Human papillomavirus vaccination and prevention of intraepithelial neoplasia and penile cancer: review article.

PURPOSE OF REVIEW: The objective of the current article is to promote a literature revision of the relationship between the prevention of intraepithelial neoplasms (PeIN) and invasive penile cancer, and human papillomavirus (HPV) vaccination, aiming to enumerate the pros and cons of immunization. RECENT FINDINGS: The immunization against the HPV is sufficiently safe and many countries have incorporated the vaccine to their immunization calendar. Compared with men, the sampling size and the evidence quality of scientific researches among the female population are more robust. Some randomized and nonrandomized studies suggest that vaccination reduces the incidence of genital warts and no PeIN and penile cancer cases were developed in the vaccinal group. However, 70% of patients can evolve with the neoplasia despite having been immunized and even among HPV infected patients, only 1% will develop cancer. SUMMARY: The studies about vaccination against HPV and prevention on penile cancer are conflicting and the main academic urology societies still have not incorporated vaccination of men in their guidelines. Future studies are necessary to confirm the efficiency and cost-benefit of the vaccine in men to prevent intraepithelial neoplasms and invasive penile cancer.

Epidemiology, diagnosis, preoperative evaluation and prognostic assessment of upper-tract urothelial carcinoma (UTUC).

PURPOSE: Upper-tract urothelial carcinoma (UTUC) is a relatively uncommon disease with limited available evidence on specific topics. The purpose of this article was to review the previous literature to summarize the current knowledge about UTUC epidemiology, diagnosis, preoperative evaluation and prognostic assessment. METHODS: Using MEDLINE, a non-systematic review was performed including articles between January 2000 and February 2016. English language original articles, reviews and editorials were selected based on their clinical relevance. RESULTS: UTUC accounts for 5-10 % of all urothelial cancers, with an increasing incidence. UTUC and bladder cancer share some common risk factors, even if they are two different entities regarding practical, biological and clinical characteristics. Aristolochic acid plays an important role in UTUC pathogenesis in certain regions. It is further estimated that approximately 10 % of UTUC are part of the hereditary non-polyposis colorectal cancer spectrum disease. UTUC diagnosis remains mainly based on imaging and endoscopy, but development of new technologies is rapidly changing the diagnosis algorithm. To help the decision-making process regarding surgical treatment, extent of lymphadenectomy and selection of neoadjuvant systemic therapies, predictive tools based on preoperative patient and tumor characteristics have been developed. CONCLUSIONS: Awareness regarding epidemiology, diagnosis, preoperative evaluation and prognostic assessment changes is essential to correctly diagnose and manage UTUC patients, thereby potentially improving their outcomes.

A prognostic model for survival after palliative urinary diversion for malignant ureteric obstruction: a prospective study of 208 patients.

OBJECTIVE: To identify factors associated with survival after palliative urinary diversion (UD) for patients with malignant ureteric obstruction (MUO) and create a risk-stratification model for treatment decisions. PATIENTS AND METHODS: We prospectively collected clinical and laboratory data for patients who underwent palliative UD by ureteric stenting or percutaneous nephrostomy (PCN) between 1 January 2009 and 1 November 2011 in two tertiary care university hospitals, with a minimum 6-month follow-up. Inclusion criteria were age >18 years and MUO confirmed by computed tomography, ultrasonography or magnetic resonance imaging. Factors related to poor prognosis were identified by Cox univariable and multivariable regression analyses, and a risk stratification model was created by Kaplan-Meier survival estimates at 1, 6 and 12 months, and log-rank tests. RESULTS: The median (range) survival was 144 (0-1084) days for the 208 patients included after UD (58 ureteric stenting, 150 PCN); 164 patients died, 44 (21.2%) during hospitalisation. Overall survival did not differ by UD type (P = 0.216). The number of events related to malignancy (≥4) and Eastern Cooperative Oncology Group (ECOG) index (≥2) were associated with short survival on multivariable analysis. These two risk factors were used to divide patients into three groups by survival type: favourable (no factors), intermediate (one factor) and unfavourable (two factors). The median survival at 1, 6, and 12 months was 94.4%, 57.3% and 44.9% in the favourable group; 78.0%, 36.3%, and 15.5% in the intermediate group; and 46.4%, 14.3%, and 7.1% in the unfavourable group (P < 0.001). CONCLUSIONS: Our stratification model may be useful to determine whether UD is indicated for patients with MUO.

