Implementation of a health system intervention to reduce time from presentation to surgical intervention for pediatric testicular torsion.

PURPOSE: Testicular salvage rates for torsion are time-dependent1. Door to detorsion time has been identified as an independent testicular survival factor2. We describe an initiative to reduce door to incision (DTI) time for pediatric testicular torsion. MATERIALS AND METHODS: An institutional multidisciplinary quality improvement initiative with a primary outcome of reducing DTI time for pediatric testicular torsion was developed with multidisciplinary stakeholders. Several process and balancing measures were used as secondary outcomes to help interpret and verify the observed change in DTI time. Interventions were implemented in cycles. Initial interventions standardized assessment of suspected torsion by Emergency Medicine utilizing a validated scoring system. A threshold Testicular Workup for Ischemia and Suspected Torsion (TWIST) score led to parallel notification of essential services for rapid assessment and case prioritization3. Subsequently, bedside ultrasound in the Emergency Department was implemented. Progress was tracked in a live dashboard and analyzed with X-mR process control charts and Nelson rules. These tools are used in quality improvement and process control to demonstrate the significance of changes as they are being implemented, prior to when traditional hypothesis testing would be able to do so. We aimed to increase the proportion of cases with DTI times under 4 h from 64% to >90% within one year. RESULTS: We observed 22 torsion cases prior to and 62 following initial implementation. The percentage of cases with DTI times under 4 h improved from 64% to 95%. At week 29, a shift identified a significant change on the X chart, with reduction in mean DTI time from 221 to 147 min. At the same time, a shift on the mR chart identified reduction in patient-to-patient variation. Mean time from arrival to Urology evaluation decreased from 140 to 56 min, mean time from arrival to scrotal ultrasound decreased from 70 to 36 min, and mean time from scrotal ultrasound to surgical incision decreased from 128 to 80 min. These improvements highlight the two key successes of our project: application of the TWIST score and bedside ultrasound for rapid assessment of suspected testicular torsions, and parallel processing of the evaluation and management. CONCLUSIONS: Implementation of a protocol for pediatric testicular torsion increased the proportion of cases with DTI time <4 h to 95%, decreased mean DTI time, and decreased variation. Our protocol provides a model to improve timeliness of care in treating pediatric testicular torsion.

Association Between Private Equity Acquisition of Urology Practices and Physician Medicare Payments.

OBJECTIVE: To assess whether private equity (PE) acquisitions of urology practices were associated with changes in Medicare payments and patient volume. METHODS: We identified PE acquisitions of urology practices through financial databases, industry news outlets, practice websites, and Google search. Using the Centers for Medicare and Medicaid Service's Medicare Provider Utilization and Payment Data: Physician and Other Supplier Public Use File (2012-2019), we conducted descriptive statistics and trends analysis to examine whether PE acquisition was associated with changes in Medicare payments and patient volume in comparison to non-PE affiliated urologists within the same states. RESULTS: We identified PE acquisitions of 10 independent urology practices across 6 states during the study period. In the preacquisition period, urologists later joining private-equity groups received greater mean inflation-adjusted Medicare payments ($246,977 vs $160,038; P <.001) and had greater patient volume (839.7 vs 674.2 patients; P = .001) than urologists who did not. In the postacquisition period, PE affiliated urologists had an 11.0% (95% CI: -0.2% to 22.3%) increase in inflation-adjusted Medicare payments (P = .054) and a 12.5% (95% CI: 6.5%-18.6%) increase in patient volume (P <.001). Non-PE affiliated urologists exhibited a 6% decline in Medicare payments (P <.001) and a 2.7% increase in patient volume (P <.001). CONCLUSION: PE affiliated urologists exhibited increases in Medicare payments even prior to acquisition, in contrast to declines for geographically similar, non-PE urologists. These findings may highlight characteristics of practices targeted by PE firms and local practice trends that may further diverge following acquisition.

Vesical clear cell adenocarcinoma of Müllerian origin treated conservatively with partial cystectomy.

