Prognostic factors and selection for clinical studies of patients with kidney cancer.

Over the past 2 decades, a greater understanding of the basic biology and genetics of kidney cancer has occurred. Surgical techniques have also evolved, and technological advances have made possible new methods of managing renal tumors. The most extensively used system to provide prognostic information for renal cell carcinoma (RCC) is currently the tumor, nodes, metastasis (TNM) staging system. Emerging data over the last few years has questioned whether further revisions are needed and if improvements can be made with the introduction of new, more accurate and predictive prognostic factors. The recent discovery of molecular tumor biomarkers are expected to revolutionize the staging of RCC and potentially lead to the development of new therapies based on molecular targeting. This review will examine the current staging modalities and prognostic factors associated with RCC as well as the selection of patients most likely to benefit from clinical trials.

Flexible ureteroscopy and laser lithotripsy for single intrarenal stones 2 cm or greater--is this the new frontier?

PURPOSE: Percutaneous nephrolithotomy has been the standard of care for intrarenal calculi greater than 2 cm. Flexible ureteroscopy with holmium laser lithotripsy is a minimally invasive treatment modality that is able to treat large intrarenal calculi with the potential to decrease morbidity, while maintaining a high level of efficacy. MATERIALS AND METHODS: A total of 15 patients with a single intrarenal calculus 2 cm or greater were treated with retrograde ureteroscopic nephrolithotripsy. Lithotripsy was performed with a 7.2Fr flexible ureteroscope and 200 micron laser fiber. The stone-free rate was defined as the absence of any stones in the kidney or residual stone fragments less than 1 mm, which is too small to be extracted with a basket or a grasper. All patients underwent followup ureteroscopy within 15 days after the last procedure and renal ultrasound 30 days after the last treatment. RESULTS: There were a total of 15 intrarenal calculi 20 to 25 mm (mean 22) in diameter. The mean number of procedures was 2.3 (range 2 to 4). The overall stone-free rate was 93.3%. One patient (6.6%) had a residual 5 mm stone fragment in the lower pole of the kidney, which was followed expectantly for 2 years with no change in size. There were no major complications. There were 3 minor complications (20%), including 1 emergency room visit for fever and pain, and 2 cases of gross hematuria. All cases were performed on an outpatient basis. CONCLUSIONS: In select patients with a single intrarenal calculus 2 cm or greater small diameter flexible ureteroscopy with holmium laser lithotripsy may represent an alternative therapy to standard percutaneous nephrolithotomy with acceptable efficacy and low morbidity.

In vivo efficacy of laparoscopic assisted percutaneous renal cryotherapy: evidence based guidelines for the practicing urologist.

PURPOSE: The treatment of small renal tumors continues to evolve in parallel with advances in ablative technology. We compared the lesion geometry of 3, 17 gauge cryoneedles to determine the most effective distance and configuration of the cryoneedles in an in vivo porcine kidney model. MATERIALS AND METHODS: Argon gas based renal cryoablation was performed in 6 pigs using a laparoscopically assisted percutaneous approach. Cryoablation using a single cryoneedle and a template of 3 cryoneedles with various ice ball shapes, including elliptical, bulb-shaped and standard 17 gauge cryoneedles (Galil Medical, Plymouth Meadow, Pennsylvania) was performed in 3 pigs. Three additional pigs underwent renal cryoablation using elliptical cryoneedles in 3 triangular template configurations with the cryoneedles spaced 1, 1.5 and 2 cm apart, respectively. The animals were sacrificed a minimum of 2 weeks following treatment. RESULTS: Elliptical cryoneedles achieved the largest area of necrosis when used in single and template configurations. When used in a template configuration of 3 needles 1, 1.5 and 2 cm apart from each other the calculated volume of necrosis was 4.3 x 4.5 x 2.5, 4.9 x 4.1 x 2.5 and 4.0 x 4.5 x 2.5 cm, respectively. CONCLUSIONS: Using a single 17 gauge cryoneedle is inadequate for treating most small renal tumors. Cryoneedles with an elliptical ice ball are most effective for achieving consistent and reliable tissue destruction. The 1.5 cm template configuration generated the largest area of necrosis. Our data suggest that with the current technology renal cryoablation should be limited to lesions not greater than 4 cm.

