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

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

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

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

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

  • 2.
    Abdulla, Maysaa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Laszlo, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Triumf, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Hedström, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden.;Karolinska Inst, Dept Biosci & Nutr, Huddinge, Sweden..
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Univ Uppsala Hosp, S-75185 Uppsala, Sweden..
    Core needle biopsies for the diagnosis of diffuse large B-cell lymphoma - a great concern for research2017In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 56, no 1, 106-109 p.Article in journal (Refereed)
  • 3. Adam, René
    et al.
    de Gramont, Aimery
    Figueras, Joan
    Kokudo, Norihiro
    Kunstlinger, Francis
    Loyer, Evelyne
    Poston, Graeme
    Rougier, Philippe
    Rubbia-Brandt, Laura
    Sobrero, Alberto
    Teh, Catherine
    Tejpar, Sabine
    Van Cutsem, Eric
    Vauthey, Jean-Nicolas
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Managing synchronous liver metastases from colorectal cancer: A multidisciplinary international consensus2015In: Cancer Treatment Reviews, ISSN 0305-7372, E-ISSN 1532-1967, Vol. 41, no 9, 729-741 p.Article in journal (Refereed)
    Abstract [en]

    An international panel of multidisciplinary experts convened to develop recommendations for managing patients with colorectal cancer (CRC) and synchronous liver metastases (CRCLM). A modified Delphi method was used. CRCLM is defined as liver metastases detected at or before diagnosis of the primary CRC. Early and late metachronous metastases are defined as those detected ⩽12months and >12months after surgery, respectively. To provide information on potential curability, use of high-quality contrast-enhanced computed tomography (CT) before chemotherapy is recommended. Magnetic resonance imaging is increasingly being used preoperatively to aid detection of subcentimetric metastases, and alongside CT in difficult situations. To evaluate operability, radiology should provide information on: nodule size and number, segmental localization and relationship with major vessels, response after neoadjuvant chemotherapy, non-tumoral liver condition and anticipated remnant liver volume. Pathological evaluation should assess response to preoperative chemotherapy for both the primary tumour and metastases, and provide information on the tumour, margin size and micrometastases. Although the treatment strategy depends on the clinical scenario, the consensus was for chemotherapy before surgery in most cases. When the primary CRC is asymptomatic, liver surgery may be performed first (reverse approach). When CRCLM are unresectable, the goal of preoperative chemotherapy is to downsize tumours to allow resection. Hepatic resection should not be denied to patients with stable disease after optimal chemotherapy, provided an adequate liver remnant with inflow and outflow preservation remains. All patients with synchronous CRCLM should be evaluated by a hepatobiliary multidisciplinary team.

  • 4.
    Adde, Magdalena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Aggressive B-cell Lymphomas: Studies of Treatment, FDG-PET Evaluation and Prognostic Factors2009Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    To improve outcome in young, high-risk lymphoma patients, treatment was intensified, adding etoposide and rituximab to standard CHOP treatment. Granulocyte-colony stimulating factor (G-CSF) enabled treatment bi-weekly. Results were promising: overall (OS) and event-free survival (EFS) 79% and 60% respectively, median follow up 27 months. Single infusion Ara-C, contrary to expectations, did not prevent relapse in CNS.

    DLBCL were classified as germinal center (GC) or non-GC derived, using immunohistochemical markers, CD10, BCL6 and MUM1. We investigated the outcome for both phenotypes after adding rituximab to chemotherapy. For 106 patients treated with CHOP alone, the GC phenotype displayed significantly better OS and EFS. In contrast, GC phenotype did not predict outcome in 95 patients treated with immunochemotherapy . Thus, addition of rituximab seems to eliminate the prognostic value of immunohistochemically defined GC phenotypes in DLBCL.

    To improve evaluation and find non-responders, mid-treatment FDG-PET CT was incorporated into clinical routine for patients with high-risk aggressive lymphoma. For those with positive PET, biopsy followed by treatment intensification was recommended. Twenty-five patients were examined, five with positive PET. Two of these had lymphoma in the biopsy. Two had a negative biopsy, and one had a false positive investigation. Seven patients had increased uptake of uncertain significance. Two patients with uncertain PET, and two with negative PET have relapsed, giving a negative predictive value of 85%.

    In case of relapse of aggressive lymphoma or if not obtaining CR, high dose chemotherapy with autologous stem cell support (HDT) is standard treatment. HDT outcome for 38 patients with transformed follicular lymphoma was compared to outcome for 79 patients with de novo B-cell lymphoma. At median follow-up of 11.5 years both OS and EFS were superior in the transformed group, OS 67% and 33%, EFS 55% and 27% respectively. Treatment related mortality was less than reported in other studies.

    List of papers
    1. Outcome for young high-risk aggressive B-cell lymphoma patients treated with CHOEP-14 and rituximab (R-CHOEP-14).
    Open this publication in new window or tab >>Outcome for young high-risk aggressive B-cell lymphoma patients treated with CHOEP-14 and rituximab (R-CHOEP-14).
    Show others...
    2006 (English)In: Med Oncol, ISSN 1357-0560, Vol. 23, no 2, 283-93 p.Article in journal (Refereed) Published
    Keyword
    Adult, Aged, Antibodies; Monoclonal/administration & dosage, Antimetabolites; Antineoplastic, Antineoplastic Combined Chemotherapy Protocols/*administration & dosage, Central Nervous System Neoplasms/mortality/*prevention & control/secondary, Cyclophosphamide/administration & dosage, Cytarabine/administration & dosage, Disease-Free Survival, Doxorubicin/administration & dosage, Etoposide/administration & dosage, Female, Follow-Up Studies, Granulocyte Colony Stimulating Factor; Recombinant, Humans, Lymphoma; B-Cell/complications/*drug therapy/mortality, Male, Middle Aged, Prednisolone/administration & dosage, Recurrence, Retrospective Studies, Vincristine/administration & dosage
    Identifiers
    urn:nbn:se:uu:diva-25280 (URN)16720929 (PubMedID)
    Available from: 2007-04-02 Created: 2007-04-02 Last updated: 2011-01-11
    2. Prognostic impact of immunohistochemically defined germinal center phenotype in diffuse large B-cell lymphoma patients treated with immunochemotherapy
    Open this publication in new window or tab >>Prognostic impact of immunohistochemically defined germinal center phenotype in diffuse large B-cell lymphoma patients treated with immunochemotherapy
    Show others...
    2007 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 109, no 11, 4930-4935 p.Article in journal (Refereed) Published
    Abstract [en]

    Germinal center (GC) and non-GC phenotypes are predictors of outcome in diffuse large B-cell lymphoma (DLBCL) and can be used to stratify chemotherapy-treated patients into low- and high-risk groups. To determine how combination of rituximab with chemotherapy influences GC-associated clinical outcome, GC and non-GC phenotypes were identified immunohistochemically from samples of 90 de novo DLBCL patients treated with rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen (immunochemotherapy). One hundred and four patients previously treated with chemotherapy served as a control group. Consistent with previous studies, chemotherapy-treated patients with immunohistochemically defined GC phenotype displayed a significantly better overall (OS) and failure-free survival (FFS) than the non-GC group (OS, 70% vs 47%, P = .012; FFS, 59% vs 30%, P = .001). In contrast, immunohistochemically defined GC phenotype did not predict outcome in immunochemotherapy-treated patients (OS, 77% vs 76%, P = ns; FFS, 68% vs 63%, P = ns). In comparison, International Prognostic Index (IPI) could separate the high-risk patients from low- and intermediate-risk groups (OS, 84% vs 63%, P = .030; FFS, 79% vs 52%, P = .028). We conclude that rituximab in combination with chemotherapy seems to eliminate the prognostic value of immunohistochemically defined GC- and non-GC phenotypes in DLBCL.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-10681 (URN)10.1182/blood-2006-09-047068 (DOI)000246946100053 ()17299093 (PubMedID)
    Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2011-01-28Bibliographically approved
    3. Little usefullness of mid-treatment FDG-PET and biopsy for treatment intensification in patients with aggressive lymphoma
    Open this publication in new window or tab >>Little usefullness of mid-treatment FDG-PET and biopsy for treatment intensification in patients with aggressive lymphoma
    Show others...
    (English)Manuscript (Other academic)
    Abstract [en]

    Purpose: To evaluate the experiences of introducing mid-treatment FDG-PET in patients with aggressive lymphoma, in a population based program with decentralized examinations, with emphasis on finding patients who would benefit from dose-escalation.

    Patients and Methods: Twenty-five patients with aggressive lymphoma were included. Twenty-four (95%) of these having an aggressive B-cell lymphoma (84% diffuse large B-cell lymphoma) were treated with CHOP-like treatment given at two week intervals + rituximab. One patient having an anaplastic T-cell lymphoma was treated with CHOEP-14. Mid-treatment FDG-PET was performed and assessed as positive, uncertain or negative for remaining lymphoma. The intention was to perform a biopsy in those with a positive FDG-PET, and, to change to a platina-containing therapy and consolidate with high-dose therapy if viable lymphoma was found. Retrospective review of the PET investigations was done. Living patients were followed for a median of 22 months.

    Results: At primary analysis five patients (20%) had positive uptake on FDG-PET. Two of them had biopsy-proven viable tumor but did not complete the planned salvage treatment, one due to chemotherapy toxicity and one due to progressive disease during salvage therapy. Two patients had a negative biopsy and one patient had no biopsy due to technical difficulties at diagnosis. These three patients remain in remission after standard treatment. Out of seven patients (28%) having “uncertain” uptake two relapsed. Thirteen patients (52%) were negative,two of whom relapsed giving a negative predictive value of 85%.

    Conclusion: Mid-treatment FDG PET-CT in order to find patients with biopsy-proven aggressive lymphoma, who can be salvaged with dose escalation, was not feasible in clinical routine.

    Identifiers
    urn:nbn:se:uu:diva-100255 (URN)
    Available from: 2009-03-29 Created: 2009-03-29 Last updated: 2010-01-14
    4. Superior outcome in transformed follicular lymphoma compared to de novo aggressive B-cell lymphoma treated with high-dose therapy and autologous stem-cell support
    Open this publication in new window or tab >>Superior outcome in transformed follicular lymphoma compared to de novo aggressive B-cell lymphoma treated with high-dose therapy and autologous stem-cell support
    Show others...
    (English)Manuscript (Other academic)
    Abstract [en]

    Purpose: To assess the outcome of high–dose therapy with autologous stem cell support (HDT) in patients with transformed follicular lymphoma compared to patients with de novo aggressive B-cell lymphoma, in a retrospective analysis of patients treated at two Swedish university hospitals.

    Patients and Methods: 117 patients, mean age 48 years (21-65), 79 with de novo aggressive B-cell lymphoma and 38 with transformed follicular lymphoma, were treated with high-dose-therapy (HDT) as consolidation. Thirteen patients with transformed follicular lymphoma had been treated with a single alkylating agent and 25 were chemonaive at transformation. After transformation, nine patients had HDT as part of first line aggressive therapy, and a further eight failed to obtain CR and had HDT upfront. Twenty-one patients received more than one treatment regimen before HDT. In the de novo aggressive lymphoma group five patients with high risk criteria, and 16 patients who failed to obtain CR, received HDT upfront (CR1), Fifty-eight patients received more than one regimen before HDT because of relapse. Rituximab was given as a single dose to five patients for in vivo purging of the stem cell graft.

    Results: With a median follow up of 11.5 years (8-20), event free survival (EFS) and overall survival (OS) were 35% and 44% respectively. When comparing the two groups, the ten- year EFS rates were 27% in the de novo group and 55% in the transformed group and the ten-year OS was 33 % and 67% respectively. Treatment related mortality was acceptable with 4% early and 3.5% late mortality. In a multivariate analysis, “transformed vs de novo aggressive” histopathology was the only factor significantly related to outcome.

    Conclusion: Both EFS and OS were much better in patients with transformed follicular lymphoma compared to patients with de novo aggressive B-cell lymphoma Although the introduction of rituximab certainly has improved the outcome in both groups, HDT should still be considered as a salvage strategy not only in cases of de novo aggressive B-cell lymphoma and especially in transformed follicular lymphoma relapsing after first line treatment..

