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  • 151. Hallqvist, A.
    et al.
    Wagenius, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Rylander, H.
    Brodin, O.
    Holmberg, E.
    Lödén, B.
    Ewers, S. -B
    Bergström, S.
    Wichardt-Johansson, G.
    Nilsson, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ekberg, L.
    Sederholm, C.
    Nyman, J.
    Concurrent cetuximab and radiotherapy after docetaxel-cisplatin induction chemotherapy in stage III NSCLC: Satellite-A phase II study from the Swedish Lung Cancer Study Group2011In: Lung Cancer, ISSN 0169-5002, E-ISSN 1872-8332, Vol. 71, no 2, p. 166-172Article in journal (Refereed)
    Abstract [en]

    Background: Several attempts to increase the locoregional control in locally advanced lung cancer including concurrent chemotherapy, accelerated fractionation and dose escalation have been made during the last years. As the EGFR directed antibody cetuximab has shown activity concurrent with radiotherapy in squamous cell carcinoma of the head and neck, as well as in stage IV NSCLC combined with chemotherapy, we wanted to investigate radiotherapy with concurrent cetuximab in locally advanced NSCLC, a tumour type often over expressing the EGF-receptor. Methods: Between February 2006 and August 2007 75 patients in stage Ill NSCLC with good performance status (PS 0 or 1) and adequate lung function (FEV1 > 1.0) were enrolled in this phase II study at eight institutions. Treatment consisted of 2 cycles of induction chemotherapy, docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2) with 3 weeks interval. An initial dose of cetuximab 400 mg/m(2) was given before start of 3D-CRT to 68 Gy with 2 Gy per fraction in 7 weeks concurrent with weekly cetuximab 250 mg/m(2). Toxicity was scored weekly during radiotherapy (CTC 3.0), and after treatment the patients were followed every third month with CT-scans, toxicity scoring and QLQ. Results: Seventy-one patients were eligible for analysis as four were incorrectly enrolled. Histology: adenocarcinoma 49%, squamous cell carcinoma 39% and other NSCLC 12%. The majority had PS 0 (62.5%), median age 62.2 (42-81), 50% were women and 37% had a pre-treatment weight loss > 5%. Toxicity: esophagitis grade 1-2: 72%; grade 3:1.4%. Hypersensitivity reactions grade 3-4: 5.6%. Febrile neutropenia grade 3-4: 15.4%. Skin reactions grade 1-2: 74%; grade 3: 4.2%. Diarrhoea grade 1-2: 38%; grade 3: 11.3%. Pneumonitis grade 1-2: 26.8%; grade 3: 4.2%; grade 5:1.4%. The median follow-up was 39 months for patients alive and the median survival was 17 months with a 1-, 2- and 3-year OS of 66%, 37% and 29% respectively. Until now local or regional failure has occurred in 20 patients and 22 patients have developed distant metastases. Weight loss, PS and stage were predictive for survival in univariate as well as in multivariate analysis. Conclusion: Induction chemotherapy followed by concurrent cetuximab and RT to 68 Gy is clearly feasible with promising survival. Toxicity, e.g. pneumonitis and esophagitis is low compared to most schedules with concurrent chemotherapy. This treatment strategy should be evaluated in a randomised manner vs. concurrent chemoradiotherapy to find out if it is a valid treatment option.

  • 152. Hallén, Karin
    et al.
    Sangfelt, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Gastroenterology/Hepatology.
    Nilsson, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Nordgren, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Pathology.
    Wanders, Alkwin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Molin, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Vanishing bile duct-like syndrome in a patient with Hodgkin lymphoma: pathological development and restitution2014In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 53, no 9, p. 1271-1275Article in journal (Refereed)
  • 153. Hammel, Pascal
    et al.
    Huguet, Florence
    Van Laethem, Jean-Luc
    Goldstein, David
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Artru, Pascal
    Borbath, Ivan
    Bouche, Olivier
    Shannon, Jenny
    Andre, Thierry
    Mineur, Laurent
    Chibaudel, Benoist
    Bonnetain, Franck
    Louvet, Christophe
    Comparison of chemoradiotherapy (CRT) and chemotherapy (CT) in patients with a locally advanced pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or without erlotinib: Final results of the international phase III LAP 07 study2013In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 31, no 18, p. LBA4003-Article in journal (Other academic)
  • 154.
    Hassan, Saadia Bashir
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Hu, Kefei
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Berenjian, Saideh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Morein, Bror
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Virology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    The Nanoparticulate Quillaja Saponin BBE Is Selectively Active Towards Renal Cell Carcinoma2013In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 33, no 1, p. 143-151Article in journal (Refereed)
    Abstract [en]

    Aim: To characterize the cytotoxic effect of BBE, the particulate of desacyl-saponin, in model systems of solid tumours. Materials and Methods: Cytotoxic activity of BBE was investigated in solid human tumour cell lines, in tumour cells from patients with renal cell carcinoma, in normal human renal cells and in peripheral blood mononuclear cells. The BBE mode of cell death was assessed in vitro. In vivo effect of BBE was evaluated in xenograft-bearing mice. Results: BBE was selectively active against renal cell carcinoma, with no or little effect on normal cells. BBE induced caspase activity and apoptosis. An inhibitory activity of BBE on xenograft tumour growth, with no apparent signs of haematological toxicity was shown. In the non-proliferative model of patient tumour cells, BBE was active on only 1/5 patient samples, suggesting association of BBE effect with cell proliferation. Conclusion: BBE has interesting activities against renal cell carcinoma and should be further explored as a drug against this resistant tumour type.

  • 155.
    Hassan, Saadia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Laryea, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Felth, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Pharmacognosy.
    Fryknäs, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Fayad, Walid
    Linder, Stig
    Rickardson, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Gullbo, Joachim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Graf, Wilhelm
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Pålman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Glimelius, Bengt
    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, Clinical Pharmacology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Novel activity of acriflavine against colorectal cancer tumor cells2011In: Cancer Science, ISSN 1347-9032, E-ISSN 1349-7006, Vol. 102, no 12, p. 2206-2213Article in journal (Refereed)
    Abstract [en]

    A high-throughput screen of the cytotoxic activity of 2000 molecules from a commercial library in three human colon cancer cell lines and two normal cell types identified the acridine acriflavin to be a colorectal cancer (CRC) active drug. Acriflavine was active in cell spheroids, indicating good drug penetration and activity against hypoxic cells. In a validation step based on primary cultures of patient tumor cells, acriflavine was found to be more active against CRC than ovarian cancer and chronic lymphocytic leukemia. This contrasted to the activity pattern of the CRC active standard drugs 5-fluorouracil, irinotecan and oxaliplatin. Mechanistic studies indicated acriflavine to be a dual topoisomerase I and II inhibitor. In conclusion, the strategy used seems promising for identification of new diagnosis-specific cancer drugs.

