Universitätsklinikum Düsseldorf

Myasthenia gravis is a well-understood autoimmune disease of the neuromuscular synapse that is medicinally treatable with favorable results and therefore should not be overlooked in the differential diagnostic evaluation of vertical diplopia. Myasthenia is primarily a clinical diagnosis. Positive indications include double vision of fluctuating severity, diurnal variations, double vision after lengthy gaze fixation on a distant object and in the primary position as well as diplopia in various visual directions, often associated with a varying extent of ptosis. Clinical tests are the Simpson test, the ice on eyes test and the probatory administration of pyridostigmine. Positive results corroborate this diagnosis but negative results do not exclude myasthenia. The same applies for the determination of specific autoantibodies. In addition to ocular symptoms it is important to search for generalized symptoms and bulbopharyngeal symptoms in particular should prompt immediate neurological diagnostics. In addition to symptomatic treatment a wide range of immunotherapeutic agents are available. Thymectomy is also used for immunomodulatory indications according to the 2023 revised guidelines. Patient-centered treatment goals, patient education and comprehensive information, also via the self-help organization German Myasthenia Society, are essential components of successful treatment of myasthenia.

Zusammenfassung Die Diagnose einer lebensbedrohlichen Erkrankung kann zu einer Reaktualisierung existenzieller Konflikte führen. Der plötzliche Verlust von Kontinuität, körperlicher Integrität, und sozialen Rollen kann die psychischen Verarbeitungsmöglichkeiten der Patient:innen überfordern. Insbesondere affektive Störungen und Symptome existenzieller Belastung erschweren die psychosoziale und medizinische Versorgung. Psychodynamische Behandlungsansätze können das Erleben von Nähe und Verbundenheit zu stärken, um Verluste zu bewältigen und Abschiedsprozesse zu ermöglichen. Das ORPHYS Manual beschreibt eine psychodynamische Kurzzeitpsychotherapie (12–24 Sitzungen), die das Ziel hat, existenzielle Belastungen schwer körperlich Erkrankter vor dem Hintergrund interaktioneller Konflikte am Lebensende zu adressieren. Die Kombination stützender und konfliktaufdeckender Interventionen, die nah am subjektiven Erleben und der individuellen Krankheitssituation der Patient:innen formuliert werden, soll diesen dabei helfen, abgewehrte affektive Zustände zu integrieren sowie einen Zugang zu eigenen Beziehungs- und Bewältigungsmustern zu erlangen. ORPHYS soll einen gemeinsamen Trauerprozess ermöglichen, bei dem der intensive Wunsch nach Beziehung am Lebensende und die Realität des Sterbens nebeneinanderstehen können.

Background In Europe, more than 300,000 persons per year experience out-of-hospital cardiac arrest (OHCA). Despite medical progress, only few patients survive with good neurological outcome. For many issues, evidence from randomized trials is scarce. OHCA often occurs for cardiac causes. Therefore, we established the national, prospective, multicentre German Cardiac Arrest Registry (G-CAR). Herein, we describe the first results of the pilot phase. Results Over a period of 16 months, 15 centres included 559 consecutive OHCA patients aged ≥ 18 years. The median age of the patients was 66 years (interquartile range 57;75). Layperson resuscitation was performed in 60.5% of all OHCA cases which were not observed by emergency medical services. The initial rhythm was shockable in 46.4%, and 29.1% of patients had ongoing CPR on hospital admission. Main presumed causes of OHCA were acute coronary syndromes (ACS) and/or cardiogenic shock in 54.8%, with ST-elevation myocardial infarction being the most common aetiology (34.6%). In total, 62.9% of the patients underwent coronary angiography; percutaneous coronary intervention (PCI) was performed in 61.4%. Targeted temperature management was performed in 44.5%. Overall in-hospital mortality was 70.5%, with anoxic brain damage being the main presumed cause of death (38.8%). Extracorporeal cardiopulmonary resuscitation (eCPR) was performed in 11.0%. In these patients, the in-hospital mortality rate was 85.2%. Conclusions G-CAR is a multicentre German registry for adult OHCA patients with a focus on cardiac and interventional treatment aspects. The results of the 16-month pilot phase are shown herein. In parallel with further analyses, scaling up of G-CAR to a national level is envisaged. Trial registration ClinicalTrials.gov identifier: NCT05142124.

Idiopathic inflammatory myopathies (IIM) are rare diseases (incidence 1:100,000) with a wide range of clinical symptoms and manifestations. Typical indicators of IIM are proximally emphasized muscle weakness and myalgias, which are usually accompanied by elevated creatine kinase levels and muscle atrophy. The autoantibody diagnostics separate IIM into different entities, which are each associated with a typical risk of organ manifestations and the occurrence of tumors. The IIM represents an interdisciplinary challenge and the diagnostics and treatment require the involvement of several disciplines including rheumatology, neurology, neuropathology, dermatology and pneumology. An accurate diagnosis and careful tumor screening are essential because of the association between certain subgroups of IIM and the occurrence of malignant tumors.

LBA5501 Background: Paclitaxel or pegylated liposomal doxorubicin (PLD) in combination with bevacizumab (bev) are standard treatment options in patients with relapsed ovarian cancer not candidates for platinum, but responses are usually short-lived. Recently, two trials have reported a numerical but non-significant advantage from the addition of atezolizumab (atezo) to chemo plus bev in the recurrent setting (ATALANTE, Kurtz JE et al., J Clin Oncol & NRG GY009, O'Cearbhaill et al, IGCS 2023). AGO-OVAR 2.29 investigated the efficacy of atezo in combination with bev and non-platinum-based chemo. Methods: AGO-OVAR 2.29 is a randomized, double blind, phase III trial evaluating the efficacy and safety of atezo plus bev and chemo in patients (pts) with recurrent ovarian cancer. Eligible patients had a 1st/2nd relapse within 6 months after completing platinum-based chemo or a 3rd relapse regardless of treatment-free interval. A fresh biopsy for central PD-L1 testing (VENTANA SP142 assay) prior to randomization was mandatory. All pts received weekly paclitaxel or PLD and bev until disease progression or intolerable toxicity and were randomized 1:1 to either atezolizumab 840 mg q14 days or placebo until progression or for a maximum duration of 24 months. Number of prior lines, planned chemo, prior bev and PD-L1 status served as stratification factors. Overall survival (OS) and progression-free survival (PFS) in the intention to treat (ITT) population were primary endpoints, both to be analyzed after observation of 391 deaths. Data cut-off (DCO) occurred on 26/01/2024. OS and PFS analysis is based on a multiple Cox regression with treatment arm and stratification factors as covariates. Safety is reported for pts who received at least one dose of study treatment. Results: 574 pts were randomly assigned to atezo (285) or placebo (289). 45.1% received PLD and 53.7% paclitaxel. 7 pts did not start study treatment. 36.1% of pts had received 3 prior lines and 72.5% prior bev. 25.8% were PD-L1 positive. At DCO 418 OS and 505 PFS events have occurred. Median OS was 14.3 months (mos) in the atezo and 13.0 mos in the placebo arm (HR 0.83, 95% CI 0.68-1.01; p=0.06) and PFS 6.3 mos for atezo vs 6.6 mos for placebo arm (HR 0.88, 95% CI 0.73-1.05; p=0.15). Similar HR were observed in PD-L1 positive and negative pts. In total, 580 SAE and 141 AESI were reported. AEs of ≥ grade 3 were reported in 71.5% in the atezo and 68.9% in the placebo arm. 63.7% of pts in the atezo and 51.4% in the placebo arm experienced serious AEs. Conclusions: The addition of atezo to chemo plus bev did not significantly improve OS or PFS in pts. with recurrent ovarian cancer who are no candidates for platinum. Safety was within the expected range. Translational research is ongoing. Clinical trial information: NCT03353831 .

