@article{MerzenichBaakenSchmidtetal.2022, author = {Merzenich, Hiltrud and Baaken, Dan and Schmidt, Marcus and Bekes, Inga and Schwentner, Lukas and Janni, Wolfgang and Woeckel, Achim and Bartkowiak, Detlef and Wiegel, Thomas and Blettner, Maria and Wollschl{\"a}ger, Daniel and Schmidberger, Heinz}, title = {Cardiac late effects after modern 3D-conformal radiotherapy in breast cancer patients: a retrospective cohort study in Germany (ESCaRa)}, series = {Breast Cancer Research and Treatment}, volume = {191}, journal = {Breast Cancer Research and Treatment}, number = {1}, issn = {0167-6806}, doi = {10.1007/s10549-021-06412-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-308606}, pages = {147-157}, year = {2022}, abstract = {Purpose Radiotherapy (RT) was identified as a risk factor for long-term cardiac effects in breast cancer patients treated until the 1990s. However, modern techniques reduce radiation exposure of the heart, but some exposure remains unavoidable. In a retrospective cohort study, we investigated cardiac mortality and morbidity of breast cancer survivors treated with recent RT in Germany. Methods A total of 11,982 breast cancer patients treated between 1998 and 2008 were included. A mortality follow-up was conducted until 06/2018. In order to assess cardiac morbidity occurring after breast cancer treatment, a questionnaire was sent out in 2014 and 2019. The effect of breast cancer laterality on cardiac mortality and morbidity was investigated as a proxy for radiation exposure. We used Cox Proportional Hazards regression analysis, taking potential confounders into account. Results After a median follow-up time of 11.1 years, there was no significant association of tumor laterality with cardiac mortality in irradiated patients (hazard ratio (HR) for left-sided versus right-sided tumor 1.09; 95\% confidence interval (CI) 0.85-1.41). Furthermore, tumor laterality was not identified as a significant risk factor for cardiac morbidity (HR = 1.05; 95\%CI 0.88-1.25). Conclusions Even though RT for left-sided breast cancer on average incurs higher radiation dose to the heart than RT for right-sided tumors, we found no evidence that laterality is a strong risk factor for cardiac disease after contemporary RT. However, larger sample sizes, longer follow-up, detailed information on individual risk factors and heart dose are needed to assess clinically manifest late effects of current cancer therapy.}, language = {en} } @article{HungKasperkowitzKurzetal.2023, author = {Hung, Sophia and Kasperkowitz, Amelie and Kurz, Florian and Dreher, Liane and Diessner, Joachim and Ibrahim, Eslam S. and Schwarz, Stefan and Ohlsen, Knut and Hertlein, Tobias}, title = {Next-generation humanized NSG-SGM3 mice are highly susceptible to Staphylococcus aureus infection}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1127709}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-306966}, year = {2023}, abstract = {Humanized hemato-lymphoid system mice, or humanized mice, emerged in recent years as a promising model to study the course of infection of human-adapted or human-specific pathogens. Though Staphylococcus aureus infects and colonizes a variety of species, it has nonetheless become one of the most successful human pathogens of our time with a wide armory of human-adapted virulence factors. Humanized mice showed increased vulnerability to S. aureus compared to wild type mice in a variety of clinically relevant disease models. Most of these studies employed humanized NSG (NOD-scid IL2Rgnull) mice which are widely used in the scientific community, but show poor human myeloid cell reconstitution. Since this immune cell compartment plays a decisive role in the defense of the human immune system against S. aureus, we asked whether next-generation humanized mice, like NSG-SGM3 (NOD-scid IL2Rgnull-3/GM/SF) with improved myeloid reconstitution, would prove to be more resistant to infection. To our surprise, we found the contrary when we infected humanized NSG-SGM3 (huSGM3) mice with S. aureus: although they had stronger human immune cell engraftment than humanized NSG mice, particularly in the myeloid compartment, they displayed even more pronounced vulnerability to S. aureus infection. HuSGM3 mice had overall higher numbers of human T cells, B