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  • 1.
    Abdulla, Maysaa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Laszlo, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Triumf, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hedström, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Dept Biosci & Nutr, Novum, Huddinge, Sweden..
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Amini, Rose-Marie
    Uppsala Univ, Dept Immunol Genet & Pathol, Unit Pathol, Uppsala, Sweden.;Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    A population-based study of cellular markers in R-CHOP treated diffuse large B-cell lymphoma patients2016In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, no 9-10, 1126-1131 p.Article in journal (Refereed)
    Abstract [en]

    Aim: To determine the prognostic significance of co-expression of MYC, BCL-2 and BCL-6 proteins in combination with other biomarkers and clinical characteristics within a population-based cohort of diffuse large B-cell lymphoma (DLBCL) patients uniformly treated with R-CHOP.

    Patients and methods: The immunohistochemical (IHC) expression of CD10, BCL-2, BCL-6, MUM1, MYC, CD5, CD30, Ki-67 and p53 was evaluated in a retrospective, population-based study comprising 188 DLBCL patients treated with R-CHOP and diagnosed in Sweden between 2002 and 2012.

    Results: Patients had a median age at diagnosis of 64 years (26-85 years) with a male:female ratio of 1.4:1. Approximately half (52%) of the patients presented with an International Prognostic Index (IPI) age adjusted (IPIaa)2. Median follow-up time was 51 months (range 0.4-158) and the five-year lymphoma-specific survival (LSS) was 76%, five-year overall survival (OS) was 65% and five-year progression-free survival (PFS) was 61%. A high Ki-67 value was found in 59% of patients, while p53 overexpression was detected in 12% of patients and MYC, BCL-2 and BCL-6 expression were detected in 42%, 55% and 74% of patients, respectively. IPIaa2 (p=0.002), Ki-6770% (p=0.04) and p53 overexpression50% (p=0.02) were associated with inferior LSS and OS. Co-expression of both MYC (>40%) and BCL-2 (>70%) proteins was detected in 27% of patients and correlated with a significantly inferior LSS (p=0.0002), OS (p=0.009) and PFS (p=0.03). In addition, triple expression of MYC, BCL-2 and BCL-6, also correlated with a significantly inferior LSS (p=0.02).

    Conclusion: Concurrent expression of MYC and BCL-2 proteins, as detected by IHC, was strongly associated with an inferior survival in DLBCL patients treated with R-CHOP. Other markers affecting survival were triple expression of MYC, BCL-2 and BCL-6, IPIaa, high Ki-67 and p53 overexpression.

  • 2.
    Abdulla, Maysaa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Laszlo, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Triumf, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Hedström, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden.;Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden..
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Core needle biopsies for the diagnosis of diffuse large B-cell lymphoma - a great concern for research2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 1, 106-109 p.Article in journal (Refereed)
  • 3.
    Agarwal, Prasoon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Alzrigat, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Párraga, Alba Atienza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Singh, Umashankar
    Ungerstedt, Johanna
    Österborg, Anders
    Brown, Peter J
    Ma, Anqi
    Jin, Jian
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Jernberg-Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 6, 6809-6923 p.Article in journal (Refereed)
    Abstract [en]

    Multiple myeloma (MM) is a malignancy of the antibody-producing plasma cells. MM is a highly heterogeneous disease, which has hampered the identification of a common underlying mechanism for disease establishment as well as the development of targeted therapy. Here we present the first genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in MM patient samples, defining a common set of active H3K4me3-enriched genes and silent genes marked by H3K27me3 (H3K27me3 alone or bivalent) unique to primary MM cells, when compared to normal bone marrow plasma cells. Using this epigenome profile, we found increased silencing of H3K27me3 targets in MM patients at advanced stages of the disease, and the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also demonstrated that pharmacological inhibition of EZH2 had anti-myeloma effects in both MM cell lines and CD138+ MM patient cells. In addition, EZH2 inhibition decreased the global H3K27 methylation and induced apoptosis. Taken together, these data suggest an important role for the Polycomb repressive complex 2 (PRC2) in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.

  • 4.
    Agarwal, Prasoon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Collier, Paul
    Fritz, Markus Hsi-Yang
    Benes, Vladimir
    Wiklund, Helena Jernberg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Westermark, Bengt
    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.
    Singh, Umashankar
    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.
    CGGBP1 mitigates cytosine methylation at repetitive DNA sequences2015In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, 390Article in journal (Refereed)
    Abstract [en]

    Background: CGGBP1 is a repetitive DNA-binding transcription regulator with target sites at CpG-rich sequences such as CGG repeats and Alu-SINEs and L1-LINEs. The role of CGGBP1 as a possible mediator of CpG methylation however remains unknown. At CpG-rich sequences cytosine methylation is a major mechanism of transcriptional repression. Concordantly, gene-rich regions typically carry lower levels of CpG methylation than the repetitive elements. It is well known that at interspersed repeats Alu-SINEs and L1-LINEs high levels of CpG methylation constitute a transcriptional silencing and retrotransposon inactivating mechanism. Results: Here, we have studied genome-wide CpG methylation with or without CGGBP1-depletion. By high throughput sequencing of bisulfite-treated genomic DNA we have identified CGGBP1 to be a negative regulator of CpG methylation at repetitive DNA sequences. In addition, we have studied CpG methylation alterations on Alu and L1 retrotransposons in CGGBP1-depleted cells using a novel bisulfite-treatment and high throughput sequencing approach. Conclusions: The results clearly show that CGGBP1 is a possible bidirectional regulator of CpG methylation at Alus, and acts as a repressor of methylation at L1 retrotransposons.

  • 5.
    Agarwal, Prasoon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Alzrigat, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Osterborg, Anders
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Jernberg-Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    An Epigenomic Map of Multiple Myeloma Reveals the Importance of Polycomb Gene Silencing for the Malignancy2014In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal (Other academic)
  • 6.
    Agathangelidis, A.
    et al.
    Ist Sci San Raffaele, Div Expt Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, I-20132 Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Bystry, V.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Hadzidimitriou, A.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Sutton, L. A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Minga, E.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Kienle, D.
    Univ Ulm, Dept Internal Med 3, D-89069 Ulm, Germany..
    Davis, Z.
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Yan, X. J.
    North Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA..
    Shanafelt, T.
    Mayo Clin, Dept Med, Dept Hematol, Rochester, MN USA..
    Boudjogra, M.
    Univ Paris 06, Hop Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Hop Pitie Salpetriere, Paris, France..
    Plevova, K.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Gounari, M.
    Ist Sci San Raffaele, Div Expt Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, I-20132 Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Xochelli, A.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Navarro, A.
    Univ Barcelona, IDIBAPS, Unidad Hematopatol, Serv Anat Patol, Barcelona, Spain..
    Chatzouli, M.
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Pedersen, L. B.
    Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Scarfo, L.
    Ist Sci San Raffaele, Div Expt Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, I-20132 Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Rossi, D.
    Amedeo Avogadro Univ Eastern Piedmont, Dept Hematol, Novara, Italy..
    Veronese, S.
    Osped Niguarda Ca Granda, Niguarda Canc Ctr, Mol Pathol Unit, Milan, Italy.;Osped Niguarda Ca Granda, Niguarda Canc Ctr, Dept Hematol, Milan, Italy..
    Facco, M.
    Univ Padua, Sch Med, Hematol & Clin Immunol Branch, Dept Med, Padua, Italy..
    Bikos, V.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Karan-Djurasevic, T.
    Univ Belgrade, Inst Mol Genet & Genet Engn, Belgrade, Serbia..
    Pavlovic, S.
    Univ Kragujevac, Kragujevac, Serbia..
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Poiron, C.
    Univ Montpellier, IMGT, LIGM, IGH, Montpellier, France..
    Chu, C. C.
    North Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA..
    Stalika, E.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Giudicelli, V.
    Univ Montpellier, IMGT, LIGM, IGH, Montpellier, France..
    Panagiotidis, P.
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece..
    Sudarikov, A.
    Natl Hematol Res Ctr, Dept Mol Hematol, Moscow, Russia..
    Anagnostopoulos, A.
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Trentin, L.
    Univ Padua, Sch Med, Hematol & Clin Immunol Branch, Dept Med, Padua, Italy..
    Catherwood, M.
    Belfast City Hosp, Dept Hematooncol, Belfast BT9 7AD, Antrim, North Ireland..
    Montillo, M.
    Osped Niguarda Ca Granda, Niguarda Canc Ctr, Mol Pathol Unit, Milan, Italy.;Osped Niguarda Ca Granda, Niguarda Canc Ctr, Dept Hematol, Milan, Italy..
    Gaidano, G.
    Amedeo Avogadro Univ Eastern Piedmont, Dept Hematol, Novara, Italy..
    Campo, E.
    Univ Barcelona, IDIBAPS, Unidad Hematopatol, Serv Anat Patol, Barcelona, Spain..
    Geisler, C. H.
    Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    Langerak, A. W.
    Erasmus MC, Univ Med Ctr, Dept Immunol, Rotterdam, Netherlands..
    Pospisilova, S.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Lefranc, M. P.
    Univ Montpellier, IMGT, LIGM, IGH, Montpellier, France..
    Chiorazzi, N.
    North Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA..
    Oscier, D.
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Jelinek, D. F.
    Mayo Clin, Dept Immunol, Rochester, MN USA..
    Stilgenbauer, S.
    Univ Ulm, Dept Internal Med 3, D-89069 Ulm, Germany..
    Belessi, C.
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Davi, F.
    Univ Paris 06, Hop Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Hop Pitie Salpetriere, Paris, France..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ghia, P.
    Ist Sci San Raffaele, Div Expt Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, I-20132 Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Darzentas, N.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. CERTH, Inst Appl Biosci, Thessaloniki, Greece.;G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    HIGHER-ORDER IMMUNOGLOBULIN SEQUENCE RELATIONS FOR MAJOR SUBSETS OF CHRONIC LYMPHOCYTIC LEUKEMIA: UNIQUENESS VERSUS EQUIVALENCE2015In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, 47-48 p.Article in journal (Other academic)
  • 7. Alcorn, Sara R
    et al.
    Chen, Michael J
    Claude, Line
    Dieckmann, Karin
    Ermoian, Ralph P
    Ford, Eric C
    Malet, Claude
    MacDonald, Shannon M
    Nechesnyuk, Alexey V
    Nilsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Villar, Rosangela C
    Winey, Brian A
    Tryggestad, Erik J
    Terezakis, Stephanie A
    Practice patterns of photon and proton pediatric image guided radiation treatment: results from an International Pediatric Research consortium2014In: Practical radiation oncology, ISSN 1879-8500, Vol. 4, no 5, 336-341 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Image guided radiation therapy (IGRT) has become common practice for both photon and proton radiation therapy, but there is little consensus regarding its application in the pediatric population. We evaluated clinical patterns of pediatric IGRT practice through an international pediatrics consortium comprised of institutions using either photon or proton radiation therapy.

    METHODS AND MATERIALS: Seven international institutions with dedicated pediatric expertise completed a 53-item survey evaluating patterns of IGRT use in definitive radiation therapy for patients ≤21 years old. Two institutions use proton therapy for children and all others use IG photon therapy. Descriptive statistics including frequencies of IGRT use and means and standard deviations for planning target volume (PTV) margins by institution and treatment site were calculated.

    RESULTS: Approximately 750 pediatric patients were treated annually across the 7 institutions. IGRT was used in tumors of the central nervous system (98%), abdomen or pelvis (73%), head and neck (100%), lung (83%), and liver (69%). Photon institutions used kV cone beam computed tomography and kV- and MV-based planar imaging for IGRT, and all proton institutions used kV-based planar imaging; 57% of photon institutions used a specialized pediatric protocol for IGRT that delivers lower dose than standard adult protocols. Immobilization techniques varied by treatment site and institution. IGRT was utilized daily in 45% and weekly in 35% of cases. The PTV margin with use of IGRT ranged from 2 cm to 1 cm across treatment sites and institution.

    CONCLUSIONS: Use of IGRT in children was prevalent at all consortium institutions. There was treatment site-specific variability in IGRT use and technique across institutions, although practices varied less at proton facilities. Despite use of IGRT, there was no consensus of optimum PTV margin by treatment site. Given the desire to restrict any additional radiation exposure in children to instances where the exposure is associated with measureable benefit, prospective studies are warranted to optimize IGRT protocols by modality and treatment site.

  • 8.
    Ali, Muhammad Akhtar
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Younis, Shady
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Wallerman, Ola
    Gupta, Rajesh
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sjoblöm, Tobias
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Transcriptional modulator ZBED6 affects cell cycle and growth of human colorectal cancer cells2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 25, 7743-7748 p.Article in journal (Refereed)
    Abstract [en]

    The transcription factor ZBED6 (zinc finger, BED-type containing 6) is a repressor of IGF2 whose action impacts development, cell proliferation, and growth in placental mammals. In human colorectal cancers, IGF2 overexpression is mutually exclusive with somatic mutations in PI3K signaling components, providing genetic evidence for a role in the PI3K pathway. To understand the role of ZBED6 in tumorigenesis, we engineered and validated somatic cell ZBED6 knock-outs in the human colorectal cancer cell lines RKO and HCT116. Ablation of ZBED6 affected the cell cycle and led to increased growth rate in RKO cells but reduced growth in HCT116 cells. This striking difference was reflected in the transcriptome analyses, which revealed enrichment of cell-cycle-related processes among differentially expressed genes in both cell lines, but the direction of change often differed between the cell lines. ChIP sequencing analyses displayed enrichment of ZBED6 binding at genes up-regulated in ZBED6-knockout clones, consistent with the view that ZBED6 modulates gene expression primarily by repressing transcription. Ten differentially expressed genes were identified as putative direct gene targets, and their down-regulation by ZBED6 was validated experimentally. Eight of these genes were linked to the Wnt, Hippo, TGF-beta, EGF receptor, or PI3K pathways, all involved in colorectal cancer development. The results of this study show that the effect of ZBED6 on tumor development depends on the genetic background and the transcriptional state of its target genes.

  • 9.
    Alit, Abir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Grönberg, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Federspiel, B.
    Dept Pathol, Copenhagen, Denmark..
    Hjortland, G. O.
    Dept Oncol, Oslo, Norway..
    Ladekarl, M.
    Dept Oncol, Aarhus, Denmark..
    Langer, S. W.
    Dept Oncol, Copenhagen, Denmark..
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Knigge, U.
    Dept Surg C, Copenhagen, Denmark.;Dept Endocrinol PE, Copenhagen, Denmark..
    Sorbye, H.
    Dept Oncol, Bergen, Norway..
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Expression of Mutated p53 Protein in Gastroenteropancreatic Neuroendocrine Carcinoma (WHO G3)2016In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, 43-43 p.Article in journal (Refereed)
  • 10.
    Alzrigat, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Targeted Inhibition of Polycomb Repressive Complexes in Multiple Myeloma: Implications for Biology and Therapy2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Multiple myeloma (MM) is a hematological malignancy of antibody producing plasmablasts/plasma cells. MM is characterized by extensive genetic and clonal heterogeneity, which have hampered the attempts to identify a common underlying mechanism for disease establishment and development of appropriate treatment regimes. This thesis is focused on understanding the role of epigenetic regulation of gene expression mediated by the polycomb repressive complexes 1 and 2 (PRC1 and 2) in MM and their impact on disease biology and therapy.

    In paper I the genome-wide distribution of two histone methylation marks; H3K27me3 and H3K4me3 were studied in plasma cells isolated from newly diagnosed MM patients or age-matched normal donors. We were able to define targets of H3K27me3, H3K4me3 and bivalent (carry both marks) which are, when compared to normal individuals, unique to MM patients. The presence of H3K27me3 correlated with silencing of MM unique H3K27me3 targets in MM patients at advanced stages of the disease. Notably, the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also showed that inhibition of the PRC2 enzymatic subunit EZH2 using highly selective inhibitors (GSK343 and UNC1999) demonstrated anti-myeloma activity using relevant in vitro models of MM. These data suggest an important role for gene repression mediated by PRC2 in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.

