The prognostic role of preoperative serum C-reactive protein in predicting the biochemical recurrence in patients treated with radical prostatectomy.

BACKGROUND: To assess the prognostic value of preoperative C-reactive protein (CRP) serum levels for prognostication of biochemical recurrence (BCR) after radical prostatectomy (RP) in a large multi-institutional cohort. METHODS: Data from 7205 patients treated with RP at five institutions for clinically localized prostate cancer (PCa) were retrospectively analyzed. Preoperative serum levels of CRP within 24 h before surgery were evaluated. A CRP level ⩾0.5 mg dl(-1) was considered elevated. Associations of elevated CRP with BCR were evaluated using univariable and multivariable Cox proportional hazards regression models. Harrel's C-index was used to assess prognostic accuracy (PA). RESULTS: Patients with higher Gleason score on biopsy and RP, extracapsular extension, seminal vesicle invasion, lymph node metastasis, and positive surgical margins status had a significantly elevated preoperative CRP compared to those without these features. Patients with elevated CRP had a lower 5-year BCR survival proportion as compared to those with normal CRP (55% vs 76%, respectively, P<0.0001). In pre- and postoperative multivariable models that adjusted for standard clinical and pathologic features, elevated CRP was independently associated with BCR (P<0.001). However, the addition of preoperative CRP did not improve the accuracy of the standard pre- and postoperative models for prediction of BCR (70.9% vs 71% and 78.9% vs 78.7%, respectively). CONCLUSIONS: Preoperative CRP is elevated in patients with pathological features of aggressive PCa and BCR after RP. While CRP has independent prognostic value, it does not add prognostically or clinically significant information to standard predictors of outcomes.

Clinical nodal staging scores for prostate cancer: a proposal for preoperative risk assessment.

BACKGROUND: Pelvic lymph node dissection in patients undergoing radical prostatectomy for clinically localised prostate cancer is not without morbidity and its therapeutical benefit is still a matter of debate. The objective of this study was to develop a model that allows preoperative determination of the minimum number of lymph nodes needed to be removed at radical prostatectomy to ensure true nodal status. METHODS: We analysed data from 4770 patients treated with radical prostatectomy and pelvic lymph node dissection between 2000 and 2011 from eight academic centres. For external validation of our model, we used data from a cohort of 3595 patients who underwent an anatomically defined extended pelvic lymph node dissection. We estimated the sensitivity of pathological nodal staging using a beta-binomial model and developed a novel clinical (preoperative) nodal staging score (cNSS), which represents the probability that a patient has lymph node metastasis as a function of the number of examined nodes. RESULTS: In the development and validation cohorts, the probability of missing a positive lymph node decreases with increase in the number of nodes examined. A 90% cNSS can be achieved in the development and validation cohorts by examining 1-6 nodes in cT1 and 6-8 nodes in cT2 tumours. With 11 nodes examined, patients in the development and validation cohorts achieved a cNSS of 90% and 80% with cT3 tumours, respectively. CONCLUSIONS: Pelvic lymph node dissection is the only reliable technique to ensure accurate nodal staging in patients treated with radical prostatectomy for clinically localised prostate cancer. The minimum number of examined lymph nodes needed for accurate nodal staging may be predictable, being strongly dependent on prostate cancer characteristics at diagnosis.

Association of perioperative blood transfusion with oncologic outcomes after radical nephroureterectomy for upper tract urothelial carcinoma.

BACKGROUND: To test the hypothesis that perioperative blood transfusion (PBT)impacts oncologic outcomes of patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). METHODS: Retrospective analysis of 2492 patients with UTUC treated at 23 institutions with RNU between 1987 and 2007.Cox regression models addressed the association of PBT with disease recurrence, cancer-specific mortality and any-cause mortality. RESULTS: A total of 510 patients (20.5%) patients received PBT. Within a median follow-up of 36 months (Interquartile range: 55 months), 663 (26.6%) patients experienced disease recurrence, 545 patients (21.9%) died of UTUC and 884 (35.5%) patients died from any cause. Patients who received PBT were at significantly higher risk of disease recurrence, cancer-specific mortality and overall mortality than patients not receiving PBT in univariable Cox regression analyses. In multivariable Cox regression analyses that adjusted for the effects of standard clinicopathologic features, PBT did not remain associated with disease recurrence (HR: 1.11; 95% CI 0.92-1.33, p = 0.25), cancer-specific mortality (HR: 1.09; 95% CI 0.89-1.33, p = 0.41) or overall mortality (HR: 1.09; 95% CI 0.93-1.28, p = 0.29). CONCLUSIONS: In patients undergoing RNU for UTUC, PBT is associated with disease recurrence, cancer-specific survival or overall survival in univariable, but not in multivariable Cox regression analyses.

