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  • 51.
    Parry, Marina
    et al.
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Rose-Zerilli, Matthew J. J.
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Ljungström, Viktor
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Gibson, Jane
    Univ Southampton, Ctr Biol Sci, Southampton, Hants, England..
    Wang, Jun
    Queen Mary Univ London, Barts Canc Inst, Ctr Mol Oncol, London, England..
    Walewska, Renata
    Royal Bournemouth Hosp, Dept Pathol, Bournemouth, Dorset, England..
    Parker, Helen
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Parker, Anton
    Royal Bournemouth Hosp, Dept Pathol, Bournemouth, Dorset, England..
    Davis, Zadie
    Royal Bournemouth Hosp, Dept Pathol, Bournemouth, Dorset, England..
    Gardiner, Anne
    Royal Bournemouth Hosp, Dept Pathol, Bournemouth, Dorset, England..
    McIver-Brown, Neil
    Royal Bournemouth Hosp, Dept Pathol, Bournemouth, Dorset, England..
    Kalpadakis, Christina
    Univ Crete, Dept Hematol, Sch Med, Iraklion, Greece..
    Xochelli, Aliki
    Ctr Res & Technol, Inst Appl Biosci, Thessaloniki, Greece..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Fazi, Claudia
    Univ Vita Salute San Raffaele, Div Mol Oncol, Dept Oncohaematol, IRCCS Ist Sci San Raffaele, Milan, Italy..
    de Castro, David Gonzalez
    Inst Canc Res, Heamatooncol Unit, Div Mol Pathol, Sutton, Surrey, England..
    Dearden, Claire
    Inst Canc Res, Heamatooncol Unit, Div Mol Pathol, Sutton, Surrey, England..
    Pratt, Guy
    Univ Birmingham, Sch Canc Studies, Birmingham, W Midlands, England.;Heart England NHS Fdn Trust, Dept Haematol, Birmingham, W Midlands, England..
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Ashton-Key, Margaret
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Forconi, Francesco
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Collins, Andrew
    Univ Southampton, Fac Med, Genet Epidemiol & Bioinformat, Southampton SO9 5NH, Hants, England..
    Ghia, Paolo
    Univ Vita Salute San Raffaele, Div Mol Oncol, Dept Oncohaematol, IRCCS Ist Sci San Raffaele, Milan, Italy..
    Matutes, Estella
    Univ Barcelona, Haematopathol Unit, Hosp Clin, Barcelona, Spain..
    Pangalis, Gerassimos
    Athens Med Ctr, Dept Hematol, Athens, Greece..
    Stamatopoulos, Kostas
    Ctr Res & Technol, Inst Appl Biosci, Thessaloniki, Greece.;G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Oscier, David
    Strefford, Jonathan C.
    Univ Southampton, Fac Med, Canc Sci, Southampton SO9 5NH, Hants, England..
    Genetics and Prognostication in Splenic Marginal Zone Lymphoma: Revelations from Deep Sequencing2015Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 21, nr 18, s. 4174-4183Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose:<bold> </bold>Mounting evidence supports the clinical significance of gene mutations and immunogenetic features in common mature B-cell malignancies. Experimental Design:<bold> </bold>We undertook a detailed characterization of the genetic background of splenic marginal zone lymphoma (SMZL), using targeted resequencing and explored potential clinical implications in a multinational cohort of 175 patients with SMZL. Results: We identified recurrent mutations in TP53 (16%), KLF2 (12%), NOTCH2 (10%), TNFAIP3 (7%), MLL2 (11%), MYD88 (7%), and ARID1A (6%), all genes known to be targeted by somatic mutation in SMZL. KLF2 mutations were early, clonal events, enriched in patients with del(7q) and IGHV1-2*04 B-cell receptor immunoglobulins, and were associated with a short median time to first treatment (0.12 vs. 1.11 years; P = 0.01). In multivariate analysis, mutations in NOTCH2 [HR, 2.12; 95% confidence interval (CI), 1.02-4.4; P = 0.044] and 100% germline IGHV gene identity (HR, 2.19; 95% CI, 1.05-4.55; P = 0.036) were independent markers of short time to first treatment, whereas TP53 mutations were an independent marker of short overall survival (HR, 2.36; 95 % CI, 1.08-5.2; P = 0.03). Conclusions:<bold> </bold>We identify key associations between gene mutations and clinical outcome, demonstrating for the first time that NOTCH2 and TP53 gene mutations are independent markers of reduced treatment-free and overall survival, respectively.

  • 52. Ponthan, Frida
    et al.
    Wickström, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Klinisk farmakologi.
    Gleissman, Helena
    Fuskevåg, Ole M.
    Segerström, Lova
    Sveinbjörnsson, Baldur
    Redfern, Christopher P. F.
    Eksborg, Staffan
    Kogner, Per
    Johnsen, John I.
    Celecoxib Prevents Neuroblastoma Tumor Development and Potentiates the Effect of Chemotherapeutic Drugs In vitro and In vivo2007Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, nr 3, s. 1036-1044Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Neuroblastoma is the most common and deadly solid tumor of childhood. Cyclooxygenase-2 is expressed in clinical neuroblastoma tumors and cell lines and inhibitors of this enzyme induce apoptosis in human neuroblastoma cells in vitro and in neuroblastoma xenografts in vivo. We hypothesized that the cyclooxygenase-2- specific inhibitor celecoxib could enhance the cytotoxic effect of chemotherapeutic drugs currently used in neuroblastoma treatment. Furthermore, we investigated if prophylactic treatment with celecoxib could prevent neuroblastoma tumor development in vivo. Experimental Design: Neuroblastoma cell cytotoxicity of chemotherapeutic drugs in combination with celecoxib was examined. In vivo, athymic rats carrying established SH-SY5Y xenografts were treated with celecoxib in combination with irinotecan, doxorubicin or etoposide, or with either drug alone. For prevention studies, rats received celecoxib in the diet, 250 to 2,500 ppm, from the time of tumor cell injection. Results: Celecoxib induced a synergistic or an additive cytotoxic effect in combination with doxorubicin, etoposide, irinotecan or vincristine in vitro. In vivo, treatment with celecoxib in combination with irinotecan or doxorubicin induced a significant growth inhibition of established neuroblastoma tumors. Rats receiving celecoxib in the diet showed a distinct dose-dependent delay in tumor development compared with untreated rats. Plasma levels of celecoxib were comparable with levels obtainable in humans. Conclusions: Celecoxib potentiates the antitumor effect of chemotherapeutic drugs currently used in neuroblastoma treatment, which argues for clinical trials combining these drugs. Celecoxib could also be a potential drug for treatment of minimal residual disease.