    Identifiers
    urn:nbn:se:uu:diva-100257 (URN)
    Available from: 2009-03-29 Created: 2009-03-29 Last updated: 2010-01-14
  • 5.
    Aftab, Obaid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Engskog, Mikael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Haglöf, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Elmsjö, Albert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Arvidsson, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Hammerling, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gustafsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    NMR spectroscopy based metabolic profiling of drug induced changes in vitro can discriminate between pharmacological classes2014In: Journal of chemical information and modeling, ISSN 1549-9596, Vol. 54, no 11, 3251-3258 p.Article in journal (Refereed)
    Abstract [en]

    Drug induced changes in mammalian cell line models have already been extensively profiled at the systemic mRNA level and subsequently used to suggest mechanisms of action for new substances as well as to support drug repurposing, i.e. identifying new potential indications for drugs already licensed for other pharmacotherapy settings. The seminal work in this field, which includes a large database and computational algorithms for pattern matching, is known as the “Connectivity Map” (CMap). The potential of similar exercises at the metabolite level is, however, still largely unexplored. Only recently the first high throughput metabolomic assay pilot study was published, involving screening of metabolic response to a set of 56 kinase inhibitors in a 96-well format. Here we report results from a separately developed metabolic profiling assay, which leverages 1H NMR spectroscopy to the quantification of metabolic changes in the HCT116 colorectal cancer cell line, in response to each of 26 compounds. These agents are distributed across 12 different pharmacological classes covering a broad spectrum of bioactivity. Differential metabolic profiles, inferred from multivariate spectral analysis of 18 spectral bins, allowed clustering of most tested drugs according to their respective pharmacological class. A more advanced supervised analysis, involving one multivariate scattering matrix per pharmacological class and using only 3 spectral bins (three metabolites), showed even more distinct pharmacology-related cluster formations. In conclusion, this kind of relatively fast and inexpensive profiling seems to provide a promising alternative to that afforded by mRNA expression analysis, which is relatively slow and costly. As also indicated by the present pilot study, the resulting metabolic profiles do not seem to provide as information rich signatures as those obtained using systemic mRNA profiling, but the methodology holds strong promise for significant refinement.

  • 6.
    Aftab, Obaid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Hassan, Saadia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Hammerling, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gustafsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Label free quantification of time evolving morphologies using time-lapse video microscopy enables identity control of cell lines and discovery of chemically induced differential activity in iso-genic cell line pairs2015In: Chemometrics and Intelligent Laboratory Systems, ISSN 0169-7439, E-ISSN 1873-3239, Vol. 141, 24-32 p.Article in journal (Refereed)
    Abstract [en]

    Label free time-lapse video microscopy based monitoring of time evolving cell population morphology has potential to offer a simple and cost effective method for identity control of cell lines. Such morphology monitoring also has potential to offer discovery of chemically induced differential changes between pairs of cell lines of interest, for example where one in a pair of cell lines is normal/sensitive and the other malignant/resistant. A new simple algorithm, pixel histogram hierarchy comparison (PHHC), for comparison of time evolving morphologies (TEM) in phase contrast time-lapse microscopy movies was applied to a set of 10 different cell lines and three different iso-genic colon cancer cell line pairs, each pair being genetically identical except for a single mutation. PHHC quantifies differences in morphology by comparing pixel histogram intensities at six different resolutions. Unsupervised clustering and machine learning based classification methods were found to accurately identify cell lines, including their respective iso-genic variants, through time-evolving morphology. Using this experimental setting, drugs with differential activity in iso-genic cell line pairs were likewise identified. Thus, this is a cost effective and expedient alternative to conventional molecular profiling techniques and might be useful as part of the quality control in research incorporating cell line models, e.g. in any cell/tumor biology or toxicology project involving drug/agent differential activity in pairs of cell line models.

  • 7.
    Aftab, Obaid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nazir, Madiha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Hammerling, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gustafsson, Mats G
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Label free high throughput screening for apoptosis inducing chemicals using time-lapse microscopy signal processing2014In: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 19, no 9, 1411-1418 p.Article in journal (Refereed)
    Abstract [en]

    Label free time-lapse microscopy has opened a new avenue to the study of time evolving events in living cells. When combined with automated image analysis it provides a powerful tool that enables automated large-scale spatiotemporal quantification at the cell population level. Very few attempts, however, have been reported regarding the design of image analysis algorithms dedicated to the detection of apoptotic cells in such time-lapse microscopy images. In particular, none of the reported attempts is based on sufficiently fast signal processing algorithms to enable large-scale detection of apoptosis within hours/days without access to high-end computers. Here we show that it is indeed possible to successfully detect chemically induced apoptosis by applying a two-dimensional linear matched filter tailored to the detection of objects with the typical features of an apoptotic cell in phase-contrast images. First a set of recorded computational detections of apoptosis was validated by comparison with apoptosis specific caspase activity readouts obtained via a fluorescence based assay. Then a large screen encompassing 2,866 drug like compounds was performed using the human colorectal carcinoma cell line HCT116. In addition to many well known inducers (positive controls) the screening resulted in the detection of two compounds here reported for the first time to induce apoptosis.

  • 8.
    Agarwal, Prasoon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Alzrigat, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Párraga, Alba Atienza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Singh, Umashankar
    Ungerstedt, Johanna
    Österborg, Anders
    Brown, Peter J
    Ma, Anqi
    Jin, Jian
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infectious Diseases.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Jernberg-Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target.2016In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 6, 6809-6923 p.Article in journal (Refereed)
    Abstract [en]

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

  • 9. Agathangelidis, Andreas
    et al.
    Vardi, Anna
    Baliakas, Panagiotis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Stamatopoulos, Kostas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Stereotyped B-cell receptors in chronic lymphocytic leukemia2014In: Leukemia and Lymphoma, ISSN 1042-8194, E-ISSN 1029-2403, Vol. 55, no 10, 2252-2261 p.Article, review/survey (Refereed)
    Abstract [en]

    Over the last decade, immunogenetic analysis of B-cell receptor immunoglobulins (BcR IGs) has proved to be a particularly fruitful field in chronic lymphocytic leukemia (CLL), not only for understanding disease pathogenesis but also for discriminating clinical subgroups with markedly distinct course and outcome. Of utmost importance was the identification of quasi-identical BcR IGs among unrelated patients with CLL, fittingly coined as "stereotypy," that set the wheels in motion for unraveling the role of antigen(s) in the selection and expansion of the leukemic clones. The categorization of CLL clones into "subsets" according to shared BcR IG structural characteristics provided a compartmentalized view of this otherwise heterogeneous disease, which eventually led to defining strikingly homogeneous groups of patients in terms of: (i) functional properties of the clonal BcR IGs, e. g. BcR reactivity and signaling; (ii) clonal genetic landscape, e. g. genomic aberrations, gene expression/methylation profiles, microRNA signatures; and (iii) clinical course and outcome. The remarkable restriction of the CLL IG gene repertoire, resulting to a great degree from the high impact of BcR IG stereotypy, may also prompt speculations regarding CLL ontogenesis. Overall, the BcR IG molecule justifiably lies at the heart of CLL clinical research, holding the promise of subset-tailored therapies.

  • 10.
    Ahlgren, Johan
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Studies on Prediction of Axillary Lymph Node Status in Invasive Breast Cancer2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Breast cancer is the most common malignancy among females in Sweden. Axillary lymph-node dissection is a standard procedure in the management of breast cancer, aiming at obtaining prognostic information for adjuvant therapy decisions. Axillary dissection entails considerable morbidity. The aims of this study were to establish more selective surgical approaches and to investigate angiogenesis, a potential predictor for lymph-node metastases and prognosis.

    Clinical nodal status, tumour size and S-phase were associated with nodal metastases in cohort of 1145 women. The proportion of nodal metastases was 13% in the subgroup with the lowest risk.

    In a study from two registries, 675 and 1035 breast cancers ≤10 mm diagnosed by screening mammography had nodal metastases in 6,5% and 7%, respectively. Clinically detected cancers had a risk of 16% and 14%, respectively.

    In a study on 415 women, a 5-node biopsy of the axilla had a sensitivity of 97,3% and a false negative rate of 2,7% in comparison with axillary dissection.

    Six sections from 21 breast cancers were analysed for microvessel density (MVD). The inter-section variation contributed more to the total variance than inter-tumour variation, 45,0% and 37,3%, respectively.

    In a cohort of 315 women, breast cancers with high MVD more frequently had p53 mutations (27,1%) compared with cases with low MVD (18,4%). This difference was not statistically significant (p=0,075). p53 mutations were associated with a worse outcome, whereas MVD was not.

    In conclusion, women with screening detected ≤10 mm breast cancers have a low risk of lymph node metastases and some may not need axillary dissection in the future. The 5-node biopsy could be an alternative to axillary dissection. MVD is associated with methodological weaknesses and routine use is not recommended.

  • 11.
    Ahlgren, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Molecular Radionuclide Imaging Using Site-specifically Labelled Recombinant Affibody Molecules: Preparation and Preclinical Evaluation2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Radionuclide molecular imaging is an emerging multidisciplinary technique that is used in modern medicine to visualise diseases at cellular and molecular levels. This thesis is based on five papers (I-V) and focuses on the development of site-specific radiolabelled recombinant anti-HER2 Affibody molecules and preclinical evaluations in vitro and in vivo of the labelled conjugates. This work is part of a preclinical development of an Affibody molecule-based tracer for molecular imaging of HER2 expressing tumours.

    Papers I and II report the evaluation of the Affibody molecule ZHER2:2395-C, site-specifically labelled with the radiometals 111In (for SPECT) and 57Co (as a surrogate for 55Co, suitable for PET applications) using a thiol reactive DOTA derivative as a chelator. Both conjugates demonstrated very suitable biodistribution properties, enabling high contrast imaging just a few hours after injection.

    Papers III and IV report the development and optimization of a technique for site-specific labelling of ZHER2:2395-C with 99mTc using an N3S chelating peptide sequence. 99mTc-ZHER2:2395-C demonstrated high and specific tumour uptake and rapid clearance of non-bound tracer from the blood, resulting in high tumour-to-non-tumour ratios shortly after injection, enabling high contrast imaging. In addition, in the study described in paper IV, freeze-dried kits previously developed for 99mTc-labelling were optimised, resulting in the development of a kit in which all the reagents and protein needed for labelling of ZHER2:2395-C with 99mTc were contained in a single vial.

    Paper V reports the evaluation of an anti-HER2 Affibody molecule, ABY-025, with a fundamentally re-engineered scaffold. Despite the profound re-engineering, the biodistribution pattern of 111In-ABY-025 was very similar to that of two variants of the parental molecule.

    It seems reasonable to believe that these results will also be applicable to Affibody molecules towards other targets. Hopefully, this work will also be helpful in the development of other small proteinaceous tracers.

    List of papers
    1. Evaluation of maleimide derivative of DOTA for site-specific labeling of recombinant affibody molecules
    Open this publication in new window or tab >>Evaluation of maleimide derivative of DOTA for site-specific labeling of recombinant affibody molecules
    Show others...
    2008 (English)In: Bioconjugate chemistry, ISSN 1043-1802, E-ISSN 1520-4812, Vol. 19, no 1, 235-243 p.Article in journal (Refereed) Published
    Abstract [en]

    Affibody molecules are a new class of small (7 kDa) scaffold affinity proteins, which demonstrate promising properties as agents for in vivo radionuclide targeting. The Affibody scaffold is cysteine-free and therefore independent of disulfide bonds. Thus, a single thiol group can be engineered into the protein by introduction of one cysteine. Coupling of thiol-reactive bifunctional chelators can enable site-specific labeling of recombinantly produced Affibody molecules. In this study, the use of 1,4,7,10-tetraazacyclododecane-1,4,7-tris-acetic acid-10-maleimidoethylacetamide (MMA-DOTA) for 111 In-labeling of anti-HER2 Affibody molecules His 6-Z HER2:342-Cys and Z HER2:2395-Cys has been evaluated. The introduction of a cysteine residue did not affect the affinity of the proteins, which was 29 pM for His 6-Z HER2:342-Cys and 27 pM for Z HER2:2395-Cys, comparable with 22 pM for the parental Z HER2:342. MMA-DOTA was conjugated to DTT-reduced Affibody molecules with a coupling efficiency of 93% using a 1:1 molar ratio of chelator to protein. The conjugates were labeled with 111 In to a specific radioactivity of up to 7 GBq/mmol, with preserved binding for the target HER2. In vivo, the non-His-tagged variant 111 In-[MMA-DOTA-Cys61]-Z HER2:2395-Cys demonstrated appreciably lower liver uptake than its His-tag-containing counterpart. In mice bearing HER2-expressing LS174T xenografts, 111 In-[MMA-DOTA-Cys61]-Z HER2:2395-Cys showed specific and rapid tumor localization, and rapid clearance from blood and nonspecific compartments, leading to a tumor-to-blood-ratio of 18 +/- 8 already 1 h p.i. Four hours p.i., the tumor-to-blood ratio was 138 +/- 8. Xenografts were clearly visualized already 1 h p.i.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-104530 (URN)10.1021/bc700307y (DOI)000252520300030 ()18163536 (PubMedID)
    Available from: 2009-05-29 Created: 2009-05-28 Last updated: 2015-03-24Bibliographically approved
    2. Evaluation of the Radiocobalt-Labeled [MMA-DOTA-Cys61]-ZHER2:2395-Cys Affibody Molecule for Targeting of HER2-Expressing Tumors
    Open this publication in new window or tab >>Evaluation of the Radiocobalt-Labeled [MMA-DOTA-Cys61]-ZHER2:2395-Cys Affibody Molecule for Targeting of HER2-Expressing Tumors
    2010 (English)In: Molecular Imaging and Biology, ISSN 1536-1632, E-ISSN 1860-2002, Vol. 12, no 1, 54-62 p.Article in journal (Refereed) Published
    Abstract [en]

