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  • 51. Jenab, Mazda
    et al.
    Bueno-de-Mesquita, H Bas
    Ferrari, Pietro
    van Duijnhoven, Franzel J B
    Norat, Teresa
    Pischon, Tobias
    Jansen, Eugène H J M
    Slimani, Nadia
    Byrnes, Graham
    Rinaldi, Sabina
    Tjønneland, Anne
    Olsen, Anja
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Morois, Sophie
    Kaaks, Rudolf
    Linseisen, Jakob
    Boeing, Heiner
    Bergmann, Manuela M
    Trichopoulou, Antonia
    Misirli, Gesthimani
    Trichopoulos, Dimitrios
    Berrino, Franco
    Vineis, Paolo
    Panico, Salvatore
    Palli, Domenico
    Tumino, Rosario
    Ros, Martine M
    van Gils, Carla H
    Peeters, Petra H
    Brustad, Magritt
    Lund, Eiliv
    Tormo, María-José
    Ardanaz, Eva
    Rodríguez, Laudina
    Sánchez, Maria-José
    Dorronsoro, Miren
    Gonzalez, Carlos A
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Roddam, Andrew
    Key, Timothy J
    Khaw, Kay-Tee
    Autier, Philippe
    Hainaut, Pierre
    Riboli, Elio
    Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations: a nested case-control study2010In: BMJ. British Medical Journal (International Ed.), ISSN 0959-8146, E-ISSN 0959-535X, Vol. 340, p. b5500-Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To examine the association between pre-diagnostic circulating vitamin D concentration, dietary intake of vitamin D and calcium, and the risk of colorectal cancer in European populations. DESIGN: Nested case-control study. Setting The study was conducted within the EPIC study, a cohort of more than 520 000 participants from 10 western European countries. PARTICIPANTS: 1248 cases of incident colorectal cancer, which developed after enrolment into the cohort, were matched to 1248 controls MAIN OUTCOME MEASURES: Circulating vitamin D concentration (25-hydroxy-vitamin-D, 25-(OH)D) was measured by enzyme immunoassay. Dietary and lifestyle data were obtained from questionnaires. Incidence rate ratios and 95% confidence intervals for the risk of colorectal cancer by 25-(OH)D concentration and levels of dietary calcium and vitamin D intake were estimated from multivariate conditional logistic regression models, with adjustment for potential dietary and other confounders. RESULTS: 25-(OH)D concentration showed a strong inverse linear dose-response association with risk of colorectal cancer (P for trend <0.001). Compared with a pre-defined mid-level concentration of 25-(OH)D (50.0-75.0 nmol/l), lower levels were associated with higher colorectal cancer risk (<25.0 nmol/l: incidence rate ratio 1.32 (95% confidence interval 0.87 to 2.01); 25.0-49.9 nmol/l: 1.28 (1.05 to 1.56), and higher concentrations associated with lower risk (75.0-99.9 nmol/l: 0.88 (0.68 to 1.13); >or=100.0 nmol/l: 0.77 (0.56 to 1.06)). In analyses by quintile of 25-(OH)D concentration, patients in the highest quintile had a 40% lower risk of colorectal cancer than did those in the lowest quintile (P<0.001). Subgroup analyses showed a strong association for colon but not rectal cancer (P for heterogeneity=0.048). Greater dietary intake of calcium was associated with a lower colorectal cancer risk. Dietary vitamin D was not associated with disease risk. Findings did not vary by sex and were not altered by corrections for season or month of blood donation. CONCLUSIONS: The results of this large observational study indicate a strong inverse association between levels of pre-diagnostic 25-(OH)D concentration and risk of colorectal cancer in western European populations. Further randomised trials are needed to assess whether increases in circulating 25-(OH)D concentration can effectively decrease the risk of colorectal cancer.

  • 52. Jenab, Mazda
    et al.
    Ferrari, Pietro
    Slimani, Nadia
    Norat, Teresa
    Casagrande, Corinne
    Overad, Kim
    Olsen, Anja
    Stripp, Connie
    Tjönneland, Anne
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Kesse, Emmanuelle
    Nieters, Alexandra
    Bergmann, Manuela
    Boeing, Heiner
    Naska, Androniki
    Trichopoulou, Antonia
    Palli, Domenico
    Krogh, Vittorio
    Celentano, Egidio
    Tumino, Rosario
    Sacerdote, Carlotta
    Bueno-de-Mesquita, Hendrik B
    Ocké, Marga C
    Peeters, Petra H M
    Engeset, Dagrun
    Quirós, José R
    Gonzcalez, Carlos A
    Martínez, Carmen
    Chirlaque, Maria D
    Ardanaz, Eva
    Dorronsoro, Miren
    Wallstrröm, Peter
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Bingham, Sheila
    San Joaquin, Miguel A
    Saracci, Rodolfo
    Kaaks, Rudolf
    Riboli, Elio
    Association of nut and seed intake with colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition.2004In: Cancer Epidemiology Biomarkers & Prevention, ISSN 1055-9965, Vol. 13, no 10, p. 1595-603Article in journal (Refereed)
  • 53. Jenab, Mazda
    et al.
    McKay, James
    Bueno-de-Mesquita, Hendrik B
    van Duijnhoven, Franzel J B
    Ferrari, Pietro
    Slimani, Nadia
    Jansen, Eugène H J M
    Pischon, Tobias
    Rinaldi, Sabina
    Tjønneland, Anne
    Olsen, Anja
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Engel, Pierre
    Kaaks, Rudolf
    Linseisen, Jakob
    Boeing, Heiner
    Fisher, Eva
    Trichopoulou, Antonia
    Dilis, Vardis
    Oustoglou, Erifili
    Berrino, Franco
    Vineis, Paolo
    Mattiello, Amalia
    Masala, Giovanna
    Tumino, Rosario
    Vrieling, Alina
    van Gils, Carla H
    Peeters, Petra H
    Brustad, Magritt
    Lund, Eiliv
    Chirlaque, María-Dolores
    Barricarte, Aurelio
    Suárez, Laudina Rodríguez
    Molina, Esther
    Dorronsoro, Miren
    Sala, Núria
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Roddam, Andrew
    Key, Timothy J
    Khaw, Kay-Tee
    Bingham, Sheila
    Boffetta, Paolo
    Autier, Philippe
    Byrnes, Graham
    Norat, Teresa
    Riboli, Elio
    Vitamin D receptor and Calcium sensing receptor Polymorphisms and the risk of Colorectal Cancer in European populations2009In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 18, p. 2485-2491Article in journal (Refereed)
    Abstract [en]

    Increased levels of vitamin D and calcium may play a protective role in colorectal cancer (CRC) risk. It has been suggested that these effects may be mediated by genetic variants of the vitamin D receptor (VDR) and the calcium sensing receptor (CASR). However, current epidemiologic evidence from European populations for a role of these genes in CRC risk is scarce. In addition, it is not clear whether these genes may modulate CRC risk independently or by interaction with blood vitamin D concentration and level of dietary calcium intake. A case-control study was conducted nested within the European Prospective Investigation into Cancer and Nutrition. CRC cases (1,248) were identified and matched to 1,248 control subjects. Genotyping for the VDR (BsmI: rs1544410; Fok1: rs2228570) and CASR (rs1801725) genes was done by Taqman, and serum vitamin D (25OHD) concentrations were measured. Conditional logistic regression was used to estimate the incidence rate ratio (RR). Compared with the wild-type bb, the BB genotype of the VDR BsmI polymorphism was associated with a reduced risk of CRC [RR, 0.76; 95% confidence interval (CI), 0.59-0.98). The association was observed for colon cancer (RR, 0.69; 95% CI, 0.45-0.95) but not rectal cancer (RR, 0.97; 95% CI, 0.62-1.49). The Fok1 and CASR genotypes were not associated with CRC risk in this study. No interactions were noted for any of the polymorphisms with serum 25OHD concentration or level of dietary calcium. These results confirm a role for the BsmI polymorphism of the VDR gene in CRC risk, independent of serum 25OHD concentration and dietary calcium intake. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2485-91).

  • 54. Jenab, Mazda
    et al.
    Riboli, Elio
    Cleveland, Rebecca J
    Norat, Teresa
    Rinaldi, Sabina
    Nieters, Alexandra
    Biessy, Carine
    Tjønneland, Ann
    Olsen, Anja
    Overvad, Kim
    Grønbaek, Henning
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Linseisen, Jakob
    Boeing, Heiner
    Pischon, Tobias
    Trichopoulos, Dimitrios
    Oikonomou, Eleni
    Trichopoulou, Antonia
    Panico, Salvatore
    Vineis, Paolo
    Berrino, Franco
    Tumino, Rosario
    Masala, Giovanna
    Peters, Petra H
    van Gils, Carla H
    Bueno-de-Mesquita, H Bas
    Ocké, Marga C
    Lund, Eiliv
    Mendez, Michelle A
    Tormo, María José
    Barricarte, Aurelio
    Martínez-García, Carmen
    Dorronsoro, Miren
    Quirós, José Ramón
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Berglund, Göran
    Manjer, Jonas
    Key, Timothy
    Allen, Naomi E
    Bingham, Sheila
    Khaw, Kay-Tee
    Cust, Anne
    Kaaks, Rudolf
    Serum C-peptide, IGFBP-1 and IGFBP-2 and risk of colon and rectal cancers in the European Prospective Investigation into Cancer and Nutrition.2007In: International Journal of Cancer, ISSN 0020-7136, Vol. 121, no 2, p. 368-76Article in journal (Refereed)
  • 55. Jenab, Mazda
    et al.
    Sabate, Joan
    Slimani, Nadia
    Ferrari, Pietro
    Mazuir, Mathieu
    Casagrande, Corinne
    Deharveng, Genevieve
    Tjonneland, Anne
    Olsen, Anja
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Boeing, Heiner
    Weikert, Cornelia
    Linseisen, Jakob
    Rohrmann, Sabine
    Trichopoulou, Antonia
    Naska, Androniki
    Palli, Domenico
    Sacerdote, Carlotta
    Tumino, Rosario
    Mattiello, Amalia
    Pala, Valeria
    Bueno-de-Mesquita, H Bas
    Ocke, Marga C
    Peeters, Petra H
    Engeset, Dagrun
    Skeie, Gurie
    Jakszyn, Paula
    Ardanaz, Eva
    Quiros, J Ramon
    Dolores Chirlaque, Maria
    Martinez, Carmen
    Amiano, Pilar
    Berglund, Göran
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Bingham, Sheila
    Key, Timothy
    Riboli, Elio
    Consumption and portion sizes of tree nuts, peanuts and seeds in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohorts from 10 European countries2006In: British Journal of Nutrition, ISSN 0007-1145, E-ISSN 1475-2662, Vol. 96, no S2, p. 12-23Article in journal (Refereed)
    Abstract [en]

    Tree nuts, peanuts and seeds are nutrient dense foods whose intake has been shown to be associated with reduced risk of some chronic diseases. They are regularly consumed in European diets either as whole, in spreads or from hidden sources (e.g. commercial products). However, little is known about their intake profiles or differences in consumption between European countries or geographic regions. The objective of this study was to analyse the population mean intake and average portion sizes in subjects reporting intake of nuts and seeds consumed as whole, derived from hidden sources or from spreads. Data was obtained from standardised 24-hour dietary recalls collected from 36 994 subjects in 10 different countries that are part of the European Prospective Investigation into Cancer and Nutrition (EPIC). Overall, for nuts and seeds consumed as whole, the percentage of subjects reporting intake on the day of the recall was: tree nuts=4 center dot 4%, peanuts=2 center dot 3 % and seeds=1 center dot 3 %. The data show a clear northern (Sweden: mean intake=0 center dot 15 g/d, average portion size=15 center dot 1 g/d) to southern (Spain: mean intake=2 center dot 99 g/d, average portion size=34 center dot 7 g/d) European gradient of whole tree nut intake. The three most popular tree nuts were walnuts, almonds and hazelnuts, respectively. In general, tree nuts were more widely consumed than peanuts or seeds. In subjects reporting intake, men consumed a significantly higher average portion size of tree nuts (28 center dot 5 v. 23 center dot 1 g/d, P < 0 center dot 01) and peanuts (46 center dot 1 v. 35 center dot 1 g/d, P < 0 center dot 01) per day than women. These data may be useful in devising research initiatives and health policy strategies based on the intake of this food group.

