Distribution of metastatic sites in renal cell carcinoma: a population-based analysis.

BACKGROUND: We assessed the distribution of site-specific metastases in patients with renal cell carcinoma (RCC) according to age. Moreover, we evaluated recommendations proposed by guidelines and focused specifically on bone and brain metastases. PATIENTS AND METHODS: Patients with metastatic RCC (mRCC) were abstracted from the Nationwide Inpatient Sample (1998-2007). Age was stratified into four groups: <55, 55-64, 65-74 and ≥ 75 years. Cochran-Armitage trend test and multivariable logistic regression analysis tested the relationship between age and the rate of multiple metastatic sites. Finally, we examined the rates of brain or bone metastases according to the presence of other metastatic sites. RESULTS: In 11,157 mRCC patients, the rate of multiple metastatic sites decreased with increasing age (P < 0.001). This phenomenon was confirmed in patients with lung, bone, liver and brain metastases (all P ≤ 0.01). The rate of bone metastases was 10% in patients with exclusive abdominal metastases and 49% in patients with abdominal, thoracic and brain metastases. The rate of brain metastases was 2% in patients with exclusive abdominal metastases and 16% in patients with thoracic and bone metastases. CONCLUSIONS: The proportion of patients with multiple metastatic sites is higher in young patients. The rates of bone (10%-49%) and brain (2%-16%) metastases are nonnegligible in mRCC patients.

[Treatment of metastatic renal cell carcinoma]. / Traitement du carcinome rénal métastatique.

The median survival of patients with metastatic renal cell carcinoma (mRCC) increased from 10 to more than 40 months since the advent of targeted therapy. The transformation of mRCC from an initially lethal disease to a more favorable entity, albeit incurable, occurred with the transition from best supportive care, to cytokines, to finally sequential targeted therapies. Sunitinib and bevacizumab (level 1b) represent the first-line standard of care for patients with clear-cell mRCC vs temsirolimus (level 2) for those with high-risk features. Additionally, exploratory analyses of the temsirolimus data indicate important benefits for those with nonclear-cell mRCC histological subtypes. In second-line, everolimus proved its efficacy (level 1b). Nonetheless, sunitinib and sorafenib are also effective for nonclear-cell histological subtypes and after failure of other first-line treatment. The PFS benefits of first- and subsequent treatment-lines were confirmed in virtually all subgroup analyses. Potential survival benefits can be derived from cytoreductive nephrectomy (CNT), as was shown for cytokines in the general population, in sunitinib and bevacizumab-exposed patients. Phase III studies are ongoing to address the importance of CNT. This information is crucial to ensure timely delivery of a combination of medical and surgical therapies in this patient population.

Adherence to Guideline Recommendations for Perioperative Chemotherapy in Patients with pN2-3 M0 Squamous Cell Carcinoma of the Penis: Temporal Trends and Survival Outcomes.

AIMS: To analyse contemporary perioperative chemotherapy (CHT) guideline adherence rates for pN2-3 M0 squamous cell carcinoma of the penis, as well as CHT association with cancer-specific (CSM) and other-cause mortality (OCM). MATERIALS AND METHODS: Within the Surveillance, Epidemiology, and End Results databases, 311 pN2-3 M0 squamous cell carcinoma of the penis patients treated with inguinal lymph node dissection were identified. Univariable and multivariable logistic regression analyses focused on CHT rates, whereas cumulative incidence plots and multivariable competing risks regression analyses tested for CSM and OCM rates. RESULTS: CHT was administered to 140 (45%) patients and rates increased from 37.5 to 62.2% (2004-2015; P = 0.02). Specifically, annual CHT rates increased over time in patients younger or equal to 65 years and in patients older than 65 years (44.4-84.6% versus 28.6-50%, respectively), but this trend was not statistically significant (P = 0.1 and P = 0.2, respectively). The median follow-up was 13 months for both CHT (interquartile range 8.0-32.2) and no-CHT subgroups (interquartile range 5.0-40.0). In multivariable logistic regression analyses, more contemporary year of diagnosis interval (odds ratio 2.08, P < 0.01) and age older than 75 years (odds ratio 0.14, P < 0.001) were independent predictors of CHT use. In multivariable competing risks regression analyses, CHT use did not affect CSM (hazard ratio 1.02; P = 0.7) or OCM (hazard ratio 1.56; P = 0.8). CONCLUSIONS: CHT adherence rates sharply increased in the most recent years. Despite this increase over time, the lack of efficacy regarding CSM benefit is disappointing.

