Pierre-Alain Hueber

A Common RET Variant Is Associated with Reduced Newborn Kidney Size and Function

Congenital nephron number varies five-fold among normal humans, and individuals at the lower end of this range may have an increased lifetime risk for essential hypertension or renal insufficiency; however, the mechanisms that determine nephron number are unknown. This study tested the hypothesis that common hypomorphic variants of the RET gene, which encodes a tyrosine kinase receptor critical for renal branching morphogenesis, might account for subtle renal hypoplasia in some normal newborns. A common single-nucleotide polymorphism (rs1800860 G/A) was identified within an exonic splicing enhancer in exon 7. The adenosine variant at mRNA position 1476 reduced affinity for spliceosome proteins, enhanced the likelihood of aberrant mRNA splicing, and diminished the level of functional transcript in human cells. In vivo, normal white newborns with an rs1800860(1476A) allele had kidney volumes 10% smaller and cord blood cystatin C levels 9% higher than those with the rs1800860(1476G) allele. These findings suggest that the RET(1476A) allele, in combination with other common polymorphic developmental genes, may account for subtle renal hypoplasia in a significant proportion of the white population. Whether this gene variant affects clinical outcomes requires further study.

Targeted Inactivation of EGF Receptor Inhibits Renal Collecting Duct Development and Function

The ureteric bud (UB) expresses high levels of the EGF receptor (EGFR) during kidney development, but its function in this setting is unclear. Here, Egfr mRNA was abundant in medullary portions of the UB trunk but absent from the branching UB tips during embryogenesis. Homozygous Egfr knockout did not affect the pattern of UB arborization, but renal papillae were hypoplastic and exhibited widespread apoptosis of tubular cells. Because these EGFR-deficient mice die within 1 week of life, we targeted Egfr inactivation to the renal collecting ducts using Cre-lox technology with a Hoxb7-Cre transgene. This targeted inactivation of Egfr led to a thin renal medulla, and at 7 weeks of age, the mice had moderate polyuria and reduced urine-concentrating ability. At 30 to 33 weeks, water deprivation demonstrated a continued urine-concentrating defect despite similar levels of vasopressin between knockout mice and littermate controls. Taken together, these results suggest that unlike other tyrosine kinases expressed at the UB tip, EGFR functions primarily to drive elongation of the emerging collecting ducts and to optimize urine-concentrating ability.

180 W vs 120 W lithium triborate photoselective vaporization of the prostate for benign prostatic hyperplasia: a global, multicenter comparative analysis of perioperative treatment parameters.

OBJECTIVE To evaluate the surgical performance of the new Greenlight XPS-180 W laser system (American Medical Systems, Minnetonka, MI) and the effect of prostate volume (PV), in comparison with the former HPS-120 W system, for the treatment of benign prostatic hyperplasia by photo-selective vaporization of the prostate. METHODS Between July 2007 and March 2012, 1809 patients underwent laser photo-selective vaporization of the prostate (1187 patients with the use of HPS-120 W and 622 patients with the use of XPS-180 W) at 7 international centers. All data were collected prospectively. Comparative analysis was performed between XPS and HPS according to PV measured by transrectal ultrasound. RESULTS The XPS compared with HPS, allowed significantly reduced laser and operative time (29.6 minutes vs 65.8 minutes and 53 minutes vs 80 minutes, respectively; P <.01 for both). The number of fiber used during the procedures was significantly reduced with the XPS system (1.11 vs 2.28; P <.01), whereas total energy delivered was lower (250.2 kJ vs 267.7 kJ; P = .043). Overall, the mean operative time, mean laser time, and mean energy were all significantly increased according to PV >80 mL vs <80 mL. However, when stratified according to PV, XPS demonstrates significant advantages compared with HPS, regardless of prostate size in all operative parameters (P <.01). CONCLUSION The new XPS-180 W system exhibits significant advantages in all surgical parameters compared with the HPS-120 W system. Overall, with XPS-180 W and HPS-120 W, mean operative time, laser time, and energy usage increased according to PV. This suggests that preoperative evaluation of PV by transrectal ultrasound should be mandatory.

Photoselective Vaporization of the Prostate for Benign Prostatic Hyperplasia Using the 180 Watt System: Multicenter Study of the Impact of Prostate Size on Safety and Outcomes

