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  • 601.
    Velikyan, Irina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper.
    Schweighoefer, Philip
    Eckert & Ziegler Eurotope GmbH, Berlin, Germany.
    Feldwisch, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Affibody AB, Solna, Sweden.
    Seemann, Johanna
    Eckert & Ziegler Eurotope GmbH, Berlin, Germany.
    Frejd, Fredrik Y.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Affibody AB, Solna, Sweden.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Diagnostic HER2-binding radiopharmaceutical, [Ga-68]Ga-ABY-025, for routine clinical use in breast cancer patients2019Inngår i: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 9, nr 1, s. 12-23Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    [Ga-68]Ga-ABY-025/PET-CT targeting human epidermal growth factor receptor type 2 (HER2) has demonstrated its potential clinical value for the detection and quantification of HER2 in a phase I clinical study with breast cancer patients. Previously, the radiopharmaceutical was prepared manually, however larger scale of multicenter clinical trials and routine healthcare requires automation of the production process to limit the operator radiation dose, improve tracer manufacturing robustness, and provide on-line documentation for good manufacturing practice (GMP) compliance. The production of [Ga-68]Ga-ABY-025 was implemented on the Modular-Lab PharmTrace synthesis platform (Eckert & Ziegler) and disposable cassettes were developed. Pharmaceutical grade Ge-68/Ga-68 generator (GalliaPharm (R)) was used in the study. The active pharmaceutical ingredient starting material ABY-025 (GMP grade) was provided by Affibody AB. The patient examinations were conducted using a Discovery MI PET/CT scanner (20 cm FOV, GE Healthcare). Reproducible and GMP compliant fully automated production of [Ga-68]Ga-ABY-025 was developed. The radiochemical purity of the product was 98.7 +/- 0.6% with total peptide content of 315 +/- 15 mu g (n = 3). Radionuclidic purity, sterility, endotoxin content, residual solvent content, and sterile filter integrity were controlled and met acceptance criteria. The product was stable at ambient temperature for at least 2 h. The primary tumor and metastasis were detected with SUVmax values of 8.3 and 16.0, respectively. Automated production of [Ga-68]Ga-ABY-025 was established and the process was validated enabling standardized multicenter phase II and III clinical trials and routine clinical use. Patient examinations conformed to the radiopharmaceutical biodistribution observed in the previous phase I study.

  • 602.
    Velikyan, Irina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för biomedicinsk strålningsvetenskap. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Wennborg, Anders
    Affibody AB, Solna.
    Feldwisch, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap. Affibody AB, Solna.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Good manufacturing practice production of [68Ga]Ga-ABY-025 for HER2 specific breast cancer imaging.2016Inngår i: American Journal of Nuclear Medicine and Molecular Imaging, ISSN 2160-8407, Vol. 6, nr 2, s. 135-153Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Therapies targeting human epidermal growth factor receptor type 2 (HER2) have revolutionized breast cancer treatment, but require invasive biopsies and rigorous histopathology for optimal patient stratification. A non-invasive and quantitative diagnostic method such as positron emission tomography (PET) for the pre-therapeutic determination of the presence and density of the HER2 would significantly improve patient management efficacy and treatment cost. The essential part of the PET methodology is the production of the radiopharmaceutical in compliance with good manufacturing practice (GMP). The use of generator produced positron emitting (68)Ga radionuclide would provide worldwide accessibility of the agent. GMP compliant, reliable and highly reproducible production of [(68)Ga]Ga-ABY-025 with control over the product peptide concentration and amount of radioactivity was accomplished within one hour. Two radiopharmaceuticals were developed differing in the total peptide content and were validated independently. The specific radioactivity could be kept similar throughout the study, and it was 6-fold higher for the low peptide content radiopharmaceutical. Intrapatient comparison of the two peptide doses allowed imaging optimization. The high peptide content decreased the uptake in healthy tissue, in particular liver, improving image contrast. The later imaging time points enhanced the contrast. The combination of high peptide content radiopharmaceutical and whole-body imaging at 2 hours post injection appeared to be optimal for routine clinical use.

  • 603.
    Velikyan, Irina
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning.
    Wennborg, Anders
    Affibody AB, Solna, Sweden..
    Feldwisch, Joachim
    Affibody AB, Solna, Sweden..
    Orlova, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för Molekylär Avbildning. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Tolmachev, Vladimir
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Carlsson, Jörgen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk fysiologi.
    Good manufacturing practice compliant production of a Ga-68-labelled Affibody agent for breast cancer imaging: first-in-human2015Inngår i: Journal of labelled compounds & radiopharmaceuticals, ISSN 0362-4803, E-ISSN 1099-1344, Vol. 58, s. S358-S358Artikkel i tidsskrift (Annet vitenskapelig)
  • 604. Vernerey, Dewi
    et al.
    Hammel, Pascal
    Paget-Bailly, Sophie
    Huguet, Florence
    Van Laethem, Jean Luc
    Goldstein, David
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Artru, Pascal
    Moore, Malcolm J.
    Andre, Thierry
    Mineur, Laurent
    Chibaudel, Benoist
    Louvet, Christophe
    Bonnetain, Franck
    Prognosis model for overall survival in locally advanced unresecable pancreatic carcinoma: An ancillary study of the LAP 07 trial2015Inngår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 33, nr 3, artikkel-id 235Artikkel i tidsskrift (Annet vitenskapelig)
  • 605.
    Vernerey, Dewi
    et al.
    Univ Hosp Besancon, Methodol & Qual Life Oncol Unit, EA 3181, 3 Blvd Alexandre Fleming, F-25030 Besancon, France..
    Huguet, Florence
    Oncol Multidisciplinary Res Grp GERCOR, 151 Rue Faubourg St Antoine, F-75011 Paris, France.;Tenon Hosp, AP HP, Dept Radiotherapy, 4 Rue Chine, F-75020 Paris, France..
    Vienot, Angelique
    Univ Hosp Besancon, Dept Gastroenterol, 3 Blvd Alexandre Fleming, F-25030 Besancon, France..
    Goldstein, David
    Prince Wales Hosp, Dept Med Oncol, Sydney, NSW 2031, Australia.;UNSW, Prince Wales Clin Sch, Sydney, NSW 2031, Australia.;AGITG Australasian Gastrointestinal Trials Grp, 119-143 Missenden Rd, Camperdown, NSW 2050, Australia..
    Paget-Bailly, Sophie
    Univ Hosp Besancon, Methodol & Qual Life Oncol Unit, EA 3181, 3 Blvd Alexandre Fleming, F-25030 Besancon, France..
    Van Laethem, Jean-Luc
    Erasme Univ Hosp, Dept Gastroenterol, Route Lennik 808, B-1070 Brussels, Belgium..
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Artru, Pascal
    Oncol Multidisciplinary Res Grp GERCOR, 151 Rue Faubourg St Antoine, F-75011 Paris, France.;Jean Mermoz Hosp, Dept Gastroenterol, 55 Ave Mermoz, F-69008 Lyon, France..
    Moore, Malcolm J.
    Princess Margaret Hosp, Dept Med Oncol, 610 Univ Ave, Toronto, ON M5G 2M9, Canada..
    Andre, Thierry
    Oncol Multidisciplinary Res Grp GERCOR, 151 Rue Faubourg St Antoine, F-75011 Paris, France.;St Antoine Hosp, AP HP, Dept Med Oncol, 184 Rue Faubourg St Antoine, F-75011 Paris, France..
    Mineur, Laurent
    St Catherine Inst, Dept Radiotherapy & Med Oncol, 250 Chemin Baigne Pieds, F-84918 Avignon, France..
    Chibaudel, Benoist
    Oncol Multidisciplinary Res Grp GERCOR, 151 Rue Faubourg St Antoine, F-75011 Paris, France.;Franco British Hosp Inst, Dept Med Oncol, 3 Rue Barbes, F-92300 Levallois Perret, France..
    Benetkiewicz, Magdalena
    Oncol Multidisciplinary Res Grp GERCOR, 151 Rue Faubourg St Antoine, F-75011 Paris, France..
    Louvet, Christophe
    Oncol Multidisciplinary Res Grp GERCOR, 151 Rue Faubourg St Antoine, F-75011 Paris, France.;Inst Mutualiste Montsouris, Dept Med Oncol, 42 Blvd Jourdan, F-75014 Paris, France..
    Hammel, Pascal
    Oncol Multidisciplinary Res Grp GERCOR, 151 Rue Faubourg St Antoine, F-75011 Paris, France.;Beaujon Hosp, AP HP, Dept Digest Oncol, 100 Blvd Gen Leclerc, F-92110 Clichy, France..
    Bonnetain, Franck
    Univ Hosp Besancon, Methodol & Qual Life Oncol Unit, EA 3181, 3 Blvd Alexandre Fleming, F-25030 Besancon, France.;Oncol Multidisciplinary Res Grp GERCOR, 151 Rue Faubourg St Antoine, F-75011 Paris, France..
    Prognostic nomogram and score to predict overall survival in locally advanced untreated pancreatic cancer (PROLAP)2016Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 115, nr 3, s. 281-289Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The management of locally advanced pancreatic cancer (LAPC) patients remains controversial. Better discrimination for overall survival (OS) at diagnosis is needed. We address this issue by developing and validating a prognostic nomogram and a score for OS in LAPC (PROLAP).

    Methods: Analyses were derived from 442 LAPC patients enrolled in the LAP07 trial. The prognostic ability of 30 baseline parameters was evaluated using univariate and multivariate Cox regression analyses. Performance assessment and internal validation of the final model were done with Harrell's C-index, calibration plot and bootstrap sample procedures. On the basis of the final model, a prognostic nomogram and a score were developed, and externally validated in 106 consecutive LAPC patients treated in Besanc, on Hospital, France.

    Results: Age, pain, tumour size, albumin and CA 19-9 were independent prognostic factors for OS. The final model had good calibration, acceptable discrimination (C-index = 0.60) and robust internal validity. The PROLAP score has the potential to delineate three different prognosis groups with median OS of 15.4, 11.7 and 8.5 months (log-rank P<0.0001). The score ability to discriminate OS was externally confirmed in 63 (59%) patients with complete clinical data derived from a data set of 106 consecutive LAPC patients; median OS of 18.3, 14.1 and 7.6 months for the three groups (log-rank P<0.0001).

    Conclusions: The PROLAP nomogram and score can accurately predict OS before initiation of induction chemotherapy in LAPC-untreated patients. They may help to optimise clinical trials design and might offer the opportunity to define risk-adapted strategies for LAPC management in the future.

  • 606.
    Vickovic, Sanja
    et al.
    KTH Royal Inst Technol, Sch Biotechnol, Div Gene Technol, Sci Life Lab, SE-11428 Stockholm, Sweden..
    Stahl, Patrik L.
    Karolinska Inst, Dept Cell & Mol Biol, SE-17177 Stockholm, Sweden..
    Salmen, Fredrik
    KTH Royal Inst Technol, Sch Biotechnol, Div Gene Technol, Sci Life Lab, SE-11428 Stockholm, Sweden..
    Giatrellis, Sarantis
    Karolinska Inst, Dept Cell & Mol Biol, SE-17177 Stockholm, Sweden..
    Westholm, Jakub Orzechowski
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, SE-10691 Stockholm, Sweden..
    Mollbrink, Annelie
    Karolinska Inst, Sci Life Lab, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden..
    Navarro, Jose Fernandez
    Karolinska Inst, Dept Cell & Mol Biol, SE-17177 Stockholm, Sweden..
    Custodio, Joaquin
    Karolinska Inst, Sci Life Lab, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden..
    Bienko, Magda
    Karolinska Inst, Sci Life Lab, Dept Med Biochem & Biophys, SE-17177 Stockholm, Sweden..
    Sutton, Lesley-Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Frisen, Jonas
    Karolinska Inst, Dept Cell & Mol Biol, SE-17177 Stockholm, Sweden..
    Lundeberg, Joakim
    KTH Royal Inst Technol, Sch Biotechnol, Div Gene Technol, Sci Life Lab, SE-11428 Stockholm, Sweden..
    Massive and parallel expression profiling using microarrayed single-cell sequencing2016Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 7, artikkel-id 13182Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Single-cell transcriptome analysis overcomes problems inherently associated with averaging gene expression measurements in bulk analysis. However, single-cell analysis is currently challenging in terms of cost, throughput and robustness. Here, we present a method enabling massive microarray-based barcoding of expression patterns in single cells, termed MASC-seq. This technology enables both imaging and high-throughput single-cell analysis, characterizing thousands of single-cell transcriptomes per day at a low cost (0.13 USD/cell), which is two orders of magnitude less than commercially available systems. Our novel approach provides data in a rapid and simple way. Therefore, MASC-seq has the potential to accelerate the study of subtle clonal dynamics and help provide critical insights into disease development and other biological processes.

  • 607.
    Vilia, Maria Giovanna
    et al.
    IRCCS, Div Expt Oncol, San Raffaele Sci Inst, Via Olgettina 58, I-201321 Milan, Italy..
    Fonte, Eleonora
    IRCCS, Div Expt Oncol, San Raffaele Sci Inst, Via Olgettina 58, I-201321 Milan, Italy..
    Rodriguez, Tania Veliz
    IRCCS, Div Expt Oncol, San Raffaele Sci Inst, Via Olgettina 58, I-201321 Milan, Italy..
    Tocchetti, Marta
    IRCCS, Div Expt Oncol, San Raffaele Sci Inst, Via Olgettina 58, I-201321 Milan, Italy..
    Ranghetti, Pamela
    IRCCS, Div Expt Oncol, San Raffaele Sci Inst, Via Olgettina 58, I-201321 Milan, Italy..
    Scarfo, Lydia
    IRCCS, Div Expt Oncol, San Raffaele Sci Inst, Via Olgettina 58, I-201321 Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Papakonstantinou, Nikos
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Ntoufa, Stavroula
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Ghia, Paolo
    IRCCS, Div Expt Oncol, San Raffaele Sci Inst, Via Olgettina 58, I-201321 Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy..
    Muzio, Marta
    IRCCS, Div Expt Oncol, San Raffaele Sci Inst, Via Olgettina 58, I-201321 Milan, Italy..
    The inhibitory receptor toll interleukin-1R 8 (TIR8/IL-1R8/SIGIRR) is downregulated in chronic lymphocytic leukemia2017Inngår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 58, nr 10, s. 2419-2425Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Toll interleukin-1 receptor 8 (also known as TIR8, SIGIRR, or IL1R8) is a transmembrane receptor that inhibits inflammation. Accordingly, genetic inactivation of this protein exacerbates chronic inflammation and inflammation-associated tumors in mice. In particular, lack of TIR8 triggers leukemia progression in a mouse model of chronic lymphocytic leukemia (CLL), supporting its role as a novel tumor restrainer. The aim of this study was to measure the amount of TIR8 mRNA and protein in CLL cells, and to analyze its regulation of expression. Circulating leukemic cells expressed lower levels of TIR8 compared to normal B-lymphocytes. Treatment of CLL cells with Azacytidine restored higher levels of TIR8 suggesting that DNA methylation may be involved in modulating TIR8 expression, with implications for novel therapeutic strategies.

  • 608.
    Vlachogiannis, Pavlos
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Gudjonsson, Olafur
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Montelius, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Grusell, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Isacsson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Nilsson, Kristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Blomquist, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Hypofractionated high-energy proton-beam irradiation is an alternative treatment for WHO grade I meningiomas2017Inngår i: Acta Neurochirurgica, ISSN 0001-6268, E-ISSN 0942-0940, Vol. 159, nr 12, s. 2391-2400Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Radiation treatment is commonly employed in the treatment of meningiomas. The aim of this study was to evaluate the effectiveness and safety of hypofractionated high-energy proton therapy as adjuvant or primary treatment for WHO grade I meningiomas. A total of 170 patients who received irradiation with protons for grade I meningiomas between 1994 and 2007 were included in the study. The majority of the tumours were located at the skull base (n = 155). Eighty-four patients were treated post subtotal resection, 42 at tumour relapse and 44 with upfront radiotherapy after diagnosis based on the typical radiological image. Irradiation was given in a hypofractionated fashion (3-8 fractions, usually 5 or 6 Gy) with a mean dose of 21.9 Gy (range, 14-46 Gy). All patients were planned for follow-up with clinical controls and magnetic resonance imaging scans at 6 months and 1, 2, 3, 5, 7 and 10 years after treatment. The median follow-up time was 84 months. Age, gender, tumour location, Simpson resection grade and target volume were assessed as possible prognostic factors for post-irradiation tumour progression and radiation related complications. The actuarial 5- and 10-year progression-free survival rates were 93% and 85% respectively. Overall mortality rate was 13.5%, while disease-specific mortality was 1.7% (3/170 patients). Older patients and patients with tumours located in the middle cranial fossa had a lower risk for tumour progression. Radiation-related complications were seen in 16 patients (9.4%), with pituitary insufficiency being the most common. Tumour location in the anterior cranial fossa was the only factor that significantly increased the risk of complications. Hypofractionated proton-beam radiation therapy may be used particularly in the treatment of larger World Health Organisation grade I meningiomas not amenable to total surgical resection. Treatment is associated with high rates of long-term tumour growth control and acceptable risk for complications.

