Glen Yang

Evolving practice patterns for the management of small renal masses in the USA

Study Type – Therapy (trend analysis)

Urology Resident Publication Output and Its Relationship to Future Academic Achievement

PURPOSE Scholarly research is considered by many to be an important component of residency training but little is known about the quantity and types of publications produced by urology residents. To our knowledge whether publication efforts during residency predict future academic publication performance is also unknown. We evaluated resident productivity, as measured by peer reviewed publication output, and determined its relation to future publication output as junior faculty. MATERIALS AND METHODS We assembled a list of graduating residents from 2002 to 2004 who were affiliated with the top 50 urology hospitals, as ranked in 2009 by U.S. News&World Report. PubMed® was queried to determine the publication total in the last 3 years of residency of each individual and during years 2 to 4 after residency graduation. Resident publication output was stratified by research time and fellowship training. The relationship between resident productivity and future achievement was assessed. RESULTS We assessed the publication output of 251 urologists from a total of 34 training programs affiliated with the top 50 urology hospitals. Subjects published a mean total of 3.5 and a mean of 2.0 first author papers during training. Greater research time during residency was associated with increased productivity during and after residency. Publication during training correlated with publication during the early academic career. CONCLUSIONS Publication output correlated with increasing dedicated research time and was associated with the pursuit of fellowship training and an academic career. Publication during residency predicted future academic achievement.

Targeted p21WAF1/CIP1 Activation by RNAa Inhibits Hepatocellular Carcinoma Cells

RNA activation (RNAa) is a mechanism of gene activation triggered by promoter-targeted small double-stranded RNA (dsRNA), also known as small activating RNA (saRNA). p21(WAF1/CIP1) (p21) is a putative tumor suppressor gene due to its role as a key negative regulator of the cell cycle and cell proliferation. It is frequently downregulated in cancer including hepatocellular carcinoma (HCC), but is rarely mutated or deleted, making it an ideal target for RNAa-based overexpression to restore its tumor suppressor function. In the present study, we investigated the antigrowth effects of p21 RNAa in HCC cells. Transfection of a p21 saRNA (dsP21-322) into HepG2 and Hep3B cells significantly induced the expression of p21 at both the mRNA and protein levels, and inhibited cell proliferation and survival. Further analysis of dsP21-322 transfected cells revealed that dsP21-322 arrested the cell cycle at the G(0)/G(1) phase in HepG2 cells but at G(2)/M phase in Hep3B cells which lack functional p53 and Rb genes, and induced both early and late stage apoptosis by activating caspase 3 in both cell lines. These results demonstrated that RNAa of p21 has in vitro antigrowth effects on HCC cells via impeding cell cycle progression and inducing apoptotic cell death. This study suggests that targeted activation of p21 by RNAa may be explored as a novel therapy for the treatment of HCC.

Mucinous Tubular and Spindle Cell Carcinoma of the Kidney

Mucinous tubular and spindle cell carcinoma (MTSC) was initially recognized as a distinctive subset of low grade collecting duct carcinomas in 1997,1 and it was incorporated in the 2004 WHO classification of renal neoplasms under its current name. Although MTSC was regarded as rare, more than 80 cases have been reported. The exact cell of origin is a matter of debate but accumulated evidence suggests that it originates from cells of the loop of Henle or from collecting duct epithelium, with more support for the latter site. MTSC occurs predominantly in females with a 1:4 male-to-female ratio and patient age is 13 to 82 years (mean 53).2 Although some tumors are symptomatic, the majority are discovered incidentally during abdominal imaging studies. Tumors are 2.2 to 12 cm (average 6 to 7) in diameter, sharply circumscribed and gray-white, tan or yellow, and sometimes have minimal hemorrhaging and/or necrosis. The cut surfaces are commonly bulging, shiny and mucoid due to the mucin content (fig. 1). Figure 1 MTSC exhibits bulging shiny mucoid cut surface. Microscopically MTSC is composed of round, ovoid or elongated tightly packed tubules separated by abundant basophilic extracellular mucin that sometimes has a bubbly myxoid consistency (fig. 2). Focally aggregates of spindled cells may be present, which may simulate sarcomatoid change but without necrosis, mitotic activity or significant nuclear pleomorphism (fig. 2, inset). The mucin stains strongly with Alcian blue at pH 2.5. Tubules are lined by uniform low cuboidal cells with scant cytoplasm, round nuclei of low nuclear grade and absent or inconspicuous nucleoli. Mitotic figures are rare.3 Figure 2 MTSC composed of tightly packed elongated tubules separated by abundant basophilic extracellular mucin with bubbly myxoid consistency. Aggregates of spindled cells may be present (inset). The histological spectrum of these tumors has been expanded to include cases in which the spindle cell component rivals or even exceeds the tubular component, as well as those with a relative paucity of mucinous matrix, aggregates of foamy macrophages, small components of well formed papillae, focal clear cell change in tubular cells, focal necrosis, oncocytic tubules, numerous small vacuoles, psammomatous calcification or heterotopic bone formation.3 Rarely neuroendocrine differentiation and true sarcomatoid components have been reported.4 Cytogenetic analyses and comparative genomic hybridization studies have revealed multiple genetic alterations, including losses of chromosomes 1, 4, 6, 8, 9, 13, 14, 15, 18 and 22.2 The prognosis for MTSC with classic morphology is generally favorable and complete surgical excision appears to be adequate treatment. These tumors are generally low pathological stage at excision and usually behave indolently. Few cases have demonstrated recurrence, regional lymph node metastases or distant metastases. However, 2 of 4 patients with MTSC exhibiting components of true sarcomatoid change died of the disease.4

