[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.

Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance.

The prevalence of type 2 diabetes mellitus is growing worldwide. By the year 2020, 250 million people will be afflicted. Most forms of type 2 diabetes are polygenic with complex inheritance patterns, and penetrance is strongly influenced by environmental factors. The specific genes involved are not yet known, but impaired glucose uptake in skeletal muscle is an early, genetically determined defect that is present in non-diabetic relatives of diabetic subjects. The rate-limiting step in muscle glucose use is the transmembrane transport of glucose mediated by glucose transporter (GLUT) 4 (ref. 4), which is expressed mainly in skeletal muscle, heart and adipose tissue. GLUT4 mediates glucose transport stimulated by insulin and contraction/exercise. The importance of GLUT4 and glucose uptake in muscle, however, was challenged by two recent observations. Whereas heterozygous GLUT4 knockout mice show moderate glucose intolerance, homozygous whole-body GLUT4 knockout (GLUT4-null) mice have only mild perturbations in glucose homeostasis and have growth retardation, depletion of fat stores, cardiac hypertrophy and failure, and a shortened life span. Moreover, muscle-specific inactivation of the insulin receptor results in minimal, if any, change in glucose tolerance. To determine the importance of glucose uptake into muscle for glucose homeostasis, we disrupted GLUT4 selectively in mouse muscles. A profound reduction in basal glucose transport and near-absence of stimulation by insulin or contraction resulted. These mice showed severe insulin resistance and glucose intolerance from an early age. Thus, GLUT4-mediated glucose transport in muscle is essential to the maintenance of normal glucose homeostasis.

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.

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.

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.

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.

A model to explore the interaction between muscle insulin resistance and beta-cell dysfunction in the development of type 2 diabetes.

Type 2 diabetes is a polygenic disease characterized by defects in both insulin secretion and insulin action. We have previously reported that isolated insulin resistance in muscle by a tissue-specific insulin receptor knockout (MIRKO mouse) is not sufficient to alter glucose homeostasis, whereas beta-cell-specific insulin receptor knockout (betaIRKO) mice manifest severe progressive glucose intolerance due to loss of glucose-stimulated acute-phase insulin release. To explore the interaction between insulin resistance in muscle and altered insulin secretion, we created a double tissue-specific insulin receptor knockout in these tissues. Surprisingly, betaIRKO-MIRKO mice show an improvement rather than a deterioration of glucose tolerance when compared to betaIRKO mice. This is due to improved glucose-stimulated acute insulin release and redistribution of substrates with increased glucose uptake in adipose tissue and liver in vivo, without a significant decrease in muscle glucose uptake. Thus, insulin resistance in muscle leads to improved glucose-stimulated first-phase insulin secretion from beta-cells and shunting of substrates to nonmuscle tissues, collectively leading to improved glucose tolerance. These data suggest that muscle, either via changes in substrate availability or by acting as an endocrine tissue, communicates with and regulates insulin sensitivity in other tissues.

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.

Diabetic ketoacidosis and hyperglycemic hyperosmolar nonketotic syndrome.

Diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar nonketotic syndrome (HHNS) are life-threatening acute metabolic complications of diabetes mellitus. Although there are some important differences, the pathophysiology, the presenting clinical challenge, and the treatment of these metabolic derangements are similar. Each of these complications can be seen in type 1 or type 2 diabetes, although DKA is usually seen in patients with type 1 diabetes and HHNS in patients with type 2 disease. The clinical management of these syndromes involves careful evaluation and correction of the metabolic and volume status of the patient, identification and treatment of precipitating and comorbid conditions, a smooth transition to a long-term treatment regimen, and a plan to prevent recurrence.

Prognostic factors and molecular markers for renal cell carcinoma.

Renal cell carcinoma is the most common cancer in the kidney, affecting nearly 30,000 Americans every year and is associated with over 12,000 deaths annually. If detected early, renal cell carcinomas can be cured surgically. However, once metastatic disease develops the prognosis for long-term survival is poor. Unfortunately, one-third of patients have metastatic disease at the time of diagnosis and approximately 50% of the patients undergoing surgical resection for less advanced disease eventually relapse. This review examines the clinical and molecular prognostic tools currently available or under investigation for kidney cancer.

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.

Predicting CAP in patients with intermediate PSA using modified PSA indices.

OBJECTIVES: To test a new PSA index: peripheral zone fraction PSA (PSA-PZ) and evaluate its' predictive value in patients with intermediate PSA. METHODS: Fifty seven of 273 patients with serum PSA 4-10 ng/ml had CAP (21%). Total prostate volume and transition zone volume were calculated. Different cut-off points were used to calculate specificity, sensitivity, efficacy, positive and negative predictive values for PSA, PSAD, PSA-TZ and PSA-PZ (PSA-PZ= serum PSA((Total gland volume-TZ volume)/(Total gland volume)) RESULTS: The distribution of PSA-PZ is presented. PSA-PZ is shown to be effective in DRE negative patients with serum PSA 4-10 ng/ml. For patients with PSA-PZ (1.5 ng/ml the biopsy may be spared with no cancer being missed. CONCLUSIONS: The mathematical formula for PSA-PZ is straightforward and easy to use. Its application is convenient in the clinical setting. We suggest the use of PSA-PZ mainly in DRE negative patients having large glands and serum PSA between 4-10.

