Prognostic Significance of Grade Discrepancy Between Primary Tumor and Venous Thrombus in Nonmetastatic Clear-cell Renal Cell Carcinoma: Analysis of the REMEMBER Registry and Implications for Adjuvant Therapy.

BACKGROUND: Further stratification of the risk of recurrence of clear-cell renal cell carcinoma (ccRCC) with venous tumor thrombus (VTT) will facilitate selection of candidates for adjuvant therapy. OBJECTIVE: To assess the impact of tumor grade discrepancy (GD) between the primary tumor (PT) and VTT in nonmetastatic ccRCC on disease-free survival (DFS), overall survival (OS), and cancer-specific survival (CSS). DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective analysis of a multi-institutional nationwide data set for patients with pT3N0M0 ccRCC who underwent radical nephrectomy and thrombectomy. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSIS: Pathology slides were centrally reviewed. GD, a bidirectional variable (upgrading or downgrading), was numerically defined as the VTT grade minus the PT grade. Multivariable models were built to predict DFS, OS, and CSS. RESULTS AND LIMITATIONS: We analyzed data for 604 patients with median follow-up of 42 mo (excluding events). Tumor GD between VTT and PT was observed for 47% (285/604) of the patients and was an independent risk factor with incremental value in predicting the outcomes of interest (all p < 0.05). Incorporation of tumor GD significantly improved the performance of the ECOG-ACRIN 2805 (ASSURE) model. A GD-based model (PT grade, GD, pT stage, PT sarcomatoid features, fat invasion, and VTT consistency) had a c index of 0.72 for DFS. The hazard ratios were 8.0 for GD = +2 (p < 0.001), 1.9 for GD = +1 (p < 0.001), 0.57 for GD = -1 (p = 0.001), and 0.22 for GD = -2 (p = 0.003) versus GD = 0 as the reference. According to model-converted risk scores, DFS, OS, and CSS significantly differed between subgroups with low, intermediate, and high risk (all p < 0.001). CONCLUSIONS: Routine reporting of VTT upgrading or downgrading in relation to the PT and use of our GD-based nomograms can facilitate more informed treatment decisions by tailoring strategies to an individual patient's risk of progression. PATIENT SUMMARY: We developed a tool to improve patient counseling and guide decision-making on other therapies in addition to surgery for patients with the clear-cell type of kidney cancer and tumor invasion of a vein.

Ventrolateral Periaqueductal Gray Neurons Are Active During Urination.

The ventrolateral periaqueductal gray (VLPAG) is thought to be the main PAG column for bladder control. PAG neurons (especially VLPAG neurons) and neurons in the pontine micturition center (PMC) innervating the bladder detrusor have anatomical and functional synaptic connections. The prevailing viewpoint on neural control of the bladder is that PAG neurons receive information on the decision to void made by upstream brain regions, and consequently activate the PMC through their direct projections to initiate urination reflex. However, the exact location of the PMC-projecting VLPAG neurons, their activity in response to urination, and their whole-brain inputs remain unclear. Here, we identified the distribution of VLPAG neurons that may participate in control of the bladder or project to the PMC through retrograde neural tracing. Population Ca2+ signals of PMC-projecting VLPAG neurons highly correlated with bladder contractions and urination as shown by in vivo recording in freely moving animals. Using a RV-based retrograde trans-synaptic tracing strategy, morphological results showed that urination-related PMC-projecting VLPAG neurons received dense inputs from multiple urination-related higher brain areas, such as the medial preoptic area, medial prefrontal cortex, and lateral hypothalamus. Thus, our findings reveal a novel insight into the VLPAG for control of bladder function and provide a potential therapeutic midbrain node for neurogenic bladder dysfunction.

Simultaneous Measurement of Neuronal Activity in the Pontine Micturition Center and Cystometry in Freely Moving Mice.

Understanding the complex neural mechanisms controlling urinary bladder activity is an extremely important topic in both neuroscience and urology. Simultaneously recording of the bladder activity and neural activity in related brain regions will largely advance this field. However, such recording approach has long been restricted to anesthetized animals, whose bladder function and urodynamic properties are largely affected by anesthetics. In our recent report, we found that it is feasible to record bladder pressure (cystometry) and the related cortical neuron activity simultaneously in freely moving mice. Here, we aimed to demonstrate the use of this combined method in freely moving mice for recording the activity of the pontine micturition center (PMC), a more difficultly approachable small region deeply located in the brainstem and a more popularly studied hub for controlling bladder function. Interestingly, we found that the duration of urination events linearly correlated to the time course of neuronal activity in the PMC. We observed that the activities of PMC neurons highly correlated with spike-like increases in bladder pressure, reflecting bladder contractions. We also found that anesthesia evoked prominent changes in the dynamics of the Ca2+ signals in the PMC during the bladder contraction and even induced the dripping overflow incontinence due to suppression of the neural activity in the PMC. In addition, we described in details both the system for cystometry in freely moving mice and the protocols for how to perform this combined method. Therefore, this work provides a powerful approach that enables the simultaneous measurement of neuronal activity of the PMC or any other brain sites and bladder function in freely behaving mice. This approach offers a promising possibility to examine the neural mechanisms underlying neurogenic bladder dysfunction.

