Combination of Tipifarnib and Sunitinib Overcomes Renal Cell Carcinoma Resistance to Tyrosine Kinase Inhibitors via Tumor-Derived Exosome and T Cell Modulation.

BACKGROUND: Tyrosine kinase inhibitors (TKI) were initially demonstrated as an efficacious treatment for renal cell carcinoma (RCC). However, after a median treatment length of 14 months, a vast majority of patients develop resistance. This study analyzed a combination therapy of tipifarnib (Tipi) + sunitinib that targeted exosome-conferred drug resistance. METHODS: 786-O, 786-O-SR (sunitinib resistant), A498, A498-SR, Caki-2, Caki-2-SR, and 293T cells were cultured. Exosomes were collected using differential ultracentrifugation. Cell proliferation, Jurkat T cell immune assay, and immunoblot analysis were used for downstream analysis. RESULTS: SR exosomes treatment displayed a cytotoxic effect on immune cells. This cytotoxic effect was associated with increased expression of PD-L1 on SR exosomes when compared to sunitinib-sensitive (SS) exosomes. Additionally, Tipi treatment downregulated PD-L1 expression on exosomes derived from SR cell lines. Tipi's ability to downregulate PD-L1 in exosomes has a significant application within patients. Exosomes collected from patients with RCC showed increased PD-L1 expression over subjects without RCC. Next, exosome concentrations were then compared after Tipi treatment, with all SS cell lines displaying an even greater reduction. On immunoblot assay, 293T cells showed a dose-dependent increase in Alix with no change in either nSMase or Rab27a. Conversely, all the SS and SR cell lines displayed a decrease in all three markers. After a cell proliferation employed a 48-h treatment on all SS and SR cell lines, the drug combination displayed synergistic ability to decrease tumor growth. CONCLUSIONS: Tipifarnib attenuates both the exosome endosomal sorting complex required for endosomal sorting complex required for transport (ESCRT)-dependent and ESCRT-independent pathways, thereby blocking exosome biogenesis and secretion as well as downregulating PD-L1 on SS and SR cells.

Interobserver Agreement and Accuracy in Interpreting mpMRI of the Prostate: a Systematic Review.

PURPOSE OF REVIEW: To present the latest evidence related to interobserver agreement and accuracy; evaluate the strengths, weaknesses, and implications of use; and outline opportunities for improvement and future development of the Prostate Imaging Reporting and Data System version 2.1 (PI-RADS v2.1) for detection of prostate cancer (PCa) on multiparametric magnetic resonance imaging (mpMRI). RECENT FINDINGS: Our review of currently available evidence suggests that recent improvements to the PI-RADS system with PI-RADS v2.1 slightly improved interobserver agreement, with generally high sensitivity and moderate specificity for the detection of clinically significant PCa. Recent evidence additionally demonstrates substantial improvement in diagnostic specificity with PI-RADS v2.1 compared with PI-RADS v2. However, results of studies examining the comparative performance of v2.1 are limited by small sample sizes and retrospective cohorts, potentially introducing selection bias. Some studies suggest a substantial improvement between v2.1 and v2, while others report no statistically significant difference. Additionally, in PI-RADS v2.1, the interpretation and reporting of certain findings remain subjective, particularly for category 2 lesions, and reader experience continues to vary significantly. These factors further contribute to a remaining degree of interobserver variability and findings of improved performance among more experienced readers. PI-RADS v2.1 appears to show at least minimal improvement in interobserver agreement, diagnostic performance, and both sensitivity and specificity, with greater improvements seen among more experienced readers. However, given the decrescent nature of these improvements and the limited power of all studies examined, the clinical impact of this progress may be marginal. Despite improvements in PI-RADS v2.1, practitioner experience in interpreting mpMRI of the prostate remains the most important factor in prostate cancer detection.

Testicular Necrosis Post Kidney Transplantation: Lessons Learned.

There is a paucity of literature on testicular complications after kidney transplant. Testicular necrosis after kidney transplantation has only been reported twice before. We present a 60- year-old man with end-stage renal disease who underwent uneventful deceased-donor kidney transplant. The patient's postoperative course was complicated by delayed graft function, urinary tract infection, epididymo-orchitis, and a necrotic testis necessitating radical orchiectomy on postoperative day 15. With their complex comorbidities compounded by a high burden of genitourinary complications, kidney transplant recipients may face testicular complications post-transplant due to the inherent risk posed by intraoperative manipulation of spermatic cord and ligation of lymphovascular structures.

