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  • 151.
    El Missiry, Mohamed
    et al.
    Univ Helsinki, Hematol Res Unit, Helsinki, Finland..
    Adnan, Shady
    Univ Helsinki, Dept Hematol, HRUH, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Rajala, Hanna
    Univ Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, HRUH, Helsinki, Finland..
    Al-Samadi, Ahmed
    Univ Helsinki, Inst Clin Med, Helsinki, Finland..
    Ekblom, Marja
    Skane Univ Hosp, Lund, Sweden..
    Markevan, Berit
    Umea Univ Hosp, Dept Hematol, S-90185 Umea, Sweden..
    Astrand-Grundstrom, Ingbritt
    Skane Univ Hosp, Lund, Sweden..
    Wold, Maren
    Norwegian Univ Sci & Technol NTNU, St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Juhl, Birgitte Ravn
    Univ Copenhagen, Rigshosp, Dept Pathol, DK-2100 Copenhagen, Denmark..
    Bjerrum, Ole Weis
    Univ Copenhagen Hosp, Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    Haulin, Inger
    Akademiska sjukhuset, Uppsala..
    Porkka, Kimmo
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Ctr Comprehens Canc, Dept Hematol, Helsinki, Finland..
    Olsson-Strömberg, Ulla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Mustjoki, Satu
    Univ Helsinki, Dept Hematol, HRUH, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland.;Univ Helsinki, Dept Clin Chem, SF-00100 Helsinki, Finland..
    Bone Marrow Lymphocytic Status during Tyrosine Kinase Inhibitor Therapy and Its Relation to Therapy Response in Chronic Phase Chronic Myeloid Leukemia Patients2015Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, nr 23Artikkel i tidsskrift (Annet vitenskapelig)
  • 152.
    El Missiry, Mohamed
    et al.
    Univ Helsinki, Hematol Res Unit, Helsinki, Finland..
    Adnan, Shady
    Univ Helsinki, Dept Hematol, HRUH, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Rajala, Hanna
    Univ Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, HRUH, Helsinki, Finland..
    Al-Samadi, Ahmed
    Univ Helsinki, Inst Clin Med, Helsinki, Finland..
    Ekblom, Marja
    Skane Univ Hosp, Lund, Sweden..
    Markevan, Berit
    Umea Univ Hosp, Dept Hematol, S-90185 Umea, Sweden..
    Astrand-Grundstrom, Ingbritt
    Skane Univ Hosp, Lund, Sweden..
    Wold, Maren
    Norwegian Univ Sci & Technol NTNU, St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Juhl, Birgitte Ravn
    Univ Copenhagen, Rigshosp, Dept Pathol, DK-2100 Copenhagen, Denmark..
    Bjerrum, Ole Weis
    Univ Copenhagen Hosp, Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    Haulin, Inger
    Univ Uppsala Hosp, Dept Pathol, S-75185 Uppsala, Sweden..
    Porkka, Kimmo
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Helsinki Univ Hosp, Ctr Comprehens Canc, Dept Hematol, Helsinki, Finland..
    Olsson-Strömberg, Ulla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Mustjoki, Satu
    Univ Helsinki, Dept Hematol, HRUH, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland.;Univ Helsinki, Dept Clin Chem, SF-00100 Helsinki, Finland..
    Bone Marrow Lymphocytic Status during Tyrosine Kinase Inhibitor Therapy and Its Relation to Therapy Response in Chronic Phase Chronic Myeloid Leukemia Patients2015Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, nr 23Artikkel i tidsskrift (Annet vitenskapelig)
  • 153.
    El Missiry, Mohamed
    et al.
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway.;Norwegian Univ Sci & Technol NTNU, St Olavs Hosp, Dept Canc Res & Mol Med, Trondheim, Norway..
    Richter, Johan
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Olsson-Strömberg, Ulla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Stenke, Leif
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Porkka, Kimmo
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Kreutzman, Anna
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland..
    Mustjoki, Satu
    Univ Helsinki, Hematol Res Unit Helsinki, Dept Hematol, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland.;Univ Helsinki, Dept Clin Chem, Helsinki, Finland..
    Early BCR-ABL1 Transcript Decline after 1 Month of Tyrosine Kinase Inhibitor Therapy as an Indicator for Treatment Response in Chronic Myeloid Leukemia2017Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, nr 1, artikkel-id e0171041Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    In chronic myeloid leukemia (CML), early treatment prediction is important to identify patients with inferior overall outcomes. We examined the feasibility of using reductions in BCR-ABL1 transcript levels after 1 month of tyrosine kinase inhibitor (TKI) treatment to predict therapy response. Fifty-two first-line TKI-treated CML patients were included (imatinib n = 26, dasatinib n = 21, nilotinib n = 5), and BCR-ABL1 transcript levels were measured at diagnosis (dg) and 1, 3, 6, 12, 18, 24, and 36 months. The fold change of the BCR-ABL1 transcripts at 1 month compared to initial BCR-ABL1 transcript levels was used to indicate early therapy response. In our cohort, 21% of patients had no decrease in BCR-ABL1 transcript levels after 1 month and were classified as poor responders. Surprisingly, these patients had lower BCR-ABL1 transcript levels at dg compared to responders (31% vs. 48%, p = 0.0083). Poor responders also significantly more often had enlarged spleen (55% vs. 15%; p< 0.01) and a higher percentage of Ph+ CD34+CD38- cells in the bone marrow (91% vs. 75%, p< 0.05). The major molecular response rates were inferior in the poor responders (at 12m 18% vs. 64%, p< 0.01; 18m 27% vs. 75%, p< 0.01; 24m 55% vs. 87%, p< 0.01). In conclusion, early treatment response analysis defines a biologically distinct patient subgroup with inferior long-term outcomes.

  • 154.
    El-Jawahri, Areej
    et al.
    Massachusetts Gen Hosp, Boston, MA 02114 USA..
    Chen, Yi-Bin
    Massachusetts Gen Hosp, Boston, MA 02114 USA..
    Brazauskas, Ruta
    Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA.;Med Coll Wisconsin, Milwaukee, WI 53226 USA..
    He, Naya
    Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA..
    Lee, Stephanie J.
    Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA..
    Knight, Jennifer M.
    Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA..
    Majhail, Navneet
    Cleveland Clin, Cleveland, OH 44106 USA..
    Buchbinder, David
    Childrens Hosp Orange Cty, Orange, CA USA..
    Schears, Raquel M.
    Brandeis Univ, Waltham, MA USA..
    Wirk, Baldeep M.
    Seattle Canc Care Alliance, Seattle, WA USA..
    Wood, William A.
    Univ N Carolina, Chapel Hill, NC USA..
    Ahmed, Ibrahim
    Childrens Mercy Hosp & Clin, Kansas City, MO USA..
    Aljurf, Mahmoud
    King Faisal Specialist Hosp & Res Ctr, Riyadh, Saudi Arabia..
    Szer, Jeff
    Royal Melbourne Hosp, Parkville, Vic, Australia..
    Beattie, Sara M.
    Univ Ottawa, Ottawa, ON, Canada..
    Battiwalla, Minoo
    NHLBI, Bldg 10, Bethesda, MD 20892 USA..
    Dandoy, Christopher
    Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USA..
    Diaz, Miguel-Angel
    Hosp Infantil Univ Nino Jesus, Madrid, Spain..
    D'Souza, Anita
    Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA..
    Freytes, Cesar O.
    Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA..
    Gajewski, James
    Oregon Hlth & Sci Univ, Portland, OR 97201 USA..
    Gergis, Usama
    New York Presbyterian Hosp, New York, NY USA..
    Hashmi, Shahrukh K.
    Brandeis Univ, Waltham, MA USA..
    Jakubowski, Ann
    Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA..
    Kamble, Rammurti T.
    Baylor Coll Med, Houston, TX 77030 USA..
    Kindwall-Keller, Tamila
    Univ Virginia Hlth Syst, Charlottesville, VA USA..
    Lazarus, Hilard M.
    Seidman Canc Ctr, Cleveland, OH USA..
    Malone, Adriana K.
    Tisch Canc Inst, New York, NY USA..
    Marks, David I.
    Univ Hosp Bristol NHS Trust, Bristol, Avon, England..
    Meehan, Kenneth
    Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA..
    Savani, Bipin N.
    Vanderbilt Univ, Med Ctr, Nashville, TN USA..
    Olsson, Richard F.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi. Karolinska Inst, Stockholm, Sweden..
    Rizzieri, David
    Duke Univ, Durham, NC USA..
    Steinberg, Amir
    Mt Sinai Hosp, New York, NY 10029 USA..
    Speckhart, Dawn
    Northside Hosp, Atlanta, GA USA..
    Szwajcer, David
    Univ Manitoba, Winnipeg, MB, Canada..
    Schoemans, Helene
    Univ Hosp Leuven, Leuven, Belgium..
    Seo, Sachiko
    East Hosp, Kashiwa, Chiba, Japan..
    Ustun, Celalettin
    Univ Minnesota, Med Ctr, Minneapolis, MN 55455 USA..
    Atsuta, Yoshiko
    Japanese Data Ctr Hematopoiet Cell Transplantat, Nagoya, Aichi, Japan.;Nagoya Univ, Grad Sch Med, Nagoya, Aichi, Japan..
    Dalal, Jignesh
    Childrens Mercy Hosp & Clin, Kansas City, MO USA..
    Sales-Bonfim, Carmem
    Univ Fed Parana, Hosp Clin, Curitiba, Parana, Brazil..
    Khera, Nandita
    Mayo Clin, Phoenix, AZ USA..
    Hahn, Theresa
    Roswell Pk Canc Inst, Buffalo, NY 14263 USA..
    Saber, Wael
    Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA..
    Impact of pre-transplant depression on outcomes of allogeneic and autologous hematopoietic stem cell transplantation2017Inngår i: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 123, nr 10, s. 1828-1838Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: To evaluate the impact of depression before autologous and allogeneic hematopoietic cell transplantation (HCT) on clinical outcomes post-transplantation.

    METHODS: We analyzed data from the Center for International Blood and Marrow Transplant Research to compare outcomes after autologous (n=3786) or allogeneic (n=7433) HCT for adult patients with hematologic malignancies with an existing diagnosis of pre-HCT depression requiring treatment versus those without pre-HCT depression. Using Cox regression models, we compared overall survival (OS) between patients with or without depression. We compared the number of days alive and out of the hospital in the first 100 days post-HCT using Poisson models. We also compared the incidence of grade 2-4 acute and chronic graft-versus-host disease (GVHD) in allogeneic HCT.

    RESULTS: The study included 1116 (15%) patients with pre-transplant depression and 6317 (85%) without depression who underwent allogeneic HCT between 2008 and 2012. Pre-transplant depression was associated with lower OS (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.04-1.23; P=0.004) and a higher incidence of grade 2-4 acute GVHD (HR, 1.25; 95% CI, 1.14-1.37; P<0.0001), but similar incidence of chronic GVHD. Pre-transplant depression was associated with fewer days-alive-and-out-of-the hospital (means ratio [MR]=0.97; 95% CI, 0.95-0.99; P=0.004). There were 512 (13.5%) patients with Pre-transplant depression and 3274 (86.5%) without depression who underwent autologous HCT. Pre-transplant depression in autologous HCT was not associated with OS (HR, 1.15; 95% CI, 0.98-1.34; P=0.096) but was associated with fewer days alive and out of the hospital (MR, 0.98; 95% CI, 0.97-0.99; P=0.002).

    CONCLUSION: Pre-transplant depression was associated with lower OS and higher risk of acute GVHD among allogeneic HCT recipients and fewer days alive and out of the hospital during the first 100 days after autologous and allogeneic HCT. Patients with pre-transplant depression represent a population that is at risk for post-transplant complications.

  • 155.
    Eloranta, Sandra
    et al.
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Brånvall, Elsa
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Celsing, Fredrik
    Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Div Hematol, Dept Med, Stockholm, Sweden..
    Papworth, Karin
    Norrlands Univ Hosp, Dept Oncol, Umea, Sweden..
    Ljungqvist, Maria
    Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Div Hematol, Dept Med, Stockholm, Sweden..
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Ekström-Smedby, Karin
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Div Hematol, Dept Med, Stockholm, Sweden..
    Increasing incidence of primary central nervous system lymphoma but no improvement in survival in Sweden 2000-20132018Inngår i: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 100, nr 1, s. 61-68Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objectives: This study aims to characterize the epidemiology of immunocompetent Primary central nervous system lymphoma (PCNSL) diagnosed 2000-2013 in Sweden.

    Methods: Cases were identified in the population-based Swedish Lymphoma Register. Incidence per 100000 person-years and 95% confidence intervals (CI) were calculated, and PCNSL-specific survival was estimated using relative survival. Tests for temporal trends were performed using Poisson regression. Population incidence of all brain tumors was retrieved for comparison.

    Results: With 359 identified PCNSL cases (median age 66years), overall incidence was 0.26 (95% CI: 0.24-0.29) and the average annual increase 4% (P=.002). The increasing trend was primarily observed among elderly individuals (70+years). Similarly, an increase in incidence of all brain tumors was noted only among the elderly. There was no significant improvement in relative survival across the study period although, among fit patients (with Eastern Cooperative Oncology Group, EGOC 0), survival plateaued 6years after diagnosis.

    Conclusion: The increasing PCNSL incidence in the elderly was consistent with an increasing incidence of brain tumors of any type and may in part be attributable to improved diagnostics and reporting in this group. New treatment options have not yet translated into general survival improvements in a population-based setting, although the presence of long-term survivors among fit patients is encouraging.

  • 156.
    El-Serafi, Ibrahim
    et al.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden;Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden;Port Said Univ, Dept Biochem, Fac Med, Port Said, Egypt.
    Remberger, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala Univ Hosp, KFUE, Uppsala, Sweden.
    Ringdén, Olle
    Karolinska Inst, Dept Lab Med, Stockholm, Sweden.
    Törlen, Johan
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden;Karolinska Univ Hosp, Cell Therapies & Allogene Stem Cell Transplantat, Stockholm, Sweden.
    Sundin, Mikael
    Karolinska Inst, Div Pediat, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden;Astrid Lindgren Childrens Hosp, Hematol Immunol Sect, Stockholm, Sweden.
    Björklund, Andreas
    Karolinska Univ Hosp, Cell Therapies & Allogene Stem Cell Transplantat, Stockholm, Sweden.
    Winiarski, Jacek
    Karolinska Inst, Div Pediat, Dept Clin Sci Intervent & Technol CLINTEC, Stockholm, Sweden;Astrid Lindgren Childrens Hosp, Hematol Immunol Sect, Stockholm, Sweden.
    Mattsson, Jonas
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden;Univ Toronto, Gloria & Seymour Epstein Chair Cell Therapy & Tra, Toronto, ON, Canada;Univ Toronto, Princess Margaret Canc Ctr, Toronto, ON, Canada.
    Reduced Risk of Sinusoidal Obstruction Syndrome of the Liver after Busulfan-Cyclophosphamide Conditioning Prior to Allogeneic Hematopoietic Stem Cell TransplantationInngår i: Clinical and Translational Science, ISSN 1752-8054, E-ISSN 1752-8062Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The aim of this study is to evaluate the incidence of sinusoidal obstruction syndrome (SOS) of the liver and the clinical outcome after hematopoietic stem cell transplantation (HSCT) based on several modifications in our protocols. We retrospectively investigated 372 patients undergoing myeloablative conditioning with oral busulfan (Bu) and cyclophosphamide before allogeneic HSCT during 1990-2015. Patients' supportive care was changed in order to reduce the regimen-related toxicities. Norethisterone use was terminated in 1998, therapeutic drug monitoring of Bu was initiated in 2000, and the use of liver supportive drugs, such as ursodeoxycholic acid and N-acetyl-L-cysteine, were started in 2002 and 2009, respectively. In total, 26 patients (7.0%) developed SOS at a median of 19 days after transplantation. Of these 26 patients, 20 died at a median of 119 days after HSCT and 102 days after the diagnosis of SOS. The incidence of SOS decreased over time in accordance with the improvements in supportive care. The highest incidence of SOS was during 1995-1999 (16.2%) compared with 2.3% during 2010-2015. Overall survival for patients with SOS was 62%, 46%, and 27% at 100 days, 1 year, and 5 years after HSCT, respectively, compared with 92%, 77%, and 66% for those who did not develop SOS (P < 0.001). In conclusion, the incidence of SOS and related deaths were significantly decreased over the last years. Our institution pursues massive preventative and personalized measures for SOS. This strategy may also be applicable in other conditioning protocols in order to reduce the incidence of SOS and, hence, improve the clinical outcome.

