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193622}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2020}, abstract = {The prevalence of cardiovascular diseases (CVD) increases dramatically with age. Nevertheless, most of the basic research in cardiology has been conducted on young healthy animals which may not necessarily reflect the situation observed in the clinic. The heart undergoes profound changes in elderly, including molecular alterations, myocardial hypertrophy, interstitial fibrosis and functional decline. To date, numerous approaches exist to explain mechanisms of the cardiac aging process whereupon inflammation and immune activity are of increasing interest. Myocardial aging is temporally associated with chronic low-grade systemic inflammation and accumulation of memory T-cells. However, a possible causal relationship between these two phenomena has not yet been investigated. Thus, aim of the present study was to assess how immunological mechanisms contribute to the myocardial aging process. Herein, the healthy murine heart was found to harbor all major resident leukocyte populations, including macrophages (CD45+CD11b+Ly6G-), granulocytes (CD45+ CD11b+Ly6G+), T-cells (CD45+CD11b-CD3e+), B-cells (CD45+CD11b-B220+) at frequencies that largely surpass those found in skeletal muscles. Age-related structural alterations and functional impairment occur simultaneously with significant shifts of the tissue resident leukocyte composition. Gene expression analyses performed on bulk myocardial samples revealed higher expression levels of TNF and INF- suggesting that in situ inflammation plays a role in the myocardial aging process. Aging was furthermore accompanied by a significant increase in size and cellularity of mediastinal, heart draining lymph nodes (med LN). Moreover, the med LNs harvested from aged mice showed a strong accumulation of effector-memory T-cells (CD44+CD62L-), mainly exhibiting a pro-inflammatory phenotype (Foxp3-, TNF+, IFN- γ+). None of these alterations were observed in popliteal lymph nodes of aged mice, indicating that they might be site-specific. Next, to go beyond mere associative evidence and examine underlying mechanisms, the myocardial aging process was comprehensively characterized in mice lacking B- (µMT) or CD4+ T-cells (CD4ko). Our analyses revealed that aged CD4+ T-cell-deficient, but not B-cell-deficient mice, exhibit a lower in situ inflammatory tone and preserved ventricular function, as compared to age-matched wild type controls. No differences in the expression levels of genes related to fibrosis were observed in the groups. Taken together, the results of this study indicate that heart-directed immune responses may spontaneously arise in the elderly, even in the absence of a clear tissue damage or concomitant infection. The T-cell-mediated immunosenescence profile might be particularly associated with age-related myocardial inflammation and functional decline, but not with tissue remodeling. These observations might shed new light on the emerging role of T cells in myocardial diseases, which primarily affect the elderly population.}, language = {en} } @article{RiedmeierDecarolisHaubitzetal.2021, author = {Riedmeier, Maria and Decarolis, Boris and Haubitz, Imme and M{\"u}ller, Sophie and Uttinger, Konstantin and B{\"o}rner, Kevin and Reibetanz, Joachim and Wiegering, Armin and H{\"a}rtel, Christoph and Schlegel, Paul-Gerhardt and Fassnacht, Martin and Wiegering, Verena}, title = {Adrenocortical carcinoma in childhood: a systematic review}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {21}, issn = {2072-6694}, doi = {10.3390/cancers13215266}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-248507}, year = {2021}, abstract = {Adrenocortical tumors are rare in children. This systematic review summarizes the published evidence on pediatric adrenocortical carcinoma (ACC) to provide a basis for a better understanding of the disease, investigate new molecular biomarkers and therapeutic targets, and define which patients may benefit from a more aggressive therapeutic approach. We included 137 studies with 3680 ACC patients (~65\% female) in our analysis. We found no randomized controlled trials, so this review mainly reflects retrospective data. Due to a specific mutation in the TP53 gene in ~80\% of Brazilian patients, that cohort was analyzed separately from series from other countries. Hormone analysis was described in 2569 of the 2874 patients (89\%). Most patients were diagnosed with localized disease, whereas 23\% had metastasis at primary diagnosis. Only 72\% of the patients achieved complete resection. In 334 children (23\%), recurrent disease was reported: 81\% — local recurrence, 19\% (n = 65) — distant metastases at relapse. Patients < 4 years old had a different distribution of tumor stages and hormone activity and better overall survival (p < 0.001). Although therapeutic approaches are typically multimodal, no consensus is available on effective standard treatments for advanced ACC. Thus, knowledge regarding pediatric ACC is still scarce and international prospective studies are needed to implement standardized clinical stratifications and risk-adapted therapeutic strategies.