Patrick A. Kenney

Novel ZEB1 expression in bladder tumorigenesis.

What’s known on the subject? and What does the study add?

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.

Integration of surgery and systemic therapy for renal cell carcinoma.

Proper integration of surgery and systemic therapy is essential for improving outcomes in renal cell carcinoma (RCC). There is no current role for adjuvant therapy after nephrectomy for clinically localized disease. The potential benefits of neoadjuvant therapy for locally advanced nonmetastatic disease are in need of further study. In metastatic disease, the proper integration of cytoreductive surgery and systemic therapy remains to be elucidated. Presurgical targeted therapy is feasible and may be beneficial. Pending the results of randomized controlled trials, upfront cytoreductive nephrectomy in appropriate patients will likely continue as the paradigm of choice in metastatic RCC.

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.

Preoperative Pulmonary Embolism Does Not Predict Poor Postoperative Outcomes in Patients with Renal Cell Carcinoma and Venous Thrombus

PURPOSE Patients with renal cell carcinoma who present with pulmonary embolism and venous thrombus may not be offered surgery because of presumed poor postoperative outcomes. In this multicenter study we evaluated perioperative mortality, recurrence and cancer specific survival in patients with renal cell carcinoma and venous thrombus diagnosed with preoperative pulmonary embolism. MATERIALS AND METHODS We reviewed consecutive patient records from our 3 tertiary hospitals to identify patients with renal cell carcinoma and venous thrombus treated with surgery from 2000 to 2011. Univariate and multivariate Cox proportional hazards analysis was used to evaluate whether preoperative pulmonary embolism or other clinical variables were associated with postoperative disease recurrence or cancer specific survival. RESULTS Pulmonary embolism was identified preoperatively in 35 of 782 patients (4.4%) with renal cell carcinoma. Those with pulmonary embolism preoperatively were more likely to have higher level thrombus and higher T stage (p <0.01). No differences were found in other clinical or pathological features between the groups. There was no difference in 90-day mortality in patients diagnosed with pulmonary embolism preoperatively. Of 395 patients without metastasis preoperatively 147 (37.2%) showed metastatic renal cell carcinoma at a median followup of 22 months. There was no difference in the recurrence rate of renal cell carcinoma in patients with pulmonary embolism (p = 0.36). Recurrence in the lung was not more common in patients with vs without pulmonary embolism preoperatively (p = 0.71). Also, preoperative pulmonary embolism was not predictive of worse cancer specific survival (p = 0.58). CONCLUSIONS Preoperative pulmonary embolism is not associated with worse early mortality, recurrence or cancer specific survival in patients with renal cell carcinoma and tumor thrombus.

Identification of Tumor and Invasion Suppressor Gene Modulators in Bladder Cancer by Different Classes of Histone Deacetylase Inhibitors Using Reverse Phase Protein Arrays

PURPOSE We assessed the ability of different classes of histone deacetylase inhibitors to target tumor and invasive suppressor genes in a panel of bladder carcinoma cell lines using reverse phase protein arrays. MATERIALS AND METHODS Three poorly, moderately and highly invasive cell lines were exposed to histone deacetylase inhibitors, trichostatin A, apicidin, valproic acid (Sigma) and MS-275 (AXXORA) for 0 to 36 hours. Lysates were harvested and arrayed in a 10-fold dilution series in duplicate. Data points were collected and analyzed using a concentration interpolation methodology after normalization. RESULTS Protein expression profiles revealed up-regulation of gamma-catenin in highly invasive lines, and alpha-catenin in moderately and highly invasive lines after exposure to all histone deacetylase inhibitors, apicidin and MS-275, respectively. Gelsolin was up-regulated in poorly and moderately invasive lines after exposure to all histone deacetylase inhibitors. Desmoglein was down-regulated in poorly and moderately invasive cell lines by all 4 histone deacetylase inhibitors, in addition to decreased FAK (Transduction Laboratories) expression in moderately and highly invasive lines exposed to valproic acid and MS-275. CONCLUSIONS Different histone deacetylase inhibitor classes have the potential to modulate tumor and invasive suppressor gene expression, identifying histone deacetylase inhibitors as potential therapeutic agents for bladder cancer. Reverse phase protein arrays enable high throughput screening of multiple compounds to assess the expression profile of specific protein groups targeted for therapy.

Mucinous tubular and spindle cell carcinoma (MTSCC) of the kidney: a detailed study of radiological, pathological and clinical outcomes

To characterise the clinical, radiological and histological features of mucinous tubular and spindle cell carcinoma (MTSCC), as well as oncological outcomes.