Background There is an increasing need for integrated real-world data generation at the patient level across different siloes and healthcare settings (e.g., secondary and primary care) for clinical, scientific, and pharmaceutical research including AI methods. However, these data are scattered between different organizations, systems, and often remain unused for secondary purposes. Connecting and unlocking these data can advance clinical research to better understand disease and improve patient care. Thus, we established a clinical and scientific research platform that brings all these data into an integrated platform for researchers in a Rheumatology setting. The platform has been designed to bridge the gaps in the patient journey by integrating data throughout the patient journey within a centralized platform. This is not done in routine clinical practice in Germany. Objectives Evaluate the informed broad consent (BC) for the platform predicated on the principles of the Medical Informatics Initiative in Germany that was implemented and administered to our patients scheduled for routine follow-ups and visits within the Rheumatology outpatient clinic at a tertiary centre. Methods The analyses focused on the consent rates and options selected to the pre-given BC options. Positive ethics vote and DRKS registration were obtained. Results From 07/2023 to 12/2023 n=254 outpatients (48% with university entrance diploma) signed the BC and agreed for their data to be processed for the purposes of the platform. The median years of age of the consented patients was 57, most of which were female (71%), and the median disease duration was 11 years. Disease groups included rheumatoid arthritis (36%), psoriatic arthritis (11%), spondyloarthritis (6%), systemic lupus erythematosus (28%), systemic sclerosis (4%), and others (6%).Apart from the signature, eight predefined BC options could be selected with either a ‘yes’ or ‘no’, with the average number of ‘yes’ answers (standard deviation (SD)) being 7.4±1.5, and the average number of ‘no’ answers being 0.2±0.5. The mean number of missings over 8 BC items was 0.4±1.5. No differences between disease groups were noted. Even where signed informed consent was given, n=6 (2%) did not select any of the BC options at all. In addition, n=198 (78%) signed with consenting to all BC options. The approval rates for the individual BC items are listed in Table 1. • Download figure • Open in new tab • Download powerpoint Conclusion Our study focuses on the individual BC for a platform that collects and pools data from various sources within a centralized platform for scientific and clinical research Rheumatology embedded in routine care. The various aspects of our established BC are based on the template of the MII were well accepted by our predominantly female patients. Our patients extensive support for the integration of real-world data generation at the patient level across different siloes and healthcare settings gives us a high flexibility for performing clinical, scientific, and pharmaceutical research including AI methods, as well as a firm legal basis to do so that is rooted in informed consent pursuant to the GDPR. Detailed analyses on patients’ motivations and fears from an accompanying evaluation questionnaire are to be explored subsequently. REFERENCES NIL Acknowledgements NIL Disclosure of Interests Jutta G. Richter: None declared, Hasan Acar: None declared, Antonia Becker: None declared, Waldemar Ockert., not grants, but professional fees for professional services performed, Dominykas Kriauciunas., not grants, but professional fees for professional services performed, Markus Schröder: None declared, Jörg Distler: None declared, Matthias Schneider: None declared.

Background Giant cell arteritis (GCA) is an immune-mediated granulomatous vasculitis affecting large and medium-sized vessels. Vascular ultrasound, the diagnostic gold standard, has limitations in evaluating the aorta. Therefore, positron emission tomography-computer tomography (PET-CT) with [¹⁸F]FDG has emerged as a diagnostic alternative. However, interpretation can be challenging as glucose metabolism also occurs in vascular remodeling. The novel radiotracer [⁶⁸Ga]Ga-DOTA-Siglec-9 could improve PET-CT diagnostic capabilities. Early studies in animals and humans have validated its safety, tolerability, and potential efficacy in identifying inflammation. Siglec-9 is the leukocyte ligand for vascular adhesion protein 1 (VAP-1). Under physiological conditions, VAP-1 resides in intracellular vesicles within various cell types, including endothelial cells. Inflammatory stimuli prompt its translocation to the endothelial cell surface, enabling immune cell adhesion and migration. This upregulation of VAP-1 during inflammation renders [⁶⁸Ga]Ga-DOTA-Siglec-9 PET-CT particularly interesting for GCA. Objectives Evaluating [⁶⁸Ga]Ga-DOTA-Siglec-9 PET-CT for Disease Activity Detection in Giant Cell Arteritis. Methods We recruited a patient with recurrent GCA disease activity. The patient underwent a [⁶⁸Ga]Ga-DOTA-Siglec-9 PET-CT scan with an injection of 120 MBq [⁶⁸Ga]Ga-DOTA-Siglec-9. Fifty-one minutes post-injection, we conducted a low-dose CT for attenuation correction and a whole-body PET scan (one minute/ bed). We also used standard imaging methods, such as vascular ultrasound for the temporal, facial, axillary, carotid, and vertebral arteries, along with aortal MRI and routine laboratory tests. Results A 90-year-old male patient with GCA, diagnosed in 2018, was enrolled. The patient reported recurrent GCA symptoms, including bitemporal headaches and night sweat. At the time of scan, he received methotrexate 15 mg per week and a daily dose of 2 mg prednisolone. His C-reactive protein level was elevated at 21 mg/l. [⁶⁸Ga]Ga-DOTA-Siglec-9 PET scan revealed increased tracer uptake (SUVmax) in the subclavian artery (2.5), aortic arch (2.9), and heart (2.9), in contrast to an uptake of 1.5 in the liver (Figure 1). Notably, the increased uptake in the descending aorta (3.5) abruptly diminished to 2.2 when passing the diaphragm, with no changes in vessel caliber observed in CT (Figure 1). Vascular ultrasound and MRI did not reveal any pathological findings (data not shown). The injection of [⁶⁸Ga]Ga-DOTA-Siglec-9 was well tolerated. • Download figure • Open in new tab • Download powerpoint Figure 1. Enhanced [68Ga]Ga-DOTA-Siglec-9 uptake in aortic and subclavian regions of a giant cell arteritis patient in positron emission tomography imaging Whole-body PET images of GCA patient (male, 90 years old) after intravenous injection of 120 MBq of [⁶⁸Ga]Ga-DOTA-Siglec-9. Distribution of [⁶⁸Ga]Ga-DOTA-Siglec-9 51 min after injection, based on imaging for one minute per bed position, revealed increased uptake in projection on the aortic and subclavian vessels and the heart. The increased uptake in the descending aorta diminishes abruptly while passing the diaphragm, without any caliber jump in the CT images. Conclusion This study presents the first application of [⁶⁸Ga]Ga-DOTA-Siglec-9 PET-CT in a GCA patient. PET-CT imaging demonstrated increased tracer uptake in the subclavian artery and aortic arch, with a localized and abrupt reduction. Notably, there were no corresponding findings in conventional imaging. We hypothesize that [⁶⁸Ga]Ga-DOTA-Siglec-9 PET-CT might offer unique potential for precise, localized mapping of affected vascular tissue in GCA, especially during relapse. This could revolutionize the current diagnostic approach, leading to more targeted strategies for monitoring disease activity. Given these encouraging findings, larger scale studies are essential to fully elucidate the potential role of [⁶⁸Ga]Ga-DOTA-Siglec-9 PET-CT in the diagnostic landscape of GCA. REFERENCES NIL Acknowledgements NIL Disclosure of Interests None declared

