| 1. |
- Andersson, Gustav, et al.
(författare)
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Reduced expression of ezrin in urothelial bladder cancer signifies more advanced tumours and an impaired survival : validatory study of two independent patient cohorts
- 2014
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Ingår i: BMC Urology. - : BioMed Central (BMC). - 1471-2490. ; 14:1, s. 36-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Reduced membranous expression of the cytoskeleton-associated protein ezrin has previously been demonstrated to correlate with tumour progression and poor prognosis in patients with T1G3 urothelial cell carcinoma of the bladder treated with non-maintenance Bacillus Calmette-Guerin (n = 92), and the associations with adverse clinicopathological factors have been validated in another, unselected, cohort (n = 104). In the present study, we examined the prognostic significance of ezrin expression in urothelial bladder cancer in a total number of 442 tumours from two independent patient cohorts. Methods: Immunohistochemical expression of ezrin was evaluated in tissue microarrays with tumours from one retrospective cohort of bladder cancer (n = 110; cohort I) and one population-based cohort (n = 342; cohort II). Classification regression tree analysis was applied for selection of prognostic cutoff. Kaplan-Meier analysis, log rank test and Cox regression proportional hazards' modeling were used to evaluate the impact of ezrin on 5-year overall survival (OS), disease-specific survival (DSS) and progression-free survival (PFS). Results: Ezrin expression could be evaluated in tumours from 100 and 342 cases, respectively. In both cohorts, reduced membranous ezrin expression was significantly associated with more advanced T-stage (p < 0.001), high grade tumours (p < 0.001), female sex (p = 0.040 and p = 0.013), and membranous expression of podocalyxin-like protein (p < 0.001 and p = 0.009). Moreover, reduced ezrin expression was associated with a significantly reduced 5-year OS in both cohorts (HR = 3.09 95% CI 1.71-5.58 and HR = 2.15(1.51-3.06), and with DSS in cohort II (HR = 2.77, 95% CI 1.78-4.31). This association also remained significant in adjusted analysis in Cohort I (HR1.99, 95% CI 1.05-3.77) but not in Cohort II. In pTa and pT1 tumours in cohort II, there was no significant association between ezrin expression and time to progression. Conclusions: The results from this study validate previous findings of reduced membranous ezrin expression in urothelial bladder cancer being associated with unfavourable clinicopathological characteristics and an impaired survival. The utility of ezrin as a prognostic biomarker in transurethral resection specimens merits further investigation.
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| 2. |
- Bergenfelz, Caroline, et al.
(författare)
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S100A9 expressed in ER(-)PgR(-) breast cancers induces inflammatory cytokines and is associated with an impaired overall survival.
- 2015
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 1532-1827 .- 0007-0920. ; 113:8, s. 1234-1243
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is the most common cancer form among women today. Depending on hormone receptor status, breast cancers are divided into different subtypes with vastly varying prognosis. S100A9 is a calcium-binding protein that is associated with inflammation and expressed not only in myeloid cells but also in some tumours. The role for S100A9 in the malignant cells is not well characterised; however, previous studies have shown that the protein could have important immune-modulating properties.
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| 3. |
- Berntsson, Jonna, et al.
(författare)
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Expression and prognostic significance of the polymeric immunoglobulin receptor in epithelial ovarian cancer
- 2014
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Ingår i: Journal of Ovarian Research. - : Springer Science and Business Media LLC. - 1757-2215. ; 7:1, s. 26-
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Tidskriftsartikel (refereegranskat)abstract
- Background: High expression of the polymeric immunoglobulin receptor (PIGR) has previously been associated with a favourable prognosis in a few cancer forms, but its expression and relationship with clinical outcome in epithelial ovarian cancer (EOC) has not yet been reported. The aim of this study was therefore to examine the clinicopathological correlates and prognostic significance of PIGR expression in EOC. Methods: After an initial screening in the Human Protein Atlas portal, a validated antibody was selected for extended analysis of immunohistochemical PIGR expression in tissue microarrays with tumours from 154 incident cases of EOC from two pooled prospective population-based cohorts. Subsets of corresponding benign-appearing fallopian tubes (n = 38) and omental metastases (n = 33) were also analysed. Kaplan-Meier analysis and Cox regression analysis were applied to examine the impact of PIGR expression on overall survival (OS) and ovarian cancer-specific survival (OCSS). Results: PIGR expression was significantly higher in fallopian tubes compared to primary tumours and metastases (p < 0.001) and lower in carcinoma of the serous subtype compared to other carcinomas (p < 0.001). PIGR expression was significantly associated with lower grade (p = 0.001), mucinous histological subtype (p = 0.002), positive progesterone receptor expression (p = 0.009) and negative or low Ki-67 expression (p = 0.003). Kaplan-Meier analysis revealed a significantly improved OS (p = 0.013) and OCSS (p = 0.009) for patients with tumours displaying high expression of PIGR. These associations were confirmed in unadjusted Cox regression analysis (HR = 0.48; 95% CI 0.26-0.87; p = 0.015 for OS and HR = 0.43, 95% CI 0.22-0.82; p = 0.011 for OCSS) but did not remain significant after adjustment for age, grade and clinical stage. Conclusions: This study provides a first demonstration of PIGR expression in human fallopian tubes, primary EOC tumours and metastases. High tumour-specific expression of PIGR was found to be associated with a favourable prognosis in unadjusted, but not in adjusted, analysis. These findings are novel and merit further investigation.
