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Peterson, Curt
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Publications (10 of 96) Show all publications
Skoglund, K., Richter, J., Olsson-Stromberg, U., Bergquist, J., Aluthgedara, W., Ubhayasekera, S. J., . . . Green, H. (2016). In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia. Therapeutic Drug Monitoring, 38(2), 230-238
Open this publication in new window or tab >>In Vivo Cytochrome P450 3A Isoenzyme Activity and Pharmacokinetics of Imatinib in Relation to Therapeutic Outcome in Patients With Chronic Myeloid Leukemia
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2016 (English)In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 38, no 2, p. 230-238Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2016
Keywords
pharmacokinetics; chronic myeloid leukemia; imatinib; CGP74588; CYP3A
National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:liu:diva-129678 (URN)10.1097/FTD.0000000000000268 (DOI)000376938000006 ()26693810 (PubMedID)
Note

Funding Agencies|Swedish Research Council; Swedish Cancer Society; Medical Research Council of Southeast Sweden; Novartis

Available from: 2016-06-27 Created: 2016-06-23 Last updated: 2018-01-10
Green, H., Hasmats, J., Kupershmidt, I., Edsgard, D., de Petris, L., Lewensohn, R., . . . Lundeberg, J. (2016). Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities. Clinical Cancer Research, 22(2), 366-373
Open this publication in new window or tab >>Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities
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2016 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 2, p. 366-373Article in journal (Refereed) Published
Abstract [en]

Purpose: Chemotherapies are associated with significant interindividual variability in therapeutic effect and adverse drug reactions. In lung cancer, the use of gemcitabine and carboplatin induces grade 3 or 4 myelosuppression in about a quarter of the patients, while an equal fraction of patients is basically unaffected in terms of myelosuppressive side effects. We therefore set out to identify genetic markers for gemcitabine/carboplatin-induced myelosuppression. Experimental Design: We exome sequenced 32 patients that suffered extremely high neutropenia and thrombocytopenia (grade 3 or 4 after first chemotherapy cycle) or were virtually unaffected (grade 0 or 1). The genetic differences/polymorphism between the groups were compared using six different bioinformatics strategies: (i) whole-exome nonsynonymous single-nucleotide variants association analysis, (ii) deviation from Hardy-Weinberg equilibrium, (iii) analysis of genes selected by a priori biologic knowledge, (iv) analysis of genes selected from gene expression meta-analysis of toxicity datasets, (v) Ingenuity Pathway Analysis, and (vi) FunCoup network enrichment analysis. Results: A total of 53 genetic variants that differed among these groups were validated in an additional 291 patients and were correlated to the patients myelosuppression. In the validation, we identified rs1453542 in OR4D6 (P = 0.0008; OR, 5.2; 95% CI, 1.8-18) as a marker for gemcitabine/carboplatin-induced neutropenia and rs5925720 in DDX53 (P = 0.0015; OR, 0.36; 95% CI, 0.17-0.71) as a marker for thrombocytopenia. Patients homozygous for the minor allele of rs1453542 had a higher risk of neutropenia, and for rs5925720 the minor allele was associated with a lower risk for thrombocytopenia. Conclusions: We have identified two new genetic markers with the potential to predict myelosuppression induced by gemcitabine/ carboplatin chemotherapy. (C)2015 AACR.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 2016
National Category
Medical Genetics Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-125314 (URN)10.1158/1078-0432.CCR-15-0964 (DOI)000369076500013 ()26378035 (PubMedID)
Note

Funding Agencies|European Commission [CHEMORES LSHC-CT-2007-037665]; Swedish Cancer Society; Swedish Research Council; Fondkistan; Stiftelsen Sigurd och Elsa Goljes Minne; Marcus Borgstroms stiftelse

Available from: 2016-02-24 Created: 2016-02-19 Last updated: 2018-01-10
Lindqvist Appell, M., Mårtensson, L.-G., Almer, S. & Peterson, C. (2015). Nyttan av farmakogenetik för en mer individualiserad behandling: Exemplet tiopuriner vid inflammatorisk tarmsjukdom och barnleukemi. Läkartidningen, 112, 1229-1233, Article ID DF7L.
Open this publication in new window or tab >>Nyttan av farmakogenetik för en mer individualiserad behandling: Exemplet tiopuriner vid inflammatorisk tarmsjukdom och barnleukemi
2015 (Swedish)In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 112, p. 1229-1233, article id DF7LArticle in journal (Refereed) Published
Abstract [en]