Background Engrailed 1 (EN1), a homeodomain-containing transcription factor (TF), is transiently expressed in the developing dermis of murine embryos within a specific fibroblast lineage [1]. We previously showed that EN1 is re-expressed in systemic sclerosis (SSc) in a TGFβ-dependent manner and that it amplifies the pro-fibrotic effects of TGFβ to promote fibroblast activation and fibrosis [2]. EN1 might thus be a promising target for antifibrotic therapies. However, TFs are widely recognized as challenging to target. The pro-fibrotic effects of EN1 are essentially dependent on its interaction with other TF, i.p. with those from the SP family. An approach for targeting EN1 by an EN1 interference peptide (EN1-iPEP) has recently been described [3]. The EN1-iPEP contains a highly conserved hexamotif WPAWVY from the EN1 homeodomain, required for binding to its interaction partners. EN1-iPEP thus prevents the effects of the endogenous EN1 by competing for binding to its interaction partners. Objectives To evaluate the therapeutic potential of EN1-iPEP for the treatment of fibrosis. Methods An EN1-iPEP and a control, mutated peptide (mut-iPEP) were designed; mut-iPEP is identical to the EN1-iPEP, except that the hexamotif for binding to interaction partners is mutated, allowing to evaluate the effects of EN1-iPEP that are specific to blocking the endogenous EN1. The antifibrotic effects of the administration of EN1-iPEP were evaluated in two-dimensional culture of human dermal fibroblasts, in three-dimensional human skin equivalent models, in the mouse model of bleomycin-induced skin fibrosis and in precision cut slices of SSc skin (SSc-PCSS). Bulk RNA-seq was performed from SSc-PCSS. Immunoprecipitation experiments were performed to validate the in silico predictions and confirm the mechanism of action of EN1-iPEP. Results Treatment with EN1-iPEP, but not with mut-iPEP ameliorates the profibrotic effects of TGFβ in human dermal fibroblasts in standard two-dimensional culture, with reduced myofibroblasts differentiation and collagen production. Furthermore, treatment with EN1-iPEP prevented TGFβ-induced increases in dermal thickness, in collagen production and myofibroblasts counts in three-dimensional human skin equivalent models. In vivo treatment with EN1-iPEP ameliorates bleomycin-induced skin fibrosis in mice, with reduced myofibroblasts counts, dermal thickness and hydroxyproline content. Furthermore, EN1-iPEP partially reverses the SSc gene expression profile in SSc-PCSS. Pathway ORA and GSEA identifies de-enrichment of terms related to extracellular matrix synthesis, actin-mediated contraction and to canonical Wnt signaling. Mechanistically, EN1-iPEP prevents the formation of a transcriptional complex of EN1, β-catenin and SP1 to inhibit the aberrant Wnt/β-catenin signaling in SSc. Conclusion By employing a series of models, including direct evaluation in SSc skin, we demonstrate that treatment with EN1-iPEP (and interference with the cooperative DNA binding of EN1) inhibits two core profibrotic pathways in SSc, TGFβ and Wnt/β-catenin in SSc, and can thus prevent fibroblast activation and collagen production. EN1-iPEP may thus offer therapeutic potential in SSc. REFERENCES [1] Rinkevich Y, Walmsley GG, Hu MS, Maan ZN, Newman AM, Drukker M, et al. Skin fibrosis. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science. 2015;348(6232):aaa2151.[2] Gyorfi AH, Matei AE, Fuchs M, Liang C, Rigau AR, Hong X, et al. Engrailed 1 coordinates cytoskeletal reorganization to induce myofibroblast differentiation. J Exp Med. 2021;218(9). [3] Sorolla A, Wang E, Clemons TD, Evans CW, Plani-Lam JH, Golden E, et al. Triple-hit therapeutic approach for triple negative breast cancers using docetaxel nanoparticles, EN1-iPeps and RGD peptides. Nanomedicine. 2019;20:102003. Acknowledgements NIL Disclosure of Interests Liyan Xu: None declared, Veda Devakumar: None declared, Andrea-Hermina Györfi: None declared, Xuezhi Hong: None declared, Yanhua Xiao: None declared, Tim Filla: None declared, Yi-nan Li: None declared, Jörg Distler Stock owner of 4D Science and Scientific head of FibroCure, Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB, Anamar, Active Biotech, Array Biopharma, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB, Alexandru-Emil Matei: None declared.

