Stanley A. Yap

Impact of Multiparametric Endorectal Coil Prostate Magnetic Resonance Imaging on Disease Reclassification Among Active Surveillance Candidates: A Prospective Cohort Study

PURPOSE We report magnetic resonance imaging findings among unselected men with low risk prostate cancer before active surveillance. MATERIALS AND METHODS We prospectively enrolled men with low grade, low risk, localized prostate cancer. All patients underwent multiparametric endorectal coil magnetic resonance imaging and were offered confirmatory biopsy within 1 year of imaging. The primary outcome was the impact of magnetic resonance imaging on identifying patients who were reclassified by confirmatory biopsy as no longer fulfilling active surveillance criteria. We further identified clinical parameters associated with reclassification. The cohort was stratified as patients with 1) normal magnetic resonance imaging, 2) cancer on magnetic resonance imaging concordant with initial biopsy (less than 1 cm) and 3) cancer on magnetic resonance imaging larger than 1 cm. We performed univariate analysis to assess differences in clinical parameters among the groups. RESULTS Magnetic resonance imaging did not detect cancer in 23 cases (38%) while magnetic resonance imaging and initial biopsy were concordant in 24 (40%). Magnetic resonance imaging detected a 1 cm or larger lesion in 13 patients (22%). Of the cases 18 (32.14%) were reclassified. When no cancer was identified on magnetic resonance imaging, only 2 cases (3.5%) were reclassified. The positive and negative predictive values for magnetic resonance imaging predicting reclassification were 83% (95% CI 73-93) and 81% (95% CI 71-91), respectively. Prostate specific antigen density was increased in patients with lesions larger than 1 cm on magnetic resonance imaging compared to those with no cancer on imaging (median 0.15 vs 0.07 ng/ml/cc, p=0.016). CONCLUSIONS Magnetic resonance imaging appears to have a high yield for predicting reclassification among men who elect active surveillance. Upon confirmation of our results magnetic resonance imaging may be used to better select and guide patients before active surveillance.

Effect of the Specific Src Family Kinase Inhibitor Saracatinib on Osteolytic Lesions Using the PC-3 Bone Model

The hematogenous metastatic spread of prostate cancer is preferentially to bone and can result in significant patient morbidity. Although these metastatic lesions are typically osteoblastic, bone resorption is believed to have a prerequisite role in their development. Src kinase has been identified to contribute to prostate cancer tumor growth and metastasis. In addition, Src is also essential in bone metabolism, especially in bone resorption. We hypothesized that inhibiting Src activity with the specific Src family kinase inhibitor saracatinib (AZD0530) would inhibit tumor cell growth and osteoclast differentiation in the tumor-bone interface, thus providing a new approach for advanced prostate cancer. We found that saracatinib inhibited PC-3 cell growth and invasion in a dose-dependent manner. Phosphorylation of Src, focal adhesion kinase, and P38 kinases was inhibited by saracatinib at the submicromolar range. Saracatinib also inhibited the expression and secretion of invasion-related molecules interlukin-8, urokinase-type plasminogen activator, and matrix metalloprotease-9. Receptor activator of NF-κB ligand (RANKL)–induced osteoclastogenesis and signaling were inhibited by saracatinib in both macrophages and PC-3 cells. In in vivo studies, control mice developed more severe osteolytic lesions compared with the treatment group. Immunohistochemical and biochemical assays of bone metabolites confirmed that saracatinib preserved bone architecture in the presence of prostate cancer tumor cells. In summary, we have shown the inhibition of PC3 cell growth and invasion by saracatinib. Src inhibition also blocked the RANKL stimulatory pathway in osteoclasts and PC3 cells. The inhibition of Src thus targets multiple sites involved in prostate cancer bone metastasis, which may offer a therapeutic advantage in treating advanced prostate cancer. Mol Cancer Ther; 9(6); 1629–37. ©2010 AACR.

