| 1. |
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| 2. |
- Bagher, Ali Mohammad, et al.
(författare)
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Outcome after red trauma alarm at an urban Swedish hospital: Implications for prevention.
- 2015
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Ingår i: Scandinavian Journal of Public Health. - : SAGE Publications. - 1651-1905 .- 1403-4948. ; 43:5, s. 506-513
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Tidskriftsartikel (refereegranskat)abstract
- We applied the new injury severity scoring system and studied mechanisms of injury and risk factors for mortality, in order to find potential preventive measures, in the present Scandinavian trauma cohort triaged through red trauma alarm according to the Medical Emergency Triage and Treatment System.
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| 3. |
- Bagher, Ali Mohammad, et al.
(författare)
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Socio-economic status and major trauma in a Scandinavian urban city: A population-based case-control study.
- 2016
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Ingår i: Scandinavian Journal of Public Health. - : SAGE Publications. - 1651-1905 .- 1403-4948. ; 44:2, s. 217-223
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiological studies of patients with major trauma, including both hospitalized and immediately deceased whom are undergoing medico-legal autopsy, are very rare. We studied the incidence and mortality of major trauma in all 10 districts in the Scandinavian city of Malmö, Sweden, and the association between socio-economic status and major trauma.
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| 4. |
- Bengtsson, Erik, et al.
(författare)
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HMG-CoA reductase expression in primary colorectal cancer correlates with favourable clinicopathological characteristics and an improved clinical outcome
- 2014
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Ingår i: Diagnostic Pathology. - : BioMed Central (BMC). - 1746-1596. ; 9:1, s. 78-
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Tidskriftsartikel (refereegranskat)abstract
- Background: An association between tumor-specific HMG-CoA reductase (HMGCR) expression and good prognosis has previously been demonstrated in breast and ovarian cancer. In this study, the expression, clinicopathological correlates and prognostic value of HMGCR expression in colorectal cancer was examined. Findings: Immunohistochemical expression of HMGCR was assessed in tissue microarrays with primary tumours from 557 incident cases of colorectal cancer in the Malmo Diet and Cancer Study. Pearson's Chi Square test was applied to explore the associations between HMGCR expression and clinicopathological factors and other investigative biomarkers. Kaplan Meier analysis and Cox proportional hazards modeling were used to assess the relationship between HMGCR expression and cancer-specific survival (CSS) according to negative vs positive HMGCR expression. A total number of 535 (96.0%) tumours were suitable for analysis, of which 61 (11.4%) were HMGCR negative. Positive cytoplasmic HMGCR expression was associated with distant metastasis-free disease at diagnosis (p = 0.002), lack of vascular invasion (p = 0.043), microsatellite-instability (p = 0.033), expression of cyclin D1 (p = <0.001) and p21 (p = <0.001). Positive HMGCR expression was significantly associated with a prolonged CSS in unadjusted Cox regression analysis in the entire cohort (HR = 1.79; 95% CI 1.20-2.66) and in Stage III-IV disease (HR = 1.71; 95% CI 1.09-2.68), but not after adjustment for established clinicopathological parameters. Conclusions: Findings from this prospective cohort study demonstrate that HMGCR is differentially expressed in colorectal cancer and that positive expression is associated with favourable tumour characteristics and a prolonged survival in unadjusted analysis. The utility of HMGCR as a predictor of response to neoadjuvant or adjuvant statin treatment in colorectal cancer merits further study. Virtual slides: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2115647072103464.
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| 5. |
- Brändstedt, Jenny, et al.
