[Interactions between radical prostatovesiculectomy and diagnosis of prostate cancer : A medical-historical inventory on the occasion of 20 years of robot-assisted treatment]. / Wechselwirkungen von radikaler Prostatovesikulektomie und Diagnostik des Prostatakarzinoms : Eine medizinhistorische Bestandsaufnahme anlässlich 20 Jahre robotisch assistierter Therapie.

The question of what came first-in this case the diagnosis of prostate cancer or its therapy-seems absurd at first glance and is reminiscent of the classic metaphor-like problem that preoccupied the Greek writer Plutarch (45-125). Today it is a matter of course that a reliable diagnosis is made before treating a disease, but this must be viewed as inconsistent in medical history. The beginnings of radical prostatectomy for the treatment of prostate cancer, like the first surgical therapies for kidney and bladder tumors, can be located in the pioneering period of organ surgery in the German Empire (1871-1918). The establishment of this procedure in its current form with larger numbers of cases is in turn thanks to the Nestor of American urology, Hugh Hampton Young, who carried out the first perineal prostatovesiculectomy, which from today's perspective can be described as complete. Although the indication has remained largely unchanged since then, this intervention has undergone extensive changes in recent decades. But how has the diagnosis of prostate cancer developed in this period? Of course, much more dynamic. While the procedure prostatovesiculectomy was already established, development of prostate cancer diagnosis began first slowly in the course of the 20th century, then more dynamically. The following article uses medical (historical) original sources to present not only the basics and further developments of the established and, at the same time, subject to constant intervention in urology, but also the essential developments in the environment of neighboring medical disciplines, for example, think of laboratory medicine, radiology, nuclear medicine or rehabilitation medicine, but especially pathology. Incidentally, it was only these developments that created the basis for the correct setting of indications and the identification of alternatives to radical prostatovesiculectomy.

Correlation of pretreatment clinical parameters and PSA nadir after high-intensity focused ultrasound (HIFU) for localised prostate cancer.

OBJECTIVE: To determine which pretreatment clinical parameters were predictive of a low prostate-specific antigen (PSA) nadir following high-intensity focused ultrasound (HIFU) treatment. PATIENTS AND METHODS: Retrospective study of patients with clinically localised prostate cancer undergoing HIFU at a single centre between December 1997 and September 2009. Whole-gland treatment was applied. Patients also included if they had previously undergone transurethral resection of the prostate (TURP). TURP was also conducted simultaneously to HIFU. Biochemical failure based on Phoenix definition (PSA nadir + 2). Univariate and multivariate analysis of pretreatment clinical parameters conducted to assess those factors predictive of a PSA nadir ≤0.2 and >0.2 ng/ml. RESULTS: Mean (SD) follow-up was 6.2 (2.8) years; median (range) was 6.3 (1.1-12.2) years. Kaplan-Meier estimate of biochemical disease-free survival rate at 8 years was 83 and 48 % for patients achieving a PSA nadir of ≤0.2 and >0.2 ng/ml, respectively. Prostate volume and incidental finding of cancer were significant predictors of low PSA nadir (≤0.2 ng/ml). CONCLUSIONS: Prostate volume and incidental finding of cancer could be predictors for oncologic success of HIFU based on post-treatment PSA nadir.

Outcome of patients with pathological tumor stage T3 urothelial carcinoma of the bladder following radical cystectomy in a single-center series with 116 patients.

OBJECTIVE: Outcome prediction of pT3 urothelial carcinoma of the bladder (UCB) after radical cystectomy (RC) remains challenging. The objective of our study was to determine high-risk patients with poor survival outcome in a heterogeneous group substaged pT3 who might profit from early adjuvant chemotherapy. MATERIALS AND METHODS: We compiled clinicopathological and immunohistochemical data of E-cadherin (E-cad) expression in 116 patients with pT3 UCB after RC in our single-center series. Multivariable Cox regression models including substaged pT3 established clinicopathological features, and the expression of the predictive immunohistochemical feature E-cad was used to identify independent predictors on progression-free (PFS), cancer-specific (CSS) and overall survival (OS), respectively. RESULTS: No significant differences were found addressing clinicopathological data and substaged pT3. In multivariable Cox regression models, lymph node involvement was an independent predictor for PFS (p < 0.001), CSS (p < 0.001) and OS (p = 0.002), respectively. Lymphovascular invasion (LVI) significantly influenced PFS (p = 0.016). ASA score 3/4 independently predicted CSS (p = 0.049) and OS (p = 0.032). Neither pT3 substages nor E-cad expression were significant prognosticators for survival. CONCLUSIONS: In pT3 UCB patients with ASA 3/4, positive lymph node status and/or presence of LVI, administration of chemotherapy should be considered due to the high risk of poor oncological outcome. The immunohistochemical marker E-cad was not an independent predictor.

