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Objectives: Carbonic anhydrase-IX (CA-IX) is a cell surface tumor-associated antigen expressed by most clear cell renal cell carcinomas (RCCs). The specificity and the prognostic value of CA-IX provide impetus to create a mouse model of CA-IX-expressing RCC for testing CA-IX-targeted therapies against RCC., Methods: A retrovirus encoding the human CA-IX gene was used to transduce the murine RCC line, RENCA. In vivo growth kinetics and CA-IX expression were compared between RENCA and RENCA/CA-IX using heterotopic, metastatic, and orthotopic models., Results: Transduction of RENCA created the RENCA/CA-IX line with nearly 100% CA-IX surface expression. In the heterotopic model, subcutaneous injection of 500,000 and 50,000 cells led to tumor formation at 2 to 2.5 weeks after injection, with similar growth kinetics between the two cell lines at either cell number. In the pulmonary metastatic model, a similar number of metastases was noted after inoculation of RENCA and RENCA/CA-IX. In the orthotopic model, autopsy revealed a CA-IX-expressing renal tumor, as well as CA-IX-expressing metastases to the lungs, liver, contralateral kidney, intestines, and lymph nodes. In all the above models, the RENCA/CA-IX tumors retained expression of CA-IX, as demonstrated by immunohistochemistry staining., Conclusions: RENCA/CA-IX is the first tumor model that manifests in immunocompetent Balb/c mice and stably expresses a defined kidney cancer-associated antigen. It maintains antigen expression, forms metastases, and produces reliable tumor growth kinetics equivalent to that of its parental cell line.

Introduction: Bladder cancer represents an ideal tumor model to test and apply cancer prevention strategies. In addition to reviewing the epidemiology of transitional cell carcinoma (TCC), we review the current status and the future directions of bladder cancer prevention., Materials and Methods: A literature review of peer-reviewed articles which address bladder cancer prevention was performed., Results: Pre-clinical and limited clinical data suggest that bladder cancer is responsive to efforts to delay or prevent its development in at-risk patients, and in reducing the risk of recurrence in patients with established disease. Many epidemiologic studies, however, investigating natural products, such as vitamins and herbal compounds, lack conclusive evidence of their chemopreventive effects., Conclusions: While many agents hold promise in the prevention of bladder cancer, none currently can be recommended as proven chemoprevention strategies. Improving the accuracy of patient risk assessment and identification of surrogate endpoint biomarkers are crucial to the testing of these strategies. Efficient study design will ensure rapid and substantial advances in the chemoprevention of bladder cancer.

Purpose: Androgen ablation remains the cornerstone of management for advanced prostate cancer. Therapeutic options in patients with progressive disease following androgen deprivation include antiandrogen withdrawal, secondary hormonal agents and chemotherapy. Multiple secondary hormonal agents have clinical activity and the sequential use of these agents may lead to prolonged periods of clinical response. We provide a state-of-the-art review of the various agents currently used for secondary hormonal manipulation and discusses their role in the systemic treatment of patients with prostate cancer., Materials and Methods: A comprehensive review of the peer reviewed literature was performed on the topic of secondary hormonal therapies, including oral antiandrogens, adrenal androgen inhibitors, corticosteroids, estrogenic compounds, gonadotropin-releasing hormone antagonists and alternative hormonal therapies for advanced prostate cancer., Results: Secondary hormonal therapies can provide a safe and effective treatment option in patients with AIPC. The use of steroids and adrenolytics, such as ketoconazole and aminoglutethimide, has resulted in symptomatic improvement and a greater than 50% prostate specific antigen decrease in a substantial percent of patients with AIPC. A similar clinical benefit has been demonstrated with estrogen based therapies. Furthermore, these therapies have demonstrated a decrease in metastatic disease burden. Other novel hormonal therapies are currently under investigation and they may also show promise as secondary hormonal therapies. Finally, guidelines from the United States Food and Drug Administration Prostate Cancer Endpoints Workshop were reviewed in the context of developing new agents., Conclusions: Secondary hormonal therapy serves as an excellent therapeutic option in patients with AIPC in whom primary hormonal therapy has failed. Practicing urologists should familiarize themselves with these oral medications, their indications and their potential side effects.

