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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, p. 1126-1131Article 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, p. 106-109Article 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, p. 6809-6923Article 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, article id 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, p. 47-48Article in journal (Other academic)
  • 7.
    Agathangelidis, Andreas
    et al.
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Ljungström, Viktor
    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.
    Scarfo, Lydia
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Fazi, Claudia
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Gounari, Maria
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy;Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Pandzic, Tatjana
    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, 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.
    Stamatopoulos, Kostas
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.
    Tonon, Giovanni
    IRCCS Ist Sci San Raffaele, Funct Genom Canc Unit, Div Expt Oncol, 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.
    Ghia, Paolo
    Univ Vita Salute San Raffaele, Strateg Res Program CLL, Milan, Italy;Univ Vita Salute San Raffaele, Div Expt Oncol, B Cell Neoplasia Unit, Milan, Italy;IRCCS Ist Sci San Raffaele, Milan, Italy.
    Highly similar genomic landscapes in monoclonal B-cell lymphocytosis and ultra-stable chronic lymphocytic leukemia with low frequency of driver mutations2018In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 103, no 5, p. 865-873Article in journal (Refereed)
    Abstract [en]

    Despite the recent discovery of recurrent driver mutations in chronic lymphocytic leukemia, the genetic factors involved in disease onset remain largely unknown. To address this issue, we per-formed whole-genome sequencing in 11 individuals with monoclonal B-cell lymphocytosis, both of the low-count and high-count subtypes, and 5 patients with ultra-stable chronic lymphocytic leukemia (>10 years without progression from initial diagnosis). All three entities were indistinguishable at the genomic level exhibiting low genomic complexity and similar types of somatic mutations. Exonic mutations were not frequently identified in putative chronic lymphocytic leukemia driver genes in all settings, including low-count monoclonal B-cell lymphocytosis. To corroborate these findings, we also performed deep sequencing in 11 known frequently mutated genes in an extended cohort of 28 monoclonal B-cell lym phocytosis/chronic lymphocytic leukemia cases. Interestingly, shared mutations were detected between clonal B cells and paired polymorphonuclear cells, strengthening the notion that at least a fraction of somatic mutations may occur before disease onset, likely at the hematopoietic stem cell level. Finally, we identified previously unreported non-coding variants targeting pathways relevant to B-cell and chronic lymphocytic leukemia development, likely associated with the acquisition of the characteristic neoplastic phenotype typical of both monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia.

  • 8.
    Ahlin, Cecilia
    et al.
    Orebro Univ, Dept Oncol, Orebro, Sweden..
    Lundgren, Claudia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Embretsen-Varro, Elin
    Orebro Univ, Dept Oncol, Orebro, Sweden..
    Jirstrom, Karin
    Lund Univ, Dept Pathol & Oncol, Lund, Sweden..
    Blomqvist, Carl
    Orebro Univ, Dept Oncol, Orebro, Sweden.;Univ Helsinki, Dept Oncol, Helsinki, Finland..
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    High expression of cyclin D1 is associated to high proliferation rate and increased risk of mortality in women with ER-positive but not in ER-negative breast cancers2017In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 164, no 3, p. 667-678Article in journal (Refereed)
    Abstract [en]

    Cyclin D1 has a central role in cell cycle control and is an important component of estrogen regulation of cell cycle progression. We have previously shown that high cyclin D expression is related to aggressive features of ER-positive but not ER-negative breast cancer. The aims of the present study were to validate this differential ER-related effect and furthermore explore the relationship between cyclin D overexpression and CCND1 gene amplification status in a node-negative breast cancer case-control study. Immunohistochemical nuclear expression of cyclin D1 (n = 364) and amplification of the gene CCND1 by fluorescent in situ hybridization (n = 255) was performed on tissue microarray sections from patients with T1-2N0M0 breast cancer. Patients given adjuvant chemotherapy were excluded. The primary event was defined as breast cancer death. Breast cancer-specific survival was analyzed in univariate and multivariable models using conditional logistic regression. Expression of cyclin D1 above the median (61.7%) in ER breast cancer was associated with an increased risk for breast cancer death (OR 3.2 95% CI 1.5-6.8) also when adjusted for tumor size and grade (OR 3.1). No significant prognostic impact of cyclin D1 expression was found among ER-negative cases. Cyclin D1 overexpression was significantly associated to high expression of the proliferation markers cyclins A (rho 0.19, p = 0.006) and B (rho 0.18, p = 0.003) in ER-positive tumors, but not in ER-negative cases. There was a significant association between CCND1 amplification and cyclin D1 expression (p = 0.003), but CCND1 amplification was not statistically significantly prognostic (HR 1.4, 95% CI 0.4-4.4). We confirmed our previous observation that high cyclin D1 expression is associated to high proliferation and a threefold higher risk of death from breast cancer in ER-positive breast cancer.