The paraventricular thalamus is a critical thalamic area for wakefulness.

Clinical observations indicate that the paramedian region of the thalamus is a critical node for controlling wakefulness. However, the specific nucleus and neural circuitry for this function remain unknown. Using in vivo fiber photometry or multichannel electrophysiological recordings in mice, we found that glutamatergic neurons of the paraventricular thalamus (PVT) exhibited high activities during wakefulness. Suppression of PVT neuronal activity caused a reduction in wakefulness, whereas activation of PVT neurons induced a transition from sleep to wakefulness and an acceleration of emergence from general anesthesia. Moreover, our findings indicate that the PVT-nucleus accumbens projections and hypocretin neurons in the lateral hypothalamus to PVT glutamatergic neurons' projections are the effector pathways for wakefulness control. These results demonstrate that the PVT is a key wakefulness-controlling nucleus in the thalamus.

Protein expression of urate transporters in renal tissue of patients with uric acid nephrolithiasis.

URAT1 and GLUT9 are two primary urate transporters involved in the renal urate handling. Renal urate underexcretion was reported in uric acid stone formers (UASF) in previous clinical studies. The aim of this study was to investigate the clinical features and possible impact of protein expression of URAT1 and GLUT9 in renal tissues of patients with uric acid (UA) nephrolithiasis. 23 UASF, 27 patients with calcium oxalate (CaOx) stones, and 22 normal controls were enrolled in this study. Clinical data revealed that older age of onset, high plasma UA concentration, low urinary PH, and relative renal urate underexcretion were associated with UASF. By immunohistochemical or western blotting analysis, a significant increase in the relative expression quantity of URAT1 in renal tissue of UASF was found compared to patients with CaOx nephrolithiasis and normal controls. In conclusion, our results suggested that upregulated URAT1 protein expression might contribute to the relative urate underexcretion from the kidney of UASF.

LXR agonist regulates the carcinogenesis of PCa via the SOCS3 pathway.

BACKGROUND: Down-regulation of suppressor of cytokine signaling 3 (SOCS3) inhibits prostate cancer (PCa) cell growth. Liver X receptors (LXRs) agonists have been recently introduced for PCa treatment. We postulated that LXR may inhibit the carcinogenesis of PCa via the SOCS3 pathway. METHODS: LNCaP cells were cultured and transfected with SOCS3 small-interfering RNA (SOCS3-siRNA) and control small-interfering RNA (control-siRNA). Then cells were treated with LXR activator (GW3965). The expressions of PCa related transcript factors, e.g. transcription 3 (STAT3), nuclear factor kappa B (NF-κB) and activation protein 1(AP1) were detected by western blot assay. In vitro cell proliferation, cell migration, cell invasion and apoptosis were analysed. Nude mice were used for in vivo tumorgenesis. RESULTS: In cells treated with control-siRNA, GW3965 enhanced SOCS3 expression and significantly inhibited the phosphorylation of STAT3, NF-κB and AP1 expressions, accompanied by dramatically reduced cellular proliferation rate, immigration and invasion of cultured cells. In cells treated with SOCS3-siRNA, the inhibitory effects of LXR activator on the phosphorylation of STAT3 and expressions of NF-κB and AP1 were totally abolished. The cell proliferation rate, immigration and invasion were markedly elevated by SOCS3 gene mutation, even with GW3965 treatment. The in vivo tumorgenesis assay showed that GW3965 significantly reduced the tumor volumes in tumor-bearing nude mice receiving saline injection, but failed to limit the tumor volume in tumor-bearing nude mice receiving SOCS3 antibody injection. CONCLUSION: Our results provide evidence in support of the notion that LXR agonist may regulate the carcinogenesis of PCa via the SOCS3 pathway.

Concomitant treatment of ureteropelvic junction obstruction and renal calculi with robotic laparoscopic surgery and rigid nephroscopy.

