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  • 1. Andersson, Gustav
    et al.
    Wennersten, Christoffer
    Gaber, Alexander
    Boman, Karolina
    Nodin, Bjorn
    Uhlen, Mathias
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Jirstrom, Karin
    Reduced expression of ezrin in urothelial bladder cancer signifies more advanced tumours and an impaired survival: validatory study of two independent patient cohorts2014In: BMC Urology, ISSN 1471-2490, E-ISSN 1471-2490, Vol. 14, p. 36-Article in journal (Refereed)
    Abstract [en]

    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.

  • 2.
    Beukers, Willemien
    et al.
    Erasmus MC, Dept Pathol, POB 2040, NL-3000 CA Rotterdam, Netherlands..
    van der Keur, Kirstin A.
    Erasmus MC, Dept Pathol, POB 2040, NL-3000 CA Rotterdam, Netherlands..
    Kandimalla, Raju
    Erasmus MC, Dept Pathol, POB 2040, NL-3000 CA Rotterdam, Netherlands..
    Vergouwe, Yvonne
    Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands..
    Steyerberg, Ewout W.
    Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands..
    Boormans, Joost L.
    Erasmus MC, Dept Urol, Rotterdam, Netherlands..
    Jensen, Jorgen B.
    Aarhus Univ Hosp, Dept Urol, Aarhus, Denmark..
    Lorente, Jose A.
    Hosp del Mar, Serv Urol, Barcelona, Spain..
    Real, Francisco X.
    Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain.;Spanish Natl Canc Res Centre CNIO, Canc Cell Biol Programme, Epithelial Carcinogenesis Grp, Madrid, Spain..
    Segersten, Ulrike
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Orntoft, Torben F.
    Aarhus Univ Hosp, Dept Mol Med, Aarhus, Denmark..
    Malats, Nuria
    Spanish Natl Canc Res Centre CNIO, Canc Cell Biol Programme, Epithelial Carcinogenesis Grp, Madrid, Spain..
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Dyrskjot, Lars
    Aarhus Univ Hosp, Dept Mol Med, Aarhus, Denmark..
    Zwarthoff, Ellen C.
    Erasmus MC, Dept Pathol, POB 2040, NL-3000 CA Rotterdam, Netherlands..
    FGFR3, TERT and OTX1 as a Urinary Biomarker Combination for Surveillance of Patients with Bladder Cancer in a Large Prospective Multicenter Study2017In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 197, no 6, p. 1410-1418Article in journal (Refereed)
    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.

  • 3. Boman, K
    et al.
    Larsson, A H
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Kuteeva, E
    Johannesson, H
    Nodin, B
    Eberhard, J
    Uhlén, M
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Jirström, K
    Membranous expression of podocalyxin-like protein is an independent factor of poor prognosis in urothelial bladder cancer2013In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 108, p. 2321-2328Article in journal (Refereed)
    Abstract [en]

    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.

  • 4. Boman, Karolina
    et al.
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Ahlgren, Göran
    Eberhard, Jakob
    Uhlén, Mathias
    Jirström, Karin
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Decreased expression of RNA-binding motif protein 3 correlates with tumour progression and poor prognosis in urothelial bladder cancer2013In: BMC Urology, ISSN 1471-2490, E-ISSN 1471-2490, Vol. 13, p. 17-Article in journal (Refereed)
    Abstract [en]

    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.

  • 5.
    Botling, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Edlund, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Tahmasebpoor, Simin
    Engström, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Sundström, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Impact of thawing on RNA integrity and gene expression analysis in fresh frozen tissue2009In: Diagnostic molecular pathology (Print), ISSN 1052-9551, E-ISSN 1533-4066, Vol. 18, no 1, p. 44-52Article in journal (Refereed)
    Abstract [en]

    Biobanks of fresh, unfixed human tissue represent a valuable source for gene expression analysis in translational research and molecular pathology. The aim of this study was to evaluate the impact of thawing on RNA integrity and gene expression in fresh frozen tissue specimens. Portions of snap frozen tonsil tissue, unfixed or immersed in RNAlater, were thawed at room temperature for 0 minute, 5 minutes, 30 minutes, 45 minutes, 1 hour, 3 hours, 6 hours, and 16 hours before RNA extraction. Additionally, tonsil tissue underwent repetitive freezing and thawing cycles. RNA integrity was analyzed by microchip gel electrophoresis and gene expression by quantitative real-time polymerase chain reaction for selected genes (FOS, TGFB1, HIF1A, BCL2, and PCNA). Minimal RNA degradation was detected after 30 minutes of thawing in unfixed samples. This degradation was accompanied by relevant changes in gene expression for FOS and BCL2 at 45 minutes. Modified primer design or the use of different housekeeping genes could not rectify the changes for FOS. Repetitive thawing cycles had similar effects on RNA integrity. The incubation of the tissue in RNAlater efficiently prevented RNA degradation. In conclusion, degradation of RNA in frozen tissue occurs first after several minutes of thawing. Already minimal decrease in RNA quality may result in significant changes in gene expression patterns in clinical tissue samples.

  • 6.
    Brattström, Daniel
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enh för onkologi.
    Wester, Kenneth
    Department of Genetics and Pathology.
    Bergqvist, Michael
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enh för onkologi.
    Hesselius, Patrik
    Malmström, Per-Uno
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Department of Surgical Sciences. BMS.
    Nordgren, Hans
    Wagenius, Gunnar
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology. Enh för onkologi.
    Brodin, Ola
    HER-2, EGFR, COX-2 expression status correlated to microvessel density and survival in resected non-small cell lung cancer.2004In: Acta Oncol, ISSN 0284-186X, Vol. 43, no 1, p. 80-6Article in journal (Refereed)
  • 7.
    Carlsson, Jörgen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Blomquist, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Gedda, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Liljegren, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Sjöström, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Westlin, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Zhao, Qinghai
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Tolmachev, Vladimir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Lundqvist, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Conjugate chemistry and cellular processing of EGF-dextran1999In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 38, no 3, p. 313-321Article in journal (Refereed)
    Abstract [en]

    Conjugates with specific binding to the epidermal growth factor receptor, EGFR, of interest for radionuclide based imaging and therapy were prepared using mouse epidermal growth factor, mEGF, and dextran. In one type of conjugate, mEGF was coupled to dextran by reductive amination in which the free amino group on the mEGF N-terminal reacted with the aldehyde group on the reductive end of dextran. The end-end coupled conjugate could be further activated by the cyanopyridinium agent CDAP, thereby introducing tyrosines to the dextran part. In the other type of conjugate, the cyanylating procedure using CDAP was applied, first to activate dextran and then allowing for the amino terminus of mEGF to randomly attach to the dextran. In the latter case, radionuclide-labelled tyrosines or glycines could be added in the same conjugation step. All types of mEGF-dextran conjugates had EGFR-specific binding since the binding could be displaced by an excess of non-radioactive mEGF. The conjugates were to a large extent internalized in the test cells and the associated radioactivity was retained intracellularly for different times depending on both the type of cells and conjugate applied. Different intracellular 'traffic routes' for the radionuclides are discussed as well as applications for both imaging and therapy.

