@article{BliziotisKluijtmansSotoetal.2022, author = {Bliziotis, Nikolaos G. and Kluijtmans, Leo A. J. and Soto, Sebastian and Tinnevelt, Gerjen H. and Langton, Katharina and Robledo, Mercedes and Pamporaki, Christina and Engelke, Udo F. H. and Erlic, Zoran and Engel, Jasper and Deutschbein, Timo and N{\"o}lting, Svenja and Prejbisz, Aleksander and Richter, Susan and Prehn, Cornelia and Adamski, Jerzy and Januszewicz, Andrzej and Reincke, Martin and Fassnacht, Martin and Eisenhofer, Graeme and Beuschlein, Felix and Kroiss, Matthias and Wevers, Ron A. and Jansen, Jeroen J. and Deinum, Jaap and Timmers, Henri J. L. M.}, title = {Pre- versus post-operative untargeted plasma nuclear magnetic resonance spectroscopy metabolomics of pheochromocytoma and paraganglioma}, series = {Endocrine}, volume = {75}, journal = {Endocrine}, number = {1}, doi = {10.1007/s12020-021-02858-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-326574}, pages = {254-265}, year = {2022}, abstract = {Purpose Pheochromocytomas and Paragangliomas (PPGL) result in chronic catecholamine excess and serious health complications. A recent study obtained a metabolic signature in plasma from PPGL patients; however, its targeted nature may have generated an incomplete picture and a broader approach could provide additional insights. We aimed to characterize the plasma metabolome of PPGL patients before and after surgery, using an untargeted approach, and to broaden the scope of the investigated metabolic impact of these tumors. Design A cohort of 36 PPGL patients was investigated. Blood plasma samples were collected before and after surgical tumor removal, in association with clinical and tumor characteristics. Methods Plasma samples were analyzed using untargeted nuclear magnetic resonance (NMR) spectroscopy metabolomics. The data were evaluated using a combination of uni- and multi-variate statistical methods. Results Before surgery, patients with a nonadrenergic tumor could be distinguished from those with an adrenergic tumor based on their metabolic profiles. Tyrosine levels were significantly higher in patients with high compared to those with low BMI. Comparing subgroups of pre-operative samples with their post-operative counterparts, we found a metabolic signature that included ketone bodies, glucose, organic acids, methanol, dimethyl sulfone and amino acids. Three signals with unclear identities were found to be affected. Conclusions Our study suggests that the pathways of glucose and ketone body homeostasis are affected in PPGL patients. BMI-related metabolite levels were also found to be altered, potentially linking muscle atrophy to PPGL. At baseline, patient metabolomes could be discriminated based on their catecholamine phenotype.}, language = {en} } @article{BuckSerflingLindneretal.2022, author = {Buck, Andreas K. and Serfling, Sebastian E. and Lindner, Thomas and H{\"a}nscheid, Heribert and Schirbel, Andreas and Hahner, Stefanie and Fassnacht, Martin and Einsele, Hermann and Werner, Rudolf A.}, title = {CXCR4-targeted theranostics in oncology}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {49}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {12}, doi = {10.1007/s00259-022-05849-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324545}, pages = {4133-4144}, year = {2022}, abstract = {A growing body of literature reports on the upregulation of C-X-C motif chemokine receptor 4 (CXCR4) in a variety of cancer entities, rendering this receptor as suitable target for molecular imaging and endoradiotherapy in a theranostic setting. For instance, the CXCR4-targeting positron emission tomography (PET) agent [\(^{68}\)Ga]PentixaFor has been proven useful for a comprehensive assessment of the current status quo of solid tumors, including adrenocortical carcinoma or small-cell lung cancer. In addition, [\(^{68}\)Ga]PentixaFor has also provided an excellent readout for hematological malignancies, such as multiple myeloma, marginal zone lymphoma, or mantle cell lymphoma. PET-based quantification