  • 157.
    Enblad, Gunilla
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Karlsson, Hannah
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Gammelgård, Gustav
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Wenthe, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Lövgren, Tanja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Wikstrom, Kristina I.
    Karolinska Univ Hosp Huddinge, VECURA, Stockholm, Sweden.
    Essand, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Savoldo, Barbara
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA.
    Hallböök, Helene
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Höglund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Dotti, Gianpietro
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA.
    Brenner, Malcolm K.
    Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA.
    Hagberg, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Loskog, Angelica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    A Phase I/IIa Trial Using CD19-Targeted Third-Generation CAR T Cells for Lymphoma and Leukemia2018Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 24, nr 24, s. 6185-6194Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: The chimeric antigen receptor (CAR) T-cell therapy has been effective for patients with CD19(+) B-cell malignancies. Most studies have investigated the second-generation CARs with either CD28 or 4-1BB costimulatory domains in the CAR receptor. Here, we describe the first clinical phase I/IIa trial using third-generation CAR T cells targeting CD19 to evaluate safety and efficacy.

    Patients and Methods: Fifteen patients with B-cell lymphoma or leukemia were treated with CAR T cells. The patients with lymphoma received chemotherapy during CAR manufacture and 11 of 15 were given low-dose cyclophosphamide and fludarabine conditioning prior to CAR infusion. Peripheral blood was sampled before and at multiple time points after CAR infusion to evaluate the persistence of CAR T cells and for immune profiling, using quantitative PCR, flow cytometry, and a proteomic array.

    Results: Treatment with third-generation CAR T cells was generally safe with 4 patients requiring hospitalization due to adverse reactions. Six of the 15 patients had initial complete responses [4/11 lymphoma and 2/4 acute lymphoblastic leukemia (ALL)], and 3 of the patients with lymphoma were in remission at 3 months. Two patients are still alive. Best predictor of response was a good immune status prior to CAR infusion with high IL12, DC-Lamp, Fas ligand, and TRAIL. Responding patients had low monocytic myeloid-derived suppressor cells (MDSCs; CD14(+)CD33(+)HLA(-)DR(-)) and low levels of IL6, IL8, NAP3, sPDL1, and sPDL2.

    Conclusions: Third-generation CARs may be efficient in patients with advanced B-cell lymphoproliferative malignancy with only modest toxicity. Immune profiling pre- and posttreatment can be used to find response biomarkers.

  • 158.
    Enblad, Gunilla
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Karlsson, Hannah
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Wikström, Kristina
    Karolinska Univ Hosp, VECURA, Stockholm, Sweden..
    Essand, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Savoldo, Barbara
    Baylor Collage Med, Ctr Cell & Gene Therapy, Houston, TX USA..
    Brenner, Malcolm K.
    Texas Childrens Hosp, Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA.;Houston Methodist Hosp, Houston, TX USA..
    Dotti, Gianpietro
    Texas Childrens Hosp, Baylor Coll Med, Ctr Cell & Gene Therapy, Houston, TX 77030 USA.;Houston Methodist Hosp, Houston, TX USA..
    Hallböök, Helene
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Höglund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Hagberg, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Loskog, Angelica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Third Generation CD19-CAR T Cells for Relapsed and Refractory Lymphoma and Leukemia Report from the Swedish Phase I/IIa Trial2015Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, nr 23Artikkel i tidsskrift (Annet vitenskapelig)
  • 159.
    Englund, Annika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden..
    Rostgaard, K.
    Statens Serum Inst, Dept Epidemiol Res, Copenhagen S, Denmark..
    Eloranta, S.
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden..
    Molin, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Kuusk, T.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Brown, P. de Nully
    Rigshosp, Dept Haematol, Copenhagen, Denmark..
    Kamper, P.
    Aarhus Univ Hosp, Dept Haematol, Aarhus, Denmark..
    Smedby, K. E.
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden..
    Hjalgrim, H.
    Statens Serum Inst, Dept Epidemiol Res, Copenhagen S, Denmark..
    Ljungman, Gustaf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Hjalgrim, L. Lyngsie
    Statens Serum Inst, Dept Epidemiol Res, Copenhagen S, Denmark.;Rigshosp, Dept Paediat Haematol & Oncol, Child & Youth Clin, Copenhagen, Denmark..
    Hodgkin Lymphoma In Children, Adolescents And Young Adults-A Comparative Study Of Clinical Presentation And Treatment Outcome2016Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, s. 36-36Artikkel i tidsskrift (Annet vitenskapelig)
  • 160.
    Eriksson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Studies of New Signal Transduction Modulators in Acute Myeloid Leukemia2012Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Acute myeloid leukemia (AML) is a life-threatening malignant disorder with dismal prognosis. AML is characterized by frequent genetic changes involving tyrosine kinases, normally acting as important mediators in many basic cellular processes. Due to the overexpression and frequent mutations of the FMS-like receptor tyrosine kinase 3 (FLT3) in AML, this tyrosine kinase receptor has become one of the most sought after targets in AML drug development.

    In this thesis, we have used a combination of high-throughput screens, direct target interaction assays and sequential cellular screens, including primary patient samples, as an approach to discover new targeted therapies. Gefitinib, a previously known inhibitor of epidermal growth factor receptor and the two novel tyrosine kinase inhibitors AKN-032 and AKN-028, have been identified as compounds with cytotoxic activity in AML.

    AKN-028 is a potent inhibitor of FLT3 with an IC50 value of 6 nM in an enzyme assay, but also displaying in vitro activity in a variety of primary AML samples, irrespective of FLT3 mutation status or quantitative FLT3 expression. AKN-028 shows a sequence dependent in vitro synergy when combined with standard cytotoxic agents cytarabine or daunorubicin, with better efficacy when cells are exposed to standard chemotherapy simultaneously or for 24 hours prior to adding AKN-028. Antagonism is observed when cells are pre-treated with AKN-028, possibly explained by the cell cycle arrest induced by the compound. In vivo cytotoxic activity and good oral bioavailability have made AKN-028 a candidate drug for clinical studies and the compound is presently investigated in an international two-part multicenter phase I/II study.

    Results from microarray studies performed to further elucidate the mechanism of action of AKN-028, revealed significantly altered gene expression induced by AKN-028 in both AML cell lines and in primary AML cells, with an enrichment of the Myc pathway among the downregulated genes.

    Furthermore, tyrosine kinase activity profiling shows a dose-dependent kinase inhibition by AKN-028 in all AML samples tested. Interestingly, cells with a high overall kinase activity were more sensitive to AKN-028. Provided conformation in a larger set of samples, kinase activity profiling may give useful information in individualizing treatment of patients with AML.

    Delarbeid
    1. Significant cytotoxic activity in vitro of the EGFR tyrosine kinase inhibitor gefitinib in acute myeloblastic leukaemia
    Åpne denne publikasjonen i ny fane eller vindu >>Significant cytotoxic activity in vitro of the EGFR tyrosine kinase inhibitor gefitinib in acute myeloblastic leukaemia
    Vise andre…
    2008 (engelsk)Inngår i: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 81, nr 5, s. 344-353Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Objectives: 

    Gefitinib inhibits epidermal growth factor receptor (EGFR) signalling, but may also act by non-EGFR dependent mechanisms. We have investigated the activity of gefitinib in haematological tumour cells, in particular acute myeloblastic leukaemia (AML).

    Methods: 

    Cytotoxic activity of gefitinib, alone or in combination with standard anti-leukaemic drugs, was assessed by the short-term fluorometric microculture cytotoxicity assay in tumour cells from 117 patients representing five haematological and five non-haematological malignancies. In AML, the EGFR status was analysed by immunochemistry. Gefitinib-induced apoptosis was investigated in a subset of AML samples, as well as in the leukaemia cell line MV-4-11, using a multiparametric high content screening assay. To confirm activation of caspase-3 in cells treated with gefitinib, a blocking test was carried out in which MV4-11 cells were pretreated with the specific caspase inhibitor DEVD-FMK.

    Results: 

    Gefitinib showed highest cytotoxic activity in AML (= 19) with many samples being sensitive at concentrations achievable in clinical practice (<10 μM), and no difference between previously untreated and relapsed patients. No correlation between the activity of gefitinib and standard antileukaemic drugs (cytarabine, doxorubicin, etoposide) was observed. Combining gefitinib with these drugs resulted in mainly additive or synergistic (etoposide) effects, with no evidence of sequence dependency. The AML cells did not express the EGFR. Gefitinib induced apoptosis, which was at least partly mediated by activation of the caspase-3 pathway.

    Conclusion: 

    In vitro, gefitinib has significant cytotoxic activity in AML by inducing apoptosis through non-EGFR dependent pathways.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-102372 (URN)10.1111/j.1600-0609.2008.01120.x (DOI)000260185700002 ()18637032 (PubMedID)
    Tilgjengelig fra: 2009-05-06 Laget: 2009-05-06 Sist oppdatert: 2017-12-13bibliografisk kontrollert
    2. Identification of AKN-032, a novel 2-aminopyrazine tyrosine kinase inhibitor, with significant preclinical activity in acute myeloid leukemia
    Åpne denne publikasjonen i ny fane eller vindu >>Identification of AKN-032, a novel 2-aminopyrazine tyrosine kinase inhibitor, with significant preclinical activity in acute myeloid leukemia
    Vise andre…
    2010 (engelsk)Inngår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 80, nr 10, s. 1507-1516Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Aberrant signal transduction by mutant or overexpressed protein kinases has emerged as a promising target for treatment of acute myeloid leukemia (AML). We here present a novel low molecular weight kinase inhibitor, AKN-032, targeting the FMS-like tyrosine kinase 3 (FLT3) and discovered in a new type of screening funnel combining the target therapy approach with sequential cellular screens. AKN-032 was identified among 150 selected hits from three different high throughput kinase screens. Further characterization showed inhibitory activity on FLT3 enzyme with an IC50 of 70 nM. Western blot analysis revealed reduced autophosphorylation of the FLT3-receptor in AML cell line MV4-11 cells after exposure to AKN-032. Flow cytometry disclosed cytotoxic activity against MV4-11, but not against non-malignant 3T3-L1 fibroblast cells. Using a fluorometric microculture cytotoxicity assay, AKN-032 was tested against 15 cell lines and displayed a potent cytotoxic activity in AML cell lines MV4-11 (IC50 = 0.4 mu M) and Kasumi-1 (IC50 = 2.3 mu M). AKN-032 was also highly cytotoxic in tumor cells from AML patients in vitro. Furthermore, AKN-032 demonstrated significant antileukemic effect in a relatively resistant in vivo hollow fiber mouse model. No major toxicity was observed in the animals. In conclusion. AKN-032 is a promising new kinase inhibitor with significant in vivo and in vitro activity in AML Results from the hollow fiber mouse assay suggest a favorable toxicity profile. Future studies will focus on pharmacokinetic properties, toxicity as well as further clarifying the mechanisms of action of AKN-032 in AML.

    Emneord
    Acute myeloid leukemia, New drug development, Tyrosine kinase inhibitor, FLT3
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-134176 (URN)10.1016/j.bcp.2010.08.002 (DOI)000282850900006 ()
    Tilgjengelig fra: 2010-11-22 Laget: 2010-11-22 Sist oppdatert: 2018-01-12bibliografisk kontrollert
    3. The novel tyrosine kinase inhibitor AKN-028 has significant antileukemic activity in cell lines and primary cultures of acute myeloid leukemia
    Åpne denne publikasjonen i ny fane eller vindu >>The novel tyrosine kinase inhibitor AKN-028 has significant antileukemic activity in cell lines and primary cultures of acute myeloid leukemia
    Vise andre…
    2012 (engelsk)Inngår i: Blood Cancer Journal, ISSN 2044-5385, E-ISSN 2044-5385, Vol. 2, s. e81-Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Aberrantly expressed tyrosine kinases have emerged as promising targets for drug development in acute myeloid leukemia (AML). We report that AKN-028, a novel tyrosine kinase inhibitor (TKI), is a potent FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor (IC50=6 nM), causing dose-dependent inhibition of FLT3 autophosphorylation. Inhibition of KIT autophosphorylation was shown in a human megakaryoblastic leukemia cell line overexpressing KIT. In a panel of 17 cell lines, AKN-028 showed cytotoxic activity in all five AML cell lines included. AKN-028 triggered apoptosis in MV4-11 by activation of caspase 3. In primary AML samples (n=15), AKN-028 induced a clear dose-dependent cytotoxic response (mean IC50 1 μM). However, no correlation between antileukemic activity and FLT3 mutation status, or to the quantitative expression of FLT3, was observed. Combination studies showed synergistic activity when cytarabine or daunorubicin was added simultaneously or 24 h before AKN-028. In mice, AKN-028 demonstrated high oral bioavailability and antileukemic effect in primary AML and MV4-11 cells, with no major toxicity observed in the experiment. In conclusion, AKN-028 is a novel TKI with significant preclinical antileukemic activity in AML. Possible sequence-dependent synergy with standard AML drugs and good oral bioavailability has made it a candidate drug for clinical trials (ongoing).

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-182062 (URN)10.1038/bcj.2012.28 (DOI)000308664500001 ()22864397 (PubMedID)
    Tilgjengelig fra: 2012-10-03 Laget: 2012-10-03 Sist oppdatert: 2018-01-12bibliografisk kontrollert
    4. AKN-028 induces cell cycle arrest, downregulation of Myc associated genes and a dose dependent reduction of kinase activity in acute myeloid leukemia
    Åpne denne publikasjonen i ny fane eller vindu >>AKN-028 induces cell cycle arrest, downregulation of Myc associated genes and a dose dependent reduction of kinase activity in acute myeloid leukemia
    Vise andre…
    2014 (engelsk)Inngår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 87, nr 2, s. 284-291Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    AKN-028 is a novel tyrosine kinase inhibitor with preclinical activity in acute myeloid leukemia (AML), presently undergoing investigation in a phase I/II study. It is a potent inhibitor of the FMS-like kinase 3 (FLT3) but shows in vitro activity in a wide range of AML samples. In the present study, we have characterized the effects of AKN-028 on AML cells in more detail. AKN-028 induced a dose-dependent G(0)/arrest in AML cell line MV4-11. Treatment with AKN-028 caused significantly altered gene expression in all AML cell types tested (430 downregulated, 280 upregulated transcripts). Subsequent gene set enrichment analysis revealed enrichment of genes associated with the proto-oncogene and cell cycle regulator c-Myc among the downregulated genes in both AKN-028 and midostaurin treated cells. Kinase activity profiling in AML cell lines and primary AML samples showed that tyrosine kinase activity, but not serine/threonine kinase activity, was inhibited by AKN-028 in a dose dependent manner in all samples tested, reaching approximately the same level of kinase activity. Cells sensitive to AKN-028 showed a higher overall tyrosine kinase activity than more resistant ones, whereas serine/threonine kinase activity was similar for all primary AML samples. In summary, AKN-028 induces cell cycle arrest in AML cells, downregulates Myc-associated genes and affect several signaling pathways. AML cells with high global tyrosine kinase activity seem to be more sensitive to the cytotoxic effect of AKN-028 in vitro.

    sted, utgiver, år, opplag, sider
    Elsevier, 2014
    Emneord
    Acute myeloid leukemia, AKN-028, Tyrosine kinase inhibitor, Signal transduction
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-182065 (URN)10.1016/j.bcp.2013.10.022 (DOI)000330332800006 ()
    Tilgjengelig fra: 2012-10-10 Laget: 2012-10-03 Sist oppdatert: 2018-01-12bibliografisk kontrollert
  • 161.
    Eriksson, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Gustafsson, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Fryknäs, Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Nygren, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Höglund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Repositioning Of Quinacrine For Treatment Of Acute Myeloid Leukemia - Synergies And In Vivo Effects2016Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, s. 367-368Artikkel i tidsskrift (Annet vitenskapelig)
  • 162.
    Eriksson, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Hermanson, Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Wickström, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Lindhagen, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Ekholm, C
    Jenmalm Jensen, A
    Löthgren, A
    Lehmann, F
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Parrow, V
    Höglund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    The novel tyrosine kinase inhibitor AKN-028 has significant antileukemic activity in cell lines and primary cultures of acute myeloid leukemia2012Inngår i: Blood Cancer Journal, ISSN 2044-5385, E-ISSN 2044-5385, Vol. 2, s. e81-Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aberrantly expressed tyrosine kinases have emerged as promising targets for drug development in acute myeloid leukemia (AML). We report that AKN-028, a novel tyrosine kinase inhibitor (TKI), is a potent FMS-like receptor tyrosine kinase 3 (FLT3) inhibitor (IC50=6 nM), causing dose-dependent inhibition of FLT3 autophosphorylation. Inhibition of KIT autophosphorylation was shown in a human megakaryoblastic leukemia cell line overexpressing KIT. In a panel of 17 cell lines, AKN-028 showed cytotoxic activity in all five AML cell lines included. AKN-028 triggered apoptosis in MV4-11 by activation of caspase 3. In primary AML samples (n=15), AKN-028 induced a clear dose-dependent cytotoxic response (mean IC50 1 μM). However, no correlation between antileukemic activity and FLT3 mutation status, or to the quantitative expression of FLT3, was observed. Combination studies showed synergistic activity when cytarabine or daunorubicin was added simultaneously or 24 h before AKN-028. In mice, AKN-028 demonstrated high oral bioavailability and antileukemic effect in primary AML and MV4-11 cells, with no major toxicity observed in the experiment. In conclusion, AKN-028 is a novel TKI with significant preclinical antileukemic activity in AML. Possible sequence-dependent synergy with standard AML drugs and good oral bioavailability has made it a candidate drug for clinical trials (ongoing).

