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  • 101.
    Rutegård, Miriam
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Båtsman, Malin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Axelsson, Jan
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Brynolfsson, Patrik
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Brännström, Fredrik
    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.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Blomqvist, Lennart
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rutegård, Martin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Riklund, Katrine
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Diagnostic Radiology.
    PET/MRI and PET/CT hybrid imaging of rectal cancer - description and initial observations from the RECTOPET (REctal Cancer trial on PET/MRI/CT) study2019In: Cancer Imaging, ISSN 1740-5025, E-ISSN 1470-7330, Vol. 19, article id 52Article in journal (Refereed)
    Abstract [en]

    PurposeThe role of hybrid imaging using F-18-fluoro-2-deoxy-D-glucose positron-emission tomography (FDG-PET), computed tomography (CT) and magnetic resonance imaging (MRI) to improve preoperative evaluation of rectal cancer is largely unknown. To investigate this, the RECTOPET (REctal Cancer Trial on PET/MRI/CT) study has been launched with the aim to assess staging and restaging of primary rectal cancer. This report presents the study workflow and the initial experiences of the impact of PET/CT on staging and management of the first patients included in the RECTOPET study.MethodsThis prospective cohort study, initiated in September 2016, is actively recruiting patients from Region Vasterbotten in Sweden. This pilot study includes patients recruited and followed up until December 2017. All patients had a biopsy-verified rectal adenocarcinoma and underwent a minimum of one preoperative FDG-PET/CT and FDG-PET/MRI examination. These patients were referred to the colorectal cancer multidisciplinary team meeting at Umea University Hospital. All available data were evaluated when making management recommendations. The clinical course was noted and changes consequent to PET imaging were described; surgical specimens underwent dedicated MRI for anatomical matching between imaging and histopathology.ResultsTwenty-four patients have so far been included in the study. Four patients were deemed unresectable, while 19 patients underwent or were scheduled for surgery; one patient was enrolled in a watch-and-wait programme after restaging. Consequent to taking part in the study, two patients were upstaged to M1 disease: one patient was diagnosed with a solitary hepatic metastasis detected using PET/CT and underwent metastasectomy prior to rectal cancer surgery, while one patient with a small, but metabolically active, lung nodulus experienced no change of management. PET/MRI did not contribute to any recorded change in patient management.ConclusionsThe RECTOPET study investigating the role of PET/CT and PET/MRI for preoperative staging of primary rectal cancer patients will provide novel data that clarify the value of adding hybrid to conventional imaging, and the role of PET/CT versus PET/MRI.Trial registrationNCT03846882.

  • 102.
    Stattin, Pär
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Lukanova, Annekatrin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Biessy, Carine
    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.
    Kaaks, Rudolf
    Olsson, Tommy
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Jellum, Egil
    Obesity and colon cancer: does leptin provide a link?2004In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 109, no 1, p. 149-152Article in journal (Refereed)
    Abstract [en]

    Obesity, a risk factor for colorectal cancer, is associated with elevated serum levels of leptin, the adipocyte-derived hormone, and insulin. Experimental and epidemiologic studies have indicated a role for insulin in the pathogenesis of colon cancer, and recent experimental studies have suggested a similar role for leptin. In a case-control study nested in the Janus Biobank, Norway, we measured serum levels of leptin and C-peptide (a marker of pancreatic insulin secretion) in cryopreserved prediagnostic sera from men (median age, 45 years) who were diagnosed with cancer of the colon (n = 235) or rectum (n = 143) after blood collection (median time, 17 years), and among 378 controls matched for age and date of blood collection. Conditional logistic regression analyses showed an approximately 3-fold increase in colon cancer risk with increasing concentrations of leptin up to an odds ratio (OR) of 2.72 (95% CI = 1.44-5.12) for top vs. bottom quartile (p(trend) = 0.008). The corresponding OR for C-peptide was 1.81 (95% CI = 0.67-4.86; p(trend) = 0.19). The risk estimates remained unchanged after mutual adjustment. No association of hormone levels with rectal cancer risk was found. Reproducibility of hormone measurements assessed by intraclass coefficients (ICCs) for paired samples taken 1 year apart was high for leptin (ICC = 0.82) but lower for C-peptide (ICC = 0.30). Our results suggest that leptin is a risk factor for colon cancer, and that leptin may provide a link between obesity and colon cancer. Leptin may be directly involved in colon tumorigenesis or it may serve as a sensitive and robust marker of an obesity-induced adverse endocrine environment. Only weak support for an association of insulin with colon cancer was found.

