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  • 1
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    Profiling of activated receptor tyrosine kinases in advanced gastric cancers identifies patients with poor prognosis.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 4011-4011
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 4011-4011
    Abstract: 4011 Background: Metastatic gastric cancer (GCA) remains a therapeutic challenge due to its poor prognosis. Trastuzumab is the only known targeted therapy that has demonstrated a survival benefit in a small subset of metastatic GCAs. Addition of molecular diagnostics for predicting prognosis and therapeutic outcomes can significantly enhance the clinical management of GCAs. Herein, we identify activated receptor tyrosine kinases (RTKs) in distinct GCA subsets that correlate with disease-free survival post-curative GCA surgery. Methods: Fresh frozen GCA tissues from 434 stage I to IV GCA patients were profiled for HER1, HER2, HER3, p95HER2, c-MET and IGF1R RTKs using the multiplexed Collaborative Enzyme Enhanced Reactive (CEER ) immunoassay. CEER is a highly sensitive and specific proximity assay that relies on the formation of a triple antibody complex surrounding the target protein. Results: p95HER2, a known trastuzumab resistance mechanism, was identified for the first time in 79% of IHC/FISH-based HER2(+) GCAs. Full-length HER2 expression was heterogeneous with ~20% of HER2(-) GCAs still expressing the HER2 protein. 232/434 GCAs expressed at least one activated RTK analyzed in our study. Of these 232 patients, 121 patients that presented with stage II or III disease at the time of surgery; demonstrated a worse progression-free survival as compared to those where none of the analyzed RTKs were activated (32.6 months vs 76.5 months, p=0.0318). HER axis members were the most commonly activated RTKs with 64% of such GCAs. Approximately 71% of activated cMET tumors demonstrated a co-activation with a HER axis member with a preference for HER1 in ~61% of cMET-activated GCAs. Patients with p-MET(+):p-HER1(+) GCAs had a worse prognosis as compared to those with p-MET(+):p-HER1(-) GCAs (46.2 months vs 82.8 months, p=0.0184). Conclusions: CEER-based RTK characterization revealed concomitantly activated signaling pathways in GCAs which could predict disease recurrence. Comprehensive molecular profiles of GCA tumors can allow for the implementation of these companion biomarkers in GCA therapeutic clinical trials.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.4011
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 2
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    Profiling of circulating tumor cells isolated from 105 metastatic gastric cancer patients revealed HER2 overexpression/activation for potential use in clinical setting.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 10535-10535
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 10535-10535
    Abstract: 10535 Background: Gastric cancer (GCA) is the second leading cause of cancer mortality in the world. Survival of patients with advanced GCA treated with chemotherapy remains low. New targeted therapies are urgently needed. There is mounting evidence of the role of HER2 overexpression in patients with GCA, and it has been highly correlated to poor outcomes with more aggressive disease. The ability to accurately determine HER2 status by testing circulating tumor cells (CTCs) may improve patient treatment by allowing ongoing assessment of HER2 status during treatment and/or identifying additional patients who could potentially benefit from HER2- targeted therapy. Methods: The Collaborative Enzyme Enhanced Reactive-immunoassay (CEER) was utilized to determine the expression and activation (phosphorylation) levels of HER2 in CTCs isolated from blood specimens obtained from 105 metastatic GCA patients. Results: Utilizing the CEER platform, the levels of HER2 expression and phosphorylation were determined for CTCs isolated from metastatic GCA patients. Evaluable CTCs were found in 33% (35/105) of enrolled patients. Out of 35 patients, 7 patients (20%) have high HER2 over expression, 6 patients (17%) have moderate HER2 expression and 11 patients (31%) have HER2 activation (phospho positive) with no HER2 over-expression. Conclusions: When CTCs were present, the CEER assay identified varying levels of HER2 involvements in 68% of metastatic GCA patients. HER2 positive CTCs could serve as a prognostic and/or predictive marker in patients with advanced GCA and CTC-HER2 profile shifts can be utilized to monitor the treatment efficacy.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.10535
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Pathway redundancy and feedback loop as drivers of nonresponse in colorectal cancer treatments.
