oru.sePublikationer
Ändra sökning
Avgränsa sökresultatet
1 - 28 av 28
RefereraExporteraLänk till träfflistan
Permanent länk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
Träffar per sida
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sortering
  • Standard (Relevans)
  • Författare A-Ö
  • Författare Ö-A
  • Titel A-Ö
  • Titel Ö-A
  • Publikationstyp A-Ö
  • Publikationstyp Ö-A
  • Äldst först
  • Nyast först
  • Skapad (Äldst först)
  • Skapad (Nyast först)
  • Senast uppdaterad (Äldst först)
  • Senast uppdaterad (Nyast först)
  • Disputationsdatum (tidigaste först)
  • Disputationsdatum (senaste först)
  • Standard (Relevans)
  • Författare A-Ö
  • Författare Ö-A
  • Titel A-Ö
  • Titel Ö-A
  • Publikationstyp A-Ö
  • Publikationstyp Ö-A
  • Äldst först
  • Nyast först
  • Skapad (Äldst först)
  • Skapad (Nyast först)
  • Senast uppdaterad (Äldst först)
  • Senast uppdaterad (Nyast först)
  • Disputationsdatum (tidigaste först)
  • Disputationsdatum (senaste först)
Markera
Maxantalet träffar du kan exportera från sökgränssnittet är 250. Vid större uttag använd dig av utsökningar.
  • 1.
    Ahlstrand, Erik
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Region Örebro län. Department of Medicine, Hematology, Örebro University Hospital, Örebro, Sweden.
    Bäckman, Anders
    Örebro universitet, Institutionen för medicinska vetenskaper. Clinical Research Centre, Örebro University Hospital, Örebro, Sweden.
    Persson, Lennart
    Region Örebro län. Department of Infectious diseases, Örebro University Hospital, Örebro, Sweden.
    Mölling, Paula
    Region Örebro län. Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Tidefelt, Ulf
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Söderquist, Bo
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Department of Infectious diseases & Department of Laboratory Medicine, Clinical Microbiology, Örebro University Hospital, Örebro, Sweden.
    Evaluation of a PCR method to determine the clinical significance of blood cultures with Staphylococcus epidermidis in patients with hematological malignancies2014Ingår i: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 122, nr 6, s. 539-544Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim was to investigate whether the detection and quantification of Staphylococcus epidermidis DNA in blood could distinguish S. epidermidis blood stream infections (BSIs) from blood culture contaminations in patients with hematological malignancies. The hld gene was chosen to identify S. epidermidis DNA and DNA in blood samples was detected by real-time PCR. Blood samples were obtained simultaneously with blood cultures positive for S. epidermidis (n = 30), during blood culture-negative episodes (n = 10) and episodes of bacteremia with other bacteria than S. epidermidis (n = 4) and from healthy blood donors (n = 10). In addition, DNA from S. epidermidis and a selection of other bacterial species were analyzed. Three different sets of criteria were used to classify episodes with positive blood cultures with S. epidermidis as BSIs or contaminations. All DNA preparations from S. epidermidis (n = 48) were hld-positive, but other bacterial species (n = 13) were negative. Sixteen (53%) of 30 blood samples from patients with blood cultures positive for S. epidermidis were hld-positive, but none of the controls. There was no clear association between a positive hld PCR and episodes interpreted as BSIs. In conclusion, hld PCR failed to distinguish S. epidermidis BSIs from blood culture contaminations in patients with hematological malignancies.

  • 2.
    Ahlstrand, Erik
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Division of Hematology, Department of Medicine,Örebro University Hospital, Örebro, Sweden.
    Persson, Lennart
    Department of Infectious Diseases, Örebro University Hospital, Örebro, Sweden.
    Tidefelt, Ulf
    Örebro universitet, Institutionen för läkarutbildning. Department of Infectious Diseases, Örebro University Hospital, Örebro, Sweden.
    Söderquist, Bo
    Örebro universitet, Institutionen för läkarutbildning. Clinical Microbiology, Department of Laboratory Medicine, Örebro University Hospital, Örebro, Sweden.
    Alteration of the colonization pattern of coagulase-negative staphylococci in patients undergoing treatment for hematological malignancy2012Ingår i: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 31, nr 7, s. 1679-1687Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim was to prospectively describe the colonization pattern of coagulase-negative staphylococci (CoNS) and the relationship between colonizing and invasive CoNS isolates among patients undergoing treatment for hematological malignancy. Fourteen newly diagnosed patients were included with either multiple myeloma or acute leukemia. Patients were repeatedly sampled from nares, throat, axillae, and perineum, and the CoNS isolates obtained were phenotypically characterized together with blood isolates of CoNS using the PhenePlate system (PhP). During the treatment a gradual reduction in the heterogeneity of colonizing CoNS was observed as well as an inter-patient accumulation of phenotypically related and multi-drug-resistant CoNS. These clusters of CoNS persisted for 2–3 months after the end of therapy. Ten positive blood cultures of CoNS were obtained and in the majority of these cases CoNS of the same PhP type were found in superficial cultures collected prior to the blood culture sampling. In conclusion, the study shows that therapy for hematological malignancy is associated with a homogenization of colonizing CoNS isolates and that this acquired flora of CoNS is persistent several months after the end of therapy. Furthermore, the results suggest that the source of bloodstream infections of CoNS in hematological patients is colonizing CoNS of the skin and mucosa.

  • 3. Ahlstrand, Erik
    et al.
    Svensson, K.
    Persson, Lennart
    Tidefelt, Ulf
    Örebro universitet, Hälsoakademin.
    Söderquist, Bo
    Örebro universitet, Hälsoakademin.
    Glycopeptide resistance in coagulase-negative staphylococci isolated in blood cultures from patients with hematological malignancies during three decades2011Ingår i: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 30, nr 11, s. 1349-1354Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of this study was to determine if there was a long-term increase in glycopeptide minimum inhibitory concentration (MIC) values, MIC creep, among bloodstream isolates of Staphylococcus epidermidis and S. haemolyticus isolated from patients with hematological malignancies. We conducted a retrospective single-center study where all positive blood cultures of S. epidermidis (n = 387) and S. haemolyticus (n = 19) isolated from patients with hematological malignancies during three decades, 1980 to 2009, were re-evaluated for the presence of reduced susceptibility to vancomycin and teicoplanin. Three different methods for the detection of reduced susceptibility to glycopeptides were used; standard Etest, macromethod Etest, and glycopeptide resistance detection (GRD) Etest. The median MIC value for vancomycin was 2 mg/L. MIC values for vancomycin and teicoplanin did not show any statistically significant increase during the study period. The presence of heterogeneously glycopeptide-intermediate staphylococci (hGIS) was analyzed among 405 coagulase-negative staphylococci (CoNS) isolates. hGIS were found in 31-45% of the CoNS isolates by the macromethod Etest and in 53-67% by the GRD Etest during the three decades. In conclusion, we did not observe any long-term glycopeptide MIC creep determined by the standard Etest, although a high and increasing proportion of heterogeneous vancomycin resistance was observed.