  • 53.
    Ramachandran, Mohanraj
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Yu, Di
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Dyczynski, Matheus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Pathol & Oncol, CCK, Stockholm, Sweden..
    Baskaran, Sathishkumar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Zhang, Lei
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lulla, Aleksei
    Institute of Technology, University of Tartu, Estonia..
    Lulla, Valeria
    Institute of Technology, University of Tartu, Estonia..
    Saul, Sirle
    Institute of Technology, University of Tartu, Estonia..
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Dimberg, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Merits, Andres
    Institute of Technology, University of Tartu, Estonia..
    Leja-Jarblad, Justyna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Essand, Magnus
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi.
    Safe and effective treatment of experimental neuroblastoma and glioblastoma using systemically administered triple microRNA-detargeted oncolytic Semliki Forest virus2017Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, nr 6, s. 1519-1530Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE:

    Glioblastoma multiforme (GBM) and high-risk neuroblastoma are cancers with poor outcome. Immunotherapy in the form of neurotropic oncolytic viruses is a promising therapeutic strategy for these malignancies. Here we evaluate the oncolytic potential of the neurovirulent and partly interferon (IFN)-β-resistant Semliki Forest virus (SFV)-4 in GBMs and neuroblastomas. To reduce neurovirulence we constructed SFV4miRT, which is attenuated in normal CNS cells through insertion of microRNA target sequences for miR124, miR125, miR134 Experimental Design:Oncolytic activity of SFV4miRT was examined in mouse neuroblastoma and GBM cell lines and in patient-derived human glioblastoma cell cultures (HGCC). In vivo neurovirulence and therapeutic efficacy was evaluated in two syngeneic orthotopic glioma models (CT-2A, GL261) and syngeneic subcutaneous neuroblastoma model (NXS2). The role of IFN-β in inhibiting therapeutic efficacy was investigated.

    RESULTS:

    The introduction of microRNA target sequences reduced neurovirulence of SFV4 in terms of attenuated replication in mouse CNS cells and ability to cause encephalitis when administered intravenously. A single intravenous injection of SFV4miRT prolonged survival and cured 4 of 8 mice (50%) with NXS2 and 3 of 11 mice (27%) with CT-2A, but not for GL261 tumor bearing mice. In vivo therapeutic efficacy in different tumor models inversely correlated to secretion of IFN-β by respective cells upon SFV4 infection in vitro Similarly, killing efficacy of HGCC lines inversely correlated to IFN-β response and interferon-α⁄β receptor (IFNAR)-1 expression.

    CONCLUSIONS:

    SFV4miRT has reduced neurovirulence, while retaining its oncolytic potential. SFV4miRT is an excellent candidate for treatment of GBMs and neuroblastomas with low IFN-β secretion.

  • 54. Schmidt, Marcus
    et al.
    Hellwig, Birte
    Hammad, Seddik
    Othman, Amnah
    Lohr, Miriam
    Chen, Zonglin
    Böhm, Daniel
    Gebhard, Susanne
    Petry, Ilka Brigitte
    Lebrecht, Antje
    Cadenas, Cristina
    Marchan, Rosemarie
    Stewart, Joanna
    Solbach, Christine
    Holmberg, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Edlund, Karolina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Molekylär och morfologisk patologi.
    Göransson Kultima, Hanna
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Rody, Achim
    Berglund, Anders
    Lambe, Mats
    Isaksson, Anders
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Botling, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Molekylär och morfologisk patologi.
    Karn, Thomas
    Müller, Volkmar
    Gerhold-Ay, Aslihan
    Cotarelo, Christina
    Sebastian, Martin
    Kronenwett, Ralf
    Bojar, Hans
    Lehr, Hans-Anton
    Sahin, Ugur
    Koelbl, Heinz
    Gehrmann, Mathias
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi, Molekylär och morfologisk patologi.
    Rahnenführer, Jörg
    Hengstler, Jan G
    A comprehensive analysis of human gene expression profiles identifies stromal immunoglobulin kappa C as a compatible prognostic marker in human solid tumors2012Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 18, nr 9, s. 2695-2703Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE:

    Although the central role of the immune system for tumor prognosis is generally accepted a single robust marker is not yet available.

    EXPERIMENTAL DESIGN:

    Based on ROC (receiver operating characteristic) analyses robust markers were identified from a 60 gene B-cell derived metagene and analyzed in gene expression profiles of 1810 breast cancer, 1056 non-small cell lung cancer, 513 colorectal and 426 ovarian cancer patients. Protein and RNA levels were examined in paraffin embedded tissue of 330 breast cancer patients. The cell types were identified using immunohistochemical co-staining and confocal fluorescence microscopy.

    RESULTS:

    We identified immunoglobulin kappa C (IGKC) which as a single marker is similarly predictive and prognostic as the entire B-cell metagene. IGKC was consistently associated with metastasis free survival across different molecular subtypes in node-negative breast cancer (n=965) and predicted response to anthracycline-based neoadjuvant chemotherapy (n=845) [P less than 0.001]. In addition, IGKC gene expression was prognostic in non-small cell lung cancer and colorectal cancer. No association was observed in ovarian cancer. IGKC protein expression was significantly associated with survival in paraffin embedded tissues of 330 breast cancer patients. Tumor infiltrating plasma cells were identified as the source of IGKC expression

    CONCLUSION:

    Our findings provide IGKC as a novel diagnostic marker for risk stratification in human cancer and support concepts to exploit the humoral immune response for anti-cancer therapy. It could be validated in several independent cohorts and performed similarly well in RNA from fresh frozen as well as from paraffin tissue and on protein level by immunostaining.

  • 55. Schmidt, Marcus
    et al.
    Micke, Patrick
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Hengstler, Jan G.
    IGKC and Prognosis in Breast Cancer-Letter2013Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 19, nr 1, s. 304-304Artikkel i tidsskrift (Fagfellevurdert)
  • 56. Sclafani, Francesco
    et al.
    de Castro, David Gonzalez
    Cunningham, David
    Wilson, Sanna Hulkki
    Peckitt, Clare
    Capdevila, Jaume
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Keraenen, Susana Rosello
    Wotherspoon, Andrew
    Brown, Gina
    Tait, Diana
    Begum, Ruwaida
    Thomas, Janet
    Oates, Jacqueline
    Chau, Ian
    Fc gamma RIIa and Fc gamma RIIIa Polymorphisms and Cetuximab Benefit in the Microscopic Disease2014Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 20, nr 17, s. 4511-4519Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Fc gamma R polymorphisms have been reported to enhance the immune-mediated effects of cetuximab in metastatic colorectal cancer. There are no data on the relationship between these polymorphisms and cetuximab in the early-stage setting. We performed a pharmacogenomic analysis of EXPERT-C, a randomized phase II trial of neoadjuvant CAPOX followed by chemoradiotherapy, surgery, and adjuvant CAPOX +/- cetuximab in high-risk, locally advanced rectal cancer. Experimental Design: Fc gamma RIIa-H131R and Fc gamma RIIIa-V158F polymorphisms were analyzed on DNA from peripheral blood samples. Kaplan-Meier method and Cox regression analysis were used to calculate survival estimates and compare treatment arms. Results: Genotyping was successfully performed in 105 of 164 (64%) patients (CAPOX = 54, CAPOX-C = 51). No deviation fromthe Hardy-Weinberg equilibrium or association of these polymorphisms with tumor RAS status was observed. Fc gamma RIIa-131R (HR, 0.38; P = 0.058) and Fc gamma RIIIa-158F alleles (HR, 0.21; P = 0.007) predicted improved progression-free survival (PFS) in patients treated with cetuximab. In the CAPOX-C arm, carriers of both 131R and 158F alleles had a statistically significant improvement in PFS (5 years: 78.4%; HR, 0.22; P = 0.002) and overall survival (OS; 5 years: 86.4%; HR, 0.24; P = 0.018) when compared with patients homozygous for 131H and/or 158V (5-year PFS: 35.7%; 5-year OS: 57.1%). An interaction between cetuximab benefit and 131R and 158F alleles was found for PFS (P = 0.017) and remained significant after adjusting for prognostic variables (P = 0.003). Conclusion: This is the first study investigating Fc gamma RIIa and Fc gamma RIIIa polymorphisms in patients with early-stage colorectal cancer treated with cetuximab. We showed an increased clinical benefit from cetuximab in the presence of 131R and 158F alleles.

