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  • 1. Aleksandrova, Krasimira
    et al.
    Boeing, Heiner
    Jenab, Mazda
    Bas Bueno-de-Mesquita, H
    Jansen, Eugene
    van Duijnhoven, Fränzel J B
    Fedirko, Veronika
    Rinaldi, Sabina
    Romieu, Isabelle
    Riboli, Elio
    Romaguera, Dora
    Overvad, Kim
    Ostergaard, Jane Nautrup
    Olsen, Anja
    Tjønneland, Anne
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Morois, Sophie
    Masala, Giovanna
    Agnoli, Claudia
    Panico, Salvatore
    Tumino, Rosario
    Vineis, Paolo
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Trichopoulou, Antonia
    Naska, Androniki
    Bamia, Christina
    Peeters, Petra H
    Rodríguez, Laudina
    Buckland, Genevieve
    Sánchez, María-José
    Dorronsoro, Miren
    Huerta, Jose-María
    Barricarte, Aurelio
    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, Nicholas
    Allen, Naomi E
    Tsilidis, Konstantinos K
    Pischon, Tobias
    Metabolic syndrome and risks of colon and rectal cancer: the European prospective investigation into cancer and nutrition study.2011In: Cancer prevention research (Philadelphia, Pa.), ISSN 1940-6215, Vol. 4, no 11, p. 1873-83Article in journal (Refereed)
    Abstract [en]

    Metabolic syndrome (MetS) is purportedly related to risk of developing colorectal cancer; however, the association of MetS, as defined according to recent international criteria, and colorectal cancer has not been yet evaluated. In particular, it remains unclear to what extent the MetS components individually account for such an association. We addressed these issues in a nested case-control study that included 1,093 incident cases matched (1:1) to controls by using incidence density sampling. Conditional logistic regression was used to estimate relative risks (RR) and 95% CIs. MetS was defined according to the criteria of the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATPIII), the International Diabetes Federation (IDF), and the 2009 harmonized definition. Among individual components, abdominal obesity (RR = 1.51; 95% CI: 1.16-1.96) was associated with colon cancer, whereas abnormal glucose metabolism was associated with both colon (RR = 2.05; 95% CI: 1.57-2.68) and rectal cancer (RR = 2.07; 95% CI: 1.45-2.96). MetS, as defined by each of the definitions, was similarly associated with colon cancer (e.g., RR = 1.91; 95% CI: 1.47-2.42 for MetS by NCEP/ATPIII), whereas MetS by NCEP/ATPIII, but not IDF or harmonized definition, was associated with rectal cancer (RR = 1.45; 95% CI: 1.02-2.06). Overall, these associations were stronger in women than in men. However, the association between MetS and colorectal cancer was accounted for by abdominal obesity and abnormal glucose metabolism such that MetS did not provide risk information beyond these components (likelihood ratio test P = 0.10 for MetS by NCEP/ATPIII). These data suggest that simple assessment of abnormal glucose metabolism and/or abdominal obesity to identify individuals at colorectal cancer risk may have higher clinical utility than applying more complex MetS definitions. Cancer Prev Res; 4(11); 1873-83. ©2011 AACR.

  • 2. Aleksandrova, Krasimira
    et al.
    Boeing, Heiner
    Jenab, Mazda
    Bueno-de-Mesquita, H. Bas
    Jansen, Eugene
    van Duijnhoven, Franzel J. B.
    Rinaldi, Sabina
    Fedirko, Veronika
    Romieu, Isabelle
    Riboli, Elio
    Gunter, Marc J.
    Westphal, Sabine
    Overvad, Kim
    Tjonneland, Anne
    Halkjaer, Jytte
    Racine, Antoine
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Francoise
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Mattiello, Amalia
    Pala, Valeria
    Palli, Domenico
    Tumino, Rosario
    Vineis, Paolo
    Buckland, Genevieve
    Sanchez, Maria-Jose
    Amiano, Pilar
    Maria Huerta, Jose
    Barricarte, Aurelio
    Menendez, Virginia
    Peeters, Petra H.
    Söderberg, Stefan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Cardiology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Allen, Naomi E.
    Crowe, Francesca L.
    Khaw, Kay-Tee
    Wareham, Nickolas
    Pischon, Tobias
    Leptin and soluble leptin receptor in risk of colorectal cancer in the European prospective investigation into Cancer and nutrition cohort2012In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 72, no 20, p. 5328-5337Article in journal (Refereed)
    Abstract [en]

    Leptin, a peptide hormone produced primarily by the adipocytes, is hypothesized to play a role in the pathogenesis of colorectal cancer (CRC). Soluble leptin receptor (sOB-R) may regulate leptin's physiologic functions; however its relation to CRC risk is unknown. This study explored the association of leptin and sOB-R with risk of CRC in a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. A total of 1,129 incident CRC cases (713 colon, 416 rectal) were matched within risk sets to 1,129 controls. Conditional logistic regression was used to calculate relative risks (RR) and 95% confidence intervals (CI). After multivariable adjustment including body mass index (BMI), waist circumference, and baseline leptin concentrations, sOB-R was strongly inversely associated with CRC (RR comparing the highest quintile vs. the lowest, 0.55; 95% CI, 0.40-0.76; P-trend = 0.0004) and colon cancer (RR, 0.42; 95% CI, 0.28-0.63, P-trend = 0.0001); whereas no association was seen for rectal cancer (RR adjusted for BMI and waist circumference, 0.83; 95% CI, 0.48-1.44, P-trend = 0.38). In contrast, leptin was not associated with risk of CRC (RR adjusted for BMI and waist circumference, 0.85; 95% CI, 0.56-1.29, P-trend = 0.23). Additional adjustments for circulating metabolic biomarkers did not attenuate these results. These novel findings suggest a strong inverse association between circulating sOB-R and CRC risk, independent of obesity measures, leptin concentrations, and other metabolic biomarkers. Further research is needed to confirm the potentially important role of sOB-R in CRC pathogenesis. Cancer Res; 72(20); 5328-37. (C) 2012 AACR.

  • 3. Aleksandrova, Krasimira
    et al.
    Boeing, Heiner
    Jenab, Mazda
    Bueno-de-Mesquita, H Bas
    Jansen, Eugene
    van Duijnhoven, Fränzel JB
    Fedirko, Veronika
    Rinaldi, Sabina
    Romieu, Isabelle
    Riboli, Elio
    Romaguera, Dora
    Westphal, Sabine
    Overvad, Kim
    Tjønneland, Anne
    Boutron-Ruault, Marie Christine
    Clavel-Chapelon, Françoise
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    Agnoli, Claudia
    Mattiello, Amalia
    Saieva, Calogero
    Vineis, Paolo
    Tumino, Rosario
    Peeters, Petra H
    Argüelles, Marcial
    Bonet, Catalina
    Sánchez, María-José
    Dorronsoro, Miren
    Huerta, Jose-María
    Barricarte, Aurelio
    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.
    Khaw, Kay-Tee
    Wareham, Nick
    Allen, Naomi E
    Crowe, Francesca L
    Pischon, Tobias
    Total and high-molecular-weight adiponectin and risk of colorectal cancer: the European prospective investigation into cancer and nutrition study2012In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 33, no 6, p. 1211-1218Article in journal (Refereed)
    Abstract [en]

    Adiponectin - an adipose-tissue-derived protein may provide a molecular link between obesity and colorectal cancer (CRC), but evidence from large prospective studies is limited. In particular, no epidemiological study explored high-molecular-weight (HMW) and non-HMW adiponectin fractions in relation to CRC risk, despite they were hypothesised to have differential biological activities, i.e. regulating insulin sensitivity (HMW-adiponectin) versus inflammatory response (non-HMW-adiponectin). In a prospective nested case-control study we investigated whether pre-diagnostic serum concentrations of total, HMW and non-HMW-adiponectin are associated with risk of CRC, independent of obesity and other known CRC risk factors. A total of 1206 incident cases (755 colon, 451 rectal) were matched to 1206 controls using incidence density sampling. In conditional logistic regression, adjusted for dietary and lifestyle factors, total adiponectin and non-HMW-adiponectin concentrations were inversely associated with risk of CRC [relative risk (RR) comparing highest versus lowest quintile = 0.71, 95% confidence interval (CI) = 0.53-0.95, P (trend)=0.03 for total adiponectin and 0.45, 95%CI=0.34-0.61, P (trend)<0.0001 for non-HMW-adiponectin]. HMW-adiponectin concentrations were not associated with CRC risk (RR=0.91, 95%CI=0.68-1.22, P (trend)=0.55). Non-HMW-adiponectin was associated with CRC risk even after adjustment for body mass index and waist circumference (RR=0.39, 95%CI=0.26-0.60, P (trend)<0.0001); whereas the association with total adiponectin was no longer significant (RR=0.81, 95%CI=0.60-1.09, P (trend)=0.23). When stratified by cancer site, non-HMW-adiponectin was inversely associated with both colon and rectal cancer. These findings suggest an important role of the relative proportion of non-HMW-adiponectin in CRC pathogenesis. Future studies are warranted to confirm these results and to elucidate the underlying mechanisms.