  • 163.
    Eriksson, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Kalushkova, Antonia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Jarvius, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Hilhorst, Riet
    Rickardson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Göransson Kultima, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    de Wijn, Rik
    Fryknäs, Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Öberg, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Parrow, Vendela
    Höglund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    AKN-028 induces cell cycle arrest, downregulation of Myc associated genes and a dose dependent reduction of kinase activity in acute myeloid leukemia2014Inngår i: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 87, nr 2, s. 284-291Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    AKN-028 is a novel tyrosine kinase inhibitor with preclinical activity in acute myeloid leukemia (AML), presently undergoing investigation in a phase I/II study. It is a potent inhibitor of the FMS-like kinase 3 (FLT3) but shows in vitro activity in a wide range of AML samples. In the present study, we have characterized the effects of AKN-028 on AML cells in more detail. AKN-028 induced a dose-dependent G(0)/arrest in AML cell line MV4-11. Treatment with AKN-028 caused significantly altered gene expression in all AML cell types tested (430 downregulated, 280 upregulated transcripts). Subsequent gene set enrichment analysis revealed enrichment of genes associated with the proto-oncogene and cell cycle regulator c-Myc among the downregulated genes in both AKN-028 and midostaurin treated cells. Kinase activity profiling in AML cell lines and primary AML samples showed that tyrosine kinase activity, but not serine/threonine kinase activity, was inhibited by AKN-028 in a dose dependent manner in all samples tested, reaching approximately the same level of kinase activity. Cells sensitive to AKN-028 showed a higher overall tyrosine kinase activity than more resistant ones, whereas serine/threonine kinase activity was similar for all primary AML samples. In summary, AKN-028 induces cell cycle arrest in AML cells, downregulates Myc-associated genes and affect several signaling pathways. AML cells with high global tyrosine kinase activity seem to be more sensitive to the cytotoxic effect of AKN-028 in vitro.

  • 164.
    Eriksson, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Lennartsson, Andreas
    Karolinska Inst, Stockholm, Sweden.
    Lehmann, Sören
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Epigenetic aberrations in acute myeloid leukemia: Early key events during leukemogenesis2015Inngår i: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 43, nr 8, s. 609-624Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    As a result of the introduction of new sequencing technologies, the molecular landscape of acute myeloid leukemia (AML) is rapidly evolving. From karyotyping, which detects only large genomic aberrations of metaphase chromosomes, we have moved into an era when sequencing of each base pair allows us to define the AML genome at highest resolution. This has revealed a new complex landscape of genetic aberrations where addition of mutations in epigenetic regulators has been one of the most important contributions to the understanding of the pathogenesis of AML. These findings, together with new insights into epigenetic mechanisms, have placed dysregulated epigenetic mechanisms at the forefront of AML development. Not only have several new mutations in genes directly involved in epigenetic regulatory mechanisms been discovered, but also previously well-known gene fusions have been found to exert aberrant effects through epigenetic mechanisms. In addition, mutations in epigenetic regulators such as DNMT3A, TET2, and ASXL1 have recently been found to be the earliest known events during AML evolution and to be present as preleukemic lesions before the onset of AML. In this article, we review epigenetic changes in AML also in relation to what is known about their mechanism of action and their prognostic role.

  • 165.
    Eriksson, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Osterros, Albin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Hassan, Sadia Bashir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Rickardson, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Jarvius, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Nygren, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Fryknäs, Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Höglund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Repositioning of Quinacrine for Treatment of Acute Myeloid Leukemia2014Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, nr 21Artikkel i tidsskrift (Annet vitenskapelig)
  • 166.
    Eriksson, Oskar
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Koagulation och inflammationsvetenskap.
    Asplund, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hegde, Geeta
    Human Prot Atlas Project, Lab Surgpath, Mumbai Site, Bombay, Maharashtra, India..
    Edqvist, Per-Henrik D
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Navani, Sanjay
    Human Prot Atlas Project, Lab Surgpath, Mumbai Site, Bombay, Maharashtra, India..
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Siegbahn, A
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    A stromal cell population in the large intestine identified by tissue factor expression that is lost during colorectal cancer progression2016Inngår i: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 116, nr 6, s. 1050-1059Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Colorectal cancer (CRC) is a major cause of morbidity and mortality, and the composition of the tumour stroma is a strong predictor of survival in this cancer type. Tissue factor (TF) functions as the trigger of haemostasis together with its ligand coagulation factor VII/ VIIa, and TF expression has been found in tumour cells of colorectal tumours. However, TF expression in the CRC tumour stroma or its relationship to patient outcome has not yet been studied. To address this question we developed and validated a specific anti-TF antibody using standardised methods within the Human Protein Atlas project. We used this antibody to investigate TF expression in normal colorectal tissue and CRC using immunofluorescence and immunohistochemistry in two patient cohorts. TF was strongly expressed in a cell population immediately adjacent to the colorectal epithelium. These TF-positive cells were ACTA2-negative but weakly vimentin-positive, defining a specific population of pericryptal sheath cells. In colorectal tumours, TF-positive sheath cells were progressively lost after the adenoma-to-carcinoma transition, demonstrating downregulation of this source of TF in CRC. Furthermore, loss of sheath cell TF was significantly associated with poor overall and disease-specific survival in rectal but not colon cancers. In conclusion, we demonstrate that TF is a marker of a specific cell population in the large intestine, which is lost during CRC progression. Our results highlight the role of the tumour stroma in this cancer type and suggest TF to be a potential prognostic biomarker in rectal cancers through the identification of pericryptal sheath cells.

  • 167.
    Eriksson, Oskar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Koagulation och inflammationsvetenskap.
    Thulin, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Koagulation och inflammationsvetenskap.
    Asplund, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Hedge, G.
    Navani, S.
    Siegbahn, Agneta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Koagulation och inflammationsvetenskap.
    Cross-talk between tissue factor and EPHA2 in cancer: potentiation of ligand-dependent EPHA2-signaling in vitro and co-expression in human colorectal cancer specimens2015Inngår i: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 13, nr S2, s. 111-111, artikkel-id OR046Artikkel i tidsskrift (Annet vitenskapelig)
  • 168. Erlinge, David
    et al.
    James, Stefan K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Duvvuru, Suman
    Jakubowski, Joseph A.
    Wagner, Henrik
    Varenhorst, Christoph
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Tantry, Udaya S.
    Brown, Patricia B.
    Small, David
    Moser, Brian A.
    Sundseth, Scott S.
    Walker, Joseph R.
    Winters, Kenneth J.
    Gurbel, Paul A.
    Clopidogrel metaboliser status based on point-of-care CYP2C19 genetic testing in patients with coronary artery disease2014Inngår i: Thrombosis and Haemostasis, ISSN 0340-6245, Vol. 111, nr 5, s. 943-950Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We compared results obtained with the Nanosphere Verigene (R) System, a novel point-of-care (POC) genetic test capable of analysing 11, CYP2C19 variants within 3 hours, to an established, validated genotyping method (Affymetrix (TM) DMET+; reference assay) for identifying extensive and reduced metabolisers of clopidogrel. Based on genotyping, patients (N=82) with stable coronary artery disease on clopidogrel 75 mg daily were defined as extensive metabolisers (*1/*1, *1/*17,*17/*17), reduced metabolisers (*1/*2,*1/*8,*2/*2,*2/*3), or of indeterminate metaboliser status (*2/*17). Pharmacokinetic exposure to clopidogrel's active metabolite and pharmacodynamic measures with P2Y12 reaction units (PRU) (VerifyNow (R) P2Y12 assay), and VASP PRI (PRI) were also assessed. There was a 99.9% overall; concordance of marker-level data between the Nanosphere Verigene and DMET+ systems in identifying the CYP2C19 variants and 100% agreement in classifying the patients as extensive (n=59) or reduced metabolisers (n=15). Extensive metabolisers had significantly higher active metabolite exposure than reduced metabolisers (LS means 12.6 ng*h/ml vs 7.7 ng*h/ml; p<0.001). Extensive metabolisers also had lower PRU (LS means 158 vs 212; p=0.003) and VASP PRI (LS means 48% vs 63%, p=0.01) compared to reduced metabolisers. Rates of high on-treatment platelet reactivity were higher in reduced metabolisers compared to extensive metabolisers (VASP PRI >= 50%: 79% vs 47%; PRU >235: 33% vs 16%). The Nanosphere Verigene CBS system identified 11 CYP2C19 alleles in less than 3 hours with a high degree of accuracy when compared to a conventional method, and was further validated against pharmacokinetic and pharmacodynamic phenotypes.

  • 169.
    Eshoj, Henrik Rode
    et al.
    Odense Univ Hosp, Dept Hematol, Qual Life Res Ctr, Odense, Denmark; Odense Univ Hosp, OPEN Odense Patient Data Explorat Network, Odense, Denmark.
    Nielsen, Lene Kongsgaard
    Odense Univ Hosp, Dept Hematol, Qual Life Res Ctr, Odense, Denmark.
    Schjesvold, Fredrik
    Oslo Univ Hosp, Dept Hematol, Oslo, Norway.
    Abildgaard, Niels
    Odense Univ Hosp, Dept Hematol, Qual Life Res Ctr, Odense, Denmark.
    Nahi, Hareth
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.
    Andersen, Niels Frost
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark.
    Vangsted, Annette Juul
    Rigshosp, Dept Hematol, Copenhagen, Denmark.
    Helleberg, Carsten
    Herlev Hosp, Dept Hematol, Herlev, Denmark.
    Frølund, Ulf Christian
    Zealand Univ Hosp, Dept Hematol, Roskilde, Denmark.
    Axelsson, Per
    Helsingborg Hosp, Dept Hematol, Helsingborg, Sweden.
    Stromberg, Olga
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.
    Blimark, Cecilie
    Sahlgrens Univ Hosp, Dept Hematol, Gothenburg, Sweden.
    Carlson, Kristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Waage, Anders
    St Olays Hosp NTNU, Dept Hematol, Trondheim, Norway.
    Remes, Kari
    Turku Univ Hosp, Dept Hematol, Turku, Finland.
    Peceliunas, Valdas
    Vilnius Univ Hosp, Dept Hematol, Vilnius, Lithuania.
    Guldbrandsen, Nina
    Oslo Univ Hosp, Dept Hematol, Oslo, Norway.
    Hansson, Markus
    Skane Univ Hosp, Dept Hematol, Lund, Sweden.
    Gregersen, Henrik
    Aalborg Univ Hosp, Dept Hematol, Aalborg, Denmark.
    Health-related quality of life in multiple myeloma patients with first relapse treated with Carfilzomib-based re-induction and salvage autologous stem cell transplantation: data from a Nordic phase II trial2018Inngår i: Quality of Life Research, ISSN 0962-9343, E-ISSN 1573-2649, Vol. 27, nr Supplement 1, s. S137-S137Artikkel i tidsskrift (Annet vitenskapelig)
  • 170.
    Eskelund, Christian Winther
    et al.
    Rigshosp, Dept Hematol, Copenhagen, Denmark;Biotech Res & Innovat Ctr, Copenhagen, Denmark.
    Albertsson-Lindblad, Alexandra
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden.
    Kolstad, Arne
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.
    Laurell, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Raty, Riikka
    Helsinki Univ Hosp, Dept Hematol, Helsinki, Finland.
    Pedersen, Lone Bredo
    Rigshosp, Dept Hematol, Copenhagen, Denmark.
    Geisler, Christian Hartmann
    Rigshosp, Dept Hematol, Copenhagen, Denmark.
    Jerkeman, Mats
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Oncol & Pathol, Lund, Sweden.
    Gronbaek, Kirsten
    Rigshosp, Dept Hematol, Copenhagen, Denmark;Biotech Res & Innovat Ctr, Copenhagen, Denmark.
    Lenalidomide plus bendamustine-rituximab does not overcome the adverse impact of TP53 mutations in mantle cell lymphoma2018Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, nr 11, s. E541-E543Artikkel i tidsskrift (Annet vitenskapelig)
  • 171.
    Espinet Sola, B.
    et al.
    Hosp Mar, Barcelona, Spain..
    Baliakas, P.
    Inst Hosp Mar Invest Med Imim, Barcelona, Spain..
    Puiggros, A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Xochelli, A.
    Hosp Mar, Barcelona, Spain..
    Sutton, L-A
    Inst Hosp Mar Invest Med Imim, Barcelona, Spain..
    Nguyen-Khac, F.
    Certh, Inst Appl Biosci, Thessaloniki, Greece..
    Gardiner, A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Plevova, K.
    Hop La Pitie Salpetriere, Paris, France..
    Ortega, M.
    Royal Bornemouth Hosp, Bornemouth, England..
    Collado, R.
    Masaryk Univ, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Gonzalez, T.
    Hosp Univ Vall Dhebron, Barcelona, Spain..
    Granada, I
    Consorcio Hosp Gen Univ, Valencia, Spain..
    Luno, E.
    Fdn Publ Galega Med Xenom, Santiago De Compostela, Spain..
    Kotaskova, J.
    Hosp Badalona Germans Trias & Pujol, Inst Recerca Josep Carreras, Badalona, Spain..
    Davis, Z.
    Hosp Univ Cent Asturias, Oviedo, Spain..
    Anagnostopoulos, A.
    Masaryk Univ, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Strefford, J.
    Royal Bornemouth Hosp, Bornemouth, England..
    Pospisilova, S.
    G Papanicolaou Hosp, Thessaloniki, Greece..
    Davi, F.
    Univ Southampton, Southampton SO9 5NH, Hants, England..
    Athanasiadou, A.
    Masaryk Univ, Brno, Czech Republic..
    Rosenquist, R.
    Hop La Pitie Salpetriere, Paris, France..
    Oscier, D.
    G Papanicolaou Hosp, Thessaloniki, Greece..
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Royal Bornemouth Hosp, Bornemouth, England..
    Clinical- Biological Characterization Of The Patients With Llc And Trisomy 12 That Exhibit Additional Trisomies: Importance Of The Accompanying Alterations2015Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, s. 67-67Artikkel i tidsskrift (Annet vitenskapelig)
  • 172. Falk, Ingrid Jakobsen
    et al.
    Fyrberg, Anna
    Paul, Esbjorn
    Nahi, Hareth
    Hermanson, Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Rosenquist, Richard Brandell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi.
    Höglund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Palmqvist, Lars
    Stockelberg, Dick
    Wei, Yuan
    Green, Henrik
    Lotfi, Kourosh
    Impact of ABCB1 single nucleotide polymorphisms 1236C>T and 2677G>T on overall survival in FLT3 wild-type de novo AML patients with normal karyotype2014Inngår i: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 167, nr 5, s. 671-680Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Drug resistance is a clinically relevant problem in the treatment of acute myeloid leukaemia (AML). We have previously reported a relationship between single nucleotide polymorphisms (SNPs) of ABCB1, encoding the multi-drug transporter P-glycoprotein, and overall survival (OS) in normal karyotype (NK)-AML. Here we extended this material, enabling subgroup analysis based on FLT3 and NPM1 status, to further elucidate the influence of ABCB1 SNPs. De novo NK-AML patients (n = 201) were analysed for 1199G>A, 1236C>T, 2677G>T/A and 3435C>T, and correlations to outcome were investigated. FLT3 wild-type 1236C/C patients have significantly shorter OS compared to patients carrying the variant allele; medians 20 vs. 49 months, respectively, P = 0.017. There was also an inferior outcome in FLT3 wild-type 2677G/G patients compared to patients carrying the variant allele, median OS 20 vs. 35 months, respectively, P = 0.039. This was confirmed in Cox regression analysis. Our results indicate that ABCB1 1236C>T and 2677G>T may be used as prognostic markers to distinguish relatively high risk patients in the intermediate risk FLT3 wild-type group, which may contribute to future individualizing of treatment strategies.