Background In heterogeneous conditions with insufficient predictable disease course, like systemic sclerosis (SSc), appropriate measurement of disease activity, as well as predictors of disease progression are necessary for optimizing individual outcome. Systemic sclerosis is associated, despite emerging new therapies with a variable unpredictable course of disease with a high morbidity and mortality. Notably, innate lymphoid cells (ILCs), specifically ILC2, are gaining recognition as significant contributors to cytokines-driven fibrotic tissue remodelling. Elevated levels of ILC2s have been observed in both skin sections and the circulation of SSc patients commpared to healthy controls. Objectives The study aims to assess the predictive value of type 2 ILCs over a period of 5-year follow-up in patients with systemic sclerosis. Methods Fifty-two consecutive patients meeting the 2013 ACR/EULAR classification criteria for SSc were included in the study. Clinical parameters were assessed according to EUSTAR recommendations by experienced rheumatologists. Blood samples were analysed using flow cytometry. Annual pulmonary function test (PFT), echocardiography and EKG were conducted. High-resolution computed tomography (HRCT) scans of the lungs were evaluated by experienced radiologists, who were blinded with regard to the clinical data and the study question and some patients underwent positron emission tomography (PET) scanning with tracers specific for fibroblast activation protein (FAP, ⁶⁸Ga-FAP inhibitor (FAPI)-04). Disease worsening was defined as decrease in pulmonary function tests (FVC or DLCOcSB decline ≥ 10%), progression of fibrotic lesions in HRCT, switch or new begin of immunosuppressive or anti-fibrotic therapy, increase in mRSS defined as increase in mRSS >5 points and ≥25% from baseline, or death. Results The baseline cohort comprised 52 patients with SSc, including 12 patients with diffuse (23.07%) cutaneous SSc (dcSSc) and 11 (21.15%) male. Mean ± SD disease duration was 7.5 ± 6.9 years. Among the 52 patients, three (5.76%) patients were lost to follow-up and eight (15.38%) died. Circulating ILC2 were significantly increased in patients with a fibrotic subtype of disease (including important skin fibrosis and lung fibrosis, adapted from DeSScipher observational studies), followed by the vascular subtype (represented by marked digital ulcers and pulmonary arterial hypertention), while musculo-skeletal (arthritis or muscular disease as leading symptoms) and normal-like subtype had similar low levels (mean ILC2 4.18 vs. 1.80 vs. 1.28 vs. 1.01/µl respectively, p<0.001). Baseline ILC2 number correlated with lung disease progression, worsening of mRSS and mortality. Patients requiring intensive immunosuppressive or anti-fibrotic therapy during the follow-up time had significantly higher ILC2 counts at baseline (3.73/µl vs 1.25/µl, p<0.001). The ILC2 cutoff value of 1.57/µl demonstrated high sensitivity (>90%) and specificity (>70%) in identifying stable patients (area under the curve 0.879, p<0.0001). Patients with ILC2 count above 1.57/µl experienced a more rapid decline in pulmonary function test, increased mRSS scores and a higher mortality. Multivariate analysis revealed that an increased ILC2 number at baseline was a significant predictor of lung disease progression (≥10% decline in FVC, ≥10% decline in DLCO, progression of lung fibrosis in HRCT scans) and death. Furthermore, high ILC2 counts correlated with increase SUVmax and SUVmean in FAPI PET-CT imaging, indicating heightened activity in these patients. Conclusion The baseline number of ILC2s correlated with disease progression and serves as a prognostic marker even in patients with longstanding disease, providing evidence for profibrotic role of ILC2 in SSc. REFERENCES NIL Acknowledgements Supported by the German Research Foundation (grant SO 1735/2-1), Novartis Pharma GmbH Disclosure of Interests Alina M Ramming: None declared, Christian Schmidkonz: None declared, Armin Atzinger: None declared, Maria Gabriella Raimondo: None declared, Simon Rauber: None declared, Jörg Distler: None declared, Georg Schett: None declared, Andreas Ramming Novartis Pharma GmbH, Novartis Pharma GmbH.

Background Systemic Sclerosis (SSc) is characterized by a significant alteration in skin structure. In normal adult human skin, the dermis consists of a papillary layer containing papillae, nerves, mechanoreceptors, vessels and lose collagen bundles, as well as a reticular dermis with coarse collagen bundles. In SSc, the skin morphology is disturbed, adopting a distinctive “reticularized” phenotype marked by the loss of dermal papillae and excessive collagen deposition. The mechanisms maintaining the physiological morphology of adult human skin remain poorly understood. Murine experiments suggest that short-distance morphogen gradients play a crucial role in three-dimensional pattern formation during embryonic skin morphogenesis in rodents [1]. Objectives • 1) To analyze if spatial WNT/β-catenin activation is observed in adult healthy human skin and investigate potential alterations in fibrosing skin disorders such as SSc. • 2) To evaluate whether perturbations in spatial WNT/β-catenin activation correlate with disruptions in the physiological structure of the skin in SSc. • 3) To assess whether changes in the spatial WNT/β-catenin activation correlate with an alteration of reticular markers in SSc skin. Methods Skin morphology was quantitatively evaluated in 40 SSc patients and 18 healthy controls through HE and trichrome staining of skin sections. The transcriptome of healthy and SSc skin was assessed to identify an enrichment of papillary and reticular marker genes and WNT target genes by gene set enrichment analysis using prepublished datasets [2],[3]. Spatial activation of WNT/β-catenin was analyzed through RNAscope®-in situ hybridization detection of AXIN2. Immunofluorescence (IF) staining was performed to visualize β-catenin distribution. Enrichment of reticular marker genes in predefined fibroblast subpopulations was assessed using Gene Ontology (GO) and gene set enrichment analysis (GSEA). Results We describe a significant reduction in number, area and height of papillary structures in SSc compared to healthy controls. Consistently, we found that the expression of papillary/reticular marker genes in SSc skin shifts towards a reticular profile compared to controls. Investigating the expression of WNT3A target genes, we observed an enrichment of WNT3A-regulated genes in papillary gene sets of healthy skin. The spatial distribution of β-catenin-positive fibroblasts in healthy skin, predominantly in the papillary dermis, contrasts with SSc skin, where a 2-fold increase in observed throughout the dermis. A gradient with enrichment of β-catenin-expressing fibroblasts in the papillary layer of healthy skin is no longer observed in SSc. Confocal imaging showed an increased nuclear staining pattern of β-catenin in the reticular dermis compared to the papillary dermis in SSc skin. The loss of spatial WNT activation in SSc was further confirmed at the transcriptional level. Notably, an enrichment of WNT/β-catenin-related genes was found in the Pl16+-population, which also relocates from the reticular to the papillary dermis in SSc. Conclusion Our study provides first evidence of the disrupted physiological WNT/β-catenin gradient in SSc, linked to the loss of papillary dermal structure. Further investigations into the spatial distribution of WNT agonists and antagonists, along with advanced in vitro models simulating a papillary skin structure, will be essential for a more comprehensive understanding of the mechanisms maintaining the skin structure in healthy adult human skin. REFERENCES [1] Matos et al. Elife 2020.[2] Skaug, Khanna et al. Ann Rheum Dis. 2020. [3] Zhu et al. J Invest Dermatol. 2023. Acknowledgements NIL Disclosure of Interests Sara Chenguiti Fakhouri: None declared, Honglin Zhu: None declared, Moritz Ronicke: None declared, Clara Dees: None declared, Laura Konstantinidis: None declared, Aleix Rius Rigau: None declared, Alexandru-Emil Matei: None declared, Yi-nan Li: None declared, Markus Eckstein: None declared, Carol Geppert: None declared, Ingo Ludolph: None declared, Alexander Kreuter: None declared, Michael Sticherling: None declared, Carola Berking: None declared, Georg Schett: None declared, Raymund Horch: None declared, Jörg Distler JHWD is stock owner of 4D Science and scientific lead of FibroCure, JHWD has consultancy relationships with Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Medac, Novartis, Pfizer, RuiYi and UCB, JHWD has received research funding from Anamar, Active Biotech, Array Biopharma, ARXX, aTyr, AstraZeneca, BMS, Bayer Pharma, BoehringerIngelheim, Cantargia, Celgene, CSL Behring, Galapagos, GSK, Inventiva, Kiniksa, Sanofi-Aventis, RedX, UCB, Christina Bergmann CB has received consultancy fees from Pfizer and Boehringer-Ingelheim.