cells, neutrophils and monocytes in the blood and the spleen. This was accompanied by elevated levels of pro-inflammatory human cytokines in the blood of huSGM3 mice. We further identified that the impaired survival of huSGM3 mice was not linked to higher bacterial burden nor to differences in the murine immune cell repertoire. Conversely, we could demonstrate a correlation of the rate of humanization and the severity of infection. Collectively, this study suggests a detrimental effect of the human immune system in humanized mice upon encounter with S. aureus which might help to guide future therapy approaches and analysis of virulence mechanisms.}, language = {en} } @article{LeonhardtWinklerKollikowskietal.2023, author = {Leonhardt, Jonas and Winkler, Marcela and Kollikowski, Anne and Schiffmann, Lisa and Quenzer, Anne and Einsele, Hermann and L{\"o}ffler, Claudia}, title = {Mind-body-medicine in oncology—from patient needs to tailored programs and interventions}, series = {Frontiers in Psychology}, volume = {14}, journal = {Frontiers in Psychology}, issn = {1664-1078}, doi = {10.3389/fpsyg.2023.1140693}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-321970}, year = {2023}, abstract = {Introduction: National and international guidelines recommend early integration of evidence-based multimodal interventions and programs, especially with a focus on relaxation techniques and other Mind-Body-based methods to maintain the quality of life of oncology patients, improve treatment tolerability, and promote healthy lifestyle behaviors. Consequently, we aim to understand what drives patients and how they navigate integrative medicine to best advise them. This study aimed to detect possible topics of particular interest to patients and identify the patient groups that could benefit most from further programs. Furthermore, we aimed to investigate if patients are open-minded toward integrative oncology concepts and learn about their motivational level to maintain or change behavior. Methods: Between August 2019 and October 2020 we surveyed patients undergoing oncological therapy in a university oncological outpatient center using a custom-developed questionnaire based on established Mind-Body Medicine concepts. Results: We included 294 patients with various cancers. More than half reported problems sleeping through (61\%) and 42\% felt stressed frequently, invariably rating this as detrimental to their health. Moreover, a slight majority (52\%) felt physically limited due to their disease and only 30\% performed defined exercise programs. Women were significantly more likely to feel stressed and reported with alarming frequency that they often feel "everything was up to them." The 40-65-year-olds reported significantly less restful sleep, more stress and were more dissatisfied with their situation. However, this group already used natural remedies most frequently and was most often motivated to use relaxation techniques in the next 6 months. The lower the perceived individual energy level (EL), the less frequently patients did sport, the more frequently they felt their disease impaired their activity, mostly feeling stressed and tense. We also found significant associations between negative emotions/thoughts and the variables "sleep," "use of relaxation techniques," "personal stress perception," and "successful lifestyle modification." Conclusion: Mind-Body programs that focus on patient's individual resources, with tools to explore impairing patterns of self-perception and cognitive biases, can be a valuable resource for oncology patients and should therefore be part of an integrative medical treatment concept.