Melissa Laudano

Predicting renal functional outcomes after surgery for renal cortical tumours: a multifactorial analysis

Study Type – Therapy (case series)
Level of Evidence 4

A Phase I Trial of Intravesical Nanoparticle Albumin-Bound Paclitaxel in the Treatment of Bacillus Calmette-Guérin Refractory Nonmuscle Invasive Bladder Cancer

PURPOSE Up to 50% of patients treated with intravesical agents for high grade nonmuscle invasive bladder cancer will have disease recurrence. Response rates to current second line intravesical therapies are low and for these high risk patients novel agents are necessary. Our previously completed phase I trial showed docetaxel was a safe agent for intravesical use. Nanoparticle albumin-bound paclitaxel (Abraxane®, ABI-007) has been shown to have increased solubility and lower toxicity compared to docetaxel in systemic therapy. Thus, we assessed the dose limiting toxicity and maximum deliverable dose of intravesical nanoparticle albumin-bound paclitaxel. MATERIALS AND METHODS Inclusion criteria for this institutional review board approved phase I trial were recurrent high grade Ta, T1 and Tis transitional cell carcinoma of the bladder for which at least 1 prior standard intravesical regimen failed. Six weekly instillations of nanoparticle albumin-bound paclitaxel were administered with a modified Fibonacci dose escalation model used until the maximum deliverable dose was achieved. The primary end point was dose limiting toxicity and the secondary end point was response rate. RESULTS A total of 18 patients were enrolled in the study. One patient demonstrated measurable systemic absorption after 1 infusion. Grade 1 local toxicities were experienced by 10 (56%) patients with dysuria being the most common, and no grade 2, 3 or 4 drug related local toxicities were encountered. Of the 18 patients 5 (28%) had no evidence of disease at posttreatment evaluation. CONCLUSIONS Intravesical nanoparticle albumin-bound paclitaxel exhibited minimal toxicity and systemic absorption in the first human intravesical phase I trial to our knowledge. A larger phase II study has begun to formally evaluate the activity of this regimen.

Long-term clinical outcomes of a phase I trial of intravesical docetaxel in the management of non-muscle-invasive bladder cancer refractory to standard intravesical therapy.

OBJECTIVES To report the long-term clinical outcomes and durability of response after treatment with induction intravesical docetaxel. Most novel agents used to treat bacillus Calmette-Guerin refractory high-grade non-muscle-invasive (NMI) bladder cancer are evaluated only after short follow-up periods. Our previously published phase I trial demonstrated that docetaxel is a safe agent for intravesical therapy with minimal toxicity and no detectable systemic absorption. We sought to determine long-term clinical outcomes after treatment with intravesical docetaxel. METHODS Eighteen patients with recurrent Ta (n = 7), T1 (n = 5), and Tis (n = 6) transitional cell carcinoma who experienced treatment failure with at least 1 prior intravesical therapy completed the phase I trial. Docetaxel was administered as 6 weekly intravesical instillations using a dose-escalation model terminated at 0.75 mg/mL. Efficacy was evaluated by interval cystoscopy with biopsies when indicated, cytology, and computed tomography imaging. Follow-up consisted of quarterly cystoscopy, cytology, computed tomography, and biopsy when indicated. RESULTS With a median follow-up of 48.3 months, 4 patients (22%) have demonstrated a complete durable response and currently remain disease-free without further treatment. Three patients (17%) had a partial response, defined as a single NMI recurrence with no further therapy for bladder cancer. Eleven patients (61%) failed treatment, and required another intervention. One patient developed stage progression. No delayed toxicities were noted. The median disease-free survival time was 13.3 months. CONCLUSIONS After 4 years of follow-up without maintenance therapy, intravesical docetaxel has demonstrated the ability to prevent recurrence in a select number of patients with refractory NMI bladder cancer and warrants further investigation.