  • 4. Aleksandrova, Krasimira
    et al.
    Jenab, Mazda
    Boeing, Heiner
    Jansen, Eugene
    Bueno-de-Mesquita, H Bas
    Rinaldi, Sabina
    Riboli, Elio
    Overvad, Kim
    Dahm, Christina C
    Olsen, Anja
    Tjønneland, Anne
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Morois, Sophie
    Palli, Domenico
    Krogh, Vittorio
    Tumino, Rosario
    Vineis, Paolo
    Panico, Salvatore
    Kaaks, Rudolf
    Rohrmann, Sabine
    Trichopoulou, Antonia
    Lagiou, Pagona
    Trichopoulos, Dimitrios
    van Duijnhoven, Fränzel JB
    Leufkens, Anke M
    Peeters, Petra H
    Rodríguez, Laudina
    Bonet, Catalina
    Sánchez, María-José
    Dorronsoro, Miren
    Navarro, Carmen
    Barricarte, Aurelio
    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.
    Khaw, Kay-Tee
    Wareham, Nicholas
    Allen, Naomi E
    Spencer, Elizabeth
    Romaguera, Dora
    Norat, Teresa
    Pischon, Tobias
    Circulating C-reactive protein concentrations and risks of colon and rectal cancer: a nested case-control study within the European Prospective Investigation into Cancer and Nutrition2010In: American Journal of Epidemiology, ISSN 0002-9262, E-ISSN 1476-6256, Vol. 172, no 4, p. 407-418Article in journal (Refereed)
    Abstract [en]

    The authors investigated associations between serum C-reactive protein (CRP) concentrations and colon and rectal cancer risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (1992-2003) among 1,096 incident cases and 1,096 controls selected using risk-set sampling and matched on study center, age, sex, time of blood collection, fasting status, menopausal status, menstrual cycle phase, and hormone replacement therapy. In conditional logistic regression with adjustment for education, smoking, nutritional factors, body mass index, and waist circumference, CRP showed a significant nonlinear association with colon cancer risk but not rectal cancer risk. Multivariable-adjusted relative risks for CRP concentrations of > or = 3.0 mg/L versus <1.0 mg/L were 1.36 (95% confidence interval (CI): 1.00, 1.85; P-trend = 0.01) for colon cancer and 1.02 (95% CI: 0.67, 1.57; P-trend = 0.65) for rectal cancer. Colon cancer risk was significantly increased in men (relative risk = 1.74, 95% CI: 1.11, 2.73; P-trend = 0.01) but not in women (relative risk = 1.06, 95% CI: 0.67, 1.68; P-trend = 0.13). Additional adjustment for C-peptide, glycated hemoglobin, and high density lipoprotein cholesterol did not attenuate these results. These data provide evidence that elevated CRP concentrations are related to a higher risk of colon cancer but not rectal cancer, predominantly among men and independently of obesity, insulin resistance, and dyslipidemia.

  • 5. Aleksandrova, Krasimira
    et al.
    Jenab, Mazda
    Bueno-de-Mesquita, H. Bas
    Fedirko, Veronika
    Kaaks, Rudolf
    Lukanova, Annekatrin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    van Duijnhoven, Franzel J. B.
    Jansen, Eugene
    Rinaldi, Sabina
    Romieu, Isabelle
    Ferrari, Pietro
    Murphy, Neil
    Gunter, Marc J.
    Riboli, Elio
    Westhpal, Sabine
    Overvad, Kim
    Tjonneland, Anne
    Halkjaer, Jytte
    Boutron-Ruault, Marie-Christine
    Dossus, Laure
    Racine, Antoine
    Trichopoulou, Antonia
    Bamia, Christina
    Orfanos, Philippos
    Agnoli, Claudia
    Palli, Domenico
    Panico, Salvatore
    Tumino, Rosario
    Vineis, Paolo
    Peeters, Petra H.
    Duell, Eric J.
    Molina-Montes, Esther
    Ramon Quiros, J.
    Dorronsoro, Miren
    Chirlaque, Maria-Dolores
    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.
    Travis, Ruth C.
    Khaw, Kay-Tee
    Wareham, Nicholas
    Pischon, Tobias
    Boeing, Heiner
    Biomarker patterns of inflammatory and metabolic pathways are associated with risk of colorectal cancer: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)2014In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 29, no 4, p. 261-275Article in journal (Refereed)
    Abstract [en]

    A number of biomarkers of inflammatory and metabolic pathways are individually related to higher risk of colorectal cancer (CRC); however, the association between biomarker patterns and CRC incidence has not been previously evaluated. Our study investigates the association of biomarker patterns with CRC in a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC). During median follow-up time of 7.0 (3.7-9.4) years, 1,260 incident CRC cases occurred and were matched to 1,260 controls using risk-set sampling. Pre-diagnostic measurements of C-peptide, glycated hemoglobin, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), C-reactive protein (CRP), reactive oxygen metabolites (ROM), insulin-like growth factor 1, adiponectin, leptin and soluble leptin receptor (sOB-R) were used to derive biomarker patterns from principal component analysis (PCA). The relation with CRC incidence was assessed using conditional logistic regression models. We identified four biomarker patterns 'HDL-C/Adiponectin fractions', 'ROM/CRP', 'TG/C-peptide' and 'leptin/sOB-R' to explain 60 % of the overall biomarker variance. In multivariable-adjusted logistic regression, the 'HDL-C/Adiponectin fractions', 'ROM/CRP' and 'leptin/sOB-R' patterns were associated with CRC risk [for the highest quartile vs the lowest, incidence rate ratio (IRR) = 0.69, 95 % CI 0.51-0.93, P-trend = 0.01; IRR = 1.70, 95 % CI 1.30-2.23, P-trend = 0.002; and IRR = 0.79, 95 % CI 0.58-1.07; P-trend = 0.05, respectively]. In contrast, the 'TG/C-peptide' pattern was not associated with CRC risk (IRR = 0.75, 95 % CI 0.56-1.00, P-trend = 0.24). After cases within the first 2 follow-up years were excluded, the 'ROM/CRP' pattern was no longer associated with CRC risk, suggesting potential influence of preclinical disease on these associations. By application of PCA, the study identified 'HDL-C/Adiponectin fractions', 'ROM/CRP' and 'leptin/sOB-R' as biomarker patterns representing potentially important pathways for CRC development.

  • 6. Bamia, Christina
    et al.
    Lagiou, Pagona
    Buckland, Genevieve
    Grioni, Sara
    Agnoli, Claudia
    Taylor, Aliki J.
    Dahm, Christina C.
    Overvad, Kim
    Olsen, Anja
    Tjonneland, Anne
    Cottet, Vanessa
    Boutron-Ruault, Marie-Christine
    Morois, Sophie
    Grote, Verena
    Teucher, Birgit
    Boeing, Heiner
    Buijsse, Brian
    Trichopoulos, Dimitrios
    Adarakis, George
    Tumino, Rosario
    Naccarati, Alessio
    Panico, Salvatore
    Palli, Domenico
    Bueno-de-Mesquita, H. Bas
    van Duijnhoven, Fraenzel J. B.
    Peeters, Petra H. M.
    Engeset, Dagrun
    Skeie, Guri
    Lund, Eiliv
    Sanchez, Maria-Jose
    Barricarte, Aurelio
    Huerta, Jose-Maria
    Ramon Quiros, J.
    Dorronsoro, Miren
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Drake, Isabel
    Key, Timothy J.
    Khaw, Kay-Tee
    Wareham, Nick
    Romieu, Isabelle
    Fedirko, Veronika
    Jenab, Mazda
    Romaguera, Dora
    Norat, Teresa
    Trichopoulou, Antonia
    Mediterranean diet and colorectal cancer risk: results from a European cohort2013In: European Journal of Epidemiology, ISSN 0393-2990, E-ISSN 1573-7284, Vol. 28, no 4, p. 317-328Article in journal (Refereed)
    Abstract [en]

    The authors investigated the association of adherence to Mediterranean diet with colorectal cancer (CRC) risk in the European Prospective Investigation into Cancer and nutrition study. Adherence to Mediterranean diet was expressed through two 10-unit scales, the Modified Mediterranean diet score (MMDS) and the Centre-Specific MMDS (CSMMDS). Both scales share the same dietary components but differ in the cut-off values that were used for these components in the construction of the scales. Adjusted hazard ratios (HR) for the associations of these scales with CRC incidence were estimated. After 5,296,617 person-years of follow-up, 4,355 incident CRC cases were identified. A decreased risk of CRC, of 8 and 11 % was estimated when comparing the highest (scores 6-9) with the lowest (scores 0-3) adherence to CSMMDS and MMDS respectively. For MMDS the HR was 0.89 (95 % confidence interval (CI): 0.80, 0.99). A 2-unit increment in either Mediterranean scale was associated with a borderline statistically significant 3 to 4 % reduction in CRC risk (HR for MMDS: 0.96; 95 % CI: 0.92, 1.00). These associations were somewhat more evident, among women, were mainly manifested for colon cancer risk and their magnitude was not altered when alcohol was excluded from MMDS. These findings suggest that following a Mediterranean diet may have a modest beneficial effect on CRC risk.

