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ZusammenfassungGesundheitsbezogene Lebensqualität ist für Brustkrebsbetroffene in allen Stadien, sowohl während als auch mittel- und langfristig nach Abschluss der Therapie, von großer Relevanz. Bei Zulassungsstudien für neue Behandlungen sowie wissenschaftlichen Studien zum Vergleich verschiedener Therapien gewinnt Lebensqualität als Endpunkt zunehmend an Bedeutung. Neben einer kurzen globalen Einschätzung der Lebensqualität sollten weitere wichtige Patient-Reported Outcomes erhoben werden. Patientinnen mit Brustkrebs berichten häufig über Einschränkungen durch Fatigue, Schlafprobleme, sexuelle bzw. klimakterische Probleme, kognitive Probleme, psychische Probleme und Verlust an körperlicher Leistungsfähigkeit. Die Lebensqualität nach Brustkrebs könnte vermutlich weiter gesteigert werden, wenn Aufklärung, Screening und Behandlung dieser Symptome systematischer Bestandteil der onkologischen Versorgung würden.

Zusammenfassung. Das schulbezogene Wohlbefinden (SBWB) ist eine wichtige Voraussetzung für schulischen Erfolg. Trotzdem existieren – insbesondere mit Blick auf die Erfassung des SBWB von Erstklässlern – im deutschsprachigen Raum nur vereinzelt Studien. Dies lässt sich möglicherweise durch das Fehlen geeigneter Instrumente begründen. Dies gilt auch und insbesondere dann, wenn der Gesundheitszustand der Kinder berücksichtigt werden soll. Das Ziel der vorliegenden Arbeit besteht in der Validierung des adaptierten Fragebogens zur Erfassung von emotionalen und sozialen Schulerfahrungen (FEESS 1 – 2; Rauer & Schuck, 2004 ) mit Fokus auf die Eignung des Instruments für chronisch kranke und gesunde Kinder. Dafür wird zunächst das Konstrukt Wohlbefinden (WB) resp. SBWB definiert und in einschlägige Theorien – die Selbstbestimmungstheorie nach Deci und Ryan (1985) und das Erwartung-mal-Wert-Modell nach Wigfield und Eccles (2000) – eingebettet. Die Bedeutung der verwendeten FEESS-Skalen und ihr Zusammenhang zum schulischen Erfolg werden aufgezeigt. 1491 Kinder wurden zu ihrer Lernfreude (LF), sozialen Integration (SI) und zu ihrem schulbezogenen Fähigkeitsselbstkonzept (SK) befragt. Die Erfassung des Gesundheitszustands wurde über Elternfragebögen und Schuleingangsuntersuchungen eruiert. Zudem wurden die Eltern zur gesundheitsbezogenen Lebensqualität (LQ) ihrer Kinder mit Hilfe eines Fragebogens zur Erfassung der Lebensqualität von Kindern (KINDL; Bullinger, Mackensen & Kirchberger, 1994 ) befragt. Die psychometrische Qualität der adaptierten FEESS-Skalen wurde für beide Gruppen (erkrankt / gesund) auf Skalen- und Itemebene untersucht. Hierzu kamen sowohl klassische Verfahren als auch Verfahren der Item-Response-Theorie zum Einsatz. Die Ergebnisse untermauern die Validität des Konstruktes SBWB und stützen die Annahme der Dreidimensionalität (LF, SI, SK). Alle drei Skalen zeigen eine zufriedenstellende bis sehr gute Reliabilität. Die Items zeigen sehr gute MNSQ-Werte (weighted mean-square; gewichtete Abweichungsquadrate) und geeignete Trennschärfen. Die externe Validität, für deren Berechnung der Zusammenhang zwischen den Angaben der Kinder und den Angaben der Eltern zur gesundheitsbezogenen LQ untersucht wurde, konnte noch nicht ausreichend nachgewiesen werden. Bis auf diese Einschränkung kann mit Hilfe der adaptierten FEESS-Skalen im nächsten Schritt das SBWB von gesunden und erkrankten Kindern verglichen werden, um mögliche Chancenungleichheiten auszugleichen.

Purpose There is growing interest in low-dose metronomic chemotherapy (LDMC) in metastatic breast cancer (MBC). In this retrospective case–control analysis, we compared the efficacy of LDMC and conventional chemotherapy (CCT) in MBC. Methods Each LDMC patient receiving oral cyclophosphamide (CTX) (50 mg daily) and methotrexate (MTX) (2.5 mg every other day) was matched with two controls who received CCT. Age, number of chemotherapy lines and metastatic sites as well as hormone receptor (HR) status were considered as matching criteria. Primary endpoint was disease control rate longer than 24 weeks (DCR). Secondary endpoints were progression-free survival (PFS), duration of response (DoR) and subgroup analyses using the matching criteria. Results 40 cases and 80 controls entered the study. 30.0% patients with LDMC and 22.5% patients with CCT showed DCR (p = 0.380). The median PFS was 12.0 weeks in both groups (p = 0.218) and the median DoR was 31.0 vs. 20.5 weeks (p = 0.383), respectively. Among younger patients, DCR was 40.0% in LDMC vs. 25.0% in the CCT group (p = 0.249). DCR was achieved in 33.3% vs. 26.2% non-heavily pretreated patients (p = 0.568) and in 36.0% vs. 18.0% patients without multiple metastases (p = 0.096), respectively. In the HR-positive group, 30.0% LDMC vs. 28.3% CCT patients showed DCR (p = 1.000). Among triple-negative patients, DCR was achieved in 30.0% LDMC and 5.0% CCT patients (p = 0.095). Conclusions We demonstrated a similar efficacy of LDMC compared to CCT in the treatment of MBC. Thus, LDMC may be a valuable treatment option in selected MBC patients.

Air pollution is a major environmental threat and each year about 7 million people reported to die as a result of air pollution. Consequently, exposure to air pollution is linked to increased morbidity and mortality world-wide. Diesel automotive engines are a major source of urban air pollution in the western societies encompassing particulate matter and diesel exhaust particles (DEP). Air pollution is envisioned as primary cause for cardiovascular dysfunction, such as ischemic heart disease, cardiac dysrhythmias, heart failure, cerebrovascular disease and stroke. Air pollution also causes lung dysfunction, such as chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), and specifically exacerbations of these diseases. DEP induces inflammation and reactive oxygen species production ultimately leading to mitochondrial dysfunction. DEP impair structural cell function and initiate the epithelial-to-mesenchymal transition, a process leading to dysfunction in endothelial as well as epithelial barrier, hamper tissue repair and eventually leading to fibrosis. Targeting cyclic adenosine monophosphate (cAMP) has been implicated to alleviate cardiopulmonary dysfunction, even more intriguingly cAMP seems to emerge as a potent regulator of mitochondrial metabolism. We propose that targeting of the mitochondrial cAMP nanodomain bear the therapeutic potential to diminish air pollutant — particularly DEP — induced decline in cardiopulmonary function.

The second messenger molecule 3'5'-cyclic adenosine monophosphate (cAMP) imparts several beneficial effects in lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). While cAMP is bronchodilatory in asthma and COPD, it also displays anti-fibrotic properties that limit fibrosis. Phosphodiesterases (PDEs) metabolize cAMP and thus regulate cAMP signaling. While some existing therapies inhibit PDEs, there are only broad family specific inhibitors. The understanding of cAMP signaling compartments, some centered around lipid rafts/caveolae, has led to interest in defining how specific PDE isoforms maintain these signaling microdomains. The possible altered expression of PDEs, and thus abnormal cAMP signaling, in obstructive lung diseases has been poorly explored. We propose that inhibition of specific PDE isoforms can improve therapy of obstructive lung diseases by amplifying specific cAMP signals in discreet microdomains.

Objective Glucosamine, an intermetabolite of the hexosamine biosynthesis pathway (HBP), is a widely used nutritional supplement in osteoarthritis patients, a subset of whom also suffer from diabetes. HBP is activated in diabetic retinopathy (DR). The aim of this study is to investigate the yet unclear effects of glucosamine on DR. Methods In this study, we tested the effect of glucosamine on vascular and neuronal pathology in a mouse model of streptozotocin-induced DR in vivo and on cultured endothelial and Müller cells to elucidate the underlying mechanisms of action in vitro. Results Glucosamine did not alter the blood glucose or HbA1c levels in the animals, but induced body weight gain in the non-diabetic animals. Interestingly, the impaired neuronal function in diabetic animals could be prevented by glucosamine treatment. Correspondingly, the activation of Müller cells was prevented in the retina as well as in cell culture. Conversely, glucosamine administration in the normal retina damaged the retinal vasculature by increasing pericyte loss and acellular capillary formation, likely by interfering with endothelial survival signals as seen in vitro in cultured endothelial cells. Nevertheless, under diabetic conditions, no further increase in the detrimental effects were observed. Conclusions In conclusion, the effects of glucosamine supplementation in the retina appear to be a double-edged sword: neuronal protection in the diabetic retina and vascular damage in the normal retina. Thus, glucosamine supplementation in osteoarthritis patients with or without diabetes should be taken with care., Highlights • The hexosamine biosynthesis pathway (HBP) is activated in diabetic retinopathy (DR), which manifests as vascular and neuronal damage in the retina. • Glucosamine, metabolized in the HBP, is a widely used oral supplement for osteoarthritis treatment. • Glucosamine supplementation improved neuronal function in retinas of mice with experimental DR, but induced vascular damage in normal retinas. • Müller cell activation and endothelial survival signals in the retina were affected by glucosamine. • Patients with or without diabetes should take caution with glucosamine supplementation.

