TY - JOUR A1 - Ruf, Katharina A1 - Badran, Alaa A1 - Siauw, Céline A1 - Haubitz, Imme A1 - Schlegel, Paul-Gerhardt A1 - Hebestreit, Helge A1 - Härtel, Christoph A1 - Wiegering, Verena T1 - Does allogeneic stem cell transplantation in survivors of pediatric leukemia impact regular physical activity, pulmonary function, and exercise capacity? JF - Molecular and Cellular Pediatrics N2 - Background Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved survival in high-risk childhood leukemia but is associated with long-term sequelae such as impaired pulmonary function and reduced exercise capacity impacting quality of life. Methods A convenience sample of 17 patients after allo-HSCT (HSCT—12 male, age 15.7±6.7 years, time after HSCT 5.3±2.8 years) underwent pulmonary function testing, echocardiography, and an incremental exercise test on a bike. Physical activity and health-related quality of life were assessed by questionnaires (7-day physical activity recall, PEDS-QL). Seventeen healthy age- and gender-matched controls served as control group (CG) for results of pulmonary function and exercise testing. Results HSCT showed reduced pulmonary function (HSCT vs. CG: FEV1 90.5±14.0 vs. 108.0±8.7%pred; FVC 88.4±19.3 vs. 107.6±6.9%pred, DLCO 75.3±23.6 vs. 104.9±12.8%pred) and exercise capacity (VO2peak 89±30.8%pred, CG 98±17.5%pred; Wmax 84±21.7%pred, CG 115±22.8%pred), but no relevant cardiac dysfunction and a good quality of life (PEDS-QL mean overall score 83.3±10.7). Differences in peak oxygen uptake between groups were mostly explained by 5 adolescent patients who underwent total body irradiation for conditioning. They showed significantly reduced diffusion capacity and reduced peak oxygen uptake. Patients reported a mean time of inactivity of 777±159min/day, moderate activity of 110±107 min/day, hard activity of 35±36 min/day, and very hard activity of 23±22 min/day. A higher amount of inactivity was associated with a lower peak oxygen uptake (correlation coefficient tau −0.48, p=0.023). Conclusions This pilot study shows that although patients after allo-HSCT reported a good quality of life, regular physical activity and exercise capacity are reduced in survivors of stem cell transplantation, especially in adolescents who are treated with total body irradiation for conditioning. Factors hindering regular physical activity need to be identified and exercise counseling should be part of follow-up visits in these patients. KW - childhood leukemia KW - exercise tolerance KW - physical activity KW - pediatric stem cell transplantation KW - exercise testing Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265528 VL - 8 ER - TY - JOUR A1 - Diessner, Joachim A1 - Wischnewsky, Manfred A1 - Stüber, Tanja A1 - Stein, Roland A1 - Krockenberger, Mathias A1 - Häusler, Sebastian A1 - Janni, Wolfgang A1 - Kreienberg, Rolf A1 - Blettner, Maria A1 - Schwentner, Lukas A1 - Wöckel, Achim A1 - Bartmann, Catharina T1 - Evaluation of clinical parameters influencing the development of bone metastasis in breast cancer JF - BMC Cancer N2 - Background The development of metastases is a negative prognostic parameter for the clinical outcome of breast cancer. Bone constitutes the first site of distant metastases for many affected women. The purpose of this retrospective multicentre study was to evaluate if and how different variables such as primary tumour stage, biological and histological subtype, age at primary diagnosis, tumour size, the number of affected lymph nodes as well as grading influence the development of bone-only metastases. Methods This retrospective German multicentre study is based on the BRENDA collective and included 9625 patients with primary breast cancer recruited from 1992 to 2008. In this analysis, we investigated a subgroup of 226 patients with bone-only metastases. Association between bone-only relapse and clinico-pathological risk factors was assessed in multivariate models using the tree-building algorithms “exhausted CHAID (Chi-square Automatic Interaction Detectors)” and CART(Classification and Regression Tree), as well as radial basis function networks (RBF-net), feedforward multilayer perceptron networks (MLP) and logistic regression. Results Multivariate analysis demonstrated that breast cancer subtypes have the strongest influence on the development of bone-only metastases (χ2 = 28). 29.9 % of patients with luminal A or luminal B (ABC-patients) and 11.4 % with triple negative BC (TNBC) or HER2-overexpressing tumours had bone-only metastases (p < 0.001). Five different mathematical models confirmed this correlation. The second important risk factor is the age at primary diagnosis. Moreover, BC subcategories influence the overall survival from date of metastatic disease of patients with bone-only metastases. Patients with bone-only metastases and TNBC (p < 0.001; HR = 7.47 (95 % CI: 3.52–15.87) or HER2 overexpressing BC (p = 0.007; HR = 3.04 (95 % CI: 1.36–6.80) have the worst outcome compared to patients with luminal A or luminal B tumours and bone-only metastases. Conclusion The bottom line of different mathematical models is the prior importance of subcategories of breast cancer and the age at primary diagnosis for the appearance of osseous metastases. The primary tumour stage, histological subtype, tumour size, the number of affected lymph nodes, grading and NPI seem to have only a minor influence on the development of bone-only metastases. KW - BRENDA KW - breast cancer KW - bone metastases KW - skeleton KW - breast cancer subtypes Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-161173 VL - 16 IS - 307 ER - TY - JOUR A1 - Soares Machado, J. A1 - Tran-Gia, J. A1 - Schlögl, S. A1 - Buck, A. K. A1 - Lassmann, M. T1 - Biokinetics, dosimetry, and radiation risk in infants after \(^{99m}\)Tc-MAG3 scans JF - EJNMMI Research N2 - Background: Renal scans are among the most frequent exams performed on infants and toddlers. Due to the young age, this patient group can be classified as a high-risk group with a higher probability for developing stochastic radiation effects compared to adults. As there are only limited data on biokinetics and dosimetry in this patient group, the aim of this study was to reassess the dosimetry and the associated radiation risk for infants undergoing \(^{99m}\)Tc-MAG3 renal scans based on a retrospective analysis of existing patient data. Consecutive data were collected from 20 patients younger than 20 months (14 males; 6 females) with normal renal function undergoing \(^{99m}\)Tc-MAG3 scans. To estimate the patient-specific organ activity, a retrospective calibration was performed based on a set of two 3D-printed infant kidneys filled with known activities. Both phantoms were scanned at different positions along the anteroposterior