The Charlson comorbidity index predicts survival after disease recurrence in patients following radical cystectomy for urothelial carcinoma of the bladder.

OBJECTIVE: To identify prognostic clinical and histopathological parameters, including comorbidity indices at the time of radical cystectomy (RC), for overall survival (OS) after recurrence following RC for urothelial carcinoma of the bladder (UCB). MATERIALS AND METHODS: A retrospective multicenter study was carried out in 555 unselected consecutive patients who underwent RC with pelvic lymph node dissection for UCB from 2000 to 2010. A total of 227 patients with recurrence comprised our study group. Cox proportional hazards regression models were calculated with established variables to assess their independent influence on OS after recurrence. RESULTS: The median time from RC to recurrence and the median OS after recurrence was 10.9 and 5.4 months, respectively. Neither the time to recurrence nor the type of recurrence (systematic vs. local) was predictive of the OS. In contrast, age (hazard ratio (HR) 1.53, p = 0.011), lymph node metastasis (HR 1.56, p = 0.007), and positive surgical margins (HR 1.53, p = 0.046) significantly affected the OS after disease recurrence. In addition, the dichotomized Charlson comorbidity index (CCI; dichotomized into >2 vs. 0-2) was the only comorbidity score with an independent prediction of OS (HR 1.41, p = 0.033). We observed a significant gain in the base model's predictive accuracy, i.e. from 68.4 to 70.3% (p < 0.001), after inclusion of the dichotomized CCI. CONCLUSIONS: We present the first outcome study of comorbidity indices used as predictors of OS after disease recurrence in patients undergoing RC for UCB. The CCI at the time of RC had no significant influence on the time to recurrence but represented an independent predictor of OS after disease recurrence.

Do young patients with renal cell carcinoma feature a distinct outcome after surgery? A comparative analysis of patient age based on the multinational CORONA database.

PURPOSE: We analyzed the distinct clinicopathological features and prognosis of patients with renal cell carcinoma age 40 years or less compared to a reference group of patients 60 to 70 years old. MATERIALS AND METHODS: Overall 2,572 patients retrieved from a multicenter international database comprised of 6,234 patients with surgically treated renal cell carcinoma were included in this retrospective study. Clinical and histopathological features of 297 patients 40 years old or younger (4.8%) were compared to those of 2,275 patients (36.5%) 60 to 70 years old, who served as the reference group. Median followup was 59 months. The impact of young age and further parameters on disease specific mortality and all cause mortality was evaluated by multivariate Cox proportional hazards regression analyses. RESULTS: Young patients more frequently underwent nephron sparing surgery (27% vs 20%, p = 0.008) and regional lymph node dissection compared to older patients (38% vs 32%, p = 0.025). Organ confined tumor stage (81% vs 70%, p <0.001), smaller tumor diameter (4.5 vs 4.7 cm, p = 0.014) and chromophobe subtype (10% vs 4%, p <0.001) were significantly more frequent in young patients. On multivariate analysis older patients had a higher disease specific (HR 2.21, p <0.001) and all cause mortality (HR 3.05, p <0.001). The c indices for the Cox models were 0.87 and 0.78, respectively. However, integration of the variable age group did not significantly increase the predictive accuracy of the disease specific and all cause mortality models. CONCLUSIONS: Young patients with renal cell carcinoma (40 years old or younger) have significantly different frequencies of clinical and histopathological features, and a significantly lower all cause and disease specific mortality compared to patients 60 to 70 years old.

Mdm2 SNP309 G-variant is associated with invasive growth of human urinary bladder cancer.

