Jason Woo

Tumor infiltrating B-cells are increased in prostate cancer tissue

BackgroundThe presence of increased B-cell tumor infiltrating lymphocytes (TILs) was seen in mouse prostate cancer (PCa) but has not been fully documented in human PCa. We, therefore, investigated the density of infiltrating B cells within human PCa utilizing a quantitative computational method.MethodsArchived radical prostatectomy specimens from 53 patients with known clinical outcome and D’Amico risk category were obtained and immunohistochemically (IHC) stained for the B cell marker, CD20. Slides were reviewed by a genitourinary pathologist who manually delineated the tumoral regions of PCa. Slides were digitally scanned and a computer algorithm quantified the area of CD20 stained B-cells as a measure of B cell density within the outlined regions of prostate cancer (intra-tumoral region), versus extra-tumoral prostate tissue. Correlations were analyzed between B-cell density and demographic and clinical variables, including D’Amico risk groups and disease recurrence.ResultsFor the entire cohort, the mean intra-tumoral B cell density was higher (3.22 SE = 0.29) than in the extra-tumoral region of each prostatectomy section (2.24, SE = 0.19) (paired t test; P < 0.001). When analyzed according to D’Amico risk group, the intra-tumoral B cell infiltration in low risk (0.0377 vs. 0.0246; p = 0.151) and intermediate risk (0.0260 vs. 0.0214; p = 0.579) patient prostatectomy specimens did not show significantly more B-cells within the PCa tumor. However, patient specimens from the high-risk group (0.0301 vs. 0.0197; p < 0.001) and from those who eventually had PCa recurrence or progression (0.0343 vs. 0.0246; p = 0.019) did show significantly more intra-tumoral CD20+ B-cell staining. Extent of B-cell infiltration in the prostatectomy specimens did not correlate with any other clinical parameters.ConclusionsOur study shows that higher B-cell infiltration was present within the intra-tumoral PCa regions compared to the extra-tumoral benign prostate tissue regions in prostatectomy sections. For this study we developed a new method to measure B-cells using computer-assisted digitized image analysis. Accurate, consistent quantitation of B-cells in prostatectomy specimens is essential for future clinical trials evaluating the effect of B cell ablating antibodies. The interaction of B-cells and PCa may serve as the basis for new therapeutic targets.

PCSD1, a new patient-derived model of bone metastatic prostate cancer, is castrate-resistant in the bone-niche.

IntroductionProstate cancer bone metastasis occurs in 50-90% of men with advanced disease for which there is no cure. Bone metastasis leads to debilitating fractures and severe bone pain. It is associated with therapy resistance and rapid decline. Androgen deprivation therapy (ADT) is standard of care for advanced prostate cancer, however, bone metastatic prostate cancer (PCa) often becomes resistant to ADT. There are few pre-clinical models to understand the interaction between the bone microenvironment and prostate cancer. Here we report the castrate resistant growth in the bone niche of PCSD1, a patient-derived intra-femoral xenograft model of prostate bone metastatic cancer treated with the anti-androgen, bicalutamide.MethodsPCSD1 bone-niche model was derived from a human prostate cancer femoral metastasis resected during hemiarthroplasty and serially transplanted into Rag2−/−;γc−/− mice intra-femorally (IF) or sub-cutaneously (SC). At 5 weeks post-transplantation mice received bicalutamide or vehicle control for 18 days. Tumor growth of PCSD1 was measured with calipers. PSA expression in PCSD1 xenograft tumors was determined using quantitative RT-PCR and immunohistochemistry. Expression of AR and PSMA, were also determined with qPCR.ResultsPCSD1 xenograft tumor growth capacity was 24 fold greater in the bone (intra-femoral, IF) than in the soft tissue (sub-cutaneous, SC) microenvironment. Treatment with the anti-androgen, bicalutamide, inhibited tumor growth in the sub-cutaneous transplantation site. However, bicalutamide was ineffective in suppressing PCSD1 tumor growth in the bone-niche. Nevertheless, bicalutamide treatment of intra-femoral tumors significantly reduced PSA expression (p < =0.008) and increased AR (p < =0.032) relative to control.ConclusionsPCSD1 tumors were castrate resistant when growing in the bone-niche compared to soft tissue. Bicalutamide had little effect on reducing tumor burden in the bone yet still decreased tumor PSA expression and increased AR expression, thus, this model closely recapitulated castrate-resistant, human prostate cancer bone metastatic disease. PCSD1 is a new primary prostate cancer bone metastasis-derived xenograft model to study bone metastatic disease and for pre-clinical drug development of novel therapies for inhibiting therapy resistant prostate cancer growth in the bone-niche.

