[Ischemia is not an independent predictive factor of chronic renal failure after partial nephrectomy in a solitary kidney in patients without pre-operative renal insufficiency]. / L'ischémie a un impact limité sur la fonction rénale après néphrectomie partielle sur rein unique chez les patients sans insuffisance rénale préopératoire.

OBJECTIVE: To assess the influence of vascular clamping and ischemia time on long-term post-operative renal function following partial nephrectomy (PN) for cancer in a solitary kidney. PATIENTS AND METHODS: This is a retrospective study including 259 patients managed by PN between 1979 and 2010 in 13 centers. Clamping use, technique choice (pedicular or parenchymal clamping), ischemia time, and peri-operative data were collected. Pre-operative and last follow-up glomerular filtration rates were compared. A multivariate analysis using a Cox model was performed to assess the impact of ischemia on post-operative chronic renal failure risk. RESULTS: Mean tumor size was 4.0±2.3cm and mean pre-operative glomerular filtration rate was 60.8±18.9mL/min. One hundred and six patients were managed with warm ischemia (40.9%) and 53 patients with cold ischemia (20.5%). Thirty patients (11.6%) have had a chronic kidney disease. In multivariate analysis, neither vascular clamping (P=0.44) nor warm ischemia time (P=0.1) were associated with a pejorative evolution of renal function. Pre-operative glomerular filtration rate (P<0.0001) and blood loss volume (P=0.02) were significant independent predictive factors of long-term renal failure. CONCLUSION: Renal function following PN in a solitary kidney seems to depend on non-reversible factors such as pre-operative glomerular filtration rate. Our findings minimize the role of vascular clamping and ischemia time, which were not significantly associated with chronic renal failure risk in our study. LEVEL OF EVIDENCE: 5.

Predictive factors of chronic kidney disease stage V after partial nephrectomy in a solitary kidney: a multi-institutional study.

OBJECTIVE: Partial Nephrectomy (PN) in a solitary kidney is at risk of chronic kidney disease (CKD) stage V and/or haemodialysis (HD). Our objective was to determine predictive factors of CKD stage V in this population. MATERIAL & METHODS: Data from 300 patients were retrospectively collected from 16 tertiary centres. Clinical and operative parameters, tumor characteristics and renal function before surgery were analyzed. Patients with and without CKD stage V (defined as MDRD<1 5 ml/min) were compared using χ2 and Student-t tests for qualitative and quantitative variables, respectively. Predictive factors of CKD stage V were evaluated with a multivariable analysis using a Cox regression model. RESULTS: Median age and BMI were 63 years old and 26 kg/m², respectively. Most of the patients (65%) were male with an anatomic solitary kidney (88.3%). Median tumor size was 4 cm and 98% were malignant tumors. Median operative time, blood loss and clamping time were 180 min, 350 ml and 20 min respectively. Renal cooling was used in 19.3% and clamping of the pedicle was performed in 61.6%. Twenty five patients (8.5%) presented post operative CKD stage V at last follow-up and 18 underwent HD (6%) post-operatively because of acute renal insufficiency. There was no difference between CKD stage V and non CKD stage V patients concerning Charlson index, operative time (180 min vs 179 min, p = 0.39), blood loss (475 ml vs 350 ml, p = 0.51), use of renal cooling and type of clamping. Patients with CKD stage V were older (70 vs 63 years old, p = 0.005), had a lower baseline renal function (clearance MDRD 41 vs. 62 ml/min, p<0.0001) and an increased tumor size (p = 0.02). Complications occurred in 91 patients (30%) with 16% of minor (Clavien 1-2) and 14% of major (Clavien > 2) complications, respectively. In multivariable analysis, baseline MDRD, BMI, and the occurrence of a minor complication were independent predictive factors of post operative CKD stage V. CONCLUSION: PN in a solitary kidney is at risk of post-operative CKD stage V and HD. Pre-operative altered renal function and post operative complications are the main predictive factors of permanent CKD stage V.

Paclitaxel, estramustine and carboplatin combination chemotherapy after initial docetaxel-based chemotherapy in castration-resistant prostate cancer.