    PURPOSE: Imaging using positron emission tomography (PET) in the field of nuclear medicine is becoming increasingly important. The aim of this study was to develop a method for labeling of affibody molecules with radiocobalt for PET applications. PROCEDURES: The human epidermal growth factor receptors type 2 (HER2) binding affibody molecule DOTA-Z(2395)-C was radiolabeled with (57)Co (used as a surrogate of (55)Co). The binding specificity and cellular processing of the labeled compound was studied in vitro followed by in vivo characterization in normal and tumor-bearing mice. Furthermore, a comparative biodistribution study was performed with a (111)In-labeled counterpart. RESULTS: DOTA-Z(2395)-C was successfully labeled with radiocobalt with nearly quantitative yield. The compound displayed good retention on cells over time and high tumor accumulation of radioactivity in animal studies. Imaging studies showed clear visualization of HER2-positive tumors. Furthermore, the radiocobalt label provided better tumor-to-organ ratios than (111)In. CONCLUSIONS: Radiocobalt is a promising label for affibody molecules for future PET applications.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-122173 (URN)10.1007/s11307-009-0238-8 (DOI)000273479300008 ()19557480 (PubMedID)
    Available from: 2010-04-07 Created: 2010-04-07 Last updated: 2015-03-24Bibliographically approved
    3. Targeting of HER2-expressing tumors with a site-specifically 99mTc-labeled recombinant affibody molecule, ZHER2:2395, with C-terminally engineered cysteine
    Open this publication in new window or tab >>Targeting of HER2-expressing tumors with a site-specifically 99mTc-labeled recombinant affibody molecule, ZHER2:2395, with C-terminally engineered cysteine
    Show others...
    2009 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 50, no 5, 781-789 p.Article in journal (Refereed) Published
    Abstract [en]

    The detection of human epidermal growth factor receptor type 2 (HER2) expression in malignant tumors provides important information influencing patient management. Radionuclide in vivo imaging of HER2 may permit the detection of HER2 in both primary tumors and metastases by a single noninvasive procedure. Small (7 kDa) high-affinity anti-HER2 Affibody molecules may be suitable tracers for SPECT visualization of HER2-expressing tumors. The use of generator-produced (99m)Tc as a label would facilitate the prompt translation of anti-HER2 Affibody molecules into use in clinics. METHODS: A C-terminal cysteine was introduced into the Affibody molecule Z(HER2:342) to enable site-specific labeling with (99m)Tc. Two recombinant variants, His(6)-Z(HER2:342)-Cys (dissociation constant [K(D)], 29 pM) and Z(HER2:2395)-Cys, lacking a His tag (K(D), 27 pM), were labeled with (99m)Tc in yields exceeding 90%. The binding specificity and the cellular processing of Affibody molecules were studied in vitro. Biodistribution and gamma-camera imaging studies were performed in mice bearing HER2-expressing xenografts. RESULTS: (99m)Tc-His(6)-Z(HER2:342)-Cys was capable of targeting HER2-expressing SKOV-3 xenografts in SCID mice, but the liver radioactivity uptake was high. A series of comparative biodistribution experiments indicated that the presence of the His tag caused elevated accumulation in the liver. (99m)Tc-Z(HER2:2395)-Cys, not containing a His tag, showed low uptake in the liver and high and specific uptake in HER2-expressing xenografts. Four hours after injection, the radioactivity uptake values (percentage of injected activity per gram of tissue [%IA/g]) were 6.9 +/- 2.5 (mean +/- SD) %IA/g in LS174T xenografts (moderate level of HER2 expression) and 15 +/- 3 %IA/g in SKOV-3 xenografts (high level of HER2 expression). The corresponding tumor-to-blood ratios were 88 +/- 24 and 121 +/- 24, respectively. Both LS174T and SKOV-3 xenografts were clearly visualized with a clinical gamma-camera 1 h after injection of (99m)Tc-Z(HER2:2395)-Cys. CONCLUSION: The Affibody molecule (99m)Tc-Z(HER2:2395)-Cys is a promising tracer for SPECT visualization of HER2-expressing tumors.

    Keyword
    Affibody molecule, technetium, imaging, HER2, C-terminal cysteine
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-122172 (URN)10.2967/jnumed.108.056929 (DOI)000272487900017 ()19372467 (PubMedID)
    Available from: 2010-04-07 Created: 2010-04-07 Last updated: 2015-03-24Bibliographically approved
    4. Kit formulation for 99mTc-labeling of recombinant anti-HER2 Affibody molecules with a C-terminally engineered cysteine
    Open this publication in new window or tab >>Kit formulation for 99mTc-labeling of recombinant anti-HER2 Affibody molecules with a C-terminally engineered cysteine
    2010 (English)In: Nuclear Medicine and Biology, ISSN 0969-8051, E-ISSN 1872-9614, Vol. 37, no 5, 539-546 p.Article in journal (Refereed) Published
    Abstract [en]

    Introduction: Molecular imaging of HER2-expression in malignant tumors provides potentially important information for patient management. Affibody molecules have shown to be suitable tracers for imaging applications using SPECT or PET. Results from an earlier evaluation of the application of site specific 99mTc-labeling on the Affibody molecule, ZHER2:2395-C, were favorable.

    Methods: As a preparation for clinical application of this tracer we have developed and evaluated a robust single-vial freeze-dried kit, allowing labeling of the Affibody molecule, ZHER2:2395-C, with 99mTc.

    Results: The composition of the kit (containing glucoheptonate, EDTA and tin(II)-chloride), as well as the protein amount and the pertechnetate volume were optimized for a high labeling yield (> 90 %) and minimal presence of reduced hydrolyzed technetium colloids (< 1 %). The specificity to HER2 receptors, the binding competence and the stability in PBS and murine serum were verified in vitro. The shelf-life was also evaluated in vitro, showing no reduction in labeling yield or binding capacity to HER2-expressing cells after over 400 days of storage of the single-vial freeze-dried kit.

    Conclusions: ZHER2:2395-C labeled with 99mTc using the lyophilized kit was stable and resulted in a favorable biodistribution in an in vivo evaluation in normal NMRI mice.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-122175 (URN)10.1016/j.nucmedbio.2010.02.009 (DOI)000279412400002 ()20610158 (PubMedID)
    Available from: 2010-04-07 Created: 2010-04-07 Last updated: 2011-10-26Bibliographically approved
    5. Targeting of HER2-Expressing Tumors Using 111In-ABY-025, a Second-Generation Affibody Molecule with a Fundamentally Reengineered Scaffold
    Open this publication in new window or tab >>Targeting of HER2-Expressing Tumors Using 111In-ABY-025, a Second-Generation Affibody Molecule with a Fundamentally Reengineered Scaffold
    Show others...
    2010 (English)In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 51, no 7, 1131-1138 p.Article in journal (Refereed) Published
    Abstract [en]

    Overexpression of HER2 in breast carcinomas predicts response to trastuzumab therapy. Affibody molecules based on a non-immunoglobulin scaffold have demon-strated high potential for in vivo molecular imaging of HER2-expressing tumors. Re-engineering of the molecular scaffold has led to a second generation of optimized Affibody molecules, having a surface distinctly different from the parental protein domain from staphylococcal protein A. The new tracer showed further increased melting point, stability and overall hydrophilicity compared to the parental molecule, and was shown to be more amenable for chemical peptide synthesis. The goal of this study was to assess potential effects of this extensive re-engineering on HER2 targeting, using ABY-025, a DOTA conjugated variant of the novel tracer.

    Methods: 111In-ABY-025 was compared with previously evaluated parent HER2-binding Affibody tracers in vitro and in vivo. The in vivo behavior was further evaluated in mice bearing SKOV-3 xenografts, in rats and in cynomolgus macaques.

    Results: 111In-ABY-025 bound specifically to HER2 in vitro and in vivo. Direct comparison with the previous generation of HER2-binding tracers showed that ABY-025 retained excellent targeting properties. Rapid blood clearance was shown in mice, rats and macaques. A highly specific tumor uptake of 16.7 ± 2.5 %IA/g was seen at 4 h after injection. The tumor-to-blood ratio was 6.3 at 0.5 h, 88 at 4 h, and increased up to 3 days after injection. Gamma camera imaging of tumors was already possible 0.5 h after injection. Furthermore, repeated i.v. administration of ABY-025 did not induce antibody formation in rats.

    Conclusions: The biodistribution of 111In-ABY-025 was in remarkably good agreement with the parent tracers, despite profound re-engineering of the non-binding surface. The molecule displayed rapid blood clearance in all species investigated and excellent targeting capacity in tumor bearing mice, leading to high tumor-to-organ-ratios and high contrast imaging shortly after injection.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-122176 (URN)10.2967/jnumed.109.073346 (DOI)000279430900021 ()20554729 (PubMedID)
    Available from: 2010-04-07 Created: 2010-04-07 Last updated: 2015-03-24Bibliographically approved
  • 12.
    Ahmadi, Zainab
    et al.
    Univ Lund Hosp, Div Resp Med & Allergol, Dept Clin Sci, SE-22100 Lund, Sweden..
    Lundstrom, Staffan
    Stockholms Sjukhem Fdn, Palliat Care Serv, Stockholm, Sweden.;Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala Univ, Dept Med Sci Resp Med & Allergol, Uppsala, Sweden..
    Strang, Peter
    Stockholms Sjukhem Fdn, Palliat Care Serv, Stockholm, Sweden.;Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Emtner, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotherapy.
    Currow, David C.
    Flinders Univ S Australia, Discipline Serv, Adelaide, SA 5001, Australia.;Flinders Univ S Australia, Palliat Serv, Adelaide, SA 5001, Australia.;Flinders Univ S Australia, Support Serv, Adelaide, SA 5001, Australia..
    Ekström, Magnus
    Univ Lund Hosp, Div Resp Med & Allergol, Dept Clin Sci, SE-22100 Lund, Sweden.;Flinders Univ S Australia, Discipline Serv, Adelaide, SA 5001, Australia.;Flinders Univ S Australia, Palliat Serv, Adelaide, SA 5001, Australia.;Flinders Univ S Australia, Support Serv, Adelaide, SA 5001, Australia..
    End-of-life care in oxygen-dependent COPD and cancer: a national population-based study2015In: European Respiratory Journal, ISSN 0903-1936, E-ISSN 1399-3003, Vol. 46, no 4, 1190-1193 p.Article in journal (Refereed)
  • 13. Akeus, Paulina
    et al.
    Langenes, Veronica
    von Mentzer, Astrid
    Yrlid, Ulf
    Sjoling, Asa
    Saksena, Pushpa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Raghavan, Sukanya
    Quiding-Jarbrink, Marianne
    Altered chemokine production and accumulation of regulatory T cells in intestinal adenomas of APC(Min/+) mice2014In: Cancer Immunology and Immunotherapy, ISSN 0340-7004, E-ISSN 1432-0851, Vol. 63, no 8, 807-819 p.Article in journal (Refereed)
    Abstract [en]

    Tumor progression in the colon moves from aberrant crypt foci to adenomatous polyps to invasive carcinomas. The composition of the tumor-infiltrating leukocyte population affects the ability of the immune system to fight the tumor. T cell infiltration into colorectal adenocarcinomas, particularly T helper 1 (Th1) type T cells as well as increased regulatory T cell (Treg) frequencies, is correlated with improved prognosis. However, whether Th1 cells and Tregs are already present at the adenoma stage is not known. In this study, the APC(Min/+) mouse model of intestinal adenomatous polyposis was used to investigate tumor-associated lymphocyte subsets and the mechanisms of their accumulation into gastrointestinal adenomas. Compared to unaffected tissue, adenomas accumulated CD4(+)FoxP3(+) putative Treg in parallel with lower frequencies of conventional T cells and B cells. The accumulation of Treg was also observed in human adenomatous polyps. Despite high Treg numbers, the function of conventional T cells present in the APC(Min/+) adenomas was not different from those in the unaffected tissue. Adenomas displayed an altered chemokine balance, with higher CCL17 and lower CXCL11 and CCL25 expression than in the unaffected tissue. In parallel, CXCR3(+) Tregs were largely absent from adenomas. The data indicate that already in early stages of tumor development, the balance of lymphocyte-recruiting chemokines is altered possibly contributing to the observed shift toward higher frequencies of Treg.