Surveillance for renal cell carcinoma: why and how? When and how often?

Patient's history, physical examination, laboratory tests, and radiographic evaluation are the cornerstones of postoperative surveillance. It has been shown that localized renal cell carcinoma (RCC) can recur in nearly all organs of the body, but most commonly in the lung, bone, liver, brain, and renal fossa. Lung metastases can be sensitively detected through radiographic evaluation. Treatment of lung metastases might prolong survival, which supports surveillance x-ray or computed tomography scans. Surgical treatment of early detected liver metastases and local recurrences may also prolong survival, which supports a close abdominal surveillance program. Brain and bone metastases are usually symptomatic when they occur, and their treatment is generally palliative. Hence, surveillance protocols do not usually include their routine radiographic evaluation. Because partial nephrectomy does not increase the risk of local recurrence over radical nephrectomy, we recommend identical surveillance for completely resected tumors regardless of surgical approach. The risk of recurrence after nephrectomy is generally related to tumor stage, tumor grade, and patient performance status. The majority of recurrences occur within the first 5 years after surgery, supporting a more intense surveillance strategy within the first 5 years. The University of California Integrated Staging System (UISS) combines TNM stage, Fuhrman grade, and performance status, and categorizes patients into 3 different risk groups. The current surveillance protocol at our institution is based on the UISS. It is expected that molecular markers such as p53 will allow more individualized surveillance strategies in the future.

Protein expression profiles in renal cell carcinoma: staging, prognosis, and patient selection for clinical trials.

Attempts to predict survival in patients with renal cell carcinoma (RCC) have traditionally relied on standard clinical variables, such as tumor-node-metastasis stage, histologic grade, and performance status. An accurate method for predicting patient survival is useful for patient counseling, planning follow-up, and selecting patients most likely to benefit from novel and established therapies. Furthermore, an improved prognostic system will allow for more accurate comparisons of clinical trials based on varying inclusion criteria. A large number of potential prognostic markers have recently been identified from methods based on gene arrays, which screen for differential expression of thousands of genes. The accepted method of clinical validation of novel markers is on formalin-fixed and paraffin-embedded specimens using immunohistochemistry. The development of tissue microarrays as a high-throughput technique has allowed for thousands of different cores of pathologic tissue to be assessed simultaneously in a timely and cost-efficient manner. This technology has enabled the analysis of protein expression profiles on specimens to determine their potential clinical significance and role in RCC biology. This article reviews the protein expression profiles in RCC and their association with pathobiology, prognosis, and response to treatment as well as their role in serving as potential molecular targets for therapy of RCC.

Importance of surgical margins in the management of renal cell carcinoma.

Surgical resection remains the standard treatment for clinically localized renal cell carcinoma. Pathological features of the surgical specimen, including the margin status, play an important part in determining the patient's prognosis. Negative surgical margins have traditionally been sought to maximize the efficacy of treatment. Initial concerns that partial nephrectomy might have high local recurrence rates compared with radical nephrectomy have now been minimized as a result of technological advances and refinements in surgical technique. Current concerns in relation to partial nephrectomy include the width of parenchymal tissue that should be removed to avoid positive surgical margins, effects of positive margins on recurrence-free survival, and the use of frozen-section analysis to determine margin status. Size of the surgical margin in partial nephrectomy does not seem to affect the risk of local tumor recurrence, and not all positive surgical margins lead to recurrent disease. Intraoperative frozen-section analysis is not definitive and its value in guiding the surgical management of renal tumors remains to be defined. Laparoscopic partial nephrectomy is emerging as an attractive approach for selected renal masses. Intraoperative use of ultrasound, cold-scissor parenchymal transection, embolization, and hilar clamping to achieve a bloodless operative field with clear visibility, may minimize the risk of positive margins during partial nephrectomy.