  • 56. Kaaks, Rudolf
    et al.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Villar, Stéphanie
    Poetsch, Anna R
    Dossus, Laure
    Nieters, Alexandra
    Riboli, Elio
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Plass, Christoph
    Friesen, Marlin D
    Insulin-like Growth Factor-II Methylation Status in Lymphocyte DNA and Colon Cancer Risk in the Northern Sweden Health and Disease Cohort2009In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 69, no 13, p. 5400-5405Article in journal (Refereed)
    Abstract [en]

    Loss of imprinting (LOI) of the insulin-like growth factor II (IGFII) gene is a frequent phenomenon in colorectal tumor tissues. Previous reports indicated that subjects with colorectal neoplasias show LOI of IGFII in circulating lymphocytes. Furthermore, LOI of IGFII is strongly related to the methylation of a differentially methylated region (DMR) in intron 2 of IGFII, suggesting that the methylation status could serve as a biomarker for early detection. Thus, hypermethylation of this DMR, even at a systemic level, e.g., in lymphocyte DNA, could be used for screening for colon cancer. To validate this, we performed a case-control study of 97 colon cancer cases and 190 age-matched and gender-matched controls, nested within the prospective Northern Sweden Health and Disease Study cohort. Methylation levels of the IGFII-DMR in lymphocyte DNA were measured at two specific CpG sites of the IGFII-DMR using a mass-spectrometric method called short oligonucleotide mass analysis, the measurements of which showed high reproducibility between replicate measurements for the two CpG sites combined and showed almost perfect validity when performed on variable mixtures of methylated and unmethylated standards. Mean fractions of CpG methylation, for the two CpG sites combined, were identical for cases and controls (0.47 and 0.46, respectively; Pdifference = 0.75), and logistic regression analyses showed no relationship between colon cancer risk and quartile levels of CpG methylation. The results from this study population do not support the hypothesis that colon cancer can be predicted from the different degrees of methylation of DMR in the IGFII gene from lymphocyte DNA. [Cancer Res 2009;69(13):5400-5].

  • 57.
    Karling, Pontus
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Lundgren, David
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Eklöf, Vincy
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Improved monitoring of inflammatory activity in patients with ulcerative colitis by combination of faecal tests for haemoglobin and calprotectin2019In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686Article in journal (Refereed)
    Abstract [en]

    Faecal calprotectin (FC) tests and faecal immunological tests (FIT) for haemoglobin have been used to monitor disease activity in patients with ulcerative colitis (UC) but used alone they have some limitation concerning the predictive ability. We aimed to test if an FC test used in combination with FIT could improve the predictive ability. Consecutive out-patients with UC (n = 93) who were admitted for colonoscopy completed a single faecal sample before the start of bowel preparation. A quantitative CALPRO (R) calprotectin ELISA test and a qualitative FIT (cut-off < 40 ng/mL) were analyzed. An estimated Mayo score and a score of histological inflammation was performed blinded to the result of the faecal tests. The sensitivity, specificity, negative predictive value and positive predictive value for endoscopic inflammation (Mayo score > 1) was for FIT 85%, 83%, 96%, 57% and for FC > 186 mu g/g 73%, 87%, 87%, 54%. Corresponding results for FIT*FC > 186 mu g/g (at least one test positive) were 92%, 69%, 97%, 43%. For detecting moderate/severe histological inflammation the results were for FIT 69%, 79%, 92%, 43%, for FC > 75 mu g/g 95%, 62%, 98%, 41%, and for FIT*FC > 75 mu g/g 100%, 60%, 100%, 36%. None of the markers alone or in combination were useful to predict deep remission (Mayo score = 0 and no histological inflammation). We conclude that using the combination of an FC test and FIT shows minor improvement in predictive ability for inflammatory activity and remission in patients with UC.

  • 58. Kyro, C.
    et al.
    Olsen, A.
    Landberg, R.
    Skeie, G.
    Loft, S.
    Aman, P.
    Leenders, M.
    Dik, V.
    Siersema, P.
    Pischon, T.
    Christensen, J.
    Overvad, K.
    Boutron-Ruault, M. C.
    Fagherazzi, G.
    Cottet, V.
    Kuehn, T.
    ChangClaude, J.
    Boeing, H.
    Trichopoulou, A.
    Bamia, C.
    Trichopoulos, D.
    Palli, D.
    Krogh, V.
    Tumino, R.
    Vineis, P.
    Panico, S.
    Peters, P.
    Weiderpass, E.
    Bakken, T.
    Asli, L.
    Argueelles, M.
    Jakszyn, P.
    Sanchez, M. J.
    Castano, J.
    Barricarte, A.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Key, T.
    Travis, R.
    Ferrari, P.
    Freisling, H.
    Jenab, M.
    Tjonneland, A.
    Bueno-de-Mesquita, B.
    ALKYLRESORCINOLS (BIOMARKERS OF WHOLE-GRAIN INTAKE) AND RISK OF COLORECTAL CANCER IN THE EUROPEAN PROSPECTIVE INVESTIGATION INTO CANCER AND NUTRITION2013In: Annals of Nutrition and Metabolism, ISSN 0250-6807, E-ISSN 1421-9697, Vol. 63, no Supplement 1, p. 1207-1208Article in journal (Other academic)
    Abstract [en]

    Background and objectives: Few studies have investigatedthe association between whole-grain intake and colorectal cancer.Whole-grain products are one of the dietary items proneto measurement errors, making the use of objective measures,such as biomarkers, highly relevant. The objective of the studywas to investigate the association between biomarkers ofwhole-grain intake, alkylresorcinols, and colorectal cancer ina nested case-control study within the European ProspectiveInvestigation into Cancer and Nutrition (EPIC). Methods: We included 1372 first incident colorectal cancercases and 1372 individually matched controls and calculatedthe incidence rate ratios (IRR) for overall and sub-sites of colorectalcancer using conditional logistic regression adjusted forpotential confounders.Results: Plasma total alkylresorcinol concentrations werenot associated with risk of overall colorectal cancer, proximalcolon cancer or rectal cancer. However, high plasma total alkylresorcinolconcentrations were statistically significantly associatedwith lower incidence of cancer located in the distal (leftor descending) part of the colon. Adjusted IRR of distal coloncancer for highest versus lowest quartile of plasma alkylresorcinolwas 0.48 (95% confidence interval = 0.28 to 0.83). Furthermore,we observed an inverse association with colon cancerfor the Scandinavian part of the participants. Alkylresorcinolsmay be more appropriate as biomarkers in Middle Europe andScandinavia i.e. in areas where whole grains are regularly consumed.Conclusions: Whole-grain intake, assessed by alkylresorcinols,was associated with a lower incidence of distal coloncancer. Alkylresorcinols seem useful as objective biomarkersof whole-grain intake in populations where whole-grains are astaple part of the diet. Acknowledgements: This work was supportedby World Cancer Research Fund International (WCRF)and WCRF Netherlands (WCRF NL) (2011/436), and NordForsk(Centre of Excellence programme HELGA (070015)).

  • 59. Kyro, Cecilie
    et al.
    Olsen, Anja
    Bueno-de-Mesquita, H. B(as).
    Skeie, Guri
    Loft, Steffen
    Aman, Per
    Leenders, Max
    Dik, Vincent K.
    Siersema, Peter D.
    Pischon, Tobias
    Christensen, Jane
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Fagherazzi, Guy
    Cottet, Vanessa
    Kuehn, Tilman
    Chang-Claude, Jenny
    Boeing, Heiner
    Trichopoulou, Antonia
    Naska, Androniki
    Oikonomidou, Despoina
    Masala, Giovanna
    Pala, Valeria
    Tumino, Rosario
    Vineis, Paolo
    Mattiello, Amalia
    Peeters, Petra H.
    Bakken, Toril
    Weiderpass, Elisabete
    Asli, Lene Angell
    Sanchez, Soledad
    Jakszyn, Paula
    Sanchez, Maria-Jose
    Amiano, Pilar
    Maria Huerta, Jose
    Barricarte, Aurelio
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Wareham, Nick
    Key, Timothy J.
    Travis, Ruth C.
    Slimani, Nadia
    Freisling, Heinz
    Ferrari, Pietro
    Gunter, Marc J.
    Murphy, Neil
    Riboli, Elio
    Tjonneland, Anne
    Landberg, Rikard
    Plasma alkylresorcinol concentrations, biomarkers of whole-grain wheat and rye intake, in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort2014In: British Journal of Nutrition, ISSN 0007-1145, E-ISSN 1475-2662, Vol. 111, no 10, p. 1881-1890Article in journal (Refereed)
    Abstract [en]

    Whole-grain intake has been reported to be associated with a lower risk of several lifestyle-related diseases such as type 2 diabetes, CVD and some types of cancers. As measurement errors in self-reported whole-grain intake assessments can be substantial, dietary biomarkers are relevant to be used as complementary tools for dietary intake assessment. Alkylresorcinols (AR) are phenolic lipids found almost exclusively in whole-grain wheat and rye products among the commonly consumed foods and are considered as valid biomarkers of the intake of these products. In the present study, we analysed the plasma concentrations of five AR homologues in 2845 participants from ten European countries from a nested case-control study in the European Prospective Investigation into Cancer and Nutrition. High concentrations of plasma total AR were found in participants from Scandinavia and Central Europe and lower concentrations in those from the Mediterranean countries. The geometric mean plasma total AR concentrations were between 35 and 41nmol/l in samples drawn from fasting participants in the Central European and Scandinavian countries and below 23nmol/l in those of participants from the Mediterranean countries. The whole-grain source (wheat or rye) could be determined using the ratio of two of the homologues. The main source was wheat in Greece, Italy, the Netherlands and the UK, whereas rye was also consumed in considerable amounts in Germany, Denmark and Sweden. The present study demonstrates a considerable variation in the plasma concentrations of total AR and concentrations of AR homologues across ten European countries, reflecting both quantitative and qualitative differences in the intake of whole-grain wheat and rye.