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| 4. |
- BORG, DAVID, et al.
(författare)
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Expression of IFITM1 as a prognostic biomarker in resected gastric and esophageal adenocarcinoma
- 2016
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Ingår i: Biomarker research. - : Springer Science and Business Media LLC. - 2050-7771. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: There is an increasing amount of reports on IFITM1 (interferon-inducible transmembrane protein 1) in various malignancies. The aim of this study was to examine the expression of IFITM1 and its prognostic significance in gastroesophageal adenocarcinoma.METHODS: Tissue samples were obtained from a consecutive cohort of 174 patients surgically treated between 2006 and 2010 for gastroesophageal (gastric, gastroesophageal junction and esophageal) adenocarcinoma, not subjected to neoadjuvant therapy. Expression of IFITM1 was examined using immunohistochemistry on tissue microarrays of primary tumors and paired samples of adjacent normal epithelium, intestinal metaplasia and lymph node metastases.RESULTS: Expression of IFITM1 was significantly elevated in primary tumors and lymph node metastases compared to adjacent normal epithelium and intestinal metaplasia, regardless of tumor location. Overexpression of IFITM1 was associated with M0-disease (no distant metastases). In gastric cancer IFITM1 expression was significantly associated with improved TTR (time to recurrence) in Kaplan-Meier analysis and Cox regression, both in the unadjusted analysis (HR 0.33, 95 % CI 0.12-0.88) and in the adjusted analysis (HR 0.32, 95 % CI 0.12-0.87) but there was no significant impact on OS (overall survival). In esophageal adenocarcinoma expression of IFITM1 had no impact on TTR or OS in Kaplan-Meier-analyses, but in the adjusted Cox regression IFITM1 expression had a negative impact on both TTR (HR 3.05, 95 % CI 1.09-8.53) and OS (HR 2.71, 95 % CI 1.11-6.67).CONCLUSIONS: IFITM1 was overexpressed in gastroesophageal adenocarcinoma and associated with M0-disease. In gastric cancer IFITM1 expression had a positive impact on TTR but in esophageal cancer it seemed to have an adverse impact on survival. The reason for the diverging prognostic impact of IFITM1 in esophageal and gastric cancer is unclear and warrants further studies.
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| 5. |
- Borgquist, Signe, et al.
(författare)
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HMG-CoA reductase expression in breast cancer is associated with a less aggressive phenotype and influenced by anthropometric factors
- 2008
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 123:5, s. 1146-53
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Tidskriftsartikel (refereegranskat)abstract
- Although several studies have reported on the anti-tumoural properties exerted by 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAR) inhibitors (statins), the in vivo expression of HMG-CoAR in human cancer has been considerably less investigated. In our study, we examined the immunohistochemical expression of HMG-CoAR in 511 incident breast cancers within the Malmö Diet and Cancer Study in order to explore its relationship to established clinicopathological and tumour biological parameters. Furthermore, the potential influence of estrogen exposure on HMG-CoAR expression was assessed by performing Cox's proportional hazards analyses of the relationship between the use of hormone replacement therapy (HRT), obesity (waist circumference) and tumour-cell specific HMG-CoAR expression. We found that HMG-CoAR was present in various fractions and intensities in the cytoplasm, sometimes with a membranous pattern, but not in the tumour cell nuclei. The expression of HMG-CoAR was associated with a smaller tumour size (p = 0.02), low histological grade (p = 0.001), low Ki67 index (p = 0.004), ERalpha+ (p = 0.02), ERbeta+ (p = 0.005), and high p27 expression (p = <0.001). The incidence of tumours with a high HMG-CoAR-expression was increased among HRT-users, although this was not statistically significant in a heterogeneity analysis. Obesity was significantly associated with a high HMG-CoAR expression assessed both as a high (>50%) fraction of positive cells (relative risk: 2.06; 95% confidence interval: 1.20-3.51), and a strong staining intensity (2.33: 1.08-5.02). In summary, we demonstrate that HMG-CoAR is differentially expressed in breast cancer and that a high expression is associated with prognostically favourable tumour parameters. Moreover, estrogen related life-style and anthropometric factors might indeed regulate HMG-CoAR expression.
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| 6. |
- 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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| 7. |
- Dahlgren, Malin, et al.
(författare)
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CITED1 as a marker of favourable outcome in anti-endocrine treated, estrogen-receptor positive, lymph-node negative breast cancer.
