Hans S Poulsen

Copenhagen University Hospital, København, Capital Region, Denmark

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Publications (60)314.42 Total impact

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    ABSTRACT: Methods: uPAR mRNA expression analysis of tumors from 19 GBM patients was performed and a cell culture derived from one of these patients was used to establish an orthotopic GBM xenograft model. Tumor growth was monitored using bioluminescence imaging. Five to six weeks after inoculation, all mice were microPET/CT scanned with two new uPAR PET ligands ((64)Cu-NOTA-AE105 and (68)Ga-NOTA-AE105) and with (18)F-fluoroethyl-1-tyrosine (FET) for comparison. One MRI scan was performed in each mouse to confirm tumor location. The uPAR specificity of (64)Cu-NOTA-AE105 was confirmed by alignment of H&E and uPAR immunohistochemistry stained slides of the brain, with distribution of activity using autoradiography. Results: uPAR expression was found in all 19 GBM patient tumors investigated and high expression of uPAR correlated with decreased overall survival (P = 0.04). Radiolabeling of NOTA-AE105 with (64)Cu and (68)Ga was straightforward resulting in a specific activity of approximately 20 GBq/µmol and a radiochemical purity of >98% for (64)Cu-NOTA-AE105 and >97% for (68)Ga-NOTA-AE105. High image contrast, resulting in clear tumor delineation, was found for both (68)Ga-NOTA-AE105 and (64)Cu-NOTA-AE105. A higher absolute uptake of (18)F-FET in tumor (3.5±0.8 %ID/g) was observed compared to (64)Cu-NOTA-AE105 (1.2±0.4 %ID/g) and (68)Ga-NOTA-AE105 (0.4±0.1 %ID/g). Similar pattern was also observed in background brain tissue, where uptake of (18)F-FLT was 1.9±0.1 %ID/g, compared to (68)Ga-NOTA-AE105 (0.05±0.01 %ID/g) and (64)Cu-NOTA-AE105 (0.11±0.02 %ID/g). This resulted in a significantly higher tumor-to-background ratio for both (68)Ga-NOTA-AE105 (7.6±2.1, p< 0.05) and (64)Cu-NOTA-AE105 (10.6±2.3, p<0.01) compared with (18)F-FET-PET (1.8±0.3). Autoradiography of brain slides confirmed that the accumulation of (64)Cu-NOTA-AE105 corresponded well with uPAR positive cancer cells. Conclusion: Based on our translational study uPAR PET could be a highly promising new imaging biomarker for GBM. Further clinical explorations of uPAR PET in GBM are therefore justified.
    Journal of Nuclear Medicine 10/2015; DOI:10.2967/jnumed.115.161703 · 6.16 Impact Factor
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    ABSTRACT: Purpose: Both [(18)F]-fluoroethyltyrosine (FET) PET and blood volume (BV) MRI supplement routine T1-weighted contrast-enhanced MRI in gliomas, but whether the two modalities provide identical or complementary information is unresolved. The aims of the study were to investigate the feasibility of simultaneous structural MRI, BV MRI and FET PET of gliomas using an integrated PET/MRI scanner and to assess the spatial and quantitative agreement in tumour imaging between BV MRI and FET PET. Methods: A total of 32 glioma patients underwent a 20-min static simultaneous PET/MRI acquisition on a Siemens mMR system 20 min after injection of 200 MBq FET. The MRI protocol included standard structural MRI and dynamic susceptibility contrast (DSC) imaging for BV measurements. Maximal relative tumour FET uptake (TBRmax) and BV (rBVmax), and Dice coefficients were calculated to assess the quantitative and spatial congruence in the tumour volumes determined by FET PET, BV MRI and contrast-enhanced MRI. Results: FET volume and TBRmax were higher in BV-positive than in BV-negative scans, and both VOLBV and rBVmax were higher in FET-positive than in FET-negative scans. TBRmax and rBVmax were positively correlated (R (2) = 0.59, p < 0.001). FET and BV positivity were in agreement in only 26 of the 32 patients and in 42 of 63 lesions, and spatial congruence in the tumour volumes as assessed by the Dice coefficients was generally poor with median Dice coefficients exceeding 0.1 in less than half the patients positive on at least one modality for any pair of modalities. In 56 % of the patients susceptibility artefacts in DSC BV maps overlapped the tumour on MRI. Conclusion: The study demonstrated that although tumour volumes determined by BV MRI and FET PET were quantitatively correlated, their spatial congruence in a mixed population of treated glioma patients was generally poor, and the modalities did not provide the same information in this population of patients. Combined imaging of brain tumour metabolism and perfusion using hybrid PET/MR systems may provide complementary information on tumour biology, but the potential clinical value remains to be determined in future trials.
