| 11. |
- Eklöf, Vincy, 1984-, et al.
(författare)
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The Combined Value of Faecal Haemoglobin andCalprotectin in Diagnosis of Colorectal Cancer inSymptomatic Patients Referred to Colonoscopy
- 2019
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Ingår i: Academic Journal of Gastroenterology & Hepatology (AJGH). - San Fransisco : Iris Publishers. ; 1:3, s. 1-7
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Aim: To investigate the diagnostic value of a combined analyses of faecal immunological haemoglobin (FIT) and faecal calprotectin (FC) in detection of colorectal cancer (CRC).Methods: Out-patients (n=1440) referred to the endoscopy unit were analysed for FIT and FC in stool samples collected before the colonoscopy bowel preparation. The samples were collected from one defecation by the patients at home. Patients with IBD were excluded leaving stool samples from 1133 patients for further analyses. FIT was analysed using the immunological Analyse F.O.B Test and FC was analysed using the CALPRO® Calprotectin Elisa Test. Sensitivity and specificity to detect CRC was calculated for the individual tests, as well as for combined FIT/FC tests.Results: Out of the included patients, 38 were diagnosed with CRC, 9 with high grade dysplasia (HGD), and 133 with low grade dysplasia (LGD). FIT was analysed in 673 (59.4%), FC in 1021 (90.1%) and both FIT and FC in 561 (49.5%) patients. A ROC curve analysis showed that the most accurate cut-off level for FC in detecting CRC in our study was 105.5 µg/g. The sensitivity for CRC when using FIT, FC (cut-off > 100 µg/g) and the combination of FIT and FC (at least one positive test) was 65.5%, 74.1% and 94.4%, respectively. The corresponding specificity was 84.8%, 74.9% and 68.3%, respectively.Conclusion: Combined analyses of FIT and FC improved sensitivity for detection of CRC. Further studies in larger cohorts are required to find the optimal cut-off levels for different combinations of tests.
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| 12. |
- Fransén-Pettersson, Nina, et al.
(författare)
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A New Mouse Model That Spontaneously Develops Chronic Liver Inflammation and Fibrosis
- 2016
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Here we characterize a new animal model that spontaneously develops chronic inflammation and fibrosis in multiple organs, the non-obese diabetic inflammation and fibrosis (N-IF) mouse. In the liver, the N-IF mouse displays inflammation and fibrosis particularly evident around portal tracts and central veins and accompanied with evidence of abnormal intrahepatic bile ducts. The extensive cellular infiltration consists mainly of macrophages, granulocytes, particularly eosinophils, and mast cells. This inflammatory syndrome is mediated by a transgenic population of natural killer T cells (NKT) induced in an immunodeficient NOD genetic background. The disease is transferrable to immunodeficient recipients, while polyclonal T cells from unaffected syngeneic donors can inhibit the disease phenotype. Because of the fibrotic component, early on-set, spontaneous nature and reproducibility, this novel mouse model provides a unique tool to gain further insight into the underlying mechanisms mediating transformation of chronic inflammation into fibrosis and to evaluate intervention protocols for treating conditions of fibrotic disorders.
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| 13. |
- Gkekas, Ioannis, et al.
(författare)
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Deficient mismatch repair as a prognostic marker in stage II colon cancer patients
- 2019
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Ingår i: European Journal of Surgical Oncology. - : Elsevier. - 0748-7983 .- 1532-2157. ; 45:10, s. 1854-1861
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A number of reports have evaluated the relationship between deficient DNA mismatch repair (dMMR) and colorectal cancer prognosis. Unfortunately, the exact prognostic role of dMMR has not been clearly established due to contradictory results. This study aims to determine the prognostic impact of dMRR in stage II colon cancer patients only. The appropriate identification of high-risk stage II colon cancers is of paramount importance in the selection of patients who may benefit from adjuvant treatment after surgery.METHODS: Four hundred and fifty-two patients with curative resection of stage II colon cancer were included. Hospital records were used as data source, providing clinical, surgical, pathology, oncology and follow-up information for statistical analysis focusing on overall survival (OS) and time to progression (TTP). Mismatch repair status was determined by immunohistochemistry. Patient survival was followed-up for a mean of 77·35 months.RESULTS: dMMR was detected in 93 of 452 patients (20·6%). No impact on overall survival (Log-Rank, p = 0·583, 95% CI 0·76-1·67). However, the hazard ratio 0·50 for TTP was highly significant (Log-Rank, p = 0·012, 95% CI 0·28-0·87) in patients with dMMR compared with those with mismatch repair proficient tumours (pMMR).CONCLUSIONS: Patients with dMMR tumours have a lower risk for recurrence compared to those with pMMR tumours, but this finding did not correlate to better overall survival.
