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van Kessel, K. E. M., van der Keur, K. A., Dyrskjot, L., Algaba, F., Welvaart, N. Y. C., Beukers, W., . . . Zwarthoff, E. C. (2018). Molecular Markers Increase Precision of the European Association of Urology Non-Muscle-Invasive Bladder Cancer Progression Risk Groups. Clinical Cancer Research, 24(7), 1586-1593
Open this publication in new window or tab >>Molecular Markers Increase Precision of the European Association of Urology Non-Muscle-Invasive Bladder Cancer Progression Risk Groups
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2018 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 24, no 7, p. 1586-1593Article in journal (Refereed) Published
Abstract [en]

Purpose: The European Association of Urology (EAU) guidelines for non-muscle-invasive bladder cancer (NMIBC) recommend risk stratification based on clinicopathologic parameters. Our aim was to investigate the added value of biomarkers to improve risk stratification of NMIBC. Experimental Design: We prospectively included 1,239 patients in follow-up for NMIBC in six European countries. Fresh-frozen tumor samples were analyzed for GATA2, TBX2, TBX3, and ZIC4 methylation and FGFR3, TERT, PIK3CA, and RAS mutation status. Cox regression analyses identified markers that were significantly associated with progression to muscle-invasive disease. The progression incidence rate (PIR = rate of progression per 100 patient-years) was calculated for subgroups. Results: In our cohort, 276 patients had a low, 273 an intermediate, and 555 a high risk of tumor progression based on the EAU NMIBC guideline. Fifty-seven patients (4.6%) progressed to muscle-invasive disease. The limited number of progressors in this large cohort compared with older studies is likely due to improved treatment in the past two decades. Overall, wild-type FGFR3 and methylation of GATA2 and TBX3 were significantly associated with progression (HR = 0.34, 2.53, and 2.64, respectively). The PIR for EAU high-risk patients was 4.25. On the basis of FGFR3 mutation status and methylation of GATA2, this cohort could be reclassified into a good class (PIR = 0.86, 26.2% of patients), a moderate class (PIR = 4.32, 49.7%), and a poor class (PIR = 7.66, 24.0%). Conclusions: We conclude that the addition of selected biomarkers to the EAU risk stratification increases its accuracy and identifies a subset of NMIBC patients with a very high risk of progression. (C) 2018 AACR.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 2018
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-351679 (URN)10.1158/1078-0432.CCR-17-2719 (DOI)000429050000010 ()29367430 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 201663
Available from: 2018-06-05 Created: 2018-06-05 Last updated: 2018-06-05Bibliographically approved
Chan, O. T. M., Furuya, H., Pagano, I., Shimizu, Y., Hokutan, K., Dyrskjot, L., . . . Rosser, C. J. (2017). Association of MMP-2, RB and PAI-1 with decreased recurrence-free survival and overall survival in bladder cancer patients. OncoTarget, 8(59), 99707-99721
Open this publication in new window or tab >>Association of MMP-2, RB and PAI-1 with decreased recurrence-free survival and overall survival in bladder cancer patients
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 59, p. 99707-99721Article in journal (Refereed) Published
Abstract [en]

Background: We previously reported an accurate urine-based bladder cancer (BCa)-associated diagnostic signature that can be used to non-invasively detect BCa. In this study, we investigated whether a component of this signature could risk stratify patients with BCa. Methods: Utilizing immunohistochemistry, we investigated angiogenin, MMP-2, p53, RB and PAI-1 expression from 939 patients with BCa. The expression levels were scored by assigning a proportion score and an intensity score to yield a total staining score for each protein. The expressions of each protein individually and as an aggregate were then correlated with progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Results: Differential expressions of these markers were noted in BCa. With multivariate analysis in non-muscle invasive bladder cancer (NMIBC) age, tumor grade portended a worse PFS, while age, tumor grade, nodal status, MMP2, RB and PAI-1 expression portended a worse OS. As for multivariate analysis in muscle invasive bladder cancer (MIBC), age MMP-2 and RB were associated with a worse PFS, while age, nodal status, MMP-2, RB and PAI-1 were associated with a worse OS. Using Kaplan-Meier survival analysis, we noted a significant reduction in OS as more of the five biomarkers were expressed in a tumor. Thus, overall, high expressions of MMP-2, RB and/or PAI-1 in bladder tumors were markers of poor prognosis. Conclusion: Individually, MMP-2, RB and PAI-1, as well as in aggregate correlated with poor survival in patients with BCa. Thus, patients whose bladder tumors express these biomarkers may benefit from early radical treatment and/or neoadjuvant or adjuvant therapies.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2017
Keywords
angiogenin, bladder cancer, IHC, MMP-2, PAI-1, survival
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-345219 (URN)10.18632/oncotarget.20686 (DOI)000419561600050 ()29245935 (PubMedID)
Available from: 2018-03-08 Created: 2018-03-08 Last updated: 2018-03-08Bibliographically approved
Häggström, C., Liedberg, F., Hagberg, O., Aljabery, F., Ströck, V., Hosseini, A., . . . Holmberg, L. (2017). Cohort profile: The Swedish National Register of Urinary Bladder Cancer (SNRUBC) and the Bladder Cancer Data Base Sweden (BladderBaSe). BMJ Open, 7(9), Article ID e016606.
Open this publication in new window or tab >>Cohort profile: The Swedish National Register of Urinary Bladder Cancer (SNRUBC) and the Bladder Cancer Data Base Sweden (BladderBaSe)
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2017 (English)In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 7, no 9, article id e016606Article in journal (Refereed) Published
Abstract [en]