    In paper II we further explored the therapeutic potential of UNC1999, a highly selective inhibitor of EZH2 in MM. We showed that EZH2 inhibition by UNC1999 downregulated important MM oncogenes; IRF-4, XBP-1, BLIMP-1and c-MYC. These oncogenes have been previously shown to be crucial for disease establishment, growth and progression. We found that EZH2 inhibition reactivated the expression of microRNAs genes previously found to be underexpressed in MM and which possess potential tumor suppressor functions. Among the reactivated microRNAs we identified miR-125a-3p and miR-320c as predicted negative regulators of the MM-associated oncogenes. Notably, we defined miR-125a-3p and miR-320c as targets of EZH2 and H3K27me3 in MM cell lines and patients samples.  These findings described for the first time PRC2/EZH2/H3K27me3 as regulators of microRNA with tumor suppressor functions in MM. This further strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.

    In paper III we evaluated the therapeutic potential of targeting PRC1 in MM using the recently developed chemical PTC-209; an inhibitor targeting the BMI-1 subunit of PRC1. Using MM cell lines and primary cells isolated from newly diagnosed or relapsed MM patients, we found that PTC-209 has a potent anti-MM activity. We showed, for the first time in MM, that PTC-209 anti-MM effects were mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, but that other subunits of the PRC1 complex were not affected. We showed that PTC-209 reduced MM cell viability via significant induction of apoptosis. More importantly, we demonstrated that PTC-209 shows synergistic anti-MM activity with other epigenetic inhibitors targeting EZH2 (UNC1999) and BET-bromodomains (JQ1). This work highlights the potential use of BMI-1 and PRC1 as potential therapeutic targets in MM alone or in combination with other anti-MM agents including epigenetic inhibitors.

    List of papers
    1. Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.
    Open this publication in new window or tab >>Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.
    Show others...
    2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 6, 6809-6923 p.Article in journal (Refereed) Published
    Abstract [en]

    Multiple myeloma (MM) is a malignancy of the antibody-producing plasma cells. MM is a highly heterogeneous disease, which has hampered the identification of a common underlying mechanism for disease establishment as well as the development of targeted therapy. Here we present the first genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in MM patient samples, defining a common set of active H3K4me3-enriched genes and silent genes marked by H3K27me3 (H3K27me3 alone or bivalent) unique to primary MM cells, when compared to normal bone marrow plasma cells. Using this epigenome profile, we found increased silencing of H3K27me3 targets in MM patients at advanced stages of the disease, and the expression pattern of H3K27me3-marked genes correlated with poor patient survival. We also demonstrated that pharmacological inhibition of EZH2 had anti-myeloma effects in both MM cell lines and CD138+ MM patient cells. In addition, EZH2 inhibition decreased the global H3K27 methylation and induced apoptosis. Taken together, these data suggest an important role for the Polycomb repressive complex 2 (PRC2) in MM, and highlights the PRC2 component EZH2 as a potential therapeutic target in MM.

    Keyword
    multiple myeloma; Polycomb; EZH2; H3K27me3; UNC1999
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-289186 (URN)10.18632/oncotarget.6843 (DOI)000376123100032 ()26755663 (PubMedID)
    Funder
    Swedish Cancer SocietySwedish Research CouncilNIH (National Institute of Health), R01GM103893
    Available from: 2016-04-29 Created: 2016-04-29 Last updated: 2017-11-30Bibliographically approved
    2. EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.
    Open this publication in new window or tab >>EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.
    Show others...
    2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 6, 10213-10224 p.Article in journal (Refereed) Published
    Abstract [en]

    Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite the fact that current treatment strategies have improved patients' median survival time, MM remains incurable. Epigenetic aberrations are emerging as important players in tumorigenesis making them attractive targets for therapy in cancer including MM. Recently, we suggested the polycomb repressive complex 2 (PRC2) as a common denominator of gene silencing in MM and presented the PRC2 enzymatic subunit enhancer of zeste homolog 2 (EZH2) as a potential therapeutic target in MM. Here we further dissect the anti-myeloma mechanisms mediated by EZH2 inhibition and show that pharmacological inhibition of EZH2 reduces the expression of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1 and c-MYC. We show that EZH2 inhibition reactivates the expression of microRNAs with tumor suppressor functions predicted to target MM-associated oncogenes; primarily miR-125a-3p and miR-320c. ChIP analysis reveals that miR-125a-3p and miR-320c are targets of EZH2 and H3K27me3 in MM cell lines and primary cells. Our results further highlight that polycomb-mediated silencing in MM includes microRNAs with tumor suppressor activity. This novel role strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-312396 (URN)10.18632/oncotarget.14378 (DOI)000394181800106 ()28052011 (PubMedID)
    Available from: 2017-01-09 Created: 2017-01-09 Last updated: 2017-11-29Bibliographically approved
    3. The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomain
    Open this publication in new window or tab >>The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomain
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keyword
    Multiple Myeloma, Epigenetics, Polycomb, BMI-1, PTC-209
    National Category
    Cancer and Oncology
    Research subject
    Medical Science; Molecular Medicine
    Identifiers
    urn:nbn:se:uu:diva-313562 (URN)
    Available from: 2017-01-20 Created: 2017-01-20 Last updated: 2017-01-25
  • 11.
    Alzrigat, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Párraga, Alba Atienza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Agarwal, Prasoon
    Zureigat, Hadil
    Österborg, Anders
    Nahi, Hareth
    Ma, Anqi
    Jin, Jian
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jernberg Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions.2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 6, 10213-10224 p.Article in journal (Refereed)
    Abstract [en]

    Multiple Myeloma (MM) is a plasma cell tumor localized to the bone marrow (BM). Despite the fact that current treatment strategies have improved patients' median survival time, MM remains incurable. Epigenetic aberrations are emerging as important players in tumorigenesis making them attractive targets for therapy in cancer including MM. Recently, we suggested the polycomb repressive complex 2 (PRC2) as a common denominator of gene silencing in MM and presented the PRC2 enzymatic subunit enhancer of zeste homolog 2 (EZH2) as a potential therapeutic target in MM. Here we further dissect the anti-myeloma mechanisms mediated by EZH2 inhibition and show that pharmacological inhibition of EZH2 reduces the expression of MM-associated oncogenes; IRF-4, XBP-1, PRDM1/BLIMP-1 and c-MYC. We show that EZH2 inhibition reactivates the expression of microRNAs with tumor suppressor functions predicted to target MM-associated oncogenes; primarily miR-125a-3p and miR-320c. ChIP analysis reveals that miR-125a-3p and miR-320c are targets of EZH2 and H3K27me3 in MM cell lines and primary cells. Our results further highlight that polycomb-mediated silencing in MM includes microRNAs with tumor suppressor activity. This novel role strengthens the oncogenic features of EZH2 and its potential as a therapeutic target in MM.

  • 12.
    Andersson, Camilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala Univ, Oncol, Uppsala, Sweden..
    Patient experience of 18F-FDG-PET/CT in a mask fixation2016In: European Journal of Nuclear Medicine and Molecular Imaging, ISSN 1619-7070, E-ISSN 1619-7089, Vol. 43, S666-S666 p.Article in journal (Refereed)
  • 13.
    Andersson, Camilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Wassberg, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Johansson, Silvia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wikehult, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Patient Experience of an 18F-FDG-PET/CT Examination:: Need for Improvements in Patient Care2015In: Journal of Radiology Nursing, ISSN 1546-0843, Vol. 34, no 2, 100-108 p.Article in journal (Refereed)
    Abstract [en]

    The aims of this study were to investigate the patients' knowledge about and experience of an 18F-fluoro-deoxy-glucose (FDG)-positron emission tomography (PET)/computed tomography (CT) examination and to investigate the self-reported feelings of stress, level of physical activity, and health-related quality of life (HRQoL) and to find out if this was related to how they experienced the examination. A cross-sectional survey was used to collect information on 198 patients with known or suspected malignancy. As many as 32% to 63% were satisfied with the nursing staff, the communication, and the professional skills. Most patients did not know beforehand what an FDG-PET/CT examination was. The HRQoL, level of perceived stress, and physical activity were relatively low. A better HRQoL, lower level of perceived stress, and a higher level of physical activity were correlated to a more positive experience and higher education to more knowledge about the examination (p < .01–.05). The information before the examination needs to be improved. The results may be used to improve patient care and optimize imaging procedures.

  • 14.
    Andersson, Camilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Wassberg, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Johansson, Silvia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ahlström, Häkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Assessment of Whether Patients' Knowledge, Satisfaction, and Experience Regarding Their 18F-Fluoride PET/CT Examination Affects Image Quality.2016In: Journal of Nuclear Medicine Technology, ISSN 0091-4916, E-ISSN 1535-5675, Vol. 44, no 1, 21-5 p.Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to investigate patients’ previous knowledge, satisfaction and experience regarding a (18F)-fluoride positron emission tomography / computed tomography examination ((18F)-fluoride PET/CT) and to explore whether experienced discomfort during the examination or pain was associated with reduced image quality. A further aim was to explore whether patients’ health-related quality of life (HRQoL) was associated with their satisfaction and experiences of the examination. Methods: Fifty consecutive patients with a histopathological diagnosis of prostate cancer who were scheduled for (18F)-fluoride PET/CT were asked to participate in the study, which was performed between November 2011 and April 2013. A questionnaire was used to collect information regarding the patients’ previous knowledge and experience of the examination. Image quality assessment was performed according to an arbitrary scale. The EORTC-QLQ-C30 and QLQ-PR25 were used to assess HRQoL. Results: Forty-six patients (96%) completed the questionnaires. Twenty-six per cent of participants did not know at all what a (18F)-fluoride PET/CT examination was. The majority (52-70%) were to a very high degree satisfied with the care provided by the nursing staff but less satisfied with the information given prior to the examination. The image quality was similar in patients who were exhausted or claustrophobic during the examination and those who were not. No correlations between HRQoL and the participants’ experience of (18F)-fluoride PET/CT were found. Conclusion: The majority of participants were satisfied with the care provided by the nursing staff, but there is still room for improvement especially regarding the information prior to the examination. Long examination time may be strenuous, for the patient but there was no difference in image quality between patients who felt discomfort during the examination or pain and those who did not.

  • 15.
    Andersson, Camilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Röing, Marta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Health Services Research.
    Ehrsson, Ylva Tiblom
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Johansson, Birgitta
    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 Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Psychology in Healthcare.
    It's a question of endurance: patients with head and neck cancer experiences of 18F-FDG PET/CT in a fixation mask2017In: European Journal of Oncology Nursing, ISSN 1462-3889, E-ISSN 1532-2122, Vol. 29, 85-90 p., S1462-3889(17)30082-0Article in journal (Refereed)
    Abstract [en]

    PURPOSE: This study aimed to explore how patients with head and neck cancer experienced undergoing an (18)F-fluoro-deoxy-glucose positrons emissions tomography/computed tomography ((18)F-FDG PET/CT) examination in a fixation mask.

    METHOD: Interviews were conducted with nine patients with known or suspected head and neck cancer who were scheduled for the examination for the first time. The phenomenological method according to van Manen and his four lifeworld existentials; lived space, lived body, lived time, and lived relation was used to analyse the interviews.

    RESULTS: The thoughts and feelings of the patients during the PET/CT examination varied, some found it very difficult, while others did not. However, for all the patients, it was an experience that required some form of coping to maintain composure for example distraction.

    CONCLUSIONS: PET/CT examnation in a fixation mask may be strenuous for some patients. Patients need more detailed information, including suggestions for coping behaviours, prior to the examination, as well as higher level of support during and after the examination. The results of this study may be used to improve patient care and optimize the procedure of PET/CT examination in a fixation mask.

  • 16.
    Andersson, Camilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Trampal Pulido, Carlos
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Effects of web-based information on patient satisfaction and image quality in patients undergoing an 18F-FDG PET/CT examination: a randomized controlled trialManuscript (preprint) (Other academic)
  • 17.
    Apollonio, Benedetta
    et al.
    Kings Coll London, Dept Haematooncol, London WC2R 2LS, England..
    Nicholas, Nicole S.
    Kings Coll London, Dept Haematooncol, London WC2R 2LS, England..
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Salisbury, Jon
    Kings Coll Hosp London, London, England..
    Patten, Piers E.
    Kings Coll Hosp London, Haematol, London, England..
    Kassam, Shireen
    Kings Coll Hosp London, London, England..
    Devereux, Stephen
    Kings Coll Hosp London, Haematol, London, England..
    Amini, Rose Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ramsay, Alan G.
    Kings Coll London, Dept Haematooncol, London WC2R 2LS, England..
    Diffuse Large B-Cell Lymphoma (DLBCL) Tumor Cells Reprogram Lymphatic Fibroblasts into Cancer-Associated Fibroblasts (CAFs) That Contribute to Tumor Microenvironment (TME)-Driven Immune Privilege2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 18.
    Armand, Marine
    et al.
    Hop La Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Paris, France..
    Boudjoghra, Myriam
    Hop La Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Paris, France..
    Xochelli, Aliki
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Canioni, Danielle
    Univ Paris 05, Hop Necker, AP HP, Dept Pathol, Paris, France..
    Tavernier, Magali Le Garff
    Hop La Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Paris, France..
    Colombo, Monica
    Azienda Osped Univ AOU San Martino IST, IRCCS, Direz Sci, Genoa, Italy..
    Rabiega, Pascaline
    Univ Paris 06, INSERM, UMR S1136, Inst Pierre Louis Epidemiol & Sante Publ, Paris, France..
    Molina, Thierry
    Univ Paris 05, Hop Necker, AP HP, Dept Pathol, Paris, France..
    Charlotte, Frederic
    Univ Paris 06, Paris, France.;Hop La Pitie Salpetriere, Dept Pathol, Paris, France..
    Michot, Jean-Marie
    Inst Gustave Roussy, Dept Hematol & Drug Developmen, Villejuif, France..
    Lesty, Claude
    Hop La Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Paris, France..
    Carrat, Fabrice
    Univ Paris 06, INSERM, UMR S1136, Inst Pierre Louis Epidemiol & Sante Publ, Paris, France..
    Ferrarini, Manlio
    Azienda Osped Univ AOU San Martino IST, IRCCS, Direz Sci, Genoa, Italy..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Besson, Caroline
    Hop Bicetre, Dept Internal Med & Clin Immunol Biol Immunol & H, Le Kremlin Bicetre, France.;Univ Paris Sud, F-94275 Le Kremlin Bicetre, France..
    Hermine, Olivier
    Hop Necker Enfants Malad, Dept Adult Hematol, Paris, France.;Paris Descartes Univ, Paris, France..
    Davi, Frederic
    Hop La Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Paris, France..
    Auto-Immune Origin of B Cells from HCV-Associated Lymphoma2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 19. Baecklund, Fredrik
    et al.
    Foo, Jia-Nee
    Askling, Johan
    Eloranta, Sandra
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.
    Liu, Jianjun
    Hjalgrim, Henrik
    Rosenquist, Richard
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Padyukov, Leonid
    Smedby, Karin E.
    Possible Interaction Between Cigarette Smoking and HLA-DRB1 Variation in the Risk of Follicular Lymphoma2017In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 185, no 8, 681-687 p.Article in journal (Refereed)
    Abstract [en]

    Follicular lymphoma (FL) risk is strongly associated with germline genetic variation in human leukocyte antigen (HLA) class II. Cigarette smoking has been suggested to increase FL risk, primarily among women. We hypothesized that amino acids in HLA-antigen D-related beta 1 subunit (DRB1) interact with smoking in FL risk, as shown for rheumatoid arthritis. We analyzed 373 patients with FL and 818 controls from 2 population-based case-control studies in Sweden and Denmark (1999-2003). Haplotypes in HLA-DRB1 were imputed at amino acid positions 11, 13, 28, 30, and 70-74 (shared epitope). We estimated the relative risk of FL as odds ratios with 95% confidence intervals for different smoking status/haplotype combinations. Interaction was defined as departure from additivity of effects and quantified by the attributable proportion (AP). Relative to never-smokers carrying no shared epitope alleles, smoking was associated with the risk of FL among all subjects (for former smokers, odds ratio (OR) = 2.20, 95% confidence interval (CI): 1.10, 4.41; ORcurrent = 3.56, 95% CI: 1.60, 7.92) and women (ORformer = 2.95, 95% CI: 1.18, 7.37; ORcurrent = 5.63, 95% CI: 2.07, 15.3) carrying 2 shared epitope alleles but not among those carrying zero or 1 shared epitope allele. Smoking and shared epitope status interacted significantly as measured by AP (overall, AP = 0.6, 95% CI: 0.15, 1.0; for women, AP = 0.5, 95% CI: 0.005, 1.0). These results suggest a possible interaction between smoking and HLA-DRB1-associated antigen presentation in FL risk and provide a model to further unravel FL etiology.

