| 1. |
- Engilbertsson, Helgi, et al.
(författare)
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TURBT Can Cause Seeding of Cancer Cells into the Bloodstream.
- 2015
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Ingår i: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 1527-3792 .- 0022-5347. ; 193:1, s. 53-57
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Tidskriftsartikel (refereegranskat)abstract
- TURBT is the initial diagnostic procedure in bladder cancer (BC). Hypothetically, tumor resection could induce seeding of cancer cells into the circulation and subsequent metastatic disease. The objective of this study was to ascertain whether TURBT induces measurable seeding of cancer cells into the vascular system.
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| 2. |
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| 3. |
- Holmkvist, Petra, et al.
(författare)
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A major population of mucosal memory CD4(+) T cells, coexpressing IL-18Rα and DR3, display innate lymphocyte functionality.
- 2015
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Ingår i: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 8:3, s. 545-558
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Tidskriftsartikel (refereegranskat)abstract
- Mucosal tissues contain large numbers of memory CD4(+) T cells that, through T-cell receptor-dependent interactions with antigen-presenting cells, are believed to have a key role in barrier defense and maintenance of tissue integrity. Here we identify a major subset of memory CD4(+) T cells at barrier surfaces that coexpress interleukin-18 receptor alpha (IL-18Rα) and death receptor-3 (DR3), and display innate lymphocyte functionality. The cytokines IL-15 or the DR3 ligand tumor necrosis factor (TNF)-like cytokine 1A (TL1a) induced memory IL-18Rα(+)DR3(+)CD4(+) T cells to produce interferon-γ, TNF-α, IL-6, IL-5, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-22 in the presence of IL-12/IL-18. TL1a synergized with IL-15 to enhance this response, while suppressing IL-15-induced IL-10 production. TL1a- and IL-15-mediated cytokine induction required the presence of IL-18, whereas induction of IL-5, IL-13, GM-CSF, and IL-22 was IL-12 independent. IL-18Rα(+)DR3(+)CD4(+) T cells with similar functionality were present in human skin, nasal polyps, and, in particular, the intestine, where in chronic inflammation they localized with IL-18-producing cells in lymphoid aggregates. Collectively, these results suggest that human memory IL-18Rα(+)DR3(+) CD4(+) T cells may contribute to antigen-independent innate responses at barrier surfaces.Mucosal Immunology advance online publication, 1 October 2014; doi:10.1038/mi.2014.87.
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| 4. |
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| 5. |
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| 6. |
- Hultman Patschan, Oliver, et al.
(författare)
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Use of bacillus Calmette-Guerin in stage T1 bladder cancer : long-term observation of a population-based cohort
- 2015
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Ingår i: Scandinavian journal of urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 49:2, s. 127-132
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Tidskriftsartikel (refereegranskat)abstract
- Objective. The aim of this study was to analyse the rate of use of bacillus Calmette-Guerin (BCG) at a population-based level, and the overall mortality and bladder cancer mortality due to stage T1 bladder cancer in a national, population-based register. Materials and methods. In total, 3758 patients with primary stage T1 bladder cancer, registered in the Swedish Bladder Cancer Register between 1997 and 2006, were included. Age, gender, tumour grade and primary treatment in the first 3-6 months were registered. High-volume hospitals registered 10 or more T1 tumours per year. Date and cause of death were obtained from the National Board of Health and Welfare Cause of Death Register. Results. BCG was given to 896 patients (24%). The use of BCG increased from 18% between 1997 and 2000, to 24% between 2001 and 2003, and to 31% between 2004 and 2006. BCG was given more often to patients with G3 tumours, patients younger than 75 years and patients attending high-volume hospitals. BCG treatment, grade 2 tumours and patient age younger than 75 years were associated with lower mortality due to bladder cancer. Hospital volume, gender and year of diagnosis were not related to bladder cancer mortality. However, selection factors might have affected the results since comorbidity, number of tumours and tumour size were unknown. Conclusions. Intravesical BCG is underused at a population-based level in stage T1 bladder cancer in Sweden, particularly in patients 75 years or older, and in those treated at low-volume hospitals. BCG should be offered more frequently to patients with stage T1 bladder cancer in Sweden.
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| 7. |
- Kollberg, Petter, et al.
