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Von Hipple-Lindau gene (VHL) inactivation represents the most frequent abnormality in clear cell renal cell carcinoma (ccRCC). Hypoxia-inducible factor-1α (HIF-1α) expression is regulated by O2 level. In normal O2 conditions, VHL binds HIF-1α and allows HIF-1α proteasomal degradation. A single-nucleotide polymorphism (SNP) has been found located in the oxygen-dependent degradation domain at codon 582 (C1772T, rs11549465, Pro582Ser). In hypoxia, VHL/HIF-1α interaction is abolished and HIF-1α activates target genes in the nucleus. This study analyzes the impact of genetic alterations and protein expression of VHL and the C1772T SNP of HIF-1α gene (HIF-1α) on prognosis in early-stage ccRCC (pT1a, pT1b, and pT2). Mutational analysis of the entire VHL sequence and the genotyping of HIF-1α C1772T SNP were performed together with VHL promoter methylation analysis and loss of heterozygosis (LOH) analysis at (3p25) locus. Data obtained were correlated with VHL and HIF-1α protein expression and with tumor-specific survival (TSS). VHL mutations, methylation status, and LOH were detected in 51, 11, and 12% of cases, respectively. Our results support the association between biallelic alterations and/or VHL silencing with a worse TSS. Moreover, we found a significant association between the HIF-1α C1772C genotype and a worse TSS. The same association was found when testing the presence of HIF-1α protein in the nucleus. Our results highlight the role of VHL/HIF-1α pathway in RCC and support the molecular heterogeneity of early-stage ccRCC. More important, we show the involvement of HIF-1α C1772T SNP in ccRCC progression.

Objective: To evaluate the long-term renal function, continence, and voiding function in 64 patients, surviving for 5 or more years after W-shaped ileal neobladder with a short afferent limb and refluxing ureterointestinal anastomoses., Materials and Methods: Kidney morphology and function were evaluated using nuclear renography, creatinine, and glomerular filtration rate. Continence and voiding function were evaluated with a diary on frequency, voided volumes, number of pads, and with the incontinence severity index (ISI) questionnaire, the American Urological Association-Symptom Index (AUA-SI), and the American Urological Association-Symptom Problem Index., Results: The renal scan showed a dilatation of the upper urinary tract in 4.8% of renoureteral units. Of the patients, 12.5% voided with intermittent or permanent catheterization. The remaining 87.5% voided spontaneously; 75% did not use pads, 12.5% used protection for safety, 7.1% 1 pad, and 5.4% more than 1 pad, during the day; during night, 55.3% did not use pads, 23.2% used protection for safety, and 12.6% and 8.9% 1 or more than 1 pad. The ISI questionnaire showed that 35.7% were fully continent, whereas 41%, 12.5%, and 10.8% had slight, moderate, and severe incontinence. The AUA-SI showed that 50% had mild, 39.3% moderate, and 10.7% severe lower urinary tract symptoms. Urinary incontinence, daytime frequency, and nocturia correlated positively with the age of patients at follow-up and negatively with voided volume., Conclusion: Long-term detrimental effect on renal function of orthotopic neobladder with no antireflux anastomoses is limited. Long-term continence and voiding function results are satisfactory. The ISI questionnaire might be useful to evaluate and grade incontinence in patients with orthotopic neobladder, whereas the AUA-SI has many limitations., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: We evaluated the ability of the phosphodiesterase-5 inhibitor vardenafil to increase prostate microcirculation during power Doppler ultrasound. We also evaluated the results of contrast and vardenafil enhanced targeted biopsies compared to those of standard 12-core random biopsies to detect cancer., Materials and Methods: Between May 2008 and January 2010, 150 consecutive patients with prostate specific antigen more than 4 ng/ml at first diagnosis with negative digital rectal examination and transrectal ultrasound, and no clinical history of prostatitis underwent contrast enhanced power Doppler ultrasound (bolus injection of 2.4 ml SonoVue® contrast agent), followed by vardenafil enhanced power Doppler ultrasound (1 hour after oral administration of vardenafil 20 mg). All patients underwent standard 12-core transrectal ultrasound guided random prostate biopsy plus 1 further sampling from each suspected hypervascular lesion detected by contrast and vardenafil enhanced power Doppler ultrasound., Results: Prostate cancer was detected in 44 patients (29.3%). Contrast and vardenafil enhanced power Doppler ultrasound detected suspicious, contrast enhanced and vardenafil enhanced areas in 112 (74.6%) and 110 patients (73.3%), and was diagnostic for cancer in 32 (28.5%) and 42 (38%), respectively. Analysis of standard technique, and contrast and vardenafil enhanced power Doppler ultrasound findings by biopsy core showed significantly higher detection using vardenafil vs contrast enhanced power Doppler ultrasound and standard technique (41.2% vs 22.7% and 8.1%, p <0.005 and <0.001, respectively). The detection rate of standard plus contrast or vardenafil enhanced power Doppler ultrasound was 10% and 11.7% (p not significant)., Conclusions: Vardenafil enhanced power Doppler ultrasound enables excellent visualization of the microvasculature associated with cancer and can improve the detection rate compared to contrast enhanced power Doppler ultrasound and the random technique., (Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the potential curative role of the intraoperative use of a dye, the Patent Blue V, for the treatment of refractory lymphoceles by mapping the lymphatic leakage and selectively ligating the opened lymphatics. Inguinal lymphocele is a well-known complication after inguinofemoral lymph node dissection for penile cancer, and a variety of curative approaches have been reported., Methods: From 1995 to 2007, 40 patients had undergone partial or total penectomy for squamous cell cancer. Superficial inguinal lymph node dissection with saphenous vein sparing or deep lymph node dissection was performed in 15 patients. It was unilateral in 14 and bilateral in 1 patient. When the lymphoceles were refractory to conventional therapy, ligation of the lymphatic vessels after mapping of the leakage with the Patent Blue V dye was the treatment of choice., Results: Overall, 5 lymphoceles were detected in 4 patients that were continuously increasing in size after discharge and were treated conventionally. In the 2 refractory lymphoceles, we then opted for the intraoperative use of a dye, the Patent Blue V, to map the lymphatic leakage and selectively ligate the opened lymphatics. In both cases, complete resolution of the lymphoceles occurred. No complications were observed with this technique., Conclusions: The presented technique is able to cure persistent lymphoceles refractory to conventional treatment after inguinal lymph node dissection.