  • 20.
    Bahlo, J.
    et al.
    Univ Hosp Cologne, Dept Internal Med 1, Cologne, Germany..
    Kutsch, N.
    Univ Hosp Cologne, Dept Internal Med 1, Cologne, Germany..
    Bergmann, M.
    Klinikum Schwabing, Dept Hematol Oncol Immunol Palliat Care Infect Di, Munich, Germany..
    Byrd, J.
    Ohio State Univ, Dept Hematol, Columbus, OH 43210 USA..
    Doehner, H.
    Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany..
    Eichhorst, B.
    Univ Hosp Cologne, Dept Internal Med 1, Cologne, Germany..
    Else, M.
    Inst Canc Res, Div Mol Pathol, London SW3 6JB, England..
    Geisler, C.
    Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    Grever, M.
    Ohio State Univ, Dept Hematol, Columbus, OH 43210 USA..
    Lepretre, S.
    Ctr Henri Becquerel, Dept Hematol, F-76038 Rouen, France..
    Neuberg, D.
    Dana Farber Canc Inst, Biostat & Computat Biol, Boston, MA 02115 USA..
    Oscier, D.
    Royal Bournemouth Hosp, Dept Hematol, Bournemouth, Dorset, England..
    Robak, T.
    Med Univ Lodz, Dept Hematol, Lodz, Poland..
    Rosenquist, Richard Brandell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Shanafelt, T.
    Mayo Clin, Div Hematol, Dept Internal Med, Rochester, NY USA..
    Stilgenbauer, S.
    Univ Hosp Ulm, Dept Internal Med 3, Ulm, Germany..
    Hallek, M.
    Univ Hosp Cologne, Dept Internal Med 1, Cologne, Germany..
    THE INTERNATIONAL PROGNOSTIC INDEX FOR PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL-IPI)-AN INTERNATIONAL META-ANALYSIS2015In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, 313-314 p.Article in journal (Other academic)
  • 21.
    Baliakas, Panagiotis
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Agathangelidis, Andreas
    Hadzidimitriou, Anastasia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sutton, Lesley-Ann
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Minga, Eva
    Tsanousa, Athina
    Scarfo, Lydia
    Davis, Zadie
    Yan, Xiao-Jie
    Shanafelt, Tait
    Plevova, Karla
    Sandberg, Yorick
    Vojdeman, Fie Juhl
    Boudjogra, Myriam
    Tzenou, Tatiana
    Chatzouli, Maria
    Chu, Charles C.
    Veronese, Silvio
    Gardiner, Anne
    Mansouri, Larry
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Smedby, Karin E.
    Pedersen, Lone Bredo
    Moreno, Denis
    Van Lom, Kirsten
    Giudicelli, Veronique
    Francova, Hana Skuhrova
    Nguyen-Khac, Florence
    Panagiotidis, Panagiotis
    Juliusson, Gunnar
    Angelis, Lefteris
    Anagnostopoulos, Achilles
    Lefranc, Marie-Paule
    Facco, Monica
    Trentin, Livio
    Catherwood, Mark
    Montillo, Marco
    Geisler, Christian H.
    Langerak, Anton W.
    Pospisilova, Sarka
    Chiorazzi, Nicholas
    Oscier, David
    Jelinek, Diane F.
    Darzentas, Nikos
    Belessi, Chrysoula
    Davi, Frederic
    Ghia, Paolo
    Rosenquist, Richard Brandell
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Stamatopoulos, Kostas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Not all IGHV3-21 chronic lymphocytic leukemias are equal: prognostic considerations2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 125, no 5, 856-859 p.Article in journal (Refereed)
    Abstract [en]

    An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset # 2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue in 8593 CLL patients of whom 437 (5%) used the IGHV3-21 gene with 254/437 (58%) classified as subset # 2. Within subset # 2, immunoglobulin heavy variable (IGHV)-mutated cases predominated, whereas non-subset # 2/IGHV3-21 was enriched for IGHV-unmutated cases (P =.002). Subset # 2 exhibited significantly shorter time-to-first-treatment (TTFT) compared with non-subset # 2/IGHV3-21 (22 vs 60 months, P =.001). No such difference was observed between non-subset # 2/IGHV3-21 vs the remaining CLL with similar IGHV mutational status. In conclusion, IGHV3-21 CLL should not be axiomatically considered a homogeneous entity with adverse prognosis, given that only subset # 2 emerges as uniformly aggressive, contrasting non-subset # 2/IGVH3-21 patients whose prognosis depends on IGHV mutational status as the remaining CLL.

  • 22.
    Baliakas, Panagiotis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hadzidimitriou, A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    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, Science for Life Laboratory, SciLifeLab.
    Xochelli, Aliki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sutton, L. A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Minga, E.
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Scarfo, L.
    Ist Sci San Raffaele, Div Expt Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, I-20132 Milan, Italy.;Fdn Ctr San Raffaele, Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Rossi, D.
    Amedeo Avogadro Univ Eastern Piedmont, Dept Translat Med, Div Hematol, Novara, Italy..
    Davis, Z.
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Agathangelidis, A.
    Ist Sci San Raffaele, Div Expt Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, I-20132 Milan, Italy.;Fdn Ctr San Raffaele, Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Villamor, N.
    Hosp Clin Barcelona, Hemopathol Unit, Barcelona, Spain..
    Parker, H.
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Kotaskova, J.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Stalika, E.
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.;G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Plevova, K.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Navarro Lopez, A.
    Hosp Clin Barcelona, Hemopathol Unit, Barcelona, Spain..
    Delgado, J.
    Hosp Clin Barcelona, Dept Hematol, Barcelona, Spain..
    Larrayoz, M.
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Anagnostopoulos, A.
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Belessi, C.
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Smedby, K. E.
    Dept Med, Solna, Sweden.;Karolinska Inst, Clin Epidemiol Unit, Stockholm, Sweden..
    Juliusson, G.
    Lund Univ, Lund, Sweden.;Lund Stem Cell Ctr, Hosp Dept Hematol, Lund, Sweden..
    Strefford, J. C.
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Pospisilova, S.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Oscier, D.
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Gaidano, G.
    Amedeo Avogadro Univ Eastern Piedmont, Dept Translat Med, Div Hematol, Novara, Italy..
    Campo, E.
    Hosp Clin Barcelona, Hemopathol Unit, Barcelona, Spain.;Univ Barcelona, Dept Pathol, Barcelona, Spain..
    Ghia, P.
    Ist Sci San Raffaele, Div Expt Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, I-20132 Milan, Italy.;Fdn Ctr San Raffaele, Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    REFINING PROGNOSIS OF CHRONIC LYMPHOCYTIC LEUKEMIA WITH SOMATICALLY HYPERMUTATED B-CELL RECEPTORS: A NOVEL PROGNOSTIC INDEX ON BEHALF OF THE EUROPEAN RESEARCH INITIATIVE ON CLL (ERIC)2015In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, 52-52 p.Article in journal (Other academic)
  • 23.
    Baliakas, Panagiotis
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hadzidimitriou, A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sutton, Lesley Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rossi, D
    Minga, E
    Villamor, N
    Larrayoz, M
    Kminkova, J
    Agathangelidis, A
    Davis, Z
    Tausch, E
    Stalika, E
    Kantorova, B
    Mansouri, Larry
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Scarfò, L
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Navrkalova, V
    Rose-Zerilli, M J J
    Smedby, K E
    Juliusson, G
    Anagnostopoulos, A
    Makris, A M
    Navarro, A
    Delgado, J
    Oscier, D
    Belessi, C
    Stilgenbauer, S
    Ghia, P
    Pospisilova, S
    Gaidano, G
    Campo, E
    Strefford, J C
    Stamatopoulos, Kostas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Recurrent mutations refine prognosis in chronic lymphocytic leukemia2015In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 29, 329-336 p.Article in journal (Refereed)
    Abstract [en]

    Through the European Research Initiative on chronic lymphocytic leukemia (CLL) (ERIC), we screened 3490 patients with CLL for mutations within the NOTCH1 (n=3334), SF3B1 (n=2322), TP53 (n=2309), MYD88 (n=1080) and BIRC3 (n=919) genes, mainly at diagnosis (75%) and before treatment (>90%). BIRC3 mutations (2.5%) were associated with unmutated IGHV genes (U-CLL), del(11q) and trisomy 12, whereas MYD88 mutations (2.2%) were exclusively found among M-CLL. NOTCH1, SF3B1 and TP53 exhibited variable frequencies and were mostly enriched within clinically aggressive cases. Interestingly, as the timespan between diagnosis and mutational screening increased, so too did the incidence of SF3B1 mutations; no such increase was observed for NOTCH1 mutations. Regarding the clinical impact, NOTCH1 mutations, SF3B1 mutations and TP53 aberrations (deletion/mutation, TP53ab) correlated with shorter time-to-first-treatment (P<0.0001) in 889 treatment-naive Binet stage A cases. In multivariate analysis (n=774), SF3B1 mutations and TP53ab along with del(11q) and U-CLL, but not NOTCH1 mutations, retained independent significance. Importantly, TP53ab and SF3B1 mutations had an adverse impact even in U-CLL. In conclusion, we support the clinical relevance of novel recurrent mutations in CLL, highlighting the adverse impact of SF3B1 and TP53 mutations, even independent of IGHV mutational status, thus underscoring the need for urgent standardization/harmonization of the detection methods.

  • 24.
    Baliakas, Panagiotis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hadzidimitriou, Anastasia
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Agathangelidis, Andreas
    Univ Vita Salute San Raffaele, I-20132 Milan, Italy.;Ist Sci San Raffaele, Ist Ricovero & Cura Carattere Sci, Div Expt Oncol, Dept Oncohematol, I-20132 Milan, Italy..
    Rossi, Davide
    Amedeo Avogadro Univ Eastern Piedmont, Dept Translat Med, Div Haematol, Novara, Italy..
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kminkova, Jana
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp, Brno, Czech Republic..
    Scarfo, Lydia
    Univ Vita Salute San Raffaele, I-20132 Milan, Italy.;Ist Sci San Raffaele, Ist Ricovero & Cura Carattere Sci, Div Expt Oncol, Dept Oncohematol, I-20132 Milan, Italy..
    Pospisilova, Sarka
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp, Brno, Czech Republic..
    Gaidano, Gianluca
    Amedeo Avogadro Univ Eastern Piedmont, Dept Translat Med, Div Haematol, Novara, Italy..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ghia, Paolo
    Univ Vita Salute San Raffaele, I-20132 Milan, Italy.;Ist Sci San Raffaele, Ist Ricovero & Cura Carattere Sci, Div Expt Oncol, Dept Oncohematol, I-20132 Milan, Italy..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Prognostic relevance of MYD88 mutations in CLL: the jury is still out2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 8, 1043-1044 p.Article in journal (Refereed)
  • 25.
    Baliakas, Panagiotis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala Univ, Sci Life Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden.;G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Hadzidimitriou, Anastasia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Minga, Eva
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Agathangelidis, Andreas
    Univ Vita Salute San Raffaele, I-20132 Milan, Italy.;Ist Sci San Raffaele, IRCCS, Div Mol Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, IRCCS, Dept Oncohematol, I-20132 Milan, Italy..
    Nichelatti, Michele
    Osped Niguarda Ca Granda, Niguarda Canc Ctr, Mol Pathol Unit, Milan, Italy.;Osped Niguarda Ca Granda, Niguarda Canc Ctr, Dept Haematol, Milan, Italy..
    Tsanousa, Athina
    Aristotle Univ Thessaloniki, Dept Informat, GR-54006 Thessaloniki, Greece..
    Scarfo, Lydia
    Univ Vita Salute San Raffaele, I-20132 Milan, Italy.;Ist Sci San Raffaele, IRCCS, Div Mol Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, IRCCS, Dept Oncohematol, I-20132 Milan, Italy..
    Davis, Zadie
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Yan, Xiao-Jie
    North Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA..
    Shanafelt, Tait
    Mayo Clin, Div Hematol, Dept Med, Rochester, MN USA..
    Plevova, Karla
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Sandberg, Yorick
    Erasmus MC, Univ Med Ctr, Dept Immunol, Rotterdam, Netherlands..
    Vojdeman, Fie Juhl
    Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    Boudjogra, Myriam
    Hop La Pitie Salpetriere, Serv Hematol Biol, Paris, France..
    Tzenou, Tatiana
    Univ Athens, Dept Propaedeut Med, Athens, Greece..
    Chatzouli, Maria
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Chu, Charles C.
    North Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA..
    Veronese, Silvio
    Osped Niguarda Ca Granda, Niguarda Canc Ctr, Mol Pathol Unit, Milan, Italy.;Osped Niguarda Ca Granda, Niguarda Canc Ctr, Dept Haematol, Milan, Italy..
    Gardiner, Anne
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Mansouri, Larry
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala Univ, Sci Life Lab, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Smedby, Karin E.
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden..
    Pedersen, Lone Bredo
    Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    van Lom, Kirsten
    Erasmus MC, Univ Med Ctr, Dept Hematol, Rotterdam, Netherlands..
    Giudicelli, Veronique
    Univ Montpellier, IMGT Int ImMunoGeneT Informat Syst, LIGM, Inst Genet Humaine, F-34059 Montpellier, France..
    Francova, Hana Skuhrova
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Nguyen-Khac, Florence
    Hop La Pitie Salpetriere, Serv Hematol Biol, Paris, France..
    Panagiotidis, Panagiotis
    Univ Athens, Dept Propaedeut Med, Athens, Greece..
    Juliusson, Gunnar
    Lund Univ & Hosp, Dept Hematol, Lund Stem Cell Ctr, Lund, Sweden..
    Angelis, Lefteris
    Aristotle Univ Thessaloniki, Dept Informat, GR-54006 Thessaloniki, Greece..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Lefranc, Marie-Paule
    Univ Montpellier, IMGT Int ImMunoGeneT Informat Syst, LIGM, Inst Genet Humaine, F-34059 Montpellier, France..
    Facco, Monica
    Univ Padua, Sch Med, Dept Med, Hematol & Clin Immunol Branch, I-35100 Padua, Italy.;Venetian Inst Mol Med, Padua, Italy..
    Trentin, Livio
    Univ Padua, Sch Med, Dept Med, Hematol & Clin Immunol Branch, I-35100 Padua, Italy.;Venetian Inst Mol Med, Padua, Italy..
    Catherwood, Mark
    Belfast City Hosp, Dept Haematooncol, Belfast BT9 7AD, Antrim, North Ireland..
    Montillo, Marco
    Osped Niguarda Ca Granda, Niguarda Canc Ctr, Mol Pathol Unit, Milan, Italy.;Osped Niguarda Ca Granda, Niguarda Canc Ctr, Dept Haematol, Milan, Italy..
    Geisler, Christian H.
    Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    Langerak, Anton W.
    Erasmus MC, Univ Med Ctr, Dept Immunol, Rotterdam, Netherlands..
    Pospisilova, Sarka
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Chiorazzi, Nicholas
    North Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA..
    Oscier, David
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Jelinek, Diane F.
    Mayo Clin, Dept Immunol, Dept Med, Rochester, MN USA..
    Darzentas, Nikos
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Belessi, Chrysoula
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Davi, Frederic
    Hop La Pitie Salpetriere, Serv Hematol Biol, Paris, France..
    Rosenquist Barndell, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ghia, Paolo
    Univ Vita Salute San Raffaele, I-20132 Milan, Italy.;Ist Sci San Raffaele, IRCCS, Div Mol Oncol, I-20132 Milan, Italy.;Ist Sci San Raffaele, IRCCS, Dept Oncohematol, I-20132 Milan, Italy..
    Stamatopoulos, Kostas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.;CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Clinical effect of stereotyped B-cell receptor immunoglobulins in chronic lymphocytic leukaemia: a retrospective multicentre study2014In: LANCET HAEMATOLOGY, ISSN 2352-3026, Vol. 1, no 2, E74-E84 p.Article in journal (Refereed)
    Abstract [en]

