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1.
  • Abrahamsson, Johan, et al. (författare)
  • Circulating tumor cells in patients with advanced urothelial carcinoma of the bladder : Association with tumor stage, lymph node metastases, FDG-PET findings, and survival
  • 2017
  • Ingår i: Urologic Oncology. - : Elsevier BV. - 1078-1439. ; 35:10, s. 9-606
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: There are currently no methods in clinical use that can detect early systemic dissemination of urothelial tumor cells. Objective: To evaluate measurement of circulating tumor cells (CTCs) as a biomarker for disseminated disease in patients with advanced bladder cancer. Design, setting, and participants: Between March 2013 and October 2015, 88 patients were prospectively included in the study: 78 were scheduled for radical cystectomy (RC) ± perioperative chemotherapy and 10 treated with palliative chemotherapy. The CellSearch CTC test was further assessed in this context by investigating expression of epithelial cell adhesion molecule (EpCAM) in primary tumors obtained at cystectomy from an independent cohort of 409 patients. Outcome measurements and statistical analysis: Presence of CTCs was tested for association with tumor stage, lymph node metastases, metastatic disease on [18 F]-fluorodeoxyglucose-positron emission tomography (FDG-PET), and cancer-specific and progression-free survival. Results: CTCs were detected in 17/88 patients (19%). In 61 patients who underwent FDG-PET-computed tomography (CT), a statistically significant association with presence of CTCs was found for radiological metastatic disease but not for normal PET-CT results (12/35 [34%] vs. 2/26 [8%], P = 0.014). After a median follow-up time of 16.5 months (95% CI: 9.6-21.4), presence of CTCs was associated with an increased risk of progression among patients treated with RC with or without perioperative chemotherapy (n = 75, P = 0.049). A multivariate analysis adjusted for clinical tumor stage, clinical lymph node status, and age showed that CTCs were an independent marker of progression (n = 75; hazard ratio = 2.78; 95% CI: 1.005-7.69; P = 0.049) but not of cancer-specific death (P = 0.596). In 409 cystectomised patients, more than 392 (96%) of the bladder tumors expressed EpCAM. Conclusions: CTCs were present in 19% of patients with advanced urothelial tumors and were associated with metastatic disease on FDG-PET-CT and with increased risk of disease progression after RC. A significant portion of urothelial cancer cells do express EpCAM and can thus be identified using EpCAM-antigen-based CTC detection methods.
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2.
  • Abrahamsson, Per-Anders (författare)
  • EAU-a work in progress-what comes next?
  • 2009
  • Ingår i: Urologic Oncology. - : Elsevier BV. - 1873-2496. ; 27:2, s. 125-126
  • Tidskriftsartikel (refereegranskat)
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3.
  • Aljabery, Firas, et al. (författare)
  • M2-macrophage infiltration and macrophage traits of tumor cells in urinary bladder cancer
  • 2018
  • Ingår i: Urologic Oncology. - : Elsevier. - 1078-1439 .- 1873-2496. ; 36:4
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundTumor-associated macrophages (TAMs) constitute a subset of nonneoplastic cells in tumor stroma and influence cancer progression in solid tumors. The clinical significance of TAMs in urinary bladder cancer(UBC) is controversial.MethodsWe prospectively studied 103 patients with stage pT1–T4 UBC treated with cystectomy and pelvic lymph node dissection. Tumor sections were immunostained with M2-specific macrophage marker CD163 and proliferation marker Ki-67. The expression of these markers in cancer cells as well as macrophage infiltration (MI) in tumor stroma was analyzed in relation to clinical data and outcome.ResultsThe mean rate of CD163 and Ki-67 expressed by cancer cells were 35% and 78%, respectively. With borderline significance, MI was associated with lower rate of lymph node metastasis (P = 0.06). CD163 expression in cancer cells was proportional to MI (P<0.014). Patients with CD163-positive tumors and strong MI had significantly longer cancer-specific survival (CSS) (76 months), compared to patient with CD163-positive tumors and weak MI (28 months) (P = 0.02).ConclusionsM2-specific MI tends to be inversely correlated with LN metastasis and improved CSS in UBC. MI might have protective impact in CD163-positive tumors. Expression of CD163 in cancer cells is significantly correlated with MI and might have a tumor promoting impact.
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4.
  • Aljabery, Firas, et al. (författare)
  • The emerging role of cell cycle protein p53 expression by tumor cells and M2-macrophage infiltration in urinary bladder cancer
  • 2023
  • Ingår i: Urologic Oncology. - : ELSEVIER SCIENCE INC. - 1078-1439 .- 1873-2496. ; 41:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: To investigate the association between p53 expression in tumor cells and intratumoral macrophage infiltration in muscle-invasive urinary bladder cancer (MIBC) in relation to clinical and pathological variables and outcomes after radical cystectomy. Methods: Tumor specimens of the primary tumor from patients treated with radical cystectomy for MIBC were immunostained with the M2-macrophage-specific marker CD163 and the cell cycle protein p53. The expression of these markers was analyzed in relation to patients and tumor characteristics and outcome. Results: Out of 100 patients with urinary bladder cancer (UBC) pathological stage T1-4 N0-3 M0, 77% were men. The patients had a median age of 69 years and 80% had nonorgan-confined tumors (pT3-4). Lymph node metastasis was found in 42 (42%) of all patients. P53-positive expressions were found in 63 (63%) patients. Strong macrophage infiltration in the tumor microenvironment was shown in 74 (74%) patients. Combinations of CD163/p53 status were as follows: CD163+/p53+, 50%; CD163+/p53-, 24%; CD163-/p53+, 13%; and CD163-/p53-, 13%. Patients with CD163+/P53+ had higher proportions of organ-confined tumors. Conclusions: In the present series of patients with MIBC treated with cystectomy, we found that high CD163+ macrophage infiltration in the tumor micro-environment often was combined with p53+ cancer cells. This simultaneous expression of p53 by tumor cells and increased infiltration of M2-macrophages in the tumor microenvironment was associated with improved CSS, which might indicate a possible protective effect of M2 macrophages in p53+ tumors. Further investigations are needed to explore the biological relation between mutational burden and immune profile in MIBC. (c) 2022 Published by Elsevier Inc.