  • 173. Falk, Ingrid Jakobsen
    et al.
    Willander, Kerstin
    Chaireti, Roza
    Lund, Johan
    Nahi, Hareth
    Hermanson, Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Green, Henrik
    Lotfi, Kourosh
    Söderkvist, Peter
    TP53 mutations and MDM2(SNP309) identify subgroups of AML patients with impaired outcome2015Inngår i: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 94, nr 4, s. 355-362Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BackgroundTP53 is commonly mutated in several cancers and confers treatment resistance and poor prognosis. Altered expression of mouse double minute 2 (MDM2), a negative regulator of p53, may also attenuate normal p53 signaling, thereby enhancing tumor transformation and resistance to apoptosis. The single nucleotide polymorphism (SNP) 309 has been reported to increase MDM2 expression and impair normal p53 response. Experimental designWe investigated the frequency and impact of TP53 mutations (TP53mut) and MDM2(SNP309) on treatment outcome and overall survival (OS) in 189 Swedish acute myeloid leukemia patients. The genetic analyses were performed using SSCA and direct sequencing (for mutations in exon 5-8 of TP53) and Pyrosequencing (for the MDM2(SNP309)). ResultsWe found a high frequency (22%) of TP53mut in patients with cytogenetic aberrations, with association to high-risk cytogenetics (P<0.001). TP53mut patients had lower response rates (22% compared with 76% CR in TP53 wild-type (wt) patients, P<0.001) and reduced OS (2 and 16months, respectively, P<0.001). In TP53wt patients with high or intermediate risk cytogenetic aberrations, the MDM2(SNP309) conferred an impaired outcome, with patients carrying the alternative G-allele having shorter OS compared with T/T patients (median 9 vs. 50months, P=0.020). ConclusionsOur results show that TP53mut analysis and MDM2(SNP309) genotyping may be useful tools for prognostication, risk stratification, and selection of patients most likely to benefit from new drugs targeting the p53 signaling pathway.

  • 174.
    Fang, Xiaotian
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Hultqvist, Greta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Meier, Silvio
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Sehlin, Dag
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    Syvänen, Stina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap.
    A small bispecific antibody-based construct based on bapineuzumab as a PET tracer for amyloid beta pathology in brain2017Inngår i: Meeting abstractArtikkel i tidsskrift (Annet vitenskapelig)
  • 175. Fellerhoff-Losch, Barbara
    et al.
    Korol, Sergiy V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Ganor, Yonatan
    Gu, Songhai
    Cooper, Itzik
    Eilam, Raya
    Besser, Michal
    Goldfinger, Meidan
    Chowers, Yehuda
    Wank, Rudolf
    Birnir, Bryndis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Levite, Mia
    Normal human CD4+ helper T cells express Kv1.1 voltage-gated K+ channels, and selective Kv1.1 block in T cells induces by itself robust TNFα production and secretion and activation of the NFκB non-canonical pathway2016Inngår i: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 123, nr 3, s. 137-157Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    TNFα is a very potent and pleiotropic pro-inflammatory cytokine, essential to the immune system for eradicating cancer and microorganisms, and to the nervous system, for brain development and ongoing function. Yet, excess and/or chronic TNFα secretion causes massive tissue damage in autoimmune, inflammatory and neurological diseases and injuries. Therefore, many patients with autoimmune/inflammatory diseases receive anti-TNFα medications. TNFα is secreted primarily by CD4+ T cells, macrophages, monocytes, neutrophils and NK cells, mainly after immune stimulation. Yet, the cause for the pathologically high and chronic TNFα secretion is unknown. Can blocking of a particular ion channel in T cells induce by itself TNFα secretion? Such phenomenon was never revealed or even hypothesized. In this interdisciplinary study we discovered that: (1) normal human T cells express Kv1.1 voltage-gated potassium channel mRNA, and the Kv1.1 membrane-anchored protein channel; (2) Kv1.1 is expressed in most CD4+CD3+ helper T cells (mean CD4+CD3+Kv1.1+ T cells of 7 healthy subjects: 53.09 ± 22.17 %), but not in CD8+CD3+ cytotoxic T cells (mean CD8+CD3+Kv1.1+ T cells: 4.12 ± 3.04 %); (3) electrophysiological whole-cell recordings in normal human T cells revealed Kv currents; (4) Dendrotoxin-K (DTX-K), a highly selective Kv1.1 blocker derived from snake toxin, increases the rate of rise and decay of Kv currents in both resting and activated T cells, without affecting the peak current; (5) DTX-K by itself induces robust TNFα production and secretion by normal human T cells, without elevating IFNγ, IL-4 and IL-10; (6) intact Ca2+ channels are required for DTX-induced TNFα secretion; (7) selective anti-Kv1.1 antibodies also induce by themselves TNFα secretion; (8) DTX-K activates NFκB in normal human T cells via the unique non-canonical-pathway; (9) injection of Kv1.1-blocked human T cells to SCID mice, causes recruitment of resident mouse cells into the liver, alike reported after TNFα injection into the brain. Based on our discoveries we speculate that abnormally blocked Kv1.1 in T cells (and other immune cells?), due to either anti-Kv1.1 autoimmune antibodies, or Kv1.1-blocking toxins alike DTX-K, or Kv1.1-blocking genetic mutations, may be responsible for the chronic/excessive TNFα in autoimmune/inflammatory diseases. Independently, we also hypothesize that selective block of Kv1.1 in CD4+ T cells of patients with cancer or chronic infectious diseases could be therapeutic, since it may: a. augment beneficial secretion and delivery of TNFα to the disease-affected sites; b. induce recruitment and extravasation of curative immune cells and factors; c. improve accessibility of drugs to the brain and few peripheral organs thanks to TNFα-induced increased permeability of organ’s barriers.

  • 176.
    Fristedt Duvefelt, Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Tumour Survival Signals and Epigenetic Gene Silencing in Multiple Myeloma: Implications for Biology and Therapy2015Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    This thesis is focused on multiple myeloma (MM), a haematological malignancy that still remains incurable. The pathogenesis of MM is not fully understood and there is a large intra-tumour and interclonal genetic variation in MM patients. One of the most challenging areas in MM research is to find mechanisms for initiation and progression of MM, but also to overcome the arising resistance to therapy.

    In paper I, a signature of under-expressed genes in MM was found to significantly correlate with already defined Polycomb target genes. In selected genes from the profile we found an enrichment of H3K27me3, a repressive mark catalysed by Polycomb repressive complex 2 (PRC2), in MM patients and MM cell lines. Treatment with LBH589 (HDAC inhibitor) and DZNep (methyltransferase inhibitor) reactivated the H3K27me3 target genes and induced apoptosis in MM cell lines. LBH589 reduced tumour load and increased overall survival in the 5T33MM mice. These results suggest an important role for Polycomb complex in MM development and highlight PRC2 as a drug target in MM.

    In paper II, the insulin-like growth factor type 1 receptor tyrosine kinase (IGF-1RTK) inhibitor picropodophyllin (PPP) in combination with LBH589 synergistically inhibited cell proliferation and enhanced the apoptotic effect in MM. Since the bone marrow microenvironment has an important role in MM disease and also contributes to drug-resistance, we therefore evaluated the drug combination in the immunocompetent 5T33MM murine model. The drug combination significantly prolonged the survival of the 5T33MM mice compared to single drug treatment. We conclude that the combination of PPP and LBH589 has a therapeutic potential in MM.

    In paper III, the role of the cellular inhibitor of apoptosis protein 2 (cIAP2) was evaluated in MM cells harbouring TRAF3 deletion/mutation. By overexpressing cIAP2 in these cells we found an increased resistance to proteasome inhibitors. cIAP2 over-expression by lentiviral constructs led to decreased caspase activation, activation of the canonical NF-κB pathway, and down-regulation of tumour suppressor genes and genes that contribute to apoptosis. Supporting the role of cIAP2 mediated drug-resistance, we here demonstrate that inhibiting cIAP2 using an IAP antagonist, increased the sensitivity to the proteasome inhibitor, bortezomib.

    Delarbeid
    1. Polycomb target genes are silenced in multiple myeloma
    Åpne denne publikasjonen i ny fane eller vindu >>Polycomb target genes are silenced in multiple myeloma
    Vise andre…
    2010 (engelsk)Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, nr 7, s. e11483-Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Multiple myeloma (MM) is a genetically heterogeneous disease, which to date remains fatal. Finding a common mechanism for initiation and progression of MM continues to be challenging. By means of integrative genomics, we identified an underexpressed gene signature in MM patient cells compared to normal counterpart plasma cells. This profile was enriched for previously defined H3K27-tri-methylated genes, targets of the Polycomb group (PcG) proteins in human embryonic fibroblasts. Additionally, the silenced gene signature was more pronounced in ISS stage III MM compared to stage I and II. Using chromatin immunoprecipitation (ChIP) assay on purified CD138+ cells from four MM patients and on two MM cell lines, we found enrichment of H3K27me3 at genes selected from the profile. As the data implied that the Polycomb-targeted gene profile would be highly relevant for pharmacological treatment of MM, we used two compounds to chemically revert the H3K27-tri-methylation mediated gene silencing. The S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin (DZNep) and the histone deacetylase inhibitor LBH589 (Panobinostat), reactivated the expression of genes repressed by H3K27me3, depleted cells from the PRC2 component EZH2 and induced apoptosis in human MM cell lines. In the immunocompetent 5T33MM in vivo model for MM, treatment with LBH589 resulted in gene upregulation, reduced tumor load and increased overall survival. Taken together, our results reveal a common gene signature in MM, mediated by gene silencing via the Polycomb repressor complex. The importance of the underexpressed gene profile in MM tumor initiation and progression should be subjected to further studies.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-133207 (URN)10.1371/journal.pone.0011483 (DOI)000279715300003 ()20634887 (PubMedID)
    Tilgjengelig fra: 2010-11-03 Laget: 2010-11-03 Sist oppdatert: 2017-12-12bibliografisk kontrollert
    2. The HDAC Inhibitor LBH589 Enhances the Antimyeloma Effects of the IGF-1RTK Inhibitor Picropodophyllin
    Åpne denne publikasjonen i ny fane eller vindu >>The HDAC Inhibitor LBH589 Enhances the Antimyeloma Effects of the IGF-1RTK Inhibitor Picropodophyllin
    Vise andre…
    2012 (engelsk)Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 18, nr 8, s. 2230-2239Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Purpose: We have previously shown the use of the insulin-like growth factor type 1 receptor tyrosine kinase (IGF-1RTK) inhibitor picropodophyllin (PPP) as an attractive strategy to combat multiple myeloma (MM) in vitro and in vivo. After a combinatorial drug screening, the histone deacetylase inhibitor LBH589 was shown to act in synergy with PPP reducing survival of MM cells. In this study, we tried to elucidate the molecular mechanisms underlying this combinatorial effect.

    Experimental Design: The in vitro anti-MM effects of PPP and LBH589 alone and in combination were evaluated by studying apoptosis, cell cycle distribution, and downstream transcriptome using both human MM cell lines and cells from the murine 5T3MM model. In vivo the effect on survival of 5T33MM-inoculated mice was evaluated.

    Results: In the human MM cell line RPMI8226, treatment with PPP and LBH589 in combination resulted in a five-fold increase of apoptosis, and an additive effect on the cleavage of the active forms of caspase-8 was observed as compared with the single drug treatments. Cell cycle analysis revealed an accumulation of cells in the G2-M phase and subsequent downregulation of cell cycle regulating proteins. These data were also confirmed in the 5T33MM cells in vitro. Also, the transcriptome was analyzed by Affymetrix arrays showing gene expression alterations mainly in categories of genes regulating apoptosis and cell adhesion. Combined treatment in vivo resulted in a significantly prolonged survival of 5T33MM-inoculated mice.

    Conclusions: The results indicate an improved MM treatment opportunity in using a combination of PPP and LBH589.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-174374 (URN)10.1158/1078-0432.CCR-11-1764 (DOI)000302907300014 ()
    Tilgjengelig fra: 2012-05-22 Laget: 2012-05-15 Sist oppdatert: 2017-12-07bibliografisk kontrollert
    3. Increased resistance to proteaome inhibitors in multiple myeloma mediated by cIAP2: implications for a combinatorial treatment
    Åpne denne publikasjonen i ny fane eller vindu >>Increased resistance to proteaome inhibitors in multiple myeloma mediated by cIAP2: implications for a combinatorial treatment
    Vise andre…
    2015 (engelsk)Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, nr 24, s. 20621-20635Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Despite the introduction of new treatment options for multiple myeloma (MM), a majority of patients relapse due to the development of resistance. Unraveling new mechanisms underlying resistance could lead to identification of possible targets for combinatorial treatment. Using TRAF3 deleted/mutated MM cell lines, we evaluated the role of the cellular inhibitor of apoptosis 2 (cIAP2) in drug resistance and uncovered the plausible mechanisms underlying this resistance and possible strategies to overcome this by combinatorial treatment. In MM, cIAP2 is part of the gene signature of aberrant NF-kappa B signaling and is heterogeneously expressed amongst MM patients. In cIAP2 overexpressing cells a decreased sensitivity to the proteasome inhibitors bortezomib, MG132 and carfilzomib was observed. Gene expression analysis revealed that 440 genes were differentially expressed due to cIAP2 overexpression. Importantly, the data imply that cIAPs are rational targets for combinatorial treatment in the population of MM with deleted/mutated TRAF3. Indeed, we found that treatment with the IAP inhibitor AT-406 enhanced the anti-MM effect of bortezomib in the investigated cell lines. Taken together, our results show that cIAP2 is an important factor mediating bortezomib resistance in MM cells harboring TRAF3 deletion/mutation and therefore should be considered as a target for combinatorial treatment.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-242568 (URN)000360138200076 ()
    Forskningsfinansiär
    Swedish Research CouncilSwedish Cancer SocietyEU, FP7, Seventh Framework Programme, 259796
    Tilgjengelig fra: 2015-01-28 Laget: 2015-01-28 Sist oppdatert: 2017-12-05bibliografisk kontrollert
  • 177.
    Fristedt Duvefelt, Charlotte
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Lub, Susanne
    Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, (VUB) Belgium..
    Prasoon, Agarwal
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Arngården, Linda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Hammarberg, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Maes, Ken
    Van Valckenborgh, Els
    Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, (VUB) Belgium..
    Vanderkerekn, Karin
    Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel, (VUB) Belgium..
    Jernberg-Wiklund, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Increased resistance to proteaome inhibitors in multiple myeloma mediated by cIAP2: implications for a combinatorial treatment2015Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 6, nr 24, s. 20621-20635Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Despite the introduction of new treatment options for multiple myeloma (MM), a majority of patients relapse due to the development of resistance. Unraveling new mechanisms underlying resistance could lead to identification of possible targets for combinatorial treatment. Using TRAF3 deleted/mutated MM cell lines, we evaluated the role of the cellular inhibitor of apoptosis 2 (cIAP2) in drug resistance and uncovered the plausible mechanisms underlying this resistance and possible strategies to overcome this by combinatorial treatment. In MM, cIAP2 is part of the gene signature of aberrant NF-kappa B signaling and is heterogeneously expressed amongst MM patients. In cIAP2 overexpressing cells a decreased sensitivity to the proteasome inhibitors bortezomib, MG132 and carfilzomib was observed. Gene expression analysis revealed that 440 genes were differentially expressed due to cIAP2 overexpression. Importantly, the data imply that cIAPs are rational targets for combinatorial treatment in the population of MM with deleted/mutated TRAF3. Indeed, we found that treatment with the IAP inhibitor AT-406 enhanced the anti-MM effect of bortezomib in the investigated cell lines. Taken together, our results show that cIAP2 is an important factor mediating bortezomib resistance in MM cells harboring TRAF3 deletion/mutation and therefore should be considered as a target for combinatorial treatment.