Sorafenib in the management of metastatic renal cell carcinoma.

PURPOSE: Sorafenib represents one of the two standards of care for patients with metastatic renal cell carcinoma (mRCC). In the present review, we provide information regarding the use of sorafenib in first and second lines. We also describe results for dose escalation strategies. Finally, we provide data addressing the efficacy of sorafenib in patients with mRCC of non-clear-cell histology. RECENT FINDINGS: Sorafenib is a valid first-line agent. Sorafenib response rates and toxicity are not affected by patient age or site of metastasis. The sequence of first-line sorafenib followed by second-line sunitinib resulted in a longer duration of response than did the opposite sequence. Sorafenib efficacy in first-line therapy can be potentiated by co-administration of low-dose interferon. Moreover, in first-line therapy, impressive response rates were recorded when the dose of sorafenib was escalated beyond the standard 400 mg twice daily. Similarly impressive response rates were observed with dose escalation in second-line therapy. It is notable that dose escalation after failure of standard sorafenib dose also prolongs progression-free survival. Finally, the efficacy of sorafenib is not limited to clear-cell histology, but also applies to chromophobe and papillary mRCC variants. SUMMARY: Sorafenib is a highly effective and well-tolerated agent for first- and second-line patients with clear-cell, chromophobe, or papillary mRCC variants.

Interleukin 8 expression regulates tumorigenicity and metastasis in human bladder cancer.

Interleukin 8 (IL-8) is mitogenic and chemotactic for endothelial cells. Within a neoplasm, IL-8 is secreted by inflammatory and neoplastic cells. The highly tumorigenic and highly metastatic human transitional cell carcinoma (TCC) cell line 253J B-V overexpresses IL-8 relative to the nontumorigenic and nometastatic 253J-P cell line. To determine whether IL-8 expression regulates tumorigenicity and metastasis in human TCC, 253J B-V cells were transfected with the full-sequence antisense (AS) cDNA for IL-8, whereas 253J-P cells were transfected with the full-length IL-8 cDNA, and control cells for each were transfected with the neomycin resistance (Neo) gene. In vitro, sense-transfected 253J-P cells overexpressed IL-8-specific mRNA and protein, whereas both of these were markedly reduced in AS-IL-8-transfected 253J B-V cells relative to controls. Moreover, sense-transfected cells showed up-regulation in matrix metalloproteinase type 9 mRNA, collagenase activity, and increased invasiveness through Matrigel-coated filters, whereas these measures were lower in AS-transfected cells relative to controls. After implantation into the bladders of athymic nude mice, the sense-transfected 253J-P cells acquired increased tumorigenicity and metastasis, whereas the AS-transfected cells significantly inhibited tumorigenicity and metastases in the 253J B-V cell lines. This effect was accompanied by reduced IL-8 expression and microvessel density. These studies demonstrate that IL-8 expression enhances angiogenic activity through the induction of matrix metalloproteinase type 9 and subsequently regulates the tumorigenesis and production of spontaneous metastases of human TCC.

Inhibition of basic fibroblast growth factor expression, angiogenesis, and growth of human bladder carcinoma in mice by systemic interferon-alpha administration.

