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  • 301. Scotch, Allison H
    et al.
    Kosiorek, Heidi
    Scherber, Robyn
    Dueck, Amylou C
    Slot, Stefanie
    Zweegman, Sonja
    Boekhorst, Peter A W Te
    Commandeur, Suzan
    Schouten, Harry
    Sackmann, Federico
    Fuentes, Ana Kerguelen
    Hernández-Maraver, Dolores
    Pahl, Heike L
    Griesshammer, Martin
    Stegelmann, Frank
    Döhner, Konstanze
    Lehmann, Thomas
    Bonatz, Karin
    Reiter, Andreas
    Boyer, Francoise
    Etienne, Gabriel
    Ianotto, Jean-Christophe
    Ranta, Dana
    Roy, Lydia
    Cahn, Jean-Yves
    Harrison, Claire N
    Radia, Deepti
    Muxi, Pablo
    Maldonado, Norman
    Besses, Carlos
    Cervantes, Francisco
    Johansson, Peter L
    Barbui, Tiziano
    Barosi, Giovanni
    Vannucchi, Alessandro M
    Paoli, Chiara
    Passamonti, Francesco
    Andreasson, Bjorn
    Ferrari, Maria L
    Rambaldi, Alessandro
    Samuelsson, Jan
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Xiao, Zhijian
    Xu, Zefeng
    Zhang, Yue
    Sun, Xiujuan
    Xu, Junqing
    Kiladjian, Jean-Jacques
    Zhang, Peihong
    Gale, Robert Peter
    Mesa, Ruben A
    Geyer, Holly L
    Symptom burden profile in myelofibrosis patients with thrombocytopenia: Lessons and unmet needs2017In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 63, p. 34-40Article in journal (Refereed)
    Abstract [en]

    Myelofibrosis is a myeloproliferative neoplasm associated with progressive cytopenias and high symptom burden. MF patients with thrombocytopenia have poor prognosis but the presence of thrombocytopenia frequently precludes the use of JAK2 inhibitors. In this study, we assessed quality of life and symptom burden in 418 MF patients with (n = 89) and without (n = 329) thrombocytopenia using prospective data from the MPN-QOL study group database, including the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and Total Symptom Score (MPN10). Thrombocytopenia, defined as platelet count < 100 x10(9)/L (moderate 51-100 x 10(9)/L; severe <= 50 x10(9)/L), was associated with anemia (76% vs. 45%, p < 0.001), leukopenia (29% vs. 11%, p < 0.001), and need for red blood cell transfusion (35% vs. 19%, p = 0.002). Thrombocytopenic patients had more fatigue, early satiety, inactivity, dizziness, sad mood, cough, night sweats, itching, fever, and weight loss; total symptom scores were also higher (33 vs. 24, p < 0.001). Patients with severe thrombocytopenia were more likely to have anemia (86% vs. 67%, p = 0.04), leukopenia (40% vs. 20%, p = 0.04), and transfusion requirements (51% vs. 20%, p = 0.002) but few differences in symptoms when compared to patients with moderate thrombocytopenia. These results suggest that MF patients with thrombocytopenia experience greater symptomatic burden than MF patients without thrombocytopenia and may benefit from additional therapies.

  • 302.
    Sevov, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Bunikis, Ignas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Häggqvist, Susana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Cavelier, Lucia
    Targeted RNA Sequencing Assay Efficiently Identifies Cryptic KMT2A (MLL)-Fusions in Acute Leukemia Patients2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 303.
    Simonson, Oscar E.
    et al.
    Karolinska Inst, Dept Mol Med & Surg, Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Dept Cardiothorac Surg & Anesthesia, Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Dept Lab Med, Karolinska Univ Hosp, Stockholm, Sweden..
    Mougiakakos, Dimitrios
    Univ Erlangen Nurnberg, Dept Internal Med Hematol & Oncol, D-91054 Erlangen, Germany..
    Heldring, Nina
    Karolinska Inst, Dept Lab Med, Karolinska Univ Hosp, Stockholm, Sweden..
    Bassi, Giulio
    Univ Verona, Dept Med, Sect Hematol, Stem Cell Res Lab, I-37100 Verona, Italy..
    Johansson, Henrik J.
    Karolinska Inst, Dept Oncol Pathol, Canc Prote Mass Spectrometry, Sci Life Lab, Stockholm, Sweden..
    Dalen, Magnus
    Karolinska Inst, Dept Mol Med & Surg, Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Dept Cardiothorac Surg & Anesthesia, Karolinska Univ Hosp, Stockholm, Sweden..
    Jitschin, Regina
    Karolinska Inst, Dept Lab Med, Karolinska Univ Hosp, Stockholm, Sweden..
    Rodin, Sergey
    Karolinska Inst, Dept Med Biochem & Biophys, Stockholm, Sweden..
    Corbascio, Matthias
    Karolinska Inst, Dept Mol Med & Surg, Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Dept Cardiothorac Surg & Anesthesia, Karolinska Univ Hosp, Stockholm, Sweden.;Vaccine & Gene Therapy Inst Florida, Ctr Dis Aging, Port St Lucie, FL USA..
    El Andaloussi, Samir
    Karolinska Inst, Dept Lab Med, Karolinska Univ Hosp, Stockholm, Sweden..
    Wiklander, Oscar P. B.
    Karolinska Inst, Dept Lab Med, Karolinska Univ Hosp, Stockholm, Sweden..
    Nordin, Joel Z.
    Karolinska Inst, Dept Lab Med, Karolinska Univ Hosp, Stockholm, Sweden..
    Skog, Johan
    Exosome Diagnost Inc, New York, NY USA..
    Romain, Charlotte
    Exosome Diagnost Inc, New York, NY USA..
    Koestler, Tina
    Exosome Diagnost Inc, New York, NY USA..
    Johansson Hellgren, Laila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Schiller, Petter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Joachimsson, Per-Olof
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Univ Uppsala Hosp, Dept Hematol, Uppsala, Sweden..
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Univ Uppsala Hosp, Dept Hematol, Uppsala, Sweden..
    Lentio, Janne
    Faridani, Omid R.
    Ludwig Inst Canc Res, S-10401 Stockholm, Sweden..
    Sandberg, Rickard
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden.;Ludwig Inst Canc Res, S-10401 Stockholm, Sweden..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Krampera, Mauro
    Univ Verona, Dept Med, Sect Hematol, Stem Cell Res Lab, I-37100 Verona, Italy..
    Weiss, Daniel J.
    Univ Vermont, Dept Med, Hlth Sci Res Facil, Burlington, VT USA..
    Grinnemo, Karl-Henrik
    Karolinska Inst, Dept Mol Med & Surg, Karolinska Univ Hosp, Stockholm, Sweden.;Karolinska Inst, Dept Cardiothorac Surg & Anesthesia, Karolinska Univ Hosp, Stockholm, Sweden.;Vaccine & Gene Therapy Inst Florida, Ctr Dis Aging, Port St Lucie, FL USA..
    Le Blanc, Katarina
    Karolinska Inst, Dept Lab Med, Karolinska Univ Hosp, Stockholm, Sweden..
    In Vivo Effects of Mesenchymal Stromal Cells in Two Patients With Severe Acute Respiratory Distress Syndrome2015In: Stem Cells Translational Medicine, ISSN 2157-6564, E-ISSN 2157-6580, Vol. 4, no 10, p. 1199-1213Article in journal (Refereed)
    Abstract [en]

    Mesenchymal stromal cells (MSCs) have been investigated as a treatment for various inflammatory diseases because of their immunomodulatory and reparative properties. However, many basic questions concerning their mechanisms of action after systemic infusion remain unanswered. We performed a detailed analysis of the immunomodulatory properties and proteomic profile of MSCs systemically administered to two patients with severe refractory acute respiratory distress syndrome (ARDS) on a compassionate use basis and attempted to correlate these with in vivo anti-inflammatory actions. Both patients received 2 x 10(6) cells per kilogram, and each subsequently improved with resolution of respiratory, hemodynamic, and multiorgan failure. In parallel, a decrease was seen in multiple pulmonary and systemic markers of inflammation, including epithelial apoptosis, alveolar-capillary fluid leakage, and proinflammatory cytokines, microRNAs, and chemokines. In vitro studies of the MSCs demonstrated a broad anti-inflammatory capacity, including suppression of T-cell responses and induction of regulatory phenotypes in T cells, monocytes, and neutrophils. Some of these in vitro potency assessments correlated with, and were relevant to, the observed in vivo actions. These experiences highlight both the mechanistic information that can be gained from clinical experience and the value of correlating in vitro potency assessments with clinical effects. The findings also suggest, but do not prove, a beneficial effect of lung protective strategies using adoptively transferred MSCs in ARDS. Appropriate randomized clinical trials are required to further assess any potential clinical efficacy and investigate the effects on in vivo inflammation. STEM CELLS TRANSLATIONAL MEDICINE 2015;4:1199-1213

  • 304.
    Simonsson, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Gedde-Dahl, Tobias
    Markevarn, Berit
    Remes, Kari
    Stentoft, Jesper
    Almqvist, Anders
    Bjoreman, Mats
    Flogegard, Max
    Koskenvesa, Perttu
    Lindblom, Anders
    Malm, Claes
    Mustjoki, Satu
    Myhr-Eriksson, Kristina
    Ohm, Lotta
    Rasanen, Anu
    Sinisalo, Marjatta
    Sjalander, Anders
    Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Bjerrum, Ole Weiss
    Ehrencrona, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gruber, Franz
    Kairisto, Veli
    Olsson, Karin
    Sandin, Fredrik
    Nagler, Arnon
    Nielsen, Johan Lanng
    Hjorth-Hansen, Henrik
    Porkka, Kimmo
    Combination of pegylated IFN-alpha 2b with imatinib increases molecular response rates in patients with low- or intermediate-risk chronic myeloid leukemia2011In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 118, no 12, p. 3228-3235Article in journal (Refereed)
    Abstract [en]

    Biologic and clinical observations suggest that combining imatinib with IFN-alpha may improve treatment outcome in chronic myeloid leukemia (CML). We randomized newly diagnosed chronic-phase CML patients with a low or intermediate Sokal risk score and in imatinib-induced complete hematologic remission either to receive a combination of pegylated IFN-alpha 2b (Peg-IFN-alpha 2b) 50 mu g weekly and imatinib 400 mg daily (n = 56) or to receive imatinib 400 mg daily monotherapy (n = 56). The primary endpoint was the major molecular response (MMR) rate at 12 months after randomization. In both arms, 4 patients (7%) discontinued imatinib treatment (1 because of blastic transformation in imatinib arm). In addition, in the combination arm, 34 patients (61%) discontinued Peg-IFN-alpha 2b, most because of toxicity. The MMR rate at 12 months was significantly higher in the imatinib plus Peg-IFN-alpha 2b arm (82%) compared with the imatinib monotherapy arm (54%; intention-to-treat, P = .002). The MMR rate increased with the duration of Peg-IFN-alpha 2b treatment (< 12-week MMR rate 67%, > 12-week MMR rate 91%). Thus, the addition of even relatively short periods of Peg-IFN-alpha 2b to imatinib markedly increased the MMR rate at 12 months of therapy. Lower doses of Peg-IFN-alpha 2b may enhance tolerability while retaining efficacy and could be considered in future protocols with curative intent.

  • 305. Skoglund, Karin
    et al.
    Richter, Johan
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Aluthgedara, Warunika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Ubhayasekera, S J Kumari A
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Vikingsson, Svante
    Svedberg, Anna
    Söderlund, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Sandstedt, Anna
    Johnsson, Anders
    Aagesen, Jesper
    Alsenhed, Jonas
    Hägg, Staffan
    Peterson, Curt
    Lotfi, Kourosh
    Gréen, Henrik
    In vivo CYP3A activity and pharmacokinetics of imatinib in relation to therapeutic outcome in chronic myeloid leukemia patients2016In: Therapeutic Drug Monitoring, ISSN 0163-4356, E-ISSN 1536-3694, Vol. 38, no 2, p. 230-238Article in journal (Refereed)
    Abstract [en]

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

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

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

    CONCLUSIONS: CYP3A activity does not influence imatinib plasma concentrations or the therapeutic outcome. These results indicate that even though imatinib is metabolized by CYP3A enzymes, this activity is not the rate-limiting step in imatinib metabolism and excretion. Future studies should focus on other pharmacokinetic processes so as to identify the major contributor to patient variability in imatinib plasma concentrations.

  • 306. Snarski, E
    et al.
    Snowden, J A
    Oliveira, M C
    Simoes, B
    Badoglio, M
    Carlson, K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Burman, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Moore, J
    Rovira, M
    Clark, R E
    Saiz, A
    Hadj-Khelifa, S
    Tan, J
    Crescimanno, A
    Musso, M
    Martin, T
    Farge, D
    Onset and outcome of pregnancy after autologous haematopoietic SCT (AHSCT) for autoimmune diseases: a retrospective study of the EBMT autoimmune diseases working party (ADWP)2015In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 50, no 2, p. 216-220Article in journal (Refereed)
    Abstract [en]

    Autologous haematopoietic SCT (AHSCT) is increasingly used to control severe and refractory autoimmune diseases (AD). Many patients are women of reproductive age with a potential desire for children. We present a multicentre retrospective analysis of pregnancy and childbirth in patients who underwent AHSCT for AD. The databases of the European Blood and Marrow Transplantation and University of Sao Paulo, Ribeirão Preto, Brazil were searched for female patients aged 18-50 years who had received AHSCT for AD between 1994-2011. In 324 adult female patients, 22 pregnancies were reported in 15 patients between 1997-2011. Indications for AHSCT included multiple sclerosis (n=7), systemic sclerosis (n=5), rheumatoid arthritis (n=1), juvenile idiopathic arthritis (n=1) and Takayasu disease (n=1). Of the 22 reported pregnancies, 20 followed natural conception. 15 pregnancies (68%) resulted in healthy life births, whereas 7 (32%) failed. Exacerbations of AD occurred in two patients during second pregnancies. No maternal mortality was associated with pregnancy or postpartum. There were no reports of congenital, developmental or any other disease in the children. This retrospective analysis confirms the possibility of pregnancy and childbirth following AHSCT for severe AD. The outcome of pregnancy is generally good and most led to the birth of a healthy child.

  • 307.
    Sohrabian, Donia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Linder, Marie
    Karolinska Inst, Med, Stockholm, Sweden..
    Ekstrand, Charlotta
    Karolinska Inst, Med, Stockholm, Sweden..
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kieler, Helle
    Karolinska Inst, Med, Stockholm, Sweden..
    Bahmanyar, Shahram
    Karolinska Inst, Med, Stockholm, Sweden..
    Infection and Anti-Infective Treatment Preceding a Diagnosis of Primary Persisting Immune Thrombocytopenia2016In: Pharmacoepidemiology and Drug Safety, ISSN 1053-8569, E-ISSN 1099-1557, Vol. 25, no Suppl. 3, p. 88-88, article id Abstr. 143Article in journal (Refereed)
  • 308.
    Strese, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Hassan, Saadia Bashir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Velander, Ebba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Haglund, Caroline
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    In vitro and in vivo anti-leukemic activity of the peptidase-potentiated alkylator melflufen in acute myeloid leukemia2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 4, p. 6341-6352Article in journal (Refereed)
    Abstract [en]

    The novel aminopeptidase potentiated alkylating agent melflufen, was evaluated for activity in acute myeloid leukemia in a range of in vitro models, as well as in a patient derived xenograft study. All tested AML cell lines were highly sensitive to melflufen while melphalan was considerably less potent. In the HL-60 cell line model, synergy was observed for the combination of melflufen and cytarabine, an interaction that appeared sequence dependent with increased synergy when melflufen was added before cytarabine. Also, in primary cultures of AML cells from patients melflufen was highly active, while normal PBMC cultures appeared less sensitive, indicating a 7-fold in vitro therapeutic index. Melphalan, on the other hand, was only 2-fold more potent in the AML patient samples compared with PBMCs. Melflufen was equally active against non-malignant, immature CD34(+) progenitor cells and a more differentiated CD34(+) derived cell population (GM14), whereas the stem cell like cells were less sensitive to melphalan. Finally, melflufen treatment showed significant anti-leukemia activity and increased survival in a patient derived xenograft of AML in mice. In conclusion, melflufen demonstrates high and significant preclinical activity in AML and further clinical evaluation seem warranted in this disease.