A 71-year-old woman presented with an intravesical bladder mass found to be a clear cell adenocarcinoma of Müllerian origin with positive PAX-8 staining after transurethral resection. Partial cystectomy along with total hysterectomy were performed, and final pathology revealed no residual tumour and extensive endometriosis. She declined adjuvant therapy and was dispositioned to surveillance.

Hydrogen peroxide vapor decontamination of N95 respirators for reuse.

OBJECTIVE: The coronavirus disease 2019 (COVID-19) pandemic has led to global shortages of N95 respirators. Reprocessing of used N95 respirators may provide a higher filtration crisis alternative, but whether effective sterilization can be achieved for a virus without impairing respirator function remains unknown. We evaluated the viricidal efficacy of Bioquell vaporized hydrogen peroxide (VHP) on contaminated N95 respirators and tested the particulate particle penetration and inhalation and exhalation resistance of respirators after multiple cycles of VHP. METHODS: For this study, 3M 1870 N95 respirators were contaminated with 3 aerosolized bacteriophages: T1, T7, and Pseudomonas phage phi-6 followed by 1 cycle of VHP decontamination using a BQ-50 system. Additionally, new and unused respirators were sent to an independent laboratory for particulate filter penetration testing and inhalation and exhalation resistance after 3 and 5 cycles of VHP. RESULTS: A single VHP cycle resulted in complete eradication of bacteriophage from respirators (limit of detection 10 PFU). Respirators showed acceptable limits for inhalation/exhalation resistance after 3 and 5 cycles of VHP. Respirators demonstrated a filtration efficiency >99 % after 3 cycles, but filtration efficiency fell below 95% after 5 cycles of HPV. CONCLUSION: Bioquell VHP demonstrated high viricidal activity for N95 respirators inoculated with aerosolized bacteriophages. Bioquell technology can be scaled for simultaneous decontamination of a large number of used but otherwise intact respirators. Reprocessing should be limited to 3 cycles due to concerns both about impact of clinical wear and tear on fit, and to decrement in filtration after 3 cycles.

Urology Practice Acquisitions by Private Equity Firms from 2011-2021.

INTRODUCTION: Private equity firms have recently acquired several large urology practices in the United States. As little is known about these acquisitions, we sought to characterize trends in urology practice consolidation. METHODS: We compiled urology practice acquisition data via financial databases, news outlets, practice websites, and Internet keyword search for the time period January 1, 2011 through March 15, 2021. For each acquisition, we determined the acquiring group, number of employed urologists, practice locations, and status of ancillary services (pathology, radiology, or surgery centers). We estimated workforce effects based on the 2019 American Urological Association workforce census. RESULTS: We identified 69 independent practice acquisitions in the study period, including 19 (28.4%) by hospital systems, 7 (10.4%) by multispecialty physician groups, 23 (34.3%) by urology practices, and 20 (29.9%) by private equity-backed platforms. Private equity firms initially targeted large urology practices (mean of 60.8±32.6 urologists) with ownership of ancillary services and consolidated local market share through acquisitions of smaller practices (mean of 15.9±14.5 urologists). As of March 2021, we estimate that 7.2% of private practice urologists in the U.S. were employed by one of 5 private equity-backed platforms; over 25% of all urologists practicing in New Jersey and Maryland are employed by a private equity-backed platform. CONCLUSIONS: Private equity acquisitions have accelerated to become a dominant form of urology practice consolidation in recent years and have achieved significant market influence in certain regions. Future research should assess the impact of private equity investment on practice patterns, health outcomes, and expenditures.

Cachexia and bladder cancer: clinical impact and management.