Purpose: To monitor the quality of bladder cancer care, the Swedish National Register of Urinary Bladder Cancer (SNRUBC) was initiated in 1997. During 2015, in order to study trends in incidence, effects of treatment and survival of men and women with bladder cancer, we linked the SNRUBC to other national healthcare and demographic registers and constructed the Bladder Cancer Data Base Sweden (BladderBaSe).

Participants: The SNRUBC is a nationwide register with detailed information on 97% of bladder cancer cases in Sweden as compared with the Swedish Cancer Register. Participants in the SNRUBC have registered data on tumour characteristics at diagnosis, and for 98% of these treatment data have been captured. From 2009, the SNRUBC holds data on 88% of eligible participants for follow-up 5 years after diagnosis of non-muscle invasive bladder cancer, and from 2011, data on surgery details and complications for 85% of participants treated with radical cystectomy. The BladderBaSe includes all data in the SNRUBC from 1997 to 2014, and additional covariates and follow-up data from linked national register sources on comorbidity, socioeconomic factors, detailed information on readmissions and treatment side effects, and causes of death.

Findings to date: Studies based on data in the SNRUBC have shown inequalities in survival and treatment indication by gender, regions and hospital volume. The BladderBaSe includes 38 658 participants registered in SNRUBC with bladder cancer diagnosed from 1 January 1997 to 31 December 2014. The BladderBaSe initiators are currently in collaboration with researchers from the SNRUBC investigating different aspects of bladder cancer survival.

Future plans: The SNRUBC and the BladderBaSe project are open for collaborations with national and international research teams. Collaborators can submit proposals for studies and study files can be uploaded to servers for remote access and analysis. For more information, please contact the corresponding author.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-337759 (URN)10.1136/bmjopen-2017-016606 (DOI)000412650700144 ()28963292 (PubMedID)
Funder
Swedish Cancer Society, CAN 2013/472
Available from: 2018-01-12 Created: 2018-01-12 Last updated: 2018-01-12Bibliographically approved
Malmström, P.-U. (2017). Drugs and risk of cancer. Scandinavian journal of urology, 51(3), 212-212
Open this publication in new window or tab >>Drugs and risk of cancer
2017 (English)In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, no 3, p. 212-212Article in journal, Editorial material (Other academic) Published
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-329719 (URN)10.1080/21681805.2017.1329905 (DOI)000403729400012 ()28657390 (PubMedID)
Available from: 2017-09-21 Created: 2017-09-21 Last updated: 2017-09-21Bibliographically approved
Styrke, J., Henriksson, H., Ljungberg, B., Hasan, M., Silfverberg, I., Einarsson, R., . . . Sherif, A. (2017). Evaluation of the diagnostic accuracy of UBC® Rapid in bladder cancer: a Swedish multicentre study. Scandinavian journal of urology, 51(4), 293-300
Open this publication in new window or tab >>Evaluation of the diagnostic accuracy of UBC® Rapid in bladder cancer: a Swedish multicentre study
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2017 (English)In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, no 4, p. 293-300Article in journal (Refereed) Published
Abstract [en]

