Evaluation of a genomic classifier in radical prostatectomy patients with lymph node metastasis.

OBJECTIVE: To evaluate the performance of the Decipher test in predicting lymph node invasion (LNI) on radical prostatectomy (RP) specimens. METHODS: We identified 1,987 consecutive patients with RP who received the Decipher test between February and August 2015 (contemporary cohort). In the contemporary cohort, only the Decipher score from RP specimens was available for analysis. In addition, we identified a consecutive cohort of patients treated with RP between 2006 and 2012 at the University of California, San Diego, with LNI upon pathologic examination (retrospective cohort). The retrospective cohort yielded seven, 22, and 18 tissue specimens from prostate biopsy, RP, and lymph nodes (LNs) for individual patients, respectively. Univariable and multivariable logistic regression analyses were used to evaluate the performance of Decipher in the contemporary cohort with LNI as the endpoint. In the retrospective cohort, concordance of risk groups was assessed using validated cut-points for low (<0.45), intermediate (0.45-0.60), and high (>0.60) Decipher scores. RESULTS: In the contemporary cohort, 51 (2.6%) patients had LNI. Decipher had an odds ratio of 1.73 (95% confidence interval, 1.46-2.05) and 1.42 (95% confidence interval, 1.19-1.7) per 10% increase in score on univariable and multivariable (adjusting for pathologic Gleason score, extraprostatic extension, and seminal vesicle invasion), respectively. No significant difference in the clinical and pathologic characteristics between the LN positive patients of contemporary and retrospective cohorts was observed (all P>0.05). Accordingly, among LN-positive patients in the contemporary cohort and retrospective cohort, 80% and 77% had Decipher high risk scores (P=1). In the retrospective cohort, prostate biopsy cores with the highest Gleason grade and percentage of tumor involvement had 86% Decipher risk concordance with both RP and LN specimens. CONCLUSION: Decipher scores were highly concordant between pre- and post-surgical specimens. Further, Decipher scores from RP tissue were predictive of LNI at RP. If validated in a larger cohort of prostate biopsy specimens for prediction of adverse pathology at RP, Decipher may be useful for improved pre-operative staging.

National risk factors and estimated costs for redo ureteroneocystostomy after pediatric renal transplant.

Approximately 800 pediatric renal transplants are performed annually in the United States. VUR or obstruction may cause graft failure requiring redo ureteroneocystostomy. We examined possible risk factors and cost using the PHIS national database. We examined the PHIS for 8.5 yr to determine the association between redo ureteroneocystostomy following pediatric renal transplant to demographics, comorbidities, GU conditions, insurance status, and hospital characteristics, and looked at relative costs using descriptive and comparative statistics. A total of 2390 pediatric renal transplants were identified, of which 69 (2.3%) underwent redo ureteroneocystostomy (median 11.6 months post-transplant). Risk factors for redo ureteroneocystostomy are younger age (p = 0.048), PUVs (p < 0.001), female gender (p = 0.005), race (p = 0.014), insurance type (p < 0.027), region (p = 0.045), and transplant surgery volume (p = 0.048). Redo ureteroneocystostomy after transplant does not significantly increase the overall cost of transplant (p = 0.175). We confirmed previous findings that younger age and PUVs increase the risk of post-transplant redo ureteroneocystostomy, with a five-yr plateau. We found an association with gender, race, insurance status, and hospital characteristics. Redo ureteroneocystostomy, which increases costs, does not statistically significantly increase overall cost of individual treatment in this database, although costs may be underreported.

Does Listening to Music During Office-Based Flexible Cystoscopy Decrease Anxiety in Patients: A Prospective Randomized Trial.

PURPOSE: To validate the effect of listening to music on perceived anxiety and pain during office-based flexible cystoscopy using the State-Trait Anxiety Inventory (STAI) and the Visual Analog Scale (VAS), in a well-matched North American veteran patient population in a prospective, randomized fashion. PATIENTS AND METHODS: A total of 137 veteran patients receiving routine urologic care in a North American Veterans Affairs (VA) healthcare system were recruited over a 2-year period (June 2011 to June 2013). All patients were prospectively randomized to undergo office-based flexible cystoscopy with or without music. The music group consisted of 73 patients who listened to the same excerpt of classical music at the time of flexible cystoscopy; the nonmusic group consisted of 64 patients. RESULTS: The median postprocedural STAI anxiety scores between the music and nonmusic groups were statistically significantly different: 30 (range 23-39) and 35 (range 28-49), respectively (P=0.0017). The median postprocedural pain VAS score between the music and nonmusic groups reached statistical significance: 0 (range 0-1) and 2 (range 1-2), respectively (P<0.0001). The median delta STAI anxiety score was statistically significantly different between the music and nonmusic groups: 0 (range -3-0) and 2 (range 0-4), respectively (P<0.0001). CONCLUSIONS: This study demonstrates that listening to music decreases anxiety and pain associated with flexible cystoscopy in a North American VA patient population. We recommend incorporating music as an effective adjunct to other maneuvers used at the time of flexible cystoscopy to reduce anxiety and pain.