  • 8.
    Carlsson, Jörgen
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medical Radiation Science.
    Wester, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    De La Torre, Manuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Gardmark, Truls
    EGFR-expression in primary urinary bladder cancer and corresponding metastases and the relation to HER2-expression. On the possibility to target these receptors with radionuclides2015In: Radiology and Oncology, ISSN 1318-2099, E-ISSN 1581-3207, Vol. 49, no 1, p. 50-58Article in journal (Refereed)
    Abstract [en]

    Background. There is limited effect of tyrosine kinase inhibitors or "naked" antibodies binding EGFR or HER2 for therapy of metastasized urinary bladder canter and these methods are therefore not routinely used. Targeting radionuclides to the extracellular domain of the receptors is potentially a better possibility. Methods. EGFR- and HER2-expression was analyzed for primary tumors and corresponding metastases from 72 patients using immunohistochemistry and the internationally recommended HercepTest. Intracellular mutations were not analyzed since only the receptors were considered as targets and intracellular abnormalities should have minor effect on radiation dose. Results. EGFR was positive in 71% of the primary tumors and 69% of corresponding metastases. Local and distant metastases were EGFR-positive in 75% and 66% of the cases, respectively. The expression frequency of HER2 in related lesions was slightly higher (data from previous study). The EGFR-positive tumors expressed EGFR in metastases in 86% of the cases. The co-expression of EGFR and HER2 was 57% for tumors and 53% for metastases. Only 3% and 10% of the lesions were negative for both receptors in tumors and metastases, respectively. Thus, targeting these receptors with radionuclides might be applied for most patients. Conclusions. At least one of the EGFR- or HER2-receptors was present in most cases and co-expressed in more than half the cases. It is therefore interesting to deliver radionuclides for whole-body receptor-analysis, dosimetry and therapy. This can hopefully compensate for resistance to other therapies and more patients can hopefully be treated with curative instead of palliative intention.

  • 9.
    Chan, Owen T. M.
    et al.
    Univ Hawaii, Ctr Canc, Clin & Translat Res Program, Honolulu, HI 96822 USA..
    Furuya, Hideki
    Univ Hawaii, Ctr Canc, Clin & Translat Res Program, Honolulu, HI 96822 USA..
    Pagano, Ian
    Univ Hawaii, Ctr Canc, Canc Prevent & Control Program Res Program, Honolulu, HI 96822 USA..
    Shimizu, Yoshiko
    Univ Hawaii, Ctr Canc, Clin & Translat Res Program, Honolulu, HI 96822 USA.;Univ Hawaii Manoa, Dept Mol Biosci & Bioengn, Honolulu, HI 96822 USA..
    Hokutan, Kanani
    Univ Hawaii, Ctr Canc, Clin & Translat Res Program, Honolulu, HI 96822 USA.;Univ Hawaii Manoa, Dept Mol Biosci & Bioengn, Honolulu, HI 96822 USA..
    Dyrskjot, Lars
    Aarhus Univ Hosp, Dept Mol Med, Aarhus, Denmark..
    Jensen, Jorgen Bjerggaard
    Aarhus Univ Hosp, Dept Urol, Aarhus, Denmark..
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Janku, Filip
    Univ Texas MD Anderson Canc Ctr, Dept Invest Canc Therapeut, Houston, TX 77030 USA..
    Rosser, Charles J.
    Univ Hawaii, Ctr Canc, Clin & Translat Res Program, Honolulu, HI 96822 USA..
    Association of MMP-2, RB and PAI-1 with decreased recurrence-free survival and overall survival in bladder cancer patients2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 59, p. 99707-99721Article in journal (Refereed)
    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.

  • 10.
    Dansk, Viktor
    et al.
    PAREXEL, HERONtm Commercializat, Stockholm, Sweden..
    Malmstrom, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Blackberg, Mats
    Helsingborg Hosp, Dept Urol & Surg, Helsingborg, Sweden..
    Malmenas, Maria
    PAREXEL, HERONtm Commercializat, Stockholm, Sweden..
    Hexaminolevulinate hydrochloride blue-light flexible cystoscopy in the detection and follow-up of nonmuscle-invasive bladder cancer: cost consequences during outpatient surveillance in Sweden2016In: Future Oncology, ISSN 1479-6694, E-ISSN 1744-8301, Vol. 12, no 8, p. 1025-1038Article in journal (Refereed)
    Abstract [en]

    Aim: This study explored the cost consequences of introducing hexaminolevulinate hydrochloride-guided blue-light flexible cystoscopy (HAL BLFC) as an adjunct to white-light flexible cystoscopy compared with white-light flexible cystoscopy alone, for the detection and management of nonmuscle invasive bladder cancer in Sweden.

    Methods: The model evaluated 231 patients in the outpatient setting after successful initial transurethral resection of the bladder tumor.

    Results: HAL BLFC introduction across all risk groups resulted in minimal budget impact (+ 1.6% total cost/5 years, or 189 Swedish Krona [SEK] per patient/year), and translated to cost savings in intermediate-and high-risk groups from year 2.

    Conclusion: HAL BLFC allowed more outpatient treatment with improved recurrence detection and reduced transurethral resection of the bladder tumors, cystectomies, bed days and operating room time, with minimal cost impact across all risk groups, demonstrating the economic benefits of introducing HAL.

  • 11. Dyrskjot, L.
    et al.
    Reinert, T.
    Novoradovsky, A.
    Zuiverloon, T. C. M.
    Beukers, W.
    Zwarthoff, E.
    Malats, N.
    Real, F. X.
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Knowles, M.
    Hurst, C.
    Sorge, J.
    Borre, M.
    Orntoft, T. F.
    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 PCR2012In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 107, no 8, p. 1392-1398Article in journal (Refereed)
    Abstract [en]

    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.

  • 12.
    Díaz de Ståhl, Teresita
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Molecular genetics of bladder cancer: an update2008In: Minerva Urologica e Nefrologica, ISSN 0393-2249, E-ISSN 1827-1758, Vol. 60, no 4, p. 205-16Article in journal (Refereed)
    Abstract [en]

    Urinary bladder cancer is a heterogeneous disease with tumors ranging from papillary non-invasive to solid muscle infiltrating high grade tumors. There are mainly three problems after initial management: recurrence, progression to higher stage and metastases. The respective risk is well known for each of the stages of the disease but not sufficiently for individual optimal risk assessments. The clinical need is initially to establish the correct risk irrespective of later treatment that is to find prognostic factors. Secondarily it is important to develop predictive factors for each specific therapy. With the advent of array-based molecular profiling it is possible to obtain a more complete picture of the cancer biology and thus hope to improve the prediction of risk. Today the microarray approach is implemented at DNA, RNA and protein level. Reported chromosomal alterations in low-grade papillary tumors are few and the most common are 9q and 9p deletions. Activation of the MAPK pathway through mutations of FGFR3, RAS or PI3K seems to be crucial in the genesis of these low malignant tumors. Muscle infiltrating bladder tumors typically have more genetic aberrations than non-muscle invasive cancers. Key genes are related to the p53 and RB pathways. Gene-expression signatures correlated to stage, CIS, progression and recurrence have been proposed but require further validation.