  • 57. Skoglund, Johanna
    et al.
    Song, Bo
    Dalén, Johan
    Dedorson, Stefan
    Edler, David
    Hjern, Fredrik
    Holm, Jörn
    Lenander, Claes
    Lindforss, Ulrik
    Lundqvist, Nils
    Olivecrona, Hans
    Olsson, Louise
    Påhlman, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Kolorektalkirurgi.
    Rutegård, Jörgen
    Smedh, Kennet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning, Västerås.
    Törnqvist, Anders
    Houlston, Richard S.
    Lindblom, Annika
    Lack of an association between the TGFBR1*6A variant and colorectal cancer risk2007Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, nr 12, s. 3748-3752Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Recently a common variant of the TGFBR1 gene, TGFBR1*6A, has been proposed to act as a low-penetrance tumor susceptibility allele for colorectal cancer, but data from published studies with individually low statistical power are conflicting. To further evaluate the relationship between TGFBR1*6A and colorectal cancer risk, we have conducted a large case-control study and a meta-analysis of previously published studies.

    Experimental Design: A total of 1,042 colorectal cancer cases and 856 population controls were genotyped for the TGFBR1*6A polymorphism. Previously published case-control studies of the relationship between TGFBR1*6A and colorectal cancer were identified, and a meta-analysis was conducted.

    Results: We found no evidence that homozygosity, heterozygosity or carrier status for the TGFBR1*6A allele confers an increased risk of colorectal cancer; respective odds ratios (OR) were 1.05 [95% confidence interval (95% CI), 0.83-1.32], 0.82 (95% CI, 0.34-1.99), and 0.92 (95% CI, 0.74-1.15), respectively. A meta-analysis of our case-control study and seven other studies that provided data on 2,627 colorectal cancer cases and 3,387 controls also yielded no evidence that possession of the TGFBR1*6A allele is associated with an elevated risk of colorectal cancer; pooled estimate of the OR were 1.20 (95% CI, 0.64-2.24) for homozygosity, 1.11 (95% CI, 0.96-1.29) for heterozygosity, and 1.13 (95% CI, 0.98-1.30) for carriers of TGFBR1*6A.

    Conclusion: Current data provide limited support for the hypothesis that sequence variation in TGFBR1 defined by the TGFBR1*6A allele confers an elevated risk of colorectal cancer.

  • 58.
    Svensson, Emma
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Milenova, Ioanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Vrije Univ, Netherlands.
    Wenthe, Jessica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ståhle, Magnus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Leja-Jarblad, Justyna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Immuneed AB, Uppsala, Sweden.
    Ullenhag, Gustav
    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.
    Dimberg, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Moreno, Raphael
    IDIBELL-Institute Catalá d'Oncologia, Barcelona, Spain.
    Alemany, Ramon
    IDIBELL-Institute Catalá d'Oncologia, Barcelona, Spain.
    Loskog, Angelica S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk immunologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Lokon Pharma AB, Uppsala, Sweden.
    Shaping the Tumor Stroma and Sparking Immune Activation by CD40 and 4-1BB Signaling Induced by an Armed Oncolytic Virus.2017Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 23, nr 19, s. 5846-5857Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Pancreatic cancer is a severe indication with short expected survival despite surgery and/or combination chemotherapeutics. Checkpoint blockade antibodies are approved for several cancer indications, but pancreatic cancer has remained refractory. However, there are clinical data suggesting that stimulation of the CD40 pathway may be of interest for these patients. Oncolytic viruses armed with immunostimulatory genes represent an interesting approach. Herein, we present LOAd703, a designed adenovirus armed with trimerized CD40L and 4-1BBL that activates the CD40 and 4-1BB pathways, respectively. As many cells in the tumor stroma, including stellate cells and the infiltrating immune cells, express CD40 and some 4-1BB, we hypothesize that LOAd703 activates immunity and simultaneously modulates the biology of the tumor stroma.Experimental Design: Tumor, stellate, endothelial, and immune cells were infected by LOAd703 and investigated by flow cytometry, proteomics, and functional analyses.Results: LOAd703-infected pancreatic cell lines were killed by oncolysis, and the virus was more effective than standard-of-care gemcitabine. In in vivo xenograft models, LOAd703 efficiently reduced established tumors and could be combined with gemcitabine for additional effect. Infected stellate and tumor cells reduced factors that promote tumor growth (Spp-1, Gal-3, HGF, TGFβ and collagen type I), while chemokines were increased. Molecules involved in lymphocyte migration were upregulated on infected endothelial cells. Dendritic cells were robustly stimulated by LOAd703 to produce costimulators, cytokines and chemokines, and such DCs potently expanded both antigen-specific T cells and NK cells.Conclusions: LOAd703 is a potent immune activator that modulates the stroma to support antitumor responses. Clin Cancer Res; 1-12. ©2017 AACR.

  • 59.
    Svensson, Susanne
    et al.
    Linkoping Univ, Dept Oncol, S-58185 Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, S-58185 Linkoping, Sweden..
    Abrahamsson, Annelie
    Linkoping Univ, Dept Oncol, S-58185 Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, S-58185 Linkoping, Sweden..
    Rodriguez, Gabriela Vazquez
    Linkoping Univ, Dept Oncol, S-58185 Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, S-58185 Linkoping, Sweden..
    Olsson, Anna-Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Jensen, Lasse
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, S-58185 Linkoping, Sweden..
    Cao, Yihai
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, S-58185 Linkoping, Sweden.;Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England.;Glenfield Hosp, NIHR Leicester Cardiovasc Biomed Res Unit, Leicester, Leics, England..
    Dabrosin, Charlotta
    Linkoping Univ, Dept Oncol, S-58185 Linkoping, Sweden.;Linkoping Univ, Dept Clin & Expt Med, S-58185 Linkoping, Sweden..
    CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer2015Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 21, nr 16, s. 3794-3805Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Novel therapeutic targets of estrogen receptor (ER)-positive breast cancers are urgently needed because current antiestrogen therapy causes severe adverse effects, nearly 50% of patients are intrinsically resistant, and the majority of recurrences have maintained ER expression. We investigated the role of estrogen-dependent chemokine expression and subsequent cancer growth in human tissues and experimental breast cancer models. Experimental Design: For in vivo sampling of human chemokines, microdialysis was used in breast cancers of women or normal human breast tissue before and after tamoxifen therapy. Estrogen exposure and targeted therapies were assessed in immune competent PyMT murine breast cancer, orthotopic human breast cancers in nude mice, cell culture of cancer cells, and freshly isolated human macrophages. Cancer cell dissemination was investigated using zebrafish. Results: ER+ cancers in women produced high levels of extracellular CCL2 and CCL5 in vivo, which was associated with infiltration of tumor-associated macrophages. In experimental breast cancer, estradiol enhanced macrophage influx and angiogenesis through increased release of CCL2, CCL5, and vascular endothelial growth factor. These effects were inhibited by anti-CCL2 or anti-CCL5 therapy, which resulted in potent inhibition of cancer growth. In addition, estradiol induced a protumorigenic activation of the macrophages. In a zebrafish model, macrophages increased cancer cell dissemination via CCL2 and CCL5 in the presence of estradiol, which was inhibited with anti-CCL2 and anti-CCL5 treatment. Conclusions: Our findings shed new light on the mechanisms underlying the progression of ER+ breast cancer and indicate the potential of novel therapies targeting CCL2 and CCL5 pathways. (C)2015 AACR.