    European Journal of Nuclear Medicine 09/2015; DOI:10.1007/s00259-015-3183-6 · 5.38 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):5310-5310. DOI:10.1158/1538-7445.AM2015-5310 · 9.33 Impact Factor
  • Cancer Research 08/2015; 75(15 Supplement):4170-4170. DOI:10.1158/1538-7445.AM2015-4170 · 9.33 Impact Factor
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    ABSTRACT: The survival times of patients with glioblastoma differ widely and biomarkers that would enable individualized treatment are needed. The objective of this study was to measure changes in the vascular physiology of tumor using T1-dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in patients with glioblastoma during early stages of radio- and chemotherapy (Tx) and explore possible correlations with treatment outcomes. An exploratory prospective study was planned. Patients underwent DCE-MRI at baseline, after approximately one and six weeks of Tx and three and six months post-Tx. DCE-MRI at three Tesla generated maps of blood flow (BF), blood volume (BV), permeability (Ki) and volume of distribution (Vd) using a combination of model-free deconvolution and Patlak plots. Regions of interest in contrast enhancing tumor and in normal appearing white matter were contoured. Progression-free survival (PFS) was the primary clinical outcome. Patients with PFS > 6 months were compared with those with PFS < 6 months. Parameters of vascular physiology and changes in these during Tx were compared for these two groups at all time points using non-parametric statistics. Eleven eligible patients were included and 46 DCE-MRI examinations were carried out. BF in tumor increased for all patients early during Tx (p = 0.005) and then fell to a level below baseline at post-Tx examinations (p = 0.016). A similar but non-significant trend was seen for tumor BV. There was no detectable difference between patients with PFS > 6 months versus PFS < 6 months with regards to baseline values or changes during and after Tx. Although no correlations to outcomes were found, the results of this exploratory study may be hypothesis generating and will be examined in a larger patient group.
    Acta oncologica (Stockholm, Sweden) 07/2015; DOI:10.3109/0284186X.2015.1063777 · 3.00 Impact Factor
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    ABSTRACT: Small cell lung cancer (SCLC) is an aggressive disease with high mortality, and the identification of effective pharmacological strategies to target SCLC biology represents an urgent need. Using a high-throughput cellular screen of a diverse chemical library, we observe that SCLC is sensitive to transcription-targeting drugs, in particular to THZ1, a recently identified covalent inhibitor of cyclin-dependent kinase 7. We find that expression of super-enhancer-associated transcription factor genes, including MYC family proto-oncogenes and neuroendocrine lineage-specific factors, is highly vulnerability to THZ1 treatment. We propose that downregulation of these transcription factors contributes, in part, to SCLC sensitivity to transcriptional inhibitors and that THZ1 represents a prototype drug for tailored SCLC therapy. Copyright © 2014 Elsevier Inc. All rights reserved.
