Short PlGF-derived peptides bind VEGFR-1 and VEGFR-2 in vitro and on the surface of endothelial cells.

The placental growth factor (PlGF), a member of VEGF family, plays a crucial role in pathological angiogenesis, especially ischemia, inflammation, and cancer. This activity is mediated by its selective binding to VEGF receptor 1 (VEGFR-1), which occurs predominantly through receptor domains 2 and 3. The PlGF ß-hairpin region spanning residues Q87 to V100 is one of the key binding elements on the protein side. We have undertaken a study on the design, preparation, and functional characterization of the peptide reproducing this region and of a set of analogues where glycine 94, occurring at the corner of the hairpin in the native protein, is replaced by charged as well as hydrophobic residues. Also, some peptides with arginine 96 replaced by other residues have been studied. We find that the parent peptide weakly binds VEGFR-1, but replacement of G94 with residues bearing H-bond donating residues significantly improves the affinity. Replacement of R96 instead blocks the interaction between the peptide and the domain. The strongest affinity is observed with the G94H (peptide PlGF-2) and G94W (peptide PlGF-10) mutants, while the peptide PlGF-8, bearing the R96G mutation, is totally inactive. The PlGF-1 and PlGF-2 peptides also bind the VEGFR-2 receptors, though with a reduced affinity, and are able to interfere with the VEGF-induced receptor signaling on endothelial cells. The peptides also bind VEGFR-2 on the surface of cells, while PlGF-8 is inactive. Data suggest that these peptides have potential applications as PlGF/VEGF mimic in various experimental settings.

Immunodominant West Nile Virus T Cell Epitopes Are Fewer in Number and Fashionably Late.

Class I HLA molecules mark infected cells for immune targeting by presenting pathogen-encoded peptides on the cell surface. Characterization of viral peptides unique to infected cells is important for understanding CD8(+) T cell responses and for the development of T cell-based immunotherapies. Having previously reported a series of West Nile virus (WNV) epitopes that are naturally presented by HLA-A*02:01, in this study we generated TCR mimic (TCRm) mAbs to three of these peptide/HLA complexes-the immunodominant SVG9 (E protein), the subdominant SLF9 (NS4B protein), and the immunorecessive YTM9 (NS3 protein)-and used these TCRm mAbs to stain WNV-infected cell lines and primary APCs. TCRm staining of WNV-infected cells demonstrated that the immunorecessive YTM9 appeared several hours earlier and at 5- to 10-fold greater density than the more immunogenic SLF9 and SVG9 ligands, respectively. Moreover, staining following inhibition of the TAP demonstrated that all three viral ligands were presented in a TAP-dependent manner despite originating from different cellular compartments. To our knowledge, this study represents the first use of TCRm mAbs to define the kinetics and magnitude of HLA presentation for a series of epitopes encoded by one virus, and the results depict a pattern whereby individual epitopes differ considerably in abundance and availability. The observations that immunodominant ligands can be found at lower levels and at later time points after infection suggest that a reevaluation of the factors that combine to shape T cell reactivity may be warranted.

Quantitative Ultrasound for Measuring Obstructive Severity in Children with Hydronephrosis.

PURPOSE: We define sonographic biomarkers for hydronephrotic renal units that can predict the necessity of diuretic nuclear renography. MATERIALS AND METHODS: We selected a cohort of 50 consecutive patients with hydronephrosis of varying severity in whom 2-dimensional sonography and diuretic mercaptoacetyltriglycine renography had been performed. A total of 131 morphological parameters were computed using quantitative image analysis algorithms. Machine learning techniques were then applied to identify ultrasound based safety thresholds that agreed with the t½ for washout. A best fit model was then derived for each threshold level of t½ that would be clinically relevant at 20, 30 and 40 minutes. Receiver operating characteristic curve analysis was performed. Sensitivity, specificity and area under the receiver operating characteristic curve were determined. Improvement obtained by the quantitative imaging method compared to the Society for Fetal Urology grading system and the hydronephrosis index was statistically verified. RESULTS: For the 3 thresholds considered and at 100% sensitivity the specificities of the quantitative imaging method were 94%, 70% and 74%, respectively. Corresponding area under the receiver operating characteristic curve values were 0.98, 0.94 and 0.94, respectively. Improvement obtained by the quantitative imaging method over the Society for Fetal Urology grade and hydronephrosis index was statistically significant (p <0.05 in all cases). CONCLUSIONS: Quantitative imaging analysis of renal sonograms in children with hydronephrosis can identify thresholds of clinically significant washout times with 100% sensitivity to decrease the number of diuretic renograms in up to 62% of children.