  • 609.
    Wahlin, B. E.
    et al.
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden..
    Overgaard, N.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Peterson, S.
    Reg Canc Ctr South, Lund, Sweden..
    Digkas, E.
    Malarsjukhuset Eskilstuna, Dept Oncol, Eskilstuna, Sweden..
    Glimelius, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Lagerlof, I.
    Linkoping Univ Hosp, Dept Haematol, Linkoping, Sweden..
    Johansson, A. -S
    Palma, M.
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden..
    Hansson, L.
    Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden..
    Linderoth, J.
    Lund Univ, Dept Oncol, Lund, Sweden..
    Goldkuhl, C.
    Sahlgrens Univ Hosp, Dept Oncol, Gothenburg, Sweden..
    Molin, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Hodgkin Lymphoma In Sweden Since 2000: Better Survival Only In Elderly Women - A Swedish Lymphoma Registry Study2016Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, s. 22-22Artikkel i tidsskrift (Annet vitenskapelig)
  • 610.
    Walters, Sarah
    et al.
    Univ London London Sch Hyg & Trop Med, Canc Survival Grp, London WC1E 7HT, England..
    Benitez-Majano, Sara
    Univ London London Sch Hyg & Trop Med, Canc Survival Grp, London WC1E 7HT, England..
    Muller, Patrick
    Univ London London Sch Hyg & Trop Med, Canc Survival Grp, London WC1E 7HT, England..
    Coleman, Michel P.
    Univ London London Sch Hyg & Trop Med, Canc Survival Grp, London WC1E 7HT, England..
    Allemani, Claudia
    Univ London London Sch Hyg & Trop Med, Canc Survival Grp, London WC1E 7HT, England..
    Butler, John
    Univ London London Sch Hyg & Trop Med, Canc Survival Grp, London WC1E 7HT, England.;Royal Marsden Hosp, Dept Gynaecol Oncol, London SW3 6JJ, England..
    Peake, Mick
    Univ Hosp Leicester, Glenfield Hosp, Leicester LE3 9QP, Leics, England..
    Guren, Marianne Gronlie
    Oslo Univ Hosp, Dept Oncol, N-0424 Oslo, Norway.;Oslo Univ Hosp, KG Jebsen Colorectal Canc Res Ctr, NO-0424 Oslo, Norway..
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Bergstrom, Stefan
    Gavle Cent Hosp, Dept Oncol, SE-80187 Gavle, Sweden..
    Påhlman, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Rachet, Bernard
    Univ London London Sch Hyg & Trop Med, Canc Survival Grp, London WC1E 7HT, England..
    Is England closing the international gap in cancer survival?2015Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 113, nr 5, s. 848-860Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: We provide an up-to-date international comparison of cancer survival, assessing whether England is 'closing the gap' compared with other high-income countries. Methods: Net survival was estimated using national, population-based, cancer registrations for 1.9 million patients diagnosed with a cancer of the stomach, colon, rectum, lung, breast (women) or ovary in England during 1995-2012. Trends during 1995-2009 were compared with estimates for Australia, Canada, Denmark, Norway and Sweden. Clinicians were interviewed to help interpret trends. Results: Survival from all cancers remained lower in England than in Australia, Canada, Norway and Sweden by 2005-2009. For some cancers, survival improved more in England than in other countries between 1995-1999 and 2005-2009; for example, 1-year survival from stomach, rectal, lung, breast and ovarian cancers improved more than in Australia and Canada. There has been acceleration in lung cancer survival improvement in England recently, with average annual improvement in 1-year survival rising to 2% during 2010-2012. Survival improved more in Denmark than in England for rectal and lung cancers between 1995-1999 and 2005-2009. Conclusions: Survival has increased in England since the mid-1990s in the context of strategic reform in cancer control, however, survival remains lower than in comparable developed countries and continued investment is needed to close the international survival gap.

  • 611.
    Wang, Sophia S.
    et al.
    City Hope Natl Med Ctr, 1500 East Duarte Rd, Duarte, CA 91010 USA;Beckman Res Inst, Dept Populat Sci, Duarte, CA USA.
    Carrington, Mary
    Ragon Inst MGH MIT & Harvard, Cambridge, MA USA;Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Canc & Inflammat Program, Frederick, MD USA.
    Berndt, Sonja I.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Slager, Susan L.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA.
    Bracci, Paige M.
    Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA.
    Voutsinas, Jenna
    City Hope Natl Med Ctr, 1500 East Duarte Rd, Duarte, CA 91010 USA;Beckman Res Inst, Dept Populat Sci, Duarte, CA USA.
    Cerhan, James R.
    Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA.
    Smedby, Karin E.
    Karolinska Univ Hosp, Hematol Ctr, Stockholm, Sweden;Karolinska Inst, Clin Epidemiol Unit, Dept Med Solna, Stockholm, Sweden.
    Hjalgrim, Henrik
    Rigshosp, Dept Hematol, Copenhagen, Denmark;Statens Serum Inst, Div Hlth Surveillance & Res, Dept Epidemiol Res, Copenhagen, Denmark.
    Vijai, Joseph
    Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA.
    Morton, Lindsay M.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Vermeulen, Roel
    Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands;Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands.
    Paltiel, Ora
    Hadassah Hebrew Univ Med Ctr, Braun Sch Publ Hlth & Community Med, Jerusalem, Israel.
    Vajdic, Claire M.
    Univ New South Wales, Ctr Big Data Res Hlth, Sydney, NSW, Australia.
    Linet, Martha S.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Nieters, Alexandra
    Univ Med Ctr Freiburg, Ctr Chron Immunodeficiency, Freiburg, Baden Wurttembe, Germany.
    de Sanjose, Silvia
    CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain;IDIBELL, Inst Catala Oncol, Canc Epidemiol Res Programme, Unit Infect & Canc, Barcelona 08908, Spain.
    Cozen, Wendy
    Univ Southern Calif, Dept Pathol, Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA USA;Univ Southern Calif, Dept Prevent Med, Keck Sch Med, Norris Comprehens Canc Ctr, Los Angeles, CA USA.
    Brown, Elizabeth E.
    Univ Alabama Birmingham, Sch Med, Dept Pathol, Birmingham, AL USA;Univ Alabama Birmingham, UAB Comprehens Canc Ctr, Birmingham, AL USA.
    Turner, Jennifer
    Douglass Hanly Moir Pathol, Dept Histopathol, Sydney, NSW, Australia;Macquarie Univ, Fac Med & Hlth Sci, Sydney, NSW, Australia.
    Spinelli, John J.
    Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC, Canada;British Columbia Canc Agcy, Canc Control Res, Vancouver, BC, Canada.
    Zheng, Tongzhang
    Brown Univ, Sch Publ Hlth, Dept Epidemiol, Providence, RI 02912 USA.
    Birmann, Brenda M.
    Harvard Med Sch, Boston, MA USA;Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA.
    Flowers, Christopher R.
    Emory Univ, Sch Med, Dept Hematol & Med Oncol, Atlanta, GA USA.
    Becker, Nikolaus
    German Canc Res Ctr, Div Clin Epidemiol, Heidelberg, Baden Wurttembe, Germany.
    Holly, Elizabeth A.
    Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA.
    Kane, Eleanor
    Univ York, Dept Hlth Sci, York, N Yorkshire, England.
    Weisenburger, Dennis
    City Hope Natl Med Ctr, Dept Pathol, Duarte, CA USA.
    Maynadie, Marc
    Univ Burgundy, INSERM, UMR1231, Registry Hematol Malignancies Cote Or, Dijon, France;Dijon Univ Hosp, Dijon, France.
    Cocco, Pierluigi
    Univ Cagliari, Dept Publ Hlth Clin & Mol Med, Cagliari, Italy.
    Albanes, Demetrius
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Weinstein, Stephanie J.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Teras, Lauren R.
    Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA.
    Diver, W. Ryan
    Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA.
    Lax, Stephanie J.
    Univ York, Dept Hlth Sci, York, N Yorkshire, England.
    Travis, Ruth C.
    Univ Oxford, Canc Epidemiol Unit, Oxford, England.
    Kaaks, Rudolph
    German Canc Res Ctr, Div Clin Epidemiol, Heidelberg, Baden Wurttembe, Germany.
    Riboli, Elio
    Imperial Coll London, Sch Publ Hlth, London, England.
    Benavente, Yolanda
    CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain;IDIBELL, Inst Catala Oncol, Canc Epidemiol Res Programme, Unit Infect & Canc, Barcelona 08908, Spain.
    Brennan, Paul
    Int Agcy Res Canc, Lyon, France.
    McKay, James
    CHU Henri Mondor, Dept Immunol, Creteil, France.
    Delfau-Larue, Marie-Helene
    CHU Henri Mondor, INSERM, U955, Creteil, France;CHU Henri Mondor, Dept Immunol, Creteil, France.
    Link, Brian K.
    Univ Iowa, Dept Internal Med, Carver Coll Med, Iowa City, IA 52242 USA.
    Magnani, Corrado
    Univ Piemonte Orientale, Unit Med Stat & Epidemiol, Dept Translat Med, Novara, Italy;Univ Piemonte Orientale, Ctr Oncol Prevent CPO Piemonte, Novara, Italy.
    Ennas, Maria Grazia
    Univ Cagliari, Dept Biomed Sci, Cagliari, Italy.
    Latte, Giancarlo
    S Francesco Hosp, Div Hematol, Nuoro, Italy.
    Feldman, Andrew L.
    Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA.
    Doo, Nicole Wong
    Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia.
    Giles, Graham G.
    Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia;Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia.
    Southey, Melissa C.
    Univ Melbourne, Dept Pathol, Genet Epidemiol Lab, Melbourne, Vic, Australia.
    Milne, Roger L.
    Univ Melbourne, Melbourne Sch Populat & Global Hlth, Ctr Epidemiol & Biostat, Melbourne, Vic, Australia;Canc Council Victoria, Canc Epidemiol & Intelligence Div, Melbourne, Vic, Australia.
    Offit, Kenneth
    Rigshosp, Dept Hematol, Copenhagen, Denmark.
    Musinsky, Jacob
    Rigshosp, Dept Hematol, Copenhagen, Denmark.
    Arslan, Alan A.
    NYU, Sch Med, Dept Obstet & Gynecol, New York, NY USA;NYU, Dept Environm Med, Sch Med, 550 1St Ave, New York, NY 10016 USA;NYU, Langone Med Ctr, Perlmutter Canc Ctr, New York, NY USA.
    Purdue, Mark P.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Adami, Hans-Olov
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden.
    Melbye, Mads
    Stanford Univ, Dept Med, Sch Med, Stanford, CA 94305 USA;Statens Serum Inst, Div Hlth Surveillance & Res, Dept Epidemiol Res, Copenhagen, Denmark.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Conde, Lucia
    UCL, UCL Canc Inst, Bill Lyons Informat Ctr, London, England.
    Camp, Nicola J.
    Univ Utah, Sch Med, Dept Internal Med, Huntsman Canc Inst, Salt Lake City, UT USA.
    Glenn, Martha
    Univ Utah, Sch Med, Dept Internal Med, Huntsman Canc Inst, Salt Lake City, UT USA.
    Curtin, Karen
    Univ Utah, Sch Med, Dept Internal Med, Huntsman Canc Inst, Salt Lake City, UT USA.
    Clavel, Jacqueline
    Univ Paris 05, Paris, France;Ctr Res Epidemiol & Stat Sorbonne Paris Cite CRES, Epidemiol Childhood & Adolescent Canc Grp, INSERM, Paris, France.
    Monnereau, Alain
    Univ Paris 05, Paris, France;Univ Bordeaux, Inst Bergonie, Registre Hemopathies Malignes Gironde, Inserm,Team EPICENE,UMR 1219, Bordeaux, France.
    Cox, David G.
    Ctr Leon Berard, INSERM, UMR1052, Canc Res Ctr Lyon, Lyon, France. Ctr Leon Berard, Dept Hematol, Lyon, France;Imperial Coll London, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England.
    Ghesquieres, Herve
    CNRS, UMR 5239, Lab Biol Mol Cellule, Pierre Benite, France;Univ Paris 05, Paris, France.
    Salles, Gilles
    CNRS, UMR 5239, Lab Biol Mol Cellule, Pierre Benite, France;Univ Claude Bernard Lyon, Lyon, France;Ctr Hosp Lyon Sud, Hosp Civils Lyon, Dept Hematol, Lyon, France.
    Bofetta, Paulo
    Icahn Sch Med Mt Sinai, Tisch Canc Inst, New York, NY 10029 USA.
    Foretova, Lenka
    MF MU, Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic.
    Staines, Anthony
    Dublin City Univ, Sch Nursing & Human Sci, Dublin, Ireland.
    Davis, Scott
    Univ Washington, Sch Publ Hlth & Community Med, Seattle, WA 98195 USA;Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA.
    Severson, Richard K.
    Wayne State Univ, Dept Family Med & Publ Hlth Sci, Detroit, MI USA.
    Lan, Qing
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Brooks-Wilson, Angela
    BC Canc Agcy, Genome Sci Ctr, Vancouver, BC, Canada;Simon Fraser Univ, Dept Biomed Physiol & Kinesiol, Burnaby, BC, Canada.
    Smith, Martyn T.
    Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA.
    Roman, Eve
    Univ York, Dept Hlth Sci, York, N Yorkshire, England.
    Kricker, Anne
    Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW, Australia.
    Zhang, Yawei
    Yale Sch Publ Hlth, Dept Environm Hlth Sci, New Haven, CT USA;Yale Sch Med, Dept Surg, New Haven, CT USA.
    Kraft, Peter
    Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA;Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA.
    Chanock, Stephen J.
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Rothman, Nathaniel
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Hartge, Patricia
    NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA.
    Skibola, Christine F.
    Emory Univ, Sch Med, Dept Hematol & Med Oncol, Atlanta, GA USA.
    HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes2018Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 78, nr 14, s. 4086-4096Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06-1.60; OR MZL = 1.45, 95% CI = 1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24-3.55; OR MZL = 2.10, 95% CI = 0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma.

  • 612.
    Wang, Xin
    et al.
    Linkoping Univ, Dept Med & Hlth Sci, S-58183 Linkoping, Sweden..
    D'Arcy, Padraig
    Linkoping Univ, Dept Med & Hlth Sci, S-58183 Linkoping, Sweden..
    Caulfield, Thomas R.
    Mayo Clin, Dept Mol Neurosci, Jacksonville, FL 32224 USA..
    Paulus, Aneel
    Mayo Clin, Dept Canc Biol, Jacksonville, FL 32224 USA..
    Chitta, Kasyapa
    Mayo Clin, Dept Canc Biol, Jacksonville, FL 32224 USA..
    Mohanty, Chitralekha
    Karolinska Inst, Dept Pathol & Oncol, Canc Ctr Karolinska, S-17176 Stockholm, Sweden..
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Chanan-Khan, Asher
    Mayo Clin, Dept Canc Biol, Jacksonville, FL 32224 USA..
    Linder, Stig
    Linkoping Univ, Dept Med & Hlth Sci, S-58183 Linkoping, Sweden.;Karolinska Inst, Dept Pathol & Oncol, Canc Ctr Karolinska, S-17176 Stockholm, Sweden..
    Synthesis and Evaluation of Derivatives of the Proteasome Deubiquitinase Inhibitor b-AP152015Inngår i: Chemical Biology and Drug Design, ISSN 1747-0277, E-ISSN 1747-0285, Vol. 86, nr 5, s. 1036-1048Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The ubiquitin-proteasome system (UPS) is increasingly recognized as a therapeutic target for the development of anticancer therapies. The success of the 20S proteasome core particle (20S CP) inhibitor bortezomib in the clinical management of multiple myeloma has raised the possibility of identifying other UPS components for therapeutic intervention. We previously identified the small molecule b-AP15 as an inhibitor of 19S proteasome deubiquitinase (DUB) activity. Building upon our previous data, we performed a structure-activity relationship (SAR) study on b-AP15 and identified VLX1570 as an analog with promising properties, including enhanced potency and improved solubility in aqueous solution. In silico modeling was consistent with interaction of VLX1570 with key cysteine residues located at the active sites of the proteasome DUBs USP14 and UCHL5. VLX1570 was found to inhibit proteasome deubiquitinase activity in vitro in a manner consistent with competitive inhibition. Furthermore, using active-site-directed probes, VLX1570 also inhibited proteasome DUB activity in exposed cells. Importantly, VLX1570 did not show inhibitory activity on a panel of recombinant non-proteasome DUBs, on recombinant kinases, or on caspase-3 activity, suggesting that VLX1570 is not an overtly reactive general enzyme inhibitor. Taken together, our data shows the chemical and biological properties of VLX1570 as an optimized proteasome DUB inhibitor.

  • 613.
    Wang, Xin
    et al.
    Linkoping Univ, Dept Med Hlth Sci IMH, S-75185 Linkoping, Sweden..
    Mazurkiewicz, Magdalena
    Karolinska Inst, Dept Pathol & Oncol, Canc Ctr Karolinska, S-17176 Stockholm, Sweden..
    Hillert, Ellin-Kristina
    Karolinska Inst, Dept Pathol & Oncol, Canc Ctr Karolinska, S-17176 Stockholm, Sweden..
    Olofsson, Maria Hagg
    Karolinska Inst, Dept Pathol & Oncol, Canc Ctr Karolinska, S-17176 Stockholm, Sweden..
    Pierrou, Stefan
    ESP Life Sci Consulting AB, Box 119, S-43122 Molndal, Sweden..
    Hillertz, Per
    Biosynchro West AB, Karl Johansgatan 142, S-41451 Gothenburg, Sweden..
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Selvaraju, Karthik
    Linkoping Univ, Dept Med Hlth Sci IMH, S-75185 Linkoping, Sweden..
    Paulus, Aneel
    Mayo Clin, Dept Hematol & Oncol, Jacksonville, FL 32224 USA..
    Akhtar, Sharoon
    Mayo Clin, Dept Canc Biol, Jacksonville, FL 32224 USA..
    Bossler, Felicitas
    DKFZ, German Canc Res Ctr, Heidelberg, Germany..
    Khan, Asher Chanan
    Mayo Clin, Dept Hematol & Oncol, Jacksonville, FL 32224 USA.;Mayo Clin, Dept Canc Biol, Jacksonville, FL 32224 USA..
    Linder, Stig
    Linkoping Univ, Dept Med Hlth Sci IMH, S-75185 Linkoping, Sweden.;Karolinska Inst, Dept Pathol & Oncol, Canc Ctr Karolinska, S-17176 Stockholm, Sweden..
    D'Arcy, Padraig
    Linkoping Univ, Dept Med Hlth Sci IMH, S-75185 Linkoping, Sweden..
    The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells2016Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikkel-id 26979Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Inhibition of deubiquitinase (DUB) activity is a promising strategy for cancer therapy. VLX1570 is an inhibitor of proteasome DUB activity currently in clinical trials for relapsed multiple myeloma. Here we show that VLX1570 binds to and inhibits the activity of ubiquitin-specific protease-14 (USP14) in vitro, with comparatively weaker inhibitory activity towards UCHL5 (ubiquitin-C-terminal hydrolase-5). Exposure of multiple myeloma cells to VLX1570 resulted in thermostabilization of USP14 at therapeutically relevant concentrations. Transient knockdown of USP14 or UCHL5 expression by electroporation of siRNA reduced the viability of multiple myeloma cells. Treatment of multiple myeloma cells with VLX1570 induced the accumulation of proteasome-bound high molecular weight polyubiquitin conjugates and an apoptotic response. Sensitivity to VLX1570 was moderately affected by altered drug uptake, but was unaffected by overexpression of BCL2-family proteins or inhibitors of caspase activity. Finally, treatment with VLX1570 was found to lead to extended survival in xenograft models of multiple myeloma. Our findings demonstrate promising antiproliferative activity of VLX1570 in multiple myeloma, primarily associated with inhibition of USP14 activity.