  • 7.
    Cederquist, Kristina
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics.
    Emanuelsson, Monica
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Wiklund, Fredrik
    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.
    Grönberg, Henrik
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Two Swedish founder MSH6 mutations, one nonsense and one missense, conferring high cumulative risk of Lynch syndrome.2005In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 68, no 6, p. 533-541Article in journal (Refereed)
    Abstract [en]

    Lynch syndrome, or hereditary non-polyposis colorectal cancer (HNPCC), is a cancer susceptibility syndrome caused by germline mutations in mismatch-repair genes, predominantly MLH1, MSH2 and MSH6. A majority of the mutations reported are truncating, but for MSH6, missense mutations constitute over one third. Few have been proven pathogenic in functional studies or shown to segregate in families. In this study, we show segregation of the putative pathogenic MSH6 missense mutation c.1346T>C p.Leu449Pro with microsatellite instability-high Lynch syndrome-related tumours lacking MSH6 expression in a large 17th century pedigree. Another large family with the MSH6 nonsense c.2931C>G, p.Tyr977X mutation is similar in tumour spectra, age of onset and cumulative risk. These MSH6 families, despite their late age of onset, have a high lifetime risk of all Lynch syndrome-related cancers, significantly higher in women (89% by age 80) than in men (69%). The gender differences are in part explained by high endometrial (70%) and ovarian (33%) cancer risks added upon the high colorectal cancer risk (60%). The several occurrences of breast cancer are not due to the MSH6 mutations. These findings are of great importance for counselling, management and surveillance of families with MSH6 mutations.

  • 8.
    Claesson, Jonas
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology. Anestesiologi och intensivvård.
    Lehtipalo, Stefan
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology. Anestesiologi och intensivvård.
    Johansson, Göran
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology. Anestesiologi och intensivvård.
    Abrahamsson, Pernilla
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology. Anestesiologi och intensivvård.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Biber, Björn
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology.
    Winsö, Ola
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Anaesthesiology. Anestesiologi och intensivvård.
    Evaluation of intestinal preconditioning in a porcine model using classic ischemic preconditioning or lung recruitment maneuvers.2008In: Shock, ISSN 1073-2322, E-ISSN 1540-0514, Vol. 21, no 1, p. 98-103Article in journal (Refereed)
    Abstract [en]

    To test the hypotheses that repeated brief intestinal ischemic insults would elicit an intestinal preconditioning response to a subsequent intestinal I/R injury and that a similar response would be elicited by repeated lung recruitment maneuvers (RMs). Randomized experimental controlled animal study. University hospital animal laboratory. Eighteen anesthetized pigs. Animals were randomized to one of three groups, with six animals in each group. Control group 75-min superior mesenteric artery (SMA) occlusion followed by 60-min reperfusion. Ischemic preconditioning group, three 5-min-long SMA occlusions preceding 75-min SMA occlusion and 60-min reperfusion. Recruitment maneuver (RM) group, three 2-min-long RMs preceding 75-min SMA occlusion and 60-min reperfusion. We measured systemic and mesenteric hemodynamic parameters, jejunal mucosal perfusion, net mesenteric lactate flux, jejunal tissue oxygen tension, and mesenteric oxygenation. Every 15 min, jejunal microdialysate samples were collected and analyzed for glucose, lactate, and glycerol. Jejunal tissue samples were collected postmortem. After occlusion of SMA, regional parameters in all groups indicated abolished perfusion and gradually increasing intraluminal microdialysate lactate and glycerol levels. At reperfusion, regional parameters indicated mesenteric hyperperfusion, whereas microdialysis markers of mucosal anaerobic metabolism and cell injury decreased, although not reaching baseline. Histological examination revealed severe mucosal injury in all groups. There were no significant differences between groups in the observed parameters. No protective preconditioning response could be observed when performing repeated brief intestinal ischemic insults or repeated lung RMs before an intestinal I/R injury.

  • 9.
    Dahlin, Anna M
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    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.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Colorectal cancer prognosis depends on T-cell infiltration and molecular characteristics of the tumor2011In: Modern Pathology, ISSN 0893-3952, E-ISSN 1530-0285, Vol. 24, p. 671-682Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to relate the density of tumor infiltrating T cells to cancer-specific survival in colorectal cancer, taking into consideration the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) screening status. The T-cell marker CD3 was stained by immunohistochemistry in 484 archival tumor tissue samples. T-cell density was semiquantitatively estimated and scored 1-4 in the tumor front and center (T cells in stroma), and intraepithelially (T cells infiltrating tumor cell nests). Total CD3 score was calculated as the sum of the three CD3 scores (range 3-12). MSI screening status was assessed by immunohistochemistry. CIMP status was determined by quantitative real-time PCR (MethyLight) using an eight-gene panel. We found that patients whose tumors were highly infiltrated by T cells (total CD3 score ≥7) had longer survival compared with patients with poorly infiltrated tumors (total CD3 score ≤4). This finding was statistically significant in multivariate analyses (multivariate hazard ratio, 0.57; 95% confidence interval, 0.31-1.00). Importantly, the finding was consistent in rectal cancer patients treated with preoperative radiotherapy. Although microsatellite unstable tumor patients are generally considered to have better prognosis, we found no difference in survival between microsatellite unstable and microsatellite stable (MSS) colorectal cancer patients with similar total CD3 scores. Patients with MSS tumors highly infiltrated by T cells had better prognosis compared with intermediately or poorly infiltrated microsatellite unstable tumors (log rank P=0.013). Regarding CIMP status, CIMP-low was associated with particularly poor prognosis in patients with poorly infiltrated tumors (multivariate hazard ratio for CIMP-low versus CIMP-negative, 3.07; 95% confidence interval, 1.53-6.15). However, some subset analyses suffered from low power and are in need of confirmation by independent studies. In conclusion, patients whose tumors are highly infiltrated by T cells have a beneficial prognosis, regardless of MSI, whereas the role of CIMP status in this context is less clear.

  • 10.
    Dahlin, Anna M
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jacobsson, Maria
    Eklöf, Vincy
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The role of the CpG island methylator phenotype in colorectal cancer prognosis depends on microsatellite instability screening status2010In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 16, no 6, p. 1845-1855Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The aim of this study was to relate the CpG island methylator phenotype (CIMP; characterized by extensive promoter hypermethylation) to cancer-specific survival in colorectal cancer, taking into consideration relevant clinicopathologic factors, such as microsatellite instability (MSI) screening status and the BRAF V600E mutation.

    EXPERIMENTAL DESIGN: Archival tumor samples from 190 patients from the Northern Sweden Health and Disease Study (NSHDS) and 414 patients from the Colorectal Cancer in Umeå Study (CRUMS), including 574 with cancer-specific survival data, were analyzed for an eight-gene CIMP panel using quantitative real-time PCR (MethyLight). MSI screening status was assessed by immunohistochemistry.

    RESULTS: CIMP-low patients had a shorter cancer-specific survival compared with CIMP-negative patients (multivariate hazard ratio in NSHDS, 2.01; 95% confidence interval, 1.20-3.37; multivariate hazard ratio in CRUMS, 1.48; 95% confidence interval, 1.00-2.22). This result was similar in subgroups based on MSI screening status and was statistically significant in microsatellite stable (MSS) tumors in NSHDS. For CIMP-high patients, a shorter cancer-specific survival compared with CIMP-negative patients was observed in the MSS subgroup. Statistical significance was lost after adjusting for the BRAF mutation, but the main findings were generally unaffected.

    CONCLUSIONS: In this study, we found a poor prognosis in CIMP-low patients regardless of MSI screening status, and in CIMP-high patients with MSS. Although not consistently statistically significant, these results were consistent in two separate patient groups and emphasize the potential importance of CIMP and MSI status in colorectal cancer research.

  • 11.
    Dahlin, Anna M
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    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.
    Plasma vitamin B12 concentrations and the risk of colorectal cancer: a nested case-referent study2008In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 32, no 2, p. 304-314Article in journal (Refereed)
    Abstract [en]

    In this nested case-referent study, we related plasma concentrations of vitamin B12 to the risk of colorectal cancer, taking into consideration prediagnostic plasma folate and total homocysteine concentrations. Subjects were 226 cases and double matched referents from the population-based Northern Sweden Health and Disease Study. Follow-up times from recruitment to diagnosis ranged from 0.1 to 12.7 years, with a median of 4.2 years. Plasma vitamin B12 concentrations were inversely associated with the risk of rectal cancer: univariate odds ratio for the highest versus lowest quintile 0.34 (95% confidence interval (95% CI) 0.13-0.83), p(trend) = 0.004. Risk estimates were attenuated slightly but remained statistically significant after adjustment for body mass index, current smoking, recreational and occupational physical activity, alcohol intake and prediagnostic plasma folate and total homocysteine concentrations: OR 0.30 (95% CI 0.08-0.99), p(trend) = 0.025. The corresponding univariate and fully adjusted odds ratios for colon cancer were 1.25 (CI 0.66-2.36), p(trend) = 0.185 and 1.42 (CI 0.67-3.05), p(trend) = 0.113, respectively. The observed over-risk was attributable to left-sided colon cancer. Interaction analyses including vitamin B12, folate and homocysteine were in line with the results for vitamin B12 alone. In conclusion, these results suggest that increasing levels of plasma vitamin B12, alone or together with other factors involved in one-carbon metabolism, may reduce the risk of rectal cancer, whereas for colon cancer, the association appears to be less clear.