OBJECTIVES: Management of castration-resistant prostate cancer after docetaxel has become an unmet need for which various agents have been investigated. We report our experience with a paclitaxel-based regimen. METHODS: From February 2004 to November 2007, 15 patients (PTS) received paclitaxel 80 mg/m(2) weekly on day 1, carboplatin (AUC = 6) on day 1 every 21 days and estramustine 140 mg on days -1, 0 and 1 every week. RESULTS: Patient characteristics are: median age 67 years (range 44-81), median performance status (Eastern Cooperative Oncology Group) 1 (range 0-2) and median prostate-specific antigen 67.5 ng/ml (range 1.5-480). All PTS had soft-tissue and 12 (80%) also had osseous disease. A >50% decrease in prostate-specific antigen levels occurred in 9 PTS (60%, 95% CI 32-84). Responses included a partial response in 6 (40%, 95% CI 16-68) and stable disease in 5 PTS (33%). Median duration of progression-free survival was 4.0 months (range 1.1-13) and median survival was 14.6 months. After a median of 4 cycles (range 1-7), significant toxicity included fatigue grade 3 in 2 PTS (13%), neuropathy grade 2 and grade 4 in 1 patient each, and a single episode of grade 3 edema. Myelosuppression was mild. Two PTS (13%) had urinary tract infection and 1 patient neutropenic fever. One patient died due to brain hemorrhage. CONCLUSIONS: Administration of second-line paclitaxel-based chemotherapy after docetaxel therapy is active in PTS with castration-resistant prostate cancer. This regimen is too toxic for palliative therapy. Careful patient selection is needed when this regimen is considered for therapy in these PTS.

Prostate cryoablation using direct transperineal placement of ultrathin probes through a 17-gauge brachytherapy template-technique and preliminary results.

OBJECTIVES: To describe a new surgical approach to third-generation cryoablation of the prostate and present our preliminary results. METHODS: The technique is detailed and demonstrated in a Web-based video- clip tutorial. Ninety-two men underwent prostate cryoablation (71 primary ablations, 19 salvage procedures, and 2 repeated cryoablations), using direct transperineal placement of ultrathin probes through a 17-gauge brachytherapy template. RESULTS: No fistulous or major complications were observed. Eight patients (8.3%) had minor complications. In 36 patients, the follow-up period was long enough to permit nadir prostate-specific antigen (PSA) evaluation. In 31 (86%), the nadir PSA was 0.5 ng/mL or less. In 5 patients, the nadir PSA was greater than 0.5 ng/mL. The workup revealed systemic failure in 3 patients and inadequate eradication of the prostate gland in 2 patients. In 18 (86%) of 21 androgen-ablation-naive patients, the nadir PSA was 0.5 ng/mL or less. Nine (43%) had an undetectable nadir PSA and 3 had a nadir PSA of greater than 0.5 ng/mL. CONCLUSIONS: A modified, less-invasive approach to cryoablation of the prostate is presented. The preliminary results do not show an increased rate of complications compared with other published series. The clinical outcome data are preliminary. Longer follow-up data are required to draw conclusions concerning efficacy.

Factors affecting tube dwelling time after percutaneous nephrolithotomy.

BACKGROUND AND PURPOSE: Little is known about the impact of nephrostomy tubes on morbidity and quality of life. PATIENTS AND METHODS: The tube dwelling time and the factors influencing it were determined in 165 patients undergoing percutaneous nephrolithotomy (PCNL). RESULTS: The mean tube dwelling time was 21+/-30 days. The duration of tube drainage after PCNL was 13+/-17 days. Most of this time was preoperative when the tube was inserted for urgent reasons--obstruction or sepsis (31+/-33 days). On multivariate analysis, the number of secondary PCNLs and postoperative complications were the most significant factors affecting tube dwelling time. Age correlated with intubation time but did not reach statistical significance (P < 0.09). Neither the stone's side and type nor the patient's sex had a significant influence. CONCLUSIONS: A significant factor affecting the duration of tube drainage is preoperative medical evaluation and patient preparation, and these steps should be completed expeditiously in order to minimize the time to PCNL. Completion of PCNL in one session should shorten the postoperative intubation time.

