Kara N. Babaian

Autotaxin-Lysophosphatidic Acid Signaling Axis Mediates Tumorigenesis and Development of Acquired Resistance to Sunitinib in Renal Cell Carcinoma.

Purpose: Sunitinib is currently considered as the standard treatment for advanced renal cell carcinoma (RCC). We aimed to better understand the mechanisms of sunitinib action in kidney cancer treatment and in the development of acquired resistance. Experimental Design: Gene expression profiles of RCC tumor endothelium in sunitinib-treated and -untreated patients were analyzed and verified by quantitative PCR and immunohistochemistry. The functional role of the target gene identified was investigated in RCC cell lines and primary cultures in vitro and in preclinical animal models in vivo. Results: Altered expression of autotaxin, an extracellular lysophospholipase D, was detected in sunitinib-treated tumor vasculature of human RCC and in the tumor endothelial cells of RCC xenograft models when adapting to sunitinib. ATX and its catalytic product, lysophosphatidic acid (LPA), regulated the signaling pathways and cell motility of RCC in vitro. However, no marked in vitro effect of ATX-LPA signaling on endothelial cells was observed. Functional blockage of LPA receptor 1 (LPA1) using an LPA1 antagonist, Ki16425, or gene silencing of LPA1 in RCC cells attenuated LPA-mediated intracellular signaling and invasion responses in vitro. Ki16425 treatment also dampened RCC tumorigenesis in vivo. In addition, coadministration of Ki16425 with sunitinib prolonged the sensitivity of RCC to sunitinib in xenograft models, suggesting that ATX-LPA signaling in part mediates the acquired resistance against sunitinib in RCC. Conclusions: Our results reveal that endothelial ATX acts through LPA signaling to promote renal tumorigenesis and is functionally involved in the acquired resistance of RCC to sunitinib. Clin Cancer Res; 19(23); 6461–72. ©2013 AACR.

Clinically nonmetastatic renal cell carcinoma with sarcomatoid dedifferentiation: Natural history and outcomes after surgical resection with curative intent

PURPOSE Renal cell carcinoma with sarcomatoid dedifferentiation (sRCC) is an aggressive malignancy associated with a poor prognosis. Although existing literature focuses on patients presenting with metastatic disease, characteristics and outcomes for patients with localized disease are not well described. We aimed to evaluate postnephrectomy characteristics, outcomes, and predictors of survival in patients with sRCC who presented with clinically localized disease. PATIENTS AND METHODS An institutional review board-approved review from 1986 to 2011 identified 77 patients who presented with clinically localized disease, underwent nephrectomy, and had sRCC in their primary kidney tumor. Clinical and pathologic variables were captured for each patient. Overall survival (OS) and recurrence-free survival (RFS) were calculated for all patients and those who had no evidence of disease (NED) following nephrectomy, respectively. Comparisons were made with categorical groupings in proportional hazards regression models for univariable and multivariable analyses. RESULTS OS for the entire cohort (n = 77) at 2 years was 50%. A total of 56 (77%) patients of the 73 who has NED following nephrectomy experienced a recurrence, with a median time to recurrence of 26.2 months. On multivariable analysis, tumor stage, pathologically positive lymph nodes, and year of nephrectomy were significant predictors of both OS and recurrence-free survival. Limitations include the retrospective nature of this study and relatively small sample size. CONCLUSIONS Long-term survival for patients with sRCC, even in clinically localized disease, is poor. Aggressive surveillance of those who have NED following nephrectomy is essential, and further prospective studies evaluating the benefit of adjuvant systemic therapies in this cohort are warranted.