Introduction/Background* We evaluated the prognostic impact of various global health assessment tools in accordance to conventional prognostic factors in patients with endometrial cancer (EC) older than 60 years. Methodology G-8 geriatric screening tool (G-8 geriatric score), Lee Schonberg prognostic index (Lee-Index), Charlson Comorbidity Index (CCI) and American Society of Anesthesiologists (ASA-PS) – Physical Status System were retrospectively determined in a consecutive cohort of elderly patients with EC. Univariate and multivariate Cox regression analyses and Kaplan-Meier method were performed to determine the impact of the global health assessment tools on progression free survival (PFS) and overall survival (OS). Result(s)* 153 patients entered the study. In multivariate analysis adjusted for common clinical-pathological risk factors (e.g. histological type and stadium, histological grading, FIGO-stadium, tumor stadium and postoperative tumor burden) and different global health assessment tools (G-8 geriatric score, Lee-Index, CCI and ASA-PS) only the G-8 geriatric score retained its significance as a considerable and independent prognostic factor of 5-year OS rate (HR: 3.173; 95%-CI [1.436-7.010]; p=0.004) but not for univariate 5-year PFS rate (HR: 2.033; 95%-CI [0.925-4.468]; p=0.078). 92 patients (61.3%) were assigned to the G-8-non-frail cohort (cut-off value > 14 points) with an increased 5-year PFS and OS rate compared to the 58 patients (38.7%) classified as G-8-frail (PFS: 82.1% vs. 65.4%; p=0.071 and OS: 88.2% vs. 49.7%; p Conclusion* Preoperative G-8 geriatric score independently predicted 5-year OS in elderly EC patients irrespectively of the maximal surgical effort.

Introduction/Background* Treatment of vulvar cancer contains surgery if applicable and often primary or neo-/adjuvant chemoradiation. Cisplatin and Mitomycin/5-FU are widely used radiosensitizers in vulvar cancer, although evidence is limited. We retrospectively investigated both radiosensitizers for outcome and toxicity. Methodology We screened the archive for patients treated with chemoradiation for pathologically-confirmed squamous cell cancer of the vulva between 01/2010 – 02/2021 at our institution. The impact of both radiosensitizers on prognosis was compared using Kaplan-Meier method and Cox-Regression analysis. Result(s)* 127 patients with vulvar cancer were screened. 24 patients received chemoradiation (Cisplatin n=11; Mitomycin/5-FU n=11; others n=2) as a neoadjuvant, primary or adjuvant treatment. Median follow-up was 17 months in both groups. Median age was 65 (35-91) years. Patients in the Cisplatin group were older than in the Mitomycin/5-FU group (Median age 73 vs. 55, p=0.007). Median radiation dose in total was 59.6 (41.4 – 85.0) Gy. 68.2% of the patients had FIGO stage III and 18.2% of the patients had FIGO stage IV before chemoradiation. Both groups showed no differences in terms of FIGO stage. 72.7% (8 out of 11) patients receiving Mitomycin/5-FU achieved clinical complete response compared to 45.5% (5 out of 11) receiving Cisplatin (p=0.309). One patient in each group was progressive during chemoradiation. Three patients stopped chemoradiation due to toxicity (Cisplatin n=2; Mitomycin/5-FU n=1) and one patient in the Cisplatin group died of treatment related sequelae. Radiodermatitis with epitheliolysis were the most common adverse events in both groups. Additionally, four patients in the Mitomycin/5-FU group required treatment for myelotoxicity. The 2 -year overall survival showed a numerical but not statistically significant difference in favour of the Mitomycin/5-FU group (59.7% vs. 30.7%; p= 0.306). The 2-year-recurrence-free-survival was comparable between Mitomycin/5-FU and Cisplatin (43.6% vs. 31.8%; p=0.829). Conclusion* Cisplatin and Mitomycin/5-FU showed a numerical but not statistically significant difference in overall survival in vulvar cancer. MitomycinC/5-FU tended to result in a clinical complete response more frequently but required more often a treatment for myelotoxicity. However, overall toxicity of Mitomycin/5-FU was acceptable and may be considered in the treatment of young, healthy patients with locally advanced vulvar cancer.

Introduction/Background* In the treatment of both platinum-resistant recurrent ovarian cancer (ROC) and metastatic breast cancer (MBC), symptom control and maintenance of quality of life (QoL) play a crucial role. In the advanced stage of disease, metronomic chemotherapy (MCT) may be a favourable treatment option. The aim of this study is to assess the QoL of heavily pretreated patients with ROC and MBC treated with MCT. Methodology PROmetronomic, FoR.UM 19-02193, is a monocentric, open-label, single-arm observational study to assess health-related patient-reported outcome data in ROC and MBC patients treated with MCT (cyclophosphamide 50 mg p.o. daily ± methotrexate 2.5 mg p.o. every other day). QoL data are evaluated using European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 version 3.0, EORTC QLQ-OV28 version 1.0 (ROC)/EORTC QLQ-BR23 version 1.0 (MBC), and Hospital anxiety and depression scale (HADS-D) questionnaires via an internet-based therapy support system CANKADO. Patients previously treated with at least 1 line of platinum-based and 1 platinum-free chemotherapy (ROC)/at least 2 lines of endocrine therapy (for hormone receptor-positive cancer) and at least 2 lines of chemotherapy (MBC) are included. Secondary endpoints are disease control rate at 12 and 24 weeks, duration of response, progression-free survival and overall survival. Assessment of safety and tolerability is conducted according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. As part of the translational research approach, potentially relevant anti-angiogenic and immunomodulatory biomarkers are being investigated. Result(s)* Until 2021-05-01, 4 ROC and 3 MBC patients have been enrolled. It is planned to include a total of 65 patients until 08/2023. Conclusion* Potentially toxic chemotherapy is often required to achieve disease control in patients with metastatic cancer. However, well-being and personal preferences must not be neglected. MCT could provide an efficacious treatment option with limited toxicities and positive impact on QoL.

Introduction/Background* The aim of this study was to evaluate the impact of the preoperative global health status on the prognosis of patients with ovarian cancer (OC) older than 60 years, who received cytoreductive surgery. Methodology G-8 geriatric screening tool (G-8 score), Lee Schonberg prognostic index, Eastern Cooperative Oncology Group (ECOG) performance status and Charlson Comorbidity Index (CCI) were determined retrospectively in a consecutive cohort of elderly patients with OC. Univariate and multivariate Cox regression analyses and Kaplan-Meier method were performed to analyze the impact of the preoperative global health status on survival. Result(s)* 116 patients entered the study. In multivariate analysis adjusted for clinical-pathological factors, only the G-8 score retained significance as a prognostic parameter of PFS (HR: 2.009; 95%-CI [1.091-3.699]. 56 patients were classified as G-8 non-frail with an increased PFS compared to 50 G-8 frail patients (53.4% vs. 16.7%; p=0.010). A higher CCI was associated with decreased PFS (45.1% vs. 22.2%; p=0.012) but it did not influence the risk of recurrences or death (p=0.360; p=0.111, respectively). The Lee Schonberg prognostic index, the ECOG and mean age were not associated with survival. Conclusion* The G-8 score independently predicted PFS in elderly OC patients regardless of maximal surgical effort. Thus, it could be useful to assess surgical treatment based on frailty rather than age alone.

Introduction/Background* This study evaluated the impact of the global health status on the rate of postoperative clinical complications in patients with ovarian cancer (OC) older than 60 years. Methodology Selected global health status assessment tools were retrospectively determined in a cohort of OC patients older than 60 years, treated at our institution between 2008 and 2019. The primary outcome was the incidence and type of postoperative clinical complications in accordance with the Veteran Affairs’ National Surgical Quality Improvement Program (NSQIP). Differences in binary and ordinal variables between independent groups were analyzed by the chi-square test. Furthermore, rank correlations were examined with Spearman-Correlation. Result(s)* 116 patients entered the study. 54 patients (46.6%) were classified as G-8 frail and 56 patients (48.3%) as G-8 non-frail. CCI classified 24 patients (20.7%) into CCI-1, 63 patients (54.3%) into CCI-2 and 29 patients (25.0%) into CCI-3. The ASA PS allocated 48 patients (44.0%) as ASA-2 and 61 patients (56.0%) as ASA-3. The Lee-Index allocated 60 patients (61.9%) to a cohort with a four-year-mortality Conclusion* Preoperative evaluation of global health status with G-8 score and CCI were significantly associated with elevated rates of postoperative complications and the need of transfusions, in contrast to age alone in elderly patients with OC.

