M Micksche

Medical University of Vienna, Wien, Vienna, Austria

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Publications (271)878.01 Total impact

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    ABSTRACT: Enhanced signalling via the epidermal growth factor receptor (EGFR) is a hallmark of multiple human carcinomas. However, in recent years data have accumulated that EGFR might also be hyperactivated in human sarcomas. Aim of this study was to investigate the influence of EGFR inhibition on cell viability and its interaction with chemotherapy response in osteosarcoma cell lines. We have investigated a panel of human osteosarcoma cell lines regarding EGFR expression and downstream signalling. To test its potential applicability as therapeutic target, inhibition of EGFR by gefitinib was combined with osteosarcoma chemotherapeutics and cell viability, migration, and cell death assays were performed. Osteosarcoma cells expressed distinctly differing levels of functional EGFR reaching in some cases high amounts. Functionality of EGFR in osteosarcoma cells was proven by EGF-mediated activation of both MAPK and PI3K/AKT pathway (determined by phosphorylation of ERK1/2, AKT, S6, and GSK3β). The EGFR-specific inhibitor gefitinib blocked EGF-mediated downstream signal activation. At standard in vitro culture conditions, clinically achievable gefitinib doses demonstrated only limited cytotoxic activity, however, significantly reduced long-term colony formation and cell migration. In contrast, under serum-starvation conditions active gefitinib doses were distinctly reduced while EGF promoted starvation survival. Importantly, gefitinib significantly supported the anti-osteosarcoma activities of doxorubicin and methotrexate regarding cell survival and migratory potential. Our data suggest that EGFR is not a major driver for osteosarcoma cell growth but contributes to starvation- and chemotherapy-induced stress survival. Consequently, combination approaches including EGFR inhibitors should be evaluated for treatment of high-grade osteosarcoma patients.
    Journal of Experimental & Clinical Cancer Research 12/2015; 34(1). DOI:10.1186/s13046-015-0251-5 · 4.43 Impact Factor
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    ABSTRACT: Human telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase and is located on chromosome 5p15, a genomic region which was found to be associated with multiple cancer types. But no associations with colorectal cancer (CRC) have been reported until recently. Therefore, the purpose of this study was to investigate the influence of seven single-nucleotide polymorphisms (SNPs) of TERT on susceptibility to colorectal polyps and CRC. The study population of our ongoing colorectal cancer study of Austria (CORSA) comprised 3,842 Caucasian participants. A total of 3,264 participants was genotyped including 142 CRC cases, 492 high-risk polyps, 837 low-risk polyps, and 1,793 polyp-free controls verified by colonoscopy. Genotyping was performed by TaqMan assay using genomic DNA. The impact of each SNP was estimated by multiple logistic regression analyses performed with R Version 2.11.1. None of the investigated TERT SNPs (rs2736122, rs2853676, rs2735940, rs2736098, rs2075786, rs2736100, rs4975605) were found to be associated with risk of CRC nor colonic polyps. However, the haplotype CGTATGG was associated with a significantly increased risk of high-risk polyps (OR = 1.48, 95% CI 1.01-2.17, P = 0.043). In accordance with other studies our results suggest no major influence of the investigated TERT SNPs on CRC and colorectal polyp risk. However, relevance of telomerase in tumorigenesis of multiple malignancies demands further investigations of the 5p15 locus concerning CRC susceptibility. © 2012 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 10/2012; 51 Suppl 1(S1):E176-82. DOI:10.1002/mc.21911 · 4.81 Impact Factor
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    ABSTRACT: Cutaneous melanoma is a tumor with rising incidence and a very poor prognosis at the disseminated stage. Melanomas are characterized by frequent mutations in BRAF and also by overexpression of fibroblast growth factor 2 (FGF2), offering opportunities for therapeutic intervention. We investigated inhibition of FGF signaling and its combination with dacarbazine or BRAF inhibitors as an antitumor strategy in melanoma. The majority of melanoma cell lines displayed overexpression of FGF2 but also FGF5 and FGF18 together with different isoforms of FGF receptors (FGFRs) 1-4. Blockade of FGF signals with dominant-negative receptor constructs (dnFGFR1, 3, or 4) or small-molecule inhibitors (SU5402 and PD166866) reduced melanoma cell proliferation, colony formation, as well as anchorage-independent growth, and increased apoptosis. DnFGFR constructs also significantly inhibited tumor growth in vivo. Combination of FGF inhibitors with dacarbazine showed additive or antagonistic effects, whereas synergistic drug interaction was observed when combining FGFR inhibition with the multikinase/BRAF inhibitor sorafenib or the V600E mutant-specific BRAF inhibitor RG7204. In conclusion, FGFR inhibition has antitumor effects against melanoma cells in vitro and in vivo. Combination with BRAF inhibition offers a potential for synergistic antimelanoma effects and represents a promising therapeutic strategy against advanced melanoma.