  • 14. Alcorn, S. R.
    et al.
    Nilsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Dieckmann, K.
    McNutt, T. R.
    Chen, M. J.
    Ermoian, R. P.
    Ford, E. C.
    MacDonald, S.
    Nechesnyuk, A.
    Tryggestad, E. J.
    Smith, K.
    Villar, R. C.
    Winey, B.
    Terezakis, S. A.
    Predictors of Setup Accuracy in Image-Guided CNS Radiation Therapy: Prospective Data From a Multinational Pediatrics Consortium2014In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 90, no S1, S723-S723 p.Article in journal (Other academic)
  • 15. Alcorn, Sara R
    et al.
    Chen, Michael J
    Claude, Line
    Dieckmann, Karin
    Ermoian, Ralph P
    Ford, Eric C
    Malet, Claude
    MacDonald, Shannon M
    Nechesnyuk, Alexey V
    Nilsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Villar, Rosangela C
    Winey, Brian A
    Tryggestad, Erik J
    Terezakis, Stephanie A
    Practice patterns of photon and proton pediatric image guided radiation treatment: results from an International Pediatric Research consortium2014In: Practical radiation oncology, ISSN 1879-8500, Vol. 4, no 5, 336-341 p.Article in journal (Refereed)
    Abstract [en]

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

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

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

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

  • 16.
    Alexandersson, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Clinical data analyses of T-DM1, an anitbody drug conjugate for metastatic breast cancer2013Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [sv]

    Användningen av Socialstyrelsens ”Indikatorer för god

     läkemedelsterapi hos äldre” i Värmland

    Erika Markberg

    Handledare: Anna Karin Lidehäll. Examinator: Margareta Hammarlund-Udenaes.

     Institutionen för farmaceutisk biovetenskap. Avdelningen för farmakokinetik och läkemedelsterapi. 30 hp.

    Introduktion: Andelen äldre personer blir allt större, vilket gör det viktigare att de äldres läkemedel uppmärksammas. För att hjälpa förskrivarna i detta arbete har Socialstyrelsen tagit fram indikatorer som skall ge god läkemedelsterapi hos de äldre.

    Syfte: Att utvärdera vetskapen om och följsamheten till Socialstyrelsens indikatorer för äldre personer hos läkare verksamma vid vårdcentralen respektive på sjukhuset samt att utvärdera om läkemedelsförskrivningen vid ett särskilt boende i Värmland är anpassad efter Socialstyrelsens indikatorer för läkemedelsförskrivning till äldre personer.

    Material och metoder: En enkät skickades ut till ett sjukhus och en vårdcentral där förskrivarna fick svara på denna. Läkemedelslistor hämtades ifrån ett särskilt boende och utvärderades.

    Resultat: Alla förskrivarna på vårdcentralen men endast 18 % av förskrivarna vid sjukhuset hade kännedom om indikatorerna. Förskrivarna på sjukhuset ville ha mer information om Socialstyrelsens indikatorer. Läkemedelslistorna till 15 % av de totalt 47 personerna innehöll ett eller flera läkemedel som klassades som olämpliga. De olämpliga läkemedel som förekom var propiomazin, långverkande bensodiazepin eller läkemedel med antikolinerga effekter. Slutsats: Förskrivarnas kännedom om Socialstyrelsens indikatorer skiljer sig beroende på om de jobbar på vårdcentral eller på sjukhus. Läkemedelslistorna följde Socialstyrelsens indikatorer i stor utsträckning.

  • 17.
    Alexandersson, Johanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Clinical data analyses of T-DM1, an antibody drug conjugate for metastatic breast cancer2013Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
  • 18.
    Ali, Dina
    et al.
    Karolinska Univ Hosp, Haematol Ctr, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Haematol & Regenerat Med HERM, Stockholm, Sweden..
    Mohammad, Dara K.
    Karolinska Inst, Karolinska Hosp Huddinge, Clin Res Ctr, Dept Lab Med, Stockholm, Sweden..
    Mujahed, Huthayfa
    Karolinska Univ Hosp, Haematol Ctr, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Haematol & Regenerat Med HERM, Stockholm, Sweden..
    Jonson-Videsater, Kerstin
    Karolinska Univ Hosp, Dept Clin Immunol, Stockholm, Sweden..
    Nore, Beston
    Karolinska Inst, Karolinska Hosp Huddinge, Clin Res Ctr, Dept Lab Med, Stockholm, Sweden..
    Paul, Christer
    Karolinska Univ Hosp, Haematol Ctr, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Haematol & Regenerat Med HERM, Stockholm, Sweden..
    Lehmann, Sören
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Karolinska Univ Hosp, Haematol Ctr, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Haematol & Regenerat Med HERM, Stockholm, Sweden..
    Anti-leukaemic effects induced by APR-246 are dependent on induction of oxidative stress and the NFE2L2/HMOX1 axis that can be targeted by PI3K and mTOR inhibitors in acute myeloid leukaemia cells2016In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 174, no 1, 117-126 p.Article in journal (Refereed)
    Abstract [en]

    The small molecule APR-246 (PRIMA-1(MET)) is a novel drug that restores the activity of mutated and unfolded TP53 protein. However, the mechanisms of action and potential off-target effects are not fully understood. Gene expression profiling in TP53 mutant KMB3 acute myeloid leukaemia (AML) cells showed that genes which protected cells from oxidative stress to be the most up-regulated. APR-246 exposure also induced reactive oxygen species (ROS) formation and depleted glutathione in AML cells. The genes most up-regulated by APR-246, confirmed by quantitative real time polymerase chain reaction, were heme oxygenase-1 (HMOX1, also termed HO-1), SLC7A11 and RIT1. Up-regulation of HMOX1, a key regulator of cellular response to ROS, was independent of TP53 mutational status. NFE2L2 (also termed Nrf2), a master regulator of HMOX1 expression, showed transcriptional up-regulation and nuclear translocation by APR-246. Down-regulation of NFE2L2 by siRNA in AML cells significantly increased the antitumoural effects of APR-246. The PI3K inhibitor wortmannin and the mTOR inhibitor rapamycin inhibited APR-246-induced nuclear translocation of NFE2L2 and counteracted the protective cellular responses to APR-246, resulting in synergistic cell killing together with APR-246. In conclusion, ROS induction is important for antileukaemic activities of APR-246 and inhibiting the protective response of the Nrf-2/HMOX1 axis using PI3K inhibitors, enhances the antileukaemic effects.

  • 19.
    Alit, Abir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Grönberg, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Federspiel, B.
    Dept Pathol, Copenhagen, Denmark..
    Hjortland, G. O.
    Dept Oncol, Oslo, Norway..
    Ladekarl, M.
    Dept Oncol, Aarhus, Denmark..
    Langer, S. W.
    Dept Oncol, Copenhagen, Denmark..
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Knigge, U.
    Dept Surg C, Copenhagen, Denmark.;Dept Endocrinol PE, Copenhagen, Denmark..
    Sorbye, H.
    Dept Oncol, Bergen, Norway..
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Expression of Mutated p53 Protein in Gastroenteropancreatic Neuroendocrine Carcinoma (WHO G3)2016In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, 43-43 p.Article in journal (Refereed)
  • 20.
    Aljaderi, Russil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Behandling av CNS-metastaserad bröstcancer i Uppsala2014Independent thesis Advanced level (degree of Master (Two Years)), 20 credits / 30 HE creditsStudent thesis
    Abstract [sv]

    Introduktion: Bröstcancer är den näst mest vanliga orsaken till hjärnmetastering. Ungefär 20-40% av bröstcancer patienterna utvecklar någon form av CNS-metastasering. Bröstcancern kan delas in i tre olika subtyper; HER2-positiva, luminala och trippelnegativa. Studier har visat en förlängd överlevnad främst hos subtypen HER2-positiva patienter. Syfte: Att belysa förekomsten av CNS-metastaser bland bröstcancerpatienterna på onkologikliniken i Uppsala sedan 2009-2013, samt att göra en praktisk indelning av patienterna med CNS-spridning beroende av tumörtyp och spridningsmönster av metastaserna samt få en överblick av vilka behandlingar som givits och effekten av dessa. Material och metoder: En retrospektiv kohortstudie baserad på patientdatabas och granskning av patientjournaler för tiden 2009-2013. Materialet bestod av 48 patienter med diagnostiserade CNS-metastaser. Genom onkologiklinikens behandlingsdatabas RealQ® identifierades patienterna. Kompletterande information hämtades från journalgranskning i Cosmic. Patienterna följdes upp efter diagnosen fram till april 2014. Resultat: 33 av de 48 patienterna (83 %) hade strålbehandlats, varav 3 av dessa 33 patienter (4 %) strålbehandlats med boost. 4 av 48 patienter (8 %) opererades i kombination med strålbehandling.  2 patienter (4 %) hade stereotaktiskt strålbehandlats och 9 patienter (19 %) fick inte någon behandling. Genomsnittlig ålder i studiepopulationen var 55 år. Medianen var 56. Högsta ålder var 80 år och lägsta ålder var 34 år. 8 patienter (17 %) utav totala populationen som bestod av 48 patienter överlevde, resterande 40 patienter (83 %) avled. Primärtumör subtyper bland studiepopulationen var (24 %) HER2, (40 %) Luminal och (38 %) trippelnegativ. Det hittades en signifikant skillnad för en längre överlevnad från första metastasen (p=0,001) och från CNS-metastasen (p=0,04). Däremot hittades inte någon signifikant överlevnads skillnad från CNS-metastasen och meningeal metastasen (p=0,11). Dessvärre hade patienterna med meningal metastasen en kortare överlevnad. Konklusion: HER2 och trippelnegativa subtyperna var de vanligaste subtyperna inom studiepopulationen. Patienterna med HER2 positiva subtypen hade en bättre överlevnad i jämförelse med de andra två subtyperna. Detta kan sannolikt förklaras av att mer effektiva läkemedelsbehandlingar är tillgängliga för patienter med denna subtyp. Förklaringen till detta måste vara skadad blodhjärnbarriär vid hjärnmetastasering då dessa läkemedel normalt ej passerar blodhjärnbarriären

  • 21.
    Altai, Mohamed
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Liu, Hao
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Gräslund, Torbjörn
    KTH Royal Inst Technol, Sch Biotechnol, Div Prot Technol, SE-10691 Stockholm, Sweden.
    Influence of molecular design on biodistribution and targeting properties of an Affibody-fused HER2-recognising anticancer toxin2016In: International Journal of Oncology, ISSN 1019-6439, Vol. 49, no 3, 1185-1194 p.Article in journal (Refereed)
    Abstract [en]

    Targeted delivery of toxins is a promising way to treat disseminated cancer. The use of monoclonal antibodies as targeting moiety has provided proof-of-principle for this approach. However, extravasation and tissue penetration rates of antibody-based immunotoxins are limited due to antibody bulkiness. The use of a novel class of targeting probes, Affibody molecules, provides smaller toxin-conjugated constructs, which may improve targeting. Earlier, we have demonstrated that affitoxins containing a HER2-targeting Affibody moiety and a deimmunized and truncated exotoxin A from Pseudomonas aeruginosa, PE38X8, provide highly selective toxicity to HER2-expressing cancer cells. To evaluate the influence of molecular design on targeting and biodistribution properties, a series of novel affitoxins were labelled with the residualizing radionuclide 111In. In this study, we have shown that the novel conjugates are more rapidly internalized compared with the parental affitoxin. The use of a (HE)3 purification tag instead of a hexahistidine tag enabled significant (p<0.05) reduction of the hepatic uptake of the affitoxin in a murine model. Fusion of the affitoxin with an albumin-binding domain (ABD) caused appreciable extension of the residence time in circulation and several-fold reduction of the renal uptake. The best variant, 111In-(HE)3-ZHER2-ABD-PE38X8, demonstrated receptor-specific accumulation in HER2-expressing SKOV-3 xenografts. In conclusion, a careful molecular design of scaffold protein based anticancer targeted toxins can appreciably improve their biodistribution and targeting properties.