}, language = {en} } @article{UttingerRiedmeierReibetanzetal.2022, author = {Uttinger, Konstantin L. and Riedmeier, Maria and Reibetanz, Joachim and Meyer, Thomas and Germer, Christoph Thomas and Fassnacht, Martin and Wiegering, Armin and Wiegering, Verena}, title = {Adrenalectomies in children and adolescents in Germany - a diagnose related groups based analysis from 2009-2017}, series = {Frontiers in Endocrinology}, volume = {13}, journal = {Frontiers in Endocrinology}, issn = {1664-2392}, doi = {10.3389/fendo.2022.914449}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-282280}, year = {2022}, abstract = {Background Adrenalectomies are rare procedures especially in childhood. So far, no large cohort study on this topic has been published with data on to age distribution, operative procedures, hospital volume and operative outcome. Methods This is a retrospective analysis of anonymized nationwide hospital billing data (DRG data, 2009-2017). All adrenal surgeries (defined by OPS codes) of patients between the age 0 and 21 years in Germany were included. Results A total of 523 patient records were identified. The mean age was 8.6 ± 7.7 years and 262 patients were female (50.1\%). The majority of patients were between 0 and 5 years old (52\% overall), while 11.1\% were between 6 and 11 and 38.8\% older than 12 years. The most common diagnoses were malignant neoplasms of the adrenal gland (56\%, mostly neuroblastoma) with the majority being younger than 5 years. Benign neoplasms in the adrenal gland (D350) account for 29\% of all cases with the majority of affected patients being 12 years or older. 15\% were not defined regarding tumor behavior. Overall complication rate was 27\% with a clear higher complication rate in resection for malignant neoplasia of the adrenal gland. Bleeding occurrence and transfusions are the main complications, followed by the necessary of relaparotomy. There was an uneven patient distribution between hospital tertiles (low volume, medium and high volume tertile). While 164 patients received surgery in 85 different "low volume" hospitals (0.2 cases per hospital per year), 205 patients received surgery in 8 different "high volume" hospitals (2.8 cases per hospital per year; p<0.001). Patients in high volume centers were significant younger, had more extended resections and more often malignant neoplasia. In multivariable analysis younger age, extended resections and open procedures were independent predictors for occurrence of postoperative complications. Conclusion Overall complication rate of adrenalectomies in the pediatric population in Germany is low, demonstrating good therapeutic quality. Our analysis revealed a very uneven distribution of patient volume among hospitals.}, language = {en} } @article{QuinklerBeuschleinHahneretal.2013, author = {Quinkler, Marcus and Beuschlein, Felix and Hahner, Stefanie and Meyer, Gesine and Sch{\"o}fl, Christof and Stalla, G{\"u}nter K.}, title = {Adrenal Cortical Insufficiency-a Life Threatening Illness With Multiple Etiologies}, series = {Deutsches {\"A}rzteblatt International}, volume = {110}, journal = {Deutsches {\"A}rzteblatt International}, doi = {10.3238/arztebl.2013.0882}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131662}, pages = {51-52}, year = {2013}, abstract = {Background: The clinical signs of adrenal cortical insufficiency (incidence, ca. 25 per million per year; prevalence, ca. 400 per million) are nonspecific, and misdiagnoses are therefore common. Glucocorticoid substitution therapy has been in use for 50 years but is not a wholly adequate treatment. Our understanding of this disease remains incomplete in many ways. Methods: We selectively searched the Medline database for publications on adrenal cortical insufficiency, with particular attention to studies from the year 2000 onward (search terms: "adrenal insufficiency" or "Addison's disease" or "hypopituitarism"). Results: Hydrocortisone substitution therapy is often given in doses of 10-25 mg/day, timed according to the circadian rhythm. Gastrointestinal and other, febrile infections account for 30-50\% of life-threatening adrenocortical crises. Such crises affect 8 of 100 persons with adrenal cortical insufficiency per year and must be treated by the immediate administration of glucocorticoids and fluids. When persons with adrenal cortical insufficiency are acutely ill or are otherwise under unusual stress, they may need additional amounts of hydrocortisone, often in the range of 5-10 mg but occasionally as high as 200 mg. The sustained administration of excessive amounts of steroid can shorten patients' lives by several years. Inappropriate substitution therapy can cause other major medical conditions, such as metabolic syndrome and osteoporosis. Conclusion: Important measures for the prevention of adrenocortical crises include improved care by treating physicians, education of patients and their families, the provision of emergency identifying documents, and the prescription of glucocorticoid emergency kits.