  • 9.
    Ajithkumar, Thankamma
    et al.
    Cambridge Univ Hosp, Dept Oncol, Cambridge, England.
    Horan, Gail
    Cambridge Univ Hosp, Dept Oncol, Cambridge, England.
    Padovani, Laetitia
    Assistance Publ Hop Marseille, Dept Radiat Oncol, Marseille, France.
    Thorp, Nicky
    Clatterbridge Canc Ctr, Dept Oncol, Liverpool, Merseyside, England.
    Timmermann, Beate
    Univ Essen Gesamthsch, West German Proton Ctr, Essen, Germany.
    Alapetite, Claire
    Inst Curie, Dept Radiat Oncol, Paris, France;Inst Curie, Proton Ctr, Paris, France;Inst Curie, Dept Radiat Oncol, Orsay, France;Inst Curie, Proton Ctr, Orsay, France.
    Gandola, Lorenza
    Fdn IRCCS Ist Nazl Tumori, Dept Radiat Oncol, Milan, Italy.
    Ramos, Monica
    Hosp Univ Vall dHebron, Barcelona, Spain.
    Van Beek, Karen
    UZ Leuven, Radiotherapie Oncol, Leuven, Belgium.
    Christiaens, Melissa
    UZ Leuven, Radiotherapie Oncol, Leuven, Belgium.
    Lassen-Ramshad, Yasmin
    Aarhus Univ Hosp, Danish Ctr Particle Therapy, Aarhus, Denmark.
    Magelssen, Henriette
    Norwegian Radium Hosp, Oslo Univ Hosp, Dept Oncol, Oslo, Norway.
    Nilsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Saran, Frank
    Royal Marsden Hosp, Dept Oncol, Sutton, Surrey, England.
    Rombi, Barbara
    Santa Chiara Hosp, Proton Therapy Ctr, Trento, Italy.
    Kortmann, Rolf
    Univ Leipzig, Dept Radiat Oncol, Leipzig, Germany.
    Janssens, Geert O.
    Univ Med Ctr Utrecht, Dept Radiat Oncol, Utrecht, Netherlands;Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands.
    SIOPE - Brain tumor group consensus guideline on craniospinal target volume delineation for high-precision radiotherapy2018In: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 128, no 2, p. 192-197Article in journal (Refereed)
    Abstract [en]

    Objective: To develop a consensus guideline for craniospinal target volume (TV) delineation in children and young adults participating in SIOPE studies in the era of high-precision radiotherapy. Methods and materials: During four consensus meetings (Cambridge, Essen, Liverpool, and Marseille), conventional field-based TV has been translated into image-guided high-precision craniospinal TV by a group of expert paediatric radiation oncologists and enhanced by MRI images of liquor distribution. Results: The CTVcranial should include the whole brain, cribriform plate, most inferior part of the temporal lobes, and the pituitary fossa. If the full length of both optic nerves is not included, the dose received by different volumes of optic nerve should be recorded to correlate with future patterns of relapse (no consensus). The CTVcranial should be modified to include the dural cuffs of cranial nerves as they pass through the skull base foramina. Attempts to spare the cochlea by excluding CSF within the internal auditory canal should be avoided. The CTVspinal should include the entire subarachnoid space, including nerve roots laterally. The lower limit of the spinal CTV is at the lower limit of the thecal sac, best visible on MRI scan. There is no need to include sacral root canals in the spinal CTV. Conclusion: This consensus guideline has the potential to improve consistency of craniospinal TV delineation in an era of high-precision radiotherapy. This proposal will be incorporated in the RTQA guidelines of future SIOPE-BTG trials using CSI.

