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  • 301. d'Amore, Francesco
    et al.
    Relander, Thomas
    Lauritzsen, Grete F.
    Jantunen, Esa
    Hagberg, Hans
    Anderson, Harald
    Holte, Harald
    Osterborg, Anders
    Merup, Mats
    Brown, Peter
    Kuittinen, Outi
    Erlanson, Martin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ostenstad, Bjorn
    Fagerli, Unn-Merete
    Gadeberg, Ole V.
    Sundstrom, Christer
    Delabie, Jan
    Ralfkiaer, Elisabeth
    Vornanen, Martine
    Toldbod, Helle E.
    Up-Front Autologous Stem-Cell Transplantation in Peripheral T-Cell Lymphoma: NLG-T-012012In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 30, no 25, p. 3093-3099Article in journal (Refereed)
    Abstract [en]

    Purpose Systemic peripheral T-cell lymphomas (PTCLs) respond poorly to conventional therapy. To evaluate the efficacy of a dose-dense approach consolidated by up-front high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) in PTCL, the Nordic Lymphoma Group (NLG) conducted a large prospective phase II study in untreated systemic PTCL. This is the final report, with a 5-year median follow-up, of the NLG-T-01 study. Patients and Methods Treatment-naive patients with PTCL age 18 to 67 years (median, 57 years) were included. Anaplastic lymphoma kinase (ALK) -positive anaplastic large-cell lymphoma (ALCL) was excluded. An induction regimen of six cycles of biweekly CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) was administered (in patients age > 60 years, etoposide was omitted). If in complete or partial remission, patients proceeded to consolidation with HDT/ASCT. Results Of 166 enrolled patients, 160 had histopathologically confirmed PTCL. The majority presented with advanced-stage disease, B symptoms, and elevated serum lactate dehydrogenase. A total of 115 underwent HDT/ASCT, with 90 in complete remission at 3 months post-transplantation. Early failures occurred in 26%. Treatment-related mortality was 4%. At 60.5 months of median follow-up, 83 patients were alive. Consolidated 5-year overall and progression-free survival (PFS) were 51% (95% CI, 43% to 59%) and 44% (95% CI, 36% to 52%), respectively. Best results were obtained in ALK-negative ALCL. Conclusion Dose-dense induction followed by HDT/ASCT was well tolerated and led to long-term PFS in 44% of treatment-naive patients with PTCL. This represents an encouraging outcome, particularly considering the high median age and adverse risk profile of the study population. Therefore, dose-dense induction and HDT/ASCT are a rational up-front strategy in transplantation-eligible patients with PTCL. J Clin Oncol 30: 3093-3099. (C) 2012 by American Society of Clinical Oncology

  • 302.
    Danielsson Borssen, Åsa
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lindgren, S
    Bergquist, A
    Almer, S
    Sangfelt, P
    Werner, Mårten
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Risk for hepatocellular carcinoma in autoimmune hepatitis: is there an indication for surveillance?2013In: Journal of Hepatology, ISSN 0168-8278, E-ISSN 1600-0641, Vol. 58, no Suppl. 1, p. S382-S383Article in journal (Refereed)
  • 303. Danneman, Daniela
    et al.
    Drevin, Linda
    Delahunt, Brett
    Samaratunga, Hemamali
    Robinson, David
    Bratt, Ola
    Loeb, Stacy
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Egevad, Lars
    Accuracy of prostate biopsies for predicting Gleason score in radical prostatectomy specimens: nationwide trends 2000-20122017In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 119, no 1, p. 50-56Article in journal (Refereed)
    Abstract [en]

    Objectives To investigate how well the Gleason score in diagnostic needle biopsies predicted the Gleason score in a subsequent radical prostatectomy (RP) specimen before and after the 2005 International Society of Urological Pathology (ISUP) revision of Gleason grading, and if the recently proposed ISUP grades 1-5 (corresponding to Gleason scores 6, 3 + 4, 4 + 3, 8 and 9-10) better predict the RP grade. Patients and Methods All prostate cancers diagnosed in Sweden are reported to the National Prostate Cancer Register (NPCR). We analysed the Gleason scores and ISUP grades from the diagnostic biopsies and the RP specimens in 15 598 men in the NPCR who: were diagnosed between 2000 and 2012 with clinical stage T1-2 M0/X prostate cancer on needle biopsy; were aged <= 70 years; had serum PSA concentration of < 20 ng/mL; and underwent a RP < 6 months after diagnosis as their primary treatment. Results Prediction of RP Gleason score increased from 55 to 68% between 2000 and 2012. Most of the increase occurred before 2005 (nine percentage points; P < 0.001); however, when adjusting for Gleason score and year of diagnosis in a multivariable analysis, the prediction of RP Gleason score decreased over time (odds ratio [OR] 0.98; P < 0.002). A change in the ISUP grades would have led to a decreasing agreement between biopsy and RP grades over time, from 68% in 2000 to 57% in 2012, with an OR of 0.95 in multivariable analysis (P < 0.001). Conclusion Agreement between biopsy and RP Gleason score improved from 2000 to 2012, with most of the improvement occurring before the 2005 ISUP grading revision. Had ISUP grades been used instead of Gleason score, the agreement between biopsy and RP grade would have decreased, probably because of its separation of Gleason score 7 into ISUP grades 2 and 3 (Gleason score 3 + 4 vs 4 + 3).

  • 304. Daskalogianni, Chrysoula
    et al.
    Pyndiah, Slovenie
    Apcher, Sebastien
    Mazars, Anne
    Manoury, Benedicte
    Ammari, Nisrine
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Voisset, Cecile
    Blondel, Marc
    Fahraeus, Robin
    Epstein-Barr virus-encoded EBNA1 and ZEBRA: targets for therapeutic strategies against EBV-carrying cancers2015In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 235, no 2, p. 334-341Article, review/survey (Refereed)
    Abstract [en]

    The EBV-encoded EBNA1 was first discovered 40 years ago, approximately 10 years after the presence of EBV had been demonstrated in Burkitt's lymphoma cells. It took another 10 years before the functions of EBNA1 in maintaining the viral genome were revealed, and it has since been shown to be an essential viral factor expressed in all EBV-carrying cells. Apart from serving to maintain the viral episome and to control viral replication and gene expression, EBNA1 also harbours a cis-acting mechanism that allows virus-carrying host cells to evade the immune system. This relates to a particular glycine-alanine repeat (GAr) within EBNA1 that has the capacity to suppress antigen presentation to the major histocompatibility complex (MHC) class I pathway. We discuss the role of the GAr sequence at the level of mRNA translation initiation, rather than at the protein level, as at least part of the mechanism to avoid MHC presentation. Interfering with this mechanism has become the focus of the development of immune-based therapies against EBV-carrying cancers, and some lead compounds that affect translation of GAr-carrying mRNAs have been identified. In addition, we describe the EBV-encoded ZEBRA factor and the switch from the latent to the lytic cycle as an alternative virus-specific target for treating EBV-carrying cancers. Understanding the molecular mechanisms of how EBNA1 and ZEBRA interfere with cellular pathways not only opens new therapeutic approaches but continues to reveal new cell-biological insights on the interplay between host and virus. This review is a tale of discoveries relating to how EBNA1 and ZEBRA have emerged as targets for specific cancer therapies against EBV-carrying diseases, and serves as an illustration of how mRNA translation can play roles in future immune-based strategies to target viral disease. 

  • 305.
    Dasu, Alexandru
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Toma-Dasu, Iuliana
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Karlsson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    The effects of hypoxia on the theoretical modelling of tumour control probability2005In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 44, no 6, p. 563-571Article in journal (Refereed)
    Abstract [en]

    Theoretical modelling of tumour response is increasingly used for the prediction of treatment result and has even been proposed as ranking criteria in some algorithms for treatment planning. Tumour response to radiation is greatly influenced by the details of tumour microenvironment, especially hypoxia, that unfortunately are not always taken into consideration for these simulations. This paper intends to investigate the effects of various assumptions regarding hypoxia distribution in tumours on the predictions of treatment outcome. A previously developed model for simulating theoretically the oxygenation in biologically relevant tissues, including results from oxygen diffusion, consumption and perfusion limitations in tumours, was used to investigate the effects of the different aspects of hypoxia on the predictions of treatment outcome. Thus, both the continuous distribution of values and the temporal variation of hypoxia patterns were taken into consideration and were compared with a `black-and-white' simplification with a fully hypoxic compartment and a fully oxic one. It was found that the full distribution of oxygenation in the tissue is needed for accurate results. The `black-and-white' simplification, while showing the same general trends for the predictions of radiation response, could lead to serious overestimations of the tumour control probability. It was also found that the presence of some hypoxia for every treatment fraction leads to a decrease in the predicted local control, regardless of the change of the hypoxic pattern throughout the duration of the whole treatment. The results thus suggest that the assumptions regarding tumour hypoxia influence very much the predictions of treatment outcome and therefore they have to be very carefully incorporated into the theoretical modelling.

  • 306.
    Dasu, Alexandru
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Toma-Dasu, Iuliana
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Karlsson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Theoretical simulation of tumour oxygenation and results from acute and chronic hypoxia2003In: Physics in Medicine and Biology, ISSN 0031-9155, E-ISSN 1361-6560, Vol. 48, no 17, p. 2829-2842Article in journal (Refereed)
    Abstract [en]

    The tumour microenvironment is considered to be responsible for the outcome of cancer treatment and therefore it is extremely important to characterize and quantify it. Unfortunately, most of the experimental techniques available now are invasive and generally it is not known how this influences the results. Non-invasive methods on the other hand have a geometrical resolution that is not always suited for the modelling of the tumour response. Theoretical simulation of the microenvironment may be an alternative method that can provide quantitative data for accurately describing tumour tissues.

    This paper presents a computerized model that allows the simulation of the tumour oxygenation. The model simulates numerically the fundamental physical processes of oxygen diffusion and consumption in a two-dimensional geometry in order to study the influence of the different parameters describing the tissue geometry. The paper also presents a novel method to simulate the effects of diffusion-limited (chronic) hypoxia and perfusion-limited (acute) hypoxia.

    The results show that all the parameters describing tissue vasculature are important for describing tissue oxygenation. Assuming that vascular structure is described by a distribution of inter-vessel distances, both the average and the width of the distribution are needed in order to fully characterize the tissue oxygenation. Incomplete data, such as distributions measured in a non-representative region of the tissue, may not give relevant tissue oxygenation.

    Theoretical modelling of tumour oxygenation also allows the separation between acutely and chronically hypoxic cells, a distinction that cannot always be seen with other methods. It was observed that the fraction of acutely hypoxic cells depends not only on the fraction of collapsed blood vessels at any particular moment, but also on the distribution of vessels in space as well.

    All these suggest that theoretical modelling of tissue oxygenation starting from the basic principles is a robust method that can be used to quantify the tissue oxygenation and to provide input parameters for other simulations.

  • 307.
    Dasu, Alexandru
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Toma-Dasu, Iuliana
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Olofsson, Jörgen
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Karlsson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    The use of risk estimation models for the induction of secondary cancers following radiotherapy2005In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 44, no 4, p. 339-347Article in journal (Refereed)
    Abstract [en]

    Theoretical predictions of cancer risk from radiotherapy may be used as a complementary criterion for the selection of successful treatment plans together with the classical approach of estimating the possible deterministic effects. However, any such attempts must take into consideration the specific features of radiation treatment. This paper explores several possible methods for estimating the risk of cancer following radiotherapy in order to investigate the influences of the fractionation and the non-uniformity of the dose to the irradiated organ. The results indicate that dose inhomogeneity plays an important role in predicting the risk for secondary cancer and therefore for predictive purposes it must be taken into account through the use of the dose volume histograms. They also suggest that the competition between cell killing and the induction of carcinogenic mutations has to be taken into consideration for more realistic risk estimations. Furthermore, more realistic parameters could be obtained if this competition is also included in analyses of epidemiological data from radiotherapy applications.

  • 308.
    Dasu, Alexandru
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Radiation Physics.
    Toma-Daşu, Iuliana
    What is the Clinically Relevant Relative Biologic Effectiveness? A Warning for Fractionated Treatments With High Linear Energy Transfer Radiation2008In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 70, no 3, p. 867-874Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To study the clinically relevant relative biologic effectiveness (RBE) of fractionated treatments with high linear energy transfer (LET) radiation and to identify the important factors that might influence the transfer of tolerance and curative levels from low LET radiation. These are important questions in the light of the growing interest for the therapeutic use of radiation with higher LET than electrons or photons.

