@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{AmerellerDeutschbeinJoshietal.2022, author = {Amereller, Felix and Deutschbein, Timo and Joshi, Mamta and Schopohl, Jochen and Schilbach, Katharina and Detomas, Mario and Duffy, Leo and Carroll, Paul and Papa, Sophie and St{\"o}rmann, Sylv{\`e}re}, title = {Differences between immunotherapy-induced and primary hypophysitis—a multicenter retrospective study}, series = {Pituitary}, volume = {25}, journal = {Pituitary}, number = {1}, issn = {1386-341X}, doi = {10.1007/s11102-021-01182-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308704}, pages = {152-158}, year = {2022}, abstract = {Objective Immune checkpoint inhibitors can cause various immune-related adverse events including secondary hypophysitis. We compared clinical characteristics of immunotherapy-induced hypophysitis (IIH) and primary hypophysitis (PH) Design Retrospective multicenter cohort study including 56 patients with IIH and 60 patients with PH. Methods All patients underwent extensive endocrine testing. Data on age, gender, symptoms, endocrine dysfunction, MRI, immunotherapeutic agents and autoimmune diseases were collected. Results Median time of follow-up was 18 months in IIH and 69 months in PH. The median time from initiation of immunotherapy to IIH diagnosis was 3 months. IIH affected males more frequently than PH (p < 0.001) and led to more impaired pituitary axes in males (p < 0.001). The distribution of deficient adenohypophysial axes was comparable between both entities, however, central hypocortisolism was more frequent (p < 0.001) and diabetes insipidus considerably less frequent in IIH (p < 0.001). Symptoms were similar except that visual impairment occurred more rarely in IIH (p < 0.001). 20 \% of IIH patients reported no symptoms at all. Regarding MRI, pituitary stalk thickening was less frequent in IIH (p = 0.009). Concomitant autoimmune diseases were more prevalent in PH patients before the diagnosis of hypophysitis (p = 0.003) and more frequent in IIH during follow-up (p = 0.002). Conclusions Clinically, IIH and PH present with similar symptoms. Diabetes insipidus very rarely occurs in IIH. Central hypocortisolism, in contrast, is a typical feature of IIH. Preexisting autoimmunity seems not to be indicative of developing IIH.}, language = {en} } @article{DornquastReinholdSolaketal.2022, author = {Dornquast, Christina and Reinhold, Thomas and Solak, Saliha and Durak, Melike and Becher, Heiko and Riens, Burgi and Icke, Katja and Danquah, Ina and Willich, Stefan N. and Keil, Thomas and Krist, Lilian}, title = {Strategies to Enhance Retention in a Cohort Study Among Adults of Turkish Descent Living in Berlin}, series = {Journal of Immigrant and Minority Health}, volume = {24}, journal = {Journal of Immigrant and Minority Health}, number = {5}, doi = {10.1007/s10903-021-01309-1}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-344776}, pages = {1309-1317}, year = {2022}, abstract = {Retention is important for statistical power and external validity in long-term cohort studies. The aims of our study were to evaluate different retention strategies within a cohort study of adults of Turkish descent in Berlin, Germany, and to compare participants and non-participants. In 2011-2012, a population-based study was conducted among adults of Turkish descent to primarily examine recruitment strategies. 6 years later, the participants were re-contacted and invited to complete a self-report questionnaire regarding their health status, health care utilization, and satisfaction with medical services. The retention strategy comprised letters in both German and Turkish, phone calls, and home visits (by bilingual staff). We calculated the response rate and retention rate, using definitions of the American Association for Public Opinion Research, as well as the relative retention rate for each level of contact. Associations of baseline recruitment strategy, sociodemographic, migration-related and health-related factors with retention were investigated by logistic regression analysis. Of 557 persons contacted, 249 (44.7\%) completed the questionnaire. This was 50.1\% of those whose contact information was available. The relative retention rate was lowest for phone calls (8.9\%) and highest for home visits (18.4\%). Participants were more often non-smokers and German citizens than non-participants. For all remaining factors, no association with retention was found. In this study, among adults of Turkish descent, the retention rate increased considerably with every additional level of contact. Implementation of comprehensive retention strategies provided by culturally matched study personnel may lead to higher validity and statistical power in studies on migrant health issues.