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Matthew J Schiewer,
Jonathan F Goodwin,
Sumin Han,
J Chad Brenner,
Michael A Augello,
Jeffry L Dean,
Fengzhi Liu,
Jamie L Planck,
Preethi Ravindranathan,
Arul M Chinnaiyan, [......], Leonard G Gomella,
Ganesh V Raj,
Adam P Dicker,
Jonathan R Brody,
John M Pascal,
Margaret M Centenera,
Lisa M Butler,
Wayne D Tilley,
Felix Y Feng,
Karen E Knudsen
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ABSTRACT: Poly(ADP-ribose) polymerase-1 (PARP-1) is an abundant nuclear enzyme that modifies substrates by poly(ADP-ribose)-ylation. PARP-1 has well-described functions in DNA damage repair, and also functions as a context-specific regulator of transcription factors. Using multiple models, data demonstrate that PARP-1 elicits pro-tumorigenic effects in androgen receptor (AR)-positive prostate cancer (PCa) cells, both in the presence and absence of genotoxic insult. Mechanistically, PARP-1 is recruited to sites of AR function, therein promoting AR occupancy and AR function. It was further confirmed in genetically-defined systems that PARP-1 supports AR transcriptional function, and that in models of advanced PCa, PARP-1 enzymatic activity is enhanced, further linking PARP-1 to AR activity and disease progression. In vivo analyses demonstrate that PARP-1 activity is required for AR function in xenograft tumors, as well as tumor cell growth in vivo and generation and maintenance of castration-resistance. Finally, in a novel explant system of primary human tumors, targeting PARP-1 potently suppresses tumor cell proliferation. Collectively, these studies identify novel functions of PARP-1 in promoting disease progression, and ultimately suggest that the dual functions of PARP-1 can be targeted in human PCa to suppress tumor growth and progression to castration-resistance.
Cancer discovery. 09/2012;
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ABSTRACT: OBJECTIVES:: With the widespread use of prostate-specific antigen testing, an increasing number of men are diagnosed with favorable-risk prostate cancer (PC). Recently, emphasis has been placed on active surveillance for selected men with favorable-risk PC to avoid unnecessary treatment for tumors that may be clinically insignificant. We performed a population-based analysis to assess patterns of initial treatment (IT) for a contemporary cohort of elderly men diagnosed with a favorable-risk PC in the United States. METHODS:: We used the Surveillance, Epidemiology, and End Results database to identify men aged more than or equal to 70 years diagnosed with a favorable-risk PC from 2004 to 2008. Multivariable logistic regression analyses were performed to determine patient, tumor, and socioeconomic factors associated with IT. RESULTS:: A total of 15,108 men more than or equal to 70 years with a favorable-risk PC were identified. Prostatectomy was performed in 2.6% of patients. Fifty-nine percent of patients were recommended to undergo radiation therapy (RT). Among patients 70 to 74 years, 66.45% were recommended to undergo RT. Fifty-nine percent, 36.6%, and 15.8% of patients between 75 and 79, 80 and 84, and more than or equal to 85 years were recommended to receive RT, respectively. Factors significantly associated with IT on multivariable logistic regression analysis included: younger age, white race, Gleason Score 6 (vs.≤5), married marital status, and no history of prior malignancy. We also identified significant geographic variations in patterns of IT. CONCLUSIONS:: A large percentage of elderly men diagnosed with favorable-risk PC undergo IT, most commonly with RT. Future research should be performed to identify barriers to patient and physician acceptance of active surveillance.
American journal of clinical oncology 08/2012; · 2.21 Impact Factor
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ABSTRACT: To evaluate the prognostic factors and outcomes for a large observational cohort of female patients with urethral cancer in the Surveillance, Epidemiology, and End Results database.
