| 1. |
- Andersson, Gustav, et al.
(author)
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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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In: BMC Urology. - : BioMed Central (BMC). - 1471-2490. ; 14:1, s. 36-
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Journal article (peer-reviewed)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. |
- Boman, Karolina, et al.
(author)
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Decreased expression of RNA-binding motif protein 3 correlates with tumour progression and poor prognosis in urothelial bladder cancer
- 2013
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In: BMC Urology. - : Springer Science and Business Media LLC. - 1471-2490. ; 13:April,8, s. 17-17
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Journal article (peer-reviewed)abstract
- BACKGROUND: Low nuclear expression of the RNA-binding motif protein 3 (RBM3) has previously been found to be associated with poor prognosis in several cancer forms e.g. breast, ovarian, colorectal, prostate cancer and malignant melanoma. The aim of this study was to examine the prognostic impact of RBM3 expression in urinary bladder cancer.METHODS: Immunohistochemical RBM3 expression was examined in tumours from 343 patients with urothelial bladder cancer. Chi-square and Spearman's correlation tests were applied to explore associations between RBM3 expression and clinicopathological characteristics. The impact of RBM3 expression on disease-specific survival (DSS), 5-year overall survival (OS) and progression-free survival (PFS) was assessed by Kaplan-Meier analysis and Cox proportional hazards modelling.RESULTS: Reduced nuclear RBM3 expression was significantly associated with more advanced tumour (T) stage (p <0.001) and high grade tumours (p=0.004). Negative RBM3 expression was associated with a significantly shorter DSS (HR=2.55; 95% CI 1.68-3.86)) and 5-year OS (HR=2.10; 95% CI 1.56-2.82), also in multivariable analysis (HR=1.65; 95% CI 1.07-2.53 for DSS and HR=1.54; 95% CI 1.13-2.10 for 5-year OS). In patients with Ta and T1 tumours expressing reduced RBM3 levels, Kaplan-Meier analysis revealed a significantly shorter PFS (p=0.048) and 5-year OS (p=0.006).CONCLUSION: Loss of RBM3 expression is associated with clinically more aggressive tumours and an independent factor of poor prognosis in patients with urothelial bladder cancer and a potentially useful biomarker for treatment stratification and surveillance of disease progression.
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| 3. |
- Boman, Karolina, et al.
(author)
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Membranous expression of podocalyxin-like protein is an independent factor of poor prognosis in urothelial bladder cancer
- 2013
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In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 108:11, s. 2321-2328
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Journal article (peer-reviewed)abstract
- Background: Membranous expression of the anti-adhesive glycoprotein podocalyxin-like (PODXL) has previously been found to correlate with poor prognosis in several major cancer forms. Here we examined the prognostic impact of PODXL expression in urothelial bladder cancer. Methods: Immunohistochemical PODXL expression was examined in tissue microarrays with tumours from two independent cohorts of patients with urothelial bladder cancer: n = 100 (Cohort I) and n = 343 (Cohort II). The impact of PODXL expression on disease-specific survival (DSS; Cohort II), 5-year overall survival (OS; both cohorts) and 2-year progression-free survival (PFS; Cohort II) was assessed. Results: Membranous PODXL expression was significantly associated with more advanced tumour (T) stage and high-grade tumours in both cohorts, and a significantly reduced 5-year OS (unadjusted HR = 2.25 in Cohort I and 3.10 in Cohort II, adjusted HR = 2.05 in Cohort I and 2.18 in Cohort II) and DSS (unadjusted HR = 4.36, adjusted HR = 2.70). In patients with Ta and T1 tumours, membranous PODXL expression was an independent predictor of a reduced 2-year PFS (unadjusted HR = 6.19, adjusted HR = 4.60) and DSS (unadjusted HR = 8.34, adjusted HR = 7.16). Conclusion: Membranous PODXL expression is an independent risk factor for progressive disease and death in patients with urothelial bladder cancer.
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| 4. |
- Duchek, Milos, et al.