OBJECTIVE: Human mouse double minute 2 (Mdm2) is essential in degrading p53 by acting as an ubiquitin ligase and therefore plays a vital role in cell cycle and survival. The G-variant of the Mdm2 SNP309, which is located within the promoter of the Mdm2 gene, increases expression of Mdm2 and thereby inhibits the p53 pathway. Several studies have investigated the influence of this SNP on disease risk and onset of various malignancies. The impact of Mdm2 SNP309 on bladder cancer is still to be established due to inconsistent data. METHODS: In a case-control study we determined the distribution of Mdm2 SNP309 genotypes in 111 patients with an early-onset bladder cancer (diagnosis <45 years of age), in 113 consecutive bladder cancer patients and in a control group consisting of 140 patients without any malignancy. RESULTS: There was no significant association between the allelic distribution of the Mdm2 SNP309 and tumor risk, early onset, gender or grade of the tumor. According to tumor stage we found a significant difference in the distribution of the Mdm2 SNP309 between patients with noninvasive and invasive (≥pT1) tumor growth (p = 0.016). In patients with invasive tumors a significant increase of the G allele was found (T/T vs. T/G + G/G; p = 0.023; OR 2.203, 95% CI 1.111-4.369). CONCLUSION: These data indicate that the G-variant of the Mdm2 SNP309 might influence the development of a more aggressive tumor phenotype in patients with bladder cancer without affecting the overall tumor risk.

Combination of CK20 and Ki-67 immunostaining analysis predicts recurrence, progression, and cancer-specific survival in pT1 urothelial bladder cancer.

BACKGROUND: The prognostic value of CK20, Ki-67, and p53 has been investigated for non-muscle-invasive urothelial bladder cancers but not for the distinct and clinically challenging subset of pT1 bladder cancers. OBJECTIVE: To evaluate the prognostic value of CK20, Ki-67, and p53 within the largest series of pT1 urothelial bladder cancers. DESIGN, SETTING, AND PARTICIPANTS: Data from 309 patients with pT1 urothelial bladder cancer from one single urologic centre were collected. INTERVENTION: Adjuvant instillation of bacillus Calmette-Guérin was performed in each patient. A second resection was performed after 4-8 wk. A total of 76 patients underwent cystectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We conducted histomorphologic analysis; immunohistochemistry for CK20, Ki-67, and p53; and univariate and multivariate Cox regression models including recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific survival (CSS). RESULTS AND LIMITATIONS: At a median follow-up of 49 mo, we found recurrence and progression and disease-specific mortality rates of 22.7%, 20.1%, and 15.9%, respectively. CK20 expression was significantly correlated with RFS in multivariate analysis (hazard ratio [HR]: 5.89; 95% confidence interval [CI], 1.44-24.15; p=0.014). In multivariate analysis, Ki-67 was the only marker significantly correlated with PFS (HR: 2.80; 95% CI, 1.45-5.43, p=0.002). Ki-67 (HR: 3.83; 95% CI, 1.59-9.26; p=0.003), and CK20 (HR: 8.44; 95% CI,1.16-61.34; p=0.035) were significantly correlated with CSS in multivariate analysis. The combination of CK20 and Ki-67 showed significantly worse RFS (p=0.026), PFS (p=0.003), and CSS (p<0.001) in tumours with a high proliferation index and abnormal CK20 expression. A retrospective study design was the major limitation of this study. CONCLUSIONS: Our present analysis of the largest series of patients with pT1 urothelial bladder cancer published to date found Ki-67 and CK20 to be potential prognostic markers improving the risk stratification of pT1 bladder tumours. They are reliable indicators of biologic aggressiveness and may contribute to decision making on therapeutic strategy for pT1 bladder carcinomas.

Computerized quantification and planimetry of prostatic capsular nerves in relation to adjacent prostate cancer foci.

BACKGROUND: Perineural invasion is discussed as a significant route of extraprostatic extension in prostate cancer (PCa). Recent in vitro studies suggested a complex mechanism of neuroepithelial interaction. OBJECTIVE: The present study was intended to investigate whether the concept of neuroepithelial interaction can be supported by a quantitative analysis and planimetry of capsular nerves in relation to adjacent PCa foci. DESIGN, SETTING, AND PARTICIPANTS: Whole-mount sections of the prostate were created from patients undergoing non-nerve-sparing laparoscopic radical prostatectomy. For each prostate, adjacent sections were created and stained both to identify capsular nerves (S100) and to localize cancer foci (hematoxylin and eosin). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Computerized quantification and planimetry of capsular nerves (ImageJ software) were performed after applying a digital grid to define 12 capsular sectors. For statistical analyses, mixed linear models were calculated using the SAS 9.3 software package. RESULTS AND LIMITATIONS: Specimens of 33 prostates were investigated. A total of 1957 capsular nerves and a total capsular nerve surface area of 26.44 mm(2) were measured. The major proportion was found in the dorsolateral (DL) region (p<0.001). Adjacent tumor was associated with a statistically significant higher capsular nerve count compared with the capsules of tumor-free sectors (p<0.005). Similar results were shown for capsular nerve surface area (p<0.006). Subsequent post hoc analyses at the sector level revealed that the effect of tumor on capsular nerve count or nerve surface area is most pronounced in the DL region. CONCLUSIONS: The presence of PCa foci resulted in a significantly increased capsular nerve count and capsular nerve surface area compared with tumor-free sectors. The present study supports former in vitro findings suggesting that the presence of PCa lesions may lead to complex neuroepithelial interactions resulting in PCa-induced nerve growth.

