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  • 1. Aaltonen, Kirsimari
    et al.
    Ahlin, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Salonen, Laura
    Fjällskog, Marie Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Heikkilä, Pävi
    Nevanlinna, Heli
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Reliability of cyclin A assessment on tissue microarrays in breast cancer compared to conventional histological slides2006In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 94, no 11, p. 1697-1702Article in journal (Refereed)
    Abstract [en]

    Cyclin A has in some studies been associated with poor breast cancer survival, although all studies have not confirmed this. Its prognostic significance in breast cancer needs evaluation in larger studies. Tissue microarray (TMA) technique allows a simultaneous analysis of large amount of tumours on a single microscopic slide. This makes a rapid screening of molecular markers in large amount of tumours possible. Because only a small tissue sample of each tumour is punched on an array, the question has arisen about the representativeness of TMA when studying markers that are expressed in only a small proportion of cells. For this reason, we wanted to compare cyclin A expression on TMA and on traditional large sections. Two breast cancer TMAs were constructed of 200 breast tumours diagnosed between 1997-1998. TMA slides and traditional large section slides of these 200 tumours were stained with cyclin A antibody and analysed by two independent readers. The reproducibility of the two readers' results was good or even very good, with kappa values 0.71-0.87. The agreement of TMA and large section results was good with kappa value 0.62-0.75. Cyclin A overexpression was significantly (P<0.001) associated with oestrogen receptor and progesterone receptor negativity and high grade both on TMA and large sections. Cyclin A overexpression was significantly associated with poor metastasis-free survival both on TMA and large sections. The relative risks for metastasis were similar on TMA and large sections. This study suggests that TMA technique could be useful to study histological correlations and prognostic significance of cyclin A on breast cancer on a large scale.

  • 2. Aaltonen, Kirsimari
    et al.
    Amini, Rose-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Heikkilä, Päivi
    Aittomäki, Kristiina
    Tamminen, A.
    Nevanlinna, Heli
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    High cyclin B1 expression is associated with poor survival in breast cancer2009In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 100, no 7, p. 1055-60Article in journal (Refereed)
    Abstract [en]

    Cyclin B1 regulates the G(2)-M transition of the cell cycle. Cyclin B1 expression is higher in premalignant and malignant than normal breast lesions. Correlation of cyclin B1 expression with other histopathological variables and prognostic role in breast cancer are not fully understood. Traditionally used prognostic criteria identify large subset of patients to receive adjuvant chemotherapy and to be exposed to adverse effects. A reliable and simple method helping prognostic evaluation in breast cancer is needed. We analysed cyclin B1 expression on 1348 invasive breast cancers and studied correlations with other histopathological variables and survival. High cyclin B1 correlated with high tumour grade, large tumour size and positive nodal status, oestrogen and progesterone receptor negativity, positive HER2 and p53 status, young age at diagnosis, and high cyclin E, cyclin A and Ki67 expression. Among patients not given adjuvant chemotherapy high cyclin B1 was a strong predictor of shorter overall and metastasis-free survival (RR 3.74, P<0.0005 and RR 3.51, P<0.0005, respectively), and remained as an independent prognostic factor also in multivariate analysis (RR 1.80, P=0.04 and RR 2.31, P=0.02, respectively). This study suggests high cyclin B1 associates with aggressive phenotype and is an independent prognostic factor in breast cancer.

  • 3. Adami, Johanna
    et al.
    Gäbel, H.
    Lindelöf, B.
    Ekström, K.
    Rydh, B.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ekbom, A.
    Adami, Hans-Olov
    Granath, F.
    Cancer risk following organ transplantation: a nationwide cohort study in Sweden2003In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 89, no 7, p. 1221-1227Article in journal (Refereed)
    Abstract [en]

    A substantial excess risk of lymphomas and nonmelanoma skin cancer has been demonstrated following organ transplantation. Large sample size and long follow-up time may, however, allow more accurate risk estimates and detailed understanding of long-term cancer risk. The objective of the study was to assess the risk of cancer following organ transplantation. A nationwide cohort study comprising 5931 patients who underwent transplantation of kidney, liver or other organs during 1970-1997 in Sweden was conducted. Complete follow-up was accomplished through linkage to nationwide databases. We used comparisons with the entire Swedish population to calculate standardised incidence ratios (SIRs), and Poisson regression for multivariate internal analyses of relative risks (RRs) with 95% confidence intervals (CI). Overall, we observed 692 incident first cancers vs 171 expected (SIR 4.0; 95% CI 3.7-4.4). We confirmed marked excesses of nonmelanoma skin cancer (SIR 56.2; 95% CI 49.8-63.2), lip cancer (SIR 53.3; 95% CI 38.0-72.5) and of non-Hodgkin's lymphoma (NHL) (SIR 6.0; 95% CI 4.4-8.0). Compared with patients who underwent kidney transplantation, those who received other organs were at substantially higher risk of NHL (RR 8.4; 95% CI 4.3-16). Besides, we found, significantly, about 20-fold excess risk of cancer of the vulva and vagina, 10-fold of anal cancer, and five-fold of oral cavity and kidney cancer, as well as two- to four-fold excesses of cancer in the oesophagus, stomach, large bowel, urinary bladder, lung and thyroid gland. In conclusion, organ transplantation entails a persistent, about four-fold increased overall cancer risk. The complex pattern of excess risk at many sites challenges current understanding of oncogenic infections that might become activated by immunologic alterations.

  • 4.
    Akre [Fall], Katja
    et al.
    Department of Medical Epidemiology, Karolinska Institutet, Stockholm.
    Ekström, A. M.
    Department of Medical Epidemiology, Karolinska Institutet, Stockholm.
    Signorello, L B
    2International Epidemiology Institute, Rockville, USA.
    Hansson, L.-E.
    Mora Hospital, Mora.
    Nyrén, O.
    Department of Medical Epidemiology, Karolinska Institutet, Stockholm.
    Aspirin and risk for gastric cancer: a population-based case-control study in Sweden2001In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 84, no 7, p. 965-8Article in journal (Refereed)
    Abstract [en]

    While aspirin and other non-steroid anti-inflammatory drugs (NSAIDs) are associated with gastric mucosal damage, they might reduce the risk for gastric cancer. In a population-based case-control study in 5 Swedish counties, we interviewed 567 incident cases of gastric cancer and 1165 controls about their use of pain relievers. The cases were uniformly classified to subsite (cardia/non-cardia) and histological type and information collected on other known risk factors for gastric cancer. Helicobacter pylori serology was tested in a subset of 542 individuals. Users of aspirin had a moderately reduced risk of gastric cancer compared to never users; odds ratio (OR) adjusted for age, gender and socioeconomic status was 0.7 (95% CI = 0.6-1.0). Gastric cancer risk fell with increasing frequency of aspirin use (P for trend = 0.02). The risk reduction was apparent for both cardia and non-cardia tumours but was uncertain for the diffuse histologic type. No clear association was observed between gastric cancer risk and non-aspirin NSAIDs or other studied pain relievers. Our finding lends support to the hypothesis that use of aspirin reduces the risk for gastric cancer.

  • 5. Andersson, Anne
    et al.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Tavelin, B.
    Björkholm, M.
    Linderoth, J.
    Lagerlöf, I.
    Merup, M.
    Sender, M.
    Malmer, B.
    Family history of cancer as a risk factor for second malignancies after Hodgkin's lymphoma2008In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 98, no 5, p. 1001-1005Article in journal (Refereed)
    Abstract [en]

    This study estimated the risk of second primary malignancies after Hodgkin's lymphoma (HL) in relation to family history of cancer, age at diagnosis and latency, among 6946 patients treated for HL in Sweden in 1965-1995 identified through the Swedish Cancer Register (SCR). First-degree relatives (FDRs) to the HL patients and their malignancies were then ascertained together with their malignancies through the Multi-Generation Registry and SCR. The HL patient cohort was stratified on the number of FDRs with cancer, and standardised incidence ratios (SIRs) of developing SM were analysed. In the HL cohort, 781 SM were observed 1 year or longer after HL diagnosis. The risk for developing SM increased with the number of FDRs with cancer, SIRs being 2.26, 3.01, and 3.45 with 0, 1, or >or=2 FDRs with cancer, respectively. Hodgkin's lymphoma long-term survivors treated at a young age with a family history of cancer carry an increased risk for developing SM and may represent a subgroup where standardised screening for the most common cancer sites could be offered in a stringent surveillance programme.

  • 6.
    Andersson, Anne
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Enblad, Gunilla
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Björkholm, Magnus
    Linderoth, Johan
    Lagerlöf, I
    Merup, Mats
    Sender, Mark
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Family history of cancer as a risk factor for second malignancies after Hodgkin's lymphoma2008In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 98, no 5, p. 1001-1005Article in journal (Refereed)
    Abstract [en]

    This study estimated the risk of second primary malignancies after Hodgkin's lymphoma (HL) in relation to family history of cancer, age at diagnosis and latency, among 6946 patients treated for HL in Sweden in 1965–1995 identified through the Swedish Cancer Register (SCR). First-degree relatives (FDRs) to the HL patients and their malignancies were then ascertained together with their malignancies through the Multi-Generation Registry and SCR. The HL patient cohort was stratified on the number of FDRs with cancer, and standardised incidence ratios (SIRs) of developing SM were analysed. In the HL cohort, 781 SM were observed 1 year or longer after HL diagnosis. The risk for developing SM increased with the number of FDRs with cancer, SIRs being 2.26, 3.01, and 3.45 with 0, 1, or ≥2 FDRs with cancer, respectively. Hodgkin's lymphoma long-term survivors treated at a young age with a family history of cancer carry an increased risk for developing SM and may represent a subgroup where standardised screening for the most common cancer sites could be offered in a stringent surveillance programme.

  • 7. Andreyev, HJN
    et al.
    Norman, AR
    Cunningham, D
    Oates, J
    Dix, BR
    Sun, Xiao-Feng
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology.
    Zhang, Hong
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Dermatology.
    Urosevic, N
    Kirsten ras mutations in patients with colorectal cancer: The 'RASCAL II' study2001In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 85, no 5, p. 692-696Article in journal (Refereed)
    Abstract [en]

    Researchers worldwide with information about the Kirsten ras (Ki-ras) tumour genotype and outcome of patients with colorectal cancer were invited to provide that data in a schematized format for inclusion in a collaborative database called RASCAL (The Kirsten ras incolorectal-cancer collaborative group). Our results from 2721 such patients have been presented previously and for the first time in any common cancer, showed conclusively that different gene mutations have different impacts on outcome, even when the mutations occur at the same site on the genome. To explore the effect of Ki-ras mutations at different stages of colorectal cancer, more patients were recruited to the database, which was reanalysed when information on 4268 patients from 42 centres in 21 countries had been entered. After predetermined exclusion criteria were applied, data on 3439 patients were entered into a multivariate analysis. This found that of the 12 possible mutations on codons 12 and 13 of Kirsten ras, only one mutation on codon 12, glycine to valine, found in 8.6% of all patients, had a statistically significant impact on failure-free survival (P=0.004, HR 1.3) and overall survival (P=0.008, HR 1.29). This mutation appeared to have a greater impact on outcome in Dukes' C cancers (failure-free survival, P=0.008, HR 1.5, overall survival P=0.02, HR 1.45) than in Dukes' B tumours (failure-free survival, P=0.46, HR 1.12, overall survival P=0.36, HR 1.15). Ki-ras mutations may occur early in the development of pre-cancerous adenomas in the colon and rectum. However, this collaborative study suggests that not only is the presence of a codon 12 glycine to valine mutation important for cancer progression but also that it may predispose to more aggressive biological behaviour in patients with advanced colorectal cancer. ⌐ 2001 Cancer Research Campaign.