    METHODS AND MATERIALS: The RBE of various fractionated schedules was analyzed with theoretical models for radiation effect, and the resulting predictions were compared with the published clinical and experimental data regarding fractionated irradiation with high LET radiation.

    RESULTS: The clinically relevant RBE increased for greater doses per fraction, in contrast to the predictions from single-dose experiments. Furthermore, the RBE for late-reacting tissues appeared to modify more quickly than that for early-reacting tissues. These aspects have quite important clinical implications, because the increased biologic effectiveness reported for this type of radiation would otherwise support the use of hypofractionation. Thus, the differential between acute and late-reacting tissues could put the late-reacting normal tissues at more risk from high LET irradiation; however, at the same time, it could increase the therapeutic window for slow-growing tumors.

    CONCLUSIONS: The modification of the RBE with the dose per fraction must be carefully taken into consideration when devising fractionated treatments with high LET radiation. Neglecting to do so might result in an avalanche of complications that could obscure the potential advantages of the therapeutic use of this type of radiation.

  • 309. Davidsson, Sabina
    et al.
    Molling, Paula
    Rider, Jennifer R.
    Unemo, Magnus
    Karlsson, Mats G.
    Carlsson, Jessica
    Andersson, Swen-Olof
    Elgh, Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Soderquis, Bo
    Andren, Ove
    Frequency and typing of Propionibacterium acnes in prostate tissue obtained from men with and without prostate cancer2016In: Infectious Agents and Cancer, ISSN 1750-9378, E-ISSN 1750-9378, Vol. 11, article id 26Article in journal (Refereed)
    Abstract [en]

    Background: Prostate cancer is the most common cancer among men in Western countries but the exact pathogenic mechanism of the disease is still largely unknown. An infectious etiology and infection-induced inflammation has been suggested to play a role in prostate carcinogenesis and Propionibacterium acneshas been reported as the most prevalent microorganism in prostatic tissue. We investigated the frequency and types of P. acnes isolated from prostate tissue samples from men with prostate cancer and from control patients without the disease.

    Methods: We included 100 cases and 50 controls in this study. Cases were men diagnosed with prostate cancer undergoing radical prostatectomy and controls were men undergoing surgery for bladder cancer without any histological findings of prostate cancer. Six biopsies taken from each patient’s prostate gland at the time of surgery were used for cultivation and further characterization of P. acnes.

    Results: The results revealed that P. acnes was more common in men with prostate carcinoma than in controls, with the bacteria cultured in 60 % of the cases vs. 26 % of the controls (p = 0.001). In multivariable analyses, men with P. acnes had a 4-fold increase in odds of a prostate cancer diagnosis after adjustment for age, calendar year of surgery and smoking status (OR: 4.46; 95 % CI: 1.93–11.26). To further support the biologic plausibility for a P. acnes infection as a contributing factor in prostate cancer development, we subsequently conducted cell-based experiments. P. acnes- isolates were co-cultured with the prostate cell line PNT1A. An increased cell proliferation and cytokine/chemokine secretion in infected cells was observed.

    Conclusion: The present study provides further evidence for a role of P. acnes in prostate cancer development.

  • 310. Davis, Faith G
    et al.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Aldape, Ken
    Barnholtz-Sloan, Jill S
    Bondy, Melissa L
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bruner, Janet M
    Burger, Peter C
    Collins, V Peter
    Inskip, Peter D
    Kruchko, Carol
    McCarthy, Bridget J
    McLendon, Roger E
    Sadetzki, Siegal
    Tihan, Tarik
    Wrensch, Margaret R
    Buffler, Patricia A
    Issues of diagnostic review in brain tumor studies: from the brain tumor epidemiology consortium2008In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 17, no 3, p. 484-489Article in journal (Refereed)
    Abstract [en]

    Epidemiologists routinely conduct centralized single pathology reviews to minimize interobserver diagnostic variability, but this practice does not facilitate the combination of studies across geographic regions and institutions where diagnostic practices differ. A meeting of neuropathologists and epidemiologists focused on brain tumor classification issues in the context of protocol needs for consortial studies (http://epi.grants.cancer.gov/btec/). It resulted in recommendations relevant to brain tumors and possibly other rare disease studies. Two categories of brain tumors have enough general agreement over time, across regions, and between individual pathologists that one can consider using existing diagnostic data without further review: glioblastomas and meningiomas (as long as uniform guidelines such as those provided by the WHO are used). Prospective studies of these tumors benefit from collection of pathology reports, at a minimum recording the pathology department and classification system used in the diagnosis. Other brain tumors, such as oligodendroglioma, are less distinct and require careful histopathologic review for consistent classification across study centers. Epidemiologic study protocols must consider the study specific aims, diagnostic changes that have taken place over time, and other issues unique to the type(s) of tumor being studied. As diagnostic changes are being made rapidly, there are no readily available answers on disease classification issues. It is essential that epidemiologists and neuropathologists collaborate to develop appropriate study designs and protocols for specific hypothesis and populations.

  • 311. de Batlle, J.
    et al.
    Ferrari, P.
    Chajes, V.
    Park, J. Y.
    Slimani, N.
    McKenzie, F.
    Overvad, K.
    Roswall, N.
    Tjønneland, A.
    Boutron-Ruault, M. C.
    Clavel-Chapelon, F.
    Fagherazzi, G.
    Katzke, V.
    Kaaks, R.
    Bergmann, M. M.
    Trichopoulou, A.
    Lagiou, P.
    Trichopoulos, D.
    Palli, D.
    Sieri, S.
    Panico, S.
    Tumino, R.
    Vineis, P.
    Bueno-de-Mesquita, H. B.
    Peeters, P. H.
    Hjartåker, A.
    Engeset, D.
    Weiderpass, E.
    Sánchez, S.
    Travier, N.
    Sanchez, M. J.
    Amiano, P.
    Chirlaque, M. D.
    Barricarte Gurrea, A.
    Khaw, K. T.
    Key, T. J.
    Bradbury, K. E.
    Ericson, U.
    Sonestedt, E.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Riboli, E.
    Romieu, I.
    Dietary folate intake and breast cancer risk: European prospective investigation into cancer and nutrition2015In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 107, no 1, article id dju367Article in journal (Refereed)
    Abstract [en]

    There is limited evidence on the association between dietary folate intake and the risk of breast cancer (BC) by hormone receptor expression in the tumors. We investigated the relationship between dietary folate and BC risk using data from the European Prospective Investigation into Cancer and Nutrition (EPIC). A total of 367993 women age 35 to 70 years were recruited in 10 European countries. During a median follow-up of 11.5 years, 11575 women with BC were identified. Dietary folate intake was estimated from country-specific dietary questionnaires. Cox proportional hazards regression models were used to quantify the association between dietary variables and BC risk. BC tumors were classified by receptor status. Subgroup analyses were performed by menopausal status and alcohol intake. Intake of other B vitamins was considered. All statistical tests were two-sided. A borderline inverse association was observed between dietary folate and BC risk (hazard ratio comparing top vs bottom quintile [HRQ5-Q1] = 0.92, 95% CI = 0.83 to 1.01, P (trend) = .037). In premenopausal women, we observed a statistically significant trend towards lower risk in estrogen receptor-negative BC (HRQ5-Q1 = 0.66, 95% CI = 0.45 to 0.96, P (trend) = .042) and progesterone receptor-negative BC (HRQ5-Q1 = 0.70, 95% CI = 0.51 to 0.97, P (trend) = .021). No associations were found in postmenopausal women. A 14% reduction in BC risk was observed when comparing the highest with the lowest dietary folate tertiles in women having a high (> 12 alcoholic drinks/week) alcohol intake (HRT3-T1 = 0.86, 95% CI = 0.75 to 0.98, P (interaction) = .035). Higher dietary folate intake may be associated with a lower risk of sex hormone receptor-negative BC in premenopausal women.

  • 312. de Boniface, Jana
    et al.
    Frisell, Jan
    Andersson, Yvette
    Bergkvist, Leif
    Ahlgren, Johan
    Ryden, Lisa
    Bagge, Roger Olofsson
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences. Surgery Center, Norrland University Hospital, Umeå, Sweden.
    Johansson, Hemming
    Lundstedt, Dan
    Survival and axillary recurrence following sentinel node-positive breast cancer without completion axillary lymph node dissection: the randomized controlled SENOMAC trial2017In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 17, article id 379Article in journal (Refereed)
    Abstract [en]

    Background: The role of axillary lymph node dissection (ALND) has increasingly been called into question among patients with positive sentinel lymph nodes. Two recent trials have failed to show a survival difference in sentinel node-positive breast cancer patients who were randomized either to undergo completion ALND or not. Neither of the trials, however, included breast cancer patients undergoing mastectomy or those with tumors larger than 5 cm, and power was debatable to show a small survival difference.

    Methods: The prospective randomized SENOMAC trial includes clinically node-negative breast cancer patients with up to two macrometastases in their sentinel lymph node biopsy. Patients with T1-T3 tumors are eligible as well as patients prior to systemic neoadjuvant therapy. Both breast-conserving surgery and mastectomy, with or without breast reconstruction, are eligible interventions. Patients are randomized 1:1 to either undergo completion ALND or not by a web-based randomization tool. This trial is designed as a non-inferiority study with breast cancer-specific survival at 5 years as the primary endpoint. Target accrual is 3500 patients to achieve 80% power in being able to detect a potential 2.5% deterioration of the breast cancer-specific 5-year survival rate. Follow-up is by annual clinical examination and mammography during 5 years, and additional controls after 10 and 15 years. Secondary endpoints such as arm morbidity and health-related quality of life are measured by questionnaires at 1, 3 and 5 years.

    Discussion: Several large subgroups of breast cancer patients, such as patients undergoing mastectomy or those with larger tumors, have not been included in key trials; however, the use of ALND is being questioned even in these groups without the support of high-quality evidence. Therefore, the SENOMAC Trial will investigate the need of completion ALND in case of limited spread to the sentinel lymph nodes not only in patients undergoing any breast surgery, but also in neoadjuvantly treated patients and patients with larger tumors.

  • 313.
    de Jong, Anna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Adherence to adjuvant endocrine therapy after breast cancer in Sweden - With focus on regional differences and review of the material.2018Independent thesis Basic level (professional degree), 20 credits / 30 HE creditsStudent thesis
  • 314. De Petris, L.
    et al.
    Forshed, J.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Branden, E.
    Koyi, H.
    Johnsson, A.
    Lewensohn, R.
    Lehtio, J.
    Plasma metabolomics in non-small-cell lung cancer2011Conference paper (Refereed)
  • 315. de Vogel, Stefan
    et al.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Ueland, Per Magne
    Vollset, Stein Emil
    Meyer, Klaus
    Fredriksen, Åse
    Midttun, Øivind
    Bjørge, Tone
    Kampman, Ellen
    Bretthauer, Michael
    Hoff, Geir
    Biomarkers related to one-carbon metabolism as potential risk factors for distal colorectal adenomas2011In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 20, no 8, p. 1726-1735Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Efficient one-carbon metabolism, which requires adequate supply of methyl group donors and B-vitamins, may protect against colorectal carcinogenesis. However, plasma folate and vitamins B2 and B12 have inconsistently been associated with colorectal cancer risk, and there have been no previous studies relating plasma concentrations of methionine, choline, and betaine to this outcome.

    METHODS: This study comprised 10,601 individuals, 50 to 64 years of age, participating in the Norwegian Colorectal Cancer Prevention (NORCCAP) screening study. Using logistic regression analyses, we crosssectionally investigated associations between distal colorectal adenoma occurrence-potential precursor lesions of colorectal carcinomas-and plasma concentrations of methyl group donors and B-vitamins, and polymorphisms of genes related to one-carbon metabolism.

    RESULTS: Screening revealed 1,809 subjects (17.1%) with at least one adenoma. The occurrence of high-risk adenomas (observed in 421 subjects) was inversely associated with plasma concentrations of methionine (highest versus lowest quartile: odds ratio (OR) = 0.61; 95% confidence interval (CI) = 0.45-0.83), betaine: OR = 0.74; 95% CI = 0.54-1.02, the vitamin B2 form flavin-mononucleotide (FMN): OR = 0.65; 95% CI = 0.49-0.88, and the vitamin B6 form pyridoxal 5'-phosphate (PLP): OR = 0.69; 95% CI = 0.51-0.95, but not with folate, choline, vitamin B12 concentrations, or with the studied polymorphisms. High methionine concentration in combination with high vitamin B2 or B6 concentrations was associated with lower occurrence of high-risk adenomas compared with these factors individually.