  • 309.
    Svanberg, Anncarin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Mucositis Prevention for Patients Receiving High Dose Chemotherapy and Stem Cell Transplantation: Preventive Strategies - There is Always More to do2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The aim of this thesis was to investigate oral cryotherapy (OC) as prophy-laxis against oral mucositis (OM) in patients given high-dose chemotherapy for stem cell transplantation (SCT). A new mouth rinse device was tested for possible additive effect to OC.

    For study I-III, 78 patients were randomised to OC or standard oral care (SOC). Papers I and II showed that OC patients had significantly less severe mucositis, pain, opioid use, lower C-reactive protein and less parenteral nutrition treatment (TPN).

    There was no difference in relapse rate, and 5-year survival was unexpectedly significantly better in the OC group (Paper III). In paper IV, the local effect of OC on the mucosa of the mouth was investigated by the use of an infrared thermograph. Change in surface temperature in eight areas of the mouth cavity was measured after cooling of the mouth in healthy volunteers. A substantial lowering of the temperature (-12.9 °C, mean) was seen which could explain the efficacy of OC. To exclude that acute cooling in itself is traumatic, the proinflammatory cytokine IL-6 was measured in saliva and showed no increase after cooling. Paper V reported a study in 40 allogeneic SCT patients. 20 were given SOC including OC and 20 in addition received Caphosol®, a calcium phosphate mouth rinse, during chemotherapy and until day 21. Severity of mucositis, use of opioids and TPN, effects on nutrition and CRP levels were measured. No significant difference was found between the groups in any of these variables, but a non-significant trend for an advantage for the combination could be seen. IL-6 saliva levels were measured. There was a substantial increase (more than 10-fold), in mean IL-6 levels from baseline to beginning of mucositis and a weak correlation between increased IL-6 levels and severity of OM, suggesting that IL-6 in saliva may be a useful marker of the inflammatory mucosal process.

    This thesis demonstrates that OC is effective as prophylaxis against chemotherapy-induced OM. As a consequence of this work, OC has been introduced as the standard of care in all SCT patients in our institution.

    List of papers
    1. Oral cryotherapy reduces mucositis and opioid use after myeloablative therapy-a randomized controlled trial
    Open this publication in new window or tab >>Oral cryotherapy reduces mucositis and opioid use after myeloablative therapy-a randomized controlled trial
    2007 (English)In: Supportive Care in Cancer, ISSN 0941-4355, E-ISSN 1433-7339, Vol. 15, no 10, p. 1155-1161Article in journal (Refereed) Published
    Abstract [en]

    Introduction: Mucositis is a major complication in myeloablative therapy, which often necessitates advanced pharmacological pain treatment, including i.v. opioids. Attempts to prevent oral mucositis have included oral cryotherapy, which has been shown to reduce mucositis, but there is a lack of knowledge concerning the effect of oral cryotherapy on opioid use by reducing the mucositis for patients treated with myeloablative therapy before bone marrow transplantation (BMT). Aim: The aim of the present study was to evaluate if oral cryotherapy could delay or alleviate the development of mucositis and thereby reduce the number of days with i.v. opioids among patients who receive myeloablative therapy before BMT. Materials and methods: Eighty patients 18 years and older, scheduled for BMT, were included consecutively and randomised to oral cryotherapy or standard oral care. A stratified randomisation was used with regard to type of transplantation. Intensity of pain, severity of mucositis and use of opioids were recorded using pain visual analogue scale (VAS) scores, mucositis index scores and medical and nursing charts. Results: This study showed that patients receiving oral cryotherapy had less pronounced mucositis and significantly fewer days with i.v. opioids than the control group. In the autologous setting, cryotherapy patients also needed significantly lower total dose of opioids. Conclusion: Oral cryotherapy is an effective and well-tolerated therapy to alleviate mucositis and consequently reduce the number of days with i.v. opioids among patients treated with myeloablative therapy before BMT.

    Keywords
    Oral cryotherapy, Bone marrow transplantation, Mucositis, Oral pain, Opioid use
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-11834 (URN)10.1007/s00520-007-0245-8 (DOI)000249632900004 ()17393189 (PubMedID)
    Available from: 2007-10-26 Created: 2007-10-26 Last updated: 2017-12-11Bibliographically approved
    2. Oral cryotherapy reduces mucositis and improves nutrition: a randomised controlled trial
    Open this publication in new window or tab >>Oral cryotherapy reduces mucositis and improves nutrition: a randomised controlled trial
    2010 (English)In: Journal of Clinical Nursing, ISSN 0962-1067, E-ISSN 1365-2702, Vol. 19, no 15-16, p. 2146-2151Article in journal (Refereed) Published
    Abstract [en]

    Aim and objective. To investigate if oral cryotherapy during myeloablative therapy may influence frequency and severity of mucositis, nutritional status and infection rate after bone marrow transplantation. Background. Patients treated with intensive myeloablative treatment before bone marrow transplantation are all at risk to develop mucositis. Oral mucositis causes severe pain and oral dysfunction, which can contribute to local and systemic infections and bleeding; it may even interrupt cancer therapy. Oral mucositis also decreases the oral food intake, which increases the risk for malnutrition and infection. Reduced food intake, loss of fat and muscles, alterations in energy and substrate metabolism leads to malnutrition. Design. A randomised controlled trial with a random assignment to experimental or control group. Method. A stratified randomisation was used with regard to the type of transplantation. Mucositis was measured on WHO mucositis scale. Number of days of total parenteral nutrition, infection rate, weight, albumin levels and days at hospital was compared. Results. There were significantly fewer patients in the experimental group with mucositis grade 3-4 than in the control group and significantly lower number of days in the hospital (allogeneic patients). Less total parenteral nutrition was needed in the experimental group in both settings, and the S-albumin level was significantly better preserved. No significant difference could be found with regard to infection rate. Conclusion. Oral cryotherapy reduced mucositis, number of hospital days, the need for total parenteral nutrition and resulted in a better nutritional status. Relevance to clinical practice. Nurses caring for patients treated with myeloablative therapy should place high priority to prevent oral mucositis and hereby reduce its side effects.

    Keywords
    bone marrow transplantation, infection rate, mucositis, nutritional status, oral cryotherapy, total parenteral nutrition
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-135665 (URN)10.1111/j.1365-2702.2010.03255.x (DOI)000279937600009 ()
    Available from: 2010-12-08 Created: 2010-12-07 Last updated: 2017-12-11Bibliographically approved
    3. Five year follow-up of survival and relapse in patients who received cryotherapy during high dose chemotherapy for stem cell transplantation shows no safety concerns
    Open this publication in new window or tab >>Five year follow-up of survival and relapse in patients who received cryotherapy during high dose chemotherapy for stem cell transplantation shows no safety concerns
    2012 (English)In: European Journal of Cancer Care, ISSN 0961-5423, E-ISSN 1365-2354, Vol. 21, no 6, p. 822-828Article in journal (Refereed) Published
    Abstract [en]

    We have previously published a randomised controlled study of the efficacy of cryotherapy in preventing acute oral mucositis after high-dose chemotherapy for stem cell transplantation. The present study is a 5-year follow-up safety study of survival in these patients. In the previously published study oral cryotherapy (cooling of the oral cavity) during high-dose chemotherapy significantly reduced mucositis grade and opiate use in the treated group. All patients were followed up for at least 5 years with regard to relapse and death rates. Baseline data, transplant complications and mucositis data were compared. Significantly more patients (25/39) who received oral cryotherapy were alive after 5 years compared to 15/39 in the control group (P= 0.025). Relapse rates were similar. The only baseline difference was a lower proportion of patients in complete remission at transplantation in the control group (6 vs. 13, P= 0.047). This 5-year follow-up study gave no support for safety concerns with cryotherapy.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-179505 (URN)10.1111/ecc.12009 (DOI)000314038700016 ()22967016 (PubMedID)
    Available from: 2012-08-17 Created: 2012-08-17 Last updated: 2017-12-07Bibliographically approved
    4. The effect of cryotherapy on oral mucosa: a study in healthy volunteers
    Open this publication in new window or tab >>The effect of cryotherapy on oral mucosa: a study in healthy volunteers
    2012 (English)In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 29, no 5, p. 3587-3591Article in journal (Refereed) Published
    Abstract [en]

    Oral cryotherapy causes local vasoconstriction, which reduces blood flow and reduces the cytotoxic damage to the oral mucosa, has been shown to reduce oral mucositis after intense cytostatic treatment. The main object of this study was to investigate the effect of oral cryotherapy on the temperature in the oral mucosa, the level of proinflammatory cytokine interleukin-6 (IL-6) in saliva and the effect on blood pressure in healthy volunteers, before and after 1 h of cooling the oral cavity with crushed ice. Twelve healthy volunteers [mean age 32.4 (SD 13.2) (20-56) years] were treated with oral cryotherapy in the form of crushed ice. Temperature measurements were performed in the oral mucosa using infrared thermograph following a flowchart protocol. Blood pressure (BP) was measured with a sphygmomanometer. Saliva was analysed for inflammatory cytokine IL-6, using an enzyme-linked immunosorbent assay (ELISA). All participants fulfilled the cooling session. The temperature in the oral cavity decreased significantly (mean 12.9 degrees C, p < .002). The systolic BP was marginally but significantly higher after cooling (similar to 5 mmHg, p = .019). We could not detect any differences in cytokine IL-6 levels before and after oral cooling. We conclude that cryotherapy during 1 h lowers the mucosal temperature as much as similar to 12.9 degrees C, which explains the significant protective effect against mucosal damage by cytostatic drugs. The cooling caused no increase in IL-6 levels. Systemic blood pressure was marginally increased.

    Keywords
    oral cooling, thermographic measurement, interleukin (IL)-6, oral cavity temperature, blood pressure
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-179504 (URN)10.1007/s12032-012-0230-z (DOI)000311513800085 ()22476810 (PubMedID)
    Available from: 2012-08-17 Created: 2012-08-17 Last updated: 2017-12-07Bibliographically approved
    5. Caphosol® mouthwash gives no additional protection against oral mucositis compared to cryotherapy alone in stem cell transplantation: A pilot study
    Open this publication in new window or tab >>Caphosol® mouthwash gives no additional protection against oral mucositis compared to cryotherapy alone in stem cell transplantation: A pilot study
    2015 (English)In: European Journal of Oncology Nursing, ISSN 1462-3889, E-ISSN 1532-2122, Vol. 19, p. 50-53Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE: To investigate if adding Caphosol(®), a mouthwash solution, to oral cryotherapy (OC) further protects against oral mucositis (OM), a toxic painful complication to high dose chemotherapy.

    METHOD: The study was a randomised, controlled, study design. Patients ≥16 years scheduled for allogeneic stem cell transplantation were included consecutively and randomised to experimental group receiving OC combined with Caphosol(®) (n = 20) or control group receiving OC only (n = 20). OC was given from start to end of HDCT. Caphosol(®), from day 0 to day 21.

    RESULT: There were no significant differences regarding age or gender between the groups. Mucositis was assessed with the World Health Organisation (WHO) grading scale. Pain was assessed with a 10 cm visual analogue scale (VAS) from 0 = no pain to 10 = worst imaginable pain. Start and duration of therapy with pain relieving drugs, serum C-reactive protein values, and number of days of hospitalisation were collected from the medical records. Data on OM, oral pain, use of i.v. opioids and total parenteral nutrition were collected during 22 days. There was no significant difference between the groups on OM, oral pain, use of i.v. opioids or TPN between the groups.

    CONCLUSION: The study showed no additional effect of combining Caphosol(®) with OC.

    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-179503 (URN)10.1016/j.ejon.2014.07.011 (DOI)000350074400009 ()25224595 (PubMedID)
    Available from: 2012-08-17 Created: 2012-08-17 Last updated: 2017-12-07Bibliographically approved
  • 310.
    Svanberg, Anncarin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Addition of aprepitant (Emend (R)) to standard antiemetic care for seven days post-chemotherapy before stem cell transplantation gives significant reduction of vomiting2013In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 48, no Suppl.2, p. S463-S463Article in journal (Other academic)
  • 311.
    Svanberg, Anncarin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Addition of Aprepitant (Emend®) to Standard Antiemetic Regimen Continued for 7 Days after Chemotherapy for Stem Cell Transplantation Provides Significant Reduction of Vomiting2015In: Oncology, ISSN 0030-2414, E-ISSN 1423-0232, Vol. 89, no 1, p. 31-36Article in journal (Refereed)
    Abstract [en]

    Chemotherapy-induced nausea/vomiting (CINV) is a major problem for patients treated with high-dose chemotherapy (HDCT) conditioning before stem cell transplantation (SCT), both during chemotherapy and afterwards (delayed nausea/vomiting). The standard of care (5-HT3 antagonist and dexamethasone) appears to be ineffective against delayed nausea and vomiting. The objective of this study was to compare standard antiemetic treatment with standard treatment plus prolonged treatment with aprepitant (Emend®) until 7 days after the end of chemotherapy in patients treated with HDCT before autologous SCT. Ninety-six patients were randomized to the experiment (EXP) group receiving Emend in addition to standard antiemetics or to the control (CTR) group receiving placebo. Emend or placebo treatment started 1 h before the first HDCT dose for SCT and ended 7 days after HDCT. Thirty-eight patients in the EXP group experienced complete response (no vomiting) compared to 16 patients in the CTR group. There was a significant difference between the EXP (0.63 ± 2.71) and the CTR (3.72 ± 4.91) group during 10 days after the end of HDCT (p = 0.001) with regard to the number of vomiting episodes. No difference with regard to days of nausea or in the use of antiemetic rescue was noted between the groups. We conclude that standard antiemetic treatment can be improved by addition of aprepitant continued for 7 days after the end of chemotherapy.

  • 312.
    Svanberg, Anncarin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Öhrn, Kerstin
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Caphosol® mouthwash gives no additional protection against oral mucositis compared to cryotherapy alone in stem cell transplantation: A pilot study2015In: European Journal of Oncology Nursing, ISSN 1462-3889, E-ISSN 1532-2122, Vol. 19, p. 50-53Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To investigate if adding Caphosol(®), a mouthwash solution, to oral cryotherapy (OC) further protects against oral mucositis (OM), a toxic painful complication to high dose chemotherapy.

    METHOD: The study was a randomised, controlled, study design. Patients ≥16 years scheduled for allogeneic stem cell transplantation were included consecutively and randomised to experimental group receiving OC combined with Caphosol(®) (n = 20) or control group receiving OC only (n = 20). OC was given from start to end of HDCT. Caphosol(®), from day 0 to day 21.

    RESULT: There were no significant differences regarding age or gender between the groups. Mucositis was assessed with the World Health Organisation (WHO) grading scale. Pain was assessed with a 10 cm visual analogue scale (VAS) from 0 = no pain to 10 = worst imaginable pain. Start and duration of therapy with pain relieving drugs, serum C-reactive protein values, and number of days of hospitalisation were collected from the medical records. Data on OM, oral pain, use of i.v. opioids and total parenteral nutrition were collected during 22 days. There was no significant difference between the groups on OM, oral pain, use of i.v. opioids or TPN between the groups.

    CONCLUSION: The study showed no additional effect of combining Caphosol(®) with OC.

  • 313.
    Svanberg, Anncarin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Öhrn, Kerstin
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Five year follow-up of survival and relapse in patients who received cryotherapy during high dose chemotherapy for stem cell transplantation shows no safety concerns2012In: European Journal of Cancer Care, ISSN 0961-5423, E-ISSN 1365-2354, Vol. 21, no 6, p. 822-828Article in journal (Refereed)
    Abstract [en]

    We have previously published a randomised controlled study of the efficacy of cryotherapy in preventing acute oral mucositis after high-dose chemotherapy for stem cell transplantation. The present study is a 5-year follow-up safety study of survival in these patients. In the previously published study oral cryotherapy (cooling of the oral cavity) during high-dose chemotherapy significantly reduced mucositis grade and opiate use in the treated group. All patients were followed up for at least 5 years with regard to relapse and death rates. Baseline data, transplant complications and mucositis data were compared. Significantly more patients (25/39) who received oral cryotherapy were alive after 5 years compared to 15/39 in the control group (P= 0.025). Relapse rates were similar. The only baseline difference was a lower proportion of patients in complete remission at transplantation in the control group (6 vs. 13, P= 0.047). This 5-year follow-up study gave no support for safety concerns with cryotherapy.

