Risk factors for bladder cancer recurrence after nephroureterectomy for upper tract urothelial tumors: results from the Canadian Upper Tract Collaboration.

OBJECTIVE: To evaluate risk factors for bladder cancer recurrence in a cohort of patients treated with radical nephroureterectomy (RNU). PATIENTS AND METHODS: At 10 Canadian University Centers, we retrospectively evaluated data, between 1990 and 2010, from 743 patients who were free from bladder cancer and were previously treated with RNU for upper tract urothelial cancer. RESULTS: Of 743 patients, 167 (22.5%) developed bladder tumors after a median time of 17.2 months after RNU. Multivariable analysis detected age (hazard ratio [HR] = 1.028; 95% CI: 1.010-1.046; P = 0.0018), tumor location in both the renal pelvis and the ureter (HR = 2.205; 95% CI: 1.355-3.589; P = 0.0015), the use of adjuvant systemic chemotherapy (HR = 2.309; 95% CI: 1.439-3.705; P = 0.0005), and laparoscopic surgery (HR = 1.876; 95% CI: 1.226-2.87; P = 0.0037) as risk factors for bladder cancer recurrence. Open excision of a bladder cuff (HR = 0.661; 95% CI: 0.453-0.965; P = 0.0319) and transurethral resection of the intramural ureter (HR = 0.548; 95% CI: 0.306-0.981; P = 0.0429) on comparison with extravesical resection decreased the risk of bladder cancer recurrence significantly. Major limitations were the retrospective design and partially missing data, although the significance of variables did not change in the imputation analysis. CONCLUSION: Older patients, those with tumor location in both the renal pelvis and the ureter, and those treated with adjuvant systemic chemotherapy were found at higher risk for intravesical recurrence, as were those having undergone extravesical ureterectomy or laparoscopic RNU.

Gender differences in benign renal masses.

PURPOSE: To examine gender-specific differences in benign renal tumors. METHODS: This retrospective study included 135 adult Caucasian patients with 143 benign renal tumors, which were treated surgically at a single institution. Demographics, comorbidity, histology, renal function, and management were compared by gender. A systematic review and meta-analysis of the literature were performed. RESULTS: A total of 73 women were compared with 62 men. The female-to-male ratio was significantly higher in patients with benign renal tumors than in those with renal cell carcinoma (1.18:1 vs. 0.57:1, p < 0.001). Only 17 % of benign renal tumors were correctly classified by preoperative computed tomography. The most frequently observed histological types were oncocytoma (44 %) and angiomyolipoma (37 %). Angiomyolipoma occurred more than twice as often in women than in men (72 vs. 28 %), while oncocytoma was more frequently found in men (59 vs. 41 %, p = 0.001). Men with benign renal tumors were older (p = 0.002) and had higher body mass indices (p = 0.019), higher comorbidity indices (p < 0.001), lower ECOG performance status (p < 0.001), and smaller tumors (p = 0.045). No differences were seen in pack years, mode of diagnosis, bilaterality, renal function, use of laparoscopic surgery, and the rate of radical nephrectomy. In the meta-analysis of 9,665 renal tumors, women had a 2.55-fold increased chance of benign pathology and a greater chance of angiomyolipoma (OR 4.66) than men. CONCLUSIONS: This study demonstrated several gender-specific differences in benign renal tumors, especially in the histological types. Despite this, clinical-pathological features and management of benign renal tumors in men and women appear more alike than different.

The impact of solitary and multiple positive surgical margins on hard clinical end points in 1712 adjuvant treatment-naive pT2-4 N0 radical prostatectomy patients.