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 15_suppl ( 2013-05-20), p. e14626-e14626
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. e14626-e14626
    Abstract: e14626 Background: There is urgent need for rational therapy selection based on functional-pathway characterization to achieve significantly improved clinical outcome. Methods: 207 CRC patients were evaluated for 〉 100 signal transduction proteins. Receptor tyrosine kinases (RTKs, i.e. ErbBs, FGFRs, VEGFRs, cMET, IGF1R, etc) and non-RTKs (Src, FAK, etc) as well as Jak/Stat along with AKT and MAPK pathway proteins were analyzed for their level of expression and activation utilizing Collaborative Enzyme Enhanced Reactive (CEER) immunoarray. In addition to pathway profiling, samples were also molecularly characterized for 14 different mutations within the KRAS, BRAF and PIK3CA oncogenes. Results: Both ErbB/VEGFR driven and ErbB/VEGFR-independent signal transduction activation patterns were observed in the CRC patients with complex redundant pathway circuitry. Phosphorylated RTKs led to downstream AKT and MAPK pathway activation. Various mutations in KRAS, PIK3CA and BRAF were found in 42%, 11% and 4% of CRC patients, respectively. KRAS G12D and G13D mutations were the most frequent mutations. Percent of mutant alleles per input DNA increased in matching metastatic tumors when compared to the primary tumors. While downstream signal transduction via AKT and MAPK pathways were similar in both wild-type and mutant tumors, we observed higher levels of potential compensating non-ErbB driven RTK expression/activation in KRAS mutant patients. A significant pathway redundancy was detected in most tumors. Furthermore, pathway diversity in tumors with identical mutational background was evident in this analysis. Conclusions: CEER-based pathway analysis adds value towards understanding of CRC tumor¡ & hibar;s potential response under various clinical scenarios. The comprehensive characterization of pathway redundancy allows for rational selection of a combination of targeted agents. A combination of Erbitux with anti-angiogenic therapy may provide most benefit for patients with concomitant EGFR and VEGFR2 activation. Based on pathway circuitry determined by CEER, clinicians can optimize clinical decisions in selecting more effective therapies that target relevant pathway proteins.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2013.31.15_suppl.e14626
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
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  • 4
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    A pilot study of evaluation of a phosphorylation signature from pancreatic cancer tumors.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. e14584-e14584
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. e14584-e14584
    Abstract: e14584 Background: The development of targeted therapy in pancreatic cancer has been hindered by minimal material available for molecular analysis from diagnostic endoscopic ultrasound-guided fine-needle aspirations (EUS/FNA). Revealing the phosphorylation status of key pathway mediators would allow optimal selection of patients for kinase inhibitor clinical trials. We launched a pilot study to evaluate the feasibility of detecting phosphorylation signatures from FNA samples using an ultrasensitive multiplexed protein microarray platform (CEER, Prometheus). Methods: Patients who underwent routine diagnostic EUS/FNA for a suspicious lesion in the pancreas underwent two additional EUS passes. Mediators of multiple signaling pathways including HER1/EGFR, HER2, HER3, IGF-IR, and their downstream mediators, AKT, MEK, ERK, et al were evaluated by CEER. Circulating tumor cells (CTCs) and resected tumor specimens were collected as available from patients for comparison. Results: From January-September, 2011, 57 patients were enrolled with a planned final enrollment of 100. This is an interim analysis. Thirty-nine (68.4%) had carcinoma cytology, 9 had atypical and 9 had negative cytology. HER2 (median value of 18 CU vs. 2 CU, p = 0.021) and HER3 (median value of 547 CU vs. 168 CU, p = 0.008) showed significantly higher levels of phosphorylation in malignant FNAs over their counterparts with negative cytology. Robust levels of CK expression were also observed in FNAs with carcinoma cytology (median CK level 1030 CU vs. 106 CU, p = 0.007). The wide range of phosphorylation signatures detected indicates this is a feasible clinical approach. For example, the expression levels of phosphorylated PI3K were 16 (22.5% - low), 28 (39.4% - medium low), 23 (32.4% - medium high), and 2 (2.8% - high). The correlation of p PI3K between 2 passes was 0.59 (p = 0.018) based on the Spearman Correlation. A CEER comparison of FNA vs. surgical specimens and FNA vs. CTCs is forthcoming. Conclusions: Profiling the phosphorylation status of pancreatic cancer pathways from FNA samples is feasible. If further validated, patients with pancreatic cancer can be screened for targeted therapy by their phosphorylation signature.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.e14584
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 5
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    Mechanisms of resistance to PDGFR inhibition in glioblastoma.
    American Society of Clinical Oncology (ASCO) ; 2014
    In:  Journal of Clinical Oncology Vol. 32, No. 15_suppl ( 2014-05-20), p. e13030-e13030
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 15_suppl ( 2014-05-20), p. e13030-e13030
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2014.32.15_suppl.e13030
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
    detail.hit.zdb_id: 2005181-5
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  • 6
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    Roles of cMET/ErbB3 activation and overexpression in the development of resistance to EGFR inhibitors in NSCLC patients.