  • 10.
    Alcorn, Sara
    et al.
    Johns Hopkins Sch Med, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD USA.
    Nilsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Rao, Avani D.
    Johns Hopkins Sch Med, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD USA.
    Ladra, Matthew M.
    Johns Hopkins Sch Med, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD USA.
    Ermoian, Ralph P.
    Univ Washington, Dept Radiat Oncol, Seattle, WA 98195 USA.
    Villar, Rosangela C.
    Ctr Infantil Boldrini, Dept Radiat Oncol, Campinas, SP, Brazil.
    Chen, Michael J.
    Grp Apoio Adolescente & Crianca Canc, Dept Radiat, Sao Paulo, Brazil.
    Kobyzeva, Daria
    Fed Sci Clin Ctr Childrens Hematol Oncol & Immuno, Dept Radiotherapy, Moscow, Russia.
    Nechesnyuk, Alexey V.
    Fed Sci Clin Ctr Childrens Hematol Oncol & Immuno, Dept Radiotherapy, Moscow, Russia.
    Ford, Eric
    Univ Washington, Dept Radiat Oncol, Seattle, WA 98195 USA.
    MacDonald, Shannon
    Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA.
    Winey, Brian
    Massachusetts Gen Hosp, Dept Radiat Oncol, Boston, MA 02114 USA.
    Dieckmann, Karin
    Univ Klin Strahlentherapie & Strahlenbiol, Dept Radiat Oncol, Vienna, Austria.
    Terezakis, Stephanie A.
    Johns Hopkins Sch Med, Dept Radiat Oncol & Mol Radiat Sci, Baltimore, MD USA.
    Practice Patterns of Stereotactic Radiotherapy in Pediatrics: Results From an International Pediatric Research Consortium2018In: Journal of pediatric hematology/oncology (Print), ISSN 1077-4114, E-ISSN 1536-3678, Vol. 40, no 7, p. 522-526Article in journal (Refereed)
    Abstract [en]

    Purpose/Objectives: There is little consensus regarding the application of stereotactic radiotherapy (SRT) in pediatrics. We evaluated patterns of pediatric SRT practice through an international research consortium. Materials and Methods: Eight international institutions with pediatric expertise completed a 124-item survey evaluating patterns of SRT use for patients 21 years old and younger. Frequencies of SRT use and median margins applied with and without SRT were evaluated. Results: Across institutions, 75% reported utilizing SRT in pediatrics. SRT was used in 22% of brain, 18% of spine, 16% of other bone, 16% of head and neck, and <1% of abdomen/pelvis, lung, and liver cases across sites. Of the hypofractionated SRT cases, 42% were delivered with definitive intent. Median gross tumor volume to planning target volume margins for SRT versus non-SRT plans were 0.2 versus 1.4 cm for brain, 0.3 versus 1.5 cm for spine/other bone, 0.3 versus 2.0 cm for abdomen/pelvis, 0.7 versus 1.5 cm for head and neck, 0.5 versus 1.7 cm for lung, and 0.5 versus 2.0 cm for liver sites. Conclusions: SRT is commonly utilized in pediatrics across a range of treatment sites. Margins used for SRT were substantially smaller than for non-SRT planning, highlighting the utility of this approach in reducing treatment volumes.

  • 11. 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, p. 336-341Article 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.

  • 12.
    Ali, Abir Salwa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Grönberg, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Federspiel, Birgitte
    Rigshosp, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Scoazec, Jean-Yves
    Inst Gustave Roussy, Villejuif, France.
    Hjortland, Geir Olav
    Univ Oslo, Oslo, Norway.
    Gronbaek, Henning
    Aarhus Univ Hosp, Aarhus, Denmark.
    Ladekarl, Morten
    Aarhus Univ Hosp, Aarhus, Denmark.
    Langer, Seppo W.
    Rigshosp, Copenhagen Univ Hosp, Copenhagen, Denmark.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Vestermark, Lene Weber
    Odense Univ Hosp, Odense, Denmark.
    Arola, Johanna
    Univ Helsinki, Helsinki, Finland; Helsinki Univ Hosp, Helsinki, Finland.
    Osterlund, Pia
    Univ Helsinki, Helsinki, Finland; Helsinki Univ Hosp, Helsinki, Finland; Tampere Univ Hosp, Tampere, Finland.
    Knigge, Ulrich
    Univ Copenhagen, Rigshosp, Copenhagen, Denmark.
    Sorbye, Halfdan
    Haukeland Hosp, Bergen, Norway; Univ Bergen, 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, Endocrin Oncology. Uppsala Univ, Sect Endocrine Oncol, Dept Med Sci, Uppsala, Sweden..
    Expression of p53 protein in high-grade gastroenteropancreatic neuroendocrine carcinoma2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 11, article id e0187667Article in journal (Refereed)
    Abstract [en]