Early clean intermittent catheterization may not prevent dimercaptosuccinic acid renal scan abnormalities in children with spinal dysraphism

OBJECTIVES To determine whether early initiation of clean intermittent catheterization is associated with increased renal preservation in children with spinal dysraphism based on dimercaptosuccinic acid (DMSA) renal scans. METHODS A retrospective review was performed of 100 patients from a pediatric spinal defects clinic from June 2007 to October 2011 who were followed with routine studies including DMSA scans, voiding cystourethrograms, renal/bladder ultrasounds, and urodynamics. DMSA scans were reviewed for evidence of renal cortical loss as defined by presence of scarring or difference in differential function greater than 15%. Multivariate analysis was performed for risk factors for upper tract damage. RESULTS Renal cortical loss on DMSA scan was found in 43/100 (43%) of patients. CIC was started at birth in 17/100 (17%) of patients with the rest starting at a median age of 5 years (IQR 3-9). Upon multivariate regression analysis, age at DMSA scan (OR 1.21; 95% CI 1.08-1.36), history of VUR (OR 8.64; 95% CI 2.52-29.57), history of hydronephrosis (OR 3.44; 95% CI 1.12-10.5), and CIC from birth (OR 9.26; 95% CI 1.99-43.18) were statistically significant predictors of kidney damage. CONCLUSION Early initiation of CIC may not reduce the incidence of DMSA abnormalities in pediatric patients with spinal dysraphism.

Urologic Outcomes of Pediatric Pelvic Neuroblastoma Presenting in Acute Urinary Retention

Purpose: To evaluate long-term urologic outcomes of patients with pelvic neuroblastoma (NB) presenting with urinary retention. Methods: Five cases of pelvic NB presenting with urinary retention were identified between 1971 and 2011. Clinical presentation, treatment, survival and long-term voiding outcomes were analyzed. Results: All five patients presented with acute urinary retention and pelvic outlet dysfunction including bladder perforation (20%), constipation (40%), or fecal incontinence (20%). The presenting age ranged from 7 days to 4 years with female to male ratio of 3:2. Two patients presented with bilateral hydronephrosis and three patients were stage 4 at presentation. All required debulking surgery, four patients required combined anterior and posterior approaches for tumor resection, with two patients requiring concurrent laminectomy. Adjuvant or neoadjuvant chemoradiation was used in four of five cases. Follow-up ranged from 2 to 41 years. Although the long-term oncological outcome is favorable, urologic outcomes of these patients ranged from normal bladder function to the need significant reconstructive procedures. Conclusion: Urologic outcomes are related to pelvic nerve and organ preservation during resection more than the severity of urinary symptoms at presentation.

Renal Artery Embolism and Renal Vein Thrombosis

In this chapter, we explore two categories of emergencies involving the major renal vasculature: renal infarction and renal vein thrombosis (RVT). Although both conditions ultimately cause renal ischemia, the etiologies, presentation, treatment strategies, and ultimate prognoses of occlusion of the renal artery and vein are quite different. We review the current literature with an emphasis on the optimal evaluation and treatment of patients with renal artery infarction and RVT.

Surgical Management of Nephrolithiasis in the Bottlenose Dolphin: Collaborations Between the Urologist and Veterinarian

Abstract Background: Cohorts of bottlenose (Tursiops truncatus) dolphins are at significant risk for nephrolithiasis development. However, effective surgical treatment has been limited due to absence of literature and also familiarity by both veterinarians and urologists. Recently a joint veterinarian and urology team were called to treat local bottlenose dolphins in San Diego, CA, and they performed several cases. The fund of knowledge from these cases is presented for future providers who may be asked to surgically treat these animals. Case Presentation: Two surgical kidney stone cases were performed by a joint veterinarian and physician team. An effective ureteroscopic stone removal was performed on a 39-year-old female bottlenose dolphin with 9.7 mm distal ureteral calculus. The second case involved laparoscopic ureterolithotomy on a 31-year-old male bottlenose dolphin with a 6-mm right distal ureteral calculus that previously failed retrograde ureteroscopic removal. The stone was not effectively removed laparoscopically as well due to failure to progress associated with operative machinery malfunction. The dolphin was ultimately euthanized. Conclusion: Despite suboptimal outcome in one case, extremely valuable lessons were learned during both cases. We present our surgical experiences, as well as pertinent anatomical differences, in these animals with the hope that this discussion will facilitate future surgical kidney stone treatment of dolphins.