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5.
  • Aljabery, Firas, et al. (författare)
  • The expression profile of p14, p53 and p21 in tumour cells is associated with disease-specific survival and the outcome of postoperative chemotherapy treatment in muscle-invasive bladder cancer
  • 2018
  • Ingår i: Urologic Oncology. - : Elsevier. - 1078-1439 .- 1873-2496. ; 36:12, s. 530.e7-530.e18
  • Tidskriftsartikel (refereegranskat)abstract
    • Purpose: We investigated the effects of alterations in the biological markers p14, p53, p21, and p16 in relation to tumour cell proliferation, T-category, N- category, lymphovascular invasion, and the ability to predict prognosis in patients with muscle-invasive bladder cancer (MIBC) treated with cystectomy and, if applicable, chemotherapy.Materials and methods: We prospectively studied patients with urinary bladder cancer pathological stage pT1 to pT4 treated with cystectomy, pelvic lymph node dissection and postoperative chemotherapy. Tissue microarrays from paraffin-embedded cystectomy tumour samples were examined for expression of immunostaining of p14, p53, p21, p16 and Ki-67 in relation to other clinical and pathological factors as well as cancer-specific survival.Results: The median age of the 110 patients was 70 years (range 51-87 years), and 85 (77%) were male. Pathological staging was pT1 to pT2 (organ-confined) in 28 (25%) patients and pT3 to pT4 (non-organ-confined) in 82 (75%) patients. Lymph node metastases were found in 47 patients (43%). P14 expression was more common in tumours with higher T-stages (P = 0.05). The expression of p14 in p53 negative tumours was associated with a significantly shorter survival time (P=0.003). Independently of p53 expression, p14 expression was associated with an impaired response to chemotherapy (P=0.001). The expression of p21 in p53 negative tumours was associated with significantly decrease levels of tumour cell proliferation detected as Ki-67 expression (P=0.03).Conclusions: The simultaneous expression of the senescence markers involved in the p53-pathway shows a more relevant correlation to the pathological outcome of MIBC than each protein separately. P14 expression in tumours with non-altered (p53-) tumours is associated with poor prognosis. P14 expression is associated with impaired response to chemotherapy. P21 expression is related to decreased tumour cell proliferation.
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6.
  • Armstrong, Andrew J, et al. (författare)
  • Assessment of the bone scan index in a randomized placebo-controlled trial of tasquinimod in men with metastatic castration-resistant prostate cancer (mCRPC).
  • 2014
  • Ingår i: Urologic oncology. - : Elsevier BV. - 1873-2496. ; 32:8, s. 1308-1316
  • Tidskriftsartikel (refereegranskat)abstract
    • Drug development and clinical decision making for patients with metastatic prostate cancer (PC) have been hindered by a lack of quantitative methods of assessing changes in bony disease burden that are associated with overall survival (OS). Bone scan index (BSI), a quantitative imaging biomarker of bone tumor burden, is prognostic in men with metastatic PC. We evaluated an automated method for BSI calculation for the association between BSI over time with clinical outcomes in a randomized double-blind trial of tasquinimod (TASQ) in men with metastatic castration-resistant PC (mCRPC).
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7.
  • Awe, Julius Adebayo, et al. (författare)
  • Filtration-based enrichment of circulating tumor cells from all prostate cancer risk groups
  • 2017
  • Ingår i: Urologic Oncology-Seminars and Original Investigations. - : Elsevier BV. - 1078-1439 .- 1873-2496. ; 35:5, s. 300-309
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: To combine circulating tumor cell (CTC) isolation by filtration and immunohistochemistry to investigate the presence of CTCs in low, intermediate, and high-risk prostate cancer (PCa). CTCs isolated from these risk groups stained positive for both cytokeratin and androgen receptors, but negative for CD45. Patients and methods: Blood samples from 41 biopsy confirmed patients with PCa at different clinical stages such as low, intermediate, and high risk were analyzed. The samples were processed with the ScreenCell filtration device and PCa CTCs were captured for all patients. The isolated CTCs were confirmed PCa CTCs by the presence of androgen receptors and cytokeratins 8, 18, and 19 that occurred in the absence of CD45 positivity. PCa CTC nuclear sizes were measured using the TeloView program. Results: The filtration-based isolation method used permitted the measurement of the average nuclear size of the captured CTCs. CTCs were identified by immunohistochemistry in low, intermediate, and high-risk groups of patients with PCa. Conclusion: CTCs may be found in all stages of PCa. These CTCs can be used to determine the level of genomic instability at any stage of PCa; this will, in the future, enable personalized patient management. (C) 2017 The Authors. Published by Elsevier Inc.
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9.