(författare)
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Associations of anthropometric factors with KRAS and BRAF mutation status of primary colorectal cancer in men and women : a cohort study
- 2014
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6, s. 98964-98964
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is a well-established risk factor for colorectal cancer (CRC), and accumulating evidence suggests a differential influence of sex and anthropometric factors on the molecular carcinogenesis of the disease. The aim of the present study was to investigate the relationship between height, weight, bodyfat percentage, waist- and hip circumference, waist-hip ratio (WHR), body mass index (BMI) and CRC risk according to KRAS and BRAF mutation status of the tumours, with particular reference to potential sex differences. KRAS and BRAF mutations were analysed by pyrosequencing in tumours from 494 incident CRC cases in the Malmö Diet and Cancer Study. Hazard ratios of CRC risk according to anthropometric factors and mutation status were calculated using multivariate Cox regression models. While all anthropometric measures except height were associated with an increased risk of KRAS-mutated tumours, only BMI was associated with an increased risk of KRAS wild type tumours overall. High weight, hip, waist, WHR and BMI were associated with an increased risk of BRAF wild type tumours, but none of the anthropometric factors were associated with risk of BRAF-mutated CRC, neither in the overall nor in the sex-stratified analysis. In men, several anthropometric measures were associated with both KRAS-mutated and KRAS wild type tumours. In women, only a high WHR was significantly associated with an increased risk of KRAS-mutated CRC. A significant interaction was found between sex and BMI with respect to risk of KRAS-mutated tumours. In men, all anthropometric factors except height were associated with an increased risk of BRAF wild type tumours, whereas in women, only bodyfat percentage was associated with an increased risk of BRAF wild type tumours. The results from this prospective cohort study further support an influence of sex and lifestyle factors on different pathways of colorectal carcinogenesis, defined by KRAS and BRAF mutation status of the tumours.
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| 6. |
- Brändstedt, Jenny, et al.
(författare)
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Associations of hormone replacement therapy and oral contraceptives with risk of colorectal cancer defined by clinicopathological factors, beta-catenin alterations, expression of cyclin D1, p53, and microsatellite-instability
- 2014
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Postmenopausal hormone therapy (HRT) and oral contraceptive (OC) use have in several studies been reported to be associated with a decreased colorectal cancer (CRC) risk. However, data on the association between HRT and OC and risk of different clinicopathological and molecular subsets of CRC are lacking. The aim of this molecular pathological epidemiology study was therefore to evaluate the associations between HRT and OC use and risk of specific CRC subgroups, overall and by tumour site.METHOD: In the population-based prospective cohort study Mamö Diet and Cancer, including 17035 women, 304 cases of CRC were diagnosed up until 31 December 2008. Immunohistochemical expression of beta-catenin, cyclin D1, p53 and MSI-screening status had previously been assessed in tissue microarrays with tumours from 280 cases. HRT was assessed as current use of combined HRT (CHRT) or unopposed oestrogen (ERT), and analysed among 12583 peri-and postmenopausal women. OC use was assessed as ever vs never use among all women in the cohort. A multivariate Cox regression model was applied to determine hazard ratios for risk of CRC, overall and according to molecular subgroups, in relation to HRT and OC use.RESULTS: There was no significantly reduced risk of CRC by CHRT or ERT use, however a reduced risk of T-stage 1-2 tumours was seen among CHRT users (HR: 0.24; 95% CI: 0.09-0.77).Analysis stratified by tumour location revealed a reduced overall risk of rectal, but not colon, cancer among CHRT and ERT users, including T stage 1-2, lymph node negative, distant metastasis-free, cyclin D1 - and p53 negative tumours.In unadjusted analysis, OC use was significantly associated with a reduced overall risk of CRC (HR: 0.56; 95% CI: 0.44-0.71), but this significance was not retained in adjusted analysis (HR: 1.05: 95% CI: 0.80-1.37). A similar risk reduction was seen for the majority of clinicopathological and molecular subgroups.CONCLUSION: Our findings provide information on the relationship between use of HRT and OC and risk of clinicopathological and molecular subsets of CRC.
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| 7. |
- Brändstedt, Jenny, et al.
