Background: Tumour hypoxia, which is frequent in many cancer types, is associated with treatment resistance and poor prognosis. The role of hypoxia in surgically treated bladder cancer (BC) is not well described. We studied the role of hypoxia in two independent series of urothelial bladder cancers treated with radical cystectomy. Methods: 279 patients from the University Hospital Network (UHN), Toronto, Canada, and Turku University, Finland were studied. Hypoxia biomarkers (HIF1-α, CAIX, GLUT-1) and proliferation marker Ki-67 were analyzed with immunohistochemistry using defined tissue microarrays. Kaplan-Meier methods and Cox proportional hazards regression models were used to investigate prognostic role of the factors. Results: In univariate analyses, strong GLUT-1 positivity and a high Ki-67 index were associated with poor survival. In multivariate model containing clinical prognostic variables, GLUT-1 was an independent prognostic factor associated with worse disease-specific survival (HR 2.9, 95% CI 0.7–12.6, Wald p = 0.15 in the Toronto cohort and HR 3.2, 95% CI 1.3–7.5, Wald p = 0.0085 in the Turku cohort). Conclusion: GLUT-1 is frequently upregulated and is an independent prognostic factor in surgically treated bladder cancer. Further studies are needed to evaluate the potential role of hypoxia-based and targeted therapies in hypoxic bladder tumours.

Background: Benefits of adjuvant chemotherapy (AC) and extent of pelvic lymph node dissection (PLND) in radical cystectomy (RC) are debated. Results from randomized trials are still expected. Objective: To analyze the effects of AC and PLND in two academic centers with opposite policies regarding their use. Methods: 581 bladder cancer patients who underwent RC without neoadjuvant chemotherapy, from Toronto (University Health Network), Canada, and Turku University Hospital, Finland were included. Disease specific survival (DSS) and failure patterns were assessed. Results: Centers differed in PLND rate (93% and 36% in Toronto and Turku respectively, p <  0.001), PLND extent (≥10 removed nodes, 58% vs. 8%, p <  0.001) and AC rate (21% vs. 2%, p <  0.001). Survival between centers among pT≤1 or pT4 patients was similar. pT3 patients in Toronto had an improved 10 year DSS (43% vs. 22%, p = 0.025). Distant failures were less common after AC (HR 0.56, 95%  CI 0.33-0.98, p <  0.042). In node positive (N+) patients, mortality was significantly higher in Turku (HR 2.19, 95%  CI 1.44-3.34, p <  0.001) and lower in patients receiving AC (HR 0.60, 95%  CI 0.37-0.99, p = 0.044). 41% DSS at 10 years was observed in N+ Toronto patients. Limitations included the non-randomized retrospective design and absence of propensity score analysis. Conclusion: Combining AC and PLND to RC is associated with improved survival in pT3 and N+ patients. PLND did not affect survival independently but helps in selecting patients for AC. Our data adds to the growing body of evidence supporting the usefulness of AC in addition to PLND in high risk patients operated by cystectomy.

OBJECTIVE:Prostate-specific antigen (PSA) is an important tool in the follow-up of prostate cancer after radical prostatectomy (RP). However, the relevance of ultrasensitive PSA (uPSA) after RP is not well defined. The aim of this study was to investigate the value of uPSA in follow-up after RP and to determine whether ultrasensitive PSA doubling time (uDT) correlates with traditional PSA doubling time (tDT). PATIENTS AND METHODS:In total, 604 consecutive patients undergoing open RP and pelvic lymphadenectomy between 2004 and 2008 (minimum 5y of follow-up) were studied. To evaluate the postsurgical uPSA level, scatter plot statistics were used. To correlate uDT and tDT in patients with a biochemical recurrence (PSA ≥0.2ng/ml), at least 2 uPSA and 2 PSA measurements without salvage treatment were required and a weighted Cohen kappa statistic and receiver operating characteristic curve were used to test agreement across the categories. RESULTS:There were 229 patients without biochemical recurrence who did not have 3 rising PSA values after nadir within ultrasensitive area. Their highest uPSA value was between 0.003 and 0.1ng/ml. In 97.4% of patients, the highest uPSA value was less than 0.03ng/ml, and in 89% of these patients, the values were less than 0.02ng/ml. The median uDT and tDT were 10.2 and 11.4 months, respectively. The weighted Cohen kappa statistic between these 2 groups was 0.30 (95% CI:-0.09 to 0.50), demonstrating a poor agreement of PSA doubling time across categories. The predictive capability of uDT was tested with tDT <9 months. A receiver operating characteristic curve area under the curve value was 0.737 (95% CI:-0.577 to 0.897) demonstrating a fair agreement between the groups. CONCLUSIONS:uPSA values>0.03ng/ml seems to be valid and can be used in a clinical setting. There was a poor to fair agreement between tDT and uDT. The accuracy of uDT improves when it approaches the traditional PSA threshold of 0.1ng/ml. Also according to our results, there is no prognostic benefit of uDT calculation.