  • 178.
    Geelen, I.
    et al.
    Albert Schweitzer Hosp, Dordrecht, Netherlands.
    Strömberg, Ulla Ohlsson
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Mustjoki, S.
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland;Helsinki Univ Hosp, Comprehens Canc Ctr, Helsinki, Finland;Univ Helsinki, Dept Clin Chem, Helsinki, Finland.
    Richter, J.
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden.
    Blijlevens, N.
    Radboud UMC, Dept Hematol, Nijmegen, Netherlands.
    Smit, W.
    Med Spectrum Twente, Dept Hematol, Enschede, Netherlands.
    Gjertsen, B.
    Haukeland Hosp, Hematol Sect, Dept Internal Med, Bergen, Norway;Univ Bergen, Dept Clin Sci, Bergen, Norway.
    Gedde-Dahl, T.
    Oslo Univ Hosp, Rikshosp, Dept Hematol, Oslo, Norway.
    Markevärn, B.
    Umea Univ Hosp, Dept Hematol, Umea, Sweden.
    Koppes, M.
    Vrije Univ Amsterdam Med Ctr, Dept Hematol, Amsterdam, Netherlands.
    Westerweel, P.
    Albert Schweitzer Hosp, Dordrecht, Netherlands.
    Janssen, J.
    Vrije Univ Amsterdam Med Ctr, Dept Hematol, Amsterdam, Netherlands.
    Hjorth-Hansen, H.
    St Olavs Hosp, Dept Hematol, Trondheim, Norway;Norwegian Univ Sci & Technol NTNU, Dept Canc Res & Mol Med, Trondheim, Norway.
    CLINICAL AND IMMUNOLOGICAL EFFECTS OF NILOTINIB IN COMBINATION WITH PEGYLATED INTERFERON-A2B IN PATIENTS WITH SUBOPTIMAL MOLECULAR RESPONSE ON IMATINIB (NORDDUTCHCML009)2017Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 102, nr Suppl. 2, s. 435-435, artikkel-id E1057Artikkel i tidsskrift (Annet vitenskapelig)
  • 179. Geisler, Christian H.
    et al.
    Kolstad, Arne
    Laurell, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Räty, Riikka
    Jerkeman, Mats
    Eriksson, Mikael
    Nordström, Marie
    Kimby, Eva
    Boesen, Anne Marie
    Nilsson-Ehle, Herman
    Kuittinen, Outi
    Lauritzsen, Grete F.
    Ralfkiaer, Elisabeth
    Ehinger, Mats
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Delabie, Jan
    Karjalainen-Lindsberg, Marja-Liisa
    Brown, Peter
    Elonen, Erkki
    The Mantle Cell Lymphoma International Prognostic Index (MIPI) is superior to the International Prognostic Index (IPI) in predicting survival following intensive first-line immunochemotherapy and autologous stem cell transplantation (ASCT)2010Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 115, nr 8, s. 1530-1533Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Mantle cell lymphoma (MCL) has a heterogeneous clinical course. The recently proposed Mantle Cell Lymphoma International Prognostic Index (MIPI) predicted the survival of MCL better than the International Prognostic Index in MCL patients treated with conventional chemotherapy, but its validity in MCL treated with more intensive immunochemotherapy has been questioned. Applied here to 158 patients of the Nordic MCL2 trial of first-line intensive immunochemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation, the MIPI and the simplified MIPI (s-MIPI) predicted survival significantly better (P < .001) than the International Prognostic Index (P > .004). Both the MIPI and the s-MIPI mainly identified 2 risk groups, low and intermediate versus high risk, with the more easily applied s-MIPI being just as powerful as the MIPI. The MIPI(B) (biological), incorporating Ki-67 expression, identified almost half of the patients as high risk. We suggest that also a simplified MIPI(B) is feasible.

  • 180.
    Gemenetzi, K.
    et al.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Stalika, E.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Vardi, A.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Psomopoulos, F. E.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Minga, E.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Anagnostopoulos, A.
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Hadzidimitriou, A.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Sutton, Lesley Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    HIGH THROUGHPUT IMMUNOPROFILING OF CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS ASSIGNED TO STEREOTYPED SUBSET #4: NOVEL INSIGHTS INTO THE DEPTH, DIVERSITY AND TEMPORAL DYNAMICS OF CLONAL EVOLUTION2017Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 102, nr Suppl. 2, s. 67-67, artikkel-id P242Artikkel i tidsskrift (Annet vitenskapelig)
  • 181.
    Gemenetzi, Katerina
    et al.
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Galigalidou, Chrysi
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Vlachonikola, Elisavet
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki 57001, Greece..
    Stalika, Evangelia
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki 57001, Greece.; G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.; G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Xochelli, Aliki
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki , Greece.; G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Baliakas, Panagiotis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Karypidou, Maria
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Touloumenidou, Tasoula
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Minga, Evangelia
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki 57001, Greece..
    Douka, Vasiliki
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Iskas, Michalis
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Athanasiadou, Anastasia
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Makris, Antonios
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki , Greece..
    Stavroyianni, Niki
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Hadzidimitriou, Anastasia
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki 57001, Greece..
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Tp53 gene p72R polymorphism in chronic lymphocytic leukemia: incidence and clinical significance amongst cases with unmutated immunoglobulin receptors2017Inngår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 58, nr 3, s. 726-728Artikkel i tidsskrift (Fagfellevurdert)
  • 182.
    Genberg, Margareta
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Öberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Andrén, Bertil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Hedenström, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Frisk, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Flachskampf, Frank A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Cardiac Function After Hematopoietic Cell Transplantation: An Echocardiographic Cross-Sectional Study in Young Adults Treated in Childhood2015Inngår i: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 62, nr 1, s. 143-147Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BackgroundHematopoietic cell transplantation (HCT) including preparative regimens with chemotherapy and total body irradiation (TBI) is an accepted treatment for many malignant disorders but may have side-effects for several organs, including the cardiovascular system. The aim of this study was to study very long-term consequences on cardiac function after childhood HCT. ProcedureCardiac function was evaluated using echocardiography and levels of NT-proBNP and growth hormone (GHmax) in 18 patients, at a median of 18 years after HCT including TBI, and in 18 matched controls. ResultsPatients after HCT had cardiac dimensions, volumes, and left ventricular ejection fractions within normal range after correction for body size. However, compared with the control group, patients after HCT had significantly lower E/A ratio, as a measure of left ventricular diastolic function, significantly lower fractional shortening and mitral annular plane systolic excursion, as measures of left ventricular systolic function, significantly lower tricuspid annular plane systolic excursion, as a measure of right ventricular function, and significantly higher NT-proBNP, as a measure of total cardiac function. Also, pulmonary flow acceleration time was shorter in the group after HCT, indicating possible pulmonary involvement. Heart rate was significantly higher and GHmax significantly lower in patients after HCT. ConclusionsAlmost two decades after HCT, including preparative regimens with TBI, cardiac function in patients was found to be within normal range. However, when compared with a healthy control group, patients after HCT showed lower systolic and diastolic left ventricular function as well as lower right ventricular function. Pediatr Blood Cancer 2015;62:143-147.

  • 183.
    Georgiou, Konstantinos
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Dept Lab Med, Clin Immunol, Huddinge, Sweden..
    Chen, Longyun
    Karolinska Inst, Karolinska Univ Hosp, Dept Lab Med, Clin Immunol, Huddinge, Sweden.;BGI Shenzhen, Shenzhen, Peoples R China..
    Berglund, Mattias
    Karolinska Inst, Dept Biosci & Nutr, Solna, Sweden..
    Ren, Weicheng
    Karolinska Inst, Karolinska Univ Hosp, Dept Lab Med, Clin Immunol, Huddinge, Sweden..
    de Miranda, Noel F. C. C.
    Leiden Univ, Dept Pathol, Med Ctr, Leiden, Netherlands..
    Lisboa, Susana
    Univ Porto, Portuguese Oncol Inst, Dept Genet, Rua Campo Alegre 823, P-4100 Oporto, Portugal.;Univ Porto, Abel Salazar Biomed Sci Inst, Rua Campo Alegre 823, P-4100 Oporto, Portugal..
    Fangazio, Marco
    Columbia Univ, Inst Canc Genet, New York, NY USA..
    Zhu, Shida
    BGI Shenzhen, Shenzhen, Peoples R China..
    Hou, Yong
    BGI Shenzhen, Shenzhen, Peoples R China..
    Wu, Kui
    BGI Shenzhen, Shenzhen, Peoples R China..
    Fang, Wenfeng
    Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol South China, Guangzhou 510275, Guangdong, Peoples R China.;Sun Yat Sen Univ, Ctr Canc, Dept Med Oncol, Guangzhou 510275, Guangdong, Peoples R China..
    Wang, Xianhuo
    Tianjin Med Univ Canc Inst & Hosp, Dept Lymphoma, Natl Clin Res Ctr Canc, Key Lab Canc Prevent & Therapy, Tianjin, Peoples R China..
    Meng, Bin
    Tianjin Med Univ Canc Inst & Hosp, Dept Lymphoma, Natl Clin Res Ctr Canc, Key Lab Canc Prevent & Therapy, Tianjin, Peoples R China..
    Zhang, Li
    Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol South China, Guangzhou 510275, Guangdong, Peoples R China.;Sun Yat Sen Univ, Ctr Canc, Dept Med Oncol, Guangzhou 510275, Guangdong, Peoples R China..
    Zeng, Yixin
    Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol South China, Guangzhou 510275, Guangdong, Peoples R China.;Sun Yat Sen Univ, Ctr Canc, Dept Med Oncol, Guangzhou 510275, Guangdong, Peoples R China..
    Bhagat, Govind
    Columbia Univ, Dept Pathol & Cell Biol, New York, NY USA..
    Nordenskjold, Magnus
    Karolinska Inst, Dept Mol Med & Surg, Solna, Sweden.;Karolinska Univ Hosp, Solna, Sweden..
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Dalla-Favera, Riccardo
    Columbia Univ, Inst Canc Genet, New York, NY USA..
    Zhang, Huilai
    Tianjin Med Univ Canc Inst & Hosp, Dept Lymphoma, Natl Clin Res Ctr Canc, Key Lab Canc Prevent & Therapy, Tianjin, Peoples R China..
    Teixeira, Manuel R.
    Univ Porto, Portuguese Oncol Inst, Dept Genet, Rua Campo Alegre 823, P-4100 Oporto, Portugal.;Univ Porto, Abel Salazar Biomed Sci Inst, Rua Campo Alegre 823, P-4100 Oporto, Portugal..
    Pasqualucci, Laura
    Columbia Univ, Inst Canc Genet, New York, NY USA..
    Peng, Roujun
    Sun Yat Sen Univ, Ctr Canc, State Key Lab Oncol South China, Guangzhou 510275, Guangdong, Peoples R China.;Sun Yat Sen Univ, Ctr Canc, Dept Med Oncol, Guangzhou 510275, Guangdong, Peoples R China..
    Pan-Hammarstrom, Qiang
    Karolinska Inst, Karolinska Univ Hosp, Dept Lab Med, Clin Immunol, Huddinge, Sweden..
    Genetic basis of PD-L1 overexpression in diffuse large B-cell lymphomas2016Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 127, nr 24, s. 3026-3034Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Diffuse large B-cell lymphoma (DLBCL) is one of the most common and aggressive types of B-cell lymphoma. Deregulation of proto-oncogene expression after a translocation, most notably to the immunoglobulin heavy-chain locus (IGH), is one of the hallmarks of DLBCL. Using whole-genome sequencing analysis, we have identified the PD-L1/PD-L2 locus as a recurrent translocation partner for IGH in DLBCL. PIM1 and TP63 were also identified as novel translocation partners for PD-L1/PD-L2. Fluorescence in situ hybridization was furthermore used to rapidly screen an expanded DLBCL cohort. Collectively, a subset of samples was found to be affected by gains (12%), amplifications (3%), and translocations (4%) of the PD-L1/PD-L2 locus. RNA sequencing data coupled with immunohistochemistry revealed that these cytogenetic alterations correlated with increased expression of PD-L1 but not of PD-L2. Moreover, cytogenetic alterations affecting the PD-L1/PD-L2 locus were more frequently observed in the non-germinal center B cell-like (non-GCB) subtype of DLBCL. These findings demonstrate the genetic basis of PD-L1 overexpression in DLBCL and suggest that treatments targeting the PD-1-PD-L1/PD-L2 axis might benefit DLBCL patients, especially those belonging to the more aggressive non-GCB subtype.

  • 184.
    Gerds, Aaron T.
    et al.
    Cleveland Clin, Taussig Canc Inst, Hematol & Med Oncol, Cleveland, OH 44106 USA..
    Ahn, Kwang Woo
    Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA.;Med Coll Wisconsin, Inst Hlth & Soc, Div Biostat, Milwaukee, WI 53226 USA..
    Hu, Zhen-Huan
    Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA..
    Abdel-Azim, Hisham
    Univ Southern Calif, Keck Sch Med, Childrens Hosp Angeles, Div Hematol Oncol & Blood & Marrow Transplantat, Los Angeles, CA 90033 USA..
    Akpek, Gorgun
    Rush Univ, Med Ctr, Dept Internal Med, Stem Cell Transplantat & Cell Therapy, Chicago, IL 60612 USA..
    Aljurf, Mahmoud
    King Faisal Specialist Hosp & Res Ctr, Dept Oncol, Riyadh, Saudi Arabia..
    Ballen, Karen K.
    Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA..
    Beitinjaneh, Amer
    Univ Miami, Div Hematol & Oncol, Miami, FL USA..
    Bacher, Ulrike
    Inselspital Bern, Dept Hematol, Bern, Switzerland.;Univ Canc Ctr Hamburg, Interdisciplinary Clin Stem Cell Transplantat, Hamburg, Germany..
    Cahn, Jean-Yves
    Univ Hosp, Dept Hematol, Grenoble, France..
    Chhabra, Saurabh
    Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA..
    Cutler, Corey
    Dana Farber Canc Inst, Ctr Hematol Oncol, Boston, MA 02115 USA..
    Daly, Andrew
    Tom Baker Canc Clin, Calgary, AB, Canada..
    DeFilipp, Zachariah
    Massachusetts Gen Hosp, Dept Hematol Oncol, Boston, MA 02114 USA..
    Gale, Robert Peter
    Imperial Coll London, Dept Med, Div Expt Med, Hematol Res Ctr, London, England..
    Gergis, Usama
    New York Presbyterian Hosp, Weill Cornell Med Ctr, Dept Med Oncol, Hematolg Malignancies & Bone Marrow Transplant, New York, NY USA..
    Grunwald, Michael R.
    Levine Canc Inst, Charlotte, NC USA..
    Hale, Gregory A.
    Johns Hopkins All Childrens Hosp, Dept Hematol Oncol, St Petersburg, FL USA..
    Hamilton, Betty Ky
    Cleveland Clin, Taussig Canc Inst, Blood & Marrow Transplant Program, Cleveland, OH 44106 USA..
    Jagasia, Madan
    Vanderbilt Univ, Med Ctr, Div Hematol Oncol, 221 Kirkland Hall, Nashville, TN 37235 USA..
    Kamble, Rammurti T.
    Baylor Coll Med, Ctr Cell & Gene Therapy, Div Hematol & Oncol, Houston, TX 77030 USA..
    Kindwall-Keller, Tamila
    Univ Virginia Hlth Syst, Div Hematol Oncol, Charlottesville, VA USA..
    Nishihori, Taiga
    H Lee Moffitt Canc Ctr & Res Inst, Dept Blood & Marrow Transplantat, Tampa, FL USA..
    Olsson, Richard F.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Karolinska Inst, Dept Lab Med, Div Therapeut Immunol, Stockholm, Sweden..
    Ramanathan, Muthalagu
    UMass Mem Med Ctr, Dept Med, Div Hematol & Oncol, Worcester, MA USA..
    Saad, Ayman A.
    Univ Alabama Birmingham, Dept Med, Div Hematol Oncol, Birmingham, AL 35294 USA..
    Solh, Melhem
    Northside Hosp, Blood & Marrow Transplant Grp Georgia, Atlanta, GA USA..
    Ustun, Celalettin
    Univ Minnesota, Med Ctr, Dept Med, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA..
    Valcarcel, David
    Hosp Valle De Hebron, Dept Hematol, Barcelona, Spain..
    Warlick, Erica
    Univ Minnesota, Med Ctr, Dept Med, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA..
    Wirk, Baldeep M.
    Seattle Canc Care Alliance, Div Bone Marrow Transplant, Seattle, WA USA..
    Kalaycio, Matt
    Cleveland Clin, Taussig Canc Inst, Hematol & Med Oncol, Cleveland, OH 44106 USA..
    Alyea, Edwin
    Dana Farber Canc Inst, Ctr Hematol Oncol, Boston, MA 02115 USA..
    Popat, Uday
    MD Anderson Canc Ctr, Houston, TX USA..
    Sobecks, Ronald
    Cleveland Clin, Taussig Canc Inst, Hematol & Med Oncol, Cleveland, OH 44106 USA..
    Saber, Wael
    Med Coll Wisconsin, Dept Med, Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI 53226 USA..
    Outcomes after Umbilical Cord Blood Transplantation for Myelodysplastic Syndromes2017Inngår i: Biology of blood and marrow transplantation, ISSN 1083-8791, E-ISSN 1523-6536, Vol. 23, nr 6, s. 971-979Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    For patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplantation, umbilical cord blood transplantation (UCBT) has become an acceptable alternative donor source in the absence of a matched sibling or unrelated donor. To date, however, there have been few published series dedicated solely to describing the outcomes of adult patients with myelodysplastic syndrome (MDS) who have undergone UCBT. Between 2004 and 2013, 176 adults with MDS underwent UCBT as reported to the Center for International Blood and Marrow Transplant Research. Median age at the time of transplantation was 56 years (range, 18-73 years). The study group included 10% with very low, 23% with low, 19% with intermediate, 19% with high, and 13% with very high-risk Revised International Prognostic Scoring System (IPSS-R) scores. The 100-day probability of grade II-IV acute graft-versus-host disease (GVHD) was 38%, and the 3-year probability of chronic GVHD was 28%. The probabilities of relapse and transplantation-related mortality (TRM) at 3 years were 32% and 40%, respectively, leading to a 3-year disease-free survival (DFS) of 28% and an overall survival (OS) of 31%. In multivariate analysis, increasing IPSS-R score at the time of HCT was associated with inferior TRM (P = .0056), DFS (P = .018), and OS (P = .0082), but not with GVHD or relapse. The presence of pretransplantation comorbidities was associated with TRM (P = .001), DFS (P = .02), and OS (P = .001). Reduced intensity conditioning was associated with increased risk of relapse (relative risk, 3.95; 95% confidence interval, 1.78-8.75; P < .001), and although a higher proportion of myeloablative UCBTs were performed in patients with high-risk disease, the effect of conditioning regimen intensity was the same regardless of IPSS-R score. For some individuals who lack a matched sibling or unrelated donor, UCBT can result in long-term DFS; however, the success of UCBT in this population is hampered by a high rate of TRM. (C) 2017 American Society for Blood and Marrow Transplantation.