  • 60. Kyro, Cecilie
    et al.
    Olsen, Anja
    Landberg, Rikard
    Skeie, Guri
    Loft, Steffen
    Aman, Per
    Leenders, Max
    Dik, Vincent K.
    Siersema, Peter D.
    Pischon, Tobias
    Christensen, Jane
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Fagherazzi, Guy
    Cottet, Vanessa
    Kuehn, Tilman
    Chang-Claude, Jenny
    Boeing, Heiner
    Trichopoulou, Antonia
    Bamia, Christina
    Trichopoulos, Dimitrios
    Palli, Domenico
    Krogh, Vittorio
    Tumino, Rosario
    Vineis, Paolo
    Panico, Salvatore
    Peeters, Petra H.
    Weiderpass, Elisabete
    Bakken, Toril
    Asli, Lene Angell
    Argueelles, Marcial
    Jakszyn, Paula
    Sanchez, Maria-Jose
    Amiano, Pilar
    Huerta, Jose Maria
    Barricarte, Aurelio
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Wareham, Nick
    Key, Timothy J.
    Travis, Ruth C.
    Ferrari, Pietro
    Freisling, Heinz
    Jenab, Mazda
    Gunter, Marc J.
    Murphy, Neil
    Riboli, Eilo
    Tjonneland, Anne
    Bueno-de-Mesquita, H. B(as)
    Plasma Alkylresorcinols, Biomarkers of Whole-Grain Wheat and Rye Intake, and Incidence of Colorectal Cancer2014In: Journal of the National Cancer Institute, ISSN 0027-8874, E-ISSN 1460-2105, Vol. 106, no 1, p. djt352-Article in journal (Refereed)
    Abstract [en]

    Background Few studies have investigated the association between whole-grain intake and colorectal cancer. Because whole-grain intake estimation might be prone to measurement errors, more objective measures (eg, biomarkers) could assist in investigating such associations. Methods The association between alkylresorcinols, biomarkers of whole-grain rye and wheat intake, and colorectal cancer incidence were investigated using prediagnostic plasma samples from colorectal cancer case patients and matched control subjects nested within the European Prospective Investigation into Cancer and Nutrition. We included 1372 incident colorectal cancer case patients and 1372 individual matched control subjects and calculated the incidence rate ratios (IRRs) for overall and anatomical subsites of colorectal cancer using conditional logistic regression adjusted for potential confounders. Regional differences (Scandinavia, the Mediterranean, Central Europe) were also explored. Results High plasma total alkylresorcinol concentration was associated with lower incidence of distal colon cancer; the adjusted incidence rate ratio of distal colon cancer for the highest vs lowest quartile of plasma total alkylresorcinols was 0.48 (95% confidence interval [CI] = 0.28 to 0.83). An inverse association between plasma total alkylresorcinol concentrations and colon cancer was found for Scandinavian participants (IRR per doubling = 0.83; 95% CI = 0.70 to 0.98). However, plasma total alkylresorcinol concentrations were not associated with overall colorectal cancer, proximal colon cancer, or rectal cancer. Plasma alkylresorcinols concentrations were associated with colon and distal colon cancer only in Central Europe and Scandinavia (ie, areas where alkylresorcinol levels were higher). Conclusions High concentrations of plasma alkylresorcinols were associated with a lower incidence of distal colon cancer but not with overall colorectal cancer, proximal colon cancer, and rectal cancer.

  • 61. Kyro, Cecilie
    et al.
    Skeie, Guri
    Loft, Steffen
    Landberg, Rikard
    Christensen, Jane
    Lund, Eiliv
    Nilsson, Lena M.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tjonneland, Anne
    Olsen, Anja
    Intake of whole grains from different cereal and food sources and incidence of colorectal cancer in the Scandinavian HELGA cohort2013In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 24, no 7, p. 1363-1374Article in journal (Refereed)
    Abstract [en]

    A high intake of whole grains has been associated with a lower incidence of colorectal cancer, but few studies are available on the association with whole grains from different cereals, for example, wheat, rye and oats, and none has addressed these separately. The objective of this study was to investigate the association between whole-grain intake and colorectal cancer. We used data from the large population-based Scandinavian cohort HELGA consisting of 108,000 Danish, Swedish, and Norwegian persons, of whom 1,123 developed colorectal cancer during a median of 11 years of follow-up. Detailed information on daily intake of whole-grain products, including whole-grain bread, crispbread, and breakfast cereals, was available, and intakes of total whole grains and specific whole-grain species (wheat, rye, and oats) were estimated. Associations between these whole-grain variables and the incidence of colorectal cancer were investigated using Cox proportional hazards models. Intake of whole-grain products was associated with a lower incidence of colorectal cancer per 50-g increment (incidence rate ratio [IRR], 0.94; 95 % confidence interval [CI], 0.89, 0.99), and the same tendency was found for total whole-grain intake (IRR pr. 25-g increment, 0.94; 95 % CI, 0.88, 1.01). Intake of whole-grain wheat was associated with a lower incidence of colorectal cancer (IRR for highest versus lowest quartile of intake, 0.66; 95 % CI, 0.51, 0.85), but no statistical significant linear trend was observed (p for trend: 0.18). No significant association was found for whole-grain rye or oats. Whole-grain intake was associated with a lower incidence of colorectal cancer.

  • 62. Leufkens, Anke M
    et al.
    van Duijnhoven, Fränzel J B
    Boshuizen, Hendriek C
    Siersema, Peter D
    Kunst, Anton E
    Mouw, Traci
    Tjønneland, Anne
    Olsen, Anja
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Morois, Sophie
    Krogh, Vittorio
    Tumino, Rosario
    Panico, Salvatore
    Polidoro, Silvia
    Palli, Domenico
    Kaaks, Rudolf
    Teucher, Birgit
    Pischon, Tobias
    Trichopoulou, Antonia
    Orfanos, Philippos
    Goufa, Ioulia
    Peeters, Petra H M
    Skeie, Guri
    Braaten, Tonje
    Rodríguez, Laudina
    Lujan-Barroso, Leila
    Sánchez-Pérez, Maria-José
    Navarro, Carmen
    Barricarte, Aurelio
    Zackrisson, Sophia
    Almquist, Martin
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tsilidis, Konstantinos K
    Khaw, Kay-Tee
    Wareham, Nick
    Gallo, Valentina
    Jenab, Mazda
    Riboli, Elio
    Bueno-de-Mesquita, H B
    Educational level and risk of colorectal cancer in EPIC with specific reference to tumor location2011In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 130, no 3, p. 622-630Article in journal (Refereed)
    Abstract [en]

    Existing evidence is inconclusive on whether socioeconomic status (SES) and educational inequalities influence colorectal cancer (CRC) risk, and whether low or high SES/educational level is associated with developing CRC. The aim of our study was to investigate the relationship between educational level and CRC. We studied data from 400,510 participants in the EPIC (European Prospective Investigation into Cancer and Nutrition) study, of whom 2,447 developed CRC (colon: 1,551, rectum: 896, mean follow-up 8.3 years). Cox proportional hazard regression analysis stratified by age, gender and center, and adjusted for potential confounders were used to estimate hazard ratios (HR) and 95% confidence intervals (95%CI). Relative indices of inequality (RII) for education were estimated using Cox regression models. We conducted separate analyses for tumor location, gender and geographical region. Compared with participants with college/university education, participants with vocational secondary education or less had a nonsignificantly lower risk of developing CRC. When further stratified for tumor location, adjusted risk estimates for the proximal colon were statistically significant for primary education or less (HR 0.73, 95%CI 0.57–0.94) and for vocational secondary education (HR 0.76, 95%CI 0.58–0.98). The inverse association between low education and CRC risk was particularly found in women and Southern Europe. These associations were statistically significant for CRC, for colon cancer and for proximal colon cancer. In conclusion, CRC risk, especially in the proximal colon, is lower in subjects with a lower educational level compared to those with a higher educational level. This association is most pronounced in women and Southern Europe.

  • 63. Leufkens, Anke M
    et al.
    van Duijnhoven, Fränzel JB
    Woudt, Sjoukje HS
    Siersema, Peter D
    Jenab, Mazda
    Jansen, Eugene HJM
    Pischon, Tobias
    Tjønneland, Anne
    Olsen, Anja
    Overvad, Kim
    Boutron-Ruault, Marie Christine
    Clavel-Chapelon, Françoise
    Morois, Sophie
    Palli, Domenico
    Pala, Valeria
    Tumino, Rosario
    Vineis, Paolo
    Panico, Salvatore
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Boeing, Heiner
    Aleksandrova, Krasimira
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Dilis, Vardis
    Peeters, Petra H
    Skeie, Guri
    González, Carlos A
    Argüelles, Marcial
    Sánchez, María-José
    Dorronsoro, Miren
    Huerta, José María
    Ardanaz, Eva
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Wareham, Nick
    Allen, Naomi E
    Crowe, Francesca L
    Fedirko, Veronika
    Norat, Teresa
    Riboli, Elio
    Bueno-de-Mesquita, H Bas
    Biomarkers of oxidative stress and risk of developing colorectal cancer: a cohort-nested case-control study in the European Prospective Investigation into Cancer and Nutrition2012In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 175, no 7, p. 653-663Article in journal (Refereed)
    Abstract [en]

    Oxidative stress has been shown to play an important role in carcinogenesis, but prospective evidence for an association between biomarkers of oxidative stress and colorectal cancer (CRC) risk is limited. The authors investigated the association between prediagnostic serum levels of oxidative stress indicators (i.e., reactive oxygen metabolites (ROM) and ferric reducing ability of plasma (FRAP)) and CRC risk. This was examined in a nested case-control study (1,064 CRC cases, 1,064 matched controls) in the European Prospective Investigation Into Cancer and Nutrition cohort (1992-2003). Incidence rate ratios and 95% confidence intervals were calculated using conditional logistic regression analyses. ROM were associated with overall CRC risk (highest tertile vs. lowest: adjusted incidence rate ratio (IRR(adj)) = 1.91, 95% confidence interval (CI): 1.47, 2.48), proximal (IRR(adj) = 1.89, 95% CI: 1.06, 3.36) and distal (IRR(adj) = 2.31, 95% CI: 1.37, 3.89) colon cancer, and rectal cancer (IRR(adj) = 1.69, 95% CI: 1.05, 2.72). When results were stratified by tertile of follow-up time, the association remained significant only in participants with less than 2.63 years of follow-up (IRR(adj) = 2.28, 95% CI: 1.78, 2.94; P-heterogeneity < 0.01). FRAP was not associated with CRC risk. In conclusion, prediagnostic serum ROM levels were associated with increased risk of CRC. However, this association was seen only in subjects with relatively short follow-up, suggesting that the association results from production of reactive oxygen species by preclinical tumors.

  • 64.
    Lindberg, J
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery. Kirurgi.
    Surgery for neoplastic changes in ulcerative colitis - can limited resection be justified? Outcome for patients who underwent limited surgery.2006In: Colorectal Disease, ISSN 1462-8910, E-ISSN 1463-1318, Vol. 8, no 7, p. 551-556Article in journal (Refereed)
  • 65.
    Lindberg, Jan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Early onset of ulcerative colitis: long-term follow-up with special reference to colorectal cancer and primary sclerosing cholangitis.2008In: Journal of Pediatric Gastroenterology and Nutrition - JPGN, ISSN 0277-2116, E-ISSN 1536-4801, Vol. 46, no 5, p. 534-538Article in journal (Refereed)
  • 66.
    Lindberg, Jan
    et al.
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery. Kirurgi.
    Efficiency of colorectal cancer surveillance in patients with ulcerative colitis: 26 years' experience in a patient cohort from a defined population area.2005In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 40, no 9, p. 1076-1080Article in journal (Refereed)
  • 67.
    Ling, Agnes
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    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 intratumoural subsite and relation of CD8(+) and FOXP3(+) T lymphocytes in colorectal cancer provide important prognostic clues2014In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 110, no 10, p. 2551-2559Article in journal (Refereed)
    Abstract [en]

    Background: To find improved tools for prognostic evaluation in patients with colorectal cancer (CRC), we have analysed how infiltration of cytotoxic T lymphocytes (CD8(+)) and regulatory T lymphocytes (FoxP3(+)) correlates to prognosis, not only according to quantity and relation, but also to subsite within tumours of different molecular characteristics (microsatellite instability and CpG island methylator phenotype status).