  • 12.
    Edin, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Radiation Sciences.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The Distribution of Macrophages with a M1 or M2 Phenotype in Relation to Prognosis and the Molecular Characteristics of Colorectal Cancer2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 10, p. e47045-Article in journal (Refereed)
    Abstract [en]

    High macrophage infiltration has been correlated to improved survival in colorectal cancer (CRC). Tumor associated macrophages (TAMs) play complex roles in tumorigenesis since they are believed to hold both tumor preventing (M1 macrophages) and tumor promoting (M2 macrophages) activities. Here we have applied an immunohistochemical approach to determine the degree of infiltrating macrophages with a M1 or M2 phenotype in clinical specimens of CRC in relation to prognosis, both in CRC in general but also in subgroups of CRC defined by microsatellite instability (MSI) screening status and the CpG island methylator phenotype (CIMP). A total of 485 consecutive CRC specimens were stained for nitric oxide synthase 2 (NOS2) (also denoted iNOS) as a marker for the M1 macrophage phenotype and the scavenger receptor CD163 as a marker for the M2 macrophage phenotype. The average infiltration of NOS2 and CD163 expressing macrophages along the invasive tumor front was semi-quantitatively evaluated using a four-graded scale. Two subtypes of macrophages, displaying M1 (NOS2(+)) or M2 (CD163(+)) phenotypes, were recognized. We observed a significant correlation between the amount of NOS2(+) and CD163(+) cells (P<0.0001). A strong inverse correlation to tumor stage was found for both NOS2 (P<0.0001) and CD163 (P<0.0001) infiltration. Furthermore, patients harbouring tumors highly infiltrated by NOS2+ cells had a significantly better prognosis than those infiltrated by few NOS2+ cells, and this was found to be independent of MSI screening status and CIMP status. No significant difference was found on cancer-specific survival in groups of CRC with different NOS2/CD163 ratios. In conclusion, an increased infiltration of macrophages with a M1 phenotype at the tumor front is accompanied by a concomitant increase in macrophages with a M2 phenotype, and in a stage dependent manner correlated to a better prognosis in patients with CRC.

  • 13.
    Edin, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Macrophages: Good guys in colorectal cancer2013In: Oncoimmunology, ISSN 2162-4011, Vol. 2, no 2, p. e23038-Article in journal (Refereed)
    Abstract [en]

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

  • 14.
    Edin, Sofia
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Phenotypic skewing of macrophages in vitro by secreted factors from colorectal cancer cells2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 9, p. e74982-Article in journal (Refereed)
    Abstract [en]

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

  • 15.
    Ekblom, Kim
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Marklund, Stefan L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    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.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Global Health.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Iron Biomarkers in Plasma, HFE Genotypes, and the Risk for Colorectal Cancer in a Prospective Setting2012In: Diseases of the Colon & Rectum, ISSN 0012-3706, E-ISSN 1530-0358, Vol. 55, no 3, p. 337-344Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: High iron levels can increase the formation of noxious oxygen radicals, which are thought to promote carcinogenesis. OBJECTIVE: The aim of this prospective study was to determine whether iron biomarkers and HFE genotypes, which influence iron regulation, constitute risk factors for colorectal cancer. DESIGN: This is a prospective nested case-referent study. SETTINGS: The study was performed within the population-based Northern Sweden Health and Disease Study. PATIENTS: The study included 226 cases of colorectal cancer and 437 matched referents. MAIN OUTCOME MEASURES: Conditional regression analysis was performed. Adjustments for smoking, smoking and BMI, and HFE C282Y and H63D were performed. RESULTS: The highest quintile of total iron-binding capacity showed significantly higher risk for colorectal cancer, unadjusted OR 2.35 (95% CI 1.38-4.02). When stratified by sex, the findings were only present in women (OR 3.34 (95% CI 1.59-7.02)). Ferritin was associated with reduced risk throughout quintiles 2 to 5 both in univariate and multivariate models. LIMITATIONS: Colorectal cancer may influence iron markers because of occult bleeding. Homozygotes for HFE C282Y were too few to make conclusions for this group. The relatively short follow-up time might be insufficient to detect risk of iron biomarkers. CONCLUSIONS: High iron levels do not increase the risk of colorectal cancer. HFE genotypes influencing iron uptake had no effect on colorectal cancer risk.

  • 16.
    Eklöf, Vincy
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikberg, Maria L.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, A. M.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jonsson, Björn-Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Å.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The prognostic role of KRAS, BRAF, PIK3CA and PTEN in colorectal cancer2013In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 108, no 10, p. 2153-2163Article in journal (Refereed)
    Abstract [en]

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

  • 17. Enlund, Fredrik
    et al.
    Helenius, Gisela
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edsjö, Anders
    Sundström, Magnus
    [Mutational analysis of KRAS prior to targeted therapy in colorectal cancer. Quality control of molecular pathological methods in Sweden].2010In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 107, no 5, p. 255-259Article in journal (Refereed)
  • 18. Eussen, Simone JPM
    et al.
    Vollset, Stein Emil
    Hustad, Steinar
    Midttun, Øivind
    Meyer, Klaus
    Fredriksen, Ase
    Ueland, Per Magne
    Jenab, Mazda
    Slimani, Nadia
    Boffetta, Paolo
    Overvad, Kim
    Thorlacius-Ussing, Ole
    Tjønneland, Anne
    Olsen, Anja
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Morois, Sophie
    Weikert, Cornelia
    Pischon, Tobias
    Linseisen, Jakob
    Kaaks, Rudolf
    Trichopoulou, Antonia
    Zilis, Demosthenes
    Katsoulis, Michael
    Palli, Domenico
    Pala, Valeria
    Vineis, Paolo
    Tumino, Rosario
    Panico, Salvatore
    Peeters, Petra HM
    Bueno-de-Mesquita, H Bas
    van Duijnhoven, Fränzel JB
    Skeie, Guri
    Muñoz, Xavier
    Martínez, Carmen
    Dorronsoro, Miren
    Ardanaz, Eva
    Navarro, Carmen
    Rodríguez, Laudina
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Manjer, Jonas
    Ericson, Ulrika
    Bingham, Sheila
    Khaw, Kay-Tee
    Norat, Teresa
    Riboli, Elio
    Plasma vitamins B2, B6, and B12, and related genetic variants as predictors of colorectal cancer risk2010In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 19, no 10, p. 2549-2561Article in journal (Refereed)
    Abstract [en]

    This European population-based study is the first to indicate that vitamin B2 is inversely associated with colorectal cancer, and is in agreement with previously suggested inverse associations of vitamin B6 with colorectal cancer.

  • 19. Eussen, Simone JPM
    et al.
    Vollset, Stein Emil
    Igland, Jannicke
    Meyer, Klaus
    Fredriksen, Ase
    Ueland, Per Magne
    Jenab, Mazda
    Slimani, Nadia
    Boffetta, Paolo
    Overvad, Kim
    Tjønneland, Anne
    Olsen, Anja
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Morois, Sophie
    Weikert, Cornelia
    Pischon, Tobias
    Linseisen, Jakob
    Kaaks, Rudolf
    Trichopoulou, Antonia
    Zilis, Demosthenes
    Katsoulis, Michael
    Palli, Domenico
    Berrino, Franco
    Vineis, Paolo
    Tumino, Rosario
    Panico, Salvatore
    Peeters, Petra HM
    Bueno-de-Mesquita, H Bas
    van Duijnhoven, Fränzel JB
    Gram, Inger Torhild
    Skeie, Guri
    Lund, Eiliv
    González, Carlos A
    Martínez, Carmen
    Dorronsoro, Miren
    Ardanaz, Eva
    Navarro, Carmen
    Rodríguez, Laudina
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Manjer, Jonas
    Ericson, Ulrika
    Bingham, Sheila
    Khaw, Kay-Tee
    Norat, Teresa
    Riboli, Elio
    Plasma folate, related genetic variants, and colorectal cancer risk in EPIC2010In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 19, no 5, p. 1328-1340Article in journal (Refereed)
    Abstract [en]

    Findings of the present study tend to weaken the evidence that folate plays an important role in CRC carcinogenesis. However, larger sample sizes are needed to adequately address potential gene-environment interactions.