(author)
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Bacillus Calmette-Guerin Is Superior to a Combination of Epirubicin and Interferon-alpha 2b in the Intravesical Treatment of Patients with Stage T1 Urinary Bladder Cancer. A Prospective, Randomized, Nordic Study
- 2010
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In: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 57:1, s. 25-31
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Journal article (peer-reviewed)abstract
- Background: Bacillus Calmette-Guerin (BCG) instillation is regarded as the most effective bladder-sparing treatment for patients with high-grade T1 tumours and carcinoma in situ (CIS). The major problem with this therapy is the side-effects, making maintenance therapy difficult, even impossible, in a proportion of patients. Thus, alternative schedules and drugs have been proposed. Objective: To compare BCG to the combination of epirubicin and interferon-alpha 2b as adjuvant therapy of T1 tumours. Design, setting, and participants: This is a Nordic multicenter, prospective, randomised trial in patients with primary T1 G2-G3 bladder cancer. Initial transurethral resection (TUR) was followed by a second-look resection. Patients were randomised to receive either regimen, given as induction for 6 wk followed by maintenance therapy for 2 yr. Measurements: The drugs were compared with respect to time to recurrence and progression. Also, side-effects were documented. Results and limitations: A total of 250 patients were randomised. At the primary end point, 62% were disease free in the combination arm as opposed to 73% in the BCG arm (p = 0.065). At 24 mo, there was a significant difference in favour of the BCG-treated patients (p = 0.012) regarding recurrence, although there was no difference regarding progression. The subgroup analysis showed that the superiority of BCG was mainly in those with concomitant CIS. In a multivariate analysis of association with recurrence/progression status, significant variables for outcome were type of drug, tumour size, multiplicity, status at second-look resection, and grade. A corresponding analysis was performed separately in the two treatment arms. Tumour size was the only significant variable for BCG-treated patients, while multiplicity, status at second-look resection, and grade were significant for patients treated with the combination. Conclusions: For prophylaxis of recurrence, BCG was more effective than the combination. There were no differences regarding progression and adverse events between the two treatments.
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| 5. |
- Dyrskjot, L., et al.
(author)
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Analysis of molecular intra-patient variation and delineation of a prognostic 12-gene signature in non-muscle invasive bladder cancer; technology transfer from microarrays to PCR
- 2012
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In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 107:8, s. 1392-1398
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Journal article (peer-reviewed)abstract
- BACKGROUND: Multiple clinical risk factors and genetic profiles have been demonstrated to predict progression of non-muscle invasive bladder cancer; however, no easily clinical applicable gene signature has been developed to predict disease progression independent of disease stage and grade. METHODS: We measured the intra-patient variation of an 88-gene progression signature using 39 metachronous tumours from 17 patients. For delineation of the optimal quantitative reverse transcriptase PCR panel of markers, we used 115 tumour samples from patients in Denmark, Sweden, UK and Spain. RESULTS: Analysis of intra-patient variation of the molecular markers showed 71% similar classification results. A final panel of 12 genes was selected, showing significant correlation with outcome. In multivariate Cox regression analysis, we found that the 12-gene signature was an independent prognostic factor (hazard ratio = 7.4 (95% confidence interval: 3.4-15.9), P < 0.001) when adjusting for stage, grade and treatment. Independent validation of the 12-gene panel and the determined cut-off values is needed and ongoing. CONCLUSION: Intra-patient marker variation in metachronous tumours is present. Therefore, to increase test sensitivity, it may be necessary to test several metachronous tumours from a patient's disease course. A PCR-based 12-gene signature significantly predicts disease progression in patients with non-muscle invasive bladder cancer.
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| 6. |
- Fristrup, Niels, et al.