Gender Differences in Academic Productivity and Academic Career Choice Among Urology Residents

PURPOSE Gender disparities have long existed in medicine but they have not been well examined in urology. We analyzed a large cohort of graduating urology residents to investigate gender disparities in academic productivity, as measured by peer reviewed publications and academic career choice. MATERIALS AND METHODS We assembled a list of urology residents who graduated from 2002 through 2008 who were affiliated with the top 50 urology hospitals, as ranked by 2009 U.S. News & World Report. PubMed® was queried to determine the publication output of each resident during the last 3 years of residency. We used an Internet search to determine the fellowship training, career choice and academic rank of each subject. Gender effects on each factor were evaluated. RESULTS A total of 459 male (84.5%) and 84 female (15.5%) residents were included in analysis. During residency women produced fewer total publications (average 3.0 vs 4.8, p = 0.01) and fewer as first author (average 1.8 vs 2.5, p = 0.03) than men. A higher proportion of women than men underwent fellowship training (54.8% vs 48.5%, p = 0.29) and ultimately chose an academic career (40.5% vs 33.3%, p = 0.20), although these differences were not statistically significant. Of residents who chose an academic career a higher proportion of men than women (24.7% vs 2.9%, p = 0.01) obtained associate vs assistant professor rank. CONCLUSIONS Women produced fewer peer reviewed publications than men during residency but they were equally likely to undergo fellowship training and choose an academic career. During the study period a higher proportion of men achieved associate professor rank.

The incidence of erectile dysfunction after pelvic fracture urethral injury: A systematic review and meta-analysis

Abstract Background: Pelvic fracture urethral injury (PFUI) is associated with a high risk of erectile dysfunction (ED). The effect of the type of posterior urethral disruption repair on erectile function has not been clearly established. We systematically reviewed and conducted a meta-analysis of the proportion of patients with ED at (i) baseline after pelvic fracture with PFUI, (ii) after immediate primary realignment, and (iii) after delayed urethroplasty. Methods: Using search terms for primary realignment or urethroplasty and urethral disruption, we systematically reviewed PubMed and EMBASE. A meta-analysis of the proportion of patients with ED was conducted assuming a random-effects model. Results: Of 734 articles found, 24 met the inclusion criteria. The estimate of the proportion (95% confidence interval) of patients with ED after (i) PFUI was 34 (25–45)%, after (ii) immediate primary realignment was 16 (8–26)%, and after (iii) delayed urethroplasty was an additional 3 (2–5)% more than the 34% after pelvic fracture in this cohort. Conclusions: After pelvic fracture, 34% of patients had ED. After primary endoscopic alignment, patients had a lower reported rate of ED (16%). Delayed urethroplasty conferred an additional 3% risk above the 34% associated with PFUI alone, with 37% of patients having de novo ED. The difference in de novo ED after primary endoscopic alignment vs. delayed urethroplasty is probably due to reporting differences in ED and/or patients with less severe injury undergoing primary realignment.

Squamous Cell Carcinoma at the Site of a Prince Albert's Piercing

INTRODUCTION Medical practitioners should be aware of genital piercing and its potential complications. General piercings are associate with complications common to all piercings as well as some unique to urethral piercings. Specifically, the association between carcinoma and genital piercing is not well recognized. AIM The present study is a report of two cases describing squamous cell carcinoma associated with genital piercing. METHODS Case reports of two men admitted to an academic medical center. RESULTS A 60-year-old man with a history of HIV and hepatitis C as well as a Prince Albert piercing presented for treatment of a urethrocutaneous fistula. A biopsy of indurated granulation tissue surrounding the fistula revealed invasive, moderately-differentiated squamous cell carcinoma. A 56-year-old man with a history of HIV, hepatitis C, and a Prince Albert piercing presented following a single episode of gross hematuria. He also reported splitting of his urinary stream. On physical examination, areas of necrosis were noted on the glans penis; biopsy revealed invasive, poorly-differentiated squamous cell carcinoma. CONCLUSIONS The present study is the first to suggest a possible association between squamous cell carcinoma of the penis/urethra and genital piercing. Patients with genital piercings, especially those with concurrent risk factors such as HIV and HCV, should be counselled about this rare complication.