  • 20. Fedirko, Veronika
    et al.
    Riboli, Elio
    Bueno-de-Mesquita, H Bas
    Rinaldi, Sabina
    Pischon, Tobias
    Norat, Teresa
    Jansen, Eugène H J M
    van Duijnhoven, Fränzel J B
    Tjønneland, Anne
    Olsen, Anja
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Engel, Pierre
    Kaaks, Rudolf
    Teucher, Birgit
    Boeing, Heiner
    Buijsse, Brian
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Lagiou, Pagona
    Sieri, Sabina
    Vineis, Paolo
    Panico, Salvatore
    Palli, Domenico
    Tumino, Rosario
    van Gils, Carla H
    Peeters, Petra H M
    Chirlaque, Maria-Dolores
    Gurrea, Aurelio Barricarte
    Rodríguez, Laudina
    Molina-Montes, Esther
    Dorronsoro, Miren
    Bonet, Catalina
    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.
    Key, Timothy J
    Tsilidis, Konstantinos K
    Khaw, Kay-Tee
    Romieu, Isabelle
    Straif, Kurt
    Wark, Petra A
    Romaguera, Dora
    Jenab, Mazda
    Prediagnostic circulating parathyroid hormone concentration and colorectal cancer in the European Prospective Investigation into Cancer and Nutrition cohort2011In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 20, no 5, p. 767-778Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Parathyroid hormone (PTH) has been proposed to play a promoting role in carcinogenesis. However, no epidemiologic studies have yet directly investigated its role in colorectal cancer (CRC).

    METHODS: A case-control study nested within the European Prospective Investigation into Cancer and Nutrition cohort was conducted with 1,214 incident, sporadic CRC cases matched to 1,214 controls. Circulating prediagnostic PTH and 25-hydroxy vitamin D [25(OH)D] concentrations were measured by enzyme-linked immunosorbent assays. Detailed dietary and lifestyle questionnaire data were collected at baseline. Multivariable conditional logistic regression was used to estimate the incidence rate ratio (RR) with 95% confidence intervals (95% CI) for the association between circulating PTH and CRC risk.

    RESULTS: In multivariate analyses [including adjustment for 25(OH)D concentration] with a priori defined cutoff points, high levels of serum PTH (≥65 ng/L) compared with medium PTH levels of 30-65 ng/L were associated with increased CRC risk (RR = 1.41, 95% CI: 1.03-1.93). In analyses by sex, the CRC risk was 1.77 (95% CI: 1.14-2.75) and 1.15 (95% CI: 0.73-1.84) in men and women, respectively (P(heterogeneity) = 0.01). In subgroup analyses by anatomical subsite, the risk for colon cancer was RR = 1.56, 95% CI: 1.03-2.34, and for rectal cancer RR = 1.20, 95% CI: 0.72-2.01 (P(heterogeneity) = 0.21). Effect modification by various risk factors was examined.

    CONCLUSIONS: The results of this study suggest that high serum PTH levels may be associated with incident, sporadic CRC in Western European populations, and in particular among men.

    IMPACT: To our knowledge, this is the first study on PTH and CRC. The role of PTH in carcinogenesis needs to be further investigated.

  • 21. Fedirko, Veronika
    et al.
    Riboli, Elio
    Tjønneland, Anne
    Ferrari, Pietro
    Olsen, Anja
    Bueno-de-Mesquita, H Bas
    van Duijnhoven, Fränzel J B
    Norat, Teresa
    Jansen, Eugène H J M
    Dahm, Christina C
    Overvad, Kim
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Racine, Antoine
    Lukanova, Annekatrin
    Teucher, Birgit
    Boeing, Heiner
    Aleksandrova, Krasimira
    Trichopoulou, Antonia
    Benetou, Vassiliki
    Trichopoulos, Dimitrios
    Grioni, Sara
    Vineis, Paolo
    Panico, Salvatore
    Palli, Domenico
    Tumino, Rosario
    Siersema, Peter D
    Peeters, Petra H
    Skeie, Guri
    Brustad, Magritt
    Chirlaque, Maria-Dolores
    Barricarte, Aurelio
    Quirós, Jose Ramón
    Sánchez, Maria José
    Dorronsoro, Miren
    Bonet, Catalina
    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.
    Key, Timothy J
    Crowe, Francesca
    Khaw, Kay-Tee
    Wareham, Nick
    Romieu, Isabelle
    McKay, James
    Wark, Petra A
    Romaguera, Dora
    Jenab, Mazda
    Prediagnostic 25-Hydroxyvitamin D, VDR and CASR polymorphisms, and survival in patients with colorectal cancer in Western European populations2012In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 21, no 4, p. 582-593Article in journal (Refereed)
    Abstract [en]

    Background: Individuals with higher blood 25-hydroxyvitamin D [25(OH)D] levels have a lower risk of developing colorectal cancer (CRC), but the influence of 25(OH)D on mortality after CRC diagnosis is unknown.

    Methods: The association between prediagnostic 25(OH)D levels and CRC-specific (N ¼ 444) and overall mortality (N ¼ 541) was prospectively examined among 1,202 participants diagnosed with CRC between 1992 and 2003 in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.Multivariable Cox proportional hazards models were used to calculate HRs and corresponding 95% CIs according to 25(OH)D quintiles and genetic variation within the VDR and CASR genes. Potential dietary, lifestyle, and metabolic effect modifiers were also investigated.

    Results: There were 541 deaths, 444 (82%) due to CRC. Mean follow-up was 73 months. In multivariable analysis, higher 25(OH)D levels were associated with a statistically significant reduction in CRC-specific (Ptrend ¼ 0.04) and overall mortality (Ptrend ¼ 0.01). Participants with 25(OH)D levels in the highest quintile had an adjusted HR of 0.69 (95% CI: 0.50–0.93) for CRC-specific mortality and 0.67 (95% CI: 0.50–0.88) for overall mortality, compared with the lowest quintile. Except for a possible interaction by prediagnostic dietary calcium intake (Pinteraction ¼ 0.01), no other potential modifying factors related to CRC survival were noted. The VDR (FokI and BsmI) and CASR (rs1801725) genotypes were not associated with survival.

    Conclusions: High prediagnostic 25(OH)D levels are associated with improved survival of patients with CRC. 

    Impact: Our findings may stimulate further research directed at investigating the effects of blood vitamin D levels before, at, and after CRC diagnosis on outcomes in CRC patients.

  • 22. Fedirko, Veronika
    et al.
    Romieu, Isabelle
    Aleksandrova, Krasimira
    Pischon, Tobias
    Trichopoulos, Dimitrios
    Peeters, Petra H.
    Romaguera-Bosch, Dora
    Bueno-de-Mesquita, H. B(as)
    Dahm, Christina C.
    Overvad, Kim
    Chirlaque, Maria-Dolores
    Johansen, Christoffer
    Bidstrup, Pernille E.
    Dalton, Susanne O.
    Gunter, Marc J.
    Wark, Petra A.
    Norat, Teresa
    Halkjaer, Jytte
    Tjonneland, Anne
    Dik, Vincent K.
    Siersema, Peter D.
    Boutron-Ruault, Marie-Christine
    Dossus, Laure
    Bastide, Nadia
    Kuehn, Tilman
    Kaaks, Rudolf
    Boeing, Heiner
    Trichopoulou, Antonia
    Klinaki, Eleni
    Katsoulis, Michalis
    Pala, Valeria
    Panico, Salvatore
    Tumino, Rosario
    Palli, Domenico
    Vineis, Paolo
    Weiderpass, Elisabete
    Skeie, Guri
    Gonzalez, Carlos A.
    Sanchez, Maria-Jose
    Barricarte, Aurelio
    Amiano, Pilar
    Ramon Quiros, J.
    Manjer, Jonas
    Jirstroem, Karin
    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
    Bradbury, Kathryn E.
    Stepien, Magdalena
    Duarte-Salles, Talita
    Riboli, Elio
    Jenab, Mazda
    Pre-diagnostic anthropometry and survival after colorectal cancer diagnosis in Western European populations2014In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 135, no 8, p. 1949-1960Article in journal (Refereed)
    Abstract [en]

    General and abdominal adiposity are associated with a high risk of developing colorectal cancer (CRC), but the role of these exposures on cancer survival has been less studied. The association between pre-diagnostic anthropometric characteristics and CRC-specific and all-cause death was examined among 3,924 men and women diagnosed with CRC between 1992 and 2009 in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Multivariable Cox proportional hazards models were used to calculate hazard ratios (FIRS) and corresponding 95% confidence intervals (as). Over a mean follow-up period of 49 months, 1,309 deaths occurred of which 1,043 (79.7%) were due to CRC. In multivariable analysis, prediagnostic BMI kg/m2 was associated with a high risk for CRC-specific (HR = 1.26, 95% CI = 1.04-1.52) and all-cause (HR = 1.32, 95% CI = 1.12-1.56) death relative to BMI <25 kg/m(2). Every 5 kg/m(2) increase in BMI was associated with a high risk for CRC-specific (HR = 1.10, 95% CI = 1.02-1.19) and all-cause death (HR = 1.12, 95% Cl = 1.05-1.20); and every 10 cm increase in waist circumference was associated with a high risk for CRC-specific (HR = 1.09, 95% Cl = 1.02-1.16) and allcause death (HR= 1.11, 95% CI= 1.05-1.18). Similar associations were observed for waist-to-hip and waist-to-height ratios. Height was not associated with CRC-specific or all-cause death. Associations tended to be stronger among men than in women. Possible interactions by age at diagnosis, cancer stage, tumour location, and hormone replacement therapy use among postmenopausal women were noted. Pre-diagnostic general and abdominal adiposity are associated with lower survival after CRC diagnosis.

