Development and external validation of a nomogram predicting disease specific survival after nephrectomy for papillary renal cell carcinoma.

PURPOSE: We developed and externally validated a prognostic nomogram specifically for papillary renal cell carcinoma. MATERIALS AND METHODS: We retrospectively studied 435 patients who underwent radical or partial nephrectomy for papillary renal cell carcinoma at 3 institutions. Slides were reviewed by 1 uropathologist per institution. We constructed a nomogram predicting 5-year disease specific survival as a graphic representation of significant variables on multivariate Cox proportional hazards regression analysis using data on 258 patients from 2 of the 3 institutions. Nomogram discrimination and calibration were assessed by bootstrapping to obtain relatively unbiased estimates. External validation was done in 177 patients from a third institution. RESULTS: At a median 50.8-month followup 77 papillary renal cell carcinoma related deaths had occurred. In the multivariate Cox proportional hazards model incidental detection, T classification, M classification, vascular invasion and tumor necrosis extent were retained as independent prognostic factors of disease specific survival and formed the basis of the nomogram. The nomogram predicted well with a 93.6% bootstrapped corrected concordance index and showed good calibration. External independent validation revealed 94.2% predictive accuracy. CONCLUSIONS: We developed a highly accurate tool specifically for papillary renal cell carcinoma using basic clinical and pathological information to predict disease specific survival. This tool should be helpful to identify papillary renal cell carcinoma with aggressive clinical behavior and may contribute to the ability to individualize postoperative surveillance and therapy.

Long Non-Coding RNA PANTR1 is Associated with Poor Prognosis and Influences Angiogenesis and Apoptosis in Clear-Cell Renal Cell Cancer.

POU3F3 adjacent non-coding transcript 1 (PANTR1) is an oncogenic long non-coding RNA with significant influence on numerous cellular features in different types of cancer. No characterization of its role in renal cell carcinoma (RCC) is yet available. In this study, PANTR1 expression was confined to human brain and kidney tissue and was found significantly up-regulated in clear-cell renal cell carcinoma tissue (ccRCC) compared to non-cancerous kidney tissue in two independent cohorts (p < 0.001 for both cohorts). In uni- and multivariate Cox regression analysis, ccRCC patients with higher levels of PANTR1 showed significantly poorer disease-free survival in our own respective cohort (n = 175, hazard ratio: 4.3, 95% confidence interval: 1.45-12.75, p = 0.008) in accordance with significantly poorer overall survival in a large The Cancer Genome Atlas database (TCGA) cohort (n = 530, hazard ratio: 2.19, 95% confidence interval: 1.59-3.03, p ≤ 0.001). To study the underlying cellular mechanisms mediated by varying levels of PANTR1 in kidney cancer cells, we applied siRNA-mediated knock-down experiments in three independent ccRCC cell lines (RCC-FG, RCC-MF, 769-P). A decrease in PANTR1 levels led to significantly reduced cellular growth through activation of apoptosis in all tested cell lines. Moreover, as angiogenesis is a critical driver in ccRCC pathogenesis, we identified that PANTR1 expression is critical for in vitro tube formation and endothelial cell migration (p < 0.05). On the molecular level, knock-down of PANTR1 led to a decrease in Vascular Endothelial growth factor A (VEGF-A) and cell adhesion molecule laminin subunit gamma-2 (LAMC2) expression, corroborated by a positive correlation in RCC tissue (for VEGF-A R = 0.19, p < 0.0001, for LAMC2 R = 0.13, p = 0.0028). In conclusion, this study provides first evidence that PANTR1 has a relevant role in human RCC by influencing apoptosis and angiogenesis.

Bladder tumour development after urothelial carcinoma of the upper urinary tract is related to primary tumour location.

OBJECTIVE: To better define the predictors of bladder tumour development in patients operated for upper urinary tract urothelial cancer (UT-UC). PATIENTS AND METHODS: Surgical specimens from 191 consecutive patients with no history of bladder cancer and operated for UT-UC were chosen for analysis. Bladder tumour development was assessed in relation to UT-UC location, tumour multiplicity, stage and grade, margin status, mode of operation, age and gender. RESULTS: Overall, 51 of 191 (27%) patients developed subsequent bladder tumours, including 25 of 123 (20%) with pelvic, 19 of 47 (40%) with ureteric and seven of 21 (33%) with multifocal tumours (P = 0.04 for all subgroups; P = 0.01 for pelvic vs ureteric). There was no influence of the other variables. The median (mean, range) time to recurrence was 12 (18, 3-64) months. In a multivariate analysis, ureteric tumour location was an independent predictor (P = 0.02; risk ratio, RR, 2.0, 95% confidence interval, CI, 1.1-3.7). After excluding 68 patients with systemic disease progression, bladder tumour development was noted in 39 of 123 (32%), including 18 of 76 (24%) with pelvic, 16 of 34 (47%) with ureteric and five of 13 with multifocal tumours (P = 0.06 for all subgroups; P = 0.02 for pelvic vs ureteric). In a multivariate analysis, ureteric location (P = 0.03; RR 2.1, 95% CI 1.1-4.2) and high tumour grade (P = 0.04; RR 2.2, 95% CI 1.03-4.7) were independent predictors of subsequent bladder tumour development. CONCLUSION: The risk of developing a bladder tumour after surgery for UT-UC is significantly related to ureteric tumour location and high tumour grade. Clinical trials to evaluate a possible reduction of bladder cancer risk by intraoperative ureteric ligation and/or peri-operative topical intravesical chemotherapy instillation are justified.