    Background Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) are aggressive, rapidly proliferating tumors. Therapeutic response to current chemotherapy regimens is usually short lasting. The aim of this study was to examine the expression and potential clinical importance of immunoreactive p53 protein in GEP-NEC. Materials and methods Tumor tissues from 124 GEP-NEC patients with locally advanced or metastatic disease treated with platinum-based chemotherapy were collected from Nordic centers and clinical data were obtained from the Nordic NEC register. Tumor proliferation rate and differentiation were re-evaluated. All specimens were immunostained for p53 protein using a commercially available monoclonal antibody. Kaplan-Meier curves and cox regression analyses were used to assess progression-free survival (PFS) and overall survival (OS). Results All tumor tissues were immunoreactive for either one or both neuroendocrine biomarkers (chromogranin A and synaptophysin) and Ki67 index was >20% in all cases. p53 immunoreactivity was only shown in 39% of the cases and was not found to be a prognostic marker for the whole cohort. However, p53 immunoreactivity was correlated with shorter PFS in patients with colorectal tumors (HR = 2.1, p = 0.03) in a univariate analysis as well as to poorer PFS (HR = 2.6, p = 0.03) and OS (HR = 3.4, p = 0.02) in patients with colorectal tumors with distant metastases, a correlation which remained significant in the multivariate analyses. Conclusion In this cohort of GEP-NEC patients, p53 expression could not be correlated with clinical outcome. However, in patients with colorectal NECs, p53 expression was correlated with shorter PFS and OS. Further studies are needed to establish the role of immunoreactive p53 as a prognostic marker for GEP-NEC patients.

  • 13.
    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, p. 7743-7748Article 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.

  • 14.
    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, p. 43-43Article in journal (Refereed)
  • 15.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Liu, Hao
    KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
    Ding, Haozhong
    KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
    Mitran, Bogdan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Theranostics.
    Edqvist, Per-Henrik D
    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.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Gräslund, Torbjorn
    KTH Royal Inst Technol, Dept Prot Sci, Roslagstullsbacken 21, S-11417 Stockholm, Sweden.
    Affibody-derived drug conjugates: Potent cytotoxic molecules for treatment of HER2 over-expressing tumors2018In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 288, p. 84-95Article in journal (Refereed)
    Abstract [en]

    Patients with HER2-positive tumors often suffer resistance to therapy, warranting development of novel treatment modalities. Affibody molecules are small affinity proteins which can be engineered to bind to desired targets. They have in recent years been found to allow precise targeting of cancer specific molecular signatures such as the HER2 receptor. In this study, we have investigated the potential of an affibody molecule targeting HER2, Z(HER2:2891), conjugated with the cytotoxic maytansine derivate MC-DM1, for targeted cancer therapy. Z(HER2:2891) was expressed as a monomer (Z(HER2:2891)), dimer ((Z(HER2:2891)) 2) and dimer with an albumin binding domain (ABD) for half-life extension ((Z(HER2:2891)) 2-ABD). All proteins had a unique C-terminal cysteine that could be used for efficient and site-specific conjugation with MC-DM1. The resulting affibody drug conjugates were potent cytotoxic molecules for human cells over-expressing HER2, with sub-nanomolar IC50-values similar to trastuzumab emtansine, and did not affect cells with low HER2 expression. A biodistribution study of a radiolabeled version of (Z(HER2:2891))(2)-ABD-MC-DM1, showed that it was taken up by the tumor. The major site of off-target uptake was the kidneys and to some extent the liver. (Z(HER2:2891)) 2-ABD-MC-DM1 was found to have a half-life in circulation of 14 h. The compound was tolerated well by mice at 8.5 mg/kg and was shown to extend survival of mice bearing HER2 over-expressing tumors. The findings in this study show that affibody molecules are a promising class of engineered affinity proteins to specifically deliver small molecular drugs to cancer cells and that such conjugates are potential candidates for clinical evaluation on HER2-overexpressing cancers.