We identified 722 women diagnosed with urethral cancer from 1983 to 2008 in the Surveillance, Epidemiology, and End Results database. Descriptive statistics were used to explore the epidemiology, standard treatment practices, and tumor characteristics. A total of 359 women with nonmetastatic primary urethral cancer were identified for cancer-specific and survival analysis. Kaplan-Meier plots and log-rank tests were performed for each potential covariate. A multivariate Cox proportional hazards model was performed to evaluate age, demographic factors, T stage, nodal status, histologic findings, surgery, and radiotherapy.
The median overall survival time was 42 months (95% confidence interval 35-57), and the 5- and 10-year overall survival rate was 43% and 32%, respectively. The median cancer-specific survival (CSS) time was 78 months, and the 5- and 10-year CSS rate was 53% and 46%, respectively. On multivariate analysis, black race, Stage T3-T4 tumors compared with T1, node-positive disease, nonsquamous histologic features, and advanced age were associated with shortened CSS. Surgery was associated with longer CSS. Black patients presented with a statistically significant greater T stage.
Advanced age, T stage, node-positive disease, nonsquamous histologic features, and black race were associated with reduced CSS, and surgical resection was associated with longer CSS. We found that black patients present with more advanced tumors and have shorter CSS than white women with urethral cancer.
Urology 08/2012; 80(2):374-81. · 2.43 Impact Factor
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ABSTRACT: To report on assessments of face, content, and construct validity for the commercially available da Vinci Skills Simulator (dVSS).
A total of 38 subjects participated in this prospective study. Participants were classified as novice (0 robotic cases performed), intermediate (1-74 robotic cases), or expert (≥ 75 robotic cases). Each subject completed 5 exercises. Using the metrics available in the simulator software, the performances of each group were compared to evaluate construct validation. Immediately after completion of the exercises, each subject completed a questionnaire to evaluate face and content validation.
The novice group consisted of 18 medical students and 1 resident. The intermediate group included 6 residents, 1 fellow, and 2 faculty urologist. The expert group consisted of 2 residents, 1 fellow, and 7 faculty surgeons. The mean number of robotic cases performed by the intermediate and expert groups was 29.2 and 233.4, respectively. An overall significant difference was observed in favor of the more experienced group in 4 skill sets. When intermediates and experts were combined into a single "experienced" group, they significantly outperformed novices in all 5 exercises. Intermediates and experts rated various elements of the simulators realism at an average of 4.1/5 and 4.3/5, respectively. All intermediate and expert participants rated the simulator's value as a training tool as 4/5 or 5/5.
Our study supports the face, content, and construct validation attributed to the dVSS. These results indicate that the simulator may be most useful to novice surgeons seeking basic robot skills acquisition.
Urology 05/2012; 79(5):1068-72. · 2.43 Impact Factor
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ABSTRACT: In general, patients with prostate cancer are able to maintain a relatively high quality of life (QOL), commonly reporting improvements in physical, emotional, and social functioning within 1 year of treatment. However, certain subpopulations of patients are susceptible to significant reductions in QOL during the course of their treatment. Data suggest that ethnic background and sexual preference both have significant effects on QOL for patients with prostate cancer. These parameters are often poorly documented and addressed by medical practitioners. Greater attention is needed to identify patients who are at increased risk of QOL reduction as a result of these factors.
Nature Reviews Urology 04/2012; 9(5):258-65. · 4.41 Impact Factor
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ABSTRACT: In patients with non-muscle invasive bladder cancer, fluorescence cystoscopy can improve the detection and ablation of bladder tumors. In this paper we describe the technique and practical aspects of hexaminolevulinate (HAL) fluorescence cystoscopy, also known as "blue light cystoscopy".