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| 14. |
- Gkekas, Ioannis, et al.
(författare)
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Microsatellite instability as a prognostic factor in stage II colon cancer patients : a meta-analysis of published literature
- 2017
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Ingår i: Anticancer Research. - : Anticancer Research USA Inc.. - 0250-7005 .- 1791-7530. ; 37:12, s. 6563-6574
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Forskningsöversikt (refereegranskat)abstract
- BACKGROUND/AIM: The prognostic role of microsatellite instability (MSI) in stage II colon cancer patients remains controversial despite the fact that it has been investigated in a number of studies. Hazard ratios differ considerably among these studies. We performed a meta-analysis to define the significance of MSI in this group of patients.MATERIALS AND METHODS: Studies indexed in PubMed presenting separate data on MSI status and survival outcomes for stage II colon cancer patients have been analyzed using fixed-effect meta-analysis of hazard ratio (HR) according to the method of Peto.RESULTS: Analysis was performed on 19 studies including 5,998 patients. A 47.3% of patients received postoperative chemotherapy and included 52.8% males and 47.2% females. Eight studies included some rectal cancer patients although this cohort was not clearly defined in 3 of these. MSI observed in 20.8% (mean) of patients (median 19.9%). HR for overall survival (OS) of MSI vs. microsatellite stable (MSS) tumors for the entire population: 0.73 (95% confidence interval (CI)=0.33-1.65); HR for disease-free survival (DFS):0.60 (95%CI=0.27-1.32). No statistical significant difference was found when studies analyzing MSI with genotyping (MG) and immunohistochemistry (IHC) were compared separately (MG vs. IHC: HR OS 0.45, 95%CI=0.10-2.05 vs. 0.95, 95%CI=0.57-1.58; HR DFS 0.51, 95%CI=0.14-1.85 vs. 0.67, 95%CI=0.26-1.70). However, numerically MSI determination with genotyping shows significantly lower hazard ratios for both DFS and OS. Separate analysis of studies describing colon cancer patients only showed HR OS 0.72 (95%CI=0.31-1.71); HR DFS 0.60 (95%CI=0.27-1.31).CONCLUSION: No significant relation was found between MSI status and OS or DFS. Routine determination of MSI status to guide postoperative management of stage II colon cancer patients cannot be recommended. New large scale high quality studies are needed to answer this question definitively, since currently analyzed studies vary considerably.