Considering Predictive Factors in the Diagnosis of Clinically Significant Prostate Cancer in Patients with PI-RADS 3 Lesions.

The use of multi-parametric magnetic resonance imaging (mpMRI) in conjunction with the Prostate Imaging Reporting and Data System (PI-RADS) is standard practice in the diagnosis, surveillance, and staging of prostate cancer. The risk associated with lesions graded at a PI-RADS score of 3 is ambiguous. Further characterization of the risk associated with PI-RADS 3 lesions would be useful in guiding further work-up and intervention. This study aims to better characterize the utility of PI-RADS 3 and associated risk factors in detecting clinically significant prostate cancer. From a prospectively maintained IRB-approved dataset of all veterans undergoing mpMRI fusion biopsy at the Southeastern Louisiana Veterans Healthcare System, we identified a cohort of 230 PI-RADS 3 lesions from a dataset of 283 consecutive UroNav-guided biopsies in 263 patients from October 2017 to July 2020. Clinically significant prostate cancer (Gleason Grade ≥ 2) was detected in 18 of the biopsied PI-RADS 3 lesions, representing 7.8% of the overall sample. Based on binomial analysis, PSA densities of 0.15 or greater were predictive of clinically significant disease, as was PSA. The location of the lesion within the prostate was not shown to be a statistically significant predictor of prostate cancer overall (p = 0.87), or of clinically significant disease (p = 0.16). The majority of PI-RADS 3 lesions do not represent clinically significant disease; therefore, it is possible to reduce morbidity through biopsy. PSA density is a potential adjunctive factor in deciding which patients with PI-RADS 3 lesions require biopsy. Furthermore, while the risk of prostate cancer for African-American men has been debated in the literature, our findings indicate that race is not predictive of identifying prostate cancer, with comparable Gleason grade distributions on histology between races.

Prostate Cancer Lesions by Zone and Race: Does Multiparametric MRI Demonstrate Racial Difference in Prostate Cancer Lesions for African American Men?

African American (AA) men have increased risk of prostate cancer diagnosis and mortality, but the cause remains unknown. MRI fusion improves diagnosis of localized prostate cancer, particularly in anterior lesions; however, cost and access are limited in a community practice setting. By utilizing a diverse cohort of veterans with equal access to care in a single payer system, we describe prostate cancer detection. We queried a prospectively maintained institutional review board-approved database of men undergoing prostate biopsy for untreated prostate cancer. We included all consecutive patients from October 2017 to February 2020. Statistical analysis including Kaplan-Meier Curves, Fisher's exact test, and Forest plot was performed. From 246 consecutive patients, 166 were AA and 80 were non-AA. There were similar distributions of PSA, PSAD, and number of targetable lesions between the AA and non-AA cohort (p > 0.05 for all). We found no difference in location on MRI between race groups. There was similar cancer detection, focusing on anterior lesions and rate of positive Gleason grade (≥GG1) and clinically significant (≥GG2) cancer between cohorts. In a predominant AA cohort of veterans, we found similar distribution of location for MRI-targeted lesions, along with rates of tumor detection and aggressiveness of disease. In this single payer veteran population, we did not identify specific biologic differences inherent to tumor detection between AA and non-AA patients.

Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma.