of the CXCR4 capacities in vivo allows for selecting candidates that would be suitable for treatment using the theranostic equivalent [\(^{177}\)Lu]/[\(^{90}\)Y]PentixaTher. This CXCR4-directed theranostic concept has been used as a conditioning regimen prior to hematopoietic stem cell transplantation and to achieve sufficient anti-lymphoma/-tumor activity in particular for malignant tissues that are highly sensitive to radiation, such as the hematological system. Increasing the safety margin, pretherapeutic dosimetry is routinely performed to determine the optimal activity to enhance therapeutic efficacy and to reduce off-target adverse events. The present review will provide an overview of current applications for CXCR4-directed molecular imaging and will introduce the CXCR4-targeted theranostic concept for advanced hematological malignancies.}, language = {en} } @article{SerflingLapaDreheretal.2022, author = {Serfling, Sebastian E. and Lapa, Constantin and Dreher, Niklas and Hartrampf, Philipp E. and Rowe, Steven P. and Higuchi, Takahiro and Schirbel, Andreas and Weich, Alexander and Hahner, Stefanie and Fassnacht, Martin and Buck, Andreas K. and Werner, Rudolf A.}, title = {Impact of tumor burden on normal organ distribution in patients imaged with CXCR4-targeted [\(^{68}\)Ga]Ga-PentixaFor PET/CT}, series = {Molecular Imaging and Biology}, volume = {24}, journal = {Molecular Imaging and Biology}, number = {4}, doi = {10.1007/s11307-022-01717-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324622}, pages = {659-665}, year = {2022}, abstract = {Background CXCR4-directed positron emission tomography/computed tomography (PET/CT) has been used as a diagnostic tool in patients with solid tumors. We aimed to determine a potential correlation between tumor burden and radiotracer accumulation in normal organs. Methods Ninety patients with histologically proven solid cancers underwent CXCR4-targeted [\(^{68}\)Ga]Ga-PentixaFor PET/CT. Volumes of interest (VOIs) were placed in normal organs (heart, liver, spleen, bone marrow, and kidneys) and tumor lesions. Mean standardized uptake values (SUV\(_{mean}\)) for normal organs were determined. For CXCR4-positive tumor burden, maximum SUV (SUV\(_{max}\)), tumor volume (TV), and fractional tumor activity (FTA, defined as SUV\(_{mean}\) x TV), were calculated. We used a Spearman's rank correlation coefficient (ρ) to derive correlative indices between normal organ uptake and tumor burden. Results Median SUV\(_{mean}\) in unaffected organs was 5.2 for the spleen (range, 2.44 - 10.55), 3.27 for the kidneys (range, 1.52 - 17.4), followed by bone marrow (1.76, range, 0.84 - 3.98), heart (1.66, range, 0.88 - 2.89), and liver (1.28, range, 0.73 - 2.45). No significant correlation between SUV\(_{max}\) in tumor lesions (ρ ≤ 0.189, P ≥ 0.07), TV (ρ ≥ -0.204, P ≥ 0.06) or FTA (ρ ≥ -0.142, P ≥ 0.18) with the investigated organs was found. Conclusions In patients with solid tumors imaged with [\(^{68}\)Ga]Ga-PentixaFor PET/CT, no relevant tumor sink effect was noted. This observation may be of relevance for therapies with radioactive and non-radioactive CXCR4-directed drugs, as with increasing tumor burden, the dose to normal organs may remain unchanged.}, language = {en} } @article{TamburelloAltieriSbieraetal.2022, author = {Tamburello, Mariangela and Altieri, Barbara and Sbiera, Iuliu and Sigala, Sandra and Berruti, Alfredo and Fassnacht, Martin and Sbiera, Silviu}, title = {FGF/FGFR signaling in adrenocortical development and tumorigenesis: novel potential therapeutic targets in adrenocortical carcinoma}, series = {Endocrine}, volume = {77}, journal = {Endocrine}, number = {3}, doi = {10.1007/s12020-022-03074-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324420}, pages = {411-418}, year = {2022}, abstract = {FGF/FGFR signaling regulates embryogenesis, angiogenesis, tissue homeostasis and wound repair by modulating proliferation, differentiation, survival, migration and metabolism of target cells. Understandably, compelling