The Moreau Strain of Bacillus Calmette-Guerin (BCG) for High-Risk Non-Muscle Invasive Bladder Cancer: An Alternative during Worldwide BCG Shortage?

BACKGROUND: Bacillus Calmette-Guerin (BCG) is the standard of care for adjuvant intravesical instillation therapy for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC) after complete transurethral resection. Increasing evidence suggests that there are marked differences in outcomes according to BCG substrains. BCG-Moreau was recently introduced to the European market to cover the issue of BCG shortage, but there are little data regarding the oncologic efficacy. METHODS: We retrospectively analyzed 295 consecutive patients, who received adjuvant intravesical instillation therapy with BCG-Moreau for intermediate- and high-risk NMIBC between October 2007 and April 2013 at a single institution. The end points of this study were time to first recurrence and progression to muscle-invasive disease. RESULTS: Median age was 66 years (interquartile range 59-74, mean 65.9 years). According to the EAU risk group, 76 patients presented with intermediate-risk and 219 patients with high-risk NMIBC. The 5-year recurrence-free survival and progression-free survival rate was 64.8% (95% CI 52.8-74.4) and 81.4% (95% CI 65.2-90.2), respectively. CONCLUSIONS: BCG-Moreau is an effective substrain for adjuvant instillation therapies of NMIBC, and outcomes appear to be comparable to series using other substrains. During worldwide shortage of BCG-TICE, Connaught and RIVM, BCG-Moreau may serve as an equally effective alternative.

Pathological features of lymph node metastasis for predicting biochemical recurrence after radical prostatectomy for prostate cancer.

PURPOSE: Subclassification of nodal stage may have prognostic value in men with lymph node metastasis at radical prostatectomy. We explored the role of extranodal extension, size of the largest metastatic lymph node and the largest metastasis, and lymph node density as predictors of biochemical recurrence. MATERIALS AND METHODS: We reviewed pathological material from 261 patients with node positive prostate cancer. We examined the predictive value when adding the additional pathology findings to a base model including extraprostatic extension, seminal vesicle invasion, radical prostatectomy Gleason score, prostate specific antigen and number of positive lymph nodes using the Cox proportional hazards regression and Harrell concordance index. RESULTS: The median number of lymph nodes removed was 14 (IQR 9, 20) and the median number of positive lymph nodes was 1 (IQR 1, 2). At a median followup of 4.6 years (IQR 3.2, 6.0) 155 of 261 patients experienced biochemical recurrence. The mean 5-year biochemical recurrence-free survival rate was 39% (95% CI 33-46). Median diameter of the largest metastatic lymph node was 9 mm (IQR 5, 16). On Cox regression radical prostatectomy specimen Gleason score (greater than 7 vs 7 or less), number of positive lymph nodes (3 or greater vs 1 or 2), seminal vesicle invasion and prostate specific antigen were associated with significantly increased risks of biochemical recurrence. On subset analysis metastasis size significantly improved model discrimination (base model Harrell concordance index 0.700 vs 0.655, p = 0.032). CONCLUSIONS: Our study confirms that the number of positive lymph nodes is a predictor of biochemical recurrence in men with node positive disease. The improvement in prognostic value of measuring the metastatic focus warrants further investigation.

Pelvic lymph node dissection for prostate cancer: frequency and distribution of nodal metastases in a contemporary radical prostatectomy series.