- 2023
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Ingår i: BMC Research Notes. - 1756-0500. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate CITED1 as a potential biomarker of anti-endocrine response and breast cancer recurrence, given its previously determined role in mediating estrogen-dependant transcription. The study is a continuation of earlier work establishing the role of CITED1 in mammary gland development.Results: CITED1 mRNA is associated with estrogen-receptor positivity and selectively expressed in the GOBO dataset of cell lines and tumours representing the luminal-molecular subtype. In patients treated with tamoxifen, higher CITED1 correlated with better outcome, suggesting a role in anti-estrogen response. The effect was particularly evident in the subset of estrogen-receptor positive, lymph-node negative (ER+/LN-) patients although noticeable divergence of the groups was apparent only after five years. Tissue microarray (TMA) analysis further validated the association of CITED1 protein, by immunohistochemistry, with favourable outcome in ER+, tamoxifen-treated patients. Although we also found a favourable response to anti-endocrine treatment in a larger TCGA dataset, the tamoxifen-specific effect was not replicated. Finally, MCF7 cells overexpressing CITED1 showed selective amplification of AREG but not TGFα suggesting that maintenance of specific ERα-CITED1 mediated transcription is important for the long-term response to anti-endocrine therapy. These findings together confirm the proposed mechanism of action of CITED1 and support its potential use as a prognostic biomarker.
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| 8. |
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| 9. |
- Dahlman, Anna K, et al.
(författare)
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Evaluation of the prognostic significance of MSMB and CRISP3 in prostate cancer using automated image analysis.
- 2011
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Ingår i: Modern Pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. - : Elsevier BV. - 1530-0285. ; 24, s. 708-719
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Tidskriftsartikel (refereegranskat)abstract
- Despite prostate cancer being the most frequent cancer in men in the Western world, tissue biomarkers for predicting disease recurrence after surgery have not been incorporated into clinical practice. Our group has previously identified β-microseminoprotein (MSMB) and cysteine-rich secretory protein-3 (CRISP3) as independent predictors of biochemical recurrence after radical prostatectomy. The purpose of the present study was to use automated image analysis, enabling quantitative determination of MSMB and CRISP3 expressions in a large cohort and to validate the previous findings. MSMB and CRISP3 protein expressions were assessed on tissue microarrays constructed from 3268 radical prostatectomy specimens. Whole-slide digital images were captured, and a novel cytoplasmic algorithm was used to develop a quantitative scoring model for cytoplasmic staining. Classification regression tree analysis was used to group patients, with different risk for biochemical recurrence, depending on level of protein expression. Patients with tumors expressing high levels of MSMB had a significantly reduced risk for biochemical recurrence after radical prostatectomy (HR=0.468; 95% CI 0.394-0.556; P<0.001). Multivariate analysis adjusted for clinicopathological parameters revealed that MSMB expression was an independent predictor of decreased risk of recurrence (HR=0.710; 95% CI 0.578-0.872; P<0.001). We found no correlation between CRISP3 expression and biochemical recurrence. In this current study, we applied a novel image analysis on a large independent cohort and successfully verified that MSMB is a strong independent factor, predicting favorable outcome after radical prostatectomy for localized prostate cancer.Modern Pathology advance online publication, 14 January 2011; doi:10.1038/modpathol.2010.238.
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| 10. |
- 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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| 11. |
- Elebro, Jacob, et al.
(författare)
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Prognostic and treatment predictive significance of SATB1 and SATB2 expression in pancreatic and periampullary adenocarcinoma
- 2014
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 12, s. 289-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Pancreatic cancer and other pancreaticobiliary type periampullary adenocarcinomas have a dismal prognosis even after resection and neoadjuvant chemotherapy. Intestinal type periampullary adenocarcinomas generally have a better prognosis, but little is known on optimal neoadjuvant and adjuvant treatment. New prognostic and treatment predictive biomarkers are needed for improved treatment stratification of patients with both types of periampullary adenocarcinoma. Expression of the Special AT-rich sequence-binding protein 1 (SATB1) has been demonstrated to confer a worse prognosis in several tumour types, whereas its close homologue SATB2 is a proposed diagnostic and favourable prognostic marker for colorectal cancer. The prognostic value of SATB1 and SATB2 expression in periampullary adenocarcinoma has not yet been described. Methods: Immunohistochemical expression of SATB1 and SATB2 was analysed in tissue microarrays with primary tumours and a subset of paired lymph node metastases from 175 patients operated with pancreaticoduodenectomy for periampullary adenocarcinoma. Kaplan-Meier and Cox regression analysis were applied to explore the impact of SATB1 and SATB2 expression on recurrence free survival (RFS) and overall survival (OS). Results: Positive expression of SATB1 was denoted in 16/106 primary pancreatobiliary type tumours and 11/65 metastases, and in 15/63 primary intestinal type tumours and 4/26 metastases, respectively. Expression of SATB1 was an independent predictor of a significantly shorter RFS and OS in pancreatobiliary type, but not in intestinal type adenocarcinomas. Moreover, SATB1 expression predicted an improved response to adjuvant chemotherapy in both tumour types. SATB2-expression was seen in 3/107 pancreatobiliary type primary tumours, and in 8/61 intestinal type primary tumours. The small number of cases with positive SATB2 expression did not allow for any firm conclusions on its prognostic value. Conclusions: These findings demonstrate the potential utility of SATB1 as a prognostic and predictive biomarker for chemotherapy response in both intestinal type and pancreatobiliary type periampullary adenocarcinomas, including pancreatic cancer.
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| 12. |
- Fristedt, Richard, et al.