  • 614.
    Wasik, Agata M.
    et al.
    Karolinska Inst, Dept Lab Med, Div Pathol, F46,Flemingsberg Campus, SE-14186 Stockholm, Sweden.
    Wu, Chenglin
    Karolinska Inst, Dept Lab Med, Div Clin Immunol & Transfus Med, Stockholm, Sweden.
    Mansouri, Larry
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Rosenquist, Richard
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Pan-Hammarstrom, Qiang
    Karolinska Inst, Dept Lab Med, Div Clin Immunol & Transfus Med, Stockholm, Sweden.
    Sander, Birgitta
    Karolinska Inst, Dept Lab Med, Div Pathol, F46,Flemingsberg Campus, SE-14186 Stockholm, Sweden.
    Clinical and functional impact of recurrent S1PR1 mutations in mantle cell lymphoma2018Inngår i: BLOOD ADVANCES, ISSN 2473-9529, Vol. 2, nr 6, s. 621-625Artikkel i tidsskrift (Fagfellevurdert)
  • 615.
    Wassberg, Cecilia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Sörensen, Jens
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Johansson, Silvia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Repeatability of quantitative parameters of 18F-fluoride PET/CT and biochemical tumour and specific bone remodelling markers in prostate cancer bone metastases2017Inngår i: EJNMMI research, Vol. 7, nr 1, artikkel-id 42Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: 18F-fluoride PET/CT exhibits high sensitivity to delineate and measure the extent of bone metastatic disease in patients with prostate cancer. 18F-fluoride PET/CT could potentially replace traditional bone scintigraphy in clinical routine and trials. However, more studies are needed to assess repeatability and biological uptake variation. The aim of this study was to perform test-retest analysis of quantitative PET-derived parameters and blood/serum bone turnover markers at the same time point. Ten patients with prostate cancer and verified bone metastases were prospectively included. All underwent two serial 18F-fluoride PET/CT at 1 h post-injection. Up to five dominant index lesions and whole-body 18F-fluoride skeletal tumour burden were recorded per patient. Lesion-based PET parameters were SUVmax, SUVmean and functional tumour volume applying a VOI with 50% threshold (FTV50%). The total skeletal tumour burden, total lesion 18F-fluoride (TLF), was calculated using a threshold of SUV of ≥15. Blood/serum biochemical bone turnover markers obtained at the time of each PET were PSA, ALP, S-osteocalcin, S-beta-CTx, 1CTP and BAP.

    RESULTS: A total of 47 index lesions and a range of 2-122 bone metastases per patient were evaluated. Median time between 18F-fluoride PET/CT was 7 days (range 6-8 days). Repeatability coefficients were for SUVmax 26%, SUVmean 24%, FTV50% for index lesions 23% and total skeletal tumour burden (TLF) 35%. Biochemical bone marker repeatability coefficients were for PSA 19%, ALP 23%, S-osteocalcin 18%, S-beta-CTx 22%, 1CTP 18% and BAP 23%.

    CONCLUSIONS: Quantitative 18F-fluoride uptake and simultaneous biochemical bone markers measurements are reproducible for prostate cancer metastases and show similar magnitude in test-retest variation.

  • 616.
    Wasterlid, T.
    et al.
    Karolinska Inst, Div Clin Epidemiol, Dept Med Solna, Stockholm, Sweden;Lund Univ, Skane Univ Hosp, Dept Oncol, Lund, Sweden.
    Biccler, J. L.
    Aalborg Univ Hosp, Dept Hematol, Clin Canc Res Ctr, Aalborg, Denmark;Aalborg Univ, Dept Clin Med, Aalborg, Denmark.
    Brown, P. N.
    Rigshosp, Copenhagen Univ Hosp, Dept Hematol, Copenhagen, Denmark.
    Bogsted, M.
    Aalborg Univ, Dept Clin Med, Aalborg, Denmark.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jorgensen, J. Meszaros
    Aarhus Univ Hosp, Dept Hematol, Aarhus, Denmark.
    Christensen, J. H.
    Odense Univ Hosp, Dept Hematol, Odense, Denmark.
    Wahlin, B. E.
    Karolinska Inst, Div Hematol, Dept Med Huddinge, Stockholm, Sweden.
    Smedby, K. E.
    Karolinska Inst, Div Clin Epidemiol, Dept Med Solna, Stockholm, Sweden.
    El-Galaly, T. C.
    Aalborg Univ Hosp, Dept Hematol, Clin Canc Res Ctr, Aalborg, Denmark;Aalborg Univ, Dept Clin Med, Aalborg, Denmark.
    Jerkeman, M.
    Lund Univ, Skane Univ Hosp, Dept Oncol, Lund, Sweden.
    Six cycles of R-CHOP-21 are not inferior to eight cycles for treatment of diffuse large B-cell lymphoma: a Nordic Lymphoma Group Population-based Study2018Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 29, nr 8, s. 1882-1883Artikkel i tidsskrift (Annet vitenskapelig)
  • 617.
    Wasterlid, T.
    et al.
    Karolinska Inst, Div Clin Epidemiol, Dept Med Solna, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden;Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.
    Mohammadi, M.
    Karolinska Inst, Div Epidemiol, Inst Environm Med, Stockholm, Sweden.
    Smedby, K. E.
    Karolinska Inst, Div Clin Epidemiol, Dept Med Solna, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden;Karolinska Univ Hosp, Dept Hematol, Stockholm, Sweden.
    Glimelius, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Karolinska Inst, Div Clin Epidemiol, Dept Med Solna, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Jerkeman, M.
    Lund Univ Hosp, Dept Oncol, Lund, Sweden.
    Bottai, M.
    Karolinska Inst, Div Epidemiol, Inst Environm Med, Stockholm, Sweden.
    Eloranta, S.
    Karolinska Inst, Div Clin Epidemiol, Dept Med Solna, Stockholm, Sweden;Karolinska Univ Hosp, Stockholm, Sweden.
    Impact of comorbidity on disease characteristics, treatment intent and outcome in diffuse large B-cell lymphoma: a Swedish lymphoma register study2019Inngår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 285, nr 4, s. 455-468Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background

    Comorbidity impacts overall survival amongst patients with diffuse large B-cell lymphoma (DLBCL). However, associations of comorbidity with lymphoma characteristics, treatment selection and lymphoma-specific mortality are less well known.

    Objective

    To examine the impact of comorbidity on DLBCL characteristics, treatment intent and cause of death.

    Methods

    We identified 3905 adult patients diagnosed with DLBCL 2007-2013 through the Swedish Lymphoma Register. We assessed comorbid disease history according to the Charlson comorbidity index (CCI). Comorbidity data and causes of death were collected through register linkage. Associations were estimated using multinomial regression and flexible parametric survival models.

    Results

    Overall, 45% of the patients (n = 1737) had a history of at least one comorbidity at DLBCL diagnosis (cardiovascular disease, diabetes and solid cancer were most frequent), and 997 (26%) had a CCI score of 2. The relative probability of presenting with poor performance status (PS > 2) was higher amongst comorbid patients [Relative Risk Ratio (RRR)(PS>2): 2.02, 95% CI: 1.63-2.51]. Comorbid patients had a substantially lower relative probability of receiving curative treatment (RRR: 0.48, 95% CI: 0.38-0.61). Amongst all patients, CCI 1 was associated with a significantly increased risk of all-cause and lymphoma-specific death after adjustments. Amongst patients selected for curative treatment, comorbidity was associated with an increased risk of all-cause death (HRCCI>1: 1.54, 95% CI: 1.32-1.80), but not with lymphoma-specific death (HRCCI>1: 1.05, 95% CI: 0.86-1.28).

    Conclusion

    Comorbidity is associated with inferior DLBCL outcome, mainly due to a lower likelihood of receiving treatment with curative intent. Possibly, more comorbid DLBCL patients could be treated with curative intent if comorbid conditions were optimized in parallel.

  • 618.
    Weibull, Caroline E.
    et al.
    Karolinska Inst, Dept Med Epidemiol & Biostat, POB 281, SE-17177 Stockholm, Sweden.
    Björkholm, Magnus
    Karolinska Univ Hosp, Dept Med Solna, Div Haematol, Stockholm, Sweden.
    Glimelius, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Karolinska Inst, Dept Med Solna, Div Clin Epidemiol, Stockholm, Sweden.
    Lambert, Paul C.
    Karolinska Inst, Dept Med Epidemiol & Biostat, POB 281, SE-17177 Stockholm, Sweden;Univ Leicester, Dept Hlth Sci, Biostat Res Grp, Leicester, Leics, England.
    Andersson, Therese M. L.
    Karolinska Inst, Dept Med Epidemiol & Biostat, POB 281, SE-17177 Stockholm, Sweden.
    Smedby, Karin E.
    Karolinska Inst, Dept Med Solna, Div Clin Epidemiol, Stockholm, Sweden.
    Dickman, Paul W.
    Karolinska Inst, Dept Med Epidemiol & Biostat, POB 281, SE-17177 Stockholm, Sweden.
    Eloranta, Sandra
    Karolinska Inst, Dept Med Solna, Div Clin Epidemiol, Stockholm, Sweden.
    Temporal trends in treatment-related incidence of diseases of the circulatory system among Hodgkin lymphoma patients2019Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, nr 5, s. 1200-1208Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    While Hodgkin lymphoma (HL) survival has improved, treatment-related complications remain a concern. As a measure of treatment-related diseases of the circulatory system (DCS) we report excess incidence of DCS and absolute risks among HL patients diagnosed in the modern treatment era. From the Swedish Cancer Register, we identified all HL patients diagnosed 1985 through 2013, at ages 18-80 years. Excess incidence rate ratios (EIRRs) with 95% confidence intervals (CIs) comparing excess DCS incidence between calendar periods were estimated overall, and at 5 and 10 years after diagnosis using flexible parametric models. Model-based predictions were used to obtain probabilities of being diagnosed with DCS, in the presence of competing risks. During follow-up, 726 (16%) of the 4,479 HL patients experienced DCS. Overall, the excess DCS incidence was lower during all calendar periods compared to the first (2009-2013 vs. 1985-1988: EIRR = 0.63, 95% CI: 0.42-0.95). The 5- and 10-year excess incidence of DCS decreased between 1985 and 1994 for 25-year-olds (5-year-EIRR1994 = 0.32, 95% CI: 0.12-0.92) and 60-year-olds (5-year-EIRR1994 = 0.45, 95% CI: 0.24-0.88), but remained stable thereafter. No improvements were observed among 75-year-olds. The probability of excess DCS remained the same throughout the study period. In 2009, the percentage of patients aged 25, 60 and 75 experiencing excess DCS within 5 years was 3.4, 15.0 and 17.0% (males) and 2.3, 10.8 and 12.6% (females). Treatment-related incidence of DCS has declined since the mid-1980s, but more recent improvements are absent and an excess risk remains. Continued efforts towards less toxic treatments are warranted, alongside primary prevention strategies.

  • 619. Weibull, Caroline E
    et al.
    Eloranta, Sandra
    Smedby, Karin E
    Björkholm, Magnus
    Kristinsson, Sigurdur Y
    Johansson, Anna L V
    Dickman, Paul W
    Glimelius, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Pregnancy and the Risk of Relapse in Patients Diagnosed With Hodgkin Lymphoma2016Inngår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 34, nr 4, s. 337-+Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: Many patients and clinicians are worried that pregnancy after the diagnosis of Hodgkin lymphoma (HL) may increase the risk of relapse despite a lack of empirical evidence to support such concerns. We investigated if an association exists between pregnancy and relapse in women with a diagnosis of HL.

    MATERIALS AND METHODS: Using Swedish healthcare registers combined with medical records, we included 449 women who received a diagnosis of HL between 1992 and 2009 and who were age 18 to 40 years at diagnosis. Follow-up started 6 months after diagnosis, when the patients' condition was assumed to be in remission. Pregnancy-associated relapse was defined as a relapse during pregnancy or within 5 years after delivery. Hazard ratios (HRs) with 95% CIs were estimated by using the Cox proportional hazards model.

    RESULTS: Among the 449 women, 144 (32%) became pregnant during follow-up. Overall, 47 relapses were recorded, of which one was a pregnancy-associated relapse. The adjusted HR for the comparison of the pregnancy-associated relapse rate to the non-pregnancy-associated relapse rate was 0.29 (95% CI, 0.04 to 2.18). The expected number of relapses in women with a recent pregnancy, given that they would experience the same relapse rate as that of women without a recent pregnancy, was 3.76; the observed-to-expected ratio was 0.27 (95% exact CI, 0.01 to 1.51).

    CONCLUSION: We found no evidence that a pregnancy after diagnosis increases the relapse rate among women whose HL is in remission. Survivors of HL need to consider a range of factors when deciding about future reproduction. However, given the results of this study, the risk of pregnancy-associated relapse does not need to be considered.

  • 620. Weibull, Caroline E
    et al.
    Johansson, Anna L V
    Eloranta, Sandra
    Smedby, Karin E
    Björkholm, Magnus
    Lambert, Paul C
    Dickman, Paul W
    Glimelius, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala Akademiska Hospital.
    Contemporarily Treated Patients With Hodgkin Lymphoma Have Childbearing Potential in Line With Matched Comparators2018Inngår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 36, nr 26, s. 2718-2725Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose With excellent cure rates for young patients with Hodgkin lymphoma (HL), there is an increasing number of female survivors of HL interested in becoming pregnant. Here, we report childbearing among contemporarily treated HL survivors in comparison with the general population. Material and Methods Using Swedish registers, 449 women (ages 18 to 40 years) diagnosed with HL between 1992 and 2009 and in remission 9 months after diagnosis were identified. Patients were age- and calendar-year-matched to 2,210 population comparators. Rates of first postdiagnosis childbirth were calculated. Hazard ratios (HRs) with 95% CIs were estimated for different follow-up periods using Cox regression. Cumulative probabilities of first childbirth were calculated in the presence of the competing risk of death or relapse. Results Twenty-two percent of relapse-free patients with HL had a child during follow-up, and first childbirth rates increased over time, from 40.2 per 1,000 person-years (1992 to 1997) to 69.7 per 1,000 person-years (2004 to 2009). For comparators, childbirth rates remained stable (70.1 per 1,000 person-years). Patients diagnosed between 2004 and 2009 had a cumulative probability of childbirth similar to comparators. Three years or more after diagnosis, no differences in childbirth rates were observed between patients and comparators, regardless of stage or treatment. Patients who received six to eight courses of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone had a lower childbirth rate than comparators during the first 3 years (HR, 0.23; 95% CI, 0.06 to 0.94), as did patients who received six to eight courses of chemotherapy and radiotherapy (HR, 0.21; 95% CI, 0.07 to 0.65). Conclusion Childbearing potential among female survivors of HL has improved over time, and childbirth rates 3 years after diagnosis in contemporarily treated patients are, in the absence of relapse, similar to those in the general population, regardless of stage and treatment.

  • 621.
    Weishaupt, Holger
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Mainwaring, Oliver
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hutter, Sonja
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Kalushkova, Antonia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jernberg Wiklund, Helena
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Rosén, Gabriela
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Johansson, Fredrik K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    GMYC: A Novel Inducible Transgenic Model of Group 3 Medulloblastoma2018Inngår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, s. 137-137Artikkel i tidsskrift (Annet vitenskapelig)
  • 622.
    Wennerås, Christine
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis & Hematol, Gothenburg, Sweden..
    Goldblatt, David
    UCL, Great Ormond St Inst Child Hlth, Immunobiol Sect, London, England..
    Zancolli, Marta
    UCL, Great Ormond St Inst Child Hlth, Immunobiol Sect, London, England..
    Mattsson, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Wass, Linda
    Univ Gothenburg, Sahlgrenska Acad, Dept Infect Dis & Hematol, Gothenburg, Sweden..
    Horkko, Sohvi
    Univ Oulu, Med Res Ctr, Dept Med Microbiol & Immunol, Oulu, Finland.;Oulu Univ Hosp, Nordlab Oulu, Oulu, Finland..
    Rosen, Anders
    Linkoping Univ, Dept Clin & Expt Med, Linkoping, Sweden..
    Natural IgM antibodies in the immune defence against neoehrlichiosis2017Inngår i: Infectious Diseases, ISSN 2374-4235, E-ISSN 2374-4243, Vol. 49, nr 11-12, s. 809-816Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

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

  • 623.
    Wennstig, A. K.
    et al.
    Umea Univ, Sundsvall Hosp, Dept Oncol, Dept Surg & Perioperat Sci Surg, Sundsvall, Sweden..
    Garmo, H.
    Kings Coll London, Sch Canc & Pharmaceut Sci, TOUR, London, England.;Reg Canc Ctr, SE-75185 Uppsala, Sweden..
    Isacsson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Gagliardi, G.
    Karolinska Univ Hosp, Dept Med Radiat Phys & Nucl Med, SE-17176 Stockholm, Sweden..
    Rintela, N.
    Karolinska Univ Hosp, Dept Med Radiat Phys & Nucl Med, SE-17176 Stockholm, Sweden..
    Lagerqvist, B.
    Uppsala Univ, Dept Med Sci, SE-75185 Uppsala, Sweden..
    Holmberg, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi. Kings Coll London, Sch Canc & Pharmaceut Sci, TOUR, London, England..
    Blomqvist, C.
    Orebro Univ, Univ Hosp, Dept Oncol, SE-70182 Orebro, Sweden..
    Sund, M.
    Umea Univ, Dept Surg & Perioperat Sci Surg, SE-90185 Umea, Sweden..
    Nilsson, G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    The relationship between radiation doses to coronary arteries and later intervention requiring coronary stenosis in breast cancer2018Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 92, s. S61-S62Artikkel i tidsskrift (Annet vitenskapelig)
  • 624.
    Wennstig, Anna-Karin
    et al.
    Umea Univ, Dept Surg & Perioperat Sci, Surg, S-90187 Umea, Sweden.;Sundsvall Hosp, Dept Oncol, SE-85186 Sundsvall, Sweden..
    Garmo, Hans
    Kings Coll London, Fac Life Sci & Med, London WC2R 2LS, England.;Reg Canc Ctr, Uppsala, Sweden..
    Hållström, Per
    Gavle Cent Hosp, Dept Oncol, Gavle, Sweden..
    Nyström, Petra Witt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Edlund, Per
    Gavle Cent Hosp, Dept Oncol, Gavle, Sweden..
    Blomqvist, Carl
    Univ Orebro, Dept Oncol, Orebro, Sweden..
    Sund, Malin
    Umea Univ, Dept Surg & Perioperat Sci, Surg, S-90187 Umea, Sweden..
    Nilsson, Greger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Gavle Cent Hosp, Dept Oncol, Gavle, Sweden.;Visby Hosp, Dept Oncol, Visby, Sweden..
    Inter-observer variation in delineating the coronary arteries as organs at risk2017Inngår i: Radiotherapy and Oncology, ISSN 0167-8140, E-ISSN 1879-0887, Vol. 122, nr 1, s. 72-78Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: To determine the inter-observer variation in delineating the coronary arteries as organs at risk (OAR) in breast cancer (BC) radiotherapy (RT) and how this variation affects the estimated coronary artery radiation dose.