You have accessJournal of UrologyProstate Cancer: Markers I1 Apr 2014MP74-07 USE OF ULTRASENTIVE PSA DOUBLING TIME TO ESTIMATE PROGRESSION RISK OF PROSTATE CANCER AFTER RADICAL PROSTATECTOMY Heikki Seikkula, Samu Kurki, Kari Syvänen, Peter Boström, and Matti Laato Heikki SeikkulaHeikki Seikkula More articles by this author , Samu KurkiSamu Kurki More articles by this author , Kari SyvänenKari Syvänen More articles by this author , Peter BoströmPeter Boström More articles by this author , and Matti LaatoMatti Laato More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.2340AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Prostate specific antigen (PSA) is the single most important tool in follow up of prostate cancer (PC) after radical prostatectomy (RP). Biochemical relapse (BCR) is defined by two consecutive PSA values of > 0.2 ng/mL. The role of ultrasensitive PSA(uPSA) in follow-up after RP is not well defined. The objective of this study was to investigate two questions: 1) Is there a definitive value for biochemical relapse (BCR) in ultrasensitive areas, and 2) is uPSA doubling time (DT) in ultrasensitive area (uDT) a useful prognostic tool and whether it correlates with doubling time in traditional PSA (tDT) area. METHODS A total of 604 patients underwent open RPs in Turku university hospital during 2004-2008. After exclusion of patients with neoadjuvant or adjuvant androgen deprivation therapy, 548 patients were available for analysis. Median age was 61.8 years ( ± 5.8). Of these men 272 (50%) had Gleason score 6 or less, 227 (41%) Gleason 7 and 49 (9%) 8 or more. Positive margin was found in 207 (38%) patient. Local lymph nodes were positive in two men. Median follow up time was 5.6 years (±2.4). During follow-up 71 of 548 (13%) patient had BCR and 18 men received salvage radiation before psa level 0.2 The total amount of psa failures was 89 (16.2%). To analyze upper limit of uPSA in patients without BCR patients with at least two years of follow up and no tPSA relapse were analyzed. We used a Scatterplot-table to evaluate biological reflection of uPSA. To answer our second question we analyzed every man with BCR (PSA ≥0.2ng/ml). Patients with at least two uPSA and two tPSA measurements were included to calculate uDT and tDT. We excluded subjects with salvage treatment. 47 patients met these criteria. uDT was calculated using all nonzero values under 0.2 ng/ml. These two DTs were compared. To compare uDT and tDT a weighted Cohen`s kappa statistic was used to test agreement across the categories. RESULTS There were 229 patients without BCR who had three rising PSA values after nadir. Their highest PSA value was between 0.003-0.1 ng/ml. In 97.4% of patients highest PSA value was under 0.03 and in 89% under 0.02. The median DT in uPSA was 10.2 months and tPSA11.4 months. The weighted Cohen's kappa statistic between these two groups was 0.30. This demonstrates a poor agreement of PSADT across categories. CONCLUSIONS uPSA values under 0.03 should be considered non-significant and may be normal variation without risk of BCR. In current study a poor agreement between tDT and uDT was found. Accuracy of uDT improves when it is nearing threshold 0.1 ng/ml. More studies are needed to define the optimal use of uPSA. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e858 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Heikki Seikkula More articles by this author Samu Kurki More articles by this author Kari Syvänen More articles by this author Peter Boström More articles by this author Matti Laato More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer was introduced several years ago. Despite the evidence supporting its use in clinical practice, only a minority of patients who undergo radical cystectomy receive preoperative chemotherapy. In addition, recommendations and methods to detect patients who would benefit the most from NAC are still unclear. The European Association of Urology (EAU) guidelines panel on muscle-invasive and metastatic bladder cancer recommends the use of cisplatin-based NAC for T2-T4a, cN0 M0 bladder cancer if the patient has a performance status ≥2 and if the renal function is not impaired, but the American Urological Association, for example, does not have any guideline recommendations on this topic at all. In this review we describe the current literature supporting NAC in association with radical cystectomy in muscle-invasive urothelial carcinoma of the bladder. Evidence acquisition was made searching the Medline database for original articles published before 1st February 2014, with search terms: “neoadjuvant chemotherapy”, “radical cystectomy”, and “invasive bladder cancer”.

