Prescribing Trends in Post-operative Pain Management After Urologic Surgery: A Quality Care Investigation for Healthcare Providers.

OBJECTIVE: To assess prescribing and refilling trends of narcotics in postoperative urology patients at our institution. Although the opioid epidemic remains a public health threat, no series has assessed prescribing patterns across urologic surgery disciplines following discharge. METHODS: All urologic surgeries were retrospectively reviewed from May 2017-April 2018. Demographics, comorbidities, and postoperative pain management strategies were analyzed. Narcotics usage following surgery were reported in total morphine equivalents (TME). Opioid refill rate was characterized by medical specialty and stratified by urologic discipline. RESULTS: 817 cases were reviewed. Mean age and TME at discharge was 57±15.6 years and 35.43±19.5 mg, respectively. 13.6% (mean age 55±15.9) received a narcotic refill following discharge (mean TME/refill 37.7±28.9 mg). A higher proportion of patients with a pre-operative opioid prescription received a refill compared to opioid naïve patients (38.2% vs 21.6%, P < .01). Refill rate did not differ between urologic subspecialties (P = .3). Urologists were only responsible for 20.4% of all refills filled, despite all patients continuing follow-up with their surgeon. Procedures with the highest rates of post-operative refills were in oncology, male reconstruction/trauma and endourology. Patients with a history of chronic pain (OR 1.9, CI 1.1-3.3) preoperative narcotic prescription (OR 1.6, CI 1.0-2.6), and higher ASA score (OR 1.8, CI 1.6-2.8) were more likely to obtain a postoperative opioid prescription refill. CONCLUSION: Approximately 1 in 7 postoperative urology patients receive a postoperative narcotics refill; however, nearly two-thirds receive refills exclusively from non-urologic providers. Attempts to avoid overprescribing of postoperative narcotics need to account for both surgeon and nonsurgeon sources of opioid refills.

Nephron-sparing management vs radical nephroureterectomy for low- or moderate-grade, low-stage upper tract urothelial carcinoma.

OBJECTIVE: To compare overall and cancer-specific outcomes between patients with upper tract urothelial carcinoma (UTUC) managed with either radical nephroureterectomy (RNU) or nephron-sparing measures (NSM) using a large population-based dataset. PATIENTS AND METHODS: Using Surveillance, Epidemiology, and End Results (SEER) data, patients diagnosed with low- or moderate-grade, localised non-invasive UTUC were stratified into two groups: those treated with RNU or NSM (observation, endoscopic ablation, or segmental ureterectomy). Cancer-specific mortality (CSM) and other-cause mortality (OCM) rates were determined using cumulative incidence estimators. Adjusting for clinical and pathological characteristics, the associations between surgical type, all-cause mortality and CSM were tested using Cox regressions and Fine and Gray regressions, respectively. RESULTS: Of 1227 patients [mean (sd) age 70.2 (11.00) years, 63.2% male] meeting inclusion criteria, 907 (73.9%) and 320 (26.1%) patients underwent RNU and NSM for low- or moderate-grade, low-stage UTUC from 1992 to 2008. Patients undergoing NSM were older (mean age 71.6 vs 69.7 years, P < 0.01) with a greater proportion of well-differentiated tumours (26.3% vs 18.0%, P = 0.001). While there were differences in OCM between the groups (P < 0.01), CSM trends were equivalent. After adjustment, RNU treatment was associated with improved non-cancer cause survival [hazard ratio (HR) 0.78, confidence interval [CI] 0.64-0.94) while no association with CSM was demonstrable (HR 0.89, CI 0.63-1.26). CONCLUSIONS: Patients with low- or moderate-grade, low-stage UTUC managed through NSM are older and are more likely to die of other causes, but they have similar CSM rates to those patients managed with RNU. These data may be useful when counselling patients with UTUC with significant competing comorbidities.

Is there a benefit to frozen section analysis at the time of partial nephrectomy?