  • 4.
    Deneberg, Stefan
    et al.
    Department of Internal Medicine/Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Guardiola, Philippe
    Inserm, Angers, France; Service des Maladies du Sang, Centre Hospitalier Universitaire, Angers, France.
    Lennartsson, Andreas
    Institute for Biomedicine and Nutrition, NOVUM, Karolinska Institutet, Stockholm, Sweden.
    Qu, Ying
    Department of Internal Medicine/Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Gaidzik, Verena E.
    Department of Internal Medicine III, University Hospital, Ulm, Germany.
    Blanchet, Odile
    Inserm, Angers, France; Laboratoire d Hematologie, Centre Hospitalier Universitaire, Angers, France.
    Karimi, Mohsen
    Department of Internal Medicine/Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Bengtzén, Sofia
    Department of Internal Medicine/Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Nahi, Hareth
    Department of Internal Medicine/Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Uggla, Bertil
    Örebro universitet, Institutionen för medicinska vetenskaper. Department of Hematology, Örebro University Hospital, Örebro, Sweden.
    Tidefelt, Ulf
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Department of Hematology, Örebro University Hospital, Örebro, Sweden.
    Höglund, Martin
    Department of Hematology, Uppsala University Hospital, Uppsala, Sweden.
    Paul, Christer
    Department of Internal Medicine/Hematology, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden.
    Ekwall, Karl
    Institute for Biomedicine and Nutrition, NOVUM, Karolinska Institutet, Stockholm, Sweden.
    Döhner, Konstanze
    Department of Internal Medicine III, University Hospital, Ulm, Germany.
    Lehmann, Sören
    Department of Internal Medicine/Hematology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
    Prognostic DNA methylation patterns in cytogenetically normal acute myeloid leukemia are predefined by stem cell chromatin marks2011Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, nr 20, s. 5573-5582Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cytogenetically normal acute myeloid leukemia (CN-AML) comprise between forty and fifty percent of all adult acute myeloid leukemia (AML) cases. In this clinically diverse group molecular aberrations such as FLT3ITD, NPM1 and CEBPA mutations recently have added to the prognostic accuracy. Aberrant DNA methylation is a hallmark of cancer including AML. We investigated in total 118 CN-AML samples in a test and a validation cohort for genome-wide promoter DNA methylation with Illumina Methylation Bead arrays and compared them to normal myeloid precursors and global gene expression. IDH and NPM1 mutations were associated with different methylation patterns (p=0.0004 and 0.04, respectively). Genome-wide methylation levels were elevated in IDH mutated samples (p=0.006). We observed a negative impact of DNA methylation on transcription. Genes targeted by Polycomb group (PcG) proteins and genes associated with bivalent histone marks in stem cells showed increased aberrant methylation in AML (p<0.0001). Furthermore, high methylation levels of PcG target genes were independently associated with better progression free (OR 0.47, p=0.01) and overall survival (OR 0.36, p=0.001). In summary, genome wide methylation patterns show preferential methylation of PcG targets with prognostic impact in CN-AML.

  • 5.
    Fergedal, May
    et al.
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Åström, Maria
    Department of Internal Medicine, Örebro Medical Center Hospital, Örebro, Sweden.
    Tidefelt, Ulf
    Department of Internal Medicine, Örebro Medical Center Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Differences in CD14 and alpha-naphthyl acetate esterase positivity and relation to prognosis in AML1998Ingår i: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 22, nr 1, s. 25-30Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alpha-naphthyl acetate esterase (ANAE) and CD14 expression, used for determination of monocytic cells, were compared and related to prognosis in 65 AML patients. Bone marrow aspiration material from AML patients has been used for the cytochemistry as well as flow cytometry. All non-erythroid cells have been included in the evaluation in both methods. 17/65 cases showed at least 15% difference between the proportion CD14 and ANAE positive cells. Cases with 20% or more CD14 positivity had poorer prognosis. For FAB classes M0-M3, presence of 10% or more CD14 was negative for overall survival (P = 0.01). ANAE did not show significant prognostic influence.

  • 6. Hoff, Lena
    et al.
    Tidefelt, Ulf
    Örebro universitet, Hälsoakademin.
    Thaning, Lars
    Hermerén, Göran
    In the shadow of bad news - views of patients with acute leukaemia, myeloma or lung cancer about information, from diagnosis to cure or death2007Ingår i: BMC Palliative Care, ISSN 1472-684X, E-ISSN 1472-684X, Vol. 6, s. 1-Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    BACKGROUND: Many studies have been published about giving and receiving bad messages. However, only a few of them have followed the patients all the way through a disease as is done in this study. Many studies have been written about patients' coping strategies. In this study we will keep within the bounds of coping through information only. The aim of the study is to investigate patients' views of information during the trajectory of their disease, whether their reactions differ from each other and whether they differ in different phases of the disease. METHODS: Twelve patients with malignant haematological diseases or lung cancer were followed with interviews from diagnosis to recovery or into the terminal phase or at most for two years. The method is qualitative, using semi-structured interviews. SETTING: Orebro University Hospital or the patient's home. RESULTS: All patients described themselves as well informed from the start but in later phases of their disease some of them came to express a great uncertainty about the progressing disease and about the approaching death. Most of them, regardless of whether they had a haematological malignancy or lung cancer, expressed a wish to be well informed all through the disease and even when the messages were bad. Different strategies for coping with information, however, affected how they then dealt with the information received. Four such coping strategies were found: 1) Information-dependent and accepting; 2) Information-dependent but denying; 3) Medically informed and accepting; 4) Medically informed but denying. CONCLUSION: To several patients there was an unmet need for information about the progressing disease and the approaching death. To optimize the care of these patients it seems important that the physician is aware of patients' need for information even when the news is bad. Knowing the patient's information strategy could probably function as a key for the physician to communicate with patients on these matters.