  • 314.
    Svanberg, Anncarin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Öhrn, Kerstin
    Broström, Hans
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    The effect of cryotherapy on oral mucosa: a study in healthy volunteers2012In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 29, no 5, p. 3587-3591Article in journal (Refereed)
    Abstract [en]

    Oral cryotherapy causes local vasoconstriction, which reduces blood flow and reduces the cytotoxic damage to the oral mucosa, has been shown to reduce oral mucositis after intense cytostatic treatment. The main object of this study was to investigate the effect of oral cryotherapy on the temperature in the oral mucosa, the level of proinflammatory cytokine interleukin-6 (IL-6) in saliva and the effect on blood pressure in healthy volunteers, before and after 1 h of cooling the oral cavity with crushed ice. Twelve healthy volunteers [mean age 32.4 (SD 13.2) (20-56) years] were treated with oral cryotherapy in the form of crushed ice. Temperature measurements were performed in the oral mucosa using infrared thermograph following a flowchart protocol. Blood pressure (BP) was measured with a sphygmomanometer. Saliva was analysed for inflammatory cytokine IL-6, using an enzyme-linked immunosorbent assay (ELISA). All participants fulfilled the cooling session. The temperature in the oral cavity decreased significantly (mean 12.9 degrees C, p < .002). The systolic BP was marginally but significantly higher after cooling (similar to 5 mmHg, p = .019). We could not detect any differences in cytokine IL-6 levels before and after oral cooling. We conclude that cryotherapy during 1 h lowers the mucosal temperature as much as similar to 12.9 degrees C, which explains the significant protective effect against mucosal damage by cytostatic drugs. The cooling caused no increase in IL-6 levels. Systemic blood pressure was marginally increased.

  • 315.
    Svensson, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Infectious and bleeding complications in patients with hematological malignancies: Studies on diagnosis and prevention2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The overall aim of this thesis is to improve knowledge about the prevention of infectious and bleeding complications in patients with hematological malignancies, primarily in those with chronic lymphocytic leukemia (CLL) and myelodysplatic syndrome (MDS).

    Hypogammaglobulinemia, impaired production of immunoglobulins (Ig), is an established risk factor for infection, but the impact of IgG pure subclass deficiency (IgG subclass deficiency with adequate production of IgG, IgA, and IgM) has been debated. In a retrospective single institution study, we concluded that pure IgG subclass deficiency in CLL patients is rare and is not associated with an increased risk of infection. Hence, routine analysis of IgG subclasses in patients with CLL is not warranted.

    There is no consensus on recommending vaccination against Streptococcus pneumoniae to CLL patients mainly because comparative studies are lacking. In our randomized trial, the efficacy of a conjugated pneumococcal vaccine on immune response was superior or equal to a polysaccharide vaccine for all pneumococcal serotypes common for the two vaccines. A conjugate pneumococcal vaccine should therefore be included in vaccination programs for patients with CLL.

    Bronchoalveolar lavage (BAL) is a well-established invasive method to identify the cause of pulmonary infiltrates in immunocompromised patients. In a retrospective trial, we have studied the diagnostic yield of BAL in patients with hematological malignancies. We concluded that BAL is highly useful in either verifying or excluding some of the important respiratory tract infections affecting these patients, particularly invasive pulmonary aspergillosis (IPA) and Pneumocystis jirovecii pneumonia (PJP). However, standardized procedures for BAL sampling should be continually revised to avoid unnecessary microbiological tests.

    Thrombocytopenia, an adverse prognostic factor in patients with MDS, can be aggravated by azacitidine, first-line treatment for high-risk MDS. Eltrombopag, a thrombopoietin-receptor agonist (TPO-R), alleviates thrombocytopenia in patients with immune thrombocytopenic purpura (ITP). In a phase I clinical trial, we concluded that the combination of eltrombopag and azacitidine in high-risk MDS patients with thrombocytopenia is feasible and well tolerated in doses up to 200 mg eltrombopag daily.

    List of papers
    1. Clinical significance of serum immunoglobulin G subclass deficiency in patients with chronic lymphocytic leukemia
    Open this publication in new window or tab >>Clinical significance of serum immunoglobulin G subclass deficiency in patients with chronic lymphocytic leukemia
    2013 (English)In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 45, no 7, p. 537-542Article in journal (Refereed) Published
    Abstract [en]

    Background: Patients with chronic lymphocytic leukemia (CLL) and hypogammaglobulinemia who suffer from recurrent infections can be offered prophylactic intravenous immunoglobulin (Ig) substitution. Our aim was to assess the prevalence of pure IgG subclass deficiency (with normal Ig levels), its correlation to risk of infection, and the clinical value of routine measurement of serum IgG subclass levels in patients with CLL. Methods: Serum levels of Ig and IgG subclasses were determined in patients with CLL at Uppsala University Hospital. Clinical data were collected through patient records and questionnaires. Results: Hypogammaglobulinemia occurred in 52.3% out of 111 patients. These patients did not have a higher annual risk of infection than patients without hypogammaglobulinemia (79.5% vs 79.1%, p = 0.706 for all infections; 13.4% vs 11.2%, p = 0.394 for severe infection; and 1.7% vs 3.4%, p = 0.083 for sepsis). Pure subclass deficiency was uncommon and occurred in 6 patients (5.4%). The annual overall risk of infection, of severe infection, and of sepsis for these patients did not differ as compared to patients with no hypogammaglobulinemia and no subclass deficiency (70.8% vs 80.7%, p = 0.334; 11.8% vs 11.1%, p = 0.497; and 8.9% vs 2.3%, p = 0.067, respectively). Conclusions: Pure IgG subclass deficiency is rare in patients with CLL. In this heterogeneous cohort of patients, neither hypogammaglobulinemia nor pure IgG subclass deficiency were significant risk factors for infectious complications. Measurement of serum levels of Ig may be justified in patients with recurrent severe infections, but routine analysis of IgG subclass levels in patients with CLL is probably not warranted.

    Keywords
    Hypogammaglobulinemia, IgG subclass, chronic lymphocytic leukemia, immunodeficiency
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-203524 (URN)10.3109/00365548.2013.769279 (DOI)000320380900007 ()
    Available from: 2013-07-16 Created: 2013-07-15 Last updated: 2017-12-06Bibliographically approved
    2. Conjugated Pneumococcal Vaccine Triggers a Better Immune Response than Polysaccharide Pneumococcal Vaccine in Patients with Chronic Lymphocytic Leukemia: A Randomized Study by the Swedish CLL group
    Open this publication in new window or tab >>Conjugated Pneumococcal Vaccine Triggers a Better Immune Response than Polysaccharide Pneumococcal Vaccine in Patients with Chronic Lymphocytic Leukemia: A Randomized Study by the Swedish CLL group
    Show others...
    2018 (English)In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 36, no 25, p. 3701-3707Article in journal (Refereed) Published
    Abstract [en]

    Aim: To determine if patients with untreated chronic lymphocytic leukemia (CLL) benefit from vaccination with a 13-valent conjugated pneumococcal vaccine (PCV13), Prevenar13®, compared with a 23-valent capsular polysaccharide vaccine (PPSV23), Pneumovax®, in terms of immune response.

     

    Background: Patients with CLL have an increased risk for infection and Streptococcus pneumoniae is one of the most common pathogens with high morbidity.  Patients with CLL are known to respond poorly to the traditionally used polysaccharide vaccines. Conjugation of polysaccharide to protein carriers renders a thymus-dependent, memory-inducing and more immunogenic vaccine. In patients with CLL, there is no consensus on a recommendation for pneumococcal vaccination, due to a lack of comparative studies.

     

    Methods: 128 treatment naïve CLL patients from eight hematology clinics in Sweden were randomized to vaccination with PCV13 (n=63) or PPSV23 (n=65) after stratification by IgG levels and CLL clinical stage (Rai). Blood samples for evaluation of immune response were obtained at baseline, at one and at six months after vaccination. Analyses for each of the 12 pneumococcal serotypes common for PCV13 and PPSV23 were performed by opsonophagocytic assay (OPA) and enzyme-linked immunosorbent assay (ELISA).

     

    Results: PCV13 elicited a superior immune response than PPSV23 in 10/12 serotypes one month after vaccination and in 5/12 serotypes six months after vaccination, measured as OPA geometric mean titers (GMTs). Geometric mean concentrations of serotype-specific IgG antibodies elicited by PCV13 as measured by ELISA, were higher than those elicited by PPSV23 in half of the common serotypes, both after one and six months. The proportion of patients with good response (defined as response in 8 of 12 common serotypes according to predefined response criteria) was higher in PCV13 recipients than in PPSV23 recipients after one month (40% vs. 22%, p=0.034) as well as after six months (33% vs. 17%, p=0.041). Never did PPSV23 trigger a better immune response for any of the serotypes, than PCV13, regardless of analysis. For two of the serotypes, OPA GMTs were lower at the six months than at the one-month follow up. Negative predictive factors for vaccination response were hypogammaglobulinemia and long disease duration. Both vaccines were well tolerated.

     

    Conclusions: In patients with previously untreated CLL, the efficacy of PCV13 in terms of immune response is superior to PPSV23 for many serotypes common for the two vaccines. PCV13 should be considered as a part in vaccination programs against Streptococcus pneumoniae for these patients and administered as early as possible during the course of the disease. 

    Keywords
    Chronic lymphocytic leukemia (CLL), vaccine, Pneumococci, Pneumococcal vaccine, Polysaccharide vaccine, protein-conjugate vaccine, immunogenicity
    National Category
    Immunology in the medical area Infectious Medicine
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:uu:diva-316457 (URN)10.1016/j.vaccine.2018.05.012 (DOI)000436202800022 ()
    Available from: 2017-03-01 Created: 2017-03-01 Last updated: 2018-09-05Bibliographically approved
    3. Utility of bronchoalveolar lavage in diagnosing respiratory tract infections in patients with hematological malignancies: are invasive diagnostics still needed?
    Open this publication in new window or tab >>Utility of bronchoalveolar lavage in diagnosing respiratory tract infections in patients with hematological malignancies: are invasive diagnostics still needed?
    2017 (English)In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 1, p. 56-60Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Patients treated for hematological malignancies have an increased risk of serious infections. Diagnosis and prompt initiation of therapy are essential. Bronchoalveolar lavage (BAL) is a well-established investigation for identifying the cause of pulmonary infiltrates in immunocompromised patients. The aim of the study was to determine the diagnostic yield of BAL in patients treated for hematological malignancies and how often it contributed to a modification of the anti-infectious therapy.

    METHODS: We reviewed records from 151 consecutive BAL procedures in 133 adult patients with hematological malignancies, treated at a tertiary hematology unit from 2004 to 2013. Extensive microbiological work-ups on BAL samples had been performed according to a standardized protocol.

    RESULTS: A microbiological finding causing the infectious episode could be identified in 59 (39%) cases. In 44 (29%) of the cases, results from BAL had an impact on clinical management either by contributing to a specific diagnosis (25%) or by leading to cessation of ongoing microbiological therapy. The most common diagnoses were invasive pulmonary aspergillosis (IPA) and Pneumocystis jirovecii pneumonia (PJP). Diagnoses of IPA and PJP were based on results from BAL in 65% and 93% of cases, respectively. Several microbiological tests on BAL samples rendered no positive results. Complications were few and mainly mild.

    CONCLUSION: BAL is still important for either verifying or excluding some of the most important respiratory tract pathogens in patients with hematological malignancies, particularly IPA and PJP. Standardized procedures for BAL sampling should be continually revised to exclude unnecessary microbiological tests.

    Keywords
    Aspergillosis, bronchoalveolar lavage, hematological malignancies, immunodeficiency, invasive fungal disease, neutropenia, Pneumocystis jirovecii pneumonia, pulmonary infiltrates
    National Category
    General Practice Respiratory Medicine and Allergy
    Identifiers
    urn:nbn:se:uu:diva-310816 (URN)10.1080/03009734.2016.1237595 (DOI)000396476600008 ()27739337 (PubMedID)
    Available from: 2016-12-20 Created: 2016-12-20 Last updated: 2018-02-26Bibliographically approved
    4. A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine
    Open this publication in new window or tab >>A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine
    Show others...
    2014 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 93, no 5, p. 439-445Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES:

    Thrombocytopenia is an independent adverse prognostic factor in patients with Myelodysplastic syndromes (MDS). Azacitidine, first-line treatment for the majority of patients with higher-risk MDS, is associated with aggravated thrombocytopenia during the first cycles. Eltrombopag is a novel thrombopoietin receptor agonist, which also has been shown to inhibit proliferation of leukaemia cell lines in vitro. This phase I clinical trial was designed to explore the safety and tolerability of combining eltrombopag with azacitidine in patients with MDS. In addition, we assessed the potential effects of eltrombopag on hematopoietic stem and progenitor cells (HSPCs) from included patients.

    PATIENTS AND METHODS:

    Previously untreated patients with MDS eligible for treatment with azacitidine and with a platelet count <75 × 109/L were included. Patients received eltrombopag in dose escalation cohorts during three cycles of azacitidine.

    RESULTS:

    Twelve patients, with a median age of 74 yr, were included. Severe adverse events included infectious complications, deep vein thrombosis and transient ischaemic attack. The maximal tolerated eltrombopag dose was 200 mg qd. Complete remission or bone marrow remission was achieved in 4 of 12 patients. Platelet counts improved or remained stable in 9 of 12 patients despite azacitidine treatment. No increase in blast count, disease progression, or bone marrow fibrosis related to study medication was reported. Eltrombopag did not induce cycling of HSPCs.

    CONCLUSION:

    The combination of eltrombopag with azacitidine in high-risk MDS patients is feasible and well tolerated. Improvements in platelet counts and the potential antileukaemic effect of eltrombopag should be explored in a randomised study.

    National Category
    Hematology
    Identifiers
    urn:nbn:se:uu:diva-233787 (URN)10.1111/ejh.12383 (DOI)000343970700011 ()24853277 (PubMedID)
    Available from: 2014-10-10 Created: 2014-10-10 Last updated: 2017-12-05Bibliographically approved
  • 316.
    Svensson, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Answer to "Letter to the Editor, Scandinavian Journal of Infectious Diseases"2013In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 45, no 9, p. 730-730Article in journal (Refereed)
  • 317.
    Svensson, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Chowdhury, Onima
    Garelius, Hege
    Lorenz, Fryderyk
    Saft, Leonie
    Jacobsen, Sten-Eirik
    Hellström-Lindberg, Eva
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    A pilot phase I dose finding safety study of the thrombopoietin-receptor agonist, eltrombopag, in patients with myelodysplastic syndrome treated with azacitidine2014In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 93, no 5, p. 439-445Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    Thrombocytopenia is an independent adverse prognostic factor in patients with Myelodysplastic syndromes (MDS). Azacitidine, first-line treatment for the majority of patients with higher-risk MDS, is associated with aggravated thrombocytopenia during the first cycles. Eltrombopag is a novel thrombopoietin receptor agonist, which also has been shown to inhibit proliferation of leukaemia cell lines in vitro. This phase I clinical trial was designed to explore the safety and tolerability of combining eltrombopag with azacitidine in patients with MDS. In addition, we assessed the potential effects of eltrombopag on hematopoietic stem and progenitor cells (HSPCs) from included patients.

    PATIENTS AND METHODS:

    Previously untreated patients with MDS eligible for treatment with azacitidine and with a platelet count <75 × 109/L were included. Patients received eltrombopag in dose escalation cohorts during three cycles of azacitidine.

    RESULTS:

    Twelve patients, with a median age of 74 yr, were included. Severe adverse events included infectious complications, deep vein thrombosis and transient ischaemic attack. The maximal tolerated eltrombopag dose was 200 mg qd. Complete remission or bone marrow remission was achieved in 4 of 12 patients. Platelet counts improved or remained stable in 9 of 12 patients despite azacitidine treatment. No increase in blast count, disease progression, or bone marrow fibrosis related to study medication was reported. Eltrombopag did not induce cycling of HSPCs.