(författare)
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[F-18]Fluorodeoxyglucose - positron emission tomography/computed tomography improves staging in patients with high-risk muscle-invasive bladder cancer scheduled for radical cystectomy
- 2015
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Ingår i: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1813 .- 2168-1805. ; 49:4, s. 296-301
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Tidskriftsartikel (refereegranskat)abstract
- Objective. The aim of this study was to evaluate the clinical use of [F-18]-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in addition to conventional preoperative radiological investigations in a defined group of patients with high-risk muscle-invasive bladder cancer. Materials and methods. In total, 103 patients with high-risk muscle-invasive bladder cancer defined as stage T3/T4 disease or as stage T2 with hydronephrosis or high-risk histological features, who were provisionally scheduled to undergo cystectomy, were prospectively recruited to the study. The patients were referred to FDG-PET/CT in addition to standard preoperative investigation with computed tomography (CT). The final treatment decision was reached at a multidisciplinary conference based on all available information including the FDG-PET/Cf findings. Results. Compared to CT alone, FDG-PET/CT provided more supplemental findings suggesting malignant manifestations in 48 (47%) of the 103 patients. The additional FDG-PET/CT findings led to an altered provisional treatment plan in 28 out of 103 patients (27%), detection of disseminated bladder cancer and subsequent cancellation of the initially intended cystectomy in 16 patients, and identification of disseminated disease and treatment with induction chemotherapy before radical cystectomy in 12 patients. Conclusions. Preoperative FDG-PET/CT changed the treatment plan for a considerable proportion (27%) of the present patients. Accordingly, such examination can potentially improve the preoperative staging of cystectomy patients with high-risk features, and may also reduce the number of futile operations in patients with advanced disease who are beyond cure.
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| 8. |
- Krag Jakobsen, Ane, et al.
(författare)
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Is Nephrolithiasis an Unrecognized Extra-Articular Manifestation in Ankylosing Spondylitis? A Prospective Population-Based Swedish National Cohort Study with Matched General Population Comparator Subjects
- 2014
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 9:11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Ankylosing spondylitis (AS) is associated with several extra-articular manifestations. Nephrolithiasis (NL) has not been recognized as one of those, however, several factors known to increase the risk of NL are at play in AS patients. The objective was to estimate rates and predictors of NL in Swedish patients with AS compared to the general population. Methods and Findings: We performed a prospective population-based nationwide cohort study based on linkage of data from Swedish registries. 8,572 AS patients were followed for 49,258 person-years (py) and 39,639 matched general population comparators were followed for 223,985 py. Patients were followed prospectively together with comparator subjects from January 2001 through December 2009. The first occurrence of NL during follow-up was the primary outcome. Hazard Ratios (HR) were used to compare these rates adjusting for comorbidities and treatment, and to assess predictors for NL. Mean age at study entry was 46 years (inter quartile range 36-56 years), 65% were males. Based on 250 vs. 466 NL events, the adjusted HR of NL in AS patients was 2.1 (95% CI 1.8 to 2.4). Predictors of NL within the AS group included prior diagnosis of inflammatory bowel disease (IBD) (HR 2.3; 95% CI 1.7 to 3.3), prior diagnosis of NL (HR 16.4; 95% CI 11.5 to 23.4), and patients receiving anti-TNF treatment (HR 1.6; 95% CI 1.2 to 2.1). Male sex was a risk factor for NL both in AS patients and in the general population. Limitations: The risk for residual confounding and inability to study the chemical nature of NL were considered the main limitations of the study. Conclusions: Patients with AS are at increased risk of NL, which may be considered a novel extra-articular manifestation. Previous history of NL, IBD, AS disease severity and male sex were identified as predictors of NL in AS.
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| 9. |
- Krag Jakobsen, Ane, et al.