(författare)
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Gender, anthropometric factors and risk of colorectal cancer with particular reference to tumour location and TNM stage : A cohort study
- 2012
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Ingår i: Biology of Sex Differences. - : Springer Science and Business Media LLC. - 2042-6410. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: It remains unclear whether the increased risk of colorectal cancer (CRC) associated with obesity differs by gender, distribution of fat, tumour location and clinical (TNM) stage. The primary aim of this study was to examine these associations in 584 incident colorectal cancer cases from a Swedish prospective population-based cohort including 28098 men and women. Methods: Seven anthropometric factors; height, weight, bodyfat percentage, hip circumference, waist circumference, BMI and waist-hip ratio (WHR) were categorized into quartiles of baseline anthropometric measurements. Relative risks of CRC, total risk as well as risk of different TNM stages, and risk of tumours located to the colon or rectum, were calculated for all cases, women and men, respectively, using multivariate Cox regression models. Results: Obesity, as defined by all anthropometric variables, was significantly associated with an overall increased risk of CRC in both women and men. While none of the anthropometric measures was significantly associated with risk of tumour (T)-stage 1 and 2 tumours, all anthropometric variables were significantly associated with an increased risk of T-stage 3 and 4, in particular in men. In men, increasing quartiles of weight, hip, waist, BMI and WHR were significantly associated with an increased risk of lymph node positive (N1 and N2) disease, and risk of both non-metastatic (M0) and metastatic (M1) disease. In women, there were no or weak associations between obesity and risk of node-positive disease, but statistically significant associations between increased weight, bodyfat percentage, hip, BMI and M0 disease. Interestingly, there was an increased risk of colon but not rectal cancer in men, and rectal but not colon cancer in women, by increased measures of weight, hip-, waist circumference and bodyfat percentage. Conclusions: This study is the first to show a relationship between obesity, measured as several different anthropometric factors, and an increased risk of colorectal cancer of more advanced clinical stage, in particular in men. These findings suggest that risk of CRC differs according to the method of characterising obesity, and also according to gender, location, and tumour stage.
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| 8. |
- Brändstedt, Jenny, et al.
(författare)
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Influence of anthropometric factors on tumour biological characteristics of colorectal cancer in men and women : a cohort study
- 2013
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Obesity is a well established risk factor of colorectal cancer (CRC), but how body size influences risk of colorectal cancer defined by key molecular alterations remains unclear. In this study, we investigated the relationship between height, weight, body mass index (BMI), waist- and hip circumference, waist-hip ratio (WHR) and risk of CRC according to expression of beta-catenin, cyclin D1, p53 and microsatellite instability status of the tumours in men and women, respectively.METHODS: Immunohistochemical expression of beta-catenin, cyclin D1, p53 and MSI-screening status was assessed in tissue microarrays with tumours from 584 cases of incident CRC in the Malmö Diet and Cancer Study. Six anthropometric factors: height, weight, BMI, waist- and hip circumference, and WHR were categorized by quartiles of baseline measurements and relative risks of CRC according to expression of beta-catenin, cyclin D1, p53 and MSI status were calculated using multivariate Cox regression models.RESULTS: High height was associated with risk of cyclin D1 positive, and p53 negative CRC in women but not with any investigative molecular subsets of CRC in men. High weight was associated with beta-catenin positive, cyclin D1 positive, p53 negative and microsatellite stable (MSS) tumours in women, and with beta-catenin negative and p53 positive tumours in men. Increased hip circumference was associated with beta-catenin positive, p53 negative and MSS tumours in women and with beta-catenin negative, cyclin D1 positive, p53 positive and MSS tumours in men. In women, waist circumference and WHR were not associated with any molecular subsets of CRC. In men, both high WHR and high waist circumference were associated with beta-catenin positive, cyclin D1 positive and p53 positive tumours. WHR was also associated with p53 negative CRC, and waist circumference with MSS tumours. High BMI was associated with increased risk of beta-catenin positive and MSS CRC in women, and with beta-catenin positive, cyclin D1 positive and p53 positive tumours in men.CONCLUSIONS: Findings from this large prospective cohort study indicate sex-related differences in the relationship between obesity and CRC risk according to key molecular characteristics, and provide further support of an influence of lifestyle factors on different molecular pathways of colorectal carcinogenesis.
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| 9. |
- Eberhard, Jakob, et al.
