Intravesical chitosan/interleukin-12 immunotherapy induces tumor-specific systemic immunity against murine bladder cancer.

Bladder cancer is a highly recurrent disease in need of novel, durable treatment strategies. This study assessed the ability of an intravesical immunotherapy composed of a coformulation of the biopolymer chitosan with interleukin-12 (CS/IL-12) to induce systemic adaptive tumor-specific immunity. Intravesical CS/IL-12 immunotherapy was used to treat established orthotopic MB49 and MBT-2 bladder tumors. All mice receiving intravesical CS/IL-12 immunotherapy experienced high cure rates of orthotopic disease. To investigate the durability and extent of the resultant adaptive immune response, cured mice were rechallenged both locally (intravesically) and distally. Cured mice rejected 100 % of intravesical tumor rechallenges and 50-100 % of distant subcutaneous rechallenges in a tumor-specific manner. The ability of splenocytes from cured mice to lyse targets in a tumor-specific manner was assessed in vitro, revealing that lytic activity of splenocytes from cured mice was robust and tumor specific. Protective immunity was durable, lasting for at least 18 months after immunotherapy. In an advanced bladder cancer model, intravesical CS/IL-12 immunotherapy controlled simultaneous orthotopic and subcutaneous tumors in 70 % of treated mice. Intravesical CS/IL-12 immunotherapy creates a robust and durable tumor-specific adaptive immune response against bladder cancer. The specificity, durability, and potential of this therapy to treat both superficial and advanced disease are deserving of consideration for clinical translation.

The role of lymphovascular space invasion in renal cell carcinoma as a prognostic marker of survival after curative resection.

OBJECTIVES: Lymphovascular invasion (LVI) correlates with adverse outcomes in numerous malignancies. However, its role in predicting outcomes in RCC is unclear. Herein, we evaluated what effect LVI had on metastasis free survival (MFS), disease-specific survival (DSS), and overall survival (OS) in patients with RCC treated with surgical excision. METHODS: Eight hundred forty-one consecutive patients who underwent partial or radical nephrectomy from 1989 to 2004 were identified. Pathologic and gross features examined were LVI, subtype, Fuhrman grade, stage, and size. Age and gender were also analyzed. Slides were re-reviewed by a single pathologist (MS). Variables with P < 0.1 on univariate analysis were incorporated in a Cox proportional hazards multivariate model. MFS, DSS, and OS were described for patients with and without LVI using the Kaplan-Meier method, and compared with the log-rank test. RESULTS: LVI was seen on H and E stained slides in 91 patients (11%); 120 (14%) developed metastatic disease, 91 (11%) died of RCC, and 306 (36%) died during a median follow-up of 61 months. While on univariate analysis, LVI was strongly associated with decreased MFS, DSS, and OS (P < 0.0001), on multivariate analysis, LVI was no longer statistically significant for MFS, DSS, and OS with a HR of 0.976 (95% CI: 0.583-1.63; P = 0.93), 0.96 (95% CI: 0.542-1.69; P = 0.88), and 1.24 (95% CI: 0.869-1.77; P = 0.24). CONCLUSIONS: We found LVI to be associated with worse MFS, DSS, and OS on univariate analysis, but not on multivariate analysis for patients with nonmetastatic RCC. In contrast to previously reported studies, LVI may not be an independent prognostic variable in patients with localized RCC.

Percent microscopic tumor necrosis and survival after curative surgery for renal cell carcinoma.

PURPOSE: Tumor necrosis is a potential marker of recurrence and survival after surgery for renal cell carcinoma. We determined whether a correlation exists between the amount (not just the presence/absence) of tumor necrosis, and metastasis-free, disease specific and overall survival after surgery for renal cell carcinoma. MATERIALS AND METHODS: We identified 841 consecutive patients who underwent partial or radical nephrectomy from 1989 to 2004 for renal cell cancer. Specimens were re-reviewed by a single pathologist (MFS). The tumor necrosis percent was none in 586 cases, less than 50% in 198 and 50% or greater in 55. Grade, stage, subtype, size, gender and age were also analyzed. Variables at p <0.05 on univariate analysis were incorporated into a Cox proportional hazards multivariate model. Metastasis-free, disease specific and overall survival was described using the Kaplan-Meier method and compared with the log rank test. RESULTS: Tumor necrosis was found in 253 specimens (30%). Univariate analysis revealed that the percent and presence of tumor necrosis correlated with metastasis-free, disease specific and overall survival. On multivariate analysis tumor necrosis presence/absence did not remain an independent predictor of disease specific (p = 0.7), metastasis-free (p = 0.7) or overall (p = 0.2) survival. Greater than 50% tumor necrosis was no longer a statistically significant predictor of metastasis-free survival (p = 0.45) but remained significant for disease specific (p = 0.02) and overall (p = 0.01) survival. CONCLUSIONS: The presence of 50% or greater tumor necrosis correlates with worse disease specific and overall survival but not metastasis-free survival in patients with renal cell carcinoma. Results support the inclusion of percent tumor necrosis over the presence/absence of tumor necrosis in the risk assessment of patients who undergo surgical treatment for renal cell carcinoma.