Introduction/Background* In high-grade serous ovarian cancer (HGSOC) an early intraperitoneal metastatic spread is common which determines the therapeutical approach and prognosis. Integrins may be involved in metastatic spread of HGSOC. In this study, integrin expression was examined in primary tumour and metastases of HGSOC. Methodology The expression of integrin α2, α4, α5, α6, and β1 was assessed by immunostaining in tumour samples of the ovary, omentum, and peritoneum of each patient. Differences in integrin expression among tumour localisations and their association with clinicopathological parameters were examined by Fisher’s exact test. The impact of integrin expression on progression-free survival (PFS) and overall survival (OS) was examined by Cox regression and Kaplan-Meier analyses. Result(s)* 113 tumour samples of 40 HGSOC patients were examined. The expression of the integrins did not differ between the three tumour localisations (all p-values >0.05) with the exception of the expression of integrin β1 in primary tumour and omentum (77.5% versus 57.5%, p=0.014). Significant differences were also observed with respect to high expression of integrin α4 in primary tumour and omentum (52.5% versus 47.5%, p=0.008) and primary tumour and peritoneum (52.5% versus 47.5%, p=0.050). High expression of integrin α4 in peritoneum was associated with poorer PFS (HR=2.02 95% CI 1.01-4.05, p=0.047), younger age (p=0.047) and death (p=0.046). Median PFS in patients with high expression of integrin α4 was 13.00 months whereas median PFS in patients without high expression of integrin α4 was 21.00 months (p=0.040). Expression of integrin α2, α5, α6, and β1 did not correlate with PFS or OS. Conclusion* Expression of integrin α4 may be altered during the metastasic spread of HGSOC and affect the prognosis. Expression of integrin α2, α5, α6, and β1 did not reveal any prognostic value in HGSOC, even if expression of integrin β1 differed between primary tumour and omental metastases.

Cigarette smoke (CS), a highly complex mixture containing more than 4,000 compounds, causes aberrant cell responses leading to tissue damage around the airways and alveoli, which underlies various lung diseases. Phosphodiesterases (PDEs) are a family of enzymes that hydrolyze cyclic nucleotides. PDE inhibition induces bronchodilation, reduces the activation and recruitment of inflammatory cells, and the release of various cytokines. Currently, the selective PDE4 inhibitor roflumilast is an approved add-on treatment for patients with severe chronic obstructive pulmonary disease with chronic bronchitis and a history of frequent exacerbations. Additional selective PDE inhibitors are being tested in preclinical and clinical studies. However, the effect of chronic CS exposure on the expression of PDEs is unknown. Using mRNA isolated from nasal and bronchial brushes and lung tissues of never smokers and current smokers, we compared the gene expression of 25 PDE coding genes. Additionally, the expression and distribution of PDE3A and PDE4D in human lung tissues was examined. This study reveals that chronic CS exposure modulates the expression of various PDE members. Thus, CS exposure may change the levels of intracellular cyclic nucleotides and thereby impact the efficiency of PDE-targeted therapies.

Chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma, affect millions of people all over the world. Cyclic adenosine monophosphate (cAMP) which is one of the most important second messengers, plays a vital role in relaxing airway smooth muscles and suppressing inflammation. Given its vast role in regulating intracellular responses, cAMP provides an attractive pharmaceutical target in the treatment of chronic respiratory diseases. Phosphodiesterases (PDEs) are enzymes that hydrolyze cyclic nucleotides and help control cyclic nucleotide signals in a compartmentalized manner. Currently, the selective PDE4 inhibitor, roflumilast, is used as an add-on treatment for patients with severe COPD associated with bronchitis and a history of frequent exacerbations. In addition, other novel PDE inhibitors are in different phases of clinical trials. The current review provides an overview of the regulation of various PDEs and the potential application of selective PDE inhibitors in the treatment of COPD and asthma. The possibility to combine various PDE inhibitors as a way to increase their therapeutic effectiveness is also emphasized.

Over the past decades, research has defined cAMP as one of the central cellular nodes in sensing and integrating multiple pathways and as a pivotal role player in lung pathophysiology. Obstructive lung disorders, such as chronic obstructive pulmonary disease (COPD), are characterized by a persistent and progressive airflow limitation and by oxidative stress from endogenous and exogenous insults. The extent of airflow obstruction depends on the relative deposition of different constituents of the extracellular matrix, a process related to epithelial-to-mesenchymal transition, and which subsequently results in airway fibrosis. Oxidative stress from endogenous and also from exogenous sources causes a profound worsening of COPD. Here we describe how cAMP scaffolds and their different signalosomes in different subcellular compartments may contribute to COPD. Future research will require translational studies to alleviate disease symptoms by pharmacologically targeting the cAMP scaffolds. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.

Currently, there is no pharmacological treatment targeting defective tissue repair in chronic disease. Here we utilized a transcriptomics-guided drug target discovery strategy using gene signatures of smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke, identifying druggable targets expressed in alveolar epithelial progenitors of which we screened the function in lung organoids. We found several drug targets with regenerative potential of which EP and IP prostanoid receptor ligands had the most significant therapeutic potential in restoring cigarette smoke-induced defects in alveolar epithelial progenitors in vitro and in vivo. Mechanistically, we discovered by using scRNA-sequencing analysis that circadian clock and cell cycle/apoptosis signaling pathways were enriched in alveolar epithelial progenitor cells in COPD patients and in a relevant model of COPD, which was prevented by PGE2 or PGI2 mimetics. Conclusively, specific targeting of EP and IP receptors offers therapeutic potential for injury to repair in COPD.

Expression of bronchodilatory β2-adrenoceptors and bronchoconstrictive muscarinic M3-receptors alter with airway size. In COPD, (a combination of) β2-agonists and muscarinic M3-antagonists (anticholinergics) are used as bronchodilators. We studied whether differential receptor expression in large and small airways affects the response to β2-agonists and anticholinergics in COPD. Bronchoprotection by indacaterol (β2-agonist) and glycopyrrolate (anticholinergic) against methacholine- and EFS-induced constrictions of large and small airways was measured in guinea pig and human lung slices using video-assisted microscopy. In guinea pig lung slices, glycopyrrolate (1, 3 and 10 nM) concentration-dependently protected against methacholine- and EFS-induced constrictions, with no differences between large and small intrapulmonary airways. Indacaterol (0.01, 0.1, 1 and 10 μM) also provided concentration-dependent protection, which was greater in large airways against methacholine and in small airways against EFS. Indacaterol (10 μM) and glycopyrrolate (10 nM) normalized small airway hyperresponsiveness in COPD lung slices. Synergy of low indacaterol (10 nM) and glycopyrrolate (1 nM) concentrations was greater in LPS-challenged guinea pigs (COPD model) compared to saline-challenged controls. In conclusion, glycopyrrolate similarly protects large and small airways, whereas the protective effect of indacaterol in the small, but not the large, airways depends on the contractile stimulus used. Moreover, findings in a guinea pig model indicate that the synergistic bronchoprotective effect of indacaterol and glycopyrrolate is enhanced in COPD.

Background: Air pollution is caused mainly by diesel burning and is associated to increased morbidity and mortality due the potential adverse health effects caused by inflammation and oxidative stress. Dimethyl fumarate (DMF) is a fumaric acid ester and acts as an anti-oxidative and anti-inflammatory. We aimed to investigate the therapeutic effect of DMF against pulmonary damage caused by diesel exhaust particles (DEP) chronic exposure of mice. Methods: Mice were treated with DEP (30 μg/mice) of by intranasal instillation over 60 consecutive days. After day 30, the animals were treated with 30 mg/kg of DMF by gavage until the end of the experiment. Results: We demonstrated the reduction of total cell number in DEP+DMF than in DEP group. Importantly, DMF treatment was able to reduce the lung injury caused by DEP exposure. Intracellular total ROS, peroxynitrite (OONO) and nitric oxide (NO) levels reduced in DEP+DMF than in DEP group. The protein expression of kelch-like ECH-associated protein 1 (Keap-1) and nuclear factor κB (NF-κB) reduced in DEP+DMF compared to DEP group. NF-κB decreased in DEP+DMF than in control group. Nitrotyrosine, glutathione peroxidase-1/2 (GPx-1/2) and catalase expression decreased in DEP+DMF than in DEP group. Conclusion: In conclusion, our study is the first to demonstrates that treatment with DMF effectively ameliorates DEP-induced lung injury, inflammation, and oxidative and nitrosative stress. Since air pollution poses a common and serious health threat world-wide, the identification of DMF as a potent antioxidant and anti-inflammatory agent in the lungs could benefit the development of therapeutic approaches against airway pollution-associated malignancies.

