| 1. |
- Abrahamsson, Johan, et al.
(author)
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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
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In: Urologic Oncology. - : Elsevier BV. - 1078-1439. ; 35:10, s. 9-606
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Journal article (peer-reviewed)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. |
- Bain, C. C., et al.
(author)
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Resident and pro-inflammatory macrophages in the colon represent alternative context-dependent fates of the same Ly6C(hi) monocyte precursors
- 2013
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In: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 6:3, s. 498-510
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Journal article (peer-reviewed)abstract
- Macrophages (m phi) are essential for intestinal homeostasis and the pathology of inflammatory bowel disease (IBD), but it is unclear whether discrete m phi populations carry out these distinct functions or if resident m phi change during inflammation. We show here that most resident m phi in resting mouse colon express very high levels of CX3CR1, are avidly phagocytic and MHCII hi, but are resistant to Toll-like receptor (TLR) stimulation, produce interleukin 10 constitutively, and express CD163 and CD206. A smaller population of CX3CR1(int) cells is present in resting colon and it expands during experimental colitis. Ly6C(hi) CCR2(+) monocytes can give rise to all m phi subsets in both healthy and inflamed colon and we show that the CX3CR1int pool represents a continuum in which newly arrived, recently divided monocytes develop into resident CX3CR1 hi m phi. This process is arrested during experimental colitis, resulting in the accumulation of TLR-responsive pro-inflammatory m phi. Phenotypic analysis of human intestinal m phi indicates that analogous processes occur in the normal and Crohn's disease ileum. These studies show for the first time that resident and inflammatory m phi in the intestine represent alternative differentiation outcomes of the same precursor and targeting these events could offer routes for therapeutic intervention in IBD.
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| 3. |
- Boström, Peter J., et al.
(author)
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Clinical markers of morbidity, mortality and survival in bladder cancer patients treated with radical cystectomy : A systematic review
- 2020
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In: Scandinavian journal of urology. - : Taylor & Francis. - 2168-1805 .- 2168-1813. ; 54:4, s. 267-276
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Research review (peer-reviewed)abstract
- Context: Radical cystectomy and pelvic lymph node dissection (RC and PLND) are an essential part of the treatment paradigm in high risk bladder cancer. However, these patients have high rates of morbidity and mortality related both to the treatment and to the disease.Objective:To provide overview of current literature about clinical markers that can be used to predict and improve BC-patient outcomes at the time of RC and PLND and to study if they are properly validated.Evidence acquisition: A systematic literature search was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria between January 1990 and October 2018 to identify English written original and review articles relevant to this topic. Prospective and retrospective studies were included.Evidence synthesis: There are several risk factors identified from non-randomised trials that can be improved before surgery to reduce perioperative mortality and morbidity. These include poor nutritional status, anaemia, renal function and smoking. Preoperative nomograms have also been developed to help decision-making and to inform patients about the risks of surgery. They can be used to estimate risk of postoperative mortality after RC and PLND with accuracy varying from 70 to 86%. These nomograms are largely based on retrospective data. Likewise, nomograms developed to calculate estimates about patient's overall and cancer specific survival have the same limitations.Conclusion: Clinical markers to predict morbidity, mortality and survival in patients with bladder cancer treated with RC and PLND may help to improve patient outcomes and treatment decision-making, but available data come from small retrospective trials and have not been properly validated. Prospective, multi-centre studies are needed to implement and disseminate predictive clinical markers and nomograms such that they can be utilised in treatment decision-making in daily practice.
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| 4. |
- Burger, Maximilian, et al.
(author)
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ICUD-EAU International Consultation on Bladder Cancer 2012: Non-Muscle-Invasive Urothelial Carcinoma of the Bladder
- 2013
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In: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 63:1, s. 36-44
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Research review (peer-reviewed)abstract
- Context: Our aim was to present a summary of the Second International Consultation on Bladder Cancer recommendations on the diagnosis and treatment options for non-muscle-invasive urothelial cancer of the bladder (NMIBC) using an evidence-based approach. Objective: To critically review the recent data on the management of NMIBC to arrive at a general consensus. Evidence acquisition: A detailed Medline analysis was performed for original articles addressing the treatment of NMIBC with regard to diagnosis, surgery, intravesical chemotherapy, and follow-up. Proceedings from the last 5 yr of major conferences were also searched. Evidence synthesis: The major findings are presented in an evidence-based fashion. We analyzed large retrospective and prospective studies. Conclusions: Urothelial cancer of the bladder staged Ta, T1, and carcinoma in situ (CIS), also indicated as NMIBC, poses greatly varying but uniformly demanding challenges to urologic care. On the one hand, the high recurrence rate and low progression rate with Ta low-grade demand risk-adapted treatment and surveillance to provide thorough care while minimizing treatment-related burden. On the other hand, the propensity of Ta high-grade, T1, and CIS to progress demands intense care and timely consideration of radical cystectomy. (C) 2012 European Association of Urology. Published by Elsevier B. V. All rights reserved.
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| 5. |
- Engilbertsson, Helgi, et al.
(author)
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TURBT Can Cause Seeding of Cancer Cells into the Bloodstream.
- 2015
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In: Journal of Urology. - : Ovid Technologies (Wolters Kluwer Health). - 1527-3792 .- 0022-5347. ; 193:1, s. 53-57
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Journal article (peer-reviewed)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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| 6. |
- Gudjonsson, Sigurdur, et al.
(author)
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Can tissue microarray-based analysis of protein expression predict recurrence of stage Ta bladder cancer?