  • 7.
    Hultgren Hörnquist, Elisabet
    et al.
    Örebro universitet, Hälsoakademin.
    Nilsson, Kerstin
    Örebro universitet, Hälsoakademin.
    Andersson, T.
    Örebro universitet, Hälsoakademin.
    Tidefelt, Ulf
    Örebro universitet, Hälsoakademin.
    Lidskog, Marie
    Örebro universitet, Hälsoakademin.
    Building a PBL-based integrated curriculum for a new medical school in Sweden2011Konferensbidrag (Övrigt vetenskapligt)
  • 8.
    Jonsson, Thomas B.
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Department of Surgery, Örebro University Hospital, Örebro, Sweden.
    Larzon, Thomas
    Department of Surgery, University Hospital, Örebro, Sweden.
    Arfvidsson, B.
    Department of Surgery, University Hospital, Örebro, Sweden.
    Tidefelt, Ulf
    Örebro universitet, Institutionen för läkarutbildning. Department of Medicine, University Hospital, Örebro, Sweden.
    Axelsson, C.-G.
    Department of Transfusion Medicine, University Hospital, Örebro, Sweden.
    Jurstrand, M.
    Clinical Research Centre, University Hospital, Örebro, Sweden.
    Norgren, Lars
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Department of Surgery, University Hospital, Örebro, Sweden.
    Adverse events during treatment limb ischemia with autologous peripheral blood mononuclear cell implant2012Ingår i: International Journal of Angiology, ISSN 0392-9590, E-ISSN 1827-1839, Vol. 31, nr 1, s. 77-84Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim: Trials have reported clinical improvement and reduced need for amputation in critical limb ischemia (CLI) patients receiving therapeutic angiogenesis with stem cells. Our objective was to test peripheral stem cell therapy efficacy and safety to gain experiences for further work.

    Methods: We included nine CLI patients (mean age 76.7 ±9.7). Stem cells were mobilized to the peripheral blood by administration of G-CSF (Filgrastim) for 4 days, and were collected on day five, when 30 mL of a stem cell suspension was injected into 40 points of the limb. The clinical efficacy was evaluated by assessing pain relief, wound healing and changes in ankle-brachial pressure index (ABI). Local metabolic and inflammatory changes were measured with microdialysis, growth factors and cytokine level determination. Patients were followed for 24 weeks.

    Results: Four patients experienced some degree of improvement with pain relief and/or improved wound healing and ABI increase. One patient was lost to follow up due to chronic psychiatric illness; one was amputated after two weeks. Two patients had a myocardial infarction (MI), one died. One patient died from a massive mesenteric thrombosis after two weeks and one died from heart failure at week 11. Improved patients showed variable effects in cytokine-, growth factor- and local metabolic response.

    Conclusion: Even with some improvement in four patients, severe complications in four out of nine patients, and two in relation to the bone marrow stimulation, made us terminate the study prematurely. We conclude that with the increased risk and the reduced potential of the treatment, peripheral blood stem cell treatment in the older age group is less appropriate. Metabolic and inflammatory response may be of value to gain insight into mechanisms and possibly to evaluate effects of therapeutic angiogenesis.

  • 9. Juliusson, Gunnar
    et al.
    Antunovic, Petar
    Derolf, Åsa
    Lehmann, Sören
    Möllgård, Lars
    Stockelberg, Dick
    Tidefelt, Ulf
    Örebro universitet, Hälsoakademin.
    Wahlin, Anders
    Höglund, Martin
    Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry2009Ingår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 113, nr 18, s. 4179-4187Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Acute myeloid leukemia (AML) is most common in the elderly, and most elderly are thought to be unfit for intensive treatment because of the risk of fatal toxicity. The Swedish Acute Leukemia Registry covers 98% of all patients with AML (nonacute promyelocytic leukemia) diagnosed in 1997 to 2005 (n = 2767), with a median follow-up of 5 years, and reports eligibility for intensive therapy, performance status (PS), complete remission rates, and survival. Outcomes were strongly age and PS dependent. Early death rates were always lower with intensive therapy than with palliation only. Long-term survivors were found among elderly given intensive treatment despite poor initial PS. Total survival of elderly AML patients was better in the geographic regions where most of them were given standard intensive therapy. This analysis provides unique real world data from a large, complete, and unselected AML population, both treated and untreated, and gives background to treatment decisions for the elderly. Standard intensive treatment improves early death rates and long-term survival compared with palliation. Most AML patients up to 80 years of age should be considered fit for intensive therapy, and new therapies must be compared with standard induction.

  • 10. Lehmann, S
    et al.
    Bykov, VJ
    Ali, D
    Andrén, Ove
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Cherif, H
    Tidefelt, Ulf
    Örebro universitet, Institutionen för läkarutbildning.
    Uggla, Bertil
    Örebro universitet, Institutionen för läkarutbildning.
    Yachnin, J
    Juliusson, G
    Moshfegh, A
    Paul, C
    Wiman, KG
    Andersson, PO
    Targeting p53 in vivo: a first-in-man study with the p53-targeting compound APR-246 in refractory hematologic malignancies and prostate cancer2012Ingår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 30, nr 29, s. 3633-3639Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    PURPOSE: APR-246 (PRIMA-1MET) is a novel drug that restores transcriptional activity of unfolded wild-type or mutant p53. The main aims of this first-in-human trial were to determine maximum-tolerated dose (MTD), safety, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of APR-246.

    PATIENTS AND METHODS: APR-246 was administered as a 2-hour intravenous infusion once per day for 4 consecutive days in 22 patients with hematologic malignancies and prostate cancer. Acute myeloid leukemia (AML; n = 7) and prostate cancer (n = 7) were the most frequent diagnoses. Starting dose was 2 mg/kg with dose escalations up to 90 mg/kg.

    RESULTS: MTD was defined as 60 mg/kg. The drug was well tolerated, and the most common adverse effects were fatigue, dizziness, headache, and confusion. DLTs were increased ALT/AST (n = 1), dizziness, confusion, and sensory disturbances (n = 2). PK showed little interindividual variation and were neither dose nor time dependent; terminal half-life was 4 to 5 hours. Tumor cells showed cell cycle arrest, increased apoptosis, and upregulation of p53 target genes in several patients. Global gene expression analysis revealed changes in genes regulating proliferation and cell death. One patient with AML who had a p53 core domain mutation showed a reduction of blast percentage from 46% to 26% in the bone marrow, and one patient with non-Hodgkin's lymphoma with a p53 splice site mutation showed a minor response.

    CONCLUSION: We conclude that APR-246 is safe at predicted therapeutic plasma levels, shows a favorable pharmacokinetic profile, and can induce p53-dependent biologic effects in tumor cells in vivo.