  • 8.
    Andrén, Ove
    et al.
    Örebro University, School of Health and Medical Sciences.
    Fall, Katja
    Andersson, Swen-Olof
    Rubin, Mark A.
    Bismar, Tarek A.
    Karlsson, M.
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Mucci, Lorelei A.
    MUC-1 gene is associated with prostate cancer death: a 20-year follow-up of a population-based study in Sweden2007In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 97, no 6, p. 730-734Article in journal (Refereed)
    Abstract [en]

    Anti-adhesion mucins have proven to play an important part in the biology of several types of cancer. Therefore, we test the hypothesis that altered expression of MUC-1 is associated with prostate cancer progression. We retrieved archival tumour tissue from a population-based cohort of 195 men with localised prostate cancer (T1a-b, Nx, M0) that has been followed for up to 20 years with watchful waiting. Semi-automated, quantitative immunohistochemistry was undertaken to evaluate MUC-1 expression. We modelled prostate cancer-specific death as a function of MUC-1 levels accounting for age, Gleason grade and tumour extent, and calculated age-adjusted and multivariate adjusted hazard ratios (HR). Men that had tumours with an MUC-intensity lower or higher than normal tissue had a higher risk of dying in prostate cancer, independent of tumour extent and Gleason score (HR 5.1 and 4.5, respectively). Adjustment for Gleason grade and tumour stage did not alter the results. Men with a Gleason score >=7 and MUC-1 deviating from the normal had a 17 (RR=17.1 95% confidence interval=2.3–128) times higher risk to die in prostate cancer compared with men with Gleason score <7 and normal MUC-1 intensity. In summary, our data show that MUC-1 is an independent prognostic marker for prostate cancer death.

  • 9. Andrén, Ove
    et al.
    Garmo, H.
    Mucci, L.
    Andersson, Swen-Olof
    Johansson, Jan-Erik
    Örebro University, School of Health and Medical Sciences.
    Fall, Katja
    Incidence and mortality of incidental prostate cancer: a Swedish register-based study2009In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 100, no 1, p. 170-173Article in journal (Refereed)
    Abstract [en]

    In a national register-based study of incidence trends and mortality of incidental prostate cancer in Sweden, we found that a significant proportion (26.6%) of affected men diagnosed died of their disease, which challenges earlier descriptions of incidental prostate cancer as a non-lethal disease.

  • 10. Bamia, C.
    et al.
    Lagiou, P.
    Jenab, M.
    Aleksandrova, K.
    Fedirko, V.
    Trichopoulos, D.
    Overvad, K.
    Tjonneland, A.
    Olsen, A.
    Clavel-Chapelon, F.
    Boutron-Ruault, M-C
    Kvaskoff, M.
    Katzke, V. A.
    Kuehn, T.
    Boeing, H.
    Noethlings, U.
    Palli, D.
    Sieri, S.
    Panico, S.
    Tumino, R.
    Naccarati, A.
    Bueno-de-Mesquita, H. B(As)
    Peeters, P. H. M.
    Weiderpass, E.
    Skeie, G.
    Quiros, J. R.
    Agudo, A.
    Chirlaque, M-D
    Sanchez, M-J
    Ardanaz, E.
    Dorronsoro, M.
    Ericson, U.
    Nilsson, Lena Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Arctic Research Centre at Umeå University.
    Wennberg, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Khaw, K-T
    Wareham, N.
    Key, T. J.
    Travis, R. C.
    Ferrari, P.
    Stepien, M.
    Duarte-Salles, T.
    Norat, T.
    Murphy, N.
    Riboli, E.
    Trichopoulou, A.
    Fruit and vegetable consumption in relation to hepatocellular carcinoma in a multi-centre, European cohort study2015In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 112, no 7, p. 1273-1282Article in journal (Refereed)
    Abstract [en]

    Background:Vegetable and/or fruit intakes in association with hepatocellular carcinoma (HCC) risk have been investigated in case-control studies conducted in specific European countries and cohort studies conducted in Asia, with inconclusive results. No multi-centre European cohort has investigated the indicated associations. Methods: In 486 799 men/women from the European Prospective Investigation into Cancer and nutrition, we identified 201 HCC cases after 11 years median follow-up. We calculated adjusted hazard ratios (HRs) for HCC incidence for sex-specific quintiles and per 100 g d(-1) increments of vegetable/fruit intakes. Results: Higher vegetable intake was associated with a statistically significant, monotonic reduction of HCC risk: HR (100 g d(-1) increment): 0.83; 95% CI: 0.71-0.98. This association was consistent in sensitivity analyses with no apparent heterogeneity across strata of HCC risk factors. Fruit intake was not associated with HCC incidence: HR (100 g d(-1) increment): 1.01; 95% CI: 0.92-1.11. Conclusions: Vegetable, but not fruit, intake is associated with lower HCC risk with no evidence for heterogeneity of this association in strata of important HCC risk factors. Mechanistic studies should clarify pathways underlying this association. Given that HCC prognosis is poor and that vegetables are practically universally accessible, our results may be important, especially for those at high risk for the disease.

  • 11. Barnes, N. L. P.
    et al.
    Wärnberg, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Farnie, G.
    White, D.
    Jiang, W
    Anderson, E.
    Bundred, N. J.
    Cyclooxygenase-2 inhibition: effects on tumour growth, cell cycling and lymphangiogenesis in a xenograft model of breast cancer2007In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 96, no 4, p. 575-582Article in journal (Refereed)
    Abstract [en]

    Cyclooxygenase-2 (COX-2) is associated with poor-prognosis breast cancer. We used a nude mouse xenograft model to determine the effects of COX-2 inhibition in breast cancer. Oestrogen receptor (ER)-positive MCF7/HER2-18 and ER-negative MDAMB231 breast cancer cell lines were injected into nude mice and allowed to form tumours. Mice then received either chow containing Celecoxib (a COX-2 inhibitor) or control and tumour growth measured. Tumour proliferation, apoptosis, COX-2, lymphangiogenesis and angiogenesis were assessed by immunohistochemistry (IHC), Western blotting or Q-PCR. Celecoxib inhibited median tumour growth in MCF7/HER2-18 (58.7%, P=0.029) and MDAMB231 (46.3%, P=0.0002) cell lines compared to control. Cyclooxygenase-2 expression decreased following Celecoxib treatment (MCF7/HER2-18 median control 65.3% vs treated 22.5%, P=0.0001). Celecoxib increased apoptosis in MCF7/HER2-18 tumours (TUNEL 0.52% control vs 0.73% treated, P=0.0004) via inactivation of AKT (median pAKT(ser473) 57.3% control vs 35.5% treated, P=0.0001--confirmed at Western blotting). Q-PCR demonstrated decreased podoplanin RNA (lymphangiogenesis marker) in the MCF7/HER2-18 - median 2.9 copies treated vs 66.6 control (P=0.05) and MDAMB231-treated groups--median 160.7 copies vs 0.05 control copies (P=0.015), confirmed at IHC. Cyclooxygenase-2 is associated with high levels of activated AKT(ser473) and lymphangiogenesis in breast cancer. Cyclooxygenase-2 inhibition decreases tumour growth, and may potentially decrease recurrence, by inactivating AKT and decreasing lymphangiogenesis.

  • 12.
    Bellomo, Claudia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Caja, Laia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Transforming growth factor beta as regulator of cancer stemness and metastasis2016In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 115, no 7, p. 761-769Article, review/survey (Refereed)
    Abstract [en]

    Key elements of cancer progression towards metastasis are the biological actions of cancer stem cells and stromal cells in the tumour microenvironment. Cross-communication between tumour and stromal cells is mediated by secreted cytokines, one of which, the transforming growth factor beta (TGF beta), regulates essentially every cell within the malignant tissue. In this article, we focus on the actions of TGF beta on cancer stem cells, cancer-associated fibroblasts and immune cells that assist the overall process of metastatic dissemination. We aim at illustrating intricate connections made by various cells in the tumour tissue and which depend on the action of TGF beta.

  • 13.
    Bergh, Johanna
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Marklund, Ingrid
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Gustavsson, C
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wiklund, Fredrik
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grönberg, Henrik
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Allard, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Alexeyev, Olog
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    No link between viral findings in the prostate and subsequent cancer development2007In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 96, no 1, p. 137-139Article in journal (Refereed)
    Abstract [en]

    In an investigation of 201 prostate tissue samples from patients with benign prostate hyperplasia that later progressed to prostate cancer and 201 matched controls that did not, there were no differences in the prevalence of adenovirus, herpesvirus, papilloma virus, polyoma virus and Candida albicans DNA.

  • 14.
    Bergman-Jungeström, Malin
    et al.
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Wingren, Sten
    Linköping University, Department of Biomedicine and Surgery, Oncology. Linköping University, Faculty of Health Sciences.
    Catechol-O-Methyltransferase (COMT) gene polymorphism and breast cancer risk in young women2001In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 85, no 6, p. 859-862Article in journal (Refereed)
    Abstract [en]

    Oestrogen exposure has long been considered to be a main risk factor of breast cancer. More recently, interest has also focused on the possible carcinogenic influence from oestrogen metabolites, such as catechol oestrogens. O-methylation, catalysed by Catechol-O-Methyltransferase (COMT), is one pathway by which the potentially carcinogenic catechol oestrogens can be inactivated. The gene coding for COMT protein contains a single-nucleotide polymorphism (SNP), resulting in an amino acid shift Val Met, which has been shown to determine high- and low-activity configuration of the enzyme. We hypothesized that the low-activity allele, COMTMet, may be implicated in early onset breast cancer. In the present case–control study, including 126 young breast cancer patients ( 36 years) and 117 healthy female blood donors, we analysed the association between COMTMet genotype and risk of breast cancer. No significant difference in the frequency of low-/high-activity alleles was found between cases and controls, indicating that the polymorphism, as a single factor, may not contribute to breast carcinogenesis in young women.

