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  • 1.
    Jakobsen, Lasse H.
    et al.
    Aalborg Univ Hosp, Denmark; Aalborg Univ, Denmark.
    Ellin, Fredrik
    Lund Univ, Sweden.
    Smeland, Knut B.
    Oslo Univ Hosp, Norway.
    Wasterlid, Tove
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Christensen, Jacob H.
    Odense Univ Hosp, Denmark.
    Jorgensen, Judit M.
    Aarhus Univ Hosp, Denmark.
    Josefsson, Par L.
    Herlev Hosp, Denmark.
    Ovlisen, Andreas K.
    Aalborg Univ Hosp, Denmark; Aalborg Univ, Denmark.
    Holte, Harald
    Oslo Univ Hosp, Norway; Oslo Univ Hosp, Norway.
    Blaker, Yngvild N.
    Oslo Univ Hosp, Norway; Oslo Univ Hosp, Norway.
    Grauslund, Jacob H.
    Roskilde Sygehus, Denmark.
    Bjorn, Jon
    Rigshosp, Denmark.
    Molin, Daniel
    Uppsala Univ, Sweden.
    Lagerlof, Ingemar
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Smedby, Karin E.
    Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden.
    Colvin, Katherine
    Sir Charles Gairdner Hosp, Australia.
    Thanarajasingam, Gita
    Mayo Clin, MN USA.
    Maurer, Matthew J.
    Mayo Clin, MN USA.
    Habermann, Thomas M.
    Mayo Clin, MN USA.
    Song, Kevin W.
    BC Canc, Canada.
    Zhu, Katie Y.
    BC Canc, Canada.
    Gerrie, Alina S.
    BC Canc, Canada.
    Cheah, Chan Y.
    Sir Charles Gairdner Hosp, Australia; Pathwest Lab Med WA, Australia; Univ Western Australia, Australia.
    El-Galaly, Tarec C.
    Aalborg Univ Hosp, Denmark; Aalborg Univ, Denmark.
    Minimal relapse risk and early normalization of survival for patients with Burkitt lymphoma treated with intensive immunochemotherapy: an international study of 264 real-world patients2020In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141Article in journal (Refereed)
    Abstract [en]

    Non-endemic Burkitt lymphoma (BL) is a rare germinal centre B-cell-derived malignancy with the genetic hallmark of MYC gene translocation and with rapid tumour growth as a distinct clinical feature. To investigate treatment outcomes, loss of lifetime and relapse risk in adult BL patients treated with intensive immunochemotherapy, retrospective clinic-based and population-based lymphoma registries from six countries were used to identify 264 real-world patients. The median age was 47 years and the majority had advanced-stage disease and elevated LDH. Treatment protocols were R-CODOX-M/IVAC (47%), R-hyper-CVAD (16%), DA-EPOCH-R (11%), R-BFM/GMALL (25%) and other (2%) leading to an overall response rate of 89%. The two-year overall survival and event-free survival were 84% and 80% respectively. For patients in complete remission/unconfirmed, the two-year relapse risk was 6% but diminished to 0 center dot 6% for patients reaching 12 months of post-remission event-free survival (pEFS12). The loss of lifetime for pEFS12 patients was 0 center dot 4 (95% CI: -0 center dot 7 to 2) months. In conclusion, real-world outcomes of adult BL are excellent following intensive immunochemotherapy. For pEFS12 patients, the relapse risk was low and life expectancy similar to that of a general population, which is important information for developing meaningful follow-up strategies with increased focus on survivorship and less focus on routine disease surveillance.

  • 2.
    Lindberg, Oscar
    et al.
    Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping (ANOPIVA).
    de Geer, Lina
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Chew, Michelle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping (ANOPIVA).
    Nonadherence to antibiotic guidelines in patients admitted to ICU with sepsis is associated with increased mortality A registry-based, retrospective cohort study2020In: European Journal of Anaesthesiology, ISSN 0265-0215, E-ISSN 1365-2346, Vol. 37, no 2, p. 113-120Article in journal (Refereed)
    Abstract [en]