  • 156. Haugnes, Hege S.
    et al.
    Laurell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Stierner, Ulrika
    Bremnes, Roy M.
    Dahl, Olav
    Cavallin-Stahl, Eva
    Cohn-Cedermark, Gabriella
    High-dose chemotherapy with autologous stem cell support in patients with metastatic non-seminomatous testicular cancer: a report from the Swedish Norwegian Testicular Cancer Group (SWENOTECA)2012In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 2, p. 168-176Article in journal (Refereed)
    Abstract [en]

    Background. The SWENOTECA IV protocol from 1995 is a prospective population-based study in metastatic non-seminomatous germ cell testicular cancer (NSGCT), designed for early identification of patients with poor response to standard cisplatin-based chemotherapy. A slow tumor marker decline (HCG T(1/2) > 3 days, AFP T(1/2) > 7 days) after BEP or BEP plus ifosfamide was regarded as poor response. The aim of this study was to present survival and toxicity data for patients treated with high-dose chemotherapy (HDCT) within the SWENOTECA IV cancer care program. Material and methods. In total 882 adult men diagnosed with metastatic NSGCT between July 1995 and June 2007 in Sweden and Norway (except one center) were included in SWENOTECA IV and treated accordingly. Among these, 55 men (6.2%) were treated with HDCT according to three different indications in the protocol: A) poor response to standard-dose intensified chemotherapy (BEP plus ifosfamide); B) vital cancer at surgery after intensified chemotherapy; and C) selected relapses after previous chemotherapy. In situation A and C two HDCT cycles and in situation B one HDCT cycle was recommended. Situation A was the reason for HDCT in 36 patients, B in seven and C in 12 patients. The first HDCT cycle consisted of carboplatin 28 x (GFR + 25) mg, cyclofosfamide 6000 mg/m(2) and etoposide 1750 mg/m(2), administered over four days. In cycle two, etoposide was replaced by tiotepa 480 mg/m(2). Results. After a median follow-up of 7.5 years, overall survival was 72%, 100% and 58%, while failure-free survival was 64%, 71% and 42% in situation A, B and C, respectively. Three patients (5.5%) died during HDCT (renal failure or intracerebral hemorrhage). Nephrotoxicity was the most common non-hematological grade 4 toxicity (n = 5, 9%). Conclusion. The population-based SWENOTECA strategy, selecting patients who do not respond adequately to primary standard-dose chemotherapy for immediate treatment intensification with HDCT, is feasible and might be advantageous.

  • 157. Hedman, Mattias
    et al.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Brattström, Daniel
    Brodin, Ola
    Fractionated Irradiation of Five Human Lung Cancer Cell Lines and Prediction of Survival According to a Radiobiology Model2011In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 31, no 4, p. 1125-1130Article in journal (Refereed)
    Abstract [en]

    Background: This study evaluates a predictive radiobiology model by measurements of surviving fraction (SF) by the clonogenic assay or the extrapolation method and the proliferation rate in vitro. It is hypothesized that incorporating proliferation to intrinsic radiosensitivity, measured by SF, to predict radiation responsiveness after fractionated irradiation adds to the model's accuracy. Materials and Methods. Five lung cancer cell lines with known SF after 1 Gy (SF1), and also SF2 and SF5, were irradiated with three different fractionation regimes; 10x1 Gy, 5x2 Gy or 2x5 Gy during the same total time to achieve empirical SF. In addition, the SF1, SF2 and SF5 after fractionated irradiation was calculated for each cell line based on the already known single fraction SF and with or without a proliferation factor. The results were compared to the empirical data. Results and Discussion: By using the clonogenic assay to measure radiosensitivity, prediction of radiosensitivity was improved after fractionated radiotherapy when proliferation was used in the radiobiology model. However, this was not the case in the cell lines where the extrapolation method was used to calculate SF. Thus, a radiobiology model including intrinsic radiosensitivity, measured by the clonogenic assay, as well as proliferation, is better at predicting survival after fractionated radiotherapy, compared to the use of intrinsic radiosensitivity alone.

  • 158.
    Hedström, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Prognostic Markers in Diffuse Large B-cell Lymphoma: How Bad can it be2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Diffuse large B-cell lymphoma (DLBCL), which is the most common type of lymphoma, is characterised by its aggressiveness and poor outcome without adequate treatment and also for its biological and clinical heterogeneity. It is therefore highly desirable to gain a more profound understanding of the underlying biology of the disease, as well as predictive factors for the guidance of treatment. The studies presented here attempt to gain an overall grasp on DLBCL, from the epidemiological level down to the genomic level.

    The tumour microenvironment consists of both tumour cells and normal infiltrating cells in a delicate interplay. By assessing the number of infiltrating mast cells (MCs) in the microenvironment, a correlation between low numbers of MCs and poorer prognosis of DLBCL was found.

    However, malignant cells are not only affected by environmental conditions but also by intrinsic factors, such as small non-coding microRNAs. A low expression level of microRNA-129 was found to correlate with poor survival of DLBCL and the finding remained significant even for rituximab-treated patients.

    An even smaller intracellular genomic unit is one single nucleotide. The single nucleotide polymorphism 309 (SNP309) is a T to G change in the promotor region of MDM2, a regulatory protein in the p53 pathway, which results in increased transcription of MDM2 and thus decreased levels of p53. It was found that homozygous T allele patients had longer overall survival, as well as disease-specific survival and disease-free survival. However, treatment with rituximab eliminated the predictive value of the SNP309 polymorphism.

    In the last project presented in this thesis we used epidemiological methods to analyse all DLBCL cases diagnosed 2000-2013 in Sweden. Here it was possible to categorically show that higher age is an adverse prognostic factor, and most importantly, this starts from a young age.

    In conclusion, within this thesis I have applied different laboratory and analysis techniques to examine DLBCL biology in relation to the clinic. I have identified potential new prognostic markers, contributed to an enhanced understanding of DLBCL biology and described epidemiological data from one of the largest DLBCL cohorts ever presented. All of these aspects provide important information for a deeper understanding of the disease DLBCL. 

    List of papers
    1. Mast cell infiltration is a favourable prognostic factor in diffuse large B-cell lymphoma
    Open this publication in new window or tab >>Mast cell infiltration is a favourable prognostic factor in diffuse large B-cell lymphoma
    Show others...
    2007 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 138, no 1, p. 68-71Article in journal (Refereed) Published
    Abstract [en]

    Previous studies indicate that the inflammatory response in diffuse large B-cell lymphomas (DLBCL) is important for the clinical outcome. Mast cells are key regulators in this response; we investigated whether the number of tryptase-positive mast cells is correlated with clinical outcome. Patients with many mast cells had a significantly better event-free survival (EFS) compared to those with few mast cells (P < 0.03 in both germinal centre (GC) and non-GC DLBCL. This supports the idea that the infiltration of mast cells is a reflection of the host inflammatory response and is related to a favourable outcome.

    Keywords
    Aged, Biological Markers/analysis, Cell Movement, Disease-Free Survival, Female, Humans, Immunohistochemistry, Lymphoma; Large B-Cell; Diffuse/*immunology, Male, Mast Cells/enzymology/*pathology, Middle Aged, Prognosis, Proportional Hazards Models, Statistics; Nonparametric, Survival Analysis, Tryptases/analysis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-12998 (URN)10.1111/j.1365-2141.2007.06612.x (DOI)000247111300006 ()17555448 (PubMedID)
    Available from: 2008-06-04 Created: 2008-06-04 Last updated: 2017-12-11Bibliographically approved
    2. Low expression of microRNA-129-5p predicts poor clinical outcome in diffuse large B cell lymphoma (DLBCL)
    Open this publication in new window or tab >>Low expression of microRNA-129-5p predicts poor clinical outcome in diffuse large B cell lymphoma (DLBCL)
    Show others...
    2013 (English)In: International Journal of Hematology, ISSN 0925-5710, E-ISSN 1865-3774, Vol. 97, no 4, p. 465-471Article in journal (Refereed) Published
    Abstract [en]

    Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of B cell lymphomas. MicroRNA expression provides a new and interesting tool for understanding the biology and clinical course of DLBCL. The present study presents microRNA-129-5p expression data from DLBCL patients treated with CHOP or R-CHOP. Patients with low microRNA-129-5p expression had a median survival of 23 months and a significantly shorter overall survival (P = 0.0042) compared to patients with high microRNA-129-5p expression, who had a median survival of 58 months. We also found that patients treated with R-CHOP only and displaying low microRNA-129-5p expression had a significantly shorter overall survival compared to patients with high microRNA-129-5p expression; all such patients were still alive at the time of last follow-up (P = 0.043). No significant difference was found among microRNA-129-5p expression in tumor tissue, the tissue surrounding the tumor, and normal controls. To our knowledge, this is the first report to show that the expression of microRNA-129-5p can affect the clinical outcome of DLBCL patients and that microRNA-129-5p may be involved in the biology of DLBCL development, although larger studies are necessary to confirm this. Further investigations may also help to elucidate the biological role of microRNA-129-5p in DLBCL.