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| 15. |
- Gylling, Björn, 1978-
(författare)
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Biomarkers of one-carbon metabolism in colorectal cancer risk
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- One-carbon metabolism, a network of enzymatic reactions involving the transfer of methyl groups, depends on B-vitamins as cofactors, folate as a methyl group carrier, and amino acids, betaine, and choline as methyl group donors. One-carbon metabolism influences many processes in cancer initiation and development such as DNA synthesis, genome stability, and histone and epigenetic methylation. To study markers of one-carbon metabolism and inflammation in relation to colorectal cancer (CRC) risk, we used prediagnostic plasma samples from over 600 case participants and 1200 matched control participants in the population-based Northern Sweden Health and Disease Study cohort.This thesis studies CRC risk with respect to the following metabolites measured in pre-diagnostic plasma samples: 1) folate, vitamin B12, and homocysteine; 2) components of one-carbon metabolism (choline, betaine, dimethylglycine, sarcosine, and methionine); and 3) three markers of different aspects of vitamin B6 status. In addition, this thesis examines three homocysteine ratios as determinants of total B-vitamin status and their relation to CRC risk.In two previous studies, we observed an association between low plasma concentrations of folate and a lower CRC risk, but we found no significant association between plasma concentrations of homocysteine and vitamin B12 with CRC risk. We have replicated these results in a study with a larger sample size and found that low folate can inhibit the growth of established pre-cancerous lesions.Using the full study cohort of over 1800 participants, we found inverse associations between plasma concentrations of the methionine cycle metabolites betaine and methionine and CRC risk. This risk was especially low for participants with the combination of low folate and high methionine versus the combination of low folate and low methionine. Well-functioning methionine cycle lowers risk, while impaired DNA synthesis partly explains the previous results for folate.We used the full study cohort to study associations between CRC risk and the most common marker of vitamin B6 status, pyridoxal' 5-phosphate (PLP), and two metabolite ratios, PAr (4-pyridoxic acid/(PLP + pyridoxal)) estimating vitamin B6 related inflammatory processes and the functional vitamin B6 marker 3-hydroxykynurenine to xanthurenic acid (HK:XA). Increased vitamin B6-related inflammation and vitamin B6 deficiency increase CRC risk. Inflammation was not observed to initiate tumorigenesis.Total B-vitamin status can be estimated by three different recently introduced homocysteine ratios. We used the full study cohort to relate the ratios as determinants of the total B-vitamin score in case and control participants and estimated the CRC risk for each marker. Sufficient B-vitamin status as estimated with homocysteine ratios was associated with a lower CRC risk.These studies provide a deeper biochemical knowledge of the complexities inherent in the relationship between one-carbon metabolism and colorectal tumorigenesis.
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| 16. |
- Gylling, Björn, 1978-, et al.
(författare)
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One-carbon metabolite ratios as functional B-vitamin markers and in relation to colorectal cancer risk
- 2019
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 144:5, s. 947-956
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Tidskriftsartikel (refereegranskat)abstract
- Background: One-carbon metabolism biomarker are easily measured in plasma, but analyzing them one at a time in relation to disease does not take into account the interdependence of the many factors involved. The relative dynamics of major one-carbon metabolism branches can be assessed by relating the functional B-vitamin marker total homocysteine (tHcy) to transsulfuration (total cysteine) and methylation (creatinine) outputs.Objective: We validated the ratios of tHcy to total cysteine (Hcy:Cys), tHcy to creatinine (Hcy:Cre), and tHcy to cysteine to creatinine (Hcy:Cys:Cre) as functional markers of B-vitamin status. We also calculated the associations of these ratios to colorectal cancer (CRC) risk.Design: The relative contribution of potential confounders to the variance of the ratio-based B-vitamin markers was calculated by linear regression in a nested case-control study of 613 CRC cases and 1211 matched controls. Total B-vitamin status was represented by a summary score comprising Z-standardized plasma concentrations of folate, cobalamin, betaine, pyridoxal 5´-phosphate, and riboflavin. Associations with CRC risk were estimated using conditional logistic regression.Results: The ratio-based B-vitamin markers all outperformed tHcy as markers of total B-vitamin status, in both CRC cases and controls. Associations with CRC risk were similar for the ratio-based B-vitamin markers and total B-vitamin status (approximately 25% lower risk for high versus low B-vitamin status).Conclusions: Ratio-based B-vitamin markers were good predictors of total B-vitamin status, and displayed similar associations with CRC risk. Since tHcy and creatinine are routinely clinically analyzed, Hcy:Cre could be easily implemented in clinical practice to aid interpretation of tHcy results.
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| 17. |
- Gylling, Björn, et al.