Diabetes mellitus without metformin intake is associated with worse oncologic outcomes after radical nephroureterectomy for upper tract urothelial carcinoma.

AIMS: Evidence suggests a detrimental effect of diabetes mellitus (DM) on cancer incidence and outcomes. To date, the effect of DM and its treatment on prognosis in upper tract urothelial carcinoma (UTUC) remains uninvestigated. We tested the hypothesis that DM and metformin use impact oncologic outcomes of patients treated with radical nephroureterectomy (RNU) for UTUC. METHODS: Retrospective analysis of 2492 patients with UTUC treated at 23 institutions with RNU without neoadjuvant therapy. Cox regression models addressed the association of DM and metformin use with disease recurrence, cancer-specific mortality and any-cause mortality. RESULTS: A total of 365 (14.3%) patients had DM and 194 (7.8%) patients used metformin. Within a median follow-up of 36 months, 663 (26.6%) patients experienced disease recurrence, 545 patients (21.9%) died of UTUC and 884 (35.5%) patients died from any cause. Diabetic patients who did not use metformin were at significantly higher risk of disease recurrence and cancer-specific death compared to non-diabetic patients and diabetic patients who used metformin. In multivariable Cox regression analyses, DM treated without metformin was associated with worse recurrence-free survival (HR: 1.44, 95% CI 1.10-1.90, p = 0.009) and cancer-specific mortality (HR: 1.49, 95% CI 1.11-2.00, p = 0.008). CONCLUSIONS: Diabetic UTUC patients without metformin use have significantly worse oncologic outcomes than diabetics who used metformin and non-diabetics. The possible mechanism behind the impact of DM on UTUC biology and the potentially protective effect of metformin need further elucidation.

Impact of statin use on biochemical recurrence in patients treated with radical prostatectomy.

BACKGROUND: The impact of statin use on biochemical recurrence (BCR) in patients treated with radical prostatectomy (RP) remains controversial. METHODS: We retrospectively evaluated 6842 patients who underwent RP for clinically localized prostate cancer (PC) between 2000 and 2011. Uni- and multivariable cox regression models addressed the association of statin use with BCR. RESULTS: Overall, 2275 (33.3%) patients used statins. Statin users were older and had a higher rate of positive surgical margins than patients not using statins (P-values 0.05). Within a median follow-up of 25 months (interquartile range: 8-42 months), 778 (11.4%) patients experienced BCR. Actuarial estimate 5-years BCR-free survival was 82%±1 for patients without statin use and 84±1% for patients using statins (P=0.05); statin use was not associated with BCR (hazard ratio: 0.88, 95% confidence interval: 0.76-1.03, P=0.10) after adjusting for the effects of standard clinicopathologic features. CONCLUSIONS: In PC patients undergoing RP, statin use was not independently associated with lower risk of BCR.

Accuracy of the EORTC risk tables and of the CUETO scoring model to predict outcomes in non-muscle-invasive urothelial carcinoma of the bladder.

BACKGROUND: The European Organization for Research and Treatment of Cancer (EORTC) risk tables and the Spanish Urological Club for Oncological Treatment (CUETO) scoring model are the two best-established predictive tools to help decision making for patients with non-muscle-invasive bladder cancer (NMIBC). The aim of the current study was to assess the performance of these predictive tools in a large multicentre cohort of NMIBC patients. METHODS: We performed a retrospective analysis of 4689 patients with NMIBC. To evaluate the discrimination of the models, we created Cox proportional hazard regression models for time to disease recurrence and progression. We incorporated the patients calculated risk score as a predictor into both of these models and then calculated their discrimination (concordance indexes). We compared the concordance index of our models with the concordance index reported for the models. RESULTS: With a median follow-up of 57 months, 2110 patients experienced disease recurrence and 591 patients experienced disease progression. Both tools exhibited a poor discrimination for disease recurrence and progression (0.597 and 0.662, and 0.523 and 0.616, respectively, for the EORTC and CUETO models). The EORTC tables overestimated the risk of disease recurrence and progression in high-risk patients. The discrimination of the EORTC tables was even lower in the subgroup of patients treated with BCG (0.554 and 0.576 for disease recurrence and progression, respectively). Conversely, the discrimination of the CUETO model increased in BCG-treated patients (0.597 and 0.645 for disease recurrence and progression, respectively). However, both models overestimated the risk of disease progression in high-risk patients. CONCLUSION: The EORTC risk tables and the CUETO scoring system exhibit a poor discrimination for both disease recurrence and progression in NMIBC patients. These models overestimated the risk of disease recurrence and progression in high-risk patients. These overestimations remained in BCG-treated patients, especially for the EORTC tables. These results underline the need for improving our current predictive tools. However, our study is limited by its retrospective and multi-institutional design.