  • 13. Fristrup, Niels
    et al.
    Birkenkamp-Demtröder, Karin
    Reinert, Thomas
    Sanchez-Carbayo, Marta
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Palou, Joan
    Alvarez-Múgica, Miguel
    Pan, Chin-Chen
    Ulhøi, Benedicte P
    Borre, Michael
    Orntoft, Torben F
    Dyrskjøt, Lars
    Multicenter Validation of Cyclin D1, MCM7, TRIM29, and UBE2C as Prognostic Protein Markers in Non-Muscle Invasive Bladder Cancer2013In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 182, no 2, p. 339-349Article in journal (Refereed)
    Abstract [en]

    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.

  • 14. Fristrup, Niels
    et al.
    Ulhoi, Benedicte P.
    Birkenkamp-Demtroder, Karin
    Mansilla, Francisco
    Sanchez-Carbayo, Marta
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Hartmann, Arndt
    Palou, Joan
    Alvarez-Mugica, Miguel
    Zieger, Karsten
    Borre, Michael
    Orntoft, Torben F.
    Dyrskjot, Lars
    Cathepsin E, Maspin, Plk1, and Survivin Are Promising Prognostic Protein Markers for Progression in Non-Muscle Invasive Bladder Cancer2012In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 180, no 5, p. 1824-1834Article in journal (Refereed)
    Abstract [en]

    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.

  • 15.
    Gerullis, H.
    et al.
    Carl von Ossietzky Univ Oldenburg, Univ Hosp Urol, Klinikum Oldenburg, Sch Med & Hlth Sci, Oldenburg, Germany..
    Barski, D.
    Lukas Hosp, Dept Urol, Neuss, Germany..
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Sun, X.
    Univ Chengdu, Chengdu, Peoples R China..
    Ecke, T. H.
    HELIOS Hosp, Dept Urol, Bad Saarow Pieskow, Germany..
    Evidence in Urologic- and Pelvic-Surgery Research: Finding the IDEAL Way of Reporting2017In: BioMed Research International, ISSN 2314-6133, E-ISSN 2314-6141, article id 2716759Article in journal (Other academic)
  • 16. Gontero, Paolo
    et al.
    Sylvester, Richard
    Pisano, Francesca
    Joniau, Steven
    Eeckt, Kathy Vander
    Serretta, Vincenzo
    Larre, Stephane
    Di Stasi, Savino
    Van Rhijn, Bas
    Witjes, Alfred J.
    Grotenhuis, Anne J.
    Kiemeney, Lambertus A.
    Colombo, Renzo
    Briganti, Alberto
    Babjuk, Marek
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Oderda, Marco
    Irani, Jacques
    Malats, Nuria
    Baniel, Jack
    Mano, Roy
    Cai, Tommaso
    Cha, Eugene K.
    Ardelt, Peter
    Varkarakis, John
    Bartoletti, Riccardo
    Spahn, Martin
    Johansson, Robert
    Frea, Bruno
    Soukup, Viktor
    Xylinas, Evanguelos
    Dalbagni, Guido
    Karnes, R. Jeffrey
    Shariat, Shahrokh F.
    Palou, Joan
    Prognostic Factors and Risk Groups in T1G3 Non-Muscle-invasive Bladder Cancer Patients Initially Treated with Bacillus Calmette-Guerin: Results of a Retrospective Multicenter Study of 2451 Patients2015In: European Urology, ISSN 0302-2838, E-ISSN 1873-7560, Vol. 67, no 1, p. 74-82Article in journal (Refereed)
    Abstract [en]

    Background: The impact of prognostic factors in T1G3 non-muscle-invasive bladder cancer (BCa) patients is critical for proper treatment decision making. Objective: To assess prognostic factors in patients who received bacillus Calmette Guerin (BCG) as initial intravesical treatment of T1G3 tumors and to identify a subgroup of high-risk patients who should be considered for more aggressive treatment. Design, setting, and participants: Individual patient data were collected for 2451 T1G3 patients from 23 centers who received BCG between 1990 and 2011. Outcome measurements and statistical analysis: Using Cox multivariable regression, the prognostic importance of several clinical variables was assessed for time to recurrence, progression, BCa-specific survival, and overall survival (OS). Results and limitations: With a median follow-up of 5.2 yr, 465 patients (19%) progressed, 509 (21%) underwent cystectomy, and 221 (9%) died because of BCa. In multivariable analyses, the most important prognostic factors for progression were age, tumor size, and concomitant carcinoma in situ (CIS); the most important prognostic factors for BCa-specific survival and OS were age and tumor size. Patients were divided into four risk groups for progression according to the number of adverse factors among age >= 70 yr, size >= 3 cm, and presence of CIS. Progression rates at 10 yr ranged from 17% to 52%. BCa-specific death rates at 10 yr were 32% in patients >= 70 yr with tumor size >= 3 cm and 13% otherwise. Conclusions: T1G3 patients >= 70 yr with tumors >= 3 cm and concomitant CIS should be treated more aggressively because of the high risk of progression. Patient summary: Although the majority of T1G3 patients can be safely treated with intravesical bacillus Calmette-Guerin, there is a subgroup of T1G3 patients with age >= 70 yr, tumor size >= 3 cm, and concomitant CIS who have a high risk of progression and thus require aggressive treatment.

  • 17. Gontero, Paolo
    et al.
    Sylvester, Richard
    Pisano, Francesca
    Joniau, Steven
    Oderda, Marco
    Serretta, Vincenzo
    Larré, Stéphane
    Di Stasi, Savino
    Van Rhijn, Bas
    Witjes, Alfred J
    Grotenhuis, Anne J
    Colombo, Renzo
    Briganti, Alberto
    Babjuk, Marek
    Soukup, Viktor
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Irani, Jacques
    Malats, Nuria
    Baniel, Jack
    Mano, Roy
    Cai, Tommaso
    Cha, Eugene K
    Ardelt, Peter
    Vakarakis, John
    Bartoletti, Riccardo
    Dalbagni, Guido
    Shariat, Shahrokh F
    Xylinas, Evanguelos
    Karnes, Robert J
    Palou, Joan
    The impact of re-transurethral resection on clinical outcomes in a large multicentre cohort of patients with T1 high-grade/Grade 3 bladder cancer treated with bacille Calmette-Guérin2016In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 118, no 1, p. 44-52Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To determine if a re-transurethral resection (TUR), in the presence or absence of muscle at the first TUR in patients with T1-high grade (HG)/Grade 3 (G3) bladder cancer, makes a difference in recurrence, progression, cancer specific (CSS) and overall survival (OS).

    PATIENTS AND METHODS: In a large retrospective multicentre cohort of 2451 patients with T1-HG/G3 initially treated with bacille Calmette-Guérin, 935 (38%) had a re-TUR. According to the presence or absence of muscle in the specimen of the primary TUR, patients were divided in four groups: group 1 (no muscle, no re-TUR), group 2 (no muscle, re-TUR), group 3 (muscle, no re-TUR) and group 4 (muscle, re-TUR). Clinical outcomes were compared across the four groups.

