Impact of warm versus cold ischemia on renal function following partial nephrectomy.

INTRODUCTION: We evaluated renal function following partial nephrectomy with cold ischemia (CI) versus warm ischemia (WI). METHODS: Data were collected from 1,396 patients at six institutions who underwent partial nephrectomy for a renal mass with normal contralateral kidney to evaluate percent change in glomerular filtration rate (GFR) at 3-18 months. A multivariate linear regression model tested the association of percent change GFR with clinical, operative, and pathologic factors. RESULTS: A total of 874 patients (63 %) underwent PN with CI and 522 (37 %) with WI. All patients undergoing laparoscopic and robotic-assisted partial nephrectomy (n = 443) had WI, whereas 92 % of open partial nephrectomy patients (n = 953) had CI. The CI group had a lower mean baseline GFR (72 vs. 80 ml/min/1.73 m(2)), longer median ischemia time (33 vs. 29 min), and larger mean tumor size (3.2 vs. 2.9 cm) with more advanced pathologic stage (T1b-T3: 25 vs. 16 %) (all p values <0.001). Patients with CI and WI demonstrated 12.3 and 10.1 % reductions in renal function from baseline, respectively (p = 0.067). Increasing age, female gender, and increasing tumor size were associated with reduction in renal function (all p values <0.001). Neither renal hypothermia nor operative technique independently predicted reduced renal function. Sensitivity analyses limited to ischemia time >30 min, baseline estimated glomerular filtration rate <60 ml/min/1.73 m(2), or tumors >4 cm did not significantly alter the findings. CONCLUSIONS: Increasing age, female gender, and larger tumor size independently predict a decrease in renal function following partial nephrectomy with a normal contralateral kidney. Within the limitations of a non-randomized comparison, including lack of parenchymal preservation percentage, neither surgical approach (open or laparoscopic) nor presence of hypothermia appears to be associated with long-term renal function.

Increasing incidence of testicular cancer in the United States and Europe between 1992 and 2009.

PURPOSE: Increasing in incidence, testicular cancer is the most commonly diagnosed cancer in young men in the USA and in Europe. We sought to determine contemporary trends in testicular cancer incidence in the USA and Europe. METHODS: Testicular cancer incidence data covering the USA and Europe were extracted from the SEER-13 (SEER*Stat 8.0.1) and the EUREG databases, respectively. Trends were determined using JoinPoint 3.5.3. RESULTS: Testicular germ cell tumor (TGCT) incidence among US males >15 years increased from 1992 (5.7/100,000) to 2009 (6.8/100,000) with a significant annual percentage change (APC: 1.1%, p < 0.001). Seminomas were 29% of all TGCTs in 15-26 year-olds, increasing to 78% in those 40+ years of age. TGCT rates were highest in White men (1992: 7.5/100,000; 2009: 8.6/100,000) followed by Hispanic men (1992: 4.0/100,000; 2009: 6.3/100,000) and lowest among Asian (1992: 2.0/100,000; 2009: 2.8/100,000) and Black men (1992: 0.7/100,000; 2009: 1.7/100,000). Significantly increasing incidence rates were observed in White men (APC: 1.2%, p < 0.001) and most prominently in Hispanic men, especially from 2002 to 2009 (APC: 5.6%, p < 0.01). Incidence of testicular cancer increased in 15 of 19 (79%) European countries analyzed (p < 0.05). Denmark (13.4/100,000 man-years), Switzerland (12.7/100,000 man-years), and Norway (12.7/100,000 man-years) exhibited the highest age-standardized rates, while Spain had the greatest APC (APC = 5.5, 95% CI 3.9-7.0%, p < 0.001). CONCLUSIONS: Between 1992 and 2009, testicular cancer incidence in the USA and Europe continued to increase, most notably in US Hispanic, Northern European, Spanish, and younger and older populations.

How accurate is our clinical prediction of "minimal prostate cancer"?