The impact of prostate biopsy on patient well-being: a prospective study of voiding impairment.

PURPOSE: We studied the possible association of transrectal ultrasound guided prostate biopsy with voiding impairment. MATERIALS AND METHODS: A total of 211 consecutive patients were prospectively enrolled. International Prostate Symptom Score (I-PSS), subjective voiding complaints and retention were recorded in 3 personal interviews before biopsy, and on postoperative days 7 and 30. RESULTS: Of the 204 patients who voided via the urethra at biopsy 52 (25%) reported subjective voiding impairment on postoperative day 7, including 12% who defined difficult voiding as mild-1 to 2 points on a 0 to 5 scale, 8% as moderate-3/5 and 5% as severe-4 to 5/5. In 5 of the latter cases (2.5%) acute urinary retention necessitated urethral catheter insertion. Transition zone volume, which was 42 ml. or larger in all patients in urinary retention, was the only independent variable associated with patient report of subjective difficult voiding and acute urinary retention during week 1 after biopsy (p = 0.03). Baseline I-PSS greater than 20 points indicated a risk of an acute transient increase in I-PSS on postoperative day 7. CONCLUSIONS: Transient voiding impairment may be precipitated by ultrasound guided prostate biopsy. To decrease this morbidity appropriate evaluation and possible treatment for bladder outlet obstruction are justified in patients with a larger transition zone and in those with preoperative baseline I-PSS greater than 20 points.

Induction of G250-targeted and T-cell-mediated antitumor activity against renal cell carcinoma using a chimeric fusion protein consisting of G250 and granulocyte/monocyte-colony stimulating factor.

Immunotherapy targeting for the induction of a T-cell-mediated antitumor response in patients with renal cell carcinoma (RCC) appears to hold significant promise. Here we describe a novel RCC vaccine strategy that allows for the concomitant delivery of dual immune activators: G250, a widely expressed RCC associated antigen; and granulocyte/macrophage-colony stimulating factor (GM-CSF), an immunomodulatory factor for antigen-presenting cells. The G250-GM-CSF fusion gene was constructed and expressed in Sf9 cells using a baculovirus expression vector system. The Mr 66,000 fusion protein (FP) was subsequently purified through a 6xHis-Ni2+-NTA affinity column and SP Sepharose/fast protein liquid chromatography. The purified FP retains GM-CSF bioactivity, which is comparable, on a molar basis, to that of recombinant GM-CSF when tested in a GM-CSF-dependent cell line. When combined with interleukin 4 (IL-4; 1000 units/ml), FP (0.34 microg/ml) induces differentiation of monocytes (CD14+) into dendritic cells (DCs) expressing surface markers characteristic for antigen-presenting cells. Up-regulation of mature DCs (CD83+CD19-; 17% versus 6%) with enhanced expression of HLA class I and class II antigens was detected in FP-cultured DCs as compared with DCs cultured with recombinant GM-CSF. Treatment of peripheral blood mononuclear cells (PBMCs) with FP alone (2.7 microg/10(7) cells) augments both T-cell helper 1 (Th1) and Th2 cytokine mRNA expression (IL-2, IL-4, GM-CSF, IFN-gamma, and tumor necrosis factor-alpha). Comparison of various immune manipulation strategies in parallel, bulk PBMCs treated with FP (0.34 microg/ml) plus IL-4 (1000 units/ml) for 1 week and restimulated weekly with FP plus IL-2 (20 IU/ml) induced maximal growth expansion of active T cells expressing the T-cell receptor and specific anti-RCC cytotoxicity, which could be blocked by the addition of anti-HLA class I, anti-CD3, or anti-CD8 antibodies. In one tested patient, an augmented cytotoxicity against lymph node-derived RCC target was determined as compared with that against primary tumor targets, which corresponded to an 8-fold higher G250 mRNA expression in lymph node tumor as compared with primary tumor. The replacement of FP with recombinant GM-CSF as an immunostimulant completely abrogated the selection of RCC-specific killer cells in peripheral blood mononuclear cell cultures. All FP-modulated peripheral blood mononuclear cell cultures with antitumor activity showed an up-regulated CD3+CD4+ cell population. These results suggest that GM-CSF-G250 FP is a potent immunostimulant with the capacity for activating immunomodulatory DCs and inducing a T-helper cell-supported, G250-targeted, and CD8+-mediated antitumor response. These findings may have important implications for the use of GM-CSF-G250 FP as a tumor vaccine for the treatment of patients with advanced kidney cancer.