Objectives Long-term survivors of childhood cancer are at increased risk for sequelae such as poor mental health (MH) or impaired health-related quality of life (HrQoL). We aimed to evaluate early adverse effects on MH and HrQoL in young childhood cancer survivors (YCCS) before school entry. Methods In a nationwide prospective cohort study, children with cancer other than brain tumors diagnosed at preschool age and completed cancer treatments were identified from the German Childhood Cancer Registry. The comparison group was children of the same age without a cancer diagnosis who participated in the prospective population-based health survey ikidS. MH problems and HrQoL were assessed by parental versions of the Strengths and Difficulties Questionnaire (SDQ) and the questionnaire for health-related quality of life in children (KINDL), respectively. Associations between cancer and MH as well as HrQoL were analyzed by multivariable linear regression. Results Of 382 YCCS contacted, 145 were enrolled (mean age 6.6 years) and 124 analyzed. Compared to children without a cancer diagnosis (3683 contacted, 2003 enrolled, 1422 analyzed), YCCS had more MH problems (13% vs. 3%) and slightly worse HrQoL (median 78.7 vs. 80.2 points). In the adjusted analysis, YCCS had higher SDQ scores (2.2 points, 95% confidence interval [CI] 1.3, 3.0) and lower KINDL scores (-2.4 points, 95% CI -3.7, -1.1) compared to children without cancer diagnosis. Conclusion Already at preschool age, YCCS may be at increased risk of MH problems and impaired HrQoL. This could have impacts on subsequent school performance and educational attainment. Follow-up health care for YCCS may include early screening for MH problems and reasons for HrQoL deficits.

Background: COPD is characterized by irreversible airflow limitation and emphysema development associated with defective lung repair. Currently, there is no pharmacological treatment targeting lung repair in COPD. Methods: 2 microarray datasets of lung tissue from CS exposed mice and COPD patients were analyzed to select potential novel drug targets for lung repair. Murine lung organoids were set up by co-culturing epithelial cells (EpCAM+/CD45-/CD31-) with CCL206 fibroblasts in Matrigel. Results: Several common genes and pathways were identified in the experimental CS model and COPD patients. 38 upregulated and 30 downregulated genes were identified that showed concordant regulation in CS exposed mice and in COPD patients. We further filtered these genes for expression in alveolar epithelial type II cells and fibroblasts and for their potential as drug targets, yielding 19 targets which we screened in CSE-exposed lung organoids. 6 targets showed potential as drug targets for repair including PGE2 (target gene PTGES) and PGI2 (target gene PGIR), both of which completely restored the reduced alveolar epithelial organoid number in response to CSE. Progenitors isolated from CS exposed murine lungs had significantly repressed organoid formation; however, both in vivo and in vitro treatment with PGE2 (misoprostol)/PGI2 (iloprost) agonists restored organoid numbers. For PGE2, the effects were mimicked by an EP4 agonist but not by an EP2 agonist. Conclusion: A transcriptomics-guided drug discovery strategy yielded 6 potential targets that potentially restore lung repair. Of these, PGE2 and PGI2 had the most significant therapeutic potential in correcting the response to CS both in vitro and in vivo.

Diesel exhaust particles (DEP) causes air pollution and is envisioned as cause for lung disorders including COPD. DEP induces inflammation and reactive oxygen species (ROS), linked to mitochondrial dysfunction. Bronchial epithelial cell damage drives epithelial-to-mesenchymal transition (EMT) and fibrosis, processes sensitive to cAMP. Exchange proteins directly activated by cAMP (Epac’s) are mediators of fibrosis and inflammation. Epac’s expression (function) is altered by oxidative stress. Epac’s role in DEP induced lung injury is unknown. BEAS-2B cells were exposed to different concentrations (= 300 µg/ml) of DEP = 72h. Markers: inflammation (IL-8 (CXCL8), IL-8, IL-6), oxidative stress (thioredoxin (TXN), heme oxygenases (HMOX1/2), HIF1A, GPX1, CAT), mitochondrial activity (Nrf1, SOD1/2/3)), mitochondrial shape (mitotracker), viability, metabolism (Seahorse), cAMP (Epac’s), EMT (NRF1, E-cadherin), cell migration (wound healing, xCelligence). DEP increased CXCL8 and IL-6, not IL-8. DEP induced HMOX1 not HMOX2 or HIF1A; enhanced TXN and SOD2 but decreased GPX1. CAT and SOD1 were unchanged. DEP reduced cell viability. NRF1 was up- and E-cadherin reduced. DEP delayed wound healing and BEAS-2B cell adherence. DEP changed mitochondria morphology, reduced mitochondrial bioenergetics (respiration, ATP, spare capacity). Next, DEP induced transient alterations in cAMP, and Epac’s expression. DEP change inflammation, ROS handling, accompanied by EMT-like features. DEP alters mitochondrial bioenergetics and cAMP dynamics evidenced by alterations in the abundance of both Epac’s. Currently, we pharmacologically target Epac’s to restore mitochondria bioenergetics in experimental models of DEP.

Background: Air pollution has been linked to COPD development; however, the precise mechanisms involved are unclear. We hypothesized diesel exhaust particles (DEP) may reduce the functionality of lung epithelial progenitors, whereas anti-oxidants may protect against the influence from DEP. Methods: Murine lung organoids were set up by co-culturing epithelial cells (EpCAM+/CD45-/CD31-) with CCL206 fibroblasts in Matrigel. Organoids were exposed to DEP (50-, 100-, 200 µg/ml) and/or NAC (1mM)/MitoQ (1μM). Results: The total organoid number was decreased by 200 μg/mL DEP by day7, yet increased by 50 and 100 μg/mL DEP. Subclassifying the organoids into airway/alveolar organoids revealed that airway organoid number was increased by 50 and 100 μg/mL DEP, and decreased by 200 μg/mL DEP by day14. Alveolar organoid number was decreased by 200 μg/mL DEP. Immunofluorescence studies confirmed that 200 μg/mL DEP decreased the number of acetylated-α tubulin+ and pro-SPC+ organoids. The size of alveolar organoids was also reduced by 200 μg/mL DEP. In line with these findings, the gene expression of FGF2, FGF7, FGF10 and HGF was decreased in fibroblasts by 200 μg/mL DEP. Interestingly, NAC (1mM) or MitoQ (1μM) rescued the number of alveolar organoids after exposure to 200 μg/mL DEP, but had no influence on airway organoids. NAC and MitoQ had no influence on organoid size. Conclusion: DEP functionally inhibit lung organoid formation by epithelial progenitors, which may contribute to defective alveolar repair in COPD. NAC and MitoQ protect against the damage from DEP in alveolar epithelial progenitors.

Introduction Breast cancer diagnosed in young women who are 40 years (yrs) or younger is a relatively rare disease. However, it represents the most common cause of cancer-related deaths in this age-group. Furthermore, young age at diagnosis is associated with an increased risk of recurrence and worse survival. To date, general concepts concerning oncological cancer management should be driven by clinicopathological tumor characteristics and should adhere to standardized protocols for patients in general, but little is known about the oncological cancer treatment and outcome of this very young women in today's clinical practice. Patients and Methods The breast cancer in pregnancy registry study (BCP/GBG29/BIG 03-02) is a multicenter, international, observational study. BCP was established to investigate the oncological management and outcome of breast cancer in pregnancy. Since 2014 non-pregnant patients who are 40 yrs or younger are eligible if diagnosed with histological confirmed invasive breast cancer, independent of the type of treatment as control cohort. All patients received oncological treatment according to local standards. In this study the following endpoints will be analyzed descriptively for the young non-pregnant women cohort: breast cancer staging at diagnosis, biological characteristics of breast cancer at diagnosis, diagnostic procedures, treatment modalities, toxicity, pathological complete response after neoadjuvant chemotherapy, disease-free survival and overall survival. Results From February 2014 until June 2018, 969 non-pregnant patients ≤40 yrs have been registered. The median age at diagnosis was 35 yrs (range 19-40). Overall, 90.1% of patients had a stage T1-2 at diagnosis and 67.1% of patients had negative lymph nodes. 86.7% of tumors were invasive ductal carcinomas and 4.1% lobular carcinomas. Grading (G) 3 was reported in 55.5%. 26.6% of tumors were luminal A-like (ER- and/or PgR-positive, HER2-negative, G1-2), 40.0% luminal B-like (ER- and/or PgR-positive, HER2-negative, G3 or ER- and/or PgR-positive, HER2-positive, any G), 7.7% HER2 positive non-luminal-like, and 25.7% triple negative breast cancers. 3.8% of young non-pregnant patients had metastatic disease at primary diagnosis. Conclusion This registry comprises a large cohort of young non-pregnant patients with breast cancer diagnosed at the age of 40 yrs or younger and provides important data about a modern breast cancer treatment as well as oncological outcome in this setting of young women. Further results including oncological management, toxicity, and survival will be presented at the meeting. Citation Format: Seiler S, Schmatloch S, Reinisch M, Neunhöffer T, Schmidt M, Bechtner C, Marmé F, Wagner M, Möbus V, Reimer T, Kleine-Tebbe A, Sinn B, Stickeler E, Untch M, Janni W, Seither F, Loibl S. Cancer management and outcome of very young non-pregnant patients with breast cancer diagnosed at 40 years or younger– GBG 29 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-17-07.