    Methods: CD8 and FOXP3 expression was evaluated by immunohistochemistry in 426 archival tumour tissue samples from patients surgically resected for CRC. The average infiltration of CD8(+) and FOXP3(+) cells was assessed along the tumour invasive front, in the tumour centre and within the tumour epithelium (intraepithelial).

    Results: We found that infiltration of CD8(+) T lymphocytes within the tumour epithelium provided the strongest prognostic information (P < 0.001). At the tumour invasive front and tumour centre, FOXP3 expression withheld the strongest association to prognosis (P < 0.001), suggesting FOXP3(+) T-lymphocyte infiltration to be a better prognostic tool than CD8(+) T lymphocytes at these intratumoural subsites. We further analysed the possible prognostic impact of the relation between these T-cell subsets, finding that a high intraepithelial CD8 expression was associated with a better patient outcome, independent of FOXP3 infiltration. In groups of low intraepithelial CD8 expression, however, a high infiltration rate of FOXP3(+) cells at the tumour invasive front, significantly improved prognosis.

    Conclusions: Analyses of intraepithelial infiltration of CD8(+) T lymphocytes, infiltration of FOXP3(+) T lymphocytes at the tumour front or centre, and the relation between these subsets, may be a valuable tool for predicting prognosis in colon cancer.

  • 68.
    Ling, Agnes
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lundberg, Ida V.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Eklöf, Vincy
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The infiltration, and prognostic importance, of Th1 lymphocytes vary in molecular subgroups of colorectal cancer2016In: The Journal of Pathology: Clinical Research, ISSN 2056-4538, Vol. 2, no 1, p. 21-31Article in journal (Refereed)
    Abstract [en]

    Giving strong prognostic information, T-cell infiltration is on the verge of becoming an additional component in the routine clinical setting for classification of colorectal cancer (CRC). With a view to further improving the tools for prognostic evaluation, we have studied how Th1 lymphocyte infiltration correlates with prognosis not only by quantity, but also by subsite, within CRCs with different molecular characteristics (microsatellite instability, CpG island methylator phenotype status, and BRAF and KRAS mutational status). We evaluated the Th1 marker T-bet by immunohistochemistry in 418 archival tumour tissue samples from patients who underwent surgical resection for CRC. We found that a high number of infiltrating Th1 lymphocytes is strongly associated with an improved prognosis in patients with CRC, irrespective of intratumoural subsite, and that both extent of infiltration and patient outcome differ according to molecular subgroup. In brief, microsatellite instability, CpG island methylator phenotype-high and BRAF mutated tumours showed increased infiltration of Th1 lymphocytes, and the most pronounced prognostic effect of Th1 infiltration was found in these tumours. Interestingly, BRAF mutated tumours were found to be more highly infiltrated by Th1 lymphocytes than BRAF wild-type tumours whereas the opposite was seen for KRAS mutated tumours. These differences could be explained at least partly by our finding that BRAF mutated, in contrast to KRAS mutated, CRC cell lines and tumour specimens expressed higher levels of the Th1-attracting chemokine CXCL10, and reduced levels of CCL22 and TGFB1, stimulating Th2/Treg recruitment and polarisation. In conclusion, the strong prognostic importance of Th1 lymphocyte infiltration in CRC was found at all subsites evaluated, and it remained significant in multivariable analyses, indicating that T-bet may be a valuable marker in the clinical setting. Our results also indicate that T-bet is of value when analysed in molecular subgroups of CRC, allowing identification of patients with especially poor prognosis who are in need of extended treatment.

  • 69.
    Ling, Agnes
    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.
    Larsson, Pär
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Li, Xingru
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    TAP1 down-regulation elicits immune escape and poor prognosis in colorectal cancer2017In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, no 11, article id e1356143Article in journal (Refereed)
    Abstract [en]

    The anti-tumor immune response has been shown to be of great prognostic importance in colorectal cancer (CRC) and so has the tumors ability for immune evasion. Our aim of this study was to investigate tumor factors that influence immunity. We used a gene expression array to search for potential mechanisms of tumor immune escape. One candidate gene identified was TAP1, involved in antigen presentation by MHC class I. TAP1 protein expression was evaluated by immunohistochemistry in 436 CRC patients of the Colorectal Cancer in Umeå Study cohort. We found a significant association between a downregulated expression of TAP1 and low infiltration of various subtypes of lymphocytes as well as macrophages. A downregulated expression of TAP1 was further found to be independent of molecular characteristics, suggesting TAP1 down-regulation to reach beyond the well described highly immunogenic MSI CRCs. A low expression of TAP1 was also significantly associated with poor prognosis in patients with CRC, a result that stayed significant in tumor front of early stage tumors (stage I-II) through multivariable analyses. Furthermore, we found that TAP1 expression was inversely correlated with methylation at sites in close proximity to the promoter region. In summary, our results show down-regulation of TAP1 to be a general mechanism of tumor immune escape in CRC and a poor prognostic factor in stage I-II CRC patients. We also suggest that methylation of the TAP1 gene may be a putative mechanism for TAP1 downregulation.

  • 70. Linseisen, Jakob
    et al.
    Rohrmann, Sabine
    Norat, Teresa
    Gonzalez, Carlos A
    Dorronsoro Iraeta, Miren
    Morote Gomes, Patrocinio
    Chirlaque, Maria-Dolores
    Pozo, Basilio G
    Ardanaz, Eva
    Mattisson, Irene
    Pettersson, Ulrika
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Bingham, Sheila A
    McTaggart, Alison
    Spencer, Elizabeth A
    Overvad, Kim
    Tjönneland, Anne
    Stripp, Connie
    Clavel-Chapelon, Francoíse
    Kesse, Emmanuelle
    Boeing, Heiner
    Klipstein-Grobusch, Kerstin
    Trichopoulou, Antonia
    Vasilopoulou, Effie
    Bellos, George
    Pala, Valeria
    Masala, Giovanna
    Tumino, Rosario
    Sacerdote, Carlotta
    Del Pezzo, Mariarosaria
    Bueno-de-Mesquita, H Bas
    Ocke, Marga C
    Peeters, Petra H M
    Engeset, Dagrun
    Skeie, Guri
    Slimani, Nadia
    Riboli, Elio
    Dietary intake of different types and characteristics of processed meat which might be associated with cancer risk--results from the 24-hour diet recalls in the European Prospective Investigation into Cancer and Nutrition (EPIC).2006In: Public Health Nutr, ISSN 1368-9800, Vol. 9, no 4, p. 449-64Article in journal (Refereed)
  • 71.
    Ljuslinder, Ingrid
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Jonsson, Yvonne
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Hedman, Håkan
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    LRIG1 expression in colorectal cancer2007In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 46, no 8, p. 1118-1122Article in journal (Refereed)
  • 72.
    Ljuslinder, Ingrid
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Isaksson-Mettävainio, Martin
    Öberg, Åke
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    ErbB 1-4 expression alterations in primary colorectal cancers and their corresponding metastases2009In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 29, no 5, p. 1489-1494Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: EGFR (epidermal growth factor receptor) targeted therapies are important new tools in colorectal cancer treatment. EGFR analysis of the primary tumour was previously recommended to identify patients who will benefit from the EGFR targeted therapy. Previous studies have displayed diverging results regarding the expression of EGFR in the primary tumour compared to the metastases. The present study was performed to investigate whether EGFR and ErbB2-4 expression differed between 64 primary tumours and their corresponding metastases.

    PATIENTS AND METHODS: EGFR and ErbB2-4 expression were analysed in the primary tumour and in the corresponding metastases using immunohistochemistry (IHC).

    RESULTS: In 49/64 samples (76%), the primary tumours were EGFR positive; in 33% (16/49) of EGFR positive samples, the tumours lost the EGFR expression in the metastasis compared to the primary tumour. From the primary tumours, 15/64 (23%) were negative and 5 of these (33%) developed EGFR expression in the metastasis. ErbB2, ErbB3, and ErbB4 expression was evident in 54%, 67%, and 81%, respectively. There was no significant difference between ErbB2, ErbB3, and ErbB4 expression in primary tumours and metastases. The co-expression of the ErbB family members was also analysed, with a significant increase of ErbB3/ErbB4 co-expression in late stage tumours.

    CONCLUSION: The EGFR expression was lost in 33% of metastasising primary colorectal cancer tumours, a finding that agrees with at least one previous study. Thus, the present results clearly implicate the need for EGFR analysis of both the primary tumour and metastases to accurately determine EGFR status when considering the use of EGFR targeted therapies.

  • 73.
    Ljuslinder, Ingrid
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Melin, Beatrice
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Increased epidermal growth factor receptor expression at the invasive margin is a negative prognostic factor in colorectal cancer2011In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 128, no 9, p. 2031-2037Article in journal (Refereed)
    Abstract [en]

    The receptor tyrosine kinase epidermal growth factor receptor (EGFR) is often expressed in solid malignant tumours, and the expression has been correlated to disease progression. Multiple new agents targeted against the EGFR have been developed during the last decade, but treatment selecting criteria are still not clear. This immunohistochemical study includes 386 colorectal cancer patients and focuses on EGFR expression variations within the tumour, comparing central parts to the invasive margin. Positive immunostaining for EGFR was evident in the central part in 176/386 (46%) of analyzed primary tumours. The invasive margin was positive in 222/386 (58%). A similar expression in both the central part and the invasive front was evident in 286/386 (74%). An increased score at the invasive margin compared to central parts (EGFR(i)) was evident in 97/386 (25%) of the tumours. Moreover, the results show a significant survival disadvantage for the EGFR(i) group, both in potentially curatively resected colon cancer patients (n = 170, p = 0.01) and in potentially curatively resected colon and rectal cancer patients combined (n = 273, p = 0.013). Multivariate survival analysis adjusted for age, gender, bowel localisation, grade, stage and tumour type showed an increased risk of cancer death for EGFR(i) tumours (HR, 1.53; 95% CI, 1.04-2.23; p = 0.029). A significant correlation between EGFR expression at the invasive margin and the presence of budding was seen (p = 0.0001). This investigation of a large patient material implies that EGFR immunohistochemical analysis still has a role in risk evaluation of colorectal cancer patients.

  • 74.
    Lorenz, Fryderyk
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Marklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Werner, Mårten
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Wahlin, Bjorn Engelbrekt
    Wahlin, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Fecal calprotectin as a biomarker of intestinal graft versus host disease after allogeneic hematopoietic stem cell transplantation2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, p. 7920-Article in journal (Refereed)
    Abstract [en]

    The diagnosis of gastrointestinal graft versus host disease (GI-GVHD) is based on clinical symptoms and histological findings. In clinical practice, it is often difficult to decide whether abdominal symptoms in an allogeneic transplant recipient are caused by GVHD or other disorders. Endoscopic biopsies are helpful in establishing the diagnosis, but endoscopy is not always possible to perform due to poor general condition of the patients. No biomarkers are routinely used to predict GVHD. The aim of fecal calprotectin and alpha-1 antitrypsin testing in our study was to find out whether determination of the concentrations of these proteins may be used as a screening method for enteric GVHD. We studied prospectively 51 patients, 8 of whom developed GI-GVHD. Our data demonstrate that elevated fecal calprotectin levels were significantly associated with presence of GI-GVHD. We found a positive association between high F-calprotectin and severe gastrointestinal GVHD. In bivariate analysis, only calprotectin but not alpha-1 antitrypsin was independently associated with GI-GVHD. Testing for fecal calprotectin after allogeneic stem cell transplantation may be a useful screening tool.