Clinical staging and histological grading after surgery have been the “gold standard” for predicting prognosis and planning for adjuvant therapy of colorectal cancer (CRC). With the recent development of molecular markers, it has become possible to characterize tumors at the molecular level. This is important for stage II and III CRCs, in which clinicopathological features do not accurately predict heterogeneity, e.g., in their tumor response to adjuvant therapy. In the present study, archival samples from 141 patients with stage I, II, III, or IV CRC treated during 1981–1990 at Turku University Hospital (Finland) were used (as microarray blocks) to analyze MUC2 expression by immunohistochemistry. Altogether, 49.7 % of all tumors were positive for MUC2. There was no significant correlation between MUC2 expression and age ( P < 0.499), tumor invasion ( P < 0.127), tumor staging ( P < 0.470), histological grade ( P < 0.706), lymph node involvement ( P < 0.854), or tumor metastasis ( P < 0.586). However, loss of MUC2 expression was significantly associated with disease recurrence ( P < 0.031), tumor localization ( P < 0.048), and with borderline significance with gender ( P < 0.085). In univariate (Kaplan–Meier) survival analysis, positive MUC2 significantly predicted longer disease-free survival (DFS) and disease-specific survival (DSS) as well. However, in multivariate (Cox) survival analysis, MUC2 lost its power as an independent predictor of DFS and DSS. Our results implicate the value of MUC2 expression in predicting disease recurrence and long-term survival in CRC.

Decorin, a multifunctional small leucine-rich extracellular matrix proteoglycan, has been shown to possess potent antitumour activity. However, there is some uncertainty whether different cancer cells express decorin in addition to non-malignant stromal cells. In this study we clarified decorin expression by human bladder cancer cells both in vivo and in vitro. In addition, the effect of adenovirus-mediated decorin expression on human bladder cancer cells in vitro was examined. We first demonstrated using the publicly available GeneSapiens databank that decorin gene expression is present in both normal and malignant human bladder tissues. However, when we applied in situ hybridization with digoxigenin-labeled RNA probes for decorin on human bladder carcinoma tissue samples derived from a large radical cystectomy patient cohort (n = 199), we unambiguously demonstrated that invasive and non-invasive bladder carcinoma cells completely lack decorin mRNA. The cancer cells were also negative for decorin immunoreactivity. Instead, decorin expression was localized solely to original non-malignant stromal areas of bladder tissue. In accordance with the aforementioned results, human bladder cancer cells in vitro were also negative for decorin expression as shown by RT-qPCR analyses. The lack of decorin expression by bladder cancer cells was shown not to be due to the methylation of the proximal promoter region of the decorin gene. When bladder cancer cells were transfected with a decorin adenoviral vector, their proliferation was significantly decreased. In conclusion, we have shown that human bladder cancer cells are totally devoid of decorin expression. We have also shown that adenovirus-mediated decorin gene transduction of human bladder cancer cell lines markedly inhibits their proliferation. Thus, decorin gene delivery offers new potential therapeutic tools in urothelial malignancies.

Wound healing is a highly regulated process starting from coagulation and ending in tissue remodeling. The end result varies from perfectly restored tissue, such as in early fetal skin, to scars in adults. The balanced repair process is frequently disturbed by local or systemic factors, like infections and diabetes. A rapid increase of hyaluronan is an inherent feature of wounds and is associated with tissue swelling, epithelial and mesenchymal cell migration and proliferation, and induction of cytokine signaling. Hyaluronan extending from cell surface into structures called cables can trap leukocytes and platelets and change their functions. All these features of hyaluronan modulate inflammation. The present data show that mannose, a recently described inhibitor of hyaluronan synthesis, inhibits dermal fibroblast invasion and prevents the enhanced leukocyte binding to hyaluronan that takes place in cells treated with an inflammatory mediator interleukin-1β. Mannose also reduced hyaluronan in subcutaneous sponge granulation tissue, a model of skin wound, and suppressed its leukocyte recruitment and tissue growth. Mannose thus seems to suppress wounding-induced inflammation in skin by attenuating hyaluronan synthesis.