  • 16.
    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, p. 6809-6923Article 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.

    Keywords
    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.
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    2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 6, p. 10213-10224Article 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...
    2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 61, p. 103731-103743Article in journal (Refereed) Published
    Abstract [en]

    Multiple myeloma (MM) is a tumor of plasmablasts/plasma cells (PCs) characterized by the expansion of malignant PCs with complex genetic aberrations in the bone marrow (BM). Recent reports, by us and others, have highlighted the polycomb group (PcG) proteins as potential targets for therapy in MM. The PcG protein BMI-1 of the polycomb repressive complex 1 (PRC1) has been reported to be overexpressed and to possess oncogenic functions in MM. Herein, we report on the anti-myeloma effects of the BMI-1 inhibitor PTC-209 and demonstrate that PTC-209 is a potent anti-myeloma agent in vitro using MM cell lines and primary MM cells. We show that PTC-209 reduces the viability of MM cells via induction of apoptosis and reveal that the anti-MM actions of PTC-209 are mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, leaving other PRC1 subunits such as CBX-7 and the catalytic subunit RING1B unaffected. Importantly, we demonstrate that PTC-209 exhibits synergistic and additive anti-myeloma activity when combined with other epigenetic inhibitors targeting EZH2 and BET bromodomains. Collectively, these data qualify BMI-1 as a candidate for targeted therapy in MM alone or in combinations with epigenetic inhibitors directed to PRC2/EZH2 or BET bromodomains.

    Keywords
    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)10.18632/oncotarget.21909 (DOI)000419562500079 ()29262596 (PubMedID)
    Funder
    Swedish Cancer SocietySwedish Research Council
    Available from: 2017-01-20 Created: 2017-01-20 Last updated: 2018-09-18Bibliographically approved
  • 17.
    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, p. 10213-10224Article 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.

  • 18.
    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.
    Jernberg-Wiklund, Helena
    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.
    Epigenetics in multiple myeloma: From mechanisms to therapy2018In: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 51, p. 101-115Article, review/survey (Refereed)
    Abstract [en]

    Multiple myeloma (MM) is a tumor of antibody producing plasmablasts/plasma cells that resides within the bone marrow (BM). In addition to the well-established role of genetic lesions and tumor-microenvironment interactions in the development of MM, deregulated epigenetic mechanisms are emerging as important in MM pathogenesis. Recently, MM sequencing and expression projects have revealed that mutations and copy number variations as well as deregulation in the expression of epigenetic modifiers are characteristic features of MM. In the past decade, several studies have suggested epigenetic mechanisms via DNA methylation, histone modifications and non-coding RNAs as important contributing factors in MM with impacts on disease initiation, progression, clonal heterogeneity and response to treatment. Herein we review the present view and knowledge that has accumulated over the past decades on the role of epigenetics in MM, with focus on the interplay between epigenetic mechanisms and the potential use of epigenetic inhibitors as future treatment modalities for MM.

  • 19.
    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.
    Párraga, Alba Atienza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Majumder, Muntasir
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
    Ma, Anqi
    Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA..
    Jin, Jian
    Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA..
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Heckman, Caroline
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
    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.
    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 bromodomain2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 61, p. 103731-103743Article in journal (Refereed)
    Abstract [en]

    Multiple myeloma (MM) is a tumor of plasmablasts/plasma cells (PCs) characterized by the expansion of malignant PCs with complex genetic aberrations in the bone marrow (BM). Recent reports, by us and others, have highlighted the polycomb group (PcG) proteins as potential targets for therapy in MM. The PcG protein BMI-1 of the polycomb repressive complex 1 (PRC1) has been reported to be overexpressed and to possess oncogenic functions in MM. Herein, we report on the anti-myeloma effects of the BMI-1 inhibitor PTC-209 and demonstrate that PTC-209 is a potent anti-myeloma agent in vitro using MM cell lines and primary MM cells. We show that PTC-209 reduces the viability of MM cells via induction of apoptosis and reveal that the anti-MM actions of PTC-209 are mediated by on-target effects i.e. downregulation of BMI-1 protein and the associated repressive histone mark H2AK119ub, leaving other PRC1 subunits such as CBX-7 and the catalytic subunit RING1B unaffected. Importantly, we demonstrate that PTC-209 exhibits synergistic and additive anti-myeloma activity when combined with other epigenetic inhibitors targeting EZH2 and BET bromodomains. Collectively, these data qualify BMI-1 as a candidate for targeted therapy in MM alone or in combinations with epigenetic inhibitors directed to PRC2/EZH2 or BET bromodomains.