    Keywords
    DLBCL, microRNA-129-5p, Prognosis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-200079 (URN)10.1007/s12185-013-1303-2 (DOI)000317475500005 ()
    Available from: 2013-05-23 Created: 2013-05-20 Last updated: 2017-12-06Bibliographically approved
    3. The MDM2 polymorphism SNP309 is associated with clinical characteristics and outcome in diffuse large B-cell lymphoma
    Open this publication in new window or tab >>The MDM2 polymorphism SNP309 is associated with clinical characteristics and outcome in diffuse large B-cell lymphoma
    Show others...
    2014 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 93, no 6, p. 500-508Article in journal (Refereed) Published
    Abstract [en]

    Introduction: The murine double minute 2 (MDM2) gene encodes a regulatory protein of the p53 pathway. A single nucleotide polymorphism (T to G change) at position 309 (SNP309) in the promotor region of MDM2 affects the transcription activity of MDM2 and has been found to be a negative prognostic marker in several cancers. Patients and methods: In this study, the MDM2 SNP309 polymorphism was analysed in 201 patients with diffuse large B-cell lymphoma and analysed in relation to clinical characteristics and prognosis. Results: Patients homozygous for SNP309T had a significantly longer overall survival, lymphoma-specific survival and disease-free survival (P = 0.002; 0.004 and 0.006 respectively) compared to patients carrying a G allele. The longer overall survival was seen in the subgroup of patients not treated with Rituximab, however, not for Rituximab-treated patients (P = 0.01 and 0.2 respectively). The group homozygous for the T allele also had lower age at diagnosis, a tendency towards lower aaIPI and a significantly lower proportion of patients with p53 aberrations compared to the group including at least one G allele. However, the survival differences persisted even after removal of cases with known p53 aberrations from the analysis. Conclusion: Polymorphism in MDM2 SNP309 could be correlated to some clinical characteristics and for patients not treated with immunotherapy, a G allele was correlated to poor survival, whereas no survival differences were found for patients treated with Rituximab. Herewith, we provide additional information about Diffuse large B-cell Lymphoma (DLBCL) biology and highlight the importance of evaluation of molecular markers in relation to treatment.

    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-219350 (URN)10.1111/ejh.12388 (DOI)000345302700006 ()24889555 (PubMedID)
    Available from: 2014-02-27 Created: 2014-02-27 Last updated: 2017-12-05Bibliographically approved
    4. Impact of age in an unselected population of Diffuse large B-cell lymphomas
    Open this publication in new window or tab >>Impact of age in an unselected population of Diffuse large B-cell lymphomas
    2014 (English)Article in journal (Refereed) Submitted
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-219351 (URN)
    Available from: 2014-02-27 Created: 2014-02-27 Last updated: 2014-06-05Bibliographically approved
  • 159.
    Hedström, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Hagberg, Oskar
    Lunds Universitet.
    Jerkeman, Mats
    Lunds Universitet.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Impact of age in an unselected population of Diffuse large B-cell lymphomas2014Article in journal (Refereed)
  • 160.
    Hedström, Gustaf
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Thunberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Zainuddin, Norafiza
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    The MDM2 polymorphism SNP309 is associated with clinical characteristics and outcome in diffuse large B-cell lymphoma2014In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 93, no 6, p. 500-508Article in journal (Refereed)
    Abstract [en]

    Introduction: The murine double minute 2 (MDM2) gene encodes a regulatory protein of the p53 pathway. A single nucleotide polymorphism (T to G change) at position 309 (SNP309) in the promotor region of MDM2 affects the transcription activity of MDM2 and has been found to be a negative prognostic marker in several cancers. Patients and methods: In this study, the MDM2 SNP309 polymorphism was analysed in 201 patients with diffuse large B-cell lymphoma and analysed in relation to clinical characteristics and prognosis. Results: Patients homozygous for SNP309T had a significantly longer overall survival, lymphoma-specific survival and disease-free survival (P = 0.002; 0.004 and 0.006 respectively) compared to patients carrying a G allele. The longer overall survival was seen in the subgroup of patients not treated with Rituximab, however, not for Rituximab-treated patients (P = 0.01 and 0.2 respectively). The group homozygous for the T allele also had lower age at diagnosis, a tendency towards lower aaIPI and a significantly lower proportion of patients with p53 aberrations compared to the group including at least one G allele. However, the survival differences persisted even after removal of cases with known p53 aberrations from the analysis. Conclusion: Polymorphism in MDM2 SNP309 could be correlated to some clinical characteristics and for patients not treated with immunotherapy, a G allele was correlated to poor survival, whereas no survival differences were found for patients treated with Rituximab. Herewith, we provide additional information about Diffuse large B-cell Lymphoma (DLBCL) biology and highlight the importance of evaluation of molecular markers in relation to treatment.

  • 161.
    Hedström, Gustav
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Thunberg, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Berglund, Mattias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Simonsson, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Low expression of microRNA-129-5p predicts poor clinical outcome in diffuse large B cell lymphoma (DLBCL)2013In: International Journal of Hematology, ISSN 0925-5710, E-ISSN 1865-3774, Vol. 97, no 4, p. 465-471Article in journal (Refereed)
    Abstract [en]

    Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of B cell lymphomas. MicroRNA expression provides a new and interesting tool for understanding the biology and clinical course of DLBCL. The present study presents microRNA-129-5p expression data from DLBCL patients treated with CHOP or R-CHOP. Patients with low microRNA-129-5p expression had a median survival of 23 months and a significantly shorter overall survival (P = 0.0042) compared to patients with high microRNA-129-5p expression, who had a median survival of 58 months. We also found that patients treated with R-CHOP only and displaying low microRNA-129-5p expression had a significantly shorter overall survival compared to patients with high microRNA-129-5p expression; all such patients were still alive at the time of last follow-up (P = 0.043). No significant difference was found among microRNA-129-5p expression in tumor tissue, the tissue surrounding the tumor, and normal controls. To our knowledge, this is the first report to show that the expression of microRNA-129-5p can affect the clinical outcome of DLBCL patients and that microRNA-129-5p may be involved in the biology of DLBCL development, although larger studies are necessary to confirm this. Further investigations may also help to elucidate the biological role of microRNA-129-5p in DLBCL.