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The reported discordance between staging on transurethral bladder resection and on radical cystectomy pathology in the literature ranges from 20 to 80%.Correct staging in bladder cancer has direct implications for its management. The upstaging from organ‐confined (OC) to non‐organ‐confined (nOC) disease has been reported in 40% of cases. Lymphovascular invasion (LVI) is a factor known to be associated with poor clinical outcome. Pathological upstaging was observed in our cohort in 40% of cases and most cases (80%) were upstaged from OC to nOC disease. During the study period the frequency of upstaging observed increased. We found LVI (hazard ratio [HR]= 5.07, 95% CI = 3.0–8.3, P < 0.001) and any histological variant variant (HR = 2.77, 95% CI = 1.6–4.8, P < 0.001) to be strong independent predictors of upstaging. Patients with clinical T2 bladder cancer found with upstaging at the time of radical cystectomy had a poorer outcome than patients with no upstaging. Identification of patients at high risk of upstaging at radical cystectomy is key to improving their management and outcome. OBJECTIVES To analyse the details of bladder cancer (BC) staging in a large combined radical cystectomy (RC) database from two academic centres. To study rate and time trends, as well as risk factors for upstaging, especially clinical factors associated with staging errors after RC. PATIENTS AND METHODS Characteristics of patients undergoing RC at University Health Network, Toronto, Canada (1992–2010) and University of Turku, Turku, Finland (1986–2005) were analysed. RESULTS Among 602 patients undergoing RC, 306 (51%) had a discordance in clinical and pathological stages. Upstaging occurred in 240 (40%) patients and 192 (32%) patients were upstaged from organ‐confined (OC) to non‐organ‐confined (nOC) disease. During the study period, upstaging became more common in both centres. In multivariate analyses, T2 disease at initial presentation ( P = 0.001, odds ratio [OR]= 2.62, 95% confidence interval [CI]: 1.44–4.77), high grade disease ( P = 0.01, OR = 2.85, 95% CI: 1.21–6.7), lymphovascular invasion (LVI) ( P < 0.001, OR = 5.17, 95% CI: 3.48–7.68), female gender ( P = 0.038, OR = 0.6, 95% CI: 0.38–0.97, and histological variants ( P < 0.001, OR = 2.77, 95% CI: 1.6–4.8) were associated with a risk of upstaging from OC to nOC disease. Upstaged patients had worse survival rates than patients with correct staging. This was especially significant among patients with carcinoma invading bladder muscle before undergoing RC (16% vs 46% 10‐year disease‐specific mortality, P < 0.001). CONCLUSIONS Upstaging is a common problem and unfortunately no improvements have been observed during the last two decades. LVI and the presence of histological variants are strong predictors of upstaging at the time of RC. Pathologists should be encouraged to report LVI and any histological variant at the time of TURBT.

Elzagheid A, Buhmeida A, Laato M, El-Faitori O, Syrjänen K, Collan Y, Pyrhönen S. Loss of E-cadherin expression predicts disease recurrence and shorter survival in colorectal carcinoma. APMIS 2012; 120: 539–48. The traditional staging system is currently inadequate for identifying those patients with colorectal carcinoma (CRC) who carry a high risk for poor outcome. In this study, the expression of E-cadherin was evaluated in CRC to determine its correlation with clinico-pathological variables, and association with disease outcome in patients with long-term follow-up. The present series consisted of tissue samples obtained from 230 patients with stage I, II, III, or IV CRC treated during 1981–1990 at Turku University Hospital. Archival paraffin-embedded samples were used to build up tissue microarray blocks, and E-cadherin expression was assessed by immunohistochemistry using an automated staining system. Different grading systems were tested for expression of E-cadherin. Fifty-nine percent of all tumors were positive for E-Cadherin. There was no significant correlation between E-cadherin expression and gender (p < 0.83), localization (p < 0.45), tumor invasion (p < 0.32), or histologic grade (p < 0.41). However, loss of E-cadherin expression was significantly associated with older age (p < 0.03) and lymph node involvement (p < 0.02), and with borderline significance with advanced stage (p < 0.09) and tumor metastasis (p < 0.09). In univariate (Kaplan–Meier) survival analysis, positive E-cadherin significantly (p = 0.009) predicted longer disease-free survival (DFS), and the same was true with disease-specific survival (DSS) as well (p = 0.007). In multivariate (Cox) survival analysis, E-cadherin retained its significance as independent predictor of DFS (HR = 1.56; 95% CI 1.01–2.42, p = 0.043), but not DSS. A sub-group analysis revealed that E-cadherin expression also predicts DFS (p < 0.01) and DSS (p < 0.04) in stage II CRC. Our results implicate the usefulness of E-cadherin expression in predicting disease recurrence and long-term survival in CRC.

