Sporadic Angiomyolipomas Growth Kinetics While on Everolimus: Results of a Phase II Trial.

PURPOSE: Everolimus decreases tumor volume of renal angiomyolipomas in patients with tuberous sclerosis. No prospective data are available regarding the effect of everolimus on the growth kinetics in patients with sporadic angiomyolipomas. We sought to determine the safety and efficacy of everolimus in the volumetric reduction of sporadic angiomyolipomas. MATERIALS AND METHODS: This multi-institutional, prospective, phase II trial, enrolled patients with 3 cm or larger sporadic angiomyolipomas who were candidates for surgical resection or percutaneous angioembolization. Patients received 10 mg everolimus daily for 4 planned 28-day cycles. Response was defined as a 25% or greater volumetric reduction of patient angiomyolipoma. Baseline, 4, 6 and 12-month volumetric analyses were performed using magnetic resonance imaging. Everolimus was discontinued in those with less than 25% volumetric reduction after 4 cycles. Those with 25% or greater volumetric reduction received 2 additional cycles. The primary outcomes were the efficacy of everolimus in the volumetric reduction of angiomyolipomas by 25% or more, and the safety and tolerability of everolimus. RESULTS: Overall 20 patients were enrolled at 5 centers. Of these patients 11 (55%) completed 4 cycles and 7 (35%) completed 6 cycles. Efficacy was demonstrated, with 10 of 18 (55.6%) patients exhibiting a 25% or greater reduction in tumor volume at 4 months (median 58.5%) and 10 of 14 (71.4%) patients exhibiting a 25% or greater reduction in tumor volume at 6 months (median 58.2%). Four (20%) patients were withdrawn due to protocol defined toxicities and 8 (40%) self-withdrew from the study due to side effects. CONCLUSIONS: Everolimus was effective in causing volumetric reduction of angiomyolipomas by 25% or greater in most patients but was associated with a high rate of treatment discontinuation.

MicroRNAs as potential biomarkers to predict the risk of urinary retention following intradetrusor onabotulinumtoxin-A injection.

AIMS: MicroRNAs (miRs) control post-transcriptional gene expression, and this is relevant in understanding better chronic diseases and treatment outcomes. The role of miRs in the pathology and treatment outcomes of overactive bladder (OAB) is unknown. In this study, we assessed the differential expression of miRs in OAB patients responding with either normal or elevated post-void residual volumes (PVRs) ≥200 mL following intradetrusor injection of onabotulinumtoxin-A (onaBoNT-A). METHODS: Female OAB patients refractory to OAB drugs were consented for this study. Cystoscopic-guided punch bladder biopsy was obtained at the time of injection of onaBoNT-A 100 units. The expression of 13 miR species, selected for their known effect on neurotrophin expression and smooth muscle function, was measured. PVRs and urine nerve growth factor (NGF) levels were measured at baseline and at the follow-up visit. RESULTS: Fourteen patients with mean age of 66 years were consented. Of these patients, nine maintained PVRs <200 mL after onaBoNT-A injection to comprise the low PVR group. The other five patients with PVRs ≥200 mL comprised the high PVR group. The expression of miR221 and miR125b was upregulated by 11- and 2-fold, respectively, in patients who responded with low PVRs after onaBoNT-A (P < 0.05). Urine NGF levels at baseline were not different between the two groups. CONCLUSIONS: This study suggests that deficiency in the pretreatment expression of miR221 and miR125b may predispose OAB patients to high PVRs following intradetrusor onaBoNT-A. Additional studies are needed to better understand the role of miRs in OAB.

Sympathetic ß-adrenergic mechanism in pudendal inhibition of nociceptive and non-nociceptive reflex bladder activity.