INTRODUCTION: The utility of frozen section performance during partial nephrectomy (PN) is controversial. We assessed the predictive value of frozen sections on final margin status for patients undergoing PN for localized renal tumors. MATERIALS AND METHODS: We queried our prospectively maintained kidney cancer database for patients undergoing PN with localized renal tumors from 2005-2011. Patients were stratified based on the receipt of frozen section analysis into 'frozen' and 'no frozen' groups. Groups were compared using ANOVA, Chi-square, and Wilcoxon's tests. RESULTS: A total of 537 patients (mean age 58.1 years ± 12.0 years, 64.2% male) underwent PN (mean tumor size 3.7 cm ± 2.0 cm; mean Nephrometry score 7.5 ± 1.8) from 2005-2011. Comparing tumor characteristics between patients undergoing frozen sections (83.1%) and those who did not (16.9%), no differences in histology, Fuhrman grade, pathologic stage, or Nephrometry Score were observed between groups. Final margins were positive in 10 patients (11.0%) in the 'no frozen' group compared to 20 patients (4.5%) in the 'frozen' section group (p = 0.01) but in patients with a documented malignancy on final pathology, final margins were positive in 5.5% and 2.9% respectively (p = 0.16). Four patients (0.7%) had local recurrences, all of whom had negative frozen and final pathologic margins. There was no correlation between positive surgical margins and local recurrence (p = 1.0) at a median follow up of 21 months (IQR = 9-31months). CONCLUSIONS: In our institutional cohort, frozen section analysis failed to impact final margin status in patients with documented renal cell carcinoma. Given the oncologic uncertainty of positive surgical margins, further prospective evaluation is necessary to determine the clinical utility of frozen section analysis.

Pathological concordance and surgical outcomes of sporadic synchronous unilateral multifocal renal masses treated with partial nephrectomy.

PURPOSE: Patients with unilateral synchronous multifocal renal masses represent a unique population with renal cell carcinoma. While pathological concordance rates have been studied for bilateral cases, limited data exist on unilateral multifocal disease. We characterized pathological concordance rates in this population and evaluated the outcomes of nephron preservation. MATERIALS AND METHODS: Patients who underwent surgery from 2000 to 2012 for unilateral synchronous multifocal renal masses were identified from a prospectively maintained database. Demographic, surgical and pathological outcomes of this cohort were analyzed. Malignant concordance rates were defined as agreement of all malignant tumor types in a single renal unit. Histological concordance was defined as agreement of all resected mass histologies, eg all clear cell carcinomas. Nuclear grade was considered concordant if all tumors excised were low (Fuhrman 1 or 2, type 1) or high (Fuhrman 3 or 4, type 2) grade. RESULTS: Using our institutional database of 2,569 patients with renal tumors we identified 97 with unilateral synchronous multifocal renal masses. Malignant and benign concordance rates were 77.2% and 48.6%, and histological and grade concordance rates were 58.8% and 51.5%, respectively. In this cohort we identified 76 patients (76.3% male) with a median age of 62.5 years who had a total of 241 unilateral synchronous multifocal renal masses and underwent nephron sparing surgery. Median mass size was 2.0 cm (IQR 1.1-3.1), there was a median of 3 tumors per patient and median followup was 24 months (IQR 13-40). Identified renal cell carcinoma histologies included clear cell in 49.4% of cases, papillary in 33.5%, mixed in 4.5% and chromophobe in 2.8%. CONCLUSIONS: In what is to our knowledge the largest published report of unilateral synchronous multifocal renal masses we document low pathological concordance rates. As such, percutaneous biopsy of a single renal mass in these patients may not help inform treatment decisions. Nephron sparing surgery may be performed with acceptable oncological and functional results in patients with unilateral synchronous multifocal renal masses.

The effect of 5-aminolevulinic acid and its derivatives on protoporphyrin IX accumulation and apoptotic cell death in castrate-resistant prostate cancer cells.