  • 60. Sørensen, Nanna M
    et al.
    Byström, Per
    Christensen, Ib J
    Berglund, Åke
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Nielsen, Hans Jørgen
    Brünner, Nils
    Glimelius, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    TIMP-1 is significantly associated with objective response and survival in metastatic colorectal cancer patients receiving combination of irinotecan, 5-fluorouracil, and folinic acid2007Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, nr 14, s. 4117-4122Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Tissue inhibitor of metalloproteinase-1 (TIMP-1) is known to protect cells against apoptosis. We raised the hypothesis that elevated tumor tissue levels and thereby plasma levels of TIMP-1 would predict resistance to apoptosis-inducing chemotherapy.

    Experimental Design: Ninety patients with metastatic colorectal cancer were included in the study. Plasma TIMP-1 and serum carcinoembryonic antigen (CEA) were measured in samples obtained before the first cycle of chemotherapy.

    Results: Analysis of best objective response (complete or partial response versus stable or progressive disease) showed that patients with low plasma TIMP-1 had higher probability of obtaining an objective response [odds ratio (OR), 3.5; 95% confidence interval (95% CI), 1.4-8.5, P = 0.007]. CEA treated as a continuous variable was also a statistically significant predictor of no response (OR, 1.3; 95% CI, 1.0-1.7, P = 0.02, area under the curve 0.66) but much less so. Plasma TIMP-1 was the only significant covariate in a multivariable analysis of best objective response (OR, 3.6; 95% CI, 1.4-9.5; P = 0.001). Plasma TIMP-1 scored as a continuous variable on the log scale (loge) was significantly associated with overall survival [OS; hazard ratio (HR), 3.8; 95% CI, 2.4-5.9; P < 0.0001] and with time to progression (TTP; HR, 1.5; 95% CI, 1.0-2.3; P = 0.048). Multivariable analysis showed that plasma TIMP-1 was significant for OS when including routine clinical baseline covariates (HR, 3.5; 95% CI, 2.1-5.8; P < 0.0001). A multivariable analysis including TTP instead of OS showed that only plasma TIMP-1 was retained in the model (HR, 1.5). CEA was not significantly associated with TTP or OS when TIMP-1 was included in the model.

    Conclusion: This study shows that plasma TIMP-1 levels are significantly and independently associated with objective response, TTP, and OS in patients with metastatic colorectal cancer receiving combination chemotherapy.

  • 61.
    Tobin, Nicholas P.
    et al.
    Karolinska Inst, Dept Pathol & Oncol, S-17176 Stockholm, Sweden.;Univ Hosp, Canc Ctr Karolinska R8 3, Stockholm, Sweden..
    Wennmalm, Kristian
    Karolinska Inst, Dept Pathol & Oncol, S-17176 Stockholm, Sweden.;Univ Hosp, Canc Ctr Karolinska R8 3, Stockholm, Sweden..
    Lindstrom, Linda S.
    Univ Hosp, Canc Ctr Karolinska R8 3, Stockholm, Sweden.;Univ Calif San Francisco, Dept Surg, San Francisco, CA USA.;Karolinska Inst, Dept Biosci & Nutr, S-17176 Stockholm, Sweden..
    Foukakis, Theodoros
    Karolinska Inst, Dept Pathol & Oncol, S-17176 Stockholm, Sweden.;Univ Hosp, Canc Ctr Karolinska R8 3, Stockholm, Sweden..
    He, Liqun
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Genove, Guillem
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17176 Stockholm, Sweden..
    Ostman, Arne
    Karolinska Inst, Dept Pathol & Oncol, S-17176 Stockholm, Sweden.;Univ Hosp, Canc Ctr Karolinska R8 3, Stockholm, Sweden..
    Landberg, Goran
    Univ Gothenburg, Sahlgrenska Canc Ctr, Gothenburg, Sweden..
    Betsholtz, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, S-17176 Stockholm, Sweden..
    Bergh, Jonas
    Karolinska Inst, Dept Pathol & Oncol, S-17176 Stockholm, Sweden.;Univ Hosp, Canc Ctr Karolinska R8 3, Stockholm, Sweden..
    An Endothelial Gene Signature Score Predicts Poor Outcome in Patients with Endocrine-Treated, Low Genomic Grade Breast Tumors2016Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, nr 10, s. 2417-2426Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: The ability of vascular genes to provide treatment predictive information in breast cancer patients remains unclear. As such, we assessed the expression of genes representative of normal endothelial microvasculature (MV) in relation to treatment-specific patient subgroups. Experimental Design: We used expression data from 993 breast tumors to assess 57 MV genes (summarized to yield an MV score) as well as the genomic grade index (GGI) and PAM50 signatures. MV score was compared with CD31 staining by correlation and gene ontology (GO) analysis, along with clinicopathologic characteristics and PAM50 subtypes. Uni-, multivariate, and/or t-test analyses were performed in all and treatment-specific subgroups, along with a clinical trial cohort of patients with metastatic breast cancer, seven of whom received antiangiogenic therapy. Results: MV score did not correlate with microvessel density (correlation = 0.096), but displayed enrichment for angiogenic GO terms, and was lower in Luminal B tumors. In endocrine-treated patients, a high MV score was associated with decreased risk of metastasis [HR 0.58; 95% confidence interval (CI), 0.38-0.89], even after adjusting for histologic grade, but not GGI or PAM50. Subgroup analysis showed the prognostic strength of the MV score resided in low genomic grade tumors and MV score was significantly increased in metastatic breast tumors after treatment with sunitinib + docetaxel (P = 0.031). Conclusions: MV score identifies two groups of better and worse survival in low-risk endocrine-treated breast cancer patients. We also show normalization of tumor vasculature on a transcriptional level in response to an angiogenic inhibitor in human breast cancer samples.

  • 62.
    Trame, Mirjam N
    et al.
    Department of Pharmaceutical and Medical Chemistry-Clinical Pharmacy, Westfälische Wilhelms-Universität Münster.
    Bergstrand, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Karlsson, Mats O
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Boos, Joachim
    Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Germany.
    Hempel, Georg
    Department of Pharmaceutical and Medical Chemistry-Clinical Pharmacy, Westfälische Wilhelms-Universität Münster.
    Population pharmacokinetics of busulfan in children: increased evidence for body surface area and allometric body weight dosing of busulfan in children.2011Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 17, nr 21, s. 6867-6877Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: To evaluate the best method for dosing busulfan in children, we retrospectively analyzed two different data sets from three different dosing regimens by means of population pharmacokinetics using NONMEM.

    EXPERIMENTAL DESIGN: The development data set consisted of plasma samples from 94 children, in the age range of 0.4 to 18.8 years, receiving either oral or intravenous busulfan. The external model evaluation data set comprised 24 children, in the age range of 0.1 to 18.9 years, who belonged to the once-daily intravenous busulfan dosing regimen. A one-compartment model with first-order absorption using body surface area (BSA) or allometric body weight (BW) as covariate on clearance (CL) and BW as covariate on volume of distribution (V) were used to describe the results sufficiently. In addition to interindividual variability on all pharmacokinetic parameters, interoccasion variability was included for CL and V.

    RESULTS: CL values in the present study did not reflect the shape of the CL versus weight curve reported in previous investigations. By external model evaluation, we were able to confirm these findings. Furthermore, bioavailability was calculated to be between 93% and 99% for the development data set. On the basis of the final models, we simulated two dosing schemes according to allometric BW and BSA showing that we estimated to include about 30% more patients into the proposed therapeutic area under the curve (AUC) range of 900 to 1,500 μM*min and could, furthermore, achieve a reduction in the AUC variability when dosed according to the labeled European Medicines Agency (EMA) dosing recommendation.