PURPOSE We evaluated photoselective vaporization of the prostate using the GreenLight™ XPS™ 180 W system for benign prostatic hyperplasia treatment in a large multi-institutional cohort at 2 years. We particularly examined safety, outcomes and the re-treatment rate in larger prostates, defined as a prostate volume of 80 cc or greater, to assess the potential of photoselective vaporization of the prostate as a size independent procedure. MATERIALS AND METHODS A total of 1,196 patients were treated at 6 international centers in Canada, the United States, France and England. All parameters were collected retrospectively, including complications, I-PSS, maximum urinary flow rate, post-void residual urine, prostate volume, prostate specific antigen and the endoscopic re-intervention rate. Subgroup stratified comparative analysis was performed according to preoperative prostate volume less than 80 vs 80 cc or greater on transrectal ultrasound. RESULTS Median prostate size was 50 cc in 387 patients and 108 cc in 741 in the prostate volume groups less than 80 and 80 cc or greater, respectively. The rate of conversion to transurethral prostate resection was significantly higher in the 80 cc or greater group than in the less than 80 cc group (8.4% vs 0.6%, p <0.01). I-PSS, quality of life score, maximum urinary flow rate and post-void residual urine were significantly improved compared to baseline at 6, 12 and 24 months of followup without significant differences between the prostate size groups. The re-treatment rate at 2 years reported in 5 of 411 patients was associated with the delivery of decreased energy density (2.1 vs 4.4 kJ/cc) in the group without re-treatment. CONCLUSIONS Photoselective vaporization of the prostate using the XPS 180 W system is safe and efficacious, providing durable improvement in functional outcomes at 2 years independent of prostate size when treated with sufficient energy.

Predictors of early continence following robot-assisted radical prostatectomy

INTRODUCTION Functional outcomes after robot-assisted radical prostatectomy (RARP) greatly influence patient quality of life. Data regarding predictors of early continence, especially 1 month following RARP, are limited. Previous reports mainly address immediate or 3-month postoperative continence rates. We examine preoperative predictors of pad-free continence recovery at the first follow-up visit 1 month after RARP. METHODS Between January 2007 and January 2013, preoperative and follow-up data were prospectively collected for 327 RARP patients operated on by 2 fellowship-trained surgeons (AEH and KCZ). Patient and operative characteristics included age, body mass index (BMI), staging, preoperative prostate-specific antigen (PSA), prostate weight, International Prostate Symptom Score (IPSS), Sexual Health Inventory for Men (SHIM) score and type of nerve-sparing performed. Continence was defined by 0-pad usage at 1 month follow-up. Univariate and multivariate logistic regression models were used to assess for predictors of early continence. RESULTS Overall, 44% of patients were pad-free 1 month post-RARP. In multivariate regression analysis, age (odds ratio [OR] 0.946, confidence interval [CI] 95%: 0.91, 0.98) and IPSS (OR: 0.953, CI 95%: 0.92, 0.99) were independent predictors of urinary continence 1 month following RARP. Other variables (BMI, staging, preoperative PSA, SHIM score, prostate weight and type of nerve-sparing) were not statistically significant predictors of early continence. Limitations of this study include missing data for comorbidities, patient use of pelvic floor exercises and patient maximal activity. Moreover, patient-reported continence using a 0-pad usage definition represents a semiquantitative and subjective measurement. CONCLUSION In a broad population of patients who underwent RARP at our institution, 44% of patients were pad-free at 1 month. Age and IPSS were independent predictors of early continence after surgery. Men of advanced age and those with significant lower urinary tract symptoms prior to RARP should be counselled on the increased risk of urinary incontinence in the early stages.

In vivo validation of PAX2 as a target for renal cancer therapy

PAX genes are frequently overexpressed in human cancer tissue and appear to contribute to the tumor phenotype, suggesting that they may be potential targets for cancer therapy. In particular, aberrant PAX2 expression has been reported in a high proportion of primary tumors, including the majority of renal cell carcinomas (RCC). We recently demonstrated that PAX2 suppresses cisplatin-induced apoptosis in cultured RCC cells. We hypothesized that silencing of PAX2 expression might partially overcome the notorious resistance of renal cell carcinomas to chemotherapy in vivo. In this report, we show that a PAX2 shRNA successfully knocks down PAX2 mRNA and protein levels in an RCC cell line (ACHN). ACHN cells stably transfected with shRNAs targeted against the PAX2 homeodomain are 3-6-fold more susceptible to cisplatin-induced caspase-3 activation than control ACHN cells line. Furthermore, growth of subcutaneous ACHN/shPAX2 xenografts in nude mice is significantly more responsive to cisplatin therapy than control ACHN cell tumors. Our observations validate PAX2 as a potential therapeutic gene target in renal cancer and suggest that adjunctive PAX2 knockdown may enhance the efficacy of other chemotherapeutic agents.