  • 75.
    Lundberg, Ida V.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Eklöf, Vincy
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    SOX2 expression is associated with a cancer stem cell state and down-regulation of CDX2 in colorectal cancer2016In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 16, article id 471Article in journal (Refereed)
    Abstract [en]

    Background: To improve current treatment strategies for patients with aggressive colorectal cancer (CRC), the molecular understanding of subgroups of CRC with poor prognosis is of vast importance. SOX2 positive tumors have been associated with a poor patient outcome, but the functional role of SOX2 in CRC patient prognosis is still unclear. Methods: An in vitro cell culture model expressing SOX2 was used to investigate the functional role of SOX2 in CRC. In vitro findings were verified using RNA from fresh frozen tumor tissue or immunohistochemistry on formalin fixed paraffin embedded (FFPE) tumor tissue from a cohort of 445 CRC patients. Results: Using our in vitro model, we found that SOX2 expressing cells displayed several characteristics of cancer stem cells; such as a decreased proliferative rate, a spheroid growth pattern, and increased expression of stem cell markers CD24 and CD44. Cells expressing SOX2 also showed down-regulated expression of the intestinal epithelial marker CDX2. We next evaluated CDX2 expression in our patient cohort. CDX2 down-regulation was more often found in right sided tumors of high grade and high stage. Furthermore, a decreased expression of CDX2 was closely linked to MSI, CIMP-high as well as BRAF mutated tumors. A decreased expression of CDX2 was also, in a stepwise manner, strongly correlated to a poor patient prognosis. When looking at SOX2 expression in relation to CDX2, we found that SOX2 expressing tumors more often displayed a down-regulated expression of CDX2. In addition, SOX2 expressing tumors with a down-regulated CDX2 expression had a worse patient prognosis compared to those with retained CDX2 expression. Conclusions: Our results indicate that SOX2 expression induces a cellular stem cell state in human CRC with a decreased expression of CDX2. Furthermore, a down-regulated expression of CDX2 results in a poor patient prognosis in CRC and at least part of the prognostic importance of SOX2 is mediated through CDX2 down-regulation.

  • 76.
    Lundberg, Ida V
    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.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Eklöf, Vincy
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    SOX2 expression is regulated by BRAF and contributes to poor patient prognosis in colorectal cancer2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, article id e101957Article in journal (Refereed)
    Abstract [en]

    Sporadic colorectal cancer (CRC) is a common malignancy and also one of the main causes of cancer deaths worldwide. Aberrant expression of the transcription factor SOX2 has recently been observed in several cancer types, but its role in CRC has not been fully elucidated. Here we studied the expression of SOX2 in 441 CRC patients by immunohistochemistry and related the expression to clinicopathological and molecular variables and patient prognosis. SOX2 was expressed in 11% of the tumors and was significantly associated to BRAF(V600E) mutation, but not to KRAS mutations (codon 12 and 13). SOX2 positivity was correlated to poor patient survival, especially in BRAF(V600E) mutated cases. In vitro studies showed that cells expressing the constitutively active BRAF(V600E) had increased SOX2 expression, a finding not found in cells expressing KRAS(G12V). Furthermore, blocking downstream BRAF signalling using a MEK-inhibitor resulted in a decreased expression of SOX2. Since SOX2 overexpression has been correlated to increased migration and invasion, we investigated the SOX2 expression in human CRC liver metastasis and found that a SOX2 positive primary CRC also had SOX2 expression in corresponding liver metastases. Finally we found that cells overexpressing SOX2 in vitro showed enhanced expression of FGFR1, which has been reported to correlate with liver metastasis in CRC. Our novel findings suggest that SOX2 expression is partly regulated by BRAF signalling, and an increased SOX2 expression may promote CRC metastasis and mediate a poor patient prognosis.

  • 77.
    Lundberg, Ida
    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.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Li, Xingru
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Zingmark, Carl
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Löfgren-Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    MicroRNA expression in KRAS- and BRAF-mutated colorectal cancers2018In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 38, no 2, p. 677-683Article in journal (Refereed)
    Abstract [en]

    Background/Aim: KRAS and BRAF are two genes commonly mutated in colorectal cancer (CRC). Even though BRAF is a downstream target of KRAS in the MAPK signalling pathway, KRAS- and BRAF-mutated CRCs are found to display several different clinical and histopathological features. We investigated whether a differential expression of microRNAs (miRNAs) could explain the clinicopathological differences seen between KRAS-and BRAF-mutated CRCs.

    Materials and Methods: Using a PCR array, we analyzed the expression of 84 different miRNAs in CRC cell lines wild-type in KRAS and BRAF, or mutated in KRAS or BRAF.

    Results: Ten miRNAs were selected for further analyses in tumor tissue specimens (let-7a, let-7i, miR-10a, miR-10b, miR-31, miR-100, miR-181a, miR-181b, miR-372, and miR-373). BRAF-mutated tumors were found to express significantly higher levels of miR-31 as well as significantly lower levels of miR-373, compared to wild-type tumors.

    Conclusion: Our results suggest that KRAS and BRAF-mutated CRCs may have different miRNA signatures compared to CRC tumors wild-type in KRAS and BRAF. However, no difference in expression levels between KRAS-and BRAF-mutated tumors was evident for the miRNAs analyzed in this study.

  • 78.
    Lundgren, David
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Eklöf, Vincy
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Karling, Pontus
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Proton pump inhibitor use is associated with elevated faecal calprotectin levels. A cross-sectional study on subjects referred for colonoscopy2019In: Scandinavian Journal of Gastroenterology, ISSN 0036-5521, E-ISSN 1502-7708, Vol. 54, no 2, p. 152-157Article in journal (Refereed)
    Abstract [en]

    Objectives: Faecal Calprotectin (FC) is a sensitive marker for gut inflammation. However, slightly elevated FC levels are also common in subjects without inflammation. We investigated the association between FC and clinical factors including concomitant use of medical therapy in patients with a normal colonoscopy.Material and methods: Out-patients (n=1263) referred for colonoscopy, performed FC test (CALPRO) the day before the start of bowel preparation. All subjects answered questionnaires that included questions on the present and past health history, concomitant medical treatment and gastrointestinal symptoms (GSRS). A medical record chart review was performed to check for concomitant disease, cause of referral and the result of the colonoscopy including biopsies. Inclusion criteria were a normal colonoscopy. Exclusion criteria were inflammatory bowel disease, colon cancer and high-grade dysplasia.Results: Five hundred ninety subjects fulfilled the inclusion criteria and completed the study. Thirty-six per cent of the subjects had a FC >50 mu g/g. In a logistic regression analysis, age (adjusted OR: 1.051; CI: 1.032-1.071), and the use of proton pump inhibitors (adjusted OR: 3.843; CI: 2.338-6.316), non-steroid anti-inflammatory drugs (adjusted OR: 2.411; CI: 1.162-5.002) and acetylsalicylic acid (adjusted OR: 2.934; CI: 1.085-3.448) were significantly associated with an elevated FC (>50 mu g/g).Conclusions: More than one-third of the patients with a normal colonoscopy performed in clinical routine had a slightly elevated FC level. Our results emphasise the need for attention to age, the use of proton pump inhibitors, non-steroid anti-inflammatory drugs and acetylsalicylic acid in the interpretation of FC tests in clinical practice.

  • 79.
    Lundgren, David
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Eklöf, Vincy
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    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.
    Patients with longstanding ulcerative colitis in remission do not have more irritable bowel syndrome-like symptoms than controls2016In: BMC Gastroenterology, ISSN 1471-230X, E-ISSN 1471-230X, Vol. 16, article id 139Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Irritable bowel syndrome (IBS) is more common in patients with ulcerative colitis (UC) than expected. The prevalence of IBS in patients with UC with longstanding disease is not known. We investigated the prevalence of IBS-like symptoms in patients with UC in remission and longstanding disease in comparison to control subjects.

    METHODS: Sixty-eight patients with UC and 33 patients with hereditary familiar colon cancer and who underwent colonoscopy surveillance were included. Faecal calprotectin (FC), Gastrointestinal Symptoms Rating Scale-Irritable Bowel Syndrome (GSRS-IBS) and Hospital Anxiety and Depression scale were fulfilled prior to endoscopy. UC in remission was define by steroid-free clinical remission, a Mayo Score ≤ 1 on endoscopy, a FC ≤ 200 μg/g and no significant active inflammation on colon biopsies.

    RESULTS: Fifty-five UC patients met the criteria for being in remission. The median disease duration was 17 years. The patients with UC in remission tended to have lower scores on total GSRS-IBS score (6 vs 10.5; p = 0.062) and lower or equal scores on all specific IBS symptoms in comparison to controls. There was a moderate but significant correlation between diarrhoea scores and FC levels (in the span ≤ 200 μg/g) (rs 0.38; p = 0.004) in the UC in remission group.

    CONCLUSION: Patients with UC with longstanding disease and in remission do not have more IBS symptoms than controls. In UC patients in remission the FC level in the lower span showed a moderate correlation to symptoms of diarrhoea.

  • 80.
    Lundholm, Marie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hägglöf, Christina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Egevad, Lars
    Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. anders.bergh@umu.se.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Secreted Factors from Colorectal and Prostate Cancer Cells Skew the Immune Response in Opposite Directions2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 15651Article in journal (Refereed)
    Abstract [en]

    Macrophage infiltration has been associated with an improved prognosis in patients with colorectal cancer (CRC), but a poor prognosis in prostate cancer (PC) patients. In this study, the distribution and prognostic value of proinflammatory M1 macrophages (NOS2(+)) and immunosuppressive M2 macrophages (CD163(+)) was evaluated in a cohort of 234 PC patients. We found that macrophages infiltrating PC were mainly of an M2 type and correlated with a more aggressive tumor and poor patient prognosis. Furthermore, the M1/M2 ratio was significantly decreased in PC compared to CRC. Using in vitro cell culture experiments, we could show that factors secreted from CRC and PC cells induced macrophages of a proinflammatory or immunosuppressive phenotype, respectively. These macrophages differentially affected autologous T lymphocyte proliferation and activation. Consistent with this, CRC specimens were found to have higher degrees of infiltrating T-helper 1 cells and active cytotoxic T lymphocytes, while PC specimens displayed functionally inactive T cells. In conclusion, our results imply that tumour-secreted factors from cancers of different origin can drive macrophage differentiation in opposite directions and thereby regulate the organization of the anti-tumour immune response. Our findings suggest that reprogramming of macrophages could be an important tool in the development of new immunotherapeutic strategies.

  • 81. Malesci, Alberto
    et al.
    Bianchi, Paolo
    Celesti, Giuseppe
    Basso, Gianluca
    Marchesi, Federica
    Grizzi, Fabio
    Di Caro, Giuseppe
    Cavalleri, Tommaso
    Rimassa, Lorenza
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lugli, Alessandro
    Koelzer, Viktor. H.
    Roncalli, Massimo
    Mantovani, Alberto
    Ogino, Shuji
    Laghi, Luigi
    Tumor-associated macrophages and response to 5-fluorouracil adjuvant therapy in stage III colorectal cancer2017In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, no 12, article id e1342918Article in journal (Refereed)
    Abstract [en]

    Tumor-associated macrophages (TAMs) play a role in tumor development and progression. We hypothesized that abundance of TAMs might modify efficacy of 5-fluorouracil chemotherapy in colorectal cancer. We measured the density of CD68+ TAMs at the invasive front of primary tumor of colorectal carcinoma (PT-TAMs; n = 208), at available matched metastatic lymph node (LN-TAMs; n = 149), and in an independent set of primary colorectal cancers (PT-TAMs, n = 111). The hazard ratios for disease-free survival were computed by Cox proportional-hazards model. In exploratory analysis, the interaction between TAMs and 5-fluorouracil adjuvant therapy was significant (PT-TAMs, p=0.02; LN-TAMs, p D 0.005). High TAMs were independently associated with better disease-free survival only in 5-fluorouracil-treated patients (PT-TAMs, HR 0.23; 95% CI, 0.08-0.65; p=0.005; LN-TAMs, HR 0.13; 95% CI, 0.04-0.43; p D 0.001). The independent predictive value of PT-TAMs was replicated in the external set (HR, 0.14; 95% CI 0.02-1.00; p=0.05). In an in vitro experiment, 5-fluorouracil and macrophages showed a synergistic effect and increased colorectal cancer cell death. High densities of TAMs, particularly in metastatic lymph-nodes, identify stage III colorectal cancer patients benefitting from 5-fluorouracil adjuvant therapy.