MP86-17 THE 2017 AMERICAN JOINT COMMITTEE ON CANCER EIGHTH EDITION CANCER STAGING MANUAL: CHANGES IN STAGING GUIDELINES FOR CANCERS OF THE KIDNEY, RENAL PELVIS AND URETER, BLADDER, AND URETHRA

improve risk stratification for patients who are perceived as higher risk. To date, no published studies describe treatment patterns for Veterans following use of genomic tests. This study compares treatment patterns before and after introduction of the GPS assay within 6 VAMCs. METHODS: Men with newly diagnosed, NCCN very low, low, or intermediate risk PCa were eligible. We established treatment patterns in an untested patient cohort by reviewing charts from 2013-2014. From 2015-2016, we introduced the GPS assay within these same VAMCs in a prospective study. Six months after biopsy results, we reviewed charts to establish treatments patterns for both untested and tested Veterans. RESULTS: There were 200 men in the untested cohort and 190 men in the tested cohort. Patient characteristics were similar across groups. AS increased by 12% overall. The largest increase was among patients under age 60 (33% increase). AS increased in all NCCN risk groups with the largest increases in NCCN low risk (16%) and across racial subgroups (11% Caucasian, 16% Black, 20% Other). Veterans exposed to AO showed a small decrease in AS, while Veterans without exposure showed a 19% increase in AS. Median GPS was similar across racial groups and between Veterans exposed and not exposed to AO. CONCLUSIONS: In clinically similar cohorts of untested and tested Veterans, implementation of the GPS assay increased use of AS across all age, risk, and racial groups. The assay showed similar biological risk between Caucasians and Blacks and Veterans exposed and not exposed to AO. GPS may be a useful tool to refine risk assessment of PCa and to increase the already high rates of AS among clinically and biologically low risk patients, regardless of their race and AO exposure. Future studies of Black and AO exposed Veterans, including persistence on AS, are needed confirm these findings.

Nodal disease in the setting of metastatic renal cell carcionoma: Can a lymph node dissection alter outcomes?

386 Background: The impact of lymph node dissection (LND) in patients with metastatic renal cell carcinoma (mRCC) undergoing cytoreductive nephrectomy (CN) is unclear. The aims of this study were to determine the predictive ability of LN status for overall survival (OS) in patients treated with CN in the targeted therapy era and if LND increases the morbidity of CN. METHODS We performed a retrospective review of all patients with mRCC treated with CN at a single institution between 2004-2010. Patients participating in open or unpublished trials were excluded, leaving 173 patients for analysis. LNs >1cm by long axis diameter were considered clinically positive (cN+). OS was calculated using COX proportional hazard regression. Complications were classified using the modified Clavien system. RESULTS Sixty-five (37.6%) patients were clinically node positive (cN+). Median OS was significantly worse for the cN+ patients compared to cN0 patients [17.5 vs 29.1 mos;HR 1.8;(1.3-2.6)]. Clinical node status remained an independent predictor of OS on multivarible analysis (MV) [HR 1.7;CI 1.1-2.7]. LND was performed in 61/65 (93.4%) cN+ patients and in 56/108 (52%) of cN0 patients. Pathologic node positive disease (pN+) was more common in cN+ compared to cN0 patients (75% vs. 23%,p <0.001). pN+ patients had worse median OS than pN0 patients [16.0 v 35.5 mos;HR 2.3(1.5-3.6)]. Among pN+ patients (n=54), complete resection of all identifiable nodal disease was associated with an improved OS compared to patients with unresectable nodal disease (n=4) [16.0 v 5.6 mos;HR 2.9(1.0-8.3)]. On univariate analysis LND patients were more likely to have a post-operative complication (64% vs 43%,p=0.008) and more specifically chylous ascites (12 v 0,p=0.01). Despite this association, LND did not reach statistical significance when MV analysis was performed [OR 1.9;(0.9-3.8)]. CONCLUSIONS Among patients undergoing CN, those with cN+ disease had worse OS. Likewise, pN+ patients have worse OS than pN0 patients. LND is associated with higher morbidity than CN alone. Further efforts are needed to determine removal of pathologic nodes alters the natural history of the disease, and if the benefit offsets the increased morbidity.

Re: Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomised phase 3 trial

bias to invasive stage UTUC in the NU arms (26–67%) compared to EM arms (10–25%), which preclude definitive conclusions on comparative survival outcomes [1]. For low-grade (LG) disease, these studies show that EM may provide effective oncologic control, with 5-yr disease-specific survival (DSS) comparable to NU (80–100%) [1–3]. Although the 5-yr DSS is encouraging, the following factors must be appreciated when considering EM for elective patients: First, it comes at a cost of a high, 5-yr, upper-tract recurrence rate of up to 87% [3]; second, a significant proportion of these recurrences may escape endoscopic control or progress in stage (delayed NU was carried out in 28% to 43% of patients at 10–22 mo); and third, the durability of EM outcomes beyond 5 yr has yet to be determined [1]. There is reasonable evidence that supports EM for highly selected, favourable G1/LG UTUC [1,4]. However, EM of G3/high-grade (HG) UTUC should only be considered for compelling imperative cases, due to the inevitable progression (88%) and poor 5-yr DSS (G3: 32–38%; HG: 69–86%) [1]. Ultimately, NU is the gold standard of care for UTUC, principally due to the high recurrence rate and multiplicity of UTUC and the proven durable outcomes of NU [5].