(author)
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Cathepsin E, Maspin, Plk1, and Survivin Are Promising Prognostic Protein Markers for Progression in Non-Muscle Invasive Bladder Cancer
- 2012
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In: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 180:5, s. 1824-1834
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Journal article (peer-reviewed)abstract
- Bladder cancer is a common cancer with particularly high recurrence after transurethral resection. In this study, we investigated the prognostic value of the protein expression of cathepsin E, maspin, polo-like kinase 1 (Plk1), and survivin in patients with stage Ta and T1 urothelial carcinomas. Transcripts from the four genes encoding these proteins were previously included in gene expression signatures for outcome prediction for Ta/T1 bladder cancer. We used three different tissue microarrays with 693 non-muscle invasive urothelial carcinomas from Danish, Swedish, and Spanish patient cohorts with long-term follow-up. Protein expression was measured by immunohistochemistry, and antibody specificity was validated by Western blotting. In the Danish patient cohort, we found the expression of cathepsin E, maspin, Plk1, and survivin to be significantly associated with progression to stage T2 to T4 bladder cancer (for each marker: log-rank test; P < 0.001). Multivariate Cox regression analysis identified cathepsin E (P < 0.001), Plk1 (P = 0.021), maspin (P = 0.001), and survivin (P = 0.001) as independent prognostic markers. Furthermore, maspin, survivin, and cathepsin E expression significantly subgrouped patients already stratified by European Organization for Research and Treatment of Cancer risk scores. Finally, we successfully validated the results in tumors from 410 patients from both Sweden and Spain. We conclude that all four protein markers may have prognostic value in non-muscle invasive bladder cancer for guiding optimal treatment of patients. Additional prospective studies are needed for further validation of the clinical relevance of this marker panel.
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| 7. |
- Fristrup, Niels, et al.
(author)
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Multicenter Validation of Cyclin D1, MCM7, TRIM29, and UBE2C as Prognostic Protein Markers in Non-Muscle Invasive Bladder Cancer
- 2013
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In: American Journal of Pathology. - : Elsevier BV. - 0002-9440 .- 1525-2191. ; 182:2, s. 339-349
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Journal article (peer-reviewed)abstract
- Transcripts from the four genes encoding cyclin D1, MCM7, TRIM29, and UBE2C have previously been included in gene expression signatures for outcome prediction in stage Ta/T1 urothelial carcinomas. We investigated the prognostic value of the protein expressions in Ta/T1 urothelial carcinomas patients. We used four different tissue microarrays (TMAs) with a total of 859 Ta/T1 urothelial carcinomas from Danish, Swedish, Spanish, and Taiwanese patient cohorts with long-term follow-up. Protein expression was measured by IHC, and antibody specificity was validated by Western blotting. We found the expression of cyclin D1, MCM7, TRIM29, and UBE2C to be significantly associated with progression to muscle invasive bladder cancer (log-rank test; P < 0.001) in the Danish training cohort (n = 283). Multivariate Cox regression analysis identified cyclin D1 (P = 0.003), TRIM29 (P = 0.001), and UBE2C (P < 0.001) as independent prognostic markers. The prognostic value of the four proteins was validated in a joint validation cohort from Sweden, Spain, and Taiwan (n = 576). Computer-assisted image analysis of the prognostic markers produced results comparable to those obtained by manual scoring. Finally, a four-protein maximum-likelihood classifier was trained on the Danish training cohort and applied to the validation cohort. The four protein markers may help optimize treatment of patients with Ta/T1 bladder cancer. Additional prospective studies are needed for further validation of their clinical relevance.
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| 8. |
- Gontero, Paolo, et al.
(author)
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The Role of Bacillus Calmette-Guerin in the Treatment of Non-Muscle-Invasive Bladder Cancer
- 2010
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In: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 57:3, s. 410-429
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Research review (peer-reviewed)abstract
- Context: Bacillus Calmette-Guerin (BCG) remains the most effective intravesical treatment for non-muscle-invasive bladder cancer (NMIBC), but the clinical development of BCG has been accompanied by controversy. Recent publications have called into question a number of aspects related to its use. Objective: To review the current clinical role of BCG in NMIBC, focusing on efficacy and tolerability as primary objectives and on strategies to predict response and decrease toxicity as secondary objectives. Evidence acquisition: We performed a systematic literature search of published articles in PubMed, Embase, and the Cochrane Central Register of Controlled Trials databases for the period from 1976 to November 2008. The following "free text'' combination was used in the first instance: "BCG and intravesical and bladder cancer.'' Further free text searches were performed by separately adding the following keywords to the combination "BCG and intravesical'': survival, progression, recurrence, maintenance, dosing, toxicity, tolerability, side effects, prognostic factors. Evidence synthesis: BCG is the most effective intravesical agent for preventing NMIBC recurrence, but its role in disease progression remains controversial. In intermediate-risk NMIBC, the superiority of BCG over chemotherapy is well established for disease recurrence but not for progression and needs to be balanced against higher toxicity. With regard to high-risk NMIBC, there is sufficient evidence to show that BCG is the most effective treatment of carcinoma in situ for ablation, disease-free interval, and progression, but the impact of BCG on the natural history of T1G3 tumors relies on a low level of evidence. Maintenance remains crucial for efficacy. The dose can be safely and effectively reduced to decrease its toxicity, which is slightly greater than chemotherapy. Conclusions: BCG should still be viewed as the most effective intravesical agent, but its role in the progression of papillary tumors needs to be clarified. BCG remains an alternative to intravesical chemotherapy in intermediate-risk NMIBC, and it is recommended as the standard of care for high-risk NMIBC.