Effect of reclassification on the incidence of benign and malignant renal tumors.

PURPOSE: The incidence of benign renal tumors has increased in recent years. This trend is commonly attributed to the increased use of cross-sectional imaging and minimally invasive surgical approaches. An alternative hypothesis is that recent changes in histological classification are responsible for the increasing incidence. To further investigate the impact of histological reclassification we reexamined all excised renal masses using the 2004 WHO criteria and compared this histological classification to the prior criteria. MATERIALS AND METHODS: We identified 1,101 consecutive partial and radical nephrectomy cases managed at our institution from 1989 to 2003. All histopathological sections were rereviewed by a single pathologist and reclassified according to 2004 WHO criteria. The percentages of benign lesions per year according to the prior histological and current WHO 2004 histological criteria were compared. RESULTS: Of the 1,101 renal masses 132 (12.0%) and 165 (15.0%) were classified as benign using prior and current WHO criteria, respectively. On average the WHO criteria diagnosed more benign tumors per year than the prior criteria (p = 0.004). Linear regression demonstrated a similar, persistent increase in benign diagnoses per year of 0.69% (WHO) and 1.22% (prior) during the 14-year period (p = 0.33). All masses reclassified as benign were oncocytoma (33). CONCLUSIONS: Implementation of the 2004 WHO criteria is contributing to the increase in diagnosis of benign renal lesions, specifically oncocytoma. Changes in histological classification do not account for the entire increase. Other factors, which remain to be delineated, are also contributing to the increase in the diagnosis of benign renal lesions.

Prospective study of [18F]fluorodeoxyglucose positron emission tomography/computed tomography for staging of muscle-invasive bladder carcinoma.

PURPOSE: Novel imaging modalities are needed to detect occult metastatic disease in bladder carcinoma. Patients with regional lymphatic spread could be targeted for neoadjuvant chemotherapy, and patients with distant metastatic disease could be spared the unnecessary morbidity of radical cystectomy. Herein, we report a prospective study of positron emission tomography/computed tomography (PET/CT) with [(18)F]fluorodeoxyglucose (FDG) in patients undergoing radical cystectomy for cT2-3N0M0 urothelial carcinoma of the bladder. METHODS: Forty-three chemotherapy-naïve patients underwent FDG-PET/CT before planned cystectomy. All had negative conventional CT and bone scintigraphy before enrollment. Positive FDG-PET/CT was confirmed by percutaneous biopsy or open surgical exploration, whereas negative FDG-PET/CT was confirmed by complete lymphadenectomy. Recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) were described using the Kaplan-Meier method and compared using log-rank test. RESULTS: Median follow-up was 14.9 months (range, 0.4 to 46.1 months). One patient who did not undergo lymphadenectomy was excluded from the pathology data analysis (n = 42), whereas another patient who failed to return for follow-up was excluded from survival analysis (n = 42). FDG-PET/CT demonstrated a positive predictive value of 78% (seven of nine), a negative predictive value of 91% (30 of 33), sensitivity of 70% (seven of 10), and specificity of 94% (30 of 32). RFS, DSS, and OS were all significantly poorer in the patients with positive FDG-PET/CT than in those with negative FDG-PET/CT. CONCLUSION: FDG-PET/CT detected occult metastatic disease in seven of 42 patients with negative conventional preoperative evaluations. PET findings were strongly correlated with survival. As such, FDG-PET/CT may help in making treatment decisions before radical cystectomy.

Intravesical bacille Calmette-Guérin therapy for non-muscle-invasive bladder cancer: effects of concurrent statin therapy.