The purpose of these studies was to determine whether systemic administration of IFN-alpha can inhibit the expression of basic fibroblast growth factor (bFGF) in human transitional cell carcinoma, reduce its angiogenesis, and thus inhibit its growth in the bladder wall of nude mice. In vitro incubation of the highly metastatic 253J B-V cells and the IFN-alpha-resistant 253J B-V IFNR cells with noncytostatic concentrations of IFN-alpha down-regulated the steady-state mRNA transcripts and protein production of bFGF. IFN-alpha-insensitive and IFN-alpha-resistant cells were implanted in the bladder wall of nude mice. Systemic administration of IFN-alpha decreased the in vivo expression of bFGF, decreased blood vessel density in the tumors, and inhibited tumor growth of both IFN-alpha-insensitive and IFN-alpha-resistant cells. These data suggest that in addition to its well-documented antiproliferative effects, IFN-alpha can inhibit the growth of human bladder cancer cells by inhibition of angiogenesis.

Patient selection for salvage cryotherapy for locally recurrent prostate cancer after radiation therapy.

PURPOSE: Our objective was to identify clinical pretreatment factors associated with early treatment failure after salvage cryotherapy. PATIENTS AND METHODS: Between 1992 and 1995, 145 patients underwent salvage cryotherapy for locally recurrent adenocarcinoma of the prostate. Treatment failure was defined as an increasing postcryotherapy serial prostate-specific antigen (PSA) level of more than or equal to 2 ng/mL above the postcryotherapy nadir or as a positive posttreatment biopsy. We evaluated the following factors as predictors of treatment failure: tumor stage and grade at initial diagnosis, type of prior therapy, stage and grade of locally recurrent tumor, number of positive biopsy cores at recurrence, and precryotherapy PSA level. RESULTS: Among patients with a prior history of radiation therapy only, the 2-year actuarial disease-free survival (DFS) rates were 74% for patients with a precryotherapy PSA less than 10 ng/mL and 28% for patients with a precryotherapy PSA more than 10 ng/mL, P <.00001. The DFS rates were 58% for patients with a Gleason score of less than or equal to 8 recurrence and 29% for patients with a Gleason score greater than or equal to 9 recurrence, P <.004. Among patients with a precryotherapy PSA less than 10 ng/mL, DFS rates were 74% for patients with a prior history of radiation therapy only and 19% for patients with a history of prior hormonal therapy plus radiation therapy, P <.002. CONCLUSION: Patients failing initial radiation therapy with a PSA more than 10 ng/mL and Gleason score of the recurrent cancer more than or equal to 9 are unlikely to be successfully salvaged. Patients failing initial hormonal therapy and radiation therapy are less likely to be successfully salvaged than patients failing radiation therapy only.

Gene therapy of human bladder cancer with adenovirus-mediated antisense basic fibroblast growth factor.

We previously investigated the role of basic fibroblast growth factor (bFGF) as a mediator of angiogenesis, tumorigenicity, and metastasis of transitional cell carcinoma (TCC) of the bladder. In the present study, we determined whether adenoviral-mediated antisense bFGF gene transfer therapy (Ad bFGF-AS) would inhibit TCCs growing in the subcutis of nude mice. In vitro, Ad bFGF-AS inhibited endothelial cell proliferation and enhanced apoptosis. The highly metastatic human TCC cell line 253J-BV(R) was implanted ectopically in the subcutis of athymic nude mice, and therapy was begun when the tumors reached a diameter between 5 and 7 mm. Intralesional therapy with Ad bFGF-AS decreased the in vivo expression of bFGF and matrix metalloproteinase type 9 mRNA and protein, and reduced microvessel density and enhanced endothelial cell apoptosis. Tumor growth was significantly inhibited by Ad bFGF-AS (mean, 58 mg) compared with controls [saline (mean, 562 mg), beta-galactosidase adenovirus (mean, 586 mg), and sense bFGF adenoviral therapy (Ad bFGF-S; mean, 3012 mg)]. These results suggest that Ad bFGF-AS therapy affects endothelial cells directly and tumor cells indirectly through down-regulation of bFGF and matrix metalloproteinase type 9, resulting in endothelial cell apoptosis and significant tumor growth inhibition. Furthermore, these studies confirm that bFGF expression is a valid target for the therapy of bladder cancer.