PD16-02 IMPACT OF RENAL SURGERY ON OVERALL, ONCOLOGIC, AND CARDIAC MORTALITY IN PATIENTS WITH STAGE I RENAL CELL CARCINOMA AND WITHOUT PREOPERATIVE RENAL INSUFFICIENCY

INTRODUCTION AND OBJECTIVES: Renal hilar clamping during partial nephrectomy can cause ischemia/reperfusion injury to the surgically preserved parenchyma, which may disturb renal oxygenation after release of blood flow. To minimize this damage, artery-only (AO) clamping has been proposed instead of artery-vein (AV) clamping. In this study, we measured renal oxygenation before and after hilar clamping during partial nephrectomy with AO and AV occlusion. METHODS: We included 34 patients who underwent open and laparoscopic partial nephrectomy with warm ischemia at our institute between 2009 and 2012. AO and AV occlusion was performed in 26 and 8 patients, respectively. Renal parenchymal arterial oxygen saturation (SaO2) was recorded before hilar clamping and 5minute after declamping using T.OxTM Tissue Oximeter (ViOptix, Fremont, CA, USA). All patientsi effective renal plasma flow (ERPF) were evaluated by 99mTc-MAG3 renal scintigraphy and estimated glomerular filtration rate (eGFR) was measured before and 1 week after surgery. RESULTS: Mean ischemia time was 27 min and 31 min in AO and AV group, respectively (p 1⁄4 0.930). The SaO2 for AO and AV decreased by 4.0% and 15.0%, respectively (p 1⁄4 0.037). The change of ERPF in the operated kidney was -47.2 vs -49.0 ml/min/1.73m2 (p 1⁄4 0.637). The change of eGFR was -12.8 vs -18.5 ml/min/1.73m2 (p 1⁄4 0.190). Pearsoni correlation coefficient showed a significant correlation of the change of SaO2 with the change of eGFR (p 1⁄4 0.032), but not with ischemia time (p 1⁄4 0.167), or the change of ERPF in the operated kidney (p 1⁄4 0.225). The SaO2 for the group in which eGFR deteriorated <10 ml/min/1.73m2 decreased by 0.2%, while the SaO2 for the group in which eGFR deteriorated iÝ10 ml/min/1.73m2 decreased by 10.3%, respectively (p 1⁄4 0.032). CONCLUSIONS: The results of this study demonstrate a significant retrograde venous oxygen delivery by applying AO occlusion technique. The decrease of renal function tends to be smaller in the AO clamping group compared with the AV clamping group. This improvement may be the result of the minimization of renal parenchymal oxygenation deterioration.

Mp57-14 Change in Platelet Count as a Prognostic Indicator for Response to Neoadjuvant Tyrosine Kinase Inhibitor Therapy in Metastatic Renal Cell Carcinoma

INTRODUCTION AND OBJECTIVES: Biomarkers may be useful as prognostic indicators prior to and during systemic therapy. We evaluated change in platelet count (DPlt) as a biomarker for response to neoadjuvant tyrosine kinase inhibitor (TKI) therapy for metastatic renal cell carcinoma (mRCC). METHODS: Multi-center retrospective study of mRCC patients undergoing neoadjvant TKI therapy from 5/2005-8/2013. DPlt was defined as post-treatment Plt after first cycle minus pre-treatment Plt. Primary outcome was response of disease to TKI defined by RECIST criteria for partial response (PR), stable disease (SD), and progressive disease (PD). Demographic and clinical characteristics were analyzed between subgroups with stable/increased (+DPlt) and decreased (-DPlt) counts. Cox proportional hazards model evaluated factors associated with changes in tumor response. Kaplan-Meier analysis estimated overall survival (OS) and compared Plt groups with log-rank test. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) were calculated for DPlt and disease response PR/SD. RESULTS: A total of 69 patients treated with neoadjuvant TKI therapy were analyzed for DPlt. Overall, 15 patients (22%) were noted to have +DPlt and 54 (78%) had eDPlt after neoadjuvant TKI therapy. There were no other differences in clinical or demographic variables between these two groups (comorbidities, ECOG, tumor size, number of metastases, stage, grade and number of TKI cycles). Patients with +DPlt count had a lower post TKI treatment creatinine (1.0 vs. 1.3, p1⁄40.041). PD was more common among +DPlt 86.7% vs. eDPlt 33.3%, (p1⁄40.001), and SD/PR was more common in eDPlt 66.7% vs. +DPlt 13.3%, (p1⁄40.001). On MVA, -DPlt below baseline was a significant predictor of SD/PR (OR 6.96, p1⁄40.028). A Kaplan Meier analysis (Figure) demonstrated a higher overall survival in -DPlt versus +DPlt (p1⁄40.009), with median survival 13.8 of and 5.7 months respectively. -DPlt had sensitivity of 94.7%, specificity of 41.9%, PPV of 66.7% and NPV of 86.7% for PR/SD after neoadjuvant TKI therapy. CONCLUSIONS: Patients with -DPlt were more likely to respond to TKI therapy and had longer median overall survival. Further investigation is requisite to determine the utility of DPlt as a biomarker for RCC response to TKI.