  • 23. Ferrari, P
    et al.
    McKay, JD
    Jenab, M
    Brennan, P
    Canzian, F
    Vogel, U
    Tjonneland, A
    Overvad, K
    Tolstrup, JS
    Boutron-Ruault, M-C
    Clavel-Chapelon, F
    Morois, S
    Kaaks, R
    Boeing, H
    Bergmann, M
    Trichopoulou, A
    Katsoulis, M
    Trichopoulos, D
    Krogh, V
    Panico, S
    Sacerdote, C
    Palli, D
    Tumino, R
    Peeters, PH
    van Gils, CH
    Bueno-de-Mesquita, B
    Vrieling, A
    Lund, E
    Hjartaker, A
    Agudo, A
    Suarez, LR
    Arriola, L
    Chirlaque, M-D
    Ardanaz, E
    Sanchez, M-J
    Manjer, J
    Lindkvist, B
    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.
    Allen, N
    Key, T
    Khaw, K-T
    Slimani, N
    Rinaldi, S
    Romieu, I
    Boffetta, P
    Romaguera, D
    Norat, T
    Riboli, E
    Alcohol dehydrogenase and aldehyde dehydrogenase gene polymorphisms, alcohol intake and the risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition study2012In: European Journal of Clinical Nutrition, ISSN 0954-3007, E-ISSN 1476-5640, Vol. 66, no 12, p. 1303-1308Article in journal (Refereed)
    Abstract [en]

    BACKGROUND/OBJECTIVES: Heavy alcohol drinking is a risk factor of colorectal cancer (CRC), but little is known on the effect of polymorphisms in the alcohol-metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) on the alcohol-related risk of CRC in Caucasian populations.

    SUBJECTS/METHODS: A nested case-control study (1269 cases matched to 2107controls by sex, age, study centre and date of blood collection) was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the impact of rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms on CRC risk. Using the wild-type variant of each polymorphism as reference category, CRC risk estimates were calculated using conditional logistic regression, with adjustment for matching factors.

    RESULTS: Individuals carrying one copy of the rs1229984(A) (ADH1B) allele (fast metabolizers) showed an average daily alcohol intake of 4.3 g per day lower than subjects with two copies of the rs1229984(G) allele (slow metabolizers) (P-diff<0.01). None of the polymorphisms was associated with risk of CRC or cancers of the colon or rectum. Heavy alcohol intake was more strongly associated with CRC risk among carriers of the rs1573496(C) allele, with odds ratio equal to 2.13 (95% confidence interval: 1.26-3.59) compared with wild-type subjects with low alcohol consumption P-((interaction)=0.07).

    CONCLUSIONS: The rs1229984(A) (ADH1B) allele was associated with a reduction in alcohol consumption. The rs1229984 (ADH1B), rs1573496 (ADH7) and rs441 (ALDH2) polymorphisms were not associated with CRC risk overall in Western-European populations. However, the relationship between alcohol and CRC risk might be modulated by the rs1573496 (ADH7) polymorphism. European Journal of Clinical Nutrition (2012) 66, 1303-1308; doi: 10.1038/ejcn.2012.173; published online 14 November 2012

  • 24. Ferrari, Pietro
    et al.
    Jenab, Mazda
    Norat, Teresa
    Moskal, Aurelie
    Slimani, Nadia
    Olsen, Anja
    Tjønneland, Anne
    Overvad, Kim
    Jensen, Majken K
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Morois, Sophie
    Rohrmann, Sabine
    Linseisen, Jakob
    Boeing, Heiner
    Bergmann, Manuela
    Kontopoulou, Dimitra
    Trichopoulou, Antonia
    Kassapa, Christina
    Masala, Giovanna
    Krogh, Vittorio
    Vineis, Paolo
    Panico, Salvatore
    Tumino, Rosario
    van Gils, Carla H
    Peeters, Petra
    Bueno-de-Mesquita, H Bas
    Ocké, Marga C
    Skeie, Guri
    Lund, Eiliv
    Agudo, Antonio
    Ardanaz, Eva
    López, Dolores C
    Sanchez, Maria-Jose
    Quirós, José R
    Amiano, Pilar
    Berglund, Göran
    Manjer, Jonas
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Allen, Naomi
    Key, Tim
    Bingham, Sheila
    Mazuir, Mathieu
    Boffetta, Paolo
    Kaaks, Rudolf
    Riboli, Elio
    Lifetime and baseline alcohol intake and risk of colon and rectal cancers in the European prospective investigation into cancer and nutrition (EPIC).2007In: Int J Cancer, ISSN 0020-7136, Vol. 121, no 9, p. 2065-72Article in journal (Refereed)
  • 25.
    Forssell, Johan
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Jung, Andreas
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    High macrophage infiltration along the tumor front correlates with improved survival in colon cancer.2007In: Clin Cancer Res, ISSN 1078-0432, Vol. 13, no 5, p. 1472-1479Article in journal (Refereed)
  • 26. Försti, A
    et al.
    Lei, H
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Onkologi.
    Enquist, K
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Altieri, A
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hemminki, K
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology. Onkologi.
    Polymorphisms in the genes of the urokinase plasminogen activation system in relation to colorectal cancer.2007In: Ann Oncol, ISSN 0923-7534, Vol. 18, p. 1990-1994Article in journal (Refereed)
  • 27.
    Försti, Asta
    et al.
    Department of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany / Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden.
    Li, Xuchen
    Department of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
    Wagner, Kerstin
    Department of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Enquist, Kerstin
    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.
    Altieri, Andrea
    Department of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hemminki, Kari
    Department of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany / Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö, Sweden.
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Polymorphisms in the transforming growth factor beta 1 pathway in relation to colorectal cancer progression2010In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 49, no 3, p. 270-281Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor beta1 (TGFB1) acts as a growth inhibitor of normal colonic epithelial cells, however, as a tumor promoter of colorectal cancer (CRC) cells. To explore the association between genetic polymorphisms in the TGFB1 pathway and CRC susceptibility and clinical outcome, we carried out a case-control study on a Swedish population of 308 CRC cases and 585 age- and gender-matched controls. The cases were sampled prospectively and had up to 16 years follow-up, making the study material particularly suitable for survival analysis. On the basis of their reported or predicted functional effect, nine single-nucleotide polymorphisms (TGFB1: Leu10Pro; TGFBR1: 9A/6A and IVS7G+24A; FURIN: C-229T; THBS1: T+42C; LTBP1L: C-256G; LTBP4: T-893G and Thr750Ala; BAMBI: T-779A) were selected for genotyping. We evaluated the associations between genotypes and CRC and Dukes' stage. Survival probabilities were compared between different subgroups. The observed statistically significant associations included a decreased CRC risk for TGFBR1 IVS7G+24A minor allele carriers (odds ratio (OR): 0.72, 95% confidence interval (CI): 0.53-0.97), less aggressive tumors with Dukes' stage A+B for carriers of LTBP4 Thr750Ala and BAMBI T-779A minor alleles (OR: 0.58, 95%CI: 0.36-0.93 and OR: 0.51, 95%CI: 0.29-0.89, respectively) and worse survival for FURIN C-229T heterozygotes (hazard ratio: 1.63, 95%CI: 1.08-2.46). As this is the first study about the influence of the polymorphisms in the TGFB1 pathway on CRC progression, further studies in large independent cohorts are warranted.