    Cancer Cell 12/2014; 26(6):909-22. DOI:10.1016/j.ccell.2014.10.019 · 23.52 Impact Factor
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    ABSTRACT: ObjectivesBrain tumor imaging is challenging. Although 18F-FET PET is widely used in the clinic, the value of 18F-FET MicroPET to evaluate brain tumors in xenograft has not been assessed to date. The aim of this study therefore was to evaluate the performance of in vivo 18F-FET MicroPET in detecting a treatment response in xenografts. In addition, the correlations between the 18F-FET tumor accumulation and the gene expression of Ki67 and the amino acid transporters LAT1 and LAT2 were investigated. Furthermore, Ki67, LAT1 and LAT2 gene expression in xenograft and archival patient tumors was compared.MethodsHuman GBM cells were injected orthotopically in nude mice and 18F-FET uptake was followed by weekly MicroPET/CT. When tumor take was observed, mice were treated with CPT-11 or saline weekly. After two weeks of treatment the brain tumors were isolated and quantitative polymerase chain reaction were performed on the xenograft tumors and in parallel on archival patient tumor specimens.ResultsThe relative tumor-to-brain (T/B) ratio of SUVmax was significantly lower after one week (123±6%, n = 7 vs. 147±6%, n = 7; p = 0.018) and after two weeks (142±8%, n = 5 vs. 204±27%, n = 4; p = 0.047) in the CPT-11 group compared with the control group. Strong negative correlations between SUVmax T/B ratio and LAT1 (r = −0.62, p = 0.04) and LAT2 (r = −0.67, p = 0.02) were observed. In addition, a strong positive correlation between LAT1 and Ki67 was detected in xenografts. Furthermore, a 1.6 fold higher expression of LAT1 and a 23 fold higher expression of LAT2 were observed in patient specimens compared to xenografts.Conclusions18F-FET MicroPET can be used to detect a treatment response to CPT-11 in GBM xenografts. The strong negative correlation between SUVmax T/B ratio and LAT1/LAT2 indicates an export transport function. We suggest that 18F-FET PET may be used for detection of early treatment response in patients.
    PLoS ONE 06/2014; 9(6):e100009. DOI:10.1371/journal.pone.0100009 · 3.23 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):3126-3126. DOI:10.1158/1538-7445.AM2013-3126 · 9.33 Impact Factor
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    ABSTRACT: Lung cancer currently causes the majority of cancer-related deaths worldwide and new treatments are in high demand. Gene therapy could be a promising treatment but currently lacks sufficient efficiency for clinical use, primarily due to limited cellular and nuclear DNA delivery. In the present study, we investigated whether it was possible to exploit the endogenous nuclear-shuttling activity by the nuclear factor kappa B (NFκB) system, which is highly prominent in many cancers as well as lung cancer. We observed that insertion of a DNA nuclear-targeting sequence (DTS) recognized by NFκB could improve plasmid nuclear delivery and enhance the therapeutic effect of a validated transcriptionally cancer-targeted suicide gene therapy system. A clear correlation between the number of inserted NFκB-binding sites and the therapeutic effect of the suicide system was observed in both small cell lung cancer (SCLC) and non-SCLC cell lines. The effect was observed to be due to elevated nuclear translocation of the suicide gene-encoding plasmids. The results show that a significant improvement of gene therapeutic efficiency can be obtained by increasing the intracellular trafficking of therapeutic DNA. This is to our knowledge the first time a DTS strategy has been implemented for suicide gene therapy.
    Cancer gene therapy 08/2012; 19(10):675-83. DOI:10.1038/cgt.2012.54 · 2.42 Impact Factor
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    ABSTRACT: Transcriptional targeted suicide gene (SG) therapy driven by the insulinoma-associated 1 (INSM1) promoter makes it possible to target suicide toxin production and cytotoxicity exclusively to small cell lung cancer (SCLC) cells and tumors. It remains to be determined whether acquired chemoresistance, as observed in the majority of SCLC patients, desensitizes SCLC cells to INSM1 promoter-driven SG therapy. A panel of SCLC cell lines resistant to clinically relevant chemotherapeutics was characterized regarding the expression of proteins involved in response to chemotherapy and regarding INSM1 promoter activity. Sensitivity towards INSM1 promoter-driven SG therapy was tested using different systems: Yeast cytosine deaminase-uracil phosphoribosyl transferase (YCD-YUPRT) in combination with the prodrug 5-fluorocytosine (5-FC) or Escherichia coli nitroreductase (NTR) together with the bromomustard prodrug SN27686. The chemoresistant cell lines displayed heterogeneous expression profiles of molecules involved in multidrug resistance, apoptosis and survival pathways. Despite this, the INSM1 promoter activity was found to be unchanged or increased in SCLC chemoresistant cells and xenografts compared to chemosensitive variants. INSM1 promoter-driven SG therapy with YCD-YUPRT/5-FC or NTR/SN27686, was found to induce high levels of cytotoxicity in both chemosensitive and chemoresistant SCLC cells. Moreover, the combination of INSM1 promoter-driven YCD-YUPRT/5-FC therapy and chemotherapy, as well as the combination of INSM1 promoter-driven YCD-YUPRT/5-FC and NTR/SN27686 therapy, was observed to be superior to single agent therapy in chemoresistant SCLC cells. Collectively, the present study demonstrates that targeted SG therapy is a potent therapeutic approach for chemoresistant SCLC patients, with the highest efficacy achieved when applied as combination SG therapy or in combination with standard chemotherapy.