- 2011
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In: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 1651-2065 .- 0036-5599. ; 45, s. 270-277
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Journal article (peer-reviewed)abstract
- Abstract Objective. Being able to predict the recurrence or progression of non-muscle-invasive bladder cancer would facilitate effective planning of treatments and follow-up. Biomarkers are needed that can supply prognostic information beyond that provided by clinical and pathological parameters. Tissue microarray (TMA)-based analysis of Ta bladder tumours was used to investigate the prognostic value of expression of several proteins involved in bladder carcinogenesis. Material and methods. Tumour tissue from 52 patients with Ta bladder cancer was investigated. At least three 0.6 mm punch cores from each tumour were placed in a paraffin array block. Tumour expression of tumour protein 53 (TP53), CDH1 (E-cadherin), proliferating cell nuclear antigen (PCNA), cyclooxygenase-2 (COX2), fibroblast growth factor receptor-3 (FGFR3) and epidermal growth factor receptor (EGFR) was quantified by immunohistochemistry (IHC) and correlated with time to recurrence. Median follow-up time was 3.1 years. Whole-section IHC analysis was performed to validate significant findings. Results. Of all patients, 69% (36/52) experienced recurrence. In univariate analysis, recurrence was associated with multifocality, number of earlier recurrences and a low quantity score for EGFR. In a multivariate model, a low EGFR quantity score was correlated with early recurrence (hazard ratio = 5.5, p = 0.003). However, whole-section IHC results for EGFR differed markedly from the TMA findings (κ = 0.07) and no association with time to recurrence was found (p = 0.65). Conclusions. Expression of EGFR measured by TMA-IHC, but not by whole-section IHC, was associated with early recurrence. The results suggest that the proteins assessed have no predictive value for recurrences. Concerns are raised regarding the methodology and generalization of results obtained with TMA-IHC.
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| 7. |
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| 8. |
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| 9. |
- Gudjonsson, Sigurdur, et al.
(author)
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Incontinent urinary diversion.
- 2008
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In: BJU International. - 1464-4096. ; 102:9 Pt B, s. 1320-1325
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Journal article (peer-reviewed)
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| 10. |
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| 11. |
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| 12. |
- Gudjonsson, Sigurdur
(author)
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Recurrent Non-Muscle-Invasive Bladder Cancer
- 2010
-
Doctoral thesis (other academic/artistic)abstract
- A characteristic feature of non-muscle-invasive bladder cancer (NMIBC) is the high risk of recurrent disease after primary treatment. Although only a minority of cases eventually progress to a life-threatening muscle-invasive tumour, it is necessary to conduct long-term follow-up with repeated cystoscopies. In addition to the negative mental and physical impact that this has on the patient, the examinations and the treatments of recurrence, impose an economic burden on the health care system. This thesis deals with various aspects of recurrent NMIBC. Paper I describes the present study of the genetic relationship between primary and recurrent tumours which revealed that in some cases there are fewer genetic aberrations in the latter than in the former. This finding contradicts the existance of a direct monoclonal relationsship between a primary and a recurrent tumour, although those lesions do show remarkably similar gene expression, which suggests that both are derived from a common progenitor cell. Paper II reports findings demonstrating that the voided urine marker, UroVysion® assay is too insensitive to replace cystoscopy in the follow-up of NMIBC patients. The results discussed in Paper III imply that only patients at low risk of recurrence benefit from early intravesical chemotherapy, and this disagrees with the European Association of Urology, which currently recommends that this treatment be given to all patients with presumed NMIBC. Paper IV demonstrates that biopsies from non-tumourous areas of bladder and prostatic urethra offer only about 50% sensitivity for carcinoma in situ (CIS). Lastly, as outlined in Paper V, none of the gene markers studied by the tissue microarray technique (i.e, TP53, CDH1, FGFR3, COX2, EGFR) were found to be associated with recurrence, but concerns were raised regarding the reliability of this methodology.
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| 13. |
- Gudjonsson, Sigurdur, et al.
(author)
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Should All Patients with Non-Muscle-Invasive Bladder Cancer Receive Early Intravesical Chemotherapy after Transurethral Resection? The Results of a Prospective Randomised Multicentre Study.
- 2009
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In: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 55, s. 773-780
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Journal article (peer-reviewed)abstract
- BACKGROUND: To decrease recurrences in non-muscle-invasive bladder cancer (NMIBC), the European Association of Urology (EAU) guidelines recommend immediate, intravesical chemotherapy after transurethral resection (TUR) for all patients with Ta/T1 tumours. OBJECTIVE: To study the benefits of a single, early, intravesical instillation of epirubicin after TUR in patients with low- to intermediate-risk NMIBC. DESIGN, SETTING, AND PARTICIPANTS: In this prospective randomised multicentre trial, 305 patients with primary as well as recurrent low- to intermediate-risk (Ta/T1, G1/G2) tumours were enrolled between 1997 and 2004. Patients were randomly allocated to receive 80mg of epirubicin in 50ml of saline intravesically within 24h of TUR or no further treatment after TUR. MEASUREMENTS: The primary end point was time to first recurrence. RESULTS AND LIMITATIONS: A total of 219 patients remained for analysis after exclusions. The median follow-up time was 3.9 yr. During the study period, 62% (63 of 102) of the patients in the epirubicin group and 77% (90 of 117) in the control group experienced recurrence (p=0.016). In a multivariate model, the hazard ratio (HR) for recurrence was 0.56 (p=0.002) for early instillation of epirubicin versus no treatment. In a subgroup analysis, the treatment had a profound recurrence-reducing effect on patients with primary, solitary tumours, whereas it provided no benefits in patients with recurrent or multiple tumours. Furthermore, patients with a modified European Organisation for Research and Treatment of Cancer (EORTC) risk score of 0-2 with and without single instillation had recurrence rates of 41% and 69%, respectively (p=0.003), whereas the corresponding rates for those with a risk score of >/=3 were 81% and 85%, respectively (p=0.35). CONCLUSIONS: A single, early instillation of epirubicin after TUR for NMIBC reduces the likelihood of tumour recurrence; however, the benefit seems to be minimal in patients at intermediate or high risk of recurrence. Future trials will determine the value of early instillation in addition to serial instillations in NMIBC.