MP64-15 DETERMINANTS OF RENAL FUNCTIONAL DECLINE AFTER OPEN PARTIAL NEPHRECTOMY: A COMPARISON OF WARM, COLD, AND NON-ISCHEMIC MODALITIES

INTRODUCTION Renal functional decline after partial nephrectomy (PN) may be related to a variety of nonmodifiable and modifiable factors, including ischemia time (IT) and modality. We sought to determine the impact of these factors on renal functional degeneration after PN. MATERIALS AND METHODS Multicenter retrospective analysis (n = 347) was performed, identifying patients who underwent open PN using warm, cold, and non-ischemic techniques. Primary outcome was development of de novo chronic kidney disease (CKD), (estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2), at 1 year follow up. Univariate and multivariable analysis (MVA) were performed examining factors associated with ischemia technique and the development of de novo CKD. RESULTS Median follow up 34.7 months. Two hundred and forty-one patients underwent warm ischemic, 31 cold ischemic, and 75 clampless PN. Patient characteristics were similar between groups. Clampless group had lower mean RENAL scores (6.4) than cold (7.9, p = 0.005) and warm (7, p = 0.037) ischemia groups. Cold ischemia cohort had longer median IT than the warm cohort (50min versus 25 min, p = 0.001). There were no significant differences in proportion of patients developing de novo CKD (warm 14.9%, cold 15%, clampless 8.7%, p = 0.422). MVA demonstrated that neither ischemic modality nor IT ≥ 30 minutes was associated with development of de novo CKD, while RENAL scores of increasing complexity (RENAL score 7-9 OR 4.32, p = 0.003; RENAL score ≥ 10 OR 15.42, p < 0.001) were independently associated with de novo CKD. CONCLUSIONS Increasing tumor complexity, as indicated by the RENAL score, was an overriding determinant of post PN renal functional outcome. Prospective investigation is requisite to elucidate risk and protective factors for renal functional degeneration after PN.

Abstract A43: Novel prostate cancer patient-derived xenograft models of bone metastatic castrate-resistant prostate cancer

Prostate cancer metastasis to bone occurs in 50-90% of men with advanced disease for which there is no cure. Bone metastasis leads to debilitating fractures and severe bone pain. It is associated with disease progression, therapy resistance, poor prognosis, and rapid decline. Androgen ablation therapy is standard of care for advanced prostate cancer, however, the role of androgens in bone metastatic prostate cancer is not understood. The effects of anti-androgens as seen on bone scans can also be inconsistent with the biochemical PSA response. There are few pre-clinical models to understand the interaction between the bone microenvironment and prostate cancer. It is essential to understand the unique interaction of prostate cancer with the bone environment and to develop novel therapies that target these pathways. Here we report the development of novel patient-derived intra-femoral xenograft models of prostate bone metastatic cancer. METHODS: Surgical prostate cancer bone metastasis specimens were transplanted by direct injection into the femurs of Rag2-/-γc-/- mice or sub-cutaneously into the right flank. Patient-derived xenograft (PDX) tumors that grew out were analyzed for prostate cancer biomarker expression using quantitative RT-PCR and immunohistochemistry. Bone lesion formation was measured using micro-computed tomography (μCT). RESULTS: Prostate cancer surgical bone metastasis specimens have been collected from which we have established new serially transplantable, prostate cancer bone metastasis xenograft models – PCSD1, PCSD4 and PCSD5. PCSD1 (Prostate Cancer San Diego 1) was molecularly characterized as advanced, luminal epithelial-type prostate cancer. PCSD1 intra-femoral xenografts formed mixed osteoblastic/osteolytic lesions that closely mimicked those of the patient. Treatment with the anti-androgen, bicalutamide, did not inhibit intra-femoral PCSD1 xenograft growth although there was a decrease in PSA as seen in some patients treated with anti-androgen who had discordant PSA and bone scan tests. CONCLUSION: PCSD1, PCSD4 and PCSD5 are new patient-derived prostate cancer bone metastasis-derived xenograft models. PCSD1 xenograft model closely recapitulates the mixed osteolytic/osteoblastic bone metastatic lesions seen in patients, and we are using it to develop novel therapies for inhibiting prostate cancer growth in the bone-niche. Citation Format: Christina Jamieson, Christina Wu, Amy Strasner, Jason R. Woo, Michelle Muldong, Young B. Jeong, Michael A. Liss, Omer Raheem, Tomonori Yamaguchi, Heather Leu, Deborah Marshall, Sheldon Morris, Nicholas A. Cacalano, Koichi Masuda, Catriona H.M. Jamieson, Anna A. Kulidjian, Christopher J. Kane. Novel prostate cancer patient-derived xenograft models of bone metastatic castrate-resistant prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr A43.