This study investigated the role of the hypogastric nerve and ß-adrenergic mechanisms in the inhibition of nociceptive and non-nociceptive reflex bladder activity induced by pudendal nerve stimulation (PNS). In α-chloralose-anesthetized cats, non-nociceptive reflex bladder activity was induced by slowly infusing saline into the bladder, whereas nociceptive reflex bladder activity was induced by replacing saline with 0.25% acetic acid (AA) to irritate the bladder. PNS was applied at multiple threshold (T) intensities for inducing anal sphincter twitching. During saline infusion, PNS at 2T and 4T significantly (P < 0.01) increased bladder capacity to 184.7 ± 12.6% and 214.5 ± 10.4% of the control capacity. Propranolol (3 mg/kg iv) had no effect on PNS inhibition, but 3-[(2-methyl-4-thiazolyl)ethynyl]pyridine (MTEP; 1-3 mg/kg iv) significantly (P < 0.05) reduced the inhibition. During AA irritation, the control bladder capacity was significantly (P < 0.05) reduced to ∼22% of the saline control capacity. PNS at 2T and 4T significantly (P < 0.01) increased bladder capacity to 406.8 ± 47% and 415.8 ± 46% of the AA control capacity. Propranolol significantly (P < 0.05) reduced the bladder capacity to 276.3% ± 53.2% (at 2T PNS) and 266.5 ± 72.4% (at 4T PNS) of the AA control capacity, whereas MTEP (a metabotropic glutamate 5 receptor antagonist) removed the residual PNS inhibition. Bilateral transection of the hypogastric nerves produced an effect similar to that produced by propranolol. This study indicates that hypogastric nerves and a ß-adrenergic mechanism in the detrusor play an important role in PNS inhibition of nociceptive but not non-nociceptive reflex bladder activity. In addition to this peripheral mechanism, a central nervous system mechanism involving metabotropic glutamate 5 receptors also has a role in PNS inhibition.

Conduction block of mammalian myelinated nerve by local cooling to 15-30°C after a brief heating.

This study aimed at understanding thermal effects on nerve conduction and developing new methods to produce a reversible thermal block of axonal conduction in mammalian myelinated nerves. In 13 cats under α-chloralose anesthesia, conduction block of pudendal nerves (n = 20) by cooling (5-30°C) or heating (42-54°C) a small segment (9 mm) of the nerve was monitored by the urethral striated muscle contractions and increases in intraurethral pressure induced by intermittent (5 s on and 20 s off) electrical stimulation (50 Hz, 0.2 ms) of the nerve. Cold block was observed at 5-15°C while heat block occurred at 50-54°C. A complete cold block up to 10 min was fully reversible, but a complete heat block was only reversible when the heating duration was less than 1.3 ± 0.1 min. A brief (<1 min) reversible complete heat block at 50-54°C or 15 min of nonblock mild heating at 46-48°C significantly increased the cold block temperature to 15-30°C. The effect of heating on cold block fully reversed within ∼40 min. This study discovered a novel method to block mammalian myelinated nerves at 15-30°C, providing the possibility to develop an implantable device to block axonal conduction and treat many chronic disorders. The effect of heating on cold block is of considerable interest because it raises many basic scientific questions that may help reveal the mechanisms underlying cold or heat block of axonal conduction.

Pudendal but not tibial nerve stimulation inhibits bladder contractions induced by stimulation of pontine micturition center in cats.

This study examined the possibility that pudendal nerve stimulation (PNS) or tibial nerve stimulation (TNS) inhibits the excitatory pathway from the pontine micturition center (PMC) to the urinary bladder. In decerebrate cats under α-chloralose anesthesia, electrical stimulation of the PMC (40 Hz frequency, 0.2-ms pulse width, 10-25 s duration) using a microelectrode induced bladder contractions >20 cmH2O amplitude when the bladder was filled to 60-70% capacity. PNS or TNS (5 Hz, 0.2 ms) at two and four times the threshold (2T and 4T) to induce anal or toe twitch was applied to inhibit the PMC stimulation-induced bladder contractions. Propranolol, a nonselective ß-adrenergic receptor antagonist, was administered intravenously (1 mg/kg i.v.) to determine the role of sympathetic pathways in PNS/TNS inhibition. PNS at both 2T and 4T significantly (P < 0.05) reduced the amplitude and area under the curve of the bladder contractions induced by PMC stimulation, while TNS at 4T facilitated the bladder contractions. Propranolol completely eliminated PNS inhibition and TNS facilitation. This study indicates that PNS, but not TNS, inhibits PMC stimulation-induced bladder contractions via a ß-adrenergic mechanism that may occur in the detrusor muscle as a result of reflex activity in lumbar sympathetic nerves. Neither PNS nor TNS activated a central inhibitory pathway with synaptic connections to the sacral parasympathetic neurons that innervate the bladder. Understanding the site of action involved in bladder neuromodulation is important for developing new therapies for bladder disorders.

Three-Dimensional Imaging of Urethral Stricture Disease and Urethral Pathology for Operative Planning.