Laparoscopic fenestration of lymphoceles after kidney transplantation with diaphanoscopic guidance.

In laparoscopic fenestration of lymphoceles after kidney transplantation, identification of the correct site of incision is sometimes difficult. We developed a new technique, using diaphanoscopy in 3 patients. After ultrasound-guided puncture and dilation, the correct incision site is identified by white light with a cystoscope inserted into the lymphocele cavity.

Chromophobe renal cell carcinoma: comprehensive analysis of 104 cases from multicenter European database.

OBJECTIVES: To analyze the clinical behavior of chromophobe renal cell carcinoma (CRCC), we retrospectively evaluated the data from six European centers. In 1985, CRCC was identified as a new RCC histologic subtype. Because of its low frequency, only few large CRCC series are available. METHODS: We created a renal cancer database including 3228 patients who underwent surgery between 1986 and 2002 in six European centers. The relevant clinical and pathologic data were extracted from the clinical charts at each institution and collected into a unique database. RESULTS: Of the 3228 patients, 104 (3.2%) affected by CRCC were identified. The mean age at diagnosis was 57.6 years (range 22 to 83). Of the 104 patients, 51 (49%) were men and 53 (51%) were women. The mean tumor size was 6.4 +/- 3.6 cm. An incidental diagnosis accounted for 61.5% of the cases. Radical nephrectomy was performed in 88 patients (85%). After a median follow-up of 38 months (mean 44, range 1 to 153), no local recurrence was observed. The 5-year overall survival rate for CRCC was 81%. Of the 104 patients, 5 (4.8%) and 9 (8.6%) died of unrelated causes and renal cancer, respectively. CONCLUSIONS: Our series confirmed a favorable outcome for the CRCC subtype with little local aggressiveness and a low propensity for progression and death from cancer.

Comparison of predictive accuracy of four prognostic models for nonmetastatic renal cell carcinoma after nephrectomy: a multicenter European study.

BACKGROUND: The objective of the current study was to compare, in a large multicenter study, the discriminating accuracy of four prognostic models developed to predict the survival of patients undergoing nephrectomy for nonmetastatic renal cell carcinoma (RCC). METHODS: A total of 2404 records of patients from 6 European centers were retrospectively reviewed. For each patient, prognostic scores were calculated according to four models: the Kattan model, the University of California at Los Angeles integrated staging system (UISS) model, the Yaycioglu model, and the Cindolo model. Survival curves were estimated by the Kaplan-Meier method and compared by the log-rank test. Discriminating ability was assessed by the Harrell c-index for censored data. The primary end point was overall survival (OS), and the secondary end points were cancer-specific survival (CSS) and disease recurrence-free survival (RFS). RESULTS: At last follow-up, 541 subjects had died of any causes, with a 5-year OS rate of 80%. The 5-year CSS and RFS rates were 85% and 78%, respectively. All models discriminated well (P < 0.0001). The c-indexes for OS were 0.706 for the Kattan nomogram, 0.683 for the UISS model, and 0.589 and 0.615 for the Yaycioglu and Cindolo models, respectively. The Kattan nomogram was found to improve discrimination substantially in the UISS intermediate-risk patients. CONCLUSIONS: The current study appears to better define the general applicability of prognostic models for predicting survival in patients with nonmetastatic RCC treated with nephrectomy. The results suggest that postoperative models discriminate substantially better than preoperative ones. The Kattan model was consistently found to be the most accurate, although the UISS model was only slightly less well performing. The Kattan model can be useful in the UISS intermediate-risk patients.

Multiinstitutional European validation of the 2002 TNM staging system in conventional and papillary localized renal cell carcinoma.