  • 15.
    Bergström, A.
    et al.
    Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden.
    Hsieh, C. C.
    Cancer Center, UMass Medical School, Worcester, MA, USA; Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
    Lindblad, Per
    Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden; Department of Urology, Sundsvall Hospital, Sundsvall, Sweden.
    Lu, C. M.
    Cancer Center, UMass Medical School, Worcester, MA, USA; Department of Urology, Tian-Sheng Memorial Hospital, Pingtung, Taiwan.
    Cook, N. R.
    Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA.
    Wolk, A.
    Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden.
    Obesity and renal cell cancer: a quantitative review2001In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 85, no 7, p. 984-990Article in journal (Refereed)
    Abstract [en]

    Obesity has been associated with an increased risk of renal cell cancer among women, while the evidence for men is considered weaker. We conducted a quantitative summary analysis to evaluate the existing evidence that obesity increases the risk of renal cell cancer both among men and women. We identified all studies examining body weight in relation to kidney cancer, available in MEDLINE from 1966 to 1998. The quantitative summary analysis was limited to studies assessing obesity as body mass index (BMI, kg m(-2)), or equivalent. The risk estimates and the confidence intervals were extracted from the individual studies, and a mixed effect weighted regression model was used. We identified 22 unique studies on each sex, and the quantitative analysis included 14 studies on men and women, respectively. The summary relative risk estimate was 1.07 (95% CI 1.05-1.09) per unit of increase in BMI (corresponding to 3 kg body weight increase for a subject of average height). We found no evidence of effect modification by sex. Our quantitative summary shows that increased BMI is equally strongly associated with an increased risk of renal cell cancer among men and women.

  • 16. Bergström, R.
    et al.
    Sparén, Pär
    Södertörn University, Avdelning 4, SCOHOST (Stockholm Centre on Health of Societies in Transition). Karolinska Institute.
    Adami, H. -O
    Trends in cancer of the cervix uteri in Sweden following cytological screening1999In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 81, no 1, p. 159-166Article in journal (Refereed)
    Abstract [en]

    Trends in cervical cancer incidence following the introduction of screening have mostly been studied using cross-sectional data and not analysed separately for squamous cell cancer and adenocarcinomas. Using Swedish nationwide data on incidence and mortality, we analysed trends during more than 3 decades and fitted Poisson-based age-period-cohort models, and also investigated whether screening has reduced the incidence of adenocarcinomas of the cervix. The incidence of reported cancer in situ increased rapidly during 1958-1967. Incidence rates of squamous cell cancer, fairly stable before 1968, decreased thereafter by 4-6% yearly in women aged 40-64, with a much smaller magnitude in younger and older women. An age-cohort model indicated a stable 70-75% reduction in incidence for women born 1940 and later compared with those born around 1923. The incidence of adenocarcinomas doubled during the 35-year study period. The mortality rate increased by 3.6% before 1968 and decreased by 4.0% yearly thereafter. Although a combination of organized and opportunistic screening can reduce the incidence of squamous cell cancer substantially, the incidence of adenocarcinomas appears uninfluenced by screening.

  • 17. Bernhard, J.
    et al.
    Dietrich, D.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Hess, V.
    Bodoky, G.
    Scheithauer, W.
    Herrmann, R.
    Estimating prognosis and palliation based on tumour marker CA 19-9 and quality of life indicators in patients with advanced pancreatic cancer receiving chemotherapy2010In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 103, no 9, p. 1318-1324Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: To investigate the prognostic value of quality of life (QOL) relative to tumour marker carbohydrate antigen (CA) 19-9, and the role of CA 19-9 in estimating palliation in patients with advanced pancreatic cancer receiving chemotherapy. METHODS: CA 19-9 serum concentration was measured at baseline and every 3 weeks in a phase III trial (SAKK 44/00-CECOG/PAN.1.3.001). Patients scored QOL indicators at baseline, and before each administration of chemotherapy (weekly or bi-weekly) for 24 weeks or until progression. Prognostic factors were investigated by Cox models, QOL during chemotherapy by mixed-effect models. RESULTS: Patient-rated pain (P<0.02) and tiredness (P<0.03) were independent predictors for survival, although less prognostic than CA 19-9 (P<0.001). Baseline CA 19-9 did not predict QOL during chemotherapy, except for a marginal effect on pain (P<0.05). Mean changes in physical domains across the whole observation period were marginally correlated with the maximum CA 19-9 decrease. Patients in a better health status reported the most improvement in QOL within 20 days before maximum CA 19-9 decrease. They indicated substantially less pain and better physical well-being, already, early on during chemotherapy with a maximum CA 19-9 decrease of >= 50% vs <50%. CONCLUSION: In advanced pancreatic cancer, pain and tiredness are independent prognostic factors for survival, although less prognostic than CA 19-9. Quality of life improves before best CA 19-9 response but the maximum CA 19-9 decrease has no impact on subsequent QOL. To estimate palliation by chemotherapy, patient's perception needs to be taken into account.

  • 18. Bernsen, MR
    et al.
    Håkansson, Leif
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Gustafsson, Bertil
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Krysander, Lennart
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Plastic Surgery, Hand Surgery and Burns. Östergötlands Läns Landsting, Reconstruction Centre, Department of Plastic Surgery, Hand surgery UHL.
    Rettrup, B
    Ruiter, D
    Håkansson, Annika
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    On the biological relevance of MHC class II and B7 expression by tumour cells in melanoma metastases2003In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 88, no 3, p. 424-431Article in journal (Refereed)
    Abstract [en]

    A large number of studies have indicated that specific immune reactivity plays a crucial role in the control of malignant melanoma. In this context, expression of MHC I, MHC II and B7 molecules by melanoma cells is seen as relevant for the immune response against the tumour. For a better understanding of the biological relevance of MHC II and B7 expression by tumour cells in metastatic melanoma, we studied the expression of these molecules in melanoma metastases in relation to the inflammatory response, regression of the tumour and survival from 27 patients treated with biochemotherapy (30 mg m-2 Cisplatin and 250 mg m-2 decarbazine (dimethyl-triazene-imidazole-carboxamide, DTIC) on days 1-3 i.v., and 107 IU IFN-a2b 3 days a week s.c., q. 28d). In 19 out of 27 lesions studied, we found expression of MHC II by the tumour cells, while only in one out of II tumour biopsies obtained from untreated metastatic melanoma patients, MHC II expression was detected. Expression of B7.1 and B7.2 by tumour cells was found in nine out of 24 and 19 out of 24 lesions, respectively. In all cases where B7.1 expression was found, expression of B7.2 by the tumour cells was also seen. In general, no or only few inflammatory cells positive for B7 were found. Expression of MHC II by tumour cells was positively correlated with the presence of tumour-infiltrating lymphocytes, regression of the lesion, and with time to progression (TTP) and overall survival (OS) of the patient. However, no significant correlation between B7.1 or B7.2 expression and regression of the tumour, TTP or OS was found. In light of other recent findings, these data altogether do support a role as biomarker for MHC II expression by tumour cells, however, its exact immunological pathomechanism(s) remain to be established. ⌐ 2003 Cancer Research UK.

  • 19. Besevic, Jelena
    et al.
    Gunter, Marc J.
    Fortner, Renee T.
    Tsilidis, Konstantinos K.
    Weiderpass, Elisabete
    Onland-Moret, N. Charlotte
    Dossus, Laure
    Tjonneland, Anne
    Hansen, Louise
    Overvad, Kim
    Mesrine, Sylvie
    Baglietto, Laura
    Clavel-Chapelon, Francoise
    Kaaks, Rudolf
    Aleksandrova, Krasimira
    Boeing, Heiner
    Trichopoulou, Antonia
    Lagiou, Pagona
    Bamia, Christina
    Masala, Giovanna
    Agnoli, Claudia
    Tumino, Rosario
    Ricceri, Fulvio
    Panico, Salvatore
    Bueno-de-Mesquita, H. B. (as)
    Peeters, Petra H.
    Jareid, Mie
    Ramon Quiros, J.
    Duell, Eric J.
    Sanchez, Maria-Jose
    Larranaga, Nerea
    Chirlaque, Maria-Dolores
    Barricarte, Aurelio
    Dias, Joana A.
    Sonestedt, Emily
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wareham, Nicholas J.
    Khaw, Kay-Tee
    Travis, Ruth C.
    Rinaldi, Sabina
    Romieu, Isabelle
    Riboli, Elio
    Merritt, Melissa A.
    Reproductive factors and epithelial ovarian cancer survival in the EPIC cohort study2015In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 113, no 11, p. 1622-1631Article in journal (Refereed)
    Abstract [en]

    Background: Reproductive factors influence the risk of developing epithelial ovarian cancer (EOC), but little is known about their association with survival. We tested whether prediagnostic reproductive factors influenced EOC-specific survival among 1025 invasive EOC cases identified in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, which included 521 330 total participants (approximately 370 000 women) aged 25-70 years at recruitment from 1992 to 2000. Methods: Information on reproductive characteristics was collected at recruitment. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), and multivariable models were adjusted for age and year of diagnosis, body mass index, tumour stage, smoking status and stratified by study centre. Results: After a mean follow-up of 3.6 years (+/- 3.2 s.d.) following EOC diagnosis, 511 (49.9%) of the 1025 women died from EOC. We observed a suggestive survival advantage in menopausal hormone therapy (MHT) users (ever vs never use, HR = 0.80, 95% CI = 0.62-1.03) and a significant survival benefit in long-term MHT users (>= 5 years use vs never use, HR = 0.70, 95% CI = 0.50-0.99, P-trend = 0.04). We observed similar results for MHT use when restricting to serous cases. Other reproductive factors, including parity, breastfeeding, oral contraceptive use and age at menarche or menopause, were not associated with EOC-specific mortality risk. Conclusions: Further studies are warranted to investigate the possible improvement in EOC survival in MHT users.

  • 20.
    Beskow, C
    et al.
    Department of Gynaecologic Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden..
    Kanter, L
    Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden.
    Holgersson, A
    Unit of Medical Radiation Biology, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
    Nilsson, B
    Department of Oncology and Pathology, Karolinska University Hospital, Stockholm, Sweden..
    Frankendal, B
    Department of Gynaecologic Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden..
    Åvall-Lundqvist, Elisabeth
    Department of Gynaecologic Oncology, Radiumhemmet, Karolinska University Hospital, Stockholm, Sweden..
    Lewensohn, R
    Unit of Medical Radiation Biology, Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
    Expression of DNA damage response proteins and complete remission after radiotherapy of stage IB-IIA of cervical cancer.2006In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 94, no 11, p. 1683-1689Article in journal (Refereed)
    Abstract [en]

    The primary aim of this study was to investigate if the expression of the DNA damage identifying protein DNA-PKcs known to be involved in DNA repair after treatment with ionising radiation can be used as a predictive marker for radiotherapy (RT) response in cervical cancer. Formalin-fixed primary tumour biopsies from 109 patients with cervical cancer, FIGO-stage IB-IIA, treated with preoperative brachytherapy followed by radical surgery were analysed by immunohistochemistry. In addition, correlation studies between early pathological tumour response to radiation and expression of Ku86, Ku70, Mdm-2, p53 and p21 in primary tumours were also performed. We found that tumour-transformed tissue shows positive immunostaining of DNA-PKcs, Ku86 and Ku70, while non-neoplastic squamous epithelium and tumour-free cervix glands show negative immunoreactivity. Expression of DNA-PKcs positively correlated with both Ku86 and Ku70, and a statistically significant correlation between the Ku subunits was also found. After RT, 85 patients demonstrated pathologic complete remission (pCR), whereas 24 patients had residual tumour in the surgical specimen (non-pCR). The main finding of our study is that there was no correlation between the outcome of RT and the expression of DNA-PK subunits. Positive p53 tumours were significantly more common among non-pCR cases than in patients with pCR (P=0.031). Expression of p21 and Mdm-2 did not correlate with the outcome of RT.