Trends in Toilet Training and Voiding Habits among Children with Down Syndrome.

PURPOSE: Children with Down syndrome are at risk for lower urinary tract dysfunction and delayed toilet training. Comparative studies regarding voiding function in the Down syndrome population are lacking. We assessed urinary continence and voiding function in patients with Down syndrome and a control group. MATERIALS AND METHODS: A questionnaire designed to assess toilet training, continence status, symptoms of lower urinary tract dysfunction and prior evaluation of urological complaints was sent to parents of 326 children with Down syndrome who had been seen at our institution previously. The same survey was administered to parents of patients without Down syndrome. Data were compiled, and descriptive and comparative statistical analyses were performed. RESULTS: A total of 77 patients comprised the Down syndrome group and 78 patients without Down syndrome comprised the control group. Average age of reported toilet training completion was 5.5 years in children with Down syndrome and 2.2 years in controls. Of children 5 years or older 79% with Down syndrome were toilet trained, compared to 100% of those without Down syndrome. Incontinence was reported in 46% of previously toilet trained children with Down syndrome and 24.5% of controls. These findings were statistically significant. No significant difference was observed in the rate of urinary tract infection, symptoms of lower urinary tract dysfunction or evaluation for urological complaints. CONCLUSIONS: Children with Down syndrome can experience marked delay in toilet training and are more likely to suffer incontinence afterward. This study was ineffective in determining whether symptoms of lower urinary tract dysfunction could be related to decreased continence rates.

The prevalence of bell clapper anomaly in the solitary testis in cases of prior perinatal torsion.

PURPOSE: Bell clapper anomaly is associated with an increased risk of intravaginal testicular torsion. However, perinatal torsion is thought to be secondary to an extravaginal process. We quantified the contralateral prevalence of bell clapper anomaly in children found to have atrophic testicular nubbins secondary to presumed torsion during gestation to better define the subsequent risk of metachronous testicular torsion. MATERIALS AND METHODS: Inspection results for the presence of contralateral bell clapper anomaly was recorded by a single surgeon in 50 consecutive cases in which exploration for nonpalpable testes revealed a testicular nubbin. For comparison data were collected in 27 consecutive cases of acute testicular torsion. Anatomy of the normal contralateral testis was compared between the 2 groups. RESULTS: Average age at surgery in the perinatal torsion group was 15 months vs 12.7 years in the acute torsion group. One case of partial contralateral bell clapper anomaly was discovered in the perinatal torsion group but no complete anomaly was found. In contrast, in older boys with acute testicular torsion complete bell clapper anomaly was found in 21 of the 27 contralateral testes (78%). CONCLUSIONS: In older boys with acute testicular torsion contralateral bell clapper anomaly is highly prevalent, supporting the standard practice of contralateral testicular fixation in this clinical situation. However, the prevalence of contralateral bell clapper anomaly is exceedingly small in cases of monorchism after perinatal torsion, substantiating an insufficient risk of subsequent torsion to justify routine fixation of the solitary testis.

Most infants with dilating vesicoureteral reflux can be treated nonoperatively.

PURPOSE: Dilating vesicoureteral reflux provokes concern for physicians and parents that often leads to corrective surgery in young children. Since there are limited data describing the natural history of dilating vesicoureteral reflux in infants, we identified factors predictive of resolution/improvement in infants initially treated nonoperatively. MATERIALS AND METHODS: We reviewed the medical records of 90 infants 6 months old or younger from 2004 to 2010 who were referred for prenatal hydronephrosis or initial febrile urinary tract infection and found to have dilating vesicoureteral reflux (grade 3 or greater). Variables of interest included presentation, dimercapto-succinic acid results, sex, breakthrough febrile urinary tract infections, reflux grade and bilateral reflux. Cox regression analysis was performed to determine predictors of spontaneous resolution and/or improvement to reflux grade less than 3 as well as predictors of surgical intervention. RESULTS: Included in final analysis were 80 infants (113 renal units). Of the patients 51 (64%) experienced spontaneous resolution/improvement with a mean followup of 29 months before resolution, discharge home and/or end of followup. Only 20 patients (25%) underwent surgery. Cox regression analysis revealed that a normal initial dimercapto-succinic acid scan, initial reflux grade less than 5 and absent breakthrough febrile urinary tract infections were predictive of reflux resolution/improvement (p <0.05). Dimercapto-succinic acid scan abnormalities, prenatal hydronephrosis and breakthrough febrile urinary tract infections were significant predictors of surgery (p <0.05). CONCLUSIONS: Dilating vesicoureteral reflux in infancy often resolves/improves spontaneously. Therefore, surgery should be directed toward patients unlikely to experience resolution, ie those with an abnormal initial dimercapto-succinic acid scan, grade 5 vesicoureteral reflux and breakthrough febrile urinary tract infections.