Thiopurines are chemotherapeutic drugs used for treatment of inflammatory bowel diseases and childhood leukemia. Thiopurine methyltransferase (TPMT) is a polymorphic enzyme involved in the metabolism of thiopurines. Individuals lacking TPMT are at increased risk for severe side effects when treated with conventional doses of thiopurines. A research group at the division of drug research at Linköping University is studying thiopurine pharmacogenetics. Since the year 2000, the lab has determined the TPMT status in over 12000 individuals, as an aid to decide thiopurine doses before starting treatment. New knowledge of how genetic factors influence thiopurine treatment effect are anticipated to improve the possibilities for individualization of thiopurine therapy.

Place, publisher, year, edition, pages
Stockholm: Läkartidningen, 2015
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-119996 (URN)26126006 (PubMedID)
Available from: 2015-07-01 Created: 2015-07-01 Last updated: 2017-12-04
Gregers, J., Green, H., Christensen, I. J., Dalhoff, K., Schroeder, H., Carlsen, N., . . . Peterson, C. (2015). Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia. The Pharmacogenomics Journal, 15(4), 372-379
Open this publication in new window or tab >>Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia
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2015 (English)In: The Pharmacogenomics Journal, ISSN 1470-269X, E-ISSN 1473-1150, Vol. 15, no 4, p. 372-379Article in journal (Refereed) Published
Abstract [en]

The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. We hypothesized that variants of ABCB1 affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL). We studied 522 Danish children with ALL, 93% of all those eligible. Risk of relapse was increased 2.9-fold for patients with the 1199GA variant versus 1199GG (P = 0.001), and reduced 61% and 40%, respectively, for patients with the 3435CT or 3435TT variants versus 3435CC (overall P = 0.02). The degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was more prominent in patients with 3435TT variant versus 3435CT/3435CC (P = 0.01/P less than 0.0001). We observed more liver toxicity after high-dose methotrexate in patients with 3435CC variant versus 3435CT/TT ( P = 0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms, efficacy and toxicity in the treatment of ALL, and ABCB1 1199G greater than A may be a new possible predictive marker for outcome in childhood ALL.

Place, publisher, year, edition, pages
Nature Publishing Group: Open Access Hybrid Model Option B, 2015
National Category
Clinical Medicine Hematology
Identifiers
urn:nbn:se:liu:diva-120735 (URN)10.1038/tpj.2014.81 (DOI)000358448500012 ()25582575 (PubMedID)
Note

Funding Agencies|Swedish Cancer Society; Swedish Research Council; County Concil in Ostergotland; Danish Childhood Cancer Foundation; University Hospital Rigshospitalet, Denmark

Available from: 2015-08-24 Created: 2015-08-24 Last updated: 2017-12-04
Vikingsson, S., Andersson, D., Almer, S., Peterson, C. & Hindorf, U. (2014). Novel assay to improve therapeutic drug monitoring of thiopurines in inflammatory bowel disease. Journal of Crohn's & Colitis, 8(12), 1702-1709
Open this publication in new window or tab >>Novel assay to improve therapeutic drug monitoring of thiopurines in inflammatory bowel disease
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2014 (English)In: Journal of Crohn's & Colitis, ISSN 1873-9946, E-ISSN 1876-4479, Vol. 8, no 12, p. 1702-1709Article in journal (Refereed) Published
Abstract [en]