Introduction and first clinical application of a simplified immunohistochemical validation system confirms prognostic impact of KI-67 and CK20 for stage T1 urothelial bladder carcinoma: single-center analysis of eight biomarkers in a series of three hundred six patients.

BACKGROUND: Biomarkers could help to estimate the prognosis of solid tumors. One of the reasons that many immunohistochemical (IHC) markers are not used routinely is the high interobserver variability and various cutoff values. In the present study, we used a simplified IHC method with a group of 8 biomarkers in stage pT1 urothelial bladder carcinoma (UBC). PATIENTS AND METHODS: IHC expression of CK20, KI-67, STK15, MUC7, periostin, fibronectin, survivin, and CXCR4 was assessed independently by 2 reviewers in a series of 306 stage pT1 UBC specimens from a single center in 10% steps from < 10% up to > 90%. A general center < 10% vs. ≥ 10% was set for further analysis for all markers. All patients initially underwent a bladder-sparing approach. Kaplan-Meier analyses and multivariate Cox regression analyses of recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific survival (CSS) were performed. RESULTS: A cutoff point ≥ 10% was shown to be valid and reliable for marker expression, with 96% interobserver agreement. Of the studied marker expressions, ≥ 10% for Ki-67 showed a statistically significant worse RFS (54% vs. 64%; P = .004), PFS (66% vs. 73%; P = .001), and CSS (71% vs. 77%; P = .015); ≥ 10% for CK20 showed a worse RFS (57% vs. 58%; P = .009). Multivariate Cox regression analysis revealed CK20 to be an independent prognostic factor for recurrence (hazard ratio [HR], 2.08; confidence interval [95% CI]; 1.21-3.57; P = .008) and Ki-67 for progression (HR, 2.11; CI, 1.02-4.37; P = .045). CONCLUSION: We proposed and applied a simplified IHC evaluation that increases interobserver agreement and confirms the prognostic role of Ki-67 and CK20 for stage T1 UBC.

Lack of evidence for frequent MED12 p.L1224F mutation in prostate tumours from Caucasian patients.

Recently mutations in the MED12 gene have been reported in 5.4% of prostate tumours from Caucasian patients analysed by exome sequencing (Barbieri CE, Baca SC, Lawrence MS, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nature Genet 2012; 44: 685-689). In more than 70% of prostate tumours with MED12 mutation, a recurrent p.L1224F mutation in exon 26 was found. In order to validate this MED12 p.L1224F mutation, an unselected cohort of prostate tumours from Caucasian patients was analysed by Sanger sequencing. Overall, 223 prostate tumours and three lymph node metastases were analysed. The MED12 p.L1224F mutation could not be detected in any of the cases. So far, the recently reported MED12 p.L1224F mutation could not be validated in our unselected cohort of prostate tumours. Contrary to the findings of Barbieri et al, our data indicate either that the p.L1224F mutation in the MED12 gene plays no role in prostate carcinogenesis or that this alteration is only relevant in a small subgroup of tumours.

Characterization and risk stratification of prostate cancer in patients undergoing radical cystoprostatectomy.