Preoperative Predictors of Pathological Lymph Node Metastasis in Patients with Renal Cell Carcinoma Undergoing Retroperitoneal Lymph Node Dissection

PURPOSE Patients with locally advanced renal cell carcinoma represent a subset that may benefit from retroperitoneal lymph node dissection. We identified preoperative clinical predictors of positive lymph nodes in patients with renal cell carcinoma without distant metastasis who underwent retroperitoneal lymph node dissection. MATERIALS AND METHODS We retrospectively analyzed data on a consecutive cohort of 1,270 patients with cTany Nany M0 renal cell carcinoma who were treated at a single institution from 1993 to 2012. Multivariate analysis was performed to determine preoperative predictors of pathologically positive lymph nodes in patients who underwent retroperitoneal lymph node dissection. A nomogram was developed to predict the probability of lymph node metastasis. Overall, cancer specific and recurrence-free survival was estimated using the Kaplan-Meier Method. RESULTS We identified 1,270 patients with renal cell carcinoma without distant metastasis who had (564) or did not have (706) retroperitoneal lymph node dissection performed. Of the 564 patients 131 (23%) and 433 (77%) had pN1 and pN0 disease, and 60 (37%) and 29 (7.2%) had cN1pN0 and cN0pN1 disease, respectively. ECOG PS, cN stage, local symptoms and lactate dehydrogenase were associated with nodal metastasis on multivariable analysis. A nomogram was developed with a C-index of 0.89 that demonstrated excellent calibration. Differences in overall, cancer specific and recurrence-free survival among pNx, pN0 and pN1 cases were statistically significant (p <0.001). CONCLUSIONS Local symptoms, ECOG PS, cN stage and lactate dehydrogenase were independent predictors of lymph node metastasis in patients who underwent retroperitoneal lymph node dissection. Our predictive nomogram using these factors showed excellent discrimination and calibration.

Clinical Outcomes of Patients With Nondiagnostic Biopsy During Cryoablation of Small Renal Masses

OBJECTIVE To compare the outcomes of patients with biopsy-proven renal cell carcinoma (RCC), benign tumors (BTs), and nondiagnostic (ND) biopsies after renal cryoablation (RC). METHODS We retrospectively reviewed medical records of 114 patients who underwent RC between 2003 and 2013. Patients were stratified according to biopsy histopathology results-RCC, BT, and ND biopsy. We recorded patient demographics and tumor features and examined oncologic outcomes among the 3 groups. RESULTS RC was performed in 114 patients with 117 tumors. Seventy-two tumors (61.5%) were RCC, 18 (15.4%) were BTs (oncocytoma or angiomyolipoma), and 27 (23.1%) were ND. Patient characteristics and tumor features were similar among the 3 groups. The median follow-up was 26.5, 26.0, and 22.0 months in the RCC, BT, and ND biopsy groups, respectively (P = .18). Residual disease occurred in the RCC (1.4%) and ND biopsy (7.4%) groups, but not in the BT group (P = .19). All 9 patients (12.5%) who developed recurrent disease had biopsy-proven RCC. The 2- and 5-year recurrence-free survival rates (RFS) for patients with biopsy-proven RCC were 90.2% and 81.2%, respectively. Because no patient in the BT and ND biopsy groups had a recurrence, their RFS was 100%. CONCLUSION No patient with a BT or ND biopsy developed a local recurrence with short-term follow-up, whereas a recurrence developed in 12.5% of biopsy-proven RCC tumors. RFS for patients with biopsy-proven RCC was worse than the other 2 biopsy groups, although not statistically significant. Long-term follow-up in a larger cohort of patients is needed to further evaluate these preliminary findings.

Analysis of Improved Urinary Peak Flow Rates After Robot-Assisted Radical Prostatectomy