Background: The treatment of triple negative breast cancer (TNBC) is hampered by the lack of established therapeutic targets such as hormone receptors or HER-2. Chemotherapy and radiotherapy is the standard of care, yet survival rates in TNBC remain poor. Approaches tailored to the patient's individual tumor signature may lead to improved therapeutic outcome. We have set up a clinical workflow covering drug development (from target discovery to manufacturing) and drug release providing a custom-made investigational medicinal product (IMP) for each individual patient. Trial Design: A phase I/II trial assesses the feasibility, safety and biological efficacy of this personalized immunotherapy in three clinical sites in Germany and Sweden. TNBC patients (pT1cN0M0 – TxNxM0) after completion of initial standard of care therapy will be allocated to one of two study arms. Patients in ARM1 receive 8 vaccination cycles with a personalized combination of shared tumor-associated antigens, selected based on each patient tumor's antigen-expression profile out of a WAREHOUSE of pre-manufactured mRNA vaccine. Patients in ARM2 receive the personalized mRNA WAREHOUSE vaccine followed by 8 vaccination cycles of an on-demand manufactured mRNA MUTANOME vaccine encoding up to twenty unique neo-epitopes of the individual patient identified by next generation sequencing. The mRNAs are administered intravenously as a nanoparticulate lipoplex formulation, which protects RNA from degradation, activates innate immunity, transfects APCs and consequently induces highly potent antigen-specific T-cell responses. The treatment of 12 patients in ARM1 is completed and enrolment of patients for ARM2 has started. Preliminary data show that the RNA-WAREHOUSE approach is feasible and can be applied safely. Biomarker analysis is ongoing. This approach is promising as it addresses the heterogeneity of TNBC. The TNBC-MERIT trial was initially funded by the EU Commission's FP7 and led by BioNTech AG. Citation Format: Schmidt M, Bolte S, Frenzel K, Heesen L, Derhovanessian E, Bukur V, Diken M, Gruetzner J, Kreiter S, Klein A, Kuhn A, Langer D, Loewer M, Lindman H, Schneeweiss A, Tuereci O, Sahin U. Highly innovative personalized RNA-immunotherapy for patients with triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-06-01.

Introduction: Currently, a multi-center, open-label, phase I/IIA, dose-escalation study with the fetal estrogen estetrol (E4) is ongoing in Germany in postmenopausal patients with advanced breast cancer (ABCE4 study). The objective of the study is to assess safety and tolerability of different doses of E4 (range 20-60 mg per day). In addition initial anti-tumor response will be determined. Study design: Patients are treated for 12 weeks with E4; 4 weeks in Phase I and thereafter 8 weeks in Phase IIA. Phase I of the study will follow the traditional 3 + 3 design to determine the optimal dose in patients with advanced breast cancer. Patients are treated in cohorts of three all receiving the same dose. Occurrence of dose limiting toxicity (DLT) at completion of phase I (4 weeks treatment) will determine escalation to the next higher dose in the study. After completion of Phase I, patients will continue treatment for 8 weeks to assess preliminary anti-tumor response in Phase IIA. Treatment may continue beyond 12 weeks based on evaluation of the patient and her treating physician. Results: Phase I of the first treatment cohort with 20 mg E4 per day has been completed. A total of six postmenopausal women with advanced breast cancer has been included in the first cohort. One patient withdrew consent before treatment with E4 started. She was replaced. Two patients discontinued the study before completion of Phase I for reasons other than DLTs. These patients were unevaluable for toxicity and were also replaced. Three patients completed Phase I. One patient discontinued the study during Phase IIA due to disease progression after 9,5 weeks of E4 treatment. One patient completed both the Phase I and IIA part of the study. She had stable disease at study completion and wanted to continue E4 treatment because of improved well-being. Tumor assessment after 24 weeks of E4 treatment showed again stable disease. One patient is presently in Phase IIA of the study. None of the patients experienced a DLT. The 20 mg E4 dose was well tolerated by all patients. In total 17 adverse events were reported. Adverse events were mainly of mild or moderate intensity. Five of 17 events fulfilled criteria of seriousness; none of these events were considered to be related to the E4 treatment. Four events were considered to be possibly related to the E4 treatment. These events were increased endometrial thickness, dry skin, pruritus and fatigue, all of mild intensity. A remarkable finding was that three of the five patients treated with E4 reported to the investigator to “feel better” than before the start of E4 treatment. This '”feeling better” was described by one of the patients as: '”feeling less down and exhausted; instead feeling much more optimistic, powerful and positive when taking E4”. So far anti-tumor response could be estimated in one patient. This patient, who started the study with progressive disease, had stable disease as shown by tumor assessments after 12 weeks and 24 weeks of E4 treatment. Conclusion: Based on these results, we conclude that a daily dose of 20 mg E4 is well tolerated. The majority of patients experienced favorable subjective effects on wellbeing. The data obtained with the 20 mg dose E4 allow dose escalation to the next higher dose of 40 mg E4 per day. Citation Format: Schmidt M, Hönig A, Verhoeven C, Almstedt K, Battista M, Lenhard HG, Krijgh J, Coelingh Bennink H. Estetrol for treatment of advanced ER+ breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-13-12.

Background: In the pivotal BOLERO-2 trial, everolimus (EVE) + exemestane (EXE) more than doubled the median progression-free survival (PFS) vs EXE alone in hormone receptor positive (HR+), human epidermal growth factor-receptor 2-negative (HER2-) advanced breast cancer (ABC) recurring/progressing on/after prior non-steroidal aromatase inhibitors (NSAIs). BRAWO is a German non-interventional study conducted in patients (pts) with HR+, HER2–ABC receiving EVE + EXE, according to Summary of Product Characteristics (SmPC), in routine clinical practice. Here we report the final PFS and safety results. Methods: This multicenter study documented 2100 pts between October 2012 and December 2017 across 341 sites in Germany. Postmenopausal women with HR+, HER2– ABC with recurrence or progression after a NSAI were included. Primary observation parameters included the evaluation of the effectiveness of EVE + EXE used in routine care for the entire pt group. Results: In the final analysis, out of the 2100 documented pts, 2074 were included in the full analysis set. The median time since the primary diagnosis was 7.1 years and the median time from first sign of relapse (local recurrence or distant metastases) was 2.1 years. At baseline, 54.1% of pts presented with visceral metastases and 50.1% had an ECOG performance status of 0. Approximately, 63% of pts started with EVE 10 mg (median duration of exposure: 5.1 months; 95% CI, 4.6-5.4), while 34.1% started with EVE 5 mg (median duration of exposure: 4.6 months; 95% CI, 4.1-5.2). The distribution of treatment lines was as follows: first line, 28.7% (n=595); second line, 31.9% (n=662); third line, 18.1% (n=376); fourth line, 10.7% (n=221) and, fifth line and later, 10.6% (n=220). Treatment was discontinued by 55.7% of pts (n=1170) due to progressive disease and 26% of pts (n=546) due to adverse events. The Kaplan-Meier estimate of the median PFS was 6.6 months (95% CI, 6.2-7.0). The best overall responses, based on clinical routine, were complete response, 0.8% (n=17), partial response, 7.4% (n=150), and stable disease, 41.3% (n=842). The general safety profile was consistent with the previously reported safety findings. The most common adverse events were stomatitis (any grade: 42.6%, grade 3: 3.8%, grade 4: Conclusions: Data from BRAWO support EVE + EXE as a suitable treatment option with a reasonable safety profile for HR+, HER2− ABC recurring or progressing on/after prior NSAIs. Citation Format: Lüftner D, Schuetz F, Schneeweiss A, Grischke E-M, Bloch W, Decker T, Uleer C, Salat C, Förster F, Schmidt M, Mundhenke C, Tesch H, Jackisch C, Fischer T, Guderian G, Hanson S, Fasching P. Everolimus + exemestane for HR+ advanced breast cancer in routine clinical practice- Final results from the non-interventional trial, BRAWO [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-08.