}, language = {en} } @article{MinnerSchreinerSaeger2021, author = {Minner, S. and Schreiner, J. and Saeger, W.}, title = {Adrenal cancer: relevance of different grading systems and subtypes}, series = {Clinical and Translational Oncology}, volume = {23}, journal = {Clinical and Translational Oncology}, number = {7}, issn = {1699-048X}, doi = {10.1007/s12094-020-02524-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308479}, pages = {1350-1357}, year = {2021}, abstract = {Purpose The subclassification of adrenal cancers according to the WHO classification in ordinary, myxoid, oncocytic, and sarcomatoid as well as pediatric types is well established, but the criteria for each subtype are not sufficiently determined and the relative frequency of the different types of adrenal cancers has not been studied in large cohorts. Therefore, our large collection of surgically removed adrenal cancers should be reviewed o establish the criteria for the subtypes and to find out the frequency of the various types. Methods In our series of 521 adrenal cancers the scoring systems of Weiss et al., Hough et al., van Slooten et al. and the new Helsinki score system were used for the ordinary type of cancer (97\% of our series) and the myxoid type (0.8\%). For oncocytic carcinomas (2\%), the scoring system of Bisceglia et al. was applied. Results Discrepancies between benign and malignant diagnoses from the first thee classical scoring systems are not rare (22\% in our series) and could be resolved by the Helsinki score especially by Ki-67 index (more than 8\% unequivocally malignant). Since all our cancer cases are positive in the Helsinki score, this system can replace the three elder systems. For identification of sarcomatoid cancer as rarest type in our series (0.2\%), the scoring systems are not practical but additional immunostainings used for soft tissue tumors and in special cases molecular pathology are necessary to differentiate these cancers from adrenal sarcomas. According to the relative frequencies of the different subtypes of adrenal cancers the main type is the far most frequent (97\%) followed by the oncocytic type (2\%), the myxoid type (0.8\%) and the very rare sarcomatoid type (0.2\%). Conclusions The Helsinki score is the best for differentiating adrenal carcinomas of the main, the oncocytic, and the myxoid type in routine work. Additional scoring systems for these carcinomas are generally not any longer necessary. Signs of proliferation (mitoses and Ki-67 index) and necroses are the most important criteria for diagnosis of malignancy.}, 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{HaringSelvinHeetal.2018, author = {Haring, Bernhard and Selvin, Elizabeth and He, Xintong and Coresh, Josef and Steffen, Lyn M. and Folsom, Aaron R. and Tang, Weihong and Rebholz, Casey M.}, title = {Adherence to the dietary approaches to stop hypertension dietary pattern and risk of abdominal aortic aneurysm: results from the ARIC study}, series = {Journal of the American Heart Association}, volume = {7}, journal = {Journal of the American Heart Association}, number = {21}, doi = {10.1161/JAHA.118.009340}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-177442}, pages = {e009340}, year = {2018}, abstract = {Background The role of a healthy dietary pattern in the prevention of abdominal aortic aneurysms (AAA) is unknown. We aimed to evaluate the relationship between adherence to a Dietary Approaches To Stop Hypertension-style dietary pattern and the risk of incident AAAs. Methods and Results Dietary intake was assessed via a 66-item food frequency questionnaire at baseline (1987-1989) and at visit 3 (1993-1995) in 13 496 participants enrolled in the ARIC (Atherosclerosis Risk in Communities) study without clinical AAA (mean age, 54 years). A dietary scoring index based on food times was constructed to assess self-reported adherence to a dietary approaches to stop hypertension-style dietary pattern. Participants were followed for incident clinical AAAs using hospital discharge diagnoses, Medicare inpatient and outpatient diagnoses, or death certificates through December 31, 2011. Cox proportional hazards models with covariate