  • 28. Galon, Jerome
    et al.
    Mlecnik, Bernhard
    Bindea, Gabriela
    Angell, Helen K.
    Berger, Anne
    Lagorce, Christine
    Lugli, Alessandro
    Zlobec, Inti
    Hartmann, Arndt
    Bifulco, Carlo
    Nagtegaal, Iris D.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Masucci, Giuseppe V.
    Botti, Gerardo
    Tatangelo, Fabiana
    Delrio, Paolo
    Maio, Michele
    Laghi, Luigi
    Grizzi, Fabio
    Asslaber, Martin
    D'Arrigo, Corrado
    Vidal-Vanaclocha, Fernando
    Zavadova, Eva
    Chouchane, Lotfi
    Ohashi, Pamela S.
    Hafezi-Bakhtiari, Sara
    Wouters, Bradly G.
    Roehrl, Michael
    Nguyen, Linh
    Kawakami, Yutaka
    Hazama, Shoichi
    Okuno, Kiyotaka
    Ogino, Shuji
    Gibbs, Peter
    Waring, Paul
    Sato, Noriyuki
    Torigoe, Toshihiko
    Itoh, Kyogo
    Patel, Prabhu S.
    Shukla, Shilin N.
    Wang, Yili
    Kopetz, Scott
    Sinicrope, Frank A.
    Scripcariu, Viorel
    Ascierto, Paolo A.
    Marincola, Francesco M.
    Fox, Bernard A.
    Pages, Franck
    Towards the introduction of the 'Immunoscore' in the classification of malignant tumours2014In: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 232, no 2, p. 199-209Article, review/survey (Refereed)
    Abstract [en]

    The American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) TNM staging system provides the most reliable guidelines for the routine prognostication and treatment of colorectal carcinoma. This traditional tumour staging summarizes data on tumour burden (T), the presence of cancer cells in draining and regional lymph nodes (N) and evidence for distant metastases (M). However, it is now recognized that the clinical outcome can vary significantly among patients within the same stage. The current classification provides limited prognostic information and does not predict response to therapy. Multiple ways to classify cancer and to distinguish different subtypes of colorectal cancer have been proposed, including morphology, cell origin, molecular pathways, mutation status and gene expression-based stratification. These parameters rely on tumour-cell characteristics. Extensive literature has investigated the host immune response against cancer and demonstrated the prognostic impact of the in situ immune cell infiltrate in tumours. A methodology named Immunoscore' has been defined to quantify the in situ immune infiltrate. In colorectal cancer, the Immunoscore may add to the significance of the current AJCC/UICC TNM classification, since it has been demonstrated to be a prognostic factor superior to the AJCC/UICC TNM classification. An international consortium has been initiated to validate and promote the Immunoscore in routine clinical settings. The results of this international consortium may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).

  • 29. Galon, Jerome
    et al.
    Pages, Franck
    Marincola, Francesco M.
    Angell, Helen K.
    Thurin, Magdalena
    Lugli, Alessandro
    Zlobec, Inti
    Berger, Anne
    Bifulco, Carlo
    Botti, Gerardo
    Tatangelo, Fabiana
    Britten, Cedrik M.
    Kreiter, Sebastian
    Chouchane, Lotfi
    Delrio, Paolo
    Arndt, Hartmann
    Asslaber, Martin
    Maio, Michele
    Masucci, Giuseppe V.
    Mihm, Martin
    Vidal-Vanaclocha, Fernando
    Allison, James P.
    Gnjatic, Sacha
    Hakansson, Leif
    Huber, Christoph
    Singh-Jasuja, Harpreet
    Ottensmeier, Christian
    Zwierzina, Heinz
    Laghi, Luigi
    Grizzi, Fabio
    Ohashi, Pamela S.
    Shaw, Patricia A.
    Clarke, Blaise A.
    Wouters, Bradly G.
    Kawakami, Yutaka
    Hazama, Shoichi
    Okuno, Kiyotaka
    Wang, Ena
    O'Donnell-Tormey, Jill
    Lagorce, Christine
    Pawelec, Graham
    Nishimura, Michael I.
    Hawkins, Robert
    Lapointe, Rejean
    Lundqvist, Andreas
    Khleif, Samir N.
    Ogino, Shuji
    Gibbs, Peter
    Waring, Paul
    Sato, Noriyuki
    Torigoe, Toshihiko
    Itoh, Kyogo
    Patel, Prabhu S.
    Shukla, Shilin N.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nagtegaal, Iris D.
    Wang, Yili
    D'Arrigo, Corrado
    Kopetz, Scott
    Sinicrope, Frank A.
    Trinchieri, Giorgio
    Gajewski, Thomas F.
    Ascierto, Paolo A.
    Fox, Bernard A.
    Cancer classification using the Immunoscore: a worldwide task force2012In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 10, p. 205-Article, review/survey (Refereed)
    Abstract [en]

    Prediction of clinical outcome in cancer is usually achieved by histopathological evaluation of tissue samples obtained during surgical resection of the primary tumor. Traditional tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N) and evidence for metastases (M). However, it is now recognized that clinical outcome can significantly vary among patients within the same stage. The current classification provides limited prognostic information, and does not predict response to therapy. Recent literature has alluded to the importance of the host immune system in controlling tumor progression. Thus, evidence supports the notion to include immunological biomarkers, implemented as a tool for the prediction of prognosis and response to therapy. Accumulating data, collected from large cohorts of human cancers, has demonstrated the impact of immune-classification, which has a prognostic value that may add to the significance of the AJCC/UICC TNM-classification. It is therefore imperative to begin to incorporate the ` Immunoscore' into traditional classification, thus providing an essential prognostic and potentially predictive tool. Introduction of this parameter as a biomarker to classify cancers, as part of routine diagnostic and prognostic assessment of tumors, will facilitate clinical decision-making including rational stratification of patient treatment. Equally, the inherent complexity of quantitative immunohistochemistry, in conjunction with protocol variation across laboratories, analysis of different immune cell types, inconsistent region selection criteria, and variable ways to quantify immune infiltration, all underline the urgent requirement to reach assay harmonization. In an effort to promote the Immunoscore in routine clinical settings, an international task force was initiated. This review represents a follow-up of the announcement of this initiative, and of the J Transl Med. editorial from January 2012. Immunophenotyping of tumors may provide crucial novel prognostic information. The results of this international validation may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).

  • 30.
    Gustafsson, Sofia B
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Dahlin, Anna M
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Jacobsson, Stig OP
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Fowler, Christopher J
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    High tumour cannabinoid CB(1) receptor immunoreactivity negatively impacts disease-specific survival in stage II microsatellite stable colorectal cancer2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 8, p. 1-11Article in journal (Refereed)
    Abstract [en]

    Background: There is good evidence in the literature that the cannabinoid system is disturbed in colorectal cancer. In the present study, we have investigated whether CB(1) receptor immunoreactive intensity (CB(1)IR intensity) is associated with disease severity and outcome.

    Methodology/Principal Findings: CB(1)IR was assessed in formalin-fixed, paraffin-embedded specimens collected with a consecutive intent during primary tumour surgical resection from a series of cases diagnosed with colorectal cancer. Tumour centre (n = 483) and invasive front (n = 486) CB(1)IR was scored from 0 (absent) to 3 (intense staining) and the data was analysed as a median split i.e. CB(1)IR <2 and >= 2. In microsatellite stable, but not microsatellite instable tumours (as adjudged on the basis of immunohistochemical determination of four mismatch repair proteins), there was a significant positive association of the tumour grade with the CB1IR intensity. The difference between the microsatellite stable and instable tumours for this association of CB(1)IR was related to the CpG island methylation status of the cases. Cox proportional hazards regression analyses indicated a significant contribution of CB(1)IR to disease-specific survival in the microsatellite stable tumours when adjusting for tumour stage. For the cases with stage II microsatellite stable tumours, there was a significant effect of both tumour centre and front CB(1)IR upon disease specific survival. The 5 year probabilities of event-free survival were: 8565 and 66+/-8%; tumour interior, 86+/-4% and 63+/-8% for the CB(1)IR<2 and CB(1)IR >= 2 groups, respectively.

    Conclusions/Significance: The level of CB(1) receptor expression in colorectal cancer is associated with the tumour grade in a manner dependent upon the degree of CpG hypermethylation. A high CB(1)IR is indicative of a poorer prognosis in stage II microsatellite stable tumour patients.

  • 31.
    Gylling, Björn
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Ueland, Per Magne
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Low folate levels are associated with reduced risk of colorectal cancer in a population with low folate status2014In: Cancer Epidemiology, Biomarkers and Prevention, ISSN 1055-9965, E-ISSN 1538-7755, Vol. 23, no 10, p. 2136-2144Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A diet rich in folate is associated with a reduced colorectal cancer risk, whereas the role of circulating levels is less clear. The aim of this study was to relate prediagnostic plasma folate, vitamin B12, and homocysteine concentrations to the risk of colorectal cancer.

    METHODS: This was a prospective case-control study of 331 cases and 662 matched controls nested within the population-based Northern Sweden Health and Disease Study. Median follow-up time from recruitment to diagnosis was 10.8 years.

    RESULTS: Plasma folate concentrations were positively related to colorectal cancer risk; multivariate odds ratios were 1.62 [95% confidence intervals (CI), 1.08-2.42] and 1.42 (95% CI, 0.94-2.21) for the middle and highest versus lowest tertile, respectively. In subjects with follow-up <10.8 years, a statistically significant doubled risk was observed for the middle and highest versus lowest tertile, whereas findings for longer follow-up times were null. A positive risk relationship was also observed for tumor stage III-IV but not I-II. Plasma vitamin B12 concentrations were inversely associated with rectal cancer risk. Homocysteine was not significantly related to colorectal cancer risk.