Physical activity participation among Caribbean Hispanic women living in New York: relation to education, income, and age.

BACKGROUND Inadequate participation in physical activity is a serious public health issue in the United States, with significant disparities among population groups. In particular, there is a scarcity of information about physical activity among Caribbean Hispanics, a group on the rise. METHODS Our goal was to accumulate data on physical activity among Caribbean Hispanic women living in New York and determine the relation between physical activity and age, marital status, education, income, primary language, and children in the household. To this end, a survey adapted from the National Health Interview Survey of the National Center for Health Statistics assessing type, frequency, and duration of physical activity was administered. RESULTS There were 318 self-identified Hispanic women who participated. Total activity time, mean 385 +/- 26 minutes, and education (r = 0.14, p < 0.01) were significantly related. Women who had attended some college had greater total activity time than those with some high school education (p = 0.046) or < 8th grade education (p = 0.022). Walking as a form of transportation was the most frequent pursuit, 285 +/- 21 minutes. Age (r = -0.34, p < 0.001) and education (r = 0.25, p < 0.001) correlated with nonwalking activity time (leisure time). Nonwalking activity times were greater in younger, that is, 18-29 years (p < 0.001) and college-educated women (p < 0.001). Physical activity recommendations were met by 11%; and 17% reported no physical activity. CONCLUSIONS Among Caribbean Hispanic women living in New York City, the current recommendations for physical activity are met by 11%, and physical activity and education are significantly related. Our observation that education is a critical factor related to physical activity suggests that programs to address the promotion of a physically active lifestyle are needed.

Pathological tumour diameter predicts risk of conventional subtype in small renal cortical tumours

To examine whether pathological tumour diameter assists in predicting conventional vs other histological subtypes in renal cortical tumours (RCTs) of ≤4 cm diameter.

A review of high-risk prostate cancer and the role of neo-adjuvant and adjuvant therapies

High-risk, localized prostate cancer represents a complex and diverse disease with many available treatment modalities. Patients are often deemed high risk because they are at increased risk for biochemical failure after primary intervention. However, these “high-risk” men may not be at significant risk of dying from their cancer. In this review, an attempt will be made to better define high-risk patients and help identify men at increased risk for mortality, not simply biochemical failure, after a diagnosis of localized prostate cancer. A review of available monotherapies as well as previously successful multimodality treatments will also be presented. Finally, this review will provide a glimpse into the future direction of high-risk prostate cancer multimodal therapy by providing a synopsis several current randomized clinical trials using effective systemic adjuvant therapies following local treatment.

Significant Change in Predicted Risk of Biochemical Recurrence After Radical Prostatectomy More Common in Black Than in White Men

OBJECTIVES To examine by race how frequently the data after radical prostatectomy translates into a substantial change in prognosis. Many nomograms exist to predict the survival outcomes using the pretreatment clinical parameters and post-treatment pathologic parameters. Race might be an important factor affecting their predictive ability. METHODS Kattan nomograms were used to calculate the pretreatment and post-radical prostatectomy 5-year progression-free probability for each patient. The difference between the nomogram scores was used to divide the patients into 3 groups. A decrease in probability of >or=15 percentage points was classified as a significant increase in the probability of recurrence, an increase of >or=15 points was classified as a significant decrease in the probability of recurrence, and an absolute change of <15 points was considered no significant change. RESULTS The data from 1709 (132 black and 1577 white) men were analyzed. Among the black men, 26.5% had an increase in the probability of recurrence, 57.6% had no change, and 15.9% had a decrease in the probability of recurrence. Among the white men, 13.8% had an increase in the probability of recurrence, 64.5% had no change, and 21.7% had a decrease in the probability of recurrence. Black men were twice as likely to have a significant increase in the probability of recurrence postoperatively compared with white men after adjusting for preoperative prostate-specific antigen level, clinical stage, and biopsy Gleason sum (odds ratio 2.0, 95% confidence interval 1.3-3.1, P = .002). CONCLUSIONS These data could assist clinicians when counseling black men regarding their treatment options according to their preoperative risk profile.