PURPOSE Longitudinal assessment of prostatic obstruction has historically been assessed with urinary peak flow rates (PFR). In this observational study, we assess the impact of prostate removal on preoperative and postoperative PFRs after robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS A single surgeon (TA) performed RARPs between 2002 and 2007. Men underwent routine preoperative uroflowmetric testing: 550 qualified for analysis with a sufficient voided volume (VV) of 150 mL preoperatively and at least once postoperatively. Continence and self-assessed American Urological Association (AUA) symptom and urinary quality of life (QoL) questionnaires were queried. Uroflows were analyzed preoperatively, short-term (3-15 mos), long-term (>2 y), and by age decades, lower urinary tract symptoms (LUTS) groups, and pathologic weight cohorts. RESULTS AUA and QoL scores improved from 8.1 and 1.6 at baseline to 4.4 and 1.0 at intermediate-term follow-up, P<0.01. Mean PFRs improved from a baseline 18.0 mL/s to 28.3, 30.8, and 36.5 at 3 months, 9 months, and >5 years follow- up (all P<0.001). Postvoid residual (PVR) volumes declined from 99 mL preoperatively to 24 mL at >5 years (P<0.01). Likewise, all age, LUTS, and prostate weight cohorts had significant improvements in PFR and PVR and stable voided volumes throughout the study. CONCLUSION The natural history of prostatic obstruction for men 40 to 80 years typically reveals reduction of mean PFRs. We observed that removal of the prostate resulted on average with a near doubling of PFRs and decreased PVRs (>50%) by 3 months. After RARP, the average PFR was reset to 25-30 mL/s, and these results were seen across all age, LUTS, and prostate weight groups; the gains remained stable 2 to 4 years after operation.

PARTIAL NEPHRECTOMY IN THE SETTING OF METASTATIC RENAL CELL CARCINOMA

PURPOSE Cytoreductive nephrectomy remains the standard of care for appropriately selected patients with metastatic renal cell carcinoma. Although the role of partial nephrectomy is well accepted in patients with localized disease, limited data are available on partial nephrectomy in the metastatic setting. We identified the indications for and outcomes of partial nephrectomy in the setting of metastatic renal cell carcinoma with particular attention to partial nephrectomy subgroups. MATERIALS AND METHODS We analyzed data on a consecutive cohort of 33 patients with metastatic renal cell carcinoma who underwent partial nephrectomy at a single institution between 1996 and 2011. Nonparametric statistics were used to compare partial nephrectomy subgroups. Overall survival was estimated using the Kaplan-Meier method and survival functions were compared using the log rank test. RESULTS At presentation 8 patients had bilateral synchronous renal masses, 20 had a metachronous contralateral renal mass and 5 had a unilateral renal mass. A total of 22 patients (67%) died of disease a median of 27 months postoperatively. Patients who underwent partial nephrectomy for a metachronous contralateral renal mass and a renal mass 4 cm or less had the best overall survival (61 and 42 months, respectively). Median overall survival in patients with vs without metastatic disease at original diagnosis was 27 vs 63 months (p = 0.003). CONCLUSIONS Our findings suggest that metastasis at the original diagnosis and the timing of presentation of the partial nephrectomy index lesion have an important role in survival. These factors should be considered when determining which patients would benefit from partial nephrectomy in the setting of metastatic renal cell carcinoma.

Active surveillance for prostate cancer: when to recommend delayed intervention

There are no agreed upon guidelines for placing patients on active surveillance (AS). Therefore, there are no absolute criteria for taking patients off AS and when to recommend treatment. The criteria used to define progression are currently based on prostate specific antigen (PSA) kinetics, biopsy reclassification, and change in clinical stage. Multiple studies have evaluated predictors of progression such as PSA, PSA density (PSAD), prostate volume, core positivity, and visible lesion on multiparametric magnetic resonance imaging (mpMRI). Furthermore, published nomograms designed to predict indolent prostate cancer do not perform well when used to predict progression. Newer biomarkers have also not performed well to predict progression. These findings highlight that clinical and pathologic variables are not enough to identify patients that will progress while on AS. In the future, with the use of imaging, biomarkers, and gene expression assays, we should be better equipped to diagnose/stage prostate cancer and to distinguish between insignificant and significant disease.

Diminished long-term recovery of peak flow rate (PFR) after robotic prostatectomy in men with baseline PFR <10 mL/s and incidental association with high-risk prostate cancer

The aim of this study was to evaluate the effects of robot‐assisted radical prostatectomy (RARP) on uroflowmetry (UF) parameters among men with baseline peak flow rates (PFR) <10 mL/s.

Partial nephrectomy in the setting of metastatic renal cell carcinoma.