    Background About 30% of cases of chronic lymphocytic leukaemia (CLL) carry quasi-identical B-cell receptor immunoglobulins and can be assigned to distinct stereotyped subsets. Although preliminary evidence suggests that B-cell receptor immunoglobulin stereotypy is relevant from a clinical viewpoint, this aspect has never been explored in a systematic manner or in a cohort of adequate size that would enable clinical conclusions to be drawn. Methods For this retrospective, multicentre study, we analysed 8593 patients with CLL for whom immunogenetic data were available. These patients were followed up in 15 academic institutions throughout Europe (in Czech Republic, Denmark, France, Greece, Italy, Netherlands, Sweden, and the UK) and the USA, and data were collected between June 1, 2012, and June 7, 2013. We retrospectively assessed the clinical implications of CLL B-cell receptor immunoglobulin stereotypy, with a particular focus on 14 major stereotyped subsets comprising cases expressing unmutated (U-CLL) or mutated (M-CLL) immunoglobulin heavy chain variable genes. The primary outcome of our analysis was time to first treatment, defined as the time between diagnosis and date of first treatment. Findings 2878 patients were assigned to a stereotyped subset, of which 1122 patients belonged to one of 14 major subsets. Stereotyped subsets showed significant differences in terms of age, sex, disease burden at diagnosis, CD38 expression, and cytogenetic aberrations of prognostic significance. Patients within a specific subset generally followed the same clinical course, whereas patients in different stereotyped subsets-despite having the same immunoglobulin heavy variable gene and displaying similar immunoglobulin mutational status-showed substantially different times to first treatment. By integrating B-cell receptor immunoglobulin stereotypy (for subsets 1, 2, and 4) into the well established Dohner cytogenetic prognostic model, we showed these, which collectively account for around 7% of all cases of CLL and represent both U-CLL and M-CLL, constituted separate clinical entities, ranging from very indolent (subset 4) to aggressive disease (subsets 1 and 2). Interpretation The molecular classification of chronic lymphocytic leukaemia based on B-cell receptor immunoglobulin stereotypy improves the Dohner hierarchical model and refines prognostication beyond immunoglobulin mutational status, with potential implications for clinical decision making, especially within prospective clinical trials.

  • 26.
    Baliakas, Panagiotis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hadzidimitriou, A.
    Inst Appl Biosci, Thessaloniki, Greece..
    Minga, E.
    Inst Appl Biosci, Thessaloniki, Greece..
    Agathangelidis, A.
    Univ Vita Salute San Raffaele, Milan, Italy.;Ist Sci San Raffaele, Div Expt Oncol, Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, Milan, Italy..
    Sutton, L. A.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Scarfo, L.
    Univ Vita Salute San Raffaele, Milan, Italy.;Ist Sci San Raffaele, Div Expt Oncol, Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, Milan, Italy..
    Davis, Z.
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Yan, X. J.
    Northwell Hlth, Feinstein Inst Med Res, New York, NY USA..
    Plevova, K.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Sandberg, Y.
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Immunol, Rotterdam, Netherlands..
    Vojdeman, F. Juhl
    Rigshosp, Dept Hematol, Copenhagen, Denmark..
    Tzenou, T.
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece..
    Chu, C. C.
    Northwell Hlth, Feinstein Inst Med Res, New York, NY USA..
    Veroneze, S.
    Osped Niguarda Ca Granda, Niguarda Canc Ctr, Mol Pathol Unit, Milan, Italy.;Osped Niguarda Ca Granda, Niguarda Canc Ctr, Dept Haematol, Milan, Italy..
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Smedby, K. E.
    Dept Med, Solna, Sweden.;Karolinska Inst, Clin Epidemiol Unit, Stockholm, Sweden..
    Giudicelli, V.
    Univ Montpellier, IMGT, LIGM, IGH, Montpellier, France..
    Nguyen-Khac, F.
    Dept Hematol, Paris, France.;Univ Paris 06, Hop Pitie Salpetriere, Paris, France..
    Panagiotidis, P.
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece..
    Juliusson, G.
    Lund Univ, Lund, Sweden.;Lund Stem Cell Ctr, Hosp Dept Hematol, Lund, Sweden..
    Anagnostopoulos, A.
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Lefranc, M. P.
    Univ Montpellier, IMGT, LIGM, IGH, Montpellier, France..
    Trentin, L.
    Univ Padua, Dept Med, Hematol & Clin Immunol Branch, Sch Med, Padua, Italy.;Venetian Inst Mol Med, Padua, Italy..
    Catherwood, M.
    Belfast City Hosp, Dept Hematooncol, Belfast, Antrim, North Ireland..
    Montillo, M.
    Osped Niguarda Ca Granda, Niguarda Canc Ctr, Mol Pathol Unit, Milan, Italy.;Osped Niguarda Ca Granda, Niguarda Canc Ctr, Dept Haematol, Milan, Italy..
    Niemann, C. U.
    Rigshosp, Dept Hematol, Copenhagen, Denmark..
    Langerak, A. W.
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Immunol, Rotterdam, Netherlands..
    Pospisilova, S.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Stavroyianni, N.
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Chiorazzi, N.
    Northwell Hlth, Feinstein Inst Med Res, New York, NY USA..
    Oscier, D.
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Jelinek, D. F.
    Mayo Clin, Dept Immunol, Rochester, MN USA..
    Shanafelt, T.
    Mayo Clin, Dept Med, Div Hematol, Rochester, MN USA..
    Darzentas, N.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Belessi, C.
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Davi, F.
    Dept Hematol, Paris, France.;Univ Paris 06, Hop Pitie Salpetriere, Paris, France..
    Ghia, P.
    Univ Vita Salute San Raffaele, Milan, Italy.;Ist Sci San Raffaele, Div Expt Oncol, Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, Milan, Italy..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Inst Appl Biosci, Thessaloniki, Greece.;G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    No Improvement In Long-Term Overall Survival After The Introduction Of Chemo(Immuno)Therapy For Chronic Lymphocytic Leukemia Patients Belonging To Stereotyped Subset #22016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, 231-231 p.Article in journal (Other academic)
  • 27.
    Baliakas, Panagiotis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mattsson, Mattias
    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 Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Rosenquist Brandell, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Prognostic indices in chronic lymphocytic leukaemia: where do we stand how do we proceed?2016In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 279, no 4, 347-357 p.Article, review/survey (Refereed)
    Abstract [en]

    The remarkable clinical heterogeneity in chronic lymphocytic leukaemia (CLL) has highlighted the need for prognostic and predictive algorithms that can be employed in clinical practice to assist patient management and therapy decisions. Over the last 20 years, this research field has been rewarding and many novel prognostic factors have been identified, especially at the molecular genetic level. Whilst detection of recurrent cytogenetic aberrations and determination of the immunoglobulin heavy variable gene somatic hypermutation status have an established role in outcome prediction, next-generation sequencing has recently revealed novel mutated genes with clinical relevance (e.g. NOTCH1, SF3B1 and BIRC3). Efforts have been made to combine variables into prognostic indices; however, none has been universally adopted. Although a unifying model for all groups of patients and in all situations is appealing, this may prove difficult to attain. Alternatively, focused efforts on patient subgroups in the same clinical context and at certain clinically relevant 'decision points', that is at diagnosis and at initiation of first-line or subsequent treatments, may provide a more accurate approach. In this review, we discuss the advantages and disadvantages as well as the clinical applicability of three recently proposed prognostic models, the MD Anderson nomogram, the integrated cytogenetic and mutational model and the CLL-international prognostic index. We also consider future directions taking into account novel aspects of the disease, such as the tumour microenvironment and the dynamics of (sub)clonal evolution. These aspects are particularly relevant in view of the increasing number of new targeted therapies that have recently emerged.

  • 28.
    Baliakas, Panagiotis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Puiggros, A.
    Hosp del Mar, Lab Citogenet Mol, Serv Patol, Barcelona, Spain.;Spanish Cooperat Grp Hematol Cytogenet, Barcelona, Spain..
    Xochelli, Aliki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sutton, L. -A
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nguyen-Khac, F.
    Univ Paris 06, Hop Pitie Salpetriere, Hematol Dept, Paris, France.;Univ Paris 06, Hop Pitie Salpetriere, Paris, France..
    Gardiner, A.
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Plevova, K.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Ortega, M.
    Spanish Cooperat Grp Hematol Cytogenet, Barcelona, Spain.;Hosp Univ Vall dHebron, Barcelona, Spain..
    Collado, R.
    Spanish Cooperat Grp Hematol Cytogenet, Barcelona, Spain.;Consorcio Hosp Gen Univ Valencia, Valencia, Spain..
    Gonzalez, T.
    Spanish Cooperat Grp Hematol Cytogenet, Barcelona, Spain.;Fdn Publ Galega Med Xen, Santiago De Compostela, Spain..
    Granada, I.
    Spanish Cooperat Grp Hematol Cytogenet, Barcelona, Spain.;Hosp Badalona Germans Trias & Pujol, Badalona, Spain..
    Luno, E.
    Spanish Cooperat Grp Hematol Cytogenet, Barcelona, Spain.;Hosp Univ Cent Asturias, Oviedo, Spain..
    Kotaskova, J.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Davis, Z.
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Anagnostopoulos, A.
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Strefford, J.
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Pospisilova, S.
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Davi, F.
    Univ Paris 06, Hop Pitie Salpetriere, Hematol Dept, Paris, France.;Univ Paris 06, Hop Pitie Salpetriere, Paris, France..
    Athanasiadou, A.
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Rosenquist, Richard Brandell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Oscier, D.
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Sola, B. Espinet
    Hosp del Mar, Lab Citogenet Mol, Serv Patol, Barcelona, Spain.;Spanish Cooperat Grp Hematol Cytogenet, Barcelona, Spain..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    ADDITIONAL TRISOMIES AMONGST PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA CARRYING TRISOMY 12: THE PARTNER CHROMOSOME MAKES A DIFFERENCE2015In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 100, 224-224 p.Article in journal (Other academic)
  • 29.
    Baliakas, Panagiotis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Puiggros, Anna
    Hosp Mar, Lab Citogenet Mol Servei Patol, Barcelona, Spain.;IMIM Hosp Mar, Canc Res Program, Grp Recerca Translac Neoplasies Hematol, Barcelona, Spain..
    Xochelli, Aliki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Nguyen-Khac, Florence
    Hop La Pitie Salpetriere, AP HP, Dept Hematol, Paris, France.;Univ Paris 06, UMRS 1138, Paris, France..
    Gardiner, Anne
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Plevova, Karla
    Univ Hosp Brno, Brno, Czech Republic..
    Minga, Eva
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Hadzidimitriou, Anastasia
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Walewska, Renata
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    McCarthy, Helen
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Ortega, Margarita
    Hosp Univ Vall Hebron, Barcelona, Spain..
    Collado, Rosa
    Consorcio Hosp Gen Univ Valencia, Valencia, Spain..
    Gonzalez, Teresa
    Fdn Publ Galega Med Xenom, Santiago De Compostela, Spain..
    Granada, Isabel
    Univ Autonoma Barcelona, ICO Hosp Gerans Trias & Pujol, Inst Recerca Leucemia Josep Carreras IJC, Badalona, Spain..
    Luno, Elisa
    Hosp Univ Cent Asturias, Oviedo, Spain..
    Kotaskova, Jana
    Masaryk Univ, Cent European Inst Technol, CS-60177 Brno, Czech Republic.;Univ Hosp Brno, Brno, Czech Republic..
    Moysiadis, Theodoros
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Davis, Zadie
    Stavroyianni, Niki
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Strefford, Jonathan C.
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Pospisilova, Sarka
    Masaryk Univ, Cent European Inst Technol, CS-60177 Brno, Czech Republic..
    Davi, Frederic
    Athanasiadou, Anastasia
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Oscier, David
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Espinet, Blanca
    Hosp Mar, Lab Citogenet Mol Servei Patol, Barcelona, Spain.;IMIM Hosp Mar, Canc Res Program, Grp Recerca Translac Neoplasies Hematol, Barcelona, Spain..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Additional trisomies amongst patients with chronic lymphocytic leukemia carrying trisomy 12: the accompanying chromosome makes a difference2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 7, 299-302 p.Article in journal (Refereed)
  • 30.
    Baliakas, Panagiotis
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Strefford, Jonathan C.
    Bikos, Vasilis
    Parry, Marina
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Oscier, David
    Splenic marginal-zone lymphoma: ontogeny and genetics2015In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 56, no 2, 301-310 p.Article, review/survey (Refereed)
    Abstract [en]

    Splenic marginal-zone lymphoma (SMZL) is a rare tumor that has recently emerged as a prototype for how the interplay between genetics and environment shapes the natural history of lymphomas. Indeed, the recent identification of molecular immunogenetic subgroups within SMZL may prove to be relevant not only for the sub-classification of the disease but also for improved understanding of the underlying biology. In contrast to other B-cell lymphomas, SMZL lacks a characteristic genetic lesion, although the majority of cases harbor genomic aberrations, as recently revealed by high-throughput studies that identified recurrent genetic aberrations, several in pathways related to marginal-zone differentiation and B-cell signaling. Here we provide an overview of recent research into the molecular and cellular biology of SMZL and related disorders, with special emphasis on immunogenetics and genomic aberrations, and discuss the value of molecular and cellular markers for the diagnosis and differential diagnosis of these entities.