PURPOSE OF REVIEW: The purpose of this review is to describe the causes, management, and clinical outcomes associated with cachexia and related components including sarcopenia, among patients with bladder cancer (BCa). RECENT FINDINGS: Cachexia in patients with BCa is associated with poorer outcomes after radical cystectomy (RC), radiation, and chemotherapy. Nutritional supplements and novel pharmaceutical agents including magnolol, flucoidan and Anamorelin are currently undergoing investigation for their potential use in BCa patients with cachexia. SUMMARY: Cachexia is a hypercatabolic state thought to be caused by an immune-regulated release of cytokines and disruptions of molecular pathways within the tumor microenvironment and systemically. Nutritional deficiencies in patients with BCa also contribute to cachexia and sarcopenia. Patients with BCa -related cachexia and sarcopenia experience worse survival and therapeutic outcomes after RC, chemotherapy, and radiation therapy. Patients with cachexia also experience more postoperative complications after RC. The management of cachexia in patients with BCa remains challenging and requires timely identification, and multidisciplinary management including nutritional supplementation, physical therapy, palliative care, and pharmacological agents. Clinical trials and human studies are still required to determine which pharmacological agents are optimal for BCa cachexia.

Access to Urologic Care at Urgent Care Centers.

OBJECTIVE: To evaluate Medicaid insurance access disparities for urologic care at urgent care centers (UCCs) in the United States. MATERIALS AND METHODS: We conducted a cross-sectional study using a "secret shopper" methodology. We sampled 240 UCCs across 8 states. Using a standardized script, researchers posed as a patient with either Medicaid or commercial insurance in the clinical setting of obstructing nephrolithiasis. The primary study endpoint was whether a patient's insurance (Medicaid vs commercial) was accepted. We assessed factors associated with Medicaid acceptance using logistic regression models adjusted for state-level and facility-level characteristics. Additionally, we calculated triage rates, emergency department referral rates, and the ability of a UCC to refer the patient to a specialist. RESULTS: Of 240 UCCs contacted, 239 (99.6%) accepted commercial insurance and 159 (66.2%) accepted Medicaid. UCCs in Medicaid expansion states more frequently accepted patients with Medicaid insurance (74.2% vs 58.3%, respectively, P < .01). On multivariable logistic regression analysis, state Medicaid expansion (OR 1.84, 95% CI 1.04-3.26, P = .04) and affiliation with an institution (OR 2.97, 95% CI 1.59-5.57, P < .01) were independently associated with greater odds of accepting Medicaid. Medicaid-insured patients were significantly less likely to be triaged or referred to the emergency department compared to commercial patients. CONCLUSION: We identified significant disparities in access to UCCs for Medicaid patients presenting with a urologic condition. Given the expanding national role of UCCs, these findings highlight potential sources of insurance disparity in the context of a urologic emergency.

Incidence, risk factors, and outcome of Clostridioides difficile infection following urological surgeries.

PURPOSE: To assess the incidence, risk factors, and clinical outcomes associated with (Clostridioides difficile infection) CDI following urological surgery, which is the leading cause of nosocomial diarrhea and a growing public health burden. METHODS: We queried the National Surgical Quality Improvement Program (NSQIP) to identify patients undergoing urological surgery in 2015-2016. We evaluated the 30-day incidence and factors associated with postoperative CDI and 30-day hospital readmission and length of stay as secondary outcomes. Among the subset of patients undergoing radical cystectomy with urinary diversion (surgery with highest CDI incidence) we used multivariable logistic regression analysis to evaluate independent clinical and demographic factors associated with postoperative CDI. RESULTS: We identified 98,463 patients during the study period. The overall 30-day incidence of CDI was 0.31%, but varied considerably across surgery type. The risk of CDI was greatest following radical cystectomy with urinary diversion (2.72%) compared to all other urologic procedures (0.19%) and was associated with increased risk of hospital readmission (p < 0.0001), re-operation (p < 0.0001), and longer mean length of stay (p < 0.0001) in this cohort. Among patients undergoing radical cystectomy with urinary diversion, multivariable logistic regression revealed that preoperative renal failure (OR: 5.30, 95% CI 1.13-24.9, p = 0.035) and blood loss requiring transfusion (OR: 1.67, 95% CI 1.15-2.44, p = 0.0075) were independently associated with CDI. CONCLUSIONS: In a nationally representative cohort, the incidence of CDI was low but varied substantially across surgery types. CDI was most common following radical cystectomy and associated with potentially modifiable factors such as blood transfusion and significantly longer length of stay.