  • Cremers, Ruben G., et al. (författare)
  • The role of the prostate cancer gene 3 urine test in addition to serum prostate-specific antigen level in prostate cancer screening among breast cancer, early-onset gene mutation carriers
  • 2015
  • Ingår i: Urologic Oncology: Seminars and Original Investigations. - : Elsevier BV. - 1078-1439. ; 33:5, s. 19-202
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: To evaluate the additive value of the prostate cancer gene 3 (PCA3) urine test to serum prostate-specific antigen (PSA) in prostate cancer (PC) screening among breast cancer, early-onset gene (BRCA) mutation carriers. This study was performed among the Dutch participants of IMPACT, a large international study on the effectiveness of PSA screening among BRCA mutation carriers. Materials and methods: Urinary PCA3 was measured in 191 BRCA1 mutation carriers, 75 BRCA2 mutation carriers, and 308 noncarriers. The physicians and participants were blinded for the results. Serum PSA level≥3.0. ng/ml was used to indicate prostate biopsies. PCA3 was evaluated (1) as an independent indicator for prostate biopsies and (2) as an indicator for prostate biopsies among men with an elevated PSA level. PC detected up to the 2-year screening was used as gold standard as end-of-study biopsies were not performed. Results: Overall, 23 PCs were diagnosed, 20 of which were in men who had an elevated PSA level in the initial screening round. (1) PCA3, successfully determined in 552 participants, was elevated in 188 (cutoff≥25; 34%) or 134 (cutoff≥35; 24%) participants, including 2 of the 3 PCs missed by PSA. PCA3 would have added 157 (≥25; 28%) or 109 (≥35; 20%) biopsy sessions to screening with PSA only. (2) Elevated PCA3 as a requirement for biopsies in addition to PSA would have saved 37 (cutoff≥25) or 43 (cutoff≥35) of the 68 biopsy sessions, and 7 or 11 PCs would have been missed, respectively, including multiple high-risk PCs. So far, PCA3 performed best among BRCA2 mutation carriers, but the numbers are still small. Because PCA3 was not used to indicate prostate biopsies, its true diagnostic value cannot be calculated. Conclusions: The results do not provide evidence for PCA3 as a useful additional indicator of prostate biopsies in BRCA mutation carriers, as many participants had an elevated PCA3 in the absence of PC. This must be interpreted with caution because PCA3 was not used to indicate biopsies. Many participants diagnosed with PC had low PCA3, making it invalid as a restrictive marker for prostate biopsies in men with elevated PSA levels.
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13.
  • Dizeyi, Nishtman, et al. (författare)
  • Cell-based evidence regarding the role of FSH in prostate cancer
  • 2019
  • Ingår i: Urologic Oncology: Seminars and Original Investigations. - : Elsevier BV. - 1078-1439. ; 37:4, s. 1-290
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Conversion of androgen-responsive prostate cancer (CaP) to castration-resistant CaP) is associated with an acceleration of the disease that often requires treatment modalities other than androgen deprivation therapy only. Recently, follicle-stimulating hormone (FSH) has been shown to play a role in CaP growth, and clinical data showed that high serum concentration of FSH in chemically castrated CaP patients was associated with a shorter time of progression to castration-resistant CaP. In this study, we sought to investigate if FSH could have direct effects on CaP cells, possibly through the androgen receptor and androgen receptor regulated genes, such as prostate-specific antigen (PSA). Materials and methods: The human CaP cell lines PC-3, LNCaP and C4-2, and nonmalignant PNT1A cells, were utilized to investigate the effects of FSH. qPCR, Western blotting analysis, and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymetoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium assays were performed in order to analyze the FSH effects. Results: The FSH receptor was present in all cell lines except PNT1A. FSH significantly increased PSA mRNA (P < 0.01) and protein (P < 0.03) levels in C4-2 cells in a dose-dependent manner. In LNCaP cells, FSH also increased PSA protein level, although to a lesser extent than in C4-2 cells, and the expression was reduced by the antiandrogen enzalutamide. In PC-3 cells, FSH was shown to increase their proliferation (P < 0.03) and β-catenin expression. Conclusion: These findings demonstrate that FSH may have a direct effect in CaP in an androgen-depleted environment. However, further research is needed to understand the significance of direct FSH action in the maintenance of CaP growth at the different phases of transition from androgen dependence to androgen independence.
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14.
  • Dizeyi, Nishtman, et al. (författare)
  • Serotonin activates MAP kinase and PI3K/Akt signaling pathways in prostate cancer cell lines
  • 2011
  • Ingår i: Urologic Oncology. - : Elsevier. - 1078-1439 .- 1873-2496. ; 29:4, s. 436-445
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: This study was conducted to examine the effects of 5-HT on extracellular signal-regulated kinase 1/2 (Erk1/2) and Akt pathways in prostate cancer (PC) cells. METHODS: PC cell lines PC-3, Du145, and LNCaP stimulated with 5-HT in the presence of MEK or PI3K inhibitors and 5-HT receptor subtype 1A antagonist were analyzed by Western blotting and immunofluorescence. The proliferation assay BrdU and Boyden chamber were used to determine proliferation and migration, respectively. RESULTS: 5-HT dose-dependently induced rapid activation of Erk1/2 in PC-3 and Du145 cells, whereas in LNCaP cells, Erk1/2 phosphorylation was slow and sustained for up to 18 h. Similarly, 5-HT induced phosphorylation of Akt within 1 hour of stimulation, however, Akt phosphorylation was more pronounced in Du145 cells compared with PC-3 or LNCaP cells. The action of 5-HT was inhibited to varying degrees by inhibitors of MAPK and PI3K as well as by a 5-HT receptor subtype 1A antagonist. In addition to proliferation, 5-HT induced migration of PC-3 and Du145 cells, which were alleviated by the aforementioned inhibitors. The effects of 5-HT on LNCaP cells appeared to be related to neuroendocrine-phenotype acquisition and chromogranin A and neuron specific enolase expression. CONCLUSIONS: This study addresses the role of 5-HT in Erk1/2 and Akt activation in PC cells. The data presented here identify 5-HT receptors as a novel target in castration-resistant PC. Furthermore, our observations are in line with previous studies, which point towards neuroendocrine factors facilitating progression and migration of prostatic cancer cells in an androgen-deficient environment. Nonetheless, additional studies are warranted to corroborate the role of 5-HTR antagonists as a potential target for anticancer therapy.
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17.