Interferon-alpha-mediated down-regulation of angiogenesis-related genes and therapy of bladder cancer are dependent on optimization of biological dose and schedule.

The purpose of this study was to identify and optimize the antiangiogenic activity of IFN-alpha against human bladder cancer cells growing in the bladder of nude mice. 253J B-V IFN(R) cells (resistant to antiproliferative effects of IFN-alpha or IFN-beta) were implanted into the bladder wall of nude mice. Three days later, the mice were treated with s.c. injections of IFN-alpha (70,000 units/week) at different dosing schedules (1, 2, 3, or 7 times/week). Daily therapy with IFN-alpha produced the most significant inhibition of tumor growth, tumor vascularization, and down-regulation of basic fibroblast growth factor and matrix metalloprotease-9 mRNA and protein expression. Changing dose and schedule of IFN-alpha administration had minimal effects on the expression of vascular endothelial growth factor or interleukin 8. The daily s.c. administrations of 5,000 or 10,000 units IFN-alpha-2a produced maximal inhibition of bFGF and MMP-9 expression (mRNA and protein), maximal reduction in tumor vessel density, and maximal reduction in serum levels of bFGF. Daily administration of higher doses of IFN-alpha failed to produce significant antiangiogenic effects. These data suggest that the antiangiogenic activity of IFN-alpha is dependent on frequent administration of optimal biological dose and not maximal tolerated dose.

Paclitaxel enhances the effects of the anti-epidermal growth factor receptor monoclonal antibody ImClone C225 in mice with metastatic human bladder transitional cell carcinoma.

Previously we reported that when cells from the human transitional cell carcinoma cell line 253J B-V growing orthotopically within the bladder of athymic nude mice were treated with the anti-epidermal growth factor receptor monoclonal antibody C225, angiogenesis was inhibited, resulting in regression of the primary tumor and inhibition of metastasis. In this study, we evaluated whether paclitaxel enhanced this therapeutic effect of C225. In vitro, the proliferation of 253J B-V cells was inhibited more by the combination of C225 and paclitaxel than with either agent alone. In vivo therapy with C225 and paclitaxel resulted in significantly greater regression of tumors compared with either agent alone. Median bladder tumor weight was 85 mg (range, 69-133 mg) compared with 168 mg (range, 72-288 mg) after C225 alone (P < 0.05), and 273 mg (range, 83-563 mg) after paclitaxel alone (P < 0.005). The incidence of spontaneous lymph node metastasis was also reduced by the combination of C225 with paclitaxel, although this result did not significantly differ from results after the use of C225 alone. Treatment with paclitaxel and C225 down-regulated the expression of basic fibroblast growth factor, vascular endothelial cell growth factor, interleukin-8, and matrix metalloproteinase type 9 and inhibited tumor-induced neovascularity compared with untreated controls (P < 0.005). Moreover, the combination of C225 and paclitaxel enhanced apoptosis in tumor and endothelial cells compared with either agent alone (P < 0.005). These studies indicate that therapy with paclitaxel increases the ability of C225 to inhibit tumorigenicity and metastasis. This effect is mediated by inhibition of angiogenesis and induction of apoptosis.

Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice.