Background and aims: The thiopurines are widely used in the treatment of inflammatory bowel disease, but are limited by poor dose effect relationship. The objective was to assess the ability of a novel assay, determining the mono-, di-, and triphosphates, of thioguanine as well as methylthioinosine as individual metabolites in erythrocytes, to predict clinical outcome compared to a routine assay, determining metabolites as sums. Methods: Samples from 79 patients with Crohns disease or ulcerative colitis treated with azathioprine or mercaptopurine were analysed by both assays. Clinical status was determined by the Harvey-Bradshaw and Walmsley indices. The genotypes of thiopurine methyltransferase (TPMT) and inosine triphosphatase were determined. Results: TPMT wild-type patients with thioguanine nucleotide (TGN) levels below the cut-off level were more likely to have active disease when TGN was measured by the novel assay (p = 0.02), and when thioguanosine triphosphate (TGTP) was measured separately (p = 0.01). When TGN was measured by the routine assay the correlation was not evident (p = 0.12). Neither TGN levels nor TGTP correlated to disease activity in TPMT deficient patients. Patients with methyl thioinosine nucleotide (meTIN) levels above 1500 pmol/8 x 10less than^greater than8 RBCs were more likely to have active disease (p = 0.07). We observed good correlations between the mono-, di-, and triphosphates and their respective sums (R-2 greater than 0.88). Conclusions: The novel TGN assay was better in predicting clinical outcome compared to the routine assay, while determination of TGTP had no clinical advantage and TGTP ratio was not correlated to disease activity. (C) 2014 European Crohns and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
Purines; HPLC; Inflammatory bowel diseases; Individualized medicine; Thiopurine; Azathioprine
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-113783 (URN)10.1016/j.crohns.2014.08.009 (DOI)000347019600016 ()25239576 (PubMedID)
Note

Funding Agencies|Medical Research Council of Southeast Sweden (FORSS) [FORSS-161041, FORSS-235971]; Swedish Society of Medicine [SLS-178771]; County Council of Ostergotland [LIO 130231, LIO 207561, LIO 284811]; Swedish Cancer Society [CAN 2011/401]; Swedish Childhood Cancer Foundation (BCF) [12/052]; Ruth and Richard Julin Foundation; Swedish Research Council [2008-4035]

Available from: 2015-02-02 Created: 2015-01-30 Last updated: 2017-12-05
Haglund, S., Almer, S., Peterson, C. & Söderman, J. (2013). Gene Expression and Thiopurine Metabolite Profiling in Inflammatory Bowel Disease: Novel Clues to Drug Targets and Disease Mechanisms?. PLoS ONE, 8(2)
Open this publication in new window or tab >>Gene Expression and Thiopurine Metabolite Profiling in Inflammatory Bowel Disease: Novel Clues to Drug Targets and Disease Mechanisms?
2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 2Article in journal (Refereed) Published
Abstract [en]

Background and Aims

Thiopurines are effective to induce and maintain remission in inflammatory bowel disease (IBD). The methyl thioinosine monophosphate (meTIMP)/6-thioguanine nucleotide (6-TGN) concentration ratio has been associated with drug efficacy. Here we explored the molecular basis of differences in metabolite profiles and in relation to disease activity.

Methods

Transcriptional profiles in blood samples from an exploratory IBD-patient cohort (n = 21) with a normal thiopurine S-methyltransferase phenotype and meTIMP/6-TGN ratios >20, 10.0–14.0 and ≤4, respectively, were assessed by hybridization to microarrays. Results were further evaluated with RT qPCR in an expanded patient cohort (n = 54). Additionally, 30 purine/thiopurine related genes were analysed separately.

Results

Among 17 genes identified by microarray-screening, there were none with a known relationship to pathways of purines/thiopurines. For nine of them a correlation between expression level and the concentration of meTIMP, 6-TGN and/or the meTIMP/6-TGN ratio was confirmed in the expanded cohort. Nine of the purine/thiopurine related genes were identified in the expanded cohort to correlate with meTIMP, 6-TGN and/or the meTIMP/6-TGN ratio. However, only small differences in gene expression levels were noticed over the three different metabolite profiles. The expression levels of four genes identified by microarray screening (PLCB2, HVCN1, CTSS, and DEF8) and one purine/thiopurine related gene (NME6) correlated significantly with the clinical activity of Crohn’s disease. Additionally, 16 of the genes from the expanded patient cohort interacted in networks with candidate IBD susceptibility genes.

Conclusions

Seventeen of the 18 genes which correlated with thiopurine metabolite levels also correlated with disease activity or participated in networks with candidate IBD susceptibility genes involved in processes such as purine metabolism, cytokine signaling, and functioning of invariant natural killer T cells, T cells and B cells. Therefore, we conclude that the identified genes to a large extent are related to drug targets and disease mechanisms of IBD.