Purpose: We created an evidence based postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma (RCC) based on a risk group stratification system., Materials and Methods: 559 patients undergoing surgery for localized and ocally advanced RCC were stratified into low risk (LR), intermediate risk (IR) and high risk (HR) groups based on the University of California-Los Angeles Integrated Staging System (UISS). Tumor recurrences were identified and categorized according to time and location., Results: Patients with localized disease had a lower 5-year recurrence rate than patients with locally advanced (nodal) disease (27.6% vs 64%, p <0.0001). Patients in the LR, IR, and HR groups following nephrectomy demonstrated 5-year recurrence-free rates of 90.4%, 61.8%, and 41.9%, respectively (p <0.0001), and median times to recurrence of 28.9, 17.8 and 9.5 months, respectively (p <0.0001). Chest and abdomen recurrences comprised of 75% and 37.5%, 77.4% and 58.1%, and 45.2% and 67.7% of recurrences in the LR, IR and HR groups, respectively. In patients with node positive disease, chest and abdomen comprised of 58.8% and 76.5% of recurrences, respectively. Patients undergoing partial nephrectomy did not demonstrate a greater rate of local or distant recurrence compared with patients undergoing radical nephrectomy., Conclusions: Significant differences in incidence and time to recurrence following surgical resection for RCC mandates unique surveillance protocols for patients in each of the UISS risk groups. LR group patients should be followed for at least 5 years, whereas IR and HR group patients require longer surveillance. HR group patients require more stringent abdominal surveillance, whereas LR group patients should emphasize the chest. Patients with nodal disease also require stringent followup. Patients undergoing partial nephrectomy for localized disease can be followed according to the same UISS risk group based protocol.

Background: The presence of histologic necrosis in the primary tumor of patients with renal cell carcinoma (RCC) has been suggested to be an important predictor of survival. The authors investigated the relation of tumor necrosis to other clinicopathologic factors known to be important prognostic indicators for patients with RCC., Methods: The records of 311 patients undergoing treatment for RCC were evaluated for basic clinicopathologic information including TNM classification, nuclear grade, Eastern Cooperative Oncology Group (ECOG) performance status (PS), disease recurrence, and survival. The presence and extent of histologic necrosis of the primary tumors was recorded and correlated with clinicopathologic factors, carbonic anhydrase IX and Ki-67 expression, disease recurrence, and survival., Results: The presence of necrosis in the primary tumor of patients with RCC compared with patients with RCC without necrosis was associated with higher T classification (P < 0.0001), the presence of lymph node disease (P = 0.009), the presence of metastases (P < 0.0001), higher grade (P < 0.0001), greater mean tumor size (P < 0.0001), an ECOG PS score > or = 1 (P = 0.007), higher University of California-Los Angeles Integrated Staging System (UISS) category (P < 0.0001), and higher Ki-67 expression (P < 0.0001). The extent of necrosis in the primary tumor was associated with the presence of lymph node disease (P = 0.009) and the presence of metastases (P < 0.0001), and correlated with higher T classification (sigma = 0.31, P < 0.0001), poorer ECOG PS (sigma = 0.18, P = 0.002), higher grade (sigma = 0.33, P < 0.0001), greater tumor size (sigma = 0.40, P < 0.0001), higher UISS category (sigma = 0.37, P < 0.0001), and higher Ki-67 staining (sigma = 0.32, P < 0.0001). Patients with the presence of necrosis in the primary tumor demonstrated a lower 5-year disease-specific survival compared with patients without necrosis in the primary tumor (36% vs. 75%; P < 0.0001). Multivariate analysis demonstrated that T classification (P < 0.0001), distant metastases (P < 0.0001), and ECOG PS (P < 0.0001) were independent predictors of DSS, whereas the presence of necrosis was not (P = 0.1100). Substratification into localized and metastatic disease demonstrated that the presence of necrosis was an independent predictor of survival in patients with localized (P = 0.025), but not metastatic (P = 0.44), disease. The extent of necrosis was not an independent predictor of survival (P > 0.05). Patients with the presence of necrosis in the primary tumor had a lower 5-year disease recurrence-free rate compared with patients without the presence of necrosis (62% vs. 92%, P < 0.0001)., Conclusions: The presence of necrosis in the primary tumor was associated with adverse prognostic factors such as high T classification, presence of lymph node disease and metastases, high grade, large tumor size, and poor ECOG PS. The extent of necrosis was found to be associated with the presence of lymph node disease and metastases and correlated with higher T classification, higher grade, greater tumor size, poorer ECOG PS, and higher UISS category. The presence of this histologic variant was an independent predictor of poor survival in patients with localized, but not metastatic, disease. In addition, Ki-67 expression served as a valuable surrogate marker for the presence of histologic tumor necrosis., (Copyright 2005 American Cancer Society.)