    Journal of Investigative Dermatology 07/2011; 131(10):2087-95. DOI:10.1038/jid.2011.177 · 7.22 Impact Factor
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    ABSTRACT: X-ray repair cross complementation group 1 (XRCC1) plays a key role in base excision repair. The purpose of this study was to examine the association of two genetic polymorphisms in XRCC1 (rs1799782 and rs25487) with risk of colorectal polyps and colorectal cancer (CRC). In the ongoing colorectal cancer study of Austria (CORSA), a total of 3091 Caucasian participants was genotyped using 5'-nuclease TaqMan assays. Multiple logistic regression was applied to compare individuals of the control group against three different case groups namely CRC cases, high-risk and low-risk polyps. The two investigated SNPs in XRCC1 were not found to be associated with neither CRC risk nor polyp risk. Comparing the CRC cases versus the controls the OR was 0.60 (95%CI 0.27-1.31) for the heterozygous polymorphic genotype of SNP rs1799782 and 1.47 (95%CI 0.81-2.65) for the homozygous polymorphic genotype of SNP rs25487. Comparing the high-risk polyp group versus the controls the OR was 2.64 (95%CI 0.61-11.42) for the homozygous polymorphic genotype of SNP rs1799782 and 0.89 (95%CI 0.60-1.33) for SNP rs25487, respectively. In an haplotype analysis also no statistically significant association was found. Our finding that none of the two investigated SNPs of XRCC1 were significantly associated with risk of CRC or polyps is consistent with the results of a recently published meta-analysis.
    05/2011; 35(5):e38-41. DOI:10.1016/j.canep.2011.03.005
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    ABSTRACT: Telomerase reactivation and expression of human telomerase gene [human telomerase reverse transcriptase (hTERT)] are hallmarks of unlimited proliferation potential of cancer cells. A polymorphic tandem repeats minisatellite of hTERT gene, termed MNS16A was reported to influence hTERT expression. To assess the role of MNS16A as potential biomarker for colorectal cancer (CRC), we investigated for the first time the association of MNS16A genotypes with risk of colorectal polyps and CRC. In the ongoing colorectal cancer study of Austria (CORSA), 3842 Caucasian participants were recruited within a large screening project in the province Burgenland including 90 CRC cases, 308 high-risk polyps, 1022 low-risk polyps and 1822 polyp free controls verified by colonoscopy. MNS16A genotypes were determined by polymerase chain reaction from genomic DNA. Associations of MNS16A genotypes with CRC risk were estimated by logistic regression analysis computing odds ratios (ORs) and 95% confidence intervals (CIs). We identified five different variable number of tandem repeats (VNTRs) of MNS16A including VNTR-364, a newly discovered rare variant. VNTR-274 allele was associated with a 2.7-fold significantly increased risk of CRC compared with the VNTR-302 wild-type (OR = 2.69; 95% CI = 1.11-6.50; P = 0.028). In our CORSA study, the medium length VNTR-274 was identified as risk factor for CRC. Although, this population-based study herewith reports the largest cohort size concerning MNS16A thus far, further large-scale studies in diverse populations are warranted to confirm hTERT MNS16A genotype as potential biomarker for assessment of CRC risk.
    Carcinogenesis 03/2011; 32(6):866-71. DOI:10.1093/carcin/bgr053 · 5.33 Impact Factor
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    ABSTRACT: Human malignant pleural mesothelioma (MPM) is an asbestos-related malignancy characterized by frequent resistance to chemotherapy and radiotherapy. Here, we investigated the feasibility of mammalian target of rapamycin (mTOR) inhibition by temsirolimus as an antimesothelioma strategy. Phosphorylation of mTOR (p-mTOR) was assessed by immunohistochemistry in MPM surgical specimens (n = 70). Activation of mTOR and impact of mTOR inhibition by temsirolimus was determined in MPM cell lines in vitro (n = 6) and in vivo as xenografts in severe combined immunodeficiency mice (n = 2) either as single agent or in combination with cisplatin. Strong immunoreactivity for p-mTOR was predominantly detected in epitheloid and biphasic but not sarcomatoid MPM specimens while adjacent normal tissues remained widely unstained. Accordingly, all mesothelioma cell lines harbored activated mTOR, which was further confirmed by hyperphosphorylation of the downstream targets pS6K, S6, and 4EBP1. Temsirolimus potently blocked mTOR-mediated signals and exerted a cytostatic effect on mesothelioma cell lines in vitro cultured both as adherent monolayers and as nonadherent spheroids. Mesothelioma cells with intrinsic or acquired cisplatin resistance exhibited hypersensitivity against temsirolimus. Accordingly, cisplatin and temsirolimus exerted synergistic inhibition of the mTOR downstream signals and enhanced growth inhibition and/or apoptosis induction in mesothelioma cell lines. Finally, temsirolimus was highly active against MPM xenograft models in severe combined immunodeficiency mice both as a single agent and in combination with cisplatin. The mTOR inhibitor temsirolimus is active against mesothelioma in vitro and in vivo and synergizes with chemotherapy. These data suggest mTOR inhibition as a promising novel therapeutic strategy against MPM.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2011; 6(5):852-63. DOI:10.1097/JTO.0b013e31820e1a25 · 5.28 Impact Factor