    The Journal of Gene Medicine 07/2012; 14(7):445-58. DOI:10.1002/jgm.2630 · 2.47 Impact Factor
  • Cancer Research 06/2012; 72(8 Supplement):3701-3701. DOI:10.1158/1538-7445.AM2012-3701 · 9.33 Impact Factor
  • Cancer Research 06/2012; 72(8 Supplement):2732-2732. DOI:10.1158/1538-7445.AM2012-2732 · 9.33 Impact Factor
  • Cancer Research 06/2012; 72(8 Supplement):832-832. DOI:10.1158/1538-7445.AM2012-832 · 9.33 Impact Factor
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    ABSTRACT: The combination of irinotecan and bevacizumab has shown efficacy in the treatment of recurrent glioblastoma multiforme (GBM). A prospective, phase II study of 85 patients with various recurrent brain tumors was carried out. Primary endpoints were progression free survival (PFS) and response rate. Patients with recurrent primary brain tumors with performance status 0-2 were eligible. Intravenous bevacizumab 10 mg/kg and irinotecan 125/340 mg/m(2) were administered every 14 days. Evaluation was carried out every eight weeks using MRI and Macdonald response criteria. Treatment was continued until progression. In total 85 patients were included with the following histologies: GBM (n = 32), glioma WHO gr. III (n = 33), glioma WHO gr. II (n = 12) and others (n = 8). Patients received a median of four cycles. ORR (overall response rate) for glioblastoma was 25% and 59% achieved stable disease (SD). Median PFS was 5.2 months. For grade III gliomas ORR was 21% and 45% had SD. Median PFS was 3.7 months. No objective responses occurred in grade II gliomas. In the non-glioma population, one PR as well as several long PFS times were observed. The combination of bevacizumab and irinotecan is well tolerated and moderately efficacious in glioblastoma and glioma WHO gr. III. A majority of patients achieve at least disease stabilization. Prolonged progression-free survival in non-glioma patients warrants further research.
    Acta oncologica (Stockholm, Sweden) 05/2012; 51(6):797-804. DOI:10.3109/0284186X.2012.681063 · 3.00 Impact Factor
  • Mette K Nedergaard · Chris J Hedegaard · Hans S Poulsen
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    ABSTRACT: The epidermal growth factor receptor (EGFR) is over-expressed, as well as mutated, in many types of cancers. In particular, the EGFR variant type III mutant (EGFRvIII) has attracted much attention as it is frequently and exclusively found on many tumor cells, and hence both EGFR and EGFRvIII have been proposed as valid targets in many cancer therapy settings. Different strategies have been developed in order to either inhibit EGFR/EGFRvIII activity or to ablate EGFR/EGFRvIII-positive tumor cells. Drugs that inhibit these receptors include monoclonal antibodies (mAbs) that bind to the extracellular part of EGFR, blocking the binding sites for the EGFR ligands, and intracellular tyrosine kinase inhibitors (TKIs) that block the ATP binding site of the tyrosine kinase domain. Besides an EGFRvIII-targeted vaccine, conjugated anti-EGFR mAbs have been used in different settings to deliver lethal agents to the EGFR/EGFRvIII-positive cells; among these are radio-labelled mAbs and immunotoxins. This article reviews the current status and efficacy of EGFR/EGFRvIII-targeted therapies.