The changing natural history of renal cell carcinoma.

PURPOSE: Our understanding of the natural history of renal cell carcinoma, the role of nephrectomy, the benefits of immunotherapy and the possibilities of new technologies are evolving and being integrated with advances in classification and staging. We reviewed the relevant literature to clarify these pertinent questions and provide a current review of the changes in the epidemiology, treatment and prognosis of patients with renal cell carcinoma. MATERIALS AND METHODS: We comprehensively reviewed the peer reviewed literature on the current management of and results of treatment for renal cell carcinoma. RESULTS: The incidence of and mortality from renal cell carcinoma have continuously increased during the last 50 years. Despite this increase in the number of new patients and consequently the number of deaths yearly the percent of those surviving for 5 years has notably improved. Factors related to improved survival include advances in renal imaging, earlier diagnosis, improved staging, better understanding of prognostic indicators, refinement in surgical technique and the introduction of immunotherapy approaches for advanced disease. CONCLUSIONS: Currently patients with localized and metastatic renal cell carcinoma have had improvements in outlook and the therapeutic options available have expanded.

Reevaluation of the 1997 TNM classification for renal cell carcinoma: T1 and T2 cutoff point at 4.5 rather than 7 cm. better correlates with clinical outcome.

PURPOSE: We analyzed the effects of the change in TNM classification from the 1987 to the 1997 version and suggest a modified tumor size cutoff point between T stages 1 and 2 for renal cell carcinoma. MATERIALS AND METHODS: We evaluated a database containing the records of 661 patients who underwent nephrectomy between 1989 and 1999. The effect of the change in TNM classification on the distribution of patients between stages, the rates of M+ and N+ disease, and the local and distant recurrence rates were outlined for 280 patients with T stages 1 and 2 disease. The Cox model was used to identify the optimal cutoff point between T1 and T2 disease, and the resulting effect of adopting this cutoff was outlined. RESULTS: A total of 174 and 128 cases were down staged from 1987 version stage T2 to 1997 version stage T1 and from 1987 TNM stage II to 1997 TNM stage I, respectively. Survival was not significantly different in patients with 1997 TNM stages I and II disease due to a lack of survival difference during the first 2 years of followup. Stage shift also caused an increase in average tumor size, the proportion of patients with high grade cancer, and M+ and N+ disease at diagnosis in 1997 stages T1 and T2 as well as an increase in the proportion of 1997 stage T2N0M0 cases at diagnosis with systemic failure. Analysis of 11 potential cutoff points between 1 and 10 cm. revealed that 4.5 cm. was most predictive of patients survival (hazards ratio 4.99, p = 0.0001). Using this cutoff resulted in improved discriminatory power of the TNM classification and a moderating effect on the distribution of patients, average tumor size, high grade disease, M+ and N+ disease at diagnosis, and systemic failure between T(14.5) and T(24.5) compared with 1997 T1 and T2. CONCLUSIONS: Our data imply that the current cutoff point of 7 cm. between stages T1 and T2 tumors is too high. Lowering the cutoff to 4.5 cm. resulted in better discriminatory power of the TNM classification in our dataset. This observation should be further validated by external data.

Gene and immune therapy for renal cell carcinoma.