    CONCLUSION:

    The combination of eltrombopag with azacitidine in high-risk MDS patients is feasible and well tolerated. Improvements in platelet counts and the potential antileukaemic effect of eltrombopag should be explored in a randomised study.

  • 318.
    Svensson, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Clinical significance of serum immunoglobulin G subclass deficiency in patients with chronic lymphocytic leukemia2013In: Scandinavian Journal of Infectious Diseases, ISSN 0036-5548, E-ISSN 1651-1980, Vol. 45, no 7, p. 537-542Article in journal (Refereed)
    Abstract [en]

    Background: Patients with chronic lymphocytic leukemia (CLL) and hypogammaglobulinemia who suffer from recurrent infections can be offered prophylactic intravenous immunoglobulin (Ig) substitution. Our aim was to assess the prevalence of pure IgG subclass deficiency (with normal Ig levels), its correlation to risk of infection, and the clinical value of routine measurement of serum IgG subclass levels in patients with CLL. Methods: Serum levels of Ig and IgG subclasses were determined in patients with CLL at Uppsala University Hospital. Clinical data were collected through patient records and questionnaires. Results: Hypogammaglobulinemia occurred in 52.3% out of 111 patients. These patients did not have a higher annual risk of infection than patients without hypogammaglobulinemia (79.5% vs 79.1%, p = 0.706 for all infections; 13.4% vs 11.2%, p = 0.394 for severe infection; and 1.7% vs 3.4%, p = 0.083 for sepsis). Pure subclass deficiency was uncommon and occurred in 6 patients (5.4%). The annual overall risk of infection, of severe infection, and of sepsis for these patients did not differ as compared to patients with no hypogammaglobulinemia and no subclass deficiency (70.8% vs 80.7%, p = 0.334; 11.8% vs 11.1%, p = 0.497; and 8.9% vs 2.3%, p = 0.067, respectively). Conclusions: Pure IgG subclass deficiency is rare in patients with CLL. In this heterogeneous cohort of patients, neither hypogammaglobulinemia nor pure IgG subclass deficiency were significant risk factors for infectious complications. Measurement of serum levels of Ig may be justified in patients with recurrent severe infections, but routine analysis of IgG subclass levels in patients with CLL is probably not warranted.

  • 319.
    Svensson, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kättström, Magdalena
    Hammarlund, Ylva
    Roth, Daniel
    Andersson, Per-Ola
    Svensson, Magnus
    Nilsson, Ingmar
    Rombo, Lars
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Kimby, Eva
    Conjugated Pneumococcal Vaccine Triggers a Better Immune Response than Polysaccharide Pneumococcal Vaccine in Patients with Chronic Lymphocytic Leukemia: A Randomized Study by the Swedish CLL group2018In: Vaccine, ISSN 0264-410X, E-ISSN 1873-2518, Vol. 36, no 25, p. 3701-3707Article in journal (Refereed)
    Abstract [en]

    Aim: To determine if patients with untreated chronic lymphocytic leukemia (CLL) benefit from vaccination with a 13-valent conjugated pneumococcal vaccine (PCV13), Prevenar13®, compared with a 23-valent capsular polysaccharide vaccine (PPSV23), Pneumovax®, in terms of immune response.

     

    Background: Patients with CLL have an increased risk for infection and Streptococcus pneumoniae is one of the most common pathogens with high morbidity.  Patients with CLL are known to respond poorly to the traditionally used polysaccharide vaccines. Conjugation of polysaccharide to protein carriers renders a thymus-dependent, memory-inducing and more immunogenic vaccine. In patients with CLL, there is no consensus on a recommendation for pneumococcal vaccination, due to a lack of comparative studies.

     

    Methods: 128 treatment naïve CLL patients from eight hematology clinics in Sweden were randomized to vaccination with PCV13 (n=63) or PPSV23 (n=65) after stratification by IgG levels and CLL clinical stage (Rai). Blood samples for evaluation of immune response were obtained at baseline, at one and at six months after vaccination. Analyses for each of the 12 pneumococcal serotypes common for PCV13 and PPSV23 were performed by opsonophagocytic assay (OPA) and enzyme-linked immunosorbent assay (ELISA).

     

    Results: PCV13 elicited a superior immune response than PPSV23 in 10/12 serotypes one month after vaccination and in 5/12 serotypes six months after vaccination, measured as OPA geometric mean titers (GMTs). Geometric mean concentrations of serotype-specific IgG antibodies elicited by PCV13 as measured by ELISA, were higher than those elicited by PPSV23 in half of the common serotypes, both after one and six months. The proportion of patients with good response (defined as response in 8 of 12 common serotypes according to predefined response criteria) was higher in PCV13 recipients than in PPSV23 recipients after one month (40% vs. 22%, p=0.034) as well as after six months (33% vs. 17%, p=0.041). Never did PPSV23 trigger a better immune response for any of the serotypes, than PCV13, regardless of analysis. For two of the serotypes, OPA GMTs were lower at the six months than at the one-month follow up. Negative predictive factors for vaccination response were hypogammaglobulinemia and long disease duration. Both vaccines were well tolerated.

     

    Conclusions: In patients with previously untreated CLL, the efficacy of PCV13 in terms of immune response is superior to PPSV23 for many serotypes common for the two vaccines. PCV13 should be considered as a part in vaccination programs against Streptococcus pneumoniae for these patients and administered as early as possible during the course of the disease. 

  • 320.
    Svensson, Tobias
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Lundström, Kristina Lamberg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Cherif, Honar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Utility of bronchoalveolar lavage in diagnosing respiratory tract infections in patients with hematological malignancies: are invasive diagnostics still needed?2017In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 122, no 1, p. 56-60Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Patients treated for hematological malignancies have an increased risk of serious infections. Diagnosis and prompt initiation of therapy are essential. Bronchoalveolar lavage (BAL) is a well-established investigation for identifying the cause of pulmonary infiltrates in immunocompromised patients. The aim of the study was to determine the diagnostic yield of BAL in patients treated for hematological malignancies and how often it contributed to a modification of the anti-infectious therapy.

    METHODS: We reviewed records from 151 consecutive BAL procedures in 133 adult patients with hematological malignancies, treated at a tertiary hematology unit from 2004 to 2013. Extensive microbiological work-ups on BAL samples had been performed according to a standardized protocol.

    RESULTS: A microbiological finding causing the infectious episode could be identified in 59 (39%) cases. In 44 (29%) of the cases, results from BAL had an impact on clinical management either by contributing to a specific diagnosis (25%) or by leading to cessation of ongoing microbiological therapy. The most common diagnoses were invasive pulmonary aspergillosis (IPA) and Pneumocystis jirovecii pneumonia (PJP). Diagnoses of IPA and PJP were based on results from BAL in 65% and 93% of cases, respectively. Several microbiological tests on BAL samples rendered no positive results. Complications were few and mainly mild.

    CONCLUSION: BAL is still important for either verifying or excluding some of the most important respiratory tract pathogens in patients with hematological malignancies, particularly IPA and PJP. Standardized procedures for BAL sampling should be continually revised to exclude unnecessary microbiological tests.

  • 321.
    Söderlund, Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Clinical and Immunological Studies in Chronic Myeloid Leukaemia2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Chronic myeloid leukaemia (CML) is characterised by the constitutively active tyrosine kinase BCR-ABL. Standard treatment with tyrosine kinase inhibitors (TKI) in the chronic phase (CP) of CML conveys excellent long-term prognosis but is associated with side effects and costs. Treatment free remission (TFR) is possible in a proportion of patients discontinuing treatment after obtaining deep treatment responses but it is not fully known how to select the right patients for stopping attempts. Treatment of accelerated phase (AP) and blast crisis (BC) is more complicated and the prognosis more dismal. In this thesis, we have studied factors of importance for outcome in CML patients with focus on immunological factors and clinical management.

    In a cohort of 32 newly diagnosed CP-CML patients, evidence of active immune escape mechanisms were found. These declined with the course of TKI treatment and at the same time, effector lymphocyte responses were elicited. These anti-leukaemia immune responses might help in the long-term control of CML. Multiple plasma protein markers were also measured with three multiplex platforms in a smaller cohort of patients (n=14). Inflammatory cytokines and other plasma proteins were affected by TKI treatment and multiplexing seems useful for finding potential biomarkers with biologic or prognostic significance in CML.

    Patients progressing to AP/BC were studied in a population-based material from the Swedish CML register. Approximately 4% of TKI-treated CP-CML patients transformed to AP/BC within 2 years of diagnosis. Monitoring of treatment responses was suboptimal in 1/3 of these patients and the median survival was 1.4 years after diagnosis of AP/BC. Thus, minimising the risk of disease progression through strict adherence to guidelines for monitoring and treatment is essential.

    In a cohort of patients (n=50) discontinuing TKI treatment within a large European trial, musculoskeletal pain was reported by 30% of patients, starting within 1- 6 weeks of TKI discontinuation and spontaneously resolving over time in most cases. Patients (n=56) were also evaluated with a multiplex platform with a total of 162 inflammation- and cancer-related plasma proteins. No predictive protein biomarkers for successful TKI discontinuation could be found. However, profound effects of TKI-treatment were seen and plasma proteomics could be useful for understanding effects of long-term TKI-treatment.

    List of papers
    1. Musculoskeletal pain in patients with chronic myeloid leukemia after discontinuation of imatinib: a tyrosine kinase inhibitor withdrawal syndrome?
    Open this publication in new window or tab >>Musculoskeletal pain in patients with chronic myeloid leukemia after discontinuation of imatinib: a tyrosine kinase inhibitor withdrawal syndrome?
    Show others...
    2014 (English)In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 32, no 25, p. 2821-2823Article in journal (Refereed) Published
    National Category
    Clinical Medicine
    Identifiers
    urn:nbn:se:uu:diva-233785 (URN)10.1200/JCO.2014.55.6910 (DOI)000341562600033 ()25071107 (PubMedID)
    Available from: 2014-10-10 Created: 2014-10-10 Last updated: 2017-12-05Bibliographically approved
    2. The Tyrosine Kinase Inhibitors Imatinib and Dasatinib Reduce Myeloid Suppressor Cells and Release Effector Lymphocyte Responses
    Open this publication in new window or tab >>The Tyrosine Kinase Inhibitors Imatinib and Dasatinib Reduce Myeloid Suppressor Cells and Release Effector Lymphocyte Responses
    Show others...
    2015 (English)In: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 14, no 5, p. 1181-1191Article in journal (Refereed) Published
    Abstract [en]

    Immune escape mechanisms promote tumor progression and are hurdles of cancer immunotherapy. Removing immunosuppressive cells before treatment can enhance efficacy. Tyrosine kinase inhibitors (TKI) may be of interest to combine with immunotherapy, as it has been shown that the inhibitor sunitinib reduces myeloid suppressor cells in patients with renal cell carcinoma and dasatinib promotes expansion of natural killer-like lymphocytes in chronic myeloid leukemia (CML). In this study, the capacity of dasatinib and imatinib to reduce myeloid suppressor cells and to induce immunomodulation in vivo was investigated ex vivo. Samples from CML patients treated with imatinib (n = 18) or dasatinib (n = 14) within a Nordic clinical trial (clinicalTrials.gov identifier: NCT00852566) were investigated for the presence of CD11b(+)CD14(-)CD33(+) myeloid cells and inhibitorymolecules (arginase I, myeloperoxidase, IL10) as well as the presence of natural killer cells, T cells (naive/memory), and stimulatory cytokines (IL12, IFN gamma, MIG, IP10). Both imatinib and dasatinib decreased the presence of CD11b(+)CD14(-)CD33(+) myeloid cells as well as the inhibitory molecules and the remaining myeloid suppressor cells had an increased CD40 expression. Monocytes also increased CD40 after therapy. Moreover, increased levels of CD40, IL12, natural killer cells, and experienced T cells were noted after TKI initiation. The presence of experienced T cells was correlated to a higher IFNg and MIG plasma concentration. Taken together, the results demonstrate that both imatinib and dasatinib tilted the immunosuppressive CML tumor milieu towards promoting immune stimulation. Hence, imatinib and dasatinib may be of interest to combine with cancer immunotherapy. 

    National Category
    Hematology Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-269778 (URN)10.1158/1535-7163.MCT-14-0849 (DOI)000358053000010 ()25761894 (PubMedID)
    Available from: 2015-12-18 Created: 2015-12-18 Last updated: 2017-12-01Bibliographically approved
    3. Plasma proteomics in CML patients before and after initiation of tyrosine kinase inhibitor therapy reveals induced Th1 immunity and loss of angiogenic stimuli
    Open this publication in new window or tab >>Plasma proteomics in CML patients before and after initiation of tyrosine kinase inhibitor therapy reveals induced Th1 immunity and loss of angiogenic stimuli
    Show others...
    2016 (English)In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 50, p. 95-103Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND AND AIMS: The simultaneous measurement of many proteins is now possible using multiplex assays. In this pilot study we investigated a total of 124 proteins in plasma from chronic myeloid leukemia (CML) patients with the purpose of identifying proteins that are differently expressed at diagnosis and after tyrosine kinase inhibitor (TKI) treatment initiation.

    METHODS: Samples were taken from 14 CML patients at diagnosis and after three months of TKI treatment (imatinib or dasatinib). Samples were analyzed by Mesoscale Discovery, Myriad RBM MAP technology and Olink Proseek.

    RESULTS: Multiple plasma proteins were differentially expressed before and after initiation of TKI therapy. Protein patterns demonstrated a possible shift towards Th1-immunity and reduced angiogenic stimuli. Further, some plasma proteins were identified that can be of potential interest to study further for biologic, prognostic or therapeutic significance such as E-selectin, uPAR, growth hormone and carbonic anhydrase IX.

    CONCLUSIONS: Plasma proteomics seems feasible and useful in CML patients, both for studying patterns of protein expression and for identifying single proteins differentially expressed before and after treatment. Plasma proteomics may be useful to map disease activity and biological processes. Hence, plasma proteomics can be used to understand drug mechanisms and treatment responses in CML.

    Keywords
    Proteomics, Chronic myeloid leukemia, Tyrosine kinase inhibitor, Th1, Angiogenesis
    National Category
    Cancer and Oncology Hematology
    Identifiers
    urn:nbn:se:uu:diva-310831 (URN)10.1016/j.leukres.2016.09.019 (DOI)000388315500015 ()27710869 (PubMedID)
    Available from: 2016-12-20 Created: 2016-12-20 Last updated: 2017-11-29Bibliographically approved
    4. Advanced phase chronic myeloid leukaemia (CML) in the tyrosine kinase inhibitor era: a report from the Swedish CML register
    Open this publication in new window or tab >>Advanced phase chronic myeloid leukaemia (CML) in the tyrosine kinase inhibitor era: a report from the Swedish CML register
    Show others...
    2017 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 98, no 1, p. 57-66Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVES: The primary goal in management of chronic phase (CP) chronic myeloid leukaemia (CML) is to prevent disease progression to accelerated phase (AP) or blast crisis (BC). We have evaluated progression rates in a decentralised healthcare setting and characterised patients progressing to AP/BC on TKI treatment.

    METHODS: Using data from the Swedish CML register, we identified CP-CML patients diagnosed 2007-2011 who progressed to AP/BC within 2 yrs from diagnosis (n = 18) as well as patients diagnosed in advanced phase during 2007-2012 (n = 36) from a total of 544 newly diagnosed CML cases. We evaluated baseline characteristics, progression rates, outcome and adherence to guidelines for monitoring and treatment.

    RESULTS: The cumulative progression rate at 2 yrs was 4.3%. All 18 progression cases had been treated with imatinib, and six progressed within 6 months. High-risk EUTOS score was associated to a higher risk of progression. Insufficient cytogenetic and/or molecular monitoring was found in 33%. Median survival after transformation during TKI treatment was 1.4 yrs. In those presenting with BC and AP, median survival was 1.6 yrs and not reached, respectively.