Cryosurgical ablation for prostate cancer: preliminary results of a new advanced technique.

BACKGROUND: Cryosurgery is a minimally invasive treatment option for prostate cancer. OBJECTIVES: To report on the first series of cryosurgical ablation for prostate cancer performed in Israel. METHODS: Cryosurgical ablation of the prostate was undertaken in 12 patients aged 53-72 diagnosed with adenocarcinoma of the prostate. The procedures were performed percutaneously and were monitored by real-time trans-rectal ultrasound. The CRYOHIT machine applying Argon gas was used with standard or ultra-thin cryoprobes. The average follow-up was 12.8 months postsurgery (range 1-24 months). RESULTS: No rectal or urethral injuries occurred and all patients were discharged from hospital within 24-48 hours. The duration of suprapubic drainage was 14 days in 10 patients and prolonged in 2. Early complications included penoscrotal edema in four patients, perineal hematoma in three, hemorrhoids in two and epidydimitis in one. Long-term complications included extensive prostatic sloughing in one patient and a perineal fistula in another, both of whom required prolonged suprapubic drainage. Minimal stress incontinence was noted in two patients for the first 8 weeks after surgery. None of the patients has yet regained spontaneous potency. A prostate-specific antigen nadir of less than 0.5 ng/ml was achieved in eight patients and an undetectable PSA level below 0.1 ng/ml in five patients. CONCLUSION: Cryoablation for prostate cancer is safe and feasible, and the preliminary results are encouraging. Further study is needed to elucidate the efficacy of the procedure.

[Recurrent intermittent priapism following priapism].

Recurrent intermittent priapism is a rare sequela of prior priapism. We describe a patient with recurrent intermittent priapism 2 years after a prior event, without other causes of secondary priapism. We believe that this syndrome may be secondary to the initial ischemic event, resulting in alteration in penile adrenergic tone or the penile sinusoidal endothelium.

[Incomplete penile amputation: diagnostic and therapeutic challenge].

Traumatic penile amputation is a severe injury associated with a potential for multidisciplinary dysfunction. Since such injuries are rare, diagnostic and therapeutic experience is minimal. While complete penile amputation is a straight-forward diagnosis, incomplete amputations are not as evident and diagnosis may be delayed. The therapeutic endpoint includes restoration of an acceptable appearance of the phallus and a urethral meatus that allows normal voiding. Other objectives include re-establishment of sexual potency and fertility. As in other amputations, the treatment of choice is meticulous microsurgical replantation, including re-anastomosis of dorsal and cavernosal arteries, the deep dorsal vein, the urethra and nerves, as well as suturing the tunica albuginea. While appropriate cosmetic results and normal voiding can be achieved in most cases, potency is less frequently achieved due to neurological deficit leading to impaired erection and loss of sensation. Penile amputation is thus a complex therapeutic challenge, as meticulous anatomic reconstruction of blood vessels and nerves is essential for restoration of function. Since incomplete penile amputation may be overlooked when other more obvious injuries draw attention, this injury should be suspected in all cases of penetrating injury of the male genitalia. We present a 17-year-old man who sustained an incomplete penile amputation in a traffic accident.

[Obstruction of the prostatic urethra by villous adenoma].

We report a case of a benign villous adenoma of the prostatic urethra causing urethral obstruction in a 45-year-old man. Villous adenoma of the prostatic urethra is rare. Hematuria was the presenting sign in most reported cases. However, some lesions were discovered unexpectedly on endoscopic examinations for the assessment of lower urinary tract disease. Villous adenoma of the urethra is composed of prostatic type tissue. The presence of the PSA marker in its epithelium indicates a common embryologic origin with the prostate.

[Early spontaneous fragmentation of a ureteral stent].

The use of ureteral stents to assure continuity and patency of the upper urinary tract has become common in endo-urology. We present an 82-year-old bedridden woman with hydronephrosis and pseudomonas sepsis. Because of ureteropelvic junction stenosis a stent was inserted. Shortly thereafter the stent fragmented spontaneously into 5 pieces. The importance of being familiar with endo-urological manipulations and their complications is emphasized.

[Transrectal ultrasound-controlled needle aspiration of a prostatic cyst].

Prostatic cysts are common and are usually acquired and asymptomatic. Congenital prostatic cysts, which may originate from the wolffian system or from remnants of the Muellerian duct, are rare and may cause obstructive symptoms in young adults. Due to the availability of transrectal ultrasonography an increased number of cases of prostatic cysts are being diagnosed. We report a 36-year-old man with a congenital prostatic cyst which caused increasing pain during ejaculation and decreased the force of the urinary stream. It was diagnosed by ultrasonography and treated successfully by ultrasound-controlled, transrectal needle aspiration. There was immediate, complete disappearance of symptoms and no complications.

[Percutaneous choledochoscopic electrohydraulic lithotripsy].

Treatment of biliary stones impacted in the distal, common bile duct is a technical challenge. We report 2 consecutive patients, a woman aged 80 years and a man aged 64, in whom all operative attempts failed. In both, the stone was removed by percutaneous, choledochoscopic, electrohydraulic lithotripsy in a single session. To the best of our knowledge these are the first such cases reported in Israel.