}, language = {en} } @unpublished{HennigPrustyKauferetal.2022, author = {Hennig, Thomas and Prusty, Archana B. and Kaufer, Benedikt and Whisnant, Adam W. and Lodha, Manivel and Enders, Antje and Thomas, Julius and Kasimir, Francesca and Grothey, Arnhild and Herb, Stefanie and J{\"u}rges, Christopher and Meister, Gunter and Erhard, Florian and D{\"o}lken, Lars and Prusty, Bhupesh K.}, title = {Selective inhibition of miRNA 1 processing by a herpesvirus encoded miRNA}, edition = {accepted version}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-267862}, year = {2022}, abstract = {Herpesviruses have mastered host cell modulation and immune evasion to augment productive infection, life-long latency and reactivation thereof 1,2. A long appreciated, yet elusively defined relationship exists between the lytic-latent switch and viral non-coding RNAs 3,4. Here, we identify miRNA-mediated inhibition of miRNA processing as a thus far unknown cellular mechanism that human herpesvirus 6A (HHV-6A) exploits to disrupt mitochondrial architecture, evade intrinsic host defense and drive the lytic-latent switch. We demonstrate that virus-encoded miR-aU14 selectively inhibits the processing of multiple miR-30 family members by direct interaction with the respective pri-miRNA hairpin loops. Subsequent loss of miR-30 and activation of the miR-30/p53/Drp1 axis triggers a profound disruption of mitochondrial architecture. This impairs induction of type I interferons and is necessary for both productive infection and virus reactivation. Ectopic expression of miR-aU14 triggered virus reactivation from latency, identifying viral miR-aU14 as a readily drugable master regulator of the herpesvirus lytic-latent switch. Our results show that miRNA-mediated inhibition of miRNA processing represents a generalized cellular mechanism that can be exploited to selectively target individual members of miRNA families. We anticipate that targeting miR-aU14 provides exciting therapeutic options for preventing herpesvirus reactivations in HHV-6-associated disorders.}, language = {en} } @article{BaumbachHoertererOppeltetal.2022, author = {Baumbach, Sebastian Felix and H{\"o}rterer, Hubert and Oppelt, Sonja and Szeimies, Ulrike and Polzer, Hans and Walther, Markus}, title = {Do pre-operative radiologic assessment predict postoperative outcomes in patients with insertional Achilles tendinopathy?: a retrospective database study}, series = {Archives of Orthopaedic and Trauma Surgery}, volume = {142}, journal = {Archives of Orthopaedic and Trauma Surgery}, number = {11}, issn = {1434-3916}, doi = {10.1007/s00402-021-03897-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307963}, pages = {3045-3052}, year = {2022}, abstract = {Introduction Diagnosis and treatment of insertional tendinopathy of the Achilles tendon (IAT) remains a challenge. The aim of this study was to assess the influence of pre-operative radiological pathologies on the patient-reported outcomes following open debridement of all pathologies for IAT. Materials and methods In this IRB-approved retrospective correlation and comparative study, patients with pre-operative imaging were identified from the authors' retrospective IAT database comprising of 118 patients. All were treated by a standardized surgical treatment strategy utilizing a midline, transachillary approach and debridement of all pathologies. A total of fifteen radiologic parameters were measured on radiographs (RX) and MRI. The patient-reported outcomes were assessed using the Victorian Institute of Sport Assessment-Achilles questionnaire (VISA-A-G) and the general health questionnaire SF-12 at