  • 20.
    Amarasinghe, H.
    et al.
    Univ Southampton, Acad Unit Canc Sci, Southampton, Hants, England..
    Wojdacz, T.
    Aarhus Univ, Aarhus Inst Adv Studies, Aarhus, Denmark..
    Rose-Zerilli, M.
    Univ Southampton, Acad Unit Canc Sci, Southampton, Hants, England..
    Beattie, A.
    Univ Southampton, Acad Unit Canc Sci, Southampton, Hants, England..
    Forster, J.
    Univ Southampton, Acad Unit Canc Sci, Southampton, Hants, England..
    Kadalayil, L.
    Univ Southampton, Genet Epidemiol & Bioinformat, Southampton, Hants, England..
    Blakemore, S.
    Univ Cologne, Dept Internal Med, Cologne, Germany..
    Parker, H.
    Univ Southampton, Acad Unit Canc Sci, Southampton, Hants, England..
    Larrayoz, M.
    Univ Navarra, Div Hematooncol, Pamplona, Spain..
    Clifford, R.
    Univ Oxford, Oxford Natl Inst Hlth Res, Biomed Res Ctr, Mol Diagnost Ctr, Oxford, England..
    Davis, Z.
    Royal Bournemouth Hosp, Dept Mol Pathol, Bournemouth, Dorset, England..
    Else, M.
    Inst Canc Res, Div Mol Pathol, London, England..
    Cohen, D.
    Univ Leeds, Leeds Inst Clin Trials Res, Leeds, W Yorkshire, England..
    Steele, A.
    Univ Southampton, Acad Unit Canc Sci, Southampton, Hants, England..
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Collins, A.
    Univ Southampton, Human Dev & Hlth, Southampton, Hants, England..
    Pettitt, A.
    Univ Liverpool, Dept Mol & Clin Canc Med, Liverpool, Merseyside, England..
    Hillmen, P.
    St James Univ Hosp, Dept Haematol, Leeds, W Yorkshire, England..
    Plass, C.
    German Canc Res Ctr, Div Epigen & Canc Risk Factors, Heidelberg, Germany..
    Catovsky, D.
    Inst Canc Res, Div Mol Pathol, London, England..
    Schuh, A.
    Univ Oxford, Oxford Natl Inst Hlth Res, Biomed Res Ctr, Mol Diagnost Ctr, Oxford, England..
    Oscier, D.
    Royal Bournemouth Hosp, Dept Mol Pathol, Bournemouth, Dorset, England..
    Oakes, C.
    Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA..
    Strefford, J.
    Univ Southampton, Acad Unit Canc Sci, Southampton, Hants, England..
    Patients with a Memory-like DNA Methylation Signature exhibit long-term survival after first-line immuno-chemotherapy: Data from the UK CLL4, ARCTIC and ADMIRE trials2018In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 181, p. 29-29Article in journal (Other academic)
  • 21.
    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, p. S666-S666Article in journal (Refereed)
  • 22.
    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, p. 100-108Article 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.

  • 23.
    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, p. 21-5Article 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.

  • 24.
    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, p. 85-90, article id 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.