    CONCLUSIONS: High plasma concentrations of methionine and betaine, and vitamins B2 and B6 may reduce risk of developing colorectal adenomas.

    IMPACT: In addition to B-vitamins, methyl group donors such as methionine and betaine may play a role in colorectal carcinogenesis.

  • 316. Degerfält, J. E.
    et al.
    Sjöstedt, S.
    Fransson, Per
    Umeå University, Faculty of Medicine, Department of Nursing.
    Kjellén, E.
    Werner, M. U.
    E-learning programs in oncology: a nationwide experience from 2005 to 20142016In: International Journal of Radiation Oncology, Biology, Physics, ISSN 0360-3016, E-ISSN 1879-355X, Vol. 96, no 2, p. E413-E414Article in journal (Refereed)
  • 317.
    Degerman, Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landfors, Mattias
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Siwicki, Jan Konrad
    Revie, John
    Borssen, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Evelönn, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Chrzanowska, Krystyna H.
    Ryden, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Keith, W. Nicol
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Immortalization of T-Cells Is Accompanied by Gradual Changes in CpG Methylation Resulting in a Profile Resembling a Subset of T-Cell Leukemias2014In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 16, no 7, p. 606-615Article in journal (Refereed)
    Abstract [en]

    We have previously described gene expression changes during spontaneous immortalization of T-cells, thereby identifying cellular processes important for cell growth crisis escape and unlimited proliferation. Here, we analyze the same model to investigate the role of genome-wide methylation in the immortalization process at different time points pre-crisis and post-crisis using high-resolution arrays. We show that over time in culture there is an overall accumulation of methylation alterations, with preferential increased methylation close to transcription start sites (TSSs), islands, and shore regions. Methylation and gene expression alterations did not correlate for the majority of genes, but for the fraction that correlated, gain of methylation close to TSS was associated with decreased gene expression. Interestingly, the pattern of CpG site methylation observed in immortal T-cell cultures was similar to clinical T-cell acute lymphoblastic leukemia (T-ALL) samples classified as CpG island methylator phenotype positive. These sites were highly overrepresented by polycomb target genes and involved in developmental, cell adhesion, and cell signaling processes. The presence of non-random methylation events in in vitro immortalized T-cell cultures and diagnostic T-ALL samples indicates altered methylation of CpG sites with a possible role in malignant hematopoiesis.

  • 318. Delahaye-Sourdeix, Manon
    et al.
    Oliver, Javier
    Timofeeva, Maria N
    Gaborieau, Valérie
    Johansson, Mattias
    Genetic Epidemiology group (GEP), International Agency for Research on Cancer (IARC), Lyon, France .
    Chabrier, Amélie
    Wozniak, Magdalena B
    Brenner, Darren R
    Vallée, Maxime P
    Anantharaman, Devasena
    Lagiou, Pagona
    Holcátová, Ivana
    Richiardi, Lorenzo
    Kjaerheim, Kristina
    Agudo, Antonio
    Castellsagué, Xavier
    Macfarlane, Tatiana V
    Barzan, Luigi
    Canova, Cristina
    Thakker, Nalin S
    Conway, David I
    Znaor, Ariana
    Healy, Claire M
    Ahrens, Wolfgang
    Zaridze, David
    Szeszenia-Dabrowska, Neonilia
    Lissowska, Jolanta
    Fabianova, Eleonora
    Mates, Ioan Nicolae
    Bencko, Vladimir
    Foretova, Lenka
    Janout, Vladimir
    Curado, Maria Paula
    Koifman, Sergio
    Menezes, Ana
    Wünsch-Filho, Victor
    Eluf-Neto, José
    Boffetta, Paolo
    Garrote, Leticia Fernández
    Serraino, Diego
    Lener, Marcin
    Jaworowska, Ewa
    Lubiński, Jan
    Boccia, Stefania
    Rajkumar, Thangarajan
    Samant, Tanuja A
    Mahimkar, Manoj B
    Matsuo, Keitaro
    Franceschi, Silvia
    Byrnes, Graham
    Brennan, Paul
    McKay, James D
    The 12p13.33/RAD52 locus and genetic susceptibility to squamous cell cancers of upper aerodigestive tract2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 3, article id e0117639Article in journal (Refereed)
    Abstract [en]

    Genetic variants located within the 12p13.33/RAD52 locus have been associated with lung squamous cell carcinoma (LUSC). Here, within 5,947 UADT cancers and 7,789 controls from 9 different studies, we found rs10849605, a common intronic variant in RAD52, to be also associated with upper aerodigestive tract (UADT) squamous cell carcinoma cases (OR = 1.09, 95% CI: 1.04-1.15, p = 6x10(-4)). We additionally identified rs10849605 as a RAD52 cis-eQTL inUADT(p = 1x10(-3)) and LUSC (p = 9x10(-4)) tumours, with the UADT/LUSC risk allele correlated with increased RAD52 expression levels. The 12p13.33 locus, encompassing rs10849605/RAD52, was identified as a significant somatic focal copy number amplification in UADT(n = 374, q-value = 0.075) and LUSC (n = 464, q-value = 0.007) tumors and correlated with higher RAD52 tumor expression levels (p = 6x10(-48) and p = 3x10(-29) in UADT and LUSC, respectively). In combination, these results implicate increased RAD52 expression in both genetic susceptibility and tumorigenesis of UADT and LUSC tumors.

  • 319. Dewi, Nikmah Utami
    et al.
    Boshuizen, Hendriek C.
    Johansson, Mattias
    Vineis, Paolo
    Kampman, Ellen
    Steffen, Annika
    Tjonneland, Anne
    Halkjaer, Jytte
    Overvad, Kim
    Severi, Gianluca
    Fagherazzi, Guy
    Boutron-Ruault, Marie-Christine
    Kaaks, Rudolf
    Li, Kuanrong
    Boeing, Heiner
    Trichopoulou, Antonia
    Bamia, Christina
    Klinaki, Eleni
    Tumino, Rosario
    Palli, Domenico
    Mattiello, Amalia
    Tagliabue, Giovanna
    Peeters, Petra H.
    Vermeulen, Roel
    Weiderpass, Elisabete
    Gram, Inger Torhild
    Maria Huerta, Jose
    Agudo, Antonio
    Sanchez, Maria-Jose
    Ardanaz, Eva
    Dorronsoro, Miren
    Ramon Quiros, Jose
    Sonestedt, Emily
    Johansson, Mikael
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Grankvist, Kjell
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Key, Tim
    Khaw, Kay-Tee
    Wareham, Nick
    Cross, Amanda J.
    Norat, Teresa
    Riboli, Elio
    Fanidi, Anouar
    Muller, David
    Bueno-de-Mesquita, H. Bas
    Anthropometry and the Risk of Lung Cancer in EPIC2016In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 184, no 2, p. 129-139Article in journal (Refereed)
    Abstract [en]

    The associations of body mass index (BMI) and other anthropometric measurements with lung cancer were examined in 348,108 participants in the European Investigation Into Cancer and Nutrition (EPIC) between 1992 and 2010. The study population included 2,400 case patients with incident lung cancer, and the average length of follow-up was 11 years. Hazard ratios were calculated using Cox proportional hazard models in which we modeled smoking variables with cubic splines. Overall, there was a significant inverse association between BMI (weight (kg)/height (m)(2)) and the risk of lung cancer after adjustment for smoking and other confounders (for BMI of 30.0-34.9 versus 18.5-25.0, hazard ratio = 0.72, 95% confidence interval: 0.62, 0.84). The strength of the association declined with increasing follow-up time. Conversely, after adjustment for BMI, waist circumference and waist-to-height ratio were significantly positively associated with lung cancer risk (for the highest category of waist circumference vs. the lowest, hazard ratio = 1.25, 95% confidence interval: 1.05, 1.50). Given the decline of the inverse association between BMI and lung cancer over time, the association is likely at least partly due to weight loss resulting from preclinical lung cancer that was present at baseline. Residual confounding by smoking could also have influenced our findings.

  • 320. Dik, Vincent K
    et al.
    Bueno-de-Mesquita, H Bas
    Van Oijen, Martijn GH
    Siersema, Peter D
    Uiterwaal, Cuno SPM
    Van Gils, Carla H
    Van Duijnhoven, Fränzel JB
    Cauchi, Stéphane
    Yengo, Loic
    Froguel, Philippe
    Overvad, Kim
    Bech, Bodil H
    Tjønneland, Anne
    Olsen, Anja
    Boutron-Ruault, Marie-Christine
    Racine, Antoine
    Fagherazzi, Guy
    Kühn, Tilman
    Campa, Daniele
    Boeing, Heiner
    Aleksandrova, Krasimira
    Trichopoulou, Antonia
    Peppa, Eleni
    Oikonomou, Eleni
    Palli, Domenico
    Grioni, Sara
    Vineis, Paolo
    Tumino, Rosaria
    Panico, Salvatore
    Peeters, Petra HM
    Weiderpass, Elisabete
    Engeset, Dagrun
    Braaten, Tonje
    Dorronsoro, Miren
    Chirlaque, María-Dolores
    Sánchez, María-José
    Barricarte, Aurelio
    Zamora-Ros, Raul
    Argüelles, Marcial
    Jirström, Karin
    Wallström, Peter
    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.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Arctic Research Centre at Umeå University.
    Travis, Ruth C
    Khaw, Kay-Tee
    Wareham, Nick
    Freisling, Heinz
    Licaj, Idlir
    Jenab, Mazda
    Gunter, Marc J
    Murphy, Neil
    Romaguera-Bosch, Dora
    Riboli, Elio
    Coffee and tea consumption, genotype based CYP1A2 and NAT2 activity, and colorectal cancer risk: results from the EPIC cohort study2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 135, no 2, p. 401-412Article in journal (Refereed)
    Abstract [en]

    Coffee and tea contain numerous antimutagenic and antioxidant components and high levels of caffeine that may protect against colorectal cancer (CRC). We investigated the association between coffee and tea consumption and CRC risk and studied potential effect modification by CYP1A2 and NAT2 genotypes, enzymes involved in the metabolization of caffeine. Data from 477,071 participants (70.2% female) of the European Investigation into Cancer and Nutrition (EPIC) cohort study were analyzed. At baseline (1992-2000) habitual (total, caffeinated and decaffeinated) coffee and tea consumption was assessed with dietary questionnaires. Cox proportional hazards models were used to estimate adjusted hazard ratio's (HR) and 95%-confidence intervals (95%-CI). Potential effect modification by genotype-based CYP1A2 and NAT2 activity was studied in a nested case-control set of 1,252 cases and 2,175 controls. After a median follow-up of 11.6 years, 4,234 participants developed CRC (mean age 64.7±8.3 years). Total coffee consumption (high vs. non/low) was not associated with CRC risk (HR 1.06, 95%-CI 0.95-1.18) or subsite cancers, and no significant associations were found for caffeinated (HR 1.10, 95%-CI 0.97-1.26) and decaffeinated coffee (HR 0.96, 95%-CI 0.84-1.11) and tea (HR 0.97, 95%-CI 0.86-1.09). High coffee and tea consuming subjects with slow CYP1A2 or NAT2 activity had a similar CRC risk compared to non/low coffee and tea consuming subjects with a fast CYP1A2 or NAT2 activity, which suggest that caffeine metabolism does not affect the link between coffee and tea consumption and CRC risk. This study shows that coffee and tea consumption is not likely to be associated with overall CRC.