PURPOSE: We determined the frequency and distribution of metastases to pelvic lymph nodes in a contemporary American radical prostatectomy series. MATERIALS AND METHODS: In 642 consecutive patients with clinically localized prostate cancer treated by a single surgeon between 2002 and 2009 pelvic lymph nodes were removed and submitted to the pathologist in separate packets (external iliac, obturator and hypogastric). We assessed the total number of nodes and the number with metastases in each packet. RESULTS: Complete pathological information was available for 427 patients, who had a median of 16 lymph nodes removed. Of the patients 35 (8.2%) had lymph node metastases, including 1.7% with low, 8.6% with intermediate and 23.9% with high risk cancer. Of those with nodal metastases 24 (69%) had positive lymph nodes in only 1 of the 3 areas, including the external iliac in 4 (11%), the obturator in 9 (26%) and the hypogastric in 11 (31%). Only 37% of the patients had positive nodes only in the external iliac area above the obturator nerve while 60% and 49% had at least 1 positive node in the obturator and the hypogastric area, respectively. Of the patients 80% had only 1 (49%) or 2 (31%) positive nodes. CONCLUSIONS: In contemporary American patients with clinically localized prostate cancer lymph node metastases were found more often and frequently exclusively in the obturator and hypogastric areas than in the external iliac area. Pelvic lymph node dissection limited to the external iliac area above the obturator nerve would identify and remove lymph node metastases in only a third of the patients with positive nodes found at full pelvic lymph node dissection.

Combining imaging and ureteroscopy variables in a preoperative multivariable model for prediction of muscle-invasive and non-organ confined disease in patients with upper tract urothelial carcinoma.

OBJECTIVE: To create a preoperative multivariable model to identify patients at risk of muscle-invasive (pT2+) upper tract urothelial carcinoma (UTUC) and/or non-organ confined (pT3+ or N+) UTUC (NOC-UTUC) who potentially could benefit from radical nephroureterectomy (RNU), neoadjuvant chemotherapy and/or an extended lymph node dissection. PATIENTS AND METHODS: We retrospectively analysed data from 324 consecutive patients treated with RNU between 1995 and 2008 at a tertiary cancer centre. Patients with muscle-invasive bladder cancer were excluded, resulting in 274 patients for analysis. Logistic regression models were used to predict pT2+ and NOC-UTUC. Pre-specified predictors included local invasion (i.e. parenchymal, renal sinus fat, or periureteric) on imaging, hydronephrosis on imaging, high-grade tumours on ureteroscopy, and tumour location on ureteroscopy. Predictive accuracy was measured by the area under the curve (AUC). RESULTS: The median follow-up for patients without disease recurrence or death was 4.2 years. Overall, 49% of the patients had pT2+, and 30% had NOC-UTUC at the time of RNU. In the multivariable analysis, only local invasion on imaging and ureteroscopy high grade were significantly associated with pathological stage. AUC to predict pT2+ and NOC-UTUC were 0.71 and 0.70, respectively. CONCLUSIONS: We designed a preoperative prediction model for pT2+ and NOC-UTUC, based on readily available imaging and ureteroscopic grade. Further research is needed to determine whether use of this prediction model to select patients for conservative management vs RNU, neoadjuvant chemotherapy, and/or extended lymphadenectomy will improve patient outcomes.

Association of tumor-associated trypsin inhibitor (TATI) expression with molecular markers, pathologic features and clinical outcomes of urothelial carcinoma of the urinary bladder.

PURPOSES: To describe the differential tissue expression of tumor-associated trypsin inhibitor (TATI) in normal bladder urothelium, primary urothelial carcinoma of the bladder (UCB) and metastatic UCB and to assess the association of TATI expression with molecular markers commonly altered in UCB and clinical outcomes after radical cystectomy. METHODS: Slides from eight cystectomy patients without cancer, 191 radical cystectomy patients, 20 lymph nodes without metastasis and 40 lymph nodes with UCB were stained. Tissue expression of TATI, cyclin E1, cyclin D1, p53, p21, p27, pRB, Ki-67, Bcl-2, Caspase-3, Survivin and Cyclooxigenase-2 was measured in a tissue microarray. Cancer-specific and recurrence-free survival after radical cystectomy was recorded. RESULTS: TATI was expressed in 100% of patients without cancer, while 71% of radical cystectomy specimens and 90% of lymph node metastases exhibited decreased or no TATI expression. In radical cystectomy specimens, TATI expression decreased with advancing pathologic stage (P < 0.001) and lymphovascular invasion (P = 0.055). In univariate analyses, but not in multivariable Cox proportional hazard regression analyses, decreased TATI expression was associated with increased probability of tumor recurrence and cancer-specific mortality. Decreased TATI expression was correlated with altered expression of Cyclooxigenase-2 (P = 0.005), p21 (P = 0.035) and Ki-67 (P = 0.004). CONCLUSIONS: We found that normal urothelium expresses TATI and that TATI expression decreases with advancing tumor stage. While there was no prognostic benefit to TATI when adjusted for standard clinicopathologic features, it seems to play an important biologic role in UCB pathogenesis and invasion. Its association with markers involved in the cell cycle, proliferation and inflammation serves as hypothesis for molecular interactions.