}, language = {en} } @article{HaakeHaackSchaeferetal.2023, author = {Haake, Markus and Haack, Beatrice and Sch{\"a}fer, Tina and Harter, Patrick N. and Mattavelli, Greta and Eiring, Patrick and Vashist, Neha and Wedekink, Florian and Genssler, Sabrina and Fischer, Birgitt and Dahlhoff, Julia and Mokhtari, Fatemeh and Kuzkina, Anastasia and Welters, Marij J. P. and Benz, Tamara M. and Sorger, Lena and Thiemann, Vincent and Almanzar, Giovanni and Selle, Martina and Thein, Klara and Sp{\"a}th, Jacob and Gonzalez, Maria Cecilia and Reitinger, Carmen and Ipsen-Escobedo, Andrea and Wistuba-Hamprecht, Kilian and Eichler, Kristin and Filipski, Katharina and Zeiner, Pia S. and Beschorner, Rudi and Goedemans, Renske and Gogolla, Falk Hagen and Hackl, Hubert and Rooswinkel, Rogier W. and Thiem, Alexander and Romer Roche, Paula and Joshi, Hemant and P{\"u}hringer, Dirk and W{\"o}ckel, Achim and Diessner, Joachim E. and R{\"u}diger, Manfred and Leo, Eugen and Cheng, Phil F. and Levesque, Mitchell P. and Goebeler, Matthias and Sauer, Markus and Nimmerjahn, Falk and Schuberth-Wagner, Christine and Felten, Stefanie von and Mittelbronn, Michel and Mehling, Matthias and Beilhack, Andreas and van der Burg, Sjoerd H. and Riedel, Angela and Weide, Benjamin and Dummer, Reinhard and Wischhusen, J{\"o}rg}, title = {Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment}, series = {Nature Communications}, volume = {14}, journal = {Nature Communications}, doi = {10.1038/s41467-023-39817-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357333}, year = {2023}, abstract = {Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don't respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.}, language = {en} } @article{IpWischhusen2023, author = {Ip, Chi Wang and Wischhusen, J{\"o}rg}, title = {Versatile guardians: regenerative regulatory T cells in Parkinson's disease rodent models}, series = {Signal Transduction and Targeted Therapy}, volume = {8}, journal = {Signal Transduction and Targeted Therapy}, doi = {10.1038/s41392-023-01681-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357674}, year = {2023}, abstract = {No abstract available.}, language = {en} } @article{HeidtKaemmererFobkeretal.2023, author = {Heidt, Christina and K{\"a}mmerer, Ulrike and Fobker, Manfred and R{\"u}ffer, Andreas and Marquardt, Thorsten and Reuss-Borst, Monika}, title = {Assessment of intestinal permeability and inflammation bio-markers in patients with rheumatoid arthritis}, series = {Nutrients}, volume = {15}, journal = {Nutrients}, number = {10}, issn = {2072-6643}, doi = {10.3390/nu15102386}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-319377}, year = {2023}, abstract = {Increased intestinal permeability and inflammation, both fueled by dysbiosis, appear to contribute to rheumatoid arthritis (RA) pathogenesis. This single-center pilot study aimed to investigate zonulin, a marker of intestinal permeability, and calprotectin, a marker of intestinal inflammation, measured in serum and fecal samples of RA patients using commercially available kits. We also analyzed plasma lipopolysaccharide (LPS) levels, a marker of intestinal permeability and inflammation. Furthermore, univariate, and multivariate regression analyses were carried out to determine whether or not there were associations of zonulin and calprotectin with LPS, BMI, gender, age, RA-specific parameters, fiber intake, and short-chain fatty acids in the gut. Serum zonulin levels were more likely to be abnormal with a longer disease duration and fecal zonulin levels were inversely associated with age. A strong association between fecal and serum calprotectin and between fecal calprotectin and LPS were found in males, but not in females, independent of other biomarkers, suggesting that fecal calprotectin may be a more specific biomarker than serum calprotectin is of intestinal inflammation in RA. Since this was a proof-of-principle study without a healthy control group, further research is needed to validate fecal and serum zonulin as valid biomarkers of RA in comparison with other promising biomarkers.}, language = {en} } @article{ZeinerZinkeKowalewskietal.2018, author = {Zeiner, P. S. and Zinke, J. and Kowalewski, D. J. and Bernatz, S. and Tichy, J. and Ronellenfitsch, M. W. and Thorsen, F. and Berger, A. and Forster, M. T. and Muller, A. and Steinbach, J. P. and Beschorner, R. and Wischhusen, J. and Kvasnicka, H. M. and Plate, K. H. and Stefanović, S. and Weide, B. and Mittelbronn, M. and Harter, P. N.