  • Fallara, Giuseppe, et al. (författare)
  • Recurrence pattern in localized RCC : results from a European multicenter database (RECUR)
  • 2022
  • Ingår i: Urologic Oncology. - : Elsevier. - 1078-1439 .- 1873-2496. ; 40:11, s. 494.e11-494.e17
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: The impact of open versus minimally invasive surgery on recurrence pattern in the management of localized renal cell carcinoma (RCC) remains uncertain. We thus aimed to determine the impact of surgical approach on survival and recurrence pattern.Material and methods: This is a multi-institutional, matched cohort study on patients with pT1-3aN0M0 RCC from the RECUR database. After propensity score matching between open and minimally invasive surgery, disease-free (DFS) survival and risk of first recurrence according to recurrence site, namely local recurrence, abdominal/retroperitoneal, thoracic/mediastinal or uncommon site metastases were investigated with Cox regression analysis. Overall (OS) and Cancer Specific Survival (CSS) were also assessed.Results: After matching, 1,019 patients who underwent open and 1,019 who underwent minimally invasive surgery were included (of which 70 robot-assisted). At 5.2 years of median follow-up, 130 patients in open and 125 in minimally invasive group experienced disease progression. A higher risk of local recurrence (HR 2.06; 95% CI 1.18–3.58, P-value = 0.01) and uncommon site metastases (HR 1.09; 95% CI 1.01–1.16; P-value = .04) was found for minimally invasive surgery relative to open surgery, while no difference was found in terms of DFS (HR 0.83; 95% CI 0.64–1.06; P-value = .14). No differences were found in terms of OS and CSS. Main limitation is the retrospective nature of the study.Conclusions: The risk for local recurrence and uncommon site metastases was higher for minimally invasive surgery compared to open surgery, although no differences were found for OS, CSS, and DFS.
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18.
  • Fransson, Per, et al. (författare)
  • Does one have a sexual life 15 years after external beam radiotherapy for prostate cancer? Prospective patient-reported outcome of sexual function comparison with age-matched controls
  • 2011
  • Ingår i: Urologic Oncology. - : Elsevier. - 1078-1439 .- 1873-2496. ; 29:2, s. 137-144
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and purpose: We previously published research on 4- and 8-year follow-ups of patient-reported sexual function after conventional external beam radiotherapy (EBRT) for localized prostate cancer (LPC) compared with age-matched controls. The current study is a prolonged 15-year follow-up with the same cohorts.Material and methods: The cohort consisted of 29 men surviving from a group of 181 men treated between 1986 and 1989, and who were reported on previously. Of the originally reported 141 controls, 62 were eligible and 34 completed the questionnaires. Sexual function was assessed using two questionnaires, Prostate Cancer Symptom Scale (PCSS) and International Index of Erectile Function (IIEF-5).Results: Twenty-three patients (78%) and 13 controls (38%) were not sexually active. None of the patients and 14 controls had enough of an erection to perform intercourse. Seventeen patients (94%) and 14 controls (64%) had severe erectile dysfunction. Patients with clinical progression and who had received hormone treatment had decreased sexual desire. No significant differences were measured between patients without progression/hormone treatment and the controls.Conclusion: The sexual activity 15 years after EBRT for LPC was very low, as was the probability of achieving an erection. Patients with a progressive disease and treated with hormones reported worse sexual and erectile function. The LPC free men showed higher sexual activity, lower sexual bother, and better erectile function than the patients.
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19.
  • Gaffney, Christopher D., et al. (författare)
  • A brief mind-body intervention to reduce pain and anxiety during prostate needle biopsy: a clinically integrated randomized controlled trial with 2-staged consent
  • 2023
  • Ingår i: Urologic Oncology: Seminars and Original Investigations. - 1078-1439 .- 1873-2496. ; 41:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: Many patients experience pain, anxiety, and discomfort with prostate biopsy, which may discourage enrollment in active surveillance programs or follow-up biopsy. Guided meditation can significantly reduce pain and anxiety during percutaneous biopsy. We sought to evaluate the effectiveness of a brief mind-body intervention on patient-reported outcomes after prostate biopsy. Methods and materials: We performed a clinically-integrated randomized controlled trial of a brief mind-body intervention during biopsy compared to usual care at a single tertiary care center from 2018 to 2022. All patients offered transrectal ultrasound-guided prostate biopsy in the clinic with local anesthesia were eligible for enrollment. This clinically integrated trial was conducted simultaneously with a randomized controlled trial of 1-stage and 2-stage consent. The primary outcome was patient-reported pain, anxiety, discomfort, and tolerability on a visual-analog scale (0–10). A 15% improvement was prespecified as clinically relevant. We compared the proportion of men in each arm reporting a severe score (7–10) on any of the 4 scales using Fisher's exact test and then compared means for each scale separately using ANCOVA with randomization stratum (first vs. prior biopsy) as a covariate. Results: Of 263 eligible patients, 238 enrolled (119 per arm). One hundred seventy-two (72%) enrolled with 2-stage consent. A total of 37/94 (39%) and 38/102 (37%) patients randomized to usual care and intervention, respectively, reported severe scores in any of the 4 domains, a difference of 2.1% (95% confidence interval [CI] -13, 17%, P = 0.8). There was no evidence of a difference in mean postbiopsy anxiety (P = 0.3), discomfort (P = 0.09), pain (P = 0.4) or tolerability scores (P = 0.2). Conclusions: A clinically meaningful benefit for this brief mind-body intervention during prostate biopsy is unlikely. Robust patient enrollment is feasible using 2-stage consent.
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21.
  • Gerharz, EW, et al. (författare)
  • Quality of life in patients with bladder cancer
  • 2005
  • Ingår i: Urologic Oncology. - : Elsevier BV. - 1873-2496. ; 23:3, s. 201-207
  • Tidskriftsartikel (refereegranskat)abstract
    • The objective of this review is to examine the published data regarding quality of life (QOL) in patients with bladder cancer. Not a single, randomized controlled trial exists. Most studies are retrospective, cross-sectional, and have serious methodological flaws. There is no single QOL tool preferably used in bladder cancer. While there is no long-term data after therapy for Superficial cancer, most investigations compared the impact of different forms of urinary diversion on QOL. In contrast to the prevailing notion that patients who underwent cystectomy undergoing continent urinary reconstruction have superior QOL than those receiving a conduit, existing reports fail to show significant advantages of one technique over the other.