  • 103.
    Stenling, Roger
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Lindberg, Jan
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Rutegård, Jörgen
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Altered expression of CK7 and CK20 in preneoplastic and neoplastic lesions in ulcerative colitis.2007In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 115, no 11, p. 1219-1226Article in journal (Other academic)
  • 104.
    Stocks, Tanja
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Lukanova, A
    Johansson, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Rinaldi, S
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Kaaks, R
    Stattin, Pär
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology. Urologi och andrologi.
    Components of the metabolic syndrome and colorectal cancer risk: a prospective study2008In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 32, no 2, p. 304-314Article in journal (Refereed)
    Abstract [en]

    Objective: To examine the relation of well-known factors of the metabolic syndrome (MetS) as well as related circulating factors, with risk of colorectal cancer.

    Methods: We performed a case control study of 306 colorectal cancer cases and 595 matched controls nested in the Northern Sweden Health and Disease Cohort. Levels of C-peptide, glycated haemoglobin (HbA1c), leptin and adiponectin were measured in cryopreserved samples. Body mass index (BMI), systolic and diastolic blood pressure and fasting and post-load plasma glucose, had been measured in a subcohort. Conditional logistic regression was used to calculate odds ratios (OR) of disease, including risk assessments for the MetS factors: obesity (BMI>30 kg m-2), hypertension (blood pressure 140/90 mmHg or use of anti-hypertensive drugs) and hyperglycaemia (fasting glucose 6.1 mmol l-1 or post-load glucose in capillary plasma 8.9 mmol l-1).

    Results: None of the studied variables were significantly associated with risk across quartiles. Presence of obesity, hypertension and hyperglycaemia significantly increased the risk of colorectal cancer; OR for three vs null factors was 2.57 (95% Confidence Interval [CI] 1.20–5.52; P trend=0.0021), as compared to a 30 to 70% increased risk for the factors in single. Similarly, top decile levels of C-peptide, HbA1c and leptin/adiponectin ratio were associated with an increased risk; ORs for top vs deciles 1–9 were 1.56 (95% CI 0.93–2.62; P=0.090), 1.83 (95% CI 1.00–3.36; P=0.051) and 1.50 (95% CI 0.83–2.71; P=0.18), respectively.

    Conclusions: Our study support the view that components of the MetS increase risk of colorectal cancer, and further suggests that only very high levels of metabolic factors confer an increased risk.

  • 105.
    Sundkvist, Anneli
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Harlid, Sophia
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Plasma ghrelin is probably not a useful biomarker for risk prediction or early detection of colorectal cancer2019In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 68, no 2, p. 373-374Article in journal (Refereed)
  • 106.
    Svenson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Telomere length in peripheral leukocytes is associated with immune cell tumor infiltration and prognosis in colorectal cancer patients2016In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, no 8, p. 10877-10882Article in journal (Refereed)
    Abstract [en]

    Telomeres are protective structures at the end of chromosomes, essential for chromosomal integrity. A large number of studies have investigated leukocyte telomere length as a possible risk marker for various cancers, colorectal cancer (CRC) included. In contrast, studies investigating leukocyte telomere length in relation to CRC survival are lacking. We previously reported that relative telomere length (RTL) of leukocytes collected at diagnosis predicted survival in patients with breast and kidney cancer. We suggested that these findings might reflect various immunological mechanisms, affected by the presence of a tumor. In the present study, leukocyte RTL was examined in relation to immune cell tumor infiltration and prognosis in 130 patients with CRC diagnosis. RTL was measured with a well-established qPCR method. We found that patients with the highest degree of lymphocyte tumor infiltration had shorter leukocyte RTL. Consistent with our previous findings, short RTL was a favorable prognostic marker in univariate survival analysis. In the current study, RTL did not remain as an independent predictor in multivariate survival analysis, when including metastatic status in the model. However, a non-significant trend towards a similar telomere-associated survival pattern was observed in patients with limited disease. In contrast, for patients who died of other causes than CRC, short RTL was associated with significantly shorter survival time. To our knowledge, this is the first study to investigate an association between leukocyte RTL, immune cell tumor infiltration, and cancer-specific survival in CRC patients. Larger studies are warranted to verify these findings.