Background CD19-targeting CAR T cells showed remarkable improvements in autoimmune diseases including refractory lupus erythematodes [1,2] and inflammatory myopathy [3] and first experiences in patients with dcSSc have been reported [4,5]. Objectives Here we present up to 1-year follow-up data of six patients with severe dcSSc who received CD19-targeting CAR T cell treatment. The aim of this study was to assess the effects of deep B-cell depletion using CD19 CAR T cells on the disease course of fibrotic skin and organ involvement, autoimmunity and vascular phenomena one year after CD19 CAR T cell therapy. Methods CD19 CAR T cells were acquired as previously described [1]. Immunosuppression was stopped before CAR T cell infusion and the therapy was performed upon lymphodepletion with fludarabine (25 mg/m² on days -5, -4, -3) and cyclophosphamide (1g/m² on day -3) as single infusion with 1x10⁶ CAR T cells/kg. Patients were followed up for a 12 months period with the following assessments being performed: mRSS, EUSTAR activity index, patient reported outcomes, FVC, extent of ILD on CT scans and ⁶⁸Ga-04-FAPI-uptake. Consecutive skin biopsies were taken before CAR T cell therapy and in regular intervals during one year follow up. Results Six patients (4 male, 2 female) with diffuse and progressive SSc, who had failed state of the art therapies, were treated with CD19-targeting CAR T cells. The median age was 42 (IQR 36,25 – 53) with a median disease duration of 36 months (IQR 24,75 – 45,75). At baseline, patients were positive for either anti-Scl-70 antibodies (5/6) or anti-RNAP-III antibodies (1/6). After CAR T therapy, mRSS decreased by around 30-45% within the first 3 to 4 months and remained stable or decreased even further by up to 60% during one year follow up. Raynaud’s syndrome improved and digital ulcerations were less frequent to absent. Histologically, we observed reduced counts of FAP positive fibroblasts. Moreover, the papillary skin structure tended to shift to a more physiological phenotype with reduced collagen alignment and an increased number of papillae. Serologically, ANA titers showed an up to 10-fold decrease on three months follow up and declined further during the following 9 months. Anti-RNAP-III antibodies disappeared early after CAR T application and were not detectable during all follow up appointments, anti-Scl70 persisted on immunoblot with regressive titers as analyzed by ELISA. Lung function parameters remained stable in all patients with ILD during 1 year follow up, ⁶⁸GA-FAPI-04-uptake as a potential marker of fibrotic disease activity decreased within three months and remained low during the whole year follow up in the lung and in the heart. Conclusion These data on the first six SSc patients receiving CD19-targeting CAR T cell therapy show that the procedure can lead to stabilization of SSc disease activity without additional immunosuppression during a period of up to 1 year after treatment. Histological analysis furthermore show structural changes in the skin after therapy that could indicate a shift to a more physiological phenotype. Further mechanistic studies are ongoing. REFERENCES [1] Mackensen et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. 2022 Oct;28(10):2124-2132. doi: 10.1038/s41591-022-02017-5.[2] Mougiakakos et al. CD19-Targeted CAR T Cells in Refractory Systemic Lupus Erythematosus. N Engl J Med. 2021 Aug 5;385(6):567-569. doi: 10.1056/NEJMc2107725. [3] Müller et al. CD19-targeted CAR T cells in refractory antisynthetase syndrome. Lancet. 2023 Mar 11;401(10379):815-818. doi: 10.1016/S0140-6736(23)00023-5. [4] Bergmann et al. Treatment of a patient with severe systemic sclerosis (SSc) using CD19-targeted CAR T cells. Ann Rheum Dis. 2023 Aug;82(8):1117-1120. doi: 10.1136/ard-2023-223952. [5] Merkt et al. Third-generation CD19.CAR-T cell-containing combination therapy in Scl70+ systemic sclerosis. Ann Rheum Dis. 2023 Dec 22:ard-2023-225174. doi: 10.1136/ard-2023-225174. Epub ahead of print. PMID: 38135464. Acknowledgements NIL Disclosure of Interests None declared