    BACKGROUND Early appropriate antibiotic therapy is an important component of the Surviving Sepsis Guidelines bundles that are associated with decreased in-hospital mortality. National antibiotic guidelines for the treatment of sepsis in Sweden have been available since 2008. Compliance with these guidelines is largely unknown, and whether it translates to improved patient outcome has not been studied. OBJECTIVE To assess mortality and its relationship to compliance with Swedish antibiotic guidelines. A secondary aim was to assess the effect of timing of antibiotic administration and mortality. DESIGN A registry-based, retrospective cohort study. Registry data were supplemented by manual extraction of data on antibiotic treatment from patient charts. The association between guideline compliance and mortality was evaluated using multivariable analysis. Three levels of compliance were predefined: full compliance - correct antibiotics and dose; partial compliance - correct antibiotic but wrong dose and/or wrong initial antibiotic but corrected within 24 h and/or wrong combination in a combined regime that is at least one antibiotic not in line with the national antibiotic guideline; no compliance - incorrect antibiotic. SETTING Two general ICUs in Sweden between 1 January 2011 and 31 December 2015. PATIENTS Seven hundred and thirteen patients over the age of 18 with severe sepsis or septic shock identified through the Swedish ICU Registry. MAIN OUTCOME MEASURES The primary outcome was 30-day mortality. RESULTS Full compliance was observed in 47.0% of patients, partial compliance in 36.0%, and no compliance in 17.0%. Lack of compliance was independently associated with increased risk of 30-day mortality: the adjusted hazard ratio was 1.86 (95% CI 1.34 to 2.58 P amp;lt; 0.001) for partial compliance and 2.18 (95% CI 1.34 to 3.40 P amp;lt; 0.001) for no compliance. The time to first antibiotic administration was not associated with mortality. CONCLUSION Less than half of the patients with severe sepsis and septic shock received antibiotics according to Swedish national guidelines. Full compliance with the guidelines was associated with decreased mortality. The results of this study show that a strict approach to guideline compliance seems to be beneficial: half measures and inadequate doses should be avoided.

  • 3.
    Lund Hansen, Stine
    et al.
    Univ Copenhagen, Denmark.
    Johansen, Sys Stybe
    Univ Copenhagen, Denmark.
    Nielsen, Marie Katrine Klose
    Univ Copenhagen, Denmark.
    Nilsson, Gunnel
    Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Kronstrand, Robert
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Natl Board Forens Med, Dept Forens Genet and Forens Toxicol, Linkoping, Sweden.
    Distribution of zopiclone and main metabolites in hair following a single dose2020In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 306, article id 110074Article in journal (Refereed)
    Abstract [en]

    In forensic investigations, such as drug-facilitated crimes, reference values are useful for interpretation of hair results. The aim of this study was to establish levels of zopiclone and two main metabolites, N-desmethylzopiclone and zopiclone N-oxide, in hair after the administration of a single dose of zopiclone, as very limited data are published. A controlled study was performed, where 16 volunteers consumed either 5 or 10 mg zopiclone. Hair was sampled prior to consumption and 14, 30, 60, and 120 days after intake. The deposition of drug in hair segments of all sampling time points was followed in small hair segments of 5-mm, using a validated ultra-high performance liquid chromatography-tandem mass spectrometry method. In all participants, hair segments corresponding to the time of intake were positive for zopiclone, but also with lower concentrations in the neighbouring segments. The highest zopiclone concentrations were detected in samples collected 30 or 60 days after intake. For all sampling time points maximum values for the 5-mg dose ranged from 5.0-370 pg/mg for zopiclone and 5.4 to 300 pg/mg for N-desmethylzopiclone, where the maximum values for the 10-mg dose ranged from 17 to 590 pg/mg for zopiclone and 25-410 pg/mg for N-desmethylzopiclone for all sampling time points. No significant difference in concentrations was found between the two dosing groups for either zopiclone or N-desmethylzopiclone. Almost half of the participants showed lower levels 14 days after intake than in the later sampling time points. The metabolite to parent drug ratio of N-desmethylzopiclone to zopiclone varied from 0.6 to 3.4 (median = 1.2) for the maximum levels of all sampling time points. N-desmethylzopiclone are suggested to serve as an additional marker to confirm the intake of zopiclone. Traces of zopiclone N-oxide were detected in hair from only eight participants. This study showed, that it was possible to follow zopiclone and N-desmethylzopiclone in hair for 4 months even though the drugs was divided into several segments in the latest collected hair samples, and no obvious wash-out effect between the sampling time points by e.g. personal hygiene could be discerned because the cumulated amount at each sampling time point was similar. We conclude that the analysis of short segments e.g. segments of 5-mm can help determine the time of a single intake of zopiclone and that obtaining a sample 1-2 months after a drug exposure provide the best conditions to detect and interpret the results. (C) 2019 Elsevier B.V. All rights reserved.