  • 107.
    Söderström, Elisabet
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Schneede, Jörn
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Homocysteine and cotinine levels in smokers and snus users2015In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 241, no 1, p. E129-E129Article in journal (Other academic)
  • 108. Tjonneland, A
    et al.
    Overvad, K
    Bergmann, M M
    Nagel, G
    Linseisen, J
    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.
    Sjödin, Hubert
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hägglund, G
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Berglund, G
    Lindgren, S
    Grip, O
    Palli, D
    Day, N E
    Khaw, K-T
    Bingham, S
    Riboli, E
    Kennedy, H
    Hart, A
    Danielsson, A
    Linoleic acid, a dietary n-6 polyunsaturated fatty acid, and the aetiology of ulcerative colitis: a nested case-control study within a European prospective cohort study2009In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 58, no 12, p. 1606-1611Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Dietary linoleic acid, an n-6 polyunsaturated fatty acid, is metabolised to arachidonic acid, a component of colonocyte membranes. Metabolites of arachidonic acid have pro-inflammatory properties and are increased in the mucosa of patients with ulcerative colitis. The aim of this investigation was to conduct the first prospective cohort study investigating if a high dietary intake of linoleic acid increases the risk of developing incident ulcerative colitis. DESIGN AND SETTING: Dietary data from food frequency questionnaires were available for 203 193 men and women aged 30-74 years, resident in the UK, Sweden, Denmark, Germany or Italy and participating in a prospective cohort study, the European Prospective Investigation into Cancer and Nutrition (EPIC). These participants were followed up for the diagnosis of ulcerative colitis. Each case was matched with four controls and the risk of disease calculated by quartile of intake of linoleic acid adjusted for gender, age, smoking, total energy intake and centre. RESULTS: A total of 126 participants developed ulcerative colitis (47% women) after a median follow-up of 4.0 years (range, 1.7-11.3 years). The highest quartile of intake of linoleic acid was associated with an increased risk of ulcerative colitis (odds ratio (OR) = 2.49, 95% confidence interval (CI) = 1.23 to 5.07, p = 0.01) with a significant trend across quartiles (OR = 1.32 per quartile increase, 95% CI = 1.04 to 1.66, p = 0.02 for trend). CONCLUSIONS: The data support a role for dietary linoleic acid in the aetiology of ulcerative colitis. An estimated 30% of cases could be attributed to having dietary intakes higher than the lowest quartile of linoleic acid intake.

  • 109. van Duijnhoven, Fränzel J B
    et al.
    Bueno-De-Mesquita, H Bas
    Calligaro, Miriam
    Jenab, Mazda
    Pischon, Tobias
    Jansen, Eugène H J M
    Frohlich, Jiri
    Ayyobi, Amir
    Overvad, Kim
    Toft-Petersen, Anne Pernille
    Tjønneland, Anne
    Hansen, Louise
    Boutron-Ruault, Marie-Christine
    Clavel-Chapelon, Françoise
    Cottet, Vanessa
    Palli, Domenico
    Tagliabue, Giovanna
    Panico, Salvatore
    Tumino, Rosario
    Vineis, Paolo
    Kaaks, Rudolf
    Teucher, Birgit
    Boeing, Heiner
    Drogan, Dagmar
    Trichopoulou, Antonia
    Lagiou, Pagona
    Dilis, Vardis
    Peeters, Petra H M
    Siersema, Peter D
    Rodríguez, Laudina
    González, Carlos A
    Molina-Montes, Esther
    Dorronsoro, Miren
    Tormo, Maria-Jose
    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
    Tsilidis, Kostas K
    Crowe, Francesca L
    Chajes, Veronique
    Fedirko, Veronika
    Rinaldi, Sabina
    Norat, Teresa
    Riboli, Elio
    Blood lipid and lipoprotein concentrations and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition2011In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 60, no 8, p. 1094-1102Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To examine the association between serum concentrations of total cholesterol, high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol, triglycerides, apolipoprotein A-I (apoA), apolipoprotein B and the incidence of colorectal cancer (CRC).

    DESIGN: Nested case-control study.

    SETTING: The study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC), a cohort of more than 520,000 participants from 10 western European countries.

    PARTICIPANTS: 1238 cases of incident CRC, which developed after enrolment into the cohort, were matched with 1238 controls for age, sex, centre, follow-up time, time of blood collection and fasting status.

    MAIN OUTCOME MEASURES: Serum concentrations were quantitatively determined by colorimetric and turbidimetric methods. Dietary and lifestyle data were obtained from questionnaires. Conditional logistic regression models were used to estimate incidence rate ratios (RRs) and 95% CIs which were adjusted for height, weight, smoking habits, physical activity, education, consumption of fruit, vegetables, meat, fish, alcohol, fibre and energy.

    RESULTS: After adjustments, the concentrations of HDL and apoA were inversely associated with the risk of colon cancer (RR for 1 SD increase of 16.6 mg/dl in HDL and 32.0 mg/dl in apoA of 0.78 (95% CI 0.68 to 0.89) and 0.82 (95% CI 0.72 to 0.94), respectively). No association was observed with the risk of rectal cancer. Additional adjustment for biomarkers of systemic inflammation, insulin resistance and oxidative stress or exclusion of the first 2 years of follow-up did not influence the association between HDL and risk of colon cancer.

