Karl Pummer

Identification of tumor antigens in renal cell carcinoma by serological proteome analysis.

We have investigated the suitability of proteomics for identification of tumor‐associated antigens. First, we compared the proteomes of nontumorous kidney and renal cell carcinoma (RCC) by two‐dimensional gel electrophoresis (2‐DE) and silver staining. Protein patterns were markedly different (∼800 spots in RCCs versus ∼1400 spots in kidney). 2‐DE immunoblotting revealed five RCC‐specific spots, reproducibly reactive with RCC‐patient but not healthy donor control sera. Two of these antigens were isolated by preparative 2‐DE, and identified by Edman sequencing of tryptic peptides. The first antigen, smooth muscle protein 22‐alpha (SM22‐α), is an actin‐binding protein of unknown function predominantly expressed in smooth muscle cells. In situ hybridization revealed that SM22‐α is not expressed in the malignant cells but in mesenchymal cells of the tumor stroma. The second antigen represents carbonic anhydrase I (CAI), an isoform usually not expressed in kidney. Interestingly, a different isoform (CAXII) has previously been identified by serological expression cloning as an antigen overexpressed in some RCCs. In additional assays, antibodies to recombinant CAI or SM22‐α were detected in sera from 3/11 or 5/11 RCC patients, respectively, whereas sera from 13 healthy individuals did not react. In conclusion, serological proteome analysis may be a new tool for the identification of tumor‐associated antigens.

Validation of the pre-treatment neutrophil–lymphocyte ratio as a prognostic factor in a large European cohort of renal cell carcinoma patients

Background:The neutrophil–lymphocyte ratio (NLR) has been proposed as an indicator of systemic inflammatory response. Several studies suggest a negative impact of increased NLR for patient’s survival in different types of cancer. However, previous findings from small-scale studies revealed conflicting results about its prognostic significance with regard to different clinical end points in non-metastatic renal cell carcinoma (RCC) patients. Therefore, the aim of our study was the validation of the prognostic significance of NLR in a large cohort of RCC patients.Methods:Data from 678 consecutive non-metastatic clear cell RCC patients, operated between 2000 and 2010 at a single centre, were evaluated retrospectively. Cancer-specific, metastasis-free, as well as overall survival (OS) were assessed using the Kaplan–Meier method. To evaluate the independent prognostic significance of NLR, multivariate Cox regression models were applied for all three different end points. Influence of the NLR on the predictive accuracy of the Leibovich prognosis score was determined by Harrells concordance index.Results:Multivariate analysis identified increased NLR as an independent prognostic factor for overall (hazard ratio (HR)=1.59, 95% confidence interval (CI)=1.10–2.31, P=0.014), but not for cancer-specific (HR=1.59, 95% CI=0.84–2.99, P=0.148), nor for metastasis-free survival (HR=1.39, 95% CI=0.85–2.28, P=0.184). The estimated concordance index was 0.79 using the Leibovich risk score and 0.81 when NLR was added.Conclusion:Regarding patients’ OS, an increased NLR represented an independent risk factor, which might reflect a higher risk for severe cardiovascular and other comorbidities. Adding the NLR to well-established prognostic models such as the Leibovich prognosis score might improve their predictive ability.

Urothelial Carcinoma of the Upper Urinary Tract: Surgical Approach and Prognostic Factors