The Canadian Journal of Urology 04/2012; 19(2):6227-31. · 0.64 Impact Factor
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ABSTRACT: The insulin-like growth factor receptor I (IGF-IR) plays an essential role in transformation by promoting cell growth and protecting cancer cells from apoptosis. We have recently demonstrated that the IGF-IR is overexpressed in invasive bladder cancer tissues and promotes motility and invasion of urothelial carcinoma cells. These effects require IGF-I-induced Akt- and MAPK-dependent activation of paxillin. The latter co-localizes with focal adhesion kinases (FAK) at dynamic focal adhesions and is critical for promoting motility of urothelial cancer cells. FAK and its homolog Proline-rich tyrosine kinase 2 (Pyk2) modulate paxillin activation; however, their role in regulating IGF-IR-dependent signaling and motility in bladder cancer has not been established. In this study we demonstrate that FAK was not required for IGF-IR-dependent signaling and motility of invasive urothelial carcinoma cells. On the contrary, Pyk2, which was strongly activated by IGF-I, was critical for IGF-IR-dependent motility and invasion and regulated IGF-I-dependent activation of the Akt and MAPK pathways. Using immunofluorescence and AQUA analysis we further discovered that Pyk2 was overexpressed in bladder cancer tissues as compared to normal tissue controls. Significantly, in urothelial carcinoma tissues there was increased Pyk2 localization in the nuclei as compared to normal tissue controls. These results provide the first evidence of a specific Pyk2 activity in regulating IGF-IR-dependent motility and invasion of bladder cancer cells suggesting that Pyk2 and the IGF-IR may play a critical role in the invasive phenotype in urothelial neoplasia. In addition, Pyk2 and the IGF-IR may serve as novel biomarkers with diagnostic and prognostic significance in bladder cancer.
PLoS ONE 01/2012; 7(6):e40148. · 4.09 Impact Factor
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ABSTRACT: We have recently discovered that the insulin-like growth factor receptor I (IGF-IR) is up-regulated in human invasive bladder
cancer and promotes migration and invasion of transformed urothelial cells. The proteoglycan decorin, a key component of the
tumor stroma, can positively regulate the IGF-IR system in normal cells. However, there are no available data on the role
of decorin in modulating IGF-IR activity in transformed cells or in tumor models. Here we show that the expression of decorin
inversely correlated with IGF-IR expression in low and high grade bladder cancers (n = 20 each). Decorin bound with high affinity IGF-IR and IGF-I at distinct sites and negatively regulated IGF-IR activity
in urothelial cancer cells. Nanomolar concentrations of decorin promoted down-regulation of IRS-1, one of the critical proteins
of the IGF-IR pathway, and attenuated IGF-I-dependent activation of Akt and MAPK. This led to decorin-evoked inhibition of
migration and invasion upon IGF-I stimulation. Notably, decorin did not cause down-regulation of the IGF-IR in bladder, breast,
and squamous carcinoma cells. This indicates that decorin action on the IGF-IR differs from its known activity on other receptor
tyrosine kinases such as the EGF receptor and Met. Our results provide a novel mechanism for decorin in negatively modulating
both IGF-I and its receptor. Thus, decorin loss may contribute to increased IGF-IR activity in the progression of bladder
cancer and perhaps other forms of cancer where IGF-IR plays a role.