  • 185. Geyer, H.
    et al.
    Emanuel, R.
    Dueck, A.
    Kiladjian, J. J.
    Xiao, Z.
    Slot, S.
    Zweegman, S.
    Sackman, F.
    Kerguelen Fuentes, A.
    Hernandez-Maraver, D.
    Dohner, K.
    Harrison, C.
    Radia, D.
    Muxi, P.
    Besses, C.
    Cervantes, F.
    Johansson, P.
    Andreasson, B.
    Rambaldi, A.
    Barbui, T.
    Vannucchi, A.
    Passamonti, F.
    Samuelsson, J.
    Birgegård, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Bonatz, K.
    Reiter, A.
    Boyer, F.
    Etienne, G.
    Ianotto, J. C.
    Ranta, D.
    Roy, L.
    Cahn, J. Y.
    Maldonado, N.
    Barosi, G.
    Ferrari, M.
    Cannon, K.
    te Boekhorst, P. A.
    Klauke, K.
    Schouten, H.
    Pahl, H.
    Griesshammer, M.
    Stegelmann, F.
    Lehmann, T.
    Xu, Z.
    Zhang, Y.
    Sun, X.
    Xu, J.
    Zhang, P.
    Mesa, R.
    Gender Differences and MPN Symptom Burden: An Analysis by the MPN Quality of Life International Study Group (MPN-QOL ISG)2014Inngår i: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, s. 396-397Artikkel i tidsskrift (Annet vitenskapelig)
  • 186.
    Geyer, H.
    et al.
    Mayo Clin, Phoenix, AZ USA..
    Kosiorek, H.
    Mayo Clin, Phoenix, AZ USA..
    Dueck, A.
    Mayo Clin, Phoenix, AZ USA..
    Slot, S.
    Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Zweegman, S.
    Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Kiladjian, J. J.
    Hosp St Louis, Paris, France..
    Boekhorst, P.
    Erasmus MC, Rotterdam, Netherlands..
    Schouten, H.
    Maastricht Univ, Med Ctr, Maastricht, Netherlands..
    Sackmann, F.
    Fundaleu, Buenos Aires, DF, Argentina..
    Fuentes, A.
    Univ Hosp La Paz, Madrid, Spain..
    Hernandez-Maraver, D.
    Univ Hosp La Paz, Madrid, Spain..
    Pahl, H.
    Univ Hosp Freiburg, Freiburg, Germany..
    Stegelmann, F.
    Univ Hosp Ulm, Ulm, Germany..
    Doehner, K.
    Univ Hosp Ulm, Ulm, Germany..
    Bonatz, K.
    Med Klin, Mannheim, Germany..
    Reiter, A.
    Med Klin, Mannheim, Germany..
    Boyer, F.
    CHU Angers, Angers, France..
    Etienne, G.
    CHU Angers, Angers, France..
    Ianotto, J. C.
    Univ Hosp, Brest, France..
    Ranta, D.
    Univ Hosp, Nancy, France..
    Roy, L.
    Ctr Hosp Univ, Poitiers, France..
    Cahn, J. Y.
    CHU Grenoble, Grenoble, France..
    Harrison, C.
    Guys & St Thomas NHS Fdn Trust, London, England..
    Radia, D.
    Guys & St Thomas NHS Fdn Trust, London, England..
    Muxi, P.
    Hosp Britanico, Montevideo, Uruguay..
    Maldonado, N.
    Univ Puerto Rico, Sch Med, San Juan, PR 00936 USA..
    Besses, C.
    Hosp Mar, Barcelona, Spain..
    Cervantes, F.
    Univ Barcelona, Barcelona, Spain..
    Johansson, P.
    NU Hosp Org, Uddevalla, Sweden..
    Barosi, G.
    IRCCS Policlin S Matteo Fdn, Pavia, Italy..
    Passamonti, F.
    Fdn IRCCS Policlin San Matteo, Pavia, Italy..
    Andreasson, B.
    NU Hosp Org, Uddevalla, Sweden..
    Samuelsson, J.
    Stockholm South Hosp, Stockholm, Sweden..
    Birgegård, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Sun, X.
    Chinese Acad Med Sci, Tianjin, Peoples R China.;Peking Union Med Coll, Tianjin, Peoples R China..
    Xu, J.
    Chinese Acad Med Sci, Tianjin, Peoples R China.;Peking Union Med Coll, Tianjin, Peoples R China..
    Zhang, P.
    Chinese Acad Med Sci, Tianjin, Peoples R China.;Peking Union Med Coll, Tianjin, Peoples R China..
    Xu, Z.
    Chinese Acad Med Sci, Tianjin, Peoples R China.;Peking Union Med Coll, Tianjin, Peoples R China..
    Barbui, T.
    Osped Riuniti Bergamo, Bergamo, Italy.;Osped Riuniti Bergamo, Bergamo, Italy..
    Senyak, Z.
    MPN Forum, Asheville, NC USA..
    Grieshammer, M.
    Johannes Wesling Klinikum, Minden, Germany..
    Rambaldi, A.
    Osped Riuniti Bergamo, Bergamo, Italy..
    Ferrari, M.
    Osped Riuniti Bergamo, Bergamo, Italy..
    Lehmann, T.
    Univ Basel Hosp, Basel, Switzerland..
    Scherber, R.
    Mayo Clin, Phoenix, AZ USA..
    Mesa, R.
    Mayo Clin, Phoenix, AZ USA..
    Development Of An Mf Patient Reported Outcome (Pro) Tool For Fda Qualification: Comprehensive Literature Search And Physician Cognitive Debriefing Results2016Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, s. 564-564Artikkel i tidsskrift (Annet vitenskapelig)
  • 187.
    Geyer, H.
    et al.
    Mayo Clin, Scottsdale, AZ USA..
    Kosiorek, H.
    Mayo Clin, Scottsdale, AZ USA..
    Scherber, R.
    Mayo Clin, Scottsdale, AZ USA..
    Dueck, A.
    Mayo Clin, Scottsdale, AZ USA..
    Jean-Jacques, K.
    Hosp St Louis, Paris, France..
    Xiao, Z.
    Chinese Acad Med Sci, Tianjin, Peoples R China.;Peking Union Med Coll, Tianjin, Peoples R China..
    Zweegman, S.
    Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Sackman, F.
    Fundaleu, Buenos Aires, DF, Argentina..
    Hernandez-Maraver, D.
    Univ Hosp La Paz, Madrid, Spain..
    Dohner, K.
    Univ Hosp Ulm, Ulm, Germany..
    Harrison, C.
    Guys & St Tomas NHS Fdn Trust, London, England..
    Radia, D.
    Guys & St Tomas NHS Fdn Trust, London, England..
    Muxi, P.
    Hosp Britanico, Montevideo, Uruguay..
    Besses, C.
    Hosp Del Mar, Barcelona, Spain..
    Cervantes, F.
    Univ Barcelona, Barcelona, Spain..
    Johansson, P.
    NU Hosp Org, Uddevalla, Sweden..
    Andreasson, B.
    NU Hosp Org, Uddevalla, Sweden..
    Rambaldi, A.
    Azienda Ospedal, Bergamo, Italy..
    Barbui, T.
    Azienda Ospedal, Bergamo, Italy..
    Vannucchi, A.
    Osped Circolo Varese, Varese, Italy..
    Passamonti, F.
    Fdn IRCCS Policlin San Matteo, Pavia, Italy..
    Samuelsson, J.
    Stockholm South Hosp, Stockholm, Sweden..
    Birgegård, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Bonatz, K.
    Med Klin, Mannheim, Germany..
    Reiter, A.
    Med Klin, Mannheim, Germany..
    Boyer, F.
    Ctr Hosp Univ, Angers, France..
    Etienne, G.
    Inst Bergonie, Bordeaux, France..
    Ianotto, J. -C
    Ranta, D.
    Univ Hosp, Nancy, France..
    Roy, L.
    Ctr Hosp Univ, Poitiers, France..
    Cahn, J. -Y
    Maldonado, N.
    Univ Puerto Rico, Sch Med, San Juan, PR 00936 USA..
    Barosi, G.
    IRCCS Policlin S Matteo Fdn, Pavia, Italy..
    Ferrari, M.
    Osped Riuniti Bergamo, I-24100 Bergamo, Italy..
    Cannon, K.
    Mayo Clin, Scottsdale, AZ USA..
    te Boekhorst, P. A. W.
    Erasmus MC, Rotterdam, Netherlands..
    Klauke, K.
    Leiden Univ, Med Ctr, Leiden, Netherlands..
    Schouten, H.
    Maastricht Univ, Med Ctr, Maastricht, Netherlands..
    Pahl, H.
    Univ Hosp Freiburg, Freiburg, Germany..
    Griesshammer, M.
    Johannes Wesling Klinikum, Minden, Germany..
    Stegelmann, F.
    Univ Hosp Ulm, Ulm, Germany..
    Lehmann, T.
    Univ Basel Hosp, CH-4031 Basel, Switzerland..
    Xu, Z.
    Chinese Acad Med Sci, Inst Hematol, Tianjin, Peoples R China.;Blood Dis Hosp, Tianjin, Peoples R China..
    Zhang, Y.
    Chinese Acad Med Sci, Inst Hematol, Tianjin, Peoples R China.;Blood Dis Hosp, Tianjin, Peoples R China..
    Sun, X.
    Chinese Acad Med Sci, Inst Hematol, Tianjin, Peoples R China.;Blood Dis Hosp, Tianjin, Peoples R China..
    Xu, J.
    Chinese Acad Med Sci, Inst Hematol, Tianjin, Peoples R China.;Blood Dis Hosp, Tianjin, Peoples R China..
    Zhang, P.
    Chinese Acad Med Sci, Inst Hematol, Tianjin, Peoples R China.;Blood Dis Hosp, Tianjin, Peoples R China..
    Mesa, R.
    Mayo Clin, Scottsdale, AZ USA..
    PRIMARY MYELOFIBROSIS, POST-ET AND POST-PV MYELOFIBROSIS HAVE DISTINCT CLINICAL PROFILES AND SYMPTOMATIC BURDENS: AN ANALYSIS BY THE MPN QUALITY OF LIFE INTERNATIONAL STUDY GROUP (MPN-QOL ISG)2015Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, s. 261-262Artikkel i tidsskrift (Annet vitenskapelig)
  • 188.
    Geyer, H.
    et al.
    Mayo Clin, Phoenix, AZ USA..
    Scherber, R.
    OHSU, Portland, OR USA..
    Kosiorek, H.
    Mayo Clin, Phoenix, AZ USA..
    Dueck, A.
    Mayo Clin, Phoenix, AZ USA..
    Kiladjian, J. J.
    Hosp St Louis, Paris, France..
    Slot, S.
    Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Zweegman, S.
    Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands..
    Boekhorst, P.
    Erasmus Med Cener, Rotterdam, Netherlands..
    Schouten, H.
    Maastricht Univ, Med Ctr, Maastricht, Netherlands..
    Sackmann, F.
    Fundaleu, Buenos Aires, DF, Argentina..
    Fuentes, A.
    Univ Hosp La Paz, Madrid, Spain..
    Hernandez-Maraver, D.
    Univ Hosp La Paz, Madrid, Spain..
    Pahl, H.
    Univ Hosp Freiburg, Freiburg, Germany..
    Stegelmann, F.
    Univ Hosp Ulm, Ulm, Germany..
    Doehner, K.
    Univ Hosp Ulm, Ulm, Germany..
    Bonatz, K.
    Med Klin, Mannheim, Germany..
    Reiter, A.
    Med Klin, Mannheim, Germany..
    Boyer, F.
    Ctr Hosp Univ, Angers, France..
    Etienne, G.
    Ctr Hosp Univ, Angers, France..
    Ianotto, J. C.
    Hosp Univ, Brest, France..
    Ranta, D.
    Hosp Univ, Nancy, France..
    Roy, L.
    Ctr Hosp Univ, Poitiers, France..
    Cahn, J. Y.
    Ctr Hosp Univ, Grenoble, France..
    Harrison, C.
    Guys & St Thomas NHS Fdn Trust, London, England..
    Radia, D.
    Guys & St Thomas NHS Fdn Trust, London, England..
    Muxi, P.
    Hosp Britanico, Montevideo, Uruguay..
    Maldonado, N.
    Univ Puerto Rico, Sch Med, San Juan, PR 00936 USA..
    Besses, C.
    Hosp del Mar, Barcelona, Spain..
    Cervantes, F.
    Univ Barcelona, Barcelona, Spain..
    Johansson, P.
    NU Hosp Org, Uddevalla, Sweden..
    Barosi, G.
    IRCCS Policlin S Matteo Fdn, Pavia, Italy..
    Vannucchi, A.
    Osped Circolo Varese, Varese, Italy..
    Passamonti, F.
    Fdn IRCCS Policlin San Matteo, Pavia, Italy..
    Andreasson, B.
    NU Hosp Org, Uddavalla, Sweden..
    Samuelsson, J.
    Stockholm South Hosp, Stockholm, Sweden..
    Birgegård, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Sun, X.
    Chinese Acad Med Sci, Tianjin, Peoples R China.;Peking Union Med Coll, Tianjin, Peoples R China..
    Xu, J.
    Chinese Acad Med Sci, Tianjin, Peoples R China.;Peking Union Med Coll, Tianjin, Peoples R China..
    Zhang, P.
    Chinese Acad Med Sci, Tianjin, Peoples R China.;Peking Union Med Coll, Tianjin, Peoples R China..
    Xu, Z.
    Chinese Acad Med Sci, Tianjin, Peoples R China.;Peking Union Med Coll, Tianjin, Peoples R China..
    Barbui, T.
    Osped Riuniti Bergamo, Bergamo, Italy.;Osped Riuniti Bergamo, Bergamo, Italy..
    Senyak, Z.
    MPN Forum, Asheville, NC USA..
    Grieshammer, M.
    Johannes Wesling Klinikum, Minden, Germany..
    Rambaldi, A.
    Osped Riuniti Bergamo, Bergamo, Italy..
    Ferrari, M.
    Osped Riuniti Bergamo, Bergamo, Italy..
    Lehmann, T.
    Univ Basel Hosp, Basel, Switzerland..
    Mesa, R.
    Mayo Clin, Phoenix, AZ USA..
    Impact Of Splenomegaly On Mpn Symptoms And Association With Clinical Features: An Analysis By The Mpn Quality Of Life International Study Group2016Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, s. 555-555Artikkel i tidsskrift (Annet vitenskapelig)
  • 189.
    Geyer, Holly L.
    et al.
    Mayo Clin, Dept Internal Med, Scottsdale, AZ 85259 USA..
    Kosiorek, Heidi
    Mayo Clin, Sect Biostat, Scottsdale, AZ USA..
    Dueck, Amylou C.
    Mayo Clin, Sect Biostat, Scottsdale, AZ USA..
    Scherber, Robyn
    Oregon Hlth & Sci Univ, Portland, OR USA..
    Slot, Stefanie
    Vrije Univ Amsterdam Med Ctr, Dept Hematol, Amsterdam, Netherlands..
    Zweegman, Sonja
    Vrije Univ Amsterdam Med Ctr, Dept Hematol, Amsterdam, Netherlands..
    te Boekhorst, Peter A. W.
    Erasmus MC, Dept Hematol, Rotterdam, Netherlands..
    Senyak, Zhenya
    MPN Forum, Asheville, NC USA..
    Schouten, Harry C.
    MUMC, Dept Hematol, Maastricht, Netherlands..
    Sackmann, Federico
    Fundaleu, Buenos Aires, DF, Argentina..
    Kerguelen Fuentes, Ana
    Univ Hosp La Paz, Dept Haematol, Madrid, Spain..
    Hernandez-Maraver, Dolores
    Univ Hosp La Paz, Dept Haematol, Madrid, Spain..
    Pahl, Heike L.
    Univ Hosp Freiburg, Dept Mol Hematol, Freiburg, Germany..
    Griesshammer, Martin
    Johannes Wesling Klinikum, Minden, Germany..
    Stegelmann, Frank
    Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany..
    Doehner, Konstanze
    Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany..
    Lehmann, Thomas
    Univ Hosp, Dept Hematol, Basel, Switzerland..
    Bonatz, Karin
    Univ Med, Med Klin, Mannheim, Germany..
    Reiter, Andreas
    Univ Med, Med Klin, Mannheim, Germany..
    Boyer, Francoise
    Ctr Hosp Univ, Angers, France..
    Etienne, Gabriel
    Inst Bergonie, Bordeaux, France..
    Ianotto, Jean-Christophe
    Ctr Hosp Univ, Brest, France..
    Ranta, Dana
    Hosp Univ, Nancy, France..
    Roy, Lydia
    Ctr Hosp Univ, Poitiers, France..
    Cahn, Jean-Yves
    Ctr Hosp Univ, Grenoble, France..
    Harrison, Claire N.
    Guys & St Thomas NHS Fdn Trust, Dept Haematol, London, England..
    Radia, Deepti
    Guys & St Thomas NHS Fdn Trust, Dept Haematol, London, England..
    Muxi, Pablo
    Hosp Britan, Unidadde Hematol, Montevideo, Uruguay..
    Maldonado, Norman
    Univ Puerto Rico, Sch Med, San Juan, PR 00936 USA..
    Besses, Carlos
    Hosp del Mar, Dept Hematol, Barcelona, Spain..
    Cervantes, Francisco
    Univ Barcelona, Hosp Clin, Dept Hematol, IDIBAPS, Barcelona, Spain..
    Johansson, Peter L.
    NU Hosp Org, Internal Med, Uddevalla, Sweden..
    Barbui, Tiziano
    Hosp Papa Giovanni XXIII, Res Fdn FROM, Bergamo, Italy..
    Barosi, Giovanni
    IRCCS Policlin S Matteo Fdn, Lab Clin Epidemiol, Pavia, Italy..
    Vannucchi, Alessandro M.
    Univ Florence, Ctr Res & Innovat Myeloproliferat Neoplasms, Florence, Italy..
    Paoli, Chiara
    Univ Florence, Ctr Res & Innovat Myeloproliferat Neoplasms, Florence, Italy..
    Passamonti, Francesco
    Univ Insubria, Dipartimento Med Clin & Sperimentale, Ematol, Varese, Italy..
    Andreasson, Bjorn
    NU Hosp Org, Internal Med, Uddevalla, Sweden..
    Ferrari, Maria L.
    Osped Riuniti Bergamo, Biol Sci, Bergamo, Italy..
    Rambaldi, Alessandro
    Hosp Papa Giovanni XXIII, Res Fdn FROM, Bergamo, Italy..
    Samuelsson, Jan
    Stockholm South Hosp, Dept Internal Med, Stockholm, Sweden..
    Cannon, Keith
    Mayo Clin, Dept Internal Med, Scottsdale, AZ 85259 USA..
    Birgegård, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Xiao, Zhijian
    Chinese Acad Med Sci, Inst Hematol, MDS & MPN Ctr, Tianjin, Peoples R China.;Chinese Acad Med Sci, Blood Dis Hosp, Tianjin, Peoples R China.;Peking Union Med Coll, Tianjin, Peoples R China..
    Xu, Zefeng
    Chinese Acad Med Sci, Inst Hematol, MDS & MPN Ctr, Tianjin, Peoples R China.;Chinese Acad Med Sci, Blood Dis Hosp, Tianjin, Peoples R China.;Peking Union Med Coll, Tianjin, Peoples R China..
    Zhang, Yue
    Chinese Acad Med Sci, Inst Hematol, MDS & MPN Ctr, Tianjin, Peoples R China.;Chinese Acad Med Sci, Blood Dis Hosp, Tianjin, Peoples R China.;Peking Union Med Coll, Tianjin, Peoples R China..
    Sun, Xiujuan
    Chinese Acad Med Sci, Inst Hematol, MDS & MPN Ctr, Tianjin, Peoples R China.;Chinese Acad Med Sci, Blood Dis Hosp, Tianjin, Peoples R China.;Peking Union Med Coll, Tianjin, Peoples R China..
    Xu, Junqing
    Chinese Acad Med Sci, Inst Hematol, MDS & MPN Ctr, Tianjin, Peoples R China.;Chinese Acad Med Sci, Blood Dis Hosp, Tianjin, Peoples R China.;Peking Union Med Coll, Tianjin, Peoples R China..
    Kiladjian, Jean-Jacques
    Hosp St Louis, Clin Invest Ctr, Paris, France..
    Zhang, Peihong
    Chinese Acad Med Sci, Blood Dis Hosp, Tianjin, Peoples R China.;Peking Union Med Coll, Tianjin, Peoples R China.;Chinese Acad Med Sci, Inst Hematol, Dept Pathol, Tianjin, Peoples R China..
    Gale, Robert Peter
    Imperial Coll, London, England..
    Mesa, Ruben A.
    Mayo Clin, Dept Hematol & Oncol, Scottsdale, AZ 85259 USA..
    Associations between gender, disease features and symptom burden in patients with myeloproliferative neoplasms: an analysis by the MPN QOL International Working Group2017Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 102, nr 1, s. 85-93Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia and myelofibrosis, are distinguished by their debilitating symptom profiles, life-threatening complications and profound impact on quality of life. The role gender plays in the symptomatology of myeloproliferative neoplasms remains under-investigated. In this study we evaluated how gender relates to patients' characteristics, disease complications and overall symptom expression. A total of 2,006 patients (polycythemia vera=711, essential thrombocythemia=830, myelofibrosis=460, unknown=5) were prospectively evaluated, with patients completing the Myeloproliferative Neoplasm-Symptom Assessment Form and Brief Fatigue Inventory Patient Reported Outcome tools. Information on the individual patients' characteristics, disease complications and laboratory data was collected. Consistent with known literature, most female patients were more likely to have essential thrombocythemia (48.6% versus 33.0%; P<0.001) and most male patients were more likely to have polycythemia vera (41.8% versus 30.3%; P<0.001). The rate of thrombocytopenia was higher among males than females (13.9% versus 8.2%; P<0.001) and males also had greater red-blood cell transfusion requirements (7.3% versus 4.9%; P=0.02) with shorter mean disease duration (6.4 versus 7.2 years, P=0.03). Despite there being no statistical differences in risk scores, receipt of most therapies or prior complications (hemorrhage, thrombosis), females had more severe and more frequent symptoms for most individual symptoms, along with overall total symptom score (22.8 versus 20.3; P<0.001). Females had particularly high scores for abdominal-related symptoms (abdominal pain/discomfort) and microvascular symptoms (headache, fatigue, insomnia, concentration difficulties, dizziness; all P<0.01). Despite complaining of more severe symptom burden, females had similar quality of life scores to those of males. The results of this study suggest that gender contributes to the heterogeneity of myeloproliferative neoplasms by influencing phenotypic profiles and symptom expression.