Background Ruxolitinib, a JAK1 and 2, belumosudil a ROCK2 inhibitor, and ibrutinib, a BTK inhibitor, are efficacious and safe for the treatment of chronic graft vs. host disease (cGvHD) and were recently approved by the Food and Drug Administration for this indication (1). Since cGvHD, particularly in its sclerodermatous form, shares pathogenic similarities with SSc, we reasoned that these drugs might have therapeutic potential in SSc. Objectives To evaluate the therapeutic potential and the relative efficacy of ruxolitinib, ibrutinib and belumosudil for the treatment of systemic sclerosis. Methods The murine model of sclerodermatous cGvHD was generated, since it recapitulates early stages of SSc, with progressive fibrosis driven mainly by active inflammation and autoimmunity. Bone marrow and splenocytes from B10.D2 mice was transplanted in Balb/c mice (allogeneic bone marrow transplantation, alloBMT), and mice with syngeneic Balb/c →Balb/c transplant (synBMT) were used as controls. Mice were treated with ruxolitinib, ibrutinib or belumosudil, and skin and lung fibrosis were evaluated. Precision cut slices of SSc skin (SSc-PCSS) were generated from four donors, two of which had early, progressive SSc. SSc-PCSS were treated with ruxolitinib, ibrutinib or belumosudil for 48 hours. RNA was isolated from SSc-PCSS and RNA-sequencing was performed. Differential gene expression analysis, pathway overrepresentation analysis (ORA) and gene set enrichment analysis (GSEA) were subsequently performed. Results We demonstrate that ruxolitinib, belumosudil and ibrutinib are effective in ameliorating skin and lung fibrosis in alloBMT mice, with reduced skin thickness and Ashcroft scores, respectively, decreased myofibroblast counts and reduced hydroxyproline content. Of the three drugs, ruxolitinib showed the most potent effects, with almost complete prevention of fibrotic skin and lung remodeling. In SSc-PCSS, we identified 829 differentially expressed genes (DEGs) after treatment with ruxolitinib, 412 DEGs after treatment with belumosudil and 297 DEGs after treatment with ibrutinib. Pathway ORA and GSEA identified terms related to extracellular matrix production and profibrotic immune responses de-enriched upon treatment with ruxolitinib, belumosudil and ibrutinib. The DEGs after treatment with ruxolitinib showed the highest overlap with DEGs in SSc from the PRESS cohort, suggesting that ruxolitinib has the highest potential to revert an SSc signature. Conclusion By employing a model of sclerodermatous cGvHD and direct testing in SSc skin, we demonstrate that treatment with ruxolitinib, belumosudil and ibrutinib can prevent fibroblast activation and collagen production and can partially revert the aberrant gene expression profile in SSc. Of these drugs, ruxolitinib showed the most potent effects. We thus provide in vivo and ex vivo data that support the therapeutic potential of ruxolitinib, belumosudil and ibrutinib for the treatment of SSc, that might be of high translational potential, since these drugs are already approved for other indications. REFERENCES [1] Martini DJ, Chen YB, DeFilipp Z. Recent FDA Approvals in the Treatment of Graft-Versus-Host Disease. Oncologist. 2022;27(8):685-93. Acknowledgements NIL Disclosure of Interests Xuezhi Hong: None declared, Yanhua Xiao: None declared, Andrea-Hermina Györfi: None declared, Liyan Xu: None declared, Lichong Shen: None declared, Ranjana Neelagar: None declared, Veda Devakumar: None declared, Tim Filla: None declared, Thuong Trinh-Minh: None declared, Minrui Liang: None declared, Aleix Rius Rigau: None declared, Jörg Distler stock owner of 4D Science and Scientific head of FibroCure, Actelion, Active Biotech, Anamar, ARXX, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, JB Therapeutics, Medac, Pfizer, RuiYi and UCB, Anamar, Active Biotech, Array Biopharma, aTyr, BMS, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Novartis, Sanofi-Aventis, RedX, UCB, Alexandru-Emil Matei: None declared.

Background Data on the incidence and risk of opportunistic fungal infections (OFIs), rare yet life-threatening infections in rheumatoid arthritis (RA) patients[1], remain scarce due to limited patient numbers and inconsistent case definitions. Objectives To investigate associations between demographic and clinical characteristics, treatment, and the development of OFI in RA patients. Methods Data were obtained from the German biologics register RABBIT, which includes adult RA patients starting a new treatment with a biologic (b) or targeted synthetic (ts) disease-modifying anti-rheumatic drug (DMARD) or a conventional synthetic (cs) DMARD after at least one csDMARD failure. Fungal infections reported between 05/2001 and 12/2022 were considered opportunistic when meeting the consensus definitions by Winthrop et al.[2] or when causing esophagitis. Patients who had developed an OFI were matched 1:5 to RA controls by age and enrolment year. Associations between OFI development and patient characteristics at last visit prior to mycosis onset (see Table 1) were assessed using multivariable logistic regression, analysing sex, smoking history, disease duration, glucocorticoid (GC) use, disease activity (DAS28-ESR), sum of comorbidities predisposing for infection (malignancies, diabetes mellitus, kidney disease, lung disease, autoimmune disease, liver disease, blood count disorder), therapy with b/tsDMARDs, number of previous DMARDs, and type of enrolling institution. Multiple imputation of missing values was performed. Results Among 20,907 RA patients contributing 101,778 patient-years (PY) to RABBIT, 105 developed an OFI (1.03/1,000 PY), caused by Candida ssp. (60 %), Pneumocystis jirovecii (20 %), Aspergillus ssp. (7 %), and unknown fungal genus (13 %). Nineteen patients died from or with infection (18 % of all OFIs and 34 % of 56 invasive OFIs). Higher disease activity (OR 1.18, 95% CI: 1.01 – 1.37 per point of DAS28-ESR), a daily prednisolone-equivalent dose of > 5 mg (OR 2.11, 95% CI:1.16 – 3.82), smoking history among men (OR 2.69, 95% CI:1.58 – 4.59), a higher number of relevant comorbidities (OR 1.62, 95% CI: 1.29 – 2.03 per additional comorbidity), and type of enrolling institution (OR for clinic vs. practice: 1.39, 95% CI: 1.00 – 1.92) were associated with a higher odds of OFIs (see Figure 1). Conclusion Our study underlines the rarity of OFIs in RA patients, yet revealing a notable mortality. The development of OFIs was associated with higher disease activity, GC use > 5 mg per day, smoking history among men, and a higher number of relevant comorbidities. Further research is essential to investigate the risk profile by DMARD class, enhancing our understanding of potential causal relationships. • Download figure • Open in new tab • Download powerpoint • Download figure • Open in new tab • Download powerpoint REFERENCES [1] PMID: 27032792.[2] PMID: 26395500. Acknowledgements RABBIT is currently supported by a joint, unconditional grant from AbbVie, Amgen, BMS, Celltrion, Fresenius Kabi, Galapagos, Hexal, Lilly, MSD, Pfizer, Samsung Biogen, Sanofi, Biocon, UCB and previously by Roche. Disclosure of Interests Alina Purschke: None declared, Martin Schaefer: None declared, Bernhard Manger Abbvie, Alexion, Astra-Zeneca, EUSA, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Pharming, EUSA, Vifor, Matthias Schneider AstraZeneca, GSK, Pfizer, Abbvie, AstraZeneca, GSK, Otsuka, UCB, AstraZeneca, GSK, Martin Feuchtenberger Abbvie, Novartis, Rheumaakademie, Abbvie, Biogen, BMS, Boehringer, Lilly, MSD, Novartis, Pfizer, Charlotte Moebius UCB, Pfizer, Lilly, UCB, Pfizer, Lilly, Anja Strangfeld AbbVie, Biogen, Galapagos, Janssen, Lilly, Pfizer, Takeda.