    CONCLUSION: In this population-based setting, progression rates appear comparable to that reported from clinical trials, with similar dismal patient outcome. Improved adherence to CML guidelines may minimise the risk of disease progression.

    National Category
    Hematology
    Identifiers
    urn:nbn:se:uu:diva-310827 (URN)10.1111/ejh.12785 (DOI)000393166600009 ()27428357 (PubMedID)
    Available from: 2016-12-20 Created: 2016-12-20 Last updated: 2018-02-26Bibliographically approved
    5. Proximity extension assay-based plasma proteomics cannot predict relapse in chronic myeloid leukaemia patients stopping treatment with tyrosine kinase inhibitors (TKI) but reveal profound effects of long-term TKI treatment on plasma protein profiles
    Open this publication in new window or tab >>Proximity extension assay-based plasma proteomics cannot predict relapse in chronic myeloid leukaemia patients stopping treatment with tyrosine kinase inhibitors (TKI) but reveal profound effects of long-term TKI treatment on plasma protein profiles
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Hematology
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-327172 (URN)
    Available from: 2017-08-05 Created: 2017-08-05 Last updated: 2017-08-05
  • 322.
    Söderlund, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Christiansson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Persson, Inger
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Hjorth-Hansen, H.
    Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, Trondheim, Norway..
    Richter, J.
    Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden..
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mustjoki, S.
    Univ Helsinki, Dept Hematol, Hematol Res Unit, Helsinki, Finland..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Plasma Proteomics In Chronic Myeloid Leukemia Patients Before And After Initiation Of Tyrosine Kinase Inhibitor Therapy Reveals Induced Th1 Immunity And Loss Of Angiogenic Stimuli2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 730-730Article in journal (Other academic)
  • 323.
    Söderlund, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Uppsala Hosp, Sect Hematol, Entrance 50, S-75185 Uppsala, Sweden.
    Christiansson, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Persson, Inger
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway; Norwegian Univ Sci & Technol NTNU, Dept Canc Res & Mol Med, Trondheim, Norway.
    Richter, Johan
    Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden.
    Simonsson, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Mustjoki, Satu
    Univ Helsinki, Dept Hematol, Hematol Res Unit Helsinki, Helsinki, Finland; Univ Helsinki, Cent Hosp, Ctr Comprehens Canc, Helsinki, Finland; Univ Helsinki, Dept Clin Chem, Helsinki, Finland.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Loskog, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Plasma proteomics in CML patients before and after initiation of tyrosine kinase inhibitor therapy reveals induced Th1 immunity and loss of angiogenic stimuli2016In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 50, p. 95-103Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: The simultaneous measurement of many proteins is now possible using multiplex assays. In this pilot study we investigated a total of 124 proteins in plasma from chronic myeloid leukemia (CML) patients with the purpose of identifying proteins that are differently expressed at diagnosis and after tyrosine kinase inhibitor (TKI) treatment initiation.

    METHODS: Samples were taken from 14 CML patients at diagnosis and after three months of TKI treatment (imatinib or dasatinib). Samples were analyzed by Mesoscale Discovery, Myriad RBM MAP technology and Olink Proseek.

    RESULTS: Multiple plasma proteins were differentially expressed before and after initiation of TKI therapy. Protein patterns demonstrated a possible shift towards Th1-immunity and reduced angiogenic stimuli. Further, some plasma proteins were identified that can be of potential interest to study further for biologic, prognostic or therapeutic significance such as E-selectin, uPAR, growth hormone and carbonic anhydrase IX.

    CONCLUSIONS: Plasma proteomics seems feasible and useful in CML patients, both for studying patterns of protein expression and for identifying single proteins differentially expressed before and after treatment. Plasma proteomics may be useful to map disease activity and biological processes. Hence, plasma proteomics can be used to understand drug mechanisms and treatment responses in CML.

  • 324.
    Söderlund, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Dahlen, T.
    Karolinska Univ Hosp Solna, Div Hematol, Dept Med, Stockholm, Sweden..
    Creignou, M.
    Linkoping Univ Hosp, Dept Hematol, S-58185 Linkoping, Sweden..
    Sandin, F.
    Univ Uppsala Hosp, Reg Canc Ctr, Uppsala, Sweden..
    Olsson-Stromberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Dreimane, A.
    Linkoping Univ Hosp, Dept Hematol, S-58185 Linkoping, Sweden..
    Markevaem, B.
    Umea Univ Hosp, Dept Hematol, S-90185 Umea, Sweden..
    Sjaelander, A.
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden..
    Wadenvik, H.
    Sahlgrens Univ Hosp, Sect Hematol & Coagulat, Gothenburg, Sweden..
    Stenke, L.
    Karolinska Univ Hosp Solna, Div Hematol, Dept Med, Stockholm, Sweden..
    Richter, J.
    Skane Univ Hosp, Dept Hematol & Vasc Disorders, Lund, Sweden..
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    PROGRESSION OF CHRONIC PHASE CHRONIC MYELOID LEUKEMIA TO ADVANCED PHASE ON TKI THERAPY: A POPULATION BASED ANALYSIS FROM THE SWEDISH CML REGISTER2015In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, p. 233-233Article in journal (Other academic)
  • 325.
    Söderlund, Stina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Dahlén, Torsten
    Karolinska Univ Hosp, Dept Haematol, Stockholm, Sweden.; Karolinska Inst, Dept Med, Stockholm, Sweden.
    Sandin, Fredrik
    Reg Canc Ctr Uppsala-Örebro, Uppsala, Sweden.
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Creignou, Maria
    Linkoping Univ Hosp, Dept Haematol, Linkoping, Sweden.
    Dreimane, Arta
    Linkoping Univ Hosp, Dept Haematol, Linkoping, Sweden.
    Lübking, Anna
    Skane Univ Hosp, Dept Haematol Oncol & Radiat Phys, Lund, Sweden.
    Markevärn, Berit
    Umea Univ Hosp, Dept Haematol, Umea, Sweden.
    Själander, Anders
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Wadenvik, Hans
    Sahlgrens Univ Hosp, Sect Haematol & Coagulat, Gothenburg, Sweden.
    Stenke, Leif
    Karolinska Univ Hosp, Dept Haematol, Stockholm, Sweden.; Karolinska Inst, Dept Med, Stockholm, Sweden.
    Richter, Johan
    Skane Univ Hosp, Dept Haematol Oncol & Radiat Phys, Lund, Sweden.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Advanced phase chronic myeloid leukaemia (CML) in the tyrosine kinase inhibitor era: a report from the Swedish CML register2017In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 98, no 1, p. 57-66Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: The primary goal in management of chronic phase (CP) chronic myeloid leukaemia (CML) is to prevent disease progression to accelerated phase (AP) or blast crisis (BC). We have evaluated progression rates in a decentralised healthcare setting and characterised patients progressing to AP/BC on TKI treatment.

    METHODS: Using data from the Swedish CML register, we identified CP-CML patients diagnosed 2007-2011 who progressed to AP/BC within 2 yrs from diagnosis (n = 18) as well as patients diagnosed in advanced phase during 2007-2012 (n = 36) from a total of 544 newly diagnosed CML cases. We evaluated baseline characteristics, progression rates, outcome and adherence to guidelines for monitoring and treatment.

    RESULTS: The cumulative progression rate at 2 yrs was 4.3%. All 18 progression cases had been treated with imatinib, and six progressed within 6 months. High-risk EUTOS score was associated to a higher risk of progression. Insufficient cytogenetic and/or molecular monitoring was found in 33%. Median survival after transformation during TKI treatment was 1.4 yrs. In those presenting with BC and AP, median survival was 1.6 yrs and not reached, respectively.

    CONCLUSION: In this population-based setting, progression rates appear comparable to that reported from clinical trials, with similar dismal patient outcome. Improved adherence to CML guidelines may minimise the risk of disease progression.

  • 326.
    Tobiasson, Magnus
    et al.
    Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden..
    Abdulkadir, Hani
    Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden..
    Lennartsson, Andreas
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Stockholm Count, Sweden..
    Katayama, Shintaro
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Stockholm Count, Sweden..
    Marabita, Francesco
    Karolinska Inst, Dept Med, Ctr Mol Med, Unit Computat Med, Stockholm, Sweden.;Natl Bioinformat Infrastruct Sweden, Stockholm, Sweden..
    De Paepe, Ayla
    Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden..
    Karimi, Mohsen
    Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden..
    Krjutskov, Kaarel
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Stockholm Count, Sweden.;Univ Helsinki, Mol Neurol Res Program, Helsinki, Finland.;Folkhalsan Inst Genet, Helsinki, Finland.;Competence Ctr Hlth Technol, Tartu, Estonia..
    Einarsdottir, Elisabet
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Stockholm Count, Sweden.;Univ Helsinki, Mol Neurol Res Program, Helsinki, Finland.;Folkhalsan Inst Genet, Helsinki, Finland..
    Grövdal, Michael
    Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden..
    Jansson, Monika
    Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden..
    Ben Azenkoud, Asmaa
    Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden..
    Corddedu, Lina
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Stockholm Count, Sweden..
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden.
    Ekwall, Karl
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Stockholm Count, Sweden..
    Kere, Juha
    Karolinska Inst, Dept Biosci & Nutr, Stockholm, Stockholm Count, Sweden.;Univ Helsinki, Mol Neurol Res Program, Helsinki, Finland.;Folkhalsan Inst Genet, Helsinki, Finland..
    Hellström-Lindberg, Eva
    Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden..
    Ungerstedt, Johanna
    Karolinska Univ Hosp Huddinge, Ctr Hematol & Regenerat Med, Dept Med Huddinge, Div Hematol,Karolinska Inst, Huddinge, Sweden..
    Comprehensive mapping of the effects of azacitidine on DNA methylation, repressive/permissive histone marks and gene expression in primary cells from patients with MDS and MDS-related disease2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 17, p. 28812-28825Article in journal (Refereed)
    Abstract [en]

    Azacitidine (Aza) is first-line treatment for patients with high-risk myelodysplastic syndromes (MDS), although its precise mechanism of action is unknown. We performed the first study to globally evaluate the epigenetic effects of Aza on MDS bone marrow progenitor cells assessing gene expression (RNA seq), DNA methylation (Illumina 450k) and the histone modifications H3K18ac and H3K9me3 (ChIP seq). Aza induced a general increase in gene expression with 924 significantly upregulated genes but this increase showed no correlation with changes in DNA methylation or H3K18ac, and only a weak association with changes in H3K9me3. Interestingly, we observed activation of transcripts containing 15 endogenous retroviruses (ERVs) confirming previous cell line studies. DNA methylation decreased moderately in 99% of all genes, with a median beta-value reduction of 0.018; the most pronounced effects seen in heterochromatin. Aza-induced hypomethylation correlated significantly with change in H3K9me3. The pattern of H3K18ac and H3K9me3 displayed large differences between patients and healthy controls without any consistent pattern induced by Aza. We conclude that the marked induction of gene expression only partly could be explained by epigenetic changes, and propose that activation of ERVs may contribute to the clinical effects of Aza in MDS.

  • 327.
    Toft, N.
    et al.
    Herlev Univ Hosp, Dept Hematol, Herlev, Denmark.;Rigshosp, Univ Hosp, Dept Hematol, Copenhagen, Denmark..
    Birgens, H.
    Herlev Univ Hosp, Dept Hematol, Herlev, Denmark..
    Abrahamsson, J.
    Queen Silvias Childrens Hosp, Dept Clin Sci, Gothenburg, Sweden..
    Griskevicius, L.
    Vilnius Univ Hosp, Santariskiu Klin, Hematol Oncol & Transfus Med Ctr, Vilnius, Lithuania..
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Heyman, M.
    Karolinska Inst, Karolinska Univ Hosp, Astrid Lindgrens Childrens Hosp, Childhood Canc Res Unit, Stockholm, Sweden..
    Klausen, T. W.
    Herlev Univ Hosp, Dept Hematol, Herlev, Denmark..
    Jonsson, O. G.
    Landspitali Univ Hosp, Childrens Hosp, Reykjavk, Iceland..
    Palk, K.
    North Estonia Med Ctr, Dept Hematol, Tallinn, Estonia..
    Pruunsild, K.
    Tallinn Childrens Hosp, Tallinn, Estonia..
    Quist-Paulsen, P.
    Trondheim Reg & Univ Hosp, St Olavs Hosp, Dept Hematol, Trondheim, Norway..
    Vaitkeviciene, G.
    Vilnius Univ Hosp, Santariskiu Klin, Childrens Hosp, Ctr Pediat Oncol & Hematol, Vilnius, Lithuania..
    Vettenranta, K.
    Univ Helsinki, Cent Hosp, Hosp Children & Adolescents, Div Hematol Oncol & Stem Cell Transplantat, Helsinki, Finland..
    Asberg, A.
    Trondheim Reg & Univ Hosp, St Olavs Hosp, Dept Pediat, Trondheim, Norway..
    Frandsen, T. Leth
    Rigshosp, Dept Pediat & Adolescent Med, Copenhagen, Denmark..
    Marquart, H. V.
    Rigshosp, Univ Hosp, Sect 7631, Dept Clin Immunol, Copenhagen, Denmark..
    Madsen, H. O.
    Rigshosp, Univ Hosp, Sect 7631, Dept Clin Immunol, Copenhagen, Denmark..
    Noren-Nystrom, U.
    Umea Univ, Dept Clin Sci, Pediat, Umea, Sweden..
    Schmiegelow, K.
    Univ Copenhagen, Rigshosp, Dept Pediat & Adolescent Med, Copenhagen, Denmark.;Univ Copenhagen, Fac Med, Inst Clin Med, Copenhagen, Denmark..
    Adults And Children (1-45 Years) With Ph-Negative All Have Almost Identical Outcome In Risk-Stratified Analysis Of Nopho All20082016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, p. 35-35Article in journal (Other academic)
  • 328. Toft, N
    et al.
    Birgens, H
    Abrahamsson, J
    Griškevičius, L
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Heyman, M
    Klausen, T W
    Jónsson, Ó G
    Palk, K
    Pruunsild, K
    Quist-Paulsen, P
    Vaitkeviciene, G
    Vettenranta, K
    Åsberg, A
    Frandsen, T L
    Marquart, H V
    Madsen, H O
    Norén-Nyström, U
    Schmiegelow, K
    Results of NOPHO ALL2008 treatment for patients aged 1-45 years with acute lymphoblastic leukemia.2018In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 32, p. 606-615Article in journal (Refereed)
    Abstract [en]

    Adults with acute lymphoblastic leukemia (ALL) do worse than children. From 7/2008 to 12/2014, Nordic and Baltic centers treated 1509 consecutive patients aged 1-45 years with Philadelphia chromosome-negative ALL according to the NOPHO ALL2008 without cranial irradiation. Overall, 1022 patients were of age 1-9 years (A), 266 were 10-17 years (B) and 221 were 18-45 years (C). Sixteen patients (three adults) died during induction. All others achieved remission after induction or 1-3 intensive blocks. Subsequently, 45 patients (12 adults) died, 122 patients relapsed (32 adults) with a median time to relapse of 1.6 years and 13 (no adult) developed a second malignancy. Median follow-up time was 4.6 years. Among the three age groups, older patients more often had higher risk ALL due to T-ALL (32%/25%/9%, P<0.001), KMT2A rearrangements (6%/5%/3%, P<0.001) and higher day 29 residual leukemia for B-lineage (P<0.001), but not T-ALL (P = 0.53). Event-free survival rates (pEFS(5y)) were 89 +/- 1% (A), 80 +/- 3% (B) and 74 +/- 4% (C) with significant differences only for non-high risk groups. Except for thrombosis, pancreatitis and osteonecrosis, the risk of 19 specified toxicities was not enhanced by age above 10 years. In conclusion, a pediatric-based protocol is tolerable and effective for young adults, despite their increased frequency of higher risk features.