evidence for deregulated FGF signaling in the development and progression of different types of tumors continue to emerge and FGFR inhibitors arise as potential targeted therapeutic agents, particularly in tumors harboring aberrant FGFR signaling. There is first evidence of a dual role of the FGF/FGFR system in both organogenesis and tumorigenesis, of which this review aims to provide an overview. FGF-1 and FGF-2 are expressed in the adrenal cortex and are the most powerful mitogens for adrenocortical cells. Physiologically, they are involved in development and maintenance of the adrenal gland and bind to a family of four tyrosine kinase receptors, among which FGFR1 and FGFR4 are the most strongly expressed in the adrenal cortex. The repeatedly proven overexpression of these two FGFRs also in adrenocortical cancer is thus likely a sign of their participation in proliferation and vascularization, though the exact downstream mechanisms are not yet elucidated. Thus, FGFRs potentially offer novel therapeutic targets also for adrenocortical carcinoma, a type of cancer resistant to conventional antimitotic agents.}, language = {en} } @article{LenschowWennmannHendricksetal.2022, author = {Lenschow, Christina and Wennmann, Andreas and Hendricks, Anne and Germer, Christoph-Thomas and Fassnacht, Martin and Buck, Andreas and Werner, Rudolf A. and Plassmeier, Lars and Schlegel, Nicolas}, title = {Questionable value of [\(^{99m}\)Tc]-sestamibi scintigraphy in patients with pHPT and negative ultrasound}, series = {Langenbeck's Archives of Surgery}, volume = {407}, journal = {Langenbeck's Archives of Surgery}, number = {8}, doi = {10.1007/s00423-022-02648-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323926}, pages = {3661-3669}, year = {2022}, abstract = {Purpose A successful focused surgical approach in primary hyperparathyroidism (pHPT) relies on accurate preoperative localization of the parathyroid adenoma (PA). Most often, ultrasound is followed by [\(^{99m}\)Tc]-sestamibi scintigraphy, but the value of this approach is disputed. Here, we evaluated the diagnostic approach in patients with surgically treated pHPT in our center with the aim to further refine preoperative diagnostic procedures. Methods A single-center retrospective analysis of patients with pHPT from 01/2005 to 08/2021 was carried out followed by evaluation of the preoperative imaging modalities to localize PA. The localization of the PA had to be confirmed intraoperatively by the fresh frozen section and significant dropping of the intraoperative parathyroid hormone (PTH) levels. Results From 658 patients diagnosed with pHPT, 30 patients were excluded from the analysis because of surgery for recurrent or persistent disease. Median age of patients was 58.0 (13-93) years and 71\% were female. Neck ultrasound was carried out in 91.7\% and localized a PA in 76.6\%. In 23.4\% (135/576) of the patients, preoperative neck ultrasound did not detect a PA. In this group, [\(^{99m}\)Tc]-sestamibi correctly identified PA in only 25.4\% of patients. In contrast, in the same cohort, the use of [\(^{11}\)C]-methionine or [\(^{11}\)C]-choline PET resulted in the correct identification of PA in 79.4\% of patients (OR 13.23; 95\% CI 5.24-33.56). Conclusion [\(^{11}\)C]-Methionine or [\(^{11}\)C]-choline PET/CT are superior second-line imaging methods to select patients for a focused surgical approach when previous ultrasound failed to identify PA.