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Victoria H.-S.,Örebro University | Lennart B.,Örebro University | Lennart F.,Aleris Medilab
International Journal of Biomedical Science | Year: 2010

Tight junctions together with adherens junctions are important for preserving tissue integrity. In tumors the normal tissue structure is lost which results in a disorganization and change of phenotype. In this study we assessed the complexity of the invasive front of colon carcinoma using an objective morphometrical technique based on the estimation of fractal dimension and number of free tumor cell clusters. The complexity of the invasive front was correlated to Claudin 1 and Claudin 7 protein expression as well as genetic polymorphisms of their genes. Thirty-three colon carcinomas were used. Images from the invasive front of the tumors were captured and used to calculate a complexity index of the invasive front. The tight junction proteins Claudin 1 and Claudin 7 were stained immunohistochemically in the tumor and in the surrounding normal mucosa. Screening of their genes was performed using DNA sequencing. A significant aberration of protein expression was seen for both Claudin 1 and Claudin 7 compared to normal mucosa. Both homozygous and heterozygous polymorphisms in exon 2 of claudin 1 were found. In claudin 7 a homozygous polymorphism was seen in exon 4. All individuals with tumors that showed either of these polymorphisms also showed the same polymorphism in the adjacent normal mucosa. A significant correlation was found between polymorphisms in CLDN 7 and tumor differentiation p<0.02. However no correlations were found to Complexity Index, tumor size, localization or tumor stage (pT and pN). The results show that there is a perturbed expression of claudin 1 and claudin 7 proteins in colon tumors compared to normal mucosa. A high incidence of polymorphisms was found in normal tissue and tumors. It remains to be shown if these polymorphisms are coupled to the occurrence of colon carcinomas.


Klarskov L.,Copenhagen University | Ladelund S.,Copenhagen University | Holck S.,Copenhagen University | Roenlund K.,Vejle Hospital | And 7 more authors.
Human Pathology | Year: 2010

Immunohistochemical staining for mismatch repair proteins has during recent years been established as a routine analysis in many pathology laboratories with the aim to identify tumors linked to the hereditary nonpolyposis colorectal cancer syndrome. Despite widespread application, data on reliability are lacking. We therefore evaluated interobserver variability among 6 pathologists, 3 experienced gastrointestinal pathologists and 3 residents. In total, 225 immunohistochemically stained colorectal cancers were evaluated as having normal, weak, loss of, or nonevaluable mismatch repair protein staining. Full consensus was achieved in 51% of the stainings for MLH1, 61% for PMS2, 83% for MSH2, and 45% for MSH6. Weak stainings were the main cause of reduced consensus, whereas contradictory evaluations with normal as well as loss of staining were reported in 2% to 6% of the tumors. Interobserver variability was considerable, though experienced pathologists and residents reached the same level of consensus. Because results from immunohistochemical mismatch repair protein stainings are used for decisions on mutation analysis and as an aid in the interpretation of gene variants of unknown significance in hereditary nonpolyposis colorectal cancer, the interobserver variability identified highlights the need for quality assessment programs, including guidelines for classification of different expression patterns. © 2010 Elsevier Inc. All rights reserved.


Agren M.S.,Bispebjerg Hospital | Andersen T.L.,Nordic Bioscience A S | Andersen T.L.,Vejle Hospital | Andersen L.,Bispebjerg Hospital | And 11 more authors.
International Journal of Colorectal Disease | Year: 2011