adjustment were used to estimate hazard ratios with 95\% confidence intervals. During a median follow-up of 23 years, there were 517 incident AAA cases. Individuals with a Dietary Approaches To Stop Hypertension-style diet score in the highest quintile had a 40\% lower risk of hospitalization for AAA than those in the lowest quintile (hazard ratio\(_{Q5}\) vs \(_{Q1}\): 0.60; 95\% confidence intervals: 0.44, 0.83; P\(_{trend}\)=0.002). In detailed analyses, higher consumption of fruits, vegetables, whole grains, low-fat dairy, and nuts and legumes was related to a lower risk for AAA. Conclusions Greater adherence to a Dietary Approaches To Stop Hypertension-style dietary pattern was associated with lower risk for AAA. Higher consumption of fruits, vegetables, whole grains, low-fat dairy as well as nuts and legumes may help to decrease the burden of AAAs.}, language = {en} } @article{MorbachBeyersdorfKerkauetal.2021, author = {Morbach, Caroline and Beyersdorf, Niklas and Kerkau, Thomas and Ramos, Gustavo and Sahiti, Floran and Albert, Judith and Jahns, Roland and Ertl, Georg and Angermann, Christiane E. and Frantz, Stefan and Hofmann, Ulrich and St{\"o}rk, Stefan}, title = {Adaptive anti-myocardial immune response following hospitalization for acute heart failure}, series = {ESC Heart Failure}, volume = {8}, journal = {ESC Heart Failure}, number = {4}, doi = {10.1002/ehf2.13376}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-258907}, pages = {3348-3353}, year = {2021}, abstract = {Aims It has been hypothesized that cardiac decompensation accompanying acute heart failure (AHF) episodes generates a pro-inflammatory environment boosting an adaptive immune response against myocardial antigens, thus contributing to progression of heart failure (HF) and poor prognosis. We assessed the prevalence of anti-myocardial autoantibodies (AMyA) as biomarkers reflecting adaptive immune responses in patients admitted to the hospital for AHF, followed the change in AMyA titres for 6 months after discharge, and evaluated their prognostic utility. Methods and results AMyA were determined in n = 47 patients, median age 71 (quartiles 60; 80) years, 23 (49\%) female, and 24 (51\%) with HF with preserved ejection fraction, from blood collected at baseline (time point of hospitalization) and at 6 month follow-up (visit F6). Patients were followed for 18 months (visit F18). The prevalence of AMyA increased from baseline (n = 21, 45\%) to F6 (n = 36, 77\%; P < 0.001). At F6, the prevalence of AMyA was higher in patients with HF with preserved ejection fraction (n = 21, 88\%) compared with patients with reduced ejection fraction (n = 14, 61\%; P = 0.036). During the subsequent 12 months after F6, that is up to F18, patients with newly developed AMyA at F6 had a higher risk for the combined endpoint of death or rehospitalization for HF (hazard ratio 4.79, 95\% confidence interval 1.13-20.21; P = 0.033) compared with patients with persistent or without AMyA at F6. Conclusions Our results support the hypothesis that AHF may induce patterns of adaptive immune responses. More studies in larger populations and well-defined patient subgroups are needed to further clarify the role of the adaptive immune system in HF progression.}, language = {en} } @article{KurabiSchaererNoacketal.2018, author = {Kurabi, Arwa and Schaerer, Daniel and Noack, Volker and Bernhardt, Marlen and Pak, Kwang and Alexander, Thomas and Husseman, Jacob and Nguyen, Quyen and Harris, Jeffrey P. and Ryan, Allen F.}, title = {Active Transport of Peptides Across the Intact Human Tympanic Membrane}, series = {Scientific Reports}, volume = {8}, journal = {Scientific Reports}, doi = {10.1038/s41598-018-30031-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230929}, year = {2018}, abstract = {We previously identified peptides that are actively transported across the intact tympanic membrane (TM) of rats with infected middle ears. To assess the possibility that this transport would also occur across the human TM, we first developed and validated an assay to evaluate transport in vitro using fragments of the TM. Using this assay, we demonstrated the ability of phage bearing a TM-transiting peptide to cross freshly dissected TM fragments from infected rats or from uninfected rats, guinea pigs and rabbits. We then evaluated transport across fragments of the human TM that were discarded during otologic surgery. Human trans-TM transport was similar to that seen in the animal species. Finally, we found that free peptide, unconnected to phage, was transported across the TM at a rate comparable to that seen for peptide-bearing phage. These studies provide evidence supporting the concept of peptide-mediated drug delivery across the intact TM and into the middle ears of patients.