Publications by authors named "J Aagesen"

9 Publications

A validated single-cell-based strategy to identify diagnostic and therapeutic targets in complex diseases.

Genome Med 2019 07 30;11(1):47. Epub 2019 Jul 30.

Centre for Personalized Medicine, Linköping University, Linköping, Sweden.

Background: Genomic medicine has paved the way for identifying biomarkers and therapeutically actionable targets for complex diseases, but is complicated by the involvement of thousands of variably expressed genes across multiple cell types. Single-cell RNA-sequencing study (scRNA-seq) allows the characterization of such complex changes in whole organs.

Methods: The study is based on applying network tools to organize and analyze scRNA-seq data from a mouse model of arthritis and human rheumatoid arthritis, in order to find diagnostic biomarkers and therapeutic targets. Diagnostic validation studies were performed using expression profiling data and potential protein biomarkers from prospective clinical studies of 13 diseases. A candidate drug was examined by a treatment study of a mouse model of arthritis, using phenotypic, immunohistochemical, and cellular analyses as read-outs.

Results: We performed the first systematic analysis of pathways, potential biomarkers, and drug targets in scRNA-seq data from a complex disease, starting with inflamed joints and lymph nodes from a mouse model of arthritis. We found the involvement of hundreds of pathways, biomarkers, and drug targets that differed greatly between cell types. Analyses of scRNA-seq and GWAS data from human rheumatoid arthritis (RA) supported a similar dispersion of pathogenic mechanisms in different cell types. Thus, systems-level approaches to prioritize biomarkers and drugs are needed. Here, we present a prioritization strategy that is based on constructing network models of disease-associated cell types and interactions using scRNA-seq data from our mouse model of arthritis, as well as human RA, which we term multicellular disease models (MCDMs). We find that the network centrality of MCDM cell types correlates with the enrichment of genes harboring genetic variants associated with RA and thus could potentially be used to prioritize cell types and genes for diagnostics and therapeutics. We validated this hypothesis in a large-scale study of patients with 13 different autoimmune, allergic, infectious, malignant, endocrine, metabolic, and cardiovascular diseases, as well as a therapeutic study of the mouse arthritis model.

Conclusions: Overall, our results support that our strategy has the potential to help prioritize diagnostic and therapeutic targets in human disease.
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http://dx.doi.org/10.1186/s13073-019-0657-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6664760PMC
July 2019

Bortezomib retreatment for relapsed and refractory multiple myeloma in real-world clinical practice.

Health Sci Rep 2019 Jan 7;2(1):e104. Epub 2018 Dec 7.

Department of Hematology University Hospital Leuven Leuven Belgium.

Aims: Studies have shown that bortezomib retreatment is effective in relapsed/refractory multiple myeloma (MM). The observational, prospective electronic VELCADE OBservational Study (eVOBS) study assessed bortezomib-based therapies for patients with MM in everyday practice. Here, we report on those patients receiving retreatment with bortezomib.

Methods: Consenting adults scheduled to receive bortezomib for MM were enrolled at 162 sites across Europe, Canada, Brazil, Russia, and Turkey between 2006 and 2010. Retrospective data on prior therapies and prospective observational data after bortezomib initiation were captured electronically at baseline, after every bortezomib cycle, and every 12 weeks after discontinuation or progression. Investigator-assessed responses and adverse events (AEs) were evaluated.

Results: Ninety-six of 873 patients enrolled to eVOBS received bortezomib as first retreatment for progressive disease during the prospective observation period. Median age was 62 years, 53% were male, and median number of prior therapies at retreatment was 4. Overall, 41% of patients initiated bortezomib retreatment in combination with dexamethasone, 16% in combination with lenalidomide, and 21% received monotherapy. Rate of partial response or better (≥PR) was 75% at initial bortezomib therapy, including 44% complete response (CR)/near CR (nCR); at retreatment, ≥PR rate was 46%, including 15% CR/nCR. Median progression-free survival was 11.4 months (95% confidence interval [CI]: 9.1-12.7) from start of initial bortezomib treatment and 6.4 months (95% CI: 4.4-7.2) from start of retreatment. Median overall survival from start of retreatment was 17.6 months (95% CI: 14.4-23.5). Of the 96 patients retreated with bortezomib, 77% reported an AE. Peripheral neuropathy during bortezomib retreatment occurred in 49% of patients, including 10% grade 3/4.