}, language = {en} } @article{HeringDoerriesFlemmingetal.2022, author = {Hering, Ilona and D{\"o}rries, Luise and Flemming, Sven and Krietenstein, Laura and Koschker, Ann-Kathrin and Fassnacht, Martin and Germer, Christoph-Thomas and Hankir, Mohammed K. and Seyfried, Florian}, title = {Impact of preoperative weight loss achieved by gastric balloon on peri- and postoperative outcomes of bariatric surgery in super-obese patients: a retrospective matched-pair analysis}, series = {Langenbeck's Archives of Surgery}, volume = {407}, journal = {Langenbeck's Archives of Surgery}, number = {5}, doi = {10.1007/s00423-022-02472-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323909}, pages = {1873-1879}, year = {2022}, abstract = {Background An intragastric balloon is used to cause weight loss in super-obese patients (BMI > 60 kg/m\(^2\)) prior to bariatric surgery. Whether weight loss from intragastric balloon influences that from bariatric surgery is poorly studied. Methods In this retrospective, single-center study, the effects of intragastric balloon in 26 patients (BMI 69.26 ± 6.81) on weight loss after bariatric surgery (primary endpoint), postoperative complications within 30 days, hospital readmission, operation time, and MTL30 (secondary endpoints) were evaluated. Fifty-two matched-pair patients without intragastric balloon prior to bariatric surgery were used as controls. Results Intragastric balloon resulted in a weight loss of 17.3 ± 14.1 kg (BMI 5.75 ± 4.66 kg/m\(^2\)) with a nadir after 5 months. Surgical and postoperative outcomes including complications were comparable between both groups. Total weight loss was similar in both groups (29.0\% vs. 32.2\%, p = 0.362). Direct postoperative weight loss was more pronounced in the control group compared to the gastric balloon group (29.16 ± 7.53\% vs 23.78 ± 9.89\% after 1 year, p < 0.05 and 32.13 ± 10.5\% vs 22.21 ± 10.9\% after 2 years, p < 0.05), who experienced an earlier nadir and started to regain weight during the follow-up. Conclusion A multi-stage therapeutic approach with gastric balloon prior to bariatric surgery in super-obese patients may be effective to facilitate safe surgery. However, with the gastric balloon, pre-treated patients experienced an attenuated postoperative weight loss with an earlier nadir and earlier body weight regain. This should be considered when choosing the appropriate therapeutic regime and managing patients' expectations.}, language = {en} } @article{ReibetanzKelmUttingeretal.2022, author = {Reibetanz, Joachim and Kelm, Matthias and Uttinger, Konstantin L. and Reuter, Miriam and Schlegel, Nicolas and Hankir, Mohamed and Wiegering, Verena and Germer, Christoph-Thomas and Fassnacht, Martin and Lock, Johan Friso and Wiegering, Armin}, title = {Differences in morbidity and mortality between unilateral adrenalectomy for adrenal Cushing's syndrome and bilateral adrenalectomy for therapy refractory extra-adrenal Cushing's syndrome}, series = {Langenbeck's Archives of Surgery}, volume = {407}, journal = {Langenbeck's Archives of Surgery}, number = {6}, doi = {10.1007/s00423-022-02568-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-323947}, pages = {2481-2488}, year = {2022}, abstract = {Purpose In selected cases of severe Cushing's syndrome due to uncontrolled ACTH secretion, bilateral adrenalectomy appears unavoidable. Compared with unilateral adrenalectomy (for adrenal Cushing's syndrome), bilateral adrenalectomy has a perceived higher perioperative morbidity. The aim of the current study was to compare both interventions in endogenous Cushing's syndrome regarding postoperative outcomes. Methods We report a single-center, retrospective cohort study comparing patients with hypercortisolism undergoing bilateral vs. unilateral adrenalectomy during 2008-2021. Patients with adrenal Cushing's syndrome due to adenoma were compared with patients with ACTH-dependent Cushing's syndrome (Cushing's disease and ectopic ACTH production) focusing on postoperative morbidity and mortality as well as long-term survival. Results Of 83 patients with adrenalectomy for hypercortisolism (65.1\% female, median age 53 years), the indication for adrenalectomy was due to adrenal Cushing's syndrome in 60 patients (72.2\%; 59 unilateral and one bilateral), and due to hypercortisolism caused by Cushing's disease (n = 16) or non-pituitary uncontrolled ACTH secretion of unknown origin (n = 7) (27.7\% of all adrenalectomies). Compared with unilateral adrenalectomy (n = 59), patients with bilateral adrenalectomy (n = 24) had a higher rate of severe complications (0\% vs. 33\%; p < 