(författare)
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A cohort study of the prognostic and treatment predictive value of SATB2 expression in colorectal cancer
- 2012
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 106:5, s. 931-938
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Special AT-rich sequence-binding protein 2 (SATB2) is a novel diagnostic marker of colorectal cancer (CRC), and loss of SATB2 has been linked to poor survival from the disease. In this study, we validated the prognostic ability of SATB2 expression in a large, prospective CRC cohort.METHODS: Immunohistochemical SATB2 expression was assessed in 527 incident CRC cases from the Malmö Diet and Cancer Study. Kaplan-Meier analysis and Cox proportional hazards modelling were used to explore the impact of SATB2 expression on cancer-specific survival (CSS) and overall survival (OS).RESULTS: High SATB2 expression was associated with a prolonged CSS in the full cohort (hazard ratio (HR)=0.61; 95% CI 0.41-0.92) and in colon cancer (HR=0.39; 95% CI 0.20-0.75), remaining significant in multivariable analysis of colon cancer (HR=0.49; 95% CI 0.25-0.96), with similar findings for OS. In curatively resected stage III-IV patients, a significant benefit from adjuvant and/or neoadjuvant therapy was observed for SATB2 high tumours (P(interaction)=0.037 for OS) and high SATB2 expression in rectal cancer correlated with an enhanced effect of neoadjuvant therapy (P(interaction)=0.033 for OS).CONCLUSION: High SATB2 expression is an independent marker of good prognosis in colon cancer and may modulate sensitivity to chemotherapy and radiation.
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| 10. |
- Larsson, Anna H, et al.
(författare)
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Overexpression of podocalyxin-like protein is an independent factor of poor prognosis in colorectal cancer
- 2011
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 105:5, s. 666-672
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Podocalyxin-like 1 (PODXL) is a cell-adhesion glycoprotein and stem cell marker that has been associated with an aggressive tumour phenotype and poor prognosis in several forms of cancer. In this study, we investigated the prognostic impact of PODXL expression in colorectal cancer (CRC). METHODS: Using tissue microarrays and immunohistochemistry, PODXL expression was evaluated in 536 incident CRC cases from a prospective, population-based cohort study. Kaplan-Meier analysis and Cox proportional hazards modelling were used to assess the impact of PODXL expression on cancer-specific survival (CSS) and overall survival (OS). RESULTS: High PODXL expression was significantly associated with unfavourable clinicopathological characteristics, a shorter CSS (hazard ratio (HR) = 1.98; 95% confidence interval (CI) 1.38-2.84, P < 0.001) and 5-year OS (HR = 1.85; 95% CI 1.29-2.64, P = 0.001); the latter remaining significant in multivariate analysis (HR = 1.52; 95% CI 1.03-2.25, P = 0.036). In addition, in curatively resected stage III (T1-4, N1-2, M0) patients (n = 122) with tumours with high PODXL expression, a significant benefit from adjuvant chemotherapy was demonstrated (p(interaction) = 0.004 for CSS and 0.015 for 5-year OS in multivariate analysis). CONCLUSION: Podocalyxin-like 1 expression is an independent factor of poor prognosis in CRC. Our results also suggest that PODXL may be a useful marker to stratify patients for adjuvant chemotherapy.
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| 11. |
- Larsson, Anna H., et al.