    RESULTS: Re-TUR had a positive impact on recurrence, progression, CSS and OS only if muscle was not present in the primary TUR specimen. Adjusting for the most important prognostic factors, re-TUR in the absence of muscle had a borderline significant effect on time to recurrence [hazard ratio (HR) 0.67, P = 0.08], progression (HR 0.46, P = 0.06), CSS (HR 0.31, P = 0.07) and OS (HR 0.48, P = 0.05). Re-TUR in the presence of muscle in the primary TUR specimen did not improve the outcome for any of the endpoints.

    CONCLUSIONS: Our retrospective analysis suggests that re-TUR may not be necessary in patients with T1-HG/G3, if muscle is present in the specimen of the primary TUR.

  • 18. Gonterol, P.
    et al.
    Sylvester, R.
    Pisano, F.
    Joniau, S.
    Eeckt, Kathy Vander
    Serretta, V.
    Larre, S.
    di Stasi, S.
    Van Rhijn, B.
    Witjes, A.
    Grotenhuis, A.
    Colombo, R.
    Brigand, A.
    Babjukl, M.
    Soukupw, V.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Irani, J.
    Malats, N.
    Baniel, J.
    Mano, R.
    Cai, T.
    Cha, E.
    Ardelti, P.
    Vakarakisis, J.
    Bartoletti, R.
    Sphan, M.
    Dalbagnin, G.
    Shariat, S. F.
    Karnes, J.
    Palou, J.
    Prognostic Factors And Risk Groups In T1g3 Patients Initially Treated With Bcg: Results Of A Multicenter Retrospective Series In 1743 Patients2013In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 33, no 5, p. 2260-2261Article in journal (Other academic)
  • 19. Gunnarsson, Jonas
    et al.
    Dahlman, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Helenius, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Liss, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lönnemark, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Magnusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Hematurispåret – en väg att snabbare diagnostisera blåscancer2015In: Svensk Urologi, no 3, p. 38-Article in journal (Refereed)
  • 20.
    Gårdmark, Truls
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Bladström, Anna
    Hellsten, Sverker
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Analysis of clinical characteristics, management and survival of patients with Ta T1 bladder tumours in Sweden between 1997 and 20012006In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 40, no 4, p. 276-282Article in journal (Refereed)
    Abstract [en]

    Objective. To analyse the management and outcome of patients with Ta T1 urinary bladder cancer in a population-based national database. Material and methods. Between 1997 and 2001, 94% of all newly diagnosed cases of urinary bladder cancer were registered in the Swedish National Bladder Cancer Register. Data were analysed regarding gender, healthcare region, stage and grade for patients with Ta T1 tumours. The choice of initial treatment in different regions was reviewed. Survival was analysed by calculating relative survival. Results. Out of 9859 registered patients, there were 4442 Ta tumours and 2139 T1 tumours. The median age at diagnosis was 72 and 73 years for patients with Ta and T1 tumours, respectively. Seventy-six percent of the patients were men. The choice of treatment varied between different healthcare regions. A significant trend towards an increased use of intravesical therapy was seen over time. Significantly fewer older than younger patients received such therapy. There was also a tendency towards more intensive therapy in men. The bladder cancer relative 5-year survival rate was 93% for Ta and 75% for T1 tumours. Survival was similar for men and women. Conclusions. Our analysis revealed a regional variation in the treatment of bladder cancer. A large group of patients, even those at high risk, were still undertreated. However, the recent publication of guidelines may have contributed to an increased use of intravesical treatment. Urologists tended to treat TaG3 and T1G3 tumours more aggressively than T1G2 tumours. Therapeutic aggressiveness decreased as the age of the patients increased. The survival rate of patients with bladder cancer in Sweden seems to remain at the levels previously reported for the 1980s.

  • 21.
    Gårdmark, Truls
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Carringer, Malcolm
    Beckman, Eva
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Malmström, Per-Uno
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Randomized phase II marker lesion study evaluating effect of scheduling on response to intravesical gemcitabine in recurrent Stage Ta urothelial cell carcinoma of the bladder.2005In: Urology, ISSN 1527-9995, Vol. 66, no 3, p. 527-30Article in journal (Refereed)
  • 22.
    Gårdmark, Truls
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Wester, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    De la Torre, Manuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Carlsson, Jörgen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Analysis of HER2 expression in primary urinary bladder carcinoma and corresponding metastases2005In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 95, no 7, p. 982-986Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To evaluate the expression of HER2 receptors (previously reported to be over-expressed in malignant urothelium) in both primary tumours and metastases of transitional cell cancer, using two different staining methods and two different scoring techniques, considering the potential use of these receptors as targets for planned systemic anti-HER2 nuclide-based treatment. MATERIALS AND METHODS: HER2 expression was evaluated with two different immunohistochemical methods in 90 patients with primary urinary bladder cancer tumours and corresponding metastases. Sections were first stained with the commercially available breast cancer test kit (HercepTest, Dako, Glostrup, Denmark). Parallel sections were then stained with a modified HercepTest procedure. Two different evaluation criteria were compared; the HercepTest score that requires > or = 10% stained tumour cells (as for breast cancer) and a proposed 'Target score' that requires > 67% stained tumour cells. The latter score is assumed to be preferable for HER2-targeted radionuclide therapy. RESULTS: Using the HercepTest kit, the Target score gave lower fractions of positive primary tumours and metastases than the HercepTest score. The modified HercepTest staining procedure and Target score gave high HER2 values in 80% of primary tumours and 62% of metastases, which is considerably more than that obtained with the HercepTest staining and score. There was a significant decrease in HER2 positivity with increasing distance from the primary tumour. In nine sentinel-node metastases assessed, all but one were HER2-positive. Considering all regional metastases, 74% were positive, and of distant metastases, 47%; 72% of the patients with positive primary tumours also expressed HER2 in their metastases. CONCLUSIONS: When combining the modified HercepTest with customised evaluation criteria, more HER2-positive tumours were diagnosed. The degree of HER2 down-regulation was significantly higher in distant than in regional metastases. HER2-targeted therapy may be an alternative or complementary to other methods in the future treatment of metastatic urinary bladder carcinoma.

  • 23.
    Hemdan, Tammer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Johansson, Robert
    Jahnson, Staffan
    Hellstrom, Pekka
    Tasdemir, Ilker
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Five-year results of nordic T1G2-3, a randomized trial comparing bcg with epirubicin and interferon alpha 2b2013In: SCANDINAVIAN JOURNAL OF UROLOGY, ISSN 2168-1805, Vol. 47, no S219, p. 19-20Article in journal (Other academic)
  • 24.
    Hemdan, Tammer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Johansson, Robert
    Jahnson, Staffan
    Hellström, Pekka
    Tasdemir, Ilker
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Five year outcome of a randomized prospective study comparing bacillus Calmette-Guerin with epirubicin and interferon α 2b in patients with T1 bladder cancer2014In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 191, no 5, p. 1244-1249Article in journal (Refereed)
    Abstract [en]

    PURPOSE:

    In a multicenter, prospectively randomized study we evaluated the five-year outcome of bacillus Calmette-Guérin (BCG) alone compared to a combination of epirubicin and interferon α 2b in the treatment of patients with T1 bladder cancer.

    MATERIAL AND METHODS:

    The transurethral resection was followed by a second resection and bladder mapping. Stratification was for grade and cancer in situ. Follow-up entailed regular cystoscopy and cytology during the first 5 years. The end points assessed in this analysis were recurrence-free survival, time to failure of the treatment and progression, cancer-specific survival, and prognostic factors.