Background: Increased matrix metalloproteinase (MMP) activity has been implicated in the pathogenesis of colorectal anastomotic leakage. Tumor necrosis factor-α (TNF-α) induces MMPs and may influence anastomosis repair. Methods We assessed the efficacies of the nonselective hydroxamate MMP inhibitor GM6001, the selective hydroxamate MMP inhibitor AG3340 and a TNF-α antagonist with respect to anastomotic breaking strength of left-sided colon anastomoses in male Sprague - Dawley rats. Results Systemic GM6001 treatment effectively blocked MMP activity and maintained the initial breaking strength day 0 of the anastomoses when administered subcutaneously as daily depositions (100 mg/kg) or continuously (10 mg/kg/day). In contrast, the anastomotic biomechanic strength was lowered by 55% (p<0.001) in vehicle-treated rats on postoperative day 3. GM6001 treatment increased breaking strength by 88% (p<0.0005) compared with vehicle-treated rats day 3 and reduced (p=0.003) the occurrence of spontaneous anastomotic dehiscence. Histologically, the anastomotic wound was narrower (p<0.05) in the longitudinal direction in GM6001-treated animals whereas GM6001 had no significant effect on inflammatory cell infiltration or epithelialization. AG3340 (10 mg/kg) increased (p<0.012) breaking strength by 47% compared with vehicle on day 3 but did not significantly prevent the reduction of the initial breaking strength on day 0. Although the increased TNF-α levels in the wound were attenuated, the anastomotic breaking strength was not improved (p=0.62) by the TNF-α (10 mg/kg) inhibitor given systemically. Conclusions Pharmacological nonselective MMP inhibition ought to be explored as a prophylactic regimen to reduce anastomotic complications following colorectal resection. The involvement of TNF-α was insignificant in anastomotic wound healing in an experimental model. © Springer-Verlag 2010.


Hellmark B.,Örebro University | Berglund C.,Aleris MEDILAB | Nilsdotter-Augustinsson A.,Linköping University | Unemo M.,Örebro University | Soderquist B.,Örebro University
European Journal of Clinical Microbiology and Infectious Diseases | Year: 2013

The aim of the present study was to characterise the staphylococcal cassette chromosome mec (SCCmec) in Staphylococcus epidermidis isolated from prosthetic joint infections (PJIs) and, if possible, assign them to any of the presently known SCCmec types. In addition, the isolates were examined for the presence of the arginine catabolic mobile element (ACME). Sixty-one S. epidermidis isolates obtained from PJIs and 24 commensal S. epidermidis isolates were analysed. The mecA gene was detected in 49 of the 61 (80 %) PJI isolates and in four of the 24 (17 %) commensal isolates, and the composition of the SCCmec was further analysed. SCCmec types I and IV were the most common types among the PJI isolates. However, for over half (57 %) of the isolates, it was not possible to assign an SCCmec type. ACME was detected in eight (13 %) of the PJI isolates and in 14 (58 %) of the commensal isolates. The characterisation of the SCCmec elements revealed a large heterogeneity, with a high frequency of isolates carrying more than one type of the ccr gene complex. ACME was more common among the commensal isolates and may represent a survival benefit for S. epidermidis colonising healthy individuals in the community. © 2013 Springer-Verlag Berlin Heidelberg.


Munch A.,Linköping University | Bohr J.,Örebro University | Miehlke S.,Center for Digestive Disease | Benoni C.,Skåne University Hospital | And 19 more authors.
Gut | Year: 2016

Objective: This 1-year study aimed to assess low-dose budesonide therapy for maintenance of clinical remission in patients with collagenous colitis. Design: A prospective, randomised, placebo-controlled study beginning with an 8-week open-label induction phase in which patients with histologically confirmed active collagenous colitis received budesonide (Budenofalk, 9 mg/day initially, tapered to 4.5 mg/day), after which 92 patients in clinical remission were randomised to budesonide (mean dose 4.5 mg/day; Budenofalk 3 mg capsules, two or one capsule on alternate days) or placebo in a 12-month double-blind phase with 6 months treatment-free follow-up. Primary endpoint was clinical remission throughout the double-blind phase. Results: Clinical remission during open-label treatment was achieved by 84.5% (93/110 patients). The median timetoremissionwas10.5days(95%CI(9.0to 14.0 days)). The maintenance of clinical remission at 1 year was achieved by 61.4% (27/44 patients) in the budesonide group versus 16.7% (8/48 patients) receiving placebo (treatment difference 44.5% in favour of budesonide; 95% CI (26.9% to 62.7%), p<0.001). Health-related quality of life was maintained during the 12-month double-blind phase in budesonide-treated patients. During treatment-free follow-up, 82.1% (23/28 patients) formerly receiving budesonide relapsed after study drug discontinuation. Low-dose budesonide over 1 year resulted in few suspected adverse drug reactions (7/44 patients), all non-serious. Conclusions: Budesonide at a mean dose of 4.5 mg/day maintained clinical remission for at least 1 year in the majority of patients with collagenous colitis and preserved health-related quality of life without safety concerns. Treatment extension with low-dose budesonide beyond 1 year may be beneficial given the high relapse rate after budesonide discontinuation. Trial registration numbers: http://www.clinicaltrials.gov (NCT01278082) and http://www.clinicaltrialsregister.eu (EudraCT: 2007-001315-31). © 2015, BMJ Publishing Group. All rights reserved.