Conventional therapy for metastatic renal cell carcinoma is associated with a poor response rate and few patients are long-term survivors. The occurrence of spontaneous regression and the prolonged latency period between primary tumor removal and the appearance of metastases in some patients suggest the existence of important host immune responses to autologous tumor cells. With the advent of molecular gene transfer techniques and increased knowledge of the basic pathways of immune activation, the field of cancer immunotherapy has finally begun to develop novel and effective approaches for harnessing the immune system as a therapeutic agent. Current immunotherapy and gene therapy strategies, including methods of cytokine delivery and tumor-cell-based vaccines, are presented.

Glucose toxicity and the development of diabetes in mice with muscle-specific inactivation of GLUT4.

Using cre/loxP gene targeting, transgenic mice with muscle-specific inactivation of the GLUT4 gene (muscle GLUT4 KO) were generated and shown to develop a diabetes phenotype. To determine the mechanism, we examined insulin-stimulated glucose uptake and metabolism during hyperinsulinemic-euglycemic clamp in control and muscle GLUT4 KO mice before and after development of diabetes. Insulin-stimulated whole body glucose uptake was decreased by 55% in muscle GLUT4 KO mice, an effect that could be attributed to a 92% decrease in insulin-stimulated muscle glucose uptake. Surprisingly, insulin's ability to stimulate adipose tissue glucose uptake and suppress hepatic glucose production was significantly impaired in muscle GLUT4 KO mice. To address whether these latter changes were caused by glucose toxicity, we treated muscle GLUT4 KO mice with phloridzin to prevent hyperglycemia and found that insulin-stimulated whole body and skeletal muscle glucose uptake were decreased substantially, whereas insulin-stimulated glucose uptake in adipose tissue and suppression of hepatic glucose production were normal after phloridzin treatment. In conclusion, these findings demonstrate that a primary defect in muscle glucose transport can lead to secondary defects in insulin action in adipose tissue and liver due to glucose toxicity. These secondary defects contribute to insulin resistance and to the development of diabetes.

Interleukin 2 gene therapy for prostate cancer: phase I clinical trial and basic biology.

Twenty-four patients with locally advanced prostate cancer (CaP) were enrolled in a phase I clinical trial using gene-based immunotherapy. A functional DNA-lipid complex encoding the interleukin 2 (IL-2) gene (Leuvectin; Vical, San Diego, CA) was administered intraprostatically into the hypoecogenic tumor lesion, using transrectal ultrasound guidance. Two groups of patients having locally advanced tumors were enrolled to receive a treatment regimen composed of two serial intraprostatic injections of the IL-2 gene agent administered 1 week apart. The first groups of patients included radical prostatectomy candidates who subsequently underwent surgery after the completion of the treatment regimen. The second group consisted of patients who had failed a prior therapy. Prostate specimens of the treated areas were attained after treatment and compared with the transrectal biopsies performed at baseline to assess for any responses. IL-2 gene therapy was well tolerated, with no grade 3 or 4 toxic reactions occurring. The most commonly reported symptoms were mild hematuria, transient rectal bleeding, and perineal discomfort that are likely attributable to the injection itself. During the entire course of treatment, there were no significant changes in American Urologic Association (AUA) symptom scores, in hematologic disturbances, electrolyte imbalances, or hepatic functions. Evidence of systemic immune activation was observed after IL-2 gene therapy, based on an increase in the intensity of T cell infiltration seen on immunohistochemical analysis of tissue samples from the injected tumor sites, and based on increased proliferation rates of peripheral blood lymphocytes that were cocultured with patient serum collected after treatment. Furthermore, transient decreases in serum prostate-specific antigen (PSA) (responders) were seen in 16 of 24 patients (67%) on day 1. Fourteen of the patients persisted in this decrease to day 8 (58%). In eight patients the PSA level rose (nonresponders). More patients (9 to 10) in the group that failed prior therapy responded to the IL-2 gene injections (chi-square test, p = 0.04), and 6 of the 9 also had lower than baseline PSA levels at week 10 after treatment. To the best of our knowledge, this is the first clinical study of its kind aimed at exploring the role of IL-2-based gene therapy in CaP patients. This phase I trial demonstrated the safety of intraprostatic Leuvectin injection, with transient PSA-based responses seen after therapy.

