Safety and clinical efficacy of everolimus in the treatment of advanced renal cell carcinoma (RCC).

Renal cell carcinoma (RCC) is one of the most lethal genitourinary malignancies. Recently, there has been a paradigm shift in the management of advanced RCC. New targeted therapies including vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors have been developed which have shown promising results in a patient population who otherwise had very few options for treatment. The first mTOR inhibitor, temsirolimus, an intravenous prodrug, has shown improved overall survival in poor prognosis patients. More recently, an oral mTOR inhibitor, everolimus (RAD 001), has been developed which has been shown to delay disease progression in patients with metastatic RCC who have progressed on other targeted therapies. Although a survival advantage in phase III trials is seen with everolimus, associated systemic toxicities, while generally well tolerated, are not insignificant. These include mucositis, hyperglycemia, hyperlipidemia, and pneumonitis. Despite the side effects, emerging evidence points to everolimus as the optimal second-line treatment for patients with advanced renal cell carcinoma.

Medical expulsive therapy as an adjunct to improve shockwave lithotripsy outcomes: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Modern shockwave lithotripsy (SWL) is associated with inferior results compared with the original Dornier HM3. To enhance SWL outcomes, improved patient selection based on radiographic features and modulation of shockwave delivery rate have been used. A growing body of evidence demonstrates the positive effect of medical expulsive therapy (MET) to improve spontaneous passage of urinary calculi. The purpose of this review is to tabulate the current available data that examine the addition of MET to SWL to enhance outcomes. MATERIALS AND METHODS: MEDLINE was searched with a strategy developed in conjunction with a medical librarian. Trials were included if patients were randomized to receive either a medical expulsive agent or placebo or standard therapy after SWL. Study quality was assessed according to the Cochrane Renal Group criteria. The data were analyzed using RevMan meta-analysis software. Subgroup analysis was performed with respect to MET agent used, stone size, and duration of follow-up. RESULTS: Four randomized trials were identified. MET agents varied, with two trials using tamsulosin, one using nifedipine, and a single trial using Phyllanthus niruri extract. Two trials included patients with renal calculi, one had patients with ureteral calculi, and the fourth included patients with both ureteral and renal calculi. The pool results of the four trials included 212 patients who received MET and 206 who received placebo. The absolute risk difference of a successful outcome after SWL with the addition of MET was significantly superior to control at 17% (95% confidence interval [CI] 9%-24%); means six patients need to be treated with MET to prevent a single unsuccessful SWL of six (95% CI 4-11). The effect of MET post-SWL was even more pronounced for stones larger than 10 mm with an absolute risk difference of 26% (95% CI, 9%-43%). CONCLUSIONS: MET post-SWL results in a significant increase in successful treatment outcomes. Further powered, randomized studies are encouraged.

Tamsulosin oral controlled absorption system (OCAS) in the treatment of benign prostatic hypertrophy.

The efficacy of tamsulosin at the cost of a relatively benign side effect profile has been attributed to receptor selectivity directed at the alpha(1a) and alpha(1d) adrenergic receptor subtypes. The oral-controlled absorption system (OCAS((R))) represents a drug delivery refinement that incorporates a matrix of gel-forming and gel-enhancing agents to promote a constant drug release independent of environmental food or fluid. There are clinical data to support the concept that drug peaks are lessened and that drug release continues throughout the alimentary tract due to the OCAS formulation. Furthermore this equates with less adverse effects on physiologic parameters. To date however improvements in cardiovascular symptoms such as dizziness, headache and syncope have not been demonstrated in healthy men. Ejaculatory dysfunction appears less problematic with the OCAS preparation. Tamsulosin OCAS may be of greatest benefit to men with cardiovascular co-morbidities taking anti-hypertensive medications that might predispose them to symptomatic hypotensive episodes. It will be necessary to evaluate this group of men more closely in further trials to determine what they stand to gain from changing medications, and then relate this to drug costs to draw a final conclusion as to the place of tamsulosin OCAS in contemporary urological practice.

Mast cell stabilization improves cardiac contractile function following hemorrhagic shock and resuscitation.

Hemorrhagic shock (HS) is associated with cardiac contractile dysfunction. Mast cell (MC) degranulation is hypothesized to mediate the cardiodepressant effect. Cardiac function was assessed after HS and resuscitation (HS/R) with the administration of the MC stabilizers to prevent MC degranulation. Anesthetized male Sprague-Dawley rats were randomized to sham-operated control or HS/R groups and underwent 60 min of HS followed by 2 h of resuscitated reperfusion. Animals in the HS/R groups were randomized to receive cromolyn (5 mg/kg), ketotifen (1 mg/kg), or saline 15 min before shock. Hearts were excised following HS or 2 h of reperfusion, and function was assessed on a Langendorff apparatus. A second group of randomized animals had serial blood samples taken to assess MC degranulation by quantifying levels of serum beta-hexosaminidase. Hearts were excised at 0 min (before HS) and following 60 min of HS (before resuscitation) for a histological evaluation of MC density and degranulation. In vivo MC stabilization using ketotifen and cromolyn improved cardiac peak systolic pressure (P < 0.05), contractility (P < 0.05), and relaxation (P < 0.05) compared with that of HS controls. Serum beta-hexosaminidase increased during HS/R and was inhibited by MC stabilization (P < 0.05). Degranulation was inhibited when assessed by histochemistry and immune fluorescence. The inhibition of MC degranulation can significantly improve cardiac function following HS/R.

Pharmacotherapy for prostate cancer: the role of hormonal treatment.

The role of hormonal therapy in the management of prostate cancer has been known for almost half a century. However, many controversies exist regarding the place and timing of androgen deprivation therapy. An increasing spectrum for the use of androgen deprivation therapy has been assessed, including multimodal treatment with radiation therapy. New approaches to androgen deprivation have been explored, including LHRH (luteinizing hormone-releasing hormone) antagonists and improved depot formulations. Recent evidence about the chemo-sensitivity of prostate cancer has opened avenues for treatment of hormone refractory disease and the combination of hormonal and chemotherapy is being studied at various stages of the disease. We explore the evidence, controversies and future of androgen deprivation therapy and critically reexamine the dogmas surrounding hormone therapy for prostate cancer.

Ketamine-associated ulcerative cystitis: a new clinical entity.

OBJECTIVES: Ketamine hydrochloride is an N-methyl-D-aspartic acid receptor antagonist used as an anesthetic agent in human and veterinary procedures. Increasingly, it is being used as a recreational drug. Recreational ketamine users have anecdotally reported increased lower urinary tract symptoms while using the substance. METHODS: We describe a series of 9 patients, all of whom were daily ketamine users, who presented with severe dysuria, frequency, urgency, and gross hematuria. Investigations, including urine culture, microscopy, and cytology, in addition to computed tomography, cystoscopy, and bladder biopsies, were performed to identify a relationship between recreational ketamine use and these symptoms. RESULTS: The urine cultures were sterile in all cases. Computed tomography revealed marked thickening of the bladder wall, a small capacity, and perivesicular stranding, consistent with severe inflammation. At cystoscopy, all patients had severe ulcerative cystitis. Biopsies in 4 patients revealed epithelial denudation and inflammation with a mild eosinophilic infiltrate. Cessation of ketamine use, with the addition of pentosan polysulfate, appeared to provide some symptomatic relief. CONCLUSIONS: This case series has described a new clinical entity of severe ulcerative cystitis as a result of chronic ketamine use. As illicit ketamine becomes more easily available, ulcerative cystitis and potential long-term bladder sequelae related to its use may be a more prevalent problem confronting urologists.