  • 31.
    Baliakas, Panagiotis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Xochelli, Aliki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. ;G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.;CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Minga, E.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Karavalakis, G.
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Athanasiadou, A.
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Stalika, E.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Douka, V.
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Protopappa, M.
    Gen Hosp Serres, Hematol Dept, Serres, Greece..
    Mpanti, A.
    Papageorgiou Hosp, Dept Hematol, Thessaloniki, Greece..
    Kotsianidis, I.
    Democritus Univ Thrace, Dept Hematol, Alexandroupolis, Greece..
    Papaioannou, M.
    Aristotle Univ Thessaloniki, AHEPA Hosp, Dept Hematol, Thessaloniki, Greece..
    Stavroyianni, N.
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Anagnostopoulos, A.
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Belessi, C.
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Hadzidimitriou, A.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.;CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Hypogammaglobulinemia In Chronic Lymphocytic Leukemia: Clinicobiological Associations2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, 438-438 p.Article in journal (Other academic)
  • 32.
    Ballesteros, J.
    et al.
    Vivia Biotech, Tres Cantos, Spain..
    Scarfo, L.
    Univ Vita Salute San Raffaele, Milan, Italy.;Osped San Raffaele, Milan, Italy..
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Xochelli, A.
    Ctr Res & Technol Hellas, Thessaloniki, Greece..
    Ranghetti, P.
    Univ Vita Salute San Raffaele, Milan, Italy.;Osped San Raffaele, Milan, Italy..
    Primo, D.
    Vivia Biotech, Tres Cantos, Spain..
    Robles, A.
    Vivia Biotech, Tres Cantos, Spain..
    Gorrochategui, J.
    Vivia Biotech, Tres Cantos, Spain..
    Martinez Lopez, J.
    Hosp 12 Octubre, Madrid, Spain..
    de la Serna, J.
    Hosp 12 Octubre, Madrid, Spain..
    Gonzalez, M.
    Hosp Clin Univ Salamanca, Salamanca, Spain..
    Munugalavadla, V.
    Gilead Sci Inc, 353 Lakeside Dr, Foster City, CA 94404 USA..
    Tannheimer, S.
    Gilead Sci Inc, 353 Lakeside Dr, Foster City, CA 94404 USA..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Stamatopoulos, K.
    Ctr Res & Technol Hellas, Thessaloniki, Greece..
    Ghia, P.
    Univ Vita Salute San Raffaele, Milan, Italy.;Osped San Raffaele, Milan, Italy..
    Ex Vivo Lymph Node Native Microenvironment Assay Shows Novel Antiproliferative Activity For Idelalisib And Ibrutinib On Cll Cells2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, 426-426 p.Article in journal (Other academic)
  • 33.
    Ballesteros, Joan
    et al.
    Vivia Biotech, Madrid, Spain..
    Scarfo, Lydia
    Ist Sci San Raffaele, Unit Lymphoid Malignancies, Dept Oncohematol, I-20132 Milan, Italy..
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Xochelli, Aliki
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Ranghetti, Pamela
    Univ Vita Salute San Raffaele, Milan, Italy.;Osped San Raffaele, Madrid, Spain..
    Primo, Daniel
    Vivia Biotech, Madrid, Spain..
    Robles, Alicia
    Vivia Biotech, Madrid, Spain..
    Gorrochategui, Julian
    Vivia Biotech, Madrid, Spain..
    Martinez-Lopez, Joaquin
    Hosp Univ 12 Octubre, Madrid, Spain..
    De la Serna, Javier
    Hosp Univ 12 Octubre, Madrid, Spain..
    Gonzalez, Marcos
    Hosp Clin Univ Salamanca, Salamanca, Spain..
    Munugalavadla, Veerendra
    Gilead Sci, Foster City, CA USA..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Stamatopoulos, Kostas
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Queva, Christophe
    Gilead Sci, Foster City, CA USA..
    Ghia, Paolo
    Univ Vita Salute San Raffaele, Milan, Italy.;IRCCS Ist Sci San Raffaele, Milan, Italy..
    An Innovative High-Throughput Ex Vivo Drug Assay Incorporating the Native Microenvironment Reveals a Novel Mechanism of Action of Idelalisib in CLL2015In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, no 23Article in journal (Other academic)
  • 34. Barrington, Sally F
    et al.
    Kirkwood, Amy A
    Franceschetto, Antonella
    Fulham, Michael J
    Roberts, Thomas H
    Almquist, Helén
    Brun, Eva
    Hjorthaug, Karin
    Viney, Zaid N
    Pike, Lucy C
    Federico, Massimo
    Luminari, Stefano
    Radford, John
    Trotman, Judith
    Fosså, Alexander
    Berkahn, Leanne
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    D'Amore, Francesco
    Sinclair, Donald A
    Smith, Paul
    O'Doherty, Michael J
    Stevens, Lindsey
    Johnson, Peter W
    PET-CT for staging and early response: results from the Response-Adapted Therapy in Advanced Hodgkin Lymphoma study.2016In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 127, no 12, 1531-1538 p.Article in journal (Refereed)
    Abstract [en]

    International guidelines recommend that positron emission tomography-computed tomography (PET-CT) should replace CT in Hodgkin lymphoma (HL). The aims of this study were to compare PET-CT with CT for staging and measure agreement between expert and local readers, using a 5-point scale (Deauville criteria), to adapt treatment in a clinical trial: Response-Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL). Patients were staged using clinical assessment, CT, and bone marrow biopsy (RATHL stage). PET-CT was performed at baseline (PET0) and after 2 chemotherapy cycles (PET2) in a response-adapted design. PET-CT was reported centrally by experts at 5 national core laboratories. Local readers optionally scored PET2 scans. The RATHL and PET-CT stages were compared. Agreement among experts and between expert and local readers was measured. RATHL and PET0 stage were concordant in 938 (80%) patients. PET-CT upstaged 159 (14%) and downstaged 74 (6%) patients. Upstaging by extranodal disease in bone marrow (92), lung (11), or multiple sites (12) on PET-CT accounted for most discrepancies. Follow-up of discrepant findings confirmed the PET characterization of lesions in the vast majority. Five patients were upstaged by marrow biopsy and 7 by contrast-enhanced CT in the bowel and/or liver or spleen. PET2 agreement among experts (140 scans) with a κ (95% confidence interval) of 0.84 (0.76-0.91) was very good and between experts and local readers (300 scans) at 0.77 (0.68-0.86) was good. These results confirm PET-CT as the modern standard for staging HL and that response assessment using Deauville criteria is robust, enabling translation of RATHL results into clinical practice.

  • 35. Baumann, Pia
    et al.
    Nyman, Jan
    Hoyer, Morten
    Wennberg, Berit
    Gagliardi, Giovanna
    Lax, Ingmar
    Drugge, Ninni
    Ekberg, Lars
    Friesland, Signe
    Johansson, Karl-Axel
    Lund, Jo-Asmund
    Morhed, Elisabeth
    Nilsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Levin, Nina
    Paludan, Merete
    Sederholm, Christer
    Traberg, Anders
    Wittgren, Lena
    Lewensohn, Rolf
    Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy.2009In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 27, no 20, 3290-6 p.Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The impact of stereotactic body radiotherapy (SBRT) on 3-year progression-free survival of medically inoperable patients with stage I non-small-cell lung cancer (NSCLC) was analyzed in a prospective phase II study.

    PATIENTS AND METHODS: Fifty-seven patients with T1NOMO (70%) and T2N0M0 (30%) were included between August 2003 and September 2005 at seven different centers in Sweden, Norway, and Denmark and observed up to 36 months. SBRT was delivered with 15 Gy times three at the 67% isodose of the planning target volume.

    RESULTS: Progression-free survival at 3 years was 52%. Overall- and cancer-specific survival at 1, 2, and 3 years was 86%, 65%, 60%, and 93%, 88%, 88%, respectively. There was no statistically significant difference in survival between patients with T1 or T2 tumors. At a median follow-up of 35 months (range, 4 to 47 months), 27 patients (47%) were deceased, seven as a result of lung cancer and 20 as a result of concurrent disease. Kaplan-Meier estimated local control at 3 years was 92%. Local relapse was observed in four patients (7%). Regional relapse was observed in three patients (5%). Nine patients (16%) developed distant metastases. The estimated risk of all failure (local, regional, or distant metastases) was increased in patients with T2 (41%) compared with those with T1 (18%) tumors (P = .027).

    CONCLUSION: With a 3-year local tumor control rate higher than 90% with limited toxicity, SBRT emerges as state-of-the-art treatment for medically inoperable stage I NSCLC and may even challenge surgery in operable instances.

  • 36.
    Berglund, Åke
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ullen, Anders
    Karolinska Univ Hosp, Dept Oncol, Solna, Sweden..
    Lisyanskaya, Alla
    City Clin Oncol Ctr, St Petersburg State Healthcare Inst, St Petersburg, Russia..
    Orlov, Sergey
    St Petersburg State Med Univ, State Educ Inst Higher Profess Educ, St Petersburg, Russia..
    Hagberg, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Tholander, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Lewensohn, Rolf
    Karolinska Univ Hosp, Dept Oncol, Solna, Sweden..
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Spira, Jack
    Oncopeptides AB, Stockholm, Sweden..
    Harmenberg, Johan
    Oncopeptides AB, Stockholm, Sweden..
    Jerling, Markus
    Oncopeptides AB, Stockholm, Sweden..
    Alvfors, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ringbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Nordstrom, Eva
    Oncopeptides AB, Stockholm, Sweden..
    Soderlind, Karin
    Oncopeptides AB, Stockholm, Sweden..
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    First-in-human, phase I/IIa clinical study of the peptidase potentiated alkylator melflufen administered every three weeks to patients with advanced solid tumor malignancies2015In: Investigational new drugs, ISSN 0167-6997, E-ISSN 1573-0646, Vol. 33, no 6, 1232-1241 p.Article in journal (Refereed)
    Abstract [en]

    Purpose Melflufen (melphalan flufenamide, previously designated J1) is an optimized and targeted derivative of melphalan, hydrolyzed by aminopeptidases overexpressed in tumor cells resulting in selective release and trapping of melphalan, and enhanced activity in preclinical models. Methods This was a prospective, single-armed, open-label, first-in-human, dose-finding phase I/IIa study in 45 adult patients with advanced and progressive solid tumors without standard treatment options. Most common tumor types were ovarian carcinoma (n = 20) and non-small-cell lung cancer (NSCLC, n = 11). Results In the dose-escalating phase I part of the study, seven patients were treated with increasing fixed doses of melflufen (25-130 mg) Q3W. In the subsequent phase IIa part, 38 patients received in total 115 cycles of therapy at doses of 30-75 mg. No dose-limiting toxicities (DLTs) were observed at 25 and 50 mg; at higher doses DLTs were reversible neutropenias and thrombocytopenias, particularly evident in heavily pretreated patients, and the recommended phase II dose (RPTD) was set to 50 mg. Response Evaluation Criteria In Solid Tumors (RECIST) evaluation after 3 cycles of therapy (27 patients) showed partial response in one (ovarian cancer), and stable disease in 18 patients. One NSCLC patient received nine cycles of melflufen and progressed after 7 months of therapy. Conclusions In conclusion, melflufen can safely be given to cancer patients, and the toxicity profile was as expected for alkylating agents; RPTD is 50 mg Q3W. Reversible and manageable bone marrow suppression was identified as a DLT. Clinical activity is suggested in ovarian cancer, but modest activity in treatment of refractory NSCLC.

  • 37.
    Bergqvist, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Umea Univ, Dept Radiat Sci, Umea, Sweden.
    Holgersson, Georg
    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, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Bondarenko, Igor
    Grechanaya, Elena
    Maximovich, Alexey
    Andor, György
    Klockare, Maria
    Thureson, Marcus
    Jerling, Markus
    Harmenberg, Johan
    Phase II randomized study of the IGF-1R pathway modulator AXL1717 compared to docetaxel in patients with previously treated, locally advanced or metastatic non-small cell lung cancer2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, no 3, 441-447 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The primary objective of this study was to compare the progression-free survival (PFS) at 12 weeks between patients treated with IGF-1R pathway modulator AXL1717 (AXL) and patients treated with docetaxel (DCT).

    MATERIAL AND METHODS: The study was conducted at 19 study centers in five countries. A total of 99 patients with previously treated, locally advanced or metastatic non-small cell lung cancer (NSCLC) of the squamous cell carcinoma (SCC) or adenocarcinoma (AC) subtypes in need of additional treatment were randomized and treated with either 300 or 400 mg of AXL as daily BID treatment (58 patients) or DCT given as 75 mg/m(2) in three-week cycles (41 patients) as monotherapy in a 3:2 ratio for each NSCLC subtype. Patients were treated in the primary study treatment period for a maximum of four treatment cycles.

    RESULTS: The 12-week PFS rate, median PFS and overall survival (OS), as well Kaplan-Meier hazard ratio for PFS and OS, did not show any statistically significant differences between the treatment groups. For the primary endpoint, the AXL group had a lower percentage of patients (25.9%) who were progression-free at Week 12 as compared to the DCT group (39.0%), although the difference was not statistically significant. The most notable difference in the incidence of treatment emergent adverse effects (TEAEs) was the lower incidence of treatment-related grade 3/4 neutropenia in patients treated with AXL.

    CONCLUSION: These results suggest neither of the treatments to be superior of the other when treating locally advanced or metastatic NSCLC. Considering the lower incidence of grade 3/4 neutropenia in the AXL group this treatment warrants further research.