  • 4.
    Pinto, Bernardo Bollen
    et al.
    Geneva Univ Hosp, Switzerland; Geneva Perioperat Basic Translat and Clin Res Grp, Switzerland.
    Chew, Michelle
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Anaesthesiology and Intensive Care in Linköping (ANOPIVA).
    Buse, Giovanna Lurati
    Univ Hosp Dusseldorf, Germany.
    Walder, Bernhard
    Geneva Univ Hosp, Switzerland; Geneva Perioperat Basic Translat and Clin Res Grp, Switzerland.
    The concept of peri-operative medicine to prevent major adverse events and improve outcome in surgical patients A narrative review2019In: European Journal of Anaesthesiology, ISSN 0265-0215, E-ISSN 1365-2346, Vol. 36, no 12, p. 889-903Article, review/survey (Refereed)
    Abstract [en]

    Peri-operative Medicine is the patient-centred and value-based multidisciplinary peri-operative care of surgical patients. Peri-operative stress, that is the collective response to stimuli occurring before, during and after surgery, is, together with pre-existing comorbidities, the pathophysiological basis of major adverse events. The ultimate goal of Perioperative Medicine is to promote high quality recovery after surgery. Clinical! scores and/or biomarkers should be used to identify patients at high risk of developing major adverse events throughout the peri-operative period. Allocation of high-risk patients to specific care pathways with peri-operative organ protection, close surveillance and specific early interventions is likely to improve patient-relevant outcomes, such as disability, health-related quality of life and mortality.

  • 5.
    Svedberg, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Toxicity and pharmacokinetic biomarkers for personalized non-small cell lung cancer treatment2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Lung cancer is the leading cause of cancer-related deaths worldwide. Unfortunately, lung cancer is usually discovered at a late stage when the curative treatment options are limited. The treatment can include surgery, radiation, chemotherapy, targeted therapy and now also immunotherapy.

    The challenge in cancer treatment is to eradicate cancer by the use of harsh treatments, while still, keeping the patient alive. For this purpose, treatments with severe toxicities are usually accepted but regularly lead to dose reductions or postponed treatment. Large variations in response are generally observed between patients treated with the same drug at the same dose. The dose may be adequate in one patient while ineffective or cause severe adverse drug reactions in other patients. The occurrence of drug-induced toxicities can, however, also be a positive indicator of treatment response. In personalized treatment it is of importance to select the most suitable treatment option and give it at the most favorable dose, to enable the patients to stay on treatment during the time the treatment is able to affect cancer since the tumor commonly develops resistance towards the treatment eventually.

    In this thesis, inter-individual variability in pharmacokinetics and toxicity for the targeted therapy erlotinib, associated with the adverse events skin rash and diarrhea was studied. Inter-individual variability in toxicity was also studied for the chemotherapy treatment gemcitabine/carboplatin linked to the hematological toxicities neutropenia and leukopenia.

    Erlotinib was studied in papers I-IV. Erlotinib and its metabolite concentrations were determined using a validated LC-MS/MS method. Diarrhea was associated with erlotinib and the metabolite M13, while skin rash was associated with the activity of the erlotinib metabolizing enzyme CYP3A and the ABCG2 single nucleotide polymorphism rs10856870. CYP3A was also shown to be induced during treatment. Additionally, in vitro studies showed that genetic variability in ABCG2 contributes to differences in intracellular concentrations. Genes and gene variants were found to be associated with gemcitabine/carboplatininduced toxicity in paper V. The variants were partially validated, and two models were developed to estimate the risk of leukopenia or neutropenia based on a set of genetic variants.