    CONCLUSION: We recommend a BSA or an allometric BW dosing regimen for individualizing busulfan therapy in children to reduce variability in busulfan exposure and to improve safety and efficacy of busulfan treatment.

  • 63. Trame, Mirjam N.
    et al.
    Bergstrand, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Karlsson, Mats O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Hempel, Georg
    Population Pharmacokinetics of Busulfan in Children: Response2012Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 18, nr 9, s. 2717-2718Artikkel i tidsskrift (Fagfellevurdert)
  • 64.
    Ullenhag, Gustav
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för onkologi.
    Frödin, Jan-Erik
    Mosolits, Szilvia
    Kiaii, Shahryar
    Hassan, Moustapha
    Bonnet, Marie-Claude
    Moingeon, Philippe
    Mellstedt, Håkan
    Rabbani, Hodjatallah
    Immunization of colorectal carcinoma patients with a recombinant canarypox virus expressing the tumor antigen Ep-CAM/KSA (ALVAC-KSA) and granulocyte macrophage colony- stimulating factor induced a tumor-specific cellular immune response2003Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 9, nr 7, s. 2447-2456Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE: Colorectal carcinoma cells express the tumor-associated antigen epithelial cellular adhesion molecule (Ep-CAM)/KSA. Passive immunotherapy with monoclonal antibodies using this antigen has shown promising results. Ep-CAM might also be a target for active specific immunotherapy. Expression of the tumor antigen in a viral vector may facilitate appropriate antigen presentation. The feasibility of an Ep-CAM/KSA-specific therapeutic vaccination was investigated in cancer patients.

    EXPERIMENTAL DESIGN: The full-length Ep-CAM gene was inserted into the avipox virus ALVAC (ALVAC-KSA). Twelve radically operated colorectal carcinoma patients without evidence of remaining macroscopic disease (stages I, II, and III) entered the study. The first 6 patients were immunized with three injections of ALVAC-KSA (10(7.09) CCID(50) per immunization) alone in weeks 0, 3, and 6. The subsequent 6 patients received the same schedule of ALVAC-KSA together with the adjuvant cytokine granulocyte macrophage colony-stimulating factor (GM-CSF; 75 micro g/day for 4 consecutive days).

    RESULTS: The adverse reactions to the vaccinations were mild except for local skin reactions. In the ALVAC-KSA group a weak T-cell response was induced in 2 of 6 patients. In the ALVAC-KSA/GM-CSF group a marked IFN-gamma response (enzyme-linked immunospot) was induced in 5 of 6 patients. The T-cell response appeared late, 1 month after the last immunization, with a peak at 4-5 months after immunization. No IgG antibodies against Ep-CAM were detected. Before vaccination the majority of patients had a type 1 T-cell response (IFN-gamma) against the vector, which was noted in healthy donors as well. All of the patients developed high titers of IgG antibodies against the vector, and the T-cell response was vigorously boosted.

    CONCLUSIONS: ALVAC-KSA, in combination with low dose local administration of GM-CSF may induce a strong, IFN-gamma T-cell response (type 1). ALVAC-KSA seems to be an interesting candidate as a cancer vaccine for future clinical development.

  • 65. van der Bol, Jessica M.
    et al.
    Mathijssen, Ron H. J.
    Creemers, Geert-Jan M.
    Planting, Andre S. Th.
    Loos, Walter J.
    Wiemer, Erik A. C.
    Friberg, Lena E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Verweij, Jaap
    Sparreboom, Alex
    de Jong, Floris A.
    A CYP3A4 Phenotype-Based Dosing Algorithm for Individualized Treatment of Irinotecan2010Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 16, nr 2, s. 736-742Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Irinotecan, the prodrug of SN-38, is extensively metabolized by cytochrome P450-3A4 (CYP3A4). A randomized trial was done to assess the utility of an algorithm for individualized irinotecan dose calculation based on a priori CYP3A4 activity measurements by the midazolam clearance test. Experimental Design: Patients were randomized to receive irinotecan at a conventional dose level of 350 mg/m(2) (group A) or doses based on an equation consisting of midazolam clearance, gamma-glutamyl-transferase, and height (group B). Pharmacokinetics and toxicities were obtained during the first treatment course. Results: Demographics of 40 evaluable cancer patients were balanced between both groups, including UGT1A1*28 genotype and smoking status. The absolute dose of irinotecan ranged from 480 to 800 mg in group A and 380 to 1,060 mg in group B. The mean absolute dose and area under the curve of irinotecan and SN-38 were not significantly different in either group (P > 0.18). In group B, the interindividual variability in the area under the curve of irinotecan and SN-38 was reduced by 19% and 25%, respectively (P > 0.22). Compared with group A, the incidence of grades 3 to 4 neutropenia was >4-fold lower in group B (45 versus 10%; P = 0.013). The incidence of grades 3 to 4 diarrhea was equal in both groups (10%). Conclusions: Incorporation of CYP3A4 phenotyping in dose calculation resulted in an improved predictability of the pharmacokinetic and toxicity profile of irinotecan, thereby lowering the incidence of severe neutropenia. In combination with UGT1A1*28 genotyping, CYP3A4 phenotype determination should be explored further as a strategy for the individualization of irinotecan treatment.

  • 66. van der Veldt, Astrid A M
    et al.
    Lubberink, Mark
    Department of Nuclear Medicine & PET Research, VU University Medical Center, Amsterdam, The Netherlands.
    Greuter, Henri N
    Comans, Emile F I
    Herder, Gerarda J M
    Yaqub, Maqsood
    Schuit, Robert C
    van Lingen, Arthur
    Rizvi, S Nafees
    Mooijer, Martien P J
    Rijnders, Anneloes Y
    Windhorst, Albert D
    Smit, Egbert F
    Hendrikse, N Harry
    Lammertsma, Adriaan A
    Absolute Quantification of [11C]docetaxel Kinetics in Lung Cancer Patients Using Positron Emission Tomography2011Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 17, nr 14, s. 4814-4824Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose:

    Tumor resistance to docetaxel may be associated with reduced drug concentrations in tumor tissue. Positron emission tomography (PET) allows for quantification of radiolabeled docetaxel ([11C]docetaxel) kinetics and might be useful for predicting response to therapy. The primary objective was to evaluate the feasibility of quantitative [11C]docetaxel PET scans in lung cancer patients. The secondary objective was to investigate whether [11C]docetaxel kinetics were associated with tumor perfusion, tumor size, and dexamethasone administration.

    Experimental Design:

    Thirty-four lung cancer patients underwent dynamic PET–computed tomography (CT) scans using [11C]docetaxel. Blood flow was measured using oxygen-15 labeled water. The first 24 patients were premedicated with dexamethasone. For quantification of [11C]docetaxel kinetics, the optimal tracer kinetic model was developed and a noninvasive procedure was validated.

    Results:

    Reproducible quantification of [11C]docetaxel kinetics in tumors was possible using a noninvasive approach (image derived input function). Thirty-two lesions (size ≥4 cm3) were identified, having a variable net influx rate of [11C]docetaxel (range, 0.0023–0.0229 mL·cm−3·min−1). [11C]docetaxel uptake was highly related to tumor perfusion (Spearman's ρ = 0.815;P < 0.001), but not to tumor size (Spearman's ρ = −0.140; P = 0.446). Patients pretreated with dexamethasone showed lower [11C]docetaxel uptake in tumors (P = 0.013). Finally, in a subgroup of patients who subsequently received docetaxel therapy, relative high [11C]docetaxel uptake was related with improved tumor response.