  • 11. Lehmann, S.
    et al.
    Ravn, A.
    Carlsson, L.
    Antunovic, P.
    Deneberg, S.
    Möllgård, L.
    Derolf, A. R.
    Stockelberg, D.
    Tidefelt, Ulf
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    Wahlin, A.
    Wennström, L.
    Höglund, M.
    Juliusson, G.
    Continuing high early death rate in acute promyelocytic leukemia: a population-based report from the Swedish Adult Acute Leukemia Registry2011Ingår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 25, nr 7, s. 1128-1134Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Our knowledge about acute promyelocytic leukemia (APL) patients is mainly based on data from clinical trials, whereas population-based information is scarce. We studied APL patients diagnosed between 1997 and 2006 in the population-based Swedish Adult Acute Leukemia Registry. Of a total of 3897 acute leukemia cases, 3205 (82%) had non-APL acute myeloid leukemia (AML) and 105 (2.7%) had APL. The incidence of APL was 0.145 per 100 000 inhabitants per year. The median age at the time of diagnosis was 54 years; 62% were female and 38% male. Among younger APL patients, female sex predominated (89% of patients <40 years). Of the 105 APL patients, 30 (29%) died within 30 days (that is, early death (ED)) (median 4 days) and 28 (26%) within 14 days from diagnosis. In all, 41% of the EDs were due to hemorrhage; 35% of ED patients never received all-trans-retinoic acid treatment. ED rates increased with age but more clearly with poor performance status. ED was also associated with high white blood cells, lactate dehydrogenase, creatinine, C-reactive protein and low platelet count. Of non-ED patients, 97% achieved complete remission of which 16% subsequently relapsed. In total, 62% are still alive at 6.4 years median follow-up. We conclude that ED rates remain very high in an unselected APL population.

  • 12.
    Lindgren, Stefan
    et al.
    Lund university, Lund, Sweden.
    Brännström, Thomas
    Umeå university, Umeå, Sweden.
    Hanse, Eric
    University of Gothenburg, Gothenburg, Sweden.
    Ledin, Torbjörn
    Linköping university, Linköping, Sweden.
    Nilsson, Gunnar
    Karolinska Institutet, Stockholm, Sweden.
    Sandler, Stellan
    Uppsala university, Uppsala, Sweden.
    Tidefelt, Ulf
    Örebro universitet, Hälsoakademin.
    Donner, Jakob
    Lund University, Lund, Sweden.
    Medical education in Sweden2011Ingår i: Medical teacher, ISSN 0142-159X, E-ISSN 1466-187X, Vol. 33, nr 10, s. 798-803Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Undergraduate medical education in Sweden has moved from nationally regulated, subject-based courses to programmes integrated either around organ systems or physiological and patho-physiological processes, or organised around basic medical science in conjunction with clinical specialities, with individual profiles at the seven medical schools. The national regulations are restricted to overall academic and professional outcomes. The 51/2 year long university undergraduate curriculum is followed by a mandatory 18 months internship, delivered by the County Councils. While quality control and accreditation for the university curriculum is provided by the Swedish National Agency for Higher Education, no such formal control exists for the internship; undergraduate medical education is therefore in conflict with EU directives from 2005. The Government is expected to move towards 6 years long university undergraduate programmes, leading to licence, which will facilitate international mobility of both Swedish and foreign medical students and doctors. Ongoing academic development of undergraduate education is strengthened by the Bologna process. It includes outcome (competence)-based curricula, university Masters level complying with international standards, progression of competence throughout the curriculum, student directed learning, active participation and roles in practical clinical education and a national assessment model to assure professional competence. In the near future, the dimensioning of Swedish undergraduate education is likely to be decided more by international demands and aspects of quality than by national demands for doctors.

  • 13. Löfgren, Christina
    et al.
    Lehmann, Sören
    Jönsson-Videsäter, Kerstin
    Möllgård, Lars
    Linder, Olle
    Tidefelt, Ulf
    Örebro universitet, Hälsoakademin.
    Hassan, Moustapha
    Paul, Christer
    Higher plasma but not intracellular concentrations after infusion with liposomal daunorubicin compared with conventional daunorubicin in adult acute myeloid leukemia2007Ingår i: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 29, nr 5, s. 626-631Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To investigate the plasma and intracellular pharmacokinetics of liposomal daunorubicin (DaunoXome) in comparison with conventional daunorubicin, 14 patients aged 28 to 60 years with newly diagnosed acute myeloid leukemia were treated for 1 day with DaunoXome (50 mg/m) and for 2 days with daunorubicin (50 mg/m) with concomitant Ara-C (7 days, 200 mg/m, continuous IV). Eleven of the 14 patients entered complete remission; 9 are still alive. Pharmacokinetic profiles were obtained by blood sampling at appropriate intervals on days 1 to 4. Daunorubicin and daunorubicinol concentrations in plasma and in peripheral leukemic blast cells were measured by high-performance liquid chromatography. Following liposomal daunorubicin administration, the peak values and plasma area under the curve (AUC) were more than 100 times higher than after administration of conventional daunorubicin (AUC, 176 vs. 0.98 micromol/L x hour), but the intracellular AUCs were comparable (759 vs. 715 micromol/L x hour). Intracellular concentrations after DaunoXome peaked later and half as high as after daunorubicin. After DaunoXome versus daunorubicin, plasma clearance was 0.001 versus 0.4 micromol/h, respectively. The volume of distribution was 5.5 L for DaunoXome, versus 3640 L for daunorubicin, indicating low tissue affinity for the liposomal formulation. The authors conclude that liposomal daunorubicin, DaunoXome, yields 2-log higher plasma concentrations but similar intracellular concentrations of daunorubicin and its metabolite daunorubicinol than does free daunorubicin.

  • 14.
    Möllgård, Lars
    et al.
    Karolinska Institutet.
    Prenkert, Malin
    Örebro universitet, Institutionen för vårdvetenskap och omsorg.
    Smolowicz, Adam
    Paul, Christer
    Karolinska Institutet.
    Tidefelt, Ulf
    Örebro universitet, Institutionen för klinisk medicin.
    In vitro chemosensitivity testing of selected myeloid cells in acute myeloid leukemia 2003Ingår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 44, nr 5, s. 783-789Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In several studies different chemosensitivity assays have been examined in acute myeloid leukemia (AML). Some have shown that in vitro chemosensitivity testing is an independent prognostic factor but so far no one has been able to show that the use of these methods can improve treatment outcome. In an attempt to improve in vitro chemosensitivity testing in AML we wanted to establish and evaluate a new flow cytometry chemosensitivity assay. After 4 days of incubation viable mononuclear myeloid cells were identified by the exclusion of propidium iodide in CD13 or CD33 positive cells. Sixty-eight samples from 64 AML patients were included. In this study, we showed that the flow cytometry method is feasible in AML and we also found some correlations to clinical data. The secondary AML at diagnosis showed an in vitro resistance to etoposide and amsacrine that was significantly higher compared to de novo AML at diagnosis (p = 0.04 and p = 0.02). When AML patients at diagnosis were compared to resistant disease/relapse patients there was a significantly higher effect of ara-C in the diagnosis group (p = 0.03). Responders and non-responders were compared in vitro but we found no significant differences. In vitro mitoxantrone was more effective in multidrug resistance (MDR) negative cells compared to MDR positive cells (p < 0.01). This new method is feasible and makes it possible to selectively evaluate the effect of cytotoxic drugs in myeloid cells. Further studies with a larger group of patients are needed to evaluate the predictive value of the assay.