    RESULTS:

    The study recruited 250 eligible patients.The five years recurrence-free survival were 38% in the combination arm and 59% in the BCG arm (p=0.001). The corresponding rates for the other endpoints were not significantly different; free of - progression 78 and 77%, - treatment failure 75 and 75% and cancer-specific survival 90 and 92%. The type of treatment, size and tumour status at second resection were independent variables associated with recurrence. Concomitant carcinoma in situ was not predictive of failure of BCG therapy. Independent factor for treatment failure was remaining T1 stage at second resection.

    CONCLUSIONS:

    BCG therapy was more effective than the tested combination. Presently recommended management with second resection and three week maintenance BCG entails a low risk of cancer specific death. More aggressive treatment in patients with infiltrative tumours at second resection might improve these results. In particular, concomitant carcinoma in situ was not a predictive factor for poor outcome after BCG therapy.

  • 25.
    Hemdan, Tammer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Lindén, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Bergström Lind, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Namuduri, Arvind Venkat
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Sjöstedt, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    de la Torre, Manuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gårdmark, Truls
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Stathmin-1 is a promising prognostic factor and potential therapeutic target in urinary bladder cancerManuscript (preprint) (Other academic)
    Abstract [en]

    Aim: The oncoprotein 18/stathmin 1 (STMN1), involved in cell cycle progression and cell migration, has been reported to be expressed in several types of cancer, and is associated with clinical outcome in e.g. breast and liver cancer. The aims in this study were to investigate the clinical significance of STMN1 and to examine if STMN1 might be a possible therapeutic target in urinary bladder cancer.

    Experimental design: Immunohistochemical analyses of STMN1 protein expression were performed in a wide-range tissue microarray (115 Ta-, 115 T1-, 112 T2-4-tumors) and in a metastatic primary tumor/matched metastasis-material (90 patients). In the T24 cell line, the effect of STMN1 on cell proliferation was evaluated by inhibiting the cellular expression of STMN using STMN1-siRNA.

    Results: Patients with T1- or muscle-invasive disease exhibiting high expression of the STMN1 protein had a poorer overall survival (OS) and disease specific survival (DSS). In a multivariate analysis adjusting for stage, age and gender the results were for T2-T4 patients: OS (HR=1.77 95% CI 1.02-3.07; p=0.04) and DSS (HR=2.04 95% CI 1.13-3.68; p=0.02); for T1-4 patients: DSS (HR=1.83 95% CI 1.09-3.08; p=0.02). In the metastatic bladder cancer material, the majority of the patients with one metastasis (69%) and with several matched metastases (70%) were STMN1-positive in both the primary tumor and the matched metastases. Moreover, the ability of the urinary bladder cancer cell line to grow was significantly reduced after 72 hours (p<0.0001) when transfecting the cells with a siRNA targeting STMN1.

    Conclusion: Our results suggest that STMN1 protein-expression has a potential both as a prognostic marker and a novel treatment target in urinary bladder cancer.

  • 26.
    Hemdan, Tammer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lindén, Mårten
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Lind, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Namuduri, Arvind
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Sjöstedt, Evelina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    D de Ståhl, T
    Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
    Asplund, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    The prognostic value and therapeutic target role of stathmin-1 in urinary bladder cancer2014In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 111, no 6, p. 1180-1187Article in journal (Refereed)
    Abstract [en]

    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. 

  • 27.
    Hemdan, Tammer
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Jahnson, Staffan
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Emmprin Expression Predicts Response and Survival following Cisplatin Containing Chemotherapy for Bladder Cancer: A Validation Study.2015In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 194, no 6, p. 1575-1581Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Neoadjuvant chemotherapy before cystectomy is recommended. To our knowledge the subset of patients likely to benefit has not been identified. We validate emmprin and survivin as markers of chemotherapy response.

    MATERIALS AND METHODS: Tumor specimens were obtained before therapy from a total of 250 patients with T1-T4 bladder cancer enrolled in 2 randomized trials comparing neoadjuvant chemotherapy before cystectomy with a surgery only arm. Protein expression was determined by immunohistochemistry.

    RESULTS: Expression was categorized according to predefined cutoffs reported in the literature. Data were analyzed with the Kaplan-Meier method and Cox models. Patients in the chemotherapy cohort with negative emmprin expression had significantly higher down staging overall survival than those with positive expression (71% vs 38%, p <0.001). The values for cancer specific survival were 76% and 56%, respectively (p <0.027). In the cystectomy only cohort emmprin expression was not associated with overall survival (46% vs 35%, p = 0.23) or cancer specific survival (55% vs 51%, p = 0.64). Emmprin negative patients had an absolute risk reduction of 25% in overall survival (95% CI 11-40) and a number needed to treat of 4 (95% CI 2.5-9.3). Survivin expression was not useful as a biomarker in this study. Limitations were the retrospective design and heterogeneity coupled with the time difference between the trials.

    CONCLUSIONS: Patients with emmprin negative tumors have a better response to neoadjuvant chemotherapy before cystectomy than those with positive expression.

  • 28.
    Holfeld, Aleš
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Valdés, Alberto
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Bergström Lind, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Parallel Proteomic Workflow for Mass Spectrometric Analysis of Tissue Samples Preserved by Different Methods2018In: Analytical Chemistry, ISSN 0003-2700, E-ISSN 1520-6882, Vol. 90, no 9, p. 5841-5849Article in journal (Refereed)
    Abstract [en]

    Formalin-fixed and paraffin-embedded (FFPE) and optimal cutting temperature (OCT)-embedded and frozen tissue specimens in biobanks are highly valuable in clinical studies but proteomic and post-translational modification (PTM) studies using mass spectrometry (MS) have been limited due to structural arrangement of proteins and contaminations from embedding material. This study aims to develop a parallel proteomic workflow for FFPE and OCT/frozen samples that allows for large-scale, quick, reproducible, qualitative, and quantitative high-resolution MS analysis. The optimized protocol gives details on removal of embedding material, protein extraction, and multienzyme digestion using filter-aided sample preparation method. The method was evaluated by investigating the protein expression levels in nonmuscle-invasive and muscle-invasive bladder cancer samples in two cohorts and MS spectra were carefully reviewed for contaminations. More than 2000 and 3000 proteins in FFPE and OCT/frozen samples, respectively, were identified, and samples could be clustered in different tumor stages based on their protein expression. Furthermore, more than 250 and 400 phosphopeptides could be identified from specific patient samples of FFPE and OCT/frozen, respectively, using titanium dioxide enrichment. The paper presents unique data describing the similarities and differences observed in FFPE and OCT/frozen samples and shows the feasibility to detect proteins and site-specific phosphorylation even after long-term storage of clinical samples.