Atmospheric methane is the second most important anthropogenic greenhouse gas after carbon dioxide. On the global scale, methane emissions are reasonably well constrained but the contributions from individual sources are highly uncertain (Saunois, 2016). According to bottom-up estimates, methane emissions from underground coal mining excavation contribute 11% to all anthropogenic methane sources (Saunois, 2016). However, there is a lack of in situ measurement to verify these estimates. Here we present results from measurements of the methane mole fraction over the Polish part of the Upper Silesian Coal Basin (USCB). Methane mole fraction was measured using vehicles equipped with high precision laser-based instruments (Picarro G2201-i CRDS, Picarro G2301- CRDS). Basic meteorological data (wind speed, wind direction) and GPS location data were collected on the roof of the vehicles. In order to obtain emission estimates, we attempted to cross the plumes from the coal mine shafts using public roads approximately perpendicular to plume downwind from the source. When possible, the plumes were intersected several times at different distances in order to have a closer look at uncertainties. A Gaussian plume model was used to calculate the release rate from the methane single source.In addition to methane mole fraction measurements, we collected air samples for isotopic characterization (δ13C and δD) using isotope ratio mass spectrometry. We observed significant variation in measured methane isotopic composition over USCB (the results are in a range of -321 to -142 ‰ SMOW for δD and -31 to -58 ‰ VPDB for δ13CH4). The results indicated a much larger variability of the isotopic composition of methane emitted from coal mines than assumed previously, which may complicate the distinction of methane emissions from different sources by isotopic characterization.Keywords: Methane, Greenhouse Gases, Clime Change, Coal Mine Ventilation Shafts, Methane Isotopic CompositionsReference:Saunois, M., Bousquet, P., Poulter, B., et al., 2016a. The global methane budget, 2000–2012. Earth Syst. Sci. Data 8, 697–751. https://doi.org/10.5194/essd-8-697-2016. www.earth-syst-sci-data.net/8/697/2016/.This work is part of the Marie Sklodowska-Curie Initial Training Network MEMO2 , which enable us to extend these measurements to other European locations

Reducing methane emissions is an important goal of climate change mitigation policies. Recent studies focused on emissions from oil and gas industry, because fixing gas leaks presents a "no-regret" mitigation solution. Yet, uncertainties regarding the fossil fuel emission rates and locations, as well as temporal and spatial variability, are still large for individual source processes, in particular in regions without regular measurements. The Romanian Methane Emissions from Oil and gas (ROMEO) project brought 13 research teams to Romania in order to quantify emissions from this sector. Methane stable isotopes are widely used for source characterisation, but measurement data is lacking from many important geographical locations, such as Eastern Europe. A total of 380 air samples were collected in urban areas and around oil and gas extraction sites, from ground level vehicles and from an aircraft. There were measured for δ13C-CH4 and δD-CH4 using a continuous flow isotope ratio mass spectrometry (CF-IRMS) system. The results were analysed using the Keeling plot approach to derive source signatures at each sampled site. The source signatures obtained for 76 individual oil and gas operation sites range from -70.5 to -22.4 ‰ V-PDB, and from -252 to -144‰ V-SMOW, for δ13C and δD respectively. They show a large heterogeneity in δ13C, and more regularity in δD values. Variations are affected by the maturity of hydrocarbon deposits, and by different contributions from microbial and thermogenic gas. We will present how the signatures measured at the surface relate to the signatures found for larger plumes sampled from the aircraft. The results of the campaign in Bucharest city reveal a larger contribution from the waste system than fossil fuel fugitive emissions. The isotopic characterisation of methane emissions in this region will help to constrain the methane budget on a regional scale, and to improve national inventories.

Diesel exhaust particles (DEP) causes air pollution and is envisioned as cause for lung disorders including COPD. DEP induces inflammation and reactive oxygen species (ROS), linked to mitochondrial dysfunction. Bronchial epithelial cell damage drives epithelial-to-mesenchymal transition (EMT) and fibrosis, processes sensitive to cAMP. Exchange proteins directly activated by cAMP (Epac’s) are mediators of fibrosis and inflammation. Epac’s expression (function) is altered by oxidative stress. Epac’s role in DEP induced lung injury is unknown. BEAS-2B cells were exposed to different concentrations (≤ 300 µg/ml) of DEP ≤ 72h. Markers: inflammation (IL-8 (CXCL8), IL-8, IL-6), oxidative stress (thioredoxin (TXN), heme oxygenases (HMOX1/2), HIF1A, GPX1, CAT), mitochondrial activity (Nrf1, SOD1/2/3)), mitochondrial shape (mitotracker), viability, metabolism (Seahorse), cAMP (Epac’s), EMT (NRF1, E-cadherin), cell migration (wound healing, xCelligence). DEP increased CXCL8 and IL-6, not IL-8. DEP induced HMOX1 not HMOX2 or HIF1A; enhanced TXN and SOD2 but decreased GPX1. CAT and SOD1 were unchanged. DEP reduced cell viability. NRF1 was up- and E-cadherin reduced. DEP delayed wound healing and BEAS-2B cell adherence. DEP changed mitochondria morphology, reduced mitochondrial bioenergetics (respiration, ATP, spare capacity). Next, DEP induced transient alterations in cAMP, and Epac’s expression. DEP change inflammation, ROS handling, accompanied by EMT-like features. DEP alters mitochondrial bioenergetics and cAMP dynamics evidenced by alterations in the abundance of both Epac’s. Currently, we pharmacologically target Epac’s to restore mitochondria bioenergetics in experimental models of DEP.

Brain metastases (BMs) have a major impact on life expectancy and quality of life for many breast cancer patients. Knowledge about treatment patterns and outcomes is limited.We analysed clinical data of 1712 patients diagnosed with BMs from breast cancer between January 2000 and December 2016 at 80 institutions.Median age at diagnosis of BMs was 56 years (22-90 years). About 47.8% (n = 732) of patients had HER2-positive, 21.4% (n = 328) had triple-negative and 30.8% (n = 471) had hormone receptor (HR)-positive, HER2-negative (luminal-like) primary tumours. The proportion of patients with HER2-positive BMs decreased comparing the years 2000-2009 with 2010-2015 (51%-44%), whereas the percentage of patients with luminal-like tumours increased (28%-34%; p = 0.0331). Patients with BMs in the posterior fossa were more often HER2 positive (n = 169/314, 53.8%) than those diagnosed with triple-negative (n = 65/314, 20.7%) or luminal-like primary breast cancer (n = 80/314, 25.5%), (p 0.0001). Median overall survival (OS) time after development of BMs for the overall cohort was 7.4 months (95% confidence interval [CI]: 6.7-8.0 months). One-year survival rate was 37.7% (95% CI: 35.2-40.1). Patients with HER2-positive tumours had the longest median OS of 11.6 months (95% CI: 10.0-13.4) compared with 5.9 months (95% CI: 5.0-7.2) for patients with luminal-like and 4.6 months (95% CI: 3.9-5.4) for patients with triple-negative tumours. Patients with HER2-positive tumours who received anti-HER2 treatment had longer median OS than those without (17.1 months versus 7.2 months, p 0.0001).Prognosis of patients after developing BMs varies significantly according to the subtype. The outcome in this cohort is similarly poor in triple-negative and HR-positive/HER2-negative patients. Our results underline the high medical need for improvement of treatment and prevention strategies for BMs in breast cancer patients.

Background Chemotherapy (CTx) is a cornerstone in HR+/HER2- advanced/metastatic breast cancer (a/mBC) after failure of endocrine treatment. In this indication, vinorelbine (VRL) is a well-established cytotoxic drug. There is a high medical need for new options that prolong the time between endocrine failure and intensive CTx, which is commonly associated with impaired quality of life and serious side effects. Metronomic CTx was shown to induce disease control in a/mBC with a favorable safety profile. This innovative approach involving continuous daily dosing of oral VRL, which could provide anti-angiogenic and immune-modulatory properties, has not been investigated so far in this indication. Trial Design VinoMetro is an open-label, single-arm, phase II study (Simon two-stage minimax) of metronomic daily oral VRL (30 mg/day) as first-line CTx. The study involves strict safety monitoring with an initial safety run-in. It is accompanied by a steering committee and supervised by an independent data safety and monitoring board (DSMB). The main objectives are to estimate efficacy in terms of clinical benefit rate after 24 weeks of treatment (primary endpoint) and the progression-free survival, amongst others, as well as the assessment of safety and quality of life. Patients with HR+/HER2- a/mBC having failed or being no candidate for endocrine therapy (targeted combinations allowed) and being naïve to palliative CTx are eligible, if they exhibit ECOG 0-1. The main exclusion criteria are prior vinca-alkaloids, aggressive disease requiring combination CTx and CNS involvement. Until 2017-05-31, 7 patients were enrolled. It is planned to include 45 (39 evaluable) patients at 8 German sites until 09/2018. Scheduled completion date is 09/2019. Two interim analyses are planned (first analysis: safety evaluation based on the 10 initial patients with predefined stopping rules). Depending on recruitment, it is planned to include the interim safety data in the congress presentation. VinoMetro is an investigator initiated trial (NCT03007992) sponsored by the University Medical Centre of Johannes Gutenberg-University Mainz, Germany, and supported by an unrestricted grant provided by Pierre Fabre Pharma GmbH (Freiburg, Germany). Citation Format: Schmidt M, Decker T, Fehm T, Fuxius S, Harbeck N, Juhasz-Böss I, Thomssen C, Seehase M, Schollenberger L, Ruckes C, Möbus V. A phase II study of metronomic daily oral vinorelbine as first-line chemotherapy in advanced/metastatic hormone receptor positive (HR+) / human epidermal growth factor receptor 2 negative (HER2-) breast cancer resistant to endocrine therapy - VinoMetro [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-05-02.