    Conclusions:

    Quantification of [11C]docetaxel kinetics in lung cancer was feasible in a clinical setting. Variable [11C]docetaxel kinetics in tumors may reflect differential sensitivity to docetaxel therapy. Our findings warrant further studies investigating the predictive value of [11C]docetaxel uptake and the effects of comedication on [11C]docetaxel kinetics in tumors.

  • 67. van der Veldt, Astrid A. M.
    et al.
    Lubberink, Mark
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för nuklearmedicin och PET.
    Mathijssen, Ron H. J.
    Loos, Walter J.
    Herder, Gerarda J. M.
    Greuter, Henri N.
    Comans, Emile F. I.
    Rutten, Hugo B.
    Eriksson, Jonas
    VU University Medical Center Amsterdam.
    Windhorst, Albert D.
    Hendrikse, N. Harry
    Postmus, Pieter E.
    Smit, Egbert F.
    Lammertsma, Adriaan A.
    Toward Prediction of Efficacy of Chemotherapy: A Proof of Concept Study in Lung Cancer Patients Using [11C]docetaxel and Positron Emission Tomography2013Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 19, nr 15, s. 4163-4173Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose:

    Pharmacokinetics of docetaxel can be measured in vivo using positron emission tomography (PET) and a microdose of radiolabeled docetaxel ([11C]docetaxel). The objective of this study was to investigate whether a [11C]docetaxel PET microdosing study could predict tumor uptake of therapeutic doses of docetaxel.

    Experimental Design:

    Docetaxel-naïve lung cancer patients underwent 2 [11C]docetaxel PET scans; one after bolus injection of [11C]docetaxel and another during combined infusion of [11C]docetaxel and a therapeutic dose of docetaxel (75 mg·m−2). Compartmental and spectral analyses were used to quantify [11C]docetaxel tumor kinetics. [11C]docetaxel PET measurements were used to estimate the area under the curve (AUC) of docetaxel in tumors. Tumor response was evaluated using computed tomography scans.

    Results:

    Net rates of influx (Ki) of [11C]docetaxel in tumors were comparable during microdosing and therapeutic scans. [11C]docetaxel AUCTumor during the therapeutic scan could be predicted reliably using an impulse response function derived from the microdosing scan together with the plasma curve of [11C]docetaxel during the therapeutic scan. At 90 minutes, the accumulated amount of docetaxel in tumors was less than 1% of the total infused dose of docetaxel. [11C]docetaxel Ki derived from the microdosing scan correlated with AUCTumor of docetaxel (Spearman ρ = 0.715; P = 0.004) during the therapeutic scan and with tumor response to docetaxel therapy (Spearman ρ = −0.800; P = 0.010).

    Conclusions:

    Microdosing data of [11C]docetaxel PET can be used to predict tumor uptake of docetaxel during chemotherapy. The present study provides a framework for investigating the PET microdosing concept for radiolabeled anticancer drugs in patients.

  • 68. van Erp, Nielka P
    et al.
    Gelderblom, Hans
    Karlsson, Mats O
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Li, Jing
    Zhao, Ming
    Ouwerkerk, Jan
    Nortier, Johan W
    Guchelaar, Henk-Jan
    Baker, Sharyn D
    Sparreboom, Alex
    Influence of CYP3A4 Inhibition on the Steady-State Pharmacokinetics of Imatinib2007Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 13, nr 24, s. 7394-7400Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: To evaluate the effects of ritonavir, a potent inhibitor of CYP3A4, on the steady-state pharmacokinetics of imatinib. Experimental Design: Imatinib pharmacokinetics were evaluated in cancer patients receiving the drug for at least 2 months, after which ritonavir (600 mg) was administered daily for 3 days. Samples were obtained on the day before ritonavir (day 1) and on the third day (day 4).The in vitro metabolism of imatinib with or without ritonavir and the effect of imatinib on 1-OH-midazolam formation rate, a probe for CYP3A4 activity, were evaluated with human CYP3A4 and pooled liver microsomes. Results: In 11 evaluable patients, the geometric mean (95% confidence interval) area under the curve of imatinib on days 1 and 4 were 42.6 (33.0-54.9) mu g.h/mL and 41.2 (32.1-53.1) mu g.h/mL, respectively (P = 0.65). A population analysis done in NONMEM with a time-dependent covariate confirmed that ritonavir did not influence the clearance or bioavailability of imatinib. In vitro, imatinib was metabolized to the active metabolite CGP74588 by CYP3A4 and CYP3A5 and, to a lesser extent, by CYP2D6. Ritonavir (1 mu mol/L) completely inhibited CYP3A4-mediated metabolism of imatinib to CGP74588 but inhibited metabolism in microsomes by only 50%. Imatinib significantly inhibited CYP3A4 activity in vitro. Conclusion: At steady state, imatinib is insensitive to potent CYP3A4 inhibition and relies on alternate elimination pathways. For agents with complex elimination pathways that involve autoinhibition, interaction studies that are done after a single dose may not be applicable when drugs are administered chronically.