Renal Cell Carcinoma (RCC) is the most common form of kidney cancer, with clear cell RCC (ccRCC) representing about 85% of all RCC tumors. There are limited curable treatments available for metastatic ccRCC because this disease is unresponsive to conventional targeted systemic pharmacotherapy. Exosomes (Exo) are small extracellular vesicles (EVs) secreted from cancer cells with marked roles in tumoral signaling and pharmacological resistance. Ketoconazole (KTZ) is an FDA approved anti-fungal medication which has been shown to suppress exosome biogenesis and secretion, yet its role in ccRCC has not been identified. A time-course, dose-dependent analysis revealed that KTZ selectively decreased secreted Exo in tumoral cell lines. Augmented Exo secretion was further evident by decreased expression of Exo biogenesis (Alix and nSMase) and secretion (Rab27a) markers. Interestingly, KTZ-mediated inhibition of Exo biogenesis was coupled with inhibition of ERK1/2 activation. Next, selective inhibitors were employed and showed ERK signaling had a direct role in mediating KTZ's inhibition of exosomes. In sunitinib resistant 786-O cells lines, the addition of KTZ potentiates the efficacy of sunitinib by causing Exo inhibition, decreased tumor proliferation, and diminished clonogenic ability of RCC cells. Our findings suggest that KTZ should be explored as an adjunct to current RCC therapies.

Does muscle invasive bladder cancer following pelvic radiotherapy portend worse prognosis? A seer-based study.

BACKGROUND: Although emerging evidence demonstrates increased risk of secondary bladder cancer following pelvic radiotherapy, the aggressiveness of these tumors is not well-characterized. MATERIALS AND METHODS: A search of the Surveillance, Epidemiology, and End Results (SEER) 18 Database, identified 25,734 patients diagnosed with bladder cancer following definitive therapy for previous pelvic malignancy. Kaplan-Meier curve analyses were utilized to determine overall survival with significance set at p<0.05. RESULTS: Of the 25,734 patients, 11,376 (44.2%) received radiation treatment for their first cancer. Overall survival of bladder cancer was found to be 80%, 69.5%, and 49.2% at 1,2 and 5 years, respectively. There was no significant survival difference between groups whose first cancer was treated with or without radiation (p=0.8). A survival advantage was seen for the bladder cancer patients not treated with radiation for cervical (p=0.004), uterine (p=0.0006), and vaginal cancers (p<0.0001). Bladder cancer patients treated with radiation for prostate cancer showed a survival advantage (p=0.002). The average time to second cancer diagnosis was 6.5±6.1 years. Patients treated with radiation for first primary cancer showed a longer time to second cancer (7.2±6.0 years) compared to those treated without radiation (5.9±6.0 years) (p<0.01). CONCLUSION: Patients with prior history of female cancers treated without radiation demonstrated significant survival advantage in second primary bladder cancer. A small significant survival advantage was seen in bladder cancer patients previously treated for prostate cancer with radiation. This data suggests that second primary bladder cancer following pelvic radiotherapy has similar biologic aggressiveness to urothelial carcinoma developing without a history of radiotherapy. MICROABSTRACT: The overall survival of 25,734 patients diagnosed with bladder cancer following definitive therapy for a previous pelvic malignancy was 49.2% at 5 years. There was no significant survival difference between groups whose first cancer was treated with or without radiation. Second primary bladder cancer following pelvic radiotherapy has similar biologic aggressiveness to urothelial carcinoma developing without a history of radiotherapy.

Rethinking active surveillance for prostate cancer in African American men.

Active surveillance (AS) is a treatment modality for prostate cancer that aims to simultaneously avoid overtreatment and allow for the timely intervention of localized disease. AS has become the de facto standard of care for most men with low-risk prostate cancer. However, few African American (AA) men were included in the prospective observational cohorts that resulted in a paradigm shift in treatment recommendations from active intervention toward AS. It has been established that AA men have an increased prostate cancer incidence, higher baseline prostate-specific antigen (PSA) values, more aggressive prostate cancer features, greater frequency of biochemical recurrence after treatment, and higher overall cancer-specific mortality compared to their Caucasian counterparts. As such, this has given many physicians pause before initiating AS for AA patients. In the following manuscript, we will review the available literature regarding AS, with a particular focus on AA men. The preponderance of evidence demonstrates that AS is as viable a management method for AA with low-risk prostate cancer as it is with other racial groups.

Predictors of Medical and Surgical Complications After Robot-Assisted Partial Nephrectomy: An Analysis of 1139 Patients in a Multi-Institutional Kidney Cancer Database.