    BioDrugs 04/2012; 26(2):83-99. DOI:10.2165/11599760-000000000-00000 · 2.99 Impact Factor
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    Roza Zandi · Kai Xu · Hans S Poulsen · Jack A Roth · Lin Ji
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    ABSTRACT: The candidate tumor suppressor fragile histidine traid (FHIT) is frequently inactivated in small cell lung cancer (SCLC). Mutations in the p53 gene also occur in the majority of SCLC leading to the accumulation of the mutant protein. Here we evaluated the effect of FHIT gene therapy alone or in combination with the mutant p53-reactivating molecule, PRIMA-1(Met)/APR-246, in SCLC. Overexpression of FHIT by recombinant adenoviral vector (Ad-FHIT)-mediated gene transfer in SCLC cells inhibited their growth by inducing apoptosis and when combined with PRIMA-1(Met)/APR-246, a synergistic cell growth inhibition was achieved.
    Cancer Investigation 11/2011; 29(10):683-91. DOI:10.3109/07357907.2011.626475 · 2.22 Impact Factor
  • Roza Zandi · Kai Xu · Hans S. Poulsen · Jack A Roth · Lin Ji
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    ABSTRACT: FUS1, also known as tumor suppressor candidate 2 (TUSC2), is a novel candidate tumor suppressor gene (TSG) frequently inactivated in human lung cancer. Loss of FUS1 protein expression is found in almost all small cell lung cancer (SCLC) cell lines and tumor specimens. Therefore, restoration of normal FUS1 function by gene transfer could serve as a potential therapeutic strategy for the treatment of SCLC. Here we investigated the effect of exogenous expression of FUS1 by plasmid-mediated gene transfer on tumor cell growth and apoptosis induction in FUS1-defective SCLC cells. Transfection of SCLC cells with wild-type FUS1 (wt-FUS1) showed in vitro growth inhibition and a marked suppression of colony formation compared to cells transfected with an empty vector (EV) or a myristoylation-defect mutant FUS1 (mt-FUS1). Forced expression of wt-FUS1 also increased the apoptotic cell population at Sub-G0/G1 in SCLC cells compared to EV- and mt-FUS1-transfected controls, which was associated with a decreased level of pro-caspase-3 and an increased level of PARP cleavage. Our results demonstrate the potential tumor suppression function of FUS1 in SCLC cells and suggest that FUS1-mediated gene therapy could be a useful therapeutic strategy for the treatment of SCLC.
    Clinical and experimental pathology 01/2011; DOI:10.4172/2161-0681.S5-001
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    ABSTRACT: Overexpression and/or amplification of the epidermal growth factor receptor (EGFR) is present in 35-45% of primary glioblastoma multiforme tumors and has been correlated with a poor prognosis. In this study, we investigated the effect of cetuximab and intracellular signaling pathways downstream of EGFR, important for cell survival and proliferation. We show insufficient EGFR downregulation and competition with endogenous EGFR ligands upon cetuximab treatment. Dose-response experiments showed inhibition of EGFR phosphorylation without affecting two of the prominent downstream signaling pathways. Our results indicate that amplification and/or overexpression of EGFR is an unsatisfactory predictor for response to cetuximab.