0.001) and delayed recovery (median: 10.2\% vs. 79.2\%; p < 0.001). Using the MTL30 marker, patients with bilateral adrenalectomy fared worse than patients after unilateral surgery (MTL30 positive: 7.2\% vs. 25.0\% p < 0.001). Postoperative mortality was increased in patients with bilateral adrenalectomy (0\% vs. 8.3\%; p = 0.081). Conclusion While unilateral adrenalectomy for adrenal Cushing's syndrome represents a safe and definitive therapeutic option, bilateral adrenalectomy to control ACTH-dependent extra-adrenal Cushing's syndrome or Cushing's disease is a more complicated intervention with a mortality of nearly 10\%.}, language = {en} } @article{BliziotisKluijtmansTinneveltetal.2022, author = {Bliziotis, Nikolaos G. and Kluijtmans, Leo A. J. and Tinnevelt, Gerjen H. and Reel, Parminder and Reel, Smarti and Langton, Katharina and Robledo, Mercedes and Pamporaki, Christina and Pecori, Alessio and Van Kralingen, Josie and Tetti, Martina and Engelke, Udo F. H. and Erlic, Zoran and Engel, Jasper and Deutschbein, Timo and N{\"o}lting, Svenja and Prejbisz, Aleksander and Richter, Susan and Adamski, Jerzy and Januszewicz, Andrzej and Ceccato, Filippo and Scaroni, Carla and Dennedy, Michael C. and Williams, Tracy A. and Lenzini, Livia and Gimenez-Roqueplo, Anne-Paule and Davies, Eleanor and Fassnacht, Martin and Remde, Hanna and Eisenhofer, Graeme and Beuschlein, Felix and Kroiss, Matthias and Jefferson, Emily and Zennaro, Maria-Christina and Wevers, Ron A. and Jansen, Jeroen J. and Deinum, Jaap and Timmers, Henri J. L. M.}, title = {Preanalytical pitfalls in untargeted plasma nuclear magnetic resonance metabolomics of endocrine hypertension}, series = {Metabolites}, volume = {12}, journal = {Metabolites}, number = {8}, issn = {2218-1989}, doi = {10.3390/metabo12080679}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-282930}, year = {2022}, abstract = {Despite considerable morbidity and mortality, numerous cases of endocrine hypertension (EHT) forms, including primary aldosteronism (PA), pheochromocytoma and functional paraganglioma (PPGL), and Cushing's syndrome (CS), remain undetected. We aimed to establish signatures for the different forms of EHT, investigate potentially confounding effects and establish unbiased disease biomarkers. Plasma samples were obtained from 13 biobanks across seven countries and analyzed using untargeted NMR metabolomics. We compared unstratified samples of 106 PHT patients to 231 EHT patients, including 104 PA, 94 PPGL and 33 CS patients. Spectra were subjected to a multivariate statistical comparison of PHT to EHT forms and the associated signatures were obtained. Three approaches were applied to investigate and correct confounding effects. Though we found signatures that could separate PHT from EHT forms, there were also key similarities with the signatures of sample center of origin and sample age. The study design restricted the applicability of the corrections employed. With the samples that were available, no biomarkers for PHT vs. EHT could be identified. The complexity of the confounding effects, evidenced by their robustness to correction approaches, highlighted the need for a consensus on how to deal with variabilities probably attributed to preanalytical factors in retrospective, multicenter metabolomics studies.}, language = {en} } @article{WiegeringRiedmeierThompsonetal.2022, author = {Wiegering, Verena and Riedmeier, Maria and Thompson, Lester D. R. and Virgone, Calogero and Redlich, Antje and Kuhlen, Michaela and Gultekin, Melis and Yalcin, Bilgehan and Decarolis, Boris and H{\"a}rtel, Christoph and Schlegel, Paul-Gerhardt and Fassnacht, Martin and Timmermann, Beate}, title = {Radiotherapy for pediatric adrenocortical carcinoma - Review of the literature}, series = {Clinical and Translational Radiation Oncology}, volume = {35}, journal = {Clinical and Translational Radiation Oncology}, doi = {10.1016/j.ctro.2022.05.003}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-300472}, pages = {56-63}, year = {2022}, abstract = {Background and purpose Pediatric adrenocortical carcinoma (pACC) is a rare disease with poor prognosis. Publications on radiotherapy (RT) are scarce. This review summarizes the current data on RT for pACC and possibly provides first evidence to justify its use in this setting. Materials and methods We searched the PubMed and Embase database for manuscripts regarding RT for pACC. Results We included 17 manuscripts reporting on 76 patients treated with RT, after screening 2961 references and 269 full articles. In addition, we added data of 4 unreported pACC patients treated by co-authors. All reports based on retrospective data. Median age at first diagnosis was 11.1 years (70\% female); 78\% of patients presented with hormonal activity. RT was mostly performed for curative intent (78\%). 88\% of RT were administered during primary therapy. The site of RT was predominantly the local tumor bed (76\%). Doses of RT ranged from 15 to 62 Gy (median 50 Gy). Information on target volumes or fractionation were lacking. Median follow-up was 6,9 years and 64\% of the patients died of disease, with 33\% alive without disease. In 16 of 48 patients with available follow-up data after adjuvant RT (33\%) no recurrence was reported and in 3 of 9 patients palliative RT seemed to induce some benefit for the patient. Conclusions Our first systematic review on RT for pACC provides too few data for any general recommendation, but adjuvant RT in patients with high risk might be considered. International collaborative studies are urgently needed to establish better evidence on the role of RT in this rare malignancy.}, language = {en} } @article{DetomasRitzelNasiKordhishtietal.2022, author = {Detomas, Mario and Ritzel, Katrin and Nasi-Kordhishti, Isabella and Wolfsberger, Stefan and Quinkler, Marcus and Losa, Marco and Tr{\"o}ger, Viola and Kroiss, Matthias and Fassnacht, Martin and Vila, Greisa and Honegger, J{\"u}rgen Bernd and Reincke, Martin and Deutschbein, Timo}, title = {Outcome of CRH stimulation test and overnight 8 mg dexamethasone suppression test in 469 patients with ACTH-dependent Cushing's syndrome}, series = {Frontiers in Endocrinology}, volume = {13}, journal = {Frontiers in Endocrinology}, issn = {1664-2392}, doi = {10.3389/fendo.2022.955945}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-289450}, year = {2022}, abstract = {Objective To evaluate diagnostic accuracy of the corticotropin-releasing hormone (CRH) stimulation test and the overnight 8 mg dexamethasone suppression test (DST) for the differentiation of Cushing's disease (CD) and ectopic Cushing's syndrome (ECS). Methods Retrospective study in 6 European centers. Inclusion criteria: patients with a) overt adrenocorticotropin (ACTH)-dependent Cushing's syndrome at the time of dynamic testing, b) histopathological confirmed tumors and/or c) postoperative biochemical remission and/or adrenal insufficiency. Optimal cut-offs were calculated via receiver operating characteristic (ROC) analysis using CD as reference. Results 469 patients were analyzed [78\% females; median age 43 years (IQR 19)]. CRH test and overnight 8 mg DST were performed in 420 [CD, n=394 (94\%); ECS, n=26 (6\%)] and 237 patients [228 CD (96\%), 9 ECS (4\%)]. Both tests were performed in 205 patients (44\%). The post-CRH \%-increase at 30 minutes of both ACTH (cut-off ≥31\%, sensitivity 83\%, specificity 85\%, AUC 0.81) and cortisol (cut-off ≥12\%, sensitivity 82\%, specificity 89\%, AUC 0.86) discriminated best between CD and ECS. A test duration of >60 minutes did not improve diagnostic performance of the CRH test. The optimal cortisol cut-off for the \%-suppression during the 8 mg DST was ≥55\% (sensitivity 80\%, specificity 78\%, AUC 0.75). Conclusion The CRH test has equivalent sensitivity but higher specificity than the 8 mg DST and is therefore the test of first choice. The diagnostic outcome of ACTH and cortisol is well comparable, however, sampling beyond 60 minutes post-CRH does not provide diagnostic benefits.}, language = {en} }