  • 29.
    Häggström, Christel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Umeå University, Department of Biobank Research.
    Liedberg, Fredrik
    Skåne University Hospital, Department of Urology; Lund University, Department of Translational Medicine.
    Hagberg, Oskar
    Regional Cancer Centre South, Lund.
    Aljabery, Firas
    Linköping University, Division of Urology, Department of Clinical and Experimental Medicine.
    Ströck, Viveka
    Sahlgrenska University Hospital, Department of Urology.
    Hosseini, Abolfazl
    Karolinska University Hospital, Department of Urology.
    Gårdmark, Truls
    Karolinska Institute, Danderyd Hospital, Department of Clinical Sciences.
    Sherif, Amir
    Umeå University, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Garmo, Hans
    King’s College London, Faculty of Life Sciences and Medicine, Division of Cancer Studies; Regional Cancer Centre Uppsala/Örebro.
    Jahnson, Staffan
    Linköping University, Division of Urology, Department of Clinical and Experimental Medicine.
    Holmberg, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. King’s College London, Faculty of Life Sciences and Medicine, Division of Cancer Studies.
    Cohort profile: The Swedish National Register of Urinary Bladder Cancer (SNRUBC) and the Bladder Cancer Data Base Sweden (BladderBaSe)2017In: BMJ Open, ISSN 2044-6055, E-ISSN 2044-6055, Vol. 7, no 9, article id e016606Article in journal (Refereed)
    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.

  • 30. Jahnson, Staffan
    et al.
    Hosseini Aliabad, Abolfazl
    Holmäng, Sten
    Jancke, Georg
    Liedberg, Fredrik
    Ljungberg, Börje
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Rosell, Johan
    Swedish National Registry of Urinary Bladder Cancer: No difference in relative survival over time despite more aggressive treatment.2016In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 50, no 1, p. 14-20Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of this study was to use the Swedish National Registry of Urinary Bladder Cancer (SNRUBC) to investigate changes in patient and tumour characteristics, management and survival in bladder cancer cases over a period of 15 years.

    MATERIALS AND METHODS: All patients with newly detected bladder cancer reported to the SNRUBC during 1997-2011 were included in the study. The cohort was divided into three groups, each representing 5 years of the 15 year study period.

    RESULTS: The study included 31,266 patients (74% men, 26% women) with a mean age of 72 years. Mean age was 71.7 years in the first subperiod (1997-2001) and 72.5 years in the last subperiod (2007-2011). Clinical T categorization changed from the first to the last subperiod: Ta from 45% to 48%, T1 from 21.6% to 22.4%, and T2-T4 from 27% to 25%. Also from the first to the last subperiod, intravesical treatment after transurethral resection for T1G2 and T1G3 tumours increased from 15% to 40% and from 30% to 50%, respectively, and cystectomy for T2-T4 tumours increased from 30% to 40%. No differences between the analysed subperiods were found regarding relative survival in patients with T1 or T2-T4 tumours, or in the whole cohort.

    CONCLUSIONS: This investigation based on a national bladder cancer registry showed that the age of the patients at diagnosis increased, and the proportion of muscle-invasive tumours decreased. The treatment of all tumour stages became more aggressive but relative survival showed no statistically significant change over time.

  • 31. Jahnson, Staffan
    et al.
    Wiklund, Fredrik
    Duchek, Milos
    Mestad, Oddvar
    Rintala, Erkki
    Hellsten, Sverker
    Malmström, Per-Uno
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Results of second-look resection after primary resection of T1 tumour of the urinary bladder.2005In: Scand J Urol Nephrol, ISSN 0036-5599, Vol. 39, no 3, p. 206-10Article in journal (Refereed)
  • 32.
    Jancke, Georg
    et al.
    Skane Univ Hosp, Dept Urol, Malmo, Sweden.;Lund Univ, Dept Translat Med, Malmo, Sweden..
    Liedberg, Fredrik
    Skane Univ Hosp, Dept Urol, Malmo, Sweden.;Lund Univ, Dept Translat Med, Malmo, Sweden..
    Aljabery, Firas
    Linkoping Univ Hosp, Dept Urol, Linkoping, Sweden..
    Sherif, Amir
    Norrland Univ Hosp, Dept Urol, Umea, Sweden..
    Strock, Viveka
    Sahlgrens Univ Hosp, Dept Urol, Gothenburg, Sweden..
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Hosseini-Aliabad, Abolfazl
    Karolinska Univ Hosp, Dept Urol, Stockholm, Sweden..
    Jahnson, Staffan
    Linkoping Univ Hosp, Dept Urol, Linkoping, Sweden..
    Intravesical instillations and cancer-specific survival in patients with primary carcinoma in situ of the urinary bladder2017In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, no 2, p. 124-129Article in journal (Refereed)
    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.

  • 33. Jerlstrom, Tomas
    et al.
    Gardmark, Truls
    Carringer, Malcolm
    Holmang, Sten
    Liedberg, Fredrik
    Hosseini, Abolfazl
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Ljungberg, Borje
    Hagberg, Oskar
    Jahnson, Staffan
    Urinary bladder cancer treated with radical cystectomy: Perioperative parameters and early complications prospectively registered in a national population-based database2014In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 48, no 4, p. 334-340Article in journal (Refereed)
    Abstract [en]

    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.

  • 34.
    Jerlstrom, Tomas
    et al.
    Orebro Univ, Sch Hlth & Med Sci, Dept Urol, Orebro, Sweden..
    Gardmark, Truls
    Karolinska Inst, Danderyd Hosp, Dept Urol, Dept Clin Sci, Stockholm, Sweden..
    Strock, Viveka
    Sahlgrenska Univ Hostpital, Dept Urol, Gothenburg, Sweden..
    Aljabery, Firas A. -S.
    Linkoping Univ Hosp, Dept Clin & Expt Med, Linkoping, Sweden..
    Hosseini, Abolfazl A.
    Karolinska Inst, Sect Urol, Dept Mol Med & Surg, Stockholm, Sweden..
    Sherif, Amir
    Umea Univ, Dept Surg & Perioperat Sci Urol & Androl, Umea, Sweden..
    Ullen, Anders
    Karolinska Hosp, Dept Oncol Pathol, Stockholm, Sweden..
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Liedberg, Fredrik
    Lund Univ, Skane Univ Hosp, Dept Translat Med, Malmo, Sweden..
    Jahnson, Staffan
    Linkoping Univ Hosp, Dept Clin & Expt Med, Linkoping, Sweden..
    Carringer, Malcolm
    Orebro Univ, Sch Hlth & Med Sci, Dept Urol, Orebro, Sweden..
    Significantly more downstaging in patients recieving preoperative (neoadjuvant and induction) chemotherapy prior to cystectomy for muscle-invasive bladder cancer2017In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, p. 34-35Article in journal (Other academic)
  • 35. Kaasinen, Eero
    et al.
    Wijkström, Hans
    Rintala, Erkki
    Mestad, Oddvar
    Jahnson, Staffan
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Seventeen-year follow-up of the prospective randomized Nordic CIS study: BCG monotherapy versus alternating therapy with mitomycin C and BCG in patients with carcinoma in situ of the urinary bladder2016In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 50, no 5, p. 360-368Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The aim of this study was to compare the long-term efficacy of BCG monotherapy to alternating therapy of mitomycin C (MMC) and BCG in patients with carcinoma in situ (CIS).