Ekstedt M.,Linköping University | Franzen L.E.,Aleris Medilab | Mathiesen U.L.,County Hospital | Kechagias S.,Linköping University
Scandinavian Journal of Gastroenterology | Year: 2012

Background/Aims. The nonalcoholic fatty liver disease (NAFLD) activity score (NAS) is a newly proposed system to grade the necroinflammatory activity in liver biopsies of NAFLD patients. This study evaluates the usefulness of the NAS in predicting clinical deterioration and fibrosis progression in NAFLD. Methods. One hundred and twenty-nine patients with biopsy-proven NAFLD were included in a long-term histological follow-up study. Clinical course and change in fibrosis stage were compared between nonalcoholic steatohepatitis (NASH), "borderline NASH," and "not NASH" patients. Significant fibrosis progression was defined as progression of more than one fibrosis stage or development of end-stage liver disease during follow-up. Results. Eighty-eight patients accepted reevaluation and 68 underwent repeat liver biopsy. Mean time between biopsies was 13.8 ± 1.2 years (range 10.316.3). At baseline, NASH was diagnosed in 2 (1.6%) patients, and at follow-up, in 1 (1.5%) patient. A trend toward higher baseline NAS was seen in patients (n = 7) who developed end-stage liver disease (3.1 ± 0.9 vs. 2.2 ± 1.0; p = 0.050). Baseline NAS was associated with progressive disease in a univariate binary logistic regression analysis (p = 0.024), but no difference was seen in the multivariate analysis including the NAS, portal inflammation, and perisinusoidal fibrosis. Moreover, 18% of patients without NASH progressed significantly in fibrosis stage. Conclusions. The ability of the NAS to predict progression of NAFLD is poor. The clinical usefulness of the score is limited due to the significant overlap in clinical development between NAS score groups. To use the NAS as endpoint in treatment trial is not justified. © Informa Healthcare.


PubMed | Amager Hospital, Dr Falk Pharma GmbH, Regional Hospital, Lund University and 9 more.
Type: Clinical Trial, Phase III | Journal: Gut | Year: 2015

This 1-year study aimed to assess low-dose budesonide therapy for maintenance of clinical remission in patients with collagenous colitis.A prospective, randomised, placebo-controlled study beginning with an 8-week open-label induction phase in which patients with histologically confirmed active collagenous colitis received budesonide (Budenofalk, 9mg/day initially, tapered to 4.5mg/day), after which 92 patients in clinical remission were randomised to budesonide (mean dose 4.5mg/day; Budenofalk 3 mg capsules, two or one capsule on alternate days) or placebo in a 12-month double-blind phase with 6months treatment-free follow-up. Primary endpoint was clinical remission throughout the double-blind phase.Clinical remission during open-label treatment was achieved by 84.5% (93/110 patients). The median time to remission was 10.5days (95% CI (9.0 to 14.0days)). The maintenance of clinical remission at 1year was achieved by 61.4% (27/44 patients) in the budesonide group versus 16.7% (8/48 patients) receiving placebo (treatment difference 44.5% in favour of budesonide; 95% CI (26.9% to 62.7%), p<0.001). Health-related quality of life was maintained during the 12-month double-blind phase in budesonide-treated patients. During treatment-free follow-up, 82.1% (23/28 patients) formerly receiving budesonide relapsed after study drug discontinuation. Low-dose budesonide over 1year resulted in few suspected adverse drug reactions (7/44 patients), all non-serious.Budesonide at a mean dose of 4.5mg/day maintained clinical remission for at least 1year in the majority of patients with collagenous colitis and preserved health-related quality of life without safety concerns. Treatment extension with low-dose budesonide beyond 1year may be beneficial given the high relapse rate after budesonide discontinuation.http://www.clinicaltrials.gov (NCT01278082) and http://www.clinicaltrialsregister.eu (EudraCT: 2007-001315-31).