(författare)
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Surgical interventions for nephrolithiasis in ankylosing spondylitis and the general population
- 2015
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Ingår i: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 49:6, s. 486-491
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Tidskriftsartikel (refereegranskat)abstract
- Objective. The aim of this study was to estimate rates and type of definitive surgical interventions for nephrolithiasis in Swedish patients with ankylosing spondylitis (AS) compared to the general population. Materials and methods. This national prospective cohort study linked data from Swedish population and healthcare registries. Incidence rates and interventions for nephrolithiasis during follow-up in patients with AS were compared to general population comparator (GPC) subjects. Results. In total, 8572 AS patients were followed for 49,959 person-years and 39,639 matched GPCs were followed for 225,221 person-years. Mean age at study entry was 46 years [interquartile range (IQR) 36-56 years] and 65% were male. In AS patients with a diagnosis of nephrolithiasis during the study period, 29% (72/250) underwent similar intervention for nephrolithiasis compared to 24% (114/466) GPCs (p = 0.21). The incidence rate ratio (RR) in overall AS patients was 2.9 [95% confidence interval (CI) 2.1-3.8] during a median follow-up of 6.2 years (IQR 3.2-8.6 years). With prior diagnosis of nephrolithiasis, the RR for AS patients compared to GPCs was 3.7 (95% CI 1.8-7.7); without prior nephrolithiasis the RR was 2.1 (95% CI 1.5-3.0). Increasing age [odds ratio (OR) 1.02, 95% CI 1.01-1.03], prior nephrolithiasis diagnosis (OR 3.3, 95% CI 1.97-5.62) and atherosclerotic cardiac disease (OR 2.0, 95% CI 1.03-3.91) were identified as predictors of intervention for nephrolithiasis. Conclusions. Patients with AS have an almost three-fold increased risk of surgical intervention for kidney stones, with similar management, compared to the general population.
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| 10. |
- Lauss, Martin, et al.
(författare)
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DNA methylation analyses of urothelial carcinoma reveal distinct epigenetic subtypes and an association between gene copy number and methylation status.
- 2012
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Ingår i: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 7:8, s. 858-867
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Tidskriftsartikel (refereegranskat)abstract
- We assessed DNA methylation and copy number status of 27,000 CpGs in 149 urothelial carcinomas and integrated the findings with gene expression and mutation data. Methylation was associated with gene expression for 1,332 CpGs, of which 26% showed positive correlation with expression, i.e., high methylation and high gene expression levels. These positively correlated CpGs were part of specific transcription factor binding sites, such as sites for MYC and CREBP1, or located in gene bodies. Furthermore, we found genes with copy number gains, low expression and high methylation levels, revealing an association between methylation and copy number levels. This phenomenon was typically observed for developmental genes, such as HOX genes, and tumor suppressor genes. In contrast, we also identified genes with copy number gains, high expression and low methylation levels. This was for instance observed for some keratin genes. Tumor cases could be grouped into four subgroups, termed epitypes, by their DNA methylation profiles. One epitype was influenced by the presence of infiltrating immune cells, two epitypes were mainly composed of non-muscle invasive tumors, and the remaining epitype of muscle invasive tumors. The polycomb complex protein EZH2 that blocks differentiation in embryonic stem cells showed increased expression both at the mRNA and protein levels in the muscle invasive epitype, together with methylation of polycomb target genes and HOX genes. Our data highlights HOX gene silencing and EZH2 expression as mechanisms to promote a more undifferentiated and aggressive state in UC.
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| 11. |
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| 12. |
- Lindgren, David, et al.
(författare)
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Integrated genomic and gene expression profiling identifies two major genomic circuits in urothelial carcinoma.
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- Similar to other malignancies, urothelial carcinoma (UC) is characterized by specific recurrent chromosomal aberrations and gene mutations. However, the interconnection between specific genomic alterations, and how patterns of chromosomal alterations adhere to different molecular subgroups of UC, is less clear. We applied tiling resolution array CGH to 146 cases of UC and identified a number of regions harboring recurrent focal genomic amplifications and deletions. Several potential oncogenes were included in the amplified regions, including known oncogenes like E2F3, CCND1, and CCNE1, as well as new candidate genes, such as SETDB1 (1q21), and BCL2L1 (20q11). We next combined genome profiling with global gene expression, gene mutation, and protein expression data and identified two major genomic circuits operating in urothelial carcinoma. The first circuit was characterized by FGFR3 alterations, overexpression of CCND1, and 9q and CDKN2A deletions. The second circuit was defined by E3F3 amplifications and RB1 deletions, as well as gains of 5p, deletions at PTEN and 2q36, 16q, 20q, and elevated CDKN2A levels. TP53/MDM2 alterations were common for advanced tumors within the two circuits. Our data also suggest a possible RAS/RAF circuit. The tumors with worst prognosis showed a gene expression profile that indicated a keratinized phenotype. Taken together, our integrative approach revealed at least two separate networks of genomic alterations linked to the molecular diversity seen in UC, and that these circuits may reflect distinct pathways of tumor development.