Pilot study of salvage laparoscopic prostatectomy for the treatment of recurrent prostate cancer.

OBJECTIVE: • To evaluate feasibility, safety and oncological efficacy of salvage laparoscopic radical prostatectomy for pathology-proven biochemical recurrence after primary radiation therapy or cryotherapy for prostate cancer. MATERIALS AND METHODS: • This retrospective pilot study examined 15 patients from 2004 to 2010 with biochemical recurrence after external beam radiation therapy (N= 8), brachytherapy (N= 6) or cryotherapy (N= 1). • Patients were treated with salvage laparoscopic radical prostatectomy (11 conventional, four robotic-assisted) with bilateral pelvic dissection. RESULTS: • Median duration of surgery was 235 min. None of the following occurred: conversion to open surgery, transfusion, urethrovesical stenosis or perioperative or postoperative mortality. One patient presented with a rectal injury, repaired using uninterrupted sutures and a colostomy. One patient had anastomotic leak treated with prolonged Foley catheterization. • Pathological stage was pT2a in three, pT2b in three, pT3a in four, pT3b in three and pT4 in two patients; two patients had nodal metastasis. Within an 8-month median follow-up, 11 patients were disease-free and three had persistent postoperative prostate-specific antigen (PSA) elevation; the remaining patient experienced PSA recurrence after 21 months. • Seven patients achieved continence (no pads) by 8.4 months (median), one patient manifested severe incontinence corrected by implanting an artificial sphincter, and seven patients with a 12.6-month mean follow-up continued to need one or two pads per day. • Erectile dysfunction was present in five patients before surgery and in 14 patients after surgery. CONCLUSION: • Salvage laparoscopic radical prostatectomy seems to offer a safe therapeutic alternative for patients failing primary radiation or cryotherapy. However, larger studies with longer-term data are required.

Learning curve for radical retropubic prostatectomy.

PURPOSE: The learning curve is a period in which the surgical procedure is performed with difficulty and slowness, leading to a higher risk of complications and reduced effectiveness due the surgeon's inexperience. We sought to analyze the residents' learning curve for open radical prostatectomy (RP) in a training program. MATERIALS AND METHODS: We conducted a prospective study from June 2006 to January 2008 in the academic environment of the University of Sao Paulo. Five residents operated on 184 patients during a four-month rotation in the urologic oncology division, mentored by the same physician assistants. We performed sequential analyses according to the number of surgeries, as follows: ≤ 10, 11 to 19, 20 to 28, and ≥ 29. RESULTS: The residents performed an average of 37 RP each. The average psa was 9.3 ng/mL and clinical stage T1c in 71% of the patients. The pathological stage was pT2 (73%), pT3 (23%), pT4 (4%), and 46% of the patients had a Gleason score 7 or higher. In all surgeries, the average operative time and estimated blood loss was 140 minutes and 488 mL. Overall, 7.2% of patients required blood transfusion, and 23% had positive surgical margins. CONCLUSION: During the initial RP learning curve, we found a significant reduction in the operative time; blood transfusion during the procedures and positive surgical margin rate were stable in our series.

Oncological outcomes after radical cystectomy for bladder cancer: open versus minimally invasive approaches.