    Cancer Investigation 10/2010; 28(8):775-87. DOI:10.3109/07357907.2010.483506 · 2.22 Impact Factor
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    ABSTRACT: Dichloroacetate (DCA) inhibits pyruvate dehydrogenase kinase (PDK), and thus promotes glucose oxidation over glycolysis and induces apoptotic death of tumor cells. The present study investigated the potential of DCA to increase the antitumor effects of platinum- based compounds against a panel of permanent cell lines, including small cell lung cancer (SCLC), ovarian cancer, and Ewing's sarcoma in vitro. DCA at a concentration of 10 mM was combined with cisplatin, carboplatin, satraplatin, the satraplatin metabolite JM118, oxaliplatin, oxoplatin, and picoplatin, and the cytotoxic activity was evaluated in proliferation tests employing a panel of different cell lines. Additionally, cells were pretreated with DCA and then exposed to the platinum drugs and etoposide, or incubated with cisplatin or etoposide followed by application of DCA, respectively. DCA 10 mM significantly increased the cytotoxicity of the platinum-based drugs carboplatin, satraplatin, JM118, and oxoplatin, but not cisplatin, picoplatin, and oxaliplatin in vitro. Preincubation of cell lines with DCA 10 mM for three days reduced the antiproliferative activity of platinum-based agents in sequential application, but exposure of cells pretreated with cisplatin or etoposide to DCA resulted in minor sensitization. The inhibitory effect of DCA showed no correlation with sensitization to the platinum compounds. DCA alone in a concentration that shows low antiproliferative activity is capable of increasing the cytotoxicity of selected platinum compounds upon coincubation, and such combinations may be interesting for clinical application in tumors like SCLC, Ewing's sarcoma, and ovarian cancer refractory to cisplatin chemotherapy as standard care. The mechanism of this synergistic effect of DCA in combination with specific platinum species remains to be investigated.
    Clinical Pharmacology: Advances and Applications 09/2010; 2(1):177-83. DOI:10.2147/CPAA.S11795
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    ABSTRACT: Malignant gliomas, the deadliest of brain neoplasms, show rampant genetic instability and resistance to genotoxic therapies, implicating potentially aberrant DNA damage response (DDR) in glioma pathogenesis and treatment failure. Here, we report on gross, aberrant constitutive activation of DNA damage signalling in low- and high-grade human gliomas, and analyze the sources of such endogenous genotoxic stress. Based on analyses of human glioblastoma multiforme (GBM) cell lines, normal astrocytes and clinical specimens from grade II astrocytomas (n=41) and grade IV GBM (n=60), we conclude that the DDR machinery is constitutively activated in gliomas, as documented by phosphorylated histone H2AX (gammaH2AX), activation of the ATM-Chk2-p53 pathway, 53BP1 foci and other markers. Oxidative DNA damage (8-oxoguanine) was high in some GBM cell lines and many GBM tumors, while it was low in normal brain and grade II astrocytomas, despite the degree of DDR activation was higher in grade II tumors. Markers indicative of ongoing DNA replication stress (Chk1 activation, Rad17 phosphorylation, replication protein A foci and single-stranded DNA) were present in GBM cells under high- or low-oxygen culture conditions and in clinical specimens of both low- and high-grade tumors. The observed global checkpoint signaling, in contrast to only focal areas of overabundant p53 (indicative of p53 mutation) in grade II astrocytomas, are consistent with DDR activation being an early event in gliomagenesis, initially limiting cell proliferation (low Ki-67 index) and selecting for mutations of p53 and likely other genes that allow escape (higher Ki-67 index) from the checkpoint and facilitate tumor progression. Overall, these results support the potential role of the DDR machinery as a barrier to gliomagenesis and indicate that replication stress, rather than oxidative stress, fuels the DNA damage signalling in early stages of astrocytoma development.
    Oncogene 09/2010; 29(36):5095-102. DOI:10.1038/onc.2010.249 · 8.46 Impact Factor

Publication Stats

963 Citations
314.42 Total Impact Points


  • 1999–2014
    • Copenhagen University Hospital
      København, Capital Region, Denmark
  • 1991–2012
    • Rigshospitalet
      • Department of Oncology
      København, Capital Region, Denmark
  • 1999–2010
    • National University (California)
      San Diego, California, United States
  • 2007
    • Danish Cancer Society
      København, Capital Region, Denmark
  • 2005
    • Louisiana State University Health Sciences Center New Orleans
      • Department of Pediatrics
      New Orleans, Louisiana, United States
  • 1992
    • IT University of Copenhagen
      København, Capital Region, Denmark