(författare)
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Vitamin B-6 and colorectal cancer risk : a prospective population-based study using 3 distinct plasma markers of vitamin B-6 status
- 2017
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier BV. - 0002-9165 .- 1938-3207. ; 105:4, s. 897-904
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Tidskriftsartikel (refereegranskat)abstract
- Background: Higher plasma concentrations of the vitamin B-6 marker pyridoxal 5#-phosphate (PLP) have been associated with reduced colorectal cancer (CRC) risk. Inflammatory processes, including vitamin B-6 catabolism, could explain such findings. Objective: We investigated 3 biomarkers of vitamin B-6 status in relation to CRC risk. Design: This was a prospective case-control study of 613 CRC cases and 1190 matched controls nested within the Northern Sweden Health and Disease Study (n = 114,679). Participants were followed from 1985 to 2009, and the median follow-up from baseline to CRC diagnosis was 8.2 y. PLP, pyridoxal, pyridoxic acid (PA), 3-hydroxykynurenine, and xanthurenic acids (XAs) were measured in plasma with the use of liquid chromatography-tandem mass spectrometry. We calculated relative and absolute risks of CRC for PLP and the ratios 3-hydroxykynurenine: XA (HK: XA), an inverse marker of functional vitamin B-6 status, and PA:(PLP + pyridoxal) (PAr), a marker of inflammation and oxidative stress and an inverse marker of vitamin B-6 status. Results: Plasma PLP concentrations were associated with a reduced CRC risk for the third compared with the first quartile and for PLP sufficiency compared with deficiency [OR: 0.60 (95% CI: 0.44, 0.81) and OR: 0.55 (95% CI: 0.37, 0.81), respectively]. HK: XA and PAr were both associated with increased CRC risk [OR: 1.48 (95% CI: 1.08, 2.02) and OR: 1.50 (95% CI: 1.10, 2.04), respectively] for the fourth compared with the first quartile. For HK: XA and PAr, the findings were mainly observed in study participants with,10.5 y of follow-up between sampling and diagnosis. Conclusions: Vitamin B-6 deficiency as measured by plasma PLP is associated with a clear increase in CRC risk. Furthermore, our analyses of novel markers of functional vitamin B-6 status and vitamin B-6-associated oxidative stress and inflammation suggest a role in tumor progression rather than initiation.
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| 18. |
- Karling, Pontus, et al.
(författare)
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Improved monitoring of inflammatory activity in patients with ulcerative colitis by combination of faecal tests for haemoglobin and calprotectin
- 2019
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Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Taylor & Francis. - 0036-5513 .- 1502-7686. ; 79:5, s. 341-346
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Tidskriftsartikel (refereegranskat)abstract
- Faecal calprotectin (FC) tests and faecal immunological tests (FIT) for haemoglobin have been used to monitor disease activity in patients with ulcerative colitis (UC) but used alone they have some limitation concerning the predictive ability. We aimed to test if an FC test used in combination with FIT could improve the predictive ability. Consecutive out-patients with UC (n = 93) who were admitted for colonoscopy completed a single faecal sample before the start of bowel preparation. A quantitative CALPRO (R) calprotectin ELISA test and a qualitative FIT (cut-off < 40 ng/mL) were analyzed. An estimated Mayo score and a score of histological inflammation was performed blinded to the result of the faecal tests. The sensitivity, specificity, negative predictive value and positive predictive value for endoscopic inflammation (Mayo score > 1) was for FIT 85%, 83%, 96%, 57% and for FC > 186 mu g/g 73%, 87%, 87%, 54%. Corresponding results for FIT*FC > 186 mu g/g (at least one test positive) were 92%, 69%, 97%, 43%. For detecting moderate/severe histological inflammation the results were for FIT 69%, 79%, 92%, 43%, for FC > 75 mu g/g 95%, 62%, 98%, 41%, and for FIT*FC > 75 mu g/g 100%, 60%, 100%, 36%. None of the markers alone or in combination were useful to predict deep remission (Mayo score = 0 and no histological inflammation). We conclude that using the combination of an FC test and FIT shows minor improvement in predictive ability for inflammatory activity and remission in patients with UC.