Association Between Twitter Reception at a National Urology Conference and Future Publication Status.

BACKGROUND: Social media is an increasingly popular means to disseminate medical research. However, it is unknown whether the extent to which content is shared mirrors conventional measures of scientific merit or impact. OBJECTIVE: To examine whether Twitter activity (as measured by the number of "likes" and "retweets" [RTs]) relating to original research presented at a national urology meeting was associated with subsequent publication status and journal impact factor (IF). DESIGN, SETTING, AND PARTICIPANTS: We retrospectively reviewed Twitter data obtained through the Keyhole archiving platform using the hashtag "#aua15" from May 1 through June 1, 2015 reflecting the hashtag of the American Urological Association (AUA) meeting. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We analyzed all posts containing keywords related to research studies. Among posts reporting on newly presented studies with discernable attribution, we evaluated subsequent publication status within 45 mo, including journal IF. We compared social media reception (number of likes/RTs) by publication status, and assessed the relationship between social media reception and subsequent journal IF using Pearson's correlation. RESULTS AND LIMITATIONS: A total of 15 303 posts were associated with #aua15 between May 1 and June 1, 2015, which reached 2 263 438 users. The median number of likes/RTs was 2 (interquartile range 1-3). We analyzed all posts receiving at least one like/RT (n = 2964) for text content related to research and identified 496 associated with new scientific studies presented at the meeting. Forty-five months following the AUA meeting, 96 studies were identifiable on PubMed (19.4%). Research with more likes/RTs at the AUA meeting were more likely to be subsequently published (p = 0.001). Among published studies, there was a modest, positive correlation between the number of likes/RTs and publication journal IF (r2 = 0.36). CONCLUSIONS: Measures of social media engagement with data presented at a national medical meeting were positively correlated with subsequent publication and journal IF after presentation. PATIENT SUMMARY: New urological research that was shared more often at a national meeting was more likely to be published in journals that are more highly cited.

Redefining the Role of Surgical Management of Metastatic Renal Cell Carcinoma.

PURPOSE OF REVIEW: The treatment landscape for metastatic renal cell carcinoma (mRCC) continues to evolve with ongoing advancements in systemic therapy, raising further questions about the optimal role of surgery in the management of mRCC. Herein, we provide a context and review of the recent evidence concerning the role of surgical therapy for patients with mRCC including cytoreductive nephrectomy and distant metastatectomy. RECENT FINDINGS: One randomized trial has been published in the targeted therapy era suggesting that initial systemic therapy is non-inferior to cytoreductive nephrectomy among patients with intermediate and poor-risk mRCC. Delaying cytoreductive nephrectomy until after systemic therapy may be a viable treatment approach, although a high level of evidence is lacking. Additional questions remain regarding the sequence of surgery with systemic therapy, utility of distant metastatectomy, as well as the application of these findings to the current generation of immunotherapy. Recent evidence challenges the need of upfront cytoreductive nephrectomy for unselected patients with mRCC. However, surgical therapy continues to play an important role in the management of the disease.

Outcomes for urologic oncology procedures: are there differences between academic and community hospitals?