axis inside a water phantom, providing depth- and size-dependent attenuation correction factors for planar imaging. Time-activity curves were determined by drawing kidney, bladder, and whole-body regions-of-interest for each patient, and subsequently applying the calibration factor for conversion of counts to activity. Patient-specific time-integrated activity coefficients were obtained by integrating the organ-specific time-activity curves. Absorbed and effective dose coefficients for each patient were assessed with OLINDA/EXM for the provided newborn and 1-year-old model. The risk estimation was performed individually for each of the 20 patients with the NCI Radiation Risk Assessment Tool. Results: The mean age of the patients was 7.0 ± 4.5 months, with a weight between 5 and 12 kg and a body size between 60 and 89 cm. The injected activities ranged from 12 to 24 MBq of \(^{99m}\)Tc-MAG3. The patients' organ-specific mean absorbed dose coefficients were 0.04 ± 0.03 mGy/MBq for the kidneys and 0.27 ± 0.24 mGy/MBq for the bladder. The mean effective dose coefficient was 0.02 ± 0.02 mSv/MBq. Based on the dosimetry results, an evaluation of the excess lifetime risk for the development of radiation-induced cancer showed that the group of newborns has a risk of 16.8 per 100,000 persons, which is about 12% higher in comparison with the 1-year-old group with 14.7 per 100,000 persons (all values are given as mean plus/minus one standard deviation except otherwise specified). Conclusion: In this study, we retrospectively derived new data on biokinetics and dosimetry for infants with normal kidney function after undergoing renal scans with \(^{99m}\)Tc-MAG3. In addition, we analyzed the associated age- and gender-specific excess lifetime risk due to ionizing radiation. The radiation-associated stochastic risk increases with the organ doses, taking age- and gender-specific influences into account. Overall, the lifetime radiation risk associated with the \(^{99m}\)Tc-MAG3 scans is very low in comparison to the general population risk for developing cancer. KW - \(^{99m}\)Tc-MAG3 KW - absorbed dose KW - biokinetics KW - dosimetry KW - pediatric patients KW - risk assessment Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175582 VL - 8 IS - 10 ER - TY - JOUR A1 - Lorenz, Delia A1 - Kress, Wolfram A1 - Zaum, Ann-Kathrin A1 - Speer, Christian P. A1 - Hebestreit, Helge T1 - Report of two siblings with spondylodysplastic Ehlers-Danlos syndrome and B4GALT7 deficiency JF - BMC Pediatrics N2 - Background The spondylodysplastic Ehlers-Danlos subtype (OMIM #130070) is a rare connective tissue disorder characterized by a combination of connective tissue symptoms, skeletal features and short stature. It is caused by variants in genes encoding for enzymes involved in the proteoglycan biosynthesis or for a zinc transporter. Presentation of cases We report two brothers with a similar phenotype of short stature, joint hypermobility, distinct craniofacial features, developmental delay and severe hypermetropia indicative for a spondylodysplastic Ehlers-Danlos subtype. One also suffered from a recurrent pneumothorax. Gene panel analysis identified two compound heterozygous variants in the B4GALT7 gene: c.641G > A and c.723 + 4A > G. B4GALT7 encodes for galactosyltransferase I, which is required for the initiation of glycosaminoglycan side chain synthesis of proteoglycans. Conclusions This is a first full report on two cases with spondylodysplastic Ehlers-Danlos syndrome and the c.723 + 4A > G variant of B4GALT7. The recurrent pneumothoraces observed in one case expand the variable phenotype of the syndrome. KW - connective tissue disorder KW - spondylodysplastic Ehlers-Danlos syndrome KW - B4GALT7 gene KW - case report Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-261084 VL - 21 ER - TY - JOUR A1 - Ruf, Katharina A1 - Wirbelauer, Johannes A1 - Beissert, Antje A1 - Frieauff, Eric T1 - Successful treatment of severe arterial hypotension and anuria in a preterm infant with renal tubular dysgenesis– a case report JF - Maternal Health, Neonatology and Perinatology N2 - Background: Oligohydramnios sequence can be caused by renal tubular dysgenesis (RTD), a rare condition resulting in pulmonary and renal morbidity. Besides typical features of Potter-sequence, the infants present with severe arterial hypotension and anuria as main symptoms. Establishing an adequate arterial blood pressure and sufficient renal perfusion is crucial for the survival of these infants. Case presentation: We describe a male preterm infant of 34 + 0 weeks of gestation. Prenatally oligohydramnios of unknown cause was detected. After uneventful delivery and good adaptation the infant developed respiratory distress due to a spontaneous right-sided pneumothorax and required thoracocentesis and placement of a chest tube; he showed no major respiratory concerns thereafter and needed only minimal ventilatory support. Echocardiography revealed no abnormalities, especially no pulmonary hypertension. However, he suffered from severe arterial hypotension and anuria refractory to catecholamine therapy (dobutamine, epinephrine and noradrenaline). After 36 h of life, vasopressin therapy was initiated resulting in an almost immediate stabilization of arterial blood pressure and subsequent onset of diuresis. Therapy with vasopressin was necessary for three weeks to maintain adequate arterial blood pressure levels and diuresis. Sepsis and adrenal insufficiency were ruled out as inflammation markers, microbiological tests and cortisol level were normal. At two weeks of age, our patient developed electrolyte disturbances which were successfully treated with fludrocortisone. He did not need renal replacement therapy. Genetic analyses revealed a novel compound hyterozygous mutation of RTD. Now 17 months of age, the patient is in clinically stable condition with treatment of fludrocortisone and sodium bicarbonate. He suffers from stage 2 chronic kidney disease; blood pressure, motor and cognitive development are normal. Conclusions: RTD is a rare cause of oligohydramnios sequence. Next to pulmonary hypoplasia, severe arterial hypotension is responsible for poor survival. We present the only second surviving infant with RTD, who did not require renal replacement therapy during the neonatal period. It can be speculated whether the use of vasopressin prevents renal replacement therapy as vasopressin increases urinary output by improving renal blood flow. KW - potter sequence KW - oligohydramnios sequence KW - renal tubular dysgenesis KW - arterial hypotension KW - vasopressin KW - respiratory distress KW - anuria KW - preterm KW - dry lung syndrome KW - neonatal renal failure Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-177405 VL - 4 IS - 