BACKGROUND: The current study validated the 2002 edition of the TNM staging system in a multicenter, multinational European series of localized renal cell carcinoma (RCC). METHODS: The authors analyzed the clinical data of 2217 patients who had undergone radical or partial nephrectomy for localized RCC in 7 urologic centers. RESULTS: In the current study, 1065 patients (48%) were classified as having pT1a disease, 771 (34.8%) were classified as having pT1b disease, and 381 (17.2%) were classified as having pT2 disease. Tumor histotype was conventional RCC in 1886 patients (85%), papillary in 182 (8.2%) patients, chromophobe in 64 (2.9%) patients, and unclassified in 85 (3.8%) patients. The mean follow-up time was 65.36 +/- 52.09 months. The 5 and 10-year disease-specific survival probabilities were 95.3% and 91.4% in patients with pT1a disease, 91.4% and 83.4% in patients with pT1b disease, and 81.6% and 75.2% in patients with pT2 disease (log-rank test P value = 0.0000). The disease-specific survival rates of patients with pT1a RCC were significantly higher than those recorded in patients with pT1b and pT2 RCC. Similarly, the disease-specific survival probabilities of patients with pT1b RCC were significantly better than those of patients with pT2 RCC. Analyzing the seven series individually, the 2002 TNM staging system provided appropriate stratification for only one series. The 2002 TNM staging system allowed significant stratification of the cancer-related outcomes in the subgroup of patients with conventional RCC but not in those with papillary carcinomas. CONCLUSIONS: The application of the 2002 TNM staging system in the current multicenter series enabled the authors to demonstrate optimal stratification of patients with localized RCC. Stratifying by tumor histotype, the data coming from the whole group analysis were reconfirmed for clear cell RCC only.

Isolation of circulating cancer cells from whole blood by immunomagnetic cell enrichment and unenriched immunocytochemistry in vitro.

PURPOSE: We improved tumor cell detection compared with currently available immunocytochemical methods by immunomagnetic cell enrichment. MATERIALS AND METHODS: Two methods of immunomagnetic enrichment using antibody coated magnetic beads were tested and compared with unenriched immunocytochemistry, including positive selection of epithelial cells with the antiepithelial antibody BER-EP4 and depletion of mononuclear cells with the anti-leukocyte antibody CD45. Various numbers of tumor cells from the 4 tissue culture cell lines DU 145, RT-4, KTCTL-2 and KTCTL-30 obtained from urological tumors were added to whole blood and mononuclear cells were isolated by density centrifugation. After incubation of the cell suspensions with beads cell separation was done in a magnetic field. After centrifugation on glass slides immunocytochemical staining for cytokeratin was performed. A total of 96 experiments were completed and negative controls were obtained. RESULTS: The number of tumor cells detected by positive selection and depletion was significantly higher compared with immunocytochemistry (Wilcoxon test p <0.01). Mean enrichment factor and tumor cell recovery rates were 12.9% and 43.5% for positive selection, and 9.4% and 32.6% for depletion, respectively (p <0.05). With 1 tumor cell suspended in up to 30 ml. full blood unenriched immunocytochemistry failed to detect cancer cells, whereas positive selection revealed epithelial cells in 12 of 14 cases (85.5%) and depletion in all 14 (p <0.05). No false-positive results were observed. CONCLUSIONS: Compared with unenriched immunocytochemistry immunomagnetic enrichment significantly improves the detection of epithelial cells added to blood. A significant advantage was observed for positive selection. Immunomagnetic enrichment may be important for clinical practice in the future.

Did the rate of incidental prostate cancer change in the era of PSA testing? A retrospective study of 1127 patients.

OBJECTIVES: To evaluate, in a retrospective study, the impact of routine prostate-specific antigen (PSA) testing on the rate of incidental prostate cancer in patients undergoing surgery for obstructive symptoms caused by presumed benign prostatic enlargement (BPE) and to investigate the indication of a routine biopsy before alternative treatment procedures for BPE. In the pre-PSA era, the diagnosis of incidental carcinoma was exclusively based on normal digital rectal examination (DRE) findings. METHODS: Since January 1993, 2422 operations (2283 transurethral resection of the prostate, 139 retropubic adenoma enucleations) for BPE were performed at our institution. The preoperative DRE findings and PSA level were evaluated, and patients with any suspicion for cancer were excluded. The pathologic reports of all patients were reviewed. A diagnosis of incidental carcinoma of the prostate required histologic evidence of cancer and negative DRE findings and a PSA level within age-specific reference ranges preoperatively. RESULTS: Of 2422 patients, 1127 (46.5%) had both negative DRE findings and an age-specific PSA level and were evaluated for our study. Overall, prostate cancer was diagnosed by surgery in 314 (13%) of 2422 patients. The rate of incidental prostate cancer in patients with both negative age-specific PSA levels and negative DRE findings was 6.4% (72 of 1127). CONCLUSIONS: In our series, the likelihood of detecting incidental prostate cancer by surgery was 6.4%. In the PSA era, the rate of incidental prostate cancer has been decreased by more than 50%. Today, the low rate of incidental carcinoma does not warrant routine histologic evaluation of the prostate if PSA testing and DRE are negative when alternative treatment modalities without tissue sampling are offered for the treatment of BPE.

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.