INTRODUCTION: Previous robot-assisted partial nephrectomy (RAPN) studies have identified various predictors of overall and major postoperative complications, but few have evaluated the specific role of these factors in the development of medical and surgical complications. In this study, we present an analysis of the modifiable and nonmodifiable variables influencing medical and surgical complications in a contemporary series of patients who underwent RAPN and were followed in a prospectively maintained, multi-institutional kidney cancer database. METHODS: A retrospective review of all patients who underwent RAPN at four institutions between 2008 and 2015 was performed. Multivariable logistic regression models were used to determine predictors of medical and surgical postoperative complications. RESULTS: Data from 1139 patients were available for analysis. Sixty-seven patients (5.8%) experienced a medical postoperative complication, and 82 (7.1%) experienced a surgical complication. Decreasing baseline estimated glomerular filtration rate (eGFR) (odds ratio [OR] = 0.98, p = 0.003), greater estimated blood loss (EBL) (OR = 1.002, p = 0.001), and operating surgeon (OR = 8.01, p < 0.001) were associated with an increased likelihood of surgical complications, while decreasing baseline eGFR (OR = 0.99, p = 0.054) and operating surgeon (OR = 1.96, p = 0.054) were associated with an increased likelihood of medical complications. CONCLUSION: We present complication risks in a large contemporary cohort of patients undergoing robotic partial nephrectomy (RPN) with only 11.3% of patients experiencing a medical or surgical postoperative complication. Prospective candidates for robotic PN with poor baseline renal function and/or risk factors for greater EBL, including a high body mass index, or a complex renal mass should be counseled appropriately on their increased risk for a medical or surgical postoperative complication.

Determinants and prognostic implications of malignant ascites in metastatic papillary renal cancer.

OBJECTIVE: To describe the incidence of ascites in metastatic papillary renal cell cancer (pRCC), identify the factors associated with its development and evaluate its prognostic effect on the survival of these patients. METHODS: A retrospective evaluation of the medical records of patients with metastatic pRCC seen at National Cancer Institute (2000-2014) was undertaken. Logistic regression to identify predictors of the development of malignant ascites and Kaplan-Meier analysis to estimate survival was done. RESULTS: Overall, 106 consecutive patients with metastatic pRCC were identified; sufficient data were available in 100 patients to enable assessment of ascites. Further, 20% had evidence of malignant ascites. Median age at diagnosis of ascites was 48.0 years (26.1-76.6 years) and median time to development of ascites from initial diagnosis of metastatic disease was 16.0 (0-73.3) months. There was no significant difference in the incidence of ascites between patients with hereditary and sporadic pRCC (P = 0.803) or among patients with different subtypes of pRCC (P = 0.456). Elevated platelet-lymphocyte ratio predicted development of malignant ascites in our cohort (P = 0.009). Median overall survival was shorter for patients who developed ascites [25.0 (10.2-39.8) months] compared with patients who did not develop this complication [42.5 (30.5-54.4) months, P = 0.041]. CONCLUSION: To our knowledge, this is the first systematic evaluation of the incidence, predictors, and prognostic effect of ascites in metastatic pRCC. Malignant ascites is a common manifestation of metastatic pRCC and is associated with a shorter overall survival. An elevated platelet-lymphocyte ratio predicts a higher risk of developing malignant ascites.

Selective arterial clamping does not improve outcomes in robot-assisted partial nephrectomy: a propensity-score analysis of patients without impaired renal function.

OBJECTIVES: To assess the benefit of selective arterial clamping (SAC) as an alternative to main renal artery clamping (MAC) during robot-assisted partial nephrectomy (RAPN) in patients without underlying chronic kidney disease (CKD). PATIENTS AND METHODS: Our study cohort comprised 665 patients without impaired renal function undergoing MAC (n = 589) or SAC (n = 76) during RAPN from four medical institutions in the period 2008-2015. We compared complication rates, positive surgical margin (PSM) rates, and peri-operative and intermediate-term renal functional outcome between 132 patients undergoing MAC and 66 undergoing SAC after 2-to-1 nearest-neighbour propensity-score matching for age, sex, body mass index, RENAL nephrometry score, tumour size, baseline estimated glomerular filtration rate (eGFR), American Society of Anesthesiologists (ASA) score, Charlson comorbidity index (CCI) and warm ischaemia time (WIT). RESULTS: In propensity-score-matched patients, PSM (5.7 vs 3.0%; P = 0.407) and complication rates (13.8 vs 10.6%; P = 0.727) did not differ between the MAC and SAC groups. The incidence of acute kidney injury for MAC vs SAC (25.0 vs 32.0%; P = 0.315) within the first 30 days was similar. At a median follow-up of 7.5 months, the percentage reduction in eGFR (-9.3 vs -10.4%; P = 0.518) and progression to CKD ≥ stage 3 (7.2 vs 8.5%; P = 0.792) showed no difference. CONCLUSIONS: Our study findings show no difference in PSM rates, complication rates or intermediate-term renal functional outcomes between patients with unimpaired renal function who underwent SAC vs those who underwent MAC. When expected WIT is low, the routine use of SAC may not be necessary. Further studies will need to determine the role of SAC in patients with a solitary kidney or with significantly impaired renal function.