Laparoscopic heminephrectomy for upper-pole moiety in children using a 3-mm laparoscope and instruments.

PURPOSE: We report three cases of laparoscopic heminephrectomy in infants using a 3-mm laparoscope and instruments. To our knowledge, this is the first pediatric heminephrectomy series reported in the literature that utilized these small instruments. PATIENTS AND METHODS: Three pediatric patients underwent laparoscopic heminephrectomy for an upper-pole moiety in a duplicated collecting system with 3-mm laparoscopic ports and a 3-mm Storz 30 degrees laparoscope. RESULTS: All three cases were completed laparoscopically with total times of 120, 135, and 160 minutes. There were no intraoperative complications, and there was minimal blood loss. The optics of the laparoscope provided visibility and illumination similar to those available with larger-diameter laparoscopes. Two patients were discharged approximately 1 day postoperatively. The third patient required intravenous antibiotics to treat a urinary-tract infection and was discharged home 4 days postoperatively. All three patients had recovered fully by 2 weeks. CONCLUSION: The 3-mm laparoscope provides excellent visibility and illumination for performing heminephrectomy in the pediatric population. In addition, the 3-mm instruments provide excellent tissue handling, similar to that of the 5-mm tools.

Prognostic factors in renal cell carcinoma.

The identification of prognostic factors in patients with renal cell carcinoma (RCC) represents an area of increasing interest. The tumor, node, metastasis (TNM) staging system is currently the most extensively used tool for providing prognostic information for RCC. Data published in the last few years have led to significant controversies as to whether further revisions are needed in current staging systems and whether improvements can be made with the introduction of new, more accurate and predictive prognostic factors not currently included in traditional staging systems. While integrated staging systems have improved the staging of RCC, the recent discovery of molecular tumor markers is expected to revolutionize the staging of RCC in the future and lead to the development of new therapies based on molecular targeting. The aim of the current review is to highlight such controversies and provide an update on current staging modalities and prognostic factors for RCC.

Stem cells in prostate and prostate cancer development.

Most cancers comprise a heterogenous population of cells with marked differences in their potential to proliferate as well as the ability to reconstitute the tumor upon transplantation. Cancer stem cells are a minor population of tumor cells that possess the stem cell property of self-renewal. Dysregulation of stem cell self-renewal is a likely requirement for the development of cancer. Cell signaling pathways shared by stem cells and cancer cells lend further evidence for a possible link between these 2 populations of cells. Study of the differentiation pathways of normal and abnormal prostate growth has led to the development of a stem cell model for prostate cancer. The basal layer of the normal prostate is believed to be populated by prostate epithelial stem cells and a population of transit-amplifying cells intermediate in differentiation to the stem and fully differentiated cells. There is recent evidence suggesting that prostate cancer occurs from malignant transformation of stem/progenitor cells, thereby resisting apoptosis and spawning proliferation. This new model for prostate cancer will have significant ramifications for the way this disease is studied and treated. Furthermore, through targeting the prostate cancer stem cell and its dysregulated self-renewal, therapies for treatment of prostate cancer are likely to improve.

Prostate stem cell antigen is overexpressed in prostate cancer metastases.