Place, publisher, year, edition, pages
Public Library of Science, 2013
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-90198 (URN)10.1371/journal.pone.0056989 (DOI)000315186000065 ()
Note

Funding Agencies|Futurum - the Academy for Healthcare||County Council Jonkoping||Medical Research Council of Southeast Sweden (FORSS)||Swedish Society of Medicine||County Council of Ostergotland||Swedish Cancer Society||Swedish Childhood Cancer Foundation||Rut and Richard Juhlins Foundation||Swedish Research Council||

Available from: 2013-03-21 Created: 2013-03-21 Last updated: 2017-12-06
Green, H., Lindqvist Appell, M. & Peterson, C. (2013). Genetiska test för optimal dosering på väg att bli klinisk rutin. Onkologi i Sverige (3), 36-40
Open this publication in new window or tab >>Genetiska test för optimal dosering på väg att bli klinisk rutin
2013 (Swedish)In: Onkologi i Sverige, no 3, p. 36-40Article in journal (Other (popular science, discussion, etc.)) Published
Place, publisher, year, edition, pages
Novartis Sverige, 2013
National Category
Clinical Medicine
Identifiers
urn:nbn:se:liu:diva-116535 (URN)
Available from: 2015-03-27 Created: 2015-03-27 Last updated: 2015-04-14
Vikingsson, S., Almer, S., Peterson, C., Carlsson, B. & Josefsson, M. (2013). Monitoring of thiopurine metabolites - A high-performance liquid chromatography method for clinical use. Journal of Pharmaceutical and Biomedical Analysis, 75, 145-152
Open this publication in new window or tab >>Monitoring of thiopurine metabolites - A high-performance liquid chromatography method for clinical use
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2013 (English)In: Journal of Pharmaceutical and Biomedical Analysis, ISSN 0731-7085, E-ISSN 1873-264X, Vol. 75, p. 145-152Article in journal (Refereed) Published
Abstract [en]

A high-performance liquid chromatography method capable of measuring thiopurine mono-, di-, and triphosphates separately in red blood cells (RBCs) was developed. RBCs were isolated from whole blood using centrifugation. Proteins were precipitated using dichloromethane and methanol. The thioguanine nucleotides (TGNs) were derivatised using potassium permanganate before analysis. Analytes were separated by ion-pairing liquid chromatography using tetrabutylammonium ions and detected using UV absorption and fluorescence. The method was designed for use in clinical trials. Ten patient samples were analysed to demonstrate clinical application and to establish pilot ranges for all analytes. less thanbrgreater than less thanbrgreater thanThe method measured thioguanosine mono-(TGMP), di-(TGDP), and triphosphate (TGTP), as well as methylthioinosine mono- (meTIMP), di- (meTIDP) and triphosphate (meTITP) in RBCs collected from patients treated with thiopurine drugs (azathioprine, 6-mercaptopurine, and 6-thioguanine). less thanbrgreater than less thanbrgreater thanLOQ was 0.3, 3, 2, 30, 30 and 40 pmol/8 x 10(8) RBC, for TGMP, TGDP, TGTP, meTIMP, meTIDP and meTITP, respectively. Between-day precision were below 14% for all analytes at all concentrations and samples were stable at 4 degrees C for 8 h after sampling.

Place, publisher, year, edition, pages
Elsevier, 2013
Keywords
Inflammatory bowel disease (IBD), HPLC, Nucleotide, Acute lymphoid leukaemia, Pharmacogenetics
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-89732 (URN)10.1016/j.jpba.2012.11.027 (DOI)000314332500019 ()
Note

Funding Agencies|Swedish Cancer Society||Swedish Childhood Cancer Foundation||Swedish Medical Research Council||

Available from: 2013-03-05 Created: 2013-03-05 Last updated: 2017-12-06
Bergmann, T. K., Brasch-Andersen, C., Green, H., Mirza, M. R., Skougaard, K., Wihl, J., . . . Brosen, K. (2012). Impact of ABCB1 Variants on Neutrophil Depression: A Pharmacogenomic Study of Paclitaxel in 92 Women with Ovarian Cancer. Basic & Clinical Pharmacology & Toxicology, 110(2), 199-204
Open this publication in new window or tab >>Impact of ABCB1 Variants on Neutrophil Depression: A Pharmacogenomic Study of Paclitaxel in 92 Women with Ovarian Cancer
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2012 (English)In: Basic & Clinical Pharmacology & Toxicology, ISSN 1742-7835, E-ISSN 1742-7843, Vol. 110, no 2, p. 199-204Article in journal (Refereed) Published
Abstract [en]