Manuscript Publication by Urology Residents and Predictive Factors

PURPOSE Many academic institutions have set expectations for peer reviewed publications, yet there is no objective guideline to gauge the performance of a urology resident or program. We quantified and determined predictive factors for resident manuscript production. MATERIALS AND METHODS Electronic surveys were sent to 255 chief residents and recent graduates of 83 accredited urological training programs in the United States and Canada. Survey questions pertained to manuscript submission and acceptance before and during residency, months of research incorporated into residency, PhD degree status and the pursuit of fellowship training. RESULTS Surveys were completed by 127 residents from 83 programs. The median number of manuscripts submitted and accepted during residency was 3 (range 0 to 32) and 2 (range 0 to 25), respectively. Months of protected research time and the number of publications before residency were significantly predictive of the number of manuscripts submitted during residency (p <0.001 and p <0.001, respectively). The number of manuscripts submitted during residency was significantly associated with entering fellowship training (p <0.05). CONCLUSIONS Manuscript preparation and publication are important aspects of the training process at a number of urological surgery residency programs. While the majority of residents are not involved in publication before residency, most submit and publish at least 1 manuscript as first author in a peer reviewed journal during residency. The number of prior publications and months of allotted research time are significantly predictive of resident manuscript productivity. In turn, manuscript submission is indicative of the decision to pursue fellowship training.

The Role of EGFR Family Inhibitors in Muscle Invasive Bladder Cancer: A Review of Clinical Data and Molecular Evidence

PURPOSE Conventional platinum based chemotherapy for advanced urothelial carcinoma is plagued by common resistance to this regimen. Several studies implicate the EGFR family of RTKs in urothelial carcinoma progression and chemoresistance. Many groups have investigated the effects of inhibitors of this family in patients with urothelial carcinoma. This review focuses on the underlying molecular pathways that lead to urothelial carcinoma resistance to EGFR family inhibitors. MATERIALS AND METHODS We performed a PubMed® search for peer reviewed literature on bladder cancer development, EGFR family expression, clinical trials of EGFR family inhibitors and molecular bypass pathways. Research articles deemed to be relevant were examined and a summary of original data was created. Meta-analysis of expression profiles was also performed for each EGFR family member based on data sets accessible via Oncomine®. RESULTS Many clinical trials using inhibitors of EGFR family RTKs have been done or are under way. Those that have concluded with results published to date do not show an added benefit over standard of care chemotherapy in an adjuvant or second line setting. However, a neoadjuvant study using erlotinib before radical cystectomy demonstrated promising results. CONCLUSIONS Clinical and preclinical studies show that for reasons not currently clear prior treatment with chemotherapeutic agents rendered patients with urothelial carcinoma with muscle invasive bladder cancer resistant to EGFR family inhibitors as well. However, EGFR family inhibitors may be of use in patients with no prior chemotherapy in whom EGFR or ERBB2 is over expressed.

A phase 2 clinical trial of everolimus plus bicalutamide for castration-resistant prostate cancer

The mammalian target of rapamycin (mTOR) pathway is up‐regulated in castration‐resistant prostate cancer (CRPC). Nevertheless, inhibition of mTOR is ineffective in inducing apoptosis in prostate cancer cells, likely because of the compensatory up‐regulation of the androgen receptor (AR) pathway.

Partial nephrectomy for the treatment of renal cell carcinoma (RCC) and the risk of end-stage renal disease (ESRD)

To assess whether radical nephrectomy (RN) compared with partial nephrectomy (PN) for the treatment of renal cell carcinoma (RCC) is associated with greater risk of end‐stage renal disease (ESRD).

Incontinent ileovesicostomy: Long-term outcomes and complications.

Incontinent ileovesicostomy was popularized in the mid‐1990s as a surgical option for patients with neurogenic voiding dysfunction who lack the dexterity to perform clean catheterization. There are several case series in the literature, but few studies look at the long‐term outcomes and complications associated with this procedure.