  • 162.
    Hellerstedt-Börjesson, Susanne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Arving, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Nordin, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Holmström-Knutsson, Iinger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Health Services Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Women with breast cancer: Experiences and impact of chemotherapy-induced pain on daily life2014In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 50, no S2, p. S108-S108Article in journal (Other academic)
  • 163.
    Hellerstedt-Börjesson, Susanne
    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.
    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.
    Fjällskog, Marie-Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Holmström, Inger K
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Health Services Research.
    Arving, Cecilia
    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.
    Women With Breast Cancer: Experience of Chemotherapy-Induced Pain: Triangulation of Methods2015In: Cancer Nursing, ISSN 0162-220X, E-ISSN 1538-9804, Vol. 38, no 1, p. 31-39Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    Chemotherapy treatment for cancer diseases can cause body pain during adjuvant therapy.

    OBJECTIVE

    The aim was to describe the perceived impact of adjuvant chemotherapy-induced pain (CHIP) on the daily lives of women with newly diagnosed breast cancer, using triangulation.

    METHOD

    Fifty-seven women scheduled for chemotherapy in doses of 75 mg/m2 or greater of epirubicin and/or docetaxel participated. Twenty-two of these women registered pain with values of 4 or more on the visual analog scale on day 10 following chemotherapy. Of these 22, 16 participated in an interview and colored a printed body image. A qualitative thematic stepwise analysis of the interviews was performed.

    RESULTS

    Chemotherapy-induced pain had a profound impact on daily life. Ten women reported the worst possible pain, with visual analog scale scores of 8 to 10. Three different categories crystallized: perception (A) of manageable pain, which allowed the women to maintain their daily lives; perception (B) of pain beyond imagination, whereby the impact of pain had become more complex; and perception (C) of crippling pain, challenging the women's confidence in survival.

    CONCLUSIONS

    The findings highlight the inability to capture CHIP with 1 method only; it is thus necessary to use complimentary methods to capture pain. We found that pain had a considerable impact on daily life, with surprisingly high scores of perceived pain, findings that to date have been poorly investigated qualitatively.

    IMPLICATIONS FOR PRACTICE

    Nurses need to (1) better identify, understand and treat CHIP, using instruments and protocols; and (2) provide improved communication about pain and pain management.

  • 164.
    Hellström, Vivan
    et al.
    Sektionen för transplantationskirurgi, Kirurgiska kliniken, Akademiska sjukhuset, Uppsala, Sweden.
    Wilczek, Henryk
    Institutionen för klinisk vetenskap, intervention och teknik (CLINTEC), Karolinska Institutet.
    Roussos, Jana
    Sektionen för transplantation, Kirurgikliniken, Sahlgrenska universitetssjukhuset, Göteborg, Sweden.
    Lorant, Tomas
    Sektionen för transplantationskirurgi, Kirurgiska kliniken, Akademiska sjukhuset, Uppsala, Sweden.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Nyberg, Filippa
    Hudkliniken, Akademiska sjukhuset, Uppsala, Sweden.
    Tufveson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Transplantation Surgery.
    Njurtransplanterade med maligna tumörer en växande patientgrupp: [Kidney transplanted persons with malignant tumors is a growing patient group]2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 39-40, p. 1766-1769Article in journal (Refereed)
    Abstract [en]

    The incidence of malignant tumors in the organ transplanted population is increased 3-5 fold compared to the general population. The spectrum of tumors is different, the tumor growth is more aggressive and the prognosis is worse. In order to identify patients with post-transplant malignant tumors, the transplant registries in Stockholm, Uppsala and Gothenburg were cross run with the respective regional oncologic registries (ROC). It was found, that despite a generally good follow up, information about more than 50% of the malignant tumors is missing at the transplant centers. According to international guidelines this patient group should be evaluated by multidisciplinary teams consisting of transplant surgeons/nephrologists, oncologists and dermatologists with experience of transplantation to get optimal medical treatment. We would therefore like to emphasize the importance of referring all renal transplanted patients with malignant tumors to the transplant centers for multidisciplinary evaluation of the immunosuppressive as well as oncologic treatment.

  • 165. Hogberg, T.
    et al.
    Bangshoj, R.
    Bjurberg, M.
    Boman, K.
    Bulow, E.
    Dahm-Kahler, P.
    Holtenman, M.
    Rosenberg, P.
    Tholander, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Avall-Lundqvist, E.
    The Swedish Quality Registry for Gynecologic Oncology2013In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 23, no 8Article in journal (Other academic)
  • 166.
    Holgersson, Georg
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Nyman, Jan
    Hoye, Even
    Helsing, Martin
    Friesland, Signe
    Holgersson, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ekberg, Lars
    Morth, Charlotte
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Blystad, Thomas
    Ewers, Sven-Borje
    Loden, Britta
    Henriksson, Roger
    Bergstrom, Stefan
    The impact of hyperfractionated radiotherapy regimen in patients with non-small cell lung cancer2013In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 30, no 1, p. 320-Article in journal (Refereed)
    Abstract [en]

    The prognosis for patients with lung cancer is poor with an average of 5-year overall survival rate of only 10-15 % taking all clinical stages together. The aim of this study was to elucidate the impact of the radiotherapy regimen on survival. Clinical data were collected from all the Swedish Oncology Departments for 1,287 patients with a diagnosed non-small cell lung cancer (NSCLC) subjected to curatively intended irradiation (>= 50 Gy) during the years 1990 to 2000. The included patients were identified based on a manual search of all medical and radiation charts at the oncology departments from which the individual patient data were collected. Patients who did not have a histopathological diagnosis date and/or death date/last follow-up date as well as patients being surgically treated were excluded from the study (n = 592). Thus, 695 patients were included in the present study. Patients who received hyperfractionated radiotherapy (HR) had a higher local control rate compared with patients receiving conventional fractionation (CF) (38 vs. 49 % local relapse). The difference in survival between the two radiotherapy regimens was statistically significant in a univariate Cox analysis (p = 0.023) in favor of HR. This significance was, however, not retained in a multivariate Cox analysis (p = 0.56). Thus, the possible beneficial effects of hyperfractionation are still unclear and need to be further investigated in well-controlled prospective clinical trials, preferably including systemic treatment with novel drugs.

  • 167.
    Holgersson, Georg
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Bergström, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Research and Development, Gävleborg.
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Nyman, Jan
    Hoye, Even
    Helsing, Martin
    Friesland, Signe
    Holgersson, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Birath, Elisabet
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Blystad, Thomas
    Ewers, Sven-Borje
    Morth, Charlotte
    Loden, Britta
    Henriksson, Roger
    Swedish Lung Cancer Radiation Study Group: Predictive value of histology for radiotherapy response in patients with non-small cell lung cancer2011In: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 47, no 16, p. 2415-2421Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to evaluate the potential predictive value of histology in non-small cell lung cancer (NSCLC) treated with curatively intended radiotherapy. In a collaborative effort among all the Swedish Oncology Departments, clinical data were collected for 1146 patients with a diagnosed non-small cell lung cancer subjected to curatively intended irradiation (>= 50 Gy) during the years 1990 to 2000. The included patients were identified based on a manual search of all medical and radiation charts at the oncology departments from which the individual patient data were collected. Only patients who did not have a histological diagnosis date and death date/last follow-up date were excluded (n = 141). Among the 1146 patients with non-small cell carcinoma eligible for analysis, 919 were diagnosed with either adenocarcinoma (n = 323) or squamous cell carcinoma (n = 596) and included in this study. The median survival for the 919 patients was 14.8 months, while the 5-year survival rate was 9.5%. Patients with adenocarcinoma had a significantly better overall survival compared with patients with squamous cell carcinoma (p = 0.0062, log-rank test). When comparing different stages, this survival benefit was most pronounced for stages IIA-IIB (p<0.0001, log-rank test). The difference in survival between the two histological groups was statistically significant in a univariate Cox analysis (p = 0.0063) as well as in two multivariate Cox analyses including demographic and treatment variables (p = 0.037 and p = 0.048, respectively). In this large population based retrospective study we describe for the first time that patients with adenocarcinoma have a better survival after curatively intended radiation therapy in comparison with squamous cell carcinoma patients, particularly those with clinical stages IIA-IIB.