BACKGROUND: Positive surgical margins (PSMs) increase the risk of biochemical recurrence (BCR) after radical prostatectomy (RP), but their impact on hard clinical end points is a topic of ongoing discussion. OBJECTIVE: To evaluate the influence of solitary PSMs (sPSMs) and multiple PSMs (mPSMs) on important clinical end points. DESIGN, SETTING, AND PARTICIPANTS: Data from 1712 patients from the Centre Hospitalier Universitaire de Québec with pT2-4 N0 prostate cancer (PCa) and undetectable prostate-specific antigen after RP were analyzed. INTERVENTION: RP without neoadjuvant or adjuvant treatment. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier analysis estimated survival functions, and Cox proportional hazards models addressed predictors of clinical end points. RESULTS AND LIMITATIONS: Median follow-up was 74.9 mo. A total of 1121 patients (65.5%) were margin-negative, 281 patients (16.4%) had sPSMs, and 310 patients (18.1%) had mPSMs. A total of 280 patients (16.4%) experienced BCR, and 197 patients (11.5%) were treated with salvage radiotherapy (SRT). Sixty-eight patients (4.0%) received definitive androgen deprivation therapy, 19 patients (1.1%) developed metastatic disease, and 15 patients (0.9%) had castration-resistant PCa (CRPC). Thirteen patients (0.8%) died from PCa, and 194 patients (11.3%) died from other causes. Ten-year Kaplan-Meier estimates for BCR-free survival were 82% for margin-negative patients, 72% for patients with sPSMs, and 59% for patients with mPSMs (p<0.0001). Time to metastatic disease, CRPC, PCa-specific mortality (PCSM), or all-cause mortality did not differ significantly among the three groups (p=0.991, p=0.988, p=0.889, and p=0.218, respectively). On multivariable analysis, sPSMs and mPSMs were associated with BCR (hazard ratio [HR]: 1.711; p=0.001 and HR: 2.075; p<0.0001), but sPSMs and mPSMs could not predict metastatic disease (p=0.705 and p=0.242), CRPC (p=0.705 and p=0.224), PCSM (p=0.972 and p=0.260), or all-cause death (p=0.102 and p=0.067). The major limitation was the retrospective design. CONCLUSIONS: In a cohort of patients who received early SRT in 70% of cases upon BCR, sPSMs and mPSMs predicted BCR but not long-term clinical end points. Adjuvant radiotherapy for margin-positive patients might not be justified, as only a minority of patients progressed to end points other than BCR. PCSM was exceeded 15-fold by competing risk mortality.

Multicenter validation of the prognostic value of patient age in patients treated with radical cystectomy.

PURPOSE: Small studies have suggested that older patients have worse outcomes following radical cystectomy (RC) for urothelial carcinoma of the bladder (UCB). We evaluated the association of patient age with clinical outcomes in a large multi-institutional RC series. METHODS: Data were collected from 4,429 patients treated with RC and lymphadenectomy for UCB without neoadjuvant chemotherapy. Age at RC was analyzed both as a continuous and categorical variable. RESULTS: Higher age at RC, analyzed as a continuous or categorical variable, was associated with advanced pathologic stage (P < 0.001), higher tumor grade (P = 0.045), presence of lymphovascular invasion (P = 0.018), and positive soft-tissue surgical margin status (P = 0.004). Elderly patients were less likely to receive postoperative chemotherapy (P < 0.001). In multivariable analyses, higher age was associated with disease recurrence, cancer-specific, and overall mortality (P < 0.001). Patients ≥ 80 years had a significantly greater risk of cancer-specific mortality than patients <50 years (HR 1.763, P < 0.001). Age minimally improved the accuracy of a base model that included standard pathologic features for prediction of disease recurrence (+0.2-0.3%) and cancer-specific survival (+0.3%). Conversely, age improved the predictive accuracy for overall survival by a sizeable margin (+4.2-4.5%). CONCLUSIONS: This large external validation study confirms that advanced patient age is minimally but significantly associated with worse prognosis after RC. Nevertheless, a large proportion of elderly patients benefitted from RC with curative intent. We need to improve our understanding of the reasons for the worse UCB outcomes in this growing segment of the population and to develop strategies to improve cancer care in the elderly.

Perioperative, oncologic, and functional outcomes of laparoscopic renal cryoablation and open partial nephrectomy: a matched pair analysis.