OBJECTIVES Open radical nephroureterectomy (O-RNU) has been the gold standard for the treatment of upper urinary tract urothelial carcinoma (UUT-UC) for decades. With the advances in laparoscopic techniques and endourologic procedures, this concept has been increasingly challenged. Oncologic outcome prediction is mainly based on stage and grade. With progress in medical treatment, adjuvant therapies may gain importance in the future. This review assesses the values of the variety of available treatments as well as prognostic factors that may become relevant regarding patient selection for future adjuvant treatment trials. METHODS We performed a systematic literature research using MEDLINE with emphasis on open surgical, laparoscopic, and endourologic (ureteroscopic or percutaneous) techniques and prognostic contents. RESULTS Overall, no evidence level 1 information from prospective randomised trials is available for treatment of UUT-UC. Laparoscopic radical nephroureterectomy (L-RNU) is increasingly challenging open surgery. Currently, L-RNU should be reserved for low-stage, low-grade tumours. Ureteroscopy and percutaneous nephron-sparing techniques show favourable survival data but high local recurrence rates. Regarding prognosis, estimation of outcome still relies mainly on stage and grade because no additional parameters have been introduced in a routine clinical setting. CONCLUSIONS O-RNU still represents the gold standard for the treatment of UUT-UC. The laparoscopic approach is not yet standard of care and should be reserved for low-stage, low-grade tumours. Endourologic nephron-sparing treatments are still experimental in elective indications due to high local recurrence rates. For prognosis, no parameters in addition to stage and grade have been standardised.

Critical assessment of preoperative urinary prostate cancer antigen 3 on the accuracy of prostate cancer staging.

BACKGROUND Knowledge about the staging significance of the prostate cancer antigen 3 (PCA3) score to better identify pathologic features after radical prostatectomy (RP) is limited and controversial. OBJECTIVE Our aim was to study the clinical staging significance of PCA3 to identify pathologic favorable and/or unfavorable features in the RP specimen. DESIGN, SETTING, AND PARTICIPANTS Complete retrospective clinical and pathologic data of consecutive men who had undergone RP from three tertiary referral centers including preoperative PCA3 scores (n=305) and computer-assisted planimetrically measured tumor volume data (n=160) were available. INTERVENTION All patients were treated with RP. MEASUREMENTS PCA3 scores were assessed using the PROGENSA assay (Gen-Probe, San Diego, CA, USA). Beyond standard risk factors (age, digital rectal examination, prostate-specific antigen, prostate volume, biopsy Gleason score, percentage of positive cores), five different PCA3 codings were used in logistic regression models to identify five distinct pathologic end points: (1) low-volume disease (<0.5 ml), (2) insignificant prostate cancer (PCa) according to the Epstein criteria, (3) extracapsular extension (ECE), (4) seminal vesicle invasion (SVI), and (5) aggressive disease defined as Gleason sum ≥7. Accuracy estimates of each end point were quantified using the area under the curve (AUC) of the receiver operator characteristic analysis in models with and without PCA3. RESULTS AND LIMITATIONS PCA3 scores were significantly lower in low-volume disease and insignificant PCa (p ≤ 0.001). AUC of multivariable low-volume disease (+2.4 to +5.5%) and insignificant PCa models (+3 to +3.9%) increased when PCA3 was added to standard clinical risk factors. In contradistinction, regardless of its coding, PCA3 scores were not significantly elevated in pathologically confirmed ECE (p=0.4) or SVI (p=0.5), respectively. Higher PCA3 scores were associated with aggressive disease (p<0.001). Importantly, the addition of PCA3 to multivariable intermediate- and high-grade models did not improve prediction. Despite reporting the largest pathologic PCA3 study, the main limitation resides in its small sample size. CONCLUSIONS PCA3 was confirmed as a valuable predictor of pathologically confirmed low-volume disease and insignificant PCa. Further exploration of its role as an additional marker to select patients for active surveillance may be warranted. In contradistinction, assessment of pathologically advanced or aggressive PCa is not improved using PCA3.