Journal of Biological Chemistry 10/2011; 286(40):34712-34721. · 4.77 Impact Factor
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Leonard G Gomella
The Canadian Journal of Urology 10/2011; 18(5):5883. · 0.64 Impact Factor
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Leonard G Gomella
The Canadian Journal of Urology 10/2011; 18(5):5860. · 0.64 Impact Factor
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ABSTRACT: PURPOSE: The purpose of this study is to assess the acute and late genitourinary (GU) and gastrointestinal (GI) toxicities of cone-beam computed tomography (CBCT) guided conformal adjuvant and salvage post-prostatectomy radiotherapy (RT) compared with RT with port films. Materials and methods: Sixty-eight patients (group 1) were treated with RT following radical prostatectomy (RP) using CBCT-guided conformal RT to a median dose of 68.4Gy. CBCT images were acquired three to five times weekly and were automatically co-registered to a reference CT. A comparative group (group 2) included 150 patients who received post-RP RT with weekly port films to a median dose of 64.8Gy. GU and GI toxicities were graded in both the acute and late settings using Radiation Therapy Oncology Group criteria. Associations between toxicity and study variables were evaluated by odds ratios (ORs) estimated by logistic regression. Results: Grades 2 and 3 acute GU toxicity were experienced by 13% (n=9) and 2% (n=1) of patients in group 1, respectively, while 13% (n=19) had grade 2 acute GU toxicity in the control group (group 2). Grade 2 acute GI toxicity was experienced by 13% (n=9) and 15% (n=23) in groups 1 and 2, respectively. Acute GU (P=0.67) and GI (P =0.84) toxicities were not significantly different between the two groups. There were no associations detected between CBCT and acute GI toxicity (OR 0.76, P=0.57) or acute GU (OR 1.16, P=0.75). Increased odds of acute GU toxicity were observed for doses>68.4Gy (OR 12.81, P=0.04), which were only delivered in the CBCT group. CBCT mean variations (standard deviation) for 1053 fractions were 2.8mm (2.8), 2.0mm (2.4) and 3.1mm (2.9) in the left-to-right, anterior-to-posterior (AP) and superior-to-inferior (SI) axes, respectively. Corrective shifts for variance≥5mm were required for 15%, 6% and 19% of fractions in the left-to-right, anterior-to-posterior and superior-to-inferior axes, respectively. Conclusions: Rates of acute toxicity with CBCT-guided post-RP RT to 68.4Gy were similar to treatment to 64.8Gy without image-guidance RT. Acceptable early toxicity profiles suggest that CBCT is a reasonable strategy for image guidance, but the value of CBCT must be weighed against potential increased risk of secondary cancers due to increased radiation exposure.
Journal of Medical Imaging and Radiation Oncology 10/2011; 55(5):507-15. · 0.87 Impact Factor
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ABSTRACT: The robotic-assisted laparoscopic approach to radical prostatectomy is increasingly utilized and has become well documented as an effective oncologic treatment modality. In this study, we report the initial experience of a single surgeon at a single institution with robotic-assisted laparoscopic prostatectomy (RALP) drawing a comparison to his prior experience with pure laparoscopic prostatectomy (LRP) METHODS: This is a retrospective review of surgical results from a single surgeon performing LRP and transitioning to RALP. Baseline characteristics and outcomes of two hundred seventy five patients undergoing RALP by a single, fellowship-trained, urologic oncologist were analyzed and compared to 45 patients undergoing LRP by the same surgeon. Patient, tumor, and operative characteristics as well as functional outcomes were evaluated. Validated questionnaires, including the International Prostate Symptom Score (IPSS) and International Index of Erectile Function (IIEF), were utilized in the assessment of urinary and sexual parameters.
Preoperative patient and tumor characteristics (age, PSA, Gleason score) were similar in both the LRP and RALP groups. Mean operative time (195 vs. 299 minutes), estimated blood loss (223 vs. 299 mL), need for blood transfusion (1.5% vs. 4.4%) and mean length of stay (1.95 vs. 2.63 days) were significantly reduced among patients undergoing RALP as compared to those undergoing LRP. In terms of functional outcomes, continence at 12 months was better among patients undergoing RALP as compared to LRP (94% vs. 82%). In preoperatively potent men undergoing bilateral nerve sparing procedures, RALP conferred 82% potency at 24 months as opposed to only 62% following LRP.
The combination of adjustment in surgical technique from LRP to RALP along with a concurrent institutional commitment to a successful robotic surgery program, has yielded superior operative, oncologic, and functional results.
Archivos españoles de urología 10/2011; 64(8):823-9.
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ABSTRACT: Prostate cancer presents a global public health dilemma. While screening with prostate specific antigen (PSA) has led to more men diagnosed with prostate cancer than in previous years, the potential for negative effects from over-diagnosis and treatment cannot be ignored.
We reviewed Medline for recent articles that discuss clinical trials, evidence based recommendations and guidelines from major medical organizations in the United States and worldwide concerning prostate cancer screening.