287 Background: Level 1 evidence is weak for adjuvant chemotherapy (AC) after cystectomy, but surveys indicate physicians refer patients for AC more frequently than for neoadjuvant chemotherapy (NC). The exact benefit of an extended pelvic lymph node dissection (ePLND) remains debated. We addressed the issue of AC and ePLND analyzing two academic centers RC databases with opposite approaches, one using ePLND and AC, the other performing a limited lymph node dissection and no AC. Methods: Two ethics approved RC databases including consecutive BC patients undergoing RC at the University Health Network, Canada and the University of Turku, Finland were studied. Excluding non-urothelial cases and patients receiving NC, 563 patients were available for analysis. Clinicopathological variables, rate and extent of PLND and rate of adjuvant cisplatin-based chemotherapy were analyzed using the χ2-test. Kaplan-Meier method and multivariate Cox regression analysis were used to analyze survival. Results: In Toronto, patients had more extensive PLNDs (>10 nodes removed, 58% vs. 8%, p<0.001), higher rate of nodal metastases (26% vs. 7%, p<0.001), and received more often AC (21% vs. 1%, p<0.001). Positive margin rates were similar (4% in both centers). No BC specific survival difference was demonstrated in ≤ pT2a or in pT4a tumors. There was a trend for improved survival in pT2b tumors (10y BC specific survival 65% vs. 42%, p=0.23) and a significant difference favouring the Toronto cohort in pT3a and pT3b tumors (55% vs. 31%, p=0.025; 43% vs. 28% p=0.06, respectively). In multivariate analysis, N-stage (HR 2.5, 95% CI 1.5-4.1; p<0001) and ePLND (HR 0.53, 95% CI 0.31-0.93, p=0.026) significantly affected disease specific survival. The benefit of AC did not reach significance (HR 0.61, 95% CI 0.36-1.05, p=0.072). An interaction model combining ePLND and AC was significantly related to improved outcome (HR 0.49, 95% CI 0.26-0.92, p=0.026). Conclusions: Despite not being randomized, using 2 study cohorts that received completely opposite managements in terms of ePLND and AC, our results support that ePLND and AC may offer a survival advantage in T2b and especially in T3 BC treated with RC.

INTRODUCTION AND OBJECTIVES: Cisplatin-based chemotherapy is the first-line standard treatment in metastatic bladder cancer (BC), with response rates of only 50% but significant toxicity. Clinical and pathological parameters are unable to distinguish between cisplatin sensitive and resistant BCs. Therefore, predictive markers are urgently needed to avoid unnecessary toxicity. Cisplatin-based chemotherapeutic agents exhibit their cytotoxic effect by cross-linking DNA preventing DNA-duplication for mitosis in dividing cells. This process leads ultimately to apoptosis of these cells. ERCC1 has been suggested to be involved in the elimination of cisplatin-DNA adducts decreasing efficacy of the therapy. More recently, in vitro studies in various tumors demonstrated that MMP-7 plays a causal role in the development of cisplatin resistance by inhibiting chemotherapy-induced apoptosis. However, its chemotherapy predicting value in BC has not been evaluated yet. Therefore, we assessed the predictive value of MMP-7 and ERCC1 expressions in patients with metastatic BC treated with cisplatin-based chemotherapy. METHODS: Protein expressions of ERCC1 and MMP-7 were analyzed by immunostaining in chemo-naive tumor specimens of 72 patients treated with cisplatin-based chemotherapy (GC or MVAC) because of a metastatic BC. The expression levels were correlated with the clinical follow-up data. RESULTS: High ERCC1 and MMP-7 levels were associated with significantly shorter patientsâ€TM survival (p 0.025 and p 0.026 respectively). The highest predictive significance (p 0.017) could be reached when ERCC1 and MMP-7 were combined; the median survival time was 13.6 months in cases where both ERCC1 and MMP-7 levels were low, 10.2 months if one of these marker level were high and 5.7 months when both ERCC1 and MMP-7 levels were elevated. CONCLUSIONS: Our data reveals for the first time MMP-7 as a predictive factor in BC patients treated with cisplatin-based chemotherapy. The combination of MMP-7 with ERCC1 provides the highest predictive accuracy in this patient group. These data together suggest that ERCC1 and MMP-7 may help to select patients who will not benefit from a cisplatin-based therapy. These patients might be optimal candidates for studies with new chemotherapeutic agents. Furthermore, specific inhibition of these molecular factors may help to overcome chemotherapy resistance.

