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.