Oncological and Functional Outcomes of Radical Cystectomy and Orthotopic Bladder Replacement in Women

OBJECTIVE To report oncological and functional results in women undergoing radical cystectomy and orthotopic bladder replacement. MATERIALS AND METHODS The charts of all women undergoing bladder replacement after radical cystectomy at UCSF through April 2008 were reviewed. Pathologic characteristics, survival (overall and disease-specific), and urinary functional outcomes are reported. Survival was estimated using Kaplan-Meier methods, and Cox proportional hazards regression analyses were performed to determine factors associated with incontinence, retention, and mortality. RESULTS Fifty-six women with a mean follow-up of 35 months were analyzed. The cancer recurrence rate was 32%. Kaplan-Meier estimated 5-year recurrence-free, cancer-specific, and overall survival were 54%, 57%, and 47%, respectively. Pathologic lymph node status (HR 14.2, P <.001) and age at diagnosis (HR 1.7, P = .04) were the only clinical or pathologic characteristics significantly associated with survival. The overall continence rate (no pads) was 57%. Hypercontinence occurred in 24% of patients. CONCLUSIONS With careful patient selection and usage of urethral frozen section, rates of local recurrence are low. Overall rates of incontinence (43%) and hypercontinence (24%) are similar to those previously reported. When pathologically organ-confined, women have an excellent disease-specific survival. Orthotopic bladder replacement is a safe and effective form of urinary diversion after radical cystectomy in women.

An Orthotopic Bladder Tumor Model and the Evaluation of Intravesical saRNA Treatment

We present a novel method for treating bladder cancer with intravesically delivered small activating RNA (saRNA) in an orthotopic xenograft mouse bladder tumor model. The mouse model is established by urethral catheterization under inhaled general anesthetic. Chemical burn is then introduced to the bladder mucosa using intravesical silver nitrate solution to disrupt the bladder glycosaminoglycan layer and allows cells to attach. Following several washes with sterile water, human bladder cancer KU-7-luc2-GFP cells are instilled through the catheter into the bladder to dwell for 2 hours. Subsequent growth of bladder tumors is confirmed and monitored by in vivo bladder ultrasound and bioluminescent imaging. The tumors are then treated intravesically with saRNA formulated in lipid nanoparticles (LNPs). Tumor growth is monitored with ultrasound and bioluminescence. All steps of this procedure are demonstrated in the accompanying video.

Abstract LB-363: Intravesical delivery of lipid nanoparticle formulated p21(Waf1/Cip1) activating dsRNA induces tumor regression and enhances animal survival in a orthotopic bladder cancer model

Small RNA molecules are a promising new class of drugs by offering expanded targets not druggable by conventional therapies with high target specificity and low toxicity. However, their clinical use is significantly hindered by the lack of vehicles that deliver the molecules efficiently to target tissues and cells. The bladder is an easily accessible hollow organ and is ideal for local delivery of drugs or molecules such as small RNA. RNA activation (RNAa) is a newly discovered mechanism of gene induction triggered by promoter targeted double-stranded RNA, also known as small activating RNA (saRNA). In this study, we investigate, in an orthotopic bladder cancer model, antitumor effects of a saRNA (dsP21) targeting the promoter of the p21WAF1/CIP1 (p21) gene, a key negative regulator of the cell cycle rarely mutated or deleted in bladder cancer. Introducing dsP21 into bladder cancer cells activated p21 expression with subsequent inhibition of cell proliferation, arrest of the cell cycle and induction of apoptosis accompanied by the activation of caspase 3 and PARP. Chemical modification (2′-Fluoro) and subsequent formulation of dsP21 in lipid nanoparticles (LNPs) retained its RNAa activity with minimal immunostimulatory effect and extended its stability in urine, and when delivered intravesically it could well diffuse into the bladder wall. Delivery of LNP-formulated dsP21 (LNP-dsP21) into mouse bladder with established human bladder cancer significantly inhibited tumor growth and extended animal survival with demonstrated p21 activation in vivo. Of particular significance, LNP-dsP21 treatment caused the regression or disappearance of established tumors in 30% of the treated mice. Our results provide proof-of-principle that targeted activation of p21 can be applied to the treatment of bladder cancer and LNP-formulated small RNA can be successfully delivered to the bladder by intravesical instillation. Further clinical development of RNAa-based intravesical therapy is warranted for the treatment of residual and recurring bladder cancer in humans. Acknowledgement: financial support from the AACR Henry Shepard Bladder Cancer Research Grants (09-60-30-LI). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-363. doi:1538-7445.AM2012-LB-363