Stereoscopic augmented reality for laparoscopic surgery.

BACKGROUND: Conventional laparoscopes provide a flat representation of the three-dimensional (3D) operating field and are incapable of visualizing internal structures located beneath visible organ surfaces. Computed tomography (CT) and magnetic resonance (MR) images are difficult to fuse in real time with laparoscopic views due to the deformable nature of soft-tissue organs. Utilizing emerging camera technology, we have developed a real-time stereoscopic augmented-reality (AR) system for laparoscopic surgery by merging live laparoscopic ultrasound (LUS) with stereoscopic video. The system creates two new visual cues: (1) perception of true depth with improved understanding of 3D spatial relationships among anatomical structures, and (2) visualization of critical internal structures along with a more comprehensive visualization of the operating field. METHODS: The stereoscopic AR system has been designed for near-term clinical translation with seamless integration into the existing surgical workflow. It is composed of a stereoscopic vision system, a LUS system, and an optical tracker. Specialized software processes streams of imaging data from the tracked devices and registers those in real time. The resulting two ultrasound-augmented video streams (one for the left and one for the right eye) give a live stereoscopic AR view of the operating field. The team conducted a series of stereoscopic AR interrogations of the liver, gallbladder, biliary tree, and kidneys in two swine. RESULTS: The preclinical studies demonstrated the feasibility of the stereoscopic AR system during in vivo procedures. Major internal structures could be easily identified. The system exhibited unobservable latency with acceptable image-to-video registration accuracy. CONCLUSIONS: We presented the first in vivo use of a complete system with stereoscopic AR visualization capability. This new capability introduces new visual cues and enhances visualization of the surgical anatomy. The system shows promise to improve the precision and expand the capacity of minimally invasive laparoscopic surgeries.

Altering drug tolerance of surface plasmon resonance assays for the detection of anti-drug antibodies.

Anti-drug antibody (ADA) responses are a concern for both drug efficacy and safety, and high drug concentrations in patient samples may inhibit ADA assays. We evaluated strategies to improve drug tolerance of surface plasmon resonance (SPR) assays that detect ADAs against a bispecific Adnectin drug molecule that consists of an anti-VEGFR2 domain linked to an anti-IGF-1R domain (V-I-Adnectin). Samples containing ADAs against V-I-Adnectin and various drug concentrations were tested in the presence of 1 M guanidine hydrochloride (Gdn), at pH values ranging from 4.5 to 7.4 and temperatures of up to 37 °C. Temperature had a negligible effect in weakening the affinity of interaction of monoclonal antibodies with polyethylene glycol(PEG)-V-I-Adnectin and did not increase drug tolerance of the ADA assay. Low pH increased drug tolerance of the assay relative to pH 7.4 but caused nonspecific binding of the drug during competition experiments. The chaotropic agent Gdn lowered the affinity of interaction between an anti-V-Adnectin monoclonal antibody and the drug (from K(D)=0.93 nM to K(D)=348 nM). That decrease in the affinity of drug-ADA interaction correlated with an increase of assay drug tolerance. Conditions that lower drug-ADA interaction affinity could also be used to develop drug-tolerant SPR assays for other systems.

Cost analysis of open radical cystectomy versus robot-assisted radical cystectomy.