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22.
  • Höglund, Mattias (författare)
  • The bladder cancer genome; chromosomal changes as prognostic makers, opportunities, and obstacles.
  • 2012
  • Ingår i: Urologic Oncology. - : Elsevier BV. - 1873-2496. ; 30:4, s. 533-540
  • Tidskriftsartikel (refereegranskat)abstract
    • During the past decades, the complexity of the bladder cancer genome has become evident. Early cytogenetic studies identified several patterns of chromosomal changes, particularly the frequent loss of chromosome 9. The cytogenetic approach was replaced by molecular methods, such as comparative genome hybridization (CGH) and loss of heterozygosity (LOH) analyses that describe genomic changes at a molecular and higher resolution. With these methods, the full complexity of the bladder cancer genome has been better appreciated. Using CGH and LOH analyses, it also became apparent that premalignant lesions of the bladder, such as hyperplasia and dysplasia, as well as carcinoma in situ (CIS), showed genomic changes. Whole genome analyses showed that low stage, low grade tumors generally show fewer changes than tumors of higher stage and grade. In addition, several genomic alterations were shown to be highly specific for more aggressive and invasive tumors. Based on the general association between complex genomic changes and tumor behavior, several investigations have been directed towards the identification of prognostic genomic markers for urothelial cancer. A complicating factor in the analysis and understanding of bladder cancer genomic progression is that recurring and, hence, chronologically later tumors may show genomes less rearranged than preceding tumors. Furthermore, morphologically normal urothelium in patients with bladder cancer frequently show the same type of genomic alterations as the tumor proper. This makes an issue of to what extent information on genomic changes will produce reliable prognostic information when limited to the tumor proper.
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25.
  • Kollberg, Petter, et al. (författare)
  • Molecular subtypes applied to a population-based modern cystectomy series do not predict cancer-specific survival
  • 2019
  • Ingår i: Urologic Oncology: Seminars and Original Investigations. - : Elsevier BV. - 1078-1439. ; 37:10, s. 791-799
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: To investigate the preoperative prognostic value of molecular subtypes in relation to clinical information, histopathological findings, and molecular markers for patients with bladder cancer treated with radical cystectomy. Patients and methods: After standard preoperative staging, a population-based cohort of 519 patients underwent radical cystectomy between 2006 and 2011. Following pathological review of all transurethral resection of bladder tumor specimens, tissue microarrays were constructed, and RNA was extracted from formalin-fixed tissue blocks. Immunohistochemistry (IHC) was performed using markers suggested to be relevant for prognosis (ZEB2, CCND1, CD3, CD68, CDH3, HER3, KRT14, CDKN2A(p16), TP63, FGFR3, EPCAM, GATA3, FOXA1, ERBB2, and EGFR). IHC- and gene-expression-based molecular classification was also conducted. Univariate and multivariate Cox proportional hazards regression were used for survival analyses. Results: Clinical T3 stage (Hazard Ratio [HR] 1.6, Confidence Interval [CI] 1.1–2.3), hydronephrosis (HR 1.7, CI 1.2–2.3), lymphovascular invasion (LVI) (HR 2.6, CI 1.9–3.6), extensive necrosis (HR 1.6, CI 1.1–2.5), and CD68/CD3-ratio >1 (HR 1.3, CI 1.1–1.5) in the transurethral resection of bladder tumor specimen was associated with worse cancer-specific survival (CSS) and progression-free survival (data not shown). In multivariate analysis, higher clinical T stage (HR 1.3, CI 1.1–1.7; P = 0.007) and presence of LVI (HR 2.4, CI 1.7–3.5; P = 1.8 × 10 − 6 ) were associated with worse CSS, whereas only LVI was associated with progression-free survival. Molecular subtypes (assessed by Lund taxonomy and the Consensus molecular subtypes of muscle-invasive bladder cancer) and published single IHC markers were not associated with survival. Conclusions: In the present large population-based cystectomy series, LVI and clinical stage were independently associated with CSS. However, molecular subtypes determined by global gene expression showed no such association with CSS according to either the Consensus molecular subtypes of muscle-invasive bladder cancer or Lund taxonomy.
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26.
  • Kuusk, Teele, et al. (författare)
  • Topographic distribution of first landing sites of lymphatic metastases from patients with renal cancer
  • 2020
  • Ingår i: Urologic Oncology. - : Elsevier. - 1078-1439 .- 1873-2496. ; 38:5, s. 521-525
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION AND OBJECTIVE: Adjuvant studies with checkpoint inhibitors have attracted new interest in accurate pathological lymph node (LN) staging in renal cell carcinoma. Sentinel lymph node (SN) studies in cN0 patients revealed the pattern of lymphatic radiotracer drainage from renal tumors. The aim of this study was to describe the location of single- or oligometastatic LN and analyze if the topography of these first landing sites matches the drainage pattern observed in SN studies of renal tumors.MATERIALS AND METHODS: We collected data from 8 referral centers from 1990 to 2018 of all patients with pT1-4 cN0 or cN1 M0 renal cell carcinoma with pathologically confirmed single- or oligometastases in locoregional LN. The location of LN metastases, number, size of metastatic LN, and survival were analyzed using descriptive statistics with SPSS version 22 (IBM, Chicago, IL).RESULTS: From 3,794 patients with histologically confirmed pN1, a total of 76 patients (2%) with single- or oligometastatic pN1 were identified, of whom 24 (31.6%) and 52 (68.4%) were cN0 and cN1, respectively. On the left side, LN metastases were predominantly located in the para-aortal (48.0%; 95% confidence interval [CI] 29.22-63.12%) and hilar (31.42%; 95% CI 17.4-49.4%) area. On the right side, metastases located in retrocaval (26.82%; 95% CI 14.7-43.2%), hilar (26.82%; 95% CI 14.7-43.2%), interaortocaval (26.82%; 95% CI 14.7-43.2%), and paracaval (17.07%; 95% CI 7.6-32.6%) LNs. These landing sites exactly matched the lymphatic drainage pattern of intratumorally injected radiotracer reported in SN studies for both sides.CONCLUSIONS: Single- or oligometastatic LNs in renal cancer are mainly located in the hilar, retro-, para, and interaortocaval region on the right side and para-aortal region on the left side. These first landing sites match the drainage pattern reported in SN trials.