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| 14. |
- Gudjonsson, Sigurdur, et al.
(author)
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The value of bladder mapping and prostatic urethra biopsies for detection of carcinoma in situ (CIS)
- 2012
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In: BJU International. - : Wiley. - 1464-4096 .- 1464-410X. ; 110:2B, s. E41-E45
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Journal article (peer-reviewed)abstract
- OBJECTIVES To assess the value of bladder mapping and prostatic urethra biopsies for detection of urothelial carcinoma in situ (CIS). CIS of the urinary bladder is a flat high-grade lesion of the mucosa associated with a significant risk of progression to muscle-invasive disease. CIS is difficult to identify on cystoscopy, and definite diagnosis requires histopathology. Traditionally, if CIS is suspected, multiple cold-cup biopsies are taken from the bladder mucosa, and resection biopsies are obtained from the prostatic urethra in males. This approach is often called bladder mapping (BMAP). The accuracy of BMAP as a diagnostic tool is not known. PATIENTS AND METHODS Male patients with bladder cancer scheduled for cystectomy underwent cold-cup bladder biopsies (sidewalls, posterior wall, dome, trigone), and resection biopsies were taken from the prostatic urethra. After cystectomy, the surgical specimen was investigated in a standardised manner and subsequently compared with the BMAP biopsies for the presence of CIS. RESULTS The histopathology reports of 162 patients were analysed. CIS was detected in 46% of the cystoprostatectomy specimens, and multiple (greater than= 2) CIS lesions were found in 30%. BMAP (cold-cup bladder biopsies + resection biopsies from the prostatic urethra) provided sensitivity of 51% for any CIS, and 55% for multiple CIS lesions. The cold-cup biopsies for CIS in the bladder mucosa showed sensitivity and specificity of 46% and 89%, respectively. CONCLUSION Traditional cold-cup biopsies are unreliable for detecting CIS in bladder mucosa and negative findings must be interpreted with caution.
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| 15. |
- Gudjonsson, Sigurdur, et al.
(author)
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The Value of the UroVysion((R)) Assay for Surveillance of Non-Muscle-Invasive Bladder Cancer.
- 2008
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In: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 54:2, s. 402-408
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: Patients with non-muscle-invasive bladder cancer are traditionally followed by repeat cystoscopy and urine cytology. A fluorescence in situ hybridisation technique called UroVysion((R)) (UV) is now available for clinical diagnosis of urothelial cancer cells. The aim of the present study was to compare UV analysis with routine follow-up methods. METHODS: We studied an unselected cohort of patients undergoing cystoscopy follow-ups at two Swedish centres in 2004-2005. All patients were investigated by cystoscopy, cytology, and UV assay. The UV assay was evaluated with regards to sensitivity, specificity, and positive predictive value for tumour recurrence. RESULTS: In all, 159 cases were analysed. UV had a 30% overall sensitivity for the 27 biopsy-proven recurrences and 70% sensitivity for high-risk tumours (pT1 and carcinoma in situ [CIS]). The specificity of UV was 95%. UV detected all six CIS cases in the study and was predictive in two additional patients who developed CIS within 1 yr of inclusion. Cytology was positive in four of those eight CIS cases and atypical in the other four. CONCLUSIONS: The UV assay cannot replace cystoscopy for surveillance of patients with non-muscle-invasive bladder cancer, but it may be valuable as a supplement to traditional measures for detecting CIS. Before any conclusions can be drawn regarding the efficacy of novel markers of bladder cancer, they must be studied in bladder cancer patients undergoing endoscopic surveillance.
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| 16. |
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| 17. |
- Hautmann, Richard E., et al.
(author)
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ICUD-EAU International Consultation on Bladder Cancer 2012: Urinary Diversion
- 2013
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In: European Urology. - : Elsevier BV. - 1873-7560 .- 0302-2838. ; 63:1, s. 67-80
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Research review (peer-reviewed)abstract
- Context: A summary of the 2nd International Consultation on Bladder Cancer recommendations on the reconstructive options after radical cystectomy (RC), their outcomes, and their complications. Objective: To review the literature regarding indications, surgical details, postoperative care, complications, functional outcomes, as well as quality-of-life measures of patients with different forms of urinary diversion (UD). Evidence acquisition: An English-language literature review of data published between 1970 and 2012 on patients with UD following RC for bladder cancer was undertaken. No randomized controlled studies comparing conduit diversion with neobladder or continent cutaneous diversion have been performed. Consequently, almost all studies used in this report are of level 3 evidence. Therefore, the recommendations given here are grade C only, meaning expert opinion delivered without a formal analysis. Evidence synthesis: Indications and patient selection criteria have significantly changed over the past 2 decades. Renal function impairment is primarily caused by obstruction. Complications such as stone formation, urine outflow, and obstruction at any level must be recognized early and treated. In patients with orthotopic bladder substitution, daytime and nocturnal continence is achieved in 85-90% and 60-80%, respectively. Continence is inferior in elderly patients with orthotopic reconstruction. Urinary retention remains significant in female patients, ranging from 7% to 50%. Conclusions: RC and subsequent UD have been assessed as the most difficult surgical procedure in urology. Significant disparity on how the surgical complications were reported makes it impossible to compare postoperative morbidity results. Complications rates overall following RC and UD are significant, and when strict reporting criteria are incorporated, they are much higher than previously published. Fortunately, most complications are minor (Clavien grade 1 or 2). Complications can occur up to 20 yr after surgery, emphasizing the need for lifelong monitoring. Evidence suggests an association between surgical volume and outcome in RC; the challenge of optimum care for elderly patients with comorbidities is best mastered at high-volume hospitals by high-volume surgeons. Preoperative patient information, patient selection, surgical techniques, and careful postoperative follow-up are the cornerstones to achieve good long-term results. (C) 2012 European Association of Urology. Published by Elsevier B. V. All rights reserved.