PURPOSE: Prostate stem cell antigen (PSCA) is expressed by a majority of prostate cancers and is a promising therapeutic target. PSCA protein and mRNA expression was examined in prostate cancer bone, lymph node, and visceral metastases to assess the potential of PSCA as an immunotherapeutic target in advanced prostate cancer. EXPERIMENTAL DESIGN: Immunohistochemical analysis of PSCA protein expression and quantitative mRNA expression analysis of PSCA was done on clinical specimens of prostate cancer bone, lymph node, and visceral metastases. PSCA protein and mRNA expression levels were quantified and compared between available matched pairs of bone and lymph node or visceral metastases. RESULTS: Bone metastases stained with higher intensity of PSCA compared with lymph node or liver metastases in seven of eight (87.5%) matched pairs (P = 0.035). PSCA mRNA expression was equal or greater than that of LAPC-9, a PSCA expressing xenograft, in 12 of 24 (50%) cases of prostate cancer metastases and was significantly correlated with PSCA protein expression (sigma = 0.84, P = 0.0019). Overall, PSCA protein expression was detected in 41 of 47 (87.2%), four of six (66.7%), and two of three (66.7%) cases of bone, lymph node, and liver metastases, respectively. Mean PSCA staining intensity was significantly higher in prostate cancer bone metastases compared with lymph node metastases (2.0 +/- 0.02 versus 0.83 +/- 0.31, P = 0.014). CONCLUSIONS: Prostate cancer metastases express PSCA. However, greater PSCA staining intensity and level of PSCA mRNA expression was associated with bone metastases compared with lymph node metastases. This study suggests that PSCA is a promising tumor marker and potential therapeutic target for patients with metastatic prostate cancer.

Use of the University of California Los Angeles integrated staging system to predict survival in renal cell carcinoma: an international multicenter study.

PURPOSE: To evaluate ability of the University of California Los Angeles Integrated Staging System (UISS) to stratify patients with localized and metastatic renal cell carcinoma (RCC) into risk groups in an international multicenter study. PATIENTS AND METHODS: 4,202 patients from eight international academic centers were classified according to the UISS, which combines TNM stage, Fuhrman grade, and Eastern Cooperative Oncology Group performance status. Distribution of the UISS categories was assessed in the overall population and in each center. RESULTS: The UISS stratified both localized and metastatic RCC into three different risk groups (P <.001). For localized RCC, the 5-year survival rates were 92%, 67%, and 44% for low-, intermediate-, and high-risk groups, respectively. A trend toward a higher risk of death was observed in all centers for increasing UISS risk category. For metastatic RCC, the 3-year survival rates were 37%, 23%, and 12% for low-, intermediate-, and high-risk groups, respectively; in 6 of 8 centers, a trend toward a higher risk of death was observed for increasing UISS risk category. A greater variability in survival rates among centers was observed for high-risk patients. CONCLUSION: This study defines the general applicability of the UISS for predicting survival in patients with RCC. The UISS is an accurate predictor of survival for patients with localized RCC applicable to external databases. Although the UISS may be useful for patients with metastatic RCC, it may be less accurate in this subset of patients due to the heterogeneity of patients and treatments.

Tissue array-based predictions of pathobiology, prognosis, and response to treatment for renal cell carcinoma therapy.

Renal cell carcinoma is the most lethal of the common urologic malignancies, with approximately 40% of patients eventually dying of cancer progression. Approximately one third of patients present with metastatic disease, and up to 40% treated for localized disease have a recurrence. Historically, clinical factors have been used as prognostic markers for patients with renal cell carcinoma. Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of renal cell carcinoma have paved the way for developments that may enhance early diagnosis, better predict tumor prognosis, and improve survival for renal cell carcinoma patients. Furthermore, reliable predictive factors are essential for the stratification of 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. This has led to the creation of integrated staging systems that predict outcome by combining pathological and clinical variables. Although staging has been improved with the development of integrated systems, molecular tumor markers are expected to revolutionize the staging of renal cell carcinoma in the future. The development of methods based on gene and tissue arrays has created a powerful tool for evaluating hundreds to thousands of tumors simultaneously with histologic, immunohistochemical, and chromosomal analyses. Gene array analysis permits rapid molecular profiling, and tissue arrays enable the analysis of protein expression profiles on specimens to determine their potential clinical significance and role in renal cell carcinoma biology. This article reviews the tissue array-based predictors of pathobiology, prognosis, response to treatment, and potential molecular targets for therapy of renal cell carcinoma.