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| 9. |
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| 10. |
- Hemdan, Tammer, et al.
(author)
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5-Year Outcome of a Randomized Prospective Study Comparing bacillus Calmette-Guerin with Epirubicin and Interferon-alpha 2b in Patients with T1 Bladder Cancer
- 2014
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In: Journal of Urology. - : Elsevier. - 0022-5347 .- 1527-3792. ; 191:5, s. 1244-1249
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Journal article (peer-reviewed)abstract
- Purpose: In a multicenter, prospectively randomized study we evaluated the 5-year outcomes of bacillus Calmette-Guerin alone compared to a combination of epirubicin and interferon-alpha 2b in the treatment of patients with T1 bladder cancer. Materials and Methods: Transurethral resection was followed by a second resection and bladder mapping. Stratification was for grade and carcinoma in situ. Followup entailed regular cystoscopy and cytology during the first 5 years. The end points assessed in this analysis were recurrence-free survival, time to treatment failure and progression, cancer specific survival and prognostic factors. Results: The study recruited 250 eligible patients. The 5-year recurrence-free survival rate was 38% in the combination arm and 59% in the bacillus Calmette-Guerin arm (p = 0.001). The corresponding rates for the other end points were not significantly different, as free of progression 78% and 77%, treatment failure 75% and 75%, and cancer specific survival 90% and 92%, respectively. The type of treatment, tumor size and tumor status at second resection were independent variables associated with recurrence. Concomitant carcinoma in situ was not predictive of failure of bacillus Calmette-Guerin therapy. An independent factor for treatment failure was remaining T1 stage at second resection. Conclusions: Bacillus Calmette-Guerin was more effective than the tested combination therapy. The currently recommended management with second resection and 3-week maintenance bacillus Calmette-Guerin entails a low risk of cancer specific death. More aggressive treatment in patients with infiltrative tumors at second resection might improve these results. In particular, concomitant carcinoma in situ was not a predictive factor for poor outcome after bacillus Calmette-Guerin therapy.
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| 11. |
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| 12. |
- Hemdan, Tammer, et al.
(author)
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The prognostic value and therapeutic target role of stathmin-1 in urinary bladder cancer
- 2014
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In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 111:6, s. 1180-1187
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Journal article (peer-reviewed)abstract
- Background:The oncoprotein-18/stathmin 1 (STMN1), involved in cell progression and migration, is associated with clinical outcome in breast cancer. Here we aim to investigate its clinical significance in urinary bladder cancer and its possibilities as a therapeutic target.Methods:Immunohistochemical analyses of STMN1 protein expression were performed in three patient cohorts: cohort I (n=115 Ta, n=115 T1, n=112 T2-4 stages), cohort II, based on randomised controlled trials (n=239 T1-T4), and cohort III of primary tumour/matched metastasis (n=90 T1-T4). The effects of STMN1 on cell proliferation and migration were evaluated in the urinary bladder cancer cell line, T24, by inhibiting STMN1-cellular expression using siRNA.Results:In cohort I, high STMN1 expression correlated to shorter disease-specific survival hazard ratio (HR)=2.04 (95% confidence interval (CI) 1.13-3.68; P=0.02), elevated p53- (P<0.001) and Ki67-protein levels (P<0.001). The survival result was validated in cohort II: HR=1.76 (95% CI 1.04-2.99; P=0.03). In the metastatic bladder cancer material, 70% of the patients were STMN1-positive in both the primary tumour and matched metastases. In vitro, the growth and migration of the T24 cells were significantly reduced (P<0.01, P<0.0001, respectively), when transfecting the cells with STMN1-siRNA.Conclusions:STMN1 protein expression has prognostic significance but is primarily a potential treatment target in urinary bladder cancer.