BACKGROUND: Recent studies provide conflicting evidence about the association of statin use and decreased efficacy of intravesical bacille Calmette-Guérin (BCG) therapy for bladder cancer. Because statin drugs have immunomodulatory properties that could reduce the effectiveness of BCG, we investigated whether concurrent use of statin drugs was associated with worsened clinical outcomes in patients undergoing BCG treatment for non-muscle-invasive bladder cancer. STUDY DESIGN: We retrospectively analyzed records of 120 patients undergoing BCG treatment during 1997 through 2007 at a single Department of Veterans Affairs Medical Center. Tumor-progression events, total recurrences, disease-specific and overall mortality were the outcomes relative to statin use. Fisher's exact, Student's t-tests, and logistic regression were used to compare the groups. RESULTS: Among the 90 evaluable patients, there were no significant differences between groups with regard to tumor grade and stage distribution or smoking status. Statins were used during BCG therapy by 47.8% of patients. Comparing patients with no use versus use of statins, 8.5% versus 11.6% had local tumor progression (p = 0.44); 10.6% versus 9.3% underwent cystectomy, chemotherapy, or radiation therapy (p = 0.56); and metastatic disease developed in 6.7% versus 11.6% (p = 0.33). Of the 27 patients who died of any cause, 12.5% (2 of 16) versus 27.3% (3 of 11) in the nonstatin versus statin groups, respectively, died of disease (p = 0.32). CONCLUSIONS: Concurrent statin use was not associated with adverse outcomes for patients undergoing BCG treatment for bladder cancer. While statins have a plausible biologic mechanism to reduce BCG efficacy, no differences were seen in this small pilot study.

Selective versus nonselective arterial clamping during laparoscopic partial nephrectomy: impact upon renal function in the setting of a solitary kidney in a porcine model.

INTRODUCTION: Laparoscopic partial nephrectomy has emerged as a standard of care for small renal masses. Nevertheless, there remains concern over the potential for irreversible insult to the kidney as a result of exposure to warm ischemia. We aim to investigate the utility of selective segmental arterial clamping as a means to reduce the potential for ischemic damage to a solitary kidney during laparoscopic partial nephrectomy utilizing a porcine model. MATERIALS AND METHODS: A total of 20 domestic swine were randomized into four equal groups. Each subject underwent laparoscopic radical nephrectomy to create the condition of a solitary kidney. On the contralateral side, a laparoscopic lower pole partial nephrectomy was performed, employing either selective or nonselective vascular clamping for either 60 or 90 minutes. Postoperatively, clinical status and serial serum studies were closely monitored for 1 week. RESULTS: There were no intraoperative complications. The 90-minute nonselective clamping produced devastating effects, resulting in rapid deterioration into florid renal failure within 72 hours. The 60-minute nonselective clamping group experienced modest but significant rises in both blood urea nitrogen and creatinine. Both 60- and 90-minute selective clamping groups performed well, with no significant rises in creatinine over a 7-day period, and no instances of renal failure. CONCLUSIONS: Selective arterial clamping is a safe and feasible means of vascular control during laparoscopic partial nephrectomy. In the porcine model, selective clamping appears to improve functional outcomes during prolonged periods of warm ischemic insult. Prospective evaluation of the technique in humans is necessary to determine if selective arterial control confers long-term functional benefits in patients with limited renal reserve.

Open versus laparoscopic retroperitoneal lymph node dissection: assessing adequacy of dissection in a porcine model.

BACKGROUND AND PURPOSE: Laparoscopic retroperitoneal lymph node dissection (L-RPLND) is emerging as a viable alternative to traditional open retroperitoneal lymph node dissection (O-RPLND). Despite numerous reports confirming clinical oncologic equivalency between the two approaches, however, concerns still remain over the adequacy of laparoscopic dissection. We therefore sought to compare the completeness of dissection between O-RPLND and L-RPLND in a porcine model. MATERIALS AND METHODS: Fourteen domestic swine were divided into two equivalent groups. Both groups underwent bilateral retroperitoneal lymph node dissection, approximating templates used in human dissection. In one group, the procedure was performed through an open midline incision, while the other group underwent completely laparoscopic dissection. Tissue was independently analyzed by a pathologist, who recorded lymph node yield based on microscopic evaluation. RESULTS: All animals in the L-RPLND group underwent successful procedures, without the need for conversion. Two open procedures were aborted because of hemorrhage. Mean lymph node yield from O-RPLND was 32, while the mean yield for L-RPLND was 29. This difference was not statistically significant (P=0.65). CONCLUSIONS: In the porcine model, L-RPLND is capable of providing a quality of dissection equivalent to that of O-RPLND, in terms of absolute lymph node yield on microscopic examination. The applicability of this data to human patients, however, may be limited by significant anatomic differences between the human and the pig. Further prospective comparison in human patients is critically needed.