(författare)
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Expression and prognostic significance of the polymeric immunoglobulin receptor in esophageal and gastric adenocarcinoma
- 2014
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Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 12, s. 83-
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The polymeric immunoglobulin receptor (PIGR) has been proposed to be a candidate prognostic biomarker in a few cancer forms, and one previous study reported that reduced PIGR expression signifies more aggressive tumours of the distal esophagus and gastroesophageal junction (GEJ). In the present study, we examined the expression, clinicopathological correlates and prognostic significance of PIGR expression in an extended cohort of adenocarcinoma of the upper gastrointestinal tract. Materials and methods: Immunohistochemical PIGR expression was examined in a consecutive cohort of patients with surgically resected, radio-chemonaive adenocarcinoma of the esophagus, GE-junction and stomach (n = 173), including paired samples of benign-appearing squamous epithelium (n = 51), gastric mucosa (n = 114), Barrett's esophagus (BE) or intestinal metaplasia (IM) (n = 57) and lymph node metastases (n = 75). Non-parametric tests were applied to explore associations between PIGR expression in primary tumours and clinicopathological characteristics. Classification and regression tree analysis was applied for selection of prognostic cut-off. The impact of PIGR expression on overall survival (OS) and recurrence-free survival (RFS) was assessed by Kaplan-Meier analysis and hazard ratios (HR) calculated by adjusted and unadjusted Cox proportional hazards modelling. Results: PIGR expression was significantly higher in intestinal metaplasia (BE or gastric IM) compared to normal tissues and cancer (p < 0.001). Reduced PIGR expression in primary tumours was significantly associated with more advanced tumour stage (p = 0.002) and inversely associated with involved margins (p = 0.034). PIGR expression did not differ between primary tumours and lymph node metastases. There was no significant difference in PIGR expression between tumours with and without a background of intestinal metaplasia. High PIGR expression was an independent predictor of a prolonged OS (HR = 0.60, 95% CI 0.36-0.99) and RFS (HR = 0.49, 95% CI 0.27-0.90) in patients with radically resected (R0) primary tumours and of an improved RFS (HR = 0.32, 95% CI 0.15-0.69) in curatively treated patients with R0 resection/distant metastasis-free disease. Conclusion: High PIGR expression independently predicts a decreased risk of recurrence and an improved survival in patients with adenocarcinoma of the upper gastrointestinal tract. These findings are of potential clinical relevance and merit further validation.
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| 13. |
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| 14. |
- Fristedt, Richard, et al.
(författare)
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Reduced expression of the polymeric immunoglobulin receptor in pancreatic and periampullary adenocarcinoma signifies tumour progression and poor prognosis
- 2014
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:11, s. 112728-112728
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Tidskriftsartikel (refereegranskat)abstract
- The polymeric immunoglobulin receptor (pIgR) is a key component of the mucosal immune system that mediates epithelial transcytosis of immunoglobulins. High pIgR expression has been reported to correlate with a less aggressive tumour phenotype and an improved prognosis in several human cancer types. Here, we examined the expression and prognostic significance of pIgR in pancreatic and periampullary adenocarcinoma. The study cohort encompasses a consecutive series of 175 patients surgically treated with pancreaticoduodenectomy for pancreatic and periampullary adenocarcinoma in Malmö and Lund University Hospitals, Sweden, between 2001-2011. Tissue microarrays were constructed from primary tumours (n = 175) and paired lymph node metastases (n = 105). A multiplied score was calculated from the fraction and intensity of pIgR staining. Classification and regression tree analysis was used to select the prognostic cut-off. Unadjusted and adjusted hazard ratios (HR) for death and recurrence within 5 years were calculated. pIgR expression could be evaluated in 172/175 (98.3%) primary tumours and in 96/105 (91.4%) lymph node metastases. pIgR expression was significantly down-regulated in lymph node metastases as compared with primary tumours (p = 0.018). Low pIgR expression was significantly associated with poor differentiation grade (p < 0.001), perineural growth (p = 0.027), lymphatic invasion (p = 0.016), vascular invasion (p = 0.033) and infiltration of the peripancreatic fat (p = 0.039). In the entire cohort, low pIgR expression was significantly associated with an impaired 5-year survival (HR = 2.99, 95% confidence interval (CI) 1.71-5.25) and early recurrence (HR = 2.89, 95% CI 1.67-4.98). This association remained significant for survival after adjustment for conventional clinicopathological factors, tumour origin and adjuvant treatment (HR = 1.98, 95% CI 1.10-3.57). These results demonstrate, for the first time, that high tumour-specific pIgR expression signifies a more favourable tumour phenotype and that low expression independently predicts a shorter survival in patients with pancreatic and periampullary cancer. The mechanistic basis for the putative tumour suppressing properties of pIgR in these cancers merits further study.
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| 15. |
- Gaber, Alexander, et al.