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| 13. |
- Jahnson, Staffan, et al.
(author)
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Urinary diversion after cystectomy for bladder cancer: A population-based study in Sweden
- 2010
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In: SCANDINAVIAN JOURNAL OF UROLOGY AND NEPHROLOGY. - : Informa UK Limited. - 0036-5599 .- 1651-2065. ; 44:2, s. 69-75
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Journal article (peer-reviewed)abstract
- Objective. To investigate the type of urinary diversion performed after cystectomy in patients with muscle-invasive bladder cancer in Sweden, using data from a population-based national register. Material and methods. Since 1997, the Swedish Bladder Cancer Register has included more than 90% of all patients with newly diagnosed bladder cancer. The different types of urinary diversion performed in 1997-2003 were analysed, comparing non-continent diversion (ileal conduit) with continent reconstruction (bladder substitution or continent cutaneous diversion). Results. During the study period, 3463 patients were registered with clinical T2-T4 non-metastatic bladder cancer. Cystectomy was performed in 1141 patients with ileal conduit in 732 (64%) and continent reconstruction in 409 (36%). Ileal conduit was used more frequently in females than males (p = 0.019), in patients older than 75 years (p andlt; 0.00001), and in those with less favourable TNM classification. Continent reconstruction was done more often at university hospitals than at county hospitals (p andlt; 0.00001), but rarely in the northern and western healthcare regions compared with other regions (p andlt; 0.00001). Nationwide, the proportion of registered continent reconstructions decreased, although the absolute number was relatively stable (50-60 per year). Conclusions. Continent reconstruction after cystectomy for muscle-invasive bladder cancer is performed more often in some healthcare regions and in patients at university hospitals than in county hospitals, indicating a substantial provider influence on the choice of urinary diversion. Over time, the proportion of these procedures has decreased, while the absolute number has remained low and stable; therefore, concentration in high-volume hospitals specialized in bladder cancer and continent reconstruction seems appropriate.
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| 14. |
- Jerlström, Tomas, 1969-, et al.
(author)
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Urinary bladder cancer treated with radical cystectomy : Perioperative parameters and early complications prospectively registered in a national population-based database
- 2014
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In: Scandinavian journal of urology. - London : Informa Healthcare. - 2168-1805 .- 2168-1813. ; 48:4, s. 334-340
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Journal article (peer-reviewed)abstract
- Objective: Cystectomy combined with pelvic lymph-node dissection and urinary diversion entails high morbidity and mortality. Improvements are needed, and a first step is to collect information on the current situation. In 2011, this group took the initiative to start a population-based database in Sweden (population 9.5 million in 2011) with prospective registration of patients and complications until 90 days after cystectomy. This article reports findings from the first year of registration.Material and methods: Participation was voluntary, and data were reported by local urologists or research nurses. Perioperative parameters and early complications classified according to the modified Clavien system were registered, and selected variables of possible importance for complications were analysed by univariate and multivariate logistic regression.Results: During 2011, 285 (65%) of 435 cystectomies performed in Sweden were registered in the database, the majority reported by the seven academic centres. Median blood loss was 1000 ml, operating time 318 min, and length of hospital stay 15 days. Any complications were registered for 103 patients (36%). Clavien grades 1-2 and 3-5 were noted in 19% and 15%, respectively. Thirty-seven patients (13%) were reoperated on at least once. In logistic regression analysis elevated risk of complications was significantly associated with operating time exceeding 318 min in both univariate and multivariate analysis, and with age 76-89 years only in multivariate analysis.Conclusions: It was feasible to start a national population-based registry of radical cystectomies for bladder cancer. The evaluation of the first year shows an increased risk of complications in patients with longer operating time and higher age. The results agree with some previously published series but should be interpreted with caution considering the relatively low coverage, which is expected to be higher in the future.
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| 15. |
- Liedberg, Fredrik, et al.