The presence of a capsule/pseudocapsule (PS) with signs of infiltration within its layers or completely penetrated could represent the first pathological evidence of the capacity achieved by tumor cells to infiltrate and invade surrounding tissue and it could eventually have a role as prognostic factor in patients with intracapsular renal cell carcinoma (RCC). Historical reports on the PS surrounding RCC date back to the mid twentieth century with the aim to define the possible role of conservative surgery for small renal tumors. Few authors have recently investigated the morphological appearance of tumor fibrous PS and the prognostic implication of its infiltration after kidney surgery for RCC. The aim of the present review is therefore to report the historical data and the current results of a literature review on the PS status after kidney surgery and to define its prognostic implication.

Purpose: We defined the prognostic role of tumor necrosis and its extent in nonmetastatic clear cell renal cell carcinoma. Also, we further investigated its pathogenesis by correlating this tumor feature with other pathological characteristics and molecular markers related to the von Hippel Lindau-hypoxia inducible factor pathway and to tumor proliferation., Materials and Methods: A total of 213 patients with nonmetastatic clear cell renal cell carcinoma were evaluated. Mean followup was 66 months. The presence and extent of histological necrosis were correlated with clinicopathological factors, Ki-67 antigen expression calculated by the MIB-1 (Ki-67 antibody) index, pVHL, HIF-1alpha, the tumor infiltrating lymphocyte subset and cancer specific survival., Results: Histological necrosis was present in 63.8% of clear cell renal cell carcinoma cases. Necrosis was significantly associated with grade and the degree of tumor infiltrating lymphocytes, while its extent correlated significantly with grade, the degree of tumor infiltrating lymphocytes and stage. Tumor necrosis was a significant prognostic factor, which was confirmed even when limiting analysis to patients with intracapsular renal cell carcinoma. On multivariate analysis histological necrosis was not an independent predictor of cancer specific survival. The extent of tumor necrosis was not a significant prognostic factor. The presence and extent of histological necrosis was not associated with high Ki-67 expression and it did not correlate with pVHL expression or with nuclear and cytoplasmic HIF-1alpha expression., Conclusions: Based on our results we cannot support histological necrosis and its extent as prognostic factors for clear cell renal cell carcinoma. Efforts should be made to develop nomograms that use routinely available and objective predictor variables. The precise mechanism that causes tumor necrosis remains unknown but the host immune response might significantly contribute to its development.

Objectives: The most frequent genomic abnormality in clear cell renal cell carcinoma (cc-RCC) is inactivation of Von Hippel-Lindau gene (VHL). pVHL19 is a ligase promoting proteosomal degradation of hypoxia-inducible factor-1alpha (HIF-1alpha); pVHL30 is associated with microtubules. VHL exert its oncogenetic action both directly and through HIF-1alpha activation. TNM classification is unable to define a correct prognostic evaluation of intracapsular cc-RCC. The nucleo-cytoplasmic trafficking in VHL/HIF-1alpha pathway could be relevant in understanding the molecular pathogenesis of renal carcinogenesis. This study analyzes VHL/HIF-1alpha proteins in a large series of intracapsular cc-RCCs, correlating their expression and cellular localization with prognosis., Materials and Methods: Two anti-pVHL (clones Ig32 and Ig33) and 1 anti-HIF-1alpha were used on tissue microarrays from 136 intracapsular cc-RCCs (mean follow-up: 74 mo). Clone 32 recognizes both pVHLs, whereas clone 33 only pVHL30. Results were matched with clinicopathologic variables and tumor-specific survival (TSS)., Results: A strong cytoplasmic positivity was found for all antibodies in the largest part of cases, associated to a strong nuclear localization in the case of HIF-1alpha. All pVHL-negative cases were associated with high HIF-1alpha expression. pVHL negativity and HIF-1alpha nuclear positivity significantly correlated with shorter TSS. In multivariate analysis both pVHL negativity and HIF-1alpha nuclear expression were independent predictors of TSS., Conclusions: The localization of the proteins well matches with their role and with the supposed tumor molecular pathways. The correlation with prognosis of VHL/HIF-1alpha alterations confirms the relevance of their molecular pathway and of the cellular trafficking of their products in the pathogenesis of renal cancer.