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| 13. |
- Sjödahl, Gottfrid, et al.
(författare)
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A Molecular Taxonomy for Urothelial Carcinoma.
- 2012
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 18:12, s. 3377-3386
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Even though urothelial cancer is the fourth most common tumor type among males, progress in treatment has been scarce. A problem in day-to-day clinical practice is that precise assessment of individual tumors is still fairly uncertain; consequently efforts have been undertaken to complement tumor evaluation with molecular biomarkers. An extension of this approach would be to base tumor classification primarily on molecular features. Here, we present a molecular taxonomy for urothelial carcinoma based on integrated genomics. EXPERIMENTAL DESIGN: We use gene expression profiles from 308 tumor cases to define five major urothelial carcinoma subtypes: urobasal A, genomically unstable, urobasal B, squamous cell carcinoma like, and an infiltrated class of tumors. Tumor subtypes were validated in three independent publically available data sets. The expression of 11 key genes was validated at the protein level by immunohistochemistry. RESULTS: The subtypes show distinct clinical outcomes and differ with respect to expression of cell-cycle genes, receptor tyrosine kinases particularly FGFR3, ERBB2, and EGFR, cytokeratins, and cell adhesion genes, as well as with respect to FGFR3, PIK3CA, and TP53 mutation frequency. The molecular subtypes cut across pathologic classification, and class-defining gene signatures show coordinated expression irrespective of pathologic stage and grade, suggesting the molecular phenotypes as intrinsic properties of the tumors. Available data indicate that susceptibility to specific drugs is more likely to be associated with the molecular stratification than with pathologic classification. CONCLUSIONS: We anticipate that the molecular taxonomy will be useful in future clinical investigations. Clin Cancer Res; 1-10. ©2012 AACR.
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| 14. |
- Sjödahl, Gottfrid, et al.
(författare)
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Infiltration of CD3(+) and CD68(+) cells in bladder cancer is subtype specific and affects the outcome of patients with muscle-invasive tumors.
- 2014
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Ingår i: Urologic Oncology. - : Elsevier BV. - 1873-2496. ; 32:6, s. 791-797
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Tidskriftsartikel (refereegranskat)abstract
- Urothelial carcinoma (UC) aggressiveness is determined by tumor inherent molecular characteristics, such as molecular subtypes, as well as by host reactions directed toward the tumor. Cell types responsible for the host׳s response include tumor-infiltrating lymphocytes (TILs) and tumor-associated macrophages (TAMs). The aim of the present investigation was to explore the immunological response in relation to UC molecular subtypes and to evaluate the prognostic effect of TIL and TAM counts in tissue sections from muscle-invasive (MI) tumors.
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| 15. |
- Sjödahl, Gottfrid, et al.
(författare)
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Toward a Molecular Pathologic Classification of Urothelial Carcinoma.
- 2013
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 183:3, s. 681-691
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Tidskriftsartikel (refereegranskat)abstract
- We recently defined molecular subtypes of urothelial carcinomas according to whole genome gene expression. Herein we describe molecular pathologic characterization of the subtypes using 20 genes and IHC of 237 tumors. In addition to differences in expression levels, the subtypes show important differences in stratification of protein expression. The selected genes included biological features central to bladder cancer biology, eg, cell cycle activity, cellular architecture, cell-cell interactions, and key receptor tyrosine kinases. We show that the urobasal (Uro) A subtype shares features with normal urothelium such as keratin 5 (KRT5), P-cadherin (P-Cad), and epidermal growth factor receptor (EGFR) expression confined to basal cells, and cell cycle activity (CCNB1) restricted to the tumor-stroma interface. In contrast, the squamous cell cancer-like (SCCL) subtype uniformly expresses KRT5, P-Cad, EGFR, KRT14, and cell cycle genes throughout the tumor parenchyma. The genomically unstable subtype shows proliferation throughout the tumor parenchyma and high ERBB2 and E-Cad expression but absence of KRT5, P-Cad, and EGFR expression. UroB tumors demonstrate features shared by both UroA and SCCL subtypes. A major transition in tumor progression seems to be loss of dependency of stromal interaction for proliferation. We present a simple IHC/histology-based classifier that is easy to implement as a standard pathologic evaluation to differentiate the three major subtypes: urobasal, genomically unstable, and SCCL. These three major subtypes exhibit important prognostic differences.
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