  • 21. Birringer, M
    et al.
    EyTina, J H
    Salvatore, B A
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    Vitamin E analogues as inducers of apoptosis: Structure-function relation2003In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 88, no 12, p. 1948-1955Article in journal (Refereed)
    Abstract [en]

    Recent results show that a-tocopheryl succinate (a-TOS) is a proapoptotic agent with antineoplastic activity. As modifications of the vitamin E (VE) molecule may affect its apoptogenic activity, we tested a number of newly synthesised VE analogues using malignant cell lines. Analogues of a-TOS with lower number of methyl substitutions on the aromatic ring were less active than a-TOS. Replacement of the succinyl group with a maleyl group greatly enhanced the activity, while it was lower for the glutaryl esters. Methylation of the free succinyl carboxyl group on a-TOS and d-TOS completely prevented the apoptogenic activity of the parent compounds. Both Trolox and its succinylated derivative were inactive. a-tocotrienol (a-T3 H) failed to induce apoptosis, while ?-T3 H was apoptogenic, and more so when succinylated. Shortening the aliphatic side chain of ?-T3 by one isoprenyl unit increased its activity. Neither phytyl nor oleyl succinate caused apoptosis. These findings show that modifications of different functional moieties of the VE molecule can enhance apoptogenic activity. It is hoped that these observations will lead to the synthesis of analogues with even higher apoptogenic and, consequently, antineoplastic efficacy.

  • 22. Bjellerup, P
    et al.
    Theodorsson, Elvar
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Clinical Chemistry. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Chemistry.
    Jörnvall, H
    Kogner, P
    Limited neuropeptide Y precursor processing in unfavourable metastatic neuroblastoma tumours2000In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 83, no 2, p. 171-176Article in journal (Refereed)
    Abstract [en]

    Neuropeptide Y (NPY) is found at high concentrations in neural crest-derived tumours and has been implicated as a regulatory peptide in tumour growth and differentiation. Neuroblastomas, ganglioneuromas and phaeochromocytomas with significant concentrations of NPY-like immunoreactivity were investigated for different molecular forms of NPY and for significance of proNPY processing. Gel-permeation chromatography identified intact NPY (1-36) in all tumours, whereas proNPY (69 amino acids) was detected only in control adrenal tissue and malignant neuroblastomas. Purification of NPY-like immunoreactivity in tumour extracts and structural characterization revealed that both NPY (1-36) and the truncated form NPY (3-36) was present. The degree of processing of proNPY to NPY in tumour tissue was lower in advanced neuroblastomas with regional or metastatic spread (stage 3 and 4) (n = 6), (41%, 12-100%, median, range), compared to the less aggressive stage 1, 2 and 4S tumours (n = 12), (93%, 69-100%), (P = 0.012). ProNPY processing of less than 50% was correlated with poor clinical outcome (P = 0.004). MYCN oncogene amplification was also correlated to a low degree of proNPY processing (P = 0.025). In summary, a low degree of proNPY processing was correlated to clinical advanced stage and poor outcome in neuroblastomas. ProNPY/NPY processing generated molecular forms of NPY with known differences in NPY-receptor selectivity, implicating a potential for in vivo modulation of NPY-like effects in tumour tissue. (C) 2000 Cancer Research Campaign.

  • 23.
    Bjørge, Tone
    et al.
    Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway.;Canc Registry Norway, Oslo, Norway..
    Gissler, Mika
    Natl Inst Hlth & Welf THL, Helsinki, Finland..
    Ording, Anne Gulbech
    Aarhus Univ Hosp, Dept Clin Epidemiol, Aarhus, Denmark..
    Engeland, Anders
    Univ Bergen, Dept Global Publ Hlth & Primary Care, Bergen, Norway.;Norwegian Inst Publ Hlth, Dept Pharmacoepidemiol, Div Mental & Phys Hlth, Bergen, Norway..
    Glimelius, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Leinonen, Maarit
    Finnish Canc Registry, Canc Soc Finland, Helsinki, Finland..
    Sørensen, Henrik Toft
    Aarhus Univ Hosp, Dept Clin Epidemiol, Aarhus, Denmark..
    Tretli, Steinar
    Canc Registry Norway, Oslo, Norway..
    Ekbom, Anders
    Karolinska Inst, Clin Epidemiol Unit, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Stockholm, Sweden..
    Troisi, Rebecca
    NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD USA..
    Grotmol, Tom
    Canc Registry Norway, Oslo, Norway..
    Reproductive history and risk of colorectal adenocarcinoma in parous women: a Nordic population-based case-control study2016In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 115, no 11, p. 1416-1420Article in journal (Refereed)
    Abstract [en]

    Background: Data are conflicting regarding the role of endogenous sex hormones in colorectal carcinogenesis. In this large population-based study, we pooled data from birth and cancer registries in four Nordic countries, to evaluate the risk of colorectal adenocarcinoma in relation to women's reproductive history. Methods: We conducted a population-based case-control study among women registered in Nordic birth registries. The study included colorectal adenocarcinoma cases diagnosed in Denmark, Finland, Norway, and Sweden during 1967-2013 and up to 10 matched controls per case, in total 22 185 cases and 220 246 controls. Odds ratios (ORs) with 95% confidence intervals (95% CIs) were derived from conditional logistic regression models. We had limited information available on possible confounders. Results: We found no evidence for associations between colorectal adenocarcinoma and parity, age at first and last birth, and time since first and last birth. The risk estimates were also close to unity for specific cancer subsites (proximal and distal colon and rectum). As well, when the analyses were stratified on menopausal status, parity, and mother's year of birth, no indication of associations was found. Conclusions: In this large, Nordic population-based study, no evidence for associations was found between women's reproductive history and colorectal adenocarcinoma in parous women.

  • 24.
    Bogdanovic, G
    et al.
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Pou, C
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Barrientos-Somarribas, M
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Bjerkner, A
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Honkaniemi, E
    Department of Pediatrics, Södertälje Hospital, Stockholm, Swden.
    Allander, T
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Andersson, B
    Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden.
    Gustafsson, B
    Department of Clinical Science, Intervention and Technology, CLINTEC, Karolinska Institutet, Stokholm, Sweden.
    Virome characterisation from Guthrie cards in children who later developed acute lymphoblastic leukaemia.2016In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 115, no 8, p. 1008-1014Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Some childhood acute lymphoblastic leukaemias (ALL) can be traced back to a prenatal origin, where a virus infection could be involved in the first pre-leukaemic clone development. The DNA virome of 95 children who later developed ALL was characterised from neonatal blood spots (NBS) using unbiased next-generation sequencing (NGS) and compared with the virome of 95 non-ALL controls.

    METHODS: DNA was individually extracted from the ALL-patients and controls, pooled, randomly amplified and sequenced using the Illumina MiSeq Sequencing System.

    RESULTS: Virus-like sequences identified in both groups mapped to human endogenous retroviruses and propionibacterium phage, considered a part of the normal microbial flora. Potential pathogens human herpesvirus type 6 (HHV-6) and parvovirus B19 were also identified, but only few samples in both ALL and controls tested positive by PCR follow-up.

    CONCLUSIONS: Unbiased NGS was employed to search for DNA from potential infectious agents in neonatal samples of children who later developed ALL. Although several viral candidates were identified in the NBS samples, further investigation by PCR suggested that these viruses did not have a major role in ALL development.

  • 25. Boldrup, L.
    et al.
    Coates, P. J.
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Wilms, T.
    Fahraeus, R.
    Nylander, K.
    Downregulation of miRNA-424: a sign of field cancerisation in clinically normal tongue adjacent to squamous cell carcinoma2015In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 112, no 11, p. 1760-1765Article in journal (Refereed)
    Abstract [en]

    Background: The overall survival for patients with squamous cell carcinoma of the tongue is low and the search for early diagnostic and prognostic markers is thus essential. MicroRNAs have been suggested as potential prognostic and diagnostic candidates in squamous cell carcinoma of head and neck in general. Methods: On the basis of the known differences between sub-sites within the oral cavity, we investigated the expression and role of microRNA-424 in squamous cell carcinoma arising in tongue. MicroRNA levels were measured by qRT-PCR in both tissue and plasma samples. Results: Levels of microRNA-424 were upregulated in tongue squamous cell carcinoma, but not in tumours originating from gingiva or floor of the mouth. Interestingly, microRNA-424 was downregulated in clinically normal tongue tissue next to tumour compared with completely healthy tongue, indicating that microRNA-424 could be a marker of field cancerisation in this tumour type. However, expression of microRNA-424 in a tongue-derived epithelial cell line revealed no significant changes in the expression profile of proteins and genes. Conclusions: Our patient data show that microRNA-424 alterations are a marker of field cancerisation specific for tongue tumourigenesis, which also could have a role in development of tongue squamous cell carcinoma.

  • 26.
    Boldrup, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Coates, P J
    Laurell, G
    Wilms, Torben
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Fahraeus, R
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Downregulation of miRNA-424: a sign of field cancerisation in clinically normal tongue adjacent to squamous cell carcinoma2015In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 112, no 11, p. 1760-1765Article in journal (Refereed)
    Abstract [en]

    Background: The overall survival for patients with squamous cell carcinoma of the tongue is low and the search for early diagnostic and prognostic markers is thus essential. MicroRNAs have been suggested as potential prognostic and diagnostic candidates in squamous cell carcinoma of head and neck in general. Methods: On the basis of the known differences between sub-sites within the oral cavity, we investigated the expression and role of microRNA-424 in squamous cell carcinoma arising in tongue. MicroRNA levels were measured by qRT-PCR in both tissue and plasma samples. Results: Levels of microRNA-424 were upregulated in tongue squamous cell carcinoma, but not in tumours originating from gingiva or floor of the mouth. Interestingly, microRNA-424 was downregulated in clinically normal tongue tissue next to tumour compared with completely healthy tongue, indicating that microRNA-424 could be a marker of field cancerisation in this tumour type. However, expression of microRNA-424 in a tongue-derived epithelial cell line revealed no significant changes in the expression profile of proteins and genes. Conclusions: Our patient data show that microRNA-424 alterations are a marker of field cancerisation specific for tongue tumourigenesis, which also could have a role in development of tongue squamous cell carcinoma.