}, language = {en} } @article{GernerAghaiTrommeschlaegerKrausetal.2022, author = {Gerner, Bettina and Aghai-Trommeschlaeger, Fatemeh and Kraus, Sabrina and Grigoleit, G{\"o}tz Ulrich and Zimmermann, Sebastian and Kurlbaum, Max and Klinker, Hartwig and Isberner, Nora and Scherf-Clavel, Oliver}, title = {A physiologically-based pharmacokinetic model of ruxolitinib and posaconazole to predict CYP3A4-mediated drug-drug interaction frequently observed in graft versus host disease patients}, series = {Pharmaceutics}, volume = {14}, journal = {Pharmaceutics}, number = {12}, issn = {1999-4923}, doi = {10.3390/pharmaceutics14122556}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297261}, year = {2022}, abstract = {Ruxolitinib (RUX) is approved for the treatment of steroid-refractory acute and chronic graft versus host disease (GvHD). It is predominantly metabolized via cytochrome P450 (CYP) 3A4. As patients with GvHD have an increased risk of invasive fungal infections, RUX is frequently combined with posaconazole (POS), a strong CYP3A4 inhibitor. Knowledge of RUX exposure under concomitant POS treatment is scarce and recommendations on dose modifications are inconsistent. A physiologically based pharmacokinetic (PBPK) model was developed to investigate the drug-drug interaction (DDI) between POS and RUX. The predicted RUX exposure was compared to observed concentrations in patients with GvHD in the clinical routine. PBPK models for RUX and POS were independently set up using PK-Sim\(^®\) Version 11. Plasma concentration-time profiles were described successfully and all predicted area under the curve (AUC) values were within 2-fold of the observed values. The increase in RUX exposure was predicted with a DDI ratio of 1.21 (C\(_{max}\)) and 1.59 (AUC). Standard dosing in patients with GvHD led to higher RUX exposure than expected, suggesting further dose reduction if combined with POS. The developed model can serve as a starting point for further simulations of the implemented DDI and can be extended to further perpetrators of CYP-mediated PK-DDIs or disease-specific physiological changes.}, language = {en} } @article{CanuPuglisiBerchiallaetal.2021, author = {Canu, Letizia and Puglisi, Soraya and Berchialla, Paola and De Filpo, Giuseppina and Brignardello, Francesca and Schiavi, Francesca and Ferrara, Alfonso Massimiliano and Zovato, Stefania and Luconi, Michaela and Pia, Anna and Appetecchia, Marialuisa and Arvat, Emanuela and Letizia, Claudio and Maccario, Mauro and Parasiliti-Caprino, Mirko and Altieri, Barbara and Faggiano, Antongiulio and Modica, Roberta and Morelli, Valentina and Arosio, Maura and Verga, Uberta and Pellegrino, Micaela and Petramala, Luigi and Concistr{\`e}, Antonio and Razzore, Paola and Ercolino, Tonino and Rapizzi, Elena and Maggi, Mario and Stigliano, Antonio and Burrello, Jacopo and Terzolo, Massimo and Opocher, Giuseppe and Mannelli, Massimo and Reimondo, Giuseppe}, title = {A multicenter epidemiological study on second malignancy in non-syndromic pheochromocytoma/paraganglioma patients in Italy}, series = {Cancers}, volume = {13}, journal = {Cancers}, number = {22}, issn = {2072-6694}, doi = {10.3390/cancers13225831}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250148}, year = {2021}, abstract = {No studies have carried out an extensive analysis of the possible association between non-syndromic pheochromocytomas and paragangliomas (PPGLs) and other malignancies. To assess >the risk of additional malignancy in PPGL, we retrospectively evaluated 741 patients with PPGLs followed-up in twelve referral centers in Italy. Incidence of second malignant tumors was compared between this cohort and Italian patients with two subsequent malignancies. Among our patients, 95 (12.8\%) developed a second malignant tumor, which were mainly prostate, colorectal and lung/bronchial cancers in males, breast cancer, differentiated thyroid cancer and melanoma in females. The standardized incidence ratio was 9.59 (95\% CI 5.46-15.71) in males and 13.21 (95\% CI 7.52-21.63) in females. At multivariable analysis, the risk of developing a second malignant tumor increased with age at diagnosis (HR 2.50, 95\% CI 1.15-5.44, p = 0.021 for 50-59 vs. <50-year category; HR 3.46, 95\% CI 1.67-7.15, p < 0.001 for >60- vs. <50-year). In patients with available genetic evaluation, a positive genetic test was inversely associated with the risk of developing a second tumor (HR 0.25, 95\% CI 0.10-0.63, p = 0.003). In conclusion, PPGLs patients have higher incidence of additional malignant tumors compared to the general population who had a first malignancy, which could have an impact on the surveillance strategy.