BACKGROUND: Recommendations for active surveillance versus immediate treatment for low risk prostate cancer are based on biopsy and clinical data, assuming that a low volume of well-differentiated carcinoma will be associated with a low progression risk. However, the accuracy of clinical prediction of minimal prostate cancer (MPC) is unclear. OBJECTIVES: To define preoperative predictors for MPC in prostatectomy specimens and to examine the accuracy of such prediction. METHODS: Data collected on 1526 consecutive radical prostatectomy patients operated in a single center between 2003 and 2008 included: age, body mass index, preoperative prostate-specific antigen level, biopsy Gleason score, clinical stage, percentage of positive biopsy cores, and maximal core length (MCL) involvement. MPC was defined as < 5% of prostate volume involvement with organ-confined Gleason score < or = 6. Univariate and multivariate logistic regression analyses were used to define independent predictors of minimal disease. Classification and Regression Tree (CART) analysis was used to define cutoff values for the predictors and measure the accuracy of prediction. RESULTS: MPC was found in 241 patients (15.8%). Clinical stage, biopsy Gleason's score, percent of positive biopsy cores, and maximal involved core length were associated with minimal disease (OR 0.42, 0.1, 0.92, and 0.9, respectively). Independent predictors of MPC included: biopsy Gleason score, percent of positive cores and MCL (OR 0.21, 095 and 0.95, respectively). CART showed that when the MCL exceeded 11.5%, the likelihood of MPC was 3.8%. Conversely, when applying the most favorable preoperative conditions (Gleason < or = 6, < 20% positive cores, MCL < or = 11.5%) the chance of minimal disease was 41%. CONCLUSIONS: Biopsy Gleason score, the percent of positive cores and MCL are independently associated with MPC. While preoperative prediction of significant prostate cancer was accurate, clinical prediction of MPC was incorrect 59% of the time. Caution is necessary when implementing clinical data as selection criteria for active surveillance.

Short (≤ 1 mm) positive surgical margin and risk of biochemical recurrence after radical prostatectomy.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: It has been suggested that a very short positive margin does not confer additional risk of BCR after radical prostatectomy. This study shows that even very short PSM is associated with increased risk of BCR. OBJECTIVE: To re-evaluate, in a larger cohort with longer follow-up, our previously reported finding that a positive surgical margin (PSM) ≤ 1 mm may not confer an additional risk for biochemical recurrence (BCR) compared with a negative surgical margin (NSM). PATIENTS AND METHODS: Margin status and length were evaluated in 2866 men treated with radical prostatectomy (RP) for clinically localized prostate cancer at our institution from 1994 to 2009. We compared the BCR-free survival probability of men with NSMs, a PSM ≤ 1 mm, and a PSM < 1 mm using the Kaplan-Meier method and a Cox regression model adjusted for preoperative prostate-specific antigen (PSA) level, age, pathological stage and pathological Gleason score (GS). RESULTS: Compared with a NSM, a PSM ≤ 1 mm was associated with 17% lower 3-year BCR-free survival for men with pT3 and GS ≥ 7 tumours and a 6% lower 3-year BCR-free survival for men with pT2 and GS ≤ 6 tumours (log-rank P < 0.001 for all). In the multivariate model, a PSM ≤ 1 mm was associated with a probability of BCR twice as high as that for a NSM (hazard ratio [HR] 2.2), as were a higher PSA level (HR 1.04), higher pathological stage (HR 2.7) and higher pathological GS (HR 3.7 [all P < 0.001]). CONCLUSION: In men with non-organ-confined or high grade prostate cancer, a PSM ≤ 1 mm has a significant adverse impact on BCR rates.

Comparison of three different tools for prediction of seminal vesicle invasion at radical prostatectomy.