    List of papers
    1. A validated liquid chromatography tandem mass spectrometry method for quantification of erlotinib, OSI-420 and didesmethyl erlotinib and semi-quantification of erlotinib metabolites in human plasma
    Open this publication in new window or tab >>A validated liquid chromatography tandem mass spectrometry method for quantification of erlotinib, OSI-420 and didesmethyl erlotinib and semi-quantification of erlotinib metabolites in human plasma
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    2015 (English)In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 107, p. 186-195Article in journal (Refereed) Published
    Abstract [en]

    A liquid chromatography tandem mass spectrometry method was developed and validated for quantification of erlotinib and its metabolites in human plasma. The method is suitable for therapeutic drug monitoring and pharmacokinetic studies. The substances were extracted using protein precipitation, separated on a BEH XBridge C18 column (100 x 2.1 mm, 1.7 mu m) by gradient elution at 0.7 mL/min of acetonitrile and 5 mM ammonium acetate. The concentration was determined using a Waters Xevo triple quadrupole mass spectrometer in a multi reaction monitoring mode. The total run time was 7 min. Deuterated erlotinib and OSI-597 were used as internal standard for erlotinib and its metabolites, respectively. Erlotinib, OSI-420 and didesmethyl erlotinib were quantified in the concentration range 25-5000 ng/mL, 0.5-500 ng/mL and 0.15-10 ng/mL, respectively. Precision and accuracy was less than14% except for OSI-420 at LLOQ (17%). Extraction recovery was above 89%, 99% and 89% for erlotinib, OSI-420 and didesmethyl erlotinib, respectively. The human liver microsomes generated 14 metabolites, three of them not previously reported. Twelve metabolites were measured semi-quantitatively and validated with respect to selectivity, precision and stability. (C) 2014 Elsevier B.V. All rights reserved.

    Place, publisher, year, edition, pages
    Elsevier, 2015
    Keywords
    LC-MS/MS; Human liver microsomes; Non-small cell lung cancer; EGFR; Tyrosine kinase inhibitor
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:liu:diva-117227 (URN)10.1016/j.jpba.2014.12.022 (DOI)000351116900024 ()25594896 (PubMedID)
    Note

    Funding Agencies|Swedish Research Council [C0592901, A0671101]; Swedish Cancer Society [130335]; Medical Research Council of Southeast Sweden [388611]

    Available from: 2015-04-23 Created: 2015-04-21 Last updated: 2020-01-14
    2. Erlotinib treatment induces cytochrome P450 3A activity in non-small cell lung cancer patients
    Open this publication in new window or tab >>Erlotinib treatment induces cytochrome P450 3A activity in non-small cell lung cancer patients
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    2019 (English)In: British Journal of Clinical Pharmacology, ISSN 0306-5251, E-ISSN 1365-2125, Vol. 85, no 8, p. 1704-1709Article in journal (Refereed) Published
    Abstract [en]

    Aims Erlotinib is a tyrosine kinase inhibitor used in the treatment of non-small cell lung cancer highly metabolized by the cytochrome P450 (CYP) 3A. Hence, CYP3A4 activity might be a useful predictor of erlotinib pharmacokinetics in personalized medicine. The effect of erlotinib on CYP3A activity was therefore studied in non-small cell lung cancer patients. Methods The study included 32 patients scheduled for erlotinib monotherapy. CYP3A activity was assessed using quinine as a probe before and during erlotinib treatment. Plasma from blood samples drawn 16 hours post quinine administration were analysed using HPLC with fluorescence detection to determine the quinine/3-OH-quinine ratio. Results Matched samples, available from 13 patients, showed an induction of CYP3A activity (P = 0.003, Wilcoxons signed rank test) after 2 months of treatment. The quinine/3-OH-quinine ratio decreased from 20.2 (+/- 13.4) at baseline to 11.0 (+/- 4.34). Single-point samples, available from 19 patients, supported the decrease in ratio (P = 0.007, Mann-Whitney U-test). Generally, females had a higher CYP3A activity both at baseline and after two months of treatment. Statistical analysis by gender also showed significant increase in CYP3A activity (males, n = 10, P = 0.001, and females, n = 22, P = 0.001). Conclusions An induction of CYP3A activity was observed after 2 months of erlotinib treatment which was also seen when subdividing based on gender. It could be important to take this into consideration for patients co-administering other CYP3A-metabolizing drugs during erlotinib treatment and also makes it difficult to use baseline CYP3A activity to predict erlotinib pharmacokinetics.