a minimum follow-up of 12 months. The data are presented as mean ± SD (95\% CI). Results 88 patients (74.6\%) with an average age of 50 ± 12 (47-52) years were included. Radiographs were available in 68 patients and MRI in 53. The mean follow-up was 3.8 ± 1.9 (3.4-4.3) years. The overall VISA-A-G was 81 ± 22 (77-86), the SF-12 PCS 54 ± 7 (52-55), and the SF-12 MCS 52 ± 9 (50-54) points. None of the assessed radiological parameters had a significant influence on the patient-reported outcome following surgical treatment for IAT. Conclusion In this retrospective correlation study, no significant association was found between preoperative radiographic and MRI radiologic parameters for IAT and postoperative patient-reported outcomes (VISA-A-G and SF-12).}, language = {en} } @article{KraemerBeckerBleyetal.2022, author = {Kraemer, Markus and Becker, Jana and Bley, Thorsten Alexander and Steinbrecher, Andreas and Minnerup, Jens and Hellmich, Bernhard}, title = {Diagnostik und Therapie der Riesenzellarteriitis}, series = {Der Nervenarzt}, volume = {93}, journal = {Der Nervenarzt}, number = {8}, issn = {0028-2804}, doi = {10.1007/s00115-021-01216-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307771}, pages = {819-827}, year = {2022}, abstract = {Die Riesenzellarteriitis (RZA) ist in der Altersgruppe der {\"u}ber 50-J{\"a}hrigen die h{\"a}ufigste idiopathische systemische Vaskulitis. Die Erkrankung bedarf einer zeitnahen Diagnostik und Therapie, um schwere Komplikationen wie eine Erblindung oder einen Schlaganfall zu vermeiden. Die Rezidivneigung erfordert eine mehrj{\"a}hrige, zum Teil lebenslange Glukokortikoid(GC)-Therapie, was das Risiko GC-induzierter Langzeitnebenwirkungen erh{\"o}ht. Daher wird bei der Mehrzahl der Patienten eine additive GC-einsparende Therapie empfohlen. Hierzu steht der Anti-IL-6-Rezeptor-Antik{\"o}rper Tocilizumab in subkutaner Applikation als zugelassene Substanz zur Verf{\"u}gung, alternativ kann Methotrexat (MTX) eingesetzt werden (off-label).}, language = {de} } @article{GschmackMonoranuMaroufetal.2022, author = {Gschmack, Eva and Monoranu, Camelia-Maria and Marouf, Hecham and Meyer, Sarah and Lessel, Lena and Idris, Raja and Berg, Daniela and Maetzler, Walter and Steigerwald, Frank and Volkmann, Jens and Gerlach, Manfred and Riederer, Peter and Koutsilieri, Eleni and Scheller, Carsten}, title = {Plasma autoantibodies to glial fibrillary acidic protein (GFAP) react with brain areas according to Braak staging of Parkinson's disease}, series = {Journal of Neural Transmission}, volume = {129}, journal = {Journal of Neural Transmission}, number = {5-6}, doi = {10.1007/s00702-022-02495-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-325161}, pages = {545-555}, year = {2022}, abstract = {Idiopathic Parkinson's disease (PD) is characterized by a progredient degeneration of the brain, starting at deep subcortical areas such as the dorsal motor nucleus of the glossopharyngeal and vagal nerves (DM) (stage 1), followed by the coeruleus-subcoeruleus complex; (stage 2), the substantia nigra (SN) (stage 3), the anteromedial temporal mesocortex (MC) (stage 4), high-order sensory association areas and prefrontal fields (HC) (stage 5) and finally first-order sensory association areas, premotor areas, as well as primary sensory and motor field (FC) (stage 6). Autoimmunity might play a role in PD pathogenesis. Here we analyzed whether anti-brain autoantibodies differentially recognize different human brain areas and identified autoantigens that correlate with the above-described dissemination of PD pathology in the brain. Brain tissue was obtained from deceased individuals with no history of neurological or psychiatric disease and no neuropathological abnormalities. Tissue homogenates from different brain regions (DM, SN, MC, HC, FC) were subjected to SDS-PAGE and Western blot. Blots were incubated with plasma samples from 30 PD patients and 30 control subjects and stained with anti-IgG antibodies to detect anti-brain autoantibodies. Signals were quantified. Prominent autoantigens were identified by 2D-gel-coupled mass spectrometry sequencing. Anti-brain autoantibodies are frequent and occur both in healthy controls and individuals with PD. Glial fibrillary acidic protein (GFAP) was identified as a prominent autoantigen recognized in all plasma samples. GFAP immunoreactivity was highest in DM areas and lowest in FC areas with no significant differences in anti-GFAP autoantibody titers between healthy controls and individuals with PD. The anti-GFAP autoimmunoreactivity of different brain areas correlates with the dissemination of histopathological neurodegeneration in PD. We hypothesize that GFAP autoantibodies are physiological but might be involved as a cofactor in PD pathogenesis secondary to a leakage of the blood-brain barrier.