(författare)
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Significant association and synergistic adverse prognostic effect of podocalyxin-like protein and epidermal growth factor receptor expression in colorectal cancer
- 2016
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Ingår i: Journal of Translational Medicine. - : BioMed Central. - 1479-5876. ; 14
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Tidskriftsartikel (refereegranskat)abstract
- Background: Podocalyxin-like 1 (PODXL) is an anti-adhesive transmembrane protein that has been demonstrated to be an independent factor of poor prognosis in colorectal cancer (CRC). The gene encoding PODXL is located to chromosome 7, which also harbours the gene for the epidermal growth factor receptor (EGFR). The aim of this study was to examine the associations between PODXL and EGFR expression in CRC in vitro and in vivo. Methods: EGFR expression was analysed in tumours from three independent patient cohorts; cohort 1 (n = 533), cohort 2 (n = 259) and cohort 3 (n = 310), previously analysed for immunohistochemical PODXL expression and KRAS and BRAF mutations (cohort 1 and 3). Levels of EGFR and PODXL were determined by western blot in six different CRC cell lines. Results: High expression of PODXL was significantly associated with high EGFR expression (p < 0.001) in all three cohorts, and with BRAF mutation (p < 0.001) in cohort 1 and 3. High EGFR expression correlated with BRAF mutation (p < 0.001) in cohort 1. High EGFR expression was associated with adverse clinicopathological factors and independently predicted a reduced 5-year overall survival (OS) in cohort 1 (HR 1.77; 95 % CI 1.27-2.46), cohort 2 (HR 1.58; 95 % CI 1.05-2.38) and cohort 3 (HR 1.83; 95 % CI 1.19-2.81). The highest risk of death within 5 years was observed in patients with tumours displaying high expression of both EGFR and PODXL in cohort 1 and 3 (HR 1.97; 95 % CI 1.18-3.28 and HR 3.56; 95 % CI 1.75-7.22, respectively). Western blot analysis showed a uniform expression of PODXL and EGFR in all six examined CRC cell lines. Conclusions: The results from this study demonstrate that high expression of EGFR is an independent factor of poor prognosis in CRC. Moreover, strong links have been uncovered between expression of the recently proposed biomarker candidate PODXL with EGFR expression in CRC in vivo and in vitro, and with BRAF mutation in vivo. High expression of both PODXL and EGFR may also have a synergistic adverse effect on survival. These findings suggest a potential functional link in CRC between PODXL, EGFR and BRAF, all originating from chromosome 7, which may be highly relevant in the clinical setting and therefore merit future in-depth study.
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| 12. |
- MOHAMMAD BAGHER, ALI, et al.
(författare)
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Analysis of pre-hospital rescue times on mortality in trauma patients in a Scandinavian urban setting
- 2017
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Ingår i: Trauma. - : SAGE Publications. - 1460-4086 .- 1477-0350. ; 19:1, s. 28-34
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To analyze if pre-hospital rescue times were associated with mortality in a trauma cohort arriving by ambulance to hospital in a Scandinavian urban setting. Methods: Between 2011 and 2013, individuals and pre-hospital rescue times were identified in Emergency Medical Dispatcher Centre, hospital, and forensic records in red alarm trauma. Major trauma was defined as a New InjurySeverity Score (NISS)>15. Results: Overall, 89% of 378 trauma patients received hospital care within 60 min; 51% had a response time of 8 min, and 95% had response time within 20 min. The on-scene time (p<0.05) and total pre-hospital time (p<0.05) were longer for patients 65 years, in comparison with patients <65 years. The patients with penetrating trauma had shorter on-scene time (p<0.01), total pre-hospital time (p<0.01), and shorter transport distance from trauma scene to hospital (p¼0.004), compared to those with blunt trauma. Patients with NISS>15 were found to have the same pre-hospital rescue times as those with NISS15. There was a trend that the occurrence of gunshots was associatedwith increased mortality (p¼0.074). When entering age, NISS, penetrating versus blunt injury, response time, and on-scene time in a multivariate regression analysis, age (p<0.001), NISS (p<0.001), and penetrating injury (p=0.009) remained as independent factors associated with mortality and a trend for shorter on-scene time (p=0.093). Conclusions: Pre-hospital rescue times had less impact on mortality than injury severity, age, and penetrating trauma. Even though penetrating traumas were associated with shorter on-scene time and shorter transport distance to hospital, mortality was increased in this Scandinavian urban setting.
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| 13. |
- Nodin, Björn, et al.