OBJECTIVE: To compare the rate of hospital-based outcomes including costs, 30-day readmission, mortality, and length of stay in patients who underwent major urologic oncologic procedures in academic and community hospitals. METHODS: We retrospectively reviewed the Vizient Database (Irving, Texas) from September 2014 to December 2017. Vizient includes ~ 97% of academic hospitals (AH) and more than 60 community hospitals (CH). Patients aged ≥ 18 with urologic malignancies who underwent surgical treatment were included. Chi square and Student t tests were used to compare categorical and continuous variables, respectively. RESULTS: We identified a total of 37,628 cases. There were 33,290 (88%) procedures performed in AH and 4330 (12%) in CH. These included prostatectomy (18,540), radical nephrectomy (rNx) 8059, partial nephrectomy (pNx) (5287), radical cystectomy (4421), radical nephroureterectomy (rNu) (1006), and partial cystectomy (321). There were no significant differences in 30-day readmission rates or mortality for any procedure between academic and community hospitals (Table 1), p > 0.05 for all. Length of stay was significantly lower for radical cystectomy and prostatectomy in AH (p < 0.01 for both) and lower for rNx in CH (p = 0.03). The mean direct cost for index admission was significantly higher in AH for rNx, pNx, rNu, and prostatectomy. Case mix index was similar between the community and academic hospitals. CONCLUSION: Despite academic and community hospitals having similar case complexity, direct costs were lower in community hospitals without an associated increase in readmission rates or deaths. Length of stay was shorter for cystectomy in academic centers.

Bacille Calmette-Guérin Supply Disruption Emphasizes the Importance of Stewardship / La interrupción del suministro de bacilo de Calmette-Guérin subraya la importancia de la administración

Since the original trial published by Morales et al in 1976, intravesical Bacille Calmette-Guérin (BCG) has been a centerpiece in non-muscle invasive bladder cancer (NMIBC) treatment, with a rigorous induction and maintenance regimen shown to decrease cancer recurrence and progression.[1] [2] More than 50% of the 81,000 new cases of bladder cancer that are diagnosed each year in the United States (US) (550,000 in the world) are NMIBCs, and it is clear that effective and timely treatments like BCG are essential and must be readily available.

Desde el ensayo original publicado por Morales et al en 1976, el Bacilo de Calmette-Guérin (BCG) intravesical ha sido una pieza central en el tratamiento del cáncer de vejiga no músculo-invasivo (CCNMI), con un régimen riguroso de inducción y mantenimiento que ha demostrado disminuir la recurrencia y progresión del cáncer [1] [2]. [1] [2] Más del 50% de los 81.000 nuevos casos de cáncer de vejiga que se diagnostican cada año en Estados Unidos (550.000 en el mundo) son CCNMI, y está claro que los tratamientos eficaces y oportunos como el BCG son esenciales y deben estar fácilmente disponibles.

Robotic-assisted laparoscopic versus open salvage radical prostatectomy following radiotherapy.

INTRODUCTION: To describe immediate perioperative outcomes of robot-assisted laparoscopic salvage radical prostatectomy for recurrent cancer following radiation therapy, and compare outcomes to a contemporary open surgical cohort. MATERIALS AND METHODS: A total of 39 patients underwent salvage radical prostatectomy with pelvic lymphadenectomy (20 robotic, 19 open) for local recurrence following radiation therapy at a single institution between 2007 and 2011. Intraoperative parameters, postoperative complications, and oncological outcomes, were recorded. Wilcoxon rank-sum test and Fisher's exact test were used for comparison of continuous and categorical variables respectively. Mean values of numeric variables are reported with standard deviation. RESULTS: The cohorts were similar with respect to age, ethnicity, and American Society of Anesthesiologists Score classification. Estimated blood loss was lower in the robotic group versus the open group (381.3 mL versus 865.0 mL, p = 0.001). There was no difference in the rate of intraoperative complications, postoperative Clavien = 3 complications (30% versus 15.7%), anastomotic leak (40% versus 42.1%), or wound infection (0% versus 15.7%) in the robotic and open groups. Mean node yield (10.4 versus 11.8), positive surgical margins (15.0% versus 15.7%), and undetectable prostate-specific antigen rate (78% versus 60%) were also similar between the robotic and open groups. CONCLUSIONS: Robotic salvage prostatectomy appears to have no significant difference to the open approach with respect to safety and surgical quality as measured by complications, node yield and surgical margins in this retrospective single-institution series.