}, language = {en} } @article{HartrampfWeinzierlBucketal.2022, author = {Hartrampf, Philipp E. and Weinzierl, Franz-Xaver and Buck, Andreas K. and Rowe, Steven P. and Higuchi, Takahiro and Seitz, Anna Katharina and K{\"u}bler, Hubert and Schirbel, Andreas and Essler, Markus and Bundschuh, Ralph A. and Werner, Rudolf A.}, title = {Matched-pair analysis of [\(^{177}\)Lu]Lu-PSMA I\&T and [\(^{177}\)Lu]Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer}, series = {European Journal of Nuclear Medicine and Molecular Imaging}, volume = {49}, journal = {European Journal of Nuclear Medicine and Molecular Imaging}, number = {9}, doi = {10.1007/s00259-022-05744-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324581}, pages = {3269-3276}, year = {2022}, abstract = {Background Labelled with lutetium-177, the urea-based small molecules PSMA I\&T and PSMA-617 are the two agents most frequently used for radioligand therapy (RLT) in patients with advanced metastatic castration-resistant and prostate-specific membrane antigen (PSMA) expressing prostate cancer (mCRPC). In this matched-pair analysis, we aimed to compare the toxicity and efficacy of both agents for PSMA-directed RLT. Materials and methods A total of 110 mCRPC patients from two centres were accrued, 55 individuals treated with [\(^{177}\)Lu]Lu-PSMA I\&T, and a matched cohort of 55 patients treated with [\(^{177}\)Lu]Lu-PSMA-617. Matching criteria included age at the first cycle, Gleason score, prostate-specific antigen (PSA) values, and previous taxane-based chemotherapy. Using common terminology criteria for adverse events (CTCAE v. 5.0), toxicity profiles were investigated (including bone marrow and renal toxicity). Overall survival (OS) between both groups was compared. Results Toxicity assessment revealed grade III anaemia in a single patient (1.8\%) for [\(^{177}\)Lu]Lu-PSMA I\&T and five (9.1\%) for [\(^{177}\)Lu]Lu-PSMA-617. In addition, one (1.9\%) grade III thrombopenia for [\(^{177}\)Lu]Lu-PSMA-617 was recorded. Apart from that, no other grade III/IV toxicities were present. A median OS of 12 months for patients treated with [\(^{177}\)Lu]Lu-PSMA I\&T did not differ significantly when compared to patients treated with [\(^{177}\)Lu]Lu-PSMA-617 (median OS, 13 months; P = 0.89). Conclusion In this matched-pair analysis of patients receiving one of the two agents most frequently applied for PSMA RLT, the rate of clinically relevant toxicities was low for both compounds. In addition, no relevant differences for OS were observed.}, language = {en} } @article{KuonBlasiUnsoeldetal.2022, author = {Kuon, Jonas and Blasi, Miriam and Uns{\"o}ld, Laura and Vogt, Jeannette and Mehnert, Anja and Alt-Epping, Bernd and Oorschot, Birgitt van and Sistermanns, Jochen and Ahlborn, Miriam and Ritterbusch, Ulrike and Stevens, Susanne and Kahl, Christoph and Ruellan, Anne and Matthias, Kathrin and Kubin, Thomas and Stahlhut, Kerstin and Heider, Andrea and Lordick, Florian and Thomas, Michael}, title = {Impact of molecular alterations on quality of life and prognostic understanding over time in patients with incurable lung cancer: a multicenter, longitudinal, prospective cohort study}, series = {Supportive Care in Cancer}, volume = {30}, journal = {Supportive Care in Cancer}, number = {4}, organization = {Arbeitsgemeinschaft Palliativmedizin (APM) of the German Cancer Society (DKG)}, issn = {0941-4355}, doi = {10.1007/s00520-021-06736-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308211}, pages = {3131-3140}, year = {2022}, abstract = {Purpose The purpose of this study is to investigate