    CONCLUSIONS: These findings show that high concentrations of serum HDL are associated with a decreased risk of colon cancer. The mechanism behind this association needs further elucidation.

  • 110. van Duijnhoven, Fränzel J B
    et al.
    Bueno-De-Mesquita, H Bas
    Ferrari, Pietro
    Jenab, Mazda
    Boshuizen, Hendriek C
    Ros, Martine M
    Casagrande, Corinne
    Tjønneland, Anne
    Olsen, Anja
    Overvad, Kim
    Thorlacius-Ussing, Ole
    Clavel-Chapelon, Françoise
    Boutron-Ruault, Marie-Christine
    Morois, Sophie
    Kaaks, Rudolf
    Linseisen, Jakob
    Boeing, Heiner
    Nöthlings, Ute
    Trichopoulou, Antonia
    Trichopoulos, Dimitrios
    Misirli, Gesthimani
    Palli, Domenico
    Sieri, Sabina
    Panico, Salvatore
    Tumino, Rosario
    Vineis, Paolo
    Peeters, Petra Hm
    van Gils, Carla H
    Ocké, Marga C
    Lund, Eiliv
    Engeset, Dagrun
    Skeie, Guri
    Suárez, Laudina Rodríguez
    González, Carlos A
    Sánchez, María-José
    Dorronsoro, Miren
    Navarro, Carmen
    Barricarte, Aurelio
    Berglund, Göran
    Manjer, Jonas
    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.
    Bingham, Sheila A
    Khaw, Kay-Tee
    Key, Timothy J
    Allen, Naomi E
    Boffetta, Paolo
    Slimani, Nadia
    Rinaldi, Sabina
    Gallo, Valentina
    Norat, Teresa
    Riboli, Elio
    Fruit, vegetables, and colorectal cancer risk: the European Prospective Investigation into Cancer and Nutrition2009In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 89, no 5, p. 1441-1452Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A high consumption of fruit and vegetables is possibly associated with a decreased risk of colorectal cancer (CRC). However, the findings to date are inconsistent. OBJECTIVE: We examined the relation between self-reported usual consumption of fruit and vegetables and the incidence of CRC. DESIGN: In the European Prospective Investigation into Cancer and Nutrition (EPIC), 452,755 subjects (131,985 men and 320,770 women) completed a dietary questionnaire in 1992-2000 and were followed up for cancer incidence and mortality until 2006. A multivariate Cox proportional hazard model was used to estimate adjusted hazard ratios (HRs) and 95% CIs. RESULTS: After an average follow-up of 8.8 y, 2,819 incident CRC cases were reported. Consumption of fruit and vegetables was inversely associated with CRC in a comparison of the highest with the lowest EPIC-wide quintile of consumption (HR: 0.86; 95% CI: 0.75, 1.00; P for trend = 0.04), particularly with colon cancer risk (HR: 0.76; 95% CI: 0.63, 0.91; P for trend < 0.01). Only after exclusion of the first 2 y of follow-up were these findings corroborated by calibrated continuous analyses for a 100-g increase in consumption: HRs of 0.95 (95% CI: 0.91, 1.00; P = 0.04) and 0.94 (95% CI: 0.89, 0.99; P = 0.02), respectively. The association between fruit and vegetable consumption and CRC risk was inverse in never and former smokers, but positive in current smokers. This modifying effect was found for fruit and vegetables combined and for vegetables alone (P for interaction < 0.01 for both). CONCLUSIONS: These findings suggest that a high consumption of fruit and vegetables is associated with a reduced risk of CRC, especially of colon cancer. This effect may depend on smoking status.

  • 111.
    Van Guelpen, Bethany
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Eklöf, Vincy
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology.
    Henriksson, Maria L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Cullman, Inger
    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.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    One-carbon metabolism and CpG island methylator phenotype status in incident colorectal cancer: a nested case-referent study2010In: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 21, no 4, p. 557-566Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: We related prediagnostic plasma folate, vitamin B12, and total homocysteine concentrations, and the MTHFR 677C>T and 1298A>C polymorphisms, to the risk of colorectal cancer with and without the CpG island methylator phenotype (CIMP).

    METHODS: This was a nested case-referent study of 190 cases and double, matched referents from the large, population-based Northern Sweden Health and Disease Study. Using archival tumor tissue, promoter methylation in an eight-gene panel was analyzed by MethyLight.