INTRODUCTION: The treatment of ureteropelvic junction obstruction (UPJO) and concomitant calculus poses a technically challenging situation. We present our experience with using rigid nephroscopy for renal calculi removal during robot-assisted pyeloplasy (RAP) for UPJO. TECHNICAL CONSIDERATIONS: From December 2010 to November 2012, 25 patients with UPJO had RAP at our institution; 9 of those had concurrent renal calculi, which were simultaneously treated with rigid nephroscopy. For stone extraction, a rigid ureteroscope was passed through an assistant trocar under laparoscopic vision directly into a previously created pyelotomy. The stones were extracted using a rigid grasper or stone basket through the rigid ureteroscope. For the removal of the stones within the upper and lower calyces, the rigid ureteroscope was introduced into the incised renal pelvis through robotic trocars if the "assistant trocar" route failed. Complete stone clearance was achieved in 8 of 9 patients. Residual calculi in 1 patient were removed with a single session of extracorporeal shock wave lithotripsy. At the mean follow-up of 10.2 months, no patients had obstruction or recurrent stones. The mean operative time was 187.1 minutes, which was 40.9 minutes longer than the mean operative time in patients without renal calculi. There was no significant difference in blood loss, hospital stay, complications, and success rates between patients with and without renal calculi. CONCLUSION: Our data suggest that the use of a concomitant rigid nephroscope and RAP is a safe and feasible option for the treatment of UPJO complicated with renal calculi.

A report of 918 cases of circumcision with the Shang Ring: comparison between children and adults.

OBJECTIVE: To compare the clinical outcome and surgical complications in circumcision using the Shang Ring between children and adults. METHODS: Circumcision using the Shang Ring was performed on 702 adults and 216 children. Comparative analysis on indices including operative time, healing time, postoperative edema, postoperative bleeding, postoperative pain, and postoperative infection was conducted. RESULTS: When the ring was removed after surgery, the pain was tolerable in the adult group, but more substantial in the child group. The optimal time for removing the ring was 2 weeks after surgery. CONCLUSION: Special attention to the pain management is needed when using the Shang Ring to treat redundant foreskin or phimosis in children. The timing of the ring removal is critical to avoiding complications. Surgeons' knowledge in urology is also critical to the clinical outcome.

Resection of a giant renal angiomyolipoma in a solitary kidney with preoperative arterial embolization.

Renal angiomyolipoma is a type of benign tumor that occurs sporadically in addition to being associated with tuberous sclerosis. Preoperative embolization of large tumors is important to avoid excessive blood loss during surgery. We reported a patient with a 5505-g giant renal angiomyolipoma in a solitary kidney. The patient was treated with preoperative embolization and radical nephrectomy without complications. This type of treatment for an enormous angiomyolipoma can reduce the risk of uncontrolled hemorrhage caused by rupture of the tumor during the operation and should be considered for the treatment of similar tumors.

Specific management of acute renal failure caused by an upper ureteral stone in a solitary pelvic kidney.

A 36-year-old man presented with left lumbosacral region pain and 2 days of oliguria. Acute renal failure of a solitary pelvic kidney was diagnosed after a blood creatinine test, color Doppler ultrasonography, and magnetic resonance imaging. The cause of the acute renal failure was not clear; however, acute ureteral obstruction was presumed and emergency surgery was performed. The unusual anatomy of the kidney required specific management to find and relieve the cause of the obstruction. We found and cleared an upper ureteral stone by endoscopic surgery after exploring the kidney through open surgery.

Facilitation of Ih channels by P2Y1 receptors activation in Mesencephalic trigeminal neurons.

P2Y(1) receptors, a subset of G-protein coupled receptors, have been shown to participate in sensory transduction in the periphery nervous system. However, little is known about their sensory function in the central nervous system. Here, by using immunohistochemistry, we showed that P2Y(1) receptors are predominantly localized in the somata of Mesencephalic trigeminal neurons (Mes V neurons), the primary sensory neurons in brainstem. Whole-cell voltage-clamp recording revealed that ADP-beta-S, a P2Y receptor agonist, enhanced the activity of hyperpolarization-activated cation channels (Ih channels) in Mes V neurons and that the activity-enhancing effect of ADP-beta-S could be blocked by a specific P2Y(1) receptor antagonist, MRS 2179. Taken together, these results suggested a possible role of P2Y(1) receptors in the information transduction of central sensory neurons through regulating Ih channel activities.

Identification and management of emptying failure in male patients with orthotopic neobladders after radical cystectomy for bladder cancer.