Prediction of Pulmonary Metastasis in Renal Cell Carcinoma Patients with Indeterminate Pulmonary Nodules.

BACKGROUND: Indeterminate pulmonary nodules (IPN) are of uncertain significance in patients with renal cell carcinoma. OBJECTIVE: We sought to determine predictors of IPN progression to pulmonary metastasis and develop a tool for individualized risk stratification of patients who present with IPN on preoperative chest imaging in the setting of localized or locally advanced renal cell carcinoma. DESIGN, SETTING, AND PARTICIPANTS: We reviewed all patients who had radical nephrectomy with no evidence of distant metastases at a single institution from 2005-2009 who had ≥1 IPN on chest computed tomography that measured <2 cm. All chest computed tomographies were rereviewed by a radiologist who was blinded to outcomes, to independently determine number, size, and location of nodules. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary objective of the study was to develop a prognostic model to predict pulmonary metastases among radical nephrectomy patients who present with IPN based on readily available preoperative imaging and postoperative pathological criteria. Univariable and multivariable Cox regression models were used to assess the predictive factors for development of pulmonary metastasis. We developed a nomogram that predicted the 3-yr and 5-yr lung metastasis-free survival (LMFS), with assessment of discrimination and internal validation. RESULTS AND LIMITATIONS: Among 251 patients with IPN who underwent nephrectomy, 72 (29%) developed pulmonary metastases. Median follow-up for the cohort was 36.6 mo. Three-yr and 5-yr probability of LMFS for the overall cohort was 71% (95% confidence interval 65-77%) and 65% (95% confidence interval 57-72%), respectively. The nomogram developed included number and size of IPN along with postoperative pathological variables, and showed calibration with a concordance index (c-index) of 0.81 and a bootstrap corrected c-index of 0.78. Limitations include retrospective study with no external validation. CONCLUSIONS: We developed a nomogram to predict the individualized risk LMFS for patients who underwent nephrectomy for localized or locally advanced renal cell carcinoma. PATIENT SUMMARY: We reviewed outcomes among kidney cancer patients who presented with small lung nodules and developed a clinical tool to predict risk of developing lung metastases.

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

OBJECTIVE: To characterise the clinical, radiological and histological features of mucinous tubular and spindle cell carcinoma (MTSCC), as well as oncological outcomes. PATIENTS AND METHODS: This is a single institution retrospective analysis of all patients with MTSCC from 2002 to 2011. Patients were excluded if MTSCC could not be confirmed on pathology re-review (four patients). Clinical characteristics, pathology, imaging, and outcomes were reviewed for the 19 included patients. RESULTS: The median (range) age at diagnosis was 59 (17-71) years with a female predominance (78.9%). On contrast-enhanced computed tomography, MTSCC enhanced less than the cortex during the corticomedullary phase. The mean (range) tumour attenuation was 36 (24-48), 67 (41-133), 89 (49-152), and 76 (52-106) Hounsfield units in the pre-contrast, corticomedullary, nephrographic and excretory phases, respectively. In all, 16 patients were treated with partial (five patients) or radical nephrectomy (11) for pT1 (62.5%), pT2 (31.3%), and pT3a disease (6.3%). One patient underwent active surveillance. Of three patients (13.0%) managed with energy ablation, there was one recurrence that was treated with salvage surgery. One patient (5.3%) had metastatic disease at diagnosis and died from disease 64.7 months later. A patient with a pT2bN0M0 MTSCC with sarcomatoid dedifferentiation developed bone metastases 9.5 months after diagnosis and was alive at 19.0 months. The remainder were free of recurrence or progression. CONCLUSION: MTSCC is a rare renal cell carcinoma (RCC) variant. In this largest series to date, MTSCC presented at a broad range of ages and displayed a female predilection. Imaging and pathological features of MTSCC display some overlap with papillary RCC. MTSCC is associated with excellent outcomes overall, but is not universally indolent.

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.

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.