  • 22. Alvegård, T A
    et al.
    Bauer, H
    Blomqvist, Carl
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enheten för onkologi.
    Rydholm, A
    Smeland, S
    The Scandinavian Sarcoma Group--background, organization and the SSG Register--the first 25 years.2004In: Acta Orthop Scand Suppl, ISSN 0300-8827, Vol. 75, no 311, 1-7 p.Article in journal (Other scientific)
  • 23.
    Alzrigat, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Targeted Inhibition of Polycomb Repressive Complexes in Multiple Myeloma: Implications for Biology and Therapy2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

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

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

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

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

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

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

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

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

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-312396 (URN)10.18632/oncotarget.14378 (DOI)000394181800106 ()28052011 (PubMedID)
    Available from: 2017-01-09 Created: 2017-01-09 Last updated: 2017-11-29Bibliographically approved
    3. The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomain
    Open this publication in new window or tab >>The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomain
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    (English)Manuscript (preprint) (Other academic)
    Keyword
    Multiple Myeloma, Epigenetics, Polycomb, BMI-1, PTC-209
    National Category
    Cancer and Oncology
    Research subject
    Medical Science; Molecular Medicine
    Identifiers
    urn:nbn:se:uu:diva-313562 (URN)
    Available from: 2017-01-20 Created: 2017-01-20 Last updated: 2017-01-25
  • 24.
    Alzrigat, Mohammad
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University.
    Atienza Párraga, Alba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Majumder, Muntasir
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
    Ma, Anqi
    Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA..
    Jin, Jian
    Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA..
    Nilsson, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Heckman, Caroline
    Institute for Molecular Medicine Finland, FIMM, University of Helsinki, Helsinki, Finland.
    Öberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jernberg-Wiklund, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    The polycomb group protein BMI-1 inhibitor PTC-209 is a potent anti-myeloma agent alone or in combination with epigenetic inhibitors targeting EZH2 and the BET bromodomainManuscript (preprint) (Other academic)
  • 25.
    Amini, Rose-Marie
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Hodgkin Lymphoma: Studies of Advanced Stages, Relapses and the Relation to Non-Hodgkin Lymphomas2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The relationship between Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) is not entirely elucidated and a clonal relation may be present more often than previously believed. Mechanisms of tumour progression and resistance to therapy are poorly understood.

    Between 1974 and 1994 all individuals in Sweden with both HL and NHL were identified. Thirty-two cases were studied using clinical, histopathological and immunohistochemical methods. The second lymphoma often appeared in an aggressive clinical form and a significant correlation between the expression of p53 and LMP-1 in the first and second lymphoma was demonstrated.

    The treatment outcome for 307 patients with advanced stages of HL, in an unselected population was in accordance with the treatment results of large centres world-wide. Some patients were successfully selected for a shorter chemotherapy-regimen without inferior treatment results.

    In 124 patients with relapse, the survival of those primarily treated with radiotherapy according to the National guidelines was in accordance with the survival of patients of initially advanced stages. A worse outcome was found for those who received both chemotherapy and radiotherapy initially, probably because of a higher frequency of bulky disease in this group.

    Immunohistochemical analysis of the tumour suppressor protein p53 and retinoblastoma protein (Rb) of paired samples at diagnosis and at relapse in 81 patients did not reveal any specific staining pattern affecting survival.

    A novel B-cell line (U-2932) was established from a patient with a diffuse large B-cell lymphoma previously treated for advanced stage and subsequent relapses of HL. An identical rearranged IgH gene was demonstrated in tumour cells from the patient and in U-2932. A p53 point mutation was detected and over-expression of the p53 protein was found. A complex karyotype with high-level amplifications of the chromosomal regions 18q21 and 3q27, i.e. the loci for bcl-2 and bcl-6 were demonstrated.

    List of papers
    1. Patients suffering from both Hodgkin's disease and non-Hodgkin's lymphoma: a clinico-pathological and immuno-histochemical population-based study of 32 patients
    Open this publication in new window or tab >>Patients suffering from both Hodgkin's disease and non-Hodgkin's lymphoma: a clinico-pathological and immuno-histochemical population-based study of 32 patients
    1997 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 71, no 4, 510-516 p.Article in journal (Refereed) Published
    Abstract [en]

    The occurrence of Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) appearing in the same individual indicates a closer relationship between the 2 diseases than previously believed. The purpose of our study was to analyze cases of HD and NHL in a defined population clinically, histopathologically and immunohistochemically to look for similarities indicating a common cellular origin. Between 1974 and 1994, 77 individuals were identified from the Swedish Cancer Registry and the National Health Care Programme for HD as potentially having both diagnoses. Thirty-two patients who had both HD and NHL were available for histo-pathological re-examination and immunohistochemical staining with CD30, CD15, LMP, p53, CD45 (LCA), CD3, CD45R0 (UCHL-1), L26, MB2 and CD45R (4KB5). The most common relation was HD preceding a high-grade malignant NHL (16 of 32 patients), unexpectedly often of T-cell phenotype (7 of 16 patients). The next common association was NHL of B-CLL type followed by HD (7 of 32 patients). At clinical presentation, the first lymphoma did not differ from lymphomas not associated with a second lymphoma, whereas the second one often appeared with a disseminated and aggressive clinical form. There was a significant correlation between the expression of p53 and LMP in first and second lymphomas. CD3 antibody was frequently expressed both in HD and NHL, whereas positivity for B-cell-related antibodies, CD30, CD15 and CD45R0, was less frequent and generally lower than previously described. The occurrence of HD and NHL in an individual is unusual. Tumour biological features common to both HD and NHL may indicate a similar cellular origin, regardless of the time interval between the diagnoses, and may contribute to the understanding of the pathogenesis of lymphoma.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-89775 (URN)10.1002/(SICI)1097-0215(19970516)71:4<510::AID-IJC2>3.0.CO;2-X (DOI)9178801 (PubMedID)
    Available from: 2002-04-05 Created: 2002-04-05 Last updated: 2013-05-24Bibliographically approved
    2. Treatment outcome in patients younger than 60 years with advanced stages (IIB-IV) of Hodgkin's disease: the Swedish National Health Care Programme experience
    Open this publication in new window or tab >>Treatment outcome in patients younger than 60 years with advanced stages (IIB-IV) of Hodgkin's disease: the Swedish National Health Care Programme experience
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    2000 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 65, no 6, 379-389 p.Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Despite improved treatment results achieved in Hodgkin's disease (HD), only about 70% of patients with advanced stages are cured. The primary aim of this study was to evaluate the outcome of advanced stages (IIB-IVB) of HD in younger patients in an unselected population-based group of patients. The patients were recommended individualized treatment with respect to number of chemotherapy (CT) courses and post-CT radiotherapy (RT) based on pretreatment characteristics and tumour response. Secondly, we investigated if variables of prognostic importance could be detected.

    PATIENTS AND METHODS: Between 1985-92, 307 patients between 17-59 yr of age (median 36) were diagnosed with HD in stages IIB-IVB in 5/6 health care regions in Sweden. Median follow-up time was 7.8 yr (1.3-13). Retrospectively, laboratory parameters were collected.

    RESULTS: In total, 267 (87%) patients had a complete response (CR). The overall and disease-free 10-yr survivals in the whole cohort were 76% and 67%, respectively. There was no difference in survival between the groups of patients who received 6 or 8 cycles of CT. Survival was not higher for patients in CR after CT when RT was added. For those in PR after CT, additional RT raised the frequencies of CR. A selected group of pathologically staged patients was successfully treated with a short course (2 cycles) of CT + RT. In univariate analyses survival was affected by age, stage IVB, bone-marrow involvement, B-symptoms, S-LDH, S-Alb and reaching CR or not after 2, 4 and 6 cycles of CT. In a multivariate analysis, age and reaching CR after 6 cycles of CT remained statistically significant.

    CONCLUSIONS: The lack of difference in survival between the groups of patients who received 6 versus 8 cycles of CT indicates a successful selection of patients for the shorter treatment. Reaching a rapid CR significantly affected outcome. Whether some patients need less CT than the generally recommended 8 courses can properly only be evaluated in a randomised study. Additional RT may play a role in successful outcome, particularly if residual tumours are present, but its precise role can also only be defined in prospectively randomised studies. Reaching CR after CT was the most important variable affecting survival besides age.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-89776 (URN)10.1034/j.1600-0609.2000.065006379.x (DOI)11168495 (PubMedID)
    Available from: 2002-04-05 Created: 2002-04-05 Last updated: 2013-06-13Bibliographically approved
    3. A population-based study of the outcome for patients with first relapse of Hodgkin lymphoma
    Open this publication in new window or tab >>A population-based study of the outcome for patients with first relapse of Hodgkin lymphoma
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    2002 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 68, no 4, 225-232 p.Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    Our aims were to evaluate the response to salvage treatment in relation to initial treatment and to evaluate prognostic factors at the time of relapse in an unselected population of relapsing patients with Hodgkin's lymphoma (HL).

    PATIENTS AND METHODS:

    In total, 124 patients younger than 60 yr of age with initial diagnosis of HL in Sweden relapsed between 1985 and 1995.

    RESULTS:

    Fifty-eight patients relapsed after initial treatment with radiotherapy (RT) only, 62 after combination chemotherapy (CT), of whom 30 had received additional involved-field RT, and four after a short course of CT followed by extended-field RT. For 37 patients among the 58 relapsers after initial RT treated according to the recommendations of the National guidelines, the 5-yr Hodgkin-specific survival (HLS) was 85%, overall survival (OS) 73% and event-free survival (EFS) 62%, which is not inferior to survival in patients with primarily advanced stages. It was poorer in the 21 patients who initially had received RT only, even though they had been recommended for more extensive treatment. For patients initially treated with a full course (6-8 cycles) of CT the 5-yr HLS was 60%, OS 58% and EFS 22%. Bulky disease and age at diagnosis strongly affected survival in a multivariate analysis.

    CONCLUSIONS:

    Patients initially treated with RT who relapse have a favourable outcome, provided they have been treated according to the recommendations of the guidelines at the time of diagnosis. Initially bulky disease and, as a consequence, additional RT as part of the initial treatment negatively affect survival at relapse in patients initially treated with a full course of CT.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-89777 (URN)10.1034/j.1600-0609.2002.01565.x (DOI)12071938 (PubMedID)
    Available from: 2002-04-05 Created: 2002-04-05 Last updated: 2013-05-31Bibliographically approved
    4. Relapsed Hodgkin's lymphoma: immunostaining patterns in relation to survival
    Open this publication in new window or tab >>Relapsed Hodgkin's lymphoma: immunostaining patterns in relation to survival
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    2002 (English)In: Leukemia and Lymphoma, ISSN 1042-8194, Vol. 43, no 6, 1253-1260 p.Article in journal (Refereed) Published
    Abstract [en]

    Patients with relapsing Hodgkin's lymphoma (HL) have a rather poor prognosis and mechanisms that lead to resistance to therapy are poorly understood. Our aims were to investigate the immunohistochemical staining patterns of Rb (retinoblastoma protein) and the p53 tumour suppressor protein in HL at initial presentation and at relapse in order to elucidate a possible role in disease progression and resistance to therapy. Further to evaluate the presence and prognostic importance of Epstein-Barr virus (EBV) and anaplastic lymphoma kinase (ALK). Eighty-one cases of relapsing HL were reexamined histopathologically and immunostained for the expression of p53, Rb, ALK and CD30. EBV was detected with LMP-1 stainings and in situ hybridisation for EBER. Clinical data were extracted from the Swedish National Health Care Programme for HL. Median follow-up time was six years (range 0-12) from the date of relapse. The majority of cases were positive for p53 and Rb both at presentation and at relapse, though to a different extent. Both an increase and a decrease in the proportion of stained tumour cells were observed. None of our cases was ALK-positive and 44% were EBV-positive. No specific staining pattern was directly correlated to survival. In 12 patients a switch in HL subtype from diagnosis to relapse was observed and the five-year Hodgkin-specific survival (HLS) was statistically significantly inferior, 37 vs 81% (p = 0.002), in those patients. We found a significant relation between the expression of p53 and EBV at diagnosis and relapse, indicating a clonal relationship. We were unable to find any specific staining pattern of p53 or Rb, affecting survival.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-89778 (URN)10.1080/10428190290026303 (DOI)12152993 (PubMedID)
    Available from: 2002-04-05 Created: 2002-04-05 Last updated: 2013-05-31Bibliographically approved
    5. A novel B-cell line (U-2932) established from a patient with a diffuse large B-cell lymphoma following Hodgkin lymphoma
    Open this publication in new window or tab >>A novel B-cell line (U-2932) established from a patient with a diffuse large B-cell lymphoma following Hodgkin lymphoma
    Show others...
    2002 (English)In: Leukemia and Lymphoma, ISSN 1042-8194, Vol. 43, no 11, 2179-2189 p.Article in journal (Refereed) Published
    Abstract [en]