  • 69.
    van Kessel, Kim E. M.
    et al.
    Erasmus MC, Erasmus MC Canc Inst, Dept Pathol, Rotterdam, Netherlands.;Erasmus MC, Erasmus MC Canc Inst, Dept Urol, Rotterdam, Netherlands..
    van der Keur, Kirstin A.
    Erasmus MC, Erasmus MC Canc Inst, Dept Pathol, Rotterdam, Netherlands..
    Dyrskjot, Lars
    Aarhus Univ Hosp, Dept Mol Med, Aarhus, Denmark..
    Algaba, Ferran
    Univ Autonoma Barcelona, Fundacio Puigvert, Sect Pathol, Barcelona, Spain..
    Welvaart, Naeromy Y. C.
    Erasmus MC, Erasmus MC Canc Inst, Dept Pathol, Rotterdam, Netherlands..
    Beukers, Willemien
    Erasmus MC, Erasmus MC Canc Inst, Dept Pathol, Rotterdam, Netherlands..
    Segersten, Ulrika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Keck, Bastian
    Friedrich Alexander Univ Erlangen Nurnberg, Univ Hosp Erlangen, Dept Urol, Erlangen, Germany..
    Maurer, Tobias
    Tech Univ Munich, Klinikum Rechts Isar, Dept Urol, Munich, Germany..
    Simic, Tatjana
    Univ Belgrade, Fac Med, Inst Med & Clin Biochem, Belgrade, Serbia..
    Horstmann, Marcus
    Friedrich Schiller Univ Jena, Dept Urol, Jena, Germany..
    Grimm, Marc-Oliver
    Friedrich Schiller Univ Jena, Dept Urol, Jena, Germany..
    Hermann, Gregers G.
    Univ Copenhagen, Herlev & Gentofte Hosp, Dept Urol, Hellerup, Denmark..
    Mogensen, Karin
    Univ Copenhagen, Herlev & Gentofte Hosp, Dept Urol, Hellerup, Denmark..
    Hartmann, Arndt
    Friedrich Alexander Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Pathol, Erlangen, Germany..
    Harving, Niels
    Aalborg Univ Hosp, Dept Urol, Aalborg, Denmark..
    Petersen, Astrid C.
    Aalborg Univ Hosp, Dept Pathol, Aalborg, Denmark..
    Jensen, Jorgen B.
    Aarhus Univ Hosp, Dept Urol, Aarhus, Denmark..
    Junker, Kerstin
    Saarland Univ, Dept Urol, Homburg, Germany..
    Boormans, Joost L.
    Erasmus MC, Erasmus MC Canc Inst, Dept Urol, Rotterdam, Netherlands..
    Real, Francisco X.
    CIBERONC, Spanish Natl Canc Res Ctr CNIO, Epithelial Carcinogenesis Grp, Madrid, Spain.;Univ Pompeu Fabra, Dept Expt & Hlth Sci, Barcelona, Spain..
    Malats, Nuria
    CIBERONC, Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Madrid, Spain..
    Malmström, Per-Uno
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Orntoft, Torben F.
    Aarhus Univ Hosp, Dept Mol Med, Aarhus, Denmark..
    Zwarthoff, Ellen C.
    Erasmus MC, Erasmus MC Canc Inst, Dept Pathol, Rotterdam, Netherlands..
    Molecular Markers Increase Precision of the European Association of Urology Non-Muscle-Invasive Bladder Cancer Progression Risk Groups2018Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 24, nr 7, s. 1586-1593Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: The European Association of Urology (EAU) guidelines for non-muscle-invasive bladder cancer (NMIBC) recommend risk stratification based on clinicopathologic parameters. Our aim was to investigate the added value of biomarkers to improve risk stratification of NMIBC. Experimental Design: We prospectively included 1,239 patients in follow-up for NMIBC in six European countries. Fresh-frozen tumor samples were analyzed for GATA2, TBX2, TBX3, and ZIC4 methylation and FGFR3, TERT, PIK3CA, and RAS mutation status. Cox regression analyses identified markers that were significantly associated with progression to muscle-invasive disease. The progression incidence rate (PIR = rate of progression per 100 patient-years) was calculated for subgroups. Results: In our cohort, 276 patients had a low, 273 an intermediate, and 555 a high risk of tumor progression based on the EAU NMIBC guideline. Fifty-seven patients (4.6%) progressed to muscle-invasive disease. The limited number of progressors in this large cohort compared with older studies is likely due to improved treatment in the past two decades. Overall, wild-type FGFR3 and methylation of GATA2 and TBX3 were significantly associated with progression (HR = 0.34, 2.53, and 2.64, respectively). The PIR for EAU high-risk patients was 4.25. On the basis of FGFR3 mutation status and methylation of GATA2, this cohort could be reclassified into a good class (PIR = 0.86, 26.2% of patients), a moderate class (PIR = 4.32, 49.7%), and a poor class (PIR = 7.66, 24.0%). Conclusions: We conclude that the addition of selected biomarkers to the EAU risk stratification increases its accuracy and identifies a subset of NMIBC patients with a very high risk of progression. (C) 2018 AACR.

  • 70.
    Vardi, Anna
    et al.
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Agathangelidis, Andreas
    Ist Sci San Raffaele, Div Mol Oncol, Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, Milan, Italy.;Fdn Ctr San Raffaele, Milan, Italy..
    Stalika, Evangelia
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Karypidou, Maria
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.;G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Siorenta, Alexandra
    Gen Hosp Athens G Gennimatas, Immunol, Athens, Greece.;Gen Hosp Athens G Gennimatas, Natl Tissue Typing Ctr, Athens, Greece..
    Anagnostopoulos, Achilles
    G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Hadzidimitriou, Anastasia
    Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece..
    Ghia, Paolo
    Ist Sci San Raffaele, Div Mol Oncol, Milan, Italy.;Ist Sci San Raffaele, Dept Oncohematol, Milan, Italy.;Fdn Ctr San Raffaele, Milan, Italy..
    Sutton, Lesley-Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Ctr Res & Technol Hellas, Inst Appl Biosci, Thessaloniki, Greece.;G Papanicolaou Hosp, Dept Hematol, Thessaloniki, Greece.;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece..
    Antigen Selection Shapes the T-cell Repertoire in Chronic Lymphocytic Leukemia2016Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 22, nr 1, s. 167-174Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: The role of antigen(s) in shaping the T-cell repertoire in chronic lymphocytic leukemia, although relevant for understanding malignant cell interactions with cognate T cells, is largely unexplored. Experimental Design: Here we profiled the T-cell receptor beta chain gene repertoire in 58 chronic lymphocytic leukemia patients, focusing on cases assigned to well-characterized subsets with stereotyped clonotypic B-cell receptor immunoglobulins, therefore those cases most evidently selected by antigen (subsets #1, #2, and #4). Results: Remarkable repertoire skewing and oligoclonality were observed, and differences between subsets were noted regarding both T-cell receptor b chain gene usage and the extent of clonality, with subset #2 being the least oligoclonal. Longitudinal analysis of subset #4 cases revealed that although the repertoire may fluctuate over time, certain clonotypes persist, thus alluding to persistent antigenic stimulation. Shared ("stereotyped") clonotypes were found between different patients, reflecting selection by common antigenic elements. Cross-comparison of our dataset with public databases showed that some T-cell clonotypes may have expanded secondary to common viral infections; however, the majority of clonotypes proved to be disease-specific. Conclusions: Overall, the T-cell receptor b chain repertoire in chronic lymphocytic leukemia is likely shaped by antigen selection and the implicated antigenic elements may concern epitopes that also select the malignant B-cell progenitors or, more intriguingly, chronic lymphocytic leukemia-derived epitopes.

  • 71. Vardi, Anna
    et al.
    Agathangelidis, Andreas
    Sutton, Lesley-Ann
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Chatzouli, Maria
    Scarfo, Lydia
    Mansouri, Larry
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi.
    Douka, Vassiliki
    Anagnostopoulos, Achilles
    Darzentas, Nikos
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Hematologi och immunologi.
    Ghia, Paolo
    Belessi, Chrysoula
    Stamatopoulos, Kostas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    IgG-Switched CLL Has a Distinct Immunogenetic Signature from the Common MD Variant: Ontogenetic Implications2014Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 20, nr 2, s. 323-330Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE:

    IgG-switched chronic lymphocytic leukemia (G-CLL) is a rare variant of CLL, whose origin and ontogenetic relationship to the common IgM/IgD (MD-CLL) variant remains undefined. Here we sought for clues regarding the ontogeny of G-CLL versus MD-CLL by profiling the relevant IG gene repertoires.

    EXPERIMENTAL DESIGN:

    Using purpose-built bioinformatics methods, we performed detailed immunogenetic profiling of a multinational CLL cohort comprising 1256 cases, of which 1087 and 169 expressed IG mu/delta and gamma heavy chains, respectively.

    RESULTS:

    G-CLL has a highly skewed IG gene repertoire that is distinct from MD-CLL, especially in terms of: (i) overuse of the IGHV4-34 and IGHV4-39 genes; and, (ii) differential somatic hypermutation (SHM) load. Repertoire differences held also when comparing subgroups with similar SHM status and were mainly attributed to the exclusive representation in G-CLL of two major subsets with quasi-identical (stereotyped) B-cell receptors. These subsets, namely #4 (IGHV4-34/IGKV2-30) and #8 (IGHV4-39/IGKV1(D)-39), were found to display sharply contrasting SHM and clinical behavior.

    CONCLUSIONS:

    G-CLL exhibits an overall distinct immunogenetic signature from MD-CLL, prompting speculations about distinct ontogenetic derivation and/or immune triggering. The reasons underlying the differential regulation of SHM among G-CLL cases remain to be elucidated.