Webb C.,Skåne University Hospital | Norstrom F.,Umeå University | Myleus A.,Umeå University | Ivarsson A.,Umeå University | And 7 more authors.
Journal of Pediatric Gastroenterology and Nutrition | Year: 2015

Objectives: The aim of the present study was to evaluate any potential correlation between anti-tissue transglutaminase antibodies of type immunoglobulin A (tTG-IgA) and thedegree of gluten-induced enteropathy in children participating in a screening study for celiac disease (CD) and to assess to what extent the revised European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) guidelines cover this group of patients. Methods: The present study is a substudy of a cross-sectional CD screening study, Exploring the Iceberg of Celiacsin Sweden, α2-phased study performed during 2005 to 2006 and 2009 to 2010. The 13,279 participating children had a blood test obtained, and those with positive tTG-IgA were recommended a small intestinal biopsy. The tTG-IgA levels at the time of biopsy were compared with those at the assessment of the biopsy. Results: There were 267 children included, of whom 230 were diagnosed as having CD. Of all of the children, 67 children had low tTG-IgA levels (<5 U/mL), of whom 55% had Marsh 3 lesions. All of the children with tTG-IgA levels exceeding 10 times the upper limit of normal values of 5U/mL, that is, 50 U/mL, were diagnosed as having CD. Lowering the cutoff to 3U/mL, all but 1 child with 30U/mL got CD diagnosis. Conclusions: By adopting the revised ESPGHAN criteria, biopsies could have been omitted in one-fourth of all of the patients. Our results indicate that the criteria may be useful even in screened children. Further studies are needed to confirm whether the 2012 ESPGHAN guidelines should be revised to also apply to the populations being screened. Copyright © 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.


Joost P.,Helsingborg General Hospital | Joost P.,Skåne University Hospital | Bendahl P.-O.,Lund University | Halvarsson B.,Aleris Medilab | And 3 more authors.
BMC Clinical Pathology | Year: 2013

Background: The identification of mismatch-repair (MMR) defective colon cancer is clinically relevant for diagnostic, prognostic and potentially also for treatment predictive purposes. Preselection of tumors for MMR analysis can be obtained with predictive models, which need to demonstrate ease of application and favorable reproducibility. Methods. We validated the MMR index for the identification of prognostically favorable MMR deficient colon cancers and compared performance to 5 other prediction models. In total, 474 colon cancers diagnosed ≥ age 50 were evaluated with correlation between clinicopathologic variables and immunohistochemical MMR protein expression. Results: Female sex, age ≥60 years, proximal tumor location, expanding growth pattern, lack of dirty necrosis, mucinous differentiation and presence of tumor-infiltrating lymphocytes significantly correlated with MMR deficiency. Presence of at least 4 of the MMR index factors identified MMR deficient tumors with 93% sensitivity and 76% specificity and showed favorable reproducibility with a kappa value of 0.88. The MMR index also performed favorably when compared to 5 other predictive models. Conclusions: The MMR index is easy to apply and efficiently identifies MMR defective colon cancers with high sensitivity and specificity. The model shows stable performance with low inter-observer variability and favorable performance when compared to other MMR predictive models. © 2013 Joost et al.; licensee BioMed Central Ltd.


Therkildsen C.,Copenhagen University | Jonsson G.,Lund University | Dominguez-Valentin M.,Lund University | Nissen A.,Copenhagen University | And 6 more authors.
European Journal of Cancer | Year: 2013

Lynch syndrome and familial colorectal cancer type X, FCCTX, represent the two predominant colorectal cancer syndromes. Whereas Lynch syndrome is clinically and genetically well defined, the genetic cause of FCCTX is unknown and genomic differences between Lynch syndrome and FCCTX tumours are largely unknown. We applied array-based comparative genomic hybridisation to 23 colorectal cancers from FCCTX with comparison to 23 Lynch syndrome tumours and to 45 sporadic colorectal cancers. FCCTX tumours showed genomic complexity with frequent gains on chromosomes 20q, 19 and 17 and losses of 18, 8p and 15. Gain of genetic material in two separate regions encompassing, 20q12-13.12 and 20q13.2-13.32, was identified in 65% of the FCCTX tumours. Gain of material on chromosome 20q and loss on chromosome 18 significantly discriminated colorectal cancers associated with FCCTX from Lynch syndrome, which likely signifies different preferred tumourigenic pathways. © 2012 Elsevier Ltd. All rights reserved.

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