    Little is known about mechanisms leading to secondary non-Hodgkin lymphomas (NHL) in patients treated for Hodgkin lymphoma (HL). Our aim was to characterise in detail a cell line derived from a diffuse large B-cell lymphoma (DLBCL) that had developed in a patient with relapsing HL. The cell line U-2932 was established from ascites in a patient suffering from DLBCL previously treated for HL with multiple chemotherapy regimens. Characterisation was based on morphology, immunophenotype, Epstein-Barr virus (EBV)-status, IgH gene rearrangement status, tumourigenicity, p53 sequencing, and immunohistochemical expression of p53, BCL-2 and BCL-6. The karyotype was investigated using G-banding, comparative genomic hybridisation (CGH) and spectral karyotype (SKY) analysis. This cell line shows typical morphological features of a DLBCL and grows as colonies in nude mice. It expresses a B-cell phenotype with a somatically hypermutated V(H)4-39 gene and is negative for EBV. The origin of U-2932 was confirmed by demonstrating an identical V(H)4 rearrangement in ascites from the patient. A point mutation of the tumour-suppressor gene p53 was detected in amino acid position 176 and immunohistochemical over-expression of the p53 protein was also demonstrated. U-2932 carries a complex karyotype including high-level amplifications of the chromosomal bands 18q21 and 3q27 and expresses aberrant BCL-2 and BCL-6 immunohistochemically. We were unable to investigate the clonal relationship between the original HL and U-2932. In conclusion, U-2932 is a unique B cell line established from a patient suffering from HL followed by NHL. Overexpression of BCL-2, BCL-6 and p53 may play a role in the tumourigenesis and drug resistance. This cell line may become a useful tool to better understand the mechanisms responsible for development of secondary NHL in patients treated for HL.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-89779 (URN)10.1080/1042819021000032917 (DOI)12533045 (PubMedID)
    Available from: 2002-04-05 Created: 2002-04-05 Last updated: 2013-05-31Bibliographically approved
  • 26. Anclair, M
    et al.
    Hovén, E
    Lannering, B
    Boman, K K
    Parental fears following their child's brain tumor diagnosis and treatment2009In: Journal of Pediatric Oncology Nursing, ISSN 1043-4542, E-ISSN 1532-8457, Vol. 26, no 2, 68-74 p.Article in journal (Refereed)
    Abstract [en]

    The objective of this study is to portray the illness-related threats experienced by parents of children after the diagnosis of central nervous system (CNS) tumor. Parents were asked to rate the extent to which they experienced a set of specific fears related to their child's brain tumor and its treatment. Outcomes for parents of CNS tumor patients (n = 82) were compared with those of reference parents of patients treated for acute lymphoblastic leukemia (n = 208). The fears about an illness recurrence and the late effects of treatment were most prominent among parents of CNS tumor patients. For 7 out of 11 kinds of fear, parents of CNS tumor patients expressed a stronger fear than the reference group. More than a quarter of the parents of children treated for CNS tumors feared a complete decline of the child. Parents of CNS tumor patients experience relatively heightened cancer related fears in several domains. The fear of devastating consequences felt by one fourth of parents signals the need of individualized psychological support and information at diagnosis and follow-up to facilitate parental coping with the posttreatment situation.

  • 27.
    Ander, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Grönqvist, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Cernvall, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Engvall, Gunn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Hedström, Mariann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Ljungman, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Lyhagen, Johan
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Statistics.
    Mattsson, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    von Essen, Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Development of health-related quality of life and symptoms of anxiety and depression among persons diagnosed with cancer during adolescence: a 10-year follow-up study2016In: Psycho-Oncology, ISSN 1057-9249, E-ISSN 1099-1611, Vol. 25, no 5, 582-589 p.Article in journal (Refereed)
    Abstract [en]

    Objective: The main aim was to investigate the development of health-related quality of life (HRQOL) and symptoms of anxiety and depression in a cohort diagnosed with cancer during adolescence from shortly after up to 10 years after diagnosis.

    Methods: Participants (n = 61) completed the SF-36 and the HADS shortly; six, 12, and 18 months; and two, three, four, and 10 years (n = 28) after diagnosis. Polynomial change trajectories were used to model development.

    Results: Polynomial change trajectories showed an initial increase which abated over time into a decrease which abated over time for the SF-36 subscales Mental Health and Vitality; an initial decline which abated over time into an increase for HADS anxiety; and an initial decline which abated over time into an increase which abated over time for HADS depression. The SF-36 mental component summary showed no change from two to 10 years after diagnosis whereas the SF-36 physical component summary showed an increase from two years after diagnosis which declined over time. Ten years after diagnosis 29% reported possible anxiety.

    Conclusions: Development of HRQOL and symptoms of anxiety and depression appears to be nonlinear among persons diagnosed with cancer during adolescence. Well into permanent survivorship an increase in symptoms of anxiety is shown and approximately a third of the participants report possible anxiety. The findings indicate the need for: studies designed to pinpoint the times of highest psychological risk, clinical follow-up focusing on psychological problems, and development of effective psychological interventions for survivors of adolescent cancer

  • 28.
    Ander, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Norberg, Annika Lindahl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Ljungman, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ljotsson, Brjann
    von Essen, Louise
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Identification of Cancer-related Psychological Suffering Experienced by Young People Diagnosed with Cancer During Adolescence and Development of a Psychological Treatment to Reduce This Suffering2015Conference paper (Refereed)
  • 29.
    Ander, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Thorsell Cederberg, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Lindahl Norberg, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    von Essen, Louise
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Losing your context - Exploration of emotional suffering after cancer during adolescence2016Conference paper (Refereed)
  • 30.
    Ander, Malin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Wikman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare.
    Ljótsson, Brjánn
    Karolinska Inst, Div Psychol, Dept Clin Neurosci, Stockholm, Sweden.
    Grönqvist, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ljungman, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Woodford, Joanne
    Univ Exeter, Coll Life & Environm Sci, CEDAR, Psychol, Exeter, Devon, England.
    Lindahl Norberg, Annika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    von Essen, Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Psychology in Healthcare. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Guided Internet-Administered Self-Help to Reduce Symptoms Of Anxiety and Depression Among Adolescents and Young Adults Diagnosed With Cancer During Adolescence (U-CARE: YoungCan): study protocol for a feasibility trial2017In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 7, no 1, e013906Article in journal (Refereed)
    Abstract [en]

    Introduction A subgroup of adolescents and young adults diagnosed with cancer during adolescence reports elevated levels of anxiety and depressive symptoms and unmet needs for psychological support. Evidence-based psychological treatments tailored for this population are lacking. This protocol describes a feasibility study of a guided-internet-administered self-help programme (YoungCan) primarily targeting symptoms of anxiety and depression among young persons diagnosed with cancer during adolescence and of the planned study procedures for a future controlled trial. Methods/analysis The study is an uncontrolled feasibility trial with a pre-post and 3-month follow-up design. Potential participants aged 15-25years, diagnosed with cancer during adolescence, will be identified via the Swedish Childhood Cancer Registry. 30 participants will be included. Participants will receive YoungCan, a 12-week therapist-guided, internet-administered self-help programme consisting primarily of cognitive-behavioural therapy organised into individually assigned modules targeting depressive symptoms, worry and anxiety, body dissatisfaction and post-traumatic stress. Interactive peer support and psychoeducative functions are also available. Feasibility outcomes include: recruitment and eligibility criteria; data collection; attrition; resources needed to complete the study and programme; safety procedures; participants' and therapists' adherence to the programme; and participants' acceptability of the programme and study methodology. Additionally, mechanisms of impact will be explored and data regarding symptoms of anxiety, depression, post-traumatic stress, body dissatisfaction, reactions to social interactions, quality of life, axis I diagnoses according to the Mini International Neuropsychiatric Interview and healthcare service use will be collected. Exploratory analyses of changes in targeted outcomes will be conducted. Ethics/dissemination This feasibility protocol was approved by the Regional Ethical Review Board in Uppsala, Sweden (ref: 2016/210). Findings will be disseminated to relevant research, clinical, health service and patient communities through publications in peer-reviewed and popular science journals and presentations at scientific and clinical conferences.

  • 31. Andersen, Christen Lykkegaard
    et al.
    Bjorn, Mads Emil
    McMullin, Mary Frances
    Harrison, Claire
    Samuelsson, Jan
    Ejerblad, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Zweegman, Sonja
    Fernandes, Savio
    Bareford, David
    Knapper, Steven
    Lofvenberg, Eva
    Linder, Olle
    Andreasson, Bjorn
    Ahlstrand, Erik
    Jensen, Morten Krogh
    Bjerrum, Ole Weis
    Vestergaard, Hanne
    Larsen, Herdis
    Klausen, Tobias Wirenfeldt
    Mourits-Andersen, Torben
    Skov, Vibe
    Thomassen, Mads
    Kruse, Torben
    Gronbaek, Kirsten
    Hasselbalch, Hans Carl
    Circulating YKL-40 in patients with essential thrombocythemia and polycythemia vera treated with the novel histone deacetylase inhibitor vorinostat2014In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 38, no 7, 816-821 p.Article in journal (Refereed)
    Abstract [en]

    YKL-40 regulates vascular endothelial growth factors and induces tumor proliferation. We investigated YKL-40 before and after treatment with vorinostat in 31 polycythemia vera (PV) and 16 essential thrombocythemia (ET) patients. Baseline PV patient levels were 2 times higher than in healthy controls (P<0.0001) and 1.7 times higher than in ET (P = 0.02). A significant correlation between YKL-40 at baseline and neutrophils, CRP, LDH, JAK2V617F and platelets in PV patients was observed, as well as a significantly greater reduction of YKL-40 levels in PV patients responding to therapy. YKL-40 might be a novel marker of disease burden and progression in myeloproliferative neoplasms. (C) 2014 Elsevier Ltd. All rights reserved.

  • 32. Andersen, Niels S.
    et al.
    Pedersen, Lone B.
    Laurell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Elonen, Erkki
    Kolstad, Arne
    Boesen, Anne Marie
    Pedersen, Lars M.
    Lauritzsen, Grete F.
    Ekanger, Roald
    Nilsson-Ehle, Herman
    Nordstrom, Marie
    Freden, Susanne
    Jerkeman, Mats
    Eriksson, Mikael
    Vaart, Jaan
    Malmer, Beatrice
    Geisler, Christian H.
    Pre-Emptive Treatment With Rituximab of Molecular Relapse After Autologous Stem Cell Transplantation in Mantle Cell Lymphoma2009In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 27, no 26, 4365-4370 p.Article in journal (Refereed)
    Abstract [en]

    Purpose Minimal residual disease (MRD) is predictive of clinical progression in mantle-cell lymphoma (MCL). According to the Nordic MCL-2 protocol we prospectively analyzed the efficacy of pre-emptive treatment using rituximab to MCL patients in molecular relapse after autologous stem cell transplantation (ASCT). Patients and Materials MCL patients enrolled onto the study, who had polymerase chain reaction (PCR) detectable molecular markers and underwent ASCT, were followed with serial PCR assessments of MRD in consecutive bone marrow and peripheral blood samples after ASCT. In case of molecular relapse with increasing MRD levels, patients were offered pre-emptive treatment with rituximab 375 mg/m(2) weekly for 4 weeks. Results Of 160 MCL patients enrolled, 145 underwent ASCT, of whom 78 had a molecular marker. Of these, 74 were in complete remission (CR) and four had progressive disease after ASCT. Of the CR patients, 36 underwent a molecular relapse up to 6 years (mean, 18.5 months) after ASCT. Ten patients did not receive pre-emptive treatment mainly due to a simultaneous molecular and clinical relapse, while 26 patients underwent pre-emptive treatment leading to reinduction of molecular remission in 92%. Median molecular and clinical relapse-free survival after pre-emptive treatment were 1.5 and 3.7 years, respectively. Of the 38 patients who remain in molecular remission for now for a median of 3.3 years (range, 0.4 to 6.6 years), 33 are still in clinical CR. Conclusion Molecular relapse may occur many years after ASCT in MCL, and PCR based pre-emptive treatment using rituximab is feasible, reinduce molecular remission, and may prevent clinical relapse.

  • 33.
    Andersson, Jennie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Rosestedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Imaging of HER2 may improve the outcome of external irradiation therapy for prostate cancer patients2015In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 9, no 2, 950-954 p.Article in journal (Refereed)
    Abstract [en]

    Prostate cancer (PCa) is the most common type of cancer among males. Human epidermal growth factor receptor type 2 (HER2) expression in PCa has been reported by several studies and its involvement in the progression towards androgen-independent PCa has been discussed. External irradiation is one of the existing therapies, which has been demonstrated to be efficient in combination with androgen deprivation therapy for the treatment of advanced PCa. However, 20-40% of patients develop recurrent and more aggressive PCa within 10 years. The current study investigates the involvement of HER2 in survival and radioresistance in PCa cells and we hypothesized that, by monitoring HER2 expression, treatment may be personalized. The PCa cell lines, LNCap, PC3 and DU-145, received a 6 Gy single dose of external irradiation. The number of PC3 cells was not affected by a single dose of radiation, whereas a 5-fold decrease in cell number was detected in LNCap (P<0.00001) and DU-145 (P<0.0001) cells. The HER2 expression in PC3 exhibited a significant increase post irradiation, however, the expression was stable in the remaining cell lines. The administration of trastuzumab post-irradiation resulted in a 2-fold decrease in the PC3 cell number, while the drug did not demonstrate additional effects in LNCap and DU-145 cells, when compared with that of irradiation treatment alone. The results of the present study demonstrated that an increase in membranous HER2 expression in response to external irradiation may indicate cell radioresistance. Furthermore, imaging of HER2 expression prior to and following external irradiation may present a step towards personalized therapy in PCa.