Purpose: Renal cell carcinoma (RCC) has traditionally been staged using a purely anatomical staging system. Although current staging systems provide good prognostic information, data published in the last few years has led to significant controversies as to whether further revisions are needed and whether improvements can be made with the introduction of new, more accurate and predictive prognostic factors not currently included in traditional staging systems. This review highlights such controversies and provides an update on current staging modalities, prognostic factors and targeted molecular therapy for RCC., Materials and Methods: A comprehensive review of the peer reviewed literature was performed on the topic of current staging modalities, validated prognostic factors, predictive nomograms, molecular markers and targeted molecular therapy for RCC., Results: A staging system for malignant disease such as RCC uses various characteristics of tumors to stratify patients into clinically meaningful categories, which can be used to provide patients with counseling regarding prognosis, select treatment modalities and determine eligibility for clinical trials. The TNM staging system is currently the most extensively used one. However, it has undergone recent systematic revision due to rapidly emerging data from longer patient followup. The identification of various histological and symptomatic factors has led groups at many centers to develop more comprehensive staging systems that integrate these factors and include patients with metastatic and local disease. While integrated staging systems have improved RCC staging, the recent discovery of molecular tumor markers is expected to revolutionize RCC staging in the future and lead to the development of new therapies based on molecular targeting., Conclusions: Staging systems for RCC serve as a valuable prognostic tool. Several new patient and tumor characteristics have been reported to be important prognostic factors and they have been integrated into current staging systems. In addition, the field of RCC is rapidly undergoing a revolution led by molecular markers and targeted therapies. With this information urologists will be updated with the most current and comprehensive staging strategies, and be provided with a glimpse of the molecular and patient specific staging and treatment paradigms that will in our opinion transform the future management of this malignancy.

Purpose: We determined which clinical and molecular variables can predict cancer recurrence in patients following surgical management for localized renal cell carcinoma (RCC)., Materials and Methods: From a custom kidney cancer tissue microarray containing tumors specimens from 350 patients 193 undergoing nephrectomy for localized RCC at our institution between 1989 and 2000 were identified. The array was then analyzed by immunohistochemistry for certain molecular markers, namely CA9, CA12, Ki67, gelsolin, p53, EpCAM, pTEN and vimentin. The medical records of these patients were then reviewed for age, sex, TNM stage, tumor size, nuclear grade, Eastern Cooperative Oncology Group (ECOG) performance status, recurrence status and, when applicable, time to recurrence. Cox regression analyses were done to determine clinical and molecular predictors of time to tumor recurrence., Results: Of the patients 15% demonstrated evidence of tumor recurrence following nephrectomy (29 of 193). Univariate Cox regression demonstrated that tumor size, T stage, grade, ECOG performance status, Ki67, EpCAM and p53 were significantly associated with recurrence (p <0.05). A multivariate Cox regression model showed that T stage (p = 0.018), ECOG (p = 0.004) and p53 (p = 0.003) were the 3 most significant predictors. p53 expression correlated significantly with nuclear grade (Pearson correlation 0.22, p = 0.023) but not with any other clinical factors. Patients with localized tumors demonstrating mean p53 staining values above and below 20% of cells had recurrence rates of 37.7% and 14.4%, respectively (RR = 3.28, p = 0.018)., Conclusions: p53 is a significant molecular predictor of tumor recurrence, as identified in patients undergoing treatment for localized RCC.