OBJECTIVE: To examine whether pharmacologically relevant zinc-binding agents are capable of depleting X-linked inhibitor of apoptosis protein in tumor cells. Our prior work reveals that treatment with zinc-chelating agents induces selective downregulation of the X-linked inhibitor of apoptosis protein in cancer cells of various origins. A precursor of the heme synthetic pathway, 5-aminolevulinic acid, is metabolized to protoporphyrin IX, which is highly reactive with zinc. We assessed whether modified versions of 5-aminolevulinic acid with lipophilic side chains can enhance efficacy and selectivity with respect to protoporphyrin IX accumulation, X-linked inhibitor of apoptosis protein depletion, and tumor necrosis factor-related apoptosis-inducing ligand-mediated apoptosis in human castration-resistant prostate cancer cells. METHODS: Seven modified versions of 5-aminolevulinic acid (5 esters and 2 amides) were synthesized. Levels of endogenous protoporphyrin IX were examined by flow cytometry. X-linked inhibitor of apoptosis protein expression was examined by Western blotting. terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling assay was used to assess cell apoptosis. Results were compared qualitatively. RESULTS: Accumulation of endogenous protoporphyrin IX by castration-resistant prostate cancer cells was shown to be directly related to the carbon chain length of the esterified 5-aminolevulinic acid derivatives. In fact, treatment with 5-aminolevulinic acid-HE was superior to that achieved by 5-aminolevulinic acid with respect to X-linked inhibitor of apoptosis protein downregulation. 5-aminolevulinic acid and 5-aminolevulinic acid-HE in combination with tumor necrosis factor-related apoptosis-inducing ligand significantly enhanced apoptotic cell death in castration-resistant prostate cancer cell lines. CONCLUSION: Esterified derivatives of 5-aminolevulinic acid alone or in combination with other agents may provide therapeutic opportunities in the treatment of castration-resistant prostate cancer by harnessing apoptotic pathways that are triggered by cellular zinc imbalance.

Robotic dismembered pyeloplasty in a horseshoe kidney after failed endopyelotomy.

We report our experience performing a robot-assisted dismembered pyeloplasty on a patient with a ureteropelvic junction obstruction in a horseshoe kidney and a prior history of endopyelotomy. We provide 18-month follow-up demonstrating that robotic pyeloplasty is a reasonable second treatment option for patients with horseshoe kidneys with failed prior endourological management.

In vivo Schild regression analyses using nonselective 5-HT2C receptor antagonists in a rat operant behavioral assay.

RATIONALE: Although competitive antagonism experiments are critical tools in the classification of potential pharmacotherapies, no studies have quantitatively compared the potencies of 5-HT(2C) receptor antagonists using the Schild regression analysis in vivo. OBJECTIVES: To evaluate the behavioral effects of 5-HT(2C) receptor agonists and antagonists, a series of nonselective 5-HT(2C) receptor antagonists, the 5-HT(2A/2C) receptor antagonist ketanserin, the 5-HT(2B) receptor antagonist SB 204,741, the 5-HT(2B/2C) receptor antagonist SB 200,646, and the peripherally acting 5-HT(2C) receptor antagonist RS102,221 were evaluated for their capacity to competitively antagonize the agonists MK212, mCPP, or BW723C86 in rats. MATERIALS AND METHODS: Male Sprague-Dawley rats (N = 28) were trained to respond under a fixed ratio 10 schedule of food reinforcement. A multiple-trial, cumulative-dosing procedure was used to evaluate the capacity of the compounds to suppress response rates. RESULTS: MK212, mCPP, and the 5-HT(2B) receptor agonist BW723C86 dose-dependently decreased response rates. Only metergoline, mianserin, and methysergide produced a dose-dependent antagonism of the rate-decreasing effects of both mCPP and MK212. Apparent pA(2) analysis indicated that metergoline, mianserin, and methysergide were approximately equipotent as antagonists overall. Metergoline and mianserin failed to block the rate-decreasing effects of BW723C86. Ketanserin, SB 200,646, SB 204,741, and RS102,221 failed to block either mCPP or MK212, suggesting that 5-HT(2A), 5-HT(2B), or peripheral 5-HT(2C) receptors do not play a primary role in the rate-decreasing effects of these two agonists. CONCLUSIONS: Taken together, these antagonism profiles suggest that the agonists MK212 and mCPP produce their rate-decreasing effects through a combination of 5-HT receptors with the 5-HT(2C) receptor playing a prominent but not exclusive role.