(författare)
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Molecular correlates and prognostic significance of SATB1 expression in colorectal cancer
- 2012
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Ingår i: Diagnostic Pathology. - : Springer Science and Business Media LLC. - 1746-1596. ; 7:1, s. 115-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Special AT-rich sequence-binding protein 1 (SATB1) is a global gene regulator that has been reported to confer malignant behavior and associate with poor prognosis in several cancer forms. SATB1 expression has been demonstrated to correlate with unfavourable tumour characteristics in rectal cancer, but its association with clinical outcome in colorectal cancer (CRC) remains unclear. In this study, we examined the prognostic impact of SATB1 expression in CRC, and its association with important molecular characteristics; i.e. beta-catenin overexpression, microsatellite instability (MSI) screening status, and SATB2 expression. Methods: Immunohistochemical expression of SATB1 and beta-catenin was assessed in tissue microarrays with tumours from 529 incident CRC cases in the prospective population-based Malmo Diet and Cancer Study, previously analysed for SATB2 expression and MSI screening status. Spearman's Rho and Chi-Square tests were used to explore correlations between SATB1 expression, clinicopathological and investigative parameters. Kaplan Meier analysis and Cox proportional hazards modelling were used to explore the impact of SATB1 expression on cancer specific survival (CSS) and overall survival (OS). Results: SATB1 was expressed in 222 (42%) CRC cases and negative, or sparsely expressed, in adjacent colorectal mucosa (n = 16). SATB1 expression was significantly associated with microsatellite stable tumours (p < 0.001), beta-catenin overexpression (p < 0.001) and SATB2 expression (p < 0.001). While not prognostic in the full cohort, SATB1 expression was significantly associated with poor prognosis in SATB2 negative tumours (HR = 2.63; 95% CI 1.46-4.71; p(interaction) = 0.011 for CSS and HR = 2.31; 95% CI 1.32-4.04; p(interaction) = 0.015 for OS), remaining significant in multivariable analysis. Conclusions: The results of this study demonstrate that SATB1 expression in CRC is significantly associated with beta-catenin overexpression, microsatellite stability and SATB2 expression. Furthermore, SATB1 expression is a factor of poor prognosis in SATB2 negative tumours. Altogether, these data indicate an important role for SATB1 in colorectal carcinogenesis and suggest prognostically antagonistic effects of SATB1 and SATB2. The mechanistic basis for these observations warrants further study.
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| 14. |
- Wangefjord, Sakarias
(författare)
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A cohort study of sex differences and prognostic biomarkers in colorectal cancer
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer (CRC) is one of the most common forms of cancer worldwide, with an annual incidence of more than 1 million cases. Despite advancements in the management of CRC, mortality remains high. Accumulating evidence indicates that CRC is a heterogeneous disease, which affects outcome beyond what can be predicted by disease stage and other conventional prognostic factors. Thus, there is a great need to identify new biomarkers to enable a more accurate prognostication, and to help select patients for adjuvant treatment. The aim of this thesis was to investigate the associations of a series of putative biomarkers with survival, treatment response and clinicopathological factors in a large cohort of incident CRC, with special attention to sex differences. The study group consisted of tumours from 557 incident cases of CRC in the Malmö Diet and Cancer Study (MDCS). The tumours, assembled in tissue microarrays, were evaluated for expression of cyclin D1, mismatch repair proteins, beta-catenin and epidermal growth factor receptor (EGFR) by immunohistochemistry, and further, EGFR gene copy number (GCN) alterations by brightfield double-in situ hybridization. In addition, KRAS and BRAF mutational status was assessed by pyrosequencing. Associations with clinicopathological and investigative factors were explored by Chi Square and Spearman’s correlation tests, and Kaplan-Meier analysis and Cox proportional hazards modelling were applied for survival analysis. We hereby found that nuclear cyclin D1 expression was associated with female sex and a favorable prognosis, although not independently, in male, but not in female, CRC. Microsatellite instability (MSI) correlated to distinctive clinicopathological features, cyclin D1 expression, and independently predicted a good prognosis in stage III-IV CRC. Moreover, beta-catenin overexpression correlated independently with a prolonged survival from stage III-IV CRC, and was associated with microsatellite stable (MSS) tumours. We also observed that KRAS codon 13 mutation predicted a poor prognosis in female CRC, but not independently of established prognostic factors. KRAS and BRAF mutations were mutually exclusive, and correlated with MSS and MSI, respectively. BRAF mutation was independently associated with a reduced survival in male patients with MSS CRC. Furthermore, both EGFR protein expression and GCN alterations were associated with a reduced survival in stage III-IV CRC, the latter, however, not independently of established prognostic factors. EGFR protein expression correlated significantly with EGFR GCN alterations, although a substantial proportion of EGFR expressing tumours displayed a normal GCN, and vice versa. Finally, EGFR alterations were significantly associated with a reduced survival in curatively treated patients with stage III-IV disease receiving adjuvant oxaliplatin. In conclusion, the results from this thesis demonstrate several relevant associations of the investigative biomarkers with prognosis and treatment response in CRC. Moreover, substantial sex differences in the clinicopathological correlates and prognostic significance of some of the biomarkers were observed.