OBJECTIVE: To describe the prevalence of incidental prostate cancer in patients undergoing radical cystoprostatectomy for bladder malignancy; to quantify the association between incidental prostate cancer and mortality in these patients; and to quantify the association between incidental prostate cancer and age in radical cystoprostatectomy specimens. METHODS: Consecutive patients undergoing radical cystoprostatectomy for bladder malignancy at six academic institutions were assessed. End-points were the histological diagnosis of prostate cancer in the radical cystoprostatectomy specimens and mortality. The association between incidental prostate cancer and mortality was calculated by multivariable Cox regression, and the association between age and the occurrence of prostate cancer was calculated by logistic regression. RESULTS: A total of 1122 patients (aged 65.6 ± 10 years) were included in this analysis. Prostate cancer was detected in 17.8% (n = 200) of the cystoprostatectomy specimens. After multivariable adjustment, prostate cancer was significantly associated with mortality (hazard ratio 1.27, 95% confidence interval 1.03-1.56). There was a significant association between age and the presence of prostate cancer in the cystoprostatectomy specimen. The odds ratio for the presence of prostate cancer was 1.028 (95% confidence interval 1.011-1.045; P < 0.001) per each year after the age of 40 years. CONCLUSIONS: Concomitant prostate cancer is an independent prognostic factor for mortality after radical cystoprostatectomy for bladder cancer. When considering a prostate-sparing technique, urologists should consider that every fifth to sixth patient will present with a concomitant prostate cancer, and that after the age of 40 years, the odds of a concomitant prostate cancer increases by 2.8% per year, thus warranting a careful balance between the oncological risks and quality of life issues.

Fourteen-year oncological and functional outcomes of high-intensity focused ultrasound in localized prostate cancer.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: High-intensity focused ultrasound (HIFU) is an alternative treatment option for localized prostate cancer (PCa), which is applied for over 15 years. There are conflicting recommendations for HIFU among urological societies, which can be explained by the lack of prospective controlled studies, reports on preselected patient populations and limited follow-up providing little information on overall and cancer-specific survival. We report on a large, unselected consecutive patient series of patients who have undergone primary HIFU for clinically localized PCa with the longest follow-up in current literature. Our results improve the understanding of the oncological efficacy, morbidity and side effects of primary HIFU. OBJECTIVE: To assess the safety, functional and oncological long-term outcomes of high-intensity focused ultrasound (HIFU) as a primary treatment option for localized prostate cancer (PCa). PATIENTS AND METHODS: We conducted a retrospective single-centre study on 538 consecutive patients who underwent primary HIFU for clinically localized PCa between November 1997 and September 2009. Factors assessed were: biochemical disease-free survival (BDFS) according to Phoenix criteria (prostate-specific antigen nadir + 2 ng/mL); metastatic-free, overall and PCa-specific survival; salvage treatment; side effects; potency; and continence status. RESULTS: The mean (sd; range) follow-up was 8.1 (2.9; 2.1-14.0) years. The actuarial BDFS rates at 5 and 10 years were 81 and 61%, respectively. The 5-year BDFS rates for low-, intermediate- and high-risk patients were 88, 83 and 48%, while the 10-year BDFS rates were 71, 63 and 32%, respectively. Metastatic disease was reported in 0.4, 5.7 and 15.4% of low-, intermediate- and high-risk patients, respectively. The salvage treatment rate was 18%. Seventy-five (13.9%) patients died. PCa-specific death was registered in 18 (3.3%) patients (0, 3.8 and 11% in the low-, intermediate- and high-risk groups, respectively). Side effects included bladder outlet obstruction (28.3%), Grade I, II and III stress urinary incontinence (13.8, 2.4 and 0.7%, respectively) and recto-urethral fistula (0.7%). Preserved potency was 25.4% (in previously potent patients). CONCLUSIONS: The study demonstrates the efficacy and safety of HIFU for localized PCa. HIFU is a therapeutic option for patients of advanced age, in the low- or intermediate-risk groups, and with a life expectancy of ∼10 years.

Ki-67, mini-chromosome maintenance 2 protein (MCM2) and geminin have no independent prognostic relevance for cancer-specific survival in surgically treated squamous cell carcinoma of the penis.