BACKGROUND: Statistical prediction tools are increasingly common, but there is considerable disagreement about how they should be evaluated. Three tools--Partin tables, the European Society for Urological Oncology (ESUO) criteria, and the Gallina nomogram--have been proposed for the prediction of seminal vesicle invasion (SVI) in patients with clinically localized prostate cancer who are candidates for a radical prostatectomy. OBJECTIVES: Using different statistical methods, we aimed to determine which of these tools should be used to predict SVI. DESIGN, SETTINGS, AND PARTICIPANTS: The independent validation cohort consisted of 2584 patients treated surgically for clinically localized prostate cancer at four North American tertiary care centers between 2002 and 2007. INTERVENTIONS: Robot-assisted laparoscopic radical prostatectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary outcome was the presence of SVI. Traditional (area under the receiver operating characteristic [ROC] curve, calibration plots, the Brier score, sensitivity and specificity, positive and negative predictive value) and novel (decision curve analysis and predictiveness curves) statistical methods quantified the predictive abilities of the three models. RESULTS AND LIMITATIONS: Traditional statistical methods (ie, ROC plots and Brier scores) could not clearly determine which one of the three SVI prediction tools should be preferred. For example, ROC plots and Brier scores seemed biased against the binary decision tool (ESUO criteria) and gave discordant results for the continuous predictions of the Partin tables and the Gallina nomogram. The results of the calibration plots were discordant with those of the ROC plots. Conversely, the decision curve indicated that the Partin tables represent the best strategy for stratifying the risk of SVI, resulting in the highest net benefit within the whole range of threshold probabilities. CONCLUSIONS: When predicting SVI, surgeons should prefer the Partin tables over the ESUO criteria and the Gallina nomogram because this tool provided the highest net benefit. In contrast to traditional statistical methods, decision curve analysis gave an unambiguous result applicable to both continuous and binary models, providing an insight into clinical utility.

Hazard of prostate cancer specific mortality after radical prostatectomy.

PURPOSE: Hazard is defined as an event rate at a certain time that is conditional on survival until that time. For most patients with localized malignancies the mortality hazard decreases with time after an initial period of high failure risk. We assessed prostate cancer specific mortality hazard changes with time in men treated with radical prostatectomy. MATERIALS AND METHODS: The cohort included 127,236 men from the SEER (Surveillance, Epidemiology and End Results) database who were treated with RP between 1988 and 2003. Pathological stage was organ confined in 38,684 men (30%), nonorgan confined in 41,806 (33%) and unstaged in 46,746 (37%). Gleason score 7 or less was present in 100,816 men (79%) and Gleason score 8 or greater in 26,420 (21%). Patients were stratified into groups, including group 1­71,106 (59%) with Gleason score 7 or less, organ confined, group 2­23,063 (19%) with Gleason score 7 or less, nonorgan confined, group 3­13,660 (12%) with Gleason score 8 or greater, organ confined and group 4­12,158 (10%) with Gleason score 8 or greater, nonorgan confined tumors. Median followup was 7.2 years (range 0 to 19). Hazard was estimated from a Cox regression model including patient age, race, stage and grade. RESULTS: The overall annual prostate cancer specific mortality hazard rate was 0.4%, 0.7% and 1% 5, 10 and 15 years after radical prostatectomy, respectively. Between 5 and 15 years after radical prostatectomy the hazard increased annually from 0.2% to 0.5% in group 1, from 0.5% to 1.2% in group 2, from 0.7% to 1.6% in group 3 and from 1.5% to 3.7% in group 4. CONCLUSIONS: In contrast to other prevalent cancers, the hazard of prostate cancer specific mortality shows a modest, constant increase for at least 15 years after radical prostatectomy.

Laparoscopic partial nephrectomy versus laparoscopic ablative therapy: a comparison of surgical and functional outcomes in a matched control study.

BACKGROUND AND PURPOSE: Patients who are undergoing laparoscopic ablative therapy (LAT) are often older with more comorbidities in comparison with patients who are undergoing laparoscopic partial nephrectomy (LPN). A matched control study was performed to compare the surgical and functional outcomes of LPN and LAT. PATIENTS AND METHODS: A prospectively maintained database of 250 patients who underwent nephron-sparing surgery was explored. Fifty-one LAT patients (21 and 30 laparoscopic radiofrequency and cryoablation, respectively) were matched with 51 LPN patients. A comparison of preoperative, operative, and postoperative outcomes was performed. RESULTS: The groups were similar in age, sex, body mass index, preoperative estimated glomerular filtration rate (eGFR), number of comorbidities and tumor size. Patients who were undergoing LAT had a lower incidence of endophytic tumor and higher incidence of upper pole and midpolar tumors. Hilar vessels clamping was performed in LPN (47/51 patients). Mean estimated blood loss and operative time were higher in those undergoing LPN (P<0.01). There was no significant difference in transfusion rate and hospital stay, however. Mean follow-up was 27 and 18 months in LAT and LPN, respectively (P<0.01). The mean percent decline of eGFR at the last follow-up was 10 (95% confidence interval [CI]: 4-15) and 7.5 (95% CI: 4-11), respectively (P<0.43). In comparison with baseline, eGFR declined significantly (P<0. 01), but there was no difference between the groups. CONCLUSION: Despite renal ischemia, longer operative time, and higher blood loss associated with LPN, the hospital stay and long-term functional outcomes are similar to those of LAT in a matched control study.