    Place, publisher, year, edition, pages
    WILEY, 2019
    Keywords
    CYP3A activity; erlotinib; non-small cell lung cancer; quinine; Tarceva
    National Category
    Pharmaceutical Sciences
    Identifiers
    urn:nbn:se:liu:diva-159123 (URN)10.1111/bcp.13953 (DOI)000475399400007 ()30945322 (PubMedID)
    Note

    Funding Agencies|Cancerfonden [CAN 2016/602]; Forskningsradet i Sydostra Sverige [760411]; Swedish Research Council; Linkoping University

    Available from: 2019-07-30 Created: 2019-07-30 Last updated: 2020-01-14
  • 6.
    Yngman Uhlin, Pia
    et al.
    Linköping University, Department of Health, Medicine and Caring Sciences, Division of Nursing Sciences and Reproductive Health. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Operations management Region Östergötland, Research and Development Unit.
    Kjellsdotter, Anna
    Univ Skovde, Sweden.
    Uhlin, Fredrik
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Nephrology. Tallinn Univ Technol, Estonia.
    Edéll-Gustafsson, Ulla
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Medicine and Health Sciences.
    Sleep Quality, Fatigue, and Health-Related Quality of Life in Patients on Initial Peritoneal Dialysis and Multiple Modalities after Two Years: A Prospective Study2019In: Nephrology Nursing Journal : Journal of The American Nephrology Nurses Association, ISSN 1526-744X, E-ISSN 2163-5390, Vol. 46, no 6, p. 615-+Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to investigate changes in sleep quality, fatigue, mental health, and health-related quality of life (HRQoL) over a two-year period among patients undergoing peritoneal dialysis treatment at home. We further explored the extent to which sleep quality, fatigue, and mental health predicted health-related quality of life outcomes. This prospective study included 55 patients. Sleep parameters changed over two years, independently of treatment. Sleep variables at baseline, to some extent, predicted sleep quality after two years. Daytime sleepiness can be a long-term problem. Findings indicate improvements in nocturnal sleep over a two-year time period, independently of dialysis treatment. In contrast, fatigue remained unchanged over the same time period Dansplantation seems to generally benefit the outcome of HRQoL. Strategies to improve sleep and HRQoL may include systematic risk factor modification and efforts to optimise symptomatic treatment.

  • 7.
    Zimdahl, Anna
    Linköping University, Department of Biomedical and Clinical Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.
    Pharmacogenetic studies of thiopurine methyltransferase genotype-phenotype concordance and effect of methotrexate on thiopurine metabolism2020Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The thiopurines (6-mercaptopurine [6-MP], 6-thioguanine and azathioprine) are cytotoxic drugs used in the treatment of acute lymphoblastic leukemia (ALL), inflammatory bowel diseases, certain autoimmune diseases and after transplantation. The metabolism of thiopurines is complex with several enzymes involved in the conversion into active drug metabolites. One of the enzymes, thiopurine methyltransferase (TPMT), is one of the best examples of implemented pharmacogenetics so far. Due to lowered TPMT enzyme activity caused by genetic polymorphism, carriers of heterozygous or homozygous defective TPMT alleles need dose reduction to avoid cytotoxic adverse reactions like myelosuppression or hepatotoxicity if treated with thiopurines.

    To determine TPMT status before the start of treatment, genotyping (for the three most occurring TPMT alleles) and/or phenotyping (TPMT enzyme activity measurements) are used in the clinical setting. In the focus of this thesis, concordance of these methods was investigated in a large cohort of unique samples (n=12,663) collected in the routine analysis service of TPMT status determinations in Linköping. By sequencing all exons in samples where the results of the two methods differed, rare or novel TPMT alleles were discovered. Four TPMT alleles (TPMT*41, *42, *43, *44), not previously described, were characterized in terms of clinical in vivo data as well as protein structure and stability data obtained from recombinant human TPMT (rTPMT) produced by E. Coli and biophysical methods.