PD19-12 TEMPORAL EFFECTS OF CHRONIC BLADDER OVER-DISTENSION ON HIF-1α AND VEGF EXPRESSION IN MOUSE UROTHELIUM

INTRODUCTION AND OBJECTIVES: OnabotulinumtoxinA (BTX) chemodenervation is an established third-line therapy for overactive bladder. The aim of our study was to further characterize the physiologic effect of various BTX injection distributions on ambulatory and cystometric voiding function in conscious awake rats. METHODS: Adult female rats (n1⁄436) were divided into six groups. Treatment animals received injection of 7.5 units BTX (in 25125 mL saline; 25 mL/aliquot): intact control, saline vehicle control, unilateral BTX, trigone BTX, posterior-lateral BTX, whole bladder BTX. Micturition frequency and volume were assessed using metabolic cages at baseline (day 0, 7) and following injection (day 14, 21, 28). Bladder function was then assessed using anesthetized acetic acid cystometry. RESULTS: There was no overall correlation between rat weight and mean voided volume (r 1⁄4 -0.02, p 1⁄4 0.81). Small volume voids were significantly associated with increased food intake (r 1⁄4 -0.21, p 1⁄4 0.006) and greater stool output (r 1⁄4 -0.23, p 1⁄4 0.003). Mean nocturnal voided volume was similar in control, vehicle, trigone and posteriorlateral groups. The ability to void small volumes was preserved in both the control and treatment groups with the exception of unilateral and whole bladder injection which demonstrated increased minimum voided volumes. On cystometry, mean voided volume was the greatest in the control and trigone groups prior to acetic acid. Increased threshold pressure was noted in both unilateral and whole bladder injection groups. Post void residual was decreased in all groups after acetic acid. The lowest number of voids and longest interval between voids was noted after unilateral and whole bladder BTX injection. Cystometric intercontractile interval correlated with increased nocturnal mean voided volume before (r 1⁄4 0.33, p 1⁄4 0.05) and after (r 1⁄4 0.24, p 1⁄4 0.17) acetic acid. Cystometric mean voided volume correlated with ambulatory nocturnal voided volume, however was almost 10-fold lower after saline instillation (r 1⁄4 0.18, p 1⁄4 0.30), and more closely approximated ambulatory voiding after acetic acid instillation (r 1⁄4 0.30, p 1⁄4 0.08). CONCLUSIONS: Unilateral and whole bladder BTX injection resulted in elevated ambulatory nocturnal mean voided volumes, with higher pressure and smaller volume voids noted on cystometry. Trigone and posterior-lateral BTX injection patterns appear to preserve contractility, with threshold and peak contraction pressures similar to control animals.