  • 38.
    Berndt, Sonja I.
    et al.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Camp, Nicola J.
    Huntsman Canc Inst, Dept Internal Med, Div Hematol & Hematol Malignancies, Salt Lake City, UT 84112 USA.;Univ Utah, Sch Med, Salt Lake City, UT 84112 USA..
    Skibola, Christine F.
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35233 USA.;Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35233 USA.;Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA..
    Vijai, Joseph
    Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA..
    Wang, Zhaoming
    NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Gaithersburg, MD 20877 USA..
    Gu, Jian
    Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA..
    Nieters, Alexandra
    Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, D-79108 Freiburg, Baden Wurttembe, Germany..
    Kelly, Rachel S.
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, London W2 1PG, England..
    Smedby, Karin E.
    Karolinska Univ Hosp, Karolinska Inst, Dept Med, S-17176 Stockholm, Sweden..
    Monnereau, Alain
    Sorbonne Paris Cite CRESS, INSERM, Ctr Res Epidemiol & Stat, Epidemiol Childhood & Adolescent Canc Grp, F-94807 Paris, France.;Univ Paris 05, F-75270 Paris, France.;Inst Bergonie, Registre Hemopathies Malignes Gironde, F-33076 Bordeaux, France..
    Cozen, Wendy
    Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA.;Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA 90033 USA..
    Cox, Angela
    Univ Sheffield, Dept Oncol, Sheffield S10 1NS, S Yorkshire, England..
    Wang, Sophia S.
    City Hope Natl Med Ctr, Beckman Res Inst, Div Canc Etiol, Duarte, CA 91030 USA..
    Lan, Qing
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Teras, Lauren R.
    Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA..
    Machado, Moara
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.;Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Biol Geral, BR-31270901 Belo Horizonte, MG, Brazil..
    Yeager, Meredith
    NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Gaithersburg, MD 20877 USA..
    Brooks-Wilson, Angela R.
    BC Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 1L3, Canada.;Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC V5A 1S6, Canada..
    Hartge, Patricia
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Purdue, Mark P.
    Ontario Hlth Study, Toronto, ON M5G 0A3, Canada..
    Birmann, Brenda M.
    Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA..
    Vajdic, Claire M.
    Univ New S Wales, Ctr Big Data Res Hlth, Sydney, NSW 2052, Australia..
    Cocco, Pierluigi
    Univ Cagliari, Dept Publ Hlth Clin & Mol Med, I-09042 Cagliari, Italy..
    Zhang, Yawei
    Yale Univ, Sch Publ Hlth, Dept Environm Hlth Sci, New Haven, CT 06520 USA..
    Giles, Graham G.
    Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3004, Australia.;Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic 3010, Australia..
    Zeleniuch-Jacquotte, Anne
    NYU, Sch Med, Dept Populat Hlth, New York, NY 10016 USA.;NYU, Sch Med, Dept Environm Med, New York, NY 10016 USA.;NYU, Langone Med Ctr, Perlmutter Canc Ctr, New York, NY 10016 USA..
    Lawrence, Charles
    WESTAT Corp, Rockville, MD 20850 USA..
    Montalvan, Rebecca
    WESTAT Corp, Rockville, MD 20850 USA..
    Burdett, Laurie
    NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Gaithersburg, MD 20877 USA..
    Hutchinson, Amy
    NCI, Canc Genom Res Lab, Div Canc Epidemiol & Genet, Gaithersburg, MD 20877 USA..
    Ye, Yuanqing
    Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA..
    Call, Timothy G.
    Mayo Clin, Div Hematol, Rochester, MN 55905 USA..
    Shanafelt, Tait D.
    Mayo Clin, Dept Med, Rochester, MN 55905 USA..
    Novak, Anne J.
    Mayo Clin, Dept Med, Rochester, MN 55905 USA..
    Kay, Neil E.
    Mayo Clin, Div Hematol, Rochester, MN 55905 USA..
    Liebow, Mark
    Mayo Clin, Dept Med, Rochester, MN 55905 USA..
    Cunningham, Julie M.
    Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA..
    Allmer, Cristine
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Hjalgrim, Henrik
    Statens Serum Inst, Div Hlth Surveillance & Res, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark..
    Adami, Hans-Olov
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden..
    Melbye, Mads
    Statens Serum Inst, Div Hlth Surveillance & Res, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark.;Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Chang, Ellen T.
    Exponent Inc, Ctr Epidemiol & Computat Biol, Hlth Sci, Menlo Pk, CA 94025 USA.;Stanford Univ, Sch Med, Dept Hlth Res & Policy, Div Epidemiol, Stanford, CA 94305 USA..
    Glenn, Martha
    Huntsman Canc Inst, Dept Internal Med, Salt Lake City, UT 84112 USA..
    Curtin, Karen
    Univ Utah, Sch Med, Dept Internal Med, Salt Lake City, UT 84108 USA..
    Cannon-Albright, Lisa A.
    Univ Utah, Sch Med, Dept Internal Med, Salt Lake City, UT 84108 USA.;Vet Affairs Med Ctr, George E Wahlen Dept, Salt Lake City, UT 84148 USA..
    Diver, W. Ryan
    Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30303 USA..
    Link, Brian K.
    Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA..
    Weiner, George J.
    Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA..
    Conde, Lucia
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35233 USA.;Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35233 USA.;Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA..
    Bracci, Paige M.
    Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94118 USA..
    Riby, Jacques
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35233 USA.;Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35233 USA.;Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA..
    Arnett, Donna K.
    Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35233 USA.;Univ Alabama Birmingham, Ctr Comprehens Canc, Birmingham, AL 35233 USA..
    Zhi, Degui
    Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35233 USA..
    Leach, Justin M.
    Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35233 USA..
    Holly, Elizabeth A.
    Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94118 USA..
    Jackson, Rebecca D.
    Ohio State Univ, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA..
    Tinker, Lesley F.
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98117 USA..
    Benavente, Yolanda
    Catalan Inst Oncol IDIBELL, Canc Epidemiol Res Programme, Barcelona 08908, Spain.;CIBER Epidemiol & Salud Publ CIBERESP, Barcelona 08036, Spain..
    Sala, Nuria
    Catalan Inst Oncol IDIBELL, Canc Epidemiol Res Program, Unit Nutr Environm & Canc, Barcelona 08908, Spain.;Catalan Inst Oncol IDIBELL, Translat Res Lab, Barcelona 08908, Spain..
    Casabonne, Delphine
    Inst Catala Oncol, IDIBELL, Canc Epidemiol Res Programme, Unit Infect & Canc UNIC, Barcelona 08908, Spain.;CIBER Epidemiol & Salud Publ CIBERESP, Madrid 28029, Spain..
    Becker, Nikolaus
    German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Baden Wurttembe, Germany..
    Boffetta, Paolo
    Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA..
    Brennan, Paul
    Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France..
    Foretova, Lenka
    Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno 65653, Czech Republic.;MF MU, Brno 65653, Czech Republic..
    Maynadie, Marc
    Univ Burgundy, Registre Hemopathies Malignes Cote dOr, EA 4184, F-21070 Dijon, France.;Dijon Univ Hosp, F-21070 Dijon, France..
    McKay, James
    Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon, France..
    Staines, Anthony
    Dublin City Univ, Sch Nursing & Human Sci, Dublin 9, Ireland..
    Chaffee, Kari G.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Achenbach, Sara J.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Vachon, Celine M.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Goldin, Lynn R.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Strom, Sara S.
    Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA..
    Leis, Jose F.
    Mayo Clin, Div Hematol Oncol, Phoenix, AZ 85054 USA..
    Weinberg, J. Brice
    Duke Univ, Dept Med, Durham, NC 27710 USA.;VA Med Ctr, Durham, NC 27710 USA..
    Caporaso, Neil E.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Norman, Aaron D.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    De Roos, Anneclaire J.
    Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98117 USA.;Drexel Univ, Sch Publ Hlth, Dept Environm & Occupat Hlth, Philadelphia, PA 19104 USA..
    Morton, Lindsay M.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Severson, Richard K.
    Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI 48201 USA..
    Riboli, Elio
    Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, London W2 1PG, England..
    Vineis, Paolo
    Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, MRC PHE Ctr Environm & Hlth, London W2 1PG, England.;Human Genet Fdn, I-10126 Turin, Italy..
    Kaaks, Rudolph
    German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Baden Wurttembe, Germany..
    Masala, Giovanna
    Canc Res & Prevent Inst ISPO, Mol & Nutr Epidemiol Unit, I-50139 Florence, Italy..
    Weiderpass, Elisabete
    Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden.;Arctic Univ Norway, Univ Tromso, Dept Community Med, Fac Hlth Sci, N-9037 Tromso, Norway.;Canc Registry Norway, Inst Populat Based Canc Res, Dept Res, N-0304 Oslo, Norway.;Folkhalsan Res Ctr, Genet Epidemiol Grp, FI-00250 Helsinki, Finland..
    Chirlaque, Maria-Dolores
    CIBER Epidemiol & Salud Publ CIBERESP, Barcelona 08036, Spain.;Murcia Reg Hlth Author, Dept Epidemiol, E-30008 Murcia, Spain..
    Vermeulen, Roel C. H.
    Univ Utrecht, Inst Risk Assessment Sci, NL-3508 TD Utrecht, Netherlands.;Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, NL-3584 CX Utrecht, Netherlands..
    Travis, Ruth C.
    Univ Oxford, Canc Epidemiol Unit, Oxford OX3 7LF, England..
    Southey, Melissa C.
    Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic 3010, Australia..
    Milne, Roger L.
    Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic 3004, Australia.;Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Biostat & Epidemiol, Melbourne, Vic 3010, Australia..
    Albanese, Demetrius
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Virtamo, Jarmo
    Natl Inst Hlth & Welf, Chron Dis Prevent Unit, FI-00271 Helsinki, Finland..
    Weinstein, Stephanie
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Clavel, Jacqueline
    Sorbonne Paris Cite CRESS, INSERM, Ctr Res Epidemiol & Stat, Epidemiol Childhood & Adolescent Canc Grp, F-94807 Paris, France.;Univ Paris 05, F-75270 Paris, France..
    Zheng, Tongzhang
    Yale Univ, Sch Publ Hlth, Dept Environm Hlth Sci, New Haven, CT 06520 USA..
    Holford, Theodore R.
    Yale Univ, Sch Publ Hlth, Dept Stat, New Haven, CT 06520 USA..
    Villano, Danylo J.
    Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA..
    Maria, Ann
    Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA..
    Spinelli, John J.
    BC Canc Agcy, Canc Control Res, Vancouver, BC V5Z 1L3, Canada.;Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V6T 1Z3, Canada..
    Gascoyne, Randy D.
    BC Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 1L3, Canada.;Univ British Columbia, Dept Pathol, Vancouver, BC V6T 1Z3, Canada..
    Connors, Joseph M.
    BC Canc Agcy, Ctr Lymphoid Canc, Vancouver, BC V5Z 1L3, Canada.;Univ British Columbia, Dept Med, Vancouver, BC V6T 1Z3, Canada..
    Bertrand, Kimberly A.
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA..
    Giovannucci, Edward
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.;Harvard Univ, Sch Med, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA..
    Kraft, Peter
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA..
    Kricker, Anne
    Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW 2006, Australia..
    Turner, Jenny
    Macquarie Univ, Fac Med & Hlth Sci, Sydney, NSW 2109, Australia.;Douglass Hanly Moir Pathol, Dept Histopathol, N Ryde, NSW 2113, Australia..
    Ennas, Maria Grazia
    Univ Cagliari, Dept Biomed Sci, I-09042 Cagliari, Italy..
    Ferri, Giovanni M.
    Univ Bari, Interdisciplinary Dept Med, I-70124 Bari, Italy..
    Miligi, Lucia
    Canc Prevent & Res Inst ISPO, Environm & Occupat Epidemiol Unit, I-50139 Florence, Italy..
    Liang, Liming
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA..
    Ma, Baoshan
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA.;Dalian Maritime Univ, Coll Informat Sci & Technol, Dalian 116026, Liaoning Provin, Peoples R China..
    Huang, Jinyan
    Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA..
    Crouch, Simon
    Univ York, Dept Hlth Sci, York Y010 5DD, N Yorkshire, England..
    Park, Ju-Hyun
    Dongguk Univ, Dept Stat, Seoul 100715, South Korea..
    Chatterjee, Nilanjan
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    North, Kari E.
    Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA.;Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27599 USA..
    Snowden, John A.
    Univ Sheffield, Dept Oncol, Sheffield S10 1NS, S Yorkshire, England.;Sheffield Teaching Hosp NHS Fdn Trust, Royal Hallamshire Hosp, Dept Haematol, Sheffield S10 2TN, S Yorkshire, England..
    Wright, Josh
    Univ Sheffield, Dept Oncol, Sheffield S10 1NS, S Yorkshire, England.;Sheffield Teaching Hosp NHS Fdn Trust, Royal Hallamshire Hosp, Dept Haematol, Sheffield S10 2TN, S Yorkshire, England..
    Fraumeni, Joseph F.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Offit, Kenneth
    Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA..
    Wu, Xifeng
    Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA..
    de Sanjose, Silvia
    Catalan Inst Oncol IDIBELL, Canc Epidemiol Res Programme, Barcelona 08908, Spain.;CIBER Epidemiol & Salud Publ CIBERESP, Barcelona 08036, Spain..
    Cerhan, James R.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Chanock, Stephen J.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Rothman, Nathaniel
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA..
    Slager, Susan L.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA..
    Meta-analysis of genome-wide association studies discovers multiple loci for chronic lymphocytic leukemia2016In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, 10933Article in journal (Refereed)
    Abstract [en]

    Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P = 2.55 x 10(-11)), 6p25.2 (rs73718779, SERPINB6, P = 1.97 x 10(-8)) and 3q28 (rs9815073, LPP, P = 3.62 x 10(-8)), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P = 1.00 x 10(-11)) in the combined analysis. We find suggestive evidence (P<5 x 10(-7)) for two additional new loci at 4q24 (rs10028805, BANK1, P = 7.19 x 10(-8)) and 3p22.2 (rs1274963, CSRNP1, P = 2.12 x 10(-7)). Pathway analyses of new and known CLL loci consistently show a strong role for apoptosis, providing further evidence for the importance of this biological pathway in CLL susceptibility.

  • 39.
    Berntsen, Sveinung
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Aaronson, Neil K
    Buffart, Laurien
    Börjeson, Sussanne
    Demmelmaier, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Hellbom, Maria
    Hojman, Pernille
    Igelström, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Pingel, Ronnie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Raastad, Truls
    Velikova, Galina
    Åsenlöf, P.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotherapy.
    Nordin, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Design of a randomized controlled trial of physical training and cancer (Phys-Can) - the impact of exercise intensity on cancer related fatigue, quality of life and disease outcome2017In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 17, no 1, 218Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cancer-related fatigue is a common problem in persons with cancer, influencing health-related quality of life and causing a considerable challenge to society. Current evidence supports the beneficial effects of physical exercise in reducing fatigue, but the results across studies are not consistent, especially in terms of exercise intensity. It is also unclear whether use of behaviour change techniques can further increase exercise adherence and maintain physical activity behaviour. This study will investigate whether exercise intensity affects fatigue and health related quality of life in persons undergoing adjuvant cancer treatment. In addition, to examine effects of exercise intensity on mood disturbance, adherence to oncological treatment, adverse effects from treatment, activities of daily living after treatment completion and return to work, and behaviour change techniques effect on exercise adherence. We will also investigate whether exercise intensity influences inflammatory markers and cytokines, and whether gene expressions following training serve as mediators for the effects of exercise on fatigue and health related quality of life.

    METHODS/DESIGN: Six hundred newly diagnosed persons with breast, colorectal or prostate cancer undergoing adjuvant therapy will be randomized in a 2 × 2 factorial design to following conditions; A) individually tailored low-to-moderate intensity exercise with or without behaviour change techniques or B) individually tailored high intensity exercise with or without behaviour change techniques. The training consists of both resistance and endurance exercise sessions under the guidance of trained coaches. The primary outcomes, fatigue and health related quality of life, are measured by self-reports. Secondary outcomes include fitness, mood disturbance, adherence to the cancer treatment, adverse effects, return to activities of daily living after completed treatment, return to work as well as inflammatory markers, cytokines and gene expression.

    DISCUSSION: The study will contribute to our understanding of the value of exercise and exercise intensity in reducing fatigue and improving health related quality of life and, potentially, clinical outcomes. The value of behaviour change techniques in terms of adherence to and maintenance of physical exercise behaviour in persons with cancer will be evaluated.

    TRIAL REGISTRATION: NCT02473003 , October, 2014.

  • 40.
    Berntsson, Jonna
    et al.
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol..
    Svensson, Maria C.
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol..
    Leandersson, Karin
    Lund Univ, Dept Translat Med, Canc Immunol..
    Nodin, Bjorn
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol..
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Larsson, Anna H.
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol..
    Eberhard, Jakob
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol..
    Jirstrom, Karin
    Lund Univ, Dept Clin Sci Lund, Oncol & Pathol..
    The clinical impact of tumour-infiltrating lymphocytes in colorectal cancer differs by anatomical subsite: A cohort study2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 141, no 8, 1654-1666 p.Article in journal (Refereed)
    Abstract [en]

    Accumulating evidence demonstrates an association between dense infiltration of lymphocytes and prognosis in colorectal cancer (CRC), but whether this prognostic impact differs by tumour location remains unknown. This study investigated the prognostic impact of cytotoxic and regulatory T cells in CRC, with particular referennfiltrating T cce to the anatomical subsite of the primary tumour. The density of CD3(+), CD8(+) and FoxP3(+) tumour-iells was calculated in tissue microarrays with tumours from 557 incident CRC cases from a prospective population-based cohort. Kaplan-Meier and Cox regression analyses were applied to determine the impact of high and low lymphocyte density on 5-year overall survival, in subgroup analysis of right colon, left colon and rectum. High CD8(+) cell density was a favourable prognostic factor for patients with right-sided colon tumours (hazard ratio [HR]=0.53, 95% confidence interval [CI] 0.29-0.95), independent of age, sex, TNM stage, differentiation grade and vascular invasion, with a significant prognostic interaction between CD8(+) cells and right-sidedness (p=0.031). High FoxP3(+) cell density was an independent favourable prognostic factor only in patients with rectal tumours (HR=0.54, 95% CI 0.30-0.99), and CD3(+) cell density was an independent favourable prognostic factor for tumours in the right colon and rectum, but there was no significant prognostic interaction between CD3(+) or FoxP3(+) cells and sidedness. These results demonstrate that the prognostic impact of tumour-infiltrating lymphocytes in CRC differs by primary tumour site, further indicating that tumour location may be an important factor to take into consideration in therapeutic decisions, including eligibility for immunotherapy.