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| 15. |
- Wangefjord, Sakarias, et al.
(författare)
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Associations of beta-catenin alterations and MSI screening status with expression of key cell cycle regulating proteins and survival from colorectal cancer
- 2013
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Ingår i: Diagnostic Pathology. - : Springer Science and Business Media LLC. - 1746-1596. ; 8, s. 10-10
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Despite their pivotal roles in colorectal carcinogenesis, the interrelationship and prognostic significance of beta-catenin alterations and microsatellite instability (MSI) in colorectal cancer (CRC) needs to be further clarified. In this paper, we studied the associations between beta-catenin overexpression and MSI status with survival from CRC, and with expression of p21, p27, cyclin D1 and p53, in a large, prospective cohort study.METHODS: Immunohistochemical MSI-screening status and expression of p21, p27 and p53 was assessed in tissue microarrays with tumours from 557 cases of incident CRC in the Malmö Diet and Cancer Study. Chi Square and Spearman's correlation tests were used to explore the associations between beta-catenin expression, MSI status, clinicopathological characteristics and investigative parameters. Kaplan-Meier analysis and Cox proportional hazards modelling were used to assess the relationship between beta-catenin overexpression, MSI status and cancer specific survival (CSS).RESULTS: Positive MSI screening status was significantly associated with older age, female sex, proximal tumour location, non-metastatic disease, and poor differentiation, and inversely associated with beta-catenin overexpression. Beta-catenin overexpression was significantly associated with distal tumour location, low T-stage and well-differentiated tumours. Patients with MSI tumours had a significantly prolonged CSS in the whole cohort, and in stage III-IV disease, also in multivariable analysis, but not in stage I-II disease. Beta-catenin overexpression was associated with a favourable prognosis in the full cohort and in patients with stage III-IV disease. Neither MSI nor beta-catenin status were predictive for response to adjuvant chemotherapy in curatively treated stage III patients. P53 and p27 expression was positively associated with beta-catenin overexpression and inversely associated with MSI. Cyclin D1 expression was positively associated with MSI and beta-catenin overexpression, and p21 expression was positively associated with MSI but not beta-catenin overexpression.CONCLUSIONS: Findings from this large, prospective cohort study demonstrate that MSI screening status in colorectal cancer is an independent prognostic factor, but not in localized disease, and does not predict response to adjuvant chemotherapy. Beta-catenin overexpression was also associated with favourable outcome but not a treatment predictive factor. Associations of MSI and beta-catenin alterations with other investigative and clinicopathological factors were in line with the expected.VIRTUAL SLIDES: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/8778585058652609.
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| 16. |
- Wangefjord, Sakarias, et al.
(författare)
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Cyclin D1 expression in colorectal cancer is a favorable prognostic factor in men but not in women in a prospective, population-based cohort study.