  • Cancer Research 01/2011; 70(8 Supplement):5142-5142. DOI:10.1158/1538-7445.AM10-5142 · 9.33 Impact Factor

  • Cancer Research 01/2011; 70(8 Supplement):3997-3997. DOI:10.1158/1538-7445.AM10-3997 · 9.33 Impact Factor
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    ABSTRACT: The quality of communication between health care professionals is a key issue determining health outcomes in cancer care. This study aims to find out what importance cancer patients in Austria attach to information exchange between hospital-based doctors and their general practitioners (GPs) and how patients perceive this flow of information. In this cross-sectional study, cancer patients seeking help at a community-based organization in the voluntary sector (Viennese Cancer League) were polled with a 16-item questionnaire. Contingency tables were evaluated by means of the chi-squared and Mantel-Haenszel test. The mean age of the 252 respondents - 92.6% of those polled (272) - was 51.9 years (SD ± 13.6). 87.5% [female (f): 92.1%, male (m): 80.2%] considered the exchange of information between the hospital-based specialists and their GP 'very important' or 'important'; 12.5% (f: 8.0%, m: 19.8%) 'not so important' or 'not at all important'; 28.1% (f: 26.0%, m: 31.2%) of patients considered the flow of information as 'very good' or 'fairly good', but 50.9% (f: 58.7, m: 40.0%) as 'rather poor' or 'poor'. Some 34.8% of patients thought that their cancer disease was first suspected by a hospital-based specialist; 42.1% thought that it was first suspected by a doctor outside the hospital. Even when patients were counselled elsewhere they gave high importance to the provision of appropriate information to their GP. Cancer patients in Austria attach high importance to the provision of appropriate information to their GP by hospitals and perceive this exchange of information as insufficient, a finding that could well be prevalent in other European health systems.
    Journal of Evaluation in Clinical Practice 12/2010; 16(6):1309-13. DOI:10.1111/j.1365-2753.2009.01333.x · 1.08 Impact Factor
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    ABSTRACT: Aurora kinases represent promising novel cancer therapy targets. Genomic analyses of human cutaneous melanoma (CMM) models (N = 51, low passage) by classical and/or array CGH revealed frequent gains at chromosome 20q (65%, amplifications in 45%) repeatedly including the Aurora A gene locus. Accordingly, the majority of CMM cell cultures overexpressed Aurora A when compared to proliferating non-malignant cells. Moreover, CMM cells even when arrested in G1/S cell cycle phase contained readily detectable levels of Aurora A indicating incomplete degradation during mitosis. Already at low concentrations (10-100 nm), long-term (7-10 days) application of the pan-Aurora kinase inhibitor VE-465 completely prevented colony formation in all CMM models tested. In contrast, blockade of cell survival/proliferation and DNA synthesis as well as the induction of apoptosis by VE-465 distinctly differed in short-term experiments (up to 72 h exposure). Both