  • 41.
    Bhoi, Sujata
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University.
    Prognostic markers and DNA methylation profiling in lymphoid malignancies2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    In recent years, great progress has been achieved towards identifying novel biomarkers in lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), at the genomic, transcriptomic and epigenomic level for accurate risk-stratification and prediction of treatment response. In paper I, we validated the prognostic relevance of a recently proposed RNA-based marker in CLL, UGT2B17, and analyzed its expression levels in 253 early-stage patients. Besides confirming its prognostic impact in multivariate analysis, we could identify 30% of IGHV-mutated CLL (M-CLL) cases with high expression and poor outcome, which otherwise lacked any other poor-prognostic marker. In paper II, we investigated the prognostic impact of a previously reported 5 CpG signature that divides CLL patients into three clinico-biological subgroups, namely naive B-cell-like CLL (n-CLL), memory B-cell-like CLL (m-CLL) and intermediate CLL (i-CLL), in 135 CLL patients using pyrosequencing. We validated the signature as an independent marker in multivariate analysis and further reported that subset #2 cases were predominantly classified as i-CLL, although displaying a similar outcome as n-CLL. In paper III, we investigated the methylation status and expression level of miR26A1 in both CLL (n=70) and MCL (n=65) cohorts. High miR26A1 methylation was associated with IGHV-unmutated (U-CLL) and shorter overall survival (OS) in CLL, while it was uniformly hypermethylated in MCL. Furthermore, overexpression of miR26A1 resulted in significant downregulation of EZH2 that in turn led to increased apoptosis. In paper IV, we performed DNA methylation profiling in 176 CLL cases assigned to one of 8 major stereotyped subsets (#1-8) in relation to non-subset CLL (n=325) and different normal B-cell subpopulations. Principal component analysis of subset vs. non-subset CLL revealed that U-CLL and M-CLL subsets generally clustered with n-CLL and m-CLL, respectively, indicating common cellular origins. In contrast, subset #2 emerged as the first defined member of the i-CLL subgroup, which in turn alludes to a distinct cellular origin for subset #2 and i-CLL patients. Altogether, this thesis confirms the prognostic significance of RNA and epigenetic-based markers in CLL, provides insight into the mechanism of miRNA deregulation in lymphoid malignancies and further unravels the DNA methylation landscape in stereotyped subsets of CLL.

     

    List of papers
    1. UGT2B17 expression: a novel prognostic marker within IGHV-mutated chronic lymphocytic leukemia?
    Open this publication in new window or tab >>UGT2B17 expression: a novel prognostic marker within IGHV-mutated chronic lymphocytic leukemia?
    Show others...
    2016 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 2, E63-E65 p.Article in journal, Letter (Refereed) Published
    Abstract
    Keyword
    CLL; UGT2B17; prognostic markers
    National Category
    Hematology
    Identifiers
    urn:nbn:se:uu:diva-271300 (URN)10.3324/haematol.2015.136440 (DOI)000379156300007 ()26589911 (PubMedID)
    Available from: 2016-01-07 Created: 2016-01-07 Last updated: 2017-12-01Bibliographically approved
    2. Prognostic impact of epigenetic classification in chronic lymphocytic leukemia: The case of subset #2
    Open this publication in new window or tab >>Prognostic impact of epigenetic classification in chronic lymphocytic leukemia: The case of subset #2
    Show others...
    2016 (English)In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 11, no 6, 449-455 p.Article in journal (Refereed) Published
    Abstract [en]

    Based on the methylation status of 5 single CpG sites, a novel epigenetic classification of chronic lymphocytic leukemia (CLL) was recently proposed, classifying CLL patients into 3 clinico-biological subgroups with different outcome, termed memory like CLL (m-CLL), naive like CLL (n-CLL), and a third intermediate CLL subgroup (i-CLL). While m-CLL and n-CLL patients at large corresponded to patients carrying mutated and unmutated IGHV genes, respectively, limited information exists regarding the less defined i-CLL group. Using pyrosequencing, we investigated the prognostic impact of the proposed 5 CpG signature in a well-characterized CLL cohort (135 cases), including IGHV-mutated and unmutated patients as well as clinically aggressive stereotyped subset #2 patients. Overall, we confirmed the signature's association with established prognostic markers. Moreover, in the presence of the IGHV mutational status, the epigenetic signature remained independently associated with both time-to-first-treatment and overall survival in multivariate analyses. As a prime finding, we observed that subset #2 patients were predominantly classified as i-CLL, probably reflecting their borderline IGHV mutational status (97-99% germline identity), though having a similarly poor prognosis as n-CLL patients. In summary, we validated the epigenetic classifier as an independent factor in CLL prognostication and provide further evidence that subset #2 is a member of the i-CLL group, hence supporting the existence of a third, intermediate epigenetic subgroup.

    Keyword
    CLL, epigenetic classification, methylation, prognosis
    National Category
    Cancer and Oncology Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-303408 (URN)10.1080/15592294.2016.1178432 (DOI)000380902700006 ()27128508 (PubMedID)
    Funder
    Swedish Cancer SocietySwedish Research Council
    Available from: 2016-09-19 Created: 2016-09-19 Last updated: 2018-01-10Bibliographically approved
    3. Epigenetic silencing of miR-26A1 in chronic lymphocytic leukemia and mantle cell lymphoma: Impact on EZH2 expression
    Open this publication in new window or tab >>Epigenetic silencing of miR-26A1 in chronic lymphocytic leukemia and mantle cell lymphoma: Impact on EZH2 expression
    Show others...
    2016 (English)In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 11, no 5, 335-343 p.Article in journal (Refereed) Published
    Abstract [en]

    Downregulation of miR26A1 has been reported in various B-cell malignancies; however, the mechanism behind its deregulation remains largely unknown. We investigated miR26A1 methylation and expression levels in a well-characterized series of chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). From 450K methylation arrays, we first observed miR26A1 (cg26054057) as uniformly hypermethylated in MCL (n = 24) (all >75%), while CLL (n = 18) showed differential methylation between prognostic subgroups. Extended analysis using pyrosequencing confirmed our findings and real-time quantitative PCR verified low miR26A1 expression in both CLL (n = 70) and MCL (n = 38) compared to normal B-cells. Notably, the level of miR26A1 methylation predicted outcome in CLL, with higher levels seen in poor-prognostic, IGHV-unmutated CLL. Since EZH2 was recently reported as a target for miR26A1, we analyzed the expression levels of both miR26A1 and EZH2 in primary CLL samples and observed an inverse correlation. By overexpression of miR26A1 in CLL and MCL cell lines, reduced EZH2 protein levels were observed using both Western blot and flow cytometry. In contrast, methyl-inhibitor treatment led to upregulated miR26A1 expression with a parallel decrease of EZH2 expression. Finally, increased levels of apoptosis were observed in miR26A1-overexpressing cell lines, further underscoring the functional relevance of miR26A1. In summary, we propose that epigenetic silencing of miR26A1 is required for the maintenance of increased levels of EZH2, which in turn translate into a worse outcome, as shown in CLL, highlighting miR26A1 as a tumor suppressor miRNA.

    Keyword
    Chronic lymphocytic leukemia, DNA methylation, mantle cell lymphoma, microRNA, tumor suppressor
    National Category
    Cancer and Oncology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Identifiers
    urn:nbn:se:uu:diva-298924 (URN)10.1080/15592294.2016.1164375 (DOI)000377274700002 ()27052808 (PubMedID)
    Funder
    Swedish Research CouncilSwedish Cancer Society
    Available from: 2016-07-12 Created: 2016-07-12 Last updated: 2017-11-28Bibliographically approved
    4. Genome-wide DNA methylation profiling in chronic lymphocytic leukemia patients carrying stereotyped B-cell receptors
    Open this publication in new window or tab >>Genome-wide DNA methylation profiling in chronic lymphocytic leukemia patients carrying stereotyped B-cell receptors
    Show others...
    (English)Manuscript (preprint) (Other academic)
    National Category
    Hematology
    Identifiers
    urn:nbn:se:uu:diva-328613 (URN)
    Available from: 2017-08-28 Created: 2017-08-28 Last updated: 2017-09-06
  • 42.
    Bhoi, Sujata
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Cortese, Diego
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mattsson, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Engvall, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Smedby, Karin E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Juliusson, Gunnar
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    UGT2B17 expression: a novel prognostic marker within IGHV-mutated chronic lymphocytic leukemia?2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 2, E63-E65 p.Article in journal (Refereed)
    Abstract
  • 43.
    Bhoi, Sujata
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ljungström, Viktor
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    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, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Smedby, Karin E.
    Karolinska Inst, Clin Epidemiol Unit, Dept Med Solna, Stockholm, Sweden..
    Juliusson, Gunnar
    Lund Univ, Dept Lab Med, Stem Cell Ctr, Hematol & Transplantat, Lund, Sweden..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mansouri, Larry
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Prognostic impact of epigenetic classification in chronic lymphocytic leukemia: The case of subset #22016In: Epigenetics, ISSN 1559-2294, E-ISSN 1559-2308, Vol. 11, no 6, 449-455 p.Article in journal (Refereed)
    Abstract [en]

    Based on the methylation status of 5 single CpG sites, a novel epigenetic classification of chronic lymphocytic leukemia (CLL) was recently proposed, classifying CLL patients into 3 clinico-biological subgroups with different outcome, termed memory like CLL (m-CLL), naive like CLL (n-CLL), and a third intermediate CLL subgroup (i-CLL). While m-CLL and n-CLL patients at large corresponded to patients carrying mutated and unmutated IGHV genes, respectively, limited information exists regarding the less defined i-CLL group. Using pyrosequencing, we investigated the prognostic impact of the proposed 5 CpG signature in a well-characterized CLL cohort (135 cases), including IGHV-mutated and unmutated patients as well as clinically aggressive stereotyped subset #2 patients. Overall, we confirmed the signature's association with established prognostic markers. Moreover, in the presence of the IGHV mutational status, the epigenetic signature remained independently associated with both time-to-first-treatment and overall survival in multivariate analyses. As a prime finding, we observed that subset #2 patients were predominantly classified as i-CLL, probably reflecting their borderline IGHV mutational status (97-99% germline identity), though having a similarly poor prognosis as n-CLL patients. In summary, we validated the epigenetic classifier as an independent factor in CLL prognostication and provide further evidence that subset #2 is a member of the i-CLL group, hence supporting the existence of a third, intermediate epigenetic subgroup.

  • 44. Bieghs, Liesbeth
    et al.
    Lub, Susanne
    Fostier, Karel
    Maes, Ken
    Van Valckenborgh, Els
    Menu, Eline
    Johnsen, Hans E
    Overgaard, Michael T
    Larsson, Olle
    Axelson, Magnus
    Nyegaard, Mette
    Schots, Rik
    Jernberg-Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Vanderkerken, Karin
    De Bruyne, Elke
    The IGF-1 receptor inhibitor picropodophyllin potentiates the anti-myeloma activity of a BH3-mimetic2014In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 5, no 22, 11193-11208 p.Article in journal (Refereed)
    Abstract [en]

    The ABT-analogous 737, 263 and 199 are BH3 mimetics showing potent anti-myeloma (MM) activity, but only on defined molecular subgroups of MM patients presenting a Bcl-2high/Mcl-1low profile. IGF-1 is a major survival factor in MM regulating the expression of Bcl-2 proteins and might therefore be a resistance factor to these ABT-analogous. We first show that IGF-1 protected human MM cell lines (HMCLs) against ABT-737. Concurrently, the IGF-1 receptor inhibitor picropodophyllin (PPP) synergistically sensitized HMCL, primary human MM and murine 5T33MM cells to ABT-737 and ABT-199 by further decreasing cell viability and enhancing apoptosis. Knockdown of Bcl-2 by shRNA protected MM cells to ABT-737, while Mcl-1 shRNA sensitized the cells. PPP overcame the Bcl-2 dependency of ABT-737, but failed to completely overcome the protective effect of Mcl-1. In vivo, co-treatment of 5T33MM bearing mice significantly decreased tumor burden and prolonged overall survival both in a prophylactic and therapeutic setting. Interestingly, proteasome inhibitor resistant CD138- 5T33MM cells were more sensitive to ABT-737, whereas PPP alone targeted the CD138+ cells more effectively. After co-treatment, both subpopulations were targeted equally. Together, the combination of an IGF-1R inhibitor and an ABT-analogue displays synergistic anti-myeloma activity providing the rational for further (pre)clinical testing.

  • 45.
    Bikos, Vasilis
    et al.
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.;Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Karypidou, Maria
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.;CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Stalika, Evangelia
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Xochelli, Aliki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Papadopoulos, George
    CERTH, Informat Technol Inst, Thessaloniki, Greece..
    Agathangelidis, Andreas
    Univ Vita Salute San Raffaele, Div Expt Oncol, Milan, Italy.;Univ Vita Salute San Raffaele, Dept Oncohematol, Milan, Italy.;Ist Sci San Raffaele, Milan, Italy..
    Papadopoulou, Evdoxia
    CERTH, Informat Technol Inst, Thessaloniki, Greece..
    Davis, Zadie
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Algara, Patricia
    Hosp Virgen Salud, Dept Pathol, Toledo, OH, Spain..
    Kanellis, George
    Evangelismos Med Ctr, Hematopathol Dept, Athens, Greece..
    Traverse-Glehen, Alexandra
    Univ Lyon, Hosp Civils Lyon, Dept Pathol & Hematol, Lyon, France..
    Mollejo, Manuela
    Hosp Virgen Salud, Dept Pathol, Toledo, OH, Spain..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Ponzoni, Maurilio
    Ist Sci San Raffaele, Pathol Unit, I-20132 Milan, Italy..
    Gonzalez, David
    Inst Canc Res, Sect Haematooncol, London SW3 6JB, England..
    Pospisilova, Sarka
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Matutes, Estella
    Inst Canc Res, Sect Haematooncol, London SW3 6JB, England..
    Angel Piris, Miguel
    Hosp Univ Marques de Valdecilla, Santander, Spain..
    Papadaki, Theodora
    Evangelismos Med Ctr, Hematopathol Dept, Athens, Greece..
    Ghia, Paolo
    Univ Vita Salute San Raffaele, Div Expt Oncol, Milan, Italy.;Univ Vita Salute San Raffaele, Dept Oncohematol, Milan, Italy.;Ist Sci San Raffaele, Milan, Italy..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Oscier, David
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Darzentas, Nikos
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Tzovaras, Dimitrios
    CERTH, Informat Technol Inst, Thessaloniki, Greece..
    Belessi, Chrysoula
    Nikea Gen Hosp, Hematol Dept, Piraeus, Greece..
    Hadzidimitriou, Anastasia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.;CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    An Immunogenetic Signature of Ongoing Antigen Interactions in Splenic Marginal Zone Lymphoma Expressing IGHV1-2*04 Receptors2016In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, no 8, 2032-2040 p.Article in journal (Refereed)
    Abstract [en]

    Purpose: Prompted by the extensive biases in the immunoglobulin (IG) gene repertoire of splenic marginal-zone lymphoma (SMZL), supporting antigen selection in SMZL ontogeny, we sought to investigate whether antigen involvement is also relevant post-transformation. Experimental Design: We conducted a large-scale subcloning study of the IG rearrangements of 40 SMZL cases aimed at assessing intraclonal diversification (ID) due to ongoing somatic hypermutation (SHM). Results: ID was identified in 17 of 21 (81%) rearrangements using the immunoglobulin heavy variable (IGHV) 1-2*04 gene versus 8 of 19 (40%) rearrangements utilizing other IGHV genes (P = 0.001). ID was also evident in most analyzed IG light chain gene rearrangements, albeit was more limited compared with IG heavy chains. Identical sequence changes were shared by subclones from different patients utilizing the IGHV1-2*04 gene, confirming restricted ongoing SHM profiles. Non-IGHV1-2*04 cases displayed both a lower number of ongoing SHMs and a lack of shared mutations (per group of cases utilizing the same IGHV gene). Conclusions: These findings support ongoing antigen involvement in a sizable portion of SMZL and further argue that IGHV1-2*04 SMZL may represent a distinct molecular subtype of the disease.