PURPOSE: The number of centers performing robotic assisted radical cystectomy has recently increased, spurring greater concerns about oncological outcomes. In this review we summarize the most comprehensive articles published on the oncological outcomes of laparoscopic assisted, robotic assisted and open radical cystectomy. MATERIALS AND METHODS: A MEDLINE/PubMed literature search was conducted in March 2009 to review English language articles published from 1998 onward. Of 217 selected articles on the 3 techniques 19 studies were selected for this review. RESULTS: The laparoscopic series reported recurrence-free survival rates in the range of 83% to 85% at 1 to 2 years and 60% to 77% at 2 to 3 years, while the robotic assisted studies reported recurrence-free survival rates of 86% to 91% at 1 to 2 years. Large open surgery studies showed 62% to 68% recurrence-free survival at 5 years and 50% to 60% at 10 years, with overall survival of 59% to 66% at 5 years and 37% to 43% at 10 years. Overall survival in the laparoscopic cohorts was 90% to 100% at 1 to 2 years and 50% to 87% at 2 to 3 years. Publications reporting robotic cases demonstrated a 90% to 96% overall survival in 1 to 2 years of followup. CONCLUSIONS: Despite the surge of centers adopting minimally invasive approaches for radical cystectomy, the long-term effectiveness of these techniques has not yet been proven. This review of recent and landmark articles on open and minimally invasive procedures emphasizes the need for prospective controlled studies and long-term followup data to determine the proper use of laparoscopic and robotic assisted techniques in bladder cancer surgery.

Clinical outcome of primary versus secondary bladder carcinoma in situ.

PURPOSE: Differences in clinical outcome are still unclear between primary and secondary bladder carcinoma in situ. We compared the clinical outcomes of primary and secondary carcinoma in situ, and identified predictive factors. MATERIALS AND METHODS: We retrospectively analyzed the records of 476 patients with high grade cTis, including 221 with primary and 255 with secondary carcinoma in situ, from 1990 to 2008 at a high volume cancer center after transurethral resection and intravesical bacillus Calmette-Guerin therapy. End points were time to progression to invasive disease (cT1 or higher) or radical cystectomy before progression, and progression to muscle invasive disease (cT2 or higher) or radical cystectomy before progression. We used Cox proportional hazards regression models. RESULTS: Patients with primary carcinoma in situ responded significantly more within 6 months of bacillus Calmette-Guerin than those with secondary carcinoma in situ (65% vs 39%, p <0.001). In the primary vs secondary groups the 5-year cumulative incidence of progression to cT1 or higher was 43% (95% CI 36-51) vs 32% (95% CI 27-39) and for progression to cT2 or higher it was 17% (95% CI 12-23) vs 8% (95% CI 5-13). On multivariate analysis primary carcinoma in situ was significantly more likely to progress to cT1 or higher (HR 1.38, 95% CI 1.05-1.81, p = 0.020) and to cT2 or higher, or radical cystectomy (HR 1.72, 95% CI 1.27-2.33, p = 0.001). We found no significance for age, gender or response to bacillus Calmette-Guerin as outcome predictors. Median followup was 5.1 years. CONCLUSIONS: Patients presenting with primary carcinoma in situ have a worse outcome than those with secondary carcinoma in situ, suggesting a need to differentiate these 2 entities in the treatment decision process.

Clinical outcomes of primary bladder carcinoma in situ in a contemporary series.

PURPOSE: The natural history of primary bladder carcinoma in situ has not been well described. We describe patterns of disease recurrence and progression, and identify clinical outcome predictors of primary carcinoma in situ after bacillus Calmette-Guerin therapy. MATERIALS AND METHODS: We performed a retrospective analysis of 155 patients diagnosed with isolated primary high grade carcinoma in situ at a tertiary center from 1990 to 2008 who underwent transurethral resection followed by intravesical bacillus Calmette-Guerin therapy. The end points included time to disease recurrence, time to progression to invasive disease (cT1 or higher) or to muscle invasive disease (cT2 or higher), or early radical cystectomy. Predictors included gender, age, race, smoking history, presenting symptoms, carcinoma in situ pattern (focal, multiple or diffuse) and response to bacillus Calmette-Guerin. RESULTS: A total of 155 patients received bacillus Calmette-Guerin therapy within 6 months. The 5-year cumulative incidence of progression to cT1 or higher was 45% (95% CI 37-55) and to cT2 or higher was 17% (95% CI 12-25) adjusting for the competing risk of radical cystectomy. Of 130 patients evaluated for response to bacillus Calmette-Guerin 81 (62%) were considered responders. Response to bacillus Calmette-Guerin was significantly associated with progression to cT1 or higher/radical cystectomy (HR 0.59, 95% CI 0.36-0.95, p = 0.029) and to cT2 or higher/radical cystectomy (HR 0.53, 95% CI 0.32-0.88, p = 0.015). This association was largely driven by the higher rate of early radical cystectomy among nonresponders. CONCLUSIONS: Despite bacillus Calmette-Guerin therapy and early radical cystectomy, patients with primary carcinoma in situ had a high rate of disease progression. Response to bacillus Calmette-Guerin was significantly associated with a lower rate of disease progression or early radical cystectomy.