  • 15. Olsson-Strömberg, U.
    et al.
    Höglund, M.
    Björkholm, M.
    Braide, I.
    Carlson, K.
    Gahrton, G.
    Grimfors, G.
    Hast, R.
    Lerner, R.
    Linder, O.
    Ljungman, P.
    Löfvenberg, E.
    Malm, C.
    Nilsson, P. G.
    Paul, C.
    Rödjer, S.
    Stenke, L.
    Tidefelt, Ulf
    Örebro universitet, Institutionen för klinisk medicin.
    Turesson, I.
    Udén, A. M.
    Wahlin, A.
    Vilen, L.
    Winqvist, I.
    Zettervall, O.
    Öberg, G.
    Simonsson, B.
    Successful mobilization of Ph-negative blood stem cells with intensive chemotherapy + G-CSF in patients with chronic myelogenous leukemia in first chronic phase2006Ingår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 47, nr 9, s. 1768-1773Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of the study was to investigate the feasibility of mobilizing Philadelphia chromosome negative (Ph-) blood stem cells (BSC) with intensive chemotherapy and lenograstim (G-CSF) in patients with CML in first chronic phase (CP1). During 1994-1999 12 centers included 37 patients <56 years. All patients received 6 months' IFN, stopping at median 36 (1-290) days prior to the mobilization chemotherapy. All received one cycle of daunorubicin 50 mg/m2 and 1 hour infusion on days 1-3, and cytarabine (ara-C) 200 mg/m2 24 hours' i.v. infusion on days 1-7 (DA) followed by G-CSF 526 microg s.c. once daily from day 8 after the start of chemotherapy. Leukaphereses were initiated when the number of CD 34+ cells was >5/microl blood. Patients mobilizing poorly could receive a 4-day cycle of chemotherapy with mitoxantrone 12 mg/m2/day and 1 hour i.v infusion, etoposide 100 mg/m2/day and 1 hour i.v. infusion and ara-C 1 g/m2/twice a day with 2 hours' i.v infusion (MEA) or a second DA, followed by G-CSF 526 microg s.c once daily from day 8 after the start of chemotherapy. Twenty-seven patients received one cycle of chemotherapy and G-CSF, whereas 10 were mobilized twice. Twenty-three patients (62%) were successfully (MNC >3.5 x 10(8)/kg, CFU-GM >1.0 x 10(4)/kg, CD34+ cells >2.0 x 10(6)/kg and no Ph+ cells in the apheresis product) [n = 16] or partially successfully (as defined above but 1-34% Ph+ cells in the apheresis product) [n = 7] mobilized. There was no mortality during the mobilization procedure. Twenty-one/23 patients subsequently underwent auto-SCT. The time with PMN <0.5 x 10(9)/l was 10 (range 7-49) and with platelets <20 x 10(9)/l was also 10 (2-173) days. There was no transplant related mortality. The estimated 5-year overall survival after auto-SCT was 68% (95% CI 47 - 90%), with a median follow-up time of 5.2 years.We conclude that in a significant proportion of patients with CML in CP 1, intensive chemotherapy combined with G-CSF mobilizes Ph- BSC sufficient for use in auto-SCT.

  • 16. Olsson-Strömberg, Ulla
    et al.
    Höglund, Martin
    Björkholm, Magnus
    Braide, Inger
    Carlson, Karin
    Gahrton, Gösta
    Grimfors, Gunnar
    Hast, Robert
    Lerner, Rickard
    Linder, Olle
    Ljungman, Per
    Löfvenberg, Eva
    Malm, Claes
    Nilsson, Per-Gunnar
    Paul, Christer
    Rödjer, Stig
    Stenke, Leif
    Tidefelt, Ulf
    Örebro universitet, Institutionen för klinisk medicin.
    Turesson, Ingemar
    Udén, Ann-Marie
    Wahlin, Anders
    Vilén, Lars
    Winqvist, Ingemar
    Zettervall, Olle
    Öberg, Gunnar
    Simonsson, Bengt
    Successful mobilization of Ph-negative blood stem cells with intensive chemotherapy + G-CSF in patients with chronic myelogenous leukemia in first chronic phase2006Ingår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 47, nr 9, s. 1768-1773Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The aim of the study was to investigate the feasibility of mobilizing Philadelphia chromosome negative (Ph-) blood stem cells (BSC) with intensive chemotherapy and lenograstim (G-CSF) in patients with CML in first chronic phase (CP1). During 1994-1999 12 centers included 37 patients <56 years. All patients received 6 months' IFN, stopping at median 36 (1-290) days prior to the mobilization chemotherapy. All received one cycle of daunorubicin 50 mg/m2 and 1 hour infusion on days 1-3, and cytarabine (ara-C) 200 mg/m2 24 hours' i.v. infusion on days 1-7 (DA) followed by G-CSF 526 microg s.c. once daily from day 8 after the start of chemotherapy. Leukaphereses were initiated when the number of CD 34+ cells was >5/microl blood. Patients mobilizing poorly could receive a 4-day cycle of chemotherapy with mitoxantrone 12 mg/m2/day and 1 hour i.v infusion, etoposide 100 mg/m2/day and 1 hour i.v. infusion and ara-C 1 g/m2/twice a day with 2 hours' i.v infusion (MEA) or a second DA, followed by G-CSF 526 microg s.c once daily from day 8 after the start of chemotherapy. Twenty-seven patients received one cycle of chemotherapy and G-CSF, whereas 10 were mobilized twice. Twenty-three patients (62%) were successfully (MNC >3.5 x 10(8)/kg, CFU-GM >1.0 x 10(4)/kg, CD34+ cells >2.0 x 10(6)/kg and no Ph+ cells in the apheresis product) [n = 16] or partially successfully (as defined above but 1-34% Ph+ cells in the apheresis product) [n = 7] mobilized. There was no mortality during the mobilization procedure. Twenty-one/23 patients subsequently underwent auto-SCT. The time with PMN <0.5 x 10(9)/l was 10 (range 7-49) and with platelets <20 x 10(9)/l was also 10 (2-173) days. There was no transplant related mortality. The estimated 5-year overall survival after auto-SCT was 68% (95% CI 47 - 90%), with a median follow-up time of 5.2 years.We conclude that in a significant proportion of patients with CML in CP 1, intensive chemotherapy combined with G-CSF mobilizes Ph- BSC sufficient for use in auto-SCT.