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27.
  • Larsson, Anders, et al. (författare)
  • Antiprostasome antibodies : possible serum markers for prostate cancer metastasizing liability
  • 2006
  • Ingår i: Urologic Oncology. - : Elsevier BV. - 1078-1439 .- 1873-2496. ; 24:3, s. 195-200
  • Tidskriftsartikel (refereegranskat)abstract
    • Prostasomes are secretory granules synthesized, stored, and secreted by normal and neoplastic human prostate epithelial cells. In prostate cancer, they are anticipated to be released into the blood circulation where they may be immunogenic. The aim of our study was to examine whether prostasome antibody presence in serum bears any prognostic significance for men with prostate cancer. We developed a sensitive and specific immunoassay (enzyme-linked immunosorbent assay) to establish the presence of antiprostasome antibodies in serum. The antiprostasome antibody titer in serum, sampled before any kind of therapy for prostate cancer, was examined together with clinicopathologic variables and outcome over a median follow-up of 350 days in 218 patients with verified prostate cancer. We detected these antibodies in 191 (88%) of these patients. This antibody titer did not correlate to serum values of prostate-specific antigen. Significant, inverse relationships were registered for antiprostasome antibody titer, and metastases to bone and/or lymph nodes (P = 0.035) and pT (P = 0.025). These results indicate that the antiprostasome antibody titer in serum may be a novel marker for prostate cancer liability to metastasize.
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28.
  • Liedberg, Fredrik, et al. (författare)
  • Tissue microarray based analysis of prognostic markers in invasive bladder cancer: Much effort to no avail?
  • 2008
  • Ingår i: Urologic Oncology. - : Elsevier BV. - 1873-2496. ; 26:1, s. 17-24
  • Tidskriftsartikel (refereegranskat)abstract
    • PURPOSE: To evaluate altered protein expression with tissue microarray methodology for 15 different markers with potential prognostic significance in invasive bladder cancer. MATERIALS AND METHODS: Invasive tumor was sampled with the tissue-arraying instrument in 133 consecutive patients who underwent radical cystectomy, and at least 3, 0.6-mm tissue cores were obtained. With immunohistochemistry, the expressions of TP53, RB1, CDKN1A (p21), MKI67 (Ki67), PTGS2 (Cox-2), CTNNA1 (alpha-catenin), CTNNB1 (beta-catenin), AKT, PTEN, RHOA, RHOC, STAT1, VEGFC, EGFR, and ERBB2 (HER2) were quantified, and correlations were made with tumor grade, pathologic stage, lymph node status, and disease-specific survival. RESULTS: Decreased immunohistochemical expression of CTNNA1 and of PTEN correlated with higher pathologic tumor stages (P = 0.01 and P = 0.01, respectively), whereas increased AKT1 and ERBB2 correlated with lower pathologic tumor stages (P = 0.01 and P = 0.03, respectively). Increased RHOA expression was more common in grade 3 than in grade 2 tumors (P = 0.016). There were no other correlations among the 15 factors studied and pathologic stage, lymph node status, or tumor grade. No association was found between bladder cancer death and altered marker status for any of the markers studied. CONCLUSIONS: Currently, there are reasons to have a skeptical attitude toward the value of tissue microarray based immunohistochemistry as a method for evaluating prognostic markers in invasive bladder cancer. In this study, 15 antibodies were tested but were found to be of little clinical value. Whether this negative finding is related to the group of patients or factors studied, or the methodology is unclear.
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29.
  • Lindskog, Magnus, et al. (författare)
  • Overall survival in Swedish patients with renal cell carcinoma treated in the period 2002 to 2012: Update of the RENCOMP study with subgroup analysis of the synchronous metastatic and elderly populations
  • 2017
  • Ingår i: Urologic Oncology-Seminars and Original Investigations. - : Elsevier BV. - 1078-1439 .- 1873-2496. ; 35:9, s. 541.e15-541.e22
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: This retrospective study investigated overall survival (OS) and factors influencing OS in Swedish patients with metastatic renal cell carcinoma (mRCC) during the pre- (2002-2005), early (2006-2008), and late (2009-2012) targeted therapy (TT) era. Methods: Three national Swedish registries identified patients with mRCC. Median OS was estimated using the Kaplan-Meier method. Multivariate analysis was performed using Cox proportional hazards regression. Subgroup analysis was conducted for patients with synchronous metastases (Ml) and the elderly (aged >= 75 y). Results: A total of 4,217 patients with mRCC were identified, including 1,533 patients with Ml and 1,275 elderly patients. For patients with mRCC diagnosed in 2002 to 2005, 2006 to 2008, and 2009 to 2012, median OS was 10.0, 13.0, and 18.0 months. Similarly, median OS improved in the M1 and elderly populations. Elderly patients were less likely to be prescribed TT (>= 75 vs. <75 y): 18.3 vs. 63.5% (in 2006-2008) and 28.6% vs. 55.9% (in 2009-2012). Diagnosis of mRCC in 2009 to 2012, nephrectomy and TT prescription were associated with improved OS in the total mRCC, Ml, and elderly populations. Conclusion: This real-world study showed continued significant improvement in mRCC OS during the late TT era, including in Ml and elderly populations. TT should be considered for all patients with mRCC based on tolerability, regardless of age. (C) 2017 Elsevier Inc. All rights reserved.