  • 190. Geyer, Holly L.
    et al.
    Scherber, Robyn M.
    Dueck, Amylou C.
    Kiladjian, Jean-Jacques
    Xiao, Zhijian
    Slot, Stefanie
    Zweegman, Sonja
    Sackmann, Federico
    Kerguelen Fuentes, Ana
    Hernandez-Maraver, Dolores
    Doehner, Konstanze
    Harrison, Claire N.
    Radia, Deepti
    Muxi, Pablo
    Besses, Carlos
    Cervantes, Francisco
    Johansson, Peter L.
    Andreasson, Bjorn
    Rambaldi, Alessandro
    Barbui, Tiziano
    Vannucchi, Alessandro M.
    Passamonti, Francesco
    Samuelsson, Jan
    Birgegård, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Mesa, Ruben A.
    Distinct clustering of symptomatic burden among myeloproliferative neoplasm patients: retrospective assessment in 1470 patients2014Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 123, nr 24, s. 3803-3810Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Symptom burden in myeloproliferative neoplasms (MPNs) is heterogeneous even among patients within the same MPN diagnosis. Using cluster analysis from prospectively gathered symptom burden data in 1470 international patients with essential thrombocythemia (ET), polycythemia vera (PV), or myelofibrosis (MF), we assessed for the presence of clusters and relationship to disease features and prognosis. In MF (4 clusters identified), clusters significantly differed by Dynamic International Prognostic Scoring System (DIPSS) risk (P < .001), leukopenia (P = .009), thrombocytopenia (P < .001), and spleen size (P = .02). Although an association existed between clusters and DIPSS risk, high symptom burden was noted in some low and intermediate-1-risk MF patients. In PV (5 clusters identified), total symptom score increased across clusters (P < .001), but clusters did not significantly differ by PV risk or the risk assessment variable of age. Among ET patients (5 clusters identified), clusters differed by gender (P = .04), anemia (P = .01), and prior hemorrhage (P = .047). Total symptom score increased across clusters (P < .001), but clusters did not significantly differ by International Prognostic Score for ET risk including the risk assessment variables. Significant symptom heterogeneity exists within each MPN subtype, sometimes independent of disease features or prognosis.

  • 191. Geyer, Holly Lynn
    et al.
    Scherber, Robyn M.
    Dueck, Amylou Constance
    Kiladjian, Jean-Jacques
    Xiao, Zhijian
    Slot, Stephanie
    Zweegman, Sonja
    Kerguelen Fuentes, Ana
    Hernandez-Maraver, Dolores
    Dohner, Konstanze
    Harrison, Claire N.
    Radia, Deepti H.
    Muxi, Pablo J.
    Sackman, Federico
    Besses, Carlos
    Cervantes, Francisco
    Johansson, Peter L.
    Andreasson, Bjorn
    Rambaldi, Alessandro
    Barbui, Tiziano
    Vannucchi, Alessandro M.
    Passamonti, Francesco
    Samuelsson, Jan
    Birgegård, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Bonatz, Karin
    Reiter, Andreas
    Boyer, Francoise
    Etienne, Gabriel
    Ianotto, Jean-Christophe
    Ranta, Dana
    Roy, Lydia
    Cahn, Jean-Yves
    Maldonado, Norman I.
    Barosi, Giovanni
    Ferrari, Maria
    Cannon, Keith
    te Boekhorst, Peter
    Schouten, Harry C.
    Pahl, Heike L.
    Griesshammer, Martin
    Stegelmann, Frank
    Lehmann, Thomas
    Xu, Zefeng
    Zhang, Yue
    Sun, Xiujuan
    Xu, Junqing
    Zhang, Peihong
    Mesa, Ruben
    Symptom Severity and Clinical Variables of Polycythemia Vera Patients with Splenomegaly, Phlebotomy Requirements and/or Hydroxyurea Use: a Retrospective Evaluation of 1334 Patients2014Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, nr 21Artikkel i tidsskrift (Annet vitenskapelig)
  • 192. Ghia, Paolo
    et al.
    Gounari, Maria
    Minici, Claudia
    Duehren-von Minden, Marcus
    Schneider, Dunja
    Alkhatib, Alabbas
    Belhart, Rudolf
    Agathangelidis, Andreas
    Ntoufa, Stavroula
    Chiorazzi, Nicholas
    Jumaa, Hassan
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Degano, Massimo
    Crystallographic evidence of autologous recognition by a clonotypic B cell receptor in chronic lymphocytic leukemia2015Inngår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 56, nr S1, s. 110-111Artikkel i tidsskrift (Annet vitenskapelig)
  • 193.
    Giannuzzi, Diana
    et al.
    Univ Padua, Dept Comparat Biomed & Food Sci, Padua, Italy.
    Marconato, Laura
    Ctr Oncol Vet, Bologna, Italy.
    Cascione, Luciano
    USI, IOR, Bellinzona, Switzerland;SIB, Lausanne, Switzerland.
    Comazzi, Stefano
    Univ Milan, Dept Vet Med, Milan, Italy.
    Elgendy, Ramy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Pegolo, Sara
    Univ Padua, Dept Agron Food Nat Resources Anim & Environm, Padua, Italy.
    Cecchinato, Alessio
    Univ Padua, Dept Agron Food Nat Resources Anim & Environm, Padua, Italy.
    Bertoni, Francesco
    USI, IOR, Bellinzona, Switzerland.
    Aresu, Luca
    Univ Turin, Dept Vet Sci, Turin, Italy.
    Ferraresso, Serena
    Univ Padua, Dept Comparat Biomed & Food Sci, Padua, Italy.
    Mutational landscape of canine B-cell lymphoma profiled at single nucleotide resolution by RNA-seq2019Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, nr 4, artikkel-id e0215154Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The genomic landscape in human B-cell lymphoma has revealed several somatic mutations and potentially relevant germline alterations affecting therapy and prognosis. Also, mutations originally described as somatic aberrations have been shown to confer cancer predisposition when occurring in the germline. The relevance of mutations in canine B-cell lymphoma is scarcely known and gene expression profiling has shown similar molecular signatures among different B-cell histotypes, suggesting other biological mechanisms underlining differences. Here, we present a highly accurate approach to identify single nucleotide variants (SNVs) in RNA-seq data obtained from 62 completely staged canine B-cell lymphomas and 11 normal B-cells used as controls. A customized variant discovery pipeline was applied and SNVs were found in tumors and differentiated for histotype. A number of known and not previously identified SNVs were significantly associated to MAPK signaling pathway, negative regulation of apoptotic process and cell death, B-cell activation, NF-kB and JAK-STAT signaling. Interestingly, no significant genetic fingerprints were found separating diffuse large B-cell lymphoma from indolent lymphomas suggesting that differences of genetic landscape are not the pivotal causative factor of indolent behavior. We also detected several variants in expressed regions of canine B-cell lymphoma and identified SNVs having a direct impact on genes. Using this brand-new approach the consequence of a gene variant is directly associated to expression. Further investigations are in progress to deeply elucidate the mechanisms by which altered genes pathways may drive lymphomagenesis and a higher number of cases is also demanded to confirm this evidence.

  • 194.
    Giebel, Sebastian
    et al.
    Maria Sklodowska Curie Inst Canc Ctr, Gliwice Branch, Gliwice, Poland.
    Marks, David, I
    Univ Hosp Bristol Natl Hlth Serv Fdn Trust, Bristol, Avon, England.
    Boissel, Nicolas
    Hop St Louis, Paris, France.
    Baron, Frederic
    Univ Liege, CHU Sart Tilman, Liege, Belgium.
    Chiaretti, Sabina
    Sapienza Univ, Rome, Italy.
    Ciceri, Fabio
    Ist Sci San Raffaele, Milan, Italy.
    Cornelissen, Jan J.
    Erasmus MC, Univ Med Ctr, Canc Inst, Rotterdam, Netherlands.
    Doubek, Michael
    Univ Hosp, Brno, Czech Republic.
    Esteve, Jordi
    Hosp Clin Barcelona, IDIBAPS, Barcelona, Spain.
    Fielding, Adele
    Univ Coll London Hosp, North London Canc Network, London, England.
    Foa, Robin
    Sapienza Univ, Rome, Italy.
    Gorin, Norbert-Claude
    EBMT Acute Leukemia Working Party Off, Paris, France;Hosp St Antoine, Paris, France.
    Gokbuget, Nicola
    Maria Sklodowska Curie Inst Canc Ctr, Gliwice Branch, Gliwice, Poland;Hop St Louis, Paris, France.
    Hallböök, Helene
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Hoelzer, Dieter
    Goethe Univ, Univ Hosp, Frankfurt, Germany.
    Paravichnikova, Elena
    Russia Federat Minist Publ Hlth, FGBU Hematol Res Ctr, Moscow, Russia.
    Ribera, Josep-Maria
    ICO Hosp Germans Trias & Pujol, Jose Carreras Res Inst, Badalona, Spain.
    Savani, Bipin
    Vanderbilt Univ, Med Ctr, Nashville, TN USA.
    Rijneveld, Anita W.
    Erasmus MC, Univ Med Ctr, Canc Inst, Rotterdam, Netherlands.
    Schmid, Christoph
    Ludwig Maximilians Univ Munchen, Klinikum Augsburg, Munich, Germany.
    Wartiovaara-Kautto, Ulla
    Helsinki Univ Hosp, Helsinki, Finland.
    Mohty, Mohamad
    Univ Coll London Hosp, North London Canc Network, London, England;EBMT Acute Leukemia Working Party Off, Paris, France.
    Nagler, Arnon
    Univ Coll London Hosp, North London Canc Network, London, England;Cha Sheba Med Ctr, Tel Hashomer, Israel.
    Dombret, Herve
    Hop St Louis, Paris, France.
    Hematopoietic stem cell transplantation for adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in first remission: a position statement of the European Working Group for Adult Acute Lymphoblastic Leukemia (EWALL) and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT)2019Inngår i: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 54, nr 6, s. 798-809Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission is a standard of care for adult patients with Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) and high risk of relapse. However, the stratification systems vary among study groups. Inadequate response at the level of minimal residual disease is the most commonly accepted factor indicating the need for alloHSCT. In this consensus paper on behalf of the European Working Group for Adult Acute Lymphoblastic Leukemia and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we summarize available evidence and reflect current clinical practice in major European study groups regarding both indications for HSCT and particular aspects of the procedure including the choice of donor, source of stem cells and conditioning. Finally, we propose recommendations for daily clinical practice as well as for planning of prospective trials.