  • 329. Toft, Nina
    et al.
    Birgens, Henrik
    Abrahamsson, Jonas
    Bernell, Per
    Griškevičius, Laimonas
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Heyman, Mats
    Holm, Mette Skov
    Hulegårdh, Erik
    Klausen, Tobias Wirenfeldt
    Marquart, Hanne V
    Jónsson, Olafur Gísli
    Nielsen, Ove Juul
    Quist-Paulsen, Petter
    Taskinen, Mervi
    Vaitkeviciene, Goda
    Vettenranta, Kim
    Asberg, Ann
    Schmiegelow, Kjeld
    Risk group assignment differs for children and adults 1-45 years with acute lymphoblastic leukemia treated by the NOPHO ALL-2008 protocol2013In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 90, no 5, p. 404-412Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    The prognosis of acute lymphoblastic leukemia is poorer in adults than in children. Studies have indicated that young adults benefit from pediatric treatment, although no upper age limit has been defined.

    DESIGN AND METHODS:

    We analyzed 749 patients aged 1-45 years treated by the NOPHO ALL-2008 protocol. Minimal residual disease (MRD) on days 29 and 79, immunophenotype, white blood cell count (WBC), and cytogenetics were used to stratify patients to standard, intermediate, or high risk treatment with or without hematopoietic stem cell transplantation.

    RESULTS:

    Adults aged 18-45 had significantly lower WBCs at diagnosis compared to children aged 1-9 and 10-17 years, but significantly more adults were stratified to high-risk chemotherapy (8%, 14%, 17%; p < 0.0001) or high risk chemotherapy with transplantation (4%, 13%, 19%; p < 0.0001). This age dependent skewing of risk grouping reflected more T-ALL (11%, 27%, 33%, p < 0.0001), poorer MRD response day 29 (MRD < 0.1%: 75%, 61%, 52%; p < 0.0001), and more MLL gene rearrangements (3%, 3%, 10%; p = 0.005) in older patients.

    CONCLUSIONS:

    Even if identical diagnostics, treatment, and risk stratification are implemented, more adults will be stratified to high risk therapy, which should be considered when comparing pediatric and adult outcomes.

  • 330. Toft, Nina
    et al.
    Birgens, Henrik
    Abrahamsson, Jonas
    Griškevičius, Laimonas
    Hallböök, Helene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Heyman, Mats
    Klausen, Tobias Wirenfeldt
    Jónsson, Ólafur Gísli
    Palk, Katrin
    Pruunsild, Kaie
    Quist-Paulsen, Petter
    Vaitkeviciene, Goda
    Vettenranta, Kim
    Asberg, Ann
    Helt, Louise Rold
    Frandsen, Thomas
    Schmiegelow, Kjeld
    Toxicity profile and treatment delays in NOPHO ALL2008-comparing adults and children with Philadelphia chromosome-negative acute lymphoblastic leukemia2016In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 96, no 2, p. 160-169Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Cure rates improve when adolescents and young adults with acute lymphoblastic leukemia (ALL) are treated according to pediatric protocols. Assumed risks of toxicities and associated delays in treatment have played a role in setting upper age limits. The aim of this study was to examine the toxicity profile and treatment delays in NOPHO ALL2008 comparing children and adults.

    METHODS: We collected information on 19 treatment-related toxicities, systematically captured at 3-month intervals throughout therapy, and time intervals between 12 consecutive treatment phases for 1076 patients aged 1-45 yrs treated according to the Nordic/Baltic ALL2008 protocol.

    RESULTS: No adults died during induction. The duration of induction therapy and postinduction treatment phases did not differ between children and adults, except for patients 18-45 yrs being significantly delayed during two of nine high-risk blocks (median number of days for patients 1-9, 10-17, and 18-45 yrs; the glucocorticosteroid/antimetabolite-based block B1: 24, 26, and 29 d, respectively, P = 0.001, and Block 5 (in most cases also a B block): 29, 29, and 37 d, respectively, P = 0.02). A higher incidence of thrombosis with increasing age was found; highest odds ratio 5.4 (95% CI: (2.6;11.0)) for patients 15-17 yrs compared with children 1-9 yrs (P < 0.0001). Risk of avascular osteonecrosis was related to age with the highest OR for patients 10-14 yrs (OR = 10.4 (95% CI: (4.4;24.9)), P < 0.0001).

    CONCLUSION: Adults followed and tolerated the NOPHO ALL2008 protocol virtually as well as children, although thrombosis and avascular osteonecrosis was most common among adolescents.

  • 331.
    Ungerstedt, J.
    et al.
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Eriksson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Olander, E.
    Umea Univ, Dept Med, Umea, Sweden..
    Bergfelt, Emma
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Liljeholm, M.
    Umea Univ, Dept Med, Umea, Sweden..
    Kristjanssdottir, H. Lind
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Erger, T.
    Erixon, D.
    Umea Univ, Dept Med, Umea, Sweden..
    Isaksson, C.
    Umea Univ, Dept Med, Umea, Sweden..
    Birgegård, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Uppsala Univ, Dept Med Sci, Uppsala, Sweden..
    Development of a Progress Test Based on the EHA Curriculum and EHA CV Passport, Used for Yearly Evaluation of Hematology Residency In Sweden2015In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, p. 776-776Article in journal (Other academic)
  • 332. Ungerstedt, J.
    et al.
    Eriksson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Olander, E.
    Theander, J.
    Liljeholm, M.
    Isaksson, C.
    Birgegard, G.
    Development of Progress Test Based on EHA Curriculum and EHA CV Passport, Used for Yearly Evaluation of Hematology Residency in Sweden2014In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 99, p. 788-788Article in journal (Other academic)
  • 333.
    Ustun, Celalettin
    et al.
    Univ Minnesota, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA..
    Gotlib, Jason
    Stanford Univ, Div Hematol, Stanford, CA USA..
    Popat, Uday
    Univ Texas MD Anderson Canc Ctr, Dept Stem Cell Transplantat, Houston, TX USA..
    Artz, Andrew
    Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL USA..
    Litzow, Mark
    Mayo Clin, Dept Internal Med, Div Hematol, Minneapolis, MN USA..
    Reiter, Andreas
    Univ Med Ctr Mannheim, Dept Hematol & Oncol, Mannheim, Germany..
    Nakamura, Ryotaro
    City Hope Med Ctr, Dept Hematol Hematopoiet Cell Transplantat, Duarte, CA USA..
    Kluin-Nelemans, Hanneke C.
    Univ Groningen, Univ Med Ctr Groningen, Dept Hematol, Groningen, Netherlands..
    Verstovsek, Srdan
    Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX USA..
    Gajewskil, James
    Oregon Hlth & Sci Univ, Dept Hematol, Portland, OR USA..
    Perales, Miguel-Angel
    Mem Sloan Kettering Canc Ctr, Dept Med, Div Hematol Oncol, New York, NY USA..
    George, Tracy
    Univ New Mexico, Dept Pathol, Albuquerque, NM USA..
    Shore, Tsiporah
    Weill Cornell Med Coll, Div Hematol & Oncol, New York, NY USA..
    Sperr, Wolfgang
    Med Univ Vienna, Dept Internal Med 1, Div Hematol & Hemostaseol & Ludwig Boltzmann Clus, Vienna, Austria..
    Saber, Wael
    Med Coll Wisconsin, Ctr Int Blood & Marrow Transplant Res, Dept Med, Milwaukee, WI USA..
    Kota, Vamsi
    Emory Univ, Winship Canc Inst, Dept Hematol & Oncol, Div Hematol, Atlanta, GA USA..
    Yavuz, Akif Selim
    Istanbul Univ, Istanbul Med Sch, Div Hematol, Istanbul, Turkey..
    Pullarkat, Vinod
    Rogosheske, John
    Univ Minnesota, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA..
    Hogan, William
    Mayo Clin, Dept Internal Med, Div Hematol, Minneapolis, MN USA..
    Van Besien, Koen
    Weill Cornell Med Coll, Dept Med, New York, NY USA..
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Damaj, Gandhi
    Univ Basse Normandie, Univ Hosp, Sch Med, Inst Hematol,Dept Hematol, Caen, France..
    Arock, Michel
    Ecole Normale Super, CNRS UMR 8113, Cellular & Mol Oncol Unit, Cachan, France.;Univ Pitie Salpetriere, Ctr Hosp, Hematol Lab, Paris, France..
    Horny, Hans-Peter
    LMU, Inst Pathol, Munich, Germany..
    Metcalfe, Dean D.
    NIAID, Mast Cell Biol Sect, Lab Allerg Dis, NIH, Bethesda, MD USA..
    Deeg, H. Joachim
    Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA USA.;Univ Washington, Sch Med, Seattle, WA USA..
    Devine, Steven
    Ohio State Univ, Dept Med, Div Hematol, Columbus, OH 43210 USA.;Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA..
    Weisdorfl, Daniel
    Univ Minnesota, Div Hematol Oncol & Transplantat, Minneapolis, MN 55455 USA..
    Akin, Cem
    Harvard Med Sch, Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Boston, MA USA..
    Valent, Peter
    Consensus Opinion on Allogeneic Hematopoietic Cell Transplantation in Advanced Systemic Mastocytosis2016In: Biology of blood and marrow transplantation, ISSN 1083-8791, E-ISSN 1523-6536, Vol. 22, no 8, p. 1348-1356Article in journal (Other academic)
  • 334. Ustun, Celalettin
    et al.
    Reiter, Andreas
    Scott, Bart L
    Nakamura, Ryotaro
    Damaj, Gandhi
    Kreil, Sebastian
    Shanley, Ryan
    Hogan, William J
    Perales, Miguel-Angel
    Shore, Tsiporah
    Baurmann, Herrad
    Stuart, Robert
    Gruhn, Bernd
    Doubek, Michael
    Hsu, Jack W
    Tholouli, Eleni
    Gromke, Tanja
    Godley, Lucy A
    Pagano, Livio
    Gilman, Andrew
    Wagner, Eva Maria
    Shwayder, Tor
    Bornhäuser, Martin
    Papadopoulos, Esperanza B
    Böhm, Alexandra
    Vercellotti, Gregory
    Van Lint, Maria Teresa
    Schmid, Christoph
    Rabitsch, Werner
    Pullarkat, Vinod
    Legrand, Faezeh
    Yakoub-Agha, Ibrahim
    Saber, Wael
    Barrett, John
    Hermine, Olivier
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska University Hospital, Stockholm, Sweden.
    Sperr, Wolfgang R
    Popat, Uday
    Alyea, Edwin P
    Devine, Steven
    Deeg, H Joachim
    Weisdorf, Daniel
    Akin, Cem
    Valent, Peter
    Hematopoietic stem-cell transplantation for advanced systemic mastocytosis2014In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 32, no 29, p. 3264-3274Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Advanced systemic mastocytosis (SM), a fatal hematopoietic malignancy characterized by drug resistance, has no standard therapy. The effectiveness of allogeneic hematopoietic stem-cell transplantation (alloHCT) in SM remains unknown.

    PATIENTS AND METHODS: In a global effort to define the value of HCT in SM, 57 patients with the following subtypes of SM were evaluated: SM associated with clonal hematologic non-mast cell disorders (SM-AHNMD; n = 38), mast cell leukemia (MCL; n = 12), and aggressive SM (ASM; n = 7). Median age of patients was 46 years (range, 11 to 67 years). Donors were HLA-identical (n = 34), unrelated (n = 17), umbilical cord blood (n = 2), HLA-haploidentical (n = 1), or unknown (n = 3). Thirty-six patients received myeloablative conditioning (MAC), and 21 patients received reduced-intensity conditioning (RIC).

    RESULTS: Responses in SM were observed in 40 patients (70%), with complete remission in 16 patients (28%). Twelve patients (21%) had stable disease, and five patients (9%) had primary refractory disease. Overall survival (OS) at 3 years was 57% for all patients, 74% for patients with SM-AHNMD, 43% for those with ASM, and 17% for those with MCL. The strongest risk factor for poor OS was MCL. Survival was also lower in patients receiving RIC compared with MAC and in patients having progression compared with patients having stable disease or response.

    CONCLUSION: AlloHCT was associated with long-term survival in patients with advanced SM. Although alloHCT may be considered as a viable and potentially curative therapeutic option for advanced SM in the meantime, given that this is a retrospective analysis with no control group, the definitive role of alloHCT will need to be determined by a prospective trial.

  • 335. Uttervall, Katarina
    et al.
    Admasie, Johannes
    Alici, Evren
    Lund, Johan
    Liwing, Johan
    Aschan, Johan
    Barendse, Mirjam
    Deneberg, Stefan
    Mellqvist, Ulf-Henrik
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Nahi, Hareth
    A Combination Regimen of Bortezomib, Cyclophosphamide and Betamethasone Gives Quicker, Better and More Durable Response than VAD/CyBet Regimens: Results from a Swedish Retrospective Analysis2013In: Acta Haematologica, ISSN 0001-5792, E-ISSN 1421-9662, Vol. 130, no 1, p. 7-15Article in journal (Refereed)
    Abstract [en]

    Background: Induction therapy for multiple myeloma (MM) and remission status before high-dose treatment (HDT) have been shown to be prognostic factors for survival outcome, although the optimal induction therapy is yet to be defined. Methods: We conducted a retrospective analysis of the impact of induction therapy on survival outcome before and after HDT in MM patients. The study included 236 consecutive patients who underwent HDT. Results: One hundred and forty-two patients (62%) were treated with vincristine, doxorubicin and dexamethasone (VAD) or cyclophosphamide and betamethasone (CyBet) and 94 (38%) were treated with bortezomib, cyclophosphamide and betamethasone (VCB) as induction. Time to first and time to best response was faster in the VCB group than in the VAD/CyBet group, with 42 versus 75 (p < 0.001) and 54 versus 88 days (p < 0.001), respectively. After induction therapy, 49% of the patients in the VCB group and 38% in the VAD/CyBet group achieved a very good partial response or better. Multivariate analysis revealed younger age, lower International Staging System stage and induction treatment with VCB as variables associated with favourable time to progression. Conclusions:Outcome measured as response and time to progression before and after HDT in MM differs depending on type of induction treatment and suggests that VCB is a highly effective induction regimen that confers a post-HDT advantage. 

  • 336.
    Vaht, Krista
    et al.
    Sahlgrens Univ Hosp, Sect Hematol & Coagulat, Gothenburg, Sweden.;Gothenburg Univ, Sahlgrenska Acad, Gothenburg, Sweden..
    Goransson, Magnus
    Sahlgrens Univ Hosp, Queen Silvia Childrens Hosp, Dept Pediat, Gothenburg, Sweden..
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Isaksson, Cecilia
    Univ Hosp, Dept Hematol, Canc Ctr, Umea, Sweden..
    Lenhoff, Stig
    Lund Univ, Skane Univ Hosp, Dept Hematol, Lund, Sweden..
    Sandstedt, Anna
    Linkoping Univ Hosp, Dept Hematol, Linkoping, Sweden..
    Uggla, Bertil
    Orebro Univ, Fac Med & Hlth, Dept Med, Sect Hematol, Orebro, Sweden..
    Winiarski, Jacek
    Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Stockholm, Sweden..
    Ljungman, Per
    Karolinska Univ Hosp Huddinge, Ctr Allogene Stem Cell Transplantat CAST, Stockholm, Sweden..
    Brune, Mats
    Sahlgrens Univ Hosp, Sect Hematol & Coagulat, Gothenburg, Sweden.;Gothenburg Univ, Sahlgrenska Acad, Gothenburg, Sweden..
    Andersson, Per-Ola
    South Alvsborg Hosp Boras, Boras, Sweden.;Gothenburg Univ, Sahlgrenska Acad, Gothenburg, Sweden..
    Incidence and outcome of acquired aplastic anemia: real-world data from patients diagnosed in Sweden from 2000-20112017In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 102, no 10, p. 1683-1690Article in journal (Refereed)
    Abstract [en]

    A plastic anemia is a rare life-threatening disease. However, since the introduction of immunosuppressive therapy and allogeneic stem cell transplantation, the outcome has improved considerably, and the 5-year survival is reported to be 70-80% in selected patient cohorts. Yet, contemporary population-based data on incidence and survival are lacking. We performed a national retrospective study to determine the incidence, treatment, and survival of patients with aplastic anemia diagnosed in Sweden from 2000-2011. Patients were included via the National Patient Registry, and diagnosed according to the Camitta criteria. In total, 257 confirmed cases were identified, with an overall incidence of 2.35 (95% CI: 2.06-2.64) cases per million inhabitants per year. Median age was 60 years (range: 2-92), and median follow up was 76 (0-193) months. Primary treatments included immunosuppressive therapy (63%), allogenic stem cell transplantation (10%), or single-agent cyclosporine/no specific therapy (27%). The 5-year survival was 90.7% in patients aged 0-18 years, 90.5% in patients aged 19-39 years, 70.7% in patients aged 40-59 years, and 38.1% in patients aged >= 60 years. Multivariate analysis showed that age (both 40-59 and >= 60 age groups), very severe aplastic anemia and single-agent cyclosporine/no specific therapy were independent risk factors for inferior survival. In conclusion, younger aplastic anemia patients experience a very good long-term survival, while that of patients >= 60 years in particular remains poor. Apparently, the challenge today is to improve the management of older aplastic anemia patients, and prospective studies to address this medical need are warranted.