Background:Oncogene-induced senescence is considered as a barrier to tumor progression that arrests cells at risk for malignant transformation. Nevertheless, numerous findings demonstrate that senescent cells may also have the opposite function and promote tumor progression through the release of multiple factors called the senescence-associated secretory phenotype or senescence secretome. It is likely that the composition and the physiological consequences mediated by the senescence secretome are dependent on the oncogenes that trigger the senescence program. Breast cancer represents a heterogenous disease that can be divided into breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities. Therefore, tumor initiation and progression of breast cancer subtypes is triggered by variable oncogenic stimuli, and differences in the senescence secretomes within breast tumors might be responsible for tumor initiation, progression, metastasis and therapeutic response. Beside many studies concerning the role of senescence as a barrier to tumor progression using murine xenograft models very few investigations have been performed to elucidate how often senescent tumor cells appear within untreated human tumors, and if present whether these senescent tumor cells may play a role in disease progression, cancer immunosurveillance and therapy resistance. Methode: In the present study we analysed the appearance of senescent cells within invasive human breast cancers from 129 untreated patients. Cellular senescence was detected by the use of SAβ-gal staining and by immunohistochemical detection of p16, p21, p53, Ki67 and lamin B1. Results: Detection of cellular senescence by the use of SAβ-gal staining and detection of p16, p53, Ki67 and lamin B1 within invasive breast carcinomas indicate that senescent tumor cells varies strongly according to the breast cancer subtype. The highest percentages of senescent tumor cells exist within in the HER2-positive and luminal A breast carcinomas whereas no or very few senescent tumor cells were found in triple negative breast tumors. Based on these findings we suggest that the composition of secretomes released by senescent tumor cells from different breast cancer subtypes might be very distinct in respect to their ability to recruit immune cells, which can eliminate senescent tumor cells on one hand and regulate tumor growth, immune surveillance and therapy resistance on the other. Conclusion: Further characterization of senescent secretomes from HER2 and other breast cancer subtypes and their potential role in tumor progression, immune surveillance and therapy response might be warranted for the understanding of cancer biology as well as prognostic and therapeutic applications. Citation Format: Thaler S, Schad A, Kirkpatrick CJ, Sleeman JP, Springer E, Schmidt M, Cotarelo CL. Cellular senescence within HER2-amplified breast cancer: Potential implications for breast cancer immune surveillance and HER2-targeted therapy resistance [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-10-01.

Introduction: The aim of shared decision making (SDM), defined as an interaction between patient and attending physician(s), is a treatment decision in which patients are meaningfully involved. Based on mutual agreement and active participation the awareness of a choice should be created and the choice respected. Many preference-sensitive decisions have to be made in breast cancer treatment. However, little is known about the implementation of SDM in German breast cancer care. We therefore investigated the process of SDM from the patients' perspective. Methods: All breast cancer patients who underwent surgery in one of four certified breast cancer centers in Germany between 07/2016 and 12/2016 were invited by mail to participate in the survey. The experienced decision-making process was assessed using the 9-item Shared Decision Making Questionnaire (SDM-Q-9). SDM-Q-9 items were rated on a 6-point scale ranging from "completely disagree" to "completely agree", added together and transformed into a scale ranging from 0 to 100. The higher the total score the higher the experienced degree of participation in the decision-making process. The survey also assessed patients' satisfaction with treatment, satisfaction with decisions and decisional control preferences, and included a range of demographic and clinical questions. For most items we asked the participants to separately rate decision-making consultations with their inpatient hospital doctors, outpatient gynecologists, outpatient oncologists and primary care providers (PCP). The project is still ongoing, data of approximately 300 patients will be presented at the meeting in December. Results: Of 289 patients approached by mail, 143 filled in the survey (response rate: 49%). Median age at the time of the survey was 62 years (36-89). 83% had breast conserving surgery, 17% mastectomy. 74% were treated with radiation, 31% received neo-/adjuvant chemotherapy. 14% were off-treatment at the time of survey participation, 67% still received antihormonal therapy, 9% anti HER2 treatment, 7% chemotherapy and 2% radiation. Inpatient hospital doctors achieved the highest SDM-Q-9 score (mean of 75, standard deviation of 22) indicating the highest degree of SDM. Oncologists, gynecologists and PCP were rated quite comparable with a mean score of 72 each and standard deviations (SD) of 27, 22 and 31. The mean score for all groups of doctors was 73. For items concerning satisfaction with quality and amount of doctors' information and participation in medical decisions patients showed a high degree of satisfaction, resulting in mean values of 3.6 and 3.5 with SD of 0.6 on a 4-point scale ranging from "1" "very unsatisfied" to "4" "very satisfied". Conclusions: A considerable number of patients took part in the survey. Overall, patients reported to have experienced SDM in many situations where treatment decisions were necessary. Patients were quite satisfied with the quality of information and their participation in medical decisions. However, we do not know whether non-respondents might have had different experiences regarding their treatment decision-making. Further research should include SDM expert observations of breast cancer treatment decisions to validate these findings. Citation Format: Feiten S, Scholl I, Schmidt M, Dünnebacke J, Franzen A, Ernst W, Weide R. Shared decision making (SDM) in routine care treatment of breast cancer patients – a survey of patients following surgery [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-11-07.

Background Over 90% of male breast cancer (BC) patients (pts) have hormone receptor (HR) positive disease. Until today tamoxifen is considered to be the standard of care in male BC pts. Due to the low incidence of male BC, there is a lack of data regarding efficacy and safety. Therapeutic strategies are extrapolated from the standard of care of female BC. However, no prospectively randomized study in male BC pts has been conducted so far. The Male-GBG54 study is the first prospective, randomized, multicenter trial evaluating the efficacy and safety of different endocrine treatment options in male BC patients. Patients and Methods In the phase II Male-GBG54 trial (NCT01638247), pts were randomized to receive either tamoxifen 20 mg/day per os (p.o.) or tamoxifen 20mg/day p.o. + GnRHa subcutaneous (s.c.) q3m or exemestane 25 mg/day p.o. + GnRHa s.c. for 6 months as (neo)adjuvant or metastatic therapy. Further treatment was conducted as per local guidelines. Primary objective was the suppression of oestradiol in the three treatment arms after 3 months of therapy. Secondary objectives comprised oestradiol suppression after six months, compliance and safety of the three therapies, the level of different steroidal hormones (testosterone, dihydrotestosterone, SHBG, FSH, LH) and osteocalcin in the three arms. Quality of Life was assessed using the Aging Male Symptom Score, International Index of Erectile function and International Prostate Symptom Score. Tissue and blood was collected for translational research. Male BC pts with a Karnofsky Index ≥60%, normal blood lipids, and no history or evidence of prostate cancer were eligible. 14 pts per group were needed for the F-test to have 80% power to detect a difference in mean oestradiol decrease between the three therapeutic groups at the 5% significance level. The final sample size was calculated as 48 patients, as a non-parametric test (Kruskal-Wallis) was chosen in case the oestradiol levels are not normally distributed within the study population. Results Between October 2012 and May 2017, 55 pts were randomized within 24 centers in Germany. 52 pts were included in the adjuvant and 2 pts in the metastatic setting of whom 48 pts were fully evaluable and comprised the analysis set. The median age was 62 years (range 37-83 years). The baseline characteristics were well balanced between the 3 treatment groups. Karnofsky Index ranged from 60%-100%, 36.4% had received prior chemotherapy and 12.7% had HER2-positive BC. The majority had a pT2 (52%), pN0 (58.0%) BC. 3 serious adverse events were reported, none was related to the study treatment. Conclusion This is the first prospective randomized trial worldwide evaluating the impact of three different endocrine treatments in male breast cancer. The therapy was well tolerated without safety signals. At the meeting, final results of the primary and secondary endpoints will be present. Citation Format: Reinisch M, Seiler S, Hauzenberger T, Schmatloch S, Strittmatter HJ, Zahm DM, Thode C, Jackisch C, Furlanetto J, Strik D, Stickeler E, Marmé F, Janni W, Schmidt M, Kamischke A, Rudlowski C, Nekljudova V, von Minckwitz G, Loibl S. Male-GBG54: A prospective, randomised multi-centre phase II study evaluating endocrine treatment with either tamoxifen +/- gonadotropin releasing hormone analogue (GnRHa) or an aromatase inhibitor + GnRHa in male breast cancer patients [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD7-10.