Results from the European Randomized Screening for Prostate Cancer (ERSPC), the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, and Göteborg Swedish trials regarding prostate screening are controversial with the ERSPC and Göteborg showing a reduction in prostate cancer mortality and the PLCO trial showing no benefit. Recommendations from the American Urological Association (AUA), Japanese Urological Association (JUA), and National Comprehensive Cancer Network (NCCN) have recommended that all men obtain a baseline PSA beginning at age 40. The American Cancer Society (ACS) stratifies screening recommendations based on age and risk, but states that screening should take place only after an informed discussion between provider and patient. The United States Preventative Health Service Task Force (USPSTF) states that evidence is insufficient to assess the risks and benefits of prostate cancer screening in men younger than 75 years. Other major international health organizations offer a similar reserved approach or recommend against screening for prostate cancer. Most groups indicate that screening to determine who should undergo prostate biopsy typically includes both a serum PSA and digital rectal examination, with the latest ACS publications noting that the rectal exam is optional. A common theme from all groups is that an informed discussion with the patients is strongly recommended and that screening does increase the number of men diagnosed with non-metastatic, early disease.
Prostate cancer screening guidelines vary widely between countries and between different medical organizations within individual countries including the United States. Further, the evidence for and against prostate cancer screening remains highly controversial. Longitudinal follow up of completed screening trials is ongoing and may yield additional findings as the time course of prostate cancer outcomes can be protracted. The literature controversy suggests that no standard of care exists for prostate cancer screening today. Until there is agreement in guidelines between major professional organizations who have weighed in on this topic, patients and physicians should be encouraged to consider engaging in shared and informed decision process concerning screening for prostate cancer.
The Canadian Journal of Urology 10/2011; 18(5):5875-83. · 0.64 Impact Factor
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Leonard G Gomella
European urology 08/2011; 60(6):1197-9. · 7.67 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: We have recently discovered that the insulin-like growth factor receptor I (IGF-IR) is up-regulated in human invasive bladder cancer and promotes migration and invasion of transformed urothelial cells. The proteoglycan decorin, a key component of the tumor stroma, can positively regulate the IGF-IR system in normal cells. However, there are no available data on the role of decorin in modulating IGF-IR activity in transformed cells or in tumor models. Here we show that the expression of decorin inversely correlated with IGF-IR expression in low and high grade bladder cancers (n = 20 each). Decorin bound with high affinity IGF-IR and IGF-I at distinct sites and negatively regulated IGF-IR activity in urothelial cancer cells. Nanomolar concentrations of decorin promoted down-regulation of IRS-1, one of the critical proteins of the IGF-IR pathway, and attenuated IGF-I-dependent activation of Akt and MAPK. This led to decorin-evoked inhibition of migration and invasion upon IGF-I stimulation. Notably, decorin did not cause down-regulation of the IGF-IR in bladder, breast, and squamous carcinoma cells. This indicates that decorin action on the IGF-IR differs from its known activity on other receptor tyrosine kinases such as the EGF receptor and Met. Our results provide a novel mechanism for decorin in negatively modulating both IGF-I and its receptor. Thus, decorin loss may contribute to increased IGF-IR activity in the progression of bladder cancer and perhaps other forms of cancer where IGF-IR plays a role.
Journal of Biological Chemistry 08/2011; 286(40):34712-21. · 4.77 Impact Factor
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Leonard G Gomella
The Canadian Journal of Urology 06/2011; 18(3):5666. · 0.64 Impact Factor
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Timothy N Showalter,
Nitin Ohri,
Kristopher G Teti,
Kathleen A Foley,
Scott W Keith,
Edouard J Trabulsi,
Costas D Lallas,
Adam P Dicker,
Jean Hoffman-Censits,
Laura T Pizzi, Leonard G Gomella
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ABSTRACT: Despite results of randomized trials that support adjuvant radiation therapy (RT) after radical prostatectomy (RP) for prostate cancer with adverse pathologic features (APF), many clinicians favor selective use of salvage RT. This survey was conducted to evaluate the beliefs and practices of radiation oncologists (RO) and urologists (U) regarding RT after RP.