  • 168.
    Holgersson, Georg
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Hoye, Even
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Nyman, Jan
    Helsing, Martin
    Friesland, Signe
    Holgersson, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Ekberg, Lars
    Blystad, Thomas
    Ewers, Sven-Borje
    Morth, Charlotte
    Loden, Britta
    Henriksson, Roger
    Bergstrom, Stefan
    Swedish Lung Cancer Radiation Study Group: Predictive value of age at diagnosis for radiotherapy response in patients with non-small cell lung cancer2012In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 6, p. 759-767Article in journal (Refereed)
    Abstract [en]

    Introduction. The aim of the present study was to investigate the impact of age at diagnosis on prognosis in patients treated with curatively intended radiotherapy for NSCLC.

    Material and methods. This is a joint effort among all the Swedish Oncology Departments that includes all identified patients with a diagnosed non-small cell lung cancer that have been subjected to curatively intended irradiation (>= 50 Gy) treated during 1990 to 2000. Included patients had a histopathological/cytological diagnosis date as well as a death date or a last follow-up date. The following variables were studied in relation to overall and disease-specific survival: age, gender, histopathology, time period, smoking status, stage and treatment.

    Results. The median overall survival of all 1146 included patients was 14.7 months, while the five-year overall survival rate was 9.5%. Younger patients (<55 years), presented with a more advanced clinical stage but had yet a significantly better overall survival compared with patients in the age groups 55-64 years (p = 0.035) and 65-74 years (p = 0.0097) in a multivariate Cox regression analysis. The overall survival of patients aged >= 75 years was comparable to those aged <55 years.

    Conclusion. In this large retrospective study we describe that patients younger than 55 years treated with curatively intended radiotherapy for NSCLC have a better overall survival than patients aged 55-64 and 65-74 years and that younger patients seem to benefit more from the addition of surgery and/or chemotherapy to radiotherapy. Due to the exploratory nature of the study, these results should be confirmed in future prospective trials.

  • 169.
    Holgersson, Georg
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sandelin, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Hoye, Even
    Bergström, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Research and Development, Gävleborg.
    Henriksson, Roger
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Nyman, Jan
    Helsing, Martin
    Friesland, Signe
    Brodin, Ola
    Holgersson, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Lamberg Lundström, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Ekberg, Lars
    Morth, Charlotte
    Blystad, Thomas
    Ewers, Sven-Borje
    Loden, Britta
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    The Value of Induction Chemotherapy for Survival in Patients with Non-small Cell Lung Cancer Treated with Radiotherapy2012In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 32, no 4, p. 1339-1346Article in journal (Refereed)
    Abstract [en]

    Aim: The aim of the present study was to retrospectively investigate the impact of induction chemotherapy on treatment outcome in patients treated with curatively intended radiotherapy for non-small cell lung cancer (NSCLC). Patients and Methods: Patients with a diagnosed NSCLC that have been subjected to curatively intended irradiation (>= 50 Gy) and treated in an oncology department in Sweden during the years 1990-2000 were included in the study. Operated patients and patients having received concomitant chemotherapy were excluded. The included patients were localised by a manual search of all the oncology departments' medical records and radiation charts. Results: Patients treated with induction chemotherapy (n=79) had a significantly better overall survival compared with patients treated with radiotherapy alone (p=0.0097) in a univariate Cox regression analysis. A platinum/taxane combination produced the greatest survival benefit; hazard ratio=0.49 (95% confidence interval=0.31 to 0.75). Conclusion: We found that patients treated with induction chemotherapy in addition to radiotherapy for NSCLC have a better overall survival than patients treated with radiotherapy alone and that the best results are achieved using a platinum/taxane combination.

  • 170.
    Holgersson, Georg
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sandelin, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Hoye, Even
    Bergström, Stefan
    Henriksson, Roger
    Ekman, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Nyman, Jan
    Helsing, Martin
    Friesland, Signe
    Holgersson, Margareta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Lamberg, Kristina Lundström
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Janson, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Respiratory Medicine and Allergology.
    Birath, Elisabet
    Mörth, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Blystad, Thomas
    Ewers, Sven-Börje
    Löden, Britta
    Bergqvist, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Swedish lung cancer radiation study group: the prognostic value of anaemia, thrombocytosis and leukocytosis at time of diagnosis in patients with non-small cell lung cancer2012In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 29, no 5, p. 3176-3182Article in journal (Refereed)
    Abstract [en]

    There is a need to improve the prognostic and predictive indicators in non-small cell lung cancer (NSCLC). At present, the main focus is on genetic predictive markers while the prognostic value of the standard blood variables related to haematopoiesis has been subjected to relatively limited attention. To study the prognostic potential of haemoglobin (Hgb), platelet (Plt) and white blood cell (WBC) levels at time of diagnosis in NSCLC patients, 835 NSCLC patients, stage I-IV, who received radiotherapy with curative intention (> 50 Gy), were included in the study. WBC, Plt, Hgb, gender, age at diagnosis, stage, surgery and first-line chemotherapy were studied in relation to overall survival. For patients with Hgb < 110 g/L and Hgb a parts per thousand yen 110 g/L), the median survival was 11.2 and 14.5 months, respectively (p = 0.0032). For WBC > 9.0 x 10(9)/L and < 9.0 x 10(9)/L, the median survival was 11.6 and 15.4 months, respectively (p < 0.0001). For Plt > 350 x 10(9)/L and < 350 x 10(9)/L, the median survival was 11.2 and 14.9 months, respectively (p < 0.0001). The median survival in patients with pathological results in all three markers was half of that in patients with normal levels of all three markers (8.0 and 16.0 months, respectively (p < 0.0001). The level of the three studied haematological biomarkers corresponds significantly to outcome in NSCLC. These results indicate that standard haematological variables may be used as guidance for the clinician in the decision-making regarding treatment intensity and patient information.

  • 171.
    Hovstadius, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Larsson, Rolf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lindhagen, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Skov, Torsten
    Kissmeyer, Ann-Marie
    Krasilnikoff, Klaus
    Bergh, Jonas
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences, Division of Pharmacokinetics and Drug Therapy.
    Lönnebo, Anna
    Ahlgren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    A Phase I Study of CHS 828 in Patients with Solid Tumor Malignancy2002In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 8, no 9, p. 2843-2850Article in journal (Refereed)
    Abstract [en]

    CHS 828 is a cyanoguanidine, which has demonstrated potent antitumor activity in preclinical tumor models. The activity of CHS 828 in vitro showed only low to moderate correlation to other antineoplastic agents suggesting a unique mechanism of action. Ten females and 6 males (median age 58 years) with solid tumors refractory to standard therapy were included in this Phase I study. The study drug was administered to fasting patients as a single oral dose on days 1–5 of each treatment cycle. Patients received one to six cycles of treatment. The doses ranged from 30 mg to 200 mg (total dose within a cycle). Hematological toxicity was generally mild and dominated by transient thrombocytopenia and lymphocytopenia. Nonhematological toxicity most frequently consisted of nausea, vomiting, diarrhea, fatigue, and localized genital mucositis. The dose-limiting toxicities were thrombocytopenia, thrombosis, esophagitis, diarrhea, and constipation. The recommended Phase II dose of CHS 828 was 20 mg once daily for 5 days in cycles of 28 days duration. The extent of systemic exposure of CHS 828 across patients was approximately dose proportional. The time at which the highest drug concentration occurs was 2.2 ± 1.3 h and half-life was 2.1 ± 0.52 h (mean ± SD). Large intra- and interindividual variation in dose level-adjusted maximum plasma concentration and the area under the curve from time 0 h to infinity were observed. There was an apparent inverse relationship between systemic exposure of CHS 828, and thrombocyte and lymphocyte nadir levels. No objective tumor responses were observed, and 7 patients showed stable disease after two courses of therapy.