cell cycle arrest and DNA synthesis blockade depended on the level of VE-465-mediated p53/p21 activation while p53/p21 unresponsiveness led to repetitive endoreduplication (>8n DNA content). In contrast, apoptosis induction by VE-465 and Aurora A siRNA did not correlate with p53/p21 responsiveness and DNA synthesis blockade. Moreover, application of the Aurora B-specific inhibitor ZM447439 and siRNA was less efficient to induce CMM cell death proofing that apoptosis induction by VE-465 depended predominantly on Aurora A targeting. In combination experiments with chemotherapeutic agents, VE-465 acted additive to antagonistic when applied concomitantly but in several cases even synergistic when applied consecutively. In summary, we suggest that the Aurora A kinase might represent a promising target of well-designed novel antimelanoma strategies.
    Experimental Dermatology 12/2010; 19(12):1040-7. DOI:10.1111/j.1600-0625.2010.01182.x · 3.76 Impact Factor
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    ABSTRACT: The beneficial health effects of (-)-epigallocatechin-3-gallate (EGCG), the main catechin of green tea, have been attributed to complex interactions with a focus on antioxidative properties. Susceptibility to autoxidation and production of cytotoxic reactive oxygen species (ROS), mostly H(2)O(2), have been suggested to occur in vitro but also in vivo. In this study, we address whether autoxidation-derived H(2)O(2) may be involved in the cytoprotective effects of EGCG. To that end we investigated keratinocyte-derived HaCat and HL-60 promyelocytic leukemia cells with significantly different sensitivities to H(2)O(2) (IC(50) 117.3 versus 58.3 μM, respectively) and EGCG (134.1 versus 84.1 μM). HaCat cells significantly resisted cytotoxicity and DNA damage based on enhanced H(2)O(2) clearance, improved DNA repair, and reduced intracellular ROS generation. Cumulative versus bolus EGCG and H(2)O(2) treatment and H(2)O(2) pretreatment before subsequent high-dose EGCG and vice versa significantly reduced DNA damage and cytotoxicity in HaCat cells only. Addition of catalase abolished the protective activities of low-dose H(2)O(2) and EGCG. In summary, our data suggest that autoxidative generation of low-dose H(2)O(2) is a significant player in the cell-type-specific cytoprotection mediated by EGCG and support the hypothesis that regular green tea consumption can contribute as a pro-oxidant to increased resistance against high-dose oxidative stressors.
    Free Radical Biology and Medicine 11/2010; 49(9):1444-52. DOI:10.1016/j.freeradbiomed.2010.08.008 · 5.74 Impact Factor

  • EJC Supplements 11/2010; 8(7):141-141. DOI:10.1016/S1359-6349(10)72154-6 · 9.39 Impact Factor
  • P. Heffeter · B. Atil · U. Jungwirth · E. Gal · J. Gojo · M. Micksche · B. K. Keppler · W. Berger ·

    EJC Supplements 11/2010; 8(7):63-63. DOI:10.1016/S1359-6349(10)71893-0 · 9.39 Impact Factor
  • J. Gojo · U. Jungwirth · P. Heffeter · B. Atil · M. Micksche · B. K. Keppler ·

    EJC Supplements 11/2010; 8(7):53-53. DOI:10.1016/S1359-6349(10)71855-3 · 9.39 Impact Factor