}, title = {CD74 regulates complexity of tumor cell HLA class II peptidome in brain metastasis and is a positive prognostic marker for patient survival}, series = {Acta Neuropathologica Communications}, volume = {6}, journal = {Acta Neuropathologica Communications}, doi = {10.1186/s40478-018-0521-5}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-233882}, year = {2018}, abstract = {Abstract Despite multidisciplinary local and systemic therapeutic approaches, the prognosis for most patients with brain metastases is still dismal. The role of adaptive and innate anti-tumor response including the Human Leukocyte Antigen (HLA) machinery of antigen presentation is still unclear. We present data on the HLA class II-chaperone molecule CD74 in brain metastases and its impact on the HLA peptidome complexity. We analyzed CD74 and HLA class II expression on tumor cells in a subset of 236 human brain metastases, primary tumors and peripheral metastases of different entities in association with clinical data including overall survival. Additionally, we assessed whole DNA methylome profiles including CD74 promoter methylation and differential methylation in 21 brain metastases. We analyzed the effects of a siRNA mediated CD74 knockdown on HLA-expression and HLA peptidome composition in a brain metastatic melanoma cell line. We observed that CD74 expression on tumor cells is a strong positive prognostic marker in brain metastasis patients and positively associated with tumor-infiltrating T-lymphocytes (TILs). Whole DNA methylome analysis suggested that CD74 tumor cell expression might be regulated epigenetically via CD74 promoter methylation. CD74\(^{high}\) and TIL\(^{high}\) tumors displayed a differential DNA methylation pattern with highest enrichment scores for antigen processing and presentation. Furthermore, CD74 knockdown in vitro lead to a reduction of HLA class II peptidome complexity, while HLA class I peptidome remained unaffected. In summary, our results demonstrate that a functional HLA class II processing machinery in brain metastatic tumor cells, reflected by a high expression of CD74 and a complex tumor cell HLA peptidome, seems to be crucial for better patient prognosis.}, language = {en} } @article{LoebLinsmeierHerbertetal.2023, author = {L{\"o}b, Sanja and Linsmeier, Eva and Herbert, Saskia-Laureen and Schlaiß, Tanja and Kiesel, Matthias and Wischhusen, J{\"o}rg and Salmen, Jessica and Kranke, Peter and Quenzer, Anne and Kurz, Florian and Weiss, Claire and Gerhard-Hartmann, Elena and W{\"o}ckel, Achim and Diessner, Joachim}, title = {Prognostic effect of HER2 evolution from primary breast cancer to breast cancer metastases}, series = {Journal of Cancer Research and Clinical Oncology}, volume = {149}, journal = {Journal of Cancer Research and Clinical Oncology}, number = {8}, doi = {10.1007/s00432-022-04486-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324068}, pages = {5417-5428}, year = {2023}, abstract = {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.}, language = {en} } @article{HerbertHirzleBartmannetal.2023, author = {Herbert, Saskia-Laureen and Hirzle, Paula and Bartmann, Catharina and Schlaiß, Tanja and Kiesel, Matthias and Curtaz, Carolin and L{\"o}b, Sanja and W{\"o}ckel, Achim and Diessner, Joachim}, title = {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}, series = {Archives of Gynecology and Obstetrics}, volume = {307}, journal = {Archives of Gynecology and Obstetrics}, number = {4}, doi = {10.1007/s00404-022-06666-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324057}, pages = {1097-1104}, year = {2023}, abstract = {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 W{\"u}rzburg 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 W{\"u}rzburg itself. (35.7 vs. 32.2 days). The interval between histological confirmation and the first consultation at the University Hospital W{\"u}rzburg 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.}, language = {en} } @article{DiessnerAndersHerbertetal.2023, author = {Diessner, Joachim and Anders, Laura and Herbert, Saskia and Kiesel, Matthias and Bley, Thorsten and Schlaiss, Tanja and Sauer, Stephanie and W{\"o}ckel, Achim and Bartmann, Catharina}, title = {Evaluation of different imaging modalities for axillary lymph node staging in breast cancer patients to provide a personalized and optimized therapy algorithm}, series = {Journal of Cancer Research and Clinical Oncology}, volume = {149}, journal = {Journal of Cancer Research and Clinical Oncology}, number = {7}, doi = {10.1007/s00432-022-04221-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324047}, pages = {3457-3467}, year = {2023}, abstract = {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.}, language = {en} }