Purpose: We identified a subset of patients with renal cell carcinoma (RCC) who have a high likelihood of presenting with bone metastasis and would most benefit from a preoperative bone scan., Materials and Methods: A database of 1,357 patients undergoing nephrectomy and/or immunotherapy for RCC at our institution was queried. Patients presenting with metastasis to the bones were identified and stratified according to T stage, Eastern Cooperative Oncology Group (ECOG) score, musculoskeletal symptoms and alkaline phosphatase., Results: Of the patients 37% presented with metastasis. Bone metastasis was identified in 14% of patients. The incidence of bone metastasis was 5.4%, 13.8%, 15.4% and 28.2% in patients with T1 to T4 lesions, and 1.4%, 19% and 41% in those with an ECOG score of 0 to 2 and greater, respectively. T stage and ECOG score were then integrated. Bone metastasis was confirmed in 0.046%, 3.8%, 1.4% and 0% of patients with T1 to T4/ECOG 0 disease, and in 13.4%, 20%, 21.5% and 31% of those with T1 to T4/ECOG greater than 0 disease, respectively (p < 0.0001). Only 1.4% of patients with an ECOG score of 0 harbored bone metastasis, of whom 71% complained of musculoskeletal pain, 100% manifested extraosseous metastases and 25% had increased alkaline phosphatase at presentation., Conclusions: Performance status is an important predictor of bone metastasis in patients presenting with presumed RCC lesions. Bone scan should be performed in patients with an ECOG score of greater than 0 regardless of T stage but is unnecessary in those presenting with an ECOG score of 0, particularly when lacking symptoms and extraosseous metastasis.

The foundations of the generally accepted principles underlying the surgical management of renal cell carcinoma (RCC) were best annunciated in 1969 by Robson in his classic description of the radical nephrectomy [J Urol 1969;101;297]. Since then, much has changed in our understanding of the basic biology and genetics of kidney cancer, advances in renal imaging and clinical staging have led to the increased detection of incidental, lower stage, organ-confined tumors more amendable to expanded surgical options, surgical techniques themselves have evolved, and surgical equipment technology has advanced to make possible new methods of managing renal tumors in situ. Thus, the management of both localized and metastatic RCC has changed dramatically in the last 20 years, predicated on these major advancements in renal imaging, surgical techniques, and the development of effective immunotherapies for advanced disease. In this review, the evolution in thinking regarding the tenets of the radical nephrectomy will be examined, including the necessity for removal of the entire kidney, the possibility of sparing the adrenal gland, when and how extensive a lymphadenectomy should be performed, the development of laparoscopic and percutaneous nephron-sparing surgery using ablative technologies, and the role of nephrectomy and metastasectomy in patients with metastatic RCC. Here, we review current concepts and outcomes on the surgical management of RCC to help elucidate some of these changes, from the evolution of open to laparoscopic to percutaneous, from radical to partial to ablative approaches.

Purpose: We compared cancer specific survival of patients undergoing partial and radical nephrectomies for T1N0M0 renal tumors according to tumor size in a large multicenter series., Materials and Methods: A retrospective analysis of 1454 patients undergoing partial or radical nephrectomy for T1N0M0 renal tumors from 7 international academic centers was performed. Data were obtained for each patient including TNM stage (determined according to the 2002 TNM criteria), tumor size, type of surgery (partial versus radical nephrectomy) and cancer specific survival. Recurrence events were recorded when available., Results: Partial and radical nephrectomies were performed in 379 (26.1%) and 1075 (73.9%) cases, respectively. Mean followup +/- SD was 62.5 +/- 51.8 months. Recurrence data were available on 544 patients. There were no significant differences in local or distant recurrence rates between patients undergoing partial or radical nephrectomy for either T1a (p = 0.6) or T1b tumors (p = 0.5). For patients with T1a tumors, there was no significant difference in the rate of cancer specific deaths between the partial (314) and radical (499) nephrectomy groups (2.2% versus 2.6%, respectively, p = 0.8). For patients with T1b tumors there was also no significant difference in the rate of cancer specific deaths between patients undergoing partial (65) and patients undergoing radical (576) nephrectomy (6.2% versus 9%, respectively, p = 0.6)., Conclusions: Partial nephrectomy is becoming the gold standard for renal tumors less than 4 cm but this treatment is much more controversial for larger T1 tumors. This large multicenter study suggests that it is safe to expand the indications of partial nephrectomy to include patients with T1N0M0 tumors up to 7 cm. However, careful patient selection remains necessary.