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| 18. |
- Heidenblad, Markus, et al.
(author)
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Tiling resolution array CGH and high density expression profiling of urothelial carcinomas delineate genomic amplicons and candidate target genes specific for advanced tumors.
- 2008
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In: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 1:Jan 31
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Journal article (peer-reviewed)abstract
- ABSTRACT: BACKGROUND: Urothelial carcinoma (UC) is characterized by nonrandom chromosomal aberrations, varying from one or a few changes in early-stage and low-grade tumors, to highly rearranged karyotypes in muscle-invasive lesions. Recent array-CGH analyses have shed further light on the genomic changes underlying the neoplastic development of UC, and have facilitated the molecular delineation amplified and deleted regions to the level of specific candidate genes. In the present investigation we combine detailed genomic information with expression information to identify putative target genes for genomic amplifications. METHODS: We analyzed 38 urothelial carcinomas by whole-genome tiling resolution array-CGH and high density expression profiling to identify putative target genes in common genomic amplifications. When necessary expression profiling was complemented with Q-PCR of individual genes. RESULTS: Three genomic segments were frequently and exclusively amplified in high grade tumors; 1q23, 6p22 and 8q22, respectively. Detailed mapping of the 1q23 segment showed a heterogeneous amplification pattern and no obvious commonly amplified region. The 6p22 amplicon was defined by a 1.8 Mb core region present in all amplifications, flanked both distally and proximally by segments amplified to a lesser extent. By combining genomic profiles with expression profiles we could show that amplification of E2F3, CDKAL1, SOX4, and MBOAT1 as well as NUP153, AOF1, FAM8A1 and DEK in 6p22 was associated with increased gene expression. Amplification of the 8q22 segment was primarily associated with YWHAZ (14-3-3-zeta) and POLR2K over expression. The possible importance of the YWHA genes in the development of urothelial carcinomas was supported by another recurrent amplicon paralogous to 8q22, in 2p25, where increased copy numbers lead to enhanced expression of YWHAQ (14-3-3-theta). Homozygous deletions were identified at 10 different genomic locations, most frequently affecting CDKN2A/CDKN2B in 9p21 (32%). Notably, the latter occurred mutually exclusive with 6p22 amplifications. CONCLUSION: The presented data indicates 6p22 as a composite amplicon with more than one possible target gene. The data also suggests that amplification of 6p22 and homozygous deletions of 9p21 may have complementary roles. Furthermore, the analysis of paralogous regions that showed genomic amplification indicated altered expression of YWHA (14-3-3) genes as important events in the development of UC.
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| 19. |
- Holmer, Magnus, et al.
(author)
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Extended lymph node dissection in patients with urothelial cell carcinoma of the bladder: can it make a difference?
- 2009
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In: World Journal of Urology. - : Springer Science and Business Media LLC. - 1433-8726 .- 0724-4983. ; 27, s. 521-526
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Journal article (peer-reviewed)abstract
- OBJECTIVE: We compared extended and limited lymph node dissections performed during radical cystectomy with regard to impact on survival and time to recurrence in bladder cancer patients. METHODS: We analyzed 170 patients who underwent radical cystectomy for urothelial carcinoma between January 1997 and December 2005. From 1997 to 2000, 69 of the patients were subjected to limited lymph dissection that included perivesical nodes and nodes in the obturator fossa. In 2001-2005, the remaining 101 patients underwent extended lymph dissection that included perivesical nodes; nodes in the obturator fossa; the internal, external, and common iliac nodes; and the presacral nodes. RESULTS: Tumors penetrating the bladder wall (pT3 and pT4a) were more common in the extended than in the limited dissection group (48 and 33%, respectively). The median numbers of lymph nodes removed in the two groups were 37 and 8, respectively. Lymph node metastases were detected in 38% of the extended dissection patients but only in 17% of the limited dissection patients. There was no significant difference in survival or time to recurrence between the two groups. Subgroup analyses showed a significantly longer time to recurrence (HR 0.45, 95% CI 0.22-0.93; P = 0.032) in patients with non-organ-confined disease who underwent extended lymph node dissection. In a multivariate analysis adjusting for tumor stage, lymph node status, age, sex, and adjuvant chemotherapy, there was a significantly improved survival (HR 0.47, 95% CI 0.25-0.88; P = 0.018) and time to recurrence (HR 0.42, 95% CI 0.23-0.79; P = 0.007) in the patients with extended lymph node dissections. CONCLUSIONS: Extended lymph node dissection did not improve disease-specific survival, but was in multivariate analysis related to significantly improved disease-specific survival and prolonged time to recurrence in radical cystectomy patients. These results should be interpreted cautiously, since they might have been affected by stage migration and the shorter follow-up in the extended dissection group.
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| 20. |
- Holmkvist, Petra, et al.
(author)
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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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In: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 8:3, s. 545-558
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Journal article (peer-reviewed)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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| 21. |
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| 22. |
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| 23. |
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| 24. |
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| 25. |
- Jin, Yuesheng, et al.
(author)
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Distinct mitotic segregation errors mediate chromosomal instability in aggressive urothelial cancers.