  • 82. Murphy, Neil
    et al.
    Cross, Amanda J.
    Abubakar, Mustapha
    Jenab, Mazda
    Aleksandrova, Krasimira
    Boutron-Ruault, Marie-Christine
    Dossus, Laure
    Racine, Antoine
    Kuehn, Tilman
    Katzke, Verena A.
    Tjonneland, Anne
    Petersen, Kristina E. N.
    Overvad, Kim
    Ramon Quiros, J.
    Jakszyn, Paula
    Molina-Montes, Esther
    Dorronsoro, Miren
    Huerta, Jose-Maria
    Barricarte, Aurelio
    Khaw, Kay-Tee
    Wareham, Nick
    Travis, Ruth C.
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Masala, Giovanna
    Krogh, Vittorio
    Tumino, Rosario
    Vineis, Paolo
    Panico, Salvatore
    Bueno-de-Mesquita, H. Bas
    Siersema, Peter D.
    Peeters, Petra H.
    Ohlsson, Bodil
    Ericson, Ulrika
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Nyström, Hanna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Weiderpass, Elisabete
    Skeie, Guri
    Freisling, Heinz
    Kong, So Yeon
    Tsilidis, Kostas
    Muller, David C.
    Riboli, Elio
    Gunter, Marc J.
    A Nested Case-Control Study of Metabolically Defined Body Size Phenotypes and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)2016In: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 13, no 4, article id e1001988Article in journal (Refereed)
    Abstract [en]

    Background Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown.

    Methods and Findings The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m(2)), (2) metabolically healthy/overweight (BMI >= 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI >= 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [>= 80 cm for women and >= 94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of <0.05 was considered statistically significant. In multivariable-adjusted conditional logistic regression models with BMI used to define adiposity, compared with metabolically healthy/normal weight individuals, we observed a higher colorectal cancer risk among metabolically unhealthy/normal weight (odds ratio [OR] = 1.59, 95% CI 1.10-2.28) and metabolically unhealthy/overweight (OR = 1.40, 95% CI 1.01-1.94) participants, but not among metabolically healthy/overweight individuals (OR = 0.96, 95% CI 0.65-1.42). Among the overweight individuals, lower colorectal cancer risk was observed for metabolically healthy/overweight individuals compared with metabolically unhealthy/overweight individuals (OR = 0.69, 95% CI 0.49-0.96). These associations were generally consistent when waist circumference was used as the measure of adiposity. To our knowledge, there is no universally accepted clinical definition for using C-peptide level as an indication of hyperinsulinaemia. Therefore, a possible limitation of our analysis was that the classification of individuals as being hyperinsulinaemic-based on their C-peptide level-was arbitrary. However, when we used quartiles or the median of C-peptide, instead of tertiles, as the cut-point of hyperinsulinaemia, a similar pattern of associations was observed.

    Conclusions These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.

  • 83. Murphy, Neil
    et al.
    Norat, Teresa
    Ferrari, Pietro
    Jenab, Mazda
    Bueno-de-Mesquita, Bas
    Skeie, Guri
    Dahm, Christina C.
    Overvad, Kim
    Olsen, Anja
    Tjonneland, Anne
    Clavel-Chapelon, Francoise
    Boutron-Ruault, Marie Christine
    Racine, Antoine
    Kaaks, Rudolf
    Teucher, Birgit
    Boeing, Heiner
    Bergmann, Manuela M.
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Lagiou, Pagona
    Palli, Domenico
    Pala, Valeria
    Panico, Salvatore
    Tumino, Rosario
    Vineis, Paolo
    Siersema, Peter
    van Duijnhoven, Franzel
    Peeters, Petra H. M.
    Hjartaker, Anette
    Engeset, Dagrun
    Gonzalez, Carlos A.
    Sanchez, Maria-Jose
    Dorronsoro, Miren
    Navarro, Carmen
    Ardanaz, Eva
    Quiros, Jose R.
    Sonestedt, Emily
    Ericson, Ulrika
    Nilsson, Lena
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Wareham, Nick
    Key, Timothy J.
    Crowe, Francesca L.
    Fedirko, Veronika
    Wark, Petra A.
    Chuang, Shu-Chun
    Riboli, Elio
    Dietary fibre intake and risks of Cancers of the Colon and Rectum in the European prospective investigation into Cancer and Nutrition (EPIC)2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 6, p. e39361-Article in journal (Refereed)
    Abstract [en]

    Background: Earlier analyses within the EPIC study showed that dietary fibre intake was inversely associated with colorectal cancer risk, but results from some large cohort studies do not support this finding. We explored whether the association remained after longer follow-up with a near threefold increase in colorectal cancer cases, and if the association varied by gender and tumour location.

    Methodology/Principal Findings: After a mean follow-up of 11.0 years, 4,517 incident cases of colorectal cancer were documented. Total, cereal, fruit, and vegetable fibre intakes were estimated from dietary questionnaires at baseline. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models stratified by age, sex, and centre, and adjusted for total energy intake, body mass index, physical activity, smoking, education, menopausal status, hormone replacement therapy, oral contraceptive use, and intakes of alcohol, folate, red and processed meats, and calcium. After multivariable adjustments, total dietary fibre was inversely associated with colorectal cancer (HR per 10 g/day increase in fibre 0.87, 95% CI: 0.79-0.96). Similar linear associations were observed for colon and rectal cancers. The association between total dietary fibre and risk of colorectal cancer risk did not differ by age, sex, or anthropometric, lifestyle, and dietary variables. Fibre from cereals and fibre from fruit and vegetables were similarly associated with colon cancer; but for rectal cancer, the inverse association was only evident for fibre from cereals.

    Conclusions/Significance: Our results strengthen the evidence for the role of high dietary fibre intake in colorectal cancer prevention.

  • 84. Murphy, Neil
    et al.
    Norat, Teresa
    Ferrari, Pietro
    Jenab, Mazda
    Bueno-de-Mesquita, Bas
    Skeie, Guri
    Olsen, Anja
    Tjonneland, Anne
    Dahm, Christina C.
    Overvad, Kim
    Boutron-Ruault, Marie Christine
    Clavel-Chapelon, Francoise
    Nailler, Laura
    Kaaks, Rudolf
    Teucher, Birgit
    Boeing, Heiner
    Bergmann, Manuela M.
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Palli, Domenico
    Pala, Valeria
    Tumino, Rosario
    Vineis, Paolo
    Panico, Salvatore
    Peeters, Petra H. M.
    Dik, Vincent K.
    Weiderpass, Elisabete
    Lund, Eiliv
    Quiros Garcia, Jose Ramon
    Zamora-Ros, Raul
    Sanchez Perez, Maria Jose
    Dorronsoro, Miren
    Navarro, Carmen
    Ardanaz, Eva
    Manjer, Jonas
    Almquist, Martin
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Khaw, Kay-Tee
    Wareham, Nick
    Key, Timothy J.
    Crowe, Francesca L.
    Fedirko, Veronika
    Gunter, Marc J.
    Riboli, Elio
    Consumption of Dairy Products and Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC)2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e72715-Article in journal (Refereed)
    Abstract [en]

    Background: Prospective studies have consistently reported lower colorectal cancer risks associated with higher intakes of total dairy products, total milk and dietary calcium. However, less is known about whether the inverse associations vary for individual dairy products with differing fat contents. Materials and Methods: In the European Prospective Investigation into Cancer and Nutrition (EPIC), we investigated the associations between intakes of total milk and milk subtypes (whole-fat, semi-skimmed and skimmed), yoghurt, cheese, and dietary calcium with colorectal cancer risk amongst 477,122 men and women. Dietary questionnaires were administered at baseline. Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models, adjusted for relevant confounding variables. Results: During the mean 11 years of follow-up, 4,513 incident cases of colorectal cancer occurred. After multivariable adjustments, total milk consumption was inversely associated with colorectal cancer risk (HR per 200 g/day 0.93, 95% CI: 0.89-0.98). Similar inverse associations were observed for whole-fat (HR per 200 g/day 0.90, 95% CI: 0.82-0.99) and skimmed milk (HR per 200 g/day 0.90, 95% CI: 0.79-1.02) in the multivariable models. Inverse associations were observed for cheese and yoghurt in the categorical models; although in the linear models, these associations were non-significant. Dietary calcium was inversely associated with colorectal cancer risk (HR per 200 mg/day 0.95, 95% CI: 0.91-0.99); this association was limited to dairy sources of calcium only (HR per 200 mg/day 0.95, 95% CI: 0.91-0.99), with no association observed for non-dairy calcium sources (HR per 200 mg/day 1.00, 95% CI: 0.81-1.24). Conclusions: Our results strengthen the evidence for a possible protective role of dairy products on colorectal cancer risk. The inverse associations we observed did not differ by the fat content of the dairy products considered.

  • 85.
    Myte, Robin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Gylling, Björn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Häggström, Christel
    Umeå University, Faculty of Medicine, Department of Biobank Research. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden..
    Zingmark, Carl
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Löfgren Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Wallenberg Centre for Molecular Medicine at Umeå University (WCMM).
    Metabolic factors and the risk of colorectal cancer by KRAS and BRAF mutation status2019In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, no 2, p. 327-337Article in journal (Refereed)
    Abstract [en]

    Factors related to energy metabolism and the metabolic syndrome, such as higher body mass index (BMI), blood glucose, or blood lipids, and blood pressure, are associated with an increased risk of colorectal cancer (CRC). However, CRC is a heterogeneous disease, developing through distinct pathways with differences in molecular characteristics and prognosis, and possibly also in risk factors. For subtypes defined by KRAS and BRAF mutation status, BMI is the only metabolic factor previously studied, with inconsistent findings. We investigated whether associations between BMI, blood glucose, blood lipids, and blood pressure and CRC risk differed by tumor KRAS and BRAF mutation status in 117,687 participants from two population-based cohorts within the Northern Sweden Health and Disease Study (NSHDS). Hazard ratios (HRs) for overall CRC and CRC subtypes by metabolic factors were estimated with Cox proportional hazards regression, using multiple imputation to handle missing exposure and tumor data. During a median follow-up of 15.6 years, we acquired 1,250 prospective CRC cases, of which 766 cases had complete baseline and molecular tumor data. Consistent with previous evidence, higher BMI, total cholesterol, triglyceride levels, and blood pressure were associated with an increased risk of overall CRC (HRs per 1 standard deviation increase: 1.07 to 1.12). These associations were similar regardless of CRC subtype by KRAS and BRAF mutation status (all pheterogeneity > 0.05). The same was true for subtypes based on microsatellite instability status. Poor metabolic health may therefore be a universal mechanism for colorectal cancer, acting across multiple developmental pathways.