Purpose: To compare the maximal active deflection capabilities of a newly designed dual-deflection ureteroscope with those of a standard flexible ureteroscope., Materials and Methods: The dual-deflection ureteroscope is similar in design to single-deflection ureteroscopes with the addition of a second, more proximal unidirectional deflection point, which is controlled with the index finger on the contralateral side of the instrument. We evaluated the maximal deflection angles achieved with this ureteroscope with no inserted devices as well as with 200-, 365-, and 550-microm laser fibers and a 3F Nitinol wire basket in the working port. We compared these angles with those obtained with the Dur-8 single-deflection ureteroscope., Results: The dual-deflection ureteroscope allowed a superior maximum active deflection angle of 234.3 degrees with an empty working channel compared with only 143 degrees for the standard single-deflection ureteroscope. Instruments in the working channel dampened the active deflection of both ureteroscopes. The average maximum upward angles achievable with the single-deflection ureteroscope with the 200-, 365-, and 550-microm laser fibers and the 3F basket were 115.3 degrees, 92 degrees, 46.6 degrees, and 123.3 degrees, respectively. The average deflection angles with the dual-deflection endoscope deflected at the distal point were similar to those obtained with the single-deflection ureteroscope. In contrast, the average maximum deflection angles obtained with the dual-deflection endoscope deflected at both points with a 200-, 365-, and 550-microm laser fiber and a 3F basket in the working channel were 211 degrees, 183.3 degrees, 109 degrees, and 224 degrees, respectively. The degree of dampening by larger instruments was greater in the single-deflection than the dual-deflection ureteroscope., Conclusions: The double-deflection ureteroscope can achieve superior active deflection compared with a standard ureteroscope. The second active angle allows the use of larger instruments in the working port with a smaller impact on overall deflection. The double-deflection ureteroscope should be beneficial in the management of difficult-to-treat lower-pole renal calculi and may allow some patients who would have required percutaneous nephrolithotomy to undergo ureteroscopic management of their stone disease.

Objectives: To perform a retrospective study to determine whether survival and immunotherapy response are related to the site of metastases (lung versus bone) and to the number of organ sites involved (one versus multiple). The most common sites of metastatic renal cell carcinoma (mRCC) are the lung and bone., Methods: The records of 434 patients with mRCC were reviewed. Patients with pathologic evidence of nodal involvement were excluded, leaving 120 patients with mRCC to lung only, 33 patients to bone only, and 144 patients with multiple organ involvement. The response rates to immunotherapy and overall survival were compared. The variables evaluated in statistical analyses included Eastern Cooperative Oncology Group score, grade, 1997 tumor stage, and multiple organ involvement., Results: The median survival for patients with lung only and bone only mRCC was 27 months; patients with multiple organ involvement had a median survival of 11 months. In patients who underwent nephrectomy followed by immunotherapy, the median survival time was 31, 31, and 13 months in the lung, bone, and multiple sites groups, respectively. The response rate to immunotherapy after nephrectomy was 44%, 20%, and 14% in the lung, bone, and multiple organ groups, respectively. Multivariate analysis confirmed that metastatic disease to more than one organ site was associated with poor prognosis (2.05 risk ratio, P <0.001)., Conclusions: Patients with mRCC to only one organ site fared significantly better than patients who had evidence of disease in multiple organs. Survival in patients with disease limited to the lung was similar to that of patients whose disease was limited to bone.

Background: Positron emission tomography (PET) is an emerging imaging modality that is being investigated for use in urologic oncology. PET scanning using the radioactive glucose analog FDG has proven to be a highly accurate imaging test for diagnosing and staging a variety of non-urologic cancer types. This review was performed to determine the role of PET imaging in genitourinary malignancies., Methods: A review of the literature focusing on PET and urologic oncology was performed. The role of PET imaging was reviewed in prostate, bladder, renal, and testicular cancer., Results: In testicular cancer, PET has a higher diagnostic accuracy than computed tomography (CT) for both staging and re-staging and should be the test of choice for the assessment of a CT-visualized residual mass following chemotherapy. In prostate, renal, and bladder cancer, the current role of PET is still being defined, but it has a high positive predictive value and can be used for problem solving in patients with indeterminate findings on conventional imaging. Its role in the diagnosis and staging of prostate cancer is hampered by the generally low glycolytic rate of most prostate tumors and their metastases. It has shown promise for staging and re-staging patients with advanced-stage disease and aggressive tumors suspected by a high tumor grade and high prostate-specific antigen velocity. PET has also demonstrated success when applied to renal cell carcinoma in classifying indeterminate renal masses as well as residual renal fossa masses following nephrectomy, gauging response to therapy, and staging and re-staging patients with a known diagnosis of renal cell carcinoma., Conclusions: PET imaging has demonstrated great potential in certain applications, but further investigations are necessary to determine its eventual place as an imaging modality in genitourinary malignancies.