Risk stratification of pT1-3N0 patients after radical cystectomy for adjuvant chemotherapy counselling.

BACKGROUND: In pT1-T3N0 urothelial carcinoma of the bladder (UCB) patients, multi-modal therapy is inconsistently recommended. The aim of the study was to develop a prognostic tool to help decision-making regarding adjuvant therapy. METHODS: We included 2145 patients with pT1-3N0 UCB after radical cystectomy (RC), naive of neoadjuvant or adjuvant therapy. The cohort was randomly split into development cohort based on the US patients (n=1067) and validation cohort based on the Europe patients (n=1078). Predictive accuracy was quantified using the concordance index. RESULTS: With a median follow-up of 45 months, 5-year recurrence-free and cancer-specific survival estimates were 68% and 73%, respectively. pT-stage, ge, lymphovascular invasion, and positive margin were significantly associated with both disease recurrence and cancer-specific mortality (P-values ≤ 0.005). The accuracies of the multivariable models at 2, 5, and 7 years for predicting disease recurrence were 67.4%, 65%, and 64.4%, respectively. Accuracies at 2, 5, and 7 years for predicting cancer-specific mortality were 69.3%, 66.4%, and 65.5%, respectively. We developed competing-risk, conditional probability nomograms. External validation revealed minor overestimation. CONCLUSION: Despite RC, a significant number of patients with pT1-3N0 UCB experience disease recurrence and ultimately die of UCB. We developed and externally validated competing-risk, conditional probability post-RC nomograms for prediction of disease recurrence and cancer-specific mortality.

Tissue-based molecular markers for renal cell carcinoma.

Since the introduction of targeted therapies in renal cell carcinoma (RCC), more individualized treatment options have become available. Molecular markers might support treatment planning due to more accurate individual risk stratification. Current molecular markers in RCC were reviewed to elucidate clinical impact and future perspectives. An English-language literature review of the Medline database (1990 to September 2010) of published data on tissue-based molecular markers and RCC was undertaken. Histological types, clinical and oncological behaviour are variable in renal masses. Molecular markers offer potential for additional information in tumour detection and diagnosis, prognostic and predictive values, as well as determination of therapeutic targets. Investigations on molecular biomarkers in RCC include hypoxia inducible factor (HIF-α), vascular endothelial growth factor (VEGF), carbonic anhydrase IX (CAIX), mammalian target of rapamycin (mTOR), survivin, B7-H1, p53, matrix metalloproteinases (MMP), Insulin-like growth factor II mRNA-binding protein 3 (IMP3), Ki-67, C-reactive protein (CRP), Vimentin, Fascin, platelet count, hemoglobin level and combinations of these factors. Although some markers offer promising results, utilization in daily practice is compromised due to limited specificity, predictive accuracy and tumour histology variablity. There is an imminent need for novel molecular markers that allow accurate histologic and biologic classification of RCC to improve upon current outcomes. It is very likely that a panel of molecular markers will be used to achieve a sufficient degree of certainty in order to guide clinical decisions. A large concerted effort is required to advance the field of RCC molecular marker through systematic discovery, verification, and validation.

Collecting system invasion and Fuhrman grade but not tumor size facilitate prognostic stratification of patients with pT2 renal cell carcinoma.

PURPOSE: The 7th edition of TNM for renal cell carcinoma introduced a subdivision of pT2 tumors at a 10 cm cutoff. In the present multicenter study the influence of tumor size as well as further clinical and histopathological parameters on cancer specific survival in patients with pT2 tumors was evaluated. MATERIALS AND METHODS: A total of 670 consecutive patients with pT2 tumors (10.4%) of 6,442 surgically treated patients with all tumor stages were pooled (mean followup 71.4 months). Tumors were reclassified according to the current TNM classification, and subdivided in stages pT2a and pT2b. Cancer specific survival was analyzed using the Kaplan-Meier method, and univariable and multivariable analyses were used to assess the influence of several parameters on survival. RESULTS: Tumor size continuously applied and subdivided at 10 cm or alternative cutoffs did not significantly influence cancer specific survival. In addition to N/M stage, Fuhrman grade and collecting system invasion also had an independent influence on survival. Integration of a dichotomous variable subsuming Fuhrman grade and collecting system invasion (grade 3/4 and/or collecting system invasion present vs grade 1/2 and collecting system invasion absent) into multivariate models including established prognostic parameters resulted in improvement of predictive abilities by 11% (HR 2.3, p <0.001) for all pT2 cases and 151% (HR 3.1, p <0.001) for stage pT2N0M0 cases. CONCLUSIONS: Tumor size did not have a significant influence on cancer specific survival in pT2 tumors, neither continuously applied nor based on various cutoff values. To enhance prognostic discrimination, multifactorial staging systems including pathological features should be implemented. The prognostic relevance of the variable subsuming Fuhrman grade and collecting system invasion should be considered for future evaluation.