    Method: Delineation of the left main and the left anterior descending coronary artery (LMCA and LAD), and the right coronary artery (RCA), by using the heart atlas by Feng et al., was performed by three radiation oncologists in 32 women who had received adjuvant RT for BC. Centres of the arteries were calculated and distances between artery centres were measured and the artery radiation doses were estimated. The intraclass correlation coefficient (ICC) was used to quantify the variability in doses.

    Results: Along the extent of RCA, the median distance between centres of arteries varied from 2 to 9 mm with similar patterns over pairs of oncologists. For the LMCA-LAD the median distance varied from 1 to 4 mm. The estimated maximum radiation doses showed an ICC variation from 0.82 to 0.97.

    Conclusion: The coronary arteries can be reliably identified and delineated as OARs in BC RT. The spatial variance is limited and the total variation in radiation dose is almost completely determined by the between patient variation.

  • 625.
    Wennstig, Anna-Karin
    et al.
    Umea Univ, Dept Surg & Perioperat Sci, Surg, SE-90185 Umea, Sweden;Sundsvall Hosp, Dept Oncol, SE-85186 Sundsvall, Sweden.
    Garmo, Hans
    Kings Coll London, Sch Canc & Pharmaceut Sci, TOUR, London, England;Reg Canc Ctr, SE-75185 Uppsala, Sweden.
    Isacsson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Gagliardi, Giovanna
    Karolinska Univ Hosp, Dept Med Radiat Phys & Nucl Med, SE-17176 Stockholm, Sweden.
    Rintelä, Niina
    Karolinska Univ Hosp, Dept Med Radiat Phys & Nucl Med, SE-17176 Stockholm, Sweden.
    Lagerqvist, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Kardiologi.
    Holmberg, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi. Kings Coll London, Sch Canc & Pharmaceut Sci, TOUR, London, England.
    Blomqvist, Carl
    Orebro Univ, Univ Hosp, Dept Oncol, SE-70182 Orebro, Sweden.
    Sund, Malin
    Umea Univ, Dept Surg & Perioperat Sci, Surg, SE-90185 Umea, Sweden.
    Nilsson, Greger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Gavle Cent Hosp, Dept Oncol, SE-80107 Gavle, Sweden;Visby Hosp, Dept Oncol, SE-62184 Visby, Sweden.
    The relationship between radiation doses to coronary arteries and location of coronary stenosis requiring intervention in breast cancer survivors2019Inngår i: Radiation Oncology, ISSN 1748-717X, E-ISSN 1748-717X, Vol. 14, artikkel-id 40Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: To assess the relationship between radiation doses to the coronary arteries (CAs) and location of a coronary stenosis that required intervention after three-dimensional conformal radiotherapy (3DCRT) for breast cancer (BC).

    Methods: The study population consisted of 182 women treated for BC in Sweden between 1992 and 2012. All women received 3DCRT and subsequently underwent coronary angiography due to a suspected coronary event. CA segments were delineated in the patient's original planning-CT and radiation doses were recalculated based on the dose distribution of the original radiotherapy (RT) plan. The location of the CA stenosis that required intervention was identified from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). Logistic regression analysis was used to assess the relationship between CA radiation doses and risk of a later coronary intervention at this specific location.

    Results: The odds ratio (OR) varied by radiation dose to the mid left anterior descending artery (LAD) (p=0.005). Women receiving mean doses of 1-5 Gray (Gy) to the mid LAD had an adjusted OR of 0.90 (95% CI 0.47-1.74) for a later coronary intervention compared to women receiving mean doses of 0-1Gy to the mid LAD. In women receiving mean doses of 5-20Gy to the mid LAD, an adjusted OR of 1.24 (95% CI 0.52-2.95) was observed, which increased to an OR of 5.23 (95% CI 2.01-13.6) for mean doses over 20Gy, when compared to women receiving mean doses of 0-1Gy to the mid LAD.

    Conclusions: In women receiving conventional 3DCRT for BC between 1992 and 2012, radiation doses to the LAD remained high and were associated with an increased requirement of coronary intervention in mid LAD. The results support that the LAD radiation dose should be considered in RT treatment planning and that the dose should be kept as low as possible. Minimising the dose to LAD is expected to diminish the risk of later radiation-induced stenosis.

  • 626.
    Went, Molly
    et al.
    Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England.
    Sud, Amit
    Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England.
    Speedy, Helen
    Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England.
    Sunter, Nicola J.
    Newcastle Univ, Northern Inst Canc Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.
    Foersti, Asta
    German Canc Res Ctr, D-69120 Heidelberg, Germany;Lund Univ, Ctr Primary Hlth Care Res, SE-20502 Malmo, Sweden.
    Law, Philip J.
    Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England.
    Johnson, David C.
    Inst Canc Res, Div Mol Pathol, London SW7 3RP, England.
    Mirabella, Fabio
    Inst Canc Res, Div Mol Pathol, London SW7 3RP, England.
    Holroyd, Amy
    Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England.
    Li, Ni
    Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England.
    Orlando, Giulia
    Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England.
    Weinhold, Niels
    Univ Arkansas Med Sci, Myeloma Inst Res & Therapy, Little Rock, AR 72205 USA.
    van Duin, Mark
    Erasmus MC Canc Inst, Dept Hematol, NL-3075 EA Rotterdam, Netherlands.
    Chen, Bowang
    German Canc Res Ctr, D-69120 Heidelberg, Germany.
    Mitchell, Jonathan S.
    Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England.
    Mansouri, Larry
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Juliusson, Gunnar
    Lund Univ, Lund Strateg Res Ctr Stem Cell Biol & Cell Therap, Hematol & Transplantat, Lund, Sweden.
    Smedby, Karin E.
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden.
    Jayne, Sandrine
    Univ Leicester, Ernest & Helen Scott Haematol Res Inst, Leicester, Leics, England.
    Majid, Aneela
    Univ Leicester, Ernest & Helen Scott Haematol Res Inst, Leicester, Leics, England.
    Dearden, Claire
    Inst Canc Res, Div Mol Pathol, London SW7 3RP, England.
    Allsup, David J.
    Hull Royal Infirm, Dept Haematol, Kingston Upon Hull, N Humberside, England.
    Bailey, James R.
    Hull York Med Sch, Kingston Upon Hull, N Humberside, England;Univ Hull, Kingston Upon Hull, N Humberside, England.
    Pratt, Guy
    Birmingham Heartlands Hosp, Dept Haematol, Birmingham, W Midlands, England.
    Pepper, Chris
    Cardiff Univ, Sch Med, Dept Haematol, Cardiff, S Glam, Wales.
    Fegan, Chris
    Cardiff & Vale Natl Hlth Serv Trust, Heath Pk, Cardiff, S Glam, Wales.
    Rosenquist, Richard
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Kuiper, Rowan
    Erasmus MC Canc Inst, Dept Hematol, NL-3075 EA Rotterdam, Netherlands.
    Stephens, Owen W.
    Univ Arkansas Med Sci, Myeloma Inst Res & Therapy, Little Rock, AR 72205 USA.
    Bertsch, Uta
    German Canc Res Ctr, D-69120 Heidelberg, Germany;Natl Ctr Tumor Dis, D-69120 Heidelberg, Germany.
    Broderick, Peter
    Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England.
    Einsele, Hermann
    Univ Clin Wurzburg, D-97080 Wurzburg, Germany.
    Gregory, Walter M.
    Univ Leeds, Clin Trials Res Unit, Leeds LS2 9PH, W Yorkshire, England.
    Hillengass, Jens
    Heidelberg Univ, Dept Internal Med 5, D-69117 Heidelberg, Germany.
    Hoffmann, Per
    Univ Bonn, Inst Human Genet, D-53127 D- Bonn, Germany;Univ Basel, Dept Biomed, Div Med Genet, CH-4003 Basel, Switzerland.
    Jackson, Graham H.
    Royal Victoria Infirm, Newcastle Upon Tyne NE1 4LP, Tyne & Wear, England.
    Joeckel, Karl-Heinz
    Univ Duisburg Essen, Univ Hosp Essen, Inst Med Informat Biometry & Epidemiol, Essen, Germany.
    Nickel, Jolanta
    Heidelberg Univ, Dept Internal Med 5, D-69117 Heidelberg, Germany.
    Noethen, Markus M.
    Univ Bonn, Inst Human Genet, D-53127 D- Bonn, Germany;Univ Bonn, Life & Brain Ctr, Dept Genom, D-53127 Bonn, Germany.
    da Silva Filho, Miguel Inacio
    German Canc Res Ctr, D-69120 Heidelberg, Germany.
    Thomsen, Hauke
    German Canc Res Ctr, D-69120 Heidelberg, Germany.
    Walker, Brian A.
    Univ Arkansas Med Sci, Myeloma Inst Res & Therapy, Little Rock, AR 72205 USA.
    Broyl, Annemiek
    Erasmus MC Canc Inst, Dept Hematol, NL-3075 EA Rotterdam, Netherlands.
    Davies, Faith E.
    Univ Arkansas Med Sci, Myeloma Inst Res & Therapy, Little Rock, AR 72205 USA.
    Hansson, Markus
    Lund Univ, Ctr Primary Hlth Care Res, SE-20502 Malmo, Sweden;Lund Univ, Dept Lab Med, Hematol & Transfus Med, BMC B13, SE-22184 Lund, Sweden.
    Goldschmidt, Hartmut
    Heidelberg Univ, Dept Internal Med 5, D-69117 Heidelberg, Germany;Natl Ctr Tumor Dis, D-69120 Heidelberg, Germany.
    Dyer, Martin J. S.
    Univ Leicester, Ernest & Helen Scott Haematol Res Inst, Leicester, Leics, England.
    Kaiser, Martin
    Inst Canc Res, Div Mol Pathol, London SW7 3RP, England.
    Sonneveld, Pieter
    Erasmus MC Canc Inst, Dept Hematol, NL-3075 EA Rotterdam, Netherlands.
    Morgan, Gareth J.
    Univ Arkansas Med Sci, Myeloma Inst Res & Therapy, Little Rock, AR 72205 USA.
    Hemminki, Kari
    German Canc Res Ctr, D-69120 Heidelberg, Germany;Lund Univ, Ctr Primary Hlth Care Res, SE-20502 Malmo, Sweden.
    Nilsson, Bjorn
    Lund Univ, Dept Lab Med, Hematol & Transfus Med, BMC B13, SE-22184 Lund, Sweden;Broad Inst, 7 Cambridge Ctr, Cambridge, MA 02142 USA.
    Catovsky, Daniel
    Inst Canc Res, Div Mol Pathol, London SW7 3RP, England.
    Allan, James M.
    Newcastle Univ, Northern Inst Canc Res, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England.
    Houlston, Richard S.
    Inst Canc Res, Div Genet & Epidemiol, London SW7 3RP, England;Inst Canc Res, Div Mol Pathol, London SW7 3RP, England.
    Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology2018Inngår i: Blood Cancer Journal, ISSN 2044-5385, E-ISSN 2044-5385, Vol. 9, artikkel-id 1Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (R-g = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChlP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies.

  • 627.
    Whither, Stine Braendegaard
    et al.
    Odense Univ Hosp, Dept Oncol, DK-5000 Odense C, Denmark;Odense Univ Hosp, Acad Geriatr Canc Res AgeCare, Odense, Denmark;Univ Southern Denmark, Dept Clin Res, Odense, Denmark.
    Liposits, Gabor
    Haukeland Hosp, Dept Oncol, Bergen, Norway.
    Skuladottir, Haifa
    Reg Hosp West Jutland, Dept Oncol, Herning, Denmark.
    Hofsli, Eva
    Trondheim Reg & Univ Hosp, Dept Oncol, Trondheim, Norway.
    Shah, Carl-Henrik
    Karolinska Univ Hosp, Theme Canc, Stockholm, Sweden.
    Poulsen, Laurids Östergaard
    Aalborg Univ Hosp, Dept Oncol, Aalborg, Denmark.
    Ryg, Jesper
    Odense Univ Hosp, Dept Geriatr Med, Odense, Denmark;Odense Univ Hosp, Acad Geriatr Canc Res AgeCare, Odense, Denmark;Univ Southern Denmark, Dept Clin Res, Odense, Denmark.
    Osterlund, Pia
    Tampere Univ, Tampere Univ Hosp, Dept Oncol, Tampere, Finland;Univ Helsinki, Dept Oncol, Helsinki Univ Hosp, Helsinki, Finland.
    Berglund, Åke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Qvortrup, Camilla
    Odense Univ Hosp, Dept Oncol, DK-5000 Odense C, Denmark;Odense Univ Hosp, Acad Geriatr Canc Res AgeCare, Odense, Denmark.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Bergen, Norway.
    Pfeiffer, Per
    Odense Univ Hosp, Dept Oncol, DK-5000 Odense C, Denmark;Odense Univ Hosp, Acad Geriatr Canc Res AgeCare, Odense, Denmark;Odense Univ Hosp, Odense Patient Data Explorat Network, OPEN, Odense, Denmark;Univ Southern Denmark, Dept Clin Res, Odense, Denmark.
    Reduced-dose combination chemotherapy (S-1 plus oxaliplatin) versus full- dose monotherapy (S-1) in older vulnerable patients with metastatic colorectal cancer (NORDIC9): a randomised, open-label phase 2 trial2019Inngår i: The Lancet Gastroenterology & Hepatology, ISSN 2468-1253, Vol. 4, nr 5, s. 376-388Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Older or vulnerable patients with metastatic colorectal cancer are seldom included in randomised trials.The multicentre NORDIC9 trial evaluated reduced-dose combination chemotherapy compared with full-dose monotherapy in older, vulnerable patients.

    Methods: This randomised, open-label phase 2 trial was done in 23 Nordic oncology clinics and included patients aged 70 years or older with previously untreated metastatic colorectal cancer who were not candidates for full-dose combination chemotherapy. Patients were block randomised (1: 1) using a web-based tool to full-dose S-1 (30 mg/m(2) orally twice daily on days 1-14 every 3 weeks) followed by second-line treatment at progression with irinotecan (250 mg/m(2) intravenously on day 1 every 3 weeks or 180 mg/m(2) intravenously on day 1 every 2 weeks) or reduceddose combination chemotherapy with S-1 (20 mg/m(2) orally twice daily on days 1-14) and oxaliplatin (100 mg/m(2) intravenously on day 1 every 3 weeks) followed by second-line treatment at progression with S-1 (20 mg/m(2) orally twice daily on days 1-14) and irinotecan (180 mg/m(2) intravenously on day 1 every 3 weeks). Use of bevacizumab (7.5 mg/kg intravenously on day 1 of each cycle) was optional. Treatment allocation was not masked and randomisation was stratified for institution and bevacizumab. The primary outcome was progression-free survival. Survival analyses were by intention to treat and safety analyses were done on the treated population. This trial is registered with EudraCT, number 2014-000394-39, and is closed to new participants.

    Findings: From March 9, 2015, to Oct 11, 2017, 160 patients with a median age of 78 years (IQR 76-81) were randomly assigned to full-dose monotherapy (n=83) or reduced-dose combination chemotherapy (n=77). At data cutoff (Sept 1, 2018; median follow-up 23.8 months [IQR 18.8-30.9]), 81 (98%) patients in the full-dose monotherapy group and 71 (92%) patients in the reduced-dose combination group had progressed or died. Median progression-free survival was significantly longer with reduced-dose combination chemotherapy (6.2 months [95% CI 5.3-8.3]) than with full-dose monotherapy (5.3 months [4.1-6.8]; hazard ratio [HR] 0.72 [95% CI 0.52-0.99]; p=0.047). Toxicity was evaluated in 157 patients who received treatment. Significantly more patients in the full-dose monotherapy group (51 [62%] of 82 patients) experienced at least one grade 3-4 adverse event than in the reduced-dose combination group (32 [43%] of 75 patients; p=0.014). Grade 3-4 diarrhoea (12 [15%] vs two [3%]; p=0.018), fatigue (ten [12%] vs three [4%]; p=0.083), and dehydration (five [6%] vs none; p=0.060) were more frequent in the full-dose monotherapy group than in the reduced-dose combination group. Treatment-related deaths occurred in three patients during firstline treatment and three patients during second-line treatment (two in the full-dose monotherapy group vs one in the reduced-dose combination group in both cases).

    Interpretation: Reduced-dose combination chemotherapy with S-1 and oxaliplatin for older, vulnerable patients with metastatic colorectal cancer was more effective and resulted in less toxicity than full-dose monotherapy with S-1. Reduced-dose combination chemotherapy could be a preferred treatment for this population.