Purposes: The TNM classification has been revised for the 2002 edition of the UICC publication to better stratify patients with intracapsular renal cell carcinoma (RCC) but few studies have been published to date to validate this new classification. Moreover, additional prognostic factors seem to be necessary to improve the prediction of intracapsular tumor aggressiveness and the definition of patient subgroups at high risk for metastases. We report the long-term results of the new TNM scheme. We evaluated the impact of DNA content, S-phase and MIB-1 (Dako, Glostrup, Denmark) score., Materials and Methods: A total of 136 patients with intracapsular clear cell RCC and a mean followup of 74 months were reclassified. Tumor specific survival (TSS) was compared with nuclear grade (NG), DNA content and proliferative status (S-phase fraction and MIB-1 score)., Results: TSS was 92%, 81.1% and 40.1% for pT1a, pT1b and pT2, respectively (p <0.05). TSS according to DNA ploidy status (diploid vs aneuploid) was pT1a-95.2% vs 68.6% (p <0.05), pT1b-90% vs 46.7% (p <0.05) and pT2-49.2% vs 25% (p not significant). DNA ploidy was also significantly associated with survival when adjusted for NG. There was no significant association between TSS and MIB-1 score or tumor S-phase fraction., Conclusions: The 2002 TNM classification is a useful prognostic factor for evaluating organ confined RCC of the clear cell subtype. Evaluation of the DNA content in clear cell RCC appears to significantly improve the predictive value of the TNM staging system, especially in the pT1a and pT1b categories. Fuhrman NG alone or combined should be routinely used in such patients.

Purpose: Long-term renal function is crucial in orthotopic bladder substitutions, and can be influenced by several factors including ureteral obstruction, urinary infection and reflux. In this study we investigated the prevalence of renal functional impairment and the incidence of morphological alterations of the upper urinary tract in patients who had a low pressure ileal neobladder constructed with no antireflux mechanism., Materials and Methods: From 1996 to 2002, 70 men received a W-shaped neobladder using refluxing ureterointestinal anastomoses and short afferent limb. Final evaluation of patient status was in November 2003. A total of 20 patients died during followup and mean followup of the remaining 50 patients was 50 months (range 21 to 89). Kidney morphology was evaluated using technetium diethylenetetraminepentaacetic acid nuclear renography and ultrasonography. Total and separate renal function were evaluated by measuring plasma creatinine and glomerular filtration rate (GFR), the latter measured as the renal clearance of technetium diethylenetetraminepentaacetic acid. Measured values of GFR were compared with the results from a group of healthy subjects of the same age., Results: The anastomotic stricture rate was 4%, 2 severe strictures occurred 2 and 4 months after surgery, while 2 moderate strictures were detected with renal scans during the study. Renal scintigraphy revealed an excretory phase within the normal range in 67 of 99 renoureteral units (68%), a short delay in collecting system drainage associated with mild and transient pelvicaliceal dilatation in 23 (23%), and dilatation of the upper urinary tract in the remaining 9 (9%) including obstructive in 2 (2%) and not obstructive in 7 (7%). Mean (+SD) total GFR of the patients was 89.7 (19.6) ml per minute per 1.73 m. Mean total GFR of the control group was 90.6 (11.4) ml per minute per 1.73 m. The comparison between measured GFR of patients and the control group showed no statistically significant difference., Conclusions: Our medium-term data support the assumption that the lack of any antireflux mechanism in orthotopic neobladder, per se, has no detrimental effect on renal function.

We report an unusual case of solitary thrombus floating in the inferior vena cava (IVC) in a patient who underwent radical nephrectomy for a renal cell carcinoma (RCC) of the right kidney extended into the renal vein with no capsular and perinephric tissue invasion (pT3b). Twenty months after surgery, a routine computed tomography scan identified an intraluminal mass floating in the IVC. Cavotomy and thrombectomy with no caval resection were successfully performed. A review of the literature showed only three previous published cases of RCC recurring in the IVC only, with no local recurrence or distant metastases. We outline the possible etiology of these unusual and solitary recurrences in the IVC and we emphasize the need for a strict surveillance for all patients with RCC and especially for those with pT1b, pT2 and pT3 disease. An early diagnosis of this rare recurrence can permit an easy removal of the thrombus with no caval resection and graft replacement, making this disease potentially curable by surgery.