PURPOSE: To directly compare perioperative, oncologic, and functional outcomes of laparoscopic renal cryoablation and open partial nephrectomy using a matched pair analysis. PATIENTS AND METHODS: A total of 41 patients who underwent laparoscopic cryoablation for an incidental, solid clinical T(1a)N(0)M(0) renal tumor were matched with 82 patients who received partial nephrectomy in cold ischemia, using optimal matching based on propensity scores, which were created on the basis of preoperative aspects and dimensions used for an anatomic classification of renal tumors (PADUA) score, preoperative glomerular filtration rate, age-adjusted Charlson comorbidity index, and sex. Median follow-up was 33.6 months. RESULTS: No differences in the overall incidence of complications (cryoablation, 20%; partial nephrectomy, 17%; P=0.739) and grade of complications (P=0.424) were observed. After cryoablation, local recurrence developed in four patients with renal-cell carcinoma (n=35) after a median duration of 14 months (range 6-18 mos), but none after partial nephrectomy. The 3-year recurrence-free survival probabilities after laparoscopic renal cryoablation vs open partial nephrectomy were 83% vs 100%, respectively (P=0.015). The average decrease of estimated glomerular filtration rate during follow-up was 7.8±3.1 mL/min/1.73 m(2) after laparoscopic cryoablation and 9.8±2.3 mL/min/1.73 m(2) after open partial nephrectomy, which was not statistically significant (P=0.602). CONCLUSIONS: Perioperative complications and renal functional outcomes of laparoscopic cryoablation and open partial nephrectomy are similar; however, laparoscopic cryoablation confers a substantially higher local recurrence risk of about 17% after 3 years. Therefore, laparoscopic renal cryoablation should be reserved for high-risk patients with decreased life expectancy. Careful patient counseling is advocated. Study limitations include the small sample size, the lack of randomization, and the short follow-up.

Fluorescence cystoscopy with high-resolution optical coherence tomography imaging as an adjunct reduces false-positive findings in the diagnosis of urothelial carcinoma of the bladder.

BACKGROUND: The advantage of photodynamic diagnosis in detecting urothelial cell carcinoma (UCC) of the bladder has been demonstrated clearly, but it comes at the price of a higher false-positive rate. Optical coherence tomography (OCT) is a noninvasive, real-time, microstructural imaging modality that uses near-infrared light for a point analysis of the bladder-wall microstructure. OBJECTIVE: To evaluate whether adding targeted OCT analysis of lesions that are suspicious at white-light (WL) and hexaminolevulinate (HAL) fluorescence cystoscopy improves diagnostic accuracy in the detection of UCC. DESIGN, SETTING, AND PARTICIPANTS: In this prospective single-center study with same-patient comparison, patients with suspected UCC first received an intravesical instillation of HAL. Cystoscopy was performed in WL, followed by blue-light inspection and OCT scanning. INTERVENTION: Suspicious lesions identified by WL or HAL were evaluated by OCT and were subsequently resected or biopsied. MEASUREMENTS: We measured changes in sensitivity and specificity in detecting UCC using WL, HAL, and targeted OCT. RESULTS AND LIMITATIONS: In 66 patients studied, 232 lesions were detected, were scanned by OCT, and were subsequently resected or biopsied. Additionally, 132 areas of normal-appearing urothelium were investigated by all three methods and biopsied. On a per-lesion basis, sensitivity and specificity were respectively 69.3% and 83.7% for WL, 97.5% and 78.6% for HAL, and 97.5% and 97.9% for HAL combined with OCT. Overall, UCC was diagnosed in 58 patients (87.9%), with a per-patient sensitivity of 89.7% for WL and 100% for both HAL alone and HAL with targeted OCT. Per-patient specificity for HAL alone and targeted HAL was 62.5% and 87.5%, respectively. The limitation of OCT results from poor visualization of flat lesions in WL, making scanning a time-consuming procedure. CONCLUSIONS: Combining fluorescence cystoscopy with targeted OCT increases the specificity of fluorescence cystoscopy significantly, with no added morbidity, and reduces the need for unnecessary (false-positive) biopsies.

A novel approach to energy ablative therapy of small renal tumours: laparoscopic high-intensity focused ultrasound.