  • Cancer Research 04/2010; 70(8 Supplement):3215-3215. DOI:10.1158/1538-7445.AM10-3215 · 9.33 Impact Factor
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    ABSTRACT: The ruthenium compound KP1019 has demonstrated promising anticancer activity in a pilot clinical trial. This study aims to evaluate the intracellular uptake/binding patterns of KP1019 and its sodium salt KP1339, which is currently in a phase I-IIa study. Although KP1339 tended to be moderately less cytotoxic than KP1019, IC(50) values in several cancer cell models revealed significant correlation of the cytotoxicity profiles, suggesting similar targets for the two drugs. Accordingly, both drugs activated apoptosis, indicated by caspase activation via comparable pathways. Drug uptake determined by inductively coupled plasma mass spectrometry (ICP-MS) was completed after 1 h, corresponding to full cytotoxicity as early as after 3 h of drug exposure. Surprisingly, the total cellular drug uptake did not correlate with cytotoxicity. However, distinct differences in intracellular distribution patterns suggested that the major targets for the two ruthenium drugs are cytosolic rather than nuclear. Consequently, drug-protein binding in cytosolic fractions of drug-treated cells was analyzed by native size-exclusion chromatography (SEC) coupled online with ICP-MS. Ruthenium-protein binding of KP1019- and KP1339-treated cells distinctly differed from the platinum binding pattern observed after cisplatin treatment. An adapted SEC-SEC-ICP-MS system identified large protein complexes/aggregates above 700 kDa as initial major binding partners in the cytosol, followed by ruthenium redistribution to the soluble protein weight fraction below 40 kDa. Taken together, our data indicate that KP1019 and KP1339 rapidly enter tumor cells, followed by binding to larger protein complexes/organelles. The different protein binding patterns as compared with those for cisplatin suggest specific protein targets and consequently a unique mode of action for the ruthenium drugs investigated.
    European Journal of Biochemistry 03/2010; 15(5):737-48. DOI:10.1007/s00775-010-0642-1 · 2.54 Impact Factor
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    ABSTRACT: O(6)-Methylguanine DNA methyltransferase (MGMT) is implicated as a major predictive factor for treatment response to alkylating agents including temozolomide (TMZ) of glioblastoma multiforme (GBM) patients. However, whether the MGMT status in GBM patients should be detected at the level of promoter methylation or protein expression is still a matter of debate. Here, we compared promoter methylation (by methylation-specific polymerase chain reaction) and protein expression (by Western blot) in tumor cell explants with respect to prediction of TMZ response and survival of GBM patients (n = 71). Methylated MGMT gene promoter sequences were detected in 47 of 71 (66%) cases, whereas 37 of 71 (52%) samples were scored positive for MGMT protein expression. Although overall promoter methylation correlated significantly with protein expression (chi(2) test, P < .001), a small subgroup of samples did not follow this association. In the multivariate Cox regression model, a significant interaction between MGMT protein expression, but not promoter methylation, and TMZ therapy was observed (test for interaction, P = .015). In patients treated with TMZ (n = 42), MGMT protein expression predicted a significantly shorter overall survival (OS; hazard ratio [HR] for death 5.53, 95% confidence interval [CI] 1.76-17.37; P = .003), whereas in patients without TMZ therapy (n = 29), no differences in OS were observed (HR for death 1.00, 95% CI 0.45-2.20; P = .99). These data suggest that lack of MGMT protein expression is superior to promoter methylation as a predictive marker for TMZ response in GBM patients.
    Neuro-Oncology 01/2010; 12(1):28-36. DOI:10.1093/neuonc/nop003 · 5.56 Impact Factor
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    ABSTRACT: Purpose Insulin-like growth factor 1 (IGFI) is a peptide growth factor that promotes cell proliferation and inhibits apoptosis. The bioavailability of IGFI is regulated by the insulin-like growth factor binding protein 3 (IGFBP3). The purpose of this study was to examine the association of genetic variants in IGFI (rs6214, rs6220, and rs35767) and IGFBP3 (rs2854744 and rs2854746) with risk of colorectal polyps and colorectal cancer. Methods In this ongoing colorectal cancer study of Austria (CORSA), a total of 3,360 Caucasian participants, consisting of 178 colorectal cancer patients, 328 patients with high risk polyps, 1,059 patients with low risk colorectal polyps, and 1,795 colonoscopy-negative controls, were recruited within a large colorectal screening project in the province Burgenland and from three hospitals in Vienna. Multiple logistic regression was applied to compare individuals of the control group against three different risk groups, namely, colorectal cancer group, high risk polyp group, and low risk polyp group. Results Carriers of the homozygous polymorphic genotype of the SNP rs6214 were associated with an increased colorectal risk (OR = 1.79, 95% CI 1.04-1.90) compared to the colonoscopy-negative controls; this was also found when combining colorectal cancer cases and high risk polyp group (OR = 1.39, 95% CI 1.01-1.90). Conclusion Our results suggest that the SNP rs6214 of IGFI could have an impact on developing colorectal cancer and colorectal polyps with villous elements.
    Cancer Causes and Control 01/2010; 21(1):91-97. DOI:10.2307/25621332 · 2.74 Impact Factor