27 ER - TY - JOUR A1 - Girschick, Hermann A1 - Wolf, Christine A1 - Morbach, Henner A1 - Hertzberg, Christoph A1 - Lee-Kirsch, Min Ae T1 - Severe immune dysregulation with neurological impairment and minor bone changes in a child with spondyloenchondrodysplasia due to two novel mutations in the ACP5 gene JF - Pediatric Rheumatology N2 - Spondyloenchondrodysplasia (SPENCD) is a rare skeletal dysplasia, characterized by metaphyseal lesions, neurological impairment and immune dysregulation associated with lupus-like features. SPENCD is caused by biallelic mutations in the ACP5 gene encoding tartrate-resistant phosphatase. We report on a child, who presented with spasticity, multisystem inflammation, autoimmunity and immunodeficiency with minimal metaphyseal changes due to compound heterozygosity for two novel ACP5 mutations. These findings extend the phenotypic spectrum of SPENCD and indicate that ACP5 mutations can cause severe immune dysregulation and neurological impairment even in the absence of metaphyseal dysplasia. KW - resistant acid phosphatase KW - expression KW - systemic lupus erythematosus KW - cerebral calcification KW - deficiency KW - autoimmunity KW - dysplasia KW - trap KW - spondyloenchondrodysplasia KW - ACP5 KW - immunodeficiency KW - type I interferonopathy Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149990 VL - 13 IS - 37 ER - TY - JOUR A1 - Goettler, David A1 - Niekler, Patricia A1 - Liese, Johannes G. A1 - Streng, Andrea T1 - Epidemiology and direct healthcare costs of Influenza-associated hospitalizations - nationwide inpatient data (Germany 2010-2019) JF - BMC Public Health N2 - Introduction Detailed and up-to-date data on the epidemiology and healthcare costs of Influenza are fundamental for public health decision-making. We analyzed inpatient data on Influenza-associated hospitalizations (IAH), selected complications and risk factors, and their related direct costs for Germany during ten consecutive years. Methods We conducted a retrospective cost-of-illness study on patients with laboratory-confirmed IAH (ICD-10-GM code J09/J10 as primary diagnosis) by ICD-10-GM-based remote data query using the Hospital Statistics database of the German Federal Statistical Office. Clinical data and associated direct costs of hospital treatment are presented stratified by demographic and clinical variables. Results Between January 2010 to December 2019, 156,097 persons were hospitalized due to laboratory-confirmed Influenza (J09/J10 primary diagnosis). The annual cumulative incidence was low in 2010, 2012 and 2014 (1.3 to 3.1 hospitalizations per 100,000 persons) and high in 2013 and 2015-2019 (12.6 to 60.3). Overall direct per patient hospitalization costs were mean (SD) 3521 EUR (± 8896) and median (IQR) 1805 EUR (1502; 2694), with the highest mean costs in 2010 (mean 8965 EUR ± 26,538) and the lowest costs in 2012 (mean 2588 EUR ± 6153). Mean costs were highest in 60-69 year olds, and in 50-59, 70-79 and 40-49 year olds; they were lowest in 10-19 year olds. Increased costs were associated with conditions such as diabetes (frequency 15.0%; 3.45-fold increase compared to those without diabetes), adiposity (3.3%; 2.09-fold increase) or immune disorders (5.6%; 1.88-fold increase) and with Influenza-associated complications such as Influenza pneumonia (24.3%; 1.95-fold), bacterial pneumonia (6.3%; 3.86-fold), ARDS (1.2%; 10.90-fold increase) or sepsis (2.3%; 8.30-fold). Estimated overall costs reported for the 10-year period were 549.6 Million euros (95% CI 542.7-556.4 million euros). Conclusion We found that the economic burden of IAH in Germany is substantial, even when considering solely laboratory-confirmed IAH reported as primary diagnosis. The highest costs were found in the elderly, patients with certain underlying risk factors and patients who required advanced life support treatment, and median and mean costs showed considerable variations between single years. Furthermore, there was a relevant burden of disease in middle-aged adults, who are not covered by the current vaccination recommendations in Germany. KW - burden KW - influenza KW - epidemiology KW - healthcare costs KW - hospitalization KW - ICD-10 KW - Germany Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265888 VL - 22 ER - TY - JOUR A1 - Wiegering, Verena A1 - Riedmeier, Maria A1 - Thompson, Lester D. R. A1 - Virgone, Calogero A1 - Redlich, Antje A1 - Kuhlen, Michaela A1 - Gultekin, Melis A1 - Yalcin, Bilgehan A1 - Decarolis, Boris A1 - Härtel, Christoph A1 - Schlegel, Paul-Gerhardt A1 - Fassnacht, Martin A1 - Timmermann, Beate T1 - Radiotherapy for pediatric adrenocortical carcinoma - Review of the literature JF - Clinical and Translational Radiation Oncology N2 - 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. KW - pediatric adrenocortical cancer KW - pediatric adrenocortical carcinoma KW - pediatric adrenocortical tumor KW - radiotherapy KW - therapy KW - treatment Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300472 VL - 35 ER - TY - JOUR A1 - Fischer, Julia A1 - Knop, Stefan A1 - Danhof, Sophia A1 - Einsele, Hermann A1 - Keller, Daniela A1 - Löffler, Claudia T1 - The influence of baseline characteristics, treatment and depression on health-related quality of life in patients with multiple myeloma: a prospective observational study JF - BMC Cancer N2 - Background Multiple myeloma (MM) is the third most common hematologic malignancy with increasing importance due to improving treatment strategies and long-term outcomes in an aging population. This study aims to analyse influencing factors on health-related quality of life (HRQoL), such as treatment strategies, participation in a clinical trial and patient characteristics like anxiety, depression, gender, and age. A better understanding of the individual factors in context with HRQoL could provide a helpful instrument for clinical decisions. Methods In this prospective observational study, the HRQoL of MM patients with different therapies (first-line and relapse) was quantified by standardized questionnaires (EORTC QLQ-C30 and -MY20) in the context of sociodemographic data, individual anxiety and depressiveness (PHQ-4), and a selected number of clinical parameters and symptoms at defined time-points before, during, and after therapy. Results In total, 70 patients were included in the study. The median age of the study cohort was 62 years. 