Conclusion: These data suggest that retreatment with bortezomib is a feasible option for patients with relapsed/refractory MM.
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http://dx.doi.org/10.1002/hsr2.104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346989PMC
January 2019

Bortezomib-based therapy for relapsed/refractory multiple myeloma in real-world medical practice.

Eur J Haematol 2018 Oct 5;101(4):556-565. Epub 2018 Sep 5.

Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.

Objective: The efficacy and safety of bortezomib-based therapy for relapsed/refractory multiple myeloma (RRMM) in clinical trials may differ from the oncology practice experience. The electronic VELCADE OBservational Study was designed to prospectively evaluate bortezomib for multiple myeloma (MM) in real-world medical practice.

Method: Patients scheduled to receive intravenous bortezomib for MM were eligible. The primary objective was to evaluate clinical outcomes, including response, time to response, time to next therapy, treatment-free interval, progression-free survival (PFS), and overall survival (OS). Secondary objectives included safety and healthcare resource utilization.

Results: In total, 873 patients with a median of two therapy lines prior to initiating bortezomib were included. The overall response rate (≥partial response) was 69%, including 37% complete response/near-complete response. Median time to response was 1.8 months, median time to next therapy was 9.7 months, and median treatment-free interval was 7.9 months. After 22.6 months' median follow-up, median PFS was 12.0 months and median OS was 36.1 months. The most common adverse events (AEs) were neuropathy not otherwise specified (19%), diarrhea NOS, and thrombocytopenia (each 17%); 230 (26%) patients discontinued bortezomib due to AEs. Of 689 (79%) patients without baseline peripheral neuropathy (PN), the rate of new-onset any-grade PN increased to 51% (12% grade 3/4) by cycle 8. Overall, 244 (28%) patients were hospitalized, 372 (43%) attended an outpatient visit, and 341 (39%) underwent a diagnostic/therapeutic procedure during bortezomib treatment.

Conclusion: These prospective real-world data demonstrate the effectiveness and safety of bortezomib-based therapy for RRMM and confirm high response rates and long OS for this population.
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http://dx.doi.org/10.1111/ejh.13147DOI Listing
October 2018

In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia.

Ther Drug Monit 2016 Apr;38(2):230-8

*Division of Drug Research/Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University; †Department of Hematology and Coagulation, Skåne University Hospital, Lund; ‡Department of Medical Sciences, Uppsala University and Department of Hematology, University Hospital; §Analytical Chemistry, Department of Chemistry-Biomedical Center and Science for Life Laboratory, Uppsala University; ¶Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm; ‖Department of Hematology, Linköping University Hospital; **Department of Internal Medicine, Motala Hospital; ††Department of Medicine, Ryhov County Hospital, Jönköping; ‡‡Department of Internal Medicine, Västervik Hospital; and §§Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.

Background: Cytochrome P450 3A (CYP3A) isoenzyme metabolic activity varies between individuals and is therefore a possible candidate of influence on the therapeutic outcome of the tyrosine kinase inhibitor imatinib in patients with chronic myeloid leukemia (CML). The aim of this study was to investigate the influence of CYP3A metabolic activity on the plasma concentration and outcome of imatinib in patients with CML.

Methods: Forty-three patients with CML were phenotyped for CYP3A activity using quinine as a probe drug and evaluated for clinical response parameters. Plasma concentrations of imatinib and its main metabolite, CGP74588, were determined using liquid chromatography-mass spectrometry.

Results: Patients with optimal response to imatinib after 12 months of therapy did not differ in CYP3A activity compared to nonoptimal responders (quinine metabolic ratio of 14.69 and 14.70, respectively; P = 0.966). Neither the imatinib plasma concentration nor the CGP74588/imatinib ratio was significantly associated with CYP3A activity.

Conclusions: The CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that although imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.
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http://dx.doi.org/10.1097/FTD.0000000000000268DOI Listing
April 2016
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