UNLABELLED: What's known on the subject? and what does the study add?: Only little and partly contradictory data are currently published about the prognostic role of immunohistochemically detectable proliferation-associated biomarkers in surgically treated squamous cell carcinoma of the penis (SCCP), and no data are available at present about their usefulness for refining the delineation between different Broders' grading categories (e.g. still G2 or just G3 SCCP?). Moreover, the accuracy of various conventional histopathological parameters for predicting cancer-specific survival (CSS) in surgically treated SCCP has not been systematically evaluated yet. Based on the so far largest study cohort encompassing 158 consecutive patients with surgically treated PSCCs characterised by means of a central histopathological review, our data add the following to the currently available literature: (i) Ki-67, mini-chromosome maintenance 2 protein (MCM2), and geminin indicate a more aggressive behaviour in SCPP but do not represent independent prognostic parameters in the multivariable analysis in terms of CSS, (ii) these three biomarkers are not helpful for refining the delineation between different Broders' grading categories at the immunohistochemical level, and (iii) the conventional histopathological parameters staging, grading, nodal involvement, and lymphovascular invasion are independent prognostic parameters that together achieve a predictive accuracy of 82% for CSS. OBJECTIVE: To assess the role of cell proliferation-associated biomarkers to predict cancer-specific survival (CSS) in patients with surgically treated squamous cell carcinoma of the penis (SCCP). PATIENTS AND METHODS: A multicentre study enrolling 158 consecutive patients with surgically treated SCCP was performed. After conducting a central histopathological review, the staining profiles of Ki-67, mini-chromosome maintenance 2 protein (MCM2) and geminin were evaluated for their correlation with conventional histopathological criteria and their prognostic relevance for predicting CSS in a multivariable Cox proportional hazards regression model (median [interquartile range] follow-up 33 [6-63] months). RESULTS: Staining evaluation showed high interobserver agreement (92-96%). Ki-67 and MCM2 displayed a significant positive correlation with histological tumour grade, lymphovascular invasion (LVI) and nodal status, whereas geminin expression only correlated with tumour grade. The 5-year CSS for the entire study cohort was 62%. Univariable analysis showed a significant prognostic impact of Ki-67 (P = 0.026), MCM2 (P = 0.007), and geminin (P = 0.036). In multivariable analysis, only pT (hazard ratio [HR] 1.67; P = 0.003) and pN stage (HR 2.62; P = 0.015) as well as tumour grade (HR 1.89; P = 0.036) and LVI (HR 2.66; P = 0.028) were identified as independent prognostic parameters for CSS. The accuracy of the Cox model for CSS prediction was 0.820 (95% confidence interval 0.741-0.898). CONCLUSIONS: At present, conventional histopathological criteria remain the most powerful predictors of CSS in surgically treated SCCP. Due to overlapping staining profiles, Ki-67, MCM2 and geminin, either singly or in various combinations, failed to immunohistochemically refine the boundaries between Broders' grading categories. Ki-67, MCM2 and geminin do not represent independent prognostic parameters but reflect a more aggressive behaviour in surgically treated SCCP. Further studies are needed to clarify the currently contradictory predictive role of proliferation-associated biomarkers in terms of predicting nodal involvement in SCCPs.

Histone methylation defines an epigenetic entity in penile squamous cell carcinoma.

PURPOSE: Earlier studies indicate that epigenetics contribute to the pathogenesis of penile squamous cell carcinoma. Histone methylation patterns are frequently altered during carcinogenesis. Therefore, we investigated the methylation pattern of the histones H3K4, H3K9 and H3K27 in penile carcinoma and normal tissue. MATERIALS AND METHODS: A tissue microarray was constructed with 65 penile carcinomas, 6 metastatic lesions and 30 control tissues. Global histone methylation was assessed using immunohistochemistry. RESULTS: Global levels of H3K4me1, H3K9me1, H3K9me2, H3K27me2 and H3K27me3 were decreased, whereas H3K9me3 was increased in penile carcinoma. Histone methylation levels defined an epigenetic entity that allowed accurate differentiation of cancer and normal samples. We observed no correlation of histone methylation levels with clinicopathological parameters or patient outcome. CONCLUSIONS: The description of a definite epigenetic entity in penile carcinoma provides a rationale for testing epigenetic agents in patients with metastatic disease.

Does preoperative platelet count and thrombocytosis play a prognostic role in patients undergoing nephrectomy for renal cell carcinoma? Results of a comprehensive retrospective series.

PURPOSE: To evaluate the still controversially discussed prognostic role of preoperative platelet level (PPL) and thrombocytosis (TC) in patients who undergo surgery for renal cell carcinoma (RCC) based on the largest patient series reported to date. METHODS: A total of 3,139 patients, who underwent radical or nephron-sparing nephrectomy at four centres, were subdivided based on a threshold for preoperative platelets of 400 × 10(9) cells/L. Univariate and multivariable Cox regression analyses were applied to determine the prognostic influence of PPL and TC on cancer-specific survival (CSS) for patients with localized and metastatic disease at presentation. RESULTS: Group 1 (PPL ≤ 400/nl) and Group 2 (PPL > 400/nl) included 2,862 (91 %) and 277 patients (9 %), respectively. With a median follow-up (FU) of 69.5 months (IQR: 35-105), CSS of all patients after 5 years was 84.6 % in Group 1 versus 53.4 % in Group 2 (p < 0.001). At multivariable analysis, TC (HR:1.337; p = 0.007) and continuous PPL (HR:1.001; p = 0.002) independently predicted a decreased survival. However, integration of these parameters into multivariable models for the entire study group and for patients with localized tumours did only result in marginal improvement of the model quality (0.66 and 1.04 %, respectively). Interestingly, neither TC (p = 0.257) nor PPL (p = 0.132) significantly influenced survival in M1 patients. CONCLUSIONS: Preoperative TC turned out an independent predictor for decreased CSS in patients undergoing surgery for localized RCC. However, significant improvement of multivariable models comprising standard clinical and pathological parameters by the inclusion of TC is not achieved. In metastatic disease, TC did not reveal an independent influence on CSS.