Predicting biochemical recurrence-free survival for patients with positive pelvic lymph nodes at radical prostatectomy.

PURPOSE: We evaluated predictors of freedom from biochemical recurrence in patients with pelvic lymph node metastasis at radical prostatectomy. MATERIALS AND METHODS: Of 207 patients with lymph node metastasis treated with radical prostatectomy and bilateral pelvic lymph node dissection 45 received adjuvant androgen deprivation therapy and 162 did not. Cox proportional hazards regression models were used to investigate predictors of biochemical recurrence after radical prostatectomy. Recurrence probability was estimated using the Kaplan-Meier method. RESULTS: A median of 13 lymph nodes were removed. Of the patients 122 had 1, 44 had 2 and 41 had 3 or greater positive lymph nodes. Of patients without androgen deprivation therapy 103 had 1, 35 had 2 and 24 had 3 or greater positive lymph nodes while 69 experienced biochemical recurrence. Median time to recurrence in patients with 1, 2 and 3 or greater lymph nodes was 59, 13 and 3 months, respectively. Only specimen Gleason score and the number of positive lymph nodes were independent predictors of biochemical recurrence. Recurrence-free probability 2 years after prostatectomy in men without androgen deprivation with 1 positive lymph node and a prostatectomy Gleason score of 7 or less was 79% vs 29% in those with Gleason score 8 or greater and 2 or more positive lymph nodes. CONCLUSIONS: Prognosis in patients with lymph node metastasis depends on the number of positive lymph nodes and primary tumor Gleason grade. Of all patients with lymph node metastasis 80% had 1 or 2 positive nodes. A large subset of those patients had a favorable prognosis. Full bilateral pelvic lymph node dissection should be done in patients with intermediate and high risk cancer to identify those likely to benefit from metastatic node removal.

Association of angiogenesis related markers with bladder cancer outcomes and other molecular markers.

PURPOSE: We tested whether the altered immunohistochemical expression of angiogenesis related markers is associated with outcomes of patients with urothelial carcinoma of the bladder, and assessed the correlation of angiogenesis related markers with molecular markers commonly altered in urothelial bladder carcinoma. MATERIALS AND METHODS: Vascular endothelial growth factor, basic fibroblast growth factor and thrombospondin 1 expression data were collected, as were microvessel density data. Immunohistochemical staining was performed on specimens from 204 patients treated with radical cystectomy for urothelial carcinoma of the bladder. We also stained serial sections of the specimens for cyclin E1, cyclin D1, p53, p21, p27, pRB, Ki-67, Bcl-2, caspase-3, survivin and cyclooxygenase-2. We measured time to disease recurrence and cancer specific mortality, as well as the association with clinical and pathological features and other molecular markers. RESULTS: The altered expression of vascular endothelial growth factor (over expression), basic fibroblast growth factor (over expression) and thrombospondin 1 (decreased expression) was 86%, 79% and 63%, respectively. Median microvessel density was 20. All 4 markers were associated with established clinicopathological features of aggressive urothelial carcinoma of the bladder (such as stage, lymphovascular invasion and lymph node metastasis) and other molecular markers. On multivariable analyses that adjusted for standard pathological features basic fibroblast growth factor and thrombospondin 1 were independent predictors of disease recurrence (HR 3.6, p = 0.002 and HR 2.2, p = 0.001, respectively) and cancer specific mortality (HR 2.8, p = 0.02 and HR 2.3, p = 0.003, respectively). When all 4 markers were included in 1 model basic fibroblast growth factor and thrombospondin 1 retained their independent association with disease recurrence (HR 2.9, p = 0.014 and HR 1.8, p = 0.022, respectively) and only thrombospondin 1 was independently associated with cancer specific mortality (HR 1.9, p = 0.031). CONCLUSIONS: Angiogenesis related molecular markers are commonly altered in urothelial carcinoma of the bladder, making them a target for therapy. Down-regulation of thrombospondin 1 and up-regulation of basic fibroblast growth factor are independent predictors of clinical outcomes of patients with urothelial carcinoma of the bladder.