Objective: The aim of this study was to determine the diagnostic accuracy of UBC® Rapid - a urine-based marker for bladder cancer - in patients with bladder cancer and controls, and to compare the test results across risk groups. Materials and methods: This prospective phase II study was conducted at four Swedish hospitals. UBC Rapid was evaluated in four groups: A, newly diagnosed bladder cancer (n=94); B, follow-up of non-muscle-invasive bladder cancer (n=75); C, benign urinary tract diseases (n=51); and D, healthy controls (n=50). Tumours were divided into high risk (carcinoma in situ, TaG3, T1, T2 and T3) and low risk (low malignant potential, TaG1 and TaG2). Urine samples were quantitatively analysed by UBC Rapid. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated based on optimal cut-off (receiver operator characteristics curve analysis). A linear regression compared the UBC Rapid results in the different risk groups. Results: The optimal cut-off was 8.1g/l. The median UBC Rapid values were 9.3g/l [interquartile range (IQR) 30.9] and 4.3g/l (IQR 7.8) in patients with positive and negative cystoscopy, respectively (p<.001). The value for group A was 15.6g/l (IQR 37.9), group B 5.6g/l (IQR 8.6), group C 5.1g/l (IQR 9.0) and group D 3.3g/l (IQR 7.1). Sensitivity was 70.8%, specificity 61.4%, PPV 71.3% and NPV 60.8%. The high-risk group had significantly higher UBC Rapid values than the low-risk group: 20.5g/l (IQR 42.2), sensitivity 79.2% and specificity 61.4% versus 7.0g/l (IQR 9.9), sensitivity 60.0% and specificity 61.4% (p=.039). Conclusions: The UBC Rapid urine-based marker for bladder cancer gave higher values in patients with positive than in those with negative cystoscopy. The diagnostic accuracy was better in patients with high-risk than in those with low-risk tumours, and was better during primary detection than during surveillance.

Keywords
Disease monitoring, primary disease, UBC (R) Rapid point-of-care systems, urinary bladder cancer
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-331914 (URN)10.1080/21681805.2017.1313309 (DOI)000405483400011 ()
Note

Title in WoS: Evaluation of the diagnostic accuracy of UBC (R) Rapid in bladder cancer

Available from: 2017-10-19 Created: 2017-10-19 Last updated: 2017-10-19Bibliographically approved
Gerullis, H., Barski, D., Malmström, P.-U., Sun, X. & Ecke, T. H. (2017). Evidence in Urologic- and Pelvic-Surgery Research: Finding the IDEAL Way of Reporting. BioMed Research International, Article ID 2716759.
Open this publication in new window or tab >>Evidence in Urologic- and Pelvic-Surgery Research: Finding the IDEAL Way of Reporting
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2017 (English)In: BioMed Research International, ISSN 2314-6133, E-ISSN 2314-6141, article id 2716759Article in journal, Editorial material (Other academic) Published
Place, publisher, year, edition, pages
HINDAWI LTD, 2017
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-322034 (URN)10.1155/2017/2716759 (DOI)000399203200001 ()
Available from: 2017-05-16 Created: 2017-05-16 Last updated: 2017-05-16Bibliographically approved
Beukers, W., van der Keur, K. A., Kandimalla, R., Vergouwe, Y., Steyerberg, E. W., Boormans, J. L., . . . Zwarthoff, E. C. (2017). FGFR3, TERT and OTX1 as a Urinary Biomarker Combination for Surveillance of Patients with Bladder Cancer in a Large Prospective Multicenter Study. Journal of Urology, 197(6), 1410-1418
Open this publication in new window or tab >>FGFR3, TERT and OTX1 as a Urinary Biomarker Combination for Surveillance of Patients with Bladder Cancer in a Large Prospective Multicenter Study
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2017 (English)In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 197, no 6, p. 1410-1418Article in journal (Refereed) Published
Abstract [en]

Purpose: Patients with nonmuscle invasive bladder cancer are followed with frequent cystoscopies. In this study FGFR3, TERT and OTX1 were investigated as a diagnostic urinary marker combination during followup of patients with primary nonmuscle invasive bladder cancer.

Materials and Methods: In this international, multicenter, prospective study 977 patients with nonmuscle invasive bladder cancer were included. A total of 2,496 urine samples were collected prior to cystoscopy during regular visits. Sensitivity was estimated to detect concomitant recurrences. Kaplan-Meier curves were used to estimate the development of future recurrences after urinalysis and a negative cystoscopy.

Results: Sensitivity of the assay combination for recurrence detection was 57% in patients with primary low grade, nonmuscle invasive bladder cancer. However, sensitivity was 83% for recurrences that were pT1 or muscle invasive bladder cancer. Of the cases 2% progressed to muscle invasive bladder cancer. Sensitivity for recurrence detection in patients with primary high grade disease was 72% and 7% of them had progression to muscle invasive bladder cancer. When no concomitant tumor was found by cystoscopy, positive urine samples were more frequently followed by a recurrence over time compared to a negative urine sample (58% vs 36%, p < 0.001). High stage recurrences were identified within 1 year after a positive urine test and a negative cystoscopy.

Conclusions: Recurrences in patients with primary nonmuscle invasive bladder cancer can be detected by a combination of urine assays. This study supports the value of urinalysis as an alternative diagnostic tool in patients presenting with low grade tumors and as a means to identify high stage tumors earlier.