Bladder cancer is the fourth and ninth most common malignancy in males and females, respectively, in the U.S. and one of the most costly cancers to manage. With the current economic condition, physicians will need to become more aware of cost-effective therapies for the treatment of various malignancies. Robot-assisted radical cystectomy (RARC) is the latest minimally invasive surgical option for muscle-invasive bladder cancer. Current reports have shown less blood loss, a shorter hospital stay, and a lower morbidity with RARC, as compared with the traditional open radical cystectomy (ORC), although long-term oncologic results of RARC are still maturing. There are few studies that have assessed the cost outcomes of RARC as compared with ORC. Currently, ORC appears to offer a direct cost advantage due to the high purchase and maintenance cost of the robotic platform, although when the indirect costs of complications and extended hospital stay with ORC are considered, RARC may be less expensive than the traditional open procedure. In order to accurately evaluate the cost effectiveness of RARC versus ORC, prospective randomized trials between the two surgical techniques with long-term oncologic efficacy are needed.

Laparoscopic bilateral native nephrectomies with simultaneous kidney transplantation.

UNLABELLED: Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Extirpation of polycystic kidneys for various medical reasons has been performed using many different approaches in attempts to limit morbidity from such a large operation. In indicated patients, it has usually been offered in a staged approach with renal transplantation to avoid graft complications. We published the first case of simultaneous laparoscopic bilateral native nephrectomy with kidney transplant in 2008. The present study shows our continued experience with offering this minimally invasive, single surgery alternative. The results are comparable to a staged laparoscopic approach with significantly shorter total hospital stay and one recovery for the patient and his/her family. OBJECTIVE: • To analyse the perioperative outcomes of native bilateral laparoscopic nephrectomy (BLN) with simultaneous kidney transplantation. PATIENTS AND METHODS: • From November 2000 to April 2011, 37 patients were seen for renal failure secondary to autosomal-dominant polycystic kidney disease (ADPKD) and underwent renal transplant with native nephrectomies at a single tertiary academic centre. • In all, 15 patients underwent BLN for ADPKD followed by simultaneous kidney transplantation. • The other 22 patients underwent BLN for ADPKD with kidney transplant performed at a separate setting. • Demographic data, perioperative outcomes, complications regardless of need for intervention, and graft function were analysed in both groups. RESULTS: • The combined surgery was completed without intraoperative complication in all cases. • The median total operative duration was 372 min, estimated blood loss was 300 mL with two patients requiring transfusion, and the median (range) hospital stay was 5 (3-7) days. • All patients had immediate graft function with additional relief of compressive symptoms. • In comparison to our staged cohort, the simultaneous group had a significantly shorter total hospital stay. • All other outcomes and complication rates were comparable. CONCLUSION: • In ADPKD, a less invasive laparoscopic approach for native nephrectomies with simultaneous renal transplant offers comparable morbidity without graft compromise and the convenience of one operation and one recovery for the patient.

Chimeric Antigen Receptors Directed at Mutant KRAS Exhibit an Inverse Relationship Between Functional Potency and Neoantigen Selectivity.

Neoantigens are among the most intriguing potential immuno-oncology targets because, unlike many cancer targets that are expressed on normal tissues, they are by definition restricted to cancer cells. Medicines directed at common neoantigens such as mutant KRAS are especially interesting because they may offer the convenience and cost of an off-the-shelf therapy. However, all common KRAS mutations produce proteins that differ from the wild type at a single amino acid, creating challenges for molecular discrimination. We have undertaken an effort to optimize single-chain variable fragments (scFv) against peptide/major histocompatibility antigen complexes composed of HLA-A*11 and either G12V- or G12D-mutant KRAS peptides. These scFvs could in principle be used in chimeric antigen receptor (CAR) T-cell therapies for selected patients whose tumors bear either of these mutations. Here we show that optimization of such CARs involves a trade-off between potency and selectivity. We further show that targeting this family without high selectivity engenders risks of cross-reactivity against other members of the G-protein family to which KRAS belongs. Significance: We report an effort to generate high potency, selective CARs directed at mutant KRAS peptides. Although the heavily optimized CARs maintain high selectivity against wild-type KRAS, they lose selectivity against other KRAS-related peptides derived from human proteins. To our knowledge, this work is the first to examine the trade-off between potency and selectivity with regard to KRAS pMHC-directed CARs, illustrating the challenge to achieve both sufficient potency and high selectivity.

A carcinoembryonic antigen-specific cell therapy selectively targets tumor cells with HLA loss of heterozygosity in vitro and in vivo.