Epidermal growth factor receptor (EGFR) regulates the growth and progression of human transitional cell carcinoma (TCC) of the bladder. We have shown that therapy targeting EGFR inhibited the growth of human TCC established orthotopically in nude mice. The purpose of this study was to evaluate whether EGFR-directed therapy affects angiogenesis associated with the growth and metastasis of human TCC. We determined the cytostatic effect and the effect on production of angiogenic factors after in vitro treatment of the human TCC cell line 253J B-V with MAb C225, a chimerized monoclonal anti-EGFR antibody. The 253J B-V cells were implanted orthotopically into athymic nude mice, and established tumors (4 weeks) were treated with i.p. MAb C225. Expression of the angiogenic factors vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and basic fibroblast growth factor (bFGF) was evaluated by immunohistochemistry and in situ mRNA hybridization analyses and correlated with microvessel density evaluated after immunohistochemical staining with anti-CD31. In vitro treatment with MAb C225 inhibited mRNA and protein production of VEGF, IL-8, and bFGF by 253J B-V cells in a dose-dependent manner. MAb C225 therapy of nude mice with established TCCs growing orthotopically resulted in inhibition of growth and metastasis compared with controls (P <0.0005). VEGF, IL-8, and bFGF expression was significantly lower in treated tumors than in controls. The down-regulation of these angiogenic factors preceded the involution of blood vessels. These studies indicate that therapy with anti-EGFR MAb C225 has a significant antitumor effect mediated, in part, by inhibition of angiogenesis.

Interleukin 8 expression regulates tumorigenicity and metastases in androgen-independent prostate cancer.

Interleukin 8 (IL-8) is mitogenic and chemotactic for endothelial cells. Within a neoplasm, IL-8 is secreted by inflammatory and neoplastic cells. The highly metastatic PC-3M-LN4 cell line overexpresses IL-8 relative to the poorly metastatic PC-3P cell line. We evaluated whether IL-8 expression by human prostate cancer growing within the prostate of athymic nude mice regulates tumor angiogenesis, growth, and metastasis. PC-3P cells were transfected with the full-length sense IL-8 cDNA, whereas PC-3M-LN4 cells were transfected with the full-sequence antisense IL-8 cDNA. Control cells were transfected with the neomycin resistance gene (Neo). In vitro, sense-transfected PC-3P cells overexpressed IL-8-specific mRNA and protein, which resulted in up-regulation of matrix metalloproteinase 9 (MMP-9) mRNA, and collagenase activity, resulting in increased invasion through Matrigel. After antisense transfection of the PC-3M-LN4 cells, IL-8 and MMP-9 expression, collagenase activity, and invasion were markedly reduced relative to controls. After orthotopic implantation, the sense-transfected PC-3P cells were highly tumorigenic and metastatic, with significantly increased neovascularity and IL-8 expression compared with either PC-3P cells or controls. Antisense transfection significantly reduced the expression of IL-8 and MMP-9 and tumor-induced neovascularity, resulting in inhibition of tumorigenicity and metastasis. These results demonstrate that IL-8 expression regulates angiogenesis in prostate cancer, in part by induction of MMP-9 expression, and subsequently regulates the growth and metastasis of human prostate cancer.

Treatment with low-dose interferon-alpha restores the balance between matrix metalloproteinase-9 and E-cadherin expression in human transitional cell carcinoma of the bladder.

Tumor invasion and metastasis are regulated by the expression of genes such as E-cadherin, which regulates cell adhesion, and matrix metalloproteinase-9 (MMP-9), which alters the integrity of the extracellular matrix. Both up-regulation of MMP-9 and down-regulation of E-cadherin correlate with bladder cancer metastasis. The purpose of this study was first to determine whether an imbalance between MMP-9 and E-cadherin expression correlates with metastasis from human transitional cell carcinoma (TCC) of the bladder after therapy with neoadjuvant chemotherapy and radical cystectomy and then to determine whether treatment of human TCC xenografts growing in nude mice with interferon (IFN)-alpha would restore this balance, thereby limiting tumor invasion and metastasis. We used in situ hybridization to evaluate the expression of several metastasis-related genes, including MMP-9 and E-cadherin, in paraffin-embedded biopsy specimens from 55 patients with muscle-invasive TCC treated with neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin chemotherapy and radical cystectomy. By multivariate analysis, an MMP-9:E-cadherin ratio of >1.8 was an independent prognostic factor for disease progression. In vitro incubation of an IFN-resistant, highly metastatic human TCC cell line, 253J B-V(R) with noncytostatic concentrations of IFN-alpha down-regulated the activity of MMP-9, up-regulated E-cadherin, and inhibited in vitro invasion. 253J B-V(R) cells were implanted into the bladders of athymic nude mice. Systemic therapy with IFN-alpha (10,000 units s.c. daily) decreased the expression of MMP-9, increased expression of E-cadherin, reduced tumor volume, and inhibited metastasis. The MMP-9:E-cadherin ratio was 4.5 in untreated controls and 1.1 after IFN-alpha treatment. Moreover, systemic low-dose daily IFN-alpha potentiated the efficacy of paclitaxel. These studies indicate that in addition to its antiproliferative and antiangiogenic effects, IFN-alpha limits tumor invasion by restoring the normal balance between MMP-9 and E-cadherin and enhances the activity of systemic chemotherapy.