(author)
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Long-term follow-up after radical cystectomy with emphasis on complications and reoperations: A Swedish population-based survey
- 2012
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In: Scandinavian Journal of Urology and Nephrology. - : Informa Healthcare. - 0036-5599 .- 1651-2065. ; 46:1, s. 14-18
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Journal article (peer-reviewed)abstract
- Objective. To evaluate outcome after radical cystectomy for primary bladder cancer in a large population-based material. Material and methods. Between 1997 and 2002 all patients treated with radical cystectomy within 3 months after diagnosis of primary bladder cancer without distant metastasis were retrieved through the Swedish Bladder Cancer Registry. A follow-up questionnaire was distributed to all units where the primary registration of patients was performed. Follow-up data on recurrence date were retrieved from the patient charts and causes of death were obtained from the Swedish Cause of Death Registry until 2003. Results. During the study period radical cystectomy was performed in 39 units in Sweden, of which only five units were considered high-volume hospitals performing 10 or more procedures annually. Mean blood loss was 2300 ml (median 2000 ml) and the 90-day mortality rate was 5.7%. Blood loss was higher in high-volume units than in hospitals with lower hospital volumes, but the 90-day mortality rates were similar. During a median follow-up of 3.5 years, 24% of the patients were submitted to a reoperation. Reoperation rates were significantly higher in patients who received a continent urinary diversion (29%) compared with an ileal conduit (22%, p andlt; 0.015). Conclusions. Radical cystectomy was associated with a reoperation rate of 24% in Sweden during the study period. The reoperation rates were higher in patients receiving a continent cutaneous diversion or bladder substitution. Blood loss was higher in high-volume units; otherwise, surgical volume did not affect mortality rates, cancer-specific survival or reoperation rates.
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| 16. |
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| 17. |
- Lindén, Mårten, et al.
(author)
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Galectin-1, a potential therapeutic target, in primary tumors and metastases of urinary bladder carcinomas
- 2013
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Other publication (other academic/artistic)abstract
- Urinary bladder cancer would gain from new protein biomarkers due to the heterogeneity of disease. The beta-galactoside-binding protein (GAL1) is one such candidate and in present study its prognostic value and expression at protein level in metastatic bladder cancer-disease, have been evaluated. The protein expression of GAL1 was investigated by immunohistochemistry in two tumor cohorts, one with primary tumors of different stage and grade (n=344) and another with primary tumors matched with metastases (n=90). The expression in the actual cancer cells as well as in stroma and blood vessels were considered since the presence of GAL1 in different tissue compartments has shown cancer relevance. The cellular expression increased with increased tumor stage and grade (p<0.001). For the majority of the patients, cells from both primary tumor and metastasis showed a positive immunoreactivity for GAL1 (91% (n=64) for primary tumors with single metastasis (n=70) and 100% (n=20) for primary tumors with multiple metastasis (n=20). Further, strong immunoreactivity in T1 tumor cells correlated with lower risk of recurrence (p<0.05). Both tumors and metastasis exhibited strong stromal-GAL1 staining that could not be correlated with clinical parameters. The expression in vessels showed that T1 tumors surrounded by GAL1 negative blood vessels had a higher risk of progression (p<0.0001) into muscle invasive T2-4 stages. The results show that GAL1 is an important bladder cancer-protein from several aspects. Further, GAL1 is a promising therapeutic target in bladder cancer due to the general expression in advanced disease.
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| 18. |
- Lindén, Mårten, et al.
(author)
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Proteomic analysis of urinary biomarker candidates for nonmuscle invasive bladder cancer
- 2012
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In: Proteomics. - : Wiley. - 1615-9853 .- 1615-9861. ; 12:1, s. 135-144
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Journal article (peer-reviewed)abstract
- Nonmuscle invasive tumors of the bladder often recur and thereby bladder cancer patients need regular re-examinations which are invasive, unpleasant, and expensive. A noninvasive and less expensive method, e.g. a urine dipstick test, for monitoring recurrence would thus be advantageous. In this study, the complementary techniques mass spectrometry (MS) and Western blotting (WB)/dot blot (DB) were used to screen the urine samples from bladder cancer patients. High resolving MS was used to analyze and quantify the urinary proteome and 29 proteins had a significantly higher abundance (p<0.05) in bladder cancer samples compared with control urine samples. The increased abundance found in urine from bladder cancer patients compared with controls was confirmed with Western blot for four selected proteins; fibrinogen β chain precursor, apolipoprotein E, α-1-antitrypsin, and leucine-rich α-2-glycoprotein 1. Dot blot analysis of an independent urine sample set pointed out fibrinogen β chain and α-1-antitrypsin as most interesting biomarkers having sensitivity and specificity values in the range of 66-85%. Exploring the Human Protein Atlas (HPA) also revealed that bladder cancer tumors are the likely source of these proteins. They have the potential of being useful in diagnosis, monitoring of recurrence and thus may improve the treatment of bladder tumors, especially nonmuscle invasive tumors.