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34.
  • Malmström, Per-Uno, et al. (författare)
  • Validation of the ezrin, CK20, and Ki-67 as potential predictive markers for BCG instillation therapy of non-muscle-invasive bladder cancer
  • 2017
  • Ingår i: Urologic Oncology. - : Elsevier BV. - 1078-1439 .- 1873-2496. ; 35:8, s. 532.e1-532.e6
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: The aim of our study was to try to validate 3 promising predictive biomarkers in a database based on prospective trials comparing bacillus Calmette-Guerin(BCG) with mitomycin-C and a combination of epirubicin and interferon, respectively.Background: The most common form of bladder cancer is non-muscle-invasive tumors treated initially with transurethral resection. Unfortunately more than half recur and some also progress. Consequently, an attempt to prevent poor outcome is frequently made by intravesical instillations either by chemo-orimmuno therapy. The response to such treatment is unpredictable, which is why markers predicting outcome would be valuable.Patients and methods: Immunohistochemical expression of ezrin, CK20, and Ki-67 was evaluated in a tumort issue micro array based on 2 nordic multicenter trials comparing treatment with BCG vs. other intravesical adjuvant therapies. Kaplan- Meieranalysis, log-ranktest, and Cox regression were used toe valuate the effect of the biomarkers on recurrence-,progression-,and treatment failure- freesurvival.Results: Of the 294 available patients immunoreactivity could be assessed in 285 patients for ezrin (97%), 285 patients for CK20 (97%), and 294 patient's forKi- 67 (100%). The 3 biomarkers did not predict time to any of the end points. Multi focality was the only predictive factor for time to recurrence (P=0.029) and progression (P=0.031). Ezrinwas, however, predictive for treatment failure (P=0.029) in a subgroup (BCG treated in one of the trials). In a multivariate analysis among BCG treated, none of the variables correlated to recurrence and only multifocality correlated top rogression. Limitations in our study are the retrospective design and those inherentto immunohistochemistry. Conclusions: The negative results from this validation study question the ability of the tested biomarkers to predict therapy effect.
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35.
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36.
  • Offermann, Anne, et al. (författare)
  • TRIM24 as an independent prognostic biomarker for prostate cancer
  • 2019
  • Ingår i: Urologic Oncology. - : Elsevier. - 1078-1439 .- 1873-2496. ; 37:9
  • Tidskriftsartikel (refereegranskat)abstract
    • Introduction: Simply applicable biomarkers for prostate cancer patients predicting the clinical course are urgently needed. Recently, TRIM24 has been identified to promote androgen receptor signaling and to correlate with an aggressive prostate cancer phenotype. Based on these data, we proofed TRIM24 as a prognostic biomarker for risk stratification.Materials and Methods: We performed TRIM24 immunohistochemistry on 2 independent cohorts including a total of 806 primary tumors, 26 locally advanced/recurrent tumors, 30 lymph node metastases, 30 distant metastases, and 129 benign prostatic samples from 497 patients as well as on 246 prostate needle biopsies. Expression data were correlated with clinic-pathological data including biochemical recurrence-free survival (bRFS) as endpoint.Results: Benign samples show no or low TRIM24 expression in 94%, while tumor tissues demonstrate significant higher levels. Strongest expression is observed in advanced and metastatic tumors. In multivariate analyses, TRIM24 up-regulation on radical prostatectomy specimens correlates with shorter bRFS independent of other prognostic parameters. 5-(10-) year bRFS rates for TRIM24 negative, low, medium and high expressing tumors are 93.1(93.1)%, 75.4(68.5)%, 54.9(47.5)% and 43.1(32.3)%, respectively. Of interest, tumors diagnosed as indolent disease, TRIM24 expression stratifies patients into specific risk groups. Increased TRIM24 expression associates with higher grade group, positive nodal status and extraprostatic tumor growth. TRIM24 assessment on prostate needle biopsies taken prior to treatment decision at time of initial diagnosis significantly correlates with recurrence after surgery.Conclusion: Using 2 large independent radical prostatectomy specimen cohorts, we found that TRIM24 expression predicts patients' risk to develop disease recurrence with high accuracy and independent from other established biomarkers. Further, this is the first study exploring TRIM24 expression on prostate needle biopsies which represents the clinically relevant tissue type on which biomarkers guide treatment decisions. Thus, we strongly suggest introducing TRIM24 evaluation in prostate needle biopsies in clinical routine as an inexpensive and simple immunohistochemical test.
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44.
  • Sarwar, Martuza, et al. (författare)
  • Protein kinase A (PKA) pathway is functionally linked to androgen receptor (AR) in the progression of prostate cancer
  • 2014
  • Ingår i: Urologic Oncology. - : Elsevier. - 1078-1439 .- 1873-2496. ; 32:1, s. 25.e1-25.e12
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: In the present study, we investigated whether the cyclic adenosine monophosphate (cAMP)-activated protein kinase A (PKA) pathway may regulate the expression of AR and prostate-specific antigen (PSA) and whether there is a correlation between the expression of cAMP/PKA-associated genes and androgen receptor (AR) in patients with prostate cancer (CaP).MATERIALS AND METHODS: The functional studies were performed in LNCaP and PC3 cell lines. Data on the mRNA expression of sets of genes in human clinical samples, including prostate tissues from organ donors, prostate primary cancer, and metastatic cancer, were extracted from the National Center for Biotechnology Informations Gene Expression Omnibus (GEO) database. Statistical tests were applied.RESULTS: We showed that elevated levels of cAMP/PKA pathways induced an increased expression of AR and PSA proteins in LNCaP cells in the absence of androgen. A cAMP-associated phosphodiesterase-4 (PDE4) inhibitor, rolipram induced an up-regulation in AR expression, whereas a cAMP enhancer, forskolin increased PSA level without affecting AR expression. Forskolin treatment increased the level of PKA R1α in LNCaP cells, but remarkably inhibited R1α expression in aggressive PC3 cells. In patients with CaP, we found that the expression of genes encoding R1α and phosphodiesterase-4B was statistically significantly lower in the metastatic specimens than that in the primary CaP specimens or in the normal prostate tissues (P<0.01) and was reversely correlated with AR expression. Conversely, AR and PRKAR2B mRNA expressions were significantly higher in metastatic lesions than those in the primary CaP specimens or in the normal prostate tissues (P<0.01).CONCLUSION: Our study revealed a novel mechanism to precisely define the functional and clinical interrelationship between the cAMP/PKA pathway and AR signaling in the development of androgen-independent growth of CaPs and metastasis progression.