OBJECTIVE: High-intensity focused ultrasound (HIFU) permits targeted homogeneous ablation of tissue. The objective of this phase 1 study was to evaluate the feasibility of HIFU ablation of small renal tumours under laparoscopic control. PATIENTS AND METHODS: Ten kidneys with solitary renal tumours were treated with a newly developed 4.0 MHz laparoscopic HIFU probe. In the first two patients with 9-cm tumours, a defined marker lesion was placed prior to laparoscopic radical nephrectomy. In eight patients with a mean tumour size of 22 mm (range, 11-40), the tumour was completely ablated as in curative intent, followed by laparoscopic partial nephrectomy in seven tumours. One patient had post-HIFU biopsies and was followed radiologically. Specimens were studied by detailed and whole-mount histology, including NADH stains. RESULTS: Mean HIFU insonication time was 19 min (range, 8-42), with a mean targeted volume of 10.2 cm3 (range, 9-23). At histological evaluation both marker lesions showed irreversible and homogeneous thermal damage within the targeted site. Of the seven tumours treated and removed after HIFU, four showed complete ablation of the entire tumour. Two had a 1- to 3-mm rim of viable tissue immediately adjacent to where the HIFU probe was approximated, and one tumour showed a central area with about 20% vital tissue. There were no intra- or postoperative complications related to HIFU. CONCLUSION: The morbidity of laparoscopic partial nephrectomy mainly comes from the need to incise highly vascularized parenchyma. Targeted laparoscopic HIFU ablation may render this unnecessary, but further studies to refine the technique are needed.

'Skipping' is still a problem with radiofrequency ablation of small renal tumours.

OBJECTIVE: To evaluate the homogeneity and extent of necrosis obtained with next-generation radiofrequency ablation (RFA) equipment and techniques, as incomplete tumour necrosis, or 'skipping', has been documented after RFA of renal tumours and subsequent partial nephrectomy, but this was assumed to result from insufficient energy deposition with first-generation low-energy generators. PATIENTS AND METHODS: In all, 17 patients with solitary renal tumours of 0.5-1.0 cm beyond the sonographically controlled tumour borders. Target temperatures of 105 degrees C were applied in three cycles for 10-30 min at up to 150 W. Tumours were then removed by laparoscopic partial nephrectomy and specimens evaluated by detailed histology. RESULTS: The mean (range) resected tumour size was 22 (11-40) mm, the mean RFA time was 39 (27-59) min and the mean surgical resection time was 25 (12-45) min. In 13 patients, haemostasis was sufficient to avoid the renal pedicle being clamped. Intraoperative repeated positive margins in one patient required a laparoscopic radical nephrectomy. Thirteen (76%) renal masses showed histologically complete ablation of the entire tumour. Of the four RFA failures, three tumours were >3 cm in diameter, two were highly vascularized and three had a very heterogeneous tissue texture. CONCLUSION: Even with state-of-the-art technology, skipping remains a problem with RFA for small renal masses and renders the technique unreliable.

Differentiation between cell death modes using measurements of different soluble forms of extracellular cytokeratin 18.

Cytokeratins are released from carcinoma cells by unclear mechanisms and are commonly used serum tumor markers (TPA, TPS, and CYFRA 21-1). We here report that soluble cytokeratin-18 (CK18) is released from human carcinoma cells during cell death. During necrosis, the cytosolic pool of soluble CK18 was released, whereas apoptosis was associated with significant release of caspase-cleaved CK18 fragments. These results suggested that assessments of different forms of CK18 in patient sera could be used to examine cell death modes. Therefore, CK18 was measured in local venous blood collected during operation of patients with endometrial tumors. In most patient sera, caspase-cleaved fragments constituted a minor fraction of total CK18, suggesting that tumor apoptosis is not the main mechanism for generation of circulating CK18. Monitoring of different CK18 forms in peripheral blood during chemotherapy of prostate cancer patients showed individual differences in the patterns of release. Importantly, several examples were observed where the increase of apoptosis-specific caspase-cleaved CK18 fragments constituted only a minor fraction of the total increase. These results suggest that cell death of epithelially derived tumors can be assessed in patient serum and suggest that tumor apoptosis may not necessarily be the dominating death mode in many tumors in vivo.