440 Background: Up to one-third of patients with renal cell carcinoma present with metastatic disease (mRCC). Cytoreductive nephrectomy remains the standard of care for appropriately selected patients. However, cytoreductive nephrectomy is not always practical. We sought to identify the indications and outcomes for partial nephrectomy (PN) in our cohort of patients with mRCC, with particular attention to different PN subgroups. METHODS Using our institutional database, 30 patients with mRCC who underwent PN between 1996 and 2011 were identified. Demographic, clinical, and pathologic variables were collected. Non-parametric statistics and log-rank tests were used. Cancer specific survival (CSS) was estimated using Kaplan-Meier method according to presentation, tumor size, and presence of metastatic disease, from the time of PN to last follow-up or death. RESULTS The median age at PN was 57 years (range 32-84). 8 patients presented with bilateral synchronous renal masses; 17 presented with a metachronous contralateral renal mass; and 5 presented with a unilateral renal mass (including 3 in a solitary kidney). Median follow-up after PN was 32 months (range 1-184). Overall, 23 patients (77%) died of disease at a median of 27 months (range 7-86) after PN. Patients who underwent PN for a metachronous contralateral renal mass had a median CSS of 61 months compared to those with bilateral synchronous or unilateral renal masses (CSS 26.5 months, HR 2.98, p =.012 and CSS 31, HR 2.12, p =.069, respectively). Patients who underwent PN for a renal mass ≤4cm and >4cm had a median CSS of 42 and 26.5 months, respectively (HR 2.49, p =.037). Median CSS for patients with and without metastatic disease at original diagnosis was 27 and 61 months, respectively (HR 2.85, p =.013). In this study, patients who became M0 after metastasectomy did not have improved CSS compared to patients who did not (42 and 32 months, p =0.152). CONCLUSIONS Our findings suggest that the burden of disease at initial diagnosis, timing of presentation of the PN index lesion, and the size of the renal mass at PN play an important role in survival. These factors should be taken into consideration when determining which patients would benefit from PN in the setting of mRCC.

Characteristics and clinical outcomes of patients with renal cell carcinoma with sarcomatoid dedifferentiation (sRCC).

401 Background: sRCC is an aggressive subset of renal cell carcinomas that is associated with poor prognosis. We describe clinical and pathological characteristics and outcomes of the largest single-institutional cohort of patients with sRCC who underwent nephrectomy. METHODS Data were collected from 1986 to 2011 for patients identified as having sRCC. 221 patients with complete data who underwent a radical or partial nephrectomy and had a sarcomatoid component in the primary kidney tumor were included in the analysis. Clinical and pathologic variables were reviewed and Kaplan-Meier curves were used to compare differences in overall survival. RESULTS Mean age at diagnosis was 57 years and median tumor size was 11 cm (range 1.5-27.0 cm). 93% of patients were symptomatic at presentation and 96% had an ECOG performance status of 0 or 1. 12 patients had a preoperative biopsy that showed sRCC. 75% of patients were pT3 or higher at time of nephrectomy and 69% presented with metastatic disease. Of these, 11.8% had radiographic evidence of regional nodal involvement alone and 88.2% had distant metastatic disease. The associated epithelial component was clear cell in 72% of the patients, papillary in 12.7% and chromophobe in 3.1%. 29 patients received presurgical systemic therapy, while 161 patients received postoperative systemic therapy. During a median follow-up of 20.5 months, 187 patients (84%) died. Overall survival for the entire cohort at 1 year was 48%. Overall 1-, 2-, and 3-year survival rates for patients with metastatic disease at presentation versus no metastatic disease were 36, 20, and 16% versus 74, 51, and 44% respectively (p < 0.001). Patients with clear cell RCC epithelial component had a survival advantage over those with non-clear cell components with 1-, 2-, and 3-year survival rates of 52, 34, and 31% versus 38, 19, and 12% (p = 0.0057). CONCLUSIONS The majority of patients with sRCC who underwent nephrectomy present with metastatic disease and outcomes are dismal despite surgical intervention and multimodal therapy. Overall survival is better for patients who present without metastatic disease and have clear cell histology at time of nephrectomy.