    CONCLUSIONS: In this population-based, nested case-control study, low plasma folate concentrations were associated with a reduced colorectal cancer risk. This protective role was mainly observed in subjects with higher tumor stage or shorter follow-up time between recruitment and diagnosis. Low circulating folate status may protect against colorectal cancer or suppress progression of preneoplastic or neoplastic lesions.

    IMPACT: These findings may have relevance for the ongoing debate about mandatory folic acid fortification of flour.

  • 32. Hansen, Louise
    et al.
    Skeie, Guri
    Landberg, Rikard
    Lund, Eiliv
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology, Cariology.
    Dragsted, Lars O
    Egeberg, Rikke
    Johnsen, Nina F
    Christensen, Jane
    Overvad, Kim
    Tjønneland, Anne
    Olsen, Anja
    Intake of dietary fiber, especially from cereal foods, is associated with lower incidence of colon cancer in the HELGA cohort2012In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 131, no 2, p. 469-478Article in journal (Refereed)
    Abstract [en]

    The role of dietary fiber on the risk of colon and rectal cancer has been investigated in numerous studies, but findings have been inconsistent. The purpose of this study was to examine associations between intake of dietary fiber and risk of incident colon (including distal and proximal colon) and rectal cancer in the prospective Scandinavian HELGA cohort and to determine if fiber source (vegetables, fruits, potatoes, cereals) impacted the association. We included 1,168 incident cases (691 colon, 477 rectal cancer), diagnosed during a median of 11.3 years, among 108,081 cohort members. Sex-specific incidence rate ratios (IRRs) of colon and rectal cancer were related to intake of total or specific fiber source using Cox proportional hazards models. For men, an inverse association was observed between intake of total fiber and the risk of colon cancer per an incremental increase of 10 g day(-1) , IRR (95% CI): 0.74 (0.64-0.86). Intake of cereal fiber per 2 g day(-1) was associated with an IRR of 0.94 (0.91-0.98), which was also seen for intake of cereal fiber from foods with high fiber content (≥5 g per 100 g product), where the IRR per 2 g day(-1) was 0.94 (0.90-0.98). In women, intake of cereal fiber per 2 g day(-1) was also associated with lower risk of colon cancer, 0.97 (0.93-1.00). No clear associations were seen for rectal cancer. Our data indicate a protective role of total and cereal fiber intake, particularly from cereal foods with high fiber content, in the prevention of colon cancer.

  • 33. Hart, Andrew R
    et al.
    Luben, Robert
    Olsen, Anja
    Tjonneland, Anne
    Linseisen, Jakob
    Nagel, Gabriele
    Berglund, Goran
    Lindgren, Stefan
    Grip, Olof
    Key, Timothy
    Appleby, Paul
    Bergmann, Manuela M
    Boeing, Heiner
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Danielsson, Ake
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Sjodin, Hubert
    Hagglund, Gun
    Overvad, Kim
    Palli, Domenico
    Masala, Giovanna
    Riboli, Elio
    Kennedy, Hugh
    Welch, Ailsa
    Khaw, Kay-Tee
    Day, Nicholas
    Bingham, Sheila
    Diet in the Aetiology of Ulcerative Colitis: A European Prospective Cohort Study.2008In: Digestion, ISSN 1421-9867, Vol. 77, no 1, p. 57-64Article in journal (Refereed)
  • 34.
    Henriksson, Maria L
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    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.
    Colorectal Cancer Cells Activate Adjacent Fibroblasts Resulting in FGF1/FGFR3 Signaling and Increased Invasion.2011In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 178, no 3, p. 1387-1394Article in journal (Refereed)
    Abstract [en]

    Cancer-associated fibroblasts expressing fibroblast activation protein (FAP) have been implicated in the invasive behavior of colorectal cancer. In this study, we use FAP expression as a marker of fibroblast activation and analyze the effect of activated fibroblasts on colorectal cancer migration and invasion in experimental cell studies. We also investigated the expression pattern of FAP in cancer-associated fibroblasts during transformation from benign to malignant colorectal tumors. In immunohistochemical analyses, FAP was expressed in fibroblasts in all colorectal cancer samples examined, whereas all normal colon, hyperplastic polyps, or adenoma samples were negative. In in vitro studies, conditioned medium from colon cancer cells, but not adenoma cells, activated fibroblasts by inducing FAP expression. These activated fibroblasts increased the migration and invasion of colon cancer cells in Boyden chamber experiments and in a three-dimensional cell culture model. We identify fibroblast growth factor 1/fibroblast growth factor receptor 3 (FGF1/FGFR-3) signaling as mediators leading to the increased migration and invasion. Activated fibroblasts increase their expression of FGF1, and by adding a fibroblast growth factor receptor inhibitor, as well as an FGF1-neutralizing antibody, we reduced the migration of colon cancer cells. Our findings provide evidence of a possible molecular mechanism involved in the cross talk between cancer cells and fibroblasts leading to cancer cell invasion.

  • 35. Hunt, Kelly J
    et al.
    Lukanova, Annekatrin
    Rinaldi, Sabina
    Lundin, Eva
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Norat, Teresa
    Palmqvist, Richard
    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.
    Riboli, Elio
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Kaaks, Rudolf
    A potential inverse association between insulin-like growth factor I and hypertension in a cross-sectional study.2006In: Annals of Epidemiology, ISSN 1047-2797, E-ISSN 1873-2585, Vol. 16, no 7, p. 563-571Article in journal (Refereed)
  • 36. Isaksson-Mettavainio, Martin
    et al.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Forssell, Johan
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    SMAD4/DPC4 expression and prognosis in human colorectal cancer.2006In: Anticancer Res, ISSN 0250-7005, Vol. 26, no 1B, p. 507-10Article in journal (Refereed)
  • 37.
    Isaksson-Mettävainio, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High SMAD4 levels appear in MSI and hypermethylated colon cancers, and indicate a better prognosis2012In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 131, p. 779-788Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer (CRC) is one of the most common causes of cancer related deaths in western countries. CRC are commonly divided in cancers showing microsatellite stability (MSS) or microsatellite instability (MSI). A more novel classification is dependent on promoter hypermethylation of CpG islands (the CpG island methylator phenotype, CIMP), where cancers show high, low or negative methylation status. SMAD4, located on chromosome 18q, has been thoroughly investigated during the last years. Loss of SMAD4 expression has been reported to correlate with poor CRC patient prognosis. In this study we analyze the impact of SMAD4 expression on prognosis in relation to MSI screening status and CIMP status. 479 paraffin-embedded specimens of CRC were examined for nuclear SMAD4 expression using immunohistochemistry. The tumors were scored loss (-), moderate (+) and high (++) expressing tumors. Loss of SMAD4 correlated significantly with decreased survival in all colon cancer patients. High SMAD4 expression, on the other hand, was significantly associated with increased survival, especially in colon cancer patients which has undergone potential curative surgery. In addition, in MSI tumors and CIMP-high tumors, high SMAD4 expression was significantly related to increase in survival, while loss of SMAD4 resulted in a significantly poorer prognosis. SMAD4 expression was not correlated to prognosis in rectal cancer cases. We conclude, loss of SMAD4 indicates a poor prognosis in colon cancer patients. The novel findings that high SMAD4 expression predicts a better prognosis suggests that SMAD4 immunohistochemistry could constitute a prognostic marker in combination with CIMP and MSI screening status.

  • 38.
    Isaksson-Mettävainio, Martin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    c-Met expression in primary tumors and their corresponding distant metastases2009In: Molecular Medicine Reports, ISSN 1791-2997, Vol. 1, no 6, p. 787-790Article in journal (Refereed)
    Abstract [en]

    c-Met is a receptor tyrosine kinase that has beenimplicated in the pathogenesis and growth of a wide variety ofhuman malignancies, including CRC, but its role in metastasisis largely unknown. We compared c-Met expression in primaryhuman colorectal carcinomas and distant metastases from thesame patients. Formalin-fixed paraffin-embedded tissuesamples from 69 colorectal cancer patients were obtained. Theprotein expression of c-Met was evaluated immunohistochemicallyusing a commercial antibody. The difference inexpression between primary tumors and their correspondingdistant metastases was analyzed using the Wilcoxon signedranktest. c-Met expression was statistically significantlylower in the distant metastases compared to their correspondingprimary tumors (p<0.001), whereas no difference was foundbetween lymph node metastases and their correspondingprimary tumors (p=0.957). The degree of c-Met expressionwas not related to clinicopathological characteristics such astumor grade and Dukes' stage at the time of primary tumordiagnosis, or to the location of the distant metastases. Wedemonstrated that c-Met expression is often reduced in distantmetastases compared to their corresponding primary colorectaltumors. Additional studies of c-Met activation and signaltransduction will increase our knowledge about the role ofc-Met in colorectal cancer metastasis.

  • 39. 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.

  • 40. 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)
  • 41. 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).

  • 42. 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)
  • 43. 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].

  • 44. 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)).

  • 45. 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.

  • 46. 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.

  • 47. 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.

  • 48. 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.

  • 49.
    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)
  • 50.
    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)
12 1 - 50 of 84
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