Generation of kidney cancer-specific antitumor immune responses using peripheral blood monocytes transduced with a recombinant adenovirus encoding carbonic anhydrase 9.

PURPOSE: Carbonic anhydrase 9 (CA9) is the most promising molecular marker described for renal cell carcinoma (RCC) to date. We investigated whether transduction of monocytes from peripheral blood with adenovirus encoding the CA9 gene (AdV-CA9) could stimulate a T-cell mediated immune response against cancer cells expressing CA9. The ability to consistently generate a T-cell response is an important step toward the development of a CA9-specific RCC vaccine. EXPERIMENTAL DESIGN: AdV-CA9 was generated using the AdEasy system. AdV-CA9-transduced peripheral blood mononuclear cell (PBMC)-derived monocytes were used to raise CTLs from autologous peripheral blood lymphocytes (PBLs). The ability of CTLs to lyse targets expressing CA9 was assessed by (51)Cr-release. RESULTS: Monocytes were efficiently transduced with AdV-CA9. In five of six experiments, AdV-CA9-transduced monocytes were able to induce a population of CTLs from bulk PBLs. CTLs were capable of lysing autologous, but not allogeneic monocytes expressing CA9. Furthermore, CTLs were able to lyse autologous RCC tumor cells expressing CA9. The ability of CTLs to lyse relevant targets was blocked by anti-CD3, anti-CD8, and anti-MHC class I antibodies demonstrating a MHC class I restricted response. CONCLUSIONS: These results suggest that PBMC-derived monocytes transduced with AdV-CA9 can generate RCC-specific MHC class I restricted CTLs capable of lysing CA9-expressing cancer cells. Transduction of PBMC-derived monocytes with adenovirus provides a simple and effective alternative to the use of dendritic cells for the induction of antigen-specific CTL.

Bacillus Calmete-Guérin plus interferon-alpha2B intravesical therapy maintains an extended treatment plan for superficial bladder cancer with minimal toxicity.

Bacillus Calmette-Guérin (BCG) and interferon-alpha2B (IFN-alpha2B) have both been individually used for the intravesical treatment of superficial bladder cancer. We report our experience on the therapeutic efficacy and toxicity of combined intravesical BCG plus IFN-alpha2B for treating superficial bladder cancer, including patients failing previous BCG therapy. Thirty-two patients with superficial bladder cancer underwent 6 weekly treatments with full-, one-third, or one-tenth-dose of BCG plus 50 or 100 MU of IFN-alpha2B based on prior BCG exposure and tolerance. Patients with no evidence of disease proceeded onto maintenance therapy of 3 weekly treatments at 3 months followed by 2 additional maintenance cycles given 6 months apart. Response was assessed by cystoscopy/biopsy every 3 months after treatment. Before BCG plus IFN-alpha2B treatment, 20 patients (63%) had previously failed intravesical BCG therapy, 27 (84%) had aggressive disease (stage T1, grade 3, or carcinoma in situ), 27 (84%) had recurrent disease, 14 (44%) had multifocal disease, and 6 (19%) had disease of over 4 years duration. At median follow-up of 22 months, 21 patients (66%) remain disease-free and 11 patients (34%) had disease-recurrence. Nineteen of 32 patients (59%) were disease-free after the initial induction cycle. Six of 11 patients 55% ultimately failing combination therapy did so at the first 3 to 4 month evaluation. Four of 7 patients (57%) benefited from salvage re-induction therapy. Of the 20 patients previously treated with BCG, 12 patients (60%) remain disease-free. Combination BCG plus IFN-alpha2B intravesical therapy was well tolerated. Combination intravesical BCG plus IFN-alpha2B is an effective and tolerable alternative for patients with superficial bladder cancer, including those patients in whom intravesical BCG therapy had previously failed. Benefits of this combination therapy may include potentially less morbidity, improved clinical efficacy, and in the long term, fewer patients undergoing radical therapy. However, radical treatment options should be pursued for early failures of this combination regimen in those patients with risk factors for recurrence and progression.