Tissue-based molecular markers for bladder cancer.

Bladder cancer is the second most common genitourinary malignancy in the United States, and is a major cause of morbidity and mortality. Despite aggressive treatment, survival for patients with muscle-invasive urothelial carcinoma of the bladder remains poor. Cancer stage, grade, and other clinical and pathological characteristics provide only limited prognostic information, and there is significant heterogeneity in patient outcomes using current risk stratification. Recent research into the profiling of bladder cancer at the molecular level has begun to shed light on important mechanisms of pathogenesis, as well as providing a number of potential tissue markers. These may provide useful prognostic information and guide patient selection for therapeutic strategies. This review explores recent advances in tissue-based molecular markers in bladder cancer and their potential utility. We also discuss design and statistical consideration for development and validation of molecular markers. A combination of complementary and yet independent molecular markers will likely better capture the biologic potential of each individual bladder tumor resulting in improved clinical decision-making.

Differential expression of KAI1 metastasis suppressor protein in renal cell tumor histological subtypes.

PURPOSE: The similar appearance of renal tumor histological subtypes can complicate differential diagnoses. This problem is most notable for the chromophobe subtype of renal cell carcinoma, which can be histologically indistinguishable from oncocytoma with investigational molecular markers failing to provide reliable differentiation. KAI1 is a metastasis suppressor gene whose expression correlates inversely with the metastatic potential of most solid tumor cancer types. We tested the hypothesis that KAI1 is differentially expressed among renal tumor histological subtypes. MATERIALS AND METHODS: Immunohistochemical staining for KAI1 protein was performed in 152 nephrectomy specimens, including 48 clear cell, 35 papillary and 31 chromophobe renal cell carcinoma samples, 28 oncocytomas and 10 tumor-free kidneys. Staining was scored as none/minimal, low, moderate or high. KAI1 mRNA levels were compared by quantitative reverse transcriptase-polymerase chain reaction in an additional 22 chromophobe renal cell carcinoma and oncocytoma samples. RESULTS: In all 10 tumor-free kidneys KAI1 protein was detected exclusively in distal tubule cell membranes. Of the tumor specimens KAI1 protein was absent in all papillary renal cell carcinoma specimens. It was present in only 1 of 48 clear cell renal cell carcinomas (2%) and 2 of 28 oncocytomas (7%) but only at low levels. In contrast, 27 of 31 chromophobe renal cell carcinoma specimens (87%) expressed KAI1 protein, most at moderate or high levels. The diagnostic accuracy of KAI1 immunostaining for discerning chromophobe renal cell carcinoma from oncocytoma was 90% with similar results observed at the RNA level. CONCLUSIONS: KAI1 is an accurate biomarker for chromophobe renal cell carcinoma that may aid in the diagnostic differentiation of chromophobe renal cell carcinoma from oncocytoma. It remains to be determined whether KAI1 expression contributes to the low metastatic potential of chromophobe renal cell carcinoma.

Diagnosis of renal tumors on needle biopsy specimens by histological and molecular analysis.