Background Our previous studies demonstrated that S100A4 is overexpressed in scleroderma (SSc) skin, fibroblasts, and preclinical models of SSc. Inactivation of S100A4 prevented dermal fibrosis induced by bleomycin and in Tsk-1 mice. Inhibition of S100A4 by murine mAbs (6B12) prevented the progression and induced regression of established dermal fibrosis induced by bleomycin. Objectives The aim of this study was to assess the potential role of systemic S100A4 levels as a biomarker of SSc-related features and a predictor of treatment response and disease progression. Methods Systemic levels of S100A4 were measured by ELISA (CUSABIO, Houston, USA) in 104 age-/sex-matched healthy controls (HC) and four different cohorts: • 1) cross-sectional SSc patients (n=117; 67 lcSSc/50 dcSSc; mean age 55.8, disease duration 5.0 years); • 2) SSc patients with active interstitial lung disease (ILD) treated with 6 (n=24) or 12 (n=16) months of iv cyclophosphamide; • 3) SSc patients with progressive skin involvement and/or arthritis and/or ILD non-responsive to methotrexate/cyclophosphamide/mycophenolate treated with 2 (n=8) or 3 (n=16) 6-month cycles of rituximab; and • 4) VEDOSS (Very Early Diagnosis of SSc) patients with Raynaud´s phenomenon who did not progress (n=15) or progressed (n=11) to SSc. Data are presented as median (IQR). Results • 1) S100A4 was significantly increased in SSc (67.2(43.1-88.7) vs. 51.1(35.9-60.8)ng/mL in HC;p<0.0001), especially in SSc with ILD (72.7(49.1-95.2) vs. 54.7(37.5-77.1)ng/mL in SSc without ILD; p=0.0124) and borderline with gastrointestinal involvement (69.3(50.3-96.7) vs. 63.1 (38.9-84.4)ng/mL without gastrointestinal involvement;p=0.0854). S100A4 was associated with lung function tests and borderline with disease duration (Table 1). • 2) Treatment of active SSc-ILD with cyclophosphamide significantly decreased S100A4 over 6 months (76.3(52.9–98.6) vs. 73.2(44.4–98.6)ng/mL;p=0.013), whereas baseline S100A4 predicted the decrease in systemic inflammation (Table 1). • 3) Treatment of progressive SSc (non-responsive to csDMARDs) with rituximab significantly decreased S100A4 over 6 months (83.7(70.4-109.6) vs. 81.5(60.2-100.4)ng/mL;p=0.0455). Baseline S100A4 predicted an improvement in hand function, fatigue, depression, and borderline in soilage, whereas a change in S100A4 was associated with function, quality of life, fatigue, and physical activity (Table 1). • 4) Over an average of 3.5 years of follow-up in VEDOSS patients, S100A4 significantly decreased (p=0.0073) in non-progressors (13/15), whereas increased in 8/11 progressors (inter-group p=0.0429). S100A4 was associated with CRP and age in non-progressors and the titer of antinuclear antibodies in progressors (Table 1). Conclusion Systemic S100A4 levels are elevated in SSc (especially in ILD), decrease with cs/bDMARD treatment, and predict the treatment response and progression to early disease. REFERENCES NIL • Download figure • Open in new tab • Download powerpoint Acknowledgements Supported by MHCR023728. Disclosure of Interests None declared

Background I n patients with systemic sclerosis (SSc), pulmonary hypertension (PH) represents a major risk factor for morbidity and mortality. Treatment of patients with PH and interstitial lung disease (ILD) can be particularily challenging. Objectives Analysis of drug therapy for PH depending on the presence of ILD in patients with SSc included in the multicenter German DNSS registry. Comparison of disease parameters between PH patients with or without ILD. Methods Descriptive statistic analysis from the Red Cap database of the German DNSS registry for SSc patients. For the analysis of drug therapy, the subgroup of patients who did not have PH at baseline visit and developed it only during follow-up was analyzed. Comparison of disease parameters (worst during follow up) between PH patient with or without ILD with T-test for continous variables was performed. Results As of 01/16/2023, 6003 patients were included in the DNSS registry. 384 (11.6%of 3314 evaluable patients) developed PH during follow-up. 271 of the PH patients had concomitant interstitial lung disease (70.6%).Table 1 contains the baseline characteristics of these 384 patients. Only age differed significantly (by 4.70 years, p-value=0.001). In the PH with ILD group 57,6 % of patients already had ILD at first visit, the rest developed ILD during follow up. Average follow-up time was longer in the PH with ILD group. The proportion of evaluable patients who ever received a specific PAH drug was: • - For ERA (endothelin receptor antagonists) 51.4% for PH + ILD vs 30.9% for PH without ILD. • - For PDE5i (phosphodiesterase 5 inhibitors) 43.3% vs 29.9%, respectively Figure 1 shows the frequency of patients receiving monotherapy, dual therapy, triple therapy, and more intensive combination therapies ever comparing patients with and without ILD. PH patients without ILD were more likely to receive monotherapy, whereas patients with ILD were more likely to receive combination therapy. Comparing disease parameters (mean) between patients with or without ILD, patients with ILD had a significantly higher NT-pro-BNP (brain natriuretic peptide), a significantly higher uric acid, a numerically higher PAPsys and a significantly lower left ventricular ejection fraction on echocardiography, a significantly lower forced vital capacity (FVC, 70,6% vs 87,2%) and a significantly lower DLCO (diffusing capacity for carbon monoxide, 44,4% vs 56,9%). Thus, although ILD patients had significantly more severe restrictive lung disease, restrictive impairment was only mild to moderate in most ILD cases. Values for right heart catheter were available only in fewer patients (54 PH with ILD vs 23 PH without ILD), and PAP mean did not differ, while cardiac output was numerically lower in patients with ILD without reaching statistical significance. Conclusion In spite of current treatment recommendations, PH patients with ILD rather receive more intensive PH treatment under real world conditions, and they seem to have more severe pulmovascular disease. Further analysis are planned to evaluate impact of treatment on survival and change of treatment patterns over time. Table 1 • Download figure • Open in new tab • Download powerpoint • Download figure • Open in new tab • Download powerpoint Figure 1. REFERENCES NIL Acknowledgements NIL Disclosure of Interests Marc Schmalzing BMS, Novartis, Abbvie, AstraZeneca, Chugai/Roche, Janssen-Cilag, Gilead, Boeringer, Mylan, Onkowissen.de, Galapagos, EUSA-Pharma, Roche, Hexal/Sandoz, Gilead, AbbVie, Janssen, Boehringer, Onkowissen.de, EUSA Pharma, Novartis, AstraZeneca, Medac, Lilly, Galapagos, UCB, Chugai, Novartis, Pia Moinzadeh: None declared, Jithmi Weliwitage: None declared, Gabriela Riemekasten: None declared, Norbert Blank Boehringer, Janssen, BMS, EUSA, Novartis, Pfizer, Roche, Sanofi, SOBI, SOBI, Novartis, Jörg Henes Janssen, Chugai, GSK, Boehringer, Novartis, Ulf Müller-Ladner: None declared, Margitta Worm ALK, Arzneimittel GmbH, Milan, Mice GmbH, Viatris, Allergopharma, Aimmune Therapeutics, Novartis, Sanofi-Aventis, Genzyme Europe, Leo Pharma, DBV Technologies, Kymab, Lilly, Gernot Keyszer Abbvie, Astra Zeneca, Biogen, Boehringer, Chugai, Lilly, Novartis, Otsuka, Pfizer, Roche, Sanofi, UCB, Abbvie, Biogen, Boehringer, Lilly, Novartis, Roche, Sanofi, Aaron Juche: None declared, Alexander Kreuter: None declared, Jan Ehrchen Bristol Myers, Squibb, Boehringer, Sobi, Astra Zeneca, Biogen, Janssen, La Roche Posey, Mylan, Galderma, Novartis, Sobi, Boehringer, Laura Susok: None declared, Claudia Günther BI, Boehringer, GSK, Gabriele Zeidler Pfizer, Janssen, Amgen, Lilly, Bristol-Myers Squibb, Boehringer, Ilona Jandova Boehringer, Tim Schmeiser: None declared, Christiane Pfeiffer Actelion - Nurse Training about PH and DU, Actelion, Pfizer, Boehringer, Ina Kötter Boehringer, Amgen, GSK, Jörg Distler AbbVie, Active Biotech, ARXX, Astra Zeneca, Boehringer, Anamar, Bayer, Calliditas Therapeutics, Galapagos, Genentech, GSK, Inventiva, Janssen, Novartis, Pfizer, Roch and UCB, AbbVie, Active Biotech, ARXX, Astra Zeneca, Boehringer, Anamar, Bayer, Calliditas Therapeutics, Galapagos, Genentech, GSK, Inventiva, Janssen, Novartis, Pfizer, Roch and UCB, 4D Science, Scientific Lead of Fibro Cure, AbbVie, Active Biotech, ARXX, Astra Zeneca, Boehringer, Anamar, Bayer, Calliditas Therapeutics, Galapagos, Genentech, GSK, Inventiva, Janssen, Novartis, Pfizer, Roch and UCB, Anamar, ARXX, Argenx, BMS, Bayer, Boehringer Cantargia, Celgene, CSL Behring, Galapagos, GSK, Inventiva, Kiniksa, Lassen, Sanofi, RedX, UCB, Nicolas Hunzelmann Boehringer, Sanofi, Roche, Janssen, Boehringer.