    RESULTS: A reduced risk of CIMP-low/CIMP-high CRC (>/=1 gene methylated) was observed in subjects with very low plasma folate concentrations [multivariate odds ratio 2.96 (95% CI 1.24-7.08) for quintiles two to five versus one (lowest)]. With the exception of a reduced risk in MTHFR 677 TT-homozygotes, none of the other one-carbon variables were associated with the risk of CIMP-low/CIMP-high CRC. For CIMP-negative CRC, only the MTHFR polymorphisms were statistically significantly related to risk, inversely for 677C>T and positively for 1298A>C, but a tendency toward a reduced risk was observed in subjects with an adequate methyl availability, combining the plasma variables [multivariate odds ratio 0.61 (95% CI 0.32-1.15)].

    CONCLUSION: Though limited by low power, these findings suggest the possibility of different roles for one-carbon metabolism in different pathways of colorectal tumorigenesis.

  • 112.
    Van Guelpen, Bethany
    et al.
    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.
    Stenling, Roger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Riboli, E
    Winkvist, A
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Low folate levels may protect against colorectal cancer2006In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 55, no 10, p. 1461-1466Article in journal (Other academic)
    Abstract [en]

    BACKGROUND AND AIMS: Dietary folate is believed to protect against colorectal cancer (CRC). However, few studies have addressed the role of circulating levels of folate. The aim of this study was to relate prediagnostic plasma folate and homocysteine concentrations and the methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C polymorphisms to the risk of developing CRC.

    SUBJECTS: Subjects were 226 cases and 437 matched referents from the population based Northern Sweden Health and Disease Cohort.

    RESULTS: We observed a bell-shaped association between plasma folate concentrations and CRC risk; multivariate odds ratio for middle versus lowest quintile 2.00 (95% confidence interval (CI) 1.13-3.56). In subjects with follow up times greater than the median of 4.2 years however, plasma folate concentrations were strongly positively related to CRC risk; multivariate odds ratio for highest versus lowest quintile 3.87 (95% CI 1.52-9.87; p trend = 0.007). Homocysteine was not associated with CRC risk. Multivariate odds ratios for the MTHFR polymorphisms were, for 677 TT versus CC, 0.41 (95% CI 0.19-0.85; p trend = 0.062), and for 1298 CC versus AA, 1.62 (95% CI 0.94-2.81; p trend = 0.028). Interaction analysis suggested that the result for 1298A>C may have been largely due to linkage disequilibrium with 677C>T. The reduced CRC risk in 677 TT homozygotes was independent of plasma folate status.

    CONCLUSIONS: Our findings suggest a decreased CRC risk in subjects with low folate status. This possibility of a detrimental component to the role of folate in carcinogenesis could have implications in the ongoing debate in Europe concerning mandatory folate fortification of foods.

  • 113.
    Van Guelpen, Bethany
    et al.
    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.
    Stegmayr, Birgitta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Nilsson, Torbjörn K
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
    Witthoft, Cornelia
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Winkvist, Anna
    Folate, vitamin B12, and risk of ischemic and hemorrhagic stroke: a prospective, nested case-referent study of plasma concentrations and dietary intake.2005In: Stroke, ISSN 0039-2499, E-ISSN 1524-4628, Vol. 36, no 7, p. 1426-1431Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND PURPOSE: Folate metabolism has been implicated in stroke. However, the possibility of a role for folate and vitamin B12, independent of their effects on homocysteine status, remains to be explored. The aim of this prospective, nested case-referent study was to relate plasma and dietary intake levels of folate and vitamin B12 to risk of stroke, taking into consideration plasma homocysteine concentrations and methylenetetrahydrofolate reductase polymorphisms. METHODS: Subjects were 334 ischemic and 62 hemorrhagic stroke cases and matched double referents from the population-based Northern Sweden Health and Disease Cohort. RESULTS: Plasma folate was statistically significantly associated with risk of hemorrhagic stroke in an inverse linear manner, both in univariate analysis and after adjustment for conventional risk factors including hypertension (odds ratio [OR] for highest versus lowest quartile 0.21 (95% confidence interval [CI], 0.06 to 0.71; P for trend=0.008)). Risk estimates were attenuated by inclusion of homocysteine in the model (OR, 0.34; 95% CI, 0.08 to 1.40; P for trend=0.088). A similar pattern was observed for increasing folate intake (multivariate OR, 0.07; 95% CI, 0.01 to 0.55; P for trend=0.031 without homocysteine, and OR, 0.16, 95% CI, 0.02 to 1.23; P for trend=0.118 with homocysteine in the analysis). We found little evidence of an association between plasma or dietary folate and risk of ischemic stroke. Neither plasma nor dietary vitamin B12 was associated with risk of either stroke subtype. CONCLUSIONS: The results of this study suggest a protective role for folate, possibly in addition to its effects on homocysteine status, in hemorrhagic but not ischemic stroke.