  • 337.
    Vaht, Krista
    et al.
    Sahlgrens Univ Hosp, Sect Haematol & Coagulat, Gothenburg, Sweden;Gothenburg Univ, Sahlgrenska Acad, Inst Med, Gothenburg, Sweden.
    Goransson, Magnus
    Sahlgrens Univ Hosp, Dept Pediat, Queen Silvia Childrens Hosp, Gothenburg, Sweden.
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Isaksson, Cecilia
    Univ Hosp, Dept Haematol, Ctr Canc, Umea, Sweden.
    Lenhoff, Stig
    Lund Univ, Dept Haematol, Skane Univ Hosp, Lund, Sweden.
    Sandstedt, Anna
    Linkoping Univ Hosp, Dept Haematol, Linkoping, Sweden.
    Uggla, Bertil
    Orebro Univ, Sect Haematol, Dept Med, Fac Med & Hlth, Orebro, Sweden.
    Winiarski, Jacek
    Karolinska Inst, Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Stockholm, Sweden;CLINTEC, Stockholm, Sweden.
    Ljungman, Per
    Karolinska Inst, Karolinska Univ Hosp, Dept Med, Ctr Allogene Stem Cell Transplantat Unit CAST, Stockholm, Sweden.
    Brune, Mats
    Sahlgrens Univ Hosp, Sect Haematol & Coagulat, Gothenburg, Sweden;Gothenburg Univ, Sahlgrenska Acad, Inst Med, Gothenburg, Sweden.
    Andersson, Per-Ola
    Gothenburg Univ, Sahlgrenska Acad, Inst Med, Gothenburg, Sweden;Sodra Alvsborg Hosp Boras, Dept Med, Boras, Sweden.
    Low response rate to ATG-based immunosuppressive therapy in very severe aplastic anaemia A Swedish nationwide cohort study2018In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 100, no 6, p. 613-620Article in journal (Refereed)
    Abstract [en]

    ObjectivesAntithymocyte globulin (ATG)-based immunosuppression remains a cornerstone in aplastic anaemia (AA) treatment. However, most ATG studies are not population-based and knowledge about real-world results concerning response and outcome could offer important information for treating physicians. MethodsWe have recently performed a nationwide retrospective cohort study on all AA patients diagnosed in Sweden in 2000-2011 and now present treatment and outcome data on patients receiving first-line ATG. In total, 158 patients showed a 47.0% response rate which was similar in all age groups (range 41.5%-51.7%) with no difference regarding ATG formulation. The response was significantly associated with severity gradeespecially at time of treatment initiation: very severe (VSAA) 22.7%; severe (SAA) 54.5% (P<.001); and non-severe 88.5% (P<.001). A logistic regression-based predictive model indicated that VSAA patients with an absolute reticulocyte count <25x10(9)/L had only a 19% probability of response. In a multivariable analysis, age and VSAA at the time of treatment were the independent factors for inferior survival. ConclusionsReal-world VSAA patients respond poorly to ATG which indicates the need for a different treatment approach. Our findings suggest that age alone should not be a discriminating factor for administering ATG treatment.

  • 338. Waage, Anders
    et al.
    Gimsing, Peter
    Fayers, Peter
    Abildgaard, Niels
    Ahlberg, Lucia
    Björkstrand, Bo
    Carlson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Forsberg, Karin
    Dahl, Inger Marie
    Gulbrandsen, Nina
    Haukas, Einar
    Hjertner, Öyvind
    Hjorth, Martin
    Karlsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Knudsen, Lene Meldgaard
    Nielsen, Johan Lanng
    Linder, Olle
    Mellqvist, Ulf-Henrik
    Nesthus, Ingerid
    Rolke, Jurgen
    Strandberg, Maria
    Sörbo, Jon Hjalmar
    Wislöff, Finn
    Juliusson, Gunnar
    Turesson, Ingemar
    Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma2010In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 116, no 9, p. 1405-1412Article in journal (Refereed)
    Abstract [en]

    In this double-blind, placebo-controlled study, 363 patients with untreated multiple myeloma were randomized to receive either melphalan-prednisone and thalidomide (MPT) or melphalan-prednisone and placebo (MP). The dose of melphalan was 0.25 mg/kg and prednisone was 100 mg given daily for 4 days every 6 weeks until plateau phase. The dose of thalidomide/placebo was escalated to 400 mg daily until plateau phase and thereafter reduced to 200 mg daily until progression. A total of 357 patients were analyzed. Partial response was 34% and 33%, and very good partial response or better was 23% and 7% in the MPT and MP arms, respectively (P < .001). There was no significant difference in progression-free or overall survival, with median survival being 29 months in the MPT arm and 32 months in the MP arm. Most quality of life outcomes improved equally in both arms, apart from constipation, which was markedly increased in the MPT arm. Constipation, neuropathy, non-neuropathy neurologic toxicity, and skin reactions were significantly more frequent in the MPT arm. The number of thromboembolic events was equal in the 2 treatment arms. In conclusion, MPT had a significant antimyeloma effect, but this did not translate into improved survival. This trial was registered at www.clinicaltrials.

  • 339.
    Walladbegi, J.
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Odontol, Dept Oral Med & Pathol, Gothenburg, Sweden.
    Svanberg, Anncarin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Jontell, M.
    Univ Gothenburg, Sahlgrenska Acad, Inst Odontol, Dept Oral Med & Pathol, Gothenburg, Sweden.
    Optimal cooling temperature to prevent adverse effects of chemotherapeutic agents2017In: Bone Marrow Transplantation, ISSN 0268-3369, E-ISSN 1476-5365, Vol. 52, no Supplement: 1, p. S301-S302Article in journal (Other academic)
  • 340.
    Walladbegi, Java
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Odontol, Dept Oral Med & Pathol, Gothenburg.
    Gellerstedt, Martin
    Univ West, Sch Business Econ & IT, Trollhättan.
    Svanberg, Anncarin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Jontell, Mats
    Univ Gothenburg, Sahlgrenska Acad, Inst Odontol, Dept Oral Med & Pathol, Gothenburg.
    Correction to: Innovative intraoral cooling device better tolerated and equally effective as ice cooling2018In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 81, no 1, p. 225-225Article in journal (Refereed)
    Abstract [en]

    Unfortunately, the online published article has error in Table 1. The correct Table 1 is given in the following page.

  • 341.
    Walladbegi, Java
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden.
    Gellerstedt, Martin
    Univ West, Trollhättan, Sweden.
    Svanberg, Anncarin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Jontell, Mats
    Univ Gothenburg, Sahlgrenska Acad, Gothenburg, Sweden.
    Innovative intraoral cooling device better tolerated and equally effective as ice cooling2017In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 80, no 5, p. 965-972Article in journal (Refereed)
    Abstract [en]

    Most of the patients who receive myeloablative therapy prior to stem cell transplantation develop oral mucositis (OM). This adverse reaction manifests as oral mucosal erythema and ulcerations and may require high doses of morphine for pain alleviation. OM may also interfere with food intake and result in weight loss, a need for parenteral nutrition, and impaired quality of life. To date, there have been very few studies of evidence-based interventions for the prevention of OM. Cryotherapy, using ice chips, has been shown to reduce in an efficient manner the severity and extent of OM, although clinical applications are still limited due to several shortcomings, such as adverse tooth sensations, problems with infectious organisms in the water, nausea, and uneven cooling of the oral mucosa. The present proof-of-concept study was conducted to compare the tolerability, temperature reduction, and cooling distribution profiles of an intra-oral cooling device and ice chips in healthy volunteers who did not receive myeloablative treatment, and therefore, did not experience the symptoms of OM. Twenty healthy volunteers used the cooling device and ice chips for a maximum of 60 min each, using a cross-over design. The baseline and final temperatures were measured at eight intra-oral locations using an infra-red thermographic camera. The thermographic images were analysed using two digital software packages. A questionnaire was used to assess the tolerability levels of the two interventions. The intra-oral cooling device was significantly better tolerated than the ice-chips (p = 0.0118). The two interventions were equally effective regarding temperature reduction and cooling distribution. The intra-oral cooling device shows superior tolerability in healthy volunteers. Furthermore, this study shows that temperature reduction and cooling distribution are achieved equally well using either method.

  • 342.
    Wang, M.
    et al.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Nobels Vag 12A, S-17177 Stockholm, Sweden.;Uppsala Univ, Dept Med Sci, Uppsala, Sweden..
    Lindberg, J.
    Karolinska Inst, Sci Life Lab, Dept Med Epidemiol & Biostat, Stockholm, Sweden.;Uppsala Univ, Dept Med Sci, Uppsala, Sweden..
    Klevebring, D.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Nobels Vag 12A, S-17177 Stockholm, Sweden..
    Nilsson, C.
    Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden..
    Mer, A. S.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Nobels Vag 12A, S-17177 Stockholm, Sweden..
    Rantalainen, M.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Nobels Vag 12A, S-17177 Stockholm, Sweden..
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Gronberg, H.
    Karolinska Inst, Dept Med Epidemiol & Biostat, Nobels Vag 12A, S-17177 Stockholm, Sweden..
    Validation of risk stratification models in acute myeloid leukemia using sequencing-based molecular profiling2017In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, no 10, p. 2029-2036Article in journal (Refereed)
    Abstract [en]

    Risk stratification of acute myeloid leukemia (AML) patients needs improvement. Several AML risk classification models based on somatic mutations or gene-expression profiling have been proposed. However, systematic and independent validation of these models is required for future clinical implementation. We performed whole-transcriptome RNA-sequencing and panel-based deep DNA sequencing of 23 genes in 274 intensively treated AML patients (Clinseq-AML). We also utilized the The Cancer Genome Atlas (TCGA)-AML study (N = 142) as a second validation cohort. We evaluated six previously proposed molecular-based models for AML risk stratification and two revised risk classification systems combining molecular-and clinical data. Risk groups stratified by five out of six models showed different overall survival in cytogenetic normal-AML patients in the Clinseq-AML cohort (P-value < 0.05; concordance index > 40.5). Risk classification systems integrating mutational or gene-expression data were found to add prognostic value to the current European Leukemia Net (ELN) risk classification. The prognostic value varied between models and across cohorts, highlighting the importance of independent validation to establish evidence of efficacy and general applicability. All but one model replicated in the Clinseq-AML cohort, indicating the potential for molecular-based AML risk models. Risk classification based on a combination of molecular and clinical data holds promise for improved AML patient stratification in the future.

  • 343.
    Warfvinge, Rebecca
    et al.
    Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, Lund, Sweden..
    Geironson, Linda
    Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, Lund, Sweden..
    Sommarin, Mikael N. E.
    Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, Lund, Sweden..
    Lang, Stefan
    Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, Lund, Sweden..
    Karlsson, Christine
    Lund Univ, Lund Stem Cell Ctr, Div Mol Med & Gene Therapy, Lund, Sweden..
    Roschupkina, Teona
    Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, Lund, Sweden..
    Stenke, Leif
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.;Karolinska Inst, Dept Med, Stockholm, Sweden..
    Stentoft, Jesper
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark..
    Olsson-Strömberg, Ulla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Hjorth-Hansen, Henrik
    St Olavs Hosp, Dept Hematol, Trondheim, Norway.;Norwegian Univ Sci & Technol, Dept Canc Res & Mol Med, Trondheim, Norway..
    Mustjoki, Satu
    Univ Helsinki, Hematol Res Unit Helsinki, Helsinki, Finland.;Univ Helsinki, Dept Clin Chem, Helsinki, Finland.;Helsinki Univ Hosp, Comprehens Canc Ctr, Helsinki, Finland..
    Soneji, Shamit
    Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, Lund, Sweden..
    Richter, Johan
    Lund Univ, Lund Stem Cell Ctr, Div Mol Med & Gene Therapy, Lund, Sweden.;Skane Univ Hosp, Dept Hematol Oncol & Radiat Phys, Lund, Sweden..
    Karlsson, Göran
    Lund Univ, Lund Stem Cell Ctr, Div Mol Hematol, Lund, Sweden..
    Single-cell molecular analysis defines therapy response and immunophenotype of stem cell subpopulations in CML2017In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 129, no 17, p. 2384-2394Article in journal (Refereed)
    Abstract [en]

    Understanding leukemia heterogeneity is critical for the development of curative treatments as the failure to eliminate therapy-persistent leukemic stem cells (LSCs) may result in disease relapse. Here we have combined high-throughput immunopheno-typic screens with large-scale single-cell gene expression analysis to define the heterogeneity within the LSC population in chronic phase chronic myeloid leukemia (CML) patients at diagnosis and following conventional tyrosine kinase inhibitor (TKI) treatment. Our results reveal substantial heterogeneity within the putative LSC population in CML at diagnosis and demonstrate differences in response to subsequent TKI treatment between distinct subpopulations. Importantly, LSC subpopulations with myeloid and proliferative molecular signatures are proportionally reduced at a higher extent in response to TKI therapy compared with subfractions displaying primitive and quiescent signatures. Additionally, cell surface expression of the CML stem cell markers CD25, CD26, and IL1RAP is high in all subpopulations at diagnosis but downregulated and unevenly distributed across subpopulations in response to TKI treatment. The most TKI-insensitive cells of the LSC compartment can be captured within the CD45RA(-) fraction and further defined as positive for CD26 in combination with an aberrant lack of cKIT expression. Together, our results expose a considerable heterogeneity of the CML stem cell population and propose a Lin(-) CD34(+) CD38(-/low) CD45RA(-) cKIT(-) CD26(+) population as a potential therapeutic target for improved therapy response.

  • 344.
    Wass, Linda
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis, Gothenburg, Sweden.
    Grankvist, Anna
    Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis, Gothenburg, Sweden.
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Gustafsson, Helena
    Gavle Cent Hosp, Dept Hematol, Gavle, Sweden.
    Krogfelt, Karen
    Statens Serum Inst, Dept Bacteria Parasites & Fungi, Copenhagen, Denmark.
    Olsen, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology.
    Mårtensson, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, International Maternal and Child Health (IMCH).
    Quarsten, Hanne
    Sorlandet Hosp Hlth Enterprise, Dept Med Microbiol, Kristiansand, Norway.
    Henningsson, Anna J.
    Cty Hosp Ryhov, Dept Clin Microbiol, Jonkoping, Sweden.
    Wennerås, Christine
    Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis, Gothenburg, Sweden;Sahlgrens Univ Hosp, Dept Clin Microbiol, Guldhedsgatan 10, S-41346 Gothenburg, Sweden.
    Serological reactivity to Anaplasma phagocytophilum in neoehrlichiosis patients2018In: European Journal of Clinical Microbiology and Infectious Diseases, ISSN 0934-9723, E-ISSN 1435-4373, Vol. 37, no 9, p. 1673-1678Article in journal (Refereed)
    Abstract [en]

    The tick-borne bacterium Candidatus (Ca.) Neoehrlichia (N.) mikurensis is a cause of "fever of unknown origin" because this strict intracellular pathogen escapes detection by routine blood cultures. Case reports suggest that neoehrlichiosis patients may display serological reactivity to Anaplasma (A.) phagocytophilum. Since Anaplasma serology is part of the diagnostic work-up of undetermined fever in European tick-exposed patients, we wanted to investigate (1) the prevalence of A. phagocytophilum seropositivity among neoehrlichiosis patients, (2) the frequency of misdiagnosed neoehrlichiosis patients among A. phagocytophilum seropositive patients, and (3) the frequency of A. phagocytophilum and Ca. N. mikurensis co-infections. Neoehrlichiosis patients (n = 18) were analyzed for A. phagocytophilum IgM and IgG serum antibodies by indirect immunofluorescence assay. Serum samples from suspected anaplasmosis patients (n = 101) were analyzed for bacterial DNA contents by singleplex PCR specific for A. phagocytophilum and Ca. N. mikurensis, respectively. One fifth of the neoehrlichiosis patients (4/18) were seropositive for IgM and/or IgG to A. phagocytophilum at the time of diagnosis. Among the patients with suspected anaplasmosis, 2% (2/101) were positive for Ca. N. mikurensis by PCR whereas none (0/101) had detectable A. phagocytophilum DNA in the serum. To conclude, patients with suspected anaplasmosis may in fact have neoehrlichiosis. We found no evidence of A. phagocytophilum and Ca. N. mikurensis co-infections in humans with suspected anaplasmosis or confirmed neoehrlichiosis.