}, language = {en} } @article{DorschKrieterLemkeetal.2012, author = {Dorsch, Oliver and Krieter, Detlef H. and Lemke, Horst-Dieter and Fischer, Stefan and Melzer, Nima and Sieder, Christian and Bramlage, Peter and Harenberg, Job}, title = {A multi-center, prospective, open-label, 8-week study of certoparin for anticoagulation during maintenance hemodialysis - the membrane study}, series = {BMC Nephrology}, volume = {13}, journal = {BMC Nephrology}, number = {50}, doi = {10.1186/1471-2369-13-50}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124052}, year = {2012}, abstract = {Background Adequate anticoagulation is prerequisite for effective hemodialysis to prevent clotting in the extracorporeal circuit. We aimed providing first data on the efficacy and safety of the low-molecular-weight heparin certoparin in this setting. Methods Multicenter, open-label, 8-week trial. Patients received a single dose of 3,000 IU certoparin i.v. with additional titration steps of 600 IU and/or continuous infusion if necessary. Results 120 patients were screened, 109 enrolled (median age 71; range 26-90 years) and 106 available for efficacy analyses. The percentage of unsatisfactory dialysis results at 8 weeks due to clotting or bleeding, was 1.9\% (n = 2/106; 95\% confidence interval [CI] 0.23-6.65\%); no major bleeding. 1.9\% had moderate/severe clotting in the lines/bubble catcher and 2.8\% in the dialyser at week 8. 15.7 ± 14.3\% of the dialysis filters' visual surface area was showing redness. In subgroups of patients receiving median doses of 3000 ± 0, 3000 (2400-6000) and 4200 (3000-6600) IU, plasma aXa levels at baseline, 4 and 8 weeks were 0.24 [95\%CI 0.21-0.27], 0.33 [0.27-0.40] and 0.38 [0.33-0.45] aXa IU/ml at 2 h. \(C_{48h}\) was 0.01 [0.01-0.02] aXa IU at all visits. At baseline and 4 weeks \(AUC_{0-48h}\) was 2.66 [2.19-3.24] and 3.66 [3.00-4.45] aXa IU*h/ml. In 3.0\% of dialyses (n = 83/2724) prolonged fistula compression times were documented. Eight patients (7.34\%) had at least one episode of minor bleeding. 4) 85.3\% of patients had any adverse event, 9.2\% were serious without suspected drug relation; and in 32 patients a drug-relation was suspected. Conclusions Certoparin appears effective and safe for anticoagulation in patients undergoing maintenance hemodialysis.}, language = {en} } @article{DorschKrieterLemkeetal.2012, author = {Dorsch, Oliver and Krieter, Detlef H. and Lemke, Horst-Dieter and Fischer, Stefan and Melzer, Nima and Sieder, Christian and Bramlage, Peter and Harenberg, Job}, title = {A multi-center, prospective, open-label, 8-week study of certoparin for anticoagulation during maintenance hemodialysis - the membrane study}, series = {BMC Nephrology}, volume = {13}, journal = {BMC Nephrology}, number = {50}, doi = {10.1186/1471-2369-13-50}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134845}, year = {2012}, abstract = {Background: Adequate anticoagulation is prerequisite for effective hemodialysis to prevent clotting in the extracorporeal circuit. We aimed providing first data on the efficacy and safety of the low-molecular-weight heparin certoparin in this setting. Methods: Multicenter, open-label, 8-week trial. Patients received a single dose of 3,000 IU certoparin i.v. with additional titration steps of 600 IU and/or continuous infusion if necessary. Results: 120 patients were screened, 109 enrolled (median age 71; range 26-90 years) and 106 available for efficacy analyses. The percentage of unsatisfactory dialysis results at 8 weeks due to clotting or bleeding, was 1.9\% (n = 2/106; 95\% confidence interval [CI] 0.23-6.65\%); no major bleeding. 1.9\% had moderate/severe clotting in the lines/bubble catcher and 2.8\% in the dialyser at week 8.15.7 +/- 14.3\% of the dialysis filters' visual surface area was showing redness. In subgroups of patients receiving median doses of 3000 +/- 0, 3000 (2400-6000) and 4200 (3000-6600) IU, plasma aXa levels at baseline, 4 and 8 weeks were 0.24 [ 95\% CI 0.21-0.27], 0.33 [0.27-0.40] and 0.38 [0.33-0.45] aXa IU/ml at 2 h. C-48h was 0.01 [0.01-0.02] aXa IU at all visits. At baseline and 4 weeks AUC(0-48h) was 2.66 [2.19-3.24] and 3.66 [3.00-4.45] aXa IU*h/ml. In 3.0\% of dialyses (n = 83/2724) prolonged fistula compression times were documented. Eight patients (7.34\%) had at least one episode of minor bleeding. 4) 85.3\% of patients had any adverse event, 9.2\% were serious without suspected drug relation; and in 32 patients a drug-relation was suspected. Conclusions: Certoparin appears effective and safe for anticoagulation in patients undergoing maintenance hemodialysis.