    The clinical cohort was also used in the search for other factors (except genetic factors) that influence TPMT enzyme activity, and both age and gender turned out to affect TPMT enzyme activity level. In addition, TPMT enzyme activity in the early treatment of ALL was investigated and shown to be significantly lower at time of ALL diagnosis.

    In the treatment protocol of ALL, the combined treatment using 6-MP and methotrexate (MTX) has increased the positive outcomes since the start in the 1950s. Despite this, the synergistic effect of these drugs is not yet fully understood. To evaluate the effect of MTX on thiopurine metabolism specifically, TPMT enzyme activity, TPMT gene expression, and thiopurine metabolite levels were determined before and after MTX infusions in vivo and after cotreatment in lymphoblasts in vitro. In the presence of MTX, TPMT enzyme activity and metabolite levels decreased, both in vivo and in vitro, although dose- and time-dependent. In addition, MTX bound to rTPMT and caused inhibition of rTPMT enzyme activity.

    The results found in the scope of this thesis may be used for further individualization of thiopurine treatment.

    List of papers
    1. Comprehensive study of thiopurine methyltransferase genotype, phenotype, and genotype-phenotype discrepancies in Sweden
    Open this publication in new window or tab >>Comprehensive study of thiopurine methyltransferase genotype, phenotype, and genotype-phenotype discrepancies in Sweden
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    2019 (English)In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 164, p. 263-272Article in journal (Refereed) Published
    Abstract [en]

    Thiopurines are widely used in the treatment of leukemia and inflammatory bowel diseases. Thiopurine metabolism varies among individuals because of differences in the polymorphic enzyme thiopurine methyltransferase (TPMT, EC 2.1.1.67), and to avoid severe adverse reactions caused by incorrect dosing it is recommended that the patients TPMT status be determined before the start of thiopurine treatment. This study describes the concordance between genotyping for common TPMT alleles and phenotyping in a Swedish cohort of 12,663 patients sampled before or during thiopurine treatment. The concordance between TPMT genotype and enzyme activity was 94.5%. Compared to the genotype, the first measurement of TPMT enzyme activity was lower than expected for 4.6% of the patients. Sequencing of all coding regions of the TPMT gene in genotype/phenotype discrepant individuals led to the identification of rare and novel TPMT alleles. Fifteen individuals (0.1%) with rare or novel genotypes were identified, and three TPMT alleles (TPMT*42, *43, and *44) are characterized here for the first time. These 15 patients would not have been detected as carrying a deviating TPMT genotype if only genotyping of the most common TPMT variants had been performed. This study highlights the benefit of combining TPMT genotype and phenotype determination in routine testing. More accurate dose recommendations can be made, which might decrease the number of adverse reactions and treatment failures during thiopurine treatment.

    Place, publisher, year, edition, pages
    PERGAMON-ELSEVIER SCIENCE LTD, 2019
    Keywords
    Thiopurine; TPMT; Pharmacogenetics; Genotyping; Individualization
    National Category
    Hematology
    Identifiers
    urn:nbn:se:liu:diva-158047 (URN)10.1016/j.bcp.2019.04.020 (DOI)000469163900023 ()31005613 (PubMedID)
    Note

    Funding Agencies|Swedish Childrens Cancer Foundation; Medical Research Council of Southeast Sweden; Swedish Society of Medicine Linkoping; ostgOtaregionens cancerfond

    Available from: 2019-06-25 Created: 2019-06-25 Last updated: 2020-02-17
    2. One amino acid makes a difference-Characterization of a new TPMT allele and the influence of SAM on TPMT stability
    Open this publication in new window or tab >>One amino acid makes a difference-Characterization of a new TPMT allele and the influence of SAM on TPMT stability
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    2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 46428Article in journal (Refereed) Published
    Abstract [en]