  • 321. Ding, Yuan C
    et al.
    McGuffog, Lesley
    Healey, Sue
    Friedman, Eitan
    Laitman, Yael
    Paluch-Shimon, Shani-
    Kaufman, Bella
    Liljegren, Annelie
    Lindblom, Annika
    Olsson, Håkan
    Kristoffersson, Ulf
    Stenmark-Askmalm, Marie
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Domchek, Susan M
    Nathanson, Katherine L
    Rebbeck, Timothy R
    Jakubowska, Anna
    Lubinski, Jan
    Jaworska, Katarzyna
    Durda, Katarzyna
    Gronwald, Jacek
    Huzarski, Tomasz
    Cybulski, Cezary
    Byrski, Tomasz
    Osorio, Ana
    Cajal, Teresa Ramóny
    Stavropoulou, Alexandra V
    Benítez, Javier
    Hamann, Ute
    Rookus, Matti
    Aalfs, Cora M
    de Lange, Judith L
    Meijers-Heijboer, Hanne E J
    Oosterwijk, Jan C
    van Asperen, Christi J
    Gómez García, Encarna B
    Hoogerbrugge, Nicoline
    Jager, Agnes
    van der Luijt, Rob B
    Easton, Douglas F
    Peock, Susan
    Frost, Debra
    Ellis, Steve D
    Platte, Radka
    Fineberg, Elena
    Evans, D Gareth
    Lalloo, Fiona
    Izatt, Louise
    Eeles, Ros
    Adlard, Julian
    Davidson, Rosemarie
    Eccles, Diana
    Cole, Trevor
    Cook, Jackie
    Brewer, Carole
    Tischkowitz, Marc
    Godwin, Andrew K
    Pathak, Harsh
    Stoppa-Lyonnet, Dominique
    Sinilnikova, Olga M
    Mazoyer, Sylvie
    Barjhoux, Laure
    Léoné, Mélanie
    Gauthier-Villars, Marion
    Caux-Moncoutier, Virginie
    de Pauw, Antoine
    Hardouin, Agnès
    Berthet, Pascaline
    Dreyfus, Hélène
    Ferrer, Sandra Fert
    Collonge-Rame, Marie-Agnès
    Sokolowska, Johanna
    Buys, Saundra
    Daly, Mary
    Miron, Alex
    Terry, Mary Beth
    Chung, Wendy
    John, Esther M
    Southey, Melissa
    Goldgar, David
    Singer, Christian F
    Tea, Muy-Kheng Maria
    Gschwantler-Kaulich, Daphne
    Fink-Retter, Anneliese
    Hansen, Thomas V O
    Ejlertsen, Bent
    Johannsson, Oskar T
    Offit, Kenneth
    Sarrel, Kara
    Gaudet, Mia M
    Vijai, Joseph
    Robson, Mark
    Piedmonte, Marion R
    Andrews, Lesley
    Cohn, David
    Demars, Leslie R
    Disilvestro, Paul
    Rodriguez, Gustavo
    Toland, Amanda Ewart
    Montagna, Marco
    Agata, Simona
    Imyanitov, Evgeny
    Isaacs, Claudine
    Janavicius, Ramunas
    Lazaro, Conxi
    Blanco, Ignacio
    Ramus, Susan J
    Sucheston, Lara
    Karlan, Beth Y
    Gross, Jenny
    Ganz, Patricia A
    Beattie, Mary S
    Schmutzler, Rita K
    Wappenschmidt, Barbara
    Meindl, Alfons
    Arnold, Norbert
    Niederacher, Dieter
    Preisler-Adams, Sabine
    Gadzicki, Dorotehea
    Varon-Mateeva, Raymonda
    Deissler, Helmut
    Gehrig, Andrea
    Sutter, Christian
    Kast, Karin
    Nevanlinna, Heli
    Aittomäki, Kristiina
    Simard, Jacques
    Spurdle, Amanda B
    Beesley, Jonathan
    Chen, Xiaoqing
    Tomlinson, Gail E
    Weitzel, Jeffrey
    Garber, Judy E
    Olopade, Olufunmilayo I
    Rubinstein, Wendy S
    Tung, Nadine
    Blum, Joanne L
    Narod, Steven A
    Brummel, Sean
    Gillen, Daniel L
    Lindor, Noralane
    Fredericksen, Zachary
    Pankratz, Vernon S
    Couch, Fergus J
    Radice, Paolo
    Peterlongo, Paolo
    Greene, Mark H
    Loud, Jennifer T
    Mai, Phuong L
    Andrulis, Irene L
    Glendon, Gord
    Ozcelik, Hilmi
    Gerdes, Anne-Marie
    Thomassen, Mads
    Jensen, Uffe Birk
    Skytte, Anne-Bine
    Caligo, Maria A
    Lee, Andrew
    Chenevix-Trench, Georgia
    Antoniou, Antonis C
    Neuhausen, Susan L
    A nonsynonymous polymorphism in IRS1 modifies risk of developing breast and ovarian cancers in BRCA1 and ovarian cancer in BRCA2 mutation carriers2012In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 21, no 8, p. 1362-1370Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: We previously reported significant associations between genetic variants in insulin receptor substrate 1 (IRS1) and breast cancer risk in women carrying BRCA1 mutations. The objectives of this study were to investigate whether the IRS1 variants modified ovarian cancer risk and were associated with breast cancer risk in a larger cohort of BRCA1 and BRCA2 mutation carriers.

    METHODS: IRS1 rs1801123, rs1330645, and rs1801278 were genotyped in samples from 36 centers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Data were analyzed by a retrospective cohort approach modeling the associations with breast and ovarian cancer risks simultaneously. Analyses were stratified by BRCA1 and BRCA2 status and mutation class in BRCA1 carriers.

    RESULTS: Rs1801278 (Gly972Arg) was associated with ovarian cancer risk for both BRCA1 (HR, 1.43; 95% confidence interval (CI), 1.06-1.92; P = 0.019) and BRCA2 mutation carriers (HR, 2.21; 95% CI, 1.39-3.52, P = 0.0008). For BRCA1 mutation carriers, the breast cancer risk was higher in carriers with class II mutations than class I mutations (class II HR, 1.86; 95% CI, 1.28-2.70; class I HR, 0.86; 95%CI, 0.69-1.09; P(difference), 0.0006). Rs13306465 was associated with ovarian cancer risk in BRCA1 class II mutation carriers (HR, 2.42; P = 0.03).

    CONCLUSION: The IRS1 Gly972Arg single-nucleotide polymorphism, which affects insulin-like growth factor and insulin signaling, modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers and breast cancer risk in BRCA1 class II mutation carriers.

    Impact: These findings may prove useful for risk prediction for breast and ovarian cancers in BRCA1 and BRCA2 mutation carriers.

  • 322. Dong, Ying
    et al.
    Kaushal, Aneel
    Brattsand, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Dermatology and Venerology.
    Nicklin, Jim
    Clements, Judith A
    Differential splicing of KLK5 and KLK7 in epithelial ovarian cancer produces novel variants with potential as cancer biomarkers2003In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 9, no 5, p. 1710-20Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The wild-type or variant mRNAs of several kallikrein (KLK) genes, such as KLK4, are highly expressed in ovarian carcinomas and may have potential as tumor markers. Two of these KLK genes (KLK5 and KLK7) and their proteins (hK5 and hK7) were first identified in the skin epidermis, where hK5 may be the physiological activator of hK7. The purpose of this study was to reexamine the expression of KLK5/hK5 and KLK7/hK7 and their association and to determine whether cancer-related variant transcripts were expressed.

    EXPERIMENTAL DESIGN: The expression of KLK5/hK5 and KLK7/hK7 was analyzed in the same cohort (n = 37) of benign (n = 4) and malignant ovarian tissue (n = 23) samples and primary cultured cells (n = 21) and in 8 ovarian cancer cell lines using semiquantitative RT-PCR; Southern, Northern, and Western blot analyses; and immunohistochemistry techniques.

    RESULTS: We showed the concordant higher expression of both KLK5/hK5 and KLK7/hK7 in ovarian carcinomas, especially late-stage serous carcinomas, compared with normal ovaries and benign adenomas. We also found that one novel KLK5 transcript with a short 5'-untranslated region and a novel KLK7 transcript with a long 3'-untranslated region were highly expressed in the ovarian cancer cell lines OVCAR-3 and PEO1, respectively, but were expressed at very low levels in normal ovarian epithelial cells. Both Western blot and immunohistochemistry analyses showed that these two enzymes are secreted from ovarian carcinoma cells.

    CONCLUSIONS: Our study demonstrated that hK5 and hK7, or more specifically, the short KLK5 and long KLK7 transcripts, may be useful as tumor markers for epithelial-derived serous carcinomas. However, additional clinical studies assessing serum levels of these putative biomarkers are required to confirm their usefulness in the diagnosis and/or monitoring of these tumors.

  • 323. Dossus, Laure
    et al.
    Allen, Naomi
    Kaaks, Rudolf
    Bakken, Kjersti
    Lund, Eiliv
    Tjonneland, Anne
    Olsen, Anja
    Overvad, Kim
    Clavel-Chapelon, Francoise
    Fournier, Agnes
    Chabbert-Buffet, Nathalie
    Boeing, Heiner
    Schütze, Madlen
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Lagiou, Pagona
    Palli, Domenico
    Krogh, Vittorio
    Tumino, Rosario
    Vineis, Paolo
    Mattiello, Amalia
    Bueno-de-Mesquita, H Bas
    Onland-Moret, N Charlotte
    Peeters, Petra H M
    Dumeaux, Vanessa
    Redondo, Maria-Luisa
    Duell, Eric
    Sanchez-Cantalejo, Emilio
    Arriola, Larraitz
    Chirlaque, Maria-Dolores
    Ardanaz, Eva
    Manjer, Jonas
    Borgquist, Signe
    Lukanova, Annie
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Wareham, Nicholas
    Key, Tim
    Chajes, Veronique
    Rinaldi, Sabina
    Slimani, Nadia
    Mouw, Traci
    Gallo, Valentina
    Riboli, Elio
    Reproductive risk factors and endometrial cancer: the European prospective investigation into cancer and nutrition2010In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 127, no 2, p. 442-451Article in journal (Refereed)
    Abstract [en]

    Endometrial cancer risk has been associated with reproductive factors (age at menarche, age at menopause, parity, age at first and last birth, time since last birth and use of oral contraceptives (OCs)]. However, these factors are closely interrelated and whether they act independently still requires clarification. We conducted a study to examine the association of menstrual and reproductive variables with the risk of endometrial cancer among the European Prospective Investigation into Cancer and Nutrition (EPIC). Among the 302,618 women eligible for the study, 1,017 incident endometrial cancer cases were identified. A reduction in endometrial cancer risk was observed in women with late menarche, early menopause, past OC use, high parity and a shorter time since last full-term pregnancy (FTP). No association was observed for duration of breast feeding after adjustment for number of FTP or for abortion (spontaneous or induced). After mutual adjustment, late age at menarche, early age at menopause and duration of OC use showed similar risk reductions of 7-8% per year of menstrual life, whereas the decreased risk associated with cumulative duration of FTPs was stronger (22% per year). In conclusion, our findings confirmed a reduction in risk of endometrial cancer with factors associated with a lower cumulative exposure to estrogen and/or higher exposure to progesterone, such as increasing number of FTPs and shorter menstrual lifespan and, therefore, support an important role of hormonal mechanisms in endometrial carcinogenesis.

  • 324.
    Dossus, Laure
    et al.
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Becker, Susen
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Rinaldi, Sabina
    Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.
    Lukanova, Annekatrin
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Tjønneland, Anne
    Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
    Olsen, Anja
    Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark.
    Overvad, Kim
    Department of Epidemiology, School of Public Health, Aarhus University, Aarhus, Denmark.
    Chabbert-Buffet, Nathalie
    Department of Obstetrics and Gynecology, APHP Hospital Tenon and UMPC, Paris, France.
    Boutron-Ruault, Marie-Christine
    INSERM, Centre for Research in Epidemiology and Population Health, Paris South University, Gustave Roussy Institute, Villejuif, France.
    Clavel-Chapelon, Françoise
    INSERM, Centre for Research in Epidemiology and Population Health, Paris South University, Gustave Roussy Institute, Villejuif, France.
    Teucher, Birgit
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Chang-Claude, Jenny
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Pischon, Tobias
    Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
    Boeing, Heiner
    Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
    Trichopoulou, Antonia
    Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Food and Nutrition Policies, University of Athens Medical School, Athens, Greece.
    Benetou, Vasiliki
    Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Food and Nutrition Policies, University of Athens Medical School, Athens, Greece.
    Valanou, Elisavet
    Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Food and Nutrition Policies, University of Athens Medical School, Athens, Greece.
    Palli, Domenico
    Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, Italy.
    Sieri, Sabina
    Department of Preventive and Predictive Medicine, Nutritional Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
    Tumino, Rosario
    Cancer Registry and Histopathology Unit, “Civile – M.P. Arezzo” Hospital, Ragusa, Italy.
    Sacerdote, Carlotta
    Center for Cancer Prevention (CPO Piedmont), Turin, Italy.
    Galasso, Rocco
    Instituto di Ricovero e Cura a Carattere Scientifico (IRCCS-CROOB), Rionero in Vulture (PZ), Italy.
    Redondo, Maria-Luísa
    Public Health and Participation Directorate, Health and Health Care Services Council, Asturias, Spain.
    Bonet Bonet, Catalina
    Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Programme, Catalan Institute of Oncology (ICO), Barcelona, Spain.
    Molina-Montes, Esther
    Andalusian School of Public Health, Granada, Spain.
    Altzibar, Jone M
    CIBER de Epidemiología y Salud Pública (CIBERESP), Spain.
    Chirlaque, Maria-Dolores
    CIBER de Epidemiología y Salud Pública (CIBERESP), Spain.
    Ardanaz, Eva
    CIBER de Epidemiología y Salud Pública (CIBERESP), Spain.
    Bueno-de-Mesquita, H Bas
    CIBER de Epidemiología y Salud Pública (CIBERESP), Spain.
    van Duijnhoven, Fränzel J B
    National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
    Peeters, Petra H M
    Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands.
    Onland-Moret, N Charlotte
    Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands.
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Idahl, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Khaw, Kay-Tee
    Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
    Wareham, Nicholas
    MRC Epidemiology Unit, Cambridge, United Kingdom.
    Allen, Naomi
    Nuffield Department of Clinical Medicine, Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom.
    Romieu, Isabelle
    International Agency for Research on Cancer, Lyon, France.
    Fedirko, Veronika
    International Agency for Research on Cancer, Lyon, France.
    Hainaut, Pierre
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, United Kingdom.
    Romaguera, Dora
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, United Kingdom.
    Norat, Teresa
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, United Kingdom.
    Riboli, Elio
    Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, United Kingdom.
    Kaaks, Rudolf
    Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    Tumor necrosis factor (TNF)-α, soluble TNF receptors and endometrial cancer risk: the EPIC study2011In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 129, no 8, p. 2032-2037Article in journal (Refereed)
    Abstract [en]