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 15_suppl ( 2013-05-20), p. 11113-11113
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 11113-11113
    Abstract: 11113 Background: Multifaceted efforts in the molecular and cellular research of lung cancer revealed many critical pathway dysregulations due genetic and epigenetic alterations to alter balances in signal transduction leading to carcinogenesis. Methods: US guided FNAs or pleural fluid were collected from 44 NSCLC patients enrolled in on-going prospective study involving EGFR inhibitors (gefitinib, erlotinib, or afatinib) and evaluated for EGFR as well as other various receptor tyrosine kinases (RTKs, i.e. ErbB2, ErbB3, cMET, IGF1R, ALK, etc) and downstream AKT and MAPK pathway proteins for their level of expression and activation in order to 1) Compare objective response rate according to the expression/activation of RTK and pathway proteins; 2) Evaluate the modulation of the RTK and pathway proteins during the treatment of EGFRi; 3) Correlate between activating EGFR gene mutations and RTK activation in patients treated with EGFRi. Results: Majority of patients over-expressed EGFR. While not overexpressed, varying and significant levels of cMET and ErbB3 were found and quantitated in each patient. A striking difference in PFS was observed with respect to relative levels of cMET to EGFR in pretreatment FNA. Regardless of EGFR mutation status, patients with higher levels of EGFR to cMET (or higher E/M-Index) showed superior PFS. With an increase in cMET involvement (or decrease in E/M-Index; continuous variable), NSCLC patients exhibited worse clinical outcome with reduction in PFS (as shown in the Table). Furthermore, patients with shorter PFS ( 〈 8 months) had significantly higher levels of total and phosphorylated ErbB3 (67% positive) than patients with longer PFS ( 〉 8 months, 27% positive). Conclusions: This study clearly demonstrates the critical roles of cMET and ErbB3 in resistance to EGFR inhibitors in NSCLC patients. E/M-Index and activation may serve as predictive markers for treatment selection with EGFRi and cMETi, and should be validated in prospective clinical studies. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2013.31.15_suppl.11113
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
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  • 7
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    Phase I trial of daily PI3Kα inhibitor BYL719 plus letrozole (L) or exemestane (E) for patients (pts) with hormone receptor-positive (HR+) metastatic breast cancer (MBC).
    American Society of Clinical Oncology (ASCO) ; 2014
    In:  Journal of Clinical Oncology Vol. 32, No. 15_suppl ( 2014-05-20), p. 2605-2605
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 15_suppl ( 2014-05-20), p. 2605-2605
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2014.32.15_suppl.2605
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
    detail.hit.zdb_id: 2005181-5
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  • 8
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    Identifying targetable pathways in pancreatic cancer from endoscopic ultrasound-guided fine-needle aspirates (EUS/FNA): Providing a personalized approach to targeted therapy.
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 15_suppl ( 2013-05-20), p. 4051-4051
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 4051-4051
    Abstract: 4051 Background: Targeted therapy trials in pancreatic cancer patients have either failed or, at most, provided only marginal benefit. Identification of activated key signaling pathways would allow the optimal selection of patients for kinase inhibitor trials. Hence, we launched a study to profile targetable pathways from EUS/FNA samples using an ultrasensitive multiplexed protein microarray platform (CEER, Prometheus). Methods: Patients who underwent routine diagnostic FNA for a suspicious lesion in the pancreas underwent two dedicated passes for CEER profiling of the following phosphorylated (activated) key molecules: HER1, HER2, HER3, c-met, IGF-IR, PI3K, AKT, MEK, ERK, and other signaling proteins. Results: Of 100 participants, final cytology results were: 73 carcinomas, 8 indeterminate, 13 negative, and 5 neuroendocrine. Pathway activation was heterogeneous in patients with carcinoma. Among 61 pancreatic cancer patients with adequate HER evaluation, a high prevalence of HER3 activation (62%) was observed, and concomitant activation of two or more HER pathways was seen in 52% of patients. In particular, activation of HER2 and HER3 was noted in 23% of carcinoma patients. High concordance of HER, PI3K and AKT activation was seen. Conclusions: Our study confirmed the feasibility of profiling targetable pathways from FNA samples. Furthermore, it illustrates highly variable and concomitant pathway activation among pancreatic cancer patients, suggesting the feasibility of a personalized approach to targeted therapy. Future trials will need to be designed to explore the clinical benefit of combinations of HER-targeted agents in defined subsets of pancreatic cancer patients, and further evaluation of the HER3 pathway is especially warranted. An analysis of pathway interactions and prognostic effects is in progress. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2013.31.15_suppl.4051
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