44% were female and 56% were male patients. More than half of the patients were fully active with an ECOG 0. Global health status was significantly higher in patients with first-line treatment and even increased after start of therapy, while the pain level decreased. In contrast, patients with relapsed MM reported a decreasing global health status and increasing pain. Additionally, there was a higher global health status in less anxious/depressive patients. HRQoL decreased significantly after start of chemotherapy in the parameters body image, side effects of treatment, and cognitive functioning. Tandem stem-cell transplantation was not found to be a risk factor for higher impairment of HRQoL. Participation in a clinical study led to an improvement of most aspects of HRQoL. Among others, increased anxiety and depression, female gender, older age, impaired performance status, and recurrent disease can be early indicators for a reduced HRQoL. Conclusion This study showed the importance of regular longitudinal assessments of patient reported outcomes (PROs) in routine clinical care. For the first time, to our knowledge, we were able to demonstrate a potential impact between participation in clinical trials and HRQoL. However, due to frequently restrictive inclusion criteria for clinical trials, these MM patients might not be directly comparable with patients treated within standard therapy concepts. Further studies are needed to clarify the relevance of this preliminary data in order to develop an individualized, patient-centred, therapy concept. KW - multiple myeloma KW - quality of life KW - participation in clinical trials KW - depression KW - observational Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300435 VL - 22 ER - TY - THES A1 - Gruber, Lina T1 - Evaluation der psychischen Belastung bei Patientinnen mit Dysplasien der Zervix uteri abhängig von Informationsbeschaffung, Bildung und Alter T1 - Evaluation of the psychological distress in patients with dysplasia of the cervix uteri depending on information gathering, education and age N2 - Ziel dieser Arbeit war es, die psychische Belastung bei Patientinnen mit auffälligen PAP-Abstrichen oder dysplastischen Veränderungen der Zervix uteri im Rahmen der Dysplasie-Sprechstunde zu erheben. Durch Auswertung und Analyse der Daten im Rahmen des Qualitätsmanagements sollte eine Grundlage für eine verbesserte und angepasste Versorgung geschaffen werden. In dem erhobenen Fragebogen waren vier Fragen von besonderer Bedeutung - die Informationslage bei Vorstellung, die Art der Informationsbeschaffung, der mögliche Wunsch nach mehr Information und der Bildungsstand. In der Auswertung des ausgeteilten Fragebogens konnte erhoben werden, dass 56,9% der Patientinnen bei der Erstvorstellung psychisch belastet waren. Das ist ein großer Anteil in Anbetracht der Tatsache, dass das PAP-Screening eine jährliche Vorsorgeuntersuchung für über 15 Millionen Frauen darstellt [19]. Der Großteil der in der Dysplasie-Sprechstunde erhobenen PAP-Abstriche waren auffällig und somit weiter abklärungsbedürftig. Über 70% der HPV-Tests waren „high risk“ positiv. Der Mittelwert der Verteilung des Alters lag bei 44 Jahren, was bedeutet, dass viele junge Frauen mit potenziell bestehendem Kinderwunsch oder jungen Familien betroffen sind. Die jungen Frauen sind durchschnittlich besser gebildet und psychisch belasteter als die Kohorte der älteren Patientinnen. Ein Blick auf die Verteilung der Bildung zeigt, dass bei Betrachtung der gesamten Kohorte, schlechter gebildete Frauen verunsicherter sind. Viele der Patientinnen, 40,9%, fühlten sich vor der Erstvorstellung nicht ausreichend informiert und mehr als 53,8% der Patientinnen hätten sich mehr Informationen gewünscht. Sieht man sich die Antworten auf die Frage nach der Quelle der Informationsbeschaffung an, fällt auf, dass mit 68,5% weiterhin der/die betreuende Arzt/Ärztin die wichtigste Informationsquelle darstellt. Zusammenfassend lässt sich sagen, dass trotz des 2020 deutschlandweit begonnenen organisierten Screenings die betroffenen Frauen anhaltend belastet sind und sich mehr Informationen wünschen. Ein wichtiger Schritt zur Vorbeugung psychischer Belastung wäre eine verbesserte Vermittlung von Information seitens der behandelnden Ärzte/Ärztinnen, auch unter Hinweis auf die online zur Verfügung stehenden Informationen des Bundesministeriums für Gesundheit. N2 - The aim of this work was to assess the psychological stress of patients with conspicuous PAP smears or dysplastic changes of the cervical uteri during the consultation in the “Dysplasie-Sprechstunde”. By evaluating and analyzing the data within the framework of quality management, a basis for improved and adapted care should be created. In the questionnaire four questions were of particular importance - the information situation at the time of presentation, the way in which information was obtained, the possible desire for more information and the level of education. In the evaluation of the distributed questionnaire it could be found that 56.9% of the patients were psychologically stressed at the first presentation. This is a large proportion considering that PAP screening is an annual screening for over 15 million women [19]. The majority of the PAP smears taken during the dysplasia consultation were conspicuous and therefore in need of further clarification. Over 70% of HPV tests were "high risk" positive. The mean distribution of the age was 44 years, which means that many young women with a potential desire to have children or young families are affected. On average, the young women are better educated and more psychologically stressed than the cohort of older patients. A look at the distribution of education shows that if you look at the whole cohort, less educated women are more insecure. Many of the patients, 40.9%, did not feel sufficiently informed before the first presentation and more than 53.8% of the patients would have liked more information. If one looks at the answers to the question about the source of information, it is striking that with 68.5% the attending physician continues to be the most important source of information. In summary, it can be said that despite the organized screening that began throughout Germany in 2020, the affected women are still burdened and would like more information. An important step towards the prevention of psychological stress would be an improved communication of information on the part of the treating physicians, also with reference to the information available online from the Federal Ministry of Health. KW - psychische Belastung KW - PAP-Abstrich KW - Pap-Test Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-303796 ER - TY - THES A1 - Palm, Nicole T1 - Sensitivität von benignen und malignen Zellen gegenüber dem mitochondrialen Entkoppler 2,4-Dinitrophenol, gemessen mittels Mikrokalorimetrie und LDH-Aktivität T1 - Sensitivity of benign and malignant cells to the mitochondrial uncoupler 2,4-dinitrophenol measured by microcalorimetry and LDH activity N2 - Die mitochondriale Entkopplung ist ein effektiver Weg, um die Thermogenese und basale metabolische Rate einer Zelle anzuheben. Im Versuchsaufbau mit malignen Zellen führte dies zu einer Apoptose. 