Opioid antagonists differ according to negative intrinsic efficacy in a mouse model of acute dependence.

The purpose of the present study is to compare the capacity of opioid antagonists to elicit withdrawal jumping in mice following two acute pretreatment doses of the opioid agonist morphine. Antagonists that precipitate vigorous withdrawal jumping across both morphine treatment doses are hypothesized to be strong inverse agonists at the mu-opioid receptor, whereas antagonists that elicit withdrawal jumping in mice treated with the high but not the low dose of morphine are hypothesized to be weak inverse agonists. Male, Swiss-Webster mice (15-30 g) were acutely treated with 56 or 180 mg kg(-1) morphine 4 h prior to injection with naloxone, naltrexone, diprenorphine, nalorphine, or naloxonazine. Vertical jumping, paw tremors, and weight loss were recorded. Naloxone, naltrexone, and diprenorphine produced withdrawal jumping after 56 and 180 mg kg(-1)morphine pretreatment. Nalorphine and naloxonazine produced moderate withdrawal jumping after 180 mg kg(-1) morphine pretreatment, but failed to elicit significant withdrawal jumping after 56 mg kg(-1) morphine pretreatment. Nalorphine and naloxonazine blocked the withdrawal jumping produced by naloxone. All antagonists produced paw tremors and weight loss although these effects were generally not dose-dependent. Taken together, these findings reveal a rank order of negative intrinsic efficacy for these opioid antagonists as follows: naloxone=naltrexone> or =diprenorphine>nalorphine=naloxonazine. Furthermore, the observation that nalorphine and naloxonazine blocked the naloxone-induced withdrawal jumping provides additional evidence that nalorphine and naloxonazine are weaker inverse agonists than naloxone.

Opioid receptors and acetaminophen (paracetamol).

We report that the acetaminophen (paracetamol)-induced spinal (intrathecal, i.t.)/supraspinal (intracerebroventricular, i.c.v.) site/site antinociceptive 'self-synergy' in mice is attenuated by the opioid receptor subtype selective antagonists beta-funaltrexamine hydrochloride (beta-FNA; mu), naltrindole (delta), and nor-binaltorphine hydrochloride (nor-BNI; kappa). These findings further implicate endogenous opioids (viz., endorphins, enkephalins, and dynorphins) and their pathways as contributors to the central antinociceptive action of acetaminophen.

Potency differences for D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 as an antagonist of peptide and alkaloid micro-agonists in an antinociception assay.

D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) is a peptide antagonist that demonstrates potent and selective affinity for micro-opioid receptors in radioligand binding assays and in vitro bioassays. However, previous studies indicate that CTAP may possess unusual pharmacology under certain conditions. Therefore, CTAP was evaluated as an antagonist of the antinociceptive effects of a range of structurally diverse high- and low-efficacy peptide and alkaloid opioid agonists and compared with the traditional antagonist naltrexone. Male Sprague-Dawley rats (N = 227) were loosely restrained and the latency for tail withdrawal from 55 degrees C water was measured. Morphine s.c. and i.c.v., buprenorphine s.c., etorphine s.c. and i.c.v., [N-Me-Phe3,D-Pro4]-morphiceptin and [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin produced antinociceptive effects. CTAP was at least 10-fold more potent than naltrexone as an antagonist of the antinociceptive effects of all five agonists. High doses of CTAP produced a noncompetitive antagonism of etorphine s.c. and morphine s.c. suggesting that CTAP may interact with additional opioid receptors in vivo or produce insurmountable antagonism at these doses. CTAP was approximately 300-fold more potent as an antagonist of DAMGO than the other agonists, indicating that CTAP may distinguish some peptide agonists such as DAMGO from other agonists based on binding interactions within the micro-opioid receptor or pharmacodynamic properties of these peptides. Naltrexone, however, administered by either s.c. or i.c.v. routes of administration was approximately equipotent as an antagonist of the antinociceptive effects of most agonists. Taken together, these data indicate that the peptide antagonist CTAP possesses a unique pharmacology unlike traditional opioid antagonists such as naltrexone