Background: Due to continuous improvements in treatment, more and more severely and seriously injured patients are surviving. The complexity of the injury patterns of these patients means that they are difficult to map in routine data. Aim of the work: The aim of the data exploration was to identify ICD 10 diagnoses that show an association with an injury severity score (ISS) ≥ 16 and could therefore be used to operationalize severely injured patients in routine data. Material and methods: The coded four-digit ICD 10 S diagnoses and the calculated ISS of trauma patients from the Armed Forces Central Hospital Koblenz (BwZKrhs) and the University Hospital Düsseldorf (UKD) were analyzed using statistical association measures (phi and Cramer’s V), linear regressions and machine learning methods (e.g., random forest). Results: The S diagnoses of facial, head, thoracic and pelvic injuries, associated with an ISS ≥ 16 were identified. Some S diagnoses showed an association with an ISS ≥ 16 in only 1 of the 2 datasets. Likewise, facial, head, thoracic and pelvic injuries were found in the subgroup of 18–55-year-old patients. Discussion: The current evaluations show that it is possible to identify ICD 10 S-diagnoses that have a significant association with an ISS ≥ 16. According to the annual report of the trauma register of the German Society for Trauma Surgery (TR-DGU® ), injuries with an abbreviated injury scale (AIS) ≥ 3 are particularly common in the head and thoracic regions.

Germ cell tumors (GCT) are the most common solid tumors in young men of age 15 - 40. In previous studies, we profiled the interaction of GCT cells with cells of the tumor microenvironment (TM), which showed that especially the 3D interaction of fibroblasts (FB) or macrophages with GCT cells influenced the growth behavior and cisplatin response as well as the transcriptome and secretome of the tumor cells, suggesting that the crosstalk of these cells with GCT cells is crucial for tumor progression and therapy outcome. In this study, we shed light on the mechanisms of activation of cancer-associated fibroblasts (CAF) in the GCT setting and their effects on GCT cells lines and the monocyte cell line THP-1. Ex vivo cultures of GCT-derived CAF were established and characterized molecularly and epigenetically by performing DNA methylation arrays, RNA sequencing, and mass spectrometry-based secretome analysis. We demonstrated that the activation state of CAF is influenced by their former prevailing tumor environment in which they have resided. Hereby, we postulate that seminoma (SE) and embryonal carcinoma (EC) activate CAF, while teratoma (TER) play only a minor role in CAF formation. In turn, CAF influence proliferation and the expression of cisplatin sensitivity-related factors in GCT cells lines as well as polarization of in vitro-induced macrophages by the identified effector molecules IGFBP1, LGALS3BP, LYVE1, and PTX3. Our data suggests that the vital interaction of CAF with GCT cells and with macrophages has a huge influence on shaping the extracellular matrix as well as on recruitment of immune cells to the TM. In conclusion, therapeutically interfering with CAF and / or macrophages in addition to the standard therapy might slow-down progression of GCT and re-shaping of the TM to a tumor-promoting environment.

Background We were looking for an osteoporosis screening in computed tomography (CT) exams, simple and without additional examinations. We hypothesized that the criterion of “decreasing cortical thickness”, may have an influence on the hard palate. Therefore, we investigated whether thickness of the hard palate (HPT) may serve as an indicator of osteoporosis for patients imaged for other reasons. Methods Patients with dual-energy x-ray absorptiometry (DXA) and CT were identified by a radiology information system (RIS)-based, full-text search. Measurement of thickness of hard palate done in existing CT image by radiologist and dentist and compared with available findings and DXA measurements. Results We identified a “test group”: 57 patients with DXA and CT available out of 449 patient population and we selected further 70 patients without bone diseases as “control groups”. The measurements showed that HPT correlated with age and bone density. The mean HPT was 2.4 mm in normal, 0.9 mm in osteopenia, 0.8 mm in osteoporosis and 5.3 mm in osteopetrosis case. No bone “healthy” patient fell below 1 mm. The relationship between bone density and HPT has not been described previously. HPT was highest in the bone-healthy group and decreased with age, osteopenia, and osteoporosis. Osteopetrosis, as a disease with increased bone density showed an increase in HPT. Conclusions HPT correlates with bone disease. We propose a new criterion for assessment on CT and digital volume tomography (DVT) or cone beam computed tomography (CBCT). A threshold of 1.0 mm when applying a simple measurement of HPT on Head CT or DVT may serve as an indicator for potential osteopenia or osteoporosis as incidental finding without extra imaging further diagnosis and treatment leading to early notice of Osteoporosis.