  • Molecular Cancer Therapeutics 12/2009; 8(Supplement 1):C103-C103. DOI:10.1158/1535-7163.TARG-09-C103 · 5.68 Impact Factor
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    ABSTRACT: KP772 is a new lanthanum complex containing three 1,10-phenathroline molecules. Recently, we have demonstrated that the promising in vitro and in vivo anticancer properties of KP772 are based on p53-independent G(0)G(1) arrest and apoptosis induction. A National Cancer Institute (NCI) screen revealed significant correlation of KP772 activity with that of the ribonucleotide reductase (RR) inhibitor hydroxyurea (HU). Consequently, this study aimed to investigate whether KP772 targets DNA synthesis in tumor cells by RR inhibition. Indeed, KP772 treatment led to significant reduction of cytidine incorporation paralleled by a decrease of deoxynucleoside triphosphate (dNTP) pools. This strongly indicates disruption of RR activity. Moreover, KP772 protected against oxidative stress, suggesting that this drug might interfere with RR by interaction with the tyrosyl radical in subunit R2. Additionally, several observations (e.g. increase of transferrin receptor expression and protective effect of iron preloading) indicate that KP772 interferes with cellular iron homeostasis. Accordingly, co-incubation of Fe(II) with KP772 led to generation of a coloured iron complex (Fe-KP772) in cell free systems. In electron paramagnetic resonance (EPR) measurements of mouse R2 subunits, KP772 disrupted the tyrosyl radical while Fe-KP772 had no significant effects. Moreover, coincubation of KP772 with iron-loaded R2 led to formation of Fe-KP772 suggesting chelation of RR-bound Fe(II). Summarizing, our data prove that KP772 inhibits RR by targeting the iron centre of the R2 subunit. As also Fe-KP772 as well as free lanthanum exert significant -though less pronounced- cytotoxic/static activities, additional mechanisms are likely to synergise with RR inhibition in the promising anticancer activity of KP772.
    Current cancer drug targets 09/2009; 9(5):595-607. DOI:10.2174/156800909789056962 · 3.52 Impact Factor

Publication Stats

5k Citations
878.01 Total Impact Points


  • 1989-2015
    • Medical University of Vienna
      • • Department of Medicine I
      • • Institute for Cancer Research
      • • Department of Urology
      Wien, Vienna, Austria
  • 2006
    • Mayo Clinic - Scottsdale
      Scottsdale, Arizona, United States
  • 1977-2004
    • University of Vienna
      • • Institute of Cancer Research
      • • Institute of Tumor Biology-Cancer Research
      Wien, Vienna, Austria
  • 1999-2003
    • IST Austria
      Klosterneuberg, Lower Austria, Austria
    • Children's Cancer Research Institute
      Wien, Vienna, Austria
    • University of Texas MD Anderson Cancer Center
      • Department of Gynecologic Oncology
      Houston, Texas, United States
  • 1982
    • Ludwig Boltzmann Institute for Osteology
      Wien, Vienna, Austria