2,4-DNP als spezifischer Entkoppler der Atmungskette zeigte in diesem Zusammenhang mittels LDH-Analysen an HACAT-, PA1-, BT20 und MDA-MB 231- Zellen eine dosisabhängige Wirkung auf die Zellproliferation in allen verwendeten Zelllinien, unter den verwendeten Tumorzellen am eindrucksvollsten bei den Ovarialkarzinom Zellen. Allen Zellarten gemeinsam war dabei eine Wachstumshemmung abhängig von der Länge der Inkubationszeit. Die mikrokalorimetrischen Analysen wurden an HACAT-, BT20- und MDA-MB 231- Zellen durchgeführt. Eine höhere 2,4-DNP-Konzentration führte dabei ebenfalls zu einer gesteigerten Wärmefreisetzung, wobei eine positive Korrelation zwischen Einwirkdauer und Wärmefreisetzung bestand. Eine signifikante Zytotoxizität ließ sich bei hohen DNP-Konzentrationen und bei langer Inkubationszeit in den PA1- und MDA-MB 231- Zelllinien nachweisen. MDA-MB 231- Zellen reagierten dabei besonders sensibel. In der aktuellen Tumortherapie bietet die Kombination von Alterationen der mitochondrialen und glykolytischen Abläufen neben den gängigen Behandlungsoptionen einen vielversprechenden Therapieansatz (8, 28). Durch den Einsatz von mitochondrialen Entkopplern als Ergänzung zu den herkömmlichen Therapieschemata könnte effektiv in den metabolischen Stoffwechsel der Zellen eingegriffen und neben der Tumorzellproliferation auch die Regression positiv beeinflusst werden. Das Ziel wäre, eine kontrollierte Apoptose bei möglichst wenigen systemischen Nebenwirkungen auszulösen. Hierzu werden im Rahmen der optimalen Dosisfindung für den Einsatz von 2,4-DNP jedoch weitere Versuchsansätze mit Inkubationszeiten von mindestens 48h benötigt. N2 - Mitochondrial uncoupling is an effective way to raise the thermogenesis and basal metabolic rate of a cell. In the experimental setup with malignant cells, this led to apoptosis. In this context 2,4-DNP as a specific uncoupler of the respiratory chain showed a dose-dependent effect on cell proliferation in all cell lines used by means of LDH analyses on HACAT, PA1, BT20 and MDA-MB 231 cells. Among the used tumor cells this effect was most impressively documented in ovarian carcinoma cells. Common to all cell types was a growth inhibition dependent on the length of the incubation period. Microcalorimetric analyses were performed on HACAT, BT20, and MDA-MB 231 cells. A higher 2,4-DNP concentration also resulted in increased heat release, with a positive correlation between exposure time and heat release. Significant cytotoxicity was detected at high DNP concentrations and with long incubation times in the PA1 and MDA-MB 231 cell lines. MDA-MB 231 cells reacted particularly sensitively. In current tumor therapy, the combination of alterations of mitochondrial and glycolytic pathways offers a promising therapeutic approach in addition to current treatment options (8, 28). The use of mitochondrial uncouplers as an adjunct to conventional therapeutic regimens could effectively interfere with cell metabolism and positively influence regression in addition to tumor cell proliferation. The goal would be to induce controlled apoptosis with as few systemic side effects as possible. For this, however, further experimental approaches with incubation times of at least 48h are needed in the context of optimal dose finding for the use of 2,4-DNP. KW - Dinitrophenol <2,4-> KW - Hyperthermie KW - Oxidative Phosphorylierung KW - Entkoppler KW - 2,4 DNP KW - Mammacarzinom KW - Dinitrophenole KW - Atmungskette KW - Brustkrebs KW - DNP Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-330089 ER - TY - THES A1 - Sevgin, Semanur T1 - Inadäquate Sinustachykardie: Kardiovaskuläre Risikostratifizierung und Therapiekontrolle mittels Langzeit-EKG Daten von Jugendlichen T1 - Diagnosis and management of an inappropriate sinus tachycardia in adolescence based upon a Holter ECG: A retrospective analysis of 479 patients N2 - Inappropriate sinus tachycardia (IST) is a common disease of the autonomic nervous system in children and adults. Diagnosis and treatment of IST in adolescents is not well defined. In this retrospective study, we tested our hypothesis regarding autonomic dysfunction in childhood by analyzing 24-h heart rate variability (HRV) in 479 children, with a mean age of 13.7 ± 2.1 years, who were referred to the outpatient clinic in the Pediatrics Department within the last 15 years. Seventy-four adolescents with a mean 24-h heart rate ≥ 95 bpm (our cut-off for an IST based upon 66 healthy controls) were deemed to have IST. We found the risk of IST to be high in adolescents with attention deficit disorder (OR = 3.5,p<0.001), pre-hypertension (OR = 2.5, p = 0.043) and hypertension (OR = 2.1,p = 0.02); insignificantly enhanced in children with short stature (OR = 1.9,p = 0.19), surgically-treated congenital heart disease (OR = 1.4,p = 0.51) and obesity without hypertension (OR = 1.4;p = 0.25); and negligible in adolescents with anorexia nervosa (OR = 0.3, p = 0.26) and constitutional thinness (OR = 0.9,p = 0.89). IST was associated with a significant decrease in global HRV and elevated blood pressures, indicating an enhanced cardiovascular risk. Methylphenidate did not increase 24-h heart rates, whereas omega-3 fatty acid supplementation significantly decreased elevated heart rates and increased HRV in adolescents with IST. In this retrospective analysis, 15.4% of adolescents suffered from IST with a 24-h heart rate ≥ 95 bpm, predominately due to attention deficit disorder and hypertension. N2 - Die Inadäquate Sinustachykardie (IST) ist eine häufige Erkrankung des autonomen Nervensystems bei Kindern und Erwachsenen. Die Diagnose und Therapie einer IST bei Jugendlichen ist bisher nicht genau definiert. In dieser retrospektiven Studie haben wir unsere Hypothese bezüglich autonomer Dysfunktion im Kindesalter durch die Analyse von 24-h Herzfrequenzvariabilität (HRV) bei 479 Kindern mit einem Durchschnittsalter von 13,7 ± 2,1 Jahren, die innerhalb der letzten 15 Jahre an die pädiatrische Ambulanz überwiesen wurden, untersucht. 