- 2007
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In: Clinical Cancer Research. - 1078-0432. ; 13:6, s. 1703-1712
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Journal article (peer-reviewed)abstract
- Purpose: Chromosomal instability (CIN) is believed to have an important role in the pathogenesis of urothelial cancer (UC). The aim of this study was to evaluate whether disturbances of mitotic segregation contribute to CIN in UC, if these processes have any effect on the course of disease, and how deregulation of these mechanisms affects tumor cell growth. Experimental Design: We developed molecular cytogenetic methods to classify mitotic segregation abnormalities in a panel of UC cell lines. Mitotic instabilities were then scored in biopsies from 52 UC patients and compared with the outcome of tumor disease. Finally, UC cells were exposed in vitro to a telomerase inhibitor to assess how this affects mitotic stability and cell proliferation. Results: Three distinct chromosome segregation abnormalities were identified: (a) telomere dysfunction, which triggers structural rearrangements and loss of chromosomes through anaphase bridging; (b) sister chromatid nondisjunction, which generates discrete chromosomal copy number variations; and (c) supernumerary centrosomes, which cause dramatic shifts in chromosome copy number through multipolar cell division. Chromosome segregation errors were already present in preinvasive tumors and a high rate mitotic instability was an independent predictor of poor survival. However, induction of even higher levels of the same segregation abnormalities in UC cells by telomerase inhibition in vitro led to reduced tumor cell proliferation and clonogenic survival. Conclusion: Several distinct chromosome segregation errors contribute to CIN in UC, and the rate of such mitotic errors has a significant effect on the clinical course. Efficient tumor cell proliferation may depend on the tight endogenous control of these processes.
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| 26. |
- Johansson Kollberg, Petter, et al.
(author)
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[18F]Fluorodeoxyglucose-positron emission tomography/computed tomography response evaluation can predict histological response at surgery after induction chemotherapy for oligometastatic bladder cancer
- 2017
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In: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 51:4, s. 308-313
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Journal article (peer-reviewed)abstract
- Objective: Patients with limited metastatic and locally advanced bladder cancer have a poor prognosis, and no definite treatment recommendations exist. However, long-term survival is possible for selected patients if surgery is combined with multiple courses of chemotherapy (i.e. induction chemotherapy). Patients with tumours that are insensitive to chemotherapy probably have little to gain from subsequent extensive surgery. The aim of this study was to evaluate sequential FDG-PET/CT examinations as an indicator of chemotherapy response. Materials and methods: Between 2007 and 2015, 50 patients with oligometastatic invasive bladder cancer selected for induction chemotherapy underwent two FDG-PET/CT examinations: the first before the start of chemotherapy and the second after three courses of cisplatinum-based combination chemotherapy. Responders were given up to six courses of chemotherapy. FDG-PET/CT response was correlated with histological response in excised lymph-node metastases. Results: Three patients showed progression to incurable disease during chemotherapy and another two patients did not undergo surgery, for medical reasons. Lymphadenectomy was performed in the remaining 45 patients, of whom 43 had lymph-node metastasis. FDG-PET/CT prediction of the histological nodal chemotherapy response was correct in 37 (86%) of those 43. The second FDG-PET/CT examination identified four out of nine non-responders. For response, the sensitivity, specificity, and positive and negative predictive values for FDG-PET/CT accuracy were 37 out of 37 (100%), one out of six (17%), 37 out of 42 (88%) and one out of one (100%), respectively. Conclusions: Repeated FDG-PET/CT seems to predict histological response. However, with the histological response criteria used in this study, five non-responders were not identified by the second FDG-PET/CT investigation.
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| 27. |
- Karlsson, Sten, et al.
(author)
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A genetic marker for the maternal identification of Atlantic salmon x brown trout hybrids
- 2013
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In: Conservation Genetics Resources. - : Springer Science and Business Media LLC. - 1877-7252 .- 1877-7260. ; 5:1, s. 47-49
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Journal article (peer-reviewed)abstract
- Interspecific hybridization between Atlantic salmon and brown trout is well documented, but why it should vary so much among populations is not clear. Determining the maternal origin of hybrids can provide insights into the mechanisms underlying interspecific hybridization, but this information is lacking in many studies. Here we present a species-specific mitochondrial DNA marker for the identification of the maternal origin of hybrids. This marker involves only one PCR step followed by fragment analysis, can be integrated within PCR multiplexing for existing nuclear markers for hybrid identification, and is therefore faster and more cost-effective than previous methods.
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| 28. |
- Kjölhede, Henrik, et al.
(author)
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Simplified intraoperative sentinel-node detection performed by the urologist accurately determines lymph-node stage in prostate cancer
- 2015
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In: Scandinavian journal of urology. - : Informa Healthcare. - 2168-1805 .- 2168-1813. ; 49:2, s. 97-102
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Journal article (peer-reviewed)abstract
- Objective: The reference standard for lymph-node staging in prostate cancer is currently an extended pelvic lymph-node dissection (ePLND), which detects most, but not all, regional lymph-node metastases. As an alternative to ePLND, sentinel-node dissection with preoperative isotope injection and imaging has been reported. The objective was to determine whether intraoperative sentinel-node detection with a simplified protocol can accurately determine lymph-node stage in prostate cancer patients.Materials and methods: Patients with biopsy-verified high-risk prostate cancer with tumour stage T2-3 were included in the study. All patients underwent both ePLND and sentinel-node detection. Tc-99m-marked nanocolloid was injected peritumourally by the operating urologist after induction of anaesthesia just before surgery. Sentinel nodes were detected both in vivo and ex vivo intraoperatively using a gamma probe. Sentinel nodes and metastases and their locations were recorded. Sensitivity and specificity were calculated.Results: At least one sentinel node was detected in 72 (87%) of the 83 patients. In 13 (18%) of these 72 patients sentinel nodes were detected outside the ePLND template. In six of these 13 patients, the Sentinel nodes from outside the template contained metastases, which proved to be the only metastases in two. For 12 patients the only metastatic deposit found was a micrometastasis (<= 2 mm) in a sentinel node. In the 72 patients with detectable sentinel nodes, pathological analysis of the sentinel node correctly categorized 71 and ePLND 70 patients.Conclusions: This protocol yielded results comparable to the commonly used technique of sentinel-node detection, but with more cases of non-detection.
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| 29. |
- Kollberg, Petter, et al.
(author)
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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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In: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1813 .- 2168-1805. ; 49:4, s. 296-301
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Journal article (peer-reviewed)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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| 30. |
- Körner, Stefanie Korsgaard, et al.