  • 114.
    Van Guelpen, Bethany
    et al.
    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.
    Witthöft, C
    Weinehall, Lars
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Epidemiology and Public Health Sciences.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    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.
    Jansson, Jan-Håkan
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Winkvist, A
    Plasma folate and total homocysteine levels are associated with the risk of myocardial infarction, independently of each other and of renal function2009In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 266, no 2, p. 182-195Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To investigate the relationship between plasma folate, vitamin B12 and total homocysteine concentrations, dietary intake of folate and vitamins B12, B6 and B2, and the risk of first acute myocardial infarction (MI). DESIGN: Nested case-referent study with up to 13 years of follow-up. SETTING: The population-based Northern Sweden Health and Disease Study, with 73 879 participants at the time of case ascertainment. SUBJECTS: A total of 571 MI cases (406 men) and 1569 matched referents. Of the cases, 530 had plasma samples available, and 247 had dietary B-vitamin intake data. RESULTS: Plasma concentrations of folate were inversely associated, and total homocysteine positively associated, with the risk of MI, independently of each other and of a number of established and novel cardiovascular risk factors, including renal function [multivariate odds ratio for highest vs. lowest quintile of folate 0.52 (95% CI 0.31-0.84), P for trend = 0.036, and homocysteine 1.92 (95% CI 1.20-3.09), P for trend = 0.006]. For plasma vitamin B12 concentrations, and vitamin B12, B6 and B2 intake, no clear risk relationship was apparent. Though not statistically significant, the results for folate intake were consistent with those for plasma concentrations. CONCLUSIONS: In this large prospective study of a population without mandatory folic acid fortification, both folate and homocysteine were strongly associated with the risk of myocardial infarction, independently of each other and of renal function. Although randomized trials of folic acid supplementation are needed to determine causality, our findings highlight the potential importance of folate, or sources of folate, in incident cardiovascular disease.

  • 115.
    Wassermann, Stella
    et al.
    Pathologisch-Anatomisches Institut der Universität Erlangen-Nürnberg, Erlangen, Germany.
    Scheel, Silvio K
    Pathologisches Institut der Universität München, Munich, Germany.
    Hiendlmeyer, Elke
    Pathologisch-Anatomisches Institut der Universität Erlangen-Nürnberg, Erlangen, Germany.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Horst, David
    Pathologisches Institut der Universität München, Munich, Germany.
    Hlubek, Falk
    Pathologisches Institut der Universität München, Munich, Germany.
    Haynl, Angela
    Pathologisches Institut der Universität München, Munich, Germany.
    Kriegl, Lydia
    Pathologisches Institut der Universität München, Munich, Germany.
    Reu, Simone
    Pathologisches Institut der Universität München, Munich, Germany.
    Merkel, Susanne
    Chirurgische Kliniken der Universität Erlangen-Nürnberg, Erlangen, Germany.
    Brabletz, Thomas
    Universitätsklinikum Freiburg, Chirurgische Universitätsklinik, Freiburg, Germany.
    Kirchner, Thomas
    Pathologisches Institut der Universität München, Munich, Germany.
    Jung, Andreas
    Pathologisches Institut der Universität München, Munich, Germany.
    p16INK4a is a beta-catenin target gene and indicates low survival in human colorectal tumors2009In: Gastroenterology, ISSN 0016-5085, E-ISSN 1528-0012, Vol. 136, no 1, p. 196-205.e2Article in journal (Refereed)
    Abstract [en]

    BACKGROUND & AIMS: Human colorectal carcinomas display an infiltrative front of invasion where tumor cells undergo an epithelomesenchymal transition associated with low survival. Epithelomesenchymal transition is regulated by a nuclear beta-catenin accumulation, and subsequently, activation of beta-catenin/TCF4 target genes similar to CYCLIN D(1). Unexpectedly, these tumor cells are characterized by low proliferation, which correlates with the expression of the cell cycle inhibitor p16(INK4A). Therefore, we investigated the molecular mechanism of the transcriptional regulation of p16(INK4A) in colorectal cancer and its correlation with survival. METHODS: Molecular biological techniques were used for investigating the transcriptional mechanisms of the p16(INK4A) gene regulation. Moreover, p16(INK4A) expression was correlated with the 10-year survival of patients with colorectal carcinomas. RESULTS: In colorectal carcinomas, expression of the p16(INK4A) gene is regulated by beta-catenin/TCF4 and correlates with low survival rates of patients with tumors displaying an infiltrative front of invasion. CONCLUSIONS: beta-catenin/TCF4 regulates cell cycle promoting (c-MYC, CYCLIN D(1)) and inhibiting genes (p16(INK4A)) at the same time in the mesenchymally differentiated tumor cells at the front of invasion. The function of p16(INK4A) seems to supersede in this context thus leading to low proliferation. Moreover, these tumor cells seem to govern the outcome of colorectal cancer independently of their proliferation.