  • 27. Boman, K.
    et al.
    Larsson, A. H.
    Segersten, U.
    Kuteeva, E.
    Johannesson, H.
    Nodin, B.
    Eberhard, J.
    Uhlén, Mathias
    KTH, School of Biotechnology (BIO), Proteomics and Nanobiotechnology. KTH, Centres, Science for Life Laboratory, SciLifeLab.
    Malmström, P-U
    Jirström, K.
    Membranous expression of podocalyxin-like protein is an independent factor of poor prognosis in urothelial bladder cancer2013In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 108, no 11, p. 2321-2328Article in journal (Refereed)
    Abstract [en]

    Background: Membranous expression of the anti-adhesive glycoprotein podocalyxin-like (PODXL) has previously been found to correlate with poor prognosis in several major cancer forms. Here we examined the prognostic impact of PODXL expression in urothelial bladder cancer. Methods: Immunohistochemical PODXL expression was examined in tissue microarrays with tumours from two independent cohorts of patients with urothelial bladder cancer: n = 100 (Cohort I) and n = 343 (Cohort II). The impact of PODXL expression on disease-specific survival (DSS; Cohort II), 5-year overall survival (OS; both cohorts) and 2-year progression-free survival (PFS; Cohort II) was assessed. Results: Membranous PODXL expression was significantly associated with more advanced tumour (T) stage and high-grade tumours in both cohorts, and a significantly reduced 5-year OS (unadjusted HR = 2.25 in Cohort I and 3.10 in Cohort II, adjusted HR = 2.05 in Cohort I and 2.18 in Cohort II) and DSS (unadjusted HR = 4.36, adjusted HR = 2.70). In patients with Ta and T1 tumours, membranous PODXL expression was an independent predictor of a reduced 2-year PFS (unadjusted HR = 6.19, adjusted HR = 4.60) and DSS (unadjusted HR = 8.34, adjusted HR = 7.16). Conclusion: Membranous PODXL expression is an independent risk factor for progressive disease and death in patients with urothelial bladder cancer.

  • 28. Boman, K
    et al.
    Larsson, A H
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Kuteeva, E
    Johannesson, H
    Nodin, B
    Eberhard, J
    Uhlén, M
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Jirström, K
    Membranous expression of podocalyxin-like protein is an independent factor of poor prognosis in urothelial bladder cancer2013In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 108, p. 2321-2328Article in journal (Refereed)
    Abstract [en]

    Background:

    Membranous expression of the anti-adhesive glycoprotein podocalyxin-like (PODXL) has previously been found to correlate with poor prognosis in several major cancer forms. Here we examined the prognostic impact of PODXL expression in urothelial bladder cancer.

    Methods:

    Immunohistochemical PODXL expression was examined in tissue microarrays with tumours from two independent cohorts of patients with urothelial bladder cancer: n=100 (Cohort I) and n=343 (Cohort II). The impact of PODXL expression on disease-specific survival (DSS; Cohort II), 5-year overall survival (OS; both cohorts) and 2-year progression-free survival (PFS; Cohort II) was assessed.

    Results:

    Membranous PODXL expression was significantly associated with more advanced tumour (T) stage and high-grade tumours in both cohorts, and a significantly reduced 5-year OS (unadjusted HR=2.25 in Cohort I and 3.10 in Cohort II, adjusted HR=2.05 in Cohort I and 2.18 in Cohort II) and DSS (unadjusted HR=4.36, adjusted HR=2.70). In patients with Ta and T1 tumours, membranous PODXL expression was an independent predictor of a reduced 2-year PFS (unadjusted HR=6.19, adjusted HR=4.60) and DSS (unadjusted HR=8.34, adjusted HR=7.16).

    Conclusion:

    Membranous PODXL expression is an independent risk factor for progressive disease and death in patients with urothelial bladder cancer.

  • 29. Borg, A
    et al.
    Lennerstrand, Johan
    AB Sangtec Medical.
    Stenmark-Askmalm, M
    Fernö, M
    Brisfors, A
    Ohrvik, A
    Stål, O
    Killander, D
    Lane, D
    Brundell, J
    Prognostic significance of p53 overexpression in primary breast cancer: a novel luminometric immunoassay applicable on steroid receptor cytosols.1995In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 71, no 5, p. 1013-1017Article in journal (Refereed)
    Abstract [en]

    A novel quantitative luminometric immunoassay (LIA) has been developed for the measurement of wild-type and mutant p53 protein in extracts from breast tumour tissue. The LIA was found to yield reliable estimates of p53 expression in cytosol samples routinely prepared for steroid receptor analysis as compared with results obtained with immunohistochemical analysis. The LIA was evaluated on 205 primary breast tumour cytosols prepared for steroid receptor analysis and stored frozen at -80 degrees C for 6-8 years, p53 protein being detected in 65% of the samples (range 0.01-23 ng mg-1 protein). Using an arbitrary cut-off value of 0.15 ng mg-1 protein, 30% of the tumours were classified as manifesting p53 overexpression. Significant and independent correlations were found to exist between p53 overexpression and shorter disease-free (P < 0.001) and overall survival (P = 0.039) at a median duration of follow-up of 50 months. p53 overexpression was related to low oestrogen receptor content and high proliferation rate (S-phase fraction). No relationship was found to tumour size or the presence of lymph node metastasis. Three tumours possessed an extremely high p53 content (> 10 ng mg-1 protein), all of which were of medullary or high-grade ductal type, oestrogen and progesterone receptor negative, DNA non-diploid, had S-phase fractions of > 22% and recurred within 1-2 years. In summary, a new sensitive and quantitative LIA suitable for routine analysis of p53 protein in steroid receptor cytosol preparations from breast tumours has been developed to confirm the prognostic importance of p53 protein accumulation in human breast cancer.

  • 30. Bratt, O.
    et al.
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Ahlgren, G.
    Nordle, O.
    Björk, A.
    Damber, Jan-Erik
    Open-label, clinical phase I studies of tasquinimod in patients with castration-resistant prostate cancer2009In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 101, no 8, p. 1233-40Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Tasquinimod is a quinoline-3-carboxamide derivative with anti-angiogenic activity. Two open-label phase I clinical trials in patients were conducted to evaluate the safety and tolerability of tasquinimod, with additional pharmacokinetic and efficacy assessments. METHODS: Patients with castration-resistant prostate cancer with no previous chemotherapy were enrolled in this study. The patients received tasquinimod up to 1 year either at fixed doses of 0.5 or 1.0 mg per day or at an initial dose of 0.25 mg per day that escalated to 1.0 mg per day. RESULTS: A total of 32 patients were enrolled; 21 patients were maintained for >or=4 months. The maximum tolerated dose was determined to be 0.5 mg per day; but when using stepwise intra-patient dose escalation, a dose of 1.0 mg per day was well tolerated. The dose-limiting toxicity was sinus tachycardia and asymptomatic elevation in amylase. Common treatment-emergent adverse events included transient laboratory abnormalities, anaemia, nausea, fatigue, myalgia and pain. A serum prostate-specific antigen (PSA) decline of >or=50% was noted in two patients. The median time to PSA progression (>25%) was 19 weeks. Only 3 out of 15 patients (median time on study: 34 weeks) developed new bone lesions. CONCLUSION: Long-term continuous oral administration of tasquinimod seems to be safe, and the overall efficacy results indicate that tasquinimod might delay disease progression.

  • 31. Brismar-Wendel, S
    et al.
    Fröberg, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Centre for Clinical Research, County of Västmanland.
    Hjerpe, A
    Andersson, S
    Johansson, B
    Age-specific prevalence of HPV genotypes in cervical cytology samples with equivocal or low-grade lesions2009In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 101, no 3, p. 511-517Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: To define the spectrum of human papillomavirus (HPV) types and establish an age limit for triage HPV testing in atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL). MATERIALS AND METHODS: 343 liquid-based cytological samples from the population-based screening programme with minor abnormalities were subjected to HPV genotyping (Linear Array, Roche, Basel, Switzerland). RESULTS: High-risk human papillomavirus (HR-HPV) was found in 71% of LSIL and 49% of ASCUS cases (P<0.001). High-risk human papillomavirus prevalence was age-dependent in LSIL (P = 0.01), with decreasing prevalence until the age of 50 years, followed by a slight increase. Human papillomavirus type 16 was the most common HR-HPV, found in 23% of HPV-positive women. Human papillomavirus type 18 was the sixth most common, found in 9.9% (P<0.001). An age-dependent quadratic trend was observed for multiple infections (P=0.01) with a trough at about 42 years. The most common HR-HPV types to show a coinfection with HPV16 (clade 9) were HPV39 (28%), 45 (38%), and 59 (46%), belonging to HPV18 clade 7. The frequency of low-risk (LR) vs probable HR and HR-HPV also followed an age-dependent quadratic trend. CONCLUSIONS: After the age of 25 years, HR-HPV prevalence is similar in LSIL and ASCUS cases, motivating a low age limit for triage HPV testing. Multiple infections and LR/HR-HPV dominance are age-dependent. Genotyping in longitudinal design is needed to elucidate the importance of multiple infections in cancer progression and in cross-protection from vaccination. British Journal of Cancer (2009) 101, 511-517. doi:10.1038/sj.bjc.6605165 www.bjcancer.com Published online 21 July 2009 (C) 2009 Cancer Research UK

  • 32.
    Brodin, Bertha A.
    et al.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
    Wennerberg, Krister
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland; Univ Copenhagen, BRIC, Copenhagen, Denmark.
    Lidbrink, Elisabet
    Karolinska Univ Hosp, Dept Breast Canc Endocrine Tumors & Sarcoma, Stockholm, Sweden.
    Brosjö, Otte
    Karolinska Univ Hosp, Dept Tumor Orthoped, Stockholm, Sweden.
    Potdar, Swapnil
    Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland.
    Wilson, Jennifer N.
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
    Ma, Limin
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
    Moens, Lotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Hesla, Asle
    Karolinska Univ Hosp, Dept Tumor Orthoped, Stockholm, Sweden.
    Porovic, Edvin
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
    Bernhardsson, Edvin
    Karolinska Inst, Dept Microbiol Tumor & Cell Biol MTC, Stockholm, Sweden.
    Papakonstantinou, Antroula
    Karolinska Univ Hosp, Dept Breast Canc Endocrine Tumors & Sarcoma, Stockholm, Sweden; Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.
    Bauer, Henrik
    Karolinska Univ Hosp, Dept Tumor Orthoped, Stockholm, Sweden.
    Tsagkozis, Panagiotis
    Karolinska Univ Hosp, Dept Tumor Orthoped, Stockholm, Sweden; Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.
    von Sivers, Karin
    Karolinska Univ Hosp, Dept Radiol, Stockholm, Sweden.
    Wejde, Johan
    Karolinska Univ Hosp, Dept Cytol & Pathol, Stockholm, Sweden.
    Ostling, Paivi
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.
    Kallioniemi, Olli
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.
    Stragliotto, Christina Linder
    Karolinska Univ Hosp, Dept Breast Canc Endocrine Tumors & Sarcoma, Stockholm, Sweden.
    Drug sensitivity testing on patient-derived sarcoma cells predicts patient response to treatment and identifies c-Sarc inhibitors as active drugs for translocation sarcomas2019In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 120, no 4, p. 435-443Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Heterogeneity and low incidence comprise the biggest challenge in sarcoma diagnosis and treatment. Chemotherapy, although efficient for some sarcoma subtypes, generally results in poor clinical responses and is mostly recommended for advanced disease. Specific genomic aberrations have been identified in some sarcoma subtypes but few of them can be targeted with approved drugs. METHODS: We cultured and characterised patient-derived sarcoma cells and evaluated their sensitivity to 525 anti-cancer agents including both approved and non-approved drugs. In total, 14 sarcomas and 5 healthy mesenchymal primary cell cultures were studied. The sarcoma biopsies and derived cells were characterised by gene panel sequencing, cancer driver gene expression and by detecting specific fusion oncoproteins in situ in sarcomas with translocations. RESULTS: Soft tissue sarcoma cultures were established from patient biopsies with a success rate of 58%. The genomic profile and drug sensitivity testing on these samples helped to identify targeted inhibitors active on sarcomas. The cSrc inhibitor Dasatinib was identified as an active drug in sarcomas carrying chromosomal translocations. The drug sensitivity of the patient sarcoma cells ex vivo correlated with the response to the former treatment of the patient. CONCLUSIONS: Our results show that patient-derived sarcoma cells cultured in vitro are relevant and practical models for genotypic and phenotypic screens aiming to identify efficient drugs to treat sarcoma patients with poor treatment options.