(author)
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Which data are available in central registries on bladder cancer patients in the five Nordic countries
- 2021
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In: Scandinavian journal of urology. - : Taylor & Francis. - 2168-1805 .- 2168-1813. ; 55:2, s. 135-141
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Journal article (peer-reviewed)abstract
- OBJECTIVE: The aim of this study was to give a collective overview on all available data sources on bladder cancer patients in the Nordic countries including the amount of detail and coverage.METHODS: National representatives from five Nordic countries were asked to fill out a questionnaire on available information regarding bladder cancer patients from databases in their respective countries. Additional information was retrieved from descriptions of the relevant registries.RESULTS: : Information on overall survival was available in all countries whereas recurrence-free survival and cancer-specific survival were available for some but not all patients depending on treatment modality.CONCLUSIONS: Despite limitations, we found that it was possible to retrieve detailed information on diagnostics, treatment, and outcome for most aspects of bladder cancer in the Nordic countries on a population based, non-selected patient cohort.
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| 31. |
- Lauss, Martin, et al.
(author)
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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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In: Epigenetics. - : Informa UK Limited. - 1559-2294 .- 1559-2308. ; 7:8, s. 858-867
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Journal article (peer-reviewed)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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| 32. |
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| 33. |
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| 34. |
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| 35. |
- Liedberg, Fredrik, et al.
(author)
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Fast-track access to urologic care for patients with macroscopic haematuria is efficient and cost-effective : results from a prospective intervention study
- 2016
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In: British Journal of Cancer. - : Springer Science and Business Media LLC. - 0007-0920 .- 1532-1827. ; 115, s. 770-775
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Journal article (peer-reviewed)abstract
- Background:The delay between onset of macroscopic haematuria and diagnosis of bladder cancer is often long.Methods:We evaluated timely diagnosis and health-care costs for patients with macroscopic haematuria given fast-track access to diagnostics. During a 15-month period, a telephone hotline for fast-track diagnostics was provided in nine Swedish municipalities for patients aged ⩾50 years with macroscopic haematuria. The control group comprised 101 patients diagnosed with bladder cancer in the same catchment area with macroscopic haematuria who underwent regular diagnostic process.Results:In all 275 patients who called ‘the Red Phone’ hotline were investigated, and 47 of them (17%) were diagnosed with cancer and 36 of those had bladder cancer. Median time from patient-reported haematuria to diagnosis was 29 (interquartile range (IQR) 14−104) days and 50 (IQR 27−165) days in the intervention and the control group, respectively (P=0.03). The median health-care costs were lower in the intervention group (655 (IQR 655−655) EUR) than in the control group (767 (IQR 490−1096) EUR) (P=0.002).Conclusions:Direct access to urologic expertise and fast-track diagnostics is motivated for patients with macroscopic haematuria to reduce diagnostic intervals and lower health-care expenditures.British Journal of Cancer advance online publication, 25 August 2016; doi:10.1038/bjc.2016.265 www.bjcancer.com.
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| 36. |
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| 37. |
- Liedberg, Fredrik, et al.
(author)
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Long-term functional outcomes after radical cystectomy with ileal bladder substitute : does the definition of continence matter?
- 2017
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In: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 51:1, s. 44-49
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Journal article (peer-reviewed)abstract
- Objective: Functional outcomes after ileal bladder substitution reflect the expectations of future patients at a particular centre. The aim of this study was to use validated questionnaires and a pad-weighing test to investigate functional outcomes after neobladder reconstruction at long-term follow-up in patients at a single centre. Materials and methods: During 2005 − 2015, 75 patients received a Studer ileal bladder substitute at the Department of Urology, Malmö. Forty-six of these patients were alive for follow-up and were evaluated using the pad-weighing test and the International Consultation on Incontinence Questionnaire–Urinary Incontinence Short Form (ICIQ-UI-SF), the Female Sexual Function Index (FSFI) and the International Index of Erectile Function (IIEF). Results: Five of 37 evaluable patients (14%) were considered fully continent, reporting a pad-weighing test result of 0 g and an ICIQ-UI-SF score of 0. The median ICIQ-UI-SF score was 8 [interquartile range (IQR) 3–11], and seven patients (17%) were continent according to the ICIQ-UI-SF score only. In the pad-weighing test, 28 out of 37 patients (76%) reported 0 g day-time leakage whereas only 12 out of 37 patients (32%) reported 0 g night-time leakage. At follow-up, nine out of 39 (23%) of evaluable male patients were potent. The median ICIQ-UI-SF score was significantly lower during the second half of the study period [4 (IQR 0–8) vs 10 (IQR 6–14); p = .003]. The inverse applied to the median IIEF score [5 (IQR 3–12) vs 2 (IQR 1–4); p = .02]. Conclusions: Functional outcomes at long-term follow-up after radical cystectomy and Studer ileal bladder substitute were at best modest in this series. Better outcomes during the second half of the study period might be explained by improved patient selection and a refined surgical technique, but possibly also by longer follow-up of patients during the first half of the period resulting in a more pronounced time-dependent decline in functional outcomes.
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| 38. |
- Liedberg, Fredrik, et al.