changes over time in quality of life (QoL) in incurable lung cancer patients and the impact of determinants like molecular alterations (MA). Methods In a prospective, longitudinal, multicentric study, we assessed QoL, symptom burden, psychological distress, unmet needs, and prognostic understanding of patients diagnosed with incurable lung cancer at the time of the diagnosis (T0) and after 3 (T1), 6 (T2) and 12 months (T3) using validated questionnaires like FACT-L, National Comprehensive Cancer Network (NCCN) Distress Thermometer (DT), PHQ-4, SCNS-SF-34, and SEIQoL. Results Two hundred seventeen patients were enrolled, 22 (10\%) with reported MA. QoL scores improved over time, with a significant trend for DT, PHQ-4, and SCNS-SF-34. Significant determinants for stable or improving scores over time were survival > 6 months, performance status at the time of diagnosis, and presence of MA. Patients with MA showed better QoL scores (FACT-L at T1 104.4 vs 86.3; at T2 107.5 vs 90.0; at T3 100.9 vs 92.8) and lower psychological distress (NCCN DT at T1 3.3 vs 5; at T2 2.7 vs 4.5; at T3 3.7 vs 4.5; PHQ-4 at T1 2.3 vs 4.1; at T2 1.7 vs 3.6; at T3 2.2 vs 3.6), but also a worsening of the scores at 1 year and a higher percentage of inaccurate prognostic understanding (27 vs 17\%) compared to patients without MA. Conclusion Patients with tumors harboring MA are at risk of QoL deterioration during the course of the disease. Physicians should adapt their communication strategies in order to maintain or improve QoL.}, language = {en} } @article{BernhardKrumpholzKriegeretal.2022, author = {Bernhard, Lukas and Krumpholz, Roman and Krieger, Yannick and Czempiel, Tobias and Meining, Alexander and Navab, Nassir and L{\"u}th, Tim and Wilhelm, Dirk}, title = {PLAFOKON: a new concept for a patient-individual and intervention-specific flexible surgical platform}, series = {Surgical Endoscopy}, volume = {36}, journal = {Surgical Endoscopy}, number = {7}, issn = {0930-2794}, doi = {10.1007/s00464-021-08908-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-307490}, pages = {5303-5312}, year = {2022}, abstract = {Background Research in the field of surgery is mainly driven by aiming for trauma reduction as well as for personalized treatment concepts. Beyond laparoscopy, other proposed approaches for further reduction of the therapeutic trauma have failed to achieve clinical translation, with few notable exceptions. We believe that this is mainly due to a lack of flexibility and high associated costs. We aimed at addressing these issues by developing a novel minimally invasive operating platform and a preoperative design workflow for patient-individual adaptation and cost-effective rapid manufacturing of surgical manipulators. In this article, we report on the first in-vitro cholecystectomy performed with our operating platform. Methods The single-port overtube (SPOT) is a snake-like surgical manipulator for minimally invasive interventions. The system layout is highly flexible and can be adapted in design and dimensions for different kinds of surgery, based on patient- and disease-specific parameters. For collecting and analyzing this data, we developed a graphical user interface, which assists clinicians during the preoperative planning phase. Other major components of our operating platform include an instrument management system and a non-sterile user interface. For the trial surgery, we used a validated phantom which was further equipped with a porcine liver including the gallbladder. Results Following our envisioned preoperative design workflow, a suitable geometry of the surgical manipulator was determined for our trial surgery and rapidly manufactured by means of 3D printing. With this setup, we successfully performed a first in-vitro cholecystectomy, which was completed in 78 min. Conclusions By conducting the trial surgery, we demonstrated the effectiveness of our PLAFOKON operating platform. While some aspects - especially regarding usability and ergonomics - can be further optimized, the overall performance of the system is highly promising, with sufficient flexibility and strength for conducting the necessary tissue manipulations.}, language = {en} }