Changing aspects in the evaluation and treatment of patients with benign prostatic hyperplasia.

Lower urinary tract symptoms are a common clinical symptom among men and a frequent reason for referring to a urologist. The most important information comes from the patient history because evaluation of symptoms is fundamental in the diagnosis and treatment planning for LUTS. Other aspects of the initial evaluation, such as the physical examination and initial laboratory values, can provide valuable additional information about the severity of the disease and the need for treatment. If treatment is warranted based on this information, additional diagnostic tests may be appropriate to set a pretreatment baseline, rule out other conditions, and plan treatment approach. Fortunately, a variety of effective medical and surgical treatments are available to treat this common disease.

Ureteroscopic management of upper tract transitional cell carcinoma.

The expanding experience with endoscopic techniques for treating upper tract urothelial malignancy demonstrates its safety and efficacy in carefully selected patients. Diagnostic accuracy can be enhanced, and pathologic confirmation of tumor grade and stage is possible. In carefully selected patients who have low-grade and low-stage disease, the results of endourologic management have been encouraging. Patients with an anatomic or functionally solitary kidney, bilateral disease, or significant renal insufficiency can often be considered candidates for endoscopic treatment as the first line of therapy. In the setting of low-grade, low-stage disease in a patient with a normal contralateral kidney, the role of endourologic management remains controversial. Adjuvant topical therapy with mitomycin C or BCG seems to be safe and well tolerated after endoscopic management of upper tract TCC.

Tips and tricks for the management of retained ureteral stents.

BACKGROUND AND PURPOSE: Retained ureteral stents, especially those that are encrusted and associated with a stone burden, can be a difficult management problem. We review our experience and the different options employed for treating this complication. PATIENTS AND METHODS: From July 1998 to February 2002, 26 retained ureteral stents were managed in our department. The average patient age was 45.9 years (range 8-77 years). The average time the stent had been in place was 10.7 months (range 3-28 months). Prior to planning definitive therapy, a plain radiograph with tomographic views was reviewed. RESULTS: A guidewire or Glidewire was often placed adjacent to the stent in order to maintain ureteral access and in some cases was able to facilitate removal of the retained stent. The patients required an average of 2.7 endourologic procedures (range 1-4) performed at one or more sessions to remove the stent and all associated stone burden. If the stone burden could not be entirely removed then stent extraction and subsequent sessions were performed until stone-free status was achieved. Cystolitholapaxy was required to treat the distal component of stent encrustation in 20 cases. Percutaneous nephrolithotomy was performed in four patients, antegrade ureteroscopy with or without intracorporeal lithotripsy in four patients, retrograde ureteroscopy with or without laser lithotripsy in five patients, and extracorporeal shockwave lithotripsy in seven patients to treat the proximal component of stent encrustation. The stent could be removed in a single anesthetic session in 23 of 26 cases (88.5%). Analysis revealed that the major component of the encrustations was a combination of calcium oxalate and phosphate. CONCLUSION: Successful management of retained ureteral stents requires careful planning and may entail a combination of endourologic approaches. It is imperative to avoid using significant force, which can result in severe ureteral injury or breakage of the stent. If encrustations are present along the stent, we believe in treating the distal component prior to managing any proximal or ureteral components.

Metastatic Leydig cell tumor of the testicle in a young African American male.

Malignant Leydig cell tumor (LCT) of the testis are extremely rare and account for less than 0.2% of all testicular cancers. Testicular tumors of all histological types rarely occur in African American men. The authors describe a rare case of an advanced stage malignant LCT arising from the testicle of an African American man at the young age of 35, who presented with hemoptysis and a productive cough. Clinical features and treatment of Leydig cell tumor of the testis are discussed.