    MATERIALS AND METHODS: Between 1992 and 1997, 321 patients with CIS were randomized from Finland, Norway and Sweden in a prospective multicenter trial into two treatment groups. The alternating therapy comprised six weekly instillations of MMC 40 mg followed by 10 instillations of BCG (Connaught 120 mg) or MMC alternating monthly for 1 year. BCG monotherapy followed the same 6 + 10 schedule. Stratification was done by nationality and CIS category. Primary endpoints were time to first recurrence and time to progression. Secondary endpoints were disease-specific mortality and overall survival. The main statistical methods were the proportional subdistribution hazards model and Cox proportional hazards model with the cumulative incidence and Kaplan-Meier analyses.

    RESULTS: The median follow-up time was 9.9 years (maximum 19.9 years) in the BCG group and 8.9 years (maximum 20.3 years) in the alternating group. The risk of recurrence was significantly lower in the BCG group than in the alternating group (49 vs 59% at 15 years, respectively; hazard ratio 0.74, 95% confidence interval 0.54-1.00, p = 0.048). There were no significant differences in the other endpoints. Patients who progressed after 2 years were particularly prone to dying from bladder carcinoma. Younger patients performed worse than older ones.

    CONCLUSIONS: BCG monotherapy including monthly maintenance was effective and better than the alternating therapy. The risk of dying from bladder carcinoma after progression was high.

  • 36. Kamat, Ashish M
    et al.
    Hahn, Noah M
    Efstathiou, Jason A
    Lerner, Seth P
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Choi, Woonyoung
    Guo, Charles C
    Lotan, Yair
    Kassouf, Wassim
    Bladder cancer2016In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 388, no 10061, p. 2796-2810Article, review/survey (Refereed)
    Abstract [en]

    Bladder cancer is a complex disease associated with high morbidity and mortality rates if not treated optimally. Awareness of haematuria as the major presenting symptom is paramount, and early diagnosis with individualised treatment and follow-up is the key to a successful outcome. For non-muscle-invasive bladder cancer, the mainstay of treatment is complete resection of the tumour followed by induction and maintenance immunotherapy with intravesical BCG vaccine or intravesical chemotherapy. For muscle-invasive bladder cancer, multimodal treatment involving radical cystectomy with neoadjuvant chemotherapy offers the best chance for cure. Selected patients with muscle-invasive tumours can be offered bladder-sparing trimodality treatment consisting of transurethral resection with chemoradiation. Advanced disease is best treated with systemic cisplatin-based chemotherapy; immunotherapy is emerging as a viable salvage treatment for patients in whom first-line chemotherapy cannot control the disease. Developments in the past 2 years have shed light on genetic subtypes of bladder cancer that might differ from one another in response to various treatments.

  • 37.
    Kullberg, Erika Bohl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Wei, Qichun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Biomedical Radiation Sciences.
    Capala, Jacek
    NCI / NIH USA.
    Giusti, Valerio
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Gedda, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    EGF-receptor targeted liposomes with boronated acridine: growth inhibition of cultured glioma cells after neutron irradiation2005In: International Journal of Radiation Biology, ISSN 0955-3002, E-ISSN 1362-3095, Vol. 81, no 8, p. 621-629Article in journal (Refereed)
    Abstract [en]

    PURPOSE: To study survival of cultured U-343MGaCl 2:6 glioma cells after incubation with boron-containing liposomes targeting the epidermal growth factor receptor following neutron irradiation. MATERIALS AND METHODS: Epidermal growth factor-tagged liposomes were loaded with water-soluble boronated acridine developed for boron neutron capture therapy, (BNCT). Cellular uptake and distribution were studied. Further, cells were placed at 3 cm depth in a phantom and exposed to an epithermal neutron beam to study clonogenic cell survival. RESULTS: The cellular uptake of boron reached 90 ppm and it was determined by subcellular fractionation that most of the cell-associated boron was located outside of the nucleus. For clonogenic survival, the cells were incubated with epidermal growth factor receptor-targeted liposomes for 4 hours resulting in a cellular concentration of 55 ppm boron (11 ppm 10B). At a fluence of 3 x 10(12) neutrons/cm2 the cell killing effect of the boron-containing epidermal growth factor-liposomes was about ten times higher than for neutrons only. Furthermore, theoretical calculation of the survival by enriched compound (55 ppm 10B), using the parameters from non-enriched compound (11 ppm 10B), shows that the killing effect in this case would be approximately five orders of magnitude higher than for neutrons only. CONCLUSION: The results in this study show that epidermal growth factor-receptor targeted liposomes are suitable as tumor-cell delivery agents of boron for BNCT and support further studies to demonstrate their effectiveness in vivo.

  • 38. Liedberg, Fredrik
    et al.
    Hagberg, Oskar
    Holmang, Sten
    Aliabad, Abolfazl Hosseini
    Jancke, Georg
    Ljungberg, Borje
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Aberg, Hanna
    Jahnson, Staffan
    Local recurrence and progression of non-muscle-invasive bladder cancer in Sweden: a population-based follow-up study2015In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 49, no 4, p. 290-295Article in journal (Refereed)
    Abstract [en]

    Objective. The aim of this study was to investigate recurrence and progression of non-muscle-invasive bladder cancer (NMIBC) in a large population-based setting. Materials and methods. Patients with bladder cancer (stage Ta, T1 or carcinoma in situ) diagnosed in 2004-2007 (n = 5839) in Sweden were investigated 5 years after diagnosis using a questionnaire. Differences in time to recurrence and progression were analysed in relation to age, gender, tumour stage and grade, intravesical treatment, healthcare region, and hospital volume of NMIBC patients (stratified in three equally large groups). Results. Local bladder recurrence and progression occurred in 50 and 9% of the patients, respectively. The rate of local recurrence was 56% in the southern healthcare region compared to 37% in the northern region. A multivariate Cox proportional hazards model, adjusting for age, gender, tumour stage and grade, intravesical treatment, healthcare region and hospital volume, showed that recurrence was associated with TaG2 and T1 disease, no intravesical treatment and treatment in the southern healthcare region, but indicated a lower risk of recurrence in the northern healthcare region. Adjusting for the same factors in a multivariate analysis suggested that increased relative risk of progression correlated with older age, higher tumour stage and grade, and diagnosis in the Uppsala/Orebro healthcare region, whereas such risk was decreased by intravesical treatment (relative risk 0.72, 95% confidence interval 0.55-0.93, p = 0.012). Conclusions. The incidence of NMIBC recurrence and progression was found to be high in Sweden, and important disparities in outcome related to care patterns appear to exist between different healthcare regions.

  • 39. Liedberg, Fredrik
    et al.
    Holmberg, Erik
    Holmäng, Sten
    Ljungberg, Börje
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Månsson, Wiking
    Nunez, Leyla
    Wessman, Catrin
    Wijkström, Hans
    Jahnson, Staffan
    Long-term follow-up after radical cystectomy with emphasis on complications and reoperations: A Swedish population-based survey2012In: Scandinavian Journal of Urology and Nephrology, ISSN 0036-5599, E-ISSN 1651-2065, Vol. 46, no 1, p. 14-18Article in journal (Refereed)
    Abstract [en]

    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 < 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.