Canadian trend in surgical management of benign prostatic hyperplasia (BPH) and laser therapy from 2007-2008 to 2011-2012

INTRODUCTION Clinically benign prostatic hyperplasia (BPH) is classically associated by the progressive development of lower urinary tract symptoms (LUTS). The incidence of bothersome LUTS is associated with age and may vary in patients over 50 years old. In many developing countries with an aging population, BPH associated with LUTS has become a major health issue. To optimize quality of care and control of cost, there is an imperative need to examine the pattern of BPH management. The goal of this study is to capture the Canadian trend in surgical management of BPH and the use of laser therapy during the last 5 years from 2007-2008 to 2011-2012. METHODS We collected the number of transurethral resection of the prostate (TURP) procedures performed in each province in Canada from the Canadian Institute for Health Information (CIHI) reports for the fiscal years (April 1(st)-March 31(st)) of 2007-2008, 2008-2009, 2009-2010, 2010-2011 and 2011-2012. RESULTS Overall, the total number of TURP procedures remained stable from 20 294 procedures per year in 2007 to 20 629 in 2011. In terms of distribution according to provinces, in 2011, about 40% of procedures were performed in Ontario, 20% in BC, 18 in Quebec and 8% in Alberta. These proportions between provinces have remained similar and stable between 2007 and 2011. In contrast, the number of alternative minimally invasive procedures has slowly grown from 767 interventions in 2007 to 1559 in 2011. Overall, laser procedures represented 7.6% of the total number of BPH surgeries in Canada in 2011. The contribution of laser therapy to the amount of total BPH procedures largely varied between provinces. CONCLUSIONS The use of minimally invasive laser procedure alternatives to TURP is progressively growing. Among the novel laser therapies, HoLEP and GreenLight vaporization are the only procedures that have demonstrated equivalent outcomes compared to TURP in randomized clinical trials. Furthermore, due to shorter hospital stay, these novel laser modalities have the potential to reduce healthcare expenses for the treatment of BPH. We can infer that following the trend observed in the United States, the number of laser therapies for BPH in Canada may increase significantly during the coming years.

Assessment of energy density usage during 180W lithium triborate laser photoselective vaporization of the prostate for benign prostatic hyperplasia. Is there an optimum amount of kilo-Joules per gram of prostate?

To assess the effect of energy density (kJ/mL) applied on adenoma during photoselective vaporization of the prostate (PVP) treatment for benign prostate hyperplasia (BPH) on functional outcomes, prostate‐specific antigen (PSA) reduction and complications.

PAX3 is Expressed in the Stromal Compartment of the Developing Kidney and in Wilms Tumors with Myogenic Phenotype

Wilms tumor (WT) is the most frequent renal neoplasm of childhood; a myogenic component is observed in 5% to 10% of tumors. We demonstrate for the first time that myogenic WTs are associated with expression of PAX3, a transcription factor known to specify myoblast cell fate during muscle development. In a panel of 20 WTs, PAX3 was identified in 13 of 13 tumor samples with myogenic histopathology but was absent in 7 of 7 tumors lacking a myogenic component. Furthermore, we show that PAX3 is expressed in the metanephric mesenchyme and stromal compartment of developing mouse kidney. Modulation of endogenous PAX3 expression in human embryonic kidney (HEK293) cells influenced cell migration in in vitro assays. Mutations of WT1 were consistently associated with PAX3 expression in WTs, and modulation of WT1 expression in HEK293 cells was inversely correlated with the level of endogenous PAX3 protein. We demonstrate abundant PAX3 and absence of PAX2 expression in a novel cell line (WitP3) isolated from the stromal portion of a WT bearing a homozygous deletion of the WT1 gene. We hypothesize that PAX3 sets stromal cell fate in developing kidney but is normally suppressed by WT1 during the mesenchyme-to-epithelium transition leading to nephrogenesis. Loss of WT1 permits aberrant PAX3 expression in a subset of WTs with myogenic phenotype.

Factors predicting prolonged operative time for individual surgical steps of robot-assisted radical prostatectomy (RARP): A single surgeon’s experience

INTRODUCTION We evaluated the average time required to complete individual steps of robotic-assisted radical prostatectomy (RARP) by an expert RARP surgeon. The intent is to help establish a time-based benchmark to aim for during apprenticeship. In addition, we aimed to evaluate preoperative patient factors, which could prolong the operative time of these individual steps. METHODS We retrospectively identified 247 patients who underwent RARP, performed by an experienced robotic surgeon at our institution. Baseline patient characteristics and the duration of each step were recorded. Multivariate analysis was performed to predict factors of prolonged individual steps. RESULTS In multivariable analysis, obesity was a significant predictor of prolonged operative time of: docking (odds ratio [OR] 1.96), urethral division (OR 3.13), and vesico-urethral anastomosis (VUA) (OR 2.63). Prostate volume was also a significant predictor of longer operative time in dorsal vein complex ligation (OR 1.02), bladder neck division (OR 1.03), pedicle control (OR 1.04), urethral division (OR 1.02), and VUA (OR 1.03). A prolonged bladder neck division was predicted by the presence of a median lobe (OR 5.03). Only obesity (OR 2.56) and prostate volume (OR 1.04) were predictors of a longer overall operative time. CONCLUSIONS Obesity and prostate volume are powerful predictors of longer overall operative time. Furthermore, both can predict prolonged time of several individual RARP steps. The presence of a median lobe is a strong predictor of a longer bladder neck division. These factors should be taken into consideration during RARP training.