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| 19. |
- Lindén, Mårten, 1976-
(author)
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Proteomic Analysis of Urinary Bladder Cancer : Aiming for Novel Biomarkers
- 2013
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Doctoral thesis (other academic/artistic)abstract
- Urinary bladder cancer is a heterogeneous disease appearing in different forms, e.g. non-muscle invasive and muscle invasive. For all variants, the expression of proteins is interesting to analyze for diagnostic, predictive, prognostic and drug targeting purposes, since it reflects the altered gene expression causing the cancer. Since urothelial cells of the bladder are in direct contact with urine it is likely that this body fluid contains cancer-related proteins. In Paper I, unbiased analysis of proteins in urine from urinary bladder cancer patients and controls, using label-free quantification by mass spectrometry, was applied and four interesting proteins APOE, FGB, LRG and SERPINA1 were selected and further analyzed with western and dot blot. In Paper II, two more proteins, POLR1E and TOP2A, were validated as relevant proteins in bladder cancer urine. In Paper III and IV, the proteins GAL1 and STMN1 were investigated for their prognostic and therapeutic target potential in bladder cancer. In Paper II, III and IV, the expression of seven of the proteins were analyzed on tissue microarrays representing tumour tissue from 360 patients with different tumour stages. For the proteins identified by the urine screening approach, their protein expressions were confirmed in bladder cancer tissue. The expression level in tissue of five of the proteins, APOE, FGB, POLR1E (Paper II), GAL1 (Paper III) and STMN1 (Paper IV), increased with tumour stage, showing diagnostic relevance and three of the proteins, SERPINA1 (Paper II), STMN1 (Paper IV) and GAL1 (Paper III) had prognostic potential in urinary bladder cancer. In addition, GAL1 and STMN1 were demonstrated to be highly expressed in metastatic disease and inhibition of STMN1 reduced cell growth (Paper III and IV), indicating that these proteins are promising drug targets in urinary bladder cancer. In conclusion, the approach of this thesis has generated several candidate protein biomarkers in urine and tissue, validated with independent methods, which have the potential to improve the care for bladder cancer patients.
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| 20. |
- Lindén, Mårten, et al.
(author)
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Tumour expression of bladder cancer-associated urinary proteins
- 2013
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In: BJU International. - 1464-4096 .- 1464-410X. ; 112:3, s. 407-415
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Journal article (peer-reviewed)abstract
- WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?:The current basis for diagnosis and prognosis in urinary bladder cancer is based on the pathologists' assessment of a biopsy of the tumour. Urinary biomarkers are preferable as they can be non-invasively sampled. Urinary cytology is the only test with widespread use but is hampered by poor reproducibility and low sensitivity.By studying the protein expression in bladder tumour tissue samples of proteins previously found in elevated levels in the urine of patients with bladder cancer, we have been able to show that these proteins originate from the tumour. The immunoreactivity of three of the investigated proteins increased with higher stage. Also a serine peptidase inhibitor was found to be predictive of progression from non-muscle-invasive to muscle-invasive tumours.OBJECTIVES:To analyse the expression of five bladder cancer-associated urinary proteins and investigate if expression is related to the malignant phenotype of the tumour.To explore the possible prognostic value of these proteins.PATIENTS AND METHODS:Urine samples, 16 from patients with bladder cancer and 26 from controls, were used in Western Blotting experiments.Tissue microarrays with bladder tissue from 344 patients diagnosed with bladder cancer between 1984 and 2005 was used in immunohistochemistry experiments.The proteins apolipoprotein E (APOE), fibrinogen β chain precursor (FGB), leucine-rich α2-glycoprotein (LRG1), polymerase (RNA) I polypeptide E (POLR1E), α1-antitrypsin (SERPINA1) and topoisomerase 2A (TOP2A) were probed with antibodies validated by the Human Protein Atlas.RESULTS:Increased expressions of APOE, FGB and POLR1E were correlated with increased tumour stage (P < 0.001).Expression of SERPINA1 in Ta and T1 tumours was found to increase the risk of tumour progression (hazard ratio 2.57, 95% confidence interval 1.13-5.87; P = 0.025)CONCLUSIONS: All proteins previously detected in urine from patients with bladder cancer were also expressed in bladder cancer tissue.The expression of APOE, FGB and POLR1E increased with stage and they are potential diagnostic markers.SERPINA1 was identified as a prognostic marker candidate.