  • 40. Liedberg, Fredrik
    et al.
    Holmäng, Sten
    Hosseini, Abolfazl
    Ljungberg, Börje
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Jahnson, Staffan
    Snabba åtgärder vid makrohematuri både angelägna och möjliga: [Fast measures in macro hematuria are both necessary and possible]2012In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 109, no 20-21, p. 1034-1035Article in journal (Refereed)
  • 41.
    Lindén, Mårten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hemdan, Tammer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Ugge, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Bergström Lind, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    de la Torre, Manuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Galectin-1, a potential therapeutic target, in primary tumors and metastases of urinary bladder carcinomas2013Manuscript (preprint) (Other academic)
    Abstract [en]

    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.

  • 42.
    Lindén, Mårten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Lind, Sara Bergström
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Mayrhofer, Corina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Wester, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Lyutvinskiy, Yaroslav
    Zubarev, Roman
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Proteomic analysis of urinary biomarker candidates for nonmuscle invasive bladder cancer2012In: Proteomics, ISSN 1615-9853, E-ISSN 1615-9861, Vol. 12, no 1, p. 135-144Article in journal (Refereed)
    Abstract [en]

    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.

  • 43.
    Lindén, Mårten
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Segersten, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Runeson, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Wester, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Busch, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Pettersson, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Bergström Lind, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Tumour expression of bladder cancer-associated urinary proteins2013In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 112, no 3, p. 407-415Article in journal (Refereed)
    Abstract [en]

    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.
  • 44.
    Loskog, Angelica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Oncology.
    Hedlund, Titti
    Wester, Kenneth
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    de la Torre, Manuel
    Philipson, Lennart
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Tötterman, Thomas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Human urinary bladder carcinomas express adenovirus attachment and internalization receptors2002In: Gene Therapy, ISSN 0969-7128, E-ISSN 1476-5462, Vol. 9, no 9, p. 547-553Article in journal (Refereed)
    Abstract [en]

    The use of adenoviral vectors as potent gene delivery systems requires expression of the Coxsackievirus/adenovirus receptor (CVADR) on the target cell surface. This receptor is important for virus attachment to the cell surface. For effective internalization of the vector into the target cell the integrins alpha(v)beta(3) and/or alpha(v)beta(5) are needed. Since there have been reports of loss of CVADR in bladder cancer cell lines, we wanted to investigate the expression of this receptor in bladder carcinoma biopsies. Surgical biopsies, as well as five human bladder cancer cell lines, were analyzed for expression of CVADR, the integrins alpha(v)beta(3) and alpha(v)beta(5) and MHC class I. Further, we studied the ability to transduce these cell lines using adenoviral vectors. Immunohistochemistry revealed that all biopsies (27/27) were positive for CVADR. Some variation in expression was evident, and superficially growing tumors stained more strongly than invasive ones. Most human tumors expressed the integrin alpha(v)beta(5) (14/24), whereas integrin alpha(v)beta(3) was less frequently seen (3/20). The established cell lines were efficiently transduced with adenoviral vectors, and transduction could be reduced with anti-CVADR antibodies. The abundance of appropriate viral receptors on tumor biopsy cells is a further argument for using adenoviral vectors in gene therapy of bladder cancer.

  • 45.
    Loskog, Angelica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ninalga, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Hedlund, Titti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Alimohammadi, Mohammed
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Tötterman, Thomas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Optimization of the MB49 mouse bladder cancer model for adenoviral gene therapy2005In: Laboratory Animals. Journal of the Laboratory Animal Science Association, ISSN 0023-6772, E-ISSN 1758-1117, Vol. 39, no 4, p. 384-393Article in journal (Refereed)
    Abstract [en]

    Bladder cancer is regarded as a promising candidate for innovative therapies in the field of immune and gene therapy. In this paper, we present the subcutaneous, metastatic and a novel orthotopic model of murine MB49 bladder cancer in C57BL/6 mice. We further show the potential of using adenoviral vectors together with different transduction enhancers to augment in vivo gene delivery. Finally, we present candidate genes for tumour detection, therapy or targeting. The MB49 tumour grew rapidly in mice. The subcutaneous model allowed for tumour detection within a week and the possibility to monitor growth rate on a day-by-day basis. Injection of MB49 cells intravenously into the tail vein gave rise to lung metastases within 16 days, while instillation of tumour cells into pretreated bladders led to a survival time of 20-40 days. Adenoviral vectors can be used as a vehicle for gene transfer to the bladder. By far, the most potent transduction enhancer was Clorpactin, also known as oxychlorosene. Last, we show that MB49 cells express tumour-associated antigens like bladder cancer-4, prostate stem cell antigen and six-transmembrane epithelial antigen of the prostate. Given the possibility for efficient genetic modification of the bladder and the presence of known tumour antigens, the MB49 models can be used in innovative ways to explore immunogene therapy.

  • 46.
    Loskog, Angelica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Ninalga, Christina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Paul-Wetterberg, Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    de la Torre, Manuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Tötterman, Thomas H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Human bladder carcinoma is dominated by T-regulatory cells and Th1 inhibitory cytokines2007In: Journal of Urology, ISSN 0022-5347, E-ISSN 1527-3792, Vol. 177, no 1, p. 353-358Article in journal (Refereed)
    Abstract [en]

    Purpose: Immunotherapy has faced limited success, although many solutions have been proposed. Recently regulatory T cells have made a comeback in the immunological arena and the role of these cells in patients with cancer is in focus. It is under evaluation whether the immunological status of patients with cancer may affect their sensitivity to immunotherapy. We are developing immunostimulating gene therapy for treating bladder cancer. In this study we constructed an immunological profile of patients with bladder carcinoma to understand which obstacles must be circumvented. Materials and Methods: Biopsies and blood were used to identify immune cell populations by FACS®, histochemistry and proliferation assays, and cytokine production by polymerase chain reaction. Results: Results indicate that bladder carcinoma is a Tri dominated tumor, as shown by the infiltration of T-regulatory cells expressing FOXP3, and the presence of tumor necrosis factor-β and interleukin-10 mRNA copies. We further noted that circulating patient T cells were unresponsive to polyclonal T-cell activation compared to healthy donor cells. Moreover, CD4+CD25+ T cells were increased in patient blood and could suppress the expansion of allogeneic T cells from healthy donors. Conclusions: Patients with bladder carcinoma show an immunosuppressive regulatory profile, including nonresponsive T cells. Clinical protocols able to effectively counteract these mechanisms are warranted.

  • 47.
    Malmstrom, Per-Uno
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Surgical Sciences.
    Urinary bladder cancer: hard times for evidenced-based data.2006In: Curr Opin Urol, ISSN 0963-0643, Vol. 16, no 5, p. 342-3Article in journal (Refereed)
  • 48.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Bladder tumours: time for a paradigm shift?2011In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 107, no 10, p. 1543-1545Article in journal (Other academic)
    Abstract [en]

    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.

  • 49.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Drugs and risk of cancer2017In: Scandinavian journal of urology, ISSN 2168-1805, E-ISSN 2168-1813, Vol. 51, no 3, p. 212-212Article in journal (Other academic)
  • 50.
    Malmström, Per-Uno
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Editorial2013In: Scandinavian journal of urology, ISSN 2168-1813, Vol. 47, no 1, p. 3-3Article in journal (Refereed)
12 1 - 50 of 90
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