French-Canadian linguistic validation of the NIH Chronic Prostatitis Symptom Index.

INTRODUCTION: The NIH Chronic Prostatitis Symptom Index (CPSI) is recommended in the clinical evaluation of men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). However, its use is not possible in French speakers, as it has not been validated in this population. We performed a linguistic validation of the CPSI. METHODS: Linguistic translation followed the forward-backward-forward technique and relied on professional medical translators, bilingual health professionals, and patient input. Along with the SF-12, the translated version was administered to a convenience sample of men presenting for pre-vasectomy visits (controls) and to consecutive patients with established CP/CPPS (cases). Men with CP/CPPS were subsequently asked to complete a 14-day retest questionnaire. Psychometric testing addressed standard reliability and validity characteristics. RESULTS: Thirty-six cases and 38 controls with respective mean ages of 46.5 and 44.0 years participated and 33 (91.2%) cases completed the retest questionnaire. Pain (p<0.001), urinary (p<0.001) and quality-of-life (QOL) scale (p<0.001) score means differed between cases and controls. For the same scales, Cronbach's alphas for cases were respectively 0.70, 0.72 and 0.79 versus 0.80, 0.57, and 0.88 for controls. The retest product-moments were 0.83 for pain, 0.55 for urinary, and 0.83 for QOL scales. In cases, strong correlation was noted between QOL and pain scales (r=0.7), and between urinary and pain scales (r=0.6), versus moderate correlation between QOL and urinary scales (r=0.4). Negative correlation was recorded between CPSI scales and SF-12 scales, which ranged from -0.2 to -0.4. CONCLUSIONS: When applied to CPPS and control subjects, the French Canadian CPSI translation demonstrates excellent discriminant properties. Moreover, its reliability and validity characteristics confirm the qualities of the CPSI as a standard evaluative tool for men with CPPS.

Biodistribution of an adenoviral vector carrying the luciferase reporter gene following intravesical or intravenous administration to a mouse.

The biodistribution and resulting pattern of transgene expression were determined following intravesical administration of an adenoviral vector carrying the luciferase reporter gene (AdLuc). Female BALB/c mice were subjected to intravesical instillation of 1 x 10(9) or 5 x 10(9) plaque-forming units of AdLuc. After sacrifice, transgene expression was detected in tissues using luciferase assays; vector DNA was detected by vector-specific polymerase chain reaction. These experiments showed very little vector dissemination outside of the bladder by this route of administration. High-level expression of the vector transgene in the bladder was found to diminish by severalfold after 3 days. In a supporting study, vector dissemination and resulting transgene expression were determined following tail vein injection of 5 x 10(9) plaque-forming units of AdLuc. Vector was distributed to and expressed in every organ analyzed, with the highest concentration and level of expression observed in the liver.

Biosafety of in vivo adenovirus-p53 intravesical administration in mice.