Laparoscopic radical nephrectomy.

Most of the open renal procedures have been duplicated or approximated by laparoscopy. Past concerns about increased operative time, cost, resection completeness, and port site metastases are being overruled or put into perspective as experience with laparoscopic radical nephrectomy (LRN) is gained: necessary skills can be acquired, operative times are approaching those for open procedure, and a 14% difference in cost is counterbalanced by reduced postoperative expenditures. Moreover, LRN is acknowledged by its quality-of-life advantages-reduced morbidity and improved cosmetic outcome. Disease-free rate with LRN at last follow-up is 100% for TNM stage I and 89% +/- 6.6 for stage II (1997 classification). Complications are acceptable with an 8% to 35% incidence of minor complications and a 3% to 19% incidence of severe complications. Conversion to an open procedure occurs in 0% to 10% of cases. The procedure's limitations and the appropriate criteria for patient selection are evident. The learning process is believed to last for approximately 20 procedures and patient selection is based on both clinical criteria and one's insight on his location on the learning curve. Therefore, LRN is becoming the treatment of choice for most TNM stages I and II renal tumors. Moreover, recent data advocating pre-immunotherapy nephrectomy in metastatic patients may permit laparoscopic nephrectomy to further benefit selected metastatic patients by potentially shortening the time interval from nephrectomy to immunotherapy and improving immune responsiveness.

Biology of renal cell carcinoma: changing concepts in classification and staging.

Advances in our understanding of the pathogenesis, behavior, and importance of prognostic factors for renal cell carcinoma (RCC) have paved the way for increased sophistication in its classification and staging. In the past, lack of consistent classification and terminology for RCC histology and staging has complicated comparability of clinical studies looking at patient prognosis and response to treatment. In this review, the results of international consensus efforts to achieve uniform classification systems for RCC are outlined and some future directions are considered.

New biologicals for prostate cancer prevention: Genes, vaccines, and immune-based interventions.

For at least 100 years, immunologists have proposed activating the immune system to specifically target and eradicate autologous tumor cells. The idea that tumor cells can be recognized as foreign to the host's immune system is an essential concept of tumor immunology that was first postulated by Paul Ehrlich at the turn of the century. Anecdotal reports of spontaneous tumor regression have been presumed to be immunologically mediated. With the advent of molecular gene transfer techniques and increased knowledge of the regulation of the immune response, effective methods for harnessing the immune system as a therapeutic agent are finally being realized. Current results of clinical immune/gene therapy protocols will be reviewed with consideration towards the concept of cancer prevention.

Improved prognostication of renal cell carcinoma using an integrated staging system.

PURPOSE: To integrate stage, grade, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) into a clinically useful tool capable of stratifying the survival of renal cell carcinoma (RCC) patients. PATIENTS AND METHODS: The medical records of 661 patients undergoing nephrectomy at University of California Los Angeles between 1989 and 1999 were evaluated. Median age was 61 years, male-to-female ratio was 2.2:1, and median follow-up was 37 months. Survival time was the primary end point assessed. Sixty-four possible combinations of stage, grade, and ECOG PS were analyzed and collapsed into distinct groups. The internal validity of the categorized was challenged by a univariate analysis and a multivariate analysis testing for the accountability of each UCLA Integrated Staging System (UISS) category against independent variables shown to have impact on survival. RESULTS: Combining and stratifying 1997 tumor-node-metastasis stage, Fuhrman's grade and ECOG PS resulted in five survival stratification groups designated UISS, and numbered I to V. The projected 2- and 5-year survival for the UISS groups are as follows for the groups: I, 96% and 94%; II, 89% and 67%; III, 66% and 39%; IV, 42% and 23%; and V, 9% and 0%, respectively. UISS accounted for the significant variables in the variate analysis. CONCLUSION: A novel system for staging and predicting survival for RCC integrating clinical variables is offered. UISS is simple to use and is superior to stage alone in differentiating patients' survival. Our data suggests that UISS is an important prognostic tool for counseling patients with various stages of kidney cancer. Further prospective large-scale validation with external data is awaited.