  • 116.
    Wikberg, 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.
    Lundberg, Ida V.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Dahlin, Anna M.
    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.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High intratumoral expression of fibroblast activation protein (FAP) in colon cancer is associated with poorer patient prognosis.2013In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 34, no 2, p. 1013-1020Article in journal (Refereed)
    Abstract [en]

    -An active stroma is important for cancer cell invasion and metastasis. We investigated the expression of fibroblast activation protein (FAP) in relation to patient prognosis in colorectal cancer. Colorectal cancer specimens from 449 patients were immunohistochemically stained with a FAP antibody and evaluated in the tumor center and tumor front using a semiquantitative four-level scale. FAP was expressed by fibroblasts in 85-90 % of the tumors examined. High versus no/low expression in the tumor center was associated with poor prognosis (multivariate hazard ratio, HR = 1.72; 95 % CI 1.07-2.77, p = 0.025). FAP expression in the tumor front, though more frequent than in the tumor center, was not associated with prognosis. FAP expression in the tumor center was more common in specimens with positive microsatellite instability (MSI) screening status and in patients with high CpG island methylator phenotype (CIMP) status. However, inclusion of MSI screening status and CIMP status in the multivariate analysis strengthened the risk estimates for high FAP expression in the tumor center (HR = 1.89; 95 % CI 1.13-3.14; p = 0.014), emphasizing the role of FAP as an independent prognostic factor. Stromal FAP expression is common in colorectal cancer, and we conclude that high FAP expression in the tumor center, but not the tumor front, is an independent negative prognostic factor.

  • 117.
    Wikberg, Maria L.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ling, Agnes
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Li, Xingru
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Öberg, Åke
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Edin, Sofia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Neutrophil infiltration is a favorable prognostic factor in early stages of colon cancer2017In: Human Pathology, ISSN 0046-8177, E-ISSN 1532-8392, Vol. 68, p. 193-202Article in journal (Refereed)
    Abstract [en]

    The tumor immune response has been proven critical to prognosis in colorectal cancer (CRC), but studies on the prognostic role of neutrophil infiltration have shown contradictory results. The aim of this study was to elucidate the prognostic role of infiltrating neutrophils at different intratumoral subsites and in different molecular subgroups of CRC. The relations between neutrophil infiltration and infiltration of other immune cells (T-cell and macrophage subsets) were also addressed. Expression of the neutrophil marker CD66b was assessed by immunohistochemistry in 448 archival human tumor tissue samples from patients surgically resected for CRC. The infiltration of CD66b-positive cells was semi-quantitatively evaluated along the tumor invasive front, in the tumor center, and within the tumor epithelium (intraepithelial expression). We found that poor infiltration of CD66b-positive cells in the tumor front indicated a worse patient prognosis. The prognostic significance of CD66b infiltration was found to be mainly independent of tumor molecular characteristics and maintained significance in multivariable analysis of stage I-II colon cancers. We further analyzed the prognostic impact of CD66b-positive cells in relation to other immune markers (NOS2, CD163, Tbet, FOXP3, and CD8) and found that neutrophil infiltration, even though strongly correlated to infiltration of other immune cell subsets, had additional prognostic value. In conclusion, we find that low infiltration of neutrophils in the tumor front is an independent prognostic factor for a poorer patient prognosis in early stages of colon cancers. Further studies are needed to elucidate the biological role of neutrophils in colorectal carcinogenesis.

  • 118.
    Wikberg, Maria L.
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Myte, Robin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    van Guelpen, Bethany
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Ljuslinder, Ingrid
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Plasma miRNA can detect colorectal cancer, but how early?2018In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 7, no 5, p. 1697-1705Article in journal (Refereed)
    Abstract [en]

    Colorectal cancer (CRC) is a major cause of deaths worldwide but has a good prognosis if detected early. The need for efficient, preferable non‐ or minimally invasive, inexpensive screening tools is therefore critical. We analyzed 12 miRNAs in pre‐ and postdiagnostic plasma samples to evaluate their potential as CRC screening markers. We used a unique study design with two overlapping cohorts, allowing analysis of pre‐ and postdiagnostic samples from 58 patients with CRC and matched healthy controls. Plasma concentrations of miR‐15b, ‐16, ‐18a, ‐19a, 21, ‐22, ‐25, ‐26a, ‐29c, ‐142‐5p, ‐150, and ‐192 were measured by semi‐quantitative real‐time PCR. Concentrations of miR‐18a, ‐21, ‐22, and ‐25 in plasma from patients with CRC were significantly altered compared to healthy controls. Combined as a multimarker panel, they detected CRC with an AUC of 0.93. Furthermore, levels of these three miRNAs also showed different levels in the prediagnostic case samples close to diagnosis. Only miR‐21‐levels were elevated several years before diagnosis. Plasma levels of miR‐18a, ‐21, ‐22, and ‐25 show promise as screening biomarkers for CRC. However, based on our unique analysis of prediagnostic and postdiagnostic samples from the same patients, we conclude that circulating miRNAs elevated at diagnosis may not automatically be suitable for CRC screening, if the increase occurs too close to clinical diagnosis.