  • 628.
    Wickberg, Asa
    et al.
    Fac Med & Hlth, Dept Surg, SE-70182 Orebro, Sweden.
    Liljegren, Goran
    Fac Med & Hlth, Dept Surg, SE-70182 Orebro, Sweden.
    Killander, Fredrika
    Skane Univ Hosp, Lund, Sweden;Lund Univ, Lund, Sweden.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Bjohle, Judith
    Univ Hosp, Stockholm, Sweden;Karolinska Inst, Stockholm, Sweden.
    Carlberg, Michael
    Fac Med & Hlth, Dept Oncol, SE-70182 Orebro, Sweden.
    Blomqvist, Carl
    Univ Helsinki, Dept Oncol, Helsinki, Finland.
    Ahlgren, Johan
    Fac Med & Hlth, Dept Oncol, SE-70182 Orebro, Sweden.
    Villman, Kenneth
    Fac Med & Hlth, Dept Oncol, SE-70182 Orebro, Sweden.
    Omitting radiotherapy in women >= 65 years with low-risk early breast cancer after breast-conserving surgery and adjuvant endocrine therapy is safe2018Inngår i: European Journal of Surgical Oncology, ISSN 0748-7983, E-ISSN 1532-2157, Vol. 44, nr 7, s. 951-956Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: The aim of this study was to verify if radiotherapy (RT) safely can be omitted in older women treated for estrogen-receptor positive early breast cancer with breast-conserving surgery (BCS) and endocrine therapy (ET). Patients and Methods: Eligibility criteria were: consecutive patients with age >= 65 years, BCS + sentinel node biopsy, clear margins, unifocal T1N0M0 breast cancer tumor, Elston-Ellis histological grade 1 or 2 and estrogen receptor-positive tumor. After informed consent, adjuvant ET for 5 years was prescribed. Primary endpoint was ipsilateral breast tumor recurrence (IBTR). Secondary endpoints were contralateral breast cancer and overall survival. Results: Between 2006 and 2012, 603 women were included from 14 Swedish centers. Median age was 71.1 years (range 65-90). After a median follow-up of 68 months 16 IBTR (cumulative incidence at five-year follow-up; 1.2%, 95% CI, 0.6% to 2.5%), 6 regional recurrences (one combined with IBTR), 2 distant recurrences (both without IBTR or regional recurrence) and 13 contralateral breast cancers were observed. There were 48 deaths. One death (2.1%) was due to breast cancer and 13 (27.1%) were due to other cancers (2 endometrial cancers). Five-year overall survival was 93.0% (95% CI, 90.5% to 94.9%). Conclusion: BCS and ET without RT seem to be a safe treatment option in women >= 65 years with early breast cancer and favorable histopathology. The risk of IBTR is comparable to the risk of contralateral breast cancer. Moreover, concurrent morbidity dominates over breast cancer as leading cause of death in this cohort with low-risk breast tumors.

  • 629.
    Wickström, Malin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Stockholm, Sweden..
    Nygren, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Harmenberg, Johan
    Oncopeptides AB, Vastra Tradgardsgatan 15, Stockholm, Sweden..
    Lindberg, Jakob
    Oncopeptides AB, Vastra Tradgardsgatan 15, Stockholm, Sweden..
    Sjoberg, Per
    Oncopeptides AB, Vastra Tradgardsgatan 15, Stockholm, Sweden..
    Jerling, Markus
    Oncopeptides AB, Vastra Tradgardsgatan 15, Stockholm, Sweden..
    Lehmann, Fredrik
    Recipharm OT Chem AB, Uppsala, Sweden..
    Richardson, Paul
    Harvard Med Sch, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, Dept Med Oncol, Boston, MA USA.;Harvard Med Sch, Dana Farber Canc Inst, Jerome Lipper Myeloma Ctr, Boston, MA USA..
    Anderson, Kenneth
    Harvard Med Sch, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, Dept Med Oncol, Boston, MA USA.;Harvard Med Sch, Dana Farber Canc Inst, Jerome Lipper Myeloma Ctr, Boston, MA USA..
    Chauhan, Dharminder
    Harvard Med Sch, Dana Farber Canc Inst, LeBow Inst Myeloma Therapeut, Dept Med Oncol, Boston, MA USA.;Harvard Med Sch, Dana Farber Canc Inst, Jerome Lipper Myeloma Ctr, Boston, MA USA..
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Melflufen: a peptidase-potentiated alkylating agent in clinical trials2017Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 39, s. 66641-66655Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Aminopeptidases like aminopeptidase N (APN, also known as CD13) play an important role not only in normal cellular functioning but also in the development of cancer, including processes like tumor cell invasion, differentiation, proliferation, apoptosis, motility, and angiogenesis. An increased expression of APN has been described in several types of human malignancies, especially those characterized by fast-growing and aggressive phenotypes, suggesting APN as a potential therapeutic target. Melphalan flufenamide ethyl ester (melflufen, previously denoted J1) is a peptidase-potentiated alkylating agent. Melflufen readily penetrates membranes and an equilibrium is rapidly achieved, followed by enzymatic cleavage in aminopeptidase positive cells, which results in trapping of less lipophilic metabolites. This targeting effect results in very high intracellular concentrations of its metabolite melphalan and subsequent apoptotic cell death. This results in a potency increase (melflufen vs melphalan) ranging from 10- to several 100-fold in different in vitro models. Melflufen triggers a rapid, robust, and an irreversible DNA damage which may account for its ability to overcome melphalan-resistance in multiple myeloma cells. Furthermore, anti-angiogenic properties of melflufen have been described. Consequently, it is hypothesized that melflufen could provide better efficacy but no more toxicity than what is achieved with melphalan, an assumption so far supported by experiences from hollow fiber and xenograft studies in rodents as well as by clinical data from patients with solid tumors and multiple myeloma. This review summarizes the current preclinical and clinical knowledge of melflufen.

  • 630.
    Wikström, Kenneth
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Isacsson, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Nilsson, Kristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Ahnesjö, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Reproducibility of heart and thoracic wall positionin repeated deep inspiration breath holds forradiotherapy of left-sided breast cancer patients2018Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, nr 10, s. 1318-1324Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Deep inspiration breath hold (DIBH) for radiotherapy of left-sided breast cancer patientscan effectively move the heart away from the target and reduce the heart dose compared to treatmentsin free breathing. This study aims to investigate the positional reproducibility of heart edge(HE) and thoracic wall (TW) during repeated DIBHs.

    Material and methods: At three occasions, 11 left-sided breast cancer patients were CT imaged during6 minutes of repeated DIBHs with 60 cine CT series. The series were evenly distributed over threebed positions and for each bed position, the heart edge associated maximum heart distance (MHD)and thoracic wall-associated maximum lung distance (MLD) from a reference line were retrospectivelyanalyzed. The high temporal resolution of the CT series enabled intrinsic heart movements to beresolved from breath hold variations. A body surface laser scanning system continuously extracted thethorax height and displayed it in a pair of goggles for patient feedback. To check for ‘fake-breathing’movements, e.g. that the patient lifts its back from the couch to reach DIBH, the couch-to-spine distancewas also measured in all CT series.

    Results: The analysis was done for 1432 cine CTs captured during 292 breath holds. The DIBH movedthe heart on average 15mm in medial direction compared with free breathing. For the three bed positionsstudied, the mean value of the max range, across all patients, was between 11–13mm for theMHD and 4–8mm for the MLD. The MHD variation due to breath hold variation was twice as large asthe MHD variation due to intrinsic heart movement. The couch-to-spine distance varied less than3mm for all fractions, i.e., no fake-breathing was discovered.

    Conclusions: The heart edge and thoracic wall reproducibility was high in relation to the medial heartdisplacement induced by the DIBH.

  • 631.
    Winther, S. B.
    et al.
    Odense Univ Hosp, Dept Oncol, Odense, Denmark..
    Osterlund, P.
    Univ Helsinki, Cent Hosp, Dept Oncol, Helsinki, Finland..
    Berglund, Åke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Qvortrup, C.
    Odense Univ Hosp, Dept Oncol, Odense, Denmark..
    Sorbye, H.
    Haukeland Univ Sykehus, Dept Oncol, Bergen, Norway..
    Pfeiffer, P.
    Odense Univ Hosp, Dept Oncol, Odense, Denmark..
    NORDIC9: A randomized phase II trial exploring treatment of older patients with metastatic colorectal cancer (mCRC) by comparing full dose monotherapy (S-1 followed by irinotecan) with reduced combination regimen (S-1/oxaliplatin followed by S-1/irinotecan)2016Inngår i: Annals of Oncology, ISSN 0923-7534, E-ISSN 1569-8041, Vol. 27, nr suppl. 6, artikkel-id 601TiPArtikkel i tidsskrift (Fagfellevurdert)
  • 632.
    Winther, Stine Braendegaard
    et al.
    Odense Univ Hosp, Dept Oncol, Sdr Blvd 29, DK-5000 Odense C, Denmark..
    Österlund, Pia
    Univ Helsinki, Cent Hosp, Dept Oncol, Stenbackinkatu 9,POB 100, FI-00029 Helsinki, Finland.;Univ Helsinki, Clinicum, Haartmaninkatu 8,3th Floor,POB 63, Helsinki 00014, Finland..
    Berglund, Åke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Qvortrup, Camilla
    Odense Univ Hosp, Dept Oncol, Sdr Blvd 29, DK-5000 Odense C, Denmark..
    Sorbye, Halfdan
    Haukeland Hosp, Dept Oncol, Postboks 1400, N-5021 Bergen, Norway.;Haukeland Hosp, Dept Clin Sci, Postboks 1400, N-5021 Bergen, Norway..
    Pfeiffer, Per
    Odense Univ Hosp, Dept Oncol, Sdr Blvd 29, DK-5000 Odense C, Denmark..
    Randomized study comparing full dose monotherapy (S-1 followed by irinotecan) and reduced dose combination therapy (S-1/oxaliplatin followed by S-1/irinotecan) as initial therapy for older patients with metastatic colorectal cancer: NORDIC 92017Inngår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 17, artikkel-id 548Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Metastatic colorectal cancer (mCRC) is a disease of older age, but there is a relative lack of knowledge about effects of chemotherapy in older patients as they are under-represented in clinical trials. Little data can guide whether the strategy in older mCRC patients should be a sequential full-dose monotherapy chemotherapy approach or a dose-reduced combination chemotherapy approach. The oral 5FU prodrug S-1 seems to have less side effects than capecitabine and should be an optimal drug for older patients, but few data are available. Improved geriatric assessments are needed to select which older patients should receive therapy.

    Methods: The NORDIC 9 trial is a Nordic multicenter randomized phase II study comparing full dose monotherapy (S-1 30 mg/m(2) twice daily days 1-14 every 3 weeks, followed by second line irinotecan 250-350 mg/m(2) iv day 1 every 3 weeks or 180-250 mg/m(2) iv day 1 every 2 weeks) with reduced dose combination therapy (S-1 20 mg/m(2) days 1-14 + oxaliplatin 100 mg/m(2) iv day 1 every 3 weeks, followed by second line S-1 20 mg/m(2) days 1-14 + irinotecan 180 mg/m(2) day 1 every 3 week) for older patients (>= 70 years) with mCRC who are not candidates for full-dose standard combination therapy. Additional bevacizumab (7.5 mg/kg) is optional in first-line. Blood samples and tumor tissue will be collected to investigate predictive markers. Geriatric screening tools (G-8, VES-13, Timed-Up-and- Go and Handgrip strength), Charlson Comorbidty Index and quality of life (EORTC QLQ-C30) will be evaluated as predictors of efficacy and toxicity. The target sample size is 150 patients. The primary endpoint is progression-free survival and secondary endpoints are time-to-failure of strategy, overall survival, response rate, toxicity, and correlations between biomarkers, pre-treatment characteristics and geriatric assessments.

    Discussion: The study will add knowledge on how to treat older mCRC patients who are not candidates for standard combination therapy. Furthermore it may provide understanding of efficacy and tolerability of chemotherapy in older cancer patients and thus offer a better chance for tailored treatment strategies in these patients.

  • 633.
    Wu, Chenglin
    et al.
    Karolinska Inst, Karolinska Univ Hosp, Div Clin Immunol & Transfus Med, Stockholm, Sweden..
    de Miranda, Noel F. C. C.
    Karolinska Inst, Karolinska Univ Hosp, Div Clin Immunol & Transfus Med, Stockholm, Sweden..
    Chen, Longyun
    Karolinska Inst, Karolinska Univ Hosp, Div Clin Immunol & Transfus Med, Stockholm, Sweden.;Beijing Genom Inst, Shenzhen, Peoples R China..
    Wasik, Agata M.
    Karolinska Inst, Dept Lab Med, Div Pathol, Karolinska Univ Hosp, Stockholm, Sweden..
    Mansouri, Larry
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Jurczak, Wojciech
    Jagiellonian Univ, Dept Hematol, Coll Med, Krakow, Poland..
    Galazka, Krystyna
    Jagiellonian Univ, Dept Pathol, Coll Med, Krakow, Poland..
    Dlugosz-Danecka, Monika
    Jagiellonian Univ, Dept Hematol, Coll Med, Krakow, Poland..
    Machaczka, Maciej
    Jagiellonian Univ, Fac Hlth Sci, Coll Med, Krakow, Poland..
    Zhang, Huilai
    Tianjin Med Univ, Dept Lymphoma, Canc Hosp & Inst, Tianjin, Peoples R China..
    Peng, Roujun
    Sun Yat Sen Univ, Dept Med Oncol, Collaborat Innovat Ctr Canc Med, Canc Ctr,State Key Lab Oncol South China, Guangzhou 510275, Guangdong, Peoples R China..
    Morin, Ryan D.
    Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC V5A 1S6, Canada..
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sander, Birgitta
    Karolinska Inst, Dept Lab Med, Div Pathol, Karolinska Univ Hosp, Stockholm, Sweden..
    Pan-Hammarstrom, Qiang
    Karolinska Inst, Karolinska Univ Hosp, Div Clin Immunol & Transfus Med, Stockholm, Sweden..
    Genetic heterogeneity in primary and relapsed mantle cell lymphomas: Impact of recurrent CARD11 mutations2016Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 25, s. 38180-38190Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The genetic mechanisms underlying disease progression, relapse and therapy resistance in mantle cell lymphoma (MCL) remain largely unknown. Whole-exome sequencing was performed in 27 MCL samples from 13 patients, representing the largest analyzed series of consecutive biopsies obtained at diagnosis and/or relapse for this type of lymphoma. Eighteen genes were found to be recurrently mutated in these samples, including known (ATM, MEF2B and MLL2) and novel mutation targets (S1PR1 and CARD11). CARD11, a scaffold protein required for B-cell receptor (BCR)-induced NF-kappa B activation, was subsequently screened in an additional 173 MCL samples and mutations were observed in 5.5% of cases. Based on in vitro cell line-based experiments, overexpression of CARD11 mutants were demonstrated to confer resistance to the BCR-inhibitor ibrutinib and NF-kappa B-inhibitor lenalidomide. Genetic alterations acquired in the relapse samples were found to be largely non-recurrent, in line with the branched evolutionary pattern of clonal evolution observed in most cases. In summary, this study highlights the genetic heterogeneity in MCL, in particular at relapse, and provides for the first time genetic evidence of BCR/NF-kappa B activation in a subset of MCL.

  • 634. Xochelli, Aliki
    et al.
    Agathangelidis, Andreas
    Kavakiotis, Ioannis
    Minga, Evangelia
    Sutton, Lesley Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Baliakas, Panagiotis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Chouvarda, Ioanna
    Giudicelli, Veronique
    Vlahavas, Ioannis
    Maglaveras, Nikos
    Bonello, Lisa
    Trentin, Livio
    Tedeschi, Alessandra
    Panagiotidis, Panagiotis
    Geisler, Christian
    Langerak, Anton W.
    Pospisilova, Sarka
    Jelinek, Diane F.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Oscier, David
    Chiorazzi, Nicholas
    Darzentas, Nikos
    Davi, Fred
    Ghia, Paolo
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hadzidimitriou, Anastasia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Belessi, Chrysoula
    Lefranc, Marie-Paule
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Immunoglobulin heavy variable (IGHV) genes and alleles: new entities, new names and implications for research and prognostication in chronic lymphocytic leukaemia2015Inngår i: Immunogenetics, ISSN 0093-7711, E-ISSN 1432-1211, Vol. 67, nr 1, s. 61-66Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Ieext generation sequencing studies in Homo sapiens have identified novel immunoglobulin heavy variable (IGHV) genes and alleles necessitating changes in the international ImMunoGeneTics information system (IMGT) GENE-DB and reference directories of IMGT/V-QUEST. In chronic lymphocytic leukaemia (CLL), the somatic hypermutation (SHM) status of the clonotypic rearranged IGHV gene is strongly associated with patient outcome. Correct determination of this parameter strictly depends on the comparison of the nucleotide sequence of the clonotypic rearranged IGHV gene with that of the closest germline counterpart. Consequently, changes in the reference directories could, in principle, affect the correct interpretation of the IGHV mutational status in CLL. To this end, we analyzed 8066 productive IG heavy chain (IGH) rearrangement sequences from our consortium both before and after the latest update of the IMGT/V-QUEST reference directory. Differences were identified in 405 cases (5 % of the cohort). In 291/405 sequences (71.9 %), changes concerned only the IGHV gene or allele name, whereas a change in the percent germline identity (%GI) was noted in 114/405 (28.1 %) sequences; in 50/114 (43.8 %) sequences, changes in the %GI led to a change in the mutational set. In conclusion, recent changes in the IMGT reference directories affected the interpretation of SHM in a sizeable number of IGH rearrangement sequences from CLL patients. This indicates that both physicians and researchers should consider a re-evaluation of IG sequence data, especially for those IGH rearrangement sequences that, up to date, have a GI close to 98 %, where caution is warranted.