OBJECTIVES: To evaluate the biosafety and in vivo biodistribution of intravesical instillation of an adenovirus that contains human p53 gene. Mutations of p53, which are found in as many as 40% of transitional cell carcinomas, are associated with a poor prognosis and resistance to chemotherapy and radiation therapy. Restoration of wild-type p53 status by means of adenoviral-mediated therapy may enhance apoptosis and improve the response to therapy, but the issues of biosafety and toxicity have not yet been addressed. METHODS: Adenovirus-p53 (1 x 10(8), 1 x 10(9), and 5 x 10(9) pfu/mL) and luciferase reporter gene (5 x 10(9)) were instilled into the bladders of anesthetized female BALB/c mice. The mice were killed on days 1, 3, 6, and 13, and representative samples of the bladder, ureter, kidney, adrenal gland, ovary, liver, heart, and lung were removed for histologic evaluation. RESULTS: No histologic signs of toxicity were found. The hematologic and biochemical profiles of the mice were normal, with the exception of a transient elevation in liver function tests on day 1 in the three treatment groups. CONCLUSIONS: Intravesical instillation of adenovirus-p53 was well tolerated; the bladder urothelium appeared to prevent systemic dissemination. The results of these experiments support the safety of intravesical gene transfer by intravesical instillation.

Differential expression of progression-related genes in the evolution of superficial to invasive transitional cell carcinoma of the bladder.

It is generally accepted that there are dichotomous biologic pathways that lead to the development of either: i) superficial papillary (Ta) transitional cell carcinoma (TCC) or ii) precursor lesions to muscle-invasive (CIS, T1) TCC and muscle-invasive (> or =T2) TCC. We investigated the expression of several progression-related genes to characterize the phenotype of these tumors within these divergent developmental pathways. Using a colorimetric in situ hybridization technique, we examined the expression of mRNAs of several progression-related genes in archival, pathologic specimens from 77 patients with bladder TCC. These genes included basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), interleukin (IL)-8, matrix metalloproteinase (MMP)-9, and epidermal growth factor receptor (EGFR). Relative gene expression was quantified using image analysis. Gene expression was normalized using poly (dT) and the expression of each factor in a panel of specimens of normal urothelium. Patients were stratified according to disease stage, and the level of gene expression among the stratified groups was compared. VEGF, bFGF, IL-8, and MMP-9 expression was increased in muscle-invasive compared with superficial papillary tumors, (p<0.05) and VEGF expression was increased in muscle-invasive tumors compared with CIS specimens (p<0. 05). bFGF, IL-8, and EGFR expression was increased in CIS specimens compared with superficial papillary tumors (p<0.05). The pattern of expression of bFGF, VEGF, IL-8, MMP-9, and EGFR represent the divergent developmental pathways in the pathogenesis of bladder TCC, which characterizes superficial or invasive bladder cancer. bFGF, IL-8, and EGFR appear to be upregulated in early precursor lesions (CIS), whereas VEGF appears to be upregulated at later stages in the development of muscle-invasive TCC.

The effect of age at diagnosis on prostate cancer mortality: a grade-for-grade and stage-for-stage analysis.

OBJECTIVE: To evaluate the effect of advancing age on cancer-specific mortality (CSM) after radical prostatectomy (RP). MATERIALS AND METHODS: Overall, 205,551 patients with PCa diagnosed between 1988 and 2009 within the Surveillance Epidemiology and End Results (SEER) database were included in the study. Patients were stratified according to age at diagnosis: ≤ 50, 51-60, 61-70, and ≥ 71 years. The 15-year cumulative incidence CSM rates were computed. Competing-risks regression models were performed to test the effect of age on CSM in the entire cohort, and for each grade (Gleason score 2-4, 5-7, and 8-10) and stage (pT2, pT3a, and pT3b) sub-cohorts. RESULTS: Advancing age was associated with higher 15-year CSM rates (2.3 vs. 3.4 vs. 4.6 vs. 6.3% for patients aged ≤ 50 vs. 51-60 vs. 61-70 vs. ≥ 71 years, respectively; P < 0.001). In multivariable analyses, age at diagnosis was a significant predictor of CSM. This relationship was also observed in sub-analyses focusing on patients with Gleason score 5-7, and/or pT2 disease (all P ≤ 0.05). Conversely, age failed to reach the independent predictor status in men with Gleason score 2-4, 8-10, pT3a, and/or pT3b disease. CONCLUSIONS: Advancing age increases the risk of CSM. However, when considering patients affected by more aggressive disease, age was not significantly associated with higher risk of dying from PCa. In high-risk patients, tumor characteristics rather than age should be considered when making treatment decisions.