  • 17. Persson, L.
    et al.
    Strid, H.
    Tidefelt, Ulf
    Örebro universitet, Hälsoakademin.
    Söderquist, Bo
    Örebro universitet, Hälsoakademin.
    Phenotypic and genotypic characterization of coagulase-negative staphylococci isolated in blood cultures from patients with haematological malignancies2006Ingår i: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 25, nr 5, s. 299-309Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Coagulase-negative staphylococci are the predominant aetiological agents in bacteraemic patients hospitalized for haematological malignancies. The aim of this study was to determine whether differences exist in the prevalence of icaAB genes and in the phenotypic and/or genotypic pattern between blood isolates of coagulase-negative staphylococci, interpreted as representing true bacteraemia, and contaminant isolates from patients with haematological malignancies. Eighty-two isolates representing true bacteraemia and 47 contaminant isolates were found among 76 patients. The most prevalent species in both groups of patients was Staphylococcus epidermidis (n=103; 80%). Biochemical typing using the Phene Plate system and genotyping using pulsed-field gel electrophoresis showed a tendency towards a more homogeneous pattern among isolates causing true bacteraemia compared with contaminant isolates. Two major genotypic groups of S. epidermidis were found in both the true bacteraemia group and the contaminant group, with concordant pulsotypes found as well. These groups may comprise isolates carrying specific virulence factors, but the prevalence of the icaAB genes did not differ between the true bacteraemia group and the contaminant group. No significant difference was seen between the two study groups regarding clinical symptoms or complications, use of central venous catheter, and levels of absolute neutrophil count or C-reactive protein.

  • 18. Persson, Lennart
    et al.
    Söderquist, Bo
    Engervall, Per
    Vikerfors, Tomas
    Hansson, Lars-Olof
    Tidefelt, Ulf
    Örebro universitet, Institutionen för klinisk medicin.
    Assessment of systemic inflammation markers to differentiate a stable from a deteriorating clinical course in patients with febrile neutropenia2005Ingår i: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 74, nr 4, s. 297-303Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In this study, we evaluated the predictive values of procalcitonin (PCT), C-reactive protein (CRP), interleukin-6 (IL-6) and serum amyloid A (SAA) for determining the clinical course in febrile neutropenic patients. Daily plasma analyses during the fever course were performed in 101 episodes with fever and chemotherapy-induced neutropenia (neutrophil count <0.5 x 10(9)/L). Procalcitonin (PCT) and IL-6 values were significantly higher in febrile episodes in patients who developed complications. Procalcitonin with a cut-off value of < or =0.4 ng/mL or IL-6 < or =50 pg/mL 3 d after fever onset indicated daily high negative predictive values (NPVs) (91-100%) for episodes with complications. No marker could predict deterioration; however, daily low plasma concentrations of PCT or IL-6 during the first 8 d of fever were found to be a good predictor of no subsequent complications in neutropenic patients and therefore to be a helpful tool for limiting anti-microbial therapy.

  • 19.
    Prenkert, Malin
    et al.
    Örebro universitet, Hälsoakademin.
    Uggla, Bertil
    Tidefelt, Ulf
    Örebro universitet, Hälsoakademin.
    Strid, Hilja
    CRIM1 is expressed at higher levels in drug resistant than in drug sensitive myeloid leukemia HL60 cellsManuskript (preprint) (Övrigt vetenskapligt)
  • 20.
    Prenkert, Malin
    et al.
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Clinical Research Center, Örebro University Hospital, Örebro; Sweden.
    Uggla, Bertil
    Department of Medicine, Örebro University Hospital, Örebro, Sweden.
    Tidefelt, Ulf
    Örebro universitet, Institutionen för hälsovetenskap och medicin. Department of Medicine, Örebro University Hospital, Örebro, Sweden.
    Strid, Hilja
    Örebro universitet, Institutionen för hälsovetenskap och medicin.
    CRIM1 is expressed at higher levels in drug-resistant than in drug-sensitive myeloid leukemia HL60 cells2010Ingår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 30, nr 10, s. 4157-61Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Aim: The aim of this study was to explore possible differences in the mRNA expression levels of CRIM1, SMAD5, BMP4 and BMP7 in sensitive (S) and multidrug-resistant (R0.5) myeloid leukemia HL60 cells.

    Materials and Methods: HL60S and HL60R0.5 cells were exposed to daunorubicin (DNR) or cytarabine (Ara-C).

    Results: Baseline levels of CRIM1 were found to be 15-fold higher in HL60R0.5 than in HL60S. Sixteen hours of exposure to DNR resulted in a 5.6-fold increase in CRIM1 levels in HL60S. Exposure to either DNR or Ara-C resulted in modest increases in CRIM1 levels in HL60R0.5. Similarly, baseline levels of SMAD5 and BMP4 were higher in HL60R0.5 than in HL60S cells. Analysis of the drug SMAD5-resistance marker permeability-glycoprotein (Pgp) revealed that CRIM1 and Pgp exhibit a covariance pattern of expression.

    Conclusion: This study demonstrated that CRIM1 is expressed at high levels in resistant leukemia cells, indicating that CRIM1 may play a role in drug-resistance.

  • 21.
    Prenkert, Malin
    et al.
    Örebro universitet, Hälsoakademin.
    Uggla, Bertil
    Karolinska Institutet.
    Tina, Elisabet
    Örebro universitet, Hälsoakademin.
    Tidefelt, Ulf
    Örebro universitet, Hälsoakademin.
    Strid, Hilja
    Örebro universitet, Hälsoakademin.
    Rapid Induction of P-Glycoprotein mRNA and Protein Expression by Cytarabine in HL-60 Cells2009Ingår i: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 29, nr 10, s. 4071-4076Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Overexpression of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and glutathione-S-transferase π (GSTπ) is associated with drug resistance in acute myeloid leukemia (AML). The short-term effects of drug exposure on their expression levels were investigated.

    Materials and Methods: HL-60 cells and drug-resistant sublines were cultured with or without daunorubicin (DNR) and cytarabine (Ara-C). At several time-points the expression levels of P-gp, BCRP and GSTπ were determined.

    Results: After exposure to Ara-C, P-gp mRNA rapidly increased in all the cell lines. P-gp protein was detected in the sensitive cells after 8 h exposure to Ara-C. GSTπ mRNA increased in the resistant cells, but no change in BCRP mRNA was observed. Exposure to DNR revealed rapidly increased P-gp and GSTπ mRNA in the resistant cells.

    Conclusion: Ara-C rapidly increases P-gp mRNA and protein expression in sensitive and resistant cells, and GSTπ mRNA in resistant cells, in vitro. This may be of clinical importance during AML induction chemotherapy.