(författare)
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Effects of radiation therapy on tissue and serum concentrations of tumour associated trypsin inhibitor and their prognostic significance in rectal cancer patients
- 2011
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Ingår i: Radiation Oncology. - 1748-717X. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Background: We have previously demonstrated that elevated concentrations of tumour-associated trypsin inhibitor (TATI) in both tumour tissue (t-TATI) and in serum (s-TATI) are associated with a poor prognosis in colorectal cancer patients. It was also found that s-TATI concentrations were lower in patients with rectal cancer compared to patients with colon cancer. In this study, we investigated the effects of neoadjuvant radiotherapy (RT) on concentrations of t-TATI and s-TATI in patients with rectal cancer. Methods: TATI was analysed in serum, normal mucosa and tumour tissue collected at various time points in 53 rectal cancer patients enrolled in a case-control study where 12 patients received surgery alone, 20 patients 5 x 5 Gy (short-term) preoperative RT and 21 patients 25 x 2 Gy (long-term) preoperative RT. T-TATI was analysed by immunohistochemistry and s-TATI was determined by an immunofluorometric assay. Mann-Whitney U test and Wilcoxon Z (Z) test were used to assess t-TATI and s-TATI concentrations in relation to RT. Spearman's correlation (R) test was used to explore the associations between t-TATI, s-TATI and clinicopathological parameters. Overall survival (OS) according to high and low t-TATI and s-TATI concentrations was estimated by classification and regression tree analysis, Kaplan-Meier analysis and the log rank test. Results: RT did not affect concentrations of t-TATI or s-TATI. In patients receiving short-term but not long-term RT, s-TATI concentrations were significantly higher 4 weeks post surgery than in serum drawn prior to surgery (Z = -3.366, P < 0.001). T-TATI expression correlated with male gender (R = 0.406, P = 0.008). High t-TATI expression in surgical specimens was associated with a significantly shorter OS (P = 0.045). S-TATI concentrations in serum drawn at all time points were associated with an impaired OS (P = 0.035 before RT, P = 0.001 prior to surgery, P = 0.043 post surgery). At all time points, s-TATI correlated with higher age (P < 0.001-0.021) and with increased s-creatinine concentrations assessed prior to surgery (P = 0.041). Conclusions: The results presented here further validate the utility of t-TATI and s-TATI as prognostic biomarkers in patients with rectal cancer, independent of neoadjuvant RT.
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| 16. |
- Gaber, Alexander, et al.
(författare)
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High expression of tumour-associated trypsin inhibitor correlates with liver metastasis and poor prognosis in colorectal cancer
- 2009
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Ingår i: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 100:10, s. 1540-1548
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Tidskriftsartikel (refereegranskat)abstract
- Increased expression of tumour-associated trypsin inhibitor (TATI) in tumour tissue and/or serum has been associated with poor survival in various cancer forms. Moreover, a proinvasive function of TATI has been shown in colon cancer cell lines. In this study, we have examined the prognostic significance of tumour-specific TATI expression in colorectal cancer, assessed by immunohistochemistry (IHC) on tissue microarrays (TMAs) with tumour specimens from two independent patient cohorts. Kaplan-Meier analysis and Cox proportional hazards modelling were used to estimate time to recurrence, disease-free survival and overall survival. In both cohorts, a high (>50% of tumour cells) TATI expression was an independent predictor of a significantly shorter overall survival. In cohort II, in multivariate analysis including age, gender, disease stage, differentiation grade, vascular invasion and carcinoembryonal antigen (CEA), high TATI expression was associated with a significantly decreased overall survival (HR=1.82; 95% CI=1.19-2.79) and disease-free survival (HR=1.56; 95% CI=1.05-2.32) in curatively treated patients. Moreover, there was an increased risk for liver metastasis in both cohorts that remained significant in multivariate analysis in cohort II (HR=2.85; 95% CI=1.43-5.66). In conclusion, high TATI expression is associated with liver metastasis and is an independent predictor of poor prognosis in patients with colorectal cancer.
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| 17. |
- Gaber, Alexander, et al.
(författare)
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Increased serum levels of tumour-associated trypsin inhibitor independently predict a poor prognosis in colorectal cancer patients
- 2010
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 10, s. 498-
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is an insufficient number of reliable prognostic and response predictive biomarkers in colorectal cancer (CRC) management. In a previous study, we found that high tumour tissue expression of tumour-associated trypsin inhibitor (TATI) correlated with liver metastasis and an impaired prognosis in CRC. The aim of this study was to investigate the prognostic validity of serum TATI (s-TATI) in CRC. We further assessed the prognostic value of carcino-embryonic antigen in serum (s-CEA) and the interrelationship between s-TATI and TATI in tissue (t-TATI). Methods: Using an immunofluorometric assay, s-TATI levels were analysed in 334 preoperatively collected serum samples from patients with CRC. Spearman's Rho and Chi-square test were used for analysis of correlations between s-TATI and clinicopathological parameters, s-CEA and t-TATI. Kaplan-Meier analysis and Cox uni-and multivariate regression analysis were used to estimate disease free survival (DFS) and overall survival (OS) according to quartiles of s-TATI and cut-offs derived from ROC-analysis of s-TATI and s-CEA. Results: Increased levels of s-TATI were associated with a reduced DFS (HR = 2.00; 95% CI 1.40-2.84, P < 0.001) and OS (HR = 2.40; 95% CI 1.74-3.33, P < 0.001). (HR = 2.89; 95% CI 1.96-4.25). This association remained significant in multivariate analysis. The association for OS remained significant in multivariate analysis (HR = 1.51; 95% CI 1.032.22, P = 0.034 for DFS and HR = 1.78; 95% CI 1.25-2.53, P = 0.001 for OS). There was no significant association between s-TATI and t-TATI. The prognostic value of s-CEA was also evident, but somewhat weaker than for s-TATI. Conclusions: High preoperative s-TATI levels predict a poor prognosis in patients with CRC, and the prognostic value is independent of established prognostic parameters and t-TATI expression. These data suggest that s-TATI might be a useful marker for prognostic stratification in CRC.