74 Jugendliche hatten eine mittlere Herzfrequenz ≥95/min (Cut-off Werte für eine IST basieren auf der gesunden Kontrollgruppe) und hatten damit eine IST. Wir stellten fest, dass das Risiko einer IST bei Jugendlichen mit einer Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung (ADHS) (OR = 3,5, p < 0,001), Prä-Hypertonie (OR = 2,5, p = 0,043) und Hypertonie (OR = 2,1, p = 0,02) hoch ist; nicht signifikant erhöht bei Kindern mit Kleinwuchs (OR = 1,9, p = 0,19), chirurgisch behandelte angeborene Herzkrankheit (OR = 1,4). ,p = 0,51) und Adipositas ohne Bluthochdruck (OR = 1,4; p = 0,25); und unbedeutsam bei Jugendlichen mit Anorexia nervosa (OR = 0,3, p = 0,26) und konstitutioneller Dünnheit (OR = 0,9, p = 0,89). Eine IST war mit signifikant reduzierten HRV-Werten und erhöhten Blutdrücken assoziiert, was auf ein erhöhtes kardiovaskuläres Risiko hindeutet. In dieser retrospektiven Analyse litten 15,4 % der Jugendlichen an einer IST mit einer 24h HF ≥ 95 bpm hauptsächlich aufgrund einer ADHS und Hypertonie. KW - HRV KW - Omega-3-Fettsäuren KW - Kinder KW - Herzfrequenzvariabilität KW - Herzfrequenz KW - Kind KW - IST Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-330148 ER - TY - JOUR A1 - Diessner, Joachim A1 - Anders, Laura A1 - Herbert, Saskia A1 - Kiesel, Matthias A1 - Bley, Thorsten A1 - Schlaiss, Tanja A1 - Sauer, Stephanie A1 - Wöckel, Achim A1 - Bartmann, Catharina T1 - Evaluation of different imaging modalities for axillary lymph node staging in breast cancer patients to provide a personalized and optimized therapy algorithm JF - Journal of Cancer Research and Clinical Oncology N2 - Purpose The reliable detection of tumor-infiltrated axillary lymph nodes for breast cancer [BC] patients plays a decisive role in further therapy. We aimed to find out whether cross-sectional imaging techniques could improve sensitivity for pretherapeutic axillary staging in nodal-positive BC patients compared to conventional imaging such as mammography and sonography. Methods Data for breast cancer patients with tumor-infiltrated axillary lymph nodes having received surgery between 2014 and 2020 were included in this study. All examinations (sonography, mammography, computed tomography [CT] and magnetic resonance imaging [MRI]) were interpreted by board-certified specialists in radiology. The sensitivity of different imaging modalities was calculated, and binary logistic regression analyses were performed to detect variables influencing the detection of positive lymph nodes. Results All included 382 breast cancer patients had received conventional imaging, while 52.61% of the patients had received cross-sectional imaging. The sensitivity of the combination of all imaging modalities was 68.89%. The combination of MRI and CT showed 63.83% and the combination of sonography and mammography showed 36.11% sensitivity. Conclusion We could demonstrate that cross-sectional imaging can improve the sensitivity of the detection of tumor-infiltrated axillary lymph nodes in breast cancer patients. Only the safe detection of these lymph nodes at the time of diagnosis enables the evaluation of the response to neoadjuvant therapy, thereby allowing access to prognosis and improving new post-neoadjuvant therapies. KW - breast cancer imaging KW - positive nodal status KW - cross-sectional imaging KW - conventional imaging KW - post-neoadjuvant therapies KW - neoadjuvant therapies Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324047 VL - 149 IS - 7 ER - TY - JOUR A1 - Löb, Sanja A1 - Linsmeier, Eva A1 - Herbert, Saskia-Laureen A1 - Schlaiß, Tanja A1 - Kiesel, Matthias A1 - Wischhusen, Jörg A1 - Salmen, Jessica A1 - Kranke, Peter A1 - Quenzer, Anne A1 - Kurz, Florian A1 - Weiss, Claire A1 - Gerhard-Hartmann, Elena A1 - Wöckel, Achim A1 - Diessner, Joachim T1 - Prognostic effect of HER2 evolution from primary breast cancer to breast cancer metastases JF - Journal of Cancer Research and Clinical Oncology N2 - Purpose Therapeutic options for breast cancer (BC) treatment are constantly evolving. The Human Epidermal Growth Factor 2 (HER2)-low BC entity is a new subgroup, representing about 55% of all BC patients. New antibody–drug conjugates demonstrated promising results for this BC subgroup. Currently, there is limited information about the conversion of HER2 subtypes between primary tumor and recurrent disease. Methods This retrospective study included women with BC at the University Medical Centre Wuerzburg from 1998 to 2021. Data were retrieved from patients' records. HER2 evolution from primary diagnosis to the first relapse and the development of secondary metastases was investigated. Results In the HR-positive subgroup without HER2 overexpression, HER2-low expression in primary BC was 56.7 vs. 14.6% in the triple-negative subgroup (p < 0.000). In the cohort of the first relapse, HER2-low represented 64.1% of HR-positive vs. 48.2% of the triple-negative cohort (p = 0.03). In patients with secondary metastases, HER2-low was 75.6% vs. 50% in the triple negative subgroup (p = 0.10). The subgroup of HER2-positive breast cancer patients numerically increased in the course of disease; the HER2-negative overall cohort decreased. A loss of HER2 expression from primary BC to the first relapse correlated with a better OS (p = 0.018). No clinicopathological or therapeutic features could be identified as potential risk factors for HER2 conversion. Conclusion HER2 expression is rising during the progression of BC disease. In view of upcoming therapeutical options, the re-analysis of newly developed metastasis will become increasingly important. KW - breast cancer KW - HER2 conversion KW - HER2-low KW - trastuzumab deruxtecan KW - HER2 targeted therapy KW - trastuzumab Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324068 VL - 149 IS - 8 ER - TY - JOUR A1 - Herbert, Saskia-Laureen A1 - Hirzle, Paula A1 - Bartmann, Catharina A1 - Schlaiß, Tanja A1 - Kiesel, Matthias A1 - Curtaz, Carolin A1 - Löb, Sanja A1 - Wöckel, Achim A1 - Diessner, Joachim T1 - Optimized process quality in certified breast centers through adherence to stringent diagnostic and therapeutic algorithms effects of structural as well as socio-demographic factors on start of therapy JF - Archives of Gynecology and Obstetrics N2 - Purpose An increasing incidence of breast cancer can be observed worldwide. Since a delay of therapy can have a negative impact on prognosis, timely cancer care is an important quality indicator. By receiving treatment at a certified breast cancer center, the patient has the best chance of treatment in accordance with guidelines and the best prognosis. The identification of risk factors for a delay of therapy is of central importance and should be the basis for a continuous optimization of treatment at breast cancer centers. Methods This retrospective study included women with breast cancer (primary diagnosis, relapse, or secondary malignancy) at the University Hospital Würzburg in 2019 and 2020. Data were retrieved from patients’ records. Correlations and regression analyses were performed to detect potential risk factors for treatment delay. Results Patients who received the histological confirmation of breast cancer at an external institution experienced a later therapy start than those patients who received the histological confirmation at the University Hospital Würzburg itself. (35.7 vs. 32.2 days). The interval between histological confirmation and the first consultation