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45.
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46.
  • Schumacher, Martin C., et al. (författare)
  • A comparative study of tissue omega-6 and omega-3 polyunsaturated fatty acids (PUFA) in benign and malignant pathologic stage pT2a radical prostatectomy specimens
  • 2013
  • Ingår i: Urologic Oncology. - : Elsevier BV. - 1078-1439 .- 1873-2496. ; 31:3, s. 318-324
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: To analyze different polyunsaturated fatty acid (PUPA) tissue levels in malignant compared with benign prostatic tissue from the same prostate specimens. Materials and methods: Fresh frozen benign and malignant prostatic tissue was obtained from radical prostatectomy specimens in 49 men with pathologic stage pT2a prostate cancer. Histopathologic examination confirmed that all tissues from each prostate being analyzed were either completely benign or almost totally malignant. The PUFA composition in these tissues was determined by gas-liquid chromatography on a capillary column. The relative amount of each PUFA (% of total fatty acids) was quantified by integrating the area under the peak and dividing the result by the total area of all fatty acids. Results: Tissue levels of dihomo-gamma-linolenic acid, (C20:3w6), an omega-6 PUFA and a major precursor of omega-6 PUFA metabolites, were significantly higher in malignant compared with benign tissues (P = 0.002). Tissue levels of the downstream omega-6 metabolites, arachidonic acid (AA) (20:4 omega 6), and adrenic acid, (22:4 omega 6), were significantly lower in cancer tissues, (P < 0.0001 and P = 0.013, respectively). Overall, the total levels of omega-6 PUPA were lower in cancer (P = 0.001). Conclusion: We found that the omega-6 PUPA AA and adrenic acid are decreased in malignant prostatic tissues compared with benign tissues from the same prostates. These findings provide additional evidence that dietary fat is associated with prostatic carcinogenesis.
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47.
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48.
  • Segersten, Ulrika, et al. (författare)
  • The role of microRNA profiling in prognosticating progression in Ta and T1 urinary bladder cancer
  • 2014
  • Ingår i: Urologic Oncology. - : Elsevier BV. - 1078-1439 .- 1873-2496. ; 32:5, s. 613-618
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: To analyze microRNA profile in Ta and T1 urinary bladder cancers in combination and separately and to relate this to the risk of later developing higher-stage disease. Materials and methods: Formalin-fixed, paraffin-embedded samples of 44 Ta and 42 T1 bladder cancers representing cases with and without stage progression during follow-up were collected and microRNA expression levels were measured by microarray analysis. Results: In a comparison between the progressors and controls, in the Ta/T1 group, miR-10a-5p and miR-31-5p were differentially expressed. miR-10a-5p was also correlated to time to progression (P = 0.00012). In the subgroup analysis, 3 microRNAs, miR-10a-5p, miR-31-5p, and miR-130a-3p, were differentially expressed among Ta tumors and had a fold change of more than 1.5 (P < 0.038). The comparison concerning microRNA expression between the progressors and controls in category T1 cancers revealed no significant differences. Conclusions: Profiling revealed that certain microRNAs predicted the risk of developing higher-stage disease among patients with Ta cancers. Lower miR-10a-5p expression in Ta progressing tumors indicates that this microRNA could be important for later malignant potential among this group of patients. 
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49.
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50.
  • Shah, Carl-Henrik, et al. (författare)
  • Vascular endothelial growth factor receptor 2, but not S100A4 or S100A6, correlates with prolonged survival in advanced urothelial carcinoma
  • 2014
  • Ingår i: Urologic Oncology. - : Elsevier. - 1078-1439 .- 1873-2496. ; 32:8, s. 1215-1224
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVE: A major challenge in muscle-invasive urothelial carcinoma (UC) is to identify biomarkers that can predict disease prognosis and treatment response after cystectomy. Therefore, we analyzed the potential prognostic value of the proteins vascular endothelial growth factor receptor 2 (VEGFR2), S100A4, and S100A6 in UC.METHODS: Retrospective outcome data and tumor specimens from 83 cystectomy patients with histologically confirmed invasive UC were included. Expression levels of VEGFR2 (also called flk-1 and KDR), S100A4, and S100A6 were analyzed in primary tumor tissue by immunohistochemistry.RESULTS: Immunohistochemical staining and analysis of VEGFR2, S100A4, and S100A6 showed localization mainly in tumor cell cytoplasm. High VEGFR2 expression and low tumor category were independent variables associated with longer overall survival (OS) and disease-free survival, revealed by a bivariate Cox proportional hazards regression model (both P<0.001). In addition, the univariate log-rank test and the Cox model demonstrated that OS beyond 2 years was significantly greater among patients with low S100A6 expression than in those with high S100A6 expression (P = 0.017 and 0.022, respectively). Differences in tumor expression of S100A4 were not significantly associated with outcome.CONCLUSION: In this study, VEGFR2 expression was significantly correlated with risk of disease relapse and OS in a defined cohort of patients with UC of the bladder treated by cystectomy.
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