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  • 9
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    A comprehensive comparison of circulating tumor cell capturing technologies by apheresis of cancer patients.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. e21017-e21017
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. e21017-e21017
    Abstract: e21017 Background: Obtaining tumor tissue from cancer patients for diagnosis and biomarker assessment for patient selection is challenging. Circulating tumor cells (CTCs) may represent an attractive alternative as a “liquid biopsy”. However, capturing these rare cells from whole blood is a major challenge that still needs significant improvement. Here we present preliminary data of an ongoing study comparing different CTC capturing technologies. Methods: A collaboration network between Bayer Pharma AG, the University of Düsseldorf as clinical partner and providers of CTC capture methods was established. In addition logistics were organised to guarantee a fast and reliable sample transfer. For optimal comparison, CTC preparations from the same patient were used. The required high amounts of sample aliquots and CTCs was obtained by apheresis. Breast and pancreatic cancer patients (non- and metastatic) were enrolled. Blood samples were obtained, as well as buffy coat by apheresis. Samples were shipped within 48 h to partner companies for CTC analysis. At two sites the CellSearch system by Veridex was performed. Today’s standard was compared with another antigen-based method, a filter method and an approach depending on electrophysiological properties. Downstream analysis of the isolated CTCs was performed at Prometheus using their sensitive immunoassay. Results: Significantly higher CTC amounts were detected in buffy coats obtained by apheresis in comparison with CTC counts obtained from a blood draw. In contrast to the blood samples, all methods were able to detect CTCs in buffy coats from both non-metastatic and metastatic cancer patients. The included novel approaches showed in general a better yield of CTCs in comparison to CellSearch. Downstream analysis revealed individual signalling pathway activity profiles. Conclusions: Apheresis is a suitable procedure to capture high amounts of CTCs and therefore to enable an optimal technology comparison. The isolated CTCs are viable and stimulatable. The preliminary results of our study show that an improvement in CTC capturing is taken place, indicating an important step forward regarding the use of CTCs as “liquid biopsy” in a clinical setting.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.e21017
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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  • 10
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    In vivo isolation of circulating tumor cells in non-small cell lung cancer (NSCLC) patients by a medical device.
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 10536-10536
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 10536-10536
    Abstract: 10536 Background: Currently, circulating tumor cells (CTCs) are isolated in vitro from small limited volumes of blood samples. Furthermore, CTC results for NSCLC as a prognostic and stratification biomarker are scarce. The aim of the study was to assess a functionalized and structured medical wire (FSMW) for in vivo isolation of CTCs directly from the blood of NSCLC patients, and to compare it to the Cell Search method. Methods: The device was inserted in a cubital vein through a standard cannula for thirty minutes. The interaction of target CTCs with the FSMW was mediated by an antibody directed against the epithelial cell adhesion molecule (EpCAM). To confirm the CTCs binding to the wire, the immunohistochemical staining against EpCAM as well as CD45 for negative cell selection was performed. There were 72 applications of the wire in 48 stage I-IIIB NSCLC patients (12 double applications) and 12 non cancer patients. Enumeration data was available for 34 NSCLC patients and 8 non cancer patients. For 34 patients, samples were also tested in the Cell Search system. Results: The device was well tolerated in all 72 applications without side effects. We obtained in vivo isolation of CTCs in 32 of 34 NSCLC patients (94.1%) with a median (range) of 13 (0-300) CTCs. The sensitivity was similar for early and late stage NSCLC patients. In the non-cancer patients, no CTCs were detected (100 % specificity). In 2 of 34 samples (5.8%), CTCs were detected by the Cell Search method. In all matched pairs, the FSMW detected the same number or more CTCs compared to the Cell Search method. Conclusions: Whilst well tolerated without side effects, the CTC detection rate of the FSMW in NSCLC patients was 〉 90%. In contrast, 〈 10% detection was obtained using the Cell Search analysis. No CTCs were detected in non-cancer patients. This proof of concept study may have important clinical implications, as the implementation of the device into clinical practice may improve early detection, prognosis and therapy monitoring of NSCLC patients. The method may also allow the molecular analysis of the CTCs, with the possibility of establishing more personalized treatment regiments.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.10536
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
    detail.hit.zdb_id: 2005181-5
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