Combination of multiple molecular markers can improve prognostication in patients with locally advanced and lymph node positive bladder cancer.

PURPOSE: We tested whether the combination of 4 established cell cycle regulators (p53, pRB, p21 and p27) could improve the ability to predict clinical outcomes in a large multi-institutional collaboration of patients with pT3-4N0 or pTany Npositive urothelial carcinoma of the bladder. We also assessed whether the combination of molecular markers is superior to any individual biomarker. MATERIALS AND METHODS: The study comprised 692 patients with pT3-4N0 or pTany Npositive urothelial carcinoma of the bladder treated with radical cystectomy and bilateral lymphadenectomy (median followup 5.3 years). Scoring was performed using advanced cell imaging and color detection software. The base model incorporated patient age, gender, stage, grade, lymphovascular invasion, number of lymph nodes removed, number of positive lymph nodes, concomitant carcinoma in situ and adjuvant chemotherapy. RESULTS: Individual molecular markers did not improve the predictive accuracy for disease recurrence and cancer specific mortality. Combination of all 4 molecular markers into number of altered molecular markers resulted in significantly higher predictive accuracy than any single biomarker (p <0.001). Moreover addition of number of altered molecular markers to the base model significantly improved the predictive accuracy for disease recurrence (3.9%, p <0.001) and cancer specific mortality (4.3%, p <0.001). Addition of number of altered molecular markers retained statistical significance for improving the prediction of clinical outcomes in the subgroup of patients with pT3N0 (280), pT4N0 (83) and pTany Npositive (329) disease (p <0.001). CONCLUSIONS: While the status of individual molecular markers does not add sufficient value to outcome prediction in patients with advanced urothelial carcinoma of the bladder, combinations of molecular markers may improve molecular staging, prognostication and possibly prediction of response to therapy.

Characteristics and outcomes of patients with clinical carcinoma in situ only treated with radical cystectomy: an international study of 243 patients.

PURPOSE: We describe the rate of up staging and the cancer specific outcomes of patients with carcinoma in situ refractory to transurethral resection with intravesical therapy treated with radical cystectomy. MATERIALS AND METHODS: The records of 3,207 patients treated with radical cystectomy for urothelial carcinoma of the bladder at 8 centers in the United States, Canada and Europe were reviewed. RESULTS: Of the 3,207 patients who underwent radical cystectomy 243 (7.6%) had clinical carcinoma in situ only disease before radical cystectomy. At radical cystectomy 117 patients (48.1%) had carcinoma in situ only, 20 (8.2%) had pT0 urothelial carcinoma of the bladder, 19 (7.8%) had pTa urothelial carcinoma of the bladder and 36% had disease up staged (32 [13.2%] pT1, 29 [11.9%] pT2, 12 [4.9%] pT3 and 14 [5.8%] pT4). A total of 22 patients (9.1%) had lymphovascular invasion in the radical cystectomy specimen and 14 (5.8%) had metastasis to regional lymph nodes. Overall 5-year recurrence-free and cancer specific survival estimates were 74% (95% CI 68-79) and 85% (95% CI 80-89), respectively. On multivariable analysis adjusting for the effects of standard predictors, lymph node metastasis and lymphovascular invasion were associated with an increased risk of disease recurrence (p = 0.017 and p = 0.043, respectively) and cancer specific mortality (p = 0.019 and p = 0.001, respectively). Female gender was an independent risk factor for cancer specific mortality (p = 0.029) but not for disease recurrence (p = 0.173). CONCLUSIONS: Approximately a fourth of patients treated with radical cystectomy for clinical carcinoma in situ only had muscle invasive disease and 5.8% had metastasis to regional lymph nodes. Identification of those patients with a potentially aggressive natural history of carcinoma in situ is of the utmost importance as they are likely to benefit from early radical cystectomy.