The standard treatment for ovarian cancer in advanced stages is post-surgery treatment with taxane-platin chemotherapy. Despite an initial high response rate, most patients eventually relapse. The dose-limiting toxicities of paclitaxel are neutropenia and neuropathy, but the inter-individual variability is large. The aim of this prospective study was to investigate the impact of genetic variants in key drug metabolizing/transporter genes on toxicity and compliance. CYP2C8*3 and three ABCB1 polymorphisms were chosen for primary analysis, and a host of other candidate genes was explored in 92 prospectively recruited Scandinavian Caucasian women with primary ovarian cancer who were treated with paclitaxel and carboplatin. A single investigator assessed the clinical toxicity in 97% of the patients. Patients carrying variant alleles of ABCB1 C3435T experienced more pronounced neutrophil decrease (63%, 72% and 80% for 3435CC, CT and TT, respectively; p-value 0.03). A similar association was found for G2677T /A, p-value 0.02. For C1236T, there was a trend with p-value 0.06. No statistically significant correlations were found for paclitaxel compliance and sensory neuropathy in the primary analysis. Variants in the drug transporter ABCB1 gene are possibly associated with the neutrophil suppressing effect of paclitaxel in patients with ovarian cancer. This finding has implications for the understanding of bone marrow suppression and future tailored chemotherapy.

Place, publisher, year, edition, pages
WILEY-BLACKWELL, COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA, 2012
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-76539 (URN)10.1111/j.1742-7843.2011.00802.x (DOI)000301434200013 ()
Note
Funding Agencies|European Commission|LSHC-CT-2007-037665|Swedish Cancer Society||Swedish Medical Society - Linkoping branch||County Council in Ostergotland||Danish Ministry of Interior Affairs and Health|2006-12103-276|Danish Research Agency|271-05-0266|Roche Denmark||Hvidovre, Denmark||Available from: 2012-04-12 Created: 2012-04-11 Last updated: 2017-12-07
Gregers, J., Jarle Christensen, I., Dalhoff, K., Schroeder, H., Carlsen, N., Rosthoej, S., . . . Peterson, C. (2012). Pharmacogenetic polymorphisms in folate metabolism affect toxicity after high dose methotrexate in childhood acute lymphoblastic leukemia.
Open this publication in new window or tab >>Pharmacogenetic polymorphisms in folate metabolism affect toxicity after high dose methotrexate in childhood acute lymphoblastic leukemia
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2012 (English)Manuscript (preprint) (Other academic)
Abstract [en]

We hypothesized that polymorphisms in folate metabolism would affect treatment effects of the folate antagonist methotrexate (MTX). We studied whether ATIC347C>T, MTHFR677C>T, MTHFR1298C>A and SHMT1-1420C>T polymorphisms influence risk of disease or efficacy and toxicity of MTX in a large population of children with acute lymphoblastic leukaemia (ALL). The children were treated after standardized Nordic protocols with 5-8 g/m2 high-dose MTX courses and long term oral maintenance therapy with weekly MTX. Ninety-four percent (n=533) of the children diagnosed during a 16 year time period were included. The study showed that the polymorphisms had no effect on risk of ALL, MTX pharmacokinetics or outcome. However after high-dose MTX treatment, patients with MTHFR677TT/MTHFR677CT had more liver toxicity than patients with MTHFR677CC (alanine transferase: 174/154 versus 115U/L, p=0.049). Patients with MTHFR1298AA had more liver toxicity than patients with MTHFR1298CC (alanine transferase: 144 versus 108 U/L, p=0.04). More bone marrow toxicity was found in patients with MTHFR1298CC compared to MTHFR1298CT / MTHFR1298AA (Nadir means: Platelets 72 versus 109/93*109/L, p=0.0001).

In conclusion this study supports that MTHFR1298C>A and MTHFR677C>T are associated with toxicity in MTX treatment and the MTHFR variants should be considered as markers for individualization of treatment in childhood ALL in combination with other pharmacogenetic markers.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-77622 (URN)
Available from: 2012-05-24 Created: 2012-05-24 Last updated: 2012-05-24Bibliographically approved
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