Clinical and histologic predictors of renal function decline after laparoscopic partial nephrectomy.

BACKGROUND AND PURPOSE: Clinical and surgical factors predict renal function decline after laparoscopic partial nephrectomy (LPN). Additional histopathologic predictors may be found in the specimen's nonneoplastic tissue but were not studied. This study investigated the significance of histologic findings in addition to other known predictors of renal function after LPN. PATIENTS AND METHODS: Data of 150 patients who underwent LPN was analyzed. Renal function changes (median follow-up 15 months) were correlated with perioperative and histopathologic parameters. Three histopathologic features were evaluated and graded in the nonneoplastic parenchyma: Glomerulosclerosis, arteriosclerosis (AS), and interstitial fibrosis/tubular atrophy. Estimated GFR (eGFR) and percent decline on postoperative day 1 (POD1) and at the last follow-up were measured. RESULTS: Median eGFR percent decline at POD1 and last follow-up was -17 and -10, respectively (P<0.001). New-onset ≥stage III chronic kidney disease developed in only 7% of the patients. Three factors independently predicted POD1 eGFR decline: Artery and vein clamping vs artery only clamping (P=0.002), male sex (P=0.015), and larger tumor (P=0.02). Long-term loss of renal function was associated with POD1 eGFR decline (P=0.002) and the percentage of AS (P=0.01). The study limitations include a retrospective analysis leading to variability in the follow-up length and a small size cohort. CONCLUSIONS: LPN is associated with a favorable renal function outcome in most patients. Pathologic findings in the nonneoplastic tissue, in addition to clinical parameters, can be used to predict which patients are more likely to experience renal function impairment.

Positive surgical margins after robotic assisted radical prostatectomy: a multi-institutional study.

PURPOSE: Positive surgical margins are an independent predictive factor for biochemical recurrence after radical prostatectomy. We analyzed the incidence of and associative factors for positive surgical margins in a multi-institutional series of 8,418 robotic assisted radical prostatectomies. MATERIALS AND METHODS: We analyzed the records of 8,418 patients who underwent robotic assisted radical prostatectomy at 7 institutions. Of the patients 323 had missing data on margin status. Positive surgical margins were categorized into 4 groups, including apex, bladder neck, posterolateral and multifocal. The records of 6,169 patients were available for multivariate analysis. The variables entered into the logistic regression models were age, body mass index, preoperative prostate specific antigen, biopsy Gleason score, prostate weight and pathological stage. A second model was built to identify predictive factors for positive surgical margins in the subset of patients with organ confined disease (pT2). RESULTS: The overall positive surgical margin rate was 15.7% (1,272 of 8,095 patients). The positive surgical margin rate for pT2 and pT3 disease was 9.45% and 37.2%, respectively. On multivariate analysis pathological stage (pT2 vs pT3 OR 4.588, p<0.001) and preoperative prostate specific antigen (4 or less vs greater than 10 ng/ml OR 2.918, p<0.001) were the most important independent predictive factors for positive surgical margins after robotic assisted radical prostatectomy. Increasing prostate weight was associated with a lower risk of positive surgical margins after robotic assisted radical prostatectomy (OR 0.984, p<0.001) and a higher body mass index was associated with a higher risk of positive surgical margins (OR 1.032, p<0.001). For organ confined disease preoperative prostate specific antigen was the most important factor that independently correlated with positive surgical margins (4 or less vs greater than 10 ng/ml OR 3.8, p<0.001). CONCLUSIONS: The prostatic apex followed by a posterolateral site was the most common location of positive surgical margins after robotic assisted radical prostatectomy. Factors that correlated with cancer aggressiveness, such as pathological stage and preoperative prostate specific antigen, were the most important factors independently associated with an increased risk of positive surgical margins after robotic assisted radical prostatectomy.

Gleason 6 prostate cancer in one or two biopsy cores can harbor more aggressive disease.