  • 34. Andersson, Ken G.
    et al.
    Rosestedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Varasteh, Zohreh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Malm, Magdalena
    Sandström, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Lofblom, John
    Stahl, Stefan
    Orlova, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Comparative evaluation of In-111-labeled NOTA-conjugated affibody molecules for visualization of HER3 expression in malignant tumors2015In: Oncology Reports, ISSN 1021-335X, E-ISSN 1791-2431, Vol. 34, no 2, 1042-1048 p.Article in journal (Refereed)
    Abstract [en]

    Expression of human epidermal growth factor receptor type 3 (HER3) in malignant tumors has been associated with resistance to a variety of anticancer therapies. Several anti-HER3 monoclonal antibodies are currently under pre-clinical and clinical development aiming to overcome HER3-mediated resistance. Radionuclide molecular imaging of HER3 expression may improve treatment by allowing the selection of suitable patients for HER3-targeted therapy. Affibody molecules are a class of small (7 kDa) high-affinity targeting proteins with appreciable potential as molecular imaging probes. In a recent study, we selected affibody molecules with affinity to HER3 at a low picomolar range. The aim of the present study was to develop an anti-HER3 affibody molecule suitable for labeling with radiometals. The HEHEHE-Z08698-NOTA and HEHEHE-Z08699-NOTA HER3-specific affibody molecules were labeled with indium-111 (In-111) and assessed in vitro and in vivo for imaging properties using single photon emission computed tomography (SPECT). Labeling of HEHEHE-Z08698-NOTA and HEHEHE-Z08699-NOTA with In-111 provided stable conjugates. In vitro cell tests demonstrated specific binding of the two conjugates to HER3-expressing BT-474 breast carcinoma cells. In mice bearing BT-474 xenografts, the tumor uptake of the two conjugates was receptor-specific. Direct in vivo comparison of In-111-HEHEHE-Z08698-NOTA and In-111-HEHEHE-Z08699-NOTA demonstrated that the two conjugates provided equal radioactivity uptake in tumors, although the tumor-to-blood ratio was improved for In-111-HEHEHE-Z08698-NOTA [12 +/- 3 vs. 8 +/- 1,4 h post injection (p.i)] due to more efficient blood clearance. In-111-HEHEHE-Z08698-NOTA is a promising candidate for imaging of HER3-expression in malignant tumors using SPECT. Results of the present study indicate that this conjugate could be used for patient stratification for anti-HER3 therapy.

  • 35.
    Andersson, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Bergström, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    "Rehabilitering med samtalsterapi och yoga": En utvärdering av Akademiska sjukhusets projekt för cancerpatienter2010Independent thesis Basic level (degree of Bachelor), 10 credits / 15 HE creditsStudent thesis
    Abstract [en]

    ABSTRACT

    Aim: The aim of this study was to evaluate the effects of the treatment in the project “Rehabilitation with psychotherapy and yoga”, regarding physical, emotional, functional and social wellbeing, and to examine the participant’s satisfaction with the rehabilitation. Method: The evaluation was done during the spring in 2010 with a quantitative method and descriptive, longitudinal design. Everyone who was to begin the new beginners’ class was asked about participation. Questionnaires were given to the participants, before and after participation in maximum three rehabilitation courses. The number of participants was 22. The answers were analyzed with descriptive statistics and dependent T-test. Result: There are no significant differences over time regarding the physical (p=,507), social (p=,936), emotional (p=,493) and functional (p=,388) wellbeing of the participants. When analyzing the unique questions in the wellbeing-scales, no significant differences were found. According to the satisfaction questionnaires, every participants thought that the rehabilitationgroup, in different ways, helped them to cope with their situation and 95,5% (n=21) would recommend this psychotherapy and yoga group to a friend in a similar situation. Conclusion: The rehabilitationproject can be improved, but should continue to be provided as a complement to traditional oncological treatment, since it´s considered being of great value for its participants. Because of shortages a new evaluation is motivated.

  • 36. Andersson, Sonia
    et al.
    Mints, Miriam
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Lindell, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gustavsson, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Lambe, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Wilander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Uneven distribution of human papillomavirus 16111 cervical carcinoma in situ and squamous cell carcinoma in older females: A retrospective database study2014In: Oncology Letters, ISSN 1792-1074, E-ISSN 1792-1082, Vol. 8, no 4, 1528-1532 p.Article in journal (Refereed)
    Abstract [en]

    Human papillomavirus (HPV) 16 is the dominant cofactor in cervical cancer development. The present report investigated the age-specific prevalence of HPV16 in cervical carcinoma in situ (CIS) in females attending organised cervical cancer screening. A retrospective observational study was performed based on individual data from two databases. A total of 162 females aged between 20 and 65 years from Uppsala County, Sweden with CIS and an HPV test conducted between 2010 and 2011, preceding or concomitant to CIS diagnosis, were included. Females with cervical squamous cell carcinoma (SCC; n=35) were used for comparison. In total, 96% (n=156) of females with CIS were positive for high-risk HPV; HPV16 was the most prevalent (44.5%), followed by HPV33/52/58 (19.5%), HPV31 (13.1%) and HPV18145 (9.5%). HPV16 was most frequently detected in females with CIS aged between 20 and 29 years (73.6%) and least frequently detected in those aged between 50 and 65 years (33.3%), with a statistically significant age-specific difference (P=0.001). Among the HPV16-positive females, multiple infections were most frequent in the younger age groups. The prevalence of HPV16 in females with CIS decreased with age, whereas a high prevalence of HPV16 remained in females with SCC. These results may indicate that HPV16 has increased oncogenic potential in older females.

  • 37.
    Andersson, Therese M. -L.
    et al.
    Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden..
    Johansson, Anna L. V.
    Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden..
    Fredriksson, Irma
    Karolinska Inst, Dept Mol Med & Surg, SE-17177 Stockholm, Sweden.;Karolinska Univ Hosp, Dept Breast & Endocrine Surg, Stockholm, Sweden..
    Lambe, Mats
    Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden.;Univ Uppsala Hosp, Reg Canc Ctr, Uppsala, Sweden..
    Cancer during pregnancy and the postpartum period: A population-based study2015In: Cancer, ISSN 0008-543X, E-ISSN 1097-0142, Vol. 121, no 12, 2072-2077 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUNDThe purpose of this study was to assess patterns of cancer occurrence during pregnancy and the postpartum period. METHODSThis was a register-based study using data from the Swedish Multi-Generation Register and the National Cancer Register from 1963 to 2007. Pregnancy-associated cancer (PAC) was defined as a malignancy detected during pregnancy or within 2 years of delivery and was assessed in 7 time windows: pregnancy, trimesters 1-3, 0-6 months, 7-12 months, and second year postpartum. Population incidence rates by 5-year age groups and periods were used to estimate the expected number of PACs for each site. The observed versus the expected (O/E) number of cases was estimated with 95% confidence intervals (CI). RESULTSThe 3 most common malignancies during pregnancy were melanoma (n=232), breast (n=139) and cervical cancer (n=139). With a slightly different rank order, these cancers are also the most common in women of childbearing age. The number of observed cases during pregnancy was lower than expected for all cancers, with a combined O/E ratio for all sites of 0.46 (95% CI, 0.43-0.49). The O/E ratio was close to 1 during all postpartum intervals, including 0-6 months (0.93; 95% CI, 0.88-0.98), 7-12 months (0.96; 95% CI, 0.91-1.01), and during the second year after delivery (0.95; 95% CI, 0.92-0.99). CONCLUSIONSThe rate of cancer during pregnancy was lower than expected for all sites, a finding that could not be explained entirely by delayed diagnosis. A rebound in the number of observed cases after delivery was restricted to melanoma, nervous system malignancies, and breast and thyroid cancer. Cancer 2015;121:2072-2077. (c) 2015 American Cancer Society. Fewer cancers than expected are found during pregnancy, a finding that cannot be explained entirely by delayed diagnosis.

  • 38. Andersson, Therese M-L
    et al.
    Dickman, Paul W.
    Eloranta, Sandra
    Sjovall, Annika
    Lambe, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Lambert, Paul C.
    The loss in expectation of life after colon cancer: a population-based study2015In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 15, 412Article in journal (Refereed)
    Abstract [en]

    Background: To demonstrate how assessment of life expectancy and loss in expectation of life can be used to address a wide range of research questions of public health interest pertaining to the prognosis of cancer patients. Methods: We identified 135,092 cases of colon adenocarcinoma diagnosed during 1961-2011 from the population-based Swedish Cancer Register. Flexible parametric survival models for relative survival were used to estimate the life expectancy and the loss in expectation of life. Results: The loss in expectation of life for males aged 55 at diagnosis was 13.5 years (95 % CI 13.2-13.8) in 1965 and 12.8 (12.4-13.3) in 2005. For males aged 85 the corresponding figures were 3.21 (3.15-3.28) and 2.10 (2.04-2.17). The pattern was similar for females, but slightly greater loss in expectation of life. The loss in expectation of life is reduced given survival up to a certain time point post diagnosis. Among patients diagnosed in 2011, 945 life years could potentially be saved if the colon cancer survival among males could be brought to the same level as for females. Conclusion: Assessment of loss in expectation of life facilitates the understanding of the impact of cancer, both on individual and population level. Clear improvements in survival among colon cancer patients have led to a gain in life expectancy, partly due to a general increase in survival from all causes.

  • 39. Arase, Mayu
    et al.
    Horiguchi, Kana
    Ehata, Shogo
    Morikawa, Masato
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tsutsumi, Shuichi
    Aburatani, Hiroyuki
    Miyazono, Kohei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Koinuma, Daizo
    Transforming growth factor-beta-induced lncRNA-Smad7 inhibits apoptosis of mouse breast cancer JygMC(A) cells2014In: Cancer Science, ISSN 1347-9032, E-ISSN 1349-7006, Vol. 105, no 8, 974-982 p.Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor (TGF)-beta exhibits both pro-apoptotic and anti-apoptotic effects on epithelial cells in a context-dependent manner. The anti-apoptotic function of TGF-beta is mediated by several downstream regulatory mechanisms, and has been implicated in the tumor-progressive phenotype of breast cancer cells. We conducted RNA sequencing of mouse mammary gland epithelial (NMuMG) cells and identified a long non-coding RNA, termed lncRNA-Smad7, which has anti-apoptotic functions, as a target of TGF-beta lncRNA-Smad7 was located adjacent to the mouse Smad7 gene, and its expression was induced by TGF-beta in all of the mouse mammary gland epithelial cell lines and breast cancer cell lines that we evaluated. Suppression of lncRNA-Smad7 expression cancelled the anti-apoptotic function of TGF-beta In contrast, forced expression of lncRNA-Smad7 rescued apoptosis induced by a TGF-beta type I receptor kinase inhibitor in the mouse breast cancer cell line JygMC(A). The anti-apoptotic effect of lncRNA-Smad7 appeared to occur independently of the transcriptional regulation by TGF-beta of anti-apoptotic DEC1 and pro-apoptotic Bim proteins. Small interfering RNA for lncRNA-Smad7 did not alter the process of TGF-beta-induced epithelial-mesenchymal transition, phosphorylation of Smad2 or expression of the Smad7 gene, suggesting that the contribution of this lncRNA to TGF-beta functions may be restricted to apoptosis. Our findings suggest a complex mechanism for regulating the anti-apoptotic and tumor-progressive aspects of TGF-beta signaling.