The CEACAM5 gene product [carcinoembryonic antigen (CEA)] is an attractive target for colorectal cancer because of its high expression in virtually all colorectal tumors and limited expression in most healthy adult tissues. However, highly active CEA-directed investigational therapeutics have been reported to be toxic, causing severe colitis because CEA is expressed on normal gut epithelial cells. Here, we developed a strategy to address this toxicity problem: the Tmod dual-signal integrator. CEA Tmod cells use two receptors: a chimeric antigen receptor (CAR) activated by CEA and a leukocyte Ig-like receptor 1 (LIR-1)-based inhibitory receptor triggered by human leukocyte antigen (HLA)-A*02. CEA Tmod cells exploit instances of HLA heterozygous gene loss in tumors to protect the patient from on-target, off-tumor toxicity. CEA Tmod cells potently killed CEA-expressing tumor cells in vitro and in vivo. But in contrast to a traditional CEA-specific T cell receptor transgenic T cell, Tmod cells were highly selective for tumor cells even when mixed with HLA-A*02-expressing cells. These data support further development of the CEA Tmod construct as a therapeutic candidate for colorectal cancer.

Incontinence after radical prostatectomy: a patient centered analysis and implications for preoperative counseling.

PURPOSE: Incontinence after radical prostatectomy is common yet poorly defined in the current literature. We aimed to accurately characterize incontinence after robot-assisted radical prostatectomy to achieve improved preoperative patient counseling. MATERIALS AND METHODS: After receiving institutional review board approval we performed a cross-sectional survey of the first 600 patients with prostate cancer who underwent robot-assisted radical prostatectomy at our institution. The International Consultation on Incontinence Modular Questionnaire-Lower Urinary Tract Symptoms Quality of Life and Urinary Incontinence Short Form were used to evaluate incontinence and quality of life after robot-assisted radical prostatectomy. Surveys were mailed by a third party. Data were analyzed on the prevalence of incontinence after robot-assisted radical prostatectomy. More specifically we characterized in detail the nature of incontinence and its effect on quality of life. RESULTS: The response rate was 68% (408 of 600 participants). Response time since surgery was 2.5 months to 4 years. Overall incontinence bother scores and ratings of life interference were quite low. Patients reported that most incontinence occurred during physical activity but 35% reported interference with sleep. Of the patients 31% experienced some anxiety due to urinary difficulties and 51% had to occasionally change clothes due to leakage. Patients did not report much interference with traveling, visiting friends or family and family life. The most bothersome aspects of incontinence were its effects on partner relationship, sexual life and energy levels. CONCLUSIONS: Despite patient concerns of incontinence after prostatectomy they report little interference with quality of life.

Bleeding after holmium laser enucleation of the prostate: lessons learned the hard way.

OBJECTIVE: To examine specific causes of postoperative bleeding requiring transfusion after holmium laser enucleation of the prostate (HoLEP) in order to enhance preoperative screening and counseling. MATERIALS AND METHODS: After Institutional Review Board (IRB) approval, a retrospective review of a single surgeon's experience of 130 consecutive HoLEPs was performed to specifically examine patients requiring perioperative blood transfusions. All patients from August 2007 to April 2009 who underwent a HoLEP at our institution since its inception were included. These patients' charts were reviewed to gain insight into their bleeding diathesis. A case series report was compiled and compared with the relevant published literature. RESULTS: Of the 130 patients, eight (6.7%) were found to require transfusion postoperatively. Four of these patients required a second operation for completion. These patients had a variety of causes for increased bleeding and subsequent transfusion including: chronic anticoagulation (n = 1), significant cardiac disease requiring maintenance of hemoglobin (n = 4), sepsis with secondary disseminated intravascular coagulation (n = 1), large prostate size (>150 g) (n = 4), underlying prostate cancer (n = 1) and inadequate anesthesia during the procedure leading to patient movement (n = 1). All patients made a full recovery with satisfactory urinary symptom improvement except for one patient with residual incontinence at last follow-up. CONCLUSIONS: Despite the many benefits of holmium laser enucleation, all patients should be counseled regarding the real potential for postoperative blood transfusion. When feasible, any known bleeding risk should be minimized by the surgeon as long it is done safely for the benefit of the patient considering their co-morbidities.

Extensive functional comparisons between chimeric antigen receptors and T cell receptors highlight fundamental similarities.