Comparative Effectiveness of Intravesical BCG-Tice and BCG-Moreau in Patients With Non-muscle-invasive Bladder Cancer.

BACKGROUND: The purpose of this study was to compare the efficacy of 2 bacillus Calmette-Guérin (BCG) strains, BCG-Tice and BCG-Moreau, in the treatment of non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS: We retrospectively reviewed clinical data from patients treated with BCG for NMIBC at 3 academic centers. Inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves and Cox proportional hazards regression analyses were used to compare recurrence-free (RFS) and progression-free survival (PFS) of patients in the 2 treatment groups. In addition, we performed exploratory analyses of treatment effect according to the receipt of adequate BCG treatment, high-risk disease, age, gender, smoking status, pathologic stage, and pathologic grade. RESULTS: A total of 321 (48.6%) patients were treated with BCG-Tice and 339 (51.4%) with BCG-Moreau. IPTW-adjusted Cox proportional hazard regression analysis did not show a difference in RFS (hazard ratio, 0.88; 95% confidence interval, 0.56-1.38; P = .58) or PFS (hazard ratio, 0.55; 95% confidence interval, 0.25-1.21, P = .14) between BCG-Tice and BCG-Moreau. On subgroup analyses, we could not identify an association of BCG strain with outcomes. CONCLUSIONS: There was no difference in RFS and PFS between BCG-Tice and BCG-Moreau strains in the adjuvant treatment of NMIBC. However, we confirmed the importance of maintenance therapy for achieving a sustainable response in patients with intermediate- and high-risk NMIBC.

Intravesical therapy for urothelial carcinoma of the urinary bladder: a critical review.

The management of non-muscle-invasive urothelial carcinoma of the bladder (UCB) is a challenge for physicians and patients alike. This is largely due to the heterogeneous natural history of this disease, in which tumors range from indolent to rapidly progressive and eventually fatal. Moreover, the high rate of recurrence and progression cause significant morbidity, expense, and detriment to quality of life. The advent of effective and safe intravesical therapies has improved the management of non-muscle-invasive UCB. Nevertheless, despite over 30 years of research and clinical experience, the mechanism, risks, benefits, and optimal regimens and treatment algorithms remain unclear. Although immunotherapy with bacillus Calmette-Guerin (BCG) has been the mainstay of intravesical treatment and represents a significant advance in the interaction of immunology and oncology, its clinical effectiveness is accompanied by a wide range of adverse events. Here, we review the literature on intravesical immunotherapy and chemotherapy with the aim of evaluating the clinical utility of the different treatments and providing recommendations. Many studies over the years have compared efficacy and toxicities of different agents and regimens, and certain conclusions are now well supported by high-level evidence. Future perspectives and promising advances in drug development are discussed and areas of improvement are identified in order to promote better cancer control and decrease the rate and severity of side-effects.

Effects of curcumin in an orthotopic murine bladder tumor model.

Cigarette smoking (CS) is the main risk factor for bladder cancer development. There are more than 100 carcinogens present in cigarette smoke. Among the potential mediators of CS-induced alterations is nuclear factor-kappa (NF-kappaB), which is responsible for the transcription of genes related to cell transformation, tumor promotion, angiogenesis, invasion and metastasis. Curcumin is a polyphenol compound derived from Curcuma longa that suppress cellular transformation, proliferation, invasion, angiogenesis, and metastasis by down regulating NF-kappaB and its regulated genes. The aim of our study was to assess the effects of curcumin in bladder urothelial carcinoma. We studied the effects of curcumin in vitro and in vivo using the orthotropic syngeneic bladder tumor animal model MB49. Curcumin promotes apoptosis of bladder tumor cells in vitro. In vivo tumors of animals treated with curcumin were significantly smaller as compared to controls. Using immunohistochemistry, we demonstrated a decrease in the expression of Cox-2 by 8% and Cyclin D1 by 13% in the animals treated with curcumin; both genes regulated by NF-kappaB and related to cell proliferation. In this study, we showed that curcumin acts in bladder urothelial cancer, possibly dowregulating NF-kappaB-related genes, and could be an option in the treatment of urothelial neoplasms. The results of our study suggest that further research is warranted to confirm our findings.