  • 635.
    Xochelli, Aliki
    et al.
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.;Ctr Res & Technol Hellas, Thessaloniki, Greece..
    Baliakas, Panagiotis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Agathangelidis, Andreas
    Hadzidimitriou, Anastasia
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.;IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy.;IRCCS San Raffaele Sci Inst, Dept Oncohematol, Milan, Italy..
    Sutton, Lesley-Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Minga, Eva
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Tausch, Eugen
    Univ Ulm, Dept Internal Med 3, Med Ctr, D-89069 Ulm, Germany..
    Yan, Xiao J.
    North Shore LIJ Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA..
    Shanafelt, Tait D.
    Mayo Clin, Dept Hematol, Rochester, MN USA..
    Plevova, Karla
    Masaryk Univ, Dept Internal Med Hematol & Oncol, Univ Hosp Brno, Brno, Czech Republic.;Masaryk Univ, Fac Med, Brno, Czech Republic..
    Boudjogra, Myriam
    Hop La Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Paris, France..
    Rossi, Davide
    Amedeo Avogadro Univ Eastern Piedmont, Dept Translat Med, Div Hematol, Novara, Italy..
    Davis, Zadie
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Navarro, Alba
    Univ Barcelona, Hosp Clin, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain..
    Sandberg, Yorick
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Immunol, Rotterdam, Netherlands..
    Vojdeman, Fie Juhl
    Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    Scarfo, Lydia
    IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy..
    Stavroyianni, Niki
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Sudarikov, Andrey B.
    Natl Res Ctr Hematol, Moscow, Russia..
    Veronese, Silvio
    Osped Niguarda Ca Granda, Niguarda Canc Ctr, Mol Pathol Unit, Milan, Italy.;Osped Niguarda Ca Granda, Niguarda Canc Ctr, Dept Haematol, Milan, Italy..
    Tzenou, Tatiana
    Univ Athens, Laikon Univ Hosp, Sch Med, Hematol Sect,Dept Propaedeut Med 1, Athens 11528, Greece..
    Karan-Djurasevic, Teodora
    Univ Belgrade, Inst Mol Genet & Genet Engn, Belgrade, Serbia..
    Catherwood, Mark
    Belfast City Hosp, Dept Haematooncol, Belfast BT9 7AD, Antrim, North Ireland..
    Kienle, Dirk
    Univ Ulm, Dept Internal Med 3, D-89069 Ulm, Germany..
    Chatzouli, Maria
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Facco, Monica
    Univ Padua, Dept Med, Hematol & Clin Immunol Sect, Sch Med, Padua, Italy..
    Bahlo, Jasmin
    Univ Hosp, Dept Internal Med 1, Ctr Integrated Oncol Cologne Bonn, Cologne, Germany..
    Pedersen, Lone Bredo
    Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    Mansouri, Larry
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Smedby, Karin E.
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden..
    Chu, Charles C.
    North Shore LIJ Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA..
    Giudicelli, Veronique
    Univ Montpellier, LIGM, IGH, IMGT Int ImMunoGeneT informat Syst,UPR CNRS 1142, F-34059 Montpellier, France..
    Lefranc, Marie-Paule
    Univ Montpellier, LIGM, IGH, IMGT Int ImMunoGeneT informat Syst,UPR CNRS 1142, F-34059 Montpellier, France..
    Panagiotidis, Panagiotis
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece..
    Juliusson, Gunnar
    Lund Univ, Lund, Sweden.;Lund Stem Cell Ctr, Hosp Dept Hematol, Lund, Sweden..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Antic, Darko
    Univ Belgrade, Ctr Clin, Clin Hematol, YU-11000 Belgrade, Serbia.;Univ Belgrade, Fac Med, Belgrade, Serbia..
    Trentin, Livio
    Univ Sch Med, Hematol & Clin Immunol Branch, Dept Med, Padua, Italy..
    Montillo, Marco
    Osped Niguarda Ca Granda, Niguarda Canc Ctr, Mol Pathol Unit, Milan, Italy..
    Niemann, Carsten
    Rigshosp, Dept Hematol, DK-2100 Copenhagen, Denmark..
    Dohner, Hartmut
    Univ Hosp, Dept Internal Med 3, Ulm, Germany..
    Langerak, Anton W.
    Erasmus MC, Dept Immunol, Rotterdam, Netherlands..
    Darzentas, Nikos
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Pospisilova, Sarka
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Hallek, Michael
    Univ Hosp, Dept Internal Med, Cologne, Germany.;Univ Hosp, Ctr Integrated Oncol, Cologne, Germany..
    Campo, Elias
    Univ Barcelona, Hosp Clin, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Barcelona, Spain.;Univ Med Ctr Rotterdam, Erasmus MC, Dept Immunol, Rotterdam, Netherlands..
    Chiorazzi, Nicholas
    North Shore LIJ Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA..
    Oscier, David
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Gaidano, Gianluca
    Amedeo Avogadro Univ Eastern Piedmont, Dept Translat Med, Div Haematol, Novara, Italy..
    Belessi, Chrysoula
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Jelinek, Diane F.
    Mayo Clin, Dept Immunol, Rochester, MN USA..
    Stilgenbauer, Stephan
    Univ Ulm, Dept Internal Med 3, D-89069 Ulm, Germany..
    Davi, Frederic
    Hop La Pitie Salpetriere, Dept Hematol, Paris, France..
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Ghia, Paolo
    IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy..
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. CERTH, Inst Appl Biosci, Thessaloniki, Greece.;G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    CLL with Mutated IGHV4-34 Antigen Receptors Is Clinically Heterogeneous: Antigen Receptor Stereotypy Makes the Difference2015Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, nr 23Artikkel i tidsskrift (Annet vitenskapelig)
  • 636.
    Xochelli, Aliki
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Baliakas, Panagiotis
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. ..
    Kavakiotis, Ioannis
    Aristotle Univ Thessaloniki, Dept Informat, Thessaloniki, Greece..
    Agathangelidis, Andreas
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.;IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy.;IRCCS San Raffaele Sci Inst, Dept Oncohematol, Milan, Italy..
    Sutton, Lesley Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Minga, Eva
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Ntoufa, Stavroula
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Tausch, Eugen
    Ulm Univ, Dept Internal Med 3, Ulm, Germany..
    Yan, Xiao-Jie
    Northwell Hlth, Feinstein Inst Med Res, Manhasset, NY USA..
    Shanafelt, Tait
    Mayo Clin, Dept Med, Dept Hematol, Rochester, MN USA..
    Plevova, Karla
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Boudjogra, Myriam
    Hop La Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Paris, France..
    Rossi, Davide
    Univ Piemonte Orientale, Dept Translat Med, Dept Haematol, Novara, Italy..
    Davis, Zadie
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Navarro, Alba
    Univ Barcelona, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Hosp Clin, Barcelona, Spain..
    Sandberg, Yorick
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Immunol, Rotterdam, Netherlands..
    Vojdeman, Fie Juhl
    Rigshosp, Dept Haematol, Copenhagen, Denmark..
    Scarfo, Lydia
    IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy.;IRCCS San Raffaele Sci Inst, Dept Oncohematol, Milan, Italy..
    Stavroyianni, Niki
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Sudarikov, Andrey
    Natl Res Ctr Hematol, Moscow, Russia..
    Veronese, Silvio
    Osped Niguarda Ca Granda, Mol Pathol Unit, Milan, Italy.;Osped Niguarda Ca Granda, Dept Haematol, Milan, Italy..
    Tzenou, Tatiana
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece..
    Karan-Djurasevic, Teodora
    Univ Belgrade, Inst Mol Genet & Genet Engn, Belgrade, Serbia..
    Catherwood, Mark
    Belfast City Hosp, Dept Haematooncol, Belfast, Antrim, North Ireland..
    Kienle, Dirk
    Ulm Univ, Dept Internal Med 3, Ulm, Germany..
    Chatzouli, Maria
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Facco, Monica
    Univ Padua, Sch Med, Hematol & Clin Immunol Branch, Dept Med, Padua, Italy..
    Bahlo, Jasmin
    Univ Hosp Cologne, Dept Internal Med 1, Cologne, Germany.;Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany..
    Pott, Christiane
    Univ Hosp Schleswig Holstein, Med Dept 2, Campus Kiel, Kiel, Germany..
    Pedersen, Lone Bredo
    Rigshosp, Dept Haematol, Copenhagen, Denmark..
    Mansouri, Larry
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Smedby, Karin E.
    Karolinska Inst, Clin Epidemiol Unit, Dept Med Solna, Stockholm, Sweden..
    Chu, Charles C.
    Northwell Hlth, Feinstein Inst Med Res, Manhasset, NY USA..
    Giudicelli, Veronique
    Univ Montpellier, CNRS, UPR 1142, IMGT,LIGM,IGH, Montpellier, France..
    Lefranc, Marie-Paule
    Univ Montpellier, CNRS, UPR 1142, IMGT,LIGM,IGH, Montpellier, France..
    Panagiotidis, Panagiotis
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece..
    Juliusson, Gunnar
    Lund Univ, Lund, Sweden.;Lund Stem Cell Ctr, Hosp Dept Hematol, Lund, Sweden..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Vlahavas, Ioannis
    Aristotle Univ Thessaloniki, Dept Informat, Thessaloniki, Greece..
    Antic, Darko
    Ctr Clin, Clin Hematol, Belgrade, Serbia.;Univ Belgrade, Fac Med, Belgrade, Serbia..
    Trentin, Livio
    Univ Padua, Sch Med, Hematol & Clin Immunol Branch, Dept Med, Padua, Italy..
    Montillo, Marco
    Osped Niguarda Ca Granda, Mol Pathol Unit, Milan, Italy.;Osped Niguarda Ca Granda, Dept Haematol, Milan, Italy..
    Niemann, Carsten
    Rigshosp, Dept Haematol, Copenhagen, Denmark..
    Doehner, Hartmut
    Ulm Univ, Dept Internal Med 3, Ulm, Germany..
    Langerak, Anton W.
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Immunol, Rotterdam, Netherlands..
    Pospisilova, Sarka
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Hallek, Michael
    Univ Hosp Cologne, Dept Internal Med 1, Cologne, Germany.;Univ Hosp Cologne, Ctr Integrated Oncol, Cologne, Germany..
    Campo, Elias
    Univ Barcelona, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Hosp Clin, Barcelona, Spain..
    Chiorazzi, Nicholas
    Northwell Hlth, Feinstein Inst Med Res, Manhasset, NY USA..
    Maglaveras, Nikos
    Aristotle Univ Thessaloniki, Lab Med Informat, Thessaloniki, Greece..
    Oscier, David
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Gaidano, Gianluca
    Univ Piemonte Orientale, Dept Translat Med, Dept Haematol, Novara, Italy..
    Jelinek, Diane F.
    Mayo Clin, Dept Immunol, Rochester, MN USA..
    Stilgenbauer, Stephan
    Ulm Univ, Dept Internal Med 3, Ulm, Germany..
    Chouvarda, Ioanna
    Aristotle Univ Thessaloniki, Lab Med Informat, Thessaloniki, Greece..
    Darzentas, Nikos
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Belessi, Chrysoula
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Davi, Frederic
    Hop La Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Paris, France..
    Hadzidimitriou, Anastasia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Rosenquist, Richard
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Ghia, Paolo
    IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy.;IRCCS San Raffaele Sci Inst, Dept Oncohematol, Milan, Italy.;Univ Vita Salute San Raffaele, Milan, Italy.;IRCCS Ist Sci San Raffaele, Milan, Italy..
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. CERTH, Inst Appl Biosci, Thessaloniki, Greece ;G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Chronic Lymphocytic Leukemia with Mutated IGHV4-34 Receptors: Shared and Distinct Immunogenetic Features and Clinical Outcomes2017Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, nr 17, s. 5292-5301Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication. Experimental Design: In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes. Results: We identified shared and subset-specific patterns of somatic hypermutation (SHM) among patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLL. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly (P < 0.05) longer time-to-first-treatment (TTFT; median TTFT: not yet reached) compared with the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively). Conclusions: Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. In addition, the observed distinct genetic aberration landscapes and clinical heterogeneity suggest that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management.  

  • 637.
    Xochelli, Aliki
    et al.
    Ctr Res & Technol Hellas, Thessaloniki, Greece.;CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Bikos, Vasilis
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Polychronidou, Eleftheria
    CERTH, Inst Informat Technol, Thessaloniki, Greece.;Ionian Univ, Dept Informat, Corfu, Greece..
    Agathangelidis, Andreas
    IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy.;IRCCS San Raffaele Sci Inst, Dept Oncohematol, Milan, Italy..
    Charlotte, Frederic
    Hop La Pitie Salpetriere, Dept Pathol, Paris, France.;Univ Pierre Curie, Paris, France..
    Moschonas, Panagiotis
    CERTH, Inst Informat Technol, Thessaloniki, Greece..
    Davis, Zadie
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Colombo, Monica
    Ist Ricovero & Cura Carattere Sci IRCCS Azienda O, Direz Sci, Genoa, Italy..
    Roumelioti, Maria
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece..
    Sutton, Lesley-Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Groenen, Patricia
    Radboud Univ Nijmegen, Med Ctr, Dept Pathol, Nijmegen, Netherlands..
    Boudjoghra, Myriam
    Hop La Pitie Salpetriere, Dept Hematol, Paris, France.;Univ Paris 06, Paris, France..
    Algara, Patricia
    Hosp Virgen Salud, Toledo, Spain..
    Traverse-Glehen, Alexandra
    Univ Lyon 1, Hosp Civils Lyon, Dept Pathol & Hematol, F-69365 Lyon, France..
    Ferrer, Ana
    Hosp del Mar, Serv Patol, Lab Citol Hematol & Citogenet Mol, Barcelona, Spain..
    Stalika, Evangelia
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Karypidou, Maria
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Kanellis, George
    Evangelismos Med Ctr, Hematopathol Dept, Athens, Greece..
    Kalpadakis, Christina
    Univ Crete, Sch Med, Dept Hematol, Iraklion, Greece..
    Mollejo, Manuella
    Hosp Virgen Salud, Toledo, Spain..
    Pangalis, Gerasimos
    Athens Med Ctr, Dept Haematol, Athens, Greece..
    Vlamos, Panayiotis
    Ionian Univ, Dept Informat, Corfu, Greece..
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Pospisilova, Sarka
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Gonzalez, David
    Inst Canc Res, Sect Haematooncol, London SW3 6JB, England..
    Ponzoni, Maurilio
    Ist Sci San Raffaele, Pathol Unit, I-20132 Milan, Italy..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Giudicelli, Veronique
    Univ Montpellier, Int ImMunoGeneT Informat Syst, LIGM, Inst Genet Humaine IGH,UPR CNRS 1142,IMGT, F-34059 Montpellier, France..
    Lefranc, Marie-Paule
    Univ Montpellier, Int ImMunoGeneT Informat Syst, LIGM, Inst Genet Humaine IGH,UPR CNRS 1142,IMGT, F-34059 Montpellier, France..
    Espinet, Blanca
    Hosp del Mar, Serv Patol, Lab Citol Hematol & Citogenet Mol, Barcelona, Spain..
    Panagiotidis, Panagiotis
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece..
    Angel Piris, Miguel
    Hosp Univ Marques Valdecilla, Santander, Spain..
    Du, Ming
    Univ Cambridge, Dept Pathol, Div Mol Histopathol, Cambridge CB2 1QP, England..
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Papadaki, Theodora
    Evangelismos Med Ctr, Hematopathol Dept, Athens, Greece..
    Belessi, Chrysoula
    Nikea Gen Hosp, Dept Hematol, Piraeus, Greece..
    Ferrarini, Manlio
    Ist Ricovero & Cura Carattere Sci IRCCS Azienda O, Direz Sci, Genoa, Italy..
    Oscier, David
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Tzovaras, Dimitrios
    CERTH, Inst Informat Technol, Thessaloniki, Greece..
    Ghia, Paolo
    IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy.;IRCCS San Raffaele Sci Inst, Dept Oncohematol, Milan, Italy..
    Davi, Frederic
    Hop La Pitie Salpetriere, Serv Hematol Biol, Paris, France..
    Hadzidimitriou, Anastasia
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Unique Versus Common: Disease-Biased Immunoglobulin Gene Repertoires Along with Public Antigen Receptor Stereotypes in Marginal Zone B-Cell Lymphoproliferations2015Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 126, nr 23Artikkel i tidsskrift (Annet vitenskapelig)
  • 638.
    Xochelli, Aliki
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Bikos, Vasilis
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.
    Polychronidou, Eleftheria
    CERTH, Informat Technol Inst, Thessaloniki, Greece;Ionian Univ, Dept Informat, Corfu, Greece.
    Galigalidou, Chrysi
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Agathangelidis, Andreas
    IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy;IRCCS San Raffaele Sci Inst, Dept Onco Hematol, Milan, Italy;Univ Vita Salute San Raffaele, Milan, Italy.
    Charlotte, Frederic
    Hop La Pitie Salpetriere, Dept Pathol, Paris, France;Sorbonne Univ, Paris, France.
    Moschonas, Panagiotis
    CERTH, Informat Technol Inst, Thessaloniki, Greece.
    Davis, Zadie
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England.
    Colombo, Monica
    Osped Policlin SanMartino, Mol Pathol, Genoa, Italy.
    Roumelioti, Maria
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece.
    Sutton, Lesley-Ann
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Groenen, Patricia
    Radboud Univ Nijmegen, Med Ctr, Dept Pathol, Nijmegen, Netherlands.
    van den Brand, Michiel
    Radboud Univ Nijmegen, Med Ctr, Dept Pathol, Nijmegen, Netherlands.
    Boudjoghra, Myriam
    Sorbonne Univ, Paris, France;Hop La Pitie Salpetriere, Dept Hematol, Paris, France.
    Algara, Patricia
    Hosp Virgen de la Salud, Toledo, Spain.
    Traverse-Glehen, Alexandra
    Univ Lyon 1, Hosp Civils Lyon, Dept Pathol & Hematol, Lyon, France.
    Ferrer, Ana
    Hosp Mar, Serv Patol, Lab Citol Hematol & Citogenet Mol, Barcelona, Spain.
    Stalika, Evangelia
    CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Karypidou, Maria
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.
    Kanellis, George
    Evangelismos Med Ctr, Hematopathol Dept, Athens, Greece.
    Kalpadakis, Christina
    Univ Crete, Dept Haematol, Iraklion, Greece.
    Mollejo, Manuella
    Hosp Virgen de la Salud, Toledo, Spain.
    Pangalis, Gerasimos
    Athens Med Ctr, Dept Haematol, Athens, Greece.
    Vlamos, Panayiotis
    Ionian Univ, Dept Informat, Corfu, Greece.
    Amini, Rose-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Pospisilova, Sarka
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic.
    Gonzalez, David
    Univ Belfast, Ctr Canc Res & Cell Biol, Belfast, Antrim, North Ireland.
    Ponzoni, Maurilio
    Ist Sci San Raffaele, Pathol Unit, Milan, Italy.
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece.
    Giudicelli, Veronique
    Univ Montpellier, IMGTr, UMR CNRS UM, LIGM,IGH, Montpellier, France.
    Lefranc, Marie-Paule
    Univ Montpellier, IMGTr, UMR CNRS UM, LIGM,IGH, Montpellier, France.
    Espinet, Blanca
    Hosp Mar, Serv Patol, Lab Citol Hematol & Citogenet Mol, Barcelona, Spain.
    Panagiotidis, Panagiotis
    Univ Athens, Dept Propaedeut Med 1, Athens, Greece.
    Piris, Miguel Angel
    IIS Fdn Jimenez Diaz, Pathol Dept, Madrid, Spain.
    Du, Ming-Qing
    Univ Cambridge, Dept Pathol, Div Cellular & Mol Pathol, Cambridge, England.
    Rosenquist, Richard
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Papadaki, Theodora
    Evangelismos Med Ctr, Hematopathol Dept, Athens, Greece.
    Belessi, Chrysoula
    Nikea Gen Hosp, Hematol Dept, Piraeus, Greece.
    Ferrarini, Manlio
    Azienda Osped Univ AOU San Martino IST, IRCCS, Direz Sci, Genoa, Italy.
    Oscier, David
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England.
    Tzovaras, Dimitrios
    CERTH, Informat Technol Inst, Thessaloniki, Greece.
    Ghia, Paolo
    IRCCS San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy;IRCCS San Raffaele Sci Inst, Dept Onco Hematol, Milan, Italy;Univ Vita Salute San Raffaele, Milan, Italy.
    Davi, Frederic
    Sorbonne Univ, Paris, France;Hop La Pitie Salpetriere, Dept Hematol, Paris, France.
    Hadzidimitriou, Anastasia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. CERTH, Inst Appl Biosci, Thessaloniki, Greece.
    Disease-biased and shared characteristics of the immunoglobulin gene repertoires in marginal zone B cell lymphoproliferations2019Inngår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 247, nr 4, s. 416-421Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The B cell receptor immunoglobulin (Ig) gene repertoires of marginal zone (MZ) lymphoproliferations were analyzed in order to obtain insight into their ontogenetic relationships. Our cohort included cases with MZ lymphomas (n = 488), i.e. splenic (SMZL), nodal (NMZL) and extranodal (ENMZL), as well as provisional entities (n = 76), according to the WHO classification. The most striking Ig gene repertoire skewing was observed in SMZL. However, restrictions were also identified in all other MZ lymphomas studied, particularly ENMZL, with significantly different Ig gene distributions depending on the primary site of involvement. Cross-entity comparisons of the MZ Ig sequence dataset with a large dataset of Ig sequences (MZ-related or not; n = 65 837) revealed four major clusters of cases sharing homologous ('public') heavy variable complementarity-determining region 3. These clusters included rearrangements from SMZL, ENMZL (gastric, salivary gland, ocular adnexa), chronic lymphocytic leukemia, but also rheumatoid factors and non-malignant splenic MZ cells. In conclusion, different MZ lymphomas display biased immunogenetic signatures indicating distinct antigen exposure histories. The existence of rare public stereotypes raises the intriguing possibility that common, pathogen-triggered, immune-mediated mechanisms may result in diverse B lymphoproliferations due to targeting versatile progenitor B cells and/or operating in particular microenvironments.