    Thiopurine induced toxicity is associated with defects in the thiopurine methyltransferase (TPMT) gene. TPMT is a polymorphic enzyme, with most of the single nucleotide polymorphisms (SNPs) causing an amino acid change, altering the enzymatic activity of the TPMT protein. In this study, we characterize a novel patient allele c.719A amp;gt; C, named TPMT*41, together with the more common variant *3C c.719A amp;gt; G, resulting in an amino acid shift at tyrosine 240 to serine, p.Y240S and cysteine, p.Y240C respectively. We show that the patient heterozygote for c.719A amp;gt; C has intermediate enzymatic activity in red blood cells. Furthermore, in vitro studies, using recombinant protein, show that TPMT p.Y240S is less stable than both TPMTwt and TPMT p.Y240C. The addition of SAM increases the stability and, in agreement with Isothermal Titration Calorimetry (ITC) data, higher molar excess of SAM is needed in order to stabilize TPMT p.Y240C and TPMT p.Y240S compared to TPMTwt. Molecular dynamics simulations show that the loss of interactions is most severe for Y240S, which agrees with the thermal stability of the mutations. In conclusion, our study shows that SAM increases the stability of TPMT and that changing only one amino acid can have a dramatic effect on TPMT stability and activity.

    Place, publisher, year, edition, pages
    NATURE PUBLISHING GROUP, 2017
    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:liu:diva-137842 (URN)10.1038/srep46428 (DOI)000400451400001 ()28462921 (PubMedID)
    Note

    Funding Agencies|LiU Cancer Network; Medical Research Council of Southeast Sweden; Lars Hiertas Memory Foundation; Samariten Foundation; Swedish Society of Medicine Linkoping; Ostgotaregionens Cancerfond; Swedish e-Science Research Center

    Available from: 2017-06-02 Created: 2017-06-02 Last updated: 2020-02-17
    3. Methotrexate binds to recombinant thiopurine S-methyltransferase and inhibits enzyme activity after high-dose infusions in childhood leukaemia
    Open this publication in new window or tab >>Methotrexate binds to recombinant thiopurine S-methyltransferase and inhibits enzyme activity after high-dose infusions in childhood leukaemia
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    2013 (English)In: European Journal of Clinical Pharmacology, ISSN 0031-6970, E-ISSN 1432-1041, Vol. 69, no 9, p. 1641-1649Article in journal (Refereed) Published
    Abstract [en]

    Purpose

    Important drugs in the treatment of childhood acute lymphoblastic leukaemia (ALL) are 6-mercaptopurine (6-MP) and methotrexate (MTX). Thiopurine methyltransferase (TPMT) is a polymorphic enzyme causing variability in 6-MP response and toxicity. The aim of this study was to investigate the fluctuation in TPMT enzyme activity over time and the effect of high-dose MTX infusions on TPMT enzyme activity and 6-MP metabolites in paediatric ALL patients.

    Methods

    Fifty-three children with ALL treated according to the NOPHO-ALL 2000 protocol were included in the study. TPMT enzyme activity was measured at six different times starting from diagnosis until after the end of maintenance treatment. TPMT and 6-MP metabolites were measured before the initiation of high-dose MTX (HD-MTX) infusions and at 66 h post-infusion. The interaction between MTX and TPMT was investigated in vitro using recombinant TPMT protein and a leukaemic cell line.

    Results

    Forty percent of TPMT wild-type individuals had deceptively low TPMT enzyme activity according to genotype at the time of diagnosis. TPMT activity had decreased significantly 66 h after the start of HD-MTX infusions (−9.2 %; p = 0.013). MTX bound to recombinant TPMT protein severely inhibiting TPMT enzyme activity (remaining activity 16 %).

    Conclusions

    Our results show that TPMT genotyping should be performed in children with ALL, since 40 % of the children in our study who carried the wild-type TPMT gene were at risk of initial underdosing of 6-MP in cases where only TPMT enzyme activity was determined. MTX inhibits the TPMT enzyme activity after HD-MTX infusions due to protein binding.

    Place, publisher, year, edition, pages
    Springer Berlin/Heidelberg, 2013
    Keywords
    Leukaemia, 6-mercaptopurine, methotrexate, pharmacogenetics, thiopurine s-methyltransferase
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:liu:diva-80190 (URN)10.1007/s00228-013-1521-9 (DOI)000323429900003 ()
    Available from: 2012-08-22 Created: 2012-08-22 Last updated: 2020-02-17Bibliographically approved
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