The traditional staging system is currently inadequate for identifying those patients with colorectal carcinoma (CRC) who carry a high risk for poor outcome. In this study, the expression of E-cadherin was evaluated in CRC to determine its correlation with clinico-pathological variables, and association with disease outcome in patients with long-term follow-up. The present series consisted of tissue samples obtained from 230 patients with stage I, II, III, or IV CRC treated during 1981-1990 at Turku University Hospital. Archival paraffin-embedded samples were used to build up tissue microarray blocks, and E-cadherin expression was assessed by immunohistochemistry using an automated staining system. Different grading systems were tested for expression of E-cadherin. Fifty-nine percent of all tumors were positive for E-Cadherin. There was no significant correlation between E-cadherin expression and gender (p < 0.83), localization (p < 0.45), tumor invasion (p < 0.32), or histologic grade (p < 0.41). However, loss of E-cadherin expression was significantly associated with older age (p < 0.03) and lymph node involvement (p < 0.02), and with borderline significance with advanced stage (p < 0.09) and tumor metastasis (p < 0.09). In univariate (Kaplan-Meier) survival analysis, positive E-cadherin significantly (p = 0.009) predicted longer disease-free survival (DFS), and the same was true with disease-specific survival (DSS) as well (p = 0.007). In multivariate (Cox) survival analysis, E-cadherin retained its significance as independent predictor of DFS (HR = 1.56; 95% CI 1.01-2.42, p = 0.043), but not DSS. A sub-group analysis revealed that E-cadherin expression also predicts DFS (p < 0.01) and DSS (p < 0.04) in stage II CRC. Our results implicate the usefulness of E-cadherin expression in predicting disease recurrence and long-term survival in CRC.

Proteinases play a pivotal role in wound healing by regulating cell-matrix interactions and availability of bioactive molecules. The role of matrix metalloproteinase-13 (MMP-13) in granulation tissue growth was studied in subcutaneously implanted viscose cellulose sponge in MMP-13 knockout (Mmp13(-/-)) and wild type (WT) mice. The tissue samples were harvested at time points day 7, 14 and 21 and subjected to histological analysis and gene expression profiling. Granulation tissue growth was significantly reduced (42%) at day 21 in Mmp13(-/-) mice. Granulation tissue in Mmp13(-/-) mice showed delayed organization of myofibroblasts, increased microvascular density at day 14, and virtual absence of large vessels at day 21. Gene expression profiling identified differentially expressed genes in Mmp13(-/-) mouse granulation tissue involved in biological functions including inflammatory response, angiogenesis, cellular movement, cellular growth and proliferation and proteolysis. Among genes linked to angiogenesis, Adamts4 and Npy were significantly upregulated in early granulation tissue in Mmp13(-/-) mice, and a set of genes involved in leukocyte motility including Il6 were systematically downregulated at day 14. The expression of Pdgfd was downregulated in Mmp13(-/-) granulation tissue in all time points. The expression of matrix metalloproteinases Mmp2, Mmp3, Mmp9 was also significantly downregulated in granulation tissue of Mmp13(-/-) mice compared to WT mice. Mmp13(-/-) mouse skin fibroblasts displayed altered cell morphology and impaired ability to contract collagen gel and decreased production of MMP-2. These results provide evidence for an important role for MMP-13 in wound healing by coordinating cellular activities important in the growth and maturation of granulation tissue, including myofibroblast function, inflammation, angiogenesis, and proteolysis.

OBJECTIVE:To study the effect of smoking on bladder cancer presentation and outcome in a large cystectomy population.PATIENTS AND METHODS:A database including 546 patients from the University Health Network (Toronto, Canada) and Turku University Hospital (Turku, Finland) was studied. In addition to the association of smoking with clinicopathological parameters, the effect of smoking on survival was analyzed. Categorical data were analyzed by the chi-squared test and numerical data were analyzed by Student's t-test. The Kaplan-Meier method, log-rank test and a proportional hazards model were used to estimate the effect of smoking on survival.RESULTS:In total, 352 patients (64%) were smokers and 194 (36%) were non-smokers. Smokers had more frequently advanced tumours and nodal metastasis. The 10-year disease-specific survival (DSS) was 52% vs 66% for smokers and non-smokers, respectively (P = 0.039). Smokers also had significantly worse overall survival (10-year overall survival 37% vs 62%; P = 0.015). Smoking affected significant DSS among men (P = 0.012), although no effect was observed among women. In a univariate model smoking was associated with a hazard ratio (HR) of 1.4 (95% confidence interval, CI, 1.0-1.9) for bladder cancer specific mortality and 1.4 (95% CI, 1.1-1.8) for overall mortality. In a multivariate model, smoking did not impact on DSS (HR, 1.1; 95% CI, 0.8-1.6; P = 0.41). In addition to advanced stage and nodal metastasis, female sex was an independent risk factor for DSS (HR, 1.6; 95% CI, 1.1-2.3; P = 0.007).CONCLUSIONS:Smokers appear to have worse outcomes after radical cystectomy for bladder cancer; however, it does not appear to be an independent prognostic factor for survival. Smoking affected survival only among men. Women had poorer survival but smoking was not a contributing factor to this.

You have accessJournal of UrologyBladder Cancer: Invasive1 Apr 20111595 EXTENDED LYMPHADENECTOMY AND CHEMOTHERAPY OFFER SURVIVAL ADVANTAGE IN MUSCLE-INVASIVE BLADDER CANCER Peter J. Bostrom, Tuomas Mirtti, Martti Nurmi, Matti Laato, Bas W.G van Rhijn, Neil E. Fleshner, Antonio Finelli, Michael A Jewett, and Alexandre R. Zlotta Peter J. BostromPeter J. Bostrom Toronto, Canada More articles by this author , Tuomas MirttiTuomas Mirtti Helsinki, Finland More articles by this author , Martti NurmiMartti Nurmi Turku, Finland More articles by this author , Matti LaatoMatti Laato Turku, Finland More articles by this author , Bas W.G van RhijnBas W.G van Rhijn Toronto, Canada More articles by this author , Neil E. FleshnerNeil E. Fleshner Toronto, Canada More articles by this author , Antonio FinelliAntonio Finelli Toronto, Canada More articles by this author , Michael A JewettMichael A Jewett Toronto, Canada More articles by this author , and Alexandre R. ZlottaAlexandre R. Zlotta Toronto, Canada More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1645AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The role of extended pelvic lymph node dissection (ePLND) and adjuvant chemotherapy in the treatment of muscle-invasive bladder cancer (BC) remain unclear. Our large database from two centers (Turku, Finland and Toronto, Canada) offer an opportunity to study these factors, as there have been different institutional practice policies. In Turku, ePLND was not common practice and adjuvant chemotherapy was nearly never offered whereas standard of care in Toronto included ePLND and adjuvant chemotherapy when indicated. METHODS Consecutive BC patients undergoing radical cystectomy in UHN, Toronto, Canada (1992–2008) and University of Turku, Turku, Finland (1986–2005) were studied. After exclusion of non-urothelial cases and neoadjuvant treatment, 563 patients were available for analysis. Clinicopathological variables, the rate and extent of PLND and the rate of adjuvant cisplatin-based chemotherapy were analyzed using the Chi-squared-test. Kaplan-Meier method and multivariate Cox regression analysis were used to analyze survival. RESULTS In the Toronto cohort, patients were older (mean age 68 vs. 63y, p<0.001), had more extensive PLNDs (>10 nodes removed, 58% vs. 8%, p<0.001), had more nodal metastasis (26% vs. 7%, p<0.001), and adjuvant chemotherapy was administered more often (21% vs. 1%, p<0.001). Positive margin rate was similar (4% in both centers). No BC specific survival differences could be demonstrated in ≤ pT2a tumors or in pT4a/b tumors. In contrast, there was a trend for improved survival in pT2b tumors (10y BC specific survival 65% vs. 42%, p=0.23) and a significant difference favouring the Toronto cohort in pT3a and pT3b tumors (55% vs. 31%, p=0.025; 43% vs. 28% p=0.06, respectively). In multivariate analysis, pT-stage (HR 1.8, 95% CI 1.2–2.8; p<0.005), N-stage (HR 2.5, 95% CI 1.5–4.1; p<0001), and ePLND (HR 0.53, 95% CI 0.31–0.93, p=0.026) significantly affected disease specific survival. Adjuvant chemotherapy offered borderline significant benefit (HR 0.61, 95% CI 0.36–1.05, p=0.072). An interaction model combining ePLND and chemotherapy was significant when ePLND with more than 10 nodes removed and adjuvant chemotherapy were combined (HR 0.49, 95% CI 0.26–0.92, p=0.026). CONCLUSIONS With the limitations of not being a randomized study but with an unique setting as our study centers had opposite management in terms of ePLND and adjuvant chemotherapy, our results show that the combination of ePLND and adjuvant chemotherapy offer a survival advantage in muscle-invasive BCs treated with RC. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e640 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Peter J. Bostrom Toronto, Canada More articles by this author Tuomas Mirtti Helsinki, Finland More articles by this author Martti Nurmi Turku, Finland More articles by this author Matti Laato Turku, Finland More articles by this author Bas W.G van Rhijn Toronto, Canada More articles by this author Neil E. Fleshner Toronto, Canada More articles by this author Antonio Finelli Toronto, Canada More articles by this author Michael A Jewett Toronto, Canada More articles by this author Alexandre R. Zlotta Toronto, Canada More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

Background: Adhesions caused by previous operations increase operative time and the risk of peroperative complications as well as conversions. The aim of this study was to evaluate the complications and the extra operative time related to the dividing of adhesions caused by previous surgery in patients scheduled for elective colorectal surgery. Methods: In a consecutive series of patients with previous abdominal or pelvic surgery and scheduled for open or laparoscopic colorectal procedures, data on patient demography, previous operations, index operations, intraoperative complications, conversions, adhesion division time and the extra time needed for first trocar insertion were collected prospectively. Results: Data from 111 patients were collected. There were 29 open and 80 laparoscopic operations, and conversion was needed in two patients due to adhesions. The mean extra time needed to divide adhesions was 19.9 min (range 0.2-120 min) in open operations, 35.4 min (range 22.9-48 min) in converted cases and 9.5 min (range 0-67 min) in laparoscopic operations. The extra time corresponded for 12% of total operative time. The mean extra time needed to insert the first trocar was 1 min (range 0-8 min). There were two serosal lesions necessitating suturation (one in open and one in laparoscopic operation) and one inadvertent enterotomy. The extra time needed to divide adhesions was correlated with the number of previous operations. Conclusions: Adhesions caused by previous surgery increase operative time considerably. The increase correlates with the number of previous operations. The adhesiolysis is associated with certain amount of intraoperative complications.

BACKGROUND:Approximately 30% of all colorectal cancer (CRC) patients are diagnosed with stage II disease. Adjuvant therapy is not widely recommended. However, it is well established that a subgroup of patients with stage II are at high risk for recurrence within their lifetime and should be considered for adjuvant chemotherapy. The present work was designed to assess the value of group IIA phospholipase A2 (PLA2) as a predictor of disease outcome in stage II CRC patients with long-term follow-up.PATIENTS AND METHODS:The present study comprises a series of 116 patients who underwent bowel resection for stage II CRC during 1981-1990 at Turku University Hospital. Archival paraffin-embedded CRC tissue samples were used to prepare tissue microarray blocks for immunohistochemical staining with PLA2.RESULTS:Fifty-five percent of all tumors were positive for PLA2. There was no significant correlation between PLA2 expression and age, sex, depth of invasion and lymph node status. In Kaplan-Meier survival analysis, there was a significant (P = 0.010) difference in disease-free survival (DFS) between patients with negative tumors (longer DFS) and those with positive tumors. The same was true with disease-specific survival (DSS), patients with PLA2-negative tumors living significantly longer (P = 0.025). In multivariate (Cox) survival analysis, however, PLA2 was not an independent predictor of DFS or DSS. In subgroup analysis, the right-sided tumors with negative PLA2 staining had remarkably better prognosis (P = 0.010) than PLA2-positive left-sided tumors.CONCLUSIONS:Quantification of PLA2 expression seems to provide valuable prognostic information in stage II CRC, particularly in selecting the patients at high risk for recurrent disease who might benefit from adjuvant therapy.