  • 639. Xochelli, Aliki
    et al.
    Kavakiotis, Ioannis
    Agathangelidis, Andreas
    Kienle, Dirk
    Davis, Zadie
    Yan, Xiao J.
    Shanafelt, Tait
    Boudjogra, Myriam
    Plevova, Karla
    Chatzouli, Maria
    Pedersen, Lone Bredo
    Veronese, Silvio
    Facco, Monica
    Moreno, Denis
    Chu, Charles C.
    Giudicelli, Veronique
    Panagiotidis, Panagiotis
    Vlahavas, Ioannis
    Anagnostopoulos, Achilles
    Maglaveras, Nikolaos
    Trentin, Livio
    Catherwood, Mark
    Montillo, Marco
    Geisler, Christian H.
    Langerak, Anton W.
    Pospisilova, Sarka
    Lefranc, Marie-Paule
    Chiorazzi, Nicholas
    Oscier, David
    Jelinek, Diane F.
    Stilgenbauer, Stephan
    Belessi, Chrysoula
    Ghia, Paolo
    Davi, Frederic
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Darzentas, Nikos
    Chouvarda, Ioanna
    Sutton, Lesley-Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Hadzidimitriou, Anastasia
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Charting Unique Signatures of Somatic Hypermutation Amongst Chronic Lymphocytic Leukemia Patients Expressing IGHV4-34 Clonotypic B Cell Receptors2014Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, nr 21Artikkel i tidsskrift (Annet vitenskapelig)
  • 640.
    Xochelli, Aliki
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Inst Appl Biosci, CERTH, Thessaloniki 57001, Greece..
    Oscier, David
    Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England..
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Inst Appl Biosci, CERTH, Thessaloniki 57001, Greece..
    Clonal B-cell lymphocytosis of marginal zone origin2017Inngår i: Baillière's Best Practice & Research: Clinical Haematology, ISSN 1521-6926, E-ISSN 1532-1924, Vol. 30, nr 1-2, s. 77-83Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Monoclonal B cell Lymphocytosis (MBL) is the term used to characterize individuals presenting with lymphocytosis in the absence of lymphadenopathy, organomegaly or any other features suggestive of an active disease. Based on the immunophenotypic findings, MBL cases are sub-categorized into chronic lymphocytic leukemia (CLL)-like, atypical CLL and non-CLL MBL. The latter corresponds to cases with immunophenotypic features suggestive of post germinal center derivation and still represents a diagnostic conundrum. Recent studies are starting to shed light on the true biological nature and clinical significance of this entity and have led to the introduction of the novel term clonal B lymphocytosis of marginal-zone origin (CBL-MZ); as well as the acknowledgement of CBL-MZ in the latest (2016) update of the WHO classification for lymphoid malignancies. Here we provide an overview of relevant research concerning non-CLL MBL and discuss clinicobiological implications and considerations.

  • 641. Xochelli, Aliki
    et al.
    Sutton, Lesley-Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Agathangelidis, Andreas
    Stalika, Evangelia
    Karypidou, Maria
    Marantidou, Fotini
    Navarro Lopez, Alba
    Papadopoulos, Giorgos
    Supikova, Jana
    Groenen, Patricia
    Boudjogra, Myriam
    Sundström, Christer
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Ponzoni, Maudilio
    Francova, Hana Skuhrova
    Anagnostopoulos, Achilles
    Pospisilova, Sarka
    Papadaki, Theodora
    Tzovaras, Dimitris
    Ghia, Paolo
    Pott, Christiane
    Davi, Frederic
    Campo, Elias
    Rosenquist, Richard Brandell
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hadzidimitriou, Anastasia
    Belessi, Chrysoula
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Molecular Evidence for Antigen Drive in the Natural History of Mantle Cell Lymphoma2015Inngår i: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 185, nr 6, s. 1740-1748Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    To further our understanding about antigen involvement in mantle cell Lymphoma (MCL), we analyzed the expression levels of activation-induced cytidine deaminase (AID), a key player in B-cell responses to antigen triggering, in 133 MCL cases; assessed the functionality of AID by evaluating in vivo class switch recombination in 52 MCL cases; and sought for indications of ongoing antigen interactions by exploring intraclonal diversification within 14 MCL cases. The AID full-length transcript and the most frequent splice variants (AID-Delta E4a, AID-Delta E) were detected in 128 (96.2%), 96 (72.2%), and 130 cases (97.7%), respectively. Higher AID full-Length transcript levels were significantly associated (P < 0.001) with Lack of somatic hypermutation within the clonotypic immunoglobulin heavy variable (IGHV) genes. Median AID transcript levels were higher in lymph node material compared to cases in which peripheral blood was analyzed, implying that clonal behavior is influenced by the microenvironment. Switched tumor-derived IGHV-IGHD-IGHJ transcripts were identified in 5 of 52 cases (9.6%), all of which displayed somatic hypermutation and AID-mRNA expression. Finally, although most cases exhibited low levels of intraclonal diversification, analysis of the mutational activity revealed a precise targeting of somatic hypermutation indicative of an active, ongoing interaction with antigen(s). Collectively, these findings strongly allude to antigen involvement in the natural history of MCL, further challenging the notion of antigen naivety.

  • 642.
    Young, Emma
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Recurrent Genetic Mutations in Lymphoid Malignancies2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    In recent years, the genetic landscape of B-cell derived lymphoid malignancies, including chronic lymphocytic leukemia (CLL), has been rapidly unraveled, identifying recurrent genetic mutations with potential clinical impact. Interestingly, ~30% of all CLL patients can be assigned to more homogeneous subsets based on the expression of a similar or “stereotyped” B-cell receptor (BcR). Considering that biased distribution of genetic mutations was recently indicated in specific stereotyped subsets, in paper I, we screened 565 subset cases, preferentially assigned to clinically aggressive subsets, and confirm the SF3B1 mutational bias in subset #2 (45%), but also report on similarly marked enrichment in subset #3 (46%). In contrast, NOTCH1 mutations were predominantly detected in subsets #1, #8, #59 and #99 (22-34%). This data further highlights a subset-biased acquisition of genetic mutations in the pathogenesis of at least certain subsets. Aberrant NF-κB signaling due to a deletion within the NFKBIE gene previously reported in CLL warranted extended investigation in other lymphoid malignancies. Therefore, in paper II, we screened 1460 patients with various lymphoid malignancies for NFKBIE deletions and reported enrichment in classical Hodgkin lymphoma (27%) and primary mediastinal B-cell lymphoma (PMBL) (23%). NFKBIE-deleted PMBL cases had higher rates of chemorefractoriness and inferior overall survival (OS). NFKBIE-deletion status remained an independent prognostic marker in multivariate analysis. EGR2 mutations were recently reported in advanced stage CLL patients; thus, in paper III we screened 2403 CLL patients for mutations in EGR2. An overall mutational frequency of 3.8% was reported and EGR2 mutations were associated with younger age, advanced stage and del(11q). EGR2 mutational status remained an independent marker of poor outcome in multivariate analysis, both in the screening and validation cohorts. Whole-genome sequencing (WGS) of 70 CLL cases, assigned to poor-prognostic subsets #1 and #2 and indolent subset #4, were investigated in Paper IV and revealed a similar skewing of SF3B1 mutations in subset #2 and NOTCH1 mutations in subset #1 to that reported in Paper I. Additionally, an increased frequency of the recently proposed CLL driver gene RPS15 was observed in subset #1. Finally, novel non-coding mutational biases were detected in both subset #1 and #2 that warrant further investigation.

    Delarbeid
    1. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors
    Åpne denne publikasjonen i ny fane eller vindu >>Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors
    Vise andre…
    2016 (engelsk)Inngår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, nr 8, s. 959-967Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22-34%), often in association with trisomy 12, and was significantly different (P<0.001) to the frequency observed in subset #2 (4%, aggressive disease, variable somatic hypermutation status) and subset #4 (1%, indolent disease, mutated immunoglobulin genes). Interestingly, subsets harboring a high frequency of NOTCH1 mutations were found to carry few (if any) SF3B1 mutations. This starkly contrasts with subsets #2 and #3 where, despite their immunogenetic differences, SF3B1 mutations occurred in 45% and 46% of cases, respectively. In addition, mutations within TP53, whilst enriched in subset #1 (16%), were rare in subsets# 2 and #8 (both 2%), despite all being clinically aggressive. All subsets were negative for MYD88 mutations, whereas BIRC3 mutations were infrequent. Collectively, this striking bias and skewed distribution of mutations and cytogenetic aberrations within specific chronic lymphocytic leukemia subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s).

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-304419 (URN)10.3324/haematol.2016.141812 (DOI)000381941900019 ()27198719 (PubMedID)
    Tilgjengelig fra: 2016-10-05 Laget: 2016-10-05 Sist oppdatert: 2017-11-30bibliografisk kontrollert
    2. Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma
    Åpne denne publikasjonen i ny fane eller vindu >>Frequent NFKBIE deletions are associated with poor outcome in primary mediastinal B-cell lymphoma
    Vise andre…
    2016 (engelsk)Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 128, nr 23, s. 2666-2670Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    We recently reported a truncating deletion in the NFKBIE gene, which encodes IκBϵ, a negative feedback regulator of NF-κB, in clinically aggressive chronic lymphocytic leukemia (CLL). Preliminary data indicate enrichment of NFKBIE aberrations in other lymphoid malignancies, hence we screened a large patient cohort (n=1460) diagnosed with different lymphoid neoplasms. While NFKBIE deletions were infrequent in follicular lymphoma, splenic marginal-zone lymphoma, and T-cell acute lymphoblastic leukemia (<2%), slightly higher frequencies were seen in diffuse large B-cell lymphoma, mantle cell lymphoma, and primary CNS lymphoma (3-4%). In contrast, a remarkably high frequency of NFKBIE aberrations (46/203 cases, 22.7%) was observed in primary mediastinal B-cell lymphoma (PMBL) and Hodgkin lymphoma (3/11 cases, 27.3%). NFKBIE-deleted PMBL patients were more often therapy-refractory (P=.022) and displayed inferior outcome compared to wildtype patients (5-year survival: 59% vs. 78%; P=.034); however they appeared to benefit from radiotherapy (P=.022) and rituximab-containing regimens (P=.074). NFKBIEaberrations remained an independent factor in multivariate analysis (P=.003), also when restricting to immunochemotherapy-treated patients (P=.008). Whole-exome sequencing and gene expression-profiling verified the importance of NF-κB deregulation in PMBL. In summary, we identify NFKBIE aberrations as a common genetic event across B-cell malignancies and highlight NFKBIE deletions as a novel poor-prognostic marker in PMBL.

    HSV kategori
    Forskningsprogram
    Molekylär genetik; Patologi
    Identifikatorer
    urn:nbn:se:uu:diva-314939 (URN)10.1182/blood-201603-704528 (DOI)000392652300015 ()27670424 (PubMedID)
    Forskningsfinansiär
    German Research Foundation (DFG), DA1787/1-1Swedish Cancer SocietySwedish Research Council
    Merknad

    L.M., D.N., and E.Y. contributed equally to this study as joint first authors.

    R.R. and F.D. contributed equally as joint senior authors.

    Tilgjengelig fra: 2017-02-07 Laget: 2017-02-07 Sist oppdatert: 2020-01-03bibliografisk kontrollert
    3. EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia
    Åpne denne publikasjonen i ny fane eller vindu >>EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia
    Vise andre…
    2017 (engelsk)Inngår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, nr 7, s. 1547-1554Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n = 1283) and two validation cohorts (UK CLL4 trial patients, n = 366; CLL Research Consortium (CRC) patients, n = 490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2- mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.

    HSV kategori
    Forskningsprogram
    Onkologi
    Identifikatorer
    urn:nbn:se:uu:diva-314928 (URN)10.1038/leu.2016.359 (DOI)000404745300009 ()27890934 (PubMedID)
    Merknad

    E.Y. and D.N. contributed equally to this study as joint first authors.

    R.R. and F.D. contributed equally as joint senior authors.

    Tilgjengelig fra: 2017-02-07 Laget: 2017-02-07 Sist oppdatert: 2017-09-28bibliografisk kontrollert
    4. Whole-genome sequencing in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors
    Åpne denne publikasjonen i ny fane eller vindu >>Whole-genome sequencing in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-302024 (URN)
    Eksternt samarbeid:
    Forskningsfinansiär
    Swedish Cancer SocietySwedish Research Council
    Tilgjengelig fra: 2016-08-28 Laget: 2016-08-28 Sist oppdatert: 2018-01-10
  • 643.
    Young, Emma
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Noerenberg, Daniel
    Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
    Mansouri, Larry
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ljungström, Viktor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Frick, Mareike
    Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
    Sutton, Lesley Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Blakemore, Stuart James
    Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
    Galan-Sousa, Joel
    Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
    Plevova, Karla
    Central European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
    Baliakas, Panagiotis
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Rossi, Davide
    Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy and Hematology, Oncology Institute of Southern Switzerland and Institute of Oncology Research, Bellinzona, Switzerland.
    Ruth, Clifford
    Oxford National Institute for Health Research Biomedical Research Centre and Department of Oncology, University of Oxford, Oxford, UK.
    Roos-Weil, Damien
    INSERM, U1170, Institut Gustave Roussy, Villejuif, France.
    Navrklova, Veronika
    European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
    Dörken, Bernd
    Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
    Schmitt, Clemens A
    Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany.
    Ekström Smedby, Karin
    Department of Medicine Solna, Clinical Epidemiology Unit, Karolinska Institutet, and Hematology Center, Karolinska University Hospital, Stockholm, Sweden.
    Juliusson, Gunnar
    Department of Laboratory Medicine, Stem Cell Center, Lund University, Lund, Sweden.
    Giacopelli, Brian
    Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
    Blachly, James
    Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
    Belessi, Chrysoula
    Hematology Department, General Hospital of Nikea, Piraeus, Greece.
    Panayiotidis, Panayiotis
    First Department of Propaedeutic Medicine, School of Medicine, University of Athens, Athens, Greece.
    Chiorazzi, Nicholas
    Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
    Davi, Frédéric
    Laboratory of Hematology and Universite Pierre et Marie Curie, Hopital Pitie-Salpetriere, Paris, France.
    Langerak, Anton W
    Department of Immunology, Laboratory for Medical Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
    Oscier, David
    Department of Molecular Pathology, Royal Bournemouth Hospital, Bournemouth, UK.
    Schuh, Anna
    Oxford National Institute for Health Research Biomedical Research Centre and Department of Oncology, University of Oxford, Oxford, UK.
    Gaidano, Gianluca
    Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
    Ghia, Paolo
    Università Vita-Salute San Raffaele, Milan, Italy and Division of Experimental Oncology and Department of Onco-Hematology, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy.
    Xu, Wei
    Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
    Fan, Lei
    Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
    Bernard, Olivier A
    INSERM, U1170, Institut Gustave Roussy, Villejuif, France.
    Nguyen-Khac, Florence
    Laboratory of Hematology and Universite Pierre et Marie Curie, Hopital Pitie-Salpetriere, Paris, France.
    Rassenti, Laura Z
    Division of Hematology/Oncology, Department of Medicine, University of California at San Diego/Moores Cancer Center, La Jolla, CA, USA.
    Li, Jianyonglm
    Department of Hematology, the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing, China.
    Kipps, Thomas J
    Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA.
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Sweden and Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
    Pospisilova, Sarka
    Central European Institute of Technology, Masaryk University and University Hospital Brno, Brno, Czech Republic.
    Zenz, Thorsten
    Department of Molecular Therapy in Haematology and Oncology (G250) and Department of Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
    Strefford, Jonathan
    Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Damm, Frederik
    Department of Hematology, Oncology, and Tumor Immunology, Charité, University Medical Center, Berlin, Germany; German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany and Berlin Institute of Health (BIH), Berlin, Germany .
    EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia2017Inngår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 31, nr 7, s. 1547-1554Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n = 1283) and two validation cohorts (UK CLL4 trial patients, n = 366; CLL Research Consortium (CRC) patients, n = 490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2- mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%) and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.