  • 86.
    Myte, Robin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Gylling, Björn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Löfgren-Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Huyghe, Jeroen R.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Meyer, Klaus
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Ueland, Per Magne
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    One-carbon metabolism biomarkers and genetic variants in relation to colorectal cancer risk by KRAS and BRAF mutation status2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 4, article id e0196233Article in journal (Refereed)
    Abstract [en]

    Disturbances in one-carbon metabolism, intracellular reactions involved in nucleotide synthesis and methylation, likely increase the risk of colorectal cancer (CRC). However, results have been inconsistent. To explore whether this inconsistency could be explained by intertumoral heterogeneity, we evaluated a comprehensive panel of one-carbon metabolism biomarkers and some single nucleotide polymorphisms (SNPs) in relation to the risk of molecular subtypes of CRC defined by mutations in the KRAS and BRAF oncogenes. This nested case-control study included 488 CRC cases and 947 matched controls from two population-based cohorts in the Northern Sweden Health and Disease Study. We analyzed 14 biomarkers and 17 SNPs in prediagnostic blood and determined KRAS and BRAF mutation status in tumor tissue. In a multivariate network analysis, no variable displayed a strong association with the risk of specific CRC subtypes. A non-synonymous SNP in the CTH gene, rs1021737, had a stronger association compared with other variables. In subsequent univariate analyses, participants with variant rs1021737 genotype had a decreased risk of KRAS-mutated CRC (OR per allele = 0.72, 95% CI = 0.50, 1.05), and an increased risk of BRAF-mutated CRC (OR per allele = 1.56, 95% CI = 1.07, 2.30), with weak evidence for heterogeneity (Pheterogeneity = 0.01). This subtype-specific SNP association was not replicated in a case-case analysis of 533 CRC cases from The Cancer Genome Atlas (P = 0.85). In conclusion, we found no support for clear subtype-specific roles of one-carbon metabolism biomarkers and SNPs in CRC development, making differences in CRC molecular subtype distributions an unlikely explanation for the varying results on the role of one-carbon metabolism in CRC development across previous studies. Further investigation of the CTH gene in colorectal carcinogenesis with regards to KRAS and BRAF mutations or other molecular characteristics of the tumor may be warranted.

  • 87.
    Myte, Robin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Gylling, Björn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Ueland, Per Magne
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Untangling the role of one-carbon metabolism in colorectal cancer risk: a comprehensive Bayesian network analysis2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 43434Article in journal (Refereed)
    Abstract [en]

    The role of one-carbon metabolism (1CM), particularly folate, in colorectal cancer (CRC) development has been extensively studied, but with inconclusive results. Given the complexity of 1CM, the conventional approach, investigating components individually, may be insufficient. We used a machine learning-based Bayesian network approach to study, simultaneously, 14 circulating one-carbon metabolites, 17 related single nucleotide polymorphisms (SNPs), and several environmental factors in relation to CRC risk in 613 cases and 1190 controls from the prospective Northern Sweden Health and Disease Study. The estimated networks corresponded largely to known biochemical relationships. Plasma concentrations of folate (direct), vitamin B6 (pyridoxal 5-phosphate) (inverse), and vitamin B2 (riboflavin) (inverse) had the strongest independent associations with CRC risk. Our study demonstrates the importance of incorporating B-vitamins in future studies of 1CM and CRC development, and the usefulness of Bayesian network learning for investigating complex biological systems in relation to disease.

  • 88.
    Myte, Robin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Gylling, Björn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Ueland, Per Magne
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Components of One-carbon Metabolism Other than Folate and Colorectal Cancer Risk2016In: Epidemiology, ISSN 1044-3983, E-ISSN 1531-5487, Vol. 27, no 6, p. 787-796Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Despite extensive study, the role of folate in colorectal cancer remains unclear. Research has therefore begun to address the role of other elements of the folate-methionine metabolic cycles. This study investigated factors other than folate involved in one-carbon metabolism, i.e., choline, betaine, dimethylglycine, sarcosine, and methionine and relevant polymorphisms, in relation to the risk of colorectal cancer in a population with low intakes and circulating levels of folate.

    METHODS: This was a prospective case-control study of 613 case subjects and 1,190 matched control subjects nested within the population-based Northern Sweden Health and Disease Study. We estimated odds ratios (OR) by conditional logistic regression, and marginal risk differences with weighted maximum likelihood estimation using incidence data from the study cohort.

    RESULTS: Higher plasma concentrations of methionine and betaine were associated with modest colorectal cancer risk reductions (OR [95% confidence interval {CI}] for highest versus lowest tertile: 0.76 [0.57, 0.99] and 0.72 [0.55, 0.94], respectively). Estimated marginal risk differences corresponded to approximately 200 fewer colorectal cancer cases per 100,000 individuals on average. We observed no clear associations between choline, dimethylglycine, or sarcosine and colorectal cancer risk. The inverse association of methionine was modified by plasma folate concentrations (OR [95% CI] for highest/lowest versus lowest/lowest tertile of plasma methionine/folate concentrations 0.39 [0.24, 0.64], Pinteraction = 0.06).

    CONCLUSIONS: In this population-based, nested case-control study with a long follow-up time from baseline to diagnosis (median: 8.2 years), higher plasma concentrations of methionine and betaine were associated with lower colorectal cancer risk. See Video Abstract at http://links.lww.com/EDE/B83.

  • 89.
    Myte, Robin
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University.
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sundkvist, Anneli
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Gylling, Björn
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Häggström, Jenny
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Zingmark, Carl
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Löfgren Burström, Anna
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Metabolic biomarkers and the risk of molecular subtypes of colorectal cancerManuscript (preprint) (Other academic)
    Abstract [en]

    Background: Body fatness measured as high body mass index (BMI) increase the risk for colorectal cancer (CRC). The mechanisms behind the relationship are not fully understood, but might include insulin resistance and changes in adipokine concentrations produced by adipose tissue. Yet, associations between circulating biomarkers related to these mechanisms and CRC risk have been somewhat inconsistent, possibly due to CRC heterogeneity. To better understand the role of insulin resistance and adipokines in CRC development, we therefore investigated circulating biomarkers related to these mechanisms in relation to molecular subtypes of CRC.

    Methods: This was a prospective case-control study of 1010 cases and 1:1 matched controls nested within the population-based Northern Sweden Health and Disease Study (NSHDS). Concentrations of insulin, C-peptide, adiponectin, and leptin were quantified in prediagnostic plasma using immunoassays and related to CRC and CRC subtypes defined by mutations in BRAF and KRAS, and microsatellite instability (MSI) status analyzed in tumor tissue. Odds ratios (ORs) and 95% confidence intervals (CIs) for CRC by metabolic biomarker levels were calculated with conditional logistic regression.

    Results: Higher C-peptide and lower adiponectin were associated with an increased CRC risk (ORs per 1 standard deviation increase (95% CI): 1.11 (1.01, 1.23) and 0.91 (0.83, 1.00), respectively). The associations were attenuated when adjusting for BMI (ORs (95% CI): 1.07 (0.96, 1.19) and 0.93 (0.84, 1.03), respectively), with the potential exception of the association of C-peptide in women. Circulating insulin and leptin were not associated with CRC risk. We found no clear differences in the association between any biomarkers and CRC risk by molecular subtypes defined by KRAS and BRAF mutation status (Pheterogeneity>0.6), or MSI status (Pheterogeneity>0.3).

    Conclusion: Circulating biomarkers of insulin resistance and adipokines were not associated with CRC or specific molecular subtypes of CRC defined by KRAS and BRAF mutation or MSI status.

  • 90. Mårtensson, Ann
    et al.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Jung, Andreas
    Cederquist, Kristina
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Beta-catenin expression in relation to genetic instability and prognosis in colorectal cancer.2007In: Oncol Rep, ISSN 1021-335X, Vol. 17, no 2, p. 447-52Article in journal (Refereed)
  • 91. Norat, Teresa
    et al.
    Bingham, Sheila
    Ferrari, Pietro
    Slimani, Nadia
    Jenab, Mazda
    Mazuir, Mathieu
    Overvad, Kim
    Olsen, Anja
    Tjonneland, Anne
    Clavel, Francoise
    Boutron-Ruault, Marie-Christine
    Kesse, Emmanuelle
    Boeing, Heiner
    Bergmann, Manuela M
    Nieters, Alexandra
    Linseisen, Jakob
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Tountas, Yannis
    Berrino, Franco
    Palli, Domenico
    Panico, Salvatore
    Tumino, Rosario
    Vineis, Paolo
    Bueno-de-Mesquita, H Bas
    Peeters, Petra H M
    Engeset, Dagrun
    Lund, Eiliv
    Skeie, Guri
    Ardanaz, Eva
    González, Carlos
    Navarro, Carmen
    Quirós, J Ramón
    Sanchez, Mariá José
    Berglund, Göran
    Mattisson, Irene
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Day, Nicholas E
    Khaw, Kay-Tee
    Key, Timothy J
    San Joaquin, Miguel
    Hémon, Bertrand
    Saracci, Rodolfo
    Kaaks, Rudolf
    Riboli, Elio
    Meat, fish, and colorectal cancer risk: the European Prospective Investigation into cancer and nutrition.2005In: Journal of National Cancer Institute, ISSN 1460-2105, Vol. 97, no 12, p. 906-16Article in journal (Refereed)
  • 92.
    Nyström, Hanna
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Naredi, Peter
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Berglund, Anette
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Liver-metastatic potential of colorectal cancer is related to the stromal composition of the tumour2012In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 32, no 12, p. 5183-5191Article in journal (Refereed)
    Abstract [en]

    Background: The tumour stroma is an important modulator of cancer cell behaviour. The aim of this study was to compare the stromal composition between primary colorectal cancer (CRC) and colorectal liver metastases (CLM).

    Materials and Methods: The stromal composition in matched tissue sections of CRC and subsequent CLM was analysed, and related to clinical parameters.

    Results: Differences in the expression pattern of type I collagen and type IV collagen in CRC was related to a higher risk of CLM. Two types of CLM the desmoplastic and pushing type were identified. The time between CRC and diagnosis of CLM was shorter (p=0.047) for desmoplastic CLM. The mortality rate was higher for pushing CLM due to frequent extrahepatic disseminated disease. A difference in the overall survival rate between patients with desmoplastic and those with pushing CLM was seen at follow-up of more than 60 months (p=0.046).

    Conclusion: The liver-metastasizing potential is related to the stromal composition of primary CRC. There are distinct growth patterns in CLM with differences in stromal composition and clinical outcome.

  • 93.
    Ohlsson, Lina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Israelsson, Anne
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stenlund, Hans
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lindmark, Gudrun
    Lymph node CEA and MUC2 mRNA as useful predictors of outcome in colorectal cancer2012In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 130, no 8, p. 1833-1843Article in journal (Refereed)
    Abstract [en]

    The aim was to explore the utility for staging and prognostic impact of carcinoembryonic antigen (CEA), cytokeratin 20 (CK20), guanylyl cyclase C (GCC), CUB domain protein 1 (CDCP1) and mucin 2 (MUC2) mRNA levels in mesenteric lymph nodes of colorectal cancer (CRC) patients. Lymph nodes were collected at surgery and bisected; one half was subjected to biomarker mRNA analysis using real-time quantitative RT-PCR and the other half to routine histopathology. Lymph nodes from 174 CRC patients and 24 controls were analyzed. The median follow-up time was 59 (range 17-131) months. Cut-off levels were defined by analyzing quintiles by Cox regression model. CEA mRNA showed the best discriminating power between patients with recurrence in CRC after surgery and patients who were apparently disease-free (P=0.015). The risk of recurrence for the CEA(+) patients was 4.6 times greater than for the CEA(-) patients (P<0.0001). The other biomarkers gave lower hazard ratios. Cumulative survival analysis demonstrated that the average survival time was 99 months for CEA(-) patients compared to 39 months for CEA(+) patients, a difference of 60 months (P<0.0001). Six to nine percent of the stage I and II patients [H&E(-)] had CEA(+), CK20(+), GCC(+) and/or MUC2(+) lymph nodes. Two of these patients died from recurrent CRC. Low lymph node MUC2/CEA mRNA ratio identified patients with high risk for recurrence (P=0.011). Thus, qRT-PCR of CEA mRNA is a sensitive method to identify tumor cells in lymph nodes of CRC patients and, in combination with MUC2 mRNA, allows improved prediction of clinical outcome. © 2011 Wiley-Liss, Inc.