OBJECTIVE: To treat neobladder emptying failure after radical cystectomy in patients with bladder cancer. The etiology of neobladder emptying failure should be identified. METHODS: We analyzed the outcome of neobladder emptying in 231 male patients who received neobladder reconstruction after radical cystectomy. The clinical characteristics, urodynamic evaluation, and treatment information were collected from all patients with emptying failure. RESULT: The total occurrence of neobladder emptying failure was 37 of 231 (16%). Emptying failure was a result of mechanical obstruction in 25 (10.8%) patients; obstructions were caused by strictures of the neobladder-urethral anastomosis (13 cases, 5.6%), anterior urethral strictures (3 cases, 1.2%), obstructive mucosal valves (2 cases, 0.9%), primary cystolithiasis (1 case, 0.4%), mucus plugs (2 cases, 0.9%), urethral tumor recurrence (2 cases, 0.9%), and pelvic tumor recurrence (2 cases, 0.9%). In 21 of 25 patients with mechanical obstructions, bladder function was completely recovered via an endourological approach. However, in 12 of patients with dysfunctional voiding, 3 patients presented higher compliance of neobladder. Two patients were found with a narrower posterior urethral angle. Eventually, 10 patients of 12 with dysfunctional voiding performed intermittent self-catheterization. CONCLUSIONS: The obstructive outlet was the primary cause of emptying failure in neobladders. Most of the patients with mechanical obstructions could obtain satisfactory neobladder emptying by a minimally invasive surgical approach. However, nearly all the patients with dysfunctional voiding will have to receive clean intermittent catheterization until the mechanisms causing failure are better understood.

Better compliance contributes to better nocturnal continence with orthotopic ileal neobladder than ileocolonic neobladder after radical cystectomy for bladder cancer.

OBJECTIVES: To investigate, in a randomized controlled study, the degree of continence after the creation of orthotopic ileocolonic and ileal neobladders after cystectomy and to explore a possible mechanism for the difference in continence between these 2 types of orthotopic neobladder. METHODS: From 2003 to 2007, 71 male patients underwent orthotopic lower urinary tract reconstruction with either an ileocolonic or ileal neobladder after radical cystectomy. The degrees of continence and voiding patterns were individually evaluated using urodynamic examinations and a detailed patient questionnaire. The abnormal upper tract was evaluated using intravenous urography and ultrasonography. RESULTS: Complete daytime continence was achieved in 90.9% and 89.4% of the patients and functional nocturnal continence 48.5% and 76.3% of patients in the ileocolonic neobladder and ileal neobladder groups, respectively. The urodynamic data showed that the initial volume of both the ileocolonic and the ileal neobladder appeared to not be significantly different statistically, although the compliance of the ileocolonic neobladder was lower than that of the ileal neobladder (P < .05). No difference was found in the parameters such as flow rate, urethral profile length, maximal urethral pressure, or neobladder neck pressure between the 2 neobladder types. CONCLUSIONS: Although the ileocolonic and ileal neobladders can both achieve a large initial volume, the ileal neobladder has an advantage in the aspect of obtaining satisfactory nocturnal continence because of its greater compliance compared with that of the ileocolonic neobladder.

Clinical evaluation of double-pigtail stent in patients with upper urinary tract diseases: report of 2685 cases.

PURPOSE: To review the indications, procedures, complications, and related treatments of double pigtail stent (DPS) placement as an adjunct for some types of endoscopic and open urologic surgery. PATIENTS AND METHODS: From July 1998 to December 2006, 2413 patients aged 8 to 81 years underwent stent placement (2685 total placements). The indications consisted of ureteroscopic lithotripsy (1984 cases), percutaneous nephrolithotomy (329 cases), ureteral incision to remove calculi (71 cases), extracorporeal shockwave lithotripsy for upper urinary tract calculi (145 cases), ureteropelvic junction obstruction (31 cases), ureterocystoneostomy (29 cases), benign ureteral stenosis (52 cases), extrinsic ureteral stenosis (16 cases), and iatrogenic ureteral trauma (28 cases). DPSs were inserted into the ureter by cystoscopy (115 stents), ureteroscopy (2052 stents), percutaneous nephrostomy (393 stents), or open surgery (125 stents), and were kept inside the body for 28 +/- 1.7 days (range 1-193 days). The mean follow-up period was 31 +/- 1.9 days (range 1-123 days). RESULTS: Three hundred sixty-five patients (19.6%) experienced one or more problems during the stenting procedure. The main complications were gross hematuria (385 cases), pain (101 cases), bladder irritation (105 cases), high fever (6 cases), encrustation (53 cases), stent migration (42 cases), and stenosis or restenosis (51 cases). Most of the complications were mild and tolerable, and all were immediately treated appropriately. However, 60 stents had to be removed: 29 for gross hematuria, 18 for pain, 7 for bladder irritation, and 6 for high fever. CONCLUSIONS: DPS is a safe and useful adjunct for both endoscopic and open procedures to treat upper urinary tract diseases. Most of the complications of DPS placement can be well managed.