}, language = {en} } @article{SalmanHaiderSchreinerKendletal.2019, author = {Salman Haider, Malik and Schreiner, Jochen and Kendl, Sabine and Kroiss, Matthias and Luxenhofer, Robert}, title = {A Micellar Mitotane Formulation with High Drug-Loading and Solubility: Physico-Chemical Characterization and Cytotoxicity Studies in 2D and 3D In Vitro Tumor Models}, series = {Macromolecular Bioscience}, volume = {20}, journal = {Macromolecular Bioscience}, number = {1}, doi = {10.1002/mabi.201900178}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206224}, pages = {1900178}, year = {2019}, abstract = {Adrenocortical carcinoma (ACC) is a rare tumor and prognosis is overall poor but heterogeneous. Mitotane (MT) has been used for treatment of ACC for decades, either alone or in combination with cytotoxic chemotherapy. Even at doses up to 6 g per day, more than half of the patients do not achieve targeted plasma concentration (14-20 mg L\(^{-1}\)) even after many months of treatment due to low water solubility, bioavailability, and unfavorable pharmacokinetic profile. Here a novel MT nanoformulation with very high MT concentrations in physiological aqueous media is reported. The MT-loaded nanoformulations are characterized by Fourier transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction which confirms the amorphous nature of the drug. The polymer itself does not show any cytotoxicity in adrenal and liver cell lines. By using the ACC model cell line NCI-H295 both in monolayers and tumor cell spheroids, micellar MT is demonstrated to exhibit comparable efficacy to its ethanol solution. It is postulated that this formulation will be suitable for i.v. application and rapid attainment of therapeutic plasma concentrations. In conclusion, the micellar formulation is considered a promising tool to alleviate major drawbacks of current MT treatment while retaining bioactivity toward ACC in vitro.}, language = {en} } @article{HommersRichterYangetal.2018, author = {Hommers, L. G. and Richter, J. and Yang, Y. and Raab, A. and Baumann, C. and Lang, K. and Schiele, M. A. and Weber, H. and Wittmann, A. and Wolf, C. and Alpers, G. W. and Arolt, V. and Domschke, K. and Fehm, L. and Fydrich, T. and Gerlach, A. and Gloster, A. T. and Hamm, A. O. and Helbig-Lang, S. and Kircher, T. and Lang, T. and Pan{\´e}-Farr{\´e}, C. A. and Pauli, P. and Pfleiderer, B. and Reif, A. and Romanos, M. and Straube, B. and Str{\"o}hle, A. and Wittchen, H.-U. and Frantz, S. and Ertl, G. and Lohse, M. J. and Lueken, U. and Deckert, J.}, title = {A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety}, series = {Translational Psychiatry}, volume = {8}, journal = {Translational Psychiatry}, doi = {10.1038/s41398-018-0278-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-322497}, year = {2018}, abstract = {Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.}, language = {en} } @article{KistlerSiwyFranketal.2011, author = {Kistler, Andreas D. and Siwy, Justyna and Frank, Breunig and Jeevaratnam, Praveen and Scherl, Alexander and Mullen, William and Warnock, David G. and Wanner, Christoph and Hughes, Derralynn A. and Mischak, Harald and W{\"u}thrich, Rudolf P. and Serra, Andreas L.}, title = {A Distinct Urinary Biomarker Pattern Characteristic of Female Fabry Patients That Mirrors Response to Enzyme Replacement Therapy}, series = {PLoS ONE}, volume = {6}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0020534}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133526}, pages = {e20534}, year = {2011}, abstract = {Female patients affected by Fabry disease, an X-linked lysosomal storage disorder, exhibit a wide spectrum of symptoms, which renders diagnosis, and treatment decisions challenging. No diagnostic test, other than sequencing of the alpha-galactosidase A gene, is available and no biomarker has been proven useful to screen for the disease, predict disease course and monitor response to enzyme replacement therapy. Here, we used urine proteomic analysis based on capillary electrophoresis coupled to mass spectrometry and identified a biomarker profile in adult female Fabry patients. Urine samples were taken from 35 treatment-naive female Fabry patients and were compared to 89 age-matched healthy controls. We found a diagnostic biomarker pattern that exhibited 88.2\% sensitivity and 97.8\% specificity when tested in an independent validation cohort consisting of 17 treatment-naive Fabry patients and 45 controls. The model remained highly specific when applied to additional control patients with a variety of other renal, metabolic and cardiovascular diseases. Several of the 64 identified diagnostic biomarkers showed correlations with measures of disease severity. Notably, most biomarkers responded to enzyme replacement therapy, and 8 of 11 treated patients scored negative for Fabry disease in the diagnostic model. In conclusion, we defined a urinary biomarker model that seems to be of diagnostic use for Fabry disease in female patients and may be used to monitor response to enzyme replacement therapy.}, language = {en} } @article{BaurSchedelbeckPulzeretal.2015, author = {Baur, Johannes and Schedelbeck, Ulla and Pulzer, Alina and Bluemel, Christina and Wild, Vanessa and Fassnacht, Martin and Steger, U.