  • 22.
    Tidefelt, Ulf
    et al.
    Örebro universitet, Hälsoakademin.
    Prenkert, Malin
    Örebro universitet, Hälsoakademin.
    Paul, Christer
    Karolinska Institutet.
    Comparison of idarubicin and daunorubicin and their main metabolites regarding intracellular uptake and effect on sensitive and multidrug-resistant HL60 cells1996Ingår i: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 38, nr 5, s. 87s. 476-480Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To study the effect of the main metabolites on the cytotoxic effect of daunorubicin and idarubicin in human HL-60 cells, drug-sensitive and multidrug-resistant HL60 cells were incubated with idarubicin and daunorubicin and their metabolites idarubicinol and daunorubicinol over a wide range of concentrations. The intracellular uptake of the drugs was determined by photofluorometry, and the cytotoxic effect in vitro was determined by a bioluminescence assay of intracellular adenosine triphosphate (ATP) after 4 days of culture in liquid medium. The effect of intracellular drugs was calculated from the incubation-concentration versus intracellular-uptake and cytotoxic-effect curves. The intracellular uptake of idarubicin was 6 times that of daunorubicin in drug-sensitive cells and 25 times higher in resistant cells. For idarubicinol as compared with daunorubicinol the corresponding factors were 25 and 7, respectively. As compared with the parent substances, the uptake of idarubicinol and daunorubicinol was 16% and 4%, respectively, in sensitive cells and 40% and >100%, respectively, in resistant cells. An intracellular concentration of 0.5 nmol/mg protein of both parent substances caused a 50% growth inhibition in drug-sensitive cells as compared with 10 nmol/mg protein for drug-resistant cells. For the metabolites an intracellular concentration of 0.4 nmol/mg protein of idarubicinol and 2.0 nmol/mg protein of daunorubicinol was required to inhibit cells’ growth by 50% in drug-sensitive HL60 cells. In the resistant HL60 cells the corresponding values were 30 nmol/mg protein for idarubicinol and 40 nmol/mg protein for daunorubicinol. These results confirm that idarubicinol may significantly contribute to the clinical effect of idarubicin. However, in combination with previous results that have shown low intracellular concentrations of the metabolites in vivo, it appears that the pharmacokinetic properties of the mother substances provide the major explanation for the clinical effect of idarubicin.

  • 23.
    Tina, Elisabet
    et al.
    Örebro universitet, Hälsoakademin.
    Prenkert, Malin
    Örebro universitet, Hälsoakademin.
    Höglund, Martin
    Paul, Christer
    Tidefelt, Ulf
    Örebro universitet, Hälsoakademin.
    Topoisomerase IIalpha expression in acute myeloid leukaemia cells that survive after exposure to daunorubicin or ara-C2009Ingår i: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 22, nr 6, s. 1527-1531Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Patients diagnosed with acute myeloid leukaemia are often treated with a combination of daunorubicin and 1-β-D-arabinofuranosylcytosine (ara-C). Both daunorubicin and ara-C exert their effects in the cell nucleus but by different mechanisms, i.e. daunorubicin causes double stranded DNA breaks by inhibition of the nuclear enzyme, topoisomerase (topo) IIα, whereas ara-C is an anti-metabolite that integrates with DNA during DNA synthesis and causes cell cycle arrest. Despite the initial efficacy of these drugs, resistance often develops in the clinical setting. The mechanisms underlying clinical resistance to these drugs are poorly understood, but may be associated with an increase in the proportion of topo IIα negative cells. Therefore, the aim of this study was to determine whether daunorubicin treatment results in increased numbers of topo IIα negative subpopulations in vitro. Acute myeloid leukaemia cells isolated from 12 consenting patients were treated for 24 h with increasing concentrations of daunorubicin or ara-C and the proportion of topo IIα-negative cells in surviving cell populations determined by flow cytometry. Treatment with daunorubicin, but not ara-C, resulted in a significant increase in the proportion of topo IIα negative cells (p=0.0023). These results suggest that daunorubicin may act by cell cycle arrest and/or by selection of pre-existing topo IIα negative subpopulations. Both of these mechanisms can theoretically contribute to a reduced efficacy of a second dose of daunorubicin. The clinical relevance of these interactions should be further elucidated in experimental and clinical studies.

  • 24.
    Uggla, Bertil
    et al.
    Department of Medicine, Örebro Medical Center Hospital, Örebro, Sweden.
    Möllgård, Lars
    Department of Hematology, Huddinge Uniersity Hospital, Huddinge, Sweden.
    Ståhl, Elisabeth
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Mossberg, Lise-Lott Mossberg
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Karlsson, Mats G.
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden.
    Paul, Christer
    Department of Pathology, Örebro Medical Center Hospital, Örebro, Sweden; Karolinska Institute, Stockholm, Sweden.
    Tidefelt, Ulf
    Department of Medicine, Örebro Medical Center Hospital, Örebro, Sweden; Karolinska Institute, Stockholm, Sweden.
    Expression of topoisomerase IIalpha in the G0/G1 cell cycle phase of fresh leukemic cells2001Ingår i: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 25, nr 11, s. 961-966Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Topoisomerase IIalpha (topoII alpha) is the target enzyme for several antineoplastic drugs. Correlation between low expression of topo IIalpha and drug resistance has been shown in vitro, but there is limited evidence of a correlation to initial response to treatment or to overall prognosis. Normal cells express topo IIalpha in S/G2/M phase of the cell cycle but not in G0/G1 phase. However, some data suggest that topo IIalpha could be expressed in G0/G1 phase in malignant cells. We have investigated the expression of topo IIalpha in leukemic cells from 25 patients with acute leukemia by flow cytometry, separating cells of different cell cycle phases. We demonstrated that 9/25 samples showed >50% positive cells in G0/G1, and another five samples showed >20%. This finding could possibly provide an explanation to previous difficulties in correlating topo IIalpha expression with clinical outcome. Six of eight patients, where >20% of the cells in G0/G1 were positive for topo IIalpha, entered CR, compared to one of five patients with <20% topo IIalpha positive cells in G0/G1. We suggest that topo IIalpha expression in G0/G1 in leukemic cells may be of predictive value for clinical response to cytostatic drugs.