Gender-specific differences in cancer-specific survival after radical cystectomy for patients with urothelial carcinoma of the urinary bladder in pathologic tumor stage T4a.

BACKGROUND: Bladder cancer (UCB) staged pT4a show heterogeneous outcome after radical cystectomy (RC). No risk model has been established to date. Despite gender-specific differences, no comparative studies exist for this tumor stage. MATERIALS AND METHODS: Cancer-specific survival (CSS) of 245 UCB patients without neoadjuvant chemotherapy staged pT4a, pN0-2, M0 after RC were analyzed in a retrospective multi-center study. Seventeen patients were excluded from further analysis due to carcinoma in situ (CIS) of the prostatic urethra and/or positive surgical margins. Average follow-up period was 30 months (IQR: 14-45). The influence of different clinical and histopathologic variables on CSS was determined through uni- and multivariate Cox regression analyses. Two risk groups were generated using factors with independent effect in multivariate models. Internal validity of the prediction model was evaluated by bootstrapping. RESULTS: Eighty-four percent of the patients (n = 192) were male; 72% (n = 165) showed lymphovascular invasion (LVI). The 5-year CSS rate was 31%, and significantly different between male and female (35% vs. 15%, P = 0.003). Multivariate Cox regression modeling, female gender (HR = 1.83, P = 0.008), LVI (HR = 1.92, P = 0.005), and absence of adjuvant chemotherapy (HR = 0.61, P = 0.020) significantly worsened CSS. Two risk groups were generated using these 3 criteria, which differed significantly between each other in CSS (5-year-CSS: 46% vs. 12%, P < 0.001). The c-index value of the risk model was 0.61 (95% CI: 0.53-0.68, P < 0.001). CONCLUSIONS: Prognosis in UCB staged pT4a is heterogeneous. Female gender and LVI are adverse factors. Adjuvant chemotherapy seems to improve outcome. The present analysis establishes the first risk model for this demanding tumor stage.

Features associated with recurrence beyond 5 years after nephrectomy and nephron-sparing surgery for renal cell carcinoma: development and internal validation of a risk model (PRELANE score) to predict late recurrence based on a large multicenter database (CORONA/SATURN Project).

BACKGROUND: Approximately 10-20% of recurrences in patients treated with nephrectomy for renal cell carcinoma (RCC) develop beyond 5 yr after surgery (late recurrence). OBJECTIVE: To determine features associated with late recurrence. DESIGN, SETTING, AND PARTICIPANTS: A total of 5009 patients from a multicenter database comprising 13 107 RCC patients treated surgically had a minimum recurrence-free survival of 60 mo (median follow-up [FU]: 105 mo [range: 78-135]); at last FU, 4699 were disease free (median FU: 103 mo [range: 78-134]), and 310 patients (6.2%) experienced disease recurrence (median FU: 120 mo [range: 93-149]). INTERVENTIONS: Patients underwent radical nephrectomy or nephron-sparing surgery. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable regression analyses identified features associated with late recurrence. Cox regression analyses evaluated the association of features with cancer-specific mortality (CSM). RESULTS AND LIMITATIONS: Lymphovascular invasion (LVI) (odds ratio [OR]: 3.07; p<0.001), Fuhrman grade 3-4 (OR: 1.60; p=0.001), and pT stage >pT1 (OR: 2.28; p<0.001) were significantly associated with late recurrence. Based on accordant regression coefficients, these parameters were weighted with point values (LVI: 2 points; Fuhrman grade 3-4: 1 point, pT stage >1: 2 points), and a risk score was developed for the prediction of late recurrences. The calculated values (0 points: late recurrence risk 3.1%; 1-3 points: 8.4%; 4-5 points: 22.1%) resulted in a good-, intermediate- and poor-prognosis group (area under the curve value for the model: 70%; 95% confidence interval, 67-73). Multivariable Cox regression analysis showed LVI (HR: 2.75; p<0.001), pT stage (HR: 1.24; p<0.001), Fuhrman grade (HR: 2.40; p<0.001), age (HR: 1.01; p<0.001), and gender (HR: 0.71; p=0.027) to influence CSM significantly. Limitations are based on the multicenter and retrospective study design. CONCLUSIONS: LVI, Fuhrman grade 3/4, and a tumor stage >pT1 are independent predictors of late recurrence after at least 5 yr from surgery in patients with RCC. We developed a risk score that allows for prognostic stratification and individualized aftercare of patients with regard to counseling, follow-up scheduling, and clinical trial design.