Unclassified mucinous renal cell carcinoma: a rare histopathological entity.

Renal cell carcinoma (RCC) with mucin production is extremely rare. We present the case of a previously healthy 76-year-old woman who underwent a robotic-assisted laparoscopic right nephrectomy for a 5-cm heterogeneously enhancing right renal mass. Pathology revealed mucin-producing epithelial RCC. We discuss the presentation and pathological features of this case and comment on its definitive treatment.

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

INTRODUCTION: Prostate 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. METHODS: PCSD1 bone-niche model was derived from a human prostate cancer femoral metastasis resected during hemiarthroplasty and serially transplanted into Rag2(-/-); γ c(-/-) 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. RESULTS: PCSD1 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. CONCLUSIONS: PCSD1 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.

Incorporating robot-assisted prostatectomy at a Veterans Affairs hospital: outcomes.

PURPOSE: To evaluate a unique method of extended mentorship in robot-assisted laparoscopic prostatectomy (RALP) at VA San Diego Healthcare System (VASDHS). As novel robotic technologies diffuse into surgical practice, developing safe apprenticeships remains a challenge. PATIENTS AND METHODS: Between October 2008 and November 2010, 90 RALPs were prospectively divided into three phases: Proctored, Independent, and Instructor. During the first 30 Proctored cases, an experienced robotic surgeon from the affiliated university-based hospital mentored a robotic novice attending surgeon with previous open retropubic and laparoscopic experience. The novice surgeon gained proficiency during the next 30 Independent cases, then introduced increasing resident participation during the last Instructor 30 cases. Patient demographics, tumor characteristics, operative measures, and length of hospital stay were compared. Functional outcomes were assessed using the Sexual Health Inventory for Men and an incontinence questionnaire. We used independent t test, analysis of variance, Mann-Whitney U test, Fisher exact test, Kruskal-Wallis, and Pearson chi-square tests for comparison in these patient populations. RESULTS: All groups were similar in age, clinical T-stage, and D'Amico Risk Group. Preoperative prostate-specific antigen levels were significantly higher (P<0.001) and prostates were larger (P=0.044) in the middle Instructor Phase. The early Proctored Phase had the lowest Gleason scores and the lowest body mass indexes. Despite these differences favoring the Proctored Phase, immediate operative outcomes were similar with respect to safety, oncologic, and functional parameters. CONCLUSIONS: In the VASDHS cohort, RALPs were performed safely under the supervision of a newly proctored attending surgeon. Although longer follow-up could reveal subtle differences between groups, overall follow-up was similar to most existing studies. Extended mentorship by an experienced surgeon is a viable model for achieving proficiency in RALP in a setting such as a VA hospital affiliated with an academic hospital and increasing access to care for the veteran patient population.

The effect of restrictive bariatric surgery on urolithiasis.

BACKGROUND AND PURPOSE: Roux-en-Y gastric bypass (RYGB) surgery, a mixed malabsorptive/restrictive procedure, is associated with enteric hyperoxaluria and an increased risk of kidney stones. The incidence of nephrolithiasis after purely restrictive bariatric procedures such as adjustable gastric banding or sleeve gastrectomy has not been well described. We aim to analyze the incidence of kidney stones in patients who undergo either adjustable gastric banding or sleeve gastrectomy. PATIENTS AND METHODS: In a retrospective study, we analyzed a pool of 332 patients who underwent adjustable gastric banding and 85 patients who underwent sleeve gastrectomy at the University of California, San Diego Center for the Treatment for Obesity within a 54-month period (September 2006 to February 2011). The primary outcomes of urinary calculus diagnosis and surgical treatment were investigated using manual chart review and International Classification of Diseases and Related Health Problems-9 code electronic search. RESULTS: Within the adjustable gastric banding cohort, we found a person-time incidence rate of 3.40 stone diagnoses per 1000 person-years. Within the sleeve gastrectomy cohort, we found a person-time incidence rate of 5.25 stone diagnoses per 1000 person-years. CONCLUSIONS: Questions remain whether purely restrictive bariatric procedures such as sleeve gastrectomy or adjustable gastric banding avoid the risk of kidney stones. Our study demonstrates a very low incidence of kidney stones after restrictive bariatric procedures, although larger sample sizes, longer follow-up times, and controlled prospective studies are necessary to validate this finding.