  • 33. Brooks, D. R.
    et al.
    Klint, Å.
    Dickman, P. W.
    Ståhle, Elisabeth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Thoracic Surgery.
    Lambe, M.
    Temporal trends in non-small cell lung cancer survival in Sweden2007In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 96, no 3, p. 519-522Article in journal (Refereed)
    Abstract [en]

    We modeled temporal trends in the 1- and 5-year survival of 32 499 patients with adenocarcinoma and squamous cell carcinoma of the lung in the Swedish Cancer Register between 1961 and 2000. The 1-year relative survival for adenocarcinoma improved from 37% for patients diagnosed 1961–1965 to 45% for those diagnosed 1996–2000 and from 39 to 45% for squamous cell carcinoma. The adjusted excess mortality ratios for the period 1996–2000 compared with 1961–1965 were 0.80 for adenocarcinoma and 0.81 for squamous cell carcinoma. Thus, a previous report in a Dutch study of a relatively worsening prognosis for adenocarcinoma over time could not be confirmed.

  • 34.
    Carlsson, Jörgen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Nordgren, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Sjöström, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Wester, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Villman, K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Bengtsson, N. O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ostenstad, B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Blomqvist, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    HER2 expression in breast cancer primary tumours and corresponding metastases: Original data and literature review2004In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 90, no 12, p. 2344-2348Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to evaluate whether the HER2 expression in breast cancer is retained in metastases. The HER2 expression in primary tumours and the corresponding lymph node metastases were evaluated in parallel samples from 47 patients. The HercepTest was used for immunohistochemical analyses of HER2 overexpression in all cases. CISH/FISH was used for analysis of gene amplification in some cases. HER2 overexpression (HER2-scores 2+ or 3+) was found in 55% of both the primary tumours and of the lymph node metastases. There were only small changes in the HER2-scores; six from 1+ to 0 and one from 3+ to 2+ when the metastases were compared to the corresponding primary tumours. However, there were no cases with drastic changes in HER2 expression between the primary tumours and the corresponding lymph node metastases. The literature was reviewed for similar investigations, and it is concluded that breast cancer lymph node metastases generally overexpress HER2 to the same extent as the corresponding primary tumours. This also seems to be the case when distant metastases are considered. It has been noted that not all patients with HER2 overexpression respond to HER2-targeted Trastuzumab treatment. The stability in HER2 expression is encouraging for efforts to develop complementary forms of therapy, for example, therapy with radionuclide-labelled Trastuzumab.

  • 35.
    Cavalli-Björkman, Nina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Qvortrup, Camilla
    Sebjørnssen, Sigrunn
    Pfeiffer, Per
    Wentzel-Larsen, Tore
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Sorbye, Halfdan
    Lower treatment intensity and poorer survival in metastatic colorectal cancer patients who live alone2012In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 107, no 1, p. 189-194Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Socioeconomic status (SES) and social support influences cancer survival. If SES and social support affects cancer treatment has not been thoroughly explored. METHODS: A cohort consisting of all patients who were initially diagnosed with or who developed metastatic colorectal cancer (mCRC, n = 781) in three Scandinavian university hospitals from October 2003 to August 2006 was set up. Clinical and socioeconomic data were registered prospectively. RESULTS: Patients living alone more often had synchronous metastases at presentation and were less often treated with combination chemotherapy than those cohabitating (HR 0.19, 95% CI 0.04-0.85, P = 0.03). Surgical removal of metastases was less common in patients living alone (HR 0.29, 95% CI 0.10-0.86, P = 0.02) but more common among university-educated patients (HR 2.22, 95% CI 1.10-4.49, P = 0.02). Smoking, being married and having children did not influence treatment or survival. Median survival was 7.7 months in patients living alone and 11.7 months in patients living with someone (P < 0.001). Living alone remained a prognostic factor for survival after correction for age and comorbidity. CONCLUSION: Patients living alone received less combination chemotherapy and less secondary surgery. Living alone is a strong independent risk factor for poor survival in mCRC. 

  • 36.
    Charitou, Theodosia
    et al.
    South Australian Hlth & Med Res Inst, EMBL Australia Grp, Adelaide, SA 5000, Australia..
    Srihari, Sriganesh
    South Australian Hlth & Med Res Inst, EMBL Australia Grp, Adelaide, SA 5000, Australia..
    Lynn, Miriam A.
    South Australian Hlth & Med Res Inst, EMBL Australia Grp, Adelaide, SA 5000, Australia..
    Jarboui, Mohamed-Ali
    Univ Tubingen, Inst Ophthalm Res, Tubingen, Germany.;Univ Tubingen, Werner Siemens Imaging Ctr, Tubingen, Germany..
    Fasterius, Erik
    KTH, School of Engineering Sciences in Chemistry, Biotechnology and Health (CBH), Protein Science, Systems Biology.
    Moldovan, Max
    South Australian Hlth & Med Res Inst, EMBL Australia Grp, Adelaide, SA 5000, Australia..
    Shirasawa, Senji
    Fukuoka Univ, Fac Med, Fukuoka, Fukuoka 8140133, Japan..
    Tsunoda, Toshiyuki
    Fukuoka Univ, Fac Med, Fukuoka, Fukuoka 8140133, Japan..
    Ueffing, Marius
    Univ Tubingen, Inst Ophthalm Res, Tubingen, Germany..
    Xie, Jianling
    South Australian Hlth & Med Res Inst, Nutr Diabet & Metab, Adelaide, SA 5000, Australia..
    Xin, Jin
    South Australian Hlth & Med Res Inst, Nutr Diabet & Metab, Adelaide, SA 5000, Australia..
    Wang, Xuemin
    South Australian Hlth & Med Res Inst, Nutr Diabet & Metab, Adelaide, SA 5000, Australia.;Univ Adelaide, Sch Biol Sci, Adelaide, SA 5000, Australia..
    Proud, Christopher G.
    South Australian Hlth & Med Res Inst, Nutr Diabet & Metab, Adelaide, SA 5000, Australia.;Univ Adelaide, Sch Biol Sci, Adelaide, SA 5000, Australia..
    Boldt, Karsten
    Univ Tubingen, Inst Ophthalm Res, Tubingen, Germany..
    Al-Khalili Szigyarto, Cristina
    KTH, Superseded Departments (pre-2005), Biotechnology.
    Kolch, Walter
    Univ Coll Dublin, Syst Biol Ireland, Dublin, Ireland.;Univ Coll Dublin, Sch Med, Dublin, Ireland.;Univ Coll Dublin, Conway Inst, Dublin, Ireland..
    Lynn, David J.
    South Australian Hlth & Med Res Inst, EMBL Australia Grp, Adelaide, SA 5000, Australia.;Flinders Univ S Australia, Coll Med & Publ Hlth, Sch Med, Bedford Pk, SA 5042, Australia..
    Transcriptional and metabolic rewiring of colorectal cancer cells expressing the oncogenic KRAS(G13D) mutation2019In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 121, no 1, p. 37-50Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Activating mutations in KRAS frequently occur in colorectal cancer (CRC) patients, leading to resistance to EGFRtargeted therapies. METHODS: To better understand the cellular reprogramming which occurs in mutant KRAS cells, we have undertaken a systems-level analysis of four CRC cell lines which express either wild type (wt) KRAS or the oncogenic KRAS(G13D) allele (mtKRAS). RESULTS: RNAseq revealed that genes involved in ribosome biogenesis, mRNA translation and metabolism were significantly upregulated in mtKRAS cells. Consistent with the transcriptional data, protein synthesis and cell proliferation were significantly higher in the mtKRAS cells. Targeted metabolomics analysis also confirmed the metabolic reprogramming in mtKRAS cells. Interestingly, mtKRAS cells were highly transcriptionally responsive to EGFR activation by TGF alpha stimulation, which was associated with an unexpected downregulation of genes involved in a range of anabolic processes. While TGF alpha treatment strongly activated protein synthesis in wtKRAS cells, protein synthesis was not activated above basal levels in the TGF alpha-treated mtKRAS cells. This was likely due to the defective activation of the mTORC1 and other pathways by TGF alpha in mtKRAS cells, which was associated with impaired activation of PKB signalling and a transient induction of AMPK signalling. CONCLUSIONS: We have found that mtKRAS cells are substantially rewired at the transcriptional, translational and metabolic levels and that this rewiring may reveal new vulnerabilities in oncogenic KRAS CRC cells that could be exploited in future.

  • 37. Claassen, Yvette H. M.
    et al.
    Vermeer, Nina C. A.
    Iversen, Lene H.
    van Eycken, Elizabeth
    Guren, Marianne G.
    Mroczkowski, Pawel
    Martling, Anna
    Codina Cazador, Antonio
    Johansson, Robert
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Vandendael, Tamara
    Wibe, Arne
    Møller, Bjørn
    Lippert, Hans
    Rutten, Harm J. T.
    Portielje, Johanneke E. A.
    Liefers, Gerrit J.
    Holman, Fabian A.
    van de Velde, Cornelis J. H.
    Bastiaannet, Esther
    Treatment and survival of rectal cancer patients over the age of 80 years: a EURECCA international comparison2018In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 119, no 4, p. 517-522Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The optimal treatment strategy for older rectal cancer patients remains unclear. The current study aimed to compare treatment and survival of rectal cancer patients aged 80+.

    METHODS: Patients of >= 80 years diagnosed with rectal cancer between 2001 and 2010 were included. Population-based cohorts from Belgium (BE), Denmark (DK), the Netherlands (NL), Norway (NO) and Sweden (SE) were compared side by side for neighbouring countries on treatment strategy and 5-year relative survival (RS), adjusted for sex and age. Analyses were performed separately for stage I-III patients and stage IV patients.

    RESULTS: Overall, 19 634 rectal cancer patients were included. For stage I-III patients, 5-year RS varied from 61.7% in BE to 72.3% in SE. Proportion of preoperative radiotherapy ranged between 7.9% in NO and 28.9% in SE. For stage IV patients, 5-year RS differed from 2.8% in NL to 5.6% in BE. Rate of patients undergoing surgery varied from 22.2% in DK to 40.8% in NO.