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| 18. |
- Gaber, Alexander
(författare)
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Prognostic role of tumour associated trypsin inhibitor in colorectal cancer patients
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Colorectal cancer (CRC) is one of the most common forms of human cancer worldwide with approximately 1 million new cases detected every year. CEA is currently the only accepted CRC marker incorporated into clinical practice, where it is used for early detection of metastasis in follow-up of patients having stage II and III disease, and for monitoring response to adjuvant treatment. However there are no reliable prognostic and response predictive biomarkers for CRC. Tumour-associated trypsin inhibitor (TATI) is a form of antitrypsin, a 6kDa enzyme that inhibits trypsin with great affinity and TATI has previously been found to be of prognostic importance in mucinous ovarian cancer and other cancer forms. TATI is expressed in normal colonic mucosa, where its main function is to act as an antitrypsin, protecting the tissue from proteolysis. TATI has also been shown to promote migration and invasion in colorectal cancer cell lines in vitro. Moreover, TATI has a similar molecular structure to epidermal growth factor (EGF) and has been found to bind to EGFR and promote malignant behaviour in various cell line models. The prognostic significance of TATI in CRC patients had however not been reported and the main aim of the present investigation was therefore to examine levels of TATI in tumour tissue and serum samples from three independent CRC patient cohorts, with particular reference to their association with clinical outcome. In addition, we assessed the effect of neoadjuvant radiation therapy (RT) on TATI levels in tissue and serum of rectal cancer patients, and whether expression of epidermal growth factor receptor (EGFR) and markers of downstream signalling have a modifying effect on the prognostic value of TATI. In paper I, we investigated TATI expression by immunohistochemistry (IHC) in CRC tumours (t-TATI) in two cohorts adding up to 424 patients. High TATI expression was found to be significantly associated to short overall survival (OS), and disease free survival (DFS), as well as an increased risk of liver metastasis. In paper II, we analysed the prognostic value of TATI in serum (s-TATI) in one of the cohorts used in Paper I (n = 334). While no significant correlation was found between s-TATI and t-TATI concentrations, the prognostic value of s-TATI was more evident than for t-TATI, the former being a strong independent predictor of an impaired OS, DFS and time to recurrence (TTR), suggesting that elevated serum concentrations are not a result of TATI production by the tumour. Further results from paper II revealed that s-TATI concentrations were lower in rectal cancer patients, the majority of whom had received neoadjuvant radiotherapy (RT). In paper III, we therefore ventured to investigate whether neoadjuvant RT affects TATI concentrations in tissue and serum. To this end, we analysed serum and tissue samples collected at multiple timepoints from 53 patients with rectal cancer included in a in a case-control study. The results revealed that t-TATI and s-TATI levels remained unaffected by RT. S-TATI was significantly associated with shorter OS at all timepoints, and t-TATI assessed in surgical specimens was also a factor of poor prognosis. In paper IV we investigated the associations of s-TATI and t-TATI to EGFR expression and downstream signalling proteins pSTAT3 and pERK1/2, as well as KRAS mutation status. Apart from a significant association between t-TATI expression and KRAS mutation status, there was no intercorrelation between t-TATI or s-TATI and the investigative markers. Expression of pERK1/2 and pSTAT3, and KRAS mutation status, was significantly associated with poor prognosis. The prognostic value of EGFR expression, being non-significant per se, was modified by s-TATI concentrations in that patients with EGFR positive tumours/ high s-TATI levels had a significantly shorter survival compared to patients with EGFR negative tumours/ low s-TATI levels.
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| 19. |
- Hedner, Charlotta, et al.
(författare)
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SATB1 is an independent prognostic factor in radically resected upper gastrointestinal tract adenocarcinoma
- 2014
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Ingår i: Virchows Archiv. - : Springer Science and Business Media LLC. - 0945-6317 .- 1432-2307. ; 465:6, s. 649-659
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Tidskriftsartikel (refereegranskat)abstract
- Gastric cancer is the second most common cause of cancer-related death worldwide, and the incidence of esophageal adenocarcinoma is rising. While some progress has been made in treatment strategies, overall survival remains very poor for patients with adenocarcinoma in the upper gastrointestinal tract. Special AT-rich sequence binding protein 1 (SATB1) is a global genome organizer that has been demonstrated to promote aggressive tumor behavior in several different types of cancer, including gastric cancer. The prognostic value of SATB1 expression in esophageal cancer has, however, not yet been described. In this study, expression of SATB1 was examined by immunohistochemistry on tissue microarrays prepared from tissue samples from 175 patients with adenocarcinoma of the esophagus, cardia, or stomach and containing normal tissue, intestinal metaplasia, primary tumors, and metastases. A well-validated antibody was used. We found SATB1 to be an independent prognostic factor in patients with a radically resected tumor, correlating with shorter overall survival as well as with shorter recurrence-free survival. SATB1 expression was also found to be significantly lower in primary tumors associated with intestinal metaplasia than those without intestinal metaplasia. This observation is of potential biological interest as it has been proposed that intestinal metaplasia-associated tumors constitute a less aggressive phenotype.