Keywords
urinary bladder neoplasms, neoplasm recurrence, local, urinalysis, cystoscopy, neoplasm invasiveness
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-324238 (URN)10.1016/j.juro.2016.12.096 (DOI)000400896400010 ()28049011 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 201663
Available from: 2017-06-15 Created: 2017-06-15 Last updated: 2017-06-15Bibliographically approved
Malmström, P.-U. (2017). Half a decade of fluorescence in the bladder. Scandinavian journal of urology, 51(3), 219-219
Open this publication in new window or tab >>Half a decade of fluorescence in the bladder
2017 (English)In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, no 3, p. 219-219Article in journal, Editorial material (Other academic) Published
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-329720 (URN)10.1080/21681805.2017.1329903 (DOI)000403729400014 ()28657392 (PubMedID)
Available from: 2017-09-22 Created: 2017-09-22 Last updated: 2017-09-22Bibliographically approved
Jancke, G., Liedberg, F., Aljabery, F., Sherif, A., Strock, V., Malmström, P.-U., . . . Jahnson, S. (2017). Intravesical instillations and cancer-specific survival in patients with primary carcinoma in situ of the urinary bladder. Scandinavian journal of urology, 51(2), 124-129
Open this publication in new window or tab >>Intravesical instillations and cancer-specific survival in patients with primary carcinoma in situ of the urinary bladder
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2017 (English)In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, no 2, p. 124-129Article in journal (Refereed) Published
Abstract [en]

Objective: The aim of this study was to evaluate the use of intravesical treatment and cancer-specific survival of patients with primary carcinoma in situ (CIS). Materials and methods: Data acquisition was based on the Swedish National Registry of Urinary Bladder Cancer by selecting all patients with primary CIS. The analysis covered gender, age, hospital type and hospital volume. Intravesical treatment and death due to bladder cancer were evaluated by multivariate logistic regression and multivariate Cox analysis, respectively. Results: The study included 1041 patients (median age at diagnosis 72 years) with a median follow-up of 65 months. Intravesical instillation therapy was given to 745 patients (72%), and 138 (13%) died from bladder cancer during the observation period. Male gender [odds ratio (OR) = 1.56, 95% confidence interval (CI) 1.13-2.17] and treatment at county (OR = 1.65, 95% CI 1.17-2.33), university (OR =2.12, 95% CI 1.48-3.03) or high-volume (OR= 1.92, 95% CI 1.34-2.75) hospitals were significantly associated with higher odds of intravesical instillations. The age category >80 years had a significantly lower chance of receiving intravesical therapy (OR = 0.44, 95% CI 0.26-0.74) and a significantly higher risk of dying from bladder cancer (hazard ratio = 3.03, 95% CI 1.71-5.35). Conclusion: Significantly more frequent use of intravesical treatment of primary CIS was found for males and for patients treated at county, university and high-volume hospitals. Age >80 years was significantly related to less intravesical treatment and poorer cancer-specific survival.

Keywords
Cancer-specific survival, intravesical treatment, primary CIS
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-329138 (URN)10.1080/21681805.2017.1298156 (DOI)000403629400006 ()
Funder
Swedish Cancer Society, 57897
Available from: 2017-10-10 Created: 2017-10-10 Last updated: 2017-10-10Bibliographically approved
Malmström, P.-U., Agrawal, S., Blackberg, M., Boström, P. J., Malavaud, B., Zaak, D. & Hermann, G. G. (2017). Non-muscle-invasive bladder cancer: a vision for the future. Scandinavian journal of urology, 51(2), 87-94
Open this publication in new window or tab >>Non-muscle-invasive bladder cancer: a vision for the future
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2017 (English)In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, no 2, p. 87-94Article, review/survey (Refereed) Published
Abstract [en]

The management of non-muscle-invasive bladder cancer (NMIBC) has evolved from the first reports on bladder endoscopy and transurethral resection to the introduction of adjuvant intravesical treatment. However, disease recurrence and progression remain an ongoing risk, placing a heavy burden on healthcare resources and on patients' quality of life. Deeper understanding of the molecular basis of the disease and developments in optics, lasers and computer science are already offering opportunities to revolutionize care and improve long-term prognosis. This article discusses developments likely to cause a paradigm shift towards the delivery of personalized care and reduced burden of disease in NMIBC.

Keywords
Biomarkers, bladder cancer, cost effectiveness, diagnosis, flexible cystoscopy, laser, medicotechnology
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-333845 (URN)10.1080/21681805.2017.1283359 (DOI)000403629400001 ()28535714 (PubMedID)
Available from: 2017-11-17 Created: 2017-11-17 Last updated: 2017-11-17Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0001-8572-9957

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