Diagnosing urethral pathology can prove difficult, as clinically, the presentation is often nonspecific and may be suggestive of multiple etiologies. Therefore, detailed and accurate urethral imaging in both males and females is critical. Since the early 1900s, conventional imaging studies including RUG and VCUG, with adjunct cystourethroscopy, have remained the gold standard diagnostic techniques to evaluate urethral pathology. However, limitations of conventional imaging have generated interest in finding alternative imaging modalities with comparable, if not superior, diagnostic accuracy, the goal being a more complete assessment of urethral pathology and anatomy that would allow for appropriate surgical planning. Imaging modalities with three-dimensional (3D) capabilities may provide more comprehensive information regarding urethral diseases through a more detailed illustration of periurethral soft tissue structures. Whether or not these imaging modalities will replace conventional studies is unclear, though there is an increasing body of literature that support their use.

Role of µ, κ, and δ opioid receptors in tibial inhibition of bladder overactivity in cats.

In α-chloralose anesthetized cats, we examined the role of opioid receptor (OR) subtypes (µ, κ, and δ) in tibial nerve stimulation (TNS)-induced inhibition of bladder overactivity elicited by intravesical infusion of 0.25% acetic acid (AA). The sensitivity of TNS inhibition to cumulative i.v. doses of selective OR antagonists (cyprodime for µ, nor-binaltorphimine for κ, or naltrindole for δ ORs) was tested. Naloxone (1 mg/kg, i.v., an antagonist for µ, κ, and δ ORs) was administered at the end of each experiment. AA caused bladder overactivity and significantly (P < 0.01) reduced bladder capacity to 21.1% ± 2.6% of the saline control. TNS at 2 or 4 times threshold (T) intensity for inducing toe movement significantly (P < 0.01) restored bladder capacity to 52.9% ± 3.6% or 57.4% ± 4.6% of control, respectively. Cyprodime (0.3-1.0 mg/kg) completely removed TNS inhibition without changing AA control capacity. Nor-binaltorphimine (3-10 mg/kg) also completely reversed TNS inhibition and significantly (P < 0.05) increased AA control capacity. Naltrindole (1-10 mg/kg) reduced (P < 0.05) TNS inhibition but significantly (P < 0.05) increased AA control capacity. Naloxone (1 mg/kg) had no effect in cyprodime pretreated cats, but it reversed the nor-binaltorphimine-induced increase in bladder capacity and eliminated the TNS inhibition remaining in naltrindole pretreated cats. These results indicate a major role of µ and κ ORs in TNS inhibition, whereas δ ORs play a minor role. Meanwhile, κ and δ ORs also have an excitatory role in irritation-induced bladder overactivity.

A leopard never changes its spots: Development of colonic adenocarcinoma in an Indiana Pouch.

Colonic adenocarcinoma of a urinary diversion is rare. We report a case of a 70 year-old woman who developed such a malignancy 12 years after creation of an Indiana pouch urinary diversion for treatment of urothelial carcinoma of the bladder cancer.

Pediatric Testicular Hemangioma in a 10-Year-old: A Rare Entity That May Mimic Malignancy With Appraisal of the Literature.

Capillary hemangioma is a rare benign lesion in the testicle, particularly in pediatrics. It can mimic malignancy, leading to radical orchiectomy. We present a case of a testicular hemangioma in a child, and review the literature on testicular hemangiomas in this age group. A hypervascular testicular lesion without elevated tumor markers may warrant intraoperative biopsy to direct surgical management, which may include testis-sparing surgery if amenable.

Appearance of Pyelitis Emphysematosa on Computed Tomography.

Pyelitis emphysematosa is a gas-forming infection characterized by gas located within the wall of the collecting system and renal pelvis. There are only 2 reported cases of pyelitis emphysematosa in the literature, neither of which occurred in the era of cross-sectional imaging. Here we present a case of pyelitis emphysematosa occurring in an elderly female with congenital left renal atrophy and chronic right hydronephrosis secondary to ureteropelvic junction obstruction.

Neurogenic Causes of Detrusor Underactivity.

Detrusor underactivity (DU) is a poorly understood dysfunction of the lower urinary tract which arises from multiple etiologies. Symptoms of DU are non-specific, and a pressure-flow urodynamic study is necessary to differentiate DU from other conditions such as overactive bladder (OAB) or bladder outlet obstruction (BOO). The prevalence of DU ranges from 10-48%, and DU is most prevalent in elderly males. The pathophysiology underlying DU can be from both neurogenic and non-neurogenic causes. In this article, we review the neurogenic causes of detrusor underactivity, including diabetic bladder dysfunction, spinal cord injury, multiple sclerosis, Parkinson's disease, cerebrovascular accident, traumatic brain injury, and Fowler's syndrome. As knowledge about the underlying causes of DU advances, there have been several potential therapeutic approaches proposed to help those who suffer from this condition.