  • 644.
    Young, Emma
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Norenberg, Daniel
    Charite, Dept Hematol Oncol & Tumor Immunol, D-13353 Berlin, Germany..
    Ljungstrom, Viktor
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Mansouri, Larry
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Plevova, Karla
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Baliakas, Panagiotis
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Rossi, Davide
    Amedeo Avogadro Univ Eastern Piedmont, Novara, Italy..
    Navrkalova, Veronika
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Sutton, Lesley-Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Smedby, Karin Ekstrom
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden..
    Juliusson, Gunnar
    Lund Univ, Dept Lab Med, Stem Cell Ctr Hematol & Transplantat, Lund, Sweden..
    Belessi, Chrysoula
    Gen Hosp Nikea, Dept Hematol, Piraeus, Greece..
    Panagiotidis, Panagiotis
    Univ Athens, Sch Med, Dept Propaedeut Med 1, GR-11527 Athens, Greece..
    Chiorazzi, Nicholas
    Feinstein Inst Med Res, North Shore Long Isl Jewish Hlth Syst, Manhasset, NY USA..
    Davi, Frederic
    Hop La Pitie Salpetriere, Hematol Lab, Paris, France.;Univ Paris 06, 12 Rue Cuvier, Paris, France..
    Langerak, Anton W.
    Univ Med Ctr Rotterdam, Erasmus MC, Dept Immunol, Rotterdam, Netherlands..
    Gaidano, Gianluca
    Ghia, Paolo
    IRCCS, San Raffaele Sci Inst, Div Expt Oncol, Milan, Italy.;IRCCS, San Raffaele Sci Inst, Dept Oncohematol, Milan, Italy..
    Stamatopoulos, Kostas
    CERTH, Inst Appl Biosci, Thessaloniki, Greece..
    Pospisilova, Sarka
    Masaryk Univ, Cent European Inst Technol, Brno, Czech Republic..
    Zenz, Thorsten
    Univ Heidelberg Hosp, Dept Med 5, Heidelberg, Germany..
    Rosenquist, Richard
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Damm, Frederik
    Charite, Dept Hematol Oncol & Tumor Immunol, D-13353 Berlin, Germany..
    EGR2 mutations in chronic lymphocytic leukemiam - a new bad player?2015Inngår i: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 56, nr S1, s. 83-85Artikkel i tidsskrift (Annet vitenskapelig)
  • 645.
    Zaghlool, Ammar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Halvardson, Jonatan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Zhao, Jin J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Etemadikhah, Mitra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Kalushkova, Antonia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Konska, Katarzyna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jernberg-Wiklund, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Thuresson, Ann-Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Feuk, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    A Role for the Chromatin-Remodeling Factor BAZ1A in Neurodevelopment2016Inngår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 37, nr 9, s. 964-975Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Chromatin-remodeling factors are required for a wide range of cellular and biological processes including development and cognition, mainly by regulating gene expression. As these functions would predict, deregulation of chromatin-remodeling factors causes various disease syndromes, including neurodevelopmental disorders. Recent reports have linked mutations in several genes coding for chromatin-remodeling factors to intellectual disability (ID). Here, we used exome sequencing and identified a nonsynonymous de novo mutation in BAZ1A (NM_182648.2:c.4043T > G, p.Phe1348Cys), encoding the ATP-utilizing chromatin assembly and remodeling factor 1 (ACF1), in a patient with unexplained ID. ACF1 has been previously reported to bind to the promoter of the vitamin D receptor (VDR)-regulated genes and suppress their expression. Our results show that the patient displays decreased binding of ACF1 to the promoter of the VDR-regulated gene CYP24A1. Using RNA sequencing, we find that the mutation affects the expression of genes involved in several pathways including vitamin D metabolism, Wnt signaling and synaptic formation. RNA sequencing of BAZ1A knockdown cells and Baz1a knockout mice revealed that BAZ1A carry out distinctive functions in different tissues. We also demonstrate that BAZ1A depletion influence the expression of genes important for nervous system development and function. Our data point to an important role for BAZ1A in neurodevelopment, and highlight a possible link for BAZ1A to ID.

  • 646.
    Zavos, A.
    et al.
    Senol Hellen Soc, Athens, Greece..
    Valachis, Antonis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Malarsjukhuset, Dept Oncol, S-63188 Eskilstuna, Sweden..
    Risk of chemotherapy-induced amenorrhea in patients with breast cancer: a systematic review and meta-analysis2016Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 55, nr 6, s. 664-670Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Background: The aim of the study was to calculate the rate of chemotherapy-induced amenorrhea (CIA) after treatment with different adjuvant therapies in patients with breast cancer and to evaluate the risk factors for CIA based on the quality of evidence.Patient and methods: A search of PubMed and ISI Web of Science was performed. All published trials with female breast cancer patients who received adjuvant chemotherapy and presented data on the rate of CIA were considered eligible. The pooled rates of CIA were calculated by random effects model. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for each potential risk factor for CIA by using the generic inverse weighted method.Results: We identified 580 potentially relevant studies, of which 75 were included in the analysis. Among 75 eligible studies, 19 different definitions of CIA have been used. The pooled rate of CIA was 55% (95% CI 50-60%) including 23 673 patients from 74 studies. The rate of CIA was increased by age with an estimate of 26% (95% CI 12-43%), 39% (95% CI 31-58%), and 77% (95% CI 71-83%) for women<35, 35-40, and>40 years old, respectively. Two risk factors were associated with the occurrence of CIA and were supported by strong level of evidence: older age (>40 years old), and the use of tamoxifen.Conclusions: This meta-analysis summarized the updated evidence on the impact of different adjuvant treatment regimens for breast cancer in menstruation and could serve as a helpful guide for oncologists during the discussion with their patients on fertility issues before decision on adjuvant therapy is made. A uniform definition of CIA is essential in future studies to make the interpretation of results more reliable.

  • 647.
    Zetterling, Maria
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Roodakker, Kenney Roy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Berntsson, Shala Ghaderi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Edqvist, Per-Henrik D
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Latini, Francesco
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Landtblom, Anne-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi. Linköping Univ, Ctr Med Image Sci & Visualizat, Linköping, Sweden.
    Pontén, Fredrik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Larsson, Elna-Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Smits, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi. Danish Epilepsy Ctr, Dianalund, Denmark.
    Extension of diffuse low-grade gliomas beyond radiological borders as shown by the coregistration of histopathological and magnetic resonance imaging data2016Inngår i: Journal of Neurosurgery, ISSN 0022-3085, E-ISSN 1933-0693, Vol. 125, nr 5, s. 1155-1166Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Magnetic resonance imaging tends to underestimate the extent of diffuse low-grade gliomas (DLGGs). With the aim of studying the presence of tumor cells outside the radiological border, the authors developed a method of correlating MRI findings with histological data in patients with suspected DLGGs in whom en bloc resections were performed.

    Methods: Five patients with suspected DLGG suitable for en bloc resection were recruited from an ongoing prospective study. Sections of the entire tumor were immunostained with antibodies against mutated IDH1 protein (IDH1-R132H). Magnetic resonance images were coregistered with corresponding IDH1 images. The growth pattern of tumor cells in white and gray matter was assessed in comparison with signal changes on corresponding MRI slices.

    Results: Neuropathological assessment revealed DLGG in 4 patients and progression to WHO Grade III glioma in 1 patient. The tumor core consisted of a high density of IDH1-R132H–positive tumor cells and was located in both gray and white matter. Tumor cells infiltrated along the peripheral fibers of the white matter tracts. In all cases, tumor cells were found outside the radiological tumor border delineated on T2-FLAIR MRI sequences.

    Conclusions: The authors present a new method for the coregistration of histological and radiological characteristics of en bloc–removed infiltrative brain tumors that discloses tumor invasion at the radiological tumor borders. This technique can be applied to evaluate the sensitivity of alternative imaging methods to detect scattered tumor cells at tumor borders. Accurate methods for detection of infiltrative tumor cells will improve the possibility of performing radical tumor resection. In future studies, the method could also be used for in vivo studies of tumor invasion.

  • 648.
    Zhang, Xiaonan
    et al.
    Linkoping Univ, Dept Med & Hlth Sci, SE-58183 Linkoping, Sweden;Karolinska Inst, Dept Oncol Pathol, SE-17176 Stockholm, Sweden.
    De Milito, Angelo
    Karolinska Inst, Dept Oncol Pathol, SE-17176 Stockholm, Sweden.
    Demiroglu-Zergeroglu, Asuman
    Gebze Tech Univ, Dept Mol Biol & Genet, TR-41400 Gebze, Kocaeli, Turkey.
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    D'Arcy, Padraig
    Linkoping Univ, Dept Med & Hlth Sci, SE-58183 Linkoping, Sweden.
    Linder, Stig
    Linkoping Univ, Dept Med & Hlth Sci, SE-58183 Linkoping, Sweden;Karolinska Inst, Dept Oncol Pathol, SE-17176 Stockholm, Sweden.
    Eradicating Quiescent Tumor Cells by Targeting Mitochondrial Bioenergetics2016Inngår i: TRENDS IN CANCER, ISSN 2405-8025, Vol. 2, nr 11, s. 657-663Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The presence of quiescent cell populations in solid tumors represents a major challenge for disease eradication. Such cells are generally present in poorly vascularized tumor areas, show limited sensitivity to traditional chemotherapeutical drugs, and tend to resume proliferation, resulting in tumor reseeding and growth. There is growing recognition of the importance of developing therapies that target these quiescent cell populations to achieve long-lasting remission. Recent studies have shown that the combination of hypoxia and reduced nutrient availability in poorly vascularized areas results in limited tumor metabolic plasticity coupled with an increased sensitivity to perturbations in mitochondrial flux. Targeting of mitochondrial bioenergetics in these quiescent cell tumor populations may enable tumor eradication and improve the prognosis of patients with cancer.

  • 649.
    Zhang, Xiaonan
    et al.
    Linkoping Univ, Dept Med & Hlth Sci, SE-58183 Linkoping, Sweden.;Karolinska Inst, Dept Oncol Pathol, SE-17176 Stockholm, Sweden..
    de Milito, Angelo
    Karolinska Inst, Dept Oncol Pathol, SE-17176 Stockholm, Sweden..
    Olofsson, Maria Hagg
    Karolinska Inst, Dept Oncol Pathol, SE-17176 Stockholm, Sweden..
    Gullbo, Joachim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    D'Arcy, Padraig
    Linkoping Univ, Dept Med & Hlth Sci, SE-58183 Linkoping, Sweden.;Karolinska Inst, Dept Oncol Pathol, SE-17176 Stockholm, Sweden..
    Linder, Stig
    Linkoping Univ, Dept Med & Hlth Sci, SE-58183 Linkoping, Sweden.;Karolinska Inst, Dept Oncol Pathol, SE-17176 Stockholm, Sweden..
    Targeting Mitochondrial Function to Treat Quiescent Tumor Cells in Solid Tumors2015Inngår i: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 16, nr 11, s. 27313-27326Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The disorganized nature of tumor vasculature results in the generation of microenvironments characterized by nutrient starvation, hypoxia and accumulation of acidic metabolites. Tumor cell populations in such areas are often slowly proliferating and thus refractory to chemotherapeutical drugs that are dependent on an active cell cycle. There is an urgent need for alternative therapeutic interventions that circumvent growth dependency. The screening of drug libraries using multicellular tumor spheroids (MCTS) or glucose-starved tumor cells has led to the identification of several compounds with promising therapeutic potential and that display activity on quiescent tumor cells. Interestingly, a common theme of these drug screens is the recurrent identification of agents that affect mitochondrial function. Such data suggest that, contrary to the classical Warburg view, tumor cells in nutritionally-compromised microenvironments are dependent on mitochondrial function for energy metabolism and survival. These findings suggest that mitochondria may represent an Achilles heel for the survival of slowly-proliferating tumor cells and suggest strategies for the development of therapy to target these cell populations.

  • 650.
    Zucca, Emanuele
    et al.
    Oncol Inst Southern Switzerland, Div Med Oncol, Bellinzona, Switzerland;Inst Oncol Res, Bellinzona, Switzerland;Bern Univ Hosp, Dept Med Oncol, Inselspital, Bern, Switzerland.
    Rondeau, Stephanie
    SAKK Coordinating Ctr, Bern, Switzerland.
    Vanazzi, Anna
    European Inst Oncol IRCCS, Clin Hematooncol, Milan, Italy.
    Ostenstad, Bjorn
    Oslo Univ Hosp, Dept Oncol, Oslo, Norway.
    Mey, Ulrich J. M.
    Kantonsspital Graubunden, Med Oncol & Hematol, Chur, Switzerland.
    Rauch, Daniel
    Spital Thun Simmenthal, Div Oncol, Thun, Switzerland.
    Wahlin, Bjorn E.
    Karolinska Inst, Unit Hematol, Dept Med Huddinge, Stockholm, Sweden.
    Hitz, Felicitas
    Kantonsspital St Gallen, Oncol Hematol, St Gallen, Switzerland.
    Hernberg, Micaela
    Helsinki Univ Hosp, Ctr Comprehens Canc, Dept Oncol, Helsinki, Finland.
    Johansson, Ann-Sofie
    Norrlands Univ Sjukhus, Dept Oncol, Umea, Sweden.
    Brown, Peter de Nully
    Rigshosp, Dept Hematol, Copenhagen, Denmark.
    Hagberg, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Ferreri, Andres J. M.
    IRCCS San Raffaele Sci Inst, Unit Lymphoid Malignancies, Milan, Italy.
    Lohri, Andreas
    Med Univ Clin, Dept Oncol Hematol, Liestal, Switzerland.
    Novak, Urban
    Bern Univ Hosp, Dept Med Oncol, Inselspital, Bern, Switzerland.
    Zander, Thilo
    Luzerner Kantonsspital, Dept Oncol, Luzern, Switzerland.
    Bersvendsen, Hanne
    Univ Hosp North Norway, Dept Oncol, Tromso, Norway.
    Bargetzi, Mario
    Kantonsspital Aarau, Div Hematol Oncol, Aarau, Switzerland.
    Mingrone, Walter
    Kantonsspital Olten, Dept Med Oncol, Olten, Switzerland.
    Krasniqi, Fatime
    Univ Hosp Basel, Dept Oncol, Basel, Switzerland.
    Dirnhofer, Stefan
    Univ Hosp Basel, Inst Pathol, Basel, Switzerland.
    Hayoz, Stefanie
    SAKK Coordinating Ctr, Bern, Switzerland.
    Hawle, Hanne
    SAKK Coordinating Ctr, Bern, Switzerland.
    Vilei, Simona Berardi
    SAKK Coordinating Ctr, Bern, Switzerland.
    Ghielmini, Michele
    Oncol Inst Southern Switzerland, Div Med Oncol, Bellinzona, Switzerland.
    Kimby, Eva
    Karolinska Inst, Unit Hematol, Dept Med Huddinge, Stockholm, Sweden.
    Caspar, Clemens
    Koberle, Dieter
    Zenhausern, Reinhard
    Jost, Lorenz M.
    Mach, Nicolas
    Voegeli, Michele
    Tscherry, Georg
    Fischer, Natalie
    Burkhard, Roger
    Schmid, Mathias
    Panagiotis, Samaras
    Munksgaard, Lars
    Vasala, Kaija
    Lehtinen, Tuula
    Jyrkkio, Sirkku
    Ekanger, Roald
    Rolke, Jurgen
    Meyer, Peter
    Maisenholder, Martin
    Eidem, Monika
    Radlund, Anders
    Lagerlof, Ingemar
    Brandefors, Lena
    Ola, Linde Prime N.
    Arnljots, Kristina
    Strandberg, Maria
    Short regimen of rituximab plus lenalidomide in follicular lymphoma patients in need of first-line therapy2019Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 134, nr 4, s. 353-362Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The SAKK 35/10 phase 2 trial, developed by the Swiss Group for Clinical Cancer Research and the Nordic Lymphoma Group, compared the activity of rituximab vs rituximab plus lenalidomide in untreated follicular lymphoma patients in need of systemic therapy. Patients were randomized to rituximab (375 mg/m(2) IV on day 1 of weeks 1-4 and repeated during weeks 12-15 in responding patients) or rituximab (same schedule) in combination with lenalidomide (15 mg orally daily for 18 weeks). Primary end point was complete response (CR)/unconfirmed CR (CRu) rate at 6 months. In total, 77 patients were allocated to rituximab monotherapy and 77 to the combination (47% poor-risk Follicular Lymphoma International Prognostic Index score in each arm). A significantly higher CR/CRu rate at 6 months was documented in the combination arm by the investigators (36%; 95% confidence interval [CI], 26%-48% vs 25%; 95% CI, 16%-36%) and confirmed by an independent response review of computed tomography scans only (61%; 95% CI, 49%-72% vs 36%; 95% CI, 26%-48%). After a median follow-up of 4 years, significantly higher 30-month CR/CRu rates and longer progression-free survival (PFS) and time to next treatment (TTNT) were observed for the combination. Overall survival (OS) rates were similar in both arms (>= 90%). Toxicity grade >= 3 was more common in the combination arm (56% vs 22% of patients), mainly represented by neutropenia (23% vs 7%). Addition of lenalidomide to rituximab significantly improved CR/CRu rates, PFS, and TTNT, with expected higher, but manageable toxicity. The excellent OS in both arms suggests that chemotherapy-free strategies should be further explored.

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