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| 20. |
- Hjelm, Barbara, et al.
(författare)
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High nuclear RBM3 expression is associated with an improved prognosis in colorectal cancer
- 2011
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Ingår i: Proteomics Clinical Applications. - : Wiley. - 1862-8354 .- 1862-8346. ; 5:11-12, s. 624-635
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: In this study, we investigated the prognostic impact of human RBM3 expression in colorectal cancer using tissue microarray-based immunohistochemical analysis. Experimental design: One polyclonal antibody and four monoclonal anti-RBM3 antibodies were generated and epitope mapped using two different methods. Bacterial display revealed five distinct epitopes for the polydonal antibody, while the four mouse monoclonal antibodies were found to bind to three of the five epitopes. A peptide suspension bead array assay confirmed the five epitopes of the polydonal antibody, while only one of the monoclonal antibodies could be mapped using this approach. Antibody specificity was confirmed by Western blotting and immunohistochemistry, including siRNA-mediated knock-down. Two of the antibodies (polydonal and monoclonal) were subsequently used to analyze RBM3 expression in tumor samples from two independent colorectal cancer cohorts, one consecutive cohort (n = 270) and one prospectively collected cohort of patients with cancer of the sigmoid colon (n = 305). RBM3-expression was detected, with high correlation between both antibodies (R = 0.81, p < 0.001). Results: In both cohorts, tumors with high nuclear RBM3 staining had significantly prolonged the overall survival. This was also confirmed in multivariate analysis, adjusted for established prognostic factors. Conclusion and clinical relevance: These data demonstrate that high tumor-specific nuclear expression of RBM3 is an independent predictor of good prognosis in colorectal cancer.
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| 21. |
- Isaksson, Sofi, et al.
(författare)
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Detecting EGFR alterations in clinical specimens-pitfalls and necessities.
- 2013
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Ingår i: Virchows Archiv: an international journal of pathology. - : Springer Science and Business Media LLC. - 1432-2307. ; 463:6, s. 755-764
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the epidermal growth factor receptor (EGFR) status in early stage lung cancer in Southern Sweden, a population for which there are no previous reports on the EGFR mutation frequency. Three hundred fifty small cell lung cancers, adenocarcinomas (AC), squamous cell carcinomas (SqCC), and large cell carcinomas were analyzed using a combination of techniques for the analysis of protein expression, gene copy numbers, and mutations. Immunohistochemical (IHC) staining with antibodies for the EGFR mutations L858R and del E746-A750 revealed intratumoral heterogeneity and several discrepant cases when compared to mutation-specific polymerase chain reaction (PCR)-based analysis. The frequencies of these two mutations, when considering IHC staining with mutation-specific antibodies in a cohort of 298 cases and subsequent confirmation by PCR, were 10 % in AC and <2 % in SqCC. Furthermore, screening by sequencing of EGFR in a cohort of 52 lung AC and squamous carcinomas demonstrated a more diverse mutation spectrum, not covered by the mutation-specific antibodies. High expression of total EGFR protein was correlated to high gene copy numbers but did not reflect the mutational status of the tumors. We believe that the mutation spectra in a Southern Swedish population is too diverse to be covered by the mutation-specific antibodies, and we also raise some other issues regarding the use of the mutation-specific antibodies, for example concerning heterogeneous expression of the mutated protein, optimal antibody dilution, and discrepancies between staining results and PCR.
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| 22. |
- Jonsson, L., et al.
(författare)
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High expression of RNA-binding motif protein 3 in esophageal and gastric adenocarcinoma correlates with intestinal metaplasia-associated tumours and independently predicts a reduced risk of recurrence and death
- 2014
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Ingår i: Biomarker Research. - : BioMed Central Ltd.. - 2050-7771. ; 2:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: High nuclear expression of the RNA-binding motif protein 3 (RBM3) has previously been found to correlate with favourable clinicopathological characteristics and a prolonged survival in several cancer forms. Here, we examined the clinicopathological correlates and prognostic significance of RBM3 expression in tumours from a consecutive cohort of upper gastrointestinal adenocarcinoma.Material and methods: Immunohistochemical RBM3 expression was analysed in tissue microarrays with primary radiotherapy- and chemotherapy-naive adenocarcinoma of the esophagus, gastroesophageal junction and stomach (n = 173). In addition paired samples of normal squamous epithelium (n = 53), gastric mucosa (n = 117), Barrett's esophagus/gastric intestinal metaplasia (n = 61) and lymph node metastases (n = 71) were analysed. Kaplan-Meier analysis and Cox proportional hazards modelling was applied to assess the impact of RBM3 expression on overall survival (OS) and recurrence-free survival (RFS).Results: RBM3 expression was similar in primary tumours and lymph node metastases, but significantly higher in primary tumours and metastases arising in a background of intestinal metaplasia compared with cases without intestinal metaplasia (p < 0.001). RBM3 expression was significantly reduced in more advanced tumour stages (p = 0.006). Low RBM3 expression was significantly associated with a shorter OS in cases with radically resected (R0) tumours (HR 2.19, 95% CI 1.33-3.61, p = 0.002) and RFS in curatively treated patients with R0 resection/distant metastasis-free disease (HR = 3.21, 95% CI 1.64-6.30, p = 0.001). These associations remained significant in adjusted analysis (HR = 1.95, 95% CI 1.17-3.25, p = 0.010 for OS and HR = 3.02, 95% CI 1.45-6.29, p = 0.003 for RFS).Conclusion: High expression of RBM3 may signify a subset of upper gastrointestinal cancers arising in a background of intestinal metaplasia and independently predicts a reduced risk of recurrence and death in patients with these cancer forms. These findings are of potential clinical utility and merit further validation.