  • 195.
    Glimelius, Ingrid
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Eloranta, Sandra
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Ekberg, Sara
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Chang, Ellen T.
    Ctr Epidemiol & Computat Biol Hlth Sci Practice E, Menlo Pk, CA 92697 USA.;Stanford Univ, Sch Med, Dept Hlth Res & Policy, Div Epidemiol, Stanford, CA 94305 USA..
    Neovius, Martin
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Smedby, Karin E.
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Med, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden.;Karolinska Univ Hosp, Div Hematol, Stockholm, Sweden.;Karolinska Inst, Stockholm, Sweden..
    Increased healthcare use up to 10 years among relapse-free Hodgkin lymphoma survivors in the era of intensified chemotherapy and limited radiotherapy2017Inngår i: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 92, nr 3, s. 251-258Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    With today's excellent cure rates for Hodgkin lymphoma (HL), the number of long-term survivors is increasing. This study aims to provide a global assessment of late adverse effects for workingage HL survivors treated with contemporary protocols (combination chemotherapy and limited radiotherapy). From Swedish nationwide registers we identified 1017 HL survivors diagnosed in 2000-2009, aged 18-60 years (median 32) and surviving at least one year post-diagnosis, and 4031 age-,sex-, and calendar-year-matched population comparators. Incidence rate ratios (IRR) and 95% confidence intervals (95% CI) for outpatient visits and inpatient bed-days after the first year up to 14 years post-diagnosis (through 2013) were estimated across treatment subgroups, considering relapse-free time and using negative binomial regression. Scheduled outpatient visits for HL were excluded. The rate of outpatient visits was nearly double (IRR = 1.8, 95% CI: 1.6-2.0) that among comparators and higher rates persisted up to 10 years post-diagnosis. The rate of inpatient bed-days among relapse-free survivors was more than three-fold (IRR = 3.6, 95% CI: 2.74.7) that of comparators and the increase persisted up to four years post-diagnosis. Patients requiring 6-8 chemotherapy courses had higher rates of outpatient visits (IRR = 1.4, 95% CI: 1.11.7) and bed-days (IRR-4.7, 95% CI: 2.9-7.8) than patients treated with 2-4 courses+radiotherapy. Previously seldom reported reasons for the excess healthcare use included chest pain, keratitis, asthma, diabetes mellitus, and depression. Contemporary treatment, chemotherapy in particular, was associated with excess healthcare use among HL survivors during the first decade postdiagnosis. The reasons for healthcare visits reflected a wide range of disorders, indicating the need of broad individualized care in addition to specific screening programs.

  • 196.
    Glimelius, Ingrid
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Englund, Annika
    Rostgaard, Klaus
    Smedby, Karin E
    Eloranta, Sandra
    de Nully Brown, Peter
    Johansen, Christoffer
    Kamper, Peter
    Ljungman, Gustaf
    Hjalgrim, Lisa Lyngsie
    Hjalgrim, Henrik
    Distribution of hospital care among pediatric and young adult Hodgkin lymphoma survivors-A population-based cohort study from Sweden and Denmark.2019Inngår i: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 8, nr 10, s. 4918-4927Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The burden of late effects among Hodgkin lymphoma (HL) survivors treated according to contemporary protocols remains poorly characterized. We used nation-wide registers to assess number of inpatient bed-days and specialist outpatient visits among 1048 HL-patients (<25 years, diagnosed 1990-2010) and 5175 country-, sex-, and age-matched comparators. We followed them for up to 24 years, with time-dependent assessment of relapse status. International Classification of Diseases (ICD-10) chapter-specific hazard ratios (HRs) were assessed in Cox regression analyses, and nonparametric statistics described patterns of health-care-use. Relative to comparators, relapse-free survivors were at increased risk of infections, diseases of the blood, endocrine, circulatory and respiratory systems, and unspecific symptoms, HRs ranging from 1.86 to 3.05. Relative to comparators, relapsed survivors had at statistically significantly increased risk of diseases reflecting practically all investigated disease-chapters, HRs ranging from 1.60 to 18.7. Among relapse-free survivors, 10% of the patients accounted for 80% of all hospital bed days, and 55% were never hospitalized during follow-up. Among relapsed-survivors, 10% of the patients accounted for 50% of the bed days, and only 24% were never hospitalized during follow-up. In contrast, 10% of the comparators accounted for 90% of hospital bed days and 75% were never hospitalized. These findings challenge the impression of a uniformly distributed long-term morbidity among all HL survivors and emphasize the need for early identification and attention to patients particularly susceptible to late effects, such as relapsed survivors.

  • 197.
    Glimelius, Ingrid
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Rubin, Jenny
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Fischer, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Molin, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Venge, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Biokemisk struktur och funktion.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    The effect of Eosinophil cationic protein (ECP) on Hodgkin lymphoma cell lines2011Inngår i: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 39, nr 8, s. 850-858Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background In classical Hodgkin lymphoma (HL), many eosinophils in tumour tissue indicate poor prognosis, probably caused by stimulation of the tumour cells, the Hodgkin Reed Sternberg (HRS) cells. However, eosinophils are primarily known for their role in innate immunity, where one function is to secrete the toxic substances eosinophil cationic protein (ECP), and eosinophil protein X (EPX). The aim of this study was to investigate the effects of ECP on HRS cells in vitro.

    Method The fluorometric microculture cytotoxicity-assay (FMCA) measured survival index (SI) of cells from the HL cell lines HDLM-2, KMH2, and L428 after incubation with ECP or EPX. The gene products of a coding ECP polymorphism, ECP97arg and ECP97thr, and ECPs, with different levels of glycosylation were investigated. Flow cytometry was used to monitor the effects of ECP on markers of cell death.

    Results A concentration dependent reduction of SI was seen after ECP treatment. For the B-cell derived cell lines, KMH2 and L428, ECP was cytotoxic with a dose response relationship similar to a previously investigated small-cell lung cancer cell-line. In contrast, for HDLM-2, which is a cell line of T-cell origin, the cytotoxicity was even more pronounced at the lowest concentrations tested, and then reached a plateau at about 0.018µM. At a concentration of 0.14µM of ECP, an SI of 71%±1.9 was recorded for HDLM-2, which did not accentuate despite higher concentrations of ECP. ECP97arg and ECP97thr displayed similar cytotoxicity, and the level of glycosylation did not affect cytotoxicity for HDLM-2, in contrast to the small-cell lung cancer cell-line. For EPX, no or very limited reduction in SI was seen, compared to ECP (p<0.001). The majority of cells that died from ECP (the HDLM-2 cell line) were PI positive, and only a few were annexin V positive.

    Conclusions ECP is cytotoxic for HRS cells, but heterogeneity between cell lines was seen. The two cell lines of B-cell origin, KMH2 and L428, were sensitive to high ECP concentrations, but for HDLM-2, of T-cell origin, the cytotoxicity reached a plateau at higher concentrations. Thus, even at presumably high concentrations, ECP can be present around HRS cells without eradicating all cells.

  • 198.
    Glimelius, Ingrid
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Smedby, Karin Ekstroem
    Karolinska Inst, Div Clin Epidemiol, Dept Med Solna, Stockholm, Sweden.
    Jerkeman, Mats
    Lund Univ, Inst Clin Sci, Dept Oncol & Pathol, Lund, Sweden.
    Eloranta, Sandra
    Karolinska Inst, Div Clin Epidemiol, Dept Med Solna, Stockholm, Sweden.
    Weibull, Caroline
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Prognostic Implications of Specific Comorbidities in Mantle Cell Lymphoma Patients, a Swedish Lymphoma Registry Study2018Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 132Artikkel i tidsskrift (Annet vitenskapelig)
  • 199.
    Goldberg, Stuart L.
    et al.
    Hackensack Univ, Med Ctr, John Theurer Canc Ctr, 92 Second St, Hackensack, NJ 07601 USA..
    Cortes, Jorge E.
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA..
    Gambacorti-Passerini, Carlo
    Univ Milano Bicocca, San Gerardo Hosp, Monza, Italy..
    Hehlmann, Ruediger
    Heidelberg Univ, Mannheim, Germany..
    Khoury, H. Jean
    Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA..
    Michallet, Mauricette
    Ctr Hosp Lyon Sud, Pierre Benite, France..
    Paquette, Ron L.
    Univ Calif Los Angeles, Med Ctr, Los Angeles, CA 90024 USA..
    Simonsson, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi. Uppsala Univ, Uppsala, Sweden..
    Zyczynski, Teresa
    Bristol Myers Squibb Co, Princeton, NJ USA..
    Foreman, Aimee
    ICON Plc, San Francisco, CA USA..
    Abruzzese, Elisabetta
    S Eugenio Hosp, Rome, Italy..
    Andorsky, David
    Rocky Mt Canc Ctr, Boulder, CO USA..
    Beeker, Aart
    Spaarne Hosp, Hoofddorp, Netherlands..
    Cony-Makhoul, Pascale
    Ctr Hosp Annecy Genevois, Pringy, France..
    Hansen, Richard
    Inst Med, IDGGQ, Kaiserslautern, Germany..
    Lomaia, Elza
    Federal Almazov North West Med Res Ctr, St Petersburg, Russia..
    Olavarria, Eduardo
    Imperial Coll London, Hammersmith Hosp, London, England..
    Mauro, Michael J.
    Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA..
    First-line treatment selection and early monitoring patterns in chronic phase-chronic myeloid leukemia in routine clinical practice: SIMPLICITY2017Inngår i: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 92, nr 11, s. 1214-1223Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Achieving successful outcomes in chronic phase-chronic myeloid leukemia (CP-CML) requires careful monitoring of cytogenetic/molecular responses (CyR/MR). SIMPLICITY (NCT01244750) is an observational study exploring tyrosine kinase inhibitor use and management patterns in patients with CP-CML receiving first-line imatinib (n = 416), dasatinib (n = 418) or nilotinib (n = 408) in the US and 6 European countries in routine clinical practice. Twelve-month follow-up data of 1242 prospective patients (enrolled October 01 2010-September 02 2015) are reported. 81% of patients had baseline comorbidities. Treatment selection was based on perceived efficacy over patient comorbidity profile. There was a predominance of imatinib-treated patients enrolled earlier in the study, with subsequent shift toward dasatinib- and nilotinib-treated patients by 2013/2014. Monitoring for either CyR/MR improved over time and was documented for 36%, 82%, and 95% of patients by 3, 6, and 12 months, respectively; 5% had no documentation of CyR/MR monitoring during the first year of therapy. Documentation of MR/CyR testing was higher in Europe than the US (P < .001) and at academic versus community practices (P = .001). Age <65 years, patients being followed at sites within Europe, those followed at academic centers and patients no longer on first-line therapy were more likely to be monitored by 12 months. SIMPLICITY demonstrates that the NCCN and ELN recommendations on response monitoring have not been consistently translated into routine clinical practice. In the absence of appropriate monitoring practices, clinical response to TKI therapy cannot be established, any needed changes to treatment strategy will thus not be implemented, and long-term patient outcomes are likely to be impacted.

  • 200.
    Gonzalo, Blanco
    et al.
    Hosp del Mar, Serv Patol, Lab Citol Hematol, Lab Citogenet Mol, Barcelona, Spain.;Inst Hosp Mar Invest Med IMIM, Programa Recerca Canc, Grp Recerca Translac Neoplasies Hematol, Barcelona, Spain.;Univ Pompeu Fabra, Dept Ciencias Expt & Salud, Barcelona, Spain..
    Anna, Puiggros
    Hosp del Mar, Serv Patol, Lab Citol Hematol, Lab Citogenet Mol, Barcelona, Spain.;Inst Hosp Mar Invest Med IMIM, Programa Recerca Canc, Grp Recerca Translac Neoplasies Hematol, Barcelona, Spain..
    Baliakas, Panagiotis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Anastasia, Athanasiadou
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Ma Dolores, Garcia-Malo
    Hosp Univ Morales Meseguer, Serv Hematol, Murcia, Spain..
    Rosa, Collado
    Consorcio Hosp Gen Univ, Serv Hematol, Valencia, Spain..
    Aliki, Xochelli
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Maria, Rodriguez-Rivera
    Hosp del Mar, Serv Patol, Lab Citol Hematol, Lab Citogenet Mol, Barcelona, Spain.;Inst Hosp Mar Invest Med IMIM, Programa Recerca Canc, Grp Recerca Translac Neoplasies Hematol, Barcelona, Spain..
    Margarita, Ortega
    Hosp Valle De Hebron, Lab Citogenet, Barcelona, Spain.;Hosp Valle De Hebron, Serv Hematol, Barcelona, Spain..
    Ma Jose, Calasanz
    Univ Navarra, Dept Genet, Serv Citogenet, Pamplona, Spain..
    Elisa, Luno
    Hosp Univ Cent Asturias, Serv Hematol, Oviedo, Spain..
    Ma Teresa, Vargas
    Hosp Univ Virgen de la Macarena, Seville, Spain.;Univ Autonoma Barcelona, Serv Lab Hematol, ICO Hosp Germans Trias & Pujol, Inst Recerca Leucemia Josep Carreras IJC, Badalona, Spain..
    Javier, Grau
    Carolina, Martinez-Laperche
    Hosp Gen Univ Gregorio Maranon, Serv Hematol, Lab Genet Hematol, Madrid, Spain.;Inst Invest Sanitaria Gregorio Maranon, Madrid, Spain..
    Alberto, Valiente
    Complejo Hosp Navarra, Serv Genet Hematol, Pamplona, Spain..
    Jose, Cervera
    Hosp Univ La Fe, Unidad Genet, Valencia, Spain..
    Jesus Ma, Hernandez-Rivas
    Univ Salamanca, Serv Hematol, Hosp Univ Salamanca, IBSAL,IBMCC,Ctr Invest Canc,CSIC, Salamanca, Spain..
    Eva, Gimeno
    Hosp del Mar, Serv Hematol, Barcelona, Spain..
    Francisco Jose, Ortuno
    Hosp Univ Morales Meseguer, Serv Hematol, Murcia, Spain..
    Ana, Ferrer
    Hosp del Mar, Serv Patol, Lab Citol Hematol, Lab Citogenet Mol, Barcelona, Spain.;Inst Hosp Mar Invest Med IMIM, Programa Recerca Canc, Grp Recerca Translac Neoplasies Hematol, Barcelona, Spain..
    Marcos, Gonzalez
    Univ Salamanca, Serv Hematol, Hosp Univ Salamanca, IBSAL,IBMCC,Ctr Invest Canc,CSIC, Salamanca, Spain..
    Francesc, Bosch
    Hosp Valle De Hebron, Lab Citogenet, Barcelona, Spain.;Hosp Valle De Hebron, Serv Hematol, Barcelona, Spain..
    Pau, Abrisqueta
    Hosp Valle De Hebron, Lab Citogenet, Barcelona, Spain.;Hosp Valle De Hebron, Serv Hematol, Barcelona, Spain..
    Kostas, Stamatopoulos
    CERTH, Inst Appl Biosci, G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;CERTH, Inst Appl Biosci, G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Blanca, Espinet
    Hosp del Mar, Serv Patol, Lab Citol Hematol, Lab Citogenet Mol, Barcelona, Spain.;Inst Hosp Mar Invest Med IMIM, Programa Recerca Canc, Grp Recerca Translac Neoplasies Hematol, Barcelona, Spain..
    Gains of 8q and losses of 8p is associated with the presence of complex karyotype improving prognosis in patients with lymphatic leukemia chronic and alterations of tp532016Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, nr Suppl. 4, s. 196-197Artikkel i tidsskrift (Annet vitenskapelig)
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