Inherent grading characteristics of individual pathologists contribute to clinically and prognostically relevant interobserver discordance concerning Broders' grading of penile squamous cell carcinomas.

INTRODUCTION: We assessed the reproducibility and prognostic impact of the Broders' grading system (BGS) in a cohort of 147 patients with surgically treated penile squamous cell carcinomas. MATERIALS AND METHODS: Conventionally stained histology slides were graded according to the BGS in two rounds by two study pathologists. Reproducibility was assessed using ĸ statistics. Multivariable analyses were calculated to predict cancer-specific survival (CSS). The 'mean grade' per pathologist per round was calculated by allocating grade points to each study case (G1-G4: 1-4 points) and dividing the sum of all grade points by the number of cases examined. RESULTS: The BGS showed substantial interobserver variation (59-87% with ĸ = 0.38-0.69) but almost perfect intraobserver reproducibility (91% with ĸ = 0.86 and 96% with ĸ = 0.94, respectively). The 'mean grade' per pathologist remained nearly constant in both rounds of examination (differences ≤0.05 grade points) but differed between the two pathologists (up to 0.4 grade points). In multivariable analyses, the prognostic impact of the BGS in terms of CSS was strongly pathologist-dependent. CONCLUSIONS: Clinically and prognostically relevant interobserver discordance concerning the BGS seems, at least in part, to be attributable to inherent 'aggressive' versus 'reserved' grading characteristics of individual pathologists.

Prognostic value of perinodal lymphovascular invasion following radical cystectomy for lymph node-positive urothelial carcinoma.

BACKGROUND: Metastasis of urothelial carcinoma of the bladder (UCB) into regional lymph nodes (LNs) is a key prognosticator for cancer-specific survival (CSS) after radical cystectomy (RC). Perinodal lymphovascular invasion (pnLVI) has not yet been defined. OBJECTIVE: To assess the prognostic value of histopathologic prognostic factors, especially pnLVI, on survival. DESIGN, SETTING, AND PARTICIPANTS: A total of 598 patients were included in a prospective multicentre study after RC for UCB without distant metastasis and neoadjuvant and/or adjuvant chemotherapy. En bloc resection and histopathologic evaluation of regional LNs were performed based on a prospective protocol. The final study group comprised 158 patients with positive LNs (26.4%). INTERVENTION: Histopathologic analysis was performed based on prospectively defined morphologic criteria of LN metastases. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable Cox proportional hazard regression models determined prognostic impact of clinical and histopathologic variables (age, gender, tumour stage, surgical margin status, pN, diameter of LN metastasis, LN density [LND], extranodal extension [ENE], pnLVI) on CSS. The median follow-up was 20 mo (interquartile range: 11-38). RESULTS AND LIMITATIONS: Thirty-one percent of patients were staged pN1, and 69% were staged pN2/3. ENE and pnLVI was present in 52% and 39%, respectively. CSS rates after 1 yr, 3 yr, and 5 yr were 77%, 44%, and 27%, respectively. Five-year CSS rates in patients with and without pnLVI were 16% and 34% (p<0.001), respectively. PN stage, maximum diameter of LN metastasis, LND, and ENE had no independent influence on CSS. In the multivariable Cox model, the only parameters that were significant for CSS were pnLVI (hazard ratio: 2.47; p=0.003) and pT stage. However, pnLVI demonstrated only a minimal gain in predictive accuracy (0.1%; p=0.856), and the incremental accuracy of prediction is of uncertain clinical value. CONCLUSIONS: We present the first explorative study on the prognostic impact of pnLVI. In contrast to other parameters that show the extent of LN metastasis, pnLVI is an independent prognosticator for CSS.