Though TCRs have been subject to limited engineering in the context of therapeutic design and optimization, they are used largely as found in nature. On the other hand, CARs are artificial, composed of different segments of proteins that function in the immune system. This characteristic raises the possibility of altered response to immune regulatory stimuli. Here we describe a large-scale, systematic comparison of CARs and TCRs across 5 different pMHC targets, with a total of 19 constructs examined in vitro. These functional measurements include CAR- and TCR-mediated activation, proliferation, and cytotoxicity in both acute and chronic settings. Surprisingly, we find no consistent difference between CARs and TCRs as receptor classes with respect to their relative sensitivity to major regulators of T cell activation: PD-L1, CD80/86 and IL-2. Though TCRs often emerge from human blood directly as potent, selective receptors, CARs must be heavily optimized to attain these properties for pMHC targets. Nonetheless, when iteratively improved and compared head to head in functional tests, CARs appear remarkably similar to TCRs with respect to immune modulation.

Re-examination of MAGE-A3 as a T-cell Therapeutic Target.

In 2013, an innovative MAGE-A3-directed cancer therapeutic of great potential value was terminated in the clinic because of neurotoxicity. The safety problems were hypothesized to originate from off-target T-cell receptor activity against a closely related MAGE-A12 peptide. A combination of published and new data led us to test this hypothesis with current technology. Our results call into question MAGE-A12 as the source of the neurotoxicity. Rather, the data imply that an alternative related peptide from EPS8L2 may be responsible. Given the qualities of MAGE-A3 as an onco-testis antigen widely expressed in tumors and largely absent from normal adult tissues, these findings suggest that MAGE-A3 may deserve further consideration as a cancer target. As a step in this direction, the authors isolated 2 MAGE-A3 peptide-major histocompatibility complex-directed chimeric antigen receptors, 1 targeting the same peptide as the clinical T-cell receptor. Both chimeric antigen receptors have improved selectivity over the EPS8L2 peptide that represents a significant risk for MAGE-A3-targeted therapeutics, showing that there may be other options for MAGE-A3 cell therapy.

Potent, Selective CARs as Potential T-Cell Therapeutics for HPV-positive Cancers.

Next-generation T-cell therapies will likely continue to utilize T-cell receptors (TCRs) and chimeric antigen receptors (CARs) because each receptor type has advantages. TCRs often possess exceptional properties even when tested unmodified from patients' T cells. CARs are generally less sensitive, possibly because their ligand-binding domains are grafted from antibodies selected for binding affinity or avidity and not broadly optimized for a functional response. Because of the disconnect between binding and function among these receptor types, the ultimate potential of CARs optimized for sensitivity and selectivity is not clear. Here, we focus on a thoroughly studied immuno-oncology target, the HLA-A*02/HPV-E629-38 complex, and show that CARs can be optimized by a combination of high-throughput binding screens and low-throughput functional assays to have comparable activity to clinical TCRs in acute assays in vitro. These results provide a case study for the challenges and opportunities of optimizing high-performing CARs, especially in the context of targets utilized naturally by TCRs.

Robot-assisted radical cystectomy: intermediate survival results at a mean follow-up of 25 months.

OBJECTIVE: To assess the overall and disease-specific survival rates of patients undergoing robot-assisted radical cystectomy (RARC) compared with historical open cystectomy. PATIENTS AND METHODS: Survival, pathological and demographic data were collected on all patients undergoing RARC for bladder cancer from both Tulane University Medical Center and Mayo Clinic Arizona. Of a total of 80 RARCs we only included those with a follow-up of > or =6 months from surgery. Survival curves were compared with those from historical series of open cystectomy. RESULTS: Of the 80 patients 59 were identified as having a follow-up of > or =6 months from the date of surgery. The mean (range) follow-up was 25 (6-49) months. Overall survival rates at 12 and 36 months were 82% and 69%, respectively, and disease-specific survival rates were 82% and 72% at 12 and 36 months, respectively. These results are comparable to survival rates from open cystectomy. As expected, patients with lymph node-positive disease fared worse than those with lymph node-negative disease. Patients with extravesical lymph node-negative disease (pT3, pT4) fared worse than patients with organ-confined lymph node-negative disease. Also, patients with lymph node-positive disease fared worse than those with extravesical lymph node-negative disease, which is consistent with historical results of open cystectomy. CONCLUSIONS: RARC has a comparable survival rate to open cystectomy in the intermediate follow-up. Further study with a longer follow-up and more patients is necessary to determine any long-term survival benefits.