- 2011
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Ingår i: Biology of Sex Differences. - : Springer Science and Business Media LLC. - 2042-6410. ; 2
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Although colorectal cancer (CRC) is generally not considered to be a hormone-dependent malignancy, several sex-related differences in incidence, molecular characteristics and survival have been reported. Epidemiological studies have consistently shown that increased exposure to female sex hormones is associated with a lower risk of CRC in women, and cyclin D1, an important downstream effector in estrogen-mediated signaling, is commonly activated in CRC. In this study, we analyzed the prognostic significance of cyclin D1 expression in CRC, with particular reference to sex-related differences, in tumors from a large, prospective, population-based cohort. METHODS: Using tissue microarrays and immunohistochemistry, the fraction and intensity of cyclin D1 expression was evaluated in 527 incident CRC cases from the Malmö Diet and Cancer Study. The χ2 and Spearman's rho (ρ) tests were used for comparison of cyclin D1 expression and relevant clinicopathological characteristics. Kaplan-Meier analysis and Cox proportional hazards modeling were used to assess the effect of cyclin D1 expression on cancer-specific survival (CSS) in univariate and multivariate analysis, adjusted for established prognostic factors. RESULTS: Cyclin D1 intensity was significantly lower in male compared with female CRC (P = 0.018). In the full cohort, cyclin D1 expression was associated with a significantly prolonged CSS (hazard ratio (HR) = 0.69; 95% CI 0.49 to 0.96, P = 0.026) but subgroup analysis according to gender revealed a strongly accentuated prognostic effect of cyclin D1 in male CRC (HR = 0.48; 95% CI 0.31 to 0.74, P < 0.001), which was in contrast to female CRC, where cyclin D1 was not prognostic (HR = 1.05; 95% CI 0.62 to 1.78, P = 0.864) (Pinteraction = 0.024). The prognostic value of cyclin D1 was not retained in multivariate analysis, either in the full cohort or in male CRC. CONCLUSIONS: Cyclin D1 expression is strongly associated with prolonged survival in male CRC. These findings not only support an important role for cyclin D1 in colorectal carcinogenesis, but also add further weight to the accumulating evidence that CRC is indeed a hormone-dependent malignancy, for which prognostic and treatment-predictive molecular biomarkers should be evaluated differently in women and men.
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| 17. |
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| 18. |
- Wangefjord, Sakarias, et al.
(författare)
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Sex differences in the prognostic significance of KRAS codons 12 and 13, and BRAF mutations in colorectal cancer: a cohort study
- 2013
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Ingår i: Biology of Sex Differences. - : Springer Science and Business Media LLC. - 2042-6410. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Activating KRAS and BRAF mutations predict unresponsiveness to EGFR-targeting therapies in colorectal cancer (CRC), but their prognostic value needs further validation. In this study, we investigated the impact of KRAS codons 12 and 13, and BRAF mutations on survival from CRC, overall and stratified by sex, in a large prospective cohort study. Methods: KRAS codons 12 and 13, and BRAF mutations were analysed by pyrosequencing of tumours from 525 and 524 incident CRC cases in The Malmö Diet and Cancer Study. Associations with cancer-specific survival (CSS) were explored by Cox proportional hazards regression, unadjusted and adjusted for age, TNM stage, differentiation grade, vascular invasion and microsatellite instability (MSI) status. Results: KRAS and BRAF mutations were mutually exclusive. KRAS mutations were found in 191/ 525 (36.4%) cases, 82.2% of these mutations were in codon 12, 17.3% were in codon 13, and 0.5% cases had mutations in both codons. BRAF mutations were found in 78/524 (14.9%) cases. Overall, mutation in KRAS codon 13, but not codon 12, was associated with a significantly reduced CSS in unadjusted, but not in adjusted analysis, and BRAF mutation did not significantly affect survival. However, in microsatellite stable (MSS), but not in MSI tumours, an adverse prognostic impact of BRAF mutation was observed in unadjusted, but not in adjusted analysis. While KRAS mutation status was not significantly associated with sex, BRAF mutations were more common in women. BRAF mutation was not prognostic in women; but in men, BRAF mutation was associated with a significantly reduced CSS in overall adjusted analysis (HR = 3.50; 95% CI = 1.41–8.70), but not in unadjusted analysis. In men with MSS tumours, BRAF mutation was an independent factor of poor prognosis (HR = 4.91; 95% CI = 1.99–12.12). KRAS codon 13 mutation was associated with a significantly reduced CSS in women, but not in men in unadjusted, but not in adjusted analysis. Conclusions: Results from this cohort study demonstrate sex-related differences in the prognostic value of BRAF mutations in colorectal cancer, being particularly evident in men. These findings are novel and merit further validation.
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