  • 345.
    Wennerås, Christine
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis & Hematol, Gothenburg, Sweden..
    Goldblatt, David
    UCL, Great Ormond St Inst Child Hlth, Immunobiol Sect, London, England..
    Zancolli, Marta
    UCL, Great Ormond St Inst Child Hlth, Immunobiol Sect, London, England..
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Wass, Linda
    Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis & Hematol, Gothenburg, Sweden..
    Horkko, Sohvi
    Univ Oulu, Med Res Ctr, Dept Med Microbiol & Immunol, Oulu, Finland.;Oulu Univ Hosp, Nordlab Oulu, Oulu, Finland..
    Rosen, Anders
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Natural IgM antibodies in the immune defence against neoehrlichiosis2017In: Infectious Diseases, ISSN 2374-4235, E-ISSN 2374-4243, Vol. 49, no 11-12, p. 809-816Article in journal (Refereed)
    Abstract [en]

    Background: Neoehrlichiosis is an infectious disease caused by the tick-borne bacterium Candidatus Neoehrlichia mikurensis. Splenectomy and rituximab therapies are risk factors for severe neoehrlichiosis. Our aim was to examine if neoehrlichiosis patients had low levels of natural IgM antibodies and/or were hypogammaglobulinemic, and if such deficiencies were associated with asplenia and vascular complications. Methods: Neoehrlichiosis patients (n=9) and control subjects (n=10) were investigated for serum levels of IgG, IgA, and IgM, and for levels of natural IgM antibodies to pneumococcal polysaccharides (6B, 14), and to the malondialdehyde acetaldehyde epitope of oxidized LDL. The multivariate method Projection to Latent Structures was used to analyze the data. Results: The levels of natural IgM antibodies of various specificities were decreased or not measurable in half of the studied patients with neoehrlichiosis. Only one patient and one control subject were hypogammaglobulinemic. An inverse relationship was noted between the levels of natural IgM antibodies and the development of deep vein thrombosis. Unexpectedly, no association was seen between having or not having a spleen and the levels of natural IgM antibody levels in the circulation. Conclusions: Neither hypogammaglobulinemia nor lack of natural IgM antibodies alone predisposes for severe neoehrlichiosis. The importance of the spleen in the immune defence against Ca. N. mikurensis probably lies in its capacity to generate or maintain specific antibodies.

  • 346.
    Wicher, Grzegorz K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wallenquist, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lei, Ying
    Karolinska Inst, Immunol & Allergy Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Enoksson, Mattias
    Karolinska Inst, Immunol & Allergy Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Li, Xiaofei
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Karolinska Inst, Dept Neurosci, Stockholm, Sweden..
    Fuchs, Barbara
    Karolinska Inst, Immunol & Allergy Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Abu Hamdeh, Sami
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Marklund, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hillered, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Nilsson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Inst, Immunol & Allergy Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Forsberg Nilsson, Karin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Interleukin-33 Promotes Recruitment of Microglia/Macrophages in Response to Traumatic Brain Injury2017In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 34, no 22, p. 3173-3182Article in journal (Refereed)
    Abstract [en]

    Traumatic brain injury (TBI) is a devastating condition, often leading to life-long consequences for patients. Even though modern neurointensive care has improved functional and cognitive outcomes, efficient pharmacological therapies are still lacking. Targeting peripherally derived, or resident inflammatory, cells that are rapid responders to brain injury is promising, but complex, given that the contribution of inflammation to exacerbation versus improved recovery varies with time post-injury. The injury-induced inflammatory response is triggered by release of alarmins, and in the present study we asked whether interleukin-33 (IL-33), an injury-associated nuclear alarmin, is involved in TBI. Here, we used samples from human TBI microdialysate, tissue sections from human TBI, and mouse models of central nervous system injury and found that expression of IL-33 in the brain was elevated from nondetectable levels, reaching a maximum after 72 h in both human samples and mouse models. Astrocytes and oligodendrocytes were the main producers of IL-33. Post-TBI, brains of mice deficient in the IL-33 receptor, ST2, contained fewer microglia/macrophages in the injured region than wild-type mice and had an altered cytokine/chemokine profile in response to injury. These observations indicate that IL-33 plays a role in neuroinflammation with microglia/macrophages being cellular targets for this interleukin post-TBI.

  • 347. Winqvist, Maria
    et al.
    Asklid, Anna
    Andersson, P O
    Karlsson, Karin
    Karlsson, Claes
    Lauri, Birgitta
    Lundin, Jeanette
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Norin, Stefan
    Sandstedt, Anna
    Hansson, Lotta
    Österborg, Anders
    Real-world results of ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia: data from 95 consecutive patients treated in a compassionate use program. A study from the Swedish Chronic Lymphocytic Leukemia Group.2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 12, p. 1573-1580Article in journal (Refereed)
    Abstract [en]

    Ibrutinib, a Bruton's tyrosine kinase inhibitor is approved for relapsed/refractory and del(17p)/TP53 mutated chronic lymphocytic leukemia. Discrepancies between clinical trials and routine health-care are commonly observed in oncology. Herein we report real-world results for 95 poor prognosis Swedish patients treated with ibrutinib in a compassionate use program. Ninety-five consecutive patients (93 chronic lymphocytic leukemia, 2 small lymphocytic leukemia) were included in the study between May 2014 and May 2015. The median age was 69 years. 63% had del(17p)/TP53 mutation, 65% had Rai stage III/IV, 28% had lymphadenopathy ≥10cm. Patients received ibrutinib 420 mg once daily until progression. At a median follow-up of 10.2 months, the overall response rate was 84% (consistent among subgroups) and 77% remained progression-free. Progression-free survival and overall survival were significantly shorter in patients with del(17p)/TP53 mutation (P=0.017 and P=0.027, log-rank test); no other factor was significant in Cox proportional regression hazards model. Ibrutinib was well tolerated. Hematomas occurred in 46% of patients without any major bleeding. Seven patients had Richter's transformation. This real-world analysis on consecutive chronic lymphocytic leukemia patients from a well-defined geographical region shows the efficacy and safety of ibrutinib to be similar to that of pivotal trials. Yet, del(17p)/TP53 mutation remains a therapeutic challenge. Since not more than half of our patients would have qualified for the pivotal ibrutinib trial (RESONATE), our study emphasizes that real-world results should be carefully considered in future with regards to new agents and new indications in chronic lymphocytic leukemia.

  • 348.
    Worel, Nina
    et al.
    Med Univ Vienna, Dept Blood Grp Serol & Transfus Med, A-1090 Vienna, Austria..
    Buser, Andreas
    Swiss Red Cross, Ctr Blood Transfus, Basel, Switzerland.;Univ Basel Hosp, Dept Hematol, CH-4031 Basel, Switzerland..
    Greinix, Hildegard T.
    Med Univ Graz, Div Hematol, Graz, Austria..
    Hagglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Navarro, Willis
    Natl Marrow Donor Program, Minneapolis, MN USA..
    Pulsipher, Michael A.
    Univ Utah, Div Hematol & Hematol Malignancies, Huntsman Canc Inst, Primary Childrens Hosp, Salt Lake City, UT USA..
    de Faveri, Grazia Nicoloso
    Swiss Blood Stem Cell, Bern, Switzerland..
    Bengtsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Swedish Bone Marrow Donors, Tobias Registry, Uppsala, Sweden..
    Billen, Annelies
    UCL Canc Inst, London, England..
    Espino, German
    Univ Hosp Caja del Seguro Social, Hematol & Bone Marrow Transplantat Sect, Dept Internal Med, Panama City, Panama..
    Fechter, Mirjam
    Leiden Univ, Med Ctr, Europdonor Fdn Leiden, Leiden, Netherlands..
    Giudice, Valeria
    S Orsola Malpighi Univ Hosp, Dept Immunohematol & Transfus Med, Bologna, Italy..
    Hoelig, Kristina
    Tech Univ Dresden, Univ Hosp Carl Gustav Cams, Dept Internal Med 1, D-01062 Dresden, Germany..
    Kanamori, Heiwa
    Kanagawa Canc Ctr, Dept Hematol, Yokohama, Kanagawa, Japan..
    Kodera, Yoshihisa
    Aichi Med Univ, Asia Pacific Blood & Marrow Transplantat Grp, Sch Med, Nagakute, Aichi 48011, Japan.;Aichi Med Univ, Dept Promot Blood & Marrow Transplantat, Sch Med, Nagakute, Aichi 48011, Japan..
    Leitner, Gerda
    Med Univ Vienna, Dept Blood Grp Serol & Transfus Med, A-1090 Vienna, Austria..
    Netelenbos, Tanja
    Leiden Univ, Dept Immunohematol & Blood Transfus, Med Ctr, Leiden, Netherlands..
    Niedervvieser, Dietger
    Univ Hosp Leipzig, Dept Hematol, Leipzig, Germany..
    van Walraven, Suzanna M.
    Leiden Univ, Med Ctr, Europdonor Fdn Leiden, Leiden, Netherlands.;World Marrow Donor Assoc, Eth Working Grp, Leiden, Netherlands.;Oxford Univ Hosp NHS Trust, British Bone Marrow Donor Registry, Oxford, England..
    Rocha, Vanderson
    NHS BT, Cord Blood Banks, Oxford, England..
    Torosian, Tigran
    Fdn DKMS Polska, Warsaw, Poland..
    Vergueiro, Carmen
    FCM Santa Casa de Selo Paulo, Disciplina Hematol & Oncol, Sao Paulo, Brazil..
    Weisdorf, Daniel
    Univ Minnesota, Bone Marrow Transplant Program, Minneapolis, MN 55455 USA..
    Yabe, Hiromasa
    Tokai Univ, Sch Med, Dept Cell Transplantat & Regenerat Med, Tokyo 151, Japan..
    Halter, Joerg P.
    Univ Basel Hosp, Dept Hematol, CH-4031 Basel, Switzerland..
    Suitability Criteria for Adult Related Donors: A Consensus Statement from the Worldwide Network for Blood and Marrow Transplantation Standing Committee on Donor Issues2015In: Biology of blood and marrow transplantation, ISSN 1083-8791, E-ISSN 1523-6536, Vol. 21, no 12, p. 2052-2060Article in journal (Refereed)
    Abstract [en]

    The number of allogeneic hematopoietic stem cell (HSC) transplants performed globally each year continues to increase. Advances in HLA typing, better supportive care, and administration of reduced-intensity conditioning regimens allow treatment of older patients with older sibling donors. Pretransplant donor assessment and testing are very important processes affecting the quality and safety of donation. For unrelated HSC donors detailed recommendations for health assessment have been published, allowing donation only if they are unrestrictedly healthy. Eligibility criteria for related donors are less strict and vary significantly between centers. In situations where a family donor does not meet the suitability criteria for unrelated donors, involved physicians often struggle with the decision whether the matched relative is suitable for donation or not. On behalf of the Worldwide Network for Blood and Marrow Transplantation Standing Committee on Donor Issues, we intended to develop a consensus document with recommendations for donor workup and final clearance of family donors who would not be able to serve as unrelated donors because of their age or pre-existing diseases. This article covers different topics intending to support decision-making, with the goal of minimizing medical risk to the donor and protection of the recipient from transmissible diseases.

  • 349. Worel, Nina
    et al.
    Buser, Andreas
    Greinix, Hildegard T
    Hägglund, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Navarro, Willis
    Pulsipher, Michael A
    Nicoloso de Faveri, Grazia
    Bengtsson, Mats
    Billen, Annelies
    Espino, German
    Fechter, Mirjam
    Giudice, Valeria
    Hölig, Kristina
    Kanamori, Heiwa
    Kodera, Yoshihisa
    Leitner, Gerda
    Netelenbos, Tanja
    Niederwieser, Dietger
    van Walraven, Suzanna M
    Rocha, Vanderson
    Torosian, Tigran
    Vergueiro, Carmen
    Weisdorf, Daniel
    Yabe, Hiromasa
    Halter, Jörg P
    Suitability Criteria for Adult Related Donors: A Consensus Statement from the Worldwide Network for Blood and Marrow Transplantation Standing Committee on Donor Issues.2015In: Biology of blood and marrow transplantation, ISSN 1083-8791, E-ISSN 1523-6536, Vol. 21, no 12Article in journal (Refereed)
    Abstract [en]

    The number of allogeneic hematopoietic stem cell (HSC) transplants performed globally each year continues to increase. Advances in HLA typing, better supportive care, and administration of reduced-intensity conditioning regimens allow treatment of older patients with older sibling donors. Pretransplant donor assessment and testing are very important processes affecting the quality and safety of donation. For unrelated HSC donors detailed recommendations for health assessment have been published, allowing donation only if they are unrestrictedly healthy. Eligibility criteria for related donors are less strict and vary significantly between centers. In situations where a family donor does not meet the suitability criteria for unrelated donors, involved physicians often struggle with the decision whether the matched relative is suitable for donation or not. On behalf of the Worldwide Network for Blood and Marrow Transplantation Standing Committee on Donor Issues, we intended to develop a consensus document with recommendations for donor workup and final clearance of family donors who would not be able to serve as unrelated donors because of their age or pre-existing diseases. This article covers different topics intending to support decision-making, with the goal of minimizing medical risk to the donor and protection of the recipient from transmissible diseases.

  • 350. Zoltowska Nilsson, Anna Maria
    et al.
    Lei, Ying
    Adner, Mikael
    Nilsson, G P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden; Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden .
    Mast cell dependent IL-33/ST2 signaling is protective against the development of airway hyperresponsiveness in a house dust mite mouse model of asthma2018In: American Journal of Physiology - Lung cellular and Molecular Physiology, ISSN 1040-0605, E-ISSN 1522-1504, Vol. 314, no 3, p. L484-L492Article in journal (Refereed)
    Abstract [en]

    Interleukin-33 (IL-33) and its receptor ST2 have been influentially associated to the pathophysiology of asthma. Due to the divergent roles of IL-33 in regulating mast cell functions, there is a need to further characterize IL-33/ST2-dependent mast cell responses and their significance in the context of asthma. This study aimed to investigate how IL-33/ST2-dependent mast cell responses contribute to the development of airway hyperresponsiveness (AHR) and airway inflammation in a mouse model of house dust mite (HDM) induced asthma. Mast cell deficient C57BL/6-KitW-sh (Wsh) mice engrafted with either wild-type (Wsh+MC-WT) or ST2 deficient bone marrow derived mast cells (Wsh+MC-ST2KO) were exposed to HDM delivered intranasally. An exacerbated development of AHR in response to HDM was seen in Wsh+MC-ST2KO compared to Wsh+MC-WT mice. The contribution of this IL-33/ST2-dependent mast cell response to AHR seems to reside within the smaller airways in the peripheral parts of the lung, as suggested by the isolated yet marked effect on tissue resistance. Considering the absence of a parallel increase in cellular inflammation in BALF and lung, the aggravated AHR in Wsh+MC-ST2KO mice, seems to be independent of cellular inflammation. We observed an association between the elevated AHR and reduced PGE2 levels in bronchoalveolar lavage fluid. Due to the protective properties of PGE2 in airway responses, it is conceivable that IL-33/ST2-dependent mast cell induction of PGE2 could be responsible for the dampening effect on AHR. In conclusion, we reveal that IL-33/ST2-dependent mast cell responses can have a protective, rather than causative role in the development of AHR.

45678 301 - 350 of 352
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