(author)
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Long-term third-party assessment of results after continent cutaneous diversion with Lundiana pouch
- 2017
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In: BJU International. - : Wiley. - 1464-4096. ; 120:4, s. 530-536
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Journal article (peer-reviewed)abstract
- Objectives: To investigate the long-term functional outcomes and complications after continent cutaneous diversion with the Lundiana pouch. Patients and Methods: Complications, re-operations, renal function, and continence were ascertained from patient charts. Outcome variables were validated by a second and independent review of the patient files. Results: A complication of Clavien-Dindo grade ≥III, including unscheduled re-admissions, occurred in 45/193 patients (23%) at ≤90 days of surgery. At a median follow-up of 13 years, 105/193 patients (54%) had undergone at least one re-operation, with uretero-intestinal stricture being the most prevalent cause [28 patients (15%)]. Re-operations were more prevalent in patients operated during the first half of the study period than during the second half (2000-2007; 62% vs 47%; P = 0.03), and they were also more frequent in patients who underwent surgery for benign causes than in patients who underwent surgery for malignancy (60% vs 51%; P = 0.04). Continence was achieved in 172/188 patients (91%). In all, 16% of all patients required revisional surgery of the outlet to remain continent with an easily catheterisable pouch or to address stomal stenosis. The mean decrease in estimated glomerular filtration rate was more pronounced in patients with benign indications for urinary diversion than in those with malignancies, even after adjusting for younger age at surgery and longer follow-up in the former group (22 vs 11 mL/min/1.73 m2; P < 0.006). A disinterested third-party assessment revealed 10 postoperative complications, 17 re-operations during follow-up, and seven occasions of hospitalisation due to pyelonephritis (included in data above) not recorded at the primary data review. Conclusions: The Lundiana pouch is associated with a high risk of re-operation, although the functional results are good. Independent review by a third party increased the validity of the outcome data.
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| 39. |
- Liedberg, Fredrik, et al.
(author)
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Preoperative staging of locally advanced bladder cancer before radical cystectomy using 3 tesla magnetic resonance imaging with a standardized protocol
- 2013
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In: Scandinavian Journal of Urology. - : Informa UK Limited. - 2168-1813 .- 2168-1805. ; 47:2, s. 108-112
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Journal article (peer-reviewed)abstract
- Objective. The correlation between clinical tumour stage and pathological tumour stage in radical cystectomy specimens in locally advanced bladder cancer is suboptimal. Radiological methods have so far been of limited value in preoperative staging; however, the resolution with magnetic resonance imaging (MRI) has improved with further technical developments of the method. The aim of this study was to compare tumour stage at MRI with pathological tumour stage in the cystectomy specimen. Material and methods. Prospectively, 53 patients with invasive bladder cancer were preoperatively investigated with 3 tesla (3T) MRI using a standardized protocol. 3T MRI was performed at a standardized bladder volume. Clinical tumour stage, tumour stage at MRI and pathological tumour stage groups (Ta, Cis, T1/T2a, T2b/T3a, T3b/T4a), were compared, and sensitivity and specificity for organ-confined and non-organ-confined disease (stage T3a or above or lymph-node metastases) were analysed. Results. MRI overestimated tumour stage in 23 out of 47 patients (49%), whereas six patients (13%) were understaged. In the three groups of patients (those with the same stage group at MRI as in the cystectomy specimen, overestimated tumour stage and understaged patients), the time interval between transurethral resection of the bladder (TURB) and MRI did not differ significantly. Conclusions. Preoperative MRI overestimated tumour stage in almost half of the patients investigated in this study. Postoperative changes could have contributed to such overstaging with MRI.
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| 40. |
- Liedberg, Fredrik, et al.
(author)
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Preventing Parastomal Hernia After Ileal Conduit by the Use of a Prophylactic Mesh : A Randomised Study
- 2020
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In: European Urology. - : Elsevier. - 0302-2838 .- 1873-7560. ; 78:5, s. 757-763
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Journal article (peer-reviewed)abstract
- BACKGROUND: Parastomal hernia (PSH) after urinary diversion with ileal conduit is frequently a clinical problem.OBJECTIVE: To investigate whether a prophylactic lightweight mesh in the sublay position can reduce the cumulative incidence of PSH after open cystectomy with ileal conduit.DESIGN, SETTING, AND PARTICIPANTS: From 2012 to 2017, we randomised 242 patients 1:1 to conventional stoma construction (n = 124) or prophylactic mesh (n = 118) at three Swedish hospitals (ISRCTN 95093825).OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was clinical PSH, and secondary endpoints were radiological PSH assessed in prone position with the stoma in the centre of a ring, parastomal bulging, and complications from the mesh.RESULTS AND LIMITATIONS: Within 24 mo, 20/89 (23%) patients in the control arm and 10/92 (11%) in the intervention arm had developed a clinical PSH (p = 0.06) after a median follow-up of 3 yr, corresponding to a hazard ratio of 0.45 (confidence interval 0.24-0.86, p = 0.02) in the intervention arm. The proportions of radiological PSHs within 24 mo were 22/89 (25%) and 17/92 (19%) in the two study arms. During follow-up, five patients in the control arm and two in the intervention arm were operated for PSH. The median operating time was 50 min longer in patients receiving a mesh. No differences were noted in proportions of Clavien-Dindo complications at 90 d postoperatively or in complications related to the mesh during follow-up.CONCLUSIONS: Prophylactic implantation of a lightweight mesh in the sublay position decreases the risk of PSH when constructing an ileal conduit without increasing the risk of complications related to the mesh. The median surgical time is prolonged by mesh implantation.PATIENT SUMMARY: In this randomised report, we looked at the risk of parastomal hernia after cystectomy and urinary diversion with ileal conduit with or without the use of a prophylactic mesh. We conclude that such a prophylactic measure decreased the occurrence of parastomal hernias, with only a slight increase in operating time and no added risk of complications related to the mesh.
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| 41. |
- Liedberg, Fredrik, et al.