BACKGROUND AND PURPOSE: Patients with Gleason (GL) 6 prostate cancer in one or two biopsy cores can be upgraded and/or upstaged at the time of surgery, which may adversely impact long-term outcome. A novel model for prediction of adverse pathologic outcomes was developed using preoperative characteristics. PATIENTS AND METHODS: Between 2003 and 2007, 1159 patients underwent robot-assisted radical prostatectomy (RARP) at our institution. GL 6 prostate cancer in one or two biopsy cores was identified in 416 (36%) patients. Logistic regression analyses were used to assess the rate of GL ≥7 and/or extraprostatic extension at RARP. Covariates consisted of age, body mass index (BMI), number of positive cores, greatest percent of cancer in a core (GPC), clinical stage, and preoperative prostate-specific antigen (PSA) level. After backward variable selection, the developed model was internally validated using the area under the curve and subjected to methods of calibration. RESULTS: Respectively, 278 (67%) and 138 (33%) patients had one or two positive biopsy cores. At RARP, 90 (22%) patients were upgraded to GL ≥7 and 37 (9%) had extraprostatic extension. The novel model relied on age, BMI, preoperative PSA level, and GPC for prediction of adverse pathologic outcomes and was 69% accurate. Calibration plot revealed a virtually perfect relationship between predicted and observed probabilities. CONCLUSIONS: In patients with GL 6 prostate cancer in one or two biopsy cores, 25% have more ominous pathology at RARP. The model provides an individual assessment of adverse outcomes at surgery. Consequently, it may be considered when counseling patients regarding their management options.

Impact of prostate weight on probability of positive surgical margins in patients with low-risk prostate cancer after robotic-assisted laparoscopic radical prostatectomy.

OBJECTIVE: To evaluate the impact of prostate weight (PW) on probability of positive surgical margin (PSM) in patients undergoing robotic-assisted radical prostatectomy (RARP) for low-risk prostate cancer. METHODS: The cohort consisted of 690 men with low-risk prostate cancer (clinical stage T1c, prostate-specific antigen <10 ng/mL, biopsy Gleason score ≤6) who underwent RARP with bilateral nerve-sparing at our institution by 1 of 2 surgeons from 2003 to 2009. PW was obtained from the pathologic specimen. The association between probability of PSM and PW was assessed with univariate and multivariate logistic regression analysis. RESULTS: A PSM was identified in 105 patients (15.2%). Patients with PSM had significant higher prostate-specific antigen (P = .04), smaller prostates (P = .0001), higher Gleason score (P = .004), and higher pathologic stage (P < .0001). After logistic regression, we found a significant inverse relation between PSM and PW (OR 0.97%; 95% confidence interval [CI] 0.96, 0.99; P = .0003) in univariate analysis. This remained significant in the multivariate model (OR 0.98%; 95% CI 0.96, 0.99; P = .006) adjusting for age, body mass index, surgeon experience, pathologic Gleason score, and pathologic stage. In this multivariate model, the predicted probability of PSM for 25-, 50-, 100-, and 150-g prostates were 22% (95% CI 16%, 30%), 13% (95% CI 11%, 16%), 5% (95% CI 1%, 8%), and 1% (95% CI 0%, 3%), respectively. CONCLUSIONS: Lower PW is independently associated with higher probability of PSM in low-risk patients undergoing RARP with bilateral nerve-sparing.

Chronic kidney disease before and after partial nephrectomy.