    CONCLUSIONS: Substantial variation was observed in the 5-year relative survival between European countries for rectal cancer patients aged 80+, next to a wide variation in treatment, especially in the use of preoperative radiotherapy in stage I-III patients and in the rate of patients undergoing surgery in stage IV patients.

  • 38. Clamp, A. R.
    et al.
    Mäenpää, J.
    Cruickshank, D.
    Ledermann, J.
    Wilkinson, P. M.
    Welch, R.
    Chan, S.
    Vasey, P.
    Sorbe, Bengt
    Örebro University, Department of Clinical Medicine.
    Hindley, A.
    Jayson, G. C.
    SCOTROC 2B: feasibility of carboplatin followed by docetaxel or docetaxel-irinotecan as first-line therapy for ovarian cancer2006In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 94, no 1, p. 55-61Article in journal (Refereed)
    Abstract [en]

    The feasibility of combination irinotecan, carboplatin and docetaxel chemotherapy as first-line treatment for advanced epithelial ovarian carcinoma was assessed. One hundred patients were randomised to receive four 3-weekly cycles of carboplatin (area under the curve (AUC) 7) followed by four 3-weekly cycles of docetaxel 100 mg m(-2) (arm A, n=51) or docetaxel 60 mg m(-2) with irinotecan 200 mg m(-2) (arm B, n=49). Neither arm met the formal feasibility criterion of an eight-cycle treatment completion rate that was statistically greater than 60% (arm A 71% (90% confidence interval (CI) 58-81%; P=0.079; arm B 67% (90% CI 55-78%; P=0.184)). Median-dose intensities were >85% of planned dose for all agents. In arms A and B, 15.6 and 12.2% of patients, respectively, withdrew owing to treatment-related toxicity. Grade 3-4 sensory neurotoxicity was more common in arm A (1.9 vs 0%) and grade 3-4 diarrhoea was more common in arm B (0.6 vs 3.5%). Of patients with radiologically evaluable disease at baseline, 50 and 48% responded to therapy in arms A and B, respectively; at median 17.1 months' follow-up, median progression-free survival was 17.1 and 15.9 months, respectively. Although both arms just failed to meet the formal statistical feasibility criteria, the observed completion rates of around 70% were reasonable. The addition of irinotecan to first-line carboplatin and docetaxel chemotherapy was generally well tolerated although associated with increased gastrointestinal toxicity. Further exploratory studies of topoisomerase-I inhibitors in this setting may be warranted.

  • 39. Couto, E
    et al.
    Boffetta, P
    Lagiou, P
    Ferrari, P
    Buckland, G
    Overvad, K
    Dahm, C C
    Tjønneland, A
    Olsen, A
    Clavel-Chapelon, F
    Boutron-Ruault, M-C
    Cottet, V
    Trichopoulos, D
    Naska, A
    Benetou, V
    Kaaks, R
    Rohrmann, S
    Boeing, H
    von Ruesten, A
    Panico, S
    Pala, V
    Vineis, P
    Palli, D
    Tumino, R
    May, A
    Peeters, P H
    Bueno-de-Mesquita, H B
    Büchner, F L
    Lund, E
    Skeie, G
    Engeset, D
    Gonzalez, C A
    Navarro, C
    Rodríguez, L
    Sánchez, M-J
    Amiano, P
    Barricarte, A
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Manjer, J
    Wirfärt, E
    Allen, N E
    Crowe, F
    Khaw, K-T
    Wareham, N
    Moskal, A
    Slimani, N
    Jenab, M
    Romaguera, D
    Mouw, T
    Norat, T
    Riboli, E
    Trichopoulou, A
    Mediterranean dietary pattern and cancer risk in the EPIC cohort.2011In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 104, no 9, p. 1493-1499Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Although several studies have investigated the association of the Mediterranean diet with overall mortality or risk of specific cancers, data on overall cancer risk are sparse.

    METHODS: We examined the association between adherence to Mediterranean dietary pattern and overall cancer risk using data from the European Prospective Investigation Into Cancer and nutrition, a multi-centre prospective cohort study including 142,605 men and 335,873. Adherence to Mediterranean diet was examined using a score (range: 0-9) considering the combined intake of fruits and nuts, vegetables, legumes, cereals, lipids, fish, dairy products, meat products, and alcohol. Association with cancer incidence was assessed through Cox regression modelling, controlling for potential confounders.

    RESULTS: In all, 9669 incident cancers in men and 21,062 in women were identified. A lower overall cancer risk was found among individuals with greater adherence to Mediterranean diet (hazard ratio=0.96, 95% CI 0.95-0.98) for a two-point increment of the Mediterranean diet score. The apparent inverse association was stronger for smoking-related cancers than for cancers not known to be related to tobacco (P (heterogeneity)=0.008). In all, 4.7% of cancers among men and 2.4% in women would be avoided in this population if study subjects had a greater adherence to Mediterranean dietary pattern.

    CONCLUSION: Greater adherence to a Mediterranean dietary pattern could reduce overall cancer risk.

  • 40.
    Dabrosin, Charlotta
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedicine and Surgery, Oncology. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
    Palmer, K
    Gauldie, J
    Oestradiol enhances tumour regression induced by B7-I/IL-2 adenoviral gene transfer in a murine model of breast cancer2003In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 89, no 2, p. 385-390Article in journal (Refereed)
    Abstract [en]

    The majority of breast cancers are oestrogen dependent and although current treatment strategies have improved, approximately 50% of the patients will develop metastasis. New treatments that result in long-term systemic immunity are therefore being developed. We have previously shown that adenoviral gene transfer of B7-I/IL-2 to murine breast cancer induces a high rate of complete turnout regression and systemic immunity. Since oestrogens not only affect breast cancer but also have been shown to modulate immune function and secretion of immune-regulatory cytokines, we explored whether administration of oestradiol altered the immune response induced by an adenoviral vector expressing B7-I/IL-2. An oestrogen-dependent murine breast cancer tumour was used in ovariectomised mice, supplemented either oestradiol or placebo. We report the somewhat unexpected finding that intratumoral injection of adenovirus expressing B7-I/IL-2 induces complete turnout regression in 76% of oestradiol-supplemented mice, while only 18% of the tumours regressed in the oestrogen-depleted group. Cured mice in both groups exhibited a similar CTL response against the tumour antigen. However, intratumoral IFN-? levels, 2 days after B7-I/IL-2 injection, were significantly higher in mice treated with oestradiol compared to placebo. This may be one mechanism explaining the higher response rate of tumours in oestradiol-replenished mice.

  • 41. Dahlman, I
    et al.
    Mejhert, N
    Linder, K
    Agustsson, T
    Mutch, D M
    Kulyte, A
    Isaksson, B
    Permert, J
    Petrovic, Natasa
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Nedergaard, Jan
    Stockholm University, Faculty of Science, The Wenner-Gren Institute , Physiology.
    Sjölin, E
    Brodin, D
    Clement, K
    Dahlman-Wright, K
    Rydén, M
    Arner, P
    Adipose tissue pathways involved in weight loss of cancer cachexia2010In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 102, no 10, p. 1541-8Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The regulatory gene pathways that accompany loss of adipose tissue in cancer cachexia are unknown and were explored using pangenomic transcriptome profiling. METHODS: Global gene expression profiles of abdominal subcutaneous adipose tissue were studied in gastrointestinal cancer patients with (n=13) or without (n=14) cachexia. RESULTS: Cachexia was accompanied by preferential loss of adipose tissue and decreased fat cell volume, but not number. Adipose tissue pathways regulating energy turnover were upregulated, whereas genes in pathways related to cell and tissue structure (cellular adhesion, extracellular matrix and actin cytoskeleton) were downregulated in cachectic patients. Transcriptional response elements for hepatic nuclear factor-4 (HNF4) were overrepresented in the promoters of extracellular matrix and adhesion molecule genes, and adipose HNF4 mRNA was downregulated in cachexia. CONCLUSIONS: Cancer cachexia is characterised by preferential loss of adipose tissue; muscle mass is less affected. Loss of adipose tissue is secondary to a decrease in adipocyte lipid content and associates with changes in the expression of genes that regulate energy turnover, cytoskeleton and extracellular matrix, which suggest high tissue remodelling. Changes in gene expression in cachexia are reciprocal to those observed in obesity, suggesting that regulation of fat mass at least partly corresponds to two sides of the same coin.

  • 42.
    Dalen, Helge
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology. Östergötlands Läns Landsting, Centre for Laboratory Medicine, Department of Clinical Pathology and Clinical Genetics.
    Neuzil, Jiri
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Pathology.
    a-tocopheryl succinate sensitises a T lymphoma cell line to TRAIL-induced apoptosis by suppressing NF-?B activation2003In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 88, no 1, p. 153-158Article in journal (Refereed)
    Abstract [en]

    Activation of nuclear factor-?B (NF-?B) can interfere with induction of apoptosis triggered by the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL, Apo2L). Therefore, agents that suppress NF-?B activation may sensitise cells to TRAIL-dependent apoptosis. Exposure of Jurkat cells to TRAIL resulted in massive and saturable apoptosis induction, following an initial lag time. This lag was abolished by pretreatment of the cells with subapoptotic doses of a-tocopheryl succinate (a-TOS) or the proteasome inhibitor MGI32. Exposure of the cells to TRAIL led to a rapid, transient activation of NF-?B, a process that was suppressed by cell pretreatment with a-TOS or MGI32. Activation of NF-?B by TNF-a prior to TRAIL exposure increased resistance of the cells to TRAIL-mediated apoptosis. We conclude that a-TOS sensitises cells to TRAIL killing, at least in some cases, through inhibition of NF-?B activation. This further supports the possibility that this semisynthetic analogue of vitamin E is a potential adjuvant in cancer treatment, such as in the case of TRAIL-mediated inhibition of cancer.

  • 43. Dawei, X
    et al.
    Gruber, A
    Björkholm, M
    Peterson, Curt
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Medicine and Care, Clinical Pharmacology.
    Pisa, P
    Suppression of telomerase reverse transcriptase (hTERT) expression in differentiated HL-60 cells: regulatory mechanisms.1999In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 80, p. 1156-1161Article in journal (Refereed)
  • 44. Discacciati, A.
    et al.
    Orsini, N.
    Andersson, Swen-Olof
    Örebro University, School of Health and Medical Sciences.
    Andrén, Ove
    Örebro University, School of Health and Medical Sciences.
    Johansson, J-E
    Wolk, A.
    Body mass index in early and middle-late adulthood and risk of localised, advanced and fatal prostate cancer: a population-based prospective study2011In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 105, no 7, p. 1061-1068Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The relationships between body mass index (BMI) during early and middle-late adulthood and incidence of prostate cancer (PCa) by subtype of the disease (localised, advanced) and fatal PCa is unclear.

    METHODS: A population-based cohort of 36,959 Swedish men aged 45-79 years was followed up from January 1998 through December 2008 for incidence of PCa (1530 localised and 554 advanced cases were diagnosed) and through December 2007 for PCa mortality (225 fatal cases).