    Chronic inflammation has been hypothesized to play a role in endometrial cancer development. Tumor necrosis factor-α (TNF-α), one of the major pro-inflammatory cytokines, has also been implicated in endometrial physiology. We conducted a case-control study nested within the European prospective investigation into cancer and nutrition (EPIC) to examine the association of TNF-α and its two soluble receptors (sTNFR1 and sTNFR2) with endometrial cancer risk. Two-hundred-seventy cases and 518 matched controls were analyzed using conditional logistic regression. All statistical tests were two-sided. We observed an increased risk of endometrial cancer among women in the highest versus lowest quartile of TNF-α (odds ratio [OR]: 1.73, 95% CI: 1.09-2.73, Ptrend = 0.01), sTNFR1 (OR: 1.68, 95% CI: 0.99-2.86, Ptrend = 0.07) and sTNFR2 (OR: 1.53, 95%CI: 0.92-2.55, Ptrend = 0.03) after adjustment for body-mass-index, parity, age at menopause and previous postmenopausal hormone therapy use. Further adjustments for estrogens and C-peptide had minor effect on risk estimates. Our data show that elevated prediagnostic concentrations of TNF-α and its soluble receptors are related to a higher risk of endometrial cancer, particularly strong in women diagnosed within 2 years of blood donation. This is the first study of its kind and therefore deserves replication in further prospective studies.

  • 325. Dossus, Laure
    et al.
    Kaaks, Rudolf
    Canzian, Federico
    Albanes, Demetrius
    Berndt, Sonja I
    Boeing, Heiner
    Buring, Julie
    Chanock, Stephen J
    Clavel-Chapelon, Francoise
    Feigelson, Heather Spencer
    Gaziano, John M
    Giovannucci, Edward
    Gonzalez, Carlos
    Haiman, Christopher A
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hankinson, Susan E
    Hayes, Richard B
    Henderson, Brian E
    Hoover, Robert N
    Hunter, David J
    Khaw, Kay-Tee
    Kolonel, Laurence N
    Kraft, Peter
    Ma, Jing
    Le Marchand, Loic
    Lund, Eiliv
    Peeters, Petra H M
    Stampfer, Meir
    Stram, Dan O
    Thomas, Gilles
    Thun, Michael J
    Tjonneland, Anne
    Trichopoulos, Dimitrios
    Tumino, Rosario
    Riboli, Elio
    Virtamo, Jarmo
    Weinstein, Stephanie J
    Yeager, Meredith
    Ziegler, Regina G
    Cox, David G
    PTGS2 and IL6 genetic variation and risk of breast and prostate cancer: results from the Breast and Prostate Cancer Cohort Consortium (BPC3)2010In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 31, no 3, p. 455-461Article in journal (Refereed)
    Abstract [en]

    Genes involved in the inflammation pathway have been associated with cancer risk. Genetic variants in the interleukin-6 (IL6) and prostaglandin-endoperoxide synthase-2 (PTGS2, encoding for the COX-2 enzyme) genes, in particular, have been related to several cancer types, including breast and prostate cancers. We conducted a study within the Breast and Prostate Cancer Cohort Consortium to examine the association between IL6 and PTGS2 polymorphisms and breast and prostate cancer risk. Twenty-seven polymorphisms, selected by pairwise tagging, were genotyped on 6292 breast cancer cases and 8135 matched controls and 8008 prostate cancer cases and 8604 matched controls. The large sample sizes and comprehensive single nucleotide polymorphism tagging in this study gave us excellent power to detect modest effects for common variants. After adjustment for multiple testing, none of the associations examined remained statistically significant at P = 0.01. In analyses not adjusted for multiple testing, one IL6 polymorphism (rs6949149) was marginally associated with breast cancer risk (TT versus GG, odds ratios (OR): 1.32; 99% confidence intervals (CI): 1.00-1.74, P(trend) = 0.003) and two were marginally associated with prostate cancer risk (rs6969502-AA versus rs6969502-GG, OR: 0.87, 99% CI: 0.75-1.02; P(trend) = 0.002 and rs7805828-AA versus rs7805828-GG, OR: 1.11, 99% CI: 0.99-1.26; P(trend) = 0.007). An increase in breast cancer risk was observed for the PTGS2 polymorphism rs7550380 (TT versus GG, OR: 1.38, 99% CI: 1.04-1.83). No association was observed between PTGS2 polymorphisms and prostate cancer risk. In conclusion, common genetic variation in these two genes might play at best a limited role in breast and prostate cancers.

  • 326. Dossus, Laure
    et al.
    Lukanova, Annekatrin
    Rinaldi, Sabina
    Allen, Naomi
    Cust, Anne E
    Becker, Susen
    Tjonneland, Anne
    Hansen, Louise
    Overvad, Kim
    Chabbert-Buffet, Nathalie
    Mesrine, Sylvie
    Clavel-Chapelon, Francoise
    Teucher, Birgit
    Chang-Claude, Jenny
    Boeing, Heiner
    Drogan, Dagmar
    Trichopoulou, Antonia
    Benetou, Vasiliki
    Bamia, Christina
    Palli, Domenico
    Agnoli, Claudia
    Galasso, Rocco
    Tumino, Rosario
    Sacerdote, Carlotta
    Bueno-de-Mesquita, H Bas
    van Duijnhoven, Fränzel J B
    Peeters, Petra H M
    Onland-Moret, N Charlotte
    Redondo, Maria-Luisa
    Travier, Noémie
    Sanchez, Maria-Jose
    Altzibar, Jone M
    Chirlaque, Maria-Dolores
    Barricarte, Aurelio
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Wareham, Nicholas
    Fedirko, Veronika
    Romieu, Isabelle
    Romaguera, Dora
    Norat, Teresa
    Riboli, Elio
    Kaaks, Rudolf
    Hormonal, metabolic, and inflammatory profiles and endometrial cancer risk within the EPIC cohort--a factor analysis.2013In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 177, no 8, p. 787-799Article in journal (Refereed)
    Abstract [en]

    A "Western" lifestyle characterized by physical inactivity and excess weight is associated with a number of metabolic and hormonal dysregulations, including increased circulating estrogen levels, hyperinsulinemia, hyperglycemia, and chronic inflammation. The same hormonal and metabolic axes might mediate the association between this lifestyle and the development of endometrial cancer. Using data collected within the European Prospective Investigation into Cancer and Nutrition (EPIC), a prospective cohort study carried out in 10 European countries during 1992-2000, we conducted a factor analysis to delineate important components that summarize the variation explained by a set of biomarkers and to examine their association with endometrial cancer risk. Prediagnostic levels of testosterone, androstenedione, dehydroepiandrosterone sulfate, sex hormone-binding globulin, estrone, estradiol, C-peptide, insulin-like growth factor-binding proteins 1 and 2, adiponectin, high- and low-density lipoprotein cholesterol, glucose, triglycerides, tumor necrosis factor (TNF) α, soluble TNF receptors 1 and 2, C-reactive protein, interleukin-6, and interleukin-1 receptor antagonist were measured in 233 incident endometrial cancer cases and 446 matched controls. Factor analysis identified 3 components associated with postmenopausal endometrial cancer risk that could be labeled "insulin resistance/metabolic syndrome," "steroids," and "inflammation" factors. A fourth component, "lipids," was not significantly associated with endometrial cancer. In conclusion, besides the well-known associations of risk with sex hormones and insulin-regulated physiological axes, our data further support the hypothesis that inflammation factors play a role in endometrial carcinogenesis.

  • 327. Duarte-Salles, Talita
    et al.
    Fedirko, Veronika
    Stepien, Magdalena
    Aleksandrova, Krasimira
    Bamia, Christina
    Lagiou, Pagona
    Laursen, Anne Sofie Dam
    Hansen, Louise
    Overvad, Kim
    Tjønneland, Anne
    Boutron-Ruault, Marie-Christine
    Fagherazzi, Guy
    His, Mathilde
    Boeing, Heiner
    Katzke, Verena
    Kühn, Tilman
    Trichopoulou, Antonia
    Valanou, Elissavet
    Kritikou, Maria
    Masala, Giovanna
    Panico, Salvatore
    Sieri, Sabina
    Ricceri, Fulvio
    Tumino, Rosario
    Bueno-de-Mesquita, H B As
    Peeters, Petra H
    Hjartåker, Anette
    Skeie, Guri
    Weiderpass, Elisabete
    Ardanaz, Eva
    Bonet, Catalina
    Chirlaque, Maria-Dolores
    Dorronsoro, Miren
    Quirós, J Ramón
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Ohlsson, Bodil
    Sjöberg, Klas
    Wennberg, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Khaw, Kay-Tee
    Travis, Ruth C
    Wareham, Nick
    Ferrari, Pietro
    Freisling, Heinz
    Romieu, Isabelle
    Cross, Amanda J
    Gunter, Marc
    Lu, Yunxia
    Jenab, Mazda
    Dietary fat, fat subtypes and hepatocellular carcinoma in a large European cohort2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 137, no 11, p. 2715-2728Article in journal (Refereed)
    Abstract [en]

    The role of amount and type of dietary fat consumption in the etiology of hepatocellular carcinoma (HCC) is poorly understood, despite suggestive biological plausibility. The associations of total fat, fat subtypes and fat sources with HCC incidence were investigated in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, which includes 191 incident HCC cases diagnosed between 1992 and 2010. Diet was assessed by country-specific, validated dietary questionnaires. A single 24-hr diet recall from a cohort subsample was used for measurement error calibration. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated from Cox proportional hazard models. Hepatitis B and C viruses (HBV/HCV) status and biomarkers of liver function were assessed separately in a nested case-control subset with available blood samples (HCC = 122). In multivariable calibrated models, there was a statistically significant inverse association between total fat intake and risk of HCC (per 10 g/day, HR = 0.80, 95% CI: 0.65-0.99), which was mainly driven by monounsaturated fats (per 5 g/day, HR = 0.71, 95% CI: 0.55-0.92) rather than polyunsaturated fats (per 5 g/day, HR = 0.92, 95% CI: 0.68-1.25). There was no association between saturated fats (HR = 1.08, 95% CI: 0.88-1.34) and HCC risk. The ratio of polyunsaturated/monounsaturated fats to saturated fats was not significantly associated with HCC risk (per 0.2 point, HR = 0.86, 95% CI: 0.73-1.01). Restriction of analyses to HBV/HCV free participants or adjustment for liver function did not substantially alter the findings. In this large prospective European cohort, higher consumption of monounsaturated fats is associated with lower HCC risk.