at the University Hospital Würzburg correlated statistically significant with age, distress and distance to the hospital. Conclusion Patients with an in-house diagnosis of breast cancer are treated more quickly than those whose diagnosis was confirmed in an external institution. We identified factors such as increased age, greater distance to the hospital as well as increased distress to prolong the time until start of oncological treatment. Intensified patient care should be offered to these subgroups. KW - breast cancer KW - delay of therapy KW - prognosis KW - quality of care Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324057 VL - 307 IS - 4 ER - TY - THES A1 - Linsmeier, Eva Marie T1 - Untersuchung der HER2-Konversion vom primären zum fernmetastasierten Mammakarzinom T1 - Analysis of HER2 Conversion from Primary to Distant Metastatic Breast Cancer N2 - In der vorliegenden Arbeit wurden retrospektiv Daten von 321 Fällen eines fortgeschrit- tenen Mammakarzinoms ausgewertet. Beobachtungsdaten lagen bis einschließlich Juli 1998 vor. Ein Fokus dieser Arbeit lag auf der Trichotomie der HER2-Ausprägung und deren prognostischen Wert im Verlauf einer metastasierten Brustkrebserkrankung. In einer neueren Entwicklung wurde HER2-low als Nomenklatur einer Subgruppe etabliert für jene Mammakarzinome, die als IHC 1+ oder IHC 2+ gelten und ein negatives ISH- Ergebnis aufweisen. Neue Studien-Ergebnisse zeigten einen signifikanten klinischen Vorteil der Therapie mit HER2-basierten Antikörper-Wirkstoff-Konjugaten für HER2-low Patientinnen (91). Der Anteil der HER2-low Mammakarzinome nahm im Laufe einer fortgeschrittenen Brustkrebserkrankung kontinuierlich zu und lag bei 39,3 % im Primärtumor, bei 47,7 % im ersten Rezidiv und bei 47,8 % in einer zweiten Fernmetastase. Parallel vergrößerte sich die HER2-positive Subgruppe, wobei sich die HER2-negative Kohorte folglich ver- kleinerte. Es konnte entsprechend der aktuellen Literatur (117,156) eine Assoziation (p < 0.001) des HER2-low Subtypen und HR-positiven Mammakarzinomen gezeigt werden. HER2-low nahm in HR-positiven/Her2-negativen Mammakarzinomen im Laufe der Me- tastasierung zu (56,7 % - 64,1 % - 75,6 %). Der Anteil der HER2-low-Expression im Triple-negativen Subtypen initial bei 14,6 % und vergrößerte sich konstant (48,2 % - 50 %). Ein Verlust der HER2-Ausprägung im Krankheitsverlauf korrelierte statistisch signi- fikant mit einem besseren OS (Hazards Ratio 0,533, 95%-KI[0,316, 0,898], p = .018). Die Gruppe mit einer HER2-Konversion zu einer schwächeren Ausprägung wies im di- rekten Vergleich zur Gruppe mit einer Her2-Konversion zu einer stärkeren Ausprägung ein 21,0 Monate längeres Überleben auf (p = 0.177). Die Entwicklung eines HER2-posi- tiven Primärtumor zu einer HER2-low Metastase (Hazards Ratio 0,385, 95%-KI[0,17, 0.874], p = .023), eine Veränderung von einem HER2-0 Primärtumor zu einer HER2-low Metastase (Hazards Ratio 0,124, 95%-KI[0,023, 0,655], p = .014) sowie die ausblei- bende Veränderung eines HER2-low Primärtumor zu einer Fernmetastase (Hazards Ra- tio 0,169, 95%-KI[0,035, 0,813], p = .027) wurden in dieser Analyse als weitere protektive Faktoren nachgewiesen. Kein klinisch-pathologischer oder therapeutischer Faktor konnte als signifikanter Einflussfaktor auf eine Konversion im HER2-Rezeptor identifi- ziert werden. Die Ergebnisse dieser Arbeit lassen keine klare Aussage darüber treffen, ob die Anpassung der tumorspezifischen Therapie nach einer Rezeptorkonversion das OS verbessert. N2 - In the present study, data from 321 cases of advanced breast carcinoma were retrospectively analyzed. Observational data were available up to July 1998. A focal point of this study was the trichotomy of HER2 expression and its prognostic value in the course of metastatic breast cancer. In a recent development, HER2-low was established as nomenclature for a subgroup of breast carcinomas defined as IHC 1+ or IHC 2+ with a negative ISH result. New study findings indicated a significant clinical advantage of therapy using HER2-based antibody-drug conjugates for HER2-low patients (91). The proportion of HER2-low breast carcinomas steadily increased during advanced breast cancer, reaching 39.3% in the primary tumor, 47.7% in the first recurrence, and 47.8% in a second distant metastasis. Concurrently, the HER2-positive subgroup expanded, leading to a reduction in the HER2-negative cohort. Consistent with current literature (117,156), an association (p < 0.001) between the HER2-low subtype and HR-positive breast carcinomas was demonstrated. HER2-low prevalence increased during metastasis in HR-positive/HER2-negative breast carcinomas (56.7% - 64.1% - 75.6%). The proportion of HER2-low expression in the triple-negative subtype initially stood at 14.6% and steadily increased (48.2% - 50%). A loss of HER2 expression during the course of the disease significantly correlated with improved overall survival (Hazard Ratio 0.533, 95% CI [0.316, 0.898], p = .018). The group with a conversion to a weaker HER2 expression had a 21.0 months longer survival compared to the group with a conversion to a stronger expression (p = 0.177). The transition from a HER2-positive primary tumor to a HER2-low metastasis (Hazard Ratio 0.385, 95% CI [0.17, 0.874], p = .023), a change from a HER2-0 primary tumor to a HER2-low metastasis (Hazard Ratio 0.124, 95% CI [0.023, 0.655], p = .014), and the absence of transition from a HER2-low primary tumor to a distant metastasis (Hazard Ratio 0.169, 95% CI [0.035, 0.813], p = .027) were identified as additional protective factors in this analysis. No clinical-pathological or therapeutic factor was identified as a significant influencing factor on a receptor conversion in HER2. The results of this study do not provide a clear statement on whether adapting tumor-specific therapy after a receptor conversion improves overall survival. KW - Mammakarzinom KW - Rezeptorkonversion KW - Brustkrebs KW - Gynäkologie KW - HER2-Rezeptor KW - Anitkörpertherapie Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-344734 ER - TY - THES A1 - Lager, Johanna T1 - Expression immunmodulierende Marker in Zusammenhang mit Immuntherapie bei kindlichen Hirntumoren T1 - Expression of immunmodulation markers in correlation with immuntherapy in pediatric brain tumors N2 - Atypische teratoide Rhabdoidtumore sind trotz Ausschöpfen der multimodalen Therapieoptionen weiterhin mit einer schlechten Prognose belastet. Gründe hierfür liegen in den oftmals unzureichenden Resektionsmöglichkeiten, dem jungen Erkrankungsalter der PatientInnen und der Resistenz der Tumorzellen gegenüber Chemotherapeutika (Frühwald et al. 2020; Egiz et al. 2022; Richards et al. 2019). Gerade deshalb versucht man durch die aktuelle Forschung zu kindlichen Hirntumoren mit