    RESULTS: From a competing-risks analysis, incidence of localised PCa was observed to be inversely associated with BMI at baseline (middle-late adulthood; rate ratio (RR) for 35 kg m(-2) when compared with 22 kg m(-2) was 0.69 (95% CI 0.52-0.92)), but not at age 30. For fatal PCa, BMI at baseline was associated with a nonstatistically significant increased risk (RR for every five-unit increase: 1.12 (0.88-1.43)) and BMI at age 30 with a decreased risk (RR for every five-unit increase: 0.72 (0.51-1.01)).

    CONCLUSION: Our results indicate an inverse association between obesity during middle-late, but not early adulthood, and localised PCa. They also suggest a dual association between BMI and fatal PCa--a decreased risk among men who were obese during early adulthood and an increased risk among those who were obese during middle-late adulthood.

  • 45. Disney-Hogg, Linden
    et al.
    Sud, Amit
    Law, Philip J.
    Cornish, Alex J.
    Kinnersley, Ben
    Ostrom, Quinn T.
    Labreche, Karim
    Eckel-Passow, Jeanette E.
    Armstrong, Georgina N.
    Claus, Elizabeth B.
    Il'yasova, Dora
    Schildkraut, Joellen
    Barnholtz-Sloan, Jill S.
    Olson, Sara H.
    Bernstein, Jonine L.
    Lai, Rose K.
    Swerdlow, Anthony J.
    Simon, Matthias
    Hoffmann, Per
    Nöthen, Markus M.
    Jöckel, Karl-Heinz
    Chanock, Stephen
    Rajaraman, Preetha
    Johansen, Christoffer
    Jenkins, Robert B.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Wrensch, Margaret R.
    Sanson, Marc
    Bondy, Melissa L.
    Houlston, Richard S.
    Influence of obesity-related risk factors in the aetiology of glioma2018In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 118, no 7, p. 1020-1027Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Obesity and related factors have been implicated as possible aetiological factors for the development of glioma in epidemiological observation studies. We used genetic markers in a Mendelian randomisation framework to examine whether obesity-related traits influence glioma risk. This methodology reduces bias from confounding and is not affected by reverse causation. METHODS: Genetic instruments were identified for 10 key obesity-related risk factors, and their association with glioma risk was evaluated using data from a genome-wide association study of 12,488 glioma patients and 18,169 controls. The estimated odds ratio of glioma associated with each of the genetically defined obesity-related traits was used to infer evidence for a causal relationship. RESULTS: No convincing association with glioma risk was seen for genetic instruments for body mass index, waist-to-hip ratio, lipids, type-2 diabetes, hyperglycaemia or insulin resistance. Similarly, we found no evidence to support a relationship between obesity-related traits with subtypes of glioma-glioblastoma (GBM) or non-GBM tumours. CONCLUSIONS: This study provides no evidence to implicate obesity-related factors as causes of glioma.

  • 46. Duffy, SW
    et al.
    Lynge, E
    Jonsson, Håkan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Reply: estimation of lead-time and overdiagnosis in breast cancer screening2009In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 100, no 1, p. 220-220Article in journal (Other academic)
  • 47. Dyrskjot, L.
    et al.
    Reinert, T.
    Novoradovsky, A.
    Zuiverloon, T. C. M.
    Beukers, W.
    Zwarthoff, E.
    Malats, N.
    Real, F. X.
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Knowles, M.
    Hurst, C.
    Sorge, J.
    Borre, M.
    Orntoft, T. F.
    Analysis of molecular intra-patient variation and delineation of a prognostic 12-gene signature in non-muscle invasive bladder cancer; technology transfer from microarrays to PCR2012In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 107, no 8, p. 1392-1398Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Multiple clinical risk factors and genetic profiles have been demonstrated to predict progression of non-muscle invasive bladder cancer; however, no easily clinical applicable gene signature has been developed to predict disease progression independent of disease stage and grade. METHODS: We measured the intra-patient variation of an 88-gene progression signature using 39 metachronous tumours from 17 patients. For delineation of the optimal quantitative reverse transcriptase PCR panel of markers, we used 115 tumour samples from patients in Denmark, Sweden, UK and Spain. RESULTS: Analysis of intra-patient variation of the molecular markers showed 71% similar classification results. A final panel of 12 genes was selected, showing significant correlation with outcome. In multivariate Cox regression analysis, we found that the 12-gene signature was an independent prognostic factor (hazard ratio = 7.4 (95% confidence interval: 3.4-15.9), P < 0.001) when adjusting for stage, grade and treatment. Independent validation of the 12-gene panel and the determined cut-off values is needed and ongoing. CONCLUSION: Intra-patient marker variation in metachronous tumours is present. Therefore, to increase test sensitivity, it may be necessary to test several metachronous tumours from a patient's disease course. A PCR-based 12-gene signature significantly predicts disease progression in patients with non-muscle invasive bladder cancer.

  • 48. Eberhard, J.
    et al.
    Gaber, A.
    Wangefjord, S.
    Nodin, B.
    Uhlén, Mathias C. E.
    KTH, School of Biotechnology (BIO), Proteomics.
    Lindquist, K. Ericson
    Jirstrom, K.
    A cohort study of the prognostic and treatment predictive value of SATB2 expression in colorectal cancer2012In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 106, no 5, p. 931-938Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Special AT-rich sequence-binding protein 2 (SATB2) is a novel diagnostic marker of colorectal cancer (CRC), and loss of SATB2 has been linked to poor survival from the disease. In this study, we validated the prognostic ability of SATB2 expression in a large, prospective CRC cohort. METHODS: Immunohistochemical SATB2 expression was assessed in 527 incident CRC cases from the Malmo Diet and Cancer Study. Kaplan-Meier analysis and Cox proportional hazards modelling were used to explore the impact of SATB2 expression on cancer-specific survival (CSS) and overall survival (OS). RESULTS: High SATB2 expression was associated with a prolonged CSS in the full cohort (hazard ratio (HR)=0.61; 95% CI 0.41-0.92) and in colon cancer (HR=0.39; 95% CI 0.20-0.75), remaining significant in multivariable analysis of colon cancer (HR 0.49; 95% CI 0.25-0.96), with similar findings for OS. In curatively resected stage III-IV patients, a significant benefit from adjuvant and/or neoadjuvant therapy was observed for SATB2 high tumours (P-interaction 0.037 for OS) and high SATB2 expression in rectal cancer correlated with an enhanced effect of neoadjuvant therapy (P-interaction 0.033 for OS). CONCLUSION: High SATB2 expression is an independent marker of good prognosis in colon cancer and may modulate sensitivity to chemotherapy and radiation. British Journal of Cancer (2012) 106, 931-938. doi:10.1038/bjc.2012.34 www.bjcancer.com Published online 14 February 2012

  • 49.
    Eklöf, Vincy
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jonsson, Björn-Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Å.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The prognostic role of KRAS, BRAF, PIK3CA and PTEN in colorectal cancer2013In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 108, no 10, p. 2153-2163Article in journal (Refereed)
    Abstract [en]

    Background Mutations in KRAS, BRAF, PIK3CA and PTEN expression have been in focus to predict the effect of epidermal growth factor receptor-blocking therapy in colorectal cancer (CRC). Here, information on these four aberrations was collected and combined to a Quadruple index and used to evaluate the prognostic role of these factors in CRC. Patients We analysed the mutation status in KRAS, BRAF and PIK3CA and PTEN expression in two separate CRC cohorts, Northern Sweden Health Disease Study (NSHDS; n = 197) and Colorectal Cancer in Umea Study (CRUMS; n = 414). A Quadruple index was created, where Quadruple index positivity specifies cases with any aberration in KRAS, BRAF, PIK3CA or PTEN expression. Results Quadruple index positive tumours had a worse prognosis, significant in the NSHDS but not in the CRUMS cohort (NSHDS; P = 0.003 and CRUMS; P = 0.230) in univariate analyses but significance was lost in multivariate analyses. When analysing each gene separately, only BRAF was of prognostic significance in the NSHDS cohort (multivariate HR 2.00, 95% CI: 1.16-3.43) and KRAS was of prognostic significance in the CRUMS cohort (multivariate HR 1.48, 95% CI: 1.02-2.16). Aberrations in PIK3CA and PTEN did not add significant prognostic information. Conclusions Our results suggest that establishment of molecular subgroups based on KRAS and BRAF mutation status is important and should be considered in future prognostic studies in CRC.

  • 50.
    Elander, N. O.
    et al.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England..
    Aughton, K.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England..
    Ghaneh, P.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England..
    Neoptolemos, J. P.
    Heidelberg Univ, Dept Surg, Heidelberg, Germany..
    Palmer, D. H.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England..
    Cox, T. F.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England..
    Campbell, F.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England..
    Costello, E.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England..
    Halloran, C. M.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England..
    Mackey, J. R.
    Cross Canc Inst, Edmonton, AB, Canada.;Univ Alberta, Edmonton, AB, Canada..
    Scarfe, A. G.
    Cross Canc Inst, Edmonton, AB, Canada.;Univ Alberta, Edmonton, AB, Canada..
    Valle, J. W.
    Univ Manchester, Christie NHS Fdn Trust, Manchester, Lancs, England..
    McDonald, A. C.
    Beatson West Scotland Canc Ctr, Glasgow, Lanark, Scotland..
    Carter, R.
    Glasgow Royal Infirm, Glasgow, Lanark, Scotland..
    Tebbutt, N. C.
    Austin Hlth, Melbourne, Vic, Australia..
    Goldstein, D.
    Univ New South Wales, Prince Wales Hosp, Sydney, NSW, Australia.;Univ New South Wales, Clin Sch, Sydney, NSW, Australia..
    Shannon, J.
    Nepean Canc Ctr, Sydney, NSW, Australia.;Univ Sydney, Sydney, NSW, Australia..
    Dervenis, C.
    Agia Olga Hosp, Athens, Greece..
    Glimelius, B.
    Deakin, M.
    Univ Hosp, Stoke On Trent, North Staffs, England..
    Charnley, R. M.
    Freeman Rd Hosp, Newcastle Upon Tyne, Tyne & Wear, England..
    Anthoney, Alan
    St James Univ Hosp, Leeds, W Yorkshire, England..
    Lerch, M. M.
    Univ Med Greifswald, Dept Med A, Greifswald, Germany..
    Mayerle, J.
    Ludwig Maximilians Univ Munchen, Univ Hosp, Dept Med 2, Munich, Germany..
    Olah, A.
    Petz Aladar Hosp, Gyor, Hungary..
    Buechler, M. W.
    Heidelberg Univ, Dept Surg, Heidelberg, Germany..
    Greenhalf, W.
    Univ Liverpool, Canc Res UK Liverpool Canc Trials Unit, Liverpool, Merseyside, England..
    Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer2018In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 118, no 7, p. 947-954Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy.

    METHODS: DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to either postoperative gemcitabine or 5-fluorouracil/folinic acid (5FU/FA).

    RESULTS: DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91-3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6-15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009).

    CONCLUSION: DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine.

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