  • 328. Duarte-Salles, Talita
    et al.
    Fedirko, Veronika
    Stepien, Magdalena
    Trichopoulou, Antonia
    Bamia, Christina
    Lagiou, Pagona
    Lukanova, Annekatrin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Trepo, Elisabeth
    Overvad, Kim
    Tjønneland, Anne
    Halkjaer, Jytte
    Boutron-Ruault, Marie-Christine
    Racine, Antoine
    Cadeau, Claire
    Kühn, Tilman
    Aleksandrova, Krasimira
    Trichopoulos, Dimitrios
    Tsiotas, Konstantinos
    Boffetta, Paolo
    Palli, Domenico
    Pala, Valeria
    Tumino, Rosario
    Sacerdote, Carlotta
    Panico, Salvatore
    Bueno-de-Mesquita, H B as
    Dik, Vincent K
    Peeters, Petra H
    Weiderpass, Elisabete
    Torhild Gram, Inger
    Hjartåker, Anette
    Ramón Quirós, Jose
    Fonseca-Nunes, Ana
    Molina-Montes, Esther
    Dorronsoro, Miren
    Navarro Sanchez, Carmen
    Barricarte, Aurelio
    Lindkvist, Björn
    Sonestedt, Emily
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Wennberg, Maria
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Khaw, Kay-Tee
    Wareham, Nick
    Travis, Ruth C
    Romieu, Isabelle
    Riboli, Elio
    Jenab, Mazda
    Dairy products and risk of hepatocellular carcinoma: the European Prospective Investigation into Cancer and Nutrition2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 135, no 7, p. 1662-1672Article in journal (Refereed)
    Abstract [en]

    Intake of dairy products has been associated with risk of some cancers, but findings are often inconsistent and information on hepatocellular carcinoma (HCC) risk is limited, particularly from prospective settings. The aim of our study was to investigate the association between consumption of total and specific dairy products (milk/cheese/yogurt) and their components (calcium/vitamin D/fats/protein), with first incident HCC (N(cases) = 191) in the European Prospective Investigation into Cancer and Nutrition cohort, including a nested case-control subset (N(cases) = 122) with the assessment of hepatitis B virus/hepatitis C virus infections status, liver damage and circulating insulin-like growth factor (IGF)-I levels. For cohort analyses, multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI). For nested case-control analyses, conditional logistic regression was used to calculate odds ratios and 95% CI. A total of 477,206 participants were followed-up for an average of 11 years (person-years follow-up = 5,415,385). In the cohort study, a significant positive HCC risk association was observed for total dairy products (highest vs. lowest tertile, HR = 1.66, 95% CI: 1.13-2.43; p(trend) = 0.012), milk (HR = 1.51, 95% CI: 1.02-2.24; p(trend) = 0.049), and cheese (HR = 1.56, 95% CI: 1.02-2.38; p(trend) = 0.101), but not yogurt (HR = 0.94, 95% CI: 0.65-1.35). Dietary calcium, vitamin D, fat and protein from dairy sources were associated with increased HCC risk, whereas the same nutrients from nondairy sources showed inverse or null associations. In the nested case-control study, similar results were observed among hepatitis-free individuals. Results from this large prospective cohort study suggest that higher consumption of dairy products, particularly milk and cheese, may be associated with increased HCC risk. Validation of these findings in other populations is necessary. Potential biologic mechanisms require further exploration.

  • 329. Duell, Eric J
    et al.
    Bonet, Catalina
    Muñoz, Xavier
    Lujan-Barroso, Leila
    Weiderpass, Elisabete
    Boutron-Ruault, Marie-Christine
    Racine, Antoine
    Severi, Gianluca
    Canzian, Federico
    Rizzato, Cosmeri
    Boeing, Heiner
    Overvad, Kim
    Tjønneland, Anne
    Argüelles, Marcial
    Sánchez-Cantalejo, Emilio
    Chamosa, Saioa
    Huerta, José María
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nick
    Travis, Rutch C
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Yiannakouris, Nikos
    Palli, Domenico
    Agnoli, Claudia
    Tumino, Rosario
    Naccarati, Alessio
    Panico, Salvatore
    Bueno-de-Mesquita, H B As
    Siersema, Peter D
    Peeters, Petra H M
    Ohlsson, Bodil
    Lindkvist, Björn
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Ye, Weimin
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    Johansson, Matthias
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Fenger, Claus
    Riboli, Elio
    Sala, Núria
    González, Carlos A
    Variation at ABO histo-blood group and FUT loci and diffuse and intestinal gastric cancer risk in a European population2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 136, no 4, p. 880-893Article in journal (Refereed)
    Abstract [en]

    ABO blood serotype A is known to be associated with risk of gastric cancer (GC), but little is known how ABO alleles and the fucosyltransferase (FUT) enzymes and genes which are involved in Lewis antigen formation [and in Helicobacter pylori (H. pylori) binding and pathogenicity] may be related to GC risk in a European population. The authors conducted an investigation of 32 variants at ABO and FUT1-7 loci and GC risk in a case-control study of 365 cases and 1,284 controls nested within the EPIC cohort (the EPIC-Eurgast study). Four variants (including rs505922) in ABO, and allelic blood group A (AO+AA, odds ratio = 1.84, 95%CI = 1.20-2.80) were associated with diffuse-type GC; however, conditional models with other ABO variants indicated that the associations were largely due to allelic blood group A. One variant in FUT5 was also associated with diffuse-type GC, and four variants (and haplotypes) in FUT2 (Se), FUT3 (Le) and FUT6 with intestinal-type GC. Further, one variant in ABO, two in FUT3 and two in FUT6 were associated with H. pylori infection status in controls, and two of these (in FUT3 and FUT6) were weakly associated with intestinal-type GC risk. None of the individual variants surpassed a Bonferroni corrected p-value cutoff of 0.0016; however, after a gene-based permutation test, two loci [FUT3(Le)/FUT5/FUT6 and FUT2(Se)] were significantly associated with diffuse- and intestinal-type GC, respectively. Replication and functional studies are therefore recommended to clarify the role of ABO and FUT alleles in H. pylori infection and subtype-specific gastric carcinogenesis.

  • 330. Duell, Eric J.
    et al.
    Sala, Nuria
    Travier, Noemie
    Munoz, Xavier
    Christine Boutron-Ruault, Marie
    Clavel-Chapelon, Francoise
    Barricarte, Aurelio
    Arriola, Larraitz
    Navarro, Carmen
    Sanchez-Cantalejo, Emilio
    Ramon Quiros, J.
    Krogh, Vittorio
    Vineis, Paolo
    Mattiello, Amalia
    Tumino, Rosario
    Khaw, Kay-Tee
    Wareham, Nicholas
    Allen, Naomi E.
    Peeters, Petra H.
    Numans, Mattijs E.
    Bueno-de-Mesquita, H. B.
    van Oijen, M. G. H.
    Bamia, Christina
    Benetou, Vassiliki
    Trichopoulos, Dimitrios
    Canzian, Federico
    Kaaks, Rudolf
    Boeing, Heiner
    Bergmann, Manuela M.
    Lund, Eiliv
    Ehrnstrom, Roy
    Johansen, Dorthe
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tjonneland, Anne
    Overvad, Kim
    Ostergaard, Jane Nautrup
    Ferrari, Pietro
    Fedirko, Veronika
    Jenab, Mazda
    Nesi, Gabriella
    Riboli, Elio
    Gonzalez, Carlos A.
    Genetic variation in alcohol dehydrogenase (ADH1A, ADH1B, ADH1C, ADH7) and aldehyde dehydrogenase (ALDH2), alcohol consumption and gastric cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort2012In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 33, no 2, p. 361-367Article in journal (Refereed)
    Abstract [en]

    Studies that have examined the association between alcohol consumption and gastric cancer (GC) risk have been inconsistent. We conducted an investigation of 29 genetic variants in alcohol metabolism loci (alcohol dehydrogenase, ADH1 gene cluster: ADH1A, ADH1B and ADH1C; ADH7 and aldehyde dehydrogenase, ALDH2), alcohol intake and GC risk. We analyzed data from a nested case-control study (364 cases and 1272 controls) within the European Prospective Investigation into Cancer and Nutrition cohort. Single nucleotide polymorphisms (SNPs) were genotyped using a customized array. We observed a statistically significant association between a common 3'-flanking SNP near ADH1A (rs1230025) and GC risk [allelic odds ratio (OR)(A v T) = 1.30, 95% confidence interval (CI) = 1.07-1.59]. Two intronic variants, one in ADH1C (rs283411) and one in ALDH2 (rs16941667), also were associated with GC risk (ORT v C = 0.59; 95% CI = 0.38-0.91 and ORT v C = 1.34; 95% CI = 1.00-1.79, respectively). Individuals carrying variant alleles at both ADH1 (rs1230025) and ALDH2 (rs16941667) were twice as likely to develop GC (ORA+T = 2.0; 95% CI = 1.25-3.20) as those not carrying variant alleles. The association between rs1230025 and GC was modified by alcohol intake (< 5 g/day: ORA = 0.89, 95% CI = 0.57-1.39; >= 5 g/day: ORA = 1.45, 95% CI = 1.08-1.94, P-value = 0.05). The association was also modified by ethanol intake from beer. A known functional SNP in ADH1B (rs1229984) was associated with alcohol intake (P-value = 0.04) but not GC risk. Variants in ADH7 were not associated with alcohol intake or GC risk. In conclusion, genetic variants at ADH1 and ALDH2 loci may influence GC risk, and alcohol intake may further modify the effect of ADH1 rs1230025. Additional population-based studies are needed to confirm our results.

  • 331. Duell, Eric J.
    et al.
    Travier, Noemie
    Lujan-Barroso, Leila
    Dossus, Laure
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Tumino, Rosario
    Masala, Giovanna
    Krogh, Vittorio
    Panico, Salvatore
    Ricceri, Fulvio
    Luisa Redondo, Maria
    Dorronsoro, Miren
    Molina-Montes, Esther
    Huerta, Jose M.
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nick J.
    Allen, Naomi E.
    Travis, Ruth
    Siersema, Peter D.
    Peeters, Petra H. M.
    Trichopoulou, Antonia
    Fragogeorgi, Eirini
    Oikonomou, Eleni
    Boeing, Heiner
    Schuetze, Madlen
    Canzian, Federico
    Lukanova, Annekatrin
    Tjonneland, Anne
    Roswall, Nina
    Overvad, Kim
    Weiderpass, Elisabete
    Gram, Inger Torhild
    Lund, Eiliv
    Lindkvist, Bjorn
    Johansen, Dorthe
    Ye, Weimin
    Umeå University, Faculty of Medicine, Department of Biobank Research.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Fedirko, Veronika
    Jenab, Mazda
    Michaud, Dominique S.
    Riboli, Elio
    Bueno-de-Mesquita, H. Bas
    Menstrual and reproductive factors in women, genetic variation in CYP17A1, and pancreatic cancer risk in the European prospective investigation into cancer and nutrition (EPIC) cohort2013In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 132, no 9, p. 2164-2175Article in journal (Refereed)
    Abstract [en]

    Menstrual and reproductive factors and exogenous hormone use have been investigated as pancreatic cancer risk factors in case-control and cohort studies, but results have been inconsistent. We conducted a prospective examination of menstrual and reproductive factors, exogenous hormone use and pancreatic cancer risk (based on 304 cases) in 328,610 women from the EPIC cohort. Then, in a case-control study nested within the EPIC cohort, we examined 12 single nucleotide polymorphisms (SNPs) in CYP17A1 (an essential gene in sex steroid metabolism) for association with pancreatic cancer in women and men (324 cases and 353 controls). Of all factors analyzed, only younger age at menarche (<12 vs. 13 years) was moderately associated with an increased risk of pancreatic cancer in the full cohort; however, this result was marginally significant (HR = 1.44; 95% CI = 0.992.10). CYP17A1 rs619824 was associated with HRT use (p value = 0.037) in control women; however, none of the SNPs alone, in combination, or as haplotypes were associated with pancreatic cancer risk. In conclusion, with the possible exception of an early age of menarche, none of the menstrual and reproductive factors, and none of the 12 common genetic variants we evaluated at the CYP17A1 locus makes a substantial contribution to pancreatic cancer susceptibility in the EPIC cohort.