  • 40.
    Arthur, Rhonda
    et al.
    Kings Coll London, Canc Epidemiol Grp, Div Canc Studies, London, England..
    Møller, Henrik
    Kings Coll London, Canc Epidemiol Grp, Div Canc Studies, London, England..
    Garmo, Hans
    Kings Coll London, Canc Epidemiol Grp, Div Canc Studies, London, England.;Reg Canc Ctr, Uppsala, Sweden..
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences. Kings Coll London, Canc Epidemiol Grp, Div Canc Studies, London, England.;Reg Canc Ctr, Uppsala, Sweden..
    Stattin, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology. Departments of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University.
    Malmstrom, Hakan
    Karolinska Inst, Inst Environm Med, Unit Epidemiol, Stockholm, Sweden..
    Lambe, Mats
    Univ Uppsala Hosp, Dept Surg Sci, Uppsala, Sweden.;Karolinska Inst, Dept Med Epidemiol, Stockholm, Sweden.;Karolinska Inst, Dept Biostat, Stockholm, Sweden..
    Hammar, Niklas
    Karolinska Inst, Inst Environm Med, Unit Epidemiol, Stockholm, Sweden.;AstraZeneca Sverige, Sodertalje, Sweden..
    Walldius, Goran
    Karolinska Inst, Inst Environm Med, Dept Cardiovasc Epidemiol, Stockholm, Sweden..
    Robinson, David
    Departments of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University.
    Jungner, Ingmar
    Karolinska Inst, Dept Clin Epidemiol Unit, Stockholm, Sweden.;CALAB Res, Stockholm, Sweden..
    Van Hemelrijck, Mieke
    Kings Coll London, Canc Epidemiol Grp, Div Canc Studies, London, England.;Karolinska Inst, Inst Environm Med, Unit Epidemiol, Stockholm, Sweden..
    Association between baseline serum glucose, triglycerides and total cholesterol, and prostate cancer risk categories2016In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 5, no 6, 1307-1318 p.Article in journal (Refereed)
    Abstract [en]

    Lifestyle-related risk factors such as hyperglycemia and dyslipidemia have been associated with several cancers. However, studies exploring their link with prostate cancer (PCa) clinicopathological characteristics are sparse and inconclusive. Here, we investigated the associations between serum metabolic markers and PCa clinicopathological characteristics. The study comprised 14,294 men from the Swedish Apolipoprotein MOrtality RISk (AMORIS) cohort who were diagnosed with PCa between 1996 and 2011. Univariate and multivariable logistic regression were used to investigate the relation between glucose, triglycerides and total cholesterol and PCa risk categories, PSA, Gleason score, and T-stage. Mean age at time of PCa diagnosis was 69 years. Men with glucose levels >6.9 mmol/L tend to have PSA<4 mu g/L, while those with glucose levels of 5.6-6.9 mmol/L had a greater odds of PSA>20 mu g/L compared to PSA 4.0-9.9 mu g/L. Hypertriglyceridemia was also positively associated with PSA>20 mu g/L. Hyperglycemic men had a greater odds of intermediate-and high-grade PCa and advanced stage or metastatic PCa. Similarly, hypertriglyceridemia was positively associated with high-grade PCa. There was also a trend toward an increased odds of intermediate risk localized PCa and advanced stage PCa among men with hypertriglyceridemia. Total cholesterol did not have any statistically significant association with any of the outcomes studied. Our findings suggest that high serum levels of glucose and triglycerides may influence PCa aggressiveness and severity. Further investigation on the role of markers of glucose and lipid metabolism in influencing PCa aggressiveness and severity is needed as this may help define important targets for intervention.

  • 41.
    Arving, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Rissanen, Ritva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Ahlgren, Johan
    Nordin, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Effects of a Stepped Care Stress Management Intervention on Cancer-Related Traumatic Stress Symptoms Among Breast Cancer Patients: A Randomized Study of Group Versus Individual Setting2014In: Psycho-Oncology, ISSN 1057-9249, E-ISSN 1099-1611, Vol. 23, no Suppl. 3, 171-171 p., P1-0300Article in journal (Other academic)
  • 42.
    Arving, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Thormodsen, Inger
    Berntsen, Sveinung
    Nordin, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Identifying Variables Associated With the Course of Fatigue Among Cancer Patients During Adjuvant and Curative Treatment2014In: Psycho-Oncology, ISSN 1057-9249, E-ISSN 1099-1611, Vol. 23, 176-176 p.Article in journal (Other academic)
  • 43.
    Arving, Cecilia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Wadensten, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Registered Nurses' Thoughts on Blended Learning in a Postgraduate Course in Cancer care: Content Analyses of Web Surveys and a Focus Group Interview2014In: Journal of Cancer Education, ISSN 0885-8195, E-ISSN 1543-0154, Vol. 29, no 2, 278-283 p.Article in journal (Refereed)
    Abstract [en]

    Purpose of the research was to describe registered nurses' (RNs) (n = 53) thoughts on the blended learning format in a 'specialist nursing programme in cancer care'. The study was conducted in autumn 2007 and 2008. A content analysis of answers to open-ended questions in a web-based questionnaire and a focus group interview were carried out. The analysis revealed that the RNs appreciated blended learning. The web lectures facilitated learning and gave RNs access to the education at any time. However, according to the RNs, knowledge is gained through interaction between RNs and teachers, and this aspect needed to be improved. The RNs also thought that the content of the seminars on campus should focus on evidence-based nursing knowledge and practical skills, not just taught as stable facts and procedures. The result from the present study could help to improve the design and content of advanced nursing courses using a blended learning format.

  • 44. Ask, Anders
    et al.
    Björk-Eriksson, Thomas
    Zackrisson, Björn
    Blomquist, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    The potential of proton beam radiation therapy in head and neck cancer2005In: Acta Oncologica, ISSN 0284-186X, Vol. 44, no 8, 876-80 p.Article in journal (Refereed)
    Abstract [en]

    A group of Swedish oncologists and hospital physicists have estimated the number of patients in Sweden suitable for proton beam therapy. The estimations have been based on current statistics of tumour incidence, number of patients potentially eligible for radiation treatment, scientific support from clinical trials and model dose planning studies and knowledge of the dose-response relations of different tumours and normal tissues. In head and neck cancer, including thyroid cancer, it is assessed that at least 300 patients annually will gain sufficiently from proton beam therapy, both to improve tumour control and to decrease toxicity to compensate for the increased treatment costs using protons.

  • 45. Ask, Anders
    et al.
    Johansson, Bengt
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    The potential of proton beam radiation therapy in gastrointestinal cancer2005In: Acta Oncologica, ISSN 0284-186X, Vol. 44, no 8, 896-903 p.Article in journal (Refereed)
    Abstract [en]

    A group of Swedish oncologists and hospital physicists have estimated the number of patients in Sweden suitable for proton beam therapy. The estimations have been based on current statistics of tumour incidence, number of patients potentially eligible for radiation treatment, scientific support from clinical trials and model dose planning studies and knowledge of the dose-response relations of different tumours and normal tissues. In gastrointestinal cancers, it is assessed that at least 345 patients, mainly non-resectable rectal cancers, oesophageal and liver cancers, are eligible. Great uncertainties do however exist both in the number of patients with gastrointestinal cancers suitable for radiation therapy, and in the proportion of those where proton beams may give sufficiently better results.

  • 46. Asklund, Thomas
    et al.
    Malmstrom, Annika
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Bjor, Ove
    Henriksson, Roger
    Brain tumors in Sweden: Data from a population-based registry 1999-20122015In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 3, 377-384 p.Article in journal (Refereed)
    Abstract [en]

    Background. The Swedish brain tumor registry has, since it was launched in 1999, provided significant amounts of data on histopathological diagnoses and on important aspects of surgical and medical management of these patients. The purpose is mainly quality control, but also as a resource for research. Methods. Three Swedish healthcare regions, constituting 40% of the Swedish population, have had an almost complete registration. The following parameters are registered: diagnosis according to SNOMED/WHO classification, symptoms, performance status, pre- and postoperative radiology, tumor size and localization, extent of surgery and occurrence of postoperative complications, postoperative treatment, such as radiotherapy and/or chemotherapy, other treatments, complications and toxicity, occurrence of reoperation/s, participation in clinical trials, multidisciplinary conferences and availability of a contact nurse. Results. Surgical radicality has been essentially constant, whereas the use of early (within 72 hours) postoperative CT and MRI has increased, especially for high-grade glioma, which is a reflection of quality of surgery. Survival of patients with high-grade glioma has increased, especially in the age group 60-69. Patients aged 18-39 years had a five-year survival of 40%. Waiting times for the pathological report has been slightly prolonged. Geographical differences do exist for some of the variables. Conclusion. Population-based registration is valuable for assessment of clinical management, which could have impact on patient care. As a result of short survival and/or the propensity to affect cognitive functions this patient group has considerable difficulties to make their voices heard in society. We therefore believe that a report like the present one can contribute to the spread of knowledge and increase the awareness for this patient group among caregivers and policy makers.

  • 47.
    Assadian, Farzaneh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sandström, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Bondeson, Kåre
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Infection medicine.
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Lidian, Adnan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Svensson, Catharina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Akusjärvi, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Bergqvist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Punga, Tanel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Distribution and Molecular Characterization of Human Adenovirus and Epstein-Barr Virus Infections in Tonsillar Lymphocytes Isolated from Patients Diagnosed with Tonsillar Diseases2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 5, e0154814Article in journal (Refereed)
    Abstract [en]

    Surgically removed palatine tonsils provide a conveniently accessible source of T and B lymphocytes to study the interplay between foreign pathogens and the host immune system. In this study we have characterised the distribution of human adenovirus (HAdV), Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) in purified tonsillar T and B cell-enriched fractions isolated from three patient age groups diagnosed with tonsillar hypertrophy and chronic/recurrent tonsillitis. HAdV DNA was detected in 93 out of 111 patients (84%), while EBV DNA was detected in 58 patients (52%). The most abundant adenovirus type was HAdV-5 (68%). None of the patients were positive for HCMV. Furthermore, 43 patients (39%) showed a co-infection of HAdV and EBV. The majority of young patients diagnosed with tonsillar hypertrophy were positive for HAdV, whereas all adult patients diagnosed with chronic/recurrent tonsillitis were positive for either HAdV or EBV. Most of the tonsils from patients diagnosed with either tonsillar hypertrophy or chronic/recurrent tonsillitis showed a higher HAdV DNA copy number in T compared to B cell-enriched fraction. Interestingly, in the majority of the tonsils from patients with chronic/recurrent tonsillitis HAdV DNA was detected in T cells only, whereas hypertrophic tonsils demonstrated HAdV DNA in both T and B cell-enriched fractions. In contrast, the majority of EBV positive tonsils revealed a preference for EBV DNA accumulation in the B cell-enriched fraction compared to T cell fraction irrespective of the patients' age.

  • 48.
    Aström, Lennart
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Pedersen, Dorte
    Mercke, Claes
    Holmäng, Sten
    Johansson, Karl Axel
    Long-term outcome of high dose rate brachytherapy in radiotherapy of localised prostate cancer.2005In: Radiother Oncol, ISSN 0167-8140, Vol. 74, no 2, 157-61 p.Article in journal (Refereed)
  • 49.
    Aulin, Julia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Siegbahn, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Coagulation and inflammation science.
    Hijazi, Ziad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ezekowitz, Michael D.
    Lankenau Inst Med Res, Wynnewood, PA USA.;Ctr Heart, Wynnewood, PA USA..
    Andersson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Connolly, Stuart J.
    Populat Hlth Res Inst, Hamilton, ON, Canada..
    Huber, Kurt
    Dept Internal Med Cardiol & Emergency Med 3, Vienna, Austria..
    Reilly, Paul A.
    Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA..
    Wallentin, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Oldgren, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Interleukin-6 and C-reactive protein and risk for death and cardiovascular events in patients with atrial fibrillation2015In: American Heart Journal, ISSN 0002-8703, E-ISSN 1097-6744, Vol. 170, no 6, 1151-1160 p.Article in journal (Refereed)
    Abstract [en]

    Background Inflammation has been associated with cardiovascular disease and the burden of atrial fibrillation (AF). In this study we evaluate inflammatory biomarkers and future cardiovascular events in AF patients in the RE-LY study. Methods Interleukin-6 (IL-6), C-reactive protein (CRP) (n = 6,187), and fibrinogen (n = 4,893) were analyzed at randomization; outcomes were evaluated by Cox models and C-statistics. Results Adjusted for clinical risk factors IL-6 was independently associated with stroke or systemic embolism (P =.0041), major bleedings (P =.0001), vascular death (P<.0001), and a composite thromboembolic outcome (ischemic stroke, systemic embolism, myocardial infarction, pulmonary embolism and vascular death) (P<.0001). CRP was independently related to myocardial infarction (P =.0047), vascular death (P =.0004), and the composite thromboembolic outcome (P =.0001). When further adjusted for cardiac (troponin andN-terminal fragment B-type natriuretic peptide [NT-proBNP]) and renal (cystatin-C) biomarkers on top of clinical risk factors IL-6 remained significantly related to vascular death (P<.0001), major bleeding (P<.0170) and the composite thromboembolic outcome (P<.0001), and CRP to myocardial infarction (.0104). Fibrinogen was not associated with any outcome. C-index for stroke or systemic embolism increased from 0.615 to 0.642 (P =.0017) when adding IL-6 to the clinically used CHA(2)DS(2)-VASc risk score with net reclassification improvement of 28%. Conclusion In patients with AF, IL-6 is related to higher risk of stroke and major bleeding, and both markers are related to higher risk of vascular death and the composite of thromboembolic events independent of clinical risk factors. Adjustment for cardiovascular biomarkers attenuated the prognostic value, although IL-6 remained related to mortality, the composite of thromboembolic events, and major bleeding, and CRP to myocardial infarction.

  • 50. Avall-Lundqvist, Elisabeth
    et al.
    Staf, Christian
    Bjurberg, Maria
    Borgfeldt, Christer
    Dahm-Kahler, Pernilla
    Falconer, Henrik
    Holmberg, Erik
    Kjolhede, Preben
    Stålberg, Karin Glimskär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Rosenberg, Per
    Hogberg, Thomas
    A population-based study of pelvic serous carcinoma in Sweden: Primary site, FIGO stage and survival.2015In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 33, no 15Article in journal (Other academic)
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