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| 21. |
- Malmström, Per-Uno, et al.
(author)
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AdCD40L immunogene therapy for bladder carcinoma--the first phase I/IIa trial
- 2010
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In: Clinical Cancer Research. - : American Association for Cancer Research. - 1078-0432 .- 1557-3265. ; 16:12, s. 3279-3287
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Journal article (peer-reviewed)abstract
- PURPOSE: Immunotherapy with Bacillus Calmette-Guerin (BCG) instillation is recommended for high-risk, non-muscle invasive bladder cancer. Bacillus Calmette-Guerin is not effective in advanced tumors, and better alternatives are warranted. Immunostimulating gene therapy with adenoviral vectors expressing CD40 ligand (AdCD40L) has shown efficacy in tumor models. CD40 ligand stimulates systemic immunity and may be effective in local and invasive human disease.EXPERIMENTAL DESIGN: Patients with invasive bladder cancer scheduled for cystectomy or patients with T(a) tumors were enrolled in a phase I/IIa trial. Patients were treated with three cycles of intrabladder Clorpactin WCS-90 prewash, followed by AdCD40L instillation 1 week apart. Safety, gene transfer, immune effects, and antitumor responses were monitored.RESULTS: All eight recruited patients were treated as scheduled, and therapy was well tolerated. The main adverse effect was transient local pain during prewash. Postoperatively, urinary tract infections and one case of late septicemia with elevated potassium were reported. No adverse events were ascribed to vector therapy. Gene transfer was detected in biopsies, and bladders were heavily infiltrated with T cells. The effector marker IFN-gamma increased in biopsies, whereas levels of circulating T regulatory cells were reduced. Histologic evaluation indicated that AdCD40L therapy reduced the load of malignant cells.CONCLUSIONS: To our knowledge, this is the first report on immunogene therapy in bladder cancer and the first using AdCD40L in vivo. Local AdCD40L gene therapy was safe, boosted immune activation, and should be further evaluated as a single or an adjuvant therapy for urothelial malignancies.
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| 22. |
- Malmström, Per-Uno
(author)
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Bladder tumours : time for a paradigm shift?
- 2011
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In: BJU International. - 1464-4096 .- 1464-410X. ; 107:10, s. 1543-1545
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Journal article (other academic/artistic)abstract
- The results for many types of cancers have improved during later decades but not so for bladder cancer. Most patients with muscle-invasive tumors will still succumb to the disease and a high recurrence rate characterises non-muscle invasive tumors.The objective is to critically review the present model of bladder cancer based on newly acquired biological data. The definition of bladder cancer has extended with the introduction of the WHO classification. The corresponding loss of distinction between benign tumor and cancer has not been rewarding and should be reintroduced to facilitate exploration of new molecular findings. The common endpoints recurrence and progression should be redefined or replaced by more appropriate endpoints. The concept of surgery only for locally advanced cancers has proven unsuccessful and has to be complemented with early administered systemic treatment.
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| 23. |
- Malmström, Per-Uno
(author)
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Editorial
- 2013
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In: Scandinavian journal of urology. - : Medical Journals Sweden AB. - 2168-1813 .- 2168-1805. ; 47:1, s. 3-3
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Journal article (peer-reviewed)
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| 24. |
- Malmström, Per-Uno
(author)
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Editorial
- 2012
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In: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 0036-5599 .- 1651-2065. ; 46:1, s. 4-4
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Journal article (peer-reviewed)
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| 25. |
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