Background A new subcutaneous (s.c.) formulation of trastuzumab became available in 2013 based on equivalent efficacy, pharmacokinetic (PK) profile and safety with the standard intravenous (i.v.) administration, where the s.c. trastuzumab was administered only into the thigh. As an s.c. injection into the abdominal wall (abdw) might be more convenient for patients (pts) and health care professionals, the PK profile of s.c. trastuzumab injected into the thigh vs the abdw in pts with HER2+ early BC needs to be evaluated. Methods GAIN-2 study compared two intense dose-dense (idd) anthracycline/taxane containing regimens. After completion of the anthracycline and i.v. trastuzumab given concurrently with taxanes, HER2+ BC pts were randomized in a 1:1 ratio to continue adjuvant s.c. trastuzumab 600mg fixed dose injected every 3 weeks either into the thigh or the abdw. Randomization was stratified according to CT arm [(iddEnPC) vs tailored dd CT (dtEC-dtD)] and age (≤50 vs >50). Pts in the EnPC arm received 14 and in the dtEC-dtD arm 15 cycles of s.c. trastuzumab. For the PK profile of s.c. trastuzumab serum samples collected before cycle 7, on days 2, 4, 8, 15 and 21 of cycle 7 are evaluated. With a total sample size of 30 (15 per group), the simulated 90% two-sided CI for the area under the plasma concentration (AUC0-last) will be (0.79-1.27) and for the peak drug concentration (Cmax) will be (0.77-1.30). Allowing for a dropout rate of 15%, 18 pts per group will be included in the PK analysis. The primary objective was to assess the PK profile of s.c. trastuzumab injected into the thigh vs the abdw. The secondary objectives included safety and tolerability. Results The per-protocol (pp) set consists of 30 pts (17 in the thigh group and 13 in the abdw group). Baseline characteristics were well balanced between the groups. The log-transformed Geometric Least Square Means (GLSM) for Cmax were 11.77 and 11.52 in the thigh and the abdw group, respectively. The geo-mean ratio (on the original scale) for Cmax was 1.29 (90% CI 1.05-1.58). The log-transformed GLSM for AUC0-last were 14.54 and 14.28 in the thigh and the abdw group, respectively. The geo-mean ratio for AUC0-last was 1.29 (90% CI 1.02-1.63). Overall 29 pts (96.7%) reported any grade and 5 pts (16.7%) high grade adverse events (AEs). The incidence of any grade AEs was similar between the two groups. The most common AEs were anemia (70.6% for the thigh vs 61.5% for the abdw group, p=0.705), leukopenia (80.0% for both groups, p=1.000) and fatigue (47.1% for the thigh vs 76.9% for the abdw group, p=0.141). 6 serious AEs were reported (2 in the thigh vs 4 in the abdw group). The final PK results of s.c. trastuzumab will be presented at the meeting. Conclusions Bioavailability of s.c. trastuzumab as reflected by peak and total exposure measured in cycle 7 was approx. 30% higher if administered into the thigh than into the abdw in pts with HER2+ primary BC treated after dose-dense CT plus i.v. trastuzumab. However, no increased toxicity was observed. Study limitations were that no cross-over design was used and number of pts satisfying criteria for pp-set were different in the arms. Citation Format: Möbus V, Mahlberg R, Janni W, Tomé O, Marmé F, Forstbauer H, Reimer T, von der Assen A, Reinisch M, Lorenz R, Schmatloch S, Schmidt M, Sinn B, Klutinus N, Stickeler E, Untch M, Seiler S, Burchardi N, von Minckwitz G, Loibl S. Pharmacokinetic results of a subcutaneous injection of trastuzumab into the thigh versus into the abdominal wall in patients with HER2-positive primary breast cancer (BC) treated within the neo-/adjuvant GAIN-2 study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-20-09.

Background - Fatigue is one of the most common and disabling complaints in patients with breast cancer and can effectively be reduced by physical exercise, with small to moderate effect sizes. To identify heterogeneity in responses to exercise and to further personalize exercise prescriptions, moderators of exercise effects on fatigue should be investigated. However, most randomized controlled trials (RCTs) are not adequately powered for such analyses. Therefore we conducted meta-analyses using the individual patient data of several exercise RCTs. The aim is to investigate the effect and moderators of physical exercise on cancer-related fatigue in patients with breast cancer. Methods - Within the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) consortium, principal investigators of 34 exercise RCTs worldwide have shared their individual patient data. Twenty-two of these RCTs included patients with breast cancer with a total sample size of 3,061. Different questionnaires to assess level of fatigue were used, which was acknowledged by using z-scores in the analysis. A one-step individual patient data meta-analysis, using a linear mixed-effect model adjusted for baseline fatigue, with a random intercept on study (to account for study clustering) was undertaken to investigate effect of exercise on fatigue. The result, a between-group difference in z-scores, corresponds to a Cohen's d effect size. An interaction term was included in the model to assess potential moderators including demographic (age, marital status, education), clinical (body mass index, presence of distant metastasis), intervention-related (intervention timing, delivery mode and duration), and exercise-related (exercise type, frequency, intensity, duration) characteristics. Results – Exercise significantly reduced fatigue reported by women with breast cancer (β= -0.15, 95% CI -0.21;-0.09). This effect did not differ significantly between patients with different demographic and clinical characteristics (p-valuesinteraction >0.05). Also, neither timing (during or post-treatment) and duration of the intervention, nor exercise-related factors moderated intervention effects on fatigue. Supervised exercise had significantly larger effects on fatigue than unsupervised exercise (βdifference= -0.17, 95%CI -0.28;-0.05). Compared to the control group, supervised exercise significantly improved fatigue (β = -0.21, 95%CI = -0.28;-0.14), while unsupervised exercise did not (β = -0.04, 95%CI = -0.14;0.06). Conclusion – Exercise significantly reduces fatigue in patients with breast cancer across subgroups formed on the basis of age, marital status, education level, body mass index, and presence of distant metastasis. The effect of exercise is significantly larger when performed under supervision. Hence, exercise, and preferably supervised exercise, represents a viable intervention for the prevention and treatment of fatigue among patients with breast cancer. Citation Format: van Vulpen JK, Sweegers MG, Kalter J, Peeters PH, Courneya KS, Newton RU, Aaronson NK, Jacobsen PB, Steindorf K, Stuiver MM, Hayes S, Mesters I, Knoop H, Goedendorp M, Mutrie N, Thorsen L, Schmidt M, Sonke GS, Bohus M, James EL, Oldenburg HS, Velthuis MJ, Nollet F, Wenzel J, Wiskemann J, Galvão DA, Chinapaw MJ, Irwin ML, Griffith KA, van Weert E, Daley AJ, McConnachie A, Schulz K-H, Short CE, Plotnikoff RC, Potthoff K, van Beurden M, van Harten WH, Schmitz KH, Winters-Stone KM, Taaffe DR, van Mechelen W, Kersten M-J, Verdonck-de Leeuw IM, Brug J, Buffart LM, May AM. Effect and moderators of exercise on fatigue in patients with breast cancer: Meta-analysis of individual patient data [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-12-06.

Background With regard to quality of life and organ shortage, follow-up after liver transplantation (LT) should consider risk factors for allograft failure in order to avoid the need for re-LT and to improve the long-term outcome of recipients. Therefore, the aim of this study was to explore potential risk factors for allograft failure after LT. Material and methods A total of 489 consecutive LT recipients who received follow-up care at the University Hospital of Muenster were included in this study. Database research was performed, and patient data were retrospectively reviewed. Risk factors related to donor and recipient characteristics potentially leading to allograft failure were statistically investigated using binary logistic regression analysis. Graft failure was determined as graft cirrhosis, need for re-LT because of graft dysfunction, and/or allograft-associated death. Results The mean age of recipients at the time of LT was 50.3 ± 12.4 years, and 64.0 % were male. The mean age of donors was 48.7 ± 15.5 years. Multivariable statistical analysis revealed male recipient gender (p = 0.04), hepatitis C virus infection (HCV) (p = 0.014), hepatocellular carcinoma (HCC) (p = 0.03), biliary complications after LT (p Conclusion Male recipients, patients who received LT for HCV or HCC, those with pretransplant diabetes mellitus, and LT recipients with biliary complications are at high risk for allograft failure and thus should be monitored closely.

Chronic stress has been associated with the progression of cancer and antagonists for β-adrenoceptors (βAR) are regarded as therapeutic option. As they are also used to treat hemangiomas as well as retinopathy of prematurity, a role of endothelial β2AR in angiogenesis can be envisioned. We therefore investigated the role of β2AR-induced cAMP formation by analyzing the role of the cAMP effector molecules exchange factor directly activated by cAMP 1 (Epac1) and protein kinase A (PKA) in endothelial cells (EC). Epac1-deficient mice showed a reduced amount of pre-retinal neovascularizations in the model of oxygen-induced retinopathy, which is predominantly driven by vascular endothelial growth factor (VEGF). siRNA-mediated knockdown of Epac1 in human umbilical vein EC (HUVEC) decreased angiogenic sprouting by lowering the expression of the endothelial VEGF-receptor-2 (VEGFR-2). Conversely, Epac1 activation by β2AR stimulation or the Epac-selective activator cAMP analog 8-p-CPT-2'-O-Me-cAMP (8-pCPT) increased VEGFR-2 levels and VEGF-dependent sprouting. Similar to Epac1 knockdown, depletion of the monomeric GTPase Rac1 decreased VEGFR-2 expression. As Epac1 stimulation induces Rac1 activation, Epac1 might regulate VEGFR-2 expression through Rac1. In addition, we found that PKA was also involved in the regulation of angiogenesis in EC since the adenylyl cyclase (AC) activator forskolin (Fsk), but not 8-pCPT, increased sprouting in Epac1-depleted HUVEC and this increase was sensitive to a selective synthetic peptide PKA inhibitor. In accordance, β2AR- and AC-activation, but not Epac1 stimulation increased VEGF secretion in HUVEC.Our data indicate that high levels of catecholamines, which occur during chronic stress, prime the endothelium for angiogenesis through a β2AR-mediated increase in endothelial VEGFR-2 expression and VEGF secretion.