(author)
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Prospective study of transitional cell carcinoma in the prostatic urethra, and prostate in cystoprostatectomy specimen
- 2007
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In: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 0036-5599 .- 1651-2065. ; 41:4, s. 290-296
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Journal article (peer-reviewed)abstract
- Objectives. To prospectively evaluate the incidence of transitional cell carcinoma (TCC) in the prostatic urethra and prostate in the cystoprostatectomy specimen, investigate characteristics of bladder tumours in relation to the risk of involvement of the prostatic urethra and prostate and examine the sensitivity of preoperative loop biopsies from the prostatic urethra. Material and methods. Preoperatively, patients were investigated with cold cup biopsies from the bladder and transurethral loop biopsies from the bladder neck to the verumontanum. The prostate and bladder neck were submitted to sagittal whole-mount pathological analysis. Results. The incidence of TCC in the prostatic urethra and prostate in the cystoprostatectomy specimen was 29% (50/175 patients). Age, previous bacillus Calmette-Gueacuterin treatment, carcinoma in situ (Cis) in the cold cup mapping biopsies and tumour grade were not associated with the risk of TCC in the prostatic urethra/prostate. Cis, multifocal Cis (≥2 locations) and tumour location in the trigone were significantly more common in cystectomy specimens with TCC in the prostatic urethra and prostate: 21/50 (42%) vs 32/125 (26%), p=0.045; 20/50 (40%) vs 27/125 (22%), p=0.023; and 20/50 (40%) vs 26/125 (21%), p=0.01, respectively. Preoperative resectional biopsies from the prostatic urethra in the 154 patients analysed identified 31/47 (66%) of patients with TCC in the prostatic urethra/prostate, with a specificity of 89%. The detection of stromal-invasive and non-stromal involvement was similar: 66% and 65%, respectively. Conclusions. The incidence of TCC in the prostatic urethra and prostate was 29% (50/175) in the cystoprostatectomy specimen. Preoperative biopsies from the prostatic urethra identified 66% of patients with such tumour growth. Our findings suggest that preoperative cold cup mapping biopsies of the bladder for detection of Cis add little extra information with regard to the risk of TCC in the prostatic urethra and prostate.
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| 42. |
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| 43. |
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| 44. |
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| 45. |
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| 46. |
- Liedberg, Fredrik, et al.
(author)
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Tissue microarray based analysis of prognostic markers in invasive bladder cancer: Much effort to no avail?
- 2008
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In: Urologic Oncology. - : Elsevier BV. - 1873-2496. ; 26:1, s. 17-24
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Journal article (peer-reviewed)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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| 47. |
- Lindberg, Christian, et al.
(author)
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Extended pelvic lymphadenectomy for prostate cancer: Will the previously reported benefits be reproduced in hospitals with lower surgical volumes?
- 2009
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In: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 1651-2065 .- 0036-5599. ; Aug 25, s. 437-441
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Journal article (peer-reviewed)abstract
- Objective. In the European Association of Urology guidelines on prostate cancer an extended pelvic lymphadenectomy (ePLND) is now recommended, instead of a dissection limited to the obturator fossae (lPLND). This recommendation relies on studies reporting that metastatic disease is identified twice as often with ePLND as with lPLND, with only moderately increased complications. However, these studies were from high-volume centres. This study investigated whether these results could be repeated in a hospital with lower surgical volume, more typical for the Nordic countries. Material and methods. From January 2002 to September 2007 172 patients underwent radical prostatectomy and PLND at the University Hospital of Lund, 108 with ePLND and 64 with lPLND. Perioperative complications and the number of lymph-node metastases found were registered. Results. A median of 17 lymph nodes was identified with ePLND compared with seven with lPLND. Metastases were identified in four out of 64 patients in the lPLND group (6%), versus 22 out of 108 in the ePLND group (20%). In the ePLND group 10 of the patients with metastases had such exclusively outside the obturator fossae. Complications were significantly more common after ePLND (p=0.007): lymphoceles (18 vs 9%), pulmonary embolism (4.6 vs 1.6%), deep venous thrombosis(1 vs 1.5%) and other (haematomas and infectious including sepsis (8 vs 0%). Conclusions. Almost half of the patients with metastases are misclassified by lPLND. Complications are significantly more common after ePLND. This implies that ePLND should be performed, but in selected patients and by high-volume surgeons only.
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| 48. |
- Lindgren, David, et al.
(author)
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Combined Gene Expression and Genomic Profiling Define Two Intrinsic Molecular Subtypes of Urothelial Carcinoma and Gene Signatures for Molecular Grading and Outcome
- 2010
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In: Cancer Research. - 0008-5472 .- 1538-7445. ; 70:9, s. 3463-3472
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Journal article (peer-reviewed)abstract
- In the present investigation, we sought to refine the classification of urothelial carcinoma by combining information on gene expression, genomic, and gene mutation levels. For these purposes, we performed gene expression analysis of 144 carcinomas, and whole genome array-CGH analysis and mutation analyses of FGFR3, PIK3CA, KRAS, HRAS, NRAS, TP53, CDKN2A, and TSC1 in 103 of these cases. Hierarchical cluster analysis identified two intrinsic molecular subtypes, MS1 and MS2, which were validated and defined by the same set of genes in three independent bladder cancer data sets. The two subtypes differed with respect to gene expression and mutation profiles, as well as with the level of genomic instability. The data show that genomic instability was the most distinguishing genomic feature of MS2 tumors, and that this trait was not dependent on TP53/MDM2 alterations. By combining molecular and pathologic data, it was possible to distinguish two molecular subtypes of T(a) and T(1) tumors, respectively. In addition, we define gene signatures validated in two independent data sets that classify urothelial carcinoma into low-grade (G(1)/G(2)) and high-grade (G(3)) tumors as well as non-muscle and muscle-invasive tumors with high precisions and sensitivities, suggesting molecular grading as a relevant complement to standard pathologic grading. We also present a gene expression signature with independent prognostic effect on metastasis and disease-specific survival. We conclude that the combination of molecular and histopathologic classification systems might provide a strong improvement for bladder cancer classification and produce new insights into the development of this tumor type.
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| 49. |
- Lindgren, David, et al.
(author)
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Integrated genomic and gene expression profiling identifies two major genomic circuits in urothelial carcinoma.
- 2012
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In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:6
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Journal article (peer-reviewed)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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| 50. |
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