  • 172. Hoyer, Morten
    et al.
    Muren, Ludvig P.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    The evolution of radiotherapy techniques in the management of prostate cancer2015In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 54, no 6, p. 821-824Article in journal (Other academic)
  • 173. Huguet, F.
    et al.
    Racadot, S.
    Goldstein, D.
    Spry, N.
    Van Laethem, J.
    Van Houtte, P.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Gubanski, M.
    Bonnetain, F.
    Hammel, P.
    Investigation of Relation of Radiation Therapy Quality Assurance Scores (RTQASc) With Toxicity and Survival in LAP07 Phase 3 Trial for Locally Advanced Pancreatic Carcinoma (LAPC)2013In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 87, no 2, p. S29-S30Article in journal (Other academic)
  • 174.
    Hulsart-Billstrom, Gry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Estrada, Sergio
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Antoni, Gunnar
    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 Radiology, Oncology and Radiation Science, Oncology.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    BMP-2 Induced bone regeneration visualized by PET and SPECT2014In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 8, p. 513-513Article in journal (Other academic)
  • 175.
    Hultman, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Gunnarsson, Ulf
    Karolinska Institutet, Institutionen för kirurgisk vetenskap, intervention och teknik, Stockholm, Sverige.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    A population-based study of incidence of peritoneal metastases and prognostic factors in patients with loco-regionally advanced gastric cancerManuscript (preprint) (Other academic)
    Abstract [en]

    Purpose   The aim was to investigate epidemiological and prognostic factors as a knowledge base for the treatment of patients with loco-regionally advanced gastric cancer (GC). Methods   In Uppsala County between 2000 and 2009, two hundred and fifty-five patients with GC were identified. Data from patient records were analyzed for loco-regionally advanced GC, defined as tumor invading the parietal and/or visceral peritoneum, including peritoneal metastasis but excluding serosal invasion from the primary tumor only, at primary diagnosis or during follow-up. Presence or absence of distant metastasis (DM) in these patients was also assessed. Results   One hundred and twenty patients (47% of all patients with GC) experienced loco-regionally advanced disease. Forty-one percent also had DM. Median overall survival (mOS) from diagnosis of local-regionally advanced disease was 4.8 months for the whole group of patients, 5.1 months for the subgroup of patients without DM and 4.7 months for the subgroup with DM. Using multivariate Cox analysis, positive prognostic factors for survival identified were good performance status and treatment with palliative chemotherapy and/or radiotherapy. Synchronous DM was a negative predictive factor. The mOS did not differ between the first and second time period. Discussion   Peritoneal metastasis from GC is more common than previously reported. The lack of improvement in OS over the past decade signals a need for new treatment strategies.

  • 176.
    Hultman, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Lind, Pehr
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Haglund, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Phase II study of patients with peritoneal carcinomatosis from gastric cancer treated with preoperative systemic chemotherapy followed by peritonectomy and intraperitoneal chemotherapy2013In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 52, no 4, p. 824-830Article in journal (Refereed)
    Abstract [en]

    Background

    The aim was to evaluate the feasibility and the effectiveness of neoadjuvant systemic chemotherapy followed by cytoreductive surgery (CRS), hyperthermic intraperitoneal chemotherapy (HIPEC) and early postoperative intraperitoneal chemotherapy (EPIC) in patients with peritoneal carcinomatosis (PC) from gastric cancer.

    Material and methods

    Eighteen patients (median age 57 years, range 38-74) were scheduled for three months' neoadjuvant systemic chemotherapy followed by CRS + HIPEC + EPIC.

    Results

    At the time of surgery, the peritoneal tumor burden was extensive with tumor growth on the entire peritoneal cavity. Only eight patients received the entire treatment and OS was 14.3 months (range 6.1-34.3, 95% CI 6.6-20.3). Six patients had macroscopically radical (CC0) surgery and for this subgroup OS was 19.1 months (range 6.1-34.3, 95% CI 6.9-27.1). Postoperative 90-day mortality was 10% (one patient) and the perioperative grades II-IV adverse events (AE) rate was 62.5%.

    Discussion

    Neoadjuvant chemotherapy followed by CRS + HIPEC + EPIC does not seem to be associated with prolonged OS in patients with extensive PC growth from gastric cancer unless macroscopically radical surgery is achieved. However, morbidity from this treatment is considerable and it cannot be recommended for routine care until a prospective randomized trial has been performed.

  • 177.
    Hultman, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Lundkvist, Jonas
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Costs and clinical outcome of neoadjuvant systemic chemotherapy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from gastric cancer2012In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 51, no 1, p. 112-121Article in journal (Refereed)
    Abstract [en]

    Background

    The costs for loco-regional treatment of peritoneal carcinomatosis from gastric cancer are not well investigated. The aims of this study were to evaluate the costs and clinical outcome of systemic chemotherapy followed by cytoreductive surgery and intraperitoneal chemotherapy compared to systemic chemotherapy only in patients with peritoneal carcinomatosis from gastric cancer.

    Material and methods

    Ten patients were scheduled for systemic chemotherapy followed by loco-regional treatment. A reference group of 10 matched control patients treated with systemic chemotherapy only were used and both groups were evaluated with respect to clinical outcome and cost.

    Results

    The mean overall cost in the loco-regional group was $145 700 (range $49 900-$487 800) and $59 300 (range $23 000-$94 800) for the control group. The mean overall survival for the loco-regional group was 17.4 months (range 6.0-34.3), and 11.1 months (range 0.1-24.2) for the systemic chemotherapy only group. The gain in life-years was 0.52 and in quality-adjusted life-years 0.49, leading to incremental cost per life-year and quality-adjusted life-years gained of $166 716 and $175 164, for loco-regional group compared to systemic chemotherapy.

    Discussion

    Treatment of peritoneal carcinomatosis from gastric cancer is costly irrespective of treatment modality. If the survival benefit from adding loco-regional treatment to systemic chemotherapy indicated from this comparison is true, the incremental cost is considered high.

  • 178.
    Hultman, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Mahteme, Haile
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Ljungman, Martin
    Västmanlands sjukhus, Kirurgkliniken, Västerås, Sverige.
    Larsson, Rolf
    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.
    Benchmarking of gastric cancer sensitivity to anti-cancer drugs ex vivo as a basis for drug selection in systemic and intraperitoneal therapy2014In: Journal of Experimental & Clinical Cancer Research, ISSN 1756-9966, E-ISSN 1756-9966, Vol. 33, article id 110Article in journal (Refereed)
    Abstract [en]

    Background  

    The choice of drugs for treatment of advanced gastric cancer (GC) is empirical. The purpose of the current study was to benchmark ex vivo the sensitivity of GC tumor cells from patients to standard cytotoxic and some newly introduced targeted drugs (TDs), as a basis for drug selection in the treatment of GC.