  • 94.
    Ohlsson, Lina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lindmark, G
    Israelsson, Anne
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Lymph node tissue kallikrein-related peptidase 6 mRNA: a progression marker for colorectal cancer.2012In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 107, no 1, p. 150-157Article in journal (Refereed)
    Abstract [en]

    Background:A most important characteristic feature for poor prognosis in colorectal cancer (CRC) is the presence of lymph node metastasis. Determination of carcinoembryonic antigen (CEA) mRNA levels in lymph nodes has proven powerful for quantification of disseminated tumour cells. Here, we investigate the utility of human tissue kallikrein-related peptidase 6 (KLK6) mRNA as a progression biomarker to complement CEA mRNA, for improved selection of patients in need of adjuvant therapy and intensified follow-up after surgery.Methods:Lymph nodes of pTNM stage I-IV CRC- (166 patients/503 lymph nodes) and control (23/108) patients were collected at surgery and analysed by quantitative RT-PCR.Results:Lymph node KLK6 positivity was an indicator of poor outcome (hazard ratio 3.7). Risk of recurrence and cancer death increased with KLK6 lymph node levels. Patients with KLK6 lymph node levels above the 90th percentile had a hazard ratio of 6.5 and 76 months shorter average survival time compared to patients with KLK6 negative nodes. The KLK6 positivity in lymph nodes with few tumour cells, that is, low CEA mRNA levels, also indicated poor prognosis (hazard ratio 2.8).Conclusion:In CRC patients, lymph node KLK6 positivity indicated presence of aggressive tumour cells associated with poor prognosis and high risk of tumour recurrence.

  • 95.
    Ohlsson, Lina
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lindmark, Gudrun
    Israelsson, Anne
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Lymph node kallicrein 6 mRNA: a new progression marker for colorectal cancerArticle in journal (Other academic)
  • 96.
    Palmqvist, Richard
    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.
    Ling, Agnes
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The assiciation of immune cell infiltration and prognosis in colorectal cancer2013In: Current colorectal cancer reports, ISSN 1556-3790, Vol. 9, no 4, p. 372-379Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. The tumor microenvironment is of great biological importance in cancer development and progression and harbors several different immune cells representing both the innate and the adaptive immune response. These inflammatory cells may have both tumor-promoting and tumor-suppressing effects, and they have been shown to be of prognostic importance. This review summarizes the recent evidence regarding the prognostic significance of the host response to colorectal cancer.

  • 97.
    Palmqvist, Richard
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zhang, Anju
    Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Hospital and Institute, Stockholm, Sweden.
    Xu, Dawei
    Department of Medicine, Cancer Center Karolinska, Karolinska Hospital and Institute, Stockholm, Sweden.
    Golovleva, Irina
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gruber, Astrid
    Department of Medicine, Cancer Center Karolinska, Karolinska Hospital and Institute, Stockholm, Sweden.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    hTERT gene copy number is not associated with hTERT RNA expression or telomerase activity in colorectal cancer2005In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 116, no 3, p. 395-400Article in journal (Refereed)
    Abstract [en]

    In a majority of malignant human tumors telomerase activity can be detected, suggesting an immortal phenotype. Expression of the reverse transcriptase subunit, hTERT, in the human telomerase complex is required for telomerase activity. The regulation of hTERT, from gene level to a fully functional protein, is still a poorly understood process. Increased copy number of the hTERT gene has been demonstrated in a significant portion of established cell lines and tumors of different origin but its relevance for telomerase activity levels is unclear. In the present study, we examined the hTERT gene copy number using fluorescence in situ hybridization (FISH) in samples from 64 colorectal carcinomas and an increased copy number (≥ 3 hTERT gene copies/nucleus) was observed in 31 cases (48%). No statistical association existed between hTERT gene copy number and hTERT RNA expression or telomerase activity. However, a significant relationship was found between an increase in hTERT gene copy number and p53 protein accumulation (p = 0.002) and aneuploidy (p = 0.036). Only 4 tumors showed microsatellite instability, 3 of which had a normal hTERT gene copy number. The data indicated that the increased copy number of the hTERT gene in colorectal carcinoma was a result of genomic instability with no obvious consequence for telomerase activity levels.

  • 98. Pischon, Tobias
    et al.
    Lahmann, Petra H
    Boeing, Heiner
    Friedenreich, Christine
    Norat, Teresa
    Tjønneland, Anne
    Halkjaer, Jytte
    Overvad, Kim
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Guernec, Gregory
    Bergmann, Manuela M
    Linseisen, Jakob
    Becker, Nikolaus
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Sieri, Sabina
    Palli, Domenico
    Tumino, Rosario
    Vineis, Paolo
    Panico, Salvatore
    Peeters, Petra H M
    Bueno-de-Mesquita, H Bas
    Boshuizen, Hendriek C
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Berglund, Göran
    Gonzalez, Carlos Alberto
    Dorronsoro, Miren
    Barricarte, Aurelio
    Navarro, Carmen
    Martinez, Carmen
    Quirós, J Ramón
    Roddam, Andrew
    Allen, Naomi
    Bingham, Sheila
    Khaw, Kay-Tee
    Ferrari, Pietro
    Kaaks, Rudolf
    Slimani, Nadia
    Riboli, Elio
    Body size and risk of colon and rectal cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC).2006In: Journal of the National Cancer Institute, ISSN 1460-2105, Vol. 98, no 13, p. 920-931Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Body weight and body mass index (BMI) are positively related to risk of colon cancer in men, whereas weak or no associations exist in women. This discrepancy may be related to differences in fat distribution between sexes or to the use of hormone replacement therapy (HRT) in women. METHODS: We used multivariable adjusted Cox proportional hazards models to examine the association between anthropometric measures and risks of colon and rectal cancer among 368 277 men and women who were free of cancer at baseline from nine countries of the European Prospective Investigation Into Cancer and Nutrition. All statistical tests were two-sided. RESULTS: During 6.1 years of follow-up, we identified 984 and 586 patients with colon and rectal cancer, respectively. Body weight and BMI were statistically significantly associated with colon cancer risk in men (highest versus lowest quintile of BMI, relative risk [RR] = 1.55, 95% confidence interval [CI] = 1.12 to 2.15; P(trend) = .006) but not in women. In contrast, comparisons of the highest to the lowest quintile showed that several anthropometric measures, including waist circumference (men, RR = 1.39, 95% CI = 1.01 to 1.93; P(trend) = .001; women, RR = 1.48, 95% CI = 1.08 to 2.03; P(trend) = .008), waist-to-hip ratio (WHR; men, RR = 1.51, 95% CI = 1.06 to 2.15; P(trend) = .006; women, RR = 1.52, 95% CI = 1.12 to 2.05; P(trend) = .002), and height (men, RR = 1.40, 95% CI = 0.99 to 1.98; P(trend) = .04; women, RR = 1.79, 95% CI = 1.30 to 2.46; P(trend)<.001) were related to colon cancer risk in both sexes. The estimated absolute risk of developing colon cancer within 5 years was 203 and 131 cases per 100,000 men and 129 and 86 cases per 100,000 women in the highest and lowest quintiles of WHR, respectively. Upon further stratification, no association of waist circumference and WHR with risk of colon cancer was observed among postmenopausal women who used HRT. None of the anthropometric measures was statistically significantly related to rectal cancer. CONCLUSIONS: Waist circumference and WHR, indicators of abdominal obesity, were strongly associated with colon cancer risk in men and women in this population. The association of abdominal obesity with colon cancer risk may vary depending on HRT use in postmenopausal women; however, these findings require confirmation in future studies.

  • 99. Rinaldi, Sabina
    et al.
    Rohrmann, Sabine
    Jenab, Mazda
    Biessy, Carine
    Sieri, Sabina
    Palli, Domenico
    Tumino, Rosario
    Mattiello, Amalla
    Vineis, Paolo
    Nieters, Alexandra
    Linseisen, Jakob
    Pischon, Tobias
    Boeing, Heiner
    Näringsforskning.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Manjer, Jonas
    Wirfält, Elisabet
    Crowe, Francesca L
    Khaw, Kay-Tee T
    Bingham, Sheila
    Tjønneland, Anne
    Olsen, Anja
    Overvad, Kim
    Lund, Eiliv
    Skeie, Guri
    Clavel-Chapelon, Francoise
    Boutron-Ruault, Marie-Christine
    de Lauzon-Guillain, Blandine
    Ardanaz, Eva
    Jakszyn, Paula
    Ramon Quiros, Jose
    Chirlaque, Maria-Dolores
    Sanchez, Maria-Jose
    Dorronsoro, Miren
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrious
    Bueno-de-Mesquita, H Bas
    van Duijnhoven, Fränzel J B
    Peeters, Petra H M
    Slimani, Nadia
    Ferrari, Pietro
    Byrnes, Graham B
    Riboli, Elio
    Kaaks, Rudolf
    Glycosylated hemoglobin and risk of colorectal cancer in men and women, the European prospective investigation into cancer and nutrition.2008In: Cancer Epidemiol Biomarkers Prev, ISSN 1055-9965, Vol. 17, no 11, p. 3108-15Article in journal (Other academic)
  • 100.
    Rutegård, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lindberg, Jan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Efficiency of Colorectal Cancer Surveillance in Patients With Ulcerative Colitis: 38 Years' Experience in a Patient Cohort From a Defined Population Area2017In: Scandinavian Journal of Surgery, ISSN 1457-4969, E-ISSN 1799-7267, Vol. 106, no 2, p. 133-138Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Ulcerative colitis increases the risk of developing colorectal cancer. Colonoscopic surveillance is recommended although there are no randomized trials evaluating the efficacy of such a strategy. This study is an update of earlier studies from an ongoing colonoscopic surveillance program.

    MATERIAL AND METHODS: All patients with ulcerative colitis were invited to the surveillance program that started in 1977 at Örnsköldsvik Hospital, located in the northern part of Sweden. Five principal endoscopists performed the colonoscopies and harvested mucosal sampling for histopathological evaluation. Some 323 patients from the defined catchment area were studied from 1977 to 2014. At the end of the study period, 130 patients, including those operated on, had had total colitis for more than 10 years.

    RESULTS: In total, 1481 colonoscopies were performed on 323 patients during the study period without any major complications. In all, 10 cases of colorectal cancer were diagnosed in 9 patients, of whom 1 died from colorectal cancer. The cumulative incidence of colorectal cancer was 1.4% at 10 years, 2.0% at 20 years, 3.0% at 30 years, and 9.4% at 40 years of disease duration, respectively. The standardized colorectal cancer incidence ratio was 3.01 (95% confidence interval: 1.42-5.91). Major surgery was performed on 65 patients; for 20 of these, the indication for surgery was dysplasia or colorectal cancer. Panproctocolectomy was performed in 43 patients.

    CONCLUSION: This study supports that colonoscopic surveillance is a safe and effective long-term measure to detect dysplasia and progression to cancer. The low numbers of colorectal cancer-related deaths in our study suggest that early detection of neoplasia and adequate surgical intervention within a surveillance program may reduce colorectal cancer mortality in ulcerative colitis patients.

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