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| 23. |
- Jonsson, Liv, et al.
(författare)
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High RBM3 expression in prostate cancer independently predicts a reduced risk of biochemical recurrence and disease progression
- 2011
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Ingår i: Diagnostic Pathology. - : Springer Science and Business Media LLC. - 1746-1596. ; 6, s. 91-
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Tidskriftsartikel (refereegranskat)abstract
- Background: High expression of the RNA-binding protein RBM3 has previously been found to be associated with good prognosis in breast cancer, ovarian cancer, malignant melanoma and colorectal cancer. The aim of this study was to examine the prognostic impact of immunohistochemical RBM3 expression in prostate cancer. Findings: Immunohistochemical RBM3 expression was examined in a tissue microarray with malignant and benign prostatic specimens from 88 patients treated with radical prostatectomy for localized disease. While rarely expressed in benign prostate gland epithelium, RBM3 was found to be up-regulated in prostate intraepithelial neoplasia and present in various fractions and intensities in invasive prostate cancer. High nuclear RBM3 expression was significantly associated with a prolonged time to biochemical recurrence (BCR) (HR 0.56, 95% CI: 0.34-0.93, p = 0.024) and clinical progression (HR 0.09, 95% CI: 0.01-0.71, p = 0.021). These associations remained significant in multivariate analysis, adjusted for preoperative PSA level in blood, pathological Gleason score and presence or absence of extracapsular extension, seminal vesicle invasion and positive surgical margin (HR 0.41, 95% CI: 0.19-0.89, p = 0.024 for BCR and HR 0.06, 95% CI: 0.01-0.50, p = 0.009 for clinical progression). Conclusion: Our results demonstrate that high nuclear expression of RBM3 in prostate cancer is associated with a prolonged time to disease progression and, thus, a potential biomarker of favourable prognosis. The value of RBM3 for prognostication, treatment stratification and follow-up of prostate cancer patients should be further validated in larger studies.
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| 24. |
- Krzyzanowska, Agnieszka, et al.
(författare)
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Expression of tSTAT3, pSTAT3 727 , and pSTAT3 705 in the epithelial cells of hormone-naïve prostate cancer
- 2019
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Ingår i: Prostate. - : Wiley. - 0270-4137. ; 79:7, s. 784-797
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Tidskriftsartikel (refereegranskat)abstract
- Background: The signal transducer and activator of transcription 3 (STAT3) pathway is observed to be constitutively activated in several malignancies including prostate cancer (PCa). In the present study, we investigated the expression of total STAT3 (tSTAT3) and two forms of activated phosphorylated STAT3 (pSTAT3 727 and pSTAT3 705 ) in tissue microarrays (TMA) of two cohorts of localized hormone-naïve PCa patients and analyzed associations between the expression and disease outcome. Methods: The expression of tSTAT3, pSTAT3 727 , and pSTAT3 705 was scored in the nuclei and cytoplasm of prostatic gland epithelial cells in two TMAs of paraffin-embedded prostatic tissue. The TMAs consisted of tissue originated from hormone-naïve radical prostatectomy patients from two different sites: Malmö, Sweden (n = 300) and Dublin, Ireland (n = 99). Results: The nuclear expression levels of tSTAT3, pSTAT3 727 , and pSTAT3 705 in the epithelial cells of benign glands were significantly higher than in the cancerous glands. Cytoplasmic tSTAT3 levels were also higher in benign glands. Patients with low pSTAT3 727 and pSTAT3 705 levels in the cancerous glands showed reduced times to biochemical recurrence, compared with those with higher levels. No significant trends in nuclear nor in cytoplasmic tSTAT3 were observed in relation to biochemical recurrence in the Malmö cohort. Higher cytoplasmic tSTAT3 was associated with reduced time to biochemical recurrence in the Dublin cohort. Adding the tSTAT3 and pSTAT3 expression data to Gleason score or pathological T stage did not improve their prognostic values. Conclusions: Low pSTAT3 727 and pSTAT3 705 expression in epithelial cells of cancerous prostatic glands in hormone-naïve PCa was associated with faster disease progression. However, pSTAT3 and tSTAT3 expression did not improve the prognostic value of Gleason score or pathological T stage and may not be a good biomarker in the early hormone naïve stages of PCa.
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| 25. |
- 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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