    Methods  

    Tumor cell samples from patients with GC were analyzed for sensitivity to 5-fluorouracil, cisplatin, oxaliplatin, irinotecan, mito­mycin C, doxorubicin and docetaxel as well as for the targeted drugs bortezomib, sorafenib, sunitinib and rapamycin using a short-term in vitro assay based on retention of viable tumor cells of fluorescent fluorescein. Samples of normal mononuclear cells, chronic lymphocytic leukemia, ovarian cancer and colorectal cancer were included for comparison.

    Results    

    The GC samples were essentially as sensitive to the standard drugs and the TDs as those from colorectal cancer whereas the ovarian cancer samples were more sensitive. The individual GC samples varied considerably in sensitivity to increasing concentrations of the clinically used standard drugs. In GC, cisplatin was cross-resistant to oxaliplatin and 5-fluorouracil which, on the other hand, was not cross-resistant to the other cytotoxic drugs. The activity of sunitinib did not obviously correlate to that of the standard drugs.

    Conclusion    

    Ex vivo assessment of drug sensitivity of tumor cells from patients with GC is feasible and may provide information that could be useful for selection of drugs for treatment. Drug sensitivity varies considerably between and within individual samples arguing for individualized selection of drugs for chemotherapy.

  • 179.
    Häggblad Sahlberg, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Gustafsson, Ann-Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Pendekanti, Prathyusha N.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    The influence of AKT isoforms on radiation sensitivity and DNA repair in colon cancer cell lines2014In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 35, no 4, p. 3525-3534Article in journal (Refereed)
    Abstract [en]

    In response to ionizing radiation, several signaling cascades in the cell are activated to repair the DNA breaks, prevent apoptosis, and keep the cells proliferating. AKT is important for survival and proliferation and may also be an activating factor for DNA-PKcs and MRE11, which are essential proteins in the DNA repair process. AKT (PKB) is hyperactivated in several cancers and is associated with resistance to radiotherapy and chemotherapy. There are three AKT isoforms (AKT1, AKT2, and AKT3) with different expression patterns and functions in several cancer tumors. The role of AKT isoforms has been investigated in relation to radiation response and their effects on DNA repair proteins (DNA-PKcs and MRE11) in colon cancer cell lines. The knockout of AKT1 and/or AKT2 affected the radiation sensitivity, and a deficiency of both isoforms impaired the rejoining of radiation-induced DNA double strand breaks. Importantly, the active/phosphorylated forms of AKT and DNA-PKcs associate and exposure to ionizing radiation causes an increase in this interaction. Moreover, an increased expression of both DNA-PKcs and MRE11 was observed when AKT expression was ablated, yet only DNA-PKcs expression influenced AKT phosphorylation. Taken together, these results demonstrate a role for both AKT1 and AKT2 in radiotherapy response in colon cancer cells involving DNA repair capacity through the nonhomologous end joining pathway, thus suggesting that AKT in combination with DNA-PKcs inhibition may be used for radiotherapy sensitizing strategies in colon cancer.

  • 180.
    Häggblad Sahlberg, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Spiegelberg, Diana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Nestor, Marika
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Evaluation of cancer stem cell markers CD133, CD44, CD24: association with AKT isoforms and radiation resistance in colon cancer cells.2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 4, p. e94621-Article in journal (Refereed)
    Abstract [en]

    The cell surface proteins CD133, CD24 and CD44 are putative markers for cancer stem cell populations in colon cancer, associated with aggressive cancer types and poor prognosis. It is important to understand how these markers may predict treatment outcomes, determined by factors such as radioresistance. The scope of this study was to assess the connection between EGFR, CD133, CD24, and CD44 (including isoforms) expression levels and radiation sensitivity, and furthermore analyze the influence of AKT isoforms on the expression patterns of these markers, to better understand the underlying molecular mechanisms in the cell. Three colon cancer cell-lines were used, HT-29, DLD-1, and HCT116, together with DLD-1 isogenic AKT knock-out cell-lines. All three cell-lines (HT-29, HCT116 and DLD-1) expressed varying amounts of CD133, CD24 and CD44 and the top ten percent of CD133 and CD44 expressing cells (CD133(high)/CD44(high)) were more resistant to gamma radiation than the ten percent with lowest expression (CD133(low)/CD44(low)). The AKT expression was lower in the fraction of cells with low CD133/CD44. Depletion of AKT1 or AKT2 using knock out cells showed for the first time that CD133 expression was associated with AKT1 but not AKT2, whereas the CD44 expression was influenced by the presence of either AKT1 or AKT2. There were several genes in the cell adhesion pathway which had significantly higher expression in the AKT2 KO cell-line compared to the AKT1 KO cell-line; however important genes in the epithelial to mesenchymal transition pathway (CDH1, VIM, TWIST1, SNAI1, SNAI2, ZEB1, ZEB2, FN1, FOXC2 and CDH2) did not differ. Our results demonstrate that CD133(high)/CD44(high) expressing colon cancer cells are associated with AKT and increased radiation resistance, and that different AKT isoforms have varying effects on the expression of cancer stem cell markers, which is an important consideration when targeting AKT in a clinical setting.

  • 181.
    Häggblad Sahlberg, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Spiegelberg, Diana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    Lennartsson, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Stenerlöw, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Biomedical Radiation Sciences.
    The effect of a dimeric Affibody molecule (ZEGFR:1907)2 targeting EGFR in combination with radiation in colon cancer cell lines2012In: International Journal of Oncology, ISSN 1019-6439, Vol. 40, no 1, p. 176-184Article in journal (Refereed)
    Abstract [en]

    The epidermal growth factor receptor (EGFR) is frequently overexpressed in colorectal cancer and is therefore an attractive target for treatment. (ZEGFR:1907)2 is a newly developed dimeric affibody molecule with high affinity to the extracellular part of EGFR. In this study, we evaluated the cytotoxic effects of (ZEGFR:1907)2 in combination with external radiation and the possible inhibitory effects in the EGFR signalling pathways in the colon cancer cell lines HT-29 and HCT116. The effects were compared with an EGFR antibody (cetuximab) and the tyrosine kinase inhibitors (erlotinib and sunitinib). These cell lines are genotypically different with respect to e.g. KRAS and BRAF mutational status, recently shown to be of clinical significance for therapeutic effects. Both cell lines express approximately 100,000-150,000 EGFRs per cell but differ in the radiation response (HCT116, SF2=0.28 and HT-29, SF2=0.70). Exposure to (ZEGFR:1907)2 produced a small, but significant, reduction in survival in HCT116 but did not affect HT-29 cells. Similar results were obtained after exposure to EGF and the EGFR antibody cetuximab. The EGFR tyrosine kinase targeting inhibitor erlotinib and the multi-tyrosine kinase inhibitor sunitinib reduced survival in both cell lines. However, none of the drugs had any significant radiosensitizing effects in combination with radiation. Akt and Erk are central proteins in the EGFR downstream signalling and in the cellular response to ionizing radiation. The activation of Akt (Ser 473) and Erk (Thr202/Tyr204) by radiation was both dose- and time-dependent. However the activation of EGFR was not clearly affected by radiation. Neither (ZEGFR:1907)2 nor any of the other drugs were able to completely inactivate Akt or Erk. On the contrary, erlotinib stimulated Akt phosphorylation in both cell lines and in HCT116 cells Erk was activated. Overall the results illustrate the complexity in response to radiation and drugs in cells with differential phenotypic status.