  • 332. 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)
  • 333. Eckel-Passow, Jeanette
    et al.
    Decker, Paul
    Kosel, Matthew
    Kollmeyer, Thomas
    Molinaro, Annette
    Rice, Terri
    Caron, Alissa
    Drucker, Kristen
    Praska, Corinne
    Pekmezci, Melike
    Hansen, Helen
    McCoy, Lucie
    Bracci, Paige
    Erickson, Bradley
    Wiemels, Joseph
    Wiencke, John
    Bondy, Melissa
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Burns, Terry
    Giannini, Caterina
    Lachance, Daniel
    Wrensch, Margaret
    Jenkins, Robert
    USING GERMLINE VARIANTS TO PREDICT GLIOMA RISK AND IDENTIFY GLIOMA SUBTYPE PRE-OPERATIVELY2018In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, p. 82-82Article in journal (Other academic)
    Abstract [en]

    To date, 25 single nucleotide polymorphisms (SNPs) have been shown to be associated with overall glioma risk or with risk of specific subtypes of glioma. We hypothesized that the inclusion of these 25 SNPs with patient age at diagnosis and sex could predict risk of glioma as well as predict IDH mutation status. Thus, case-control design and multinomial logistic regression were used to develop models to estimate the risk of glioma development while accounting for molecular subtypes. Case-case design and logistic regression were used to develop models to predict IDH mutation status. Each model included all 25 glioma risk SNPs, patient age at diagnosis and sex. A total of 1273 glioma cases and 443 controls from Mayo Clinic were used in the discovery set, and 852 glioma cases and 231 controls from UCSF were used in the validation set. All samples were genotyped using a custom Illumina OncoArray. We observed that patients in the highest 5% of the risk score had more than a 14-fold increased relative risk of developing an IDH-mutant glioma, compared to patients with median risk score. Large differences in lifetime absolute risk were observed at the extremes of the risk score percentile categories. For both IDH-mutated 1p/19q non-codeleted glioma and IDH-mutated 1p/19q-codeleted glioma, the lifetime risk increased from almost null to 2.3% and almost null to 1.7%, respectively. The SNP-based model that predicted IDH mutation status had a validation c-index of 0.85. These results suggest that germline genotyping has the potential to provide a new tool for clinicians for the initial management of newly-discovered brain lesions. Specifically, given the low lifetime risk of glioma, SNP-based risk scores should not be useful for general population screening. However, with further research these risk scores may be useful in certain clinically-defined high-risk groups.

  • 334. Eckel-Passow, Jeanette
    et al.
    Decker, Paul
    Kosel, Matthew
    Kollmeyer, Thomas
    Sarkar, Gobinda
    Caron, Alissa
    Bracci, Paige
    Hansen, Helen
    Madsen, Nils
    McCoy, Lucie
    Molinaro, Annette
    Rice, Terri
    Walsh, Kyle
    Giannini, Caterina
    Parney, Ian
    Wiemels, Joseph
    Wiencke, John
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bondy, Melissa
    Lachance, Daniel
    Wrensch, Margaret
    Jenkins, Robert
    ASSOCIATION OF KNOWN GLIOMA GERMLINE RISK SNPs WITHIN MOLECULARLY-DEFINED GROUPS2016In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 18, p. 57-57Article in journal (Refereed)
  • 335. Eckel-Passow, Jeanette E.
    et al.
    Decker, Paul A.
    Kosel, Matt L.
    Kollmeyer, Thomas M.
    Molinaro, Annette M.
    Rice, Terri
    Caron, Alissa A.
    Drucker, Kristen L.
    Praska, Corinne E.
    Pekmezci, Melike
    Hansen, Helen M.
    McCoy, Lucie S.
    Bracci, Paige M.
    Erickson, Bradley J.
    Lucchinetti, Claudia F.
    Wiemels, Joseph L.
    Wiencke, John K.
    Bondy, Melissa L.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Burns, Terry C.
    Giannini, Caterina
    Lachance, Daniel H.
    Wrensch, Margaret R.
    Jenkins, Robert B.
    Using germline variants to estimate glioma and subtype risks2019In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 21, no 4, p. 451-461Article in journal (Refereed)
    Abstract [en]

    Background: Twenty-five single nucleotide polymorphisms (SNPs) are associated with adult diffuse glioma risk. We hypothesized that the inclusion of these 25 SNPs with age at diagnosis and sex could estimate risk of glioma as well as identify glioma subtypes.

    Methods: Case-control design and multinomial logistic regression were used to develop models to estimate the risk of glioma development while accounting for histologic and molecular subtypes. Case-case design and logistic regression were used to develop models to predict isocitrate dehydrogenase (IDH) mutation status. A total of 1273 glioma cases and 443 controls from Mayo Clinic were used in the discovery set, and 852 glioma cases and 231 controls from UCSF were used in the validation set. All samples were genotyped using a custom Illumina OncoArray.

    Results: Patients in the highest 5% of the risk score had more than a 14-fold increase in relative risk of developing an IDH mutant glioma. Large differences in lifetime absolute risk were observed at the extremes of the risk score percentile. For both IDH mutant 1p/19q non-codeleted glioma and IDH mutant 1p/19q codeleted glioma, the lifetime risk increased from almost null to 2.3% and almost null to 1.7%, respectively. The SNP-based model that predicted IDH mutation status had a validation concordance index of 0.85.

    Conclusions: These results suggest that germline genotyping can provide new tools for the initial management of newly discovered brain lesions. Given the low lifetime risk of glioma, risk scores will not be useful for population screening; however, they may be useful in certain clinically defined high-risk groups.

  • 336.
    Edin, Sofia
    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.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Macrophages: Good guys in colorectal cancer2013In: Oncoimmunology, ISSN 2162-4011, Vol. 2, no 2, p. e23038-Article in journal (Refereed)
    Abstract [en]

    Macrophages play a complex role in tumor progression since they can exert both tumor-preventing (M1 macrophages) and tumor-promoting (M2 macrophages) activities. In colorectal carcinoma (CRC), at odds to many other cancers, macrophage infiltration has been correlated with an improved patient survival. In a recent study, we have evaluated the distribution of M1 and M2 macrophage subtypes in CRC and their impact on patient prognosis.

  • 337.
    Edin, Sofia
    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.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Phenotypic skewing of macrophages in vitro by secreted factors from colorectal cancer cells2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e74982-Article in journal (Refereed)
    Abstract [en]

    Macrophages are cells with many important functions in both innate and adaptive immune responses and have been shown to play a complex role in tumor progression since they harbour both tumor preventing (M1 macrophages) and tumor promoting (M2 macrophages) activities. In many human cancers, infiltrating macrophages have been associated with a poor patient prognosis, and therefore suggested to be mainly of an M2 phenotype. However, we and others have previously shown that increased macrophage density in colorectal cancer (CRC) instead is correlated with an improved prognosis. It is an intriguing question if the different roles played by macrophages in various cancers could be explained by variations in the balance between M1 and M2 macrophage attributes, driven by tumor- or organ-specific factors in the tumor microenvironment of individual cancers. Here, we utilized an in vitro cell culture system of macrophage differentiation to compare differences and similarities in the phenotype (morphology, antigen-presentation, migration, endocytosis, and expression of cytokine and chemokine genes) between M1/M2 and tumor activated macrophages (TAMs), that could explain the positive role of macrophages in CRC. We found that secreted factors from CRC cells induced TAMs of a "mixed" M1/M2 phenotype, which in turn could contribute to a "good inflammatory response". This suggests that re-education of macrophages might allow for important therapeutic advances in the treatment of human cancer.

  • 338.
    Edlinger, M.
    et al.
    Medical University Innsbruck, Innsbruck, Austria.
    Bjorge, T.
    University of Bergen, Bergen, Norway; Norwegian Institute of Public Health, Oslo, Norway.
    Manjer, J.
    Skåne University Hospital Malmö and Lund University, Malmö, Sweden.
    Stattin, Pär
    Ulmer, H.
    Umeå University.
    Metabolic syndrome and risk of brain tumour in a large population-based cohort study2011In: IEA World Congress of Epidemiology, 7–11 August 2011, Edinburgh International Conference Centre, Edinburgh, Scotland: Programme and abstracts, 2011, Vol. 65Conference paper (Refereed)
    Abstract [en]

    Background: There are few established determinants of brain tumour. We assessed among adults the risk of brain tumour in relation to metabolic syndrome factors.

    Methods: 580 000 subjects from Sweden, Austria, and Norway were followed for a median of 10 years (Me-Can). Brain tumour information was obtained from national cancer registries. The factors of metabolic syndrome, body mass index, blood pressure, and blood levels of glucose, cholesterol, and triglycerides, were analysed in quintiles and for transformed z-scores (mean of 0 and SD of 1). Cox proportional hazards regression models were applied, stratified by cohort and corrected for measurement error.

    Results: In total 1312 primary brain tumours were diagnosed during follow-up, predominantly high-grade glioma (n=436) and meningioma (n=348). For meningioma, the HR was increased for systolic blood pressure (HR=1.27 per unit SD, 95% CI 1.03 to 1.57), for diastolic blood pressure (HR=1.29, 95% CI 1.04 to 1.58), and for the combined metabolic syndrome score (HR=1.31, 95% CI 1.11 to 1.54). For high-grade glioma the risk was increased for diastolic blood pressure (HR=1.23, 95% CI 1.01 to 1.50) and triglycerides (HR=1.35, 95% CI 1.05 to 1.72). For both meningioma and high-grade glioma, the risk was more than doubled in the fifth quintiles of diastolic blood pressure compared to the first quintile. For systolic blood pressure the meningioma risk was even larger.

    Conclusion: Increased blood pressure was related to risk of brain tumour, particularly of meningiomas.

  • 339. Edmund, Jens M.
    et al.
    Nyholm, Tufve
    Umeå University, Faculty of Medicine, Department of Radiation Sciences. Medical Radiation Physics, Department of Immunology, Genetics and Pathology, Uppsala University.
    A review of substitute CT generation for MRI-only radiation therapy2017In: Radiation Oncology, ISSN 1748-717X, E-ISSN 1748-717X, Vol. 12, article id 28Article, review/survey (Refereed)
    Abstract [en]

    Radiotherapy based on magnetic resonance imaging as the sole modality (MRI-only RT) is an area of growing scientific interest due to the increasing use of MRI for both target and normal tissue delineation and the development of MR based delivery systems. One major issue in MRI-only RT is the assignment of electron densities (ED) to MRI scans for dose calculation and a similar need for attenuation correction can be found for hybrid PET/MR systems. The ED assigned MRI scan is here named a substitute CT (sCT). In this review, we report on a collection of typical performance values for a number of main approaches encountered in the literature for sCT generation as compared to CT. A literature search in the Scopus database resulted in 254 papers which were included in this investigation. A final number of 50 contributions which fulfilled all inclusion criteria were categorized according to applied method, MRI sequence/contrast involved, number of subjects included and anatomical site investigated. The latter included brain, torso, prostate and phantoms. The contributions geometric and/or dosimetric performance metrics were also noted. The majority of studies are carried out on the brain for 5-10 patients with PET/MR applications in mind using a voxel based method. T1 weighted images are most commonly applied. The overall dosimetric agreement is in the order of 0.3-2.5%. A strict gamma criterion of 1% and 1mm has a range of passing rates from 68 to 94% while less strict criteria show pass rates > 98%. The mean absolute error (MAE) is between 80 and 200 HU for the brain and around 40 HU for the prostate. The Dice score for bone is between 0.5 and 0.95. The specificity and sensitivity is reported in the upper 80s% for both quantities and correctly classified voxels average around 84%. The review shows that a variety of promising approaches exist that seem clinical acceptable even with standard clinical MRI sequences. A consistent reference frame for method benchmarking is probably necessary to move the field further towards a widespread clinical implementation.

  • 340.
    Edwinsdotter Ardnor, Christina
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Rosén, Anna
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice S.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    The BRCA1 exon 13 duplication: clinical characteristics of 22 families in Northern Sweden2019In: Familial Cancer, ISSN 1389-9600, E-ISSN 1573-7292, Vol. 18, no 1, p. 37-42Article in journal (Refereed)
    Abstract [en]

    The clinical management of BRCA1/2 mutation carriers requires accurate cancer risk estimates. Cancer risks vary according to type and location of the mutation and since there is limited information about mutation-specific cancer risks, genotype-phenotype correlation studies are needed. This is a report of 22 families with the same mutation, BRCA1 duplication exon 13, a mutation that is found world-wide, with the objective to describe the cancer history found in these families. We studied 69 confirmed carriers, 53 women and 16 men, and additionally 29 women who were clinically expected carriers. Among the confirmed carriers, 27 women (51%) were diagnosed with breast cancer, 10 (19%) with ovarian cancer, 5 (9%) with breast and ovarian cancer and 17 (32%) without cancer. Nine women (17%) with breast cancer were 35 years or younger at diagnose. Also, two cases of early onset colon cancer were found, and 37,5% of the male carriers were diagnosed with prostate cancer. These data may have implications for risk assessment and cancer prevention decision making for carriers of the BRCA1 duplication exon 13 mutation.