Is repeated transurethral resection justified in patients with newly diagnosed superficial bladder cancer

OBJECTIVES To assess the value of repeated transurethral resection (TUR) in patients with newly diagnosed superficial bladder cancer. METHODS A second TUR was performed in 110 consecutive patients (24 women and 86 men) with newly diagnosed superficial bladder cancer. The mean age was 66 years (range 30 to 85). A second TUR was performed within 4 to 6 weeks after the initial TUR. After the first TUR, the pathologic stage was pTa in 31 patients (28%), pT1 in 76 (70%), and carcinoma in situ in 3 (2%). The pathologic records of the second TUR were reviewed and compared with the findings of the first operation. RESULTS Cystoscopy before the second TUR was negative in 79 patients. Of these cases, 14 (17.7%) had cancer histologically. The second TUR was negative in 70 patients (63.6%). Twenty-two (20%) had residual cancer of the same stage, 9 (8.2%) had a lower stage, and 9 (8.2%) had a higher stage. Of 31 patients with Stage pTa and 76 patients with Stage pT1 at the first TUR, 19 (61.3%) and 51 (67.1%) had a negative second TUR, respectively. CONCLUSIONS We recommend a second TUR for patients with superficial bladder cancer for several reasons. A negative second TUR provides important prognostic information. In addition, removal of residual cancer is achieved early. Finally, patients with pT1 G3 tumors are at high risk of residual, or even invasive, cancer and should be offered definitive therapy as early as possible.

The Impact of Tumor Multifocality on Outcomes in Patients Treated With Radical Nephroureterectomy

BACKGROUND The prognostic impact of multifocal upper-tract urothelial carcinoma (UTUC) is poorly understood. OBJECTIVE To investigate the association between tumor multifocality and clinicopathologic features and outcomes of UTUC in patients managed by radical nephroureterectomy (RNU). DESIGN, SETTING, AND PARTICIPANTS The study included 2492 patients treated with either open or laparoscopic RNU. Tumor and patient characteristics included tumor stage, tumor grade, lymph node status, lymphovascular invasion (LVI), tumor architecture, tumor location, unifocal or multifocal disease, gender, age, history of bladder cancer (BCa), Eastern Cooperative Oncology Group (ECOG) performance status (PS), and adjuvant chemotherapy. tumor multifocality of UTUC was defined as the synchronous presence of multiple tumors in the renal pelvis or ureter. INTERVENTION All patients were treated with either open or laparoscopic RNU. MEASUREMENTS Univariable and multivariable models tested the effect of tumor multifocality on disease progression and cancer-specific mortality. RESULTS AND LIMITATIONS Five hundred ninety patients (23.7%) had tumor multifocality at the time of RNU. The median follow-up was 45 mo (interquartile range [IQR]: 0-101). Tumor multifocality was significantly associated with a history of previous BCa (p=0.032), lymph node involvement (p=0.036), tumor location in the ureter (p=0.003), higher tumor stage (p<0.001), higher tumor grade (p<0.001), sessile tumor architecture (p=0.003), and LVI (p=0.001). In organ-confined patients, tumor multifocality was an independent predictor of both disease progression (hazard ratio [HR]: 1.43; p=0.019) and cancer-specific mortality (HR: 1.46; p=0.027). When assessed in all patients, tumor multifocality was associated with both disease progression and cancer-specific mortality in univariable (p=0.005 and p=0.006, respectively) but not in multivariable analyses (p=0.468 and p=0.798, respectively). The main limitation is the retrospective design of the study. CONCLUSIONS Tumor multifocality is an independent prognosticator of disease progression and cancer-specific mortality in patients with organ-confined UTUC treated with RNU. Multifocal organ-confined patients with UTUC may need closer follow-up. Integration of tumor multifocality with other factors may help identify those patients who would benefit from multimodal therapy.

External validation of the Mayo Clinic stage, size, grade, and necrosis (SSIGN) score for clear-cell renal cell carcinoma in a single European centre applying routine pathology.