PURPOSE: We performed a multi-institutional retrospective cohort study to evaluate baseline renal function of patients who underwent partial nephrectomy for renal tumors, and determined rates of progression to higher stages of chronic kidney disease. MATERIALS AND METHODS: The Modification of Diet in Renal Disease study equation was used to estimate glomerular filtration rate. Preoperative and postoperative serum creatinine values were obtained from patients who underwent partial nephrectomy at 6 institutions with a normal contralateral kidney, and had baseline chronic kidney disease stage I (estimated glomerular filtration rate greater than 90 ml/minute/1.73 m(2)), II (estimated glomerular filtration rate 60 to 89 ml/minute/1.73 m(2)) or III (estimated glomerular filtration rate 30 to 59 ml/minute/1.73 m(2)). The end point was change in chronic kidney disease stage at long-term followup (3 to 18 months). Multivariate logistic and Cox regression models tested the association of newly acquired chronic kidney disease stage III or greater with pertinent demographic, tumor and surgical factors. RESULTS: For 1,228 patients with followup creatinine data at least 3 months after partial nephrectomy median baseline glomerular filtration rate was 74 ml/minute/1.73 m(2). At baseline 19%, 59% and 22% of patients had chronic kidney disease stage I, II and III, respectively. At long-term followup for patients with baseline chronic kidney disease stage I or II median postoperative glomerular filtration rate was 67 ml/minute/1.73 m(2) with 29% having progression to chronic kidney disease stage III or greater. Increasing age, female gender, increasing tumor size, clamping of the renal artery and vein, and lower preoperative estimated glomerular filtration rate were independently associated with newly acquired chronic kidney disease stage III or greater. The presence of comorbid conditions such as coronary artery disease, diabetes mellitus or hypertension did not independently predict an increased risk of higher chronic kidney disease stage. CONCLUSIONS: Chronic kidney disease stage III or greater will develop postoperatively in approximately a third of patients with an estimated glomerular filtration rate greater than 60 ml/minute/1.73 m(2), and this progression is associated with definable demographic, tumor and surgical factors.

Cisplatin tumor biodistribution and efficacy after intratumoral injection of a biodegradable extended release implant.

Local delivery of chemotherapeutic drugs has long been recognized as a potential method for reaching high drug doses at the target site while minimizing systemic exposure. Cisplatin is one of the most effective chemotherapeutic agents for the treatment of various tumors; however, its systemic toxicity remains the primary dose-limiting factor. Here we report that incorporation of cisplatin into a fatty acid-based polymer carrier followed by a local injection into the solid tumor resulted in a successful tumor growth inhibition in heterotopic mouse bladder tumor model in mice. Platinum concentration in the tumor tissue surrounding the injected implant remained above the therapeutic level up to 14 days after the injection, while the plasma levels were several orders of magnitude lower comparing to systemic delivery. The reported delivery system increased the maximum tolerated dose of cisplatin 5 times compared to systemic delivery, thus potentially improving antitumor efficacy of cisplatin in solid tumor model.

Application of ice cold irrigation during vascular pedicle control of robot-assisted radical prostatectomy: EnSeal instrument cooling to reduce collateral thermal tissue damage.

BACKGROUND AND PURPOSE: Energy-based hemostasis of the prostatic vascular pedicles (PVP) during robot-assisted radical prostatectomy (RARP) may cause collateral thermal injury to adjacent neural tissue and has been shown to negatively impact sexual function recovery. The unique engineering design of the EnSeal(®) (Ethicon, Cincinnati, OH) has been demonstrated to limit collateral thermal tissue damage to <1.0 mm. Use of tissue and instrument cooling before and during device activation may potentially further reduce thermal spread. As such, we sought to evaluate the collateral tissue effects of EnSeal with or without cold saline irrigation (CSI) during PVP control. PATIENTS AND METHODS: The EnSeal Trio device was used for PVP control in 20 consecutive men undergoing bilateral, non-nerve-sparing RARP. Ipsilateral vascular pedicles were randomly selected to EnSeal plus CSI (<4 °C) application to the tissue before and during device activation or EnSeal alone. The primary end point was the distance of thermal injury from the inked margin using both hematoxylin and eosin (H&E) and terminal transferase uridyl nick end-labeling (TUNEL) apoptosis staining. A mean of three measurements was taken for each pedicle. Pathologic analysis was performed by a single, blinded uropathologist. RESULTS: Mean distance of thermal injury from the inked margin using H&E staining was 0.31 mm (range 0.15-0.40 mm) and 0.98 mm (range 0.7-1.2 mm) for the EnSeal plus CSI and EnSeal alone, respectively (P < 0.0001). TUNEL staining also demonstrated lateral tissue damage of 0.39 mm (range 0.2-0.5 mm) and 1.12 mm (range 0.9-1.3 mm), respectively (P < 0.001). No complications related to hemostasis or postoperative bleeding were observed in the study. CONCLUSIONS: The hemostatic properties of EnSeal work effectively when submerged in CSI. Adjacent thermal tissue damage is significantly minimized with the addition of CSI. This may have a beneficial impact on nerve preservation and sexual function outcomes after RARP.