The impact of robot-assisted radical prostatectomy on the use and extent of pelvic lymph node dissection in the "post-dissemination" period.

INTRODUCTION: Previous series during the dissemination era of minimally invasive techniques for treatment of prostate cancer (PCa) showed a declining use of pelvic lymph node dissection (PLND). The aim of our study was to re-assess the impact of robot-assisted radical prostatectomy (RARP) on the utilization rate of PLND and its extent in the post-dissemination period. METHODS: Relying on the Surveillance Epidemiology and End Results (SEER) Medicare-linked database, 5804 patients with non-metastatic PCa undergoing open radical prostatectomy (ORP) or RARP between years 2008 and 2009 were identified. Uni- and multivariable logistic regression analyses tested the relationship between surgical approach (RARP vs. ORP) and: 1 - the rate of PLND (pNx vs. pN0-1); and 2 - the extent of PLND (limited vs. extended). RESULTS: Overall, 3357 (57.8%) patients underwent a PLND. The proportion of patients treated with PLND was significantly higher among ORP vs. RARP patients: 71.2 vs. 48.6%, respectively (P < 0.001). In addition, the median number of lymph nodes removed was significantly higher for patients treated with ORP vs. RARP: 5 vs. 4, respectively (P < 0.001). In multivariable analyses, ORP was associated with 2.7- and 1.3-fold higher odds of undergoing PLND and of receiving an extended PLND compared to RARP, respectively (both P ≤ 0.001). Stratified analyses according to disease risk classifications revealed similar trends. CONCLUSIONS: In the post-dissemination era, RARP remains associated with a decreased use of PLND and suboptimum extent. Efforts should be made to improve guideline adherence in performing a PLND whenever indicated according to tumor aggressiveness, despite surgical approach.

Propensity-score matched comparison of complications, blood transfusions, length of stay, and in-hospital mortality between open and laparoscopic partial nephrectomy: a national series.

BACKGROUND: To examine the use of open partial nephrectomy (OPN) and laparoscopic partial nephrectomy (LPN), as well as intraoperative and postoperative morbidity. MATERIALS AND METHODS: A retrospective cohort analysis of the Nationwide Inpatient Sample for years 1998-2007. Patients with non-metastatic kidney cancer who underwent OPN or LPN were identified. Propensity-based matching was performed to adjust for potential baseline differences between the two groups. The rates of intraoperative and postoperative complications, blood transfusions, length of stay, and in-hospital mortality were assessed for both procedures. RESULTS: Overall, 7990 (93.9%) and 523 (6.1%) patients underwent OPN and LPN, respectively. Use of LPN increased 19-fold over the study period (P < 0.001). For OPN and LPN respectively, the following rates were recorded: blood transfusions, 9.3 vs. 3.8% (P < 0.001); intraoperative complications, 2.9 vs. 1.5% (P = 0.06); postoperative complications, 15.4 vs. 11.3% (P = 0.01); length of stay ≥5 days, 46.7 vs. 20.8% (P < 0.001); in-hospital mortality, 0.4 vs. 0.4% (P = 0.98). In multivariable logistic regression analyses, LPN patients were less likely to have a blood transfusion (odds ratio [OR]: 0.40, P < 0.001), to experience any postoperative complication (OR: 0.74, P = 0.03), and to be hospitalized for more than 5 days (OR: 0.32, P < 0.001). Post-propensity score matched analyses revealed virtually the same results. CONCLUSIONS: After adjustment for potential selection biases, LPN is associated with fewer adverse outcomes than OPN. However, the current results should be interpreted with caution, given the lack of tumor characteristics. Furthermore, statistical adjustment is not a substitute for a needed randomized trial.