We designed a Web-based survey of post-RP RT beliefs and policies. Survey invitations were e-mailed to a list of 926 RO and 591 U. APF were defined as extracapsular extension, seminal vesicle invasion, or positive surgical margin. Differences between U and RO in adjuvant RT recommendations were evaluated by comparative statistics. Multivariate analyses were performed to evaluate factors predictive of adjuvant RT recommendation.
Analyzable surveys were completed by 218 RO and 92 U (overallresponse rate, 20%). Adjuvant RT was recommended based on APF by 68% of respondents (78% RO, 44% U, p <0.001). U were less likely than RO to agree that adjuvant RT improves survival and/or biochemical control (p < 0.0001). PSA thresholds for salvage RT were higher among U than RO (p < 0.001). Predicted rates of erectile dysfunction due to RT were higher among U than RO (p <0.001). On multivariate analysis, respondent specialty was the only predictor of adjuvant RT recommendations.
U are less likely than RO to recommend adjuvant RT. Future research efforts should focus on defining the toxicities of post-RP RT and on identifying the subgroups of patients who will benefit from adjuvant vs. selective salvage RT.
International journal of radiation oncology, biology, physics 05/2011; 82(2):e233-8. · 4.59 Impact Factor
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ABSTRACT: Coordination of care between the urologist and primary care physician is critical to effective treatment of a variety of urologic conditions. Medical therapies for benign prostatic hyperplasia, erectile dysfunction, hypogonadism, overactive bladder, and prostate cancer are widely available and a basic understanding of the pathophysiology of these disease states as well as the pharmacology of existing treatment options are necessary to avoid complications and maximize efficacy associated with patient outcomes. Important regulatory decisions have been made concerning the approval and lack of approval of several important urologic medications. Major advances have been made in the therapy of castrate resistant prostate cancer as well as hormonal related skeletal events secondary to advanced carcinoma of the prostate. We provide a 2011 update of the available medications for treatment of several common urologic diseases.
The Canadian Journal of Urology 04/2011; 18 Suppl:24-38. · 0.64 Impact Factor
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ABSTRACT: • To investigate both the feasibility and the adequacy of pelvic lymph node dissection (PLND) during robot-assisted laparoscopic prostatectomy (RALP) by comparing lymph node yields obtained during RALP with those obtained during traditional open retropubic radical prostatectomy (RRP).
• We retrospectively reviewed 1047 patients who underwent radical prostatectomy between 2001 and 2009. • In all, 626 patients underwent RALP while 421 patients had traditional open RRP. All patients undergoing bilateral PLND were included in our analysis. • Lymph node yields and lymph node involvement for each surgical approach were calculated and examined. • PLND-related complications were analysed.
• Of the 1047 patients, 816 patients underwent bilateral PLND of whom 473 underwent RALP, while 343 underwent RRP. The mean lymph node yields for the RALP cohort (7.1, interquartile range 4-10) was significantly higher (P < 0.001) than for the RRP cohort (6.0, interquartile range 3-8). • The percentage of patients with nodal involvement was 1.1 for RALP and 2.3 for RRP (P= 0.167). • Mean age, preoperative PSA values, and pre- and postoperative Gleason scores were similar between the two cohorts. • PLND-related complications were similar between both cohorts.
• In patients undergoing RALP, PLND is feasible and provides lymph node yields comparable with those of the standard open approach. • PLND should be strongly considered in all radical prostatectomy patients when clinically indicated, regardless of surgical technique.
BJU International 04/2011; 107(7):1136-40. · 2.84 Impact Factor
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Leonard G Gomella
The Canadian Journal of Urology 02/2011; 18(1):5500. · 0.64 Impact Factor