  • 182. Höglund, Johanna
    et al.
    Shirvan, Anat
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Gustavsson, Sven-Åke
    Uppsala University.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Ringheim, Anna
    Sörensen, Jens
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science.
    Ben-Ami, Miri
    Ziv, Ilan
    F-18-ML-10, a PET Tracer for Apoptosis: First Human Study2011In: Journal of Nuclear Medicine, ISSN 0161-5505, E-ISSN 1535-5667, Vol. 52, no 5, p. 720-725Article in journal (Refereed)
    Abstract [en]

    Clinical PET of apoptosis may have substantial value in advancing patient care. We report here the first-in-humans study with F-18-labeled 2-(5-fluoropentyl)-2-methyl malonic acid (F-18-ML-10), a small-molecule PET tracer for apoptosis. Presented are the dosimetry, biodistribution, stability, and safety profiles of this PET tracer in healthy human volunteers. Also reported is tracer binding to targeted apoptotic cells in testicular tissue, where a relative abundance of apoptotic cells is normally observed. Methods: F-18-ML-10 (233 +/- 90 MBq) was intravenously administered to 8 healthy subjects, followed by whole-body PET/CT for 220 min. Serial blood and urine samples were collected for radioactivity measurement, and plasma tracer stability was assessed by high-performance liquid chromatography. Dosimetry calculations were performed using OLINDA/EXM software. Results: F-18-ML-10 manifested high stability in vivo and rapid distribution followed by fast clearance, with an elimination half-life of 1.3 +/- 0.1 and 1.1 +/- 0.2 h from the blood and from all other organs, respectively, and excretion through the urine. Dosimetry showed an average effective whole-body dose of 15.4 +/- 3.7 mu Sv/MBq, with the urinary bladder being the dose-limiting organ. Selective accumulation and retention of the tracer in the testes was observed in all male subjects, a finding also demonstrated in mice using both small-animal PET and histopathology, confirming binding to apoptotic cells. Administration of F-18-ML-10 was safe, without adverse effects. Conclusion: F-18-ML-10 administered to healthy humans demonstrated a favorable dosimetry, biodistribution, stability, and safety profile. Binding to apoptotic sites was also demonstrated. These data support further development of this small-molecule probe for clinical PET of apoptosis.

  • 183.
    Høyer, Marie
    et al.
    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.
    Nordin, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Ahlgren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Lidin-Lindqvist, Annika
    Regional Oncologic Center, Uppsala University Hospital.
    Lambe, Mats
    Regional Oncologic Centre, Uppsala University Hospital; Department of medical epidemiology and biostatistics, Karolinska Institutet.
    Lampic, Claudia
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet.
    Health-related quality of life among women with breast cancer: a population-based study2011In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 50, no 7, p. 1015-1026Article in journal (Refereed)
    Abstract [en]

    Background:

    High incidence rates of breast cancer emphasize the importance of increased knowledge about the health-related quality of life (HRQoL) in this patient group. The aim of the present study was to describe and compare HRQoL among breast cancer patients shortly after diagnosis with normative data from the general population, and to investigate how clinical, demographic, and socio-economic factors and social support are associated with HRQoL.

    Material and methods:

    Participants were identified in a population-based Breast Cancer Quality Register in central Sweden. Of 1573 women newly diagnosed with breast cancer during a one-year period (2007 – 2008), 69% (n =1086) completed a questionnaire including the EORTC QLQ-C30, BR23 and the HADS.

    Results:

    Compared to age-adjusted normative data, breast cancer patients (mean age 62 years, range 25–94), especially younger women (<50 years), experienced clinically meaningful poorer HRQoL. Clinically significant levels of anxiety and depressive symptoms were found among 14% and 6% of the patients, respectively. Factors associated with more problems/symptoms among study participants included chemotherapy, lack of social support, sick leave and a poor financial situation. Adding socio-economic factors diminished the association between age and HRQoL (p > 0.05).

    Conclusion:

    Recently diagnosed breast cancer patients reported poorer HRQoL in several dimensions compared to normative data. In addition to clinical and demographic factors, an unfavorable socio-economic standing was associated with more problems/symptoms. The present findings emphasize the importance of taking a variety of factors into account when assessing HRQoL in the clinical setting.

  • 184.
    Høyer, Marie
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Nordin, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Caring Sciences.
    Ahlgren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Research and Development, Gävleborg.
    Bergkvist, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Lambe, Mats
    Regionalt Cancer Center Uppsala Örebro, Uppsala University Hospital; Department of medical epidemiology och biostatistics, Karolinska Institutet.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Lampic, Claudia
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet.
    Change in working time in a population-based cohort of patients with breast cancer2012In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 30, no 23, p. 2853-2860Article in journal (Refereed)
    Abstract [en]

    Purpose:

    We examined changes in working time 16 months after a breast cancer diagnosis and identified factors associated with job discontinuation and/or decreased working time.

    Patients and Methods:

    This was a population-based cohort study with 735 patients identified in the Regional Breast Cancer Quality Register of Central Sweden. The study sample consisted of 505 women (age <63 years at diagnosis) who completed questionnaires at baseline and at follow-up (on average 4 and 16 months after diagnosis, respectively). Clinical register data and questionnaire data on sociodemographic factors were obtained at baseline. Self-reported work-related data were obtained at follow-up. Odds ratios were estimated by using logistic regression models.

    Results:

    Compared with prediagnosis working time, 72% reported no change in working time, 2% reported an increase, 15% reported a decrease, and 11% did not work at follow-up. Chemotherapy increased the likelihood (odds ratio [OR], 2.45; 95% CI, 1.38 to 4.34) of job discontinuation/decreased working time. Among chemotherapy recipients, associated factors included full-time work prediagnosis (OR, 3.25; 95% CI, 1.51 to 7.01), cancer-related work limitations (OR, 5.26; 95% CI, 2.30 to 12.03), and less value attached to work (OR, 3.69; 95% CI, 1.80 to 7.54). In the nonchemotherapy group, older age (OR, 1.09; 95% CI, 1.02 to 1.17) and less value attached to work (OR, 5.00; 95% CI, 2.01 to 12.45) were associated with the outcome.

    Conclusion:

    The majority of women treated for breast cancer returned to their prediagnosis working time. Chemotherapy and cancer-related work limitations are important factors to take into account in identifying women in need of support. Moreover, it is important to consider the woman’s own valuation of labor market participation.

  • 185.
    Igelström, Helena
    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.
    Berntsen, Sveinung
    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.
    Hetlelid, Ken
    Åsenlöf, Pernilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiotherapy.
    Demmelmaier, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Henriksson, Anna
    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.
    Arving, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Lifestyle and rehabilitation in long term illness.
    Johansson, Birgitta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    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.
    Phys-Can feasibility Study: Preparing for Physical Training and Behavioral Medicine Strategies2014Conference paper (Other academic)
  • 186. Ivanchenko, Margarita
    et al.
    Brauner, Susanna
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Backlin, Carin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Baecklund, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Wahren-Herlenius, Marie
    Ro52/TRIM21 Expression is Decreased in Malignant B Cells2014In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 79, no 6, p. 453-454Article in journal (Other academic)