  • 25.
    Uggla, Bertil
    et al.
    Department of Medicine, Örebro University Hospital, Örebro; Karolinska Institute, Stockholm.
    Ståhl, Elisabet
    Clinical Research Centre, Örebro University Hospital, Örebro.
    Wågsäter, Dick
    Örebro universitet, Institutionen för vårdvetenskap och omsorg.
    Paul, Christer
    Department of Haematology, Huddinge University Hospital, Stockholm; Karolinska Institute, Stockholm.
    Karlsson, Mats G.
    Department of Pathology, Örebro University Hospital, Örebro.
    Sirsjö, Allan
    Örebro universitet, Institutionen för vårdvetenskap och omsorg.
    Tidefelt, Ulf
    Örebro universitet, Institutionen för klinisk medicin. Department of Medicine, Örebro University Hospital, Örebro.
    BCRP mRNA expression v. clinical outcome in 40 adult AML patients2005Ingår i: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 29, nr 2, s. 141-146Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Efflux pumps are considered being mechanisms behind drug resistance in acute myeloid leukaemia (AML). A recently described efflux pump, breast cancer resistance protein (BCRP), can be expressed in AML, but its clinical importance is uncertain. In this study BCRP mRNA expression was determined in samples from 40 AML patients by real-time RT-PCR. The expression varied from negative to 76 times that of control cells. There was no difference in BCRP mRNA expression between patients responding to induction treatment and non-responders. However, in the group of responders, the 14 patients with the highest expression had significantly shorter overall survival (mean 38 months, SEM 15 months) than the 14 patients with the lowest (74 months, SEM 16 months) (P = 0.047). This suggests a possible role of BCRP in drug resistance in AML.

  • 26.
    Uggla, Bertil
    et al.
    Department of Medicine, Örebro University Hospital, Örebro.
    Tina, Elisabet
    Clinical Research Centre, Örebro University Hospital, Örebro.
    Nahi, Hareth
    Department of Clinical Hematology, Karolinska University Hospital, Huddinge, Stockholm; Karolinska Institute, Stockholm.
    Paul, Christer
    Department of Clinical Hematology, Karolinska University Hospital, Huddinge, Stockholm; Karolinska Institute, Stockholm.
    Höglund, Martin
    Department of Haematology, Uppsala University Hospital, Uppsala,.
    Sirsjö, Allan
    Örebro universitet, Institutionen för klinisk medicin.
    Tidefelt, Ulf
    Örebro universitet, Institutionen för klinisk medicin. Department of Medicine, Örebro University Hospital, Örebro.
    Topoisomerase IIα mRNA and protein expression vs. in vitro drug resistance and clinical outcome in acute leukaemia2007Ingår i: International Journal of Oncology, ISSN 1019-6439, Vol. 31, nr 1, s. 153-160Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The objective of this study was to correlate the expression of topoisomerase (topo) IIalpha to in vitro drug sensitivity and to the clinical outcome in patients with acute leukaemia. Leukaemic cells were isolated from bone marrow or blood from 94 patients. Topo IIalpha mRNA (n=58) and protein (n=60) expression was determined by real-time RT-PCR and flow cytometry, respectively. In both groups, chemosensitivity testing by a bioluminescence ATP assay was performed to a variable extent for both topo IIalpha poisons and non-topo IIalpha targeting drugs. Topo IIalpha mRNA expression varied with relative values ranging from 0.03 to 14.20 (median 1.10). The median value for topo IIalpha protein-positive cells was 23% (range 0-99%). Cell samples from patients with a high (>median value) percentage of topo IIalpha-positive cells were significantly more sensitive to the topo IIalpha active drugs etoposide and daunorubicin, and showed a borderline value for idarubicin (p=0.08), while there was no difference for non-topo IIalpha targeting drugs. However, we did not find any significant differences in mRNA expression or the percentage of topo IIalpha-positive cells in patients who achieved complete remission after at most two induction courses compared with those who did not, nor did we find any difference in survival when patients with high mRNA expression/percentage of topo IIalpha-positive cells were compared with patients with low values. We conclude that expression of topo IIalpha, determined as percentage of topo IIalpha-positive cells, in leukaemic cells correlates to chemosensitivity in vitro against topoisomerase poisons but that it does not predict clinical outcome in acute leukaemia.

  • 27.
    Villman, Kenneth
    et al.
    Department of Oncology, Örebro University Hospital, Örebro, Sweden.
    Ståhl, Elisabeth
    2Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Liljegren, Göran
    Department of Surgery, Örebro University Hospital, Örebro, Sweden.
    Tidefelt, Ulf
    Department of Medicine, Örebro University Hospital, Örebro, Sweden; Karolinska Institute, Stockholm, Sweden.
    Karlsson, Mats G.
    2Department of Pathology, Örebro University Hospital, Örebro, Sweden.
    Topoisomerase II-alpha expression in different cell cycle phases in fresh human breast carcinomas2002Ingår i: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 15, nr 5, s. 486-491Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Topoisomerase II-alpha (topo II alpha) is the key target enzyme for the topoisomerase inhibitor class of anti-cancer drugs. In normal cells, topo II alpha is expressed predominantly in the S/G2/M phase of the cell cycle. In malignant cells, in vitro studies have indicated that the expression of topo II alpha is both higher and less dependent on proliferation state in the cell. We studied fresh specimens from 50 cases of primary breast cancer. The expression of topo II alpha in different cell cycle phases was analyzed with two-parameter flow cytometry using the monoclonal antibody SWT3D1 and propidium iodide staining. The expression of topo II alpha was significantly higher in the S/G2/M phase of the cell cycle than in the G0/G1 phase in both DNA diploid and DNA non-diploid tumors. In 18 of 21 diploid tumors, and in 25 of 29 non-diploid tumors, >50% of the topo II alpha-positive cells were in the G0/G1 phase. This significant expression of topo II alpha in the G0/G1 phase of the cell cycle may have clinically important implications for treatment efficacy of topoisomerase II inhibitors.

  • 28. Villman, Kenneth
    et al.
    Ståhl, Elisabeth
    Liljegren, Göran
    Örebro universitet, Hälsoakademin.
    Tidefelt, Ulf
    Örebro universitet, Hälsoakademin.
    Karlsson, Mats G.
    Örebro universitet, Hälsoakademin.
    Topoisomerase II-α expression in different cell cycle phases in fresh human breast carcinomas2002Ingår i: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 15, nr 5, s. 486-491Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Topoisomerase II-alfa (topo IIalfa) is the key target enzyme for the topoisomerase inhibitor class of anti-cancer drugs. In normal cells, topo IIalfa is expressed predominantly in the S/G2/M phase of the cell cycle. In malignant cells, in vitro studies have indicated that the expression of topo IIalfa is both higher and less dependent on proliferation state in the cell. We studied fresh specimens from 50 cases of primary breast cancer. The expression of topo IIalfa in different cell cycle phases was analyzed with two-parameter flow cytometry using the monoclonal antibody SWT3D1 and propidium iodide staining. The expression of topo IIalfa was significantly higher in the S/G2/M phase of the cell cycle than in the G0/G1 phase in both DNA diploid and DNA nondiploid tumors. In 18 of 21 diploid tumors, and in 25 of 29 nondiploid tumors, >50% of the topo IIalfa–positive cells were in the G0/G1 phase. This significant expression of topo IIalfa in the G0/G1 phase of the cell cycle may have clinically important implications for treatment efficacy of topoisomerase II inhibitors.

1 - 28 av 28
RefereraExporteraLänk till träfflistan
Permanent länk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf