Impact of E-Cadherin and ß-Catenin as Prognostic Factor in Renal Cell Carcinoma with Tumor Thrombus of the Vena Cava.

PURPOSE: Renal cell carcinoma (RCC) forming tumor thrombus (TT) of vena cava (VC) is characterized by poor prognosis. Nevertheless, the outcome of patients after radical surgery varies. To date only limited data concerning prognostic biomarkers in this RCC subgroup are available. METHODS: Out of 159 patients with pT3b/c RCC, 95 patients without synchronous distant metastases at time of diagnosis were included in the study cohort. After immunohistochemical (IHC) evaluation of E-cadherin and ß-Catenin expression, association with clinical, histopathological and survival was assessed by univariate analysis, multivariate analysis, and Kaplan-Meier-analysis. Cancer-specific survival (CSS) rates and overall survival (OS) rates were estimated using Kaplan-Meier analysis and compared using Log rank test. RESULTS: We found a significant correlation between E-cadherin overexpression and initial lymph node metastasis (ρ = 0.300, p = 0.003), positive surgical margins (ρ = 0.210, p = 0.043), and the development of distant metastases (ρ = 0.258, p = 0.012). Furthermore, we observed a significant correlation of ß-Catenin overexpression with higher tumor stage pT3c (ρ = 0.230, p = 0.028) and initial lymph node metastases (ρ = 0.236, p = 0.025). Survival analysis revealed a statistically significant association of both E-cadherin and ß-Catenin overexpression with worse CSS (p < 0.001 and p = 0.007, respectively) and OS (p < 0.001 and p = 0.041, respectively). Multivariate analysis revealed initial lymph node metastasis as the only predictive factor for worse OS (HR 4.54, 95% CI 2.30-8.93; p < 0.001). E-Cadherin and ß-Catenin expression failed to be significant in multivariable analysis for OS and CSS. CONCLUSIONS: In a large series of RCC with TT of VC high IHC expression of E-cadherin and ß-Catenin was associated with initial lymph node metastasis and with both worse OS and worse CSS. This might help to identify patients at risk for recurrence who might benefit from adjuvant therapy or stricter follow-up.

Strong Expression of Cancertestis Antigens CTAG1B and MAGEA3 Is Correlated with Unfavourable Histopathological Features and MAGEA3 Is Associated with Worse Progression-Free Survival in Urothelial Bladder Cancer.

BACKGROUND: Cancer/testis antigens (CTA) are expressed in urothelial bladder cancer (UBC). Their therapeutical and prognostic relevance remains unclear. We studied the correlation of MAGEA3 and CTAG1B with histopathological factors in UBC and their prognostic value. METHODS: Retrospective analysis of 93 patients who underwent treatment for UBC was conducted. Besides clinical and histopathological parameters, the expression of MAGEA3 and CTAG1B was assessed by immunohistochemistry. RESULTS: Median follow-up was 75 months. Fifteen per cent of patients showed strong positive reaction to MAGEA3 staining. These tumours were statistically and significantly more often correlated with unfavourable World Health Organization (WHO) grading (G1: 0%, G2: 10.3%, G3: 23.4%, p = 0.048; low grade 0%, high grade 18.4%, p = 0.046 respectively). Correlation of CTAG1B with WHO grading was impressive with strong expression in no G1, 31.1% of G2 and 51.1% of G3 tumours (low grade 0%, high grade 43.4%, p = 0.001, respectively). Concomitant carcinoma in situ (Cis) was associated with strong CTAG1B expression (54.2% in concomitant Cis vs. 29% without concomitant Cis, p = 0.026). Kaplan-Meier analysis revealed statistically and significantly worse 5 years progression-free survival (PFS) associated with a strong expression of MAGEA3 (59 vs. 84%, p = 0.032). CONCLUSIONS: Strong CTA expression was correlated with unfavourable histopathological features. A strong expression of MAGEA3 was statistically and significantly associated with worse PFS across all stages of UBC.

Improved prediction of nephron-sparing surgery versus radical nephrectomy by the optimized R.E.N.A.L. Score in patients undergoing surgery for renal masses.

BACKGROUND: One major objective of currently available morphometric scores (MS) for renal masses, i.e., R.E.N.A.L., PADUA classification, Centrality-Index, is the prediction of type of surgery (nephron-sparin surgery [NSS] or radical nephrectomy [RN]). METHODS: Based on a prospective study protocol, various MS were assigned and calculated for 108 patients undergoing surgical treatment for renal masses at a single academic center. MS calculation was based on preoperative computed-tomography or magnet-resonance-imaging and performed by two independent readers blinded for surgical approach and outcome. Multivariable logistic-regression- and ROC-analyses were performed to assess the predictive value of various MS for surgical approach and the correlation of clinical parameters with nephrectomy type. Furthermore, the association with perioperative outcome parameters was evaluated. RESULTS: None of the tested MS was significantly superior to tumor size alone (area under the curve [AUC]=0.82) in predicting RN, with Centrality-Index showing the best association (AUC=0.88). Based on these findings, a simplified and optimized R.E.N.A.L. Score (optR.E.N.A.L.) was developed with different weightings of included parameters, which did not only show a significantly enhanced association with surgery type (AUC=0.93) than tumor size, but also outperformed all 1st and 2nd generation MS tested in the study cohort. Besides a modest correlation with postoperative change in renal function, no association with perioperative outcome variables was found for all MS including optR.E.N.A.L. CONCLUSIONS: optR.E.N.A.L. represents a promising improvement of the preexisting R.E.N.A.L. Score with higher predictive ability for nephrectomy type than established MS and may serve as a benchmarking tool for nephrectomy assessment and comparison of surgical strategies.

Holmium Laser Enucleation of the Prostate Provides Similar Incidental Prostate Cancer Detection Rates as Open Prostatectomy: A Matched Pair Analysis.

INTRODUCTION: Whereas the excellent functional outcomes after Holmium laser enucleation of the prostate (HoLEP) and its equivalency to open prostatectomy (OP) have been studied in detail in the past years, the oncological equivalency has yet to be investigated. Therefore, we conducted a matched pair analysis to evaluate and compare incidental prostate cancer detection rates after HoLEP and OP. PATIENTS AND METHODS: Preoperative patient age, total prostate-specific antigen (PSA), and prostate volume were used as primary matching criteria. Descriptive statistics were used to confirm matching quality. Statistical analyses were performed using Fisher´s exact test and T-test or Mann-Whitney U-test for dichotomous and continuous variables, respectively. RESULTS: After the matching procedure, 72 out of 145 patients after HoLEP and 72 out of 477 patients after OP were included. Mean patient age (70 vs. 71 years), median prostate volume (106 vs. 107 mL), and median preoperative total PSA (4.32 vs. 4.36 ng/mL) were almost identical. The amount of removed tissue did not differ between HoLEP and OP. Incidental prostate cancer detection rate was similar with 9.7% after HoLEP and 8.3% after OP (p = 1.000). CONCLUSION: This first matched pair analysis shows that HoLEP does not have a disadvantage regarding cancer detection rate during desobstructive surgery for large prostates.

HoLEP provides a higher prostate cancer detection rate compared to bipolar TURP: a matched-pair analysis.

PURPOSE: Holmium laser enucleation of the prostate (HoLEP) has become a popular alternative to TURP for desobstructive prostate surgery. The prevalence of incidental prostate cancer (iPCa) during surgery varies depending on many preoperative factors. To evaluate whether the surgical procedure itself (HoLEP vs. TURP) influences iPCa detection, we performed a case-by-case matched-pair analysis. METHODS: Preoperative patient age, total PSA, and prostate volume were used as matching criteria. Descriptive statistics were used to confirm matching quality. Parameters were analyzed by Fisher's exact test and T test or Mann-Whitney U test for dichotomous and continuous variables, respectively. Uni- and multivariate logistic regression analyses were performed to identify predictors for iPCa detection. RESULTS: 60 out of 136 patients after HoLEP and 60 out of 1220 patients after bipolar TURP (bTURP) could be included. Mean patient age was 71.5 and 70.3 years in the HoLEP and bTURP group, respectively. Median preoperative total PSA was 4.42 ng/ml for HoLEP and 4.33 ng/ml for bTURP patients. Median preoperative prostate volume was 75.0 cc in both groups. Mean percentage of tissue removed by HoLEP and bTURP was 63.5 and 49.5% (p < 0.001), respectively. IPCa was found in 23.3% of HoLEP specimens compared to 8.3% in bTURP (p = 0.043). PSA density was the only independent predictor for iPCa detection. CONCLUSIONS: In this first matched-pair analysis, HoLEP provides a significantly higher iPCa detection rate than bTURP. This might be a result of a more efficient tissue removal during HoLEP. PSA density was the only independent risk factor for iPCa.

Infiltrative lamina propria invasion pattern as an independent predictor for cancer-specific and overall survival of instillation treatment-naïve stage T1 high-grade urothelial bladder cancer.

OBJECTIVES: To investigate established prognostic factors and relatively new histopathological tumor characteristics including metric substage and lamina propria invasion patterns in a large series of T1 high-grade non-muscle-invasive bladder cancer. METHODS: Between 1989 and 2012, 322 patients with initial stage T1 high-grade bladder cancer underwent transurethral resection, followed by re-transurethral resection and a conservative approach with follow-up regime alone or instillation treatment. Transurethral resection specimens were reassessed by two experienced urological pathologists for tumor grade according to the World Health Organization 1973 classification, metric T1 substage, lamina propria invasion pattern and associated carcinoma in situ. The median follow-up period was 42 months (interquartile range 25-72 months). In addition to Kaplan-Meier analyses, uni- and multivariable Cox regression analyses were used to compare progression-free survival, cancer-specific survival and overall survival for the studied parameters comparing two subcohorts. RESULTS: While in patients after instillation treatment no examined feature was shown as an independent predictor for prognosis, there were predictive histopathological features in multivariable Cox regression analyses in instillation treatment-naïve patients: associated carcinoma in situ (hazard ratio 2.278, 95% confidence interval 1.119-4.634, P = 0.023) and World Health Organization 1973 grade 3 (hazard ratio 2.950, 95% confidence interval 1.021-8.536, P = 0.046) for worse progression-free survival, infiltrative lamina propria tumor pattern for worse cancer-specific survival (hazard ratio 2.369, 95% confidence interval 1.034-5.429, P = 0.042) and overall survival (hazard ratio 1.049, 95% confidence interval 1.024-1.075, P = 0.001). CONCLUSIONS: The results of the present T1 high-grade bladder cancer series suggest that lamina propria invasion pattern is a promising parameter to predict the prognosis of T1 high-grade bladder cancer in an instillation treatment-naïve subcohort. Prospective multicenter evaluations are warranted. The need for instillation treatment in T1 high-grade bladder cancer is clearly demanded.

Increased Proliferation as Independent Predictor of Disease Recurrence in Initial Stage pTa Urothelial Bladder Cancer.

OBJECTIVES: To investigate the predictive impact of the proliferation biomarker Ki-67 on the clinical course of patients with initial stage pTa urothelial carcinoma of the bladder (UCB). METHODS: We retrospectively analyzed all patients treated by transurethral resection of bladder tumors (TUR-B) for UCB between 1992-2004 in a single-center. Disease recurrence (≥pTa UCB) and absent tumor in histopathology, assessed by TUR-B with a non-malignant result for endoscopic suspect bladder lesion displayed endpoints. Immunohistochemical (IHC) analysis of formalin-fixed and paraffin-embedded tissue blocks was performed with an immunostainer using a primary antibody for Ki-67. Semiquantitative evaluation of Ki-67 was performed by three reviewers. Increased proliferation was defined with a cut-off value of ≥50%. Uni- and multivariable binary regression analyses were applied to address prediction of disease recurrence. RESULTS: 215 patients (84% male, median age 69 years at first diagnosis) were evaluable and included to the study. 89 patients stayed disease-free (41%), 126 patients showed recurrence (59%). Recurrence rates of patients with Ki-67 expression <10%, 10-24%, 25-49% and ≥50% were 14.8% vs. 30.8% vs. 63.9% and 80.7%, respectively (p < 0.001). In Kaplan-Meier analysis patients with increased proliferation ≥50% showed a statistically significant worse 10-year recurrence-free survival (19% vs. 57%, p < 0.001). Multivariable regression analysis revealed instillation treatment (p = 0.001) and high proliferation of Ki-67 (p < 0.001) to be independent predictors of recurrence in stage pTa UCB. CONCLUSIONS: High proliferation with Ki-67 expression ≥50% was strongly associated with worse recurrence-free survival in patients with initial stage pTa UCB. Stage pTa UCB patients with increased Ki-67 expression should undergo a strictly follow-up regime comparable to stage pT1 bladder carcinoma, while at least patients with Ki-67 expression <10% might be feasible for more liberate follow-up regime after evaluation of our data in randomized, prospective and multicenter studies.

[Clinical and pathological prognostic factors for the long-term survival of patients with pT1 renal cell carcinoma]. / Klinische und pathologische Prognosefaktoren für das Langzeitüberleben von Patienten mit pT1 Nierenzellkarzinom.

Introduction The incidence of renal cell carcinoma (RCC) has been increasing over the past few decades. Simultaneously, due to improved imaging, small renal masses at stage pT1 have been diagnosed more frequently. However, it is known that even small RCCs may recur and metastasize at a late point of time. This study aimed to identify easy-to-assess clinical and histopathological prognostic markers for long-term survival. Patients/Methods We performed a retrospective analysis of patients who underwent surgical treatment of a pT1 RCC in a single centre between 1993 and 2007. The prognostic impact of clinical and histopathological parameters was investigated regarding recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). Univariate Kaplan-Meier analysis and multivariate Cox regression analysis were performed using SPSS 23. Results Overall, 571 patients were included with a median follow-up of 111 months. Univariate analysis revealed that higher grading (p = 0.031) and stage pT1b (p < 0.001) were statistically significantly associated with worse RFS. Likewise, stage pT1b (p = 0.001) and grading G2/3 (p = 0.019) were significantly associated with shorter CSS. Multivariate analysis revealed that stage pT1b was the only predictor for reduced RFS (p = 0.001) and CSS (p = 0.009). Total nephrectomy (p = 0.024), and diabetes (p < 0.001) were significantly associated with reduced OS. Multivariate analysis revealed that multifocal tumours (p = 0.041) and diabetes (p < 0.001) were the best predictive factors for OS.  Conclusion The identified prognostic parameters may help to provide a risk-adapted after follow-up for patients with small renal tumours.

WHO 1973 grade 3 and infiltrative growth pattern proved, aberrant E-cadherin expression tends to be of predictive value for progression in a series of stage T1 high-grade bladder cancer after organ-sparing approach.

PURPOSE: Stage pT1 urothelial bladder cancer (UBC) is characterized as a challenging subentity of urothelial carcinoma with an unforeseeable clinical course. In addition to more or less established clinical and histopathological features, we evaluated the role of epithelial-mesenchymal transition (EMT) marker E-cadherin, shown to be of prognostic value in muscle-invasive disease, regarding the prognosis of stage pT1 high-grade (hg) UBC. METHODS: Tissue of 226 stage pT1 hg UBC patients from transurethral resection could be immunostained for E-cadherin. Kaplan-Meier analysis and univariate and multivariate Cox regression analyses regarding progression-free (PFS) and cancer-specific survival (CSS) were performed. RESULTS: Aberrant expression of E-cadherin was recognized in 74% of patients. Kaplan-Meier analysis showed that aberrant E-cadherin expression was associated with worse 10-year PFS (62 vs. 90%, p = 0.045). In univariate analysis, aberrant E-cadherin staining, associated carcinoma in situ, grading 3 after WHO classification 1973 and infiltrative growth pattern at the invasion front were the statistically significant predictive factors for worse PFS, only infiltrative growth pattern for CSS. With regard to progression, grading 3 after WHO classification of 1973 (HR 6.49; CI 1.54-27.28, p = 0.011) and infiltrative tumor invasion pattern (HR 2.06; CI 1.10-3.86, p = 0.024) revealed as independent factors for PFS, and there was a trend also for E-cadherin expression (HR 0.45; CI 0.19-1.06; p = 0.068). Regarding CSS, infiltrative tumor growth pattern (HR 3.79; CI 1.67-8.60, p = 0.001) was the only statistically significantly independent predictive factor in multivariate Cox regression analysis. CONCLUSIONS: Beside invasion growth pattern and WHO grading 1973 that achieved to be independent prognostic factors, there was a trend for the parameter E-cadherin expression to be of predictive value for PFS in stage pT1 hg urothelial bladder carcinoma after organ-sparing approach. Further studies on genetic level are warranted to define the distinct role of EMT in early-invasive UBC.

Maintenance monotherapy with Gemcitabine following cisplatin-based primary combination chemotherapy in surgically treated advanced urothelial carcinoma: A matched-pair single institution analysis.

The role of maintenance therapy with Gemcitabine (GEM) following cisplatin-based combination chemotherapy (CBCC) in patients with surgically treated advanced urothelial carcinoma (UC) remains to be fully elucidated. In the present case control study, a retrospective analysis was performed to evaluate the role of GEM monotherapy following surgical intervention for advanced UC. Between 1999 and 2013, 38 patients were identified with surgically treated advanced UC after having completed CBCC, who were additionally treated quarterly with two consecutive GEM (1,250 mg/m2) infusions as maintenance therapy. This collective was matched by propensity score matching to a control collective (n=38) that received primary CBCC alone, and the overall survival (OS), cancer-specific survival (CSS) and progression-free survival (PFS) rates were determined for the two collectives using Kaplan-Meier estimates and the log-rank test. Regression analysis was performed using the Cox proportional hazards model. The median follow-up time was 37 months (interquartile range: 9-148). Interestingly, patients treated with GEM following primary chemotherapy had a significantly improved outcome with respect to the 5-year OS (46.2 vs. 26.4%, P=0.0314) and 5-year CSS (61.3 vs. 33.4%, P=0.0386) rates. Notably, the 5-year PFS rate did not differ between the two groups (10.3 vs. 16.1%, P=0.134). It is proposed that additional GEM maintenance monotherapy is able to improve survival rates following primary CBCC in surgically treated patients with advanced UC, suggesting a possible treatment option for patients with, e.g., unclear disease status, or those who would require an active maintenance therapy in the future. Prospective studies should further determine the impact of GEM monotherapy with respect to PFS rates in groups comprising larger numbers of patients.

Fractalkine activates a signal transduction pathway similar to P2Y12 and is associated with impaired clopidogrel responsiveness.

OBJECTIVE: Fractalkine (FKN) activates a G(αi) protein-coupled signaling pathway similar to the one activated by ADP via P2Y(12), which is the drug target of clopidogrel. FKN levels are increased under several disease conditions associated with impaired clopidogrel responsiveness. METHODS AND RESULTS: Blood samples were obtained from healthy volunteers and from 40 patients under chronic clopidogrel treatment. FKN reduced prostaglandin E1-induced vasodilator-stimulated phosphoprotein phosphorylation by ≈ 25% (P<0.01) at least partially mimicking the effect of ADP via P2Y(12). In vitro, FKN increased platelet reactivity index in clopidogrel-treated patients indicating potential activation of downstream targets of P2Y(12). When stratifying patients by their FKN levels, patients within the highest quartile of FKN (2042 ± 25 pg/mL) had the weakest response to clopidogrel (platelet reactivity index, 68 ± 4%), and patients within the lowest quartile (479 ± 50 pg/mL) had the strongest response (platelet reactivity index, 48 ± 7%; P=0.0106). FKN by itself induced phosphoinositide 3-kinase activation leading to Akt phosphorylation at Ser(473) (P<0.01 versus basal). CONCLUSIONS: In addition to desensitizing platelets to prostaglandin E1 via G(αi), FKN induces phosphoinositide 3-kinase-dependent Akt phosphorylation via a G(ßγ) protein similar to ADP signaling through P2Y(12). FKN increased the platelet ADP response in clopidogrel-treated patients. Once released from an atherosclerotic lesion, this mechanism could contribute locally to impaired clopidogrel responsiveness at the vulnerable plaque.