  • 341.
    Egenvall, Monika
    et al.
    CLINTEC and Department of Surgical Gastroenterology, Karolinska University Hospital.
    Schubert Samuelsson, Katja
    CLINTEC and Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Department of Geriatrics, Karolinska University Hospital.
    Klarin, Inga
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Department of Geriatrics, Karolinska University Hospital.
    Lökk, Johan
    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet and Department of Geriatrics, Karolinska University Hospital.
    Sjövall, Annika
    Department of Surgical Gastroenterology, Karolinska University Hospital and Department of Molecular Medicine and Surgery, Karolinska Institutet.
    Martling, Anna
    Department of Surgical Gastroenterology, Karolinska University Hospital and Department of Molecular Medicine and Surgery, Karolinska Institutet.
    Gunnarsson, Ulf
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. CLINTEC and Department of Surgical Gastroenterology, Karolinska University Hospital.
    Management of colon cancer in the elderly: a population-based study2014In: Colorectal Disease, ISSN 1462-8910, E-ISSN 1463-1318, Vol. 16, no 6, p. 433-441Article in journal (Refereed)
    Abstract [en]

    AIM: although the median age of patients diagnosed with colon cancer is above 70 years, little is known about specific characteristics and management in the elderly. The aim of the study was to define characteristics of colon cancer in elderly patients and compare the quality of preoperative assessment and surgery with that of younger patients undergoing surgery for colon cancer.

    METHOD: data on 15.255 patients diagnosed with colon cancer between 2007 and 2010 were retrieved from the Swedish National Colon Cancer Register. Of these, 12.959 underwent surgical resection, 6.141 were 75 years or older while 6.818 were younger. The χ(2) test, Mann-Whitney U test and uni- and multivariable logistic regression analyses were used for comparison between groups.

    RESULTS: older patients were more likely to be female (54% older/48% younger) and have right-sided cancer (60% older/49% younger). Among patients who underwent resection, the elderly were less often evaluated regarding tumour stage prior to surgery (59% older/65% younger) and they were less often evaluated at a multidisciplinary team conference (26% older/34% younger). Elderly patients more frequently underwent emergency surgery (22% older/19% younger) despite having an earlier cancer stage. When adjusted for stage, fewer elderly patients underwent a radical curative procedure (OR for non-curative resection 1.19; 95% CI 1.06-1.33)

    CONCLUSION: routine management of patients with colon cancer is age-dependent. Patients 75 years and older are less often completely staged and less often evaluated at a multi-disciplinary team conference prior to surgery. Adjusted for stage, fewer elderly patients undergo curative resection.

  • 342.
    Ehrsson, Ylva Tiblom
    et al.
    Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
    Hellström, Per M
    Department of Medical Science, Uppsala University Hospital, 751 85 Uppsala, Sweden.
    Brismar, Kerstin
    Department of Molecular Medicine and Surgery, Karolinska Institutet, 171 77 Stockholm, Sweden.
    Sharp, Lena
    Department of Oncology, Karolinska University Hospital, 118 83 Stockholm, Sweden.
    Langius-Eklöf, Ann
    School of Medical and Health Sciences, Örebro University, 701 82 Örebro, Sweden.
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Explorative study on the predictive value of systematic inflammatory and metabolic markers on weight loss in head and neck cancer patients undergoing radiotherapy2010In: Supportive Care in Cancer, ISSN 0941-4355, E-ISSN 1433-7339, Vol. 18, no 11, p. 1385-1391Article in journal (Refereed)
    Abstract [en]

    PURPOSE: This study aimed to explore the predictive value of systematic inflammatory and metabolic markers in head and neck (H&N) cancer patients during radiotherapy (RT).

    METHODS: Twenty-seven patients were evaluated. The protocol included serial blood tests [highly sensitive C-reactive protein (hsCRP), albumin, insulin-like growth factor 1 (IGF-1), IGF binding protein 1 (IGFBP-1) and ghrelin], measurements of body weight and assessment of oral mucositis.

    RESULTS: The mean nadir of weight loss was observed at the end of RT. At the time of diagnosis, mean hsCRP was 5.2 ± 1.0 mg/L. HsCRP significantly increased during RT and decreased during the post-RT period. Mean maximum hsCRP was 35.8 ± 8.5 mg/L, with seven patients reaching >40 mg/L. A numerical decrease of albumin (by 18.2%) and only small changes in IGF-1, IGFBP-1 and ghrelin levels were observed. None of the metabolic parameters was significantly associated with weight loss.

    CONCLUSIONS: HsCRP increased in response to RT for H&N cancer as a sign of irradiation-induced inflammation. Weight loss was not preceded by changes of the metabolic parameters, indicating that assessment of the blood markers used in this study is of little value. Regular body weight measurement and assessment of oral mucositis are feasible, cheap and important procedures to control the metabolic homeostasis during RT.

  • 343. Ehrsson, Ylva Tiblom
    et al.
    Langius-Eklöf, Ann
    Laurell, Göran
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Otorhinolaryngology.
    Nutritional surveillance and weight loss in head and neck cancer patients2012In: Supportive Care in Cancer, ISSN 0941-4355, E-ISSN 1433-7339, Vol. 20, no 4, p. 757-765Article in journal (Refereed)
    Abstract [en]

    This retrospective single-institution cohort study aims to evaluate if therapeutic approach, tumour site, tumour stage, BMI, gender, age and civil status predict body weight loss and to establish the association between weight loss on postoperative infections and mortality. Consecutive patients with head and neck cancer were seen for nutritional control at a nurse-led outpatient clinic and followed-up for 2 years after radiotherapy. Demographic, disease-specific and nutrition data were collected from case records. The primary outcome measure was maximum body weight loss during the whole study period. The nadir of body weight loss was observed 6 months after radiotherapy. In total, 92 patients of 157 (59%) with no evidence of residual tumour after treatment received enteral nutrition. The mean maximum weight loss for patients receiving enteral nutrition and per oral feeding was 13% and 6%, respectively (p < 0.001). Using multivariate analysis, tumour stage (p < 0.001) was the only independent factor of maximum weight loss. Weight loss was not significantly related to risk for postoperative infection. Weight loss is frequently noted among head and neck cancer patients during and after treatment. Weight loss was not found to be associated with postoperative infections and mortality. Nutritional surveillance is important in all patients, but special attention should be given to those on enteral nutrition and those with more advanced disease.

  • 344.
    Ekblad, Lars
    et al.
    Lund Univ, Dept Oncol, Lund, Sweden.
    Lindgren, Gustaf
    Lund Univ, Dept Otorhinolaryngol Head & Neck Surg, Lund, Sweden.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Kjellen, Elisabeth
    Lund Univ, Dept Oncol, Lund, Sweden.
    Wennerberg, Johan
    Lund Univ, Dept Otorhinolaryngol Head & Neck Surg, Lund, Sweden.
    Cell-line-specific stimulation of tumor cell aggressiveness by wound healing factors - a central role for STAT32013In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 13, p. 33-Article in journal (Refereed)
    Abstract [en]

    Background: Local recurrence is a major factor affecting survival after treatment for head and neck squamous cell carcinoma (HNSCC). It is possible that the normal processes involved in wound healing after surgical removal of a primary tumor can boost the regrowth of residual cancer cells, thereby contributing to the recurrent growth. In this work, we collected human wound fluids and used them to investigate the effect of wound healing factors on HNSCC cell lines in vitro. Methods: Wound fluids were collected from thyroidectomized patients diagnosed with benign disease and were included in assays of cell proliferation, migration, cell scattering, and invasion. The involvement of intracellular signaling pathways and membrane receptors were investigated by western blotting and the inclusion of specific inhibitors. Results: One out of four cell lines was greatly stimulated in proliferation, migration, cell scattering, and invasion by the addition of wound fluid as compared with addition of fetal bovine or human serum. These effects were accompanied by a sharp increase in activation of signal transducer and activator of transcription 3 (STAT3). Inhibition of STAT3 activation abolished the wound fluid response, showing that STAT3 plays an important role in the wound healing response. Several of the observed phenotypic changes were epithelial-to-mesenchymal transition (EMT)-like, but the appropriate changes were not seen in any of the EMT markers investigated. The involvement of c-Met or epidermal growth factor receptor family members was excluded, while the interleukin-6 receptor was found to be partly responsible for the activation of STAT3. Conclusions: In conclusion, we found cell-line-specific effects of wound healing factors on HNSCC, setting the stage for therapy development and predictive opportunities.

  • 345.
    Eklund, Johan
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Searching for genetical cancer risks using a database of familial cancer: part I1999Report (Other academic)
    Abstract [en]

    A method to estimate cancer risks, when a recessive genetic defect is assumed to influence the risk to develop cancer, is presented. The proportion of the recessive defect is also estimated. The method uses cancer diagnosis data from a large sample of biological families. A family is here parents and two children. The information used is the frequencies of cancer diagnoses among siblings. Estimations are performed with the method of moments. The work is methodological, meaning that no specific type of cancer is considered.

  • 346.
    Eklöf, Vincy
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Faecal markers and mutations in diagnosis and prognosis of colorectal cancer2018Licentiate thesis, comprehensive summary (Other academic)
  • 347.
    Eklöf, Vincy
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundgren, David
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    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.
    Löfgren Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    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 combined diagnostic value of faecal haemoglobin and calprotectin in colorectal cancerManuscript (preprint) (Other academic)
  • 348.
    Eklöf, Vincy
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Löfgren-Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zingmark, Carl
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Larsson, Pär
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Alexeyev, Oleg
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Wikberg, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Cancer-associated fecal microbial markers in colorectal cancer detection2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 141, no 12, p. 2528-2536Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer (CRC) is the second most common cause of cancer death in the western world. An effective screening program leading to early detection of disease would severely reduce the mortality of CRC. Alterations in the gut microbiota have been linked to CRC, but the potential of microbial markers for use in CRC screening has been largely unstudied. We used a nested case-control study of 238 study subjects to explore the use of microbial markers for clbA+ bacteria harboring the pks pathogenicity island, afa-C+ diffusely adherent Escherichia coli harboring the afa-1 operon, and Fusobacterium nucleatum in stool as potential screening markers for CRC. We found that individual markers for clbA+ bacteria and F. nucleatum were more abundant in stool of patients with CRC, and could predict cancer with a relatively high specificity (81.5% and 76.9%, respectively) and with a sensitivity of 56.4% and 69.2%, respectively. In a combined test of clbA+ bacteria and F. nucleatum, CRC was detected with a specificity of 63.1% and a sensitivity of 84.6%. Our findings support a potential value of microbial factors in stool as putative noninvasive biomarkers for CRC detection. We propose that microbial markers may represent an important future screening strategy for CRC, selecting patients with a "high-risk" microbial pattern to other further diagnostic procedures such as colonoscopy.

  • 349.
    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.

  • 350. Ekman, Maria
    et al.
    Mu, Yabing
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lee, So Young
    Edlund, Sofia
    Kozakai, Takaharu
    Thakur, Noopur
    Tran, Hoanh
    Qian, Jiang
    Groeden, Joanna
    Heldin, Carl-Henrik
    Landström, Marene
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    APC and Smad7 link TGF beta type I receptors to the microtubule system to promote cell migration2012In: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 23, no 11, p. 2109-2121Article in journal (Refereed)
    Abstract [en]

    Cell migration occurs by activation of complex regulatory pathways that are spatially and temporally integrated in response to extracellular cues. Binding of adenomatous polyposis coli (APC) to the microtubule plus ends in polarized cells is regulated by glycogen synthase kinase 3 beta (GSK-3 beta). This event is crucial for establishment of cell polarity during directional migration. However, the role of APC for cellular extension in response to extracellular signals is less clear. Smad7 is a direct target gene for transforming growth factor-beta (TGF beta) and is known to inhibit various TGF beta-induced responses. Here we report a new function for Smad7. We show that Smad7 and p38 mitogen-activated protein kinase together regulate the expression of APC and cell migration in prostate cancer cells in response to TGF beta stimulation. In addition, Smad7 forms a complex with APC and acts as an adaptor protein for p38 and GSK-3 beta kinases to facilitate local TGF beta/p38-dependent inactivation of GSK-3 beta, accumulation of beta-catenin, and recruitment of APC to the microtubule plus end in the leading edge of migrating prostate cancer cells. Moreover, the Smad7-APC complex links the TGF beta type I receptor to the microtubule system to regulate directed cellular extension and migratory responses evoked by TGF beta.

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