Podocalyxin-like and RNA-binding motif protein 3 are prognostic biomarkers in urothelial bladder cancer: a validatory study.

BACKGROUND: Urothelial bladder cancer (UBC) is a disease that often is discovered when the tumour is non-muscle invasive, i.e. in Ta or T1 stage. Some patients will progress into muscle-invasive disease, a potentially deadly condition. Although there are some prognostic models, the need for prognostic and predictive biomarkers is considerate and urgent. Membranous expression of podocalyxin-like protein 1 (PODXL) and low expression of the RNA-binding motif 3 (RBM3) has previously been shown to be associated with an aggressive tumour phenotype and poor prognosis in several forms of cancer, including UBC. In this study, we sought to validate the prognostic impact of PODXL and RBM3 in an independent cohort of UBC. METHODS: Using tissue microarrays and immunohistochemistry, PODXL and RBM3 expression was evaluated in 272 incident UBC cases from the prospective, population-based cohort study Malmö Diet and Cancer. Kaplan-Meier analysis and Cox proportional hazards modelling were used to evaluate the prognostic impact of these markers on 5-year overall survival (OS). RESULTS: In line with previous studies, both membranous PODXL expression and low RBM3 expression was significantly associated with disadvantageous clinicopathological features. Membranous PODXL expression was significantly associated with a reduced 5-year overall survival in the entire cohort (univariable HR 3.28; 95% CI 1.89-5.69), but this association did not remain significant in multivariable analysis. In T1 tumours, PODXL was significantly associated with reduced survival in univariable analysis (HR = 2.83; 95% CI 1.04-7.72) and borderline significant in multivariable analysis (HR = 2.60; 95% CI 0.91-7.39). Low RBM3 expression was an independent predictor of a reduced survival in the entire cohort (univariable HR 3.19; 95% CI 2.02-5.04, and multivariable HR 1.85; 95% CI 1.11-3.09), and in T1 tumours (univariable HR 2.64; 95% CI 1.11-6.27, and multivariable HR 2.63; 95% CI 1.01-6.84). CONCLUSIONS: A link between membranous PODXL expression and clinically more aggressive tumours was further confirmed, but PODXL expression was not an independent prognostic biomarker in this study. Low RBM3 expression was validated as an independent factor of poor prognosis in UBC, including T1 disease. These findings suggest that these biomarkers could be useful in stratifying patients with non-muscle invasive disease for more aggressive first line treatment.

Pancreatic cancer risk in relation to sex, lifestyle factors, and pre-diagnostic anthropometry in the Malmö Diet and Cancer Study.

BACKGROUND: Lifestyle factors may influence the risk of developing pancreatic cancer. Whereas cigarette smoking is an established risk factor, the effects of high alcohol intake and obesity are more uncertain. The aim of the present study was to examine the associations of pre-diagnostic anthropometry, alcohol consumption, and smoking habits with pancreatic cancer risk in a Swedish prospective, population-based cohort, with particular reference to potential sex differences. METHODS: The studied cohort consists of 28,098 participants, including all incident cases of pancreatic cancer, in the Malmö Diet and Cancer Study up until December 31, 2013 (n = 163). Non-parametric and chi-squared tests were applied to compare the distribution of risk factors between cases and non-cases. Cox regression proportional hazards models were used to estimate the relationship between investigative factors and pancreatic cancer risk. Anthropometric factors included height, weight, body mass index (BMI), waist and hip circumference, waist-hip ratio (WHR), and body fat percentage. RESULTS: BMI was not a significant risk factor for pancreatic cancer, but a higher WHR was significantly associated with an increased risk in the entire cohort (hazard ratio (HR) 2.36, 95% confidence interval (CI) 1.28-4.35, p for trend = 0.009). Regular smoking was a significant risk factor among both women (HR 2.62, 95% CI 1.61-4.27) and men (HR 3.57, 95% CI 1.70-7.47), whereas occasional smoking was a significant risk factor only in women (HR 3.29, 95% CI 1.50-7.19). Passive smoking at work for >20 years was significantly associated with an increased risk in the entire cohort (HR 1.73, 95% CI 1.15-2.58) and in women selectively (HR 2.01, 95% CI 1.21-3.31). Alcohol consumption was not a significant risk factor. A significant interaction was found between female sex and age (p = 0.045), but no other factor, in relation to pancreatic cancer risk. CONCLUSIONS: WHR was the only pre-diagnostic anthropometric factor associated with pancreatic cancer risk, with no sex-related differences. Regular smoking was confirmed as a significant risk factor in both sexes, whereas occasional and passive smoking were significant risk factors only in women. Despite the lack of a significant interaction between smoking and sex in relation with pancreatic cancer risk, potential sex differences should be considered in future epidemiological studies.

Incident urothelial cancer in the Malmö Diet and Cancer Study: cohort characteristics and further validation of ezrin as a prognostic biomarker.

BACKGROUND: Reduced membranous expression of the cytoskeleton-associated protein ezrin has previously been demonstrated to correlate with poor prognosis in urothelial bladder cancer in several independent studies. The present study provides a first description of clinicopathological characteristics of incident urothelial cancers, not only located to the bladder, in the prospective, population-based cohort study Malmö Diet and Cancer. In addition, the prognostic value of ezrin expression is validated in primary tumours, and the longitudinal expression of ezrin examined in a subset of primary and recurrent tumours (n=28). METHODS: Among a total number of 355 incident tumours registered up until Dec 31 2010, 335 were located to the bladder. Immunohistochemical expression of cytoplasmic and membranous ezrin was evaluated in tissue microarrays with primary tumours from 272 cases and recurrent tumours from 28 cases. A combined score of the minimum, mean and maximum fraction and percentage of staining was calculated. Classification regression tree analysis was applied for selection of prognostic cutoff. Kaplan-Meier analysis, log rank test, univariable and multivariable Cox regression proportional hazards' modeling were used to evaluate the impact of ezrin expression on 5-year overall survival (OS). RESULTS: Ezrin expression could be evaluated in 263/272 primary and all 28 recurrent tumours. Membranous but not cytoplasmic ezrin was significantly reduced in recurrent compared to primary tumours (p < 0.001). Low cytoplasmic and membranous ezrin expression were associated with more advanced T-stage (p = 0.004, p < 0.001) and high-grade tumours (p = 0.025, p < 0.001), but not with age, sex, tumour location or smoking status. Both low cytoplasmic and membranous ezrin staining were associated with a significantly reduced 5-year OS (HR = 1.65; 95% CI 1.06-2.57 and HR = 2.51, 95% CI 1.52-4.17), but only low membranous ezrin remained prognostic after adjustment for age, sex, stage, grade and smoking status (HR = 1.69, 95% CI 1.00-2.85). CONCLUSIONS: This study provides a first description of the clinicopathological characteristics of 355 incident urothelial cancers in the Malmö Diet and Cancer Study up until 2010. In addition, the value of ezrin expression as a prognostic biomarker is further consolidated in this type of cancer. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_189.

Reduced expression of ezrin in urothelial bladder cancer signifies more advanced tumours and an impaired survival: validatory study of two independent patient cohorts.

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-Guérin (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.