BACKGROUND The stage, size, grade, and necrosis (SSIGN) score has been created as an outcome prediction tool for clear-cell renal cell carcinoma (ccRCC) using review pathology. OBJECTIVE We evaluated the prognostic accuracy of the SSIGN score model using routine pathology records. DESIGN, SETTING, AND PARTICIPANTS We retrospectively evaluated pathology records of 1862 consecutive ccRCC patients with complete data including follow-up who had been operated between 1984 and 2006. INTERVENTION Surgical treatment of patients with ccRCC. MEASUREMENTS TNM stage, largest tumour diameter, tumour grade, and presence of histologic tumour necrosis were recorded. ccRCC were categorised according to the SSIGN-score algorithm as 0-15. Cancer-specific survival (CSS) was assessed using the Kaplan-Meier method for individual SSIGN-score categories (scores 0-1 and > or =10, respectively, were combined). For evaluation of the prognostic impact of stage, size, grade, and necrosis regarding CSS, a multivariate analysis using a Cox regression model was performed, and for assessment of prognostic accuracy, Harrells concordance index was performed. RESULTS AND LIMITATIONS Median tumour diameter was 5.0 cm (range: 0.6-22 cm). Tumour necrosis was noted in 607 tumours (32.6%). Median follow-up was 72.5 mo (range: 0-281 mo); 359 of 1862 patients (19.3%) died of RCC. Ten-year CSS rates for respective SSIGN scores in our study ranged from 96.5% (scores 0-1) to 19.2% (scores > or =10). pT categories, lymph-node status, distant metastases, high tumour grade (size > or =5 cm), and necrosis were each independent predictors of CSS. The Harrells concordance index was 0.823. Limitations included smaller sample sizes in higher risk categories and limited numbers of patients at risk after 10 yr. CONCLUSIONS Outcome prediction with the SSIGN score using routine pathology records was comparable to the original data based on review pathology. Combining scores into five categories improved discrimination. Our data support the routine use of the SSIGN score in clinical practice with regard to follow-up decisions and patient selection for adjuvant trials.

External Validation of Urinary PCA3-Based Nomograms to Individually Predict Prostate Biopsy Outcome

BACKGROUND Prior to safely adopting risk stratification tools, their performance must be tested in an external patient cohort. OBJECTIVE To assess accuracy and generalizability of previously reported, internally validated, prebiopsy prostate cancer antigen 3 (PCA3) gene-based nomograms when applied to a large, external, European cohort of men at risk of prostate cancer (PCa). DESIGN, SETTING, AND PARTICIPANTS Biopsy data, including urinary PCA3 score, were available for 621 men at risk of PCa who were participating in a European multi-institutional study. INTERVENTION All patients underwent a ≥10-core prostate biopsy. Biopsy indication was based on suspicious digital rectal examination, persistently elevated prostate-specific antigen level (2.5-10 ng/ml) and/or suspicious histology (atypical small acinar proliferation of the prostate, >/= two cores affected by high-grade prostatic intraepithelial neoplasia in first set of biopsies). MEASUREMENTS PCA3 scores were assessed using the Progensa assay (Gen-Probe Inc, San Diego, CA, USA). According to the previously reported nomograms, different PCA3 score codings were used. The probability of a positive biopsy was calculated using previously published logistic regression coefficients. Predicted outcomes were compared to the actual biopsy results. Accuracy was calculated using the area under the curve as a measure of discrimination; calibration was explored graphically. RESULTS AND LIMITATIONS Biopsy-confirmed PCa was detected in 255 (41.1%) men. Median PCA3 score of biopsy-negative versus biopsy-positive men was 20 versus 48 in the total cohort, 17 versus 47 at initial biopsy, and 37 versus 53 at repeat biopsy (all p≤0.002). External validation of all four previously reported PCA3-based nomograms demonstrated equally high accuracy (0.73-0.75) and excellent calibration. The main limitations of the study reside in its early detection setting, referral scenario, and participation of only tertiary-care centers. CONCLUSIONS In accordance with the original publication, previously developed PCA3-based nomograms achieved high accuracy and sufficient calibration. These novel nomograms represent robust tools and are thus generalizable to European men at risk of harboring PCa. Consequently, in presence of a PCA3 score, these nomograms may be safely used to assist clinicians when prostate biopsy is contemplated.