  • 46.
    Birgisson, Helgi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Edlund, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Wallin, Ulrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Kultima, Hanna Göransson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mayrhofer, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sundström, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Microsatellite instability and mutations in BRAF and KRAS are significant predictors of disseminated disease in colon cancer2015In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 15, 125Article in journal (Refereed)
    Abstract [en]

    Background: Molecular alterations are well studied in colon cancer, however there is still need for an improved understanding of their prognostic impact. This study aims to characterize colon cancer with regard to KRAS, BRAF, and PIK3CA mutations, microsatellite instability (MSI), and average DNA copy number, in connection with tumour dissemination and recurrence in patients with colon cancer. Methods: Disease stage II-IV colon cancer patients (n = 121) were selected. KRAS, BRAF, and PIK3CA mutation status was assessed by pyrosequencing and MSI was determined by analysis of mononucleotide repeat markers. Genome-wide average DNA copy number and allelic imbalance was evaluated by SNP array analysis. Results: Patients with mutated KRAS were more likely to experience disease dissemination (OR 2.75; 95% CI 1.28-6.04), whereas the opposite was observed for patients with BRAF mutation (OR 0.34; 95% 0.14-0.81) or MSI (OR 0.24; 95% 0.09-0.64). Also in the subset of patients with stage II-III disease, both MSI (OR 0.29; 95% 0.10-0.86) and BRAF mutation (OR 0.32; 95% 0.16-0.91) were related to lower risk of distant recurrence. However, average DNA copy number and PIK3CA mutations were not associated with disease dissemination. Conclusions: The present study revealed that tumour dissemination is less likely to occur in colon cancer patients with MSI and BRAF mutation, whereas the presence of a KRAS mutation increases the likelihood of disseminated disease.

  • 47.
    Bjersand, Kathrine
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Sundström-Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Nygren, Peter
    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, Cancer Pharmacology and Computational Medicine.
    Drug Sensitivity Testing In Cytoreductive Surgery And Intraperitoneal Chemotherapy Of Pseudomyxoma Peritonei2015In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 25, no 9, 326-326 p.Article in journal (Other academic)
  • 48.
    Bjørge, Tone
    et al.
    Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway.;Canc Registry Norway, Oslo, Norway..
    Gissler, Mika
    Natl Inst Hlth & Welf THL, Helsinki, Finland..
    Ording, Anne Gulbech
    Aarhus Univ Hosp, Dept Clin Epidemiol, Aarhus, Denmark..
    Engeland, Anders
    Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway.;Norwegian Inst Publ Hlth, Dept Pharmacoepidemiol, Div Mental & Phys Hlth, Bergen, Norway..
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Leinonen, Maarit
    Finnish Canc Registry, Canc Soc Finland, Helsinki, Finland..
    Sørensen, Henrik Toft
    Aarhus Univ Hosp, Dept Clin Epidemiol, Aarhus, Denmark..
    Tretli, Steinar
    Canc Registry Norway, Oslo, Norway..
    Ekbom, Anders
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Troisi, Rebecca
    NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD USA..
    Grotmol, Tom
    Canc Registry Norway, Oslo, Norway..
    Reproductive history and risk of colorectal adenocarcinoma in parous women: a Nordic population-based case-control study2016In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 115, no 11, 1416-1420 p.Article in journal (Refereed)
    Abstract [en]

    Background: Data are conflicting regarding the role of endogenous sex hormones in colorectal carcinogenesis. In this large population-based study, we pooled data from birth and cancer registries in four Nordic countries, to evaluate the risk of colorectal adenocarcinoma in relation to women's reproductive history. Methods: We conducted a population-based case-control study among women registered in Nordic birth registries. The study included colorectal adenocarcinoma cases diagnosed in Denmark, Finland, Norway, and Sweden during 1967-2013 and up to 10 matched controls per case, in total 22 185 cases and 220 246 controls. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were derived from conditional logistic regression models. We had limited information available on possible confounders. Results: We found no evidence for associations between colorectal adenocarcinoma and parity, age at first and last birth, and time since first and last birth. The risk estimates were also close to unity for specific cancer subsites (proximal and distal colon and rectum). As well, when the analyses were stratified on menopausal status, parity, and mother's year of birth, no indication of associations was found. Conclusions: In this large, Nordic population-based study, no evidence for associations was found between women's reproductive history and colorectal adenocarcinoma in parous women.

  • 49.
    Blanco, G.
    et al.
    Hosp del Mar, Inst Hosp Mar Invest Med IMIM, Grp Recerca Translac Neoplasies Hematol, Lab Citol Hematol,Serv Patol,Lab Citogenet Mol, Barcelona, Spain..
    Puiggros, A.
    Hosp del Mar, Inst Hosp Mar Invest Med IMIM, Grp Recerca Translac Neoplasies Hematol, Lab Citol Hematol,Serv Patol,Lab Citogenet Mol, Barcelona, Spain..
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Athanasiadou, A.
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Garcia-Malo, M. D.
    Hosp Univ Morales Meseguer, Serv Hematol, Murcia, Spain..
    Collado, R.
    Consorcio Hosp Gen Univ, Serv Hematol, Valencia, Spain..
    Xochelli, A.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Rodriguez-Rivera, M.
    Hosp del Mar, Inst Hosp Mar Invest Med IMIM, Grp Recerca Translac Neoplasies Hematol, Lab Citol Hematol,Serv Patol,Lab Citogenet Mol, Barcelona, Spain..
    Ortega, M.
    Hosp Valle De Hebron, Lab Citogenet, Barcelona, Spain.;Hosp Valle De Hebron, Serv Hematol, Barcelona, Spain..
    Calasanz, M. J.
    Univ Navarra, Dept Genet, Serv Citogenet, Pamplona, Spain..
    Luno, E.
    Hosp Univ Cent Asturias, Serv Hematol, Oviedo, Spain..
    Vargas, M. T.
    Hosp Univ Virgen de la Macarena, Seville, Spain..
    Grau, J.
    Univ Autonoma Barcelona, Inst Recerca Leucemia Josep Carreras IJC, ICO Hosp Germans Trias & Pujol, Serv Lab Hematol, Badalona, Spain..
    Martinez-Laperche, C.
    Hosp GU Gregorio Maranon, Serv Hematol, Lab Genet Hematol, Madrid, Spain.;Inst Invest Sanitaria Gregorio Maranon, Madrid, Spain..
    Valiente, A.
    Complejo Hospitalario Navarra, Serv Genet, Pamplona, Spain.;Complejo Hospitalario Navarra, Serv Hematol, Pamplona, Spain..
    Papaioannou, G.
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Cervera, J.
    Hosp Univ La Fe, Unidad Genet, Valencia, Spain..
    Anagnostopoulos, A.
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Pinan, M. A.
    Hosp Cruces, Serv Hematol, Bilbao, Spain..
    Stalika, E.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Hernandez-Rivas, J. M.
    Univ Salamanca, Hosp Univ Salamanca, Ctr Invest Canc, IBSAL,IBMCC,CSIC,Serv Hematol, Salamanca, Spain..
    Batlle, A.
    Hosp Univ Marques de Valdecilla, Serv Hematol, Santander, Spain..
    Salido, M.
    Hosp del Mar, Inst Hosp Mar Invest Med IMIM, Grp Recerca Translac Neoplasies Hematol, Lab Citol Hematol,Serv Patol,Lab Citogenet Mol, Barcelona, Spain..
    Ortuno, F.
    Hosp Univ Morales Meseguer, Serv Hematol, Murcia, Spain..
    Melero, C.
    Hosp del Mar, Inst Hosp Mar Invest Med IMIM, Grp Recerca Translac Neoplasies Hematol, Lab Citol Hematol,Serv Patol,Lab Citogenet Mol, Barcelona, Spain..
    Robles, D.
    Hosp Txagorritxu, Serv Hematol, Vitoria, Spain..
    Ferrer, A.
    Hosp del Mar, Inst Hosp Mar Invest Med IMIM, Grp Recerca Translac Neoplasies Hematol, Lab Citol Hematol,Serv Patol,Lab Citogenet Mol, Barcelona, Spain..
    Ivars, D.
    Consorcio Hosp Gen Univ, Serv Hematol, Valencia, Spain..
    Rodriguez, A.
    Hosp Univ Virgen de la Macarena, Seville, Spain..
    Gonzalez, M.
    Univ Salamanca, Hosp Univ Salamanca, Ctr Invest Canc, IBSAL,IBMCC,CSIC,Serv Hematol, Salamanca, Spain..
    Bosch, F.
    Hosp Valle De Hebron, Lab Citogenet, Barcelona, Spain.;Hosp Valle De Hebron, Serv Hematol, Barcelona, Spain..
    Abrisqueta, P.
    Hosp Valle De Hebron, Lab Citogenet, Barcelona, Spain.;Hosp Valle De Hebron, Serv Hematol, Barcelona, Spain..
    Stamatopoulos, K.
    G Papanicolaou Hosp, Inst Appl Biosci, CERTH, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, Inst Appl Biosci, CERTH, HCT Unit, Thessaloniki, Greece..
    Espinet, B.
    Hosp del Mar, Inst Hosp Mar Invest Med IMIM, Grp Recerca Translac Neoplasies Hematol, Lab Citol Hematol,Serv Patol,Lab Citogenet Mol, Barcelona, Spain..
    Chromosome 8 Abnormalities Are Associated With An Even Worse Outcome And Karyotype Complexity In Patients With Chronic Lymphocytic Leukemia And Tp53 Aberrations2016In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, 229-230 p.Article in journal (Other academic)
  • 50.
    Blanco, Gonzalo
    et al.
    Hosp del Mar, Serv Patol, Lab Citol Hematol, Lab Citogenet Mol, Barcelona, Spain.;Hosp del Mar, IMIM, Canc Res Programme, Grp Recerca Translac Neoplasies Hematol, Barcelona, Spain.;Univ Pompeu Fabra, Dept Expt & Hlth Sci, Barcelona, Spain..
    Puiggros, Anna
    Hosp del Mar, Serv Patol, Lab Citol Hematol, Lab Citogenet Mol, Barcelona, Spain.;Hosp del Mar, IMIM, Canc Res Programme, Grp Recerca Translac Neoplasies Hematol, Barcelona, Spain..
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Athanasiadou, Anastasia
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Garcia-Malo, MaDolores
    Hosp Univ Morales Meseguer, Serv Hematol, Murcia, Spain..
    Collado, Rosa
    Consorcio Hosp Gen Univ, Serv Hematol, Valencia, Spain..
    Xochelli, Aliki
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Rodriguez-Rivera, Maria
    Hosp del Mar, Serv Patol, Lab Citol Hematol, Lab Citogenet Mol, Barcelona, Spain.;Hosp del Mar, IMIM, Canc Res Programme, Grp Recerca Translac Neoplasies Hematol, Barcelona, Spain..
    Ortega, Margarita
    Hosp Valle De Hebron, Lab Citogenet, Barcelona, Spain.;Hosp Valle De Hebron, Serv Hematol, Barcelona, Spain..
    Jose Calasanz, Ma
    Univ Navarra, Dept Genet, Serv Citogenet, Pamplona, Spain..
    Luno, Elisa
    Hosp Univ Cent Asturias, Serv Hematol, Oviedo, Spain..
    Vargas, MaTeresa
    Hosp Univ Virgen del Rocio, Inst Biomed Sevilla IBIS, UGC Hematol, Seville, Spain..
    Grau, Javier
    Univ Autonoma Barcelona, Inst Recerca Leucemia Josep Carreras IJC, ICO Hosp Germans Trias & Pujol, Serv Hematol, Badalona, Spain..
    Martinez-Laperche, Carolina
    Hosp GU Gregorio Maranon, Inst Invest Sanitaria Gregorio Maranon, Serv Hematol, Lab Genet Hematol, Madrid, Spain..
    Valiente, Alberto
    Complejo Hospitalario Navarra, Serv Genet & Hematol, Pamplona, Spain..
    Cervera, Jose
    Hosp Univ La Fe, Unidad Genet, Valencia, Spain..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Gimeno, Eva
    Hosp del Mar, Serv Hematol, Barcelona, Spain..
    Abella, Eugenia
    Hosp del Mar, Serv Hematol, Barcelona, Spain..
    Stalika, Evangelia
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Ma Hernandez-Rivas, Jesus
    Univ Salamanca, Hosp Univ Salamanca, Ctr Invest Canc, CSIC,Serv Hematol,IBSAL,IBMCC, Salamanca, Spain..
    Jose Ortuno, Francisco
    Hosp Univ Morales Meseguer, Serv Hematol, Murcia, Spain..
    Robles, Diego
    Hosp Txagorritxu, Serv Hematol, Vitoria, Spain..
    Ferrer, Ana
    Hosp del Mar, Serv Patol, Lab Citol Hematol, Lab Citogenet Mol, Barcelona, Spain.;Hosp del Mar, IMIM, Canc Res Programme, Grp Recerca Translac Neoplasies Hematol, Barcelona, Spain..
    Ivars, David
    Consorcio Hosp Gen Univ, Serv Hematol, Valencia, Spain..
    Gonzalez, Marcos
    Univ Salamanca, Hosp Univ Salamanca, Ctr Invest Canc, CSIC,Serv Hematol,IBSAL,IBMCC, Salamanca, Spain..
    Bosch, Francesc
    Hosp Valle De Hebron, Lab Citogenet, Barcelona, Spain.;Hosp Valle De Hebron, Serv Hematol, Barcelona, Spain..
    Abrisqueta, Pau
    Hosp Valle De Hebron, Lab Citogenet, Barcelona, Spain.;Hosp Valle De Hebron, Serv Hematol, Barcelona, Spain..
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.;CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Espinet, Blanca
    Hosp del Mar, Serv Patol, Lab Citol Hematol, Lab Citogenet Mol, Barcelona, Spain.;Hosp del Mar, IMIM, Canc Res Programme, Grp Recerca Translac Neoplasies Hematol, Barcelona, Spain..
    Karyotypic complexity rather than chromosome 8 abnormalities aggravates the outcome of chronic lymphocytic leukemia patients with TP53 aberrations2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 49, 80916-80924 p.Article in journal (Refereed)
    Abstract [en]

    Patients with chronic lymphocytic leukemia (CLL) harboring TP53 aberrations (TP53abs; chromosome 17p deletion and/or TP53 mutation) exhibit an unfavorable clinical outcome. Chromosome 8 abnormalities, namely losses of 8p (8p-) and gains of 8q (8q+) have been suggested to aggravate the outcome of patients with TP53abs. However, the reported series were small, thus hindering definitive conclusions. To gain insight into this issue, we assessed a series of 101 CLL patients harboring TP53 disruption. The frequency of 8p- and 8q+ was 14.7% and 17.8% respectively. Both were associated with a significantly (P < 0.05) higher incidence of a complex karyotype (CK, >= 3 abnormalities) detected by chromosome banding analysis (CBA) compared to cases with normal 8p (N-8p) and 8q (N-8q), respectively. In univariate analysis for 10- year overall survival (OS), 8p- (P = 0.002), 8q+ (P = 0.012) and CK (P = 0.009) were associated with shorter OS. However, in multivariate analysis only CK (HR = 2.47, P = 0.027) maintained independent significance, being associated with a dismal outcome regardless of chromosome 8 abnormalities. In conclusion, our results highlight the association of chromosome 8 abnormalities with CK amongst CLL patients with TP53abs, while also revealing that CK can further aggravate the prognosis of this aggressive subgroup.

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