PURPOSE: We diagnosed the subtypes of renal cell carcinoma on needle core biopsies using a combination of histopathology and a molecular diagnostic algorithm. MATERIALS AND METHODS: Core biopsies were taken of renal tumors following nephrectomy. RNA was extracted and quantitative real-time polymerase chain reaction was performed for 4 gene products to differentiate among renal cell carcinoma subtypes. Histopathological diagnosis was achieved on a second core before and after obtaining the molecular diagnostic algorithm results. RESULTS: Based on the nephrectomy diagnosis 6 of 77 renal masses were nonneoplastic and 71 were tumors, including 65 renal cell carcinoma/oncocytomas. The overall diagnostic accuracy using histology and our molecular diagnostic algorithm combined was 90.0% (70 of 77). Side by side comparison of histology vs molecular diagnostic algorithm was feasible for 60 classifiable renal cell carcinoma/oncocytomas (31 clear cell, 14 papillary renal cell carcinoma, 6 chromophobe renal cell carcinoma, 2 mucinous tubular and spindle cell carcinoma, and 7 oncocytoma). In this group histology correctly predicted the final histological subtype in 83.3% (50 of 60) of cores. Addition of the molecular diagnostic algorithm to histology improved the subtyping accuracy to 95% (57 of 60), whereas the molecular diagnostic algorithm alone was accurate in 50 of 60 cases (83.3%). Dividing these 60 specimens into clear cell and nonclear cell neoplasms, the addition of the molecular diagnostic algorithm improved the sensitivity for the diagnosis of clear cell carcinoma from 87.1% (27 of 31) to 100% and the negative predictive value from 87.5% to 100%. CONCLUSIONS: Core biopsies of renal tumors provide adequate material for diagnosing and subtyping renal cell carcinoma. The addition of our molecular diagnostic algorithm to histology improved the diagnostic accuracy of core biopsies of renal masses.

Laser tissue welding - poised for the new millenium.

Laser tissue welding is a relatively new technique, which was initially described only about 30 years ago. Over the past 10 years, the implementation of protein solders has redefined the field. Alternative methods of wound closure and of tissue approximation have been quickly accepted in clinical medicine. The techniques and theory involved in performing laser tissue welding may soon be essential knowledge for all surgeons. Just as laparoscopy has become a mainstay for general surgeons and urologists, novel mechanisms of tissue approximation will continue to replace older, less efficacious techniques.

BCL-2 and p53 expression in clinically localized prostate cancer predicts response to external beam radiotherapy.

PURPOSE: Clinicians have long been hampered by the inability to distinguish patients with localized prostate cancer who will and will not respond to radiotherapy. In a significant proportion of patients therapy fails as determined by increasing posttreatment serum prostate specific antigen (PSA). We evaluated the expression of 2 key regulators of apoptosis, bcl-2 and p53, relative to treatment outcomes in patients who received external beam radiotherapy for clinically organ confined carcinoma of the prostate. MATERIALS AND METHODS: Immunohistochemical staining for bcl-2 and p53 on pretreatment needle biopsies was performed in 54 patients who were treated with radiotherapy for localized prostate cancer. Expression was scored using strict criteria. Nadir PSA less than 1 ng./ml. after therapy was considered a successful treatment response. RESULTS: There was a predominance of stage T1c cancer (74%) with a mean Gleason score of 6.9 and an average pretreatment PSA of 25.3 ng./ml. Overall 54% of the patients did not have a nadir PSA of less than 1 ng./ml. Of the bcl-2 positive cases therapy ultimately failed in 85%. Similarly 88% of the patients with p53 positive biopsies had treatment failure and in all with bcl-2 as well as p53 expression radiotherapy failed. Expression of bcl-2 and p53 was an independent prognostic variable for treatment failure with odds ratios (95% confidence interval) of 7.3 and 10.8, respectively. CONCLUSIONS: Expression of bcl-2 and p53 was associated with treatment failure after external beam radiation therapy. These findings suggest that bcl-2 and p53 expression in pretreatment biopsies may be helpful for predicting response to definitive radiotherapy.

Laser tissue welding.

Laser tissue welding is a technologic innovation that is beginning to move from the theoretical laboratory environment to the reality of clinical application. This article reviews the concepts, potential advantages, and techniques involved in laser tissue welding as they apply to urology.

Laser tissue welding: a urological surgeon's perspective.

Laser tissue welding has proven its efficacy in the laboratory setting when compared with more traditional modalities of tissue reapproximation. In the clinical environment, several areas including urethral reconstructive surgery have shown great promise. Several technological advancements including solder development, chromophore enhancement and temperature control have improved upon the welding process and have added more precision and reproducibility to the technique. The current potential applications for laser welding in urology are numerous. On a molecular level, growth factor supplementation has certain potential in improving upon weld site healing and wound strength. Laparoscopic surgery with its need for less cumbersome modes of tissue closure is a field that will greatly benefit from the technology of laser tissue welding. Surgical specialties outside of urology are also participating in developing the field of laser welding. In particular, cardiothoracic surgery, otolaryngology, plastic surgery, neurosurgery among others, have utilized the concept of laser tissue welding. There are many ares that have potential use for laser welding that have yet to be explored. Further investigation will likely reveal more applications for this valuable technology.