  • 119. Wilkening, Stefan
    et al.
    Tavelin, Björn
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Canzian, Federico
    Enquist, Kerstin
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Altieri, Andrea
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hemminki, Kari
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Försti, Asta
    Interleukin promoter polymorphisms and prognosis in colorectal cancer.2008In: Carcinogenesis, ISSN 1460-2180, Vol. 29, no 6, p. 1202-1206Article in journal (Refereed)
    Abstract [en]

    There is strong evidence that cancer-associated inflammation promotes tumor growth and progression. This is especially true for colorectal cancer (CRC). Interleukins (ILs) are important modulators for inflammation. We examined whether promoter polymorphisms in key IL genes (IL4, IL4R, IL6, IL8 and IL10) are associated with the risk or clinical outcome of CRC. Five single-nucleotide polymorphisms (SNPs) were analyzed in genomic DNA from a cohort including 308 Swedish incident cases of CRC with data on Dukes' stage and up to 16 years of follow-up and 585 healthy controls. The selected SNPs have previously been shown to be functional and/or associated with cancer. None of the analyzed SNPs associated with the risk of CRC. When stratifying by tumor stage, significantly more patients carrying at least one G allele of IL10-1082 had tumors with Dukes' stages A + B than with stages C + D (P(trend) = 0.035 for genotype distribution). Analyzing associations with overall survival time, we found the rare T allele of IL4-590 to be related to a longer survival [CT versus CC Cox proportional hazard ratio 0.69, 95% confidence intervals 0.46-1.03, TT versus CC 0.32 (0.10-1.03)]. For IL6-174, the CG genotype was associated with a longer survival when compared with the CC genotype [0.64 (0.40-1.01)]. The present study was particularly suitable for survival analysis because all patients were sampled before the diagnosis of CRC. Our results suggest that the SNPs IL4-590 and IL6-174 may be useful markers for CRC prognosis. The predicted biological effect of these SNPs in relation to promotion of cancer progression is consistent with the observed increased survival time.

  • 120.
    Winbo, Annika
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Sandström, Olof
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Palmqvist, Richard
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rydberg, Annika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Iron-deficiency anaemia, gastric hyperplasia, and elevated gastrin levels due to potassium channel dysfunction in the Jervell and Lange-Nielsen Syndrome2013In: Cardiology in the Young, ISSN 1047-9511, E-ISSN 1467-1107, Vol. 23, no 3, p. 325-334Article in journal (Refereed)
    Abstract [en]

    Aim We investigated extra-cardiac clinical symptoms and signs in the rare Jervell and Lange-Nielsen Syndrome, characterised by impaired KCNQ1 function, a gene essential for gastric acid secretion. METHODS: All Swedish Jervell and Lange-Nielsen cases with double KCNQ1 mutations (14 cases) were investigated by medical record review, an interview, and were offered laboratory testing for iron-deficiency anaemia and gastrointestinal markers. RESULTS: A history of iron-deficiency anaemia in 12 of 14 patients and subjective gastrointestinal symptoms in 13 of 14 patients was revealed. Previous endoscopy in five cases had revealed no case of coeliac or inflammatory bowel disease but three cases of mucosal hyperplasia/dysplasia. Current signs of anaemia or iron substitution were present in 9 of 12 tested cases. Elevated levels of gastrin in seven of nine cases, pepsinogen in six of seven cases, and faecal calprotectin in nine of nine cases were present. A significant correlation between elevated gastrin levels and concurrent iron-deficiency and/or anaemia was revealed (p-value 0.039). CONCLUSIONS: A high frequency of extra-cardiac clinical symptoms and previous medical investigations was found. We propose that the Jervell and Lange-Nielsen Syndrome phenotypically includes gastrointestinal symptoms/signs and secondary iron-deficiency anaemia owing to hypochlorhydria on the basis of KCNQ1 mutations. The resultant elevated gastrin level is a potential risk factor for later gastrointestinal cancer. Clinical monitoring with regard to developing anaemia and hypergastrinaemia should be considered in the Jervell and Lange-Nielsen Syndrome.

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