MP82-13 BLADDER DISTENSION REGULATES PANNEXIN 1 EXPRESSION IN THE BLADDER UROTHELIUM

INTRODUCTION AND OBJECTIVES: Pannexin 1 (Panx1) channels play essential roles in urothelial mechanotransduction and signaling by providing a mechanosensitive conduit for ATP release in response to bladder distension. It has been proposed that urothelial ATP signaling to bladder sensory fibers relays the degree of bladder fullness and modulates detrusor activity, which are essential for proper micturition. Panx1 channels have been implicated in neurogenic bladder and bladder overactivity. However, little is known about the mechanisms that regulate Panx1 in the bladder. Our goal was to investigate the extent to which mechanical stimulation and bladder overdistension, as occurs with polyuria in diabetes, regulates Panx1 expression and function. METHODS: Studies were performed with a) mouse urothelial cell cultures and b) 10 week old C57BL/6 mice treated for 2 and 4 weeks with 5% sucrose in the drinking water (diuresis mouse model), and non-treated age-match control mice. Urothelial cells cultured on custom made stretchable silicone culture chambers were submitted to uniaxial stretch for 0, 2 and 5 hours (30 sec cycle duration; maximum strain ~10%) and then immediately harvested and processed for quantification of Panx1 mRNA by real-time quantitative PCR (qPCR). Voided urine samples from sucrose-fed and control mice were collected for quantification of ATP levels using the luciferin-luciferase assay. Bladders were then isolated, the urothelium dissected and processed for qPCR analysis of Panx1 mRNA levels. RESULTS: Prolonged cyclic mechanical stimulation (5hrs) resulted in significant reduction of Panx1 expression in urothelial cells when compared to non-stimulated cells or to shorter (2hrs) stimulation (5 hrs: 0.66 0.07*; 2 hrs: 1.02 0.05; 0 hrs: 1.01 0.05; mRNA norm. to mean 0 hrs levels; N 1⁄4 6, *P<0.01). Panx1 expression in the bladder urothelium of mice after 2 and 4 weeks of sucrose-induced diuresis was significantly lower than in control mice (2 wks: 0.88 0.05*; 4 wks: 0.74 0.07*; Ctrl: 1.00 0.03; mRNA norm. to mean Ctrl value; N 1⁄4 4, *P<0.01). Urine ATP levels (nM) in 2 and 4 weeks diuresis mice were also significantly lower when compared to those in control mice (2 wks: 7.1 0.6*; 4 wks: 6.3 0.5*; Ctrl: 38.7 1.8; N 1⁄4 4, *P<0.0001), consistent with observed Panx1 downregulation. CONCLUSIONS: Prolonged mechanical loading and overdistension reduce urothelial Panx1 expression and ATP release. This impairs proper urothelial ATP signaling and bladder mechanosensory activation, and may thereby contribute to development of detrusor underactivity.

MP4-01 SAFETY AND EFFICACY OF THE UROGUIDE, A NOVEL STRESS URINARY INCONTINENCE DEVICE IN THE FEMALE RODENT

Indications included medical stone disease that was refractory to endoscopic management 23 (37%), proximal ureteral obstruction 18 (29%), renovascular disease 17 (27%), and loin pain-hematuria syndrome (LPHS) 5 (9%). Forty patients (63%) had prior open abdominal surgery with 16 (25%) having 3 or more operations. Median ASA score was 2 with 40% of patients with a score of 3. Operative approaches included a single midline intraperitoneal incision in 44 patients (70%), separate extraperitoneal (flank and lower quadrant) incisions in 17 patients (27%) and laparoscopic nephrectomy followed by an extraperitoneal lower quadrant incision in 2 patients (3%). Mean autograft nephrectomy time was 152 79 minutes. Mean vascular anastomosis time was 50 21 minutes. Median follow-up was 7 (IQR 2-23) months. Immediate technical success was achieved in 62 patients (98%). 2 grafts (3%), transplanted for stone disease and a proximal ureteral obstruction, failed and were removed on post-operative days 0 and 2, respectively. Resolution of the primary indication was noted in 53 (84%) patients. Chronic pain was associated with a worse outcome. Of the failed treatments, 2 had LPHS and 4 had stone disease with refractory pain despite resolution of obstruction. Median hospital stay was 8 (IQR 7-10) days with 2 readmissions within 30 days of discharge. 12 patients (19%) had Clavien Grade II, 2 (3%) had Clavien Grade III, and 1 had a Clavien Grade IV surgical complication. There were no deaths. All postoperative complications resolved without autograft compromise. CONCLUSIONS: Renal autotransplantation can provide excellent outcomes for difficult to treat urologic and vascular conditions in a complex patient population. Utilization of 2 extraperitoneal incisions aids in cases of multiple prior abdominal surgeries and facilitates decreased nephrectomy and vascular anastomosis times. Patients undergoing autotransplantation for chronic pain have a greater chance of continued symptoms however the majority have resolution.