IL-7 uniquely maintains FoxP3(+) adaptive Treg cells that reverse diabetes in NOD mice via integrin-ß7-dependent localization.

Type 1 diabetes (T1D) develops as a consequence of a progressive autoimmune response that destroys insulin-producing ß-cells in pancreatic islets. Because of their role(s) in controlling immune responses, considerable effort has been directed toward resolving whether regulatory T cells (Tregs) offer a clinical treatment to restore tolerance in T1D. We previously reported that in vitro-induced adaptive Treg cells (aTregs) can reverse T1D and persist as protective memory cells in the NOD mouse model. In the current study, we investigated mechanisms that regulate aTregs. We found that these FoxP3(+) aTregs expressed high levels of the IL-7 receptor, IL-7Rα, without the high affinity receptor for IL-2, CD25, which is found on natural Treg cells (nTregs). IL-7Rα expression was mirrored by the dependency of aTregs on IL-7 for persistence. IL-10 and TGF-ß, effector cytokines of aTregs, were not essential for their maintenance at the level of systemic antibody blocking. Nevertheless, IL-10 modulated cytokine production by aTregs and TGF-ß was critical for protection. aTregs were found to infiltrate islets and the expression of integrin-ß7 was required for their localization in the pancreas. Furthermore, blocking aTreg entry into the pancreas prevented their control of diabetogenic effector T cells, implying the need for local control of the autoimmune response. The distinct homeostatic regulation of aTregs independently of a response to IL-2, which is defective in T1D patients, suggests that these cells represent a translatable candidate to control the autoimmune response.

Polyclonal adaptive regulatory CD4 cells that can reverse type I diabetes become oligoclonal long-term protective memory cells.

Type 1 diabetes is a CD4 cell-dependent disease that results from destruction of insulin-producing beta cells in pancreatic islets. An ideal therapy would reverse diabetes shortly after onset when islet function in not yet fully ablated, and also prevent re-emergence of disease through the generation of memory cells that control the autoimmune response. In this study, we show that adaptive/induced polyclonal regulatory (TR) cells, which contain islet-reactive cells, fulfill these criteria in the NOD mouse model. CD4 cells induced to express FoxP3, IL-10, and TGF-beta1 in response to TCR signaling and TGF-beta1 can reverse diabetes with clinical restoration of prediabetic serum levels of IL-10. Unlike naturally occurring TR cells, these adaptive TR cells persist indefinitely (>1 year) as FoxP3(+), CD25(-) memory cells that self-renew. Establishment of memory is accompanied by narrowing of the T cell repertoire to usage of a single TCR beta-chain, Vbeta11, implying selection by Ag. With islet-specific adaptive TR cells, we show that memory is functionally stable and transferable. Therefore, adaptive TR cells, which can be readily generated from normal CD4 populations and become focused by Ag with induction of memory, may provide a treatment and a vaccine for the long-term cure of diabetes making them attractive as immunotherapeutic agents.

Adaptive islet-specific regulatory CD4 T cells control autoimmune diabetes and mediate the disappearance of pathogenic Th1 cells in vivo.

Adaptive regulatory T cells that develop from naive CD4 cells in response to exposure to Ag can act as immunotherapeutic agents to control immune responses. We show that effectors generated from murine islet-specific CD4 cells by TCR stimulation with IL-2 and TGF-beta1 have potent suppressive activity. They prevent spontaneous development of type 1 diabetes in NOD mice and inhibit development of pancreatic infiltrates and disease onset orchestrated by Th1 effectors. These regulatory T cells do not require innate CD25+ regulatory cells for generation or function, nor do they share some characteristics typically associated with them, including expression of CD25. However, the adaptive population does acquire the X-linked forkhead/winged helix transcription factor, FoxP3, which is associated with regulatory T cell function and maintains expression in vivo. One mechanism by which they may inhibit Th1 cells is via FasL-dependent cytotoxicity, which occurs in vitro. In vivo, they eliminate Th1 cells in lymphoid tissues, where Fas/FasL interactions potentially play a role because Th1 cells persist when this pathway is blocked. The results suggest that adaptive regulatory CD4 cells may control diabetes in part by impairing the survival of islet-specific Th1 cells, and thereby inhibiting the localization and response of autoaggressive T cells in the pancreatic islets.