  • 25.
    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)
  • 26.
    Antonodimitrakis, Pantelis Clewemar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Olofsson, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Grimelius, Lars
    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.
    Wassberg, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Neuroendocrine tumors with syndromic vasoactive intestinal polypeptide hypersecretion: a retrospective study2017In: International Journal of Endocrine Oncology, Vol. 4, no 1, p. 9-22Article in journal (Refereed)
    Abstract [en]

    Aim: Vasoactive intestinal polypeptide producing neuroendocrine tumors are rare and cause severe hormonal symptoms. Patients/methods: Eighteen patients with vasoactive intestinal polypeptide producing neuroendocrine tumors were analyzed with reviews of medical records, radiology and tumor tissue specimens. Results: Twelve patients (67%) had liver metastases at diagnosis. Chemotherapy, somatostatin analogs and interferon were given as medical therapies. Streptozocin/5-fluorouracil produced an objective response in 40% of the evaluable patients. Somatostatin analogs gave a clinical/biochemical response in eight out of nine patients. Transarterial embolization of the liver and peptide receptor radionuclide therapy was given to refractory cases. Sixteen patients died during the observation period. The median overall survival from diagnosis was 102 months. Conclusion: Systemic chemotherapy and somatostatin analogs should be given in cases of advanced disease or for hormonal symptoms.

  • 27.
    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)
  • 28.
    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)
  • 29.
    Babaei, Masoud
    et al.
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.;German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany.;Natl Ctr Tumor Dis NCT, Heidelberg, Germany..
    Balavarca, Yesilda
    German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany.;Natl Ctr Tumor Dis NCT, Heidelberg, Germany..
    Jansen, Lina
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany..
    Lemmens, Valery
    Netherlands Comprehens Canc Org IKNL, Utrecht, Netherlands.;Erasmus MC Univ, Med Ctr, Dept Publ Hlth, Rotterdam, Netherlands..
    van Erning, Felice N.
    Netherlands Comprehens Canc Org IKNL, Utrecht, Netherlands.;Erasmus MC Univ, Med Ctr, Dept Publ Hlth, Rotterdam, Netherlands..
    van Eycken, Liesbet
    Belgian Canc Registry, Brussels, Belgium..
    Vaes, Evelien
    Belgian Canc Registry, Brussels, Belgium..
    Sjövall, Annika
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ulrich, Cornelia M.
    German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany.;Natl Ctr Tumor Dis NCT, Heidelberg, Germany.;Huntsman Canc Inst, Salt Lake City, UT USA.;Univ Utah, Salt Lake City, UT USA..
    Schrotz-King, Petra
    German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany.;Natl Ctr Tumor Dis NCT, Heidelberg, Germany..
    Brenner, Hermann
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany.;German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany.;Natl Ctr Tumor Dis NCT, Heidelberg, Germany.;German Canc Res Ctr, German Canc Consortium DKTK, Heidelberg, Germany..
    Administration of adjuvant chemotherapy for stage II-III colon cancer patients: An European population-based study2018In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 142, no 7, p. 1480-1489Article in journal (Refereed)
    Abstract [en]

    The advantage of adjuvant chemotherapy (ACT) for treating Stage III colon cancer patients is well established and widely accepted. However, many patients with Stage III colon cancer do not receive ACT. Moreover, there are controversies around the effectiveness of ACT for Stage II patients. We investigated the administration of ACT and its association with overall survival in resected Stage II (overall and stratified by low-/high-risk) and Stage III colon cancer patients in three European countries including The Netherlands (2009-2014), Belgium (2009-2013) and Sweden (2009-2014). Hazard ratios (HR) for death were obtained by Cox regression models adjusted for potential confounders. A total of 60244 resected colon cancer patients with pathological Stages II and III were analyzed. A small proportion (range 9-24%) of Stage II and over half (range 55-68%) of Stage III patients received ACT. Administration of ACT in Stages II and III tumors decreased with higher age of patients. Administration of ACT was significantly associated with higher overall survival in high-risk Stage II patients (in The Netherlands (HR; 95%CI = 0.82 (0.67-0.99), Belgium (0.73; 0.59-0.90) and Sweden (0.58; 0.44-0.75)), and in Stage III patients (in The Netherlands (0.47; 0.43-0.50), Belgium (0.46; 0.41-0.50) and Sweden (0.48; 0.43-0.54)). In Stage III, results were consistent across subgroups including elderly patients. Our results show an association of ACT with higher survival among Stage III and high-risk Stage II colon cancer patients. Further investigations are needed on the selection criteria of Stages II and III colon cancer patients for ACT.