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| 19. |
- Ling, Agnes, 1976-
(författare)
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Immune cell infiltration and prognosis in colorectal cancer
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Colorectal cancer (CRC) is globally the second most common form of cancer among women, and third in men. It is also one of the most common causes of cancer-related death in high-income countries. Surgical resection is the basis for curative therapy but still almost half of the patients die from metastatic disease. It is therefore imperative to strive on in the search for more efficient strategies to improve patient survival. The success scores for accurate prediction of patient prognosis remain discouraging and novel markers to identify high-risk patients are called for.The tumour immune response has proven critical to prognosis in CRC. A high amount of tumour infiltrating lymphocytes have in studies been found to significantly improve patient outcome. The opposite has been seen in patients with sparsely infiltrated tumours. Findings in this area have driven forth the design of the Immunoscore® system, which may be implemented in clinic as a complement to the TNM staging system. Ongoing research is also focusing on which immune evading mechanisms CRC might deploy in order to progress and metastasize.Aim: To study immune cell infiltration in relation to prognosis in CRC. More specifically the aim has been to investigate the prognostic importance of different subsets of immune cells infiltrating the tumour, not only according to quantity but also to intratumoural subsite (tumour invasive front, tumour centre and within the tumour epithelium). The tumour immune response was also evaluated in different molecular subgroups of CRC. Another part of this thesis concerns possible molecular mechanisms involved in tumour immune escape in CRC.Methods: CRC cases in the Colorectal Cancer in Umeå Study (CRUMS) were evaluated using immunohistochemistry, gene expression analyses as well as methylation analyses. Cytokine and chemokine expression was evaluated in CRC tumour tissues and one CRC cell line (Caco2) and derivatives using semi-quantitative real-time PCR. Methylation was analysed using methylation-specific pyrosequencing.Results: We found high quantities of both cytotoxic T cells (CTLs) as well as of regulatory T cells (Tregs) to associate with a better patient outcome. The infiltration of CTLs within the tumour epithelium provided the strongest prognostic information, whilst Tregs withheld the strongest association to prognosis at the tumour invasive front and tumour centre. We could further show that a high Th1 lymphocyte infiltration was strongly associated with a better prognosis in patients with CRC, independently of intratumoural subsite. Another finding was that the extent of Th1 infiltration and patient outcome differed in different molecular subgroups of CRC. We also found down-regulation of TAP1, a protein involved in antigen presentation by MHC class I, to be significantly associated with low infiltration of various subtypes of immune cells. Down-regulation of TAP1 was also correlated to poor prognosis in patients with early stages of CRC. Furthermore, we found TAP1 expression to be inversely correlated with methylation at sites close to the TAP1 promoter region.Conclusion: Tumour infiltrating T lymphocytes have a significant positive impact on prognosis in CRC patients. Different subsets of T lymphocytes vary in their dependency on intratumoural subsite, in to what extent they exert their prognostic influence. We moreover found varying Th1 lymphocyte infiltration rates as well as prognostic impact thereof, in different molecular subgroups of CRC. Our results also show down-regulation of TAP1 to be a mechanism of tumour immune escape in CRC. Further findings suggest methylation of the TAP1 gene to be a putative mechanism for TAP1 down-regulation.
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| 20. |
- Ling, Agnes, 1976-, et al.
(författare)
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TAP1 down-regulation elicits immune escape and poor prognosis in colorectal cancer
- 2017
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Ingår i: Oncoimmunology. - 2162-4011 .- 2162-402X. ; 6:11
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Tidskriftsartikel (refereegranskat)abstract
- The anti-tumor immune response has been shown to be of great prognostic importance in colorectal cancer (CRC) and so has the tumors ability for immune evasion. Our aim of this study was to investigate tumor factors that influence immunity. We used a gene expression array to search for potential mechanisms of tumor immune escape. One candidate gene identified was TAP1, involved in antigen presentation by MHC class I. TAP1 protein expression was evaluated by immunohistochemistry in 436 CRC patients of the Colorectal Cancer in Umeå Study cohort. We found a significant association between a downregulated expression of TAP1 and low infiltration of various subtypes of lymphocytes as well as macrophages. A downregulated expression of TAP1 was further found to be independent of molecular characteristics, suggesting TAP1 down-regulation to reach beyond the well described highly immunogenic MSI CRCs. A low expression of TAP1 was also significantly associated with poor prognosis in patients with CRC, a result that stayed significant in tumor front of early stage tumors (stage I-II) through multivariable analyses. Furthermore, we found that TAP1 expression was inversely correlated with methylation at sites in close proximity to the promoter region. In summary, our results show down-regulation of TAP1 to be a general mechanism of tumor immune escape in CRC and a poor prognostic factor in stage I-II CRC patients. We also suggest that methylation of the TAP1 gene may be a putative mechanism for TAP1 downregulation.
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