Initial Prostate Biopsy: Development and Internal Validation of a Biopsy-specific Nomogram Based on the Prostate Cancer Antigen 3 Assay

BACKGROUND Urinary prostate cancer antigen 3 (PCA3) assay in combination with established clinical risk factors improves the identification of men at risk of harboring prostate cancer (PCa) at initial biopsy (IBX). OBJECTIVE To develop and validate internally the first IBX-specific PCA3-based nomogram that allows an individual assessment of a mans risk of harboring any PCa and high-grade PCa (HGPCa). DESIGN, SETTING, AND PARTICIPANTS Clinical and biopsy data including urinary PCA3 score of 692 referred IBX men at risk of PCa were collected within two prospective multi-institutional studies. INTERVENTION IBX (≥ 10 biopsy cores) with standard risk factor assessment including prebiopsy urinary PCA3 measurement. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS PCA3 assay cut-off thresholds were investigated. Regression coefficients of logistic risk factor analyses were used to construct specific sets of PCA3-based nomograms to predict any PCa and HGPCa at IBX. Accuracy estimates for the presence of any PCa and HGPCa were quantified using area under the curve of the receiver operator characteristic analysis and compared with a clinical model. Bootstrap resamples were used for internal validation. Decision curve analyses quantified the clinical net benefit related to the novel PCA3-based IBX nomogram versus the clinical model. RESULTS AND LIMITATIONS Any PCa and HGPCa were diagnosed in 46% (n=318) and 20% (n=137), respectively. Age, prostate-specific antigen, digital rectal examination, prostate volume, and PCA3 were independent predictors of PCa at IBX (all p<0.001). The PCA3-based IBX nomograms significantly outperformed the clinical models without PCA3 (all p<0.001). Accuracy was increased by 4.5-7.1% related to PCA3 inclusion. When applying nomogram-derived PCa probability thresholds ≤ 30%, only a few patients with HGPCa (≤ 2%) will be missed while avoiding up to 55% of unnecessary biopsies. External validation of the PCA3-based IBX-specific nomogram is warranted. CONCLUSIONS The internally validated PCA3-based IBX-specific nomogram outperforms a clinical prediction model without PCA3 for the prediction of any PCa, leading to the avoidance of unnecessary biopsies while missing only a few cases of HGPCa. Our findings support the concepts of a combination of novel markers with established clinical risk factors and the superiority of decision tools that are specific to a clinical scenario.

Patient Self-Reporting Questionnaire on Urological Morbidity and Bother after Radical Retropubic Prostatectomy

OBJECTIVES We assessed the incidence of morbidity and bother on quality-of-life (QL) after radical retropubic prostatectomy for prostate cancer. METHODS At least 12 months after surgery, self-reporting questionnaires were completed and returned by 368 (77.8%) of 473 eligible patients. Surgery related morbidity was evaluated by adhoc constructed questions. QL was assessed by the European Organization for Research and Treatment of Cancer QL core questionnaire (EORTC QLQ-C30). Multivariate and univariate analysis as well as regression analysis were used to assess the bother factors. RESULTS Postoperative urinary incontinence significant enough for the patient to use some kind of protection was reported by 27.2%. After surgery, 14.2% of preoperative potent men were able to get and maintain an erection sufficient enough for sexual intercourse without any aid. Overall 10.6% of respondents had undergone surgery for anastomotic stricture and 23.6% reported on adjuvant therapy. Furthermore, 43.2% reported on fear of not being cured from cancer. Postoperative urinary incontinence and fear of not being cured were associated with significant lower global QL scores and turned out as independent predictors for global QL. In contrast, postoperative erectile dysfunction, anastomotic stricture and adjuvant therapy were not independent predictors. In addition, 82.1% would vote for surgery again. CONCLUSION The majority of the patients would opt for surgical treatment again, although morbidity is common after radical prostatectomy and may impair QL. Particularly urinary incontinence and fear of not being cured are independent predictors for global QL after surgery. Therefore, surgical techniques with a low morbidity are requested as well as some kind of psychological support in order to cope with existential fear.