  • 30.
    Babaei, Masoud
    et al.
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, INF 581, Heidelberg, Germany..
    Jansen, Lina
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, INF 581, Heidelberg, Germany..
    Balavarca, Yesilda
    German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany.;Natl Ctr Tumor Dis, Heidelberg, Germany..
    Sjovall, Annika
    Karolinska Inst, Ctr Digest Dis, Stockholm, Sweden..
    Bos, Amanda
    Comprehens Canc Org Netherlands, Utrecht, Netherlands.;Erasmus MC Univ Med Ctr, Dept Publ Hlth, Rotterdam, Netherlands..
    van de Velde, Tony
    Netherlands Canc Inst, Biometr Dept, Amsterdam, Netherlands..
    Moreau, Michel
    Inst Jules Bordet, Datactr, Brussels, Belgium..
    Liberale, Gabriel
    Inst Jules Bordet, Datactr, Brussels, Belgium..
    Goncalves, Ana Filipa
    Portuguese Oncol Inst Porto, Porto, Portugal..
    Bento, Maria Jose
    Portuguese Oncol Inst Porto, Porto, Portugal..
    Ulrich, Cornelia M.
    German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany.;Natl Ctr Tumor Dis, Heidelberg, Germany.;German Canc Res Ctr, German Canc Consortium, Heidelberg, Germany..
    Schrotz-King, Petra
    German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany.;Natl Ctr Tumor Dis, Heidelberg, Germany..
    Lemmens, Valery
    Comprehens Canc Org Netherlands, Utrecht, Netherlands.;Erasmus MC Univ Med Ctr, Dept Publ Hlth, Rotterdam, Netherlands..
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Brenner, Hermann
    German Canc Res Ctr, Div Clin Epidemiol & Aging Res, INF 581, Heidelberg, Germany.;German Canc Res Ctr, Div Prevent Oncol, Heidelberg, Germany.;Natl Ctr Tumor Dis, Heidelberg, Germany.;German Canc Res Ctr, German Canc Consortium, Heidelberg, Germany..
    Neoadjuvant Therapy in Rectal Cancer Patients With Clinical Stage II to III Across European Countries: Variations and Outcomes2018In: Clinical colorectal cancer, ISSN 1533-0028, Vol. 17, no 1, p. E129-E142Article in journal (Refereed)
    Abstract [en]

    This study is the largest observational study on neoadjuvant therapy in patients with stage II & III rectal cancer by including high-quality data from large population-based and clinical cancer registries. We observed large variations in administration of neoadjuvant chemo(radio) therapy across European countries. Our results support major survival advantages of patients treated with neoadjuvant radiotherapy. Background: Neoadjuvant therapy improves survival of patients with clinical stage II and III rectal cancer in clinical trials. In this study, we investigated the administration of neoadjuvant radiotherapy (neo-RT) and neoadjuvant chemoradiotherapy (neo-CRT) and its association with survival in resected patients in 2 European countries (The Netherlands and Sweden) and at 3 specialist centers. Materials and Methods: Administration of neoadjuvant treatment (all registries) and overall survival after surgery in The Netherlands and Sweden were assessed. Hazard ratios (HRs) were obtained using Cox regression adjusted for potential confounders. Results: A total of 16,095 rectal cancer patients with clinical stage II and III were eligible for analyses. Large variations in administration of neo-RT and neo-CRT were observed. Elderly patients less often received neo-RT and neo-CRT. Patients with stage III disease received neo-CRT more frequently than neo-RT. Administration of neo-RT versus surgery without neoadjuvant treatment was significantly associated with improved survival in The Netherlands (HR, 0.62; 95% confidence interval [CI], 0.53-0.73) as well as in Sweden (HR, 0.79; 95% CI, 0.69-0.90). Administration of neo-CRT was associated with enhanced survival in The Netherlands (HR, 0.62; 95% CI, 0.50-0.78) but not in Sweden (HR, 0.97; 95% CI, 0.80-1.18). The mortality of patients treated with neo-CRT compared with neo-RT showed inconsistent results in population-based centers. Conclusions: Our results support an association of neo-RT with enhanced survival among stage II and III rectal cancer patients. Comparing neo-CRT with neo-RT, larger variations and inconsistent results with respect to survival were observed across centers.

  • 31. 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, p. 681-687Article 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.

  • 32.
    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, p. 313-314Article in journal (Other academic)
  • 33.
    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, p. 856-859Article 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.

  • 34.
    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..