Current Perceptions of Resident Training in Laparoscopic Nephrectomy

OBJECTIVES To determine the perceived degree of training of residents in laparoscopic nephrectomy. Laparoscopic nephrectomy is well established in the field of urology and has seen increasing penetrance in urologic practice. The degree to which this recent technical shift has been integrated into urologic training at the residency level has not been characterized. METHODS An electronic survey was sent to 518 urology residents and recent graduates and to 85 laparoscopic specialists at academic medical centers. Both residents and practicing urologists were queried regarding the level of resident participation for each step of laparoscopic nephrectomy and opinions on the necessity of fellowship training. The data were analyzed using the Wilcoxon rank-sum and chi(2) tests. RESULTS Attending surgeons perceived a significantly greater level of resident involvement in performing all aspects of laparoscopic nephrectomy, with the exception of hilar dissection and port closure. To perform laparoscopic nephrectomy, 12.5% of attending physicians and 5% of residents reported that a fellowship is necessary. CONCLUSIONS Significant disagreement exists between attending surgeons and residents on the perceived degree of resident involvement in most aspects of laparoscopic nephrectomy. This could have significant implications on resident education for a procedure that is arguably the standard of care for treatment of uncomplicated renal masses. Most attending physicians and residents were in agreement that fellowship is not necessary to perform this procedure. These results raise questions regarding the future of laparoscopic training and bring to light the need for better regulation of laparoscopic training.

Effect of age on transitional cell carcinoma of the upper urinary tract: Presentation, treatment, and outcomes

OBJECTIVES To determine the effect of age on the disease characteristics, treatment administered, and disease-specific survival (DSS) for patients with upper tract urothelial carcinoma. The effect of advancing age on the disease extent and survival has not been well delineated in patients with upper tract urothelial carcinoma. METHODS Using the Surveillance, Epidemiology, and End Results database from the National Cancer Institute, we identified patients diagnosed with UTUC from 1984 to 2004. The data were analyzed for age (40-49, 50-59, 60-69, 70-79, and ≥80 years), sex, race, disease extent, treatment type, and cause of death. Relationships among age, clinicopathologic features, and treatment were tabulated. The effect of age on overall and DSS were calculated using Cox proportional hazards ratio analyses. RESULTS The final cohort consisted of 12 639 patients. Advancing age was associated with greater T stage and grade at presentation. Of those 40-49 years old, 41% presented with invasive tumors (T2-T4) compared with 50% of octogenarians. Poor or undifferentiated tumors increased in frequency from 42% among those 40-49 years old to 59% among those≥80 years old. Extirpative surgery was less likely among those with Stage T1 or less disease (88.3% vs 92.8%). Octogenarians were less likely to have undergone extirpative surgery than those 40-49 years old (86% vs 95%). Despite adjustments for T stage, grade, and treatment, DSS (hazard ratio 2.64) worsened with increasing age. CONCLUSIONS With advancing age, we found a corresponding increase in stage and grade at presentation. After adjustment for stage, grade, and treatment type, older patients still had worse DSS.

Current laparoscopy training in urology: a comparison of fellowships governed by the Society of Urologic Oncology and the Endourological Society.

BACKGROUND AND PURPOSE Laparoscopic surgery is now an integral technique in the practice of urology, particularly in the management of certain urologic malignancies. Advanced laparoscopy training in urology is primarily reserved for those pursuing fellowship training and is offered both by traditional endourology fellowships and increasingly in urologic oncology fellowships. The purpose of our study was to evaluate and compare current laparoscopy training at the fellowship level. MATERIALS AND METHODS A 17-item questionnaire was developed with support from both the Endourological Society (EUS) and Society of Urologic Oncology (SUO). Surveys were sent to program directors of fellowships recognized by the EUS and SUO. Directors were surveyed on the laparoscopic case volume, degree of oncology training, and career choice of their graduates. Data were analyzed with Wilcoxon rank-sum and Student t tests. RESULTS Our survey had an overall response rate of 60%. Fellows performed more than 100 laparoscopies during their training period in 57% of EUS and 25% of SUO fellowship programs. Similar trends are demonstrated when analyzing robotic procedures, with 73% of EUS fellows performing more than 50 procedures compared with 43% of SUO fellows. The majority (59%) of EUS programs provide oncologic training. Between 44% and 100% of graduates from EUS and SUO fellowships obtain academic positions. The majority of SUO directors (63%) believe that fellowship training in laparoscopy should be provided in fellowships governed solely by the SUO, while 41% of EUS directors believe this training should be governed solely by the EUS. CONCLUSIONS Endourology fellowships currently provide a greater exposure to laparoscopy and robotics than SUO fellowships. The percentage of fellows seeking academic positions is similar for EUS and SUO fellowship programs and has remained stable for several years. Directors of fellowship programs that offer advanced laparoscopic training have divergent views as to which administrative body should govern its future.