Immuntherapie ein besseres Outcome zu erreichen. Wichtige Grundlagen hierzu sind durch diese Arbeit dargestellt worden. Erstmals wurde gezeigt, dass Tumorzellen der AT/RT sowohl HLA-Klasse I und -Klasse II Antigene präsentieren. Es wurde außerdem die Expression von PD-L1 nachgewiesen. Des Weiteren konnte die Anwesenheit von Immunzellen durch den Nachweis CD 3+ Zellen bewiesen werden. Insgesamt zeigte sich eine große Heterogenität innerhalb des einzelnen und unter den verschiedenen Tumoren. Es zeigte sich eine negative Korrelation zwischen der Expression von MHC I und CD 3+ Zellen, welche insgesamt für einen Tumor Escape Mechanismus sprechen könnte, wie er bereits bei Glioblastomen nachgewiesen wurde (Bagley et al. 2018; Marcu et al. 2021). Es sollte eine Ausweitung der hier begonnen Forschung mit Einbeziehung der personenbezogenen Daten und Vergrößerung der untersuchten Fallzahl erfolgen. N2 - Even with using the multimodal therapy options available, atypical teratoid rhabdoid tumors still have a poor prognosis. This is caused by limited chirurgical resection, the young age of the patient cohort and resistence to chemotherapeutics (Frühwald et al.2020; Egiz et al. 2022; Richards et al. 2019). Hence, current research is trying to acchieve a better outcome through immunotherapy. Important fundamental research is done by this work. For the first time, it has been shown that tumorcells of AT/RT express HLA-class I and -class II antigens. Furthermore PD-L1 is expressed by these tumorcells. The presence of immuncells is proved by the evidence of CD 3+ cells. In total, a great heterogeneity presented in one tumor itself and in between the diffrent tumors examined. This work pointed out a negativ correlation between the expression of MHC I and CD 3+ cells, which could show a tumor escape mechanism, like it is already proven for glioblastoma multiforme (Bagley et al. 2018; Marcu et al. 2021). Beside that here is need for further studys with a bigger case number and link to personal and clinical data. KW - Immuntherapie KW - Hirntumor KW - Tumor KW - Oberflächenantigen KW - ATRT KW - immunmodulierende Marker Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-352202 ER - TY - THES A1 - Fischer, Jonas Maria T1 - Phänotyp und Funktion von Follikulären Helfer Zell-ähnlichen T-Zellen im entzündeten Gelenk von Patientinnen und Patienten mit Juveniler Idiopathischer Arthritis T1 - Phenotype and Function of Follicular Helper Cell-like T Cells in the inflamed Joint of Patients with Antinuclear Antibody-positive Juvenile Idiopathic Arthritis N2 - Innerhalb der Juvenilen Idiopathischen Arthritis (JIA) bilden Patienten mit Antinukleären Antikörpern (ANA) Subgruppen-übergreifend eine klinisch homogene Erkrankungsgruppe. Ob diesen klinischen Gemeinsamkeiten jedoch auch eine einheitliche Pathogenese zugrunde liegt, ist bisher unbekannt. Sogenannte periphere T-Helferzellen (TPH) spielen im Kontext zahlreicher Autoimmunerkrankungen eine entscheidende Rolle bei der Aktivierung autoreaktiver B-Zellen. Ziel dieser Arbeit war daher die phänotypische und funktionelle Analyse von PD-1hiCXCR5-CD4+ TPH-Zellen, sowie deren Verteilung in der Synovialflüssigkeit von Patienten unterschiedlicher Subgruppen der JIA. Hierzu wurden Phänotyp und Zytokinprofil von PD-1hiCD4+ T-Zellen durchflusszytometrisch analysiert. Der funktionelle Einfluss von PD-1hiCD4+ T-Zellen auf die B-Zell-Differenzierung wurde mittels in vitro Kokulturen FACS-sortierter TPH-Zellen der Synovialflüssigkeit untersucht. IL-21- und IL-17-produzierende T-Gedächtniszellen der Synovialflüssigkeit zeigten eine negative Korrelation zueinander. Die IL-21-Produktion ging besonders von PD-1hiCXCR5-HLA-DR+CD4+ T-Zellen aus, welche besonders in den Gelenken ANA-positiver JIA-Patienten akkumulierten. Diese Population zeigte phänotypische Ähnlichkeit mit TPH-Zellen und leistete in vitro effiziente B-Zell-Hilfe zu Plasmazelldifferenzierung und Immunglobulinsekretion, induzierte jedoch zudem einen CD21lo/-CD11c+T-bet+ Phänotyp in B-Zellen. Passend hierzu bestand auch ex vivo eine signifikante Korrelation zwischen TPH und CD21lo/-CD11c+T-bet+ doppelt-negativen B-Zellen (BDN). Es konnte also die Expansion einer spezifischen T-Zellpopulation mit phänotypischen und funktionellen Charakteristika von TPH-Zellen beobachtet und deren funktioneller Zusammenhang mit CD21lo/-CD11c+T-bet+ BDN in der Synovialflüssigkeit von JIA-Patienten aufgezeigt werden. Dies könnte die Autoimmunantwort auf ubiquitäre Autoantigene innerhalb betroffener Gelenke ANA-positiver JIA-Patienten widerspiegeln. N2 - Within Juvenile Idiopathic Arthritis (JIA), patients with antinuclear antibodies (ANA) form a clinically homogeneous group across different subgroups. However, it is currently unknown whether ANA-positive patients also share a common pathogenesis. Peripheral T helper cells (TPH) play a crucial role in the activation of autoreactive B cells in the context of numerous autoimmune diseases. Therefore, the aim of this study was the phenotypic and functional analysis of PD-1hiCXCR5-CD4+ TPH cells, as well as their distribution in the synovial fluid of patients from different JIA subgroups. For this purpose, the phenotype and cytokine profile of PD-1hiCD4+ T cells were analyzed using flow cytometry. The functional influence of PD-1hiCD4+ T cells on B cell differentiation was examined using in vitro co-cultures of FACS-sorted TPH cells from the synovial fluid. IL-21 and IL-17 producing T memory cells in the synovial fluid showed a negative correlation with each other. IL-21 production primarily originated from PD-1hiCXCR5-HLA-DR+CD4+ T cells, which particularly accumulated in the joints of ANA-positive JIA patients. This population exhibited phenotypic similarity to TPH cells and efficiently provided B cell help in in vitro experiments for plasma cell differentiation and immunoglobulin secretion, but also induced a CD21lo/-CD11c+T-bet+ phenotype in B cells. Correspondingly, there was a significant ex vivo correlation between TPH and CD21lo/-CD11c+T-bet+ double-negative B cells (BDN). Thus, an expansion of a specific T cell population with phenotypic and functional characteristics of TPH cells was observed, and their functional association with CD21lo/-CD11c+T-bet+ BDN in the synovial fluid of JIA patients was demonstrated. This could reflect the autoimmune response to ubiquitous autoantigens within the affected joints of ANA-positive JIA patients. KW - Rheumatologie KW - Juvenile chronische Arthritis KW - Helferzelle KW - T-Lymphozyt KW - Antinukleärer Antikörper KW - Periphere T-Helferzellen KW - PD-1 KW - TPH KW - CD21lo B-Zellen KW - peripheral T helper cells KW - CD21lo B cells KW - antinuclear antibodies KW - memory T cells Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-363022 ER -