}, title = {A case report of a solitary pancreatic metastasis of an adrenocortical carcinoma}, series = {BMC Surgery}, volume = {15}, journal = {BMC Surgery}, number = {93}, doi = {10.1186/s12893-015-0076-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126130}, year = {2015}, abstract = {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.}, language = {en} } @article{ZopfFreyKienitzetal.2017, author = {Zopf, Kathrin and Frey, Kathrin R. and Kienitz, Tina and Ventz, Manfred and Bauer, Britta and Quinkler, Marcus}, title = {\(Bcl\)I polymorphism of the glucocorticoid receptor and adrenal crisis in primary adrenal insufficiency}, series = {Endocrine Connections}, volume = {6}, journal = {Endocrine Connections}, number = {8}, doi = {10.1530/EC-17-0269}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173276}, pages = {685-691}, year = {2017}, abstract = {Context: Patients with primary adrenal insufficiency (PAI) or congenital adrenal hyperplasia (CAH) are at a high risk of adrenal crisis (AC). Glucocorticoid sensitivity is at least partially genetically determined by polymorphisms of the glucocorticoid receptor (GR). Objectives: To determine if a number of intercurrent illnesses and AC are associated with the GR gene polymorphism \(Bcl\)I in patients with PAI and CAH. Design and patients: This prospective, longitudinal study over 37.7 ± 10.1 months included 47 PAI and 25 CAH patients. During the study period, intercurrent illness episodes and AC were documented. Results: The study period covered 223 patient years in which 21 AC occurred (9.4 AC/100 pat years). There were no significant differences between \(Bcl\)I polymorphisms (CC (n=29), CG (n=34) and GG (n=9)) regarding BMI, hydrocortisone equivalent daily dose and blood pressure. We did not find a difference in the number of intercurrent illnesses/patient year among \(Bcl\)I polymorphisms (CC (1.5±1.4/pat year), CG (1.2±1.2/pat year) and GG (1.6±2.2/pat year)). The occurrence of AC was not significantly different among the homozygous (GG) genotype (32.5 AC/100 pat years), the CC genotype (6.7 AC/100 pat years) and the CG genotype (4.9 AC/100 pat years). Concomitant hypothyroidism was the highest in the GG genotype group (5/9), compared to others (CC (11/29) and CG (11/34)). Conclusions: Although sample sizes were relatively small and results should be interpreted with caution, this study suggests that the GR gene polymorphism \(Bcl\)I may not be associated with the frequencies of intercurrent illnesses and AC.}, language = {en} } @article{BloemerPachelHofmannetal.2013, author = {Bl{\"o}mer, Nadja and Pachel, Christina and Hofmann, Urlich and Nordbeck, Peter and Bauer, Wolfgang and Mathes, Denise and Frey, Anna and Bayer, Barbara and Vogel, Benjamin and Ertl, Georg}, title = {5-Lipoxygenase facilitates healing after myocardial infarction}, series = {Basic Research in Cardiology}, volume = {108}, journal = {Basic Research in Cardiology}, number = {4}, doi = {10.1007/s00395-013-0367-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-132602}, year = {2013}, abstract = {Early healing after myocardial infarction (MI) is characterized by a strong inflammatory reaction. Most leukotrienes are pro-inflammatory and are therefore potential mediators of healing and remodeling after myocardial ischemia. The enzyme 5-lipoxygenase (5-LOX) has a key role in the transformation of arachidonic acid in leukotrienes. Thus, we tested the effect of 5-LOX on healing after MI. After chronic coronary artery ligation, early mortality was significantly increased in 5-LOX\(^{-/-}\) when compared to matching wildtype (WT) mice due to left ventricular rupture. This effect could be reproduced in mice treated with the 5-LOX inhibitor Zileuton. A perfusion mismatch due to the vasoactive potential of leukotrienes is not responsible for left ventricular rupture since local blood flow assessed by magnetic resonance perfusion measurements was not different. However, after MI, there was an accentuation of the inflammatory reaction with an increase of pro-inflammatory macrophages. Yet, mortality was not changed in chimeric mice (WT vs. 5-LOX\(^{-/-}\) bone marrow in 5-LOX\(^{-/-}\) animals), indicating that an altered function of 5-LOX\(^{-/-}\) inflammatory cells is not responsible for the phenotype. Collagen production and accumulation of fibroblasts were significantly reduced in 5-LOX\(^{-/-}\) mice in vivo after MI. This might be due to an impaired migration of 5-LOX\(^{-/-}\) fibroblasts, as shown in vitro to serum. In conclusion, a lack or inhibition of 5-LOX increases mortality after MI because of healing defects. This is not mediated by a change in local blood flow, but through an altered inflammation and/or fibroblast function.}, language = {en} }