  • 72. Wahlin, Björn Engelbrekt
    et al.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylär och morfologisk patologi.
    Holte, Harald
    Hagberg, Hans
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för radiologi, onkologi och strålningsvetenskap, Enheten för onkologi.
    Erlanson, Martin
    Nilsson-Ehle, Herman
    Lindén, Ola
    Nordström, Marie
    Ostenstad, Bjørn
    Geisler, Christian H
    Brown, Peter de Nully
    Lehtinen, Tuula
    Maisenhölder, Martin
    Tierens, Anne M
    Sander, Birgitta
    Christensson, Birger
    Kimby, Eva
    T cells in tumors and blood predict outcome in follicular lymphoma treated with rituximab2011Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 17, nr 12, s. 4136-4144Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose:

    T cells influence outcome in follicular lymphoma, but their contributions seem to be modified by therapy. Their impact in patients receiving rituximab without chemotherapy is unknown.

    Experimental Design:

    Using flow cytometry, we evaluated the T cells in tumors and/or blood in a total of 250 follicular lymphoma patients included in two Nordic Lymphoma Group randomized trials that compared single rituximab with IFN-α2a–rituximab combinations.

    Results:

    In univariate analysis, higher levels of CD3+, CD4+, and CD8+ T cells in both tumors and blood correlated with superior treatment responses, and in multivariate analysis, tumor-CD3+ (P = 0.011) and blood-CD4+ (P = 0.029) cells were independent. CD4+ cells were favorable regardless of treatment arm, but CD8+ cells were favorable only in patients treated with single rituximab, because IFN-α2a improved responses especially in patients with low CD8+ cell levels. Higher levels of blood-CD3+ (P = 0.003) and blood-CD4+ (P = 0.046) cells predicted longer overall survival, and higher levels of blood-CD8+ cells longer times to next treatment (P = 0.046).

    Conclusions:

    We conclude that therapeutic effects of rituximab are augmented by tumor-associated T cells for rapid responses and by systemic T cells for sustained responses. CD4+ and CD8+ cells are both favorable in patients treated with rituximab. IFN-α2a abrogates the negative impact of few CD8+ cells.

  • 73.
    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.  

  • 74. Zhao, Mei
    et al.
    Sano, Daisuke
    Pickering, Curtis R.
    Jasser, Samar A.
    Henderson, Ying C.
    Clayman, Gary L.
    Sturgis, Erich M.
    Ow, Thomas J.
    Lotan, Reuben
    Carey, Thomas E.
    Sacks, Peter G.
    Grandis, Jennifer R.
    Sidransky, David
    Heldin, Nils-Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Myers, Jeffrey N.
    Assembly and Initial Characterization of a Panel of 85 Genomically Validated Cell Lines from Diverse Head and Neck Tumor Sites2011Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 17, nr 23, s. 7248-7264Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Human cell lines are useful for studying cancer biology and preclinically modeling cancer therapy, but can be misidentified and cross-contamination is unfortunately common. The purpose of this study was to develop a panel of validated head and neck cell lines representing the spectrum of tissue sites and histologies that could be used for studying the molecular, genetic, and phenotypic diversity of head and neck cancer.

    Methods: A panel of 122 clinically and phenotypically diverse head and neck cell lines from head and neck squamous cell carcinoma, thyroid cancer, cutaneous squamous cell carcinoma, adenoid cystic carcinoma, oral leukoplakia, immortalized primary keratinocytes, and normal epithelium was assembled from the collections of several individuals and institutions. Authenticity was verified by carrying out short tandem repeat analysis. Human papillomavirus (HPV) status and cell morphology were also determined.

    Results: Eighty-five of the 122 cell lines had unique genetic profiles. HPV-16 DNA was detected in 2 cell lines. These 85 cell lines included cell lines from the major head and neck primary tumor sites, and close examination shows a wide range of in vitro phenotypes.

    Conclusions: This panel of 85 genomically validated head and neck cell lines represents a valuable resource for the head and neck cancer research community that can help advance understanding of the disease by providing a standard reference for cell lines that can be used for biological as well as preclinical studies.

  • 75.
    Öberg, Daniel
    et al.
    Centre for Molecular Oncology and Imaging, Institute of Cancer, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom .
    Yanover, Eva
    Adam, Virginie
    Sweeney, Katrina
    Costas, Celina
    Lemoine, Nick R
    Halldén, Gunnel
    Improved potency and selectivity of an oncolytic E1ACR2 and E1B19K deleted adenoviral mutant in prostate and pancreatic cancers.2010Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 16, nr 2, s. 541-53Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    PURPOSE Replication-selective oncolytic adenoviruses are a promising class of tumor-targeting agents with proven safety in hundreds of patients. However, clinical responses have been limited and viral mutants with higher potency are needed. Here, we report on the generation of a novel set of mutants with improved efficacy in prostate and pancreatic carcinoma models. Currently, no curative treatments are available for late-stage metastatic prostate or rapidly progressing pancreatic cancers.

    EXPERIMENTAL DESIGN Adenovirus type 5 mutants were created with deletions in the E1ACR2 region for tumor selectivity and/or the E1B19K gene for attenuated replication in vivo; all constructs retain the E3 genes intact. Cell-killing efficacy, replication, and cytotoxicity in combination with chemotherapeutics were investigated in normal cells (PrEC and NHBE), seven carcinoma cell lines, and human (PC3 and DU145) and murine (TRAMPC, CMT-64, and CMT-93) tumor models in vivo.

    RESULTS The double-deleted AdDeltaDelta (DeltaE1ACR2 and DeltaE1B19K) mutant had high cell-killing activity in prostate, pancreatic, and lung carcinomas. Replication was similar to wild-type in all tumor cells and was attenuated in normal cells to levels less than the single-deleted AdDeltaCR2 mutant. AdDeltaDelta combined with the chemotherapeutics docetaxel and mitoxantrone resulted in synergistically enhanced cell killing and greatly improved antitumor efficacy in prostate xenografts in vivo. In murine immunocompetent in vivo models efficacy was greater for mutants with the E3B genes intact even in the absence of viral replication, indicating attenuated macrophage-dependent clearance.

    CONCLUSIONS These data suggest that the novel oncolytic mutant AdDeltaDelta is a promising candidate for targeting of solid tumors specifically in combination with chemotherapeutics.

  • 76.
    Öberg, Kjell
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Onkologisk endokrinologi.
    Casanovas, Oriol
    Castaño, Justo P
    Chung, Daniel
    Delle Fave, Gianfranco
    Denèfle, Patrice
    Harris, Philip
    Khan, Mohid S
    Kulke, Matthew H
    Scarpa, Aldo
    Tang, Laura H
    Wiedenmann, Bertram
    Molecular Pathogenesis of Neuroendocrine Tumors: Implications for Current and Future Therapeutic Approaches2013Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 19, nr 11, s. 2842-2849Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The treatment landscape and biologic understanding of neuroendocrine tumors (NET) has shifted dramatically in recent years. Recent studies have shown that somatostatin analogues have the potential not only to control symptoms of hormone hypersecretion but also have the ability to slow tumor growth in patients with advanced carcinoid. The results of clinical trials have further shown that the VEGF pathway inhibitor sunitinib and the mTOR inhibitor everolimus have efficacy in patients with advanced pancreatic NETs. The efficacy of these targeted therapies in NET suggests that the molecular characterization of NETs may provide an avenue to predict both which patients may benefit most from the treatment and to overcome potential drug resistance. Recent genomic studies of NETs have further suggested that pathways regulating chromatin remodeling and epigenetic modification may play a key role in regulating NET growth. These observations offer the potential for new therapeutic and diagnostic advances for patients with NET.

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