A randomized double blinded placebo controlled trial of sildenafil for renoprotection prior to hilar clamping in patients undergoing robotic assisted laparoscopic partial nephrectomy.

OBJECTIVE: To perform a randomized control trial (RCT) assessing the effect of phosphodiesterase 5 inhibitor (PDE5i) used prior to hilar clamping during robot assisted partial nephrectomy (RAPN) for renoprotection. MATERIALS AND METHODS: We performed an institutional review board approved, placebo controlled, double blinded RCT evaluating a single 100 mg oral dose of sildenafil immediately prior to RAPN. Primary end point was accrual, participation and retention of patients with secondary endpoints assessing post-operative renal functional outcomes and safety. Exclusion criteria included history of coronary artery disease, solitary kidney, suspected benign pathology, PDE5i intolerance or pregnant females. RESULTS: Of 40 eligible consecutive patients undergoing RPN between 9/2013 and 12/2014, 30 (75%) were randomized to treatment and there was 100% participation and retention. The groups were well matched for all measured comorbidities. Intraoperative outcomes including warm ischemia time (median 15 vs. 16.5 min, P = 0.29) were similar. Change in eGFR demonstrated similar decrease between sildenafil versus placebo at 1 day (-8% vs. -10%, P = 0.53), 2 days (-9% vs. -9%, P = 0.77), and 1 month (-4% vs. -6%, P = 0.31) following RAPN. Intermediate follow up (median 183 days) demonstrated similar results (-8% vs. -1%, P = 0.16) between the two cohorts. Safety profiles were similar between the two cohorts without any adverse reactions to the sildenafil. CONCLUSIONS: Successful retention of patients was achieved in this RCT. The secondary outcome of renoprotection was not identified. J. Surg. Oncol. 2016;114:785-788. © 2016 2016 Wiley Periodicals, Inc.

Main Renal Artery Clamping With or Without Renal Vein Clamping During Robotic Partial Nephrectomy for Clinical T1 Renal Masses: Perioperative and Long-term Functional Outcomes.

OBJECTIVE: To compare renal function outcome between a contemporary cohort of propensity score-matched patients undergoing main renal artery clamping (MAC) alone and those undergoing main renal artery clamping with renal vein clamping (MVAC) during robotic partial nephrectomy. MATERIALS AND METHODS: Patients with a solitary T1 renal mass undergoing robotic partial nephrectomy were propensity score-matched on American Society of Anesthesiologists score, RENAL Nephrometry score, tumor size, tumor laterality, and operating surgeon to provide 66 patients undergoing MAC and 66 patients undergoing MVAC for analysis. Demographic and tumor-specific characteristics in addition to perioperative and renal function outcomes at discharge and 9 months were compared. RESULTS: No differences in any baseline characteristics including age (P = .847), baseline estimated glomerular filtration rate (eGFR) (P = .358), RENAL Nephrometry score (P = .617), and tumor size (P = .551) were identified. Warm ischemia time was longer in patients undergoing MVAC than in patients undergoing MAC (21.0 minutes vs 15.0, P <.001), with no differences in estimated blood loss (P = .413), length of hospitalization (P = .112), and postoperative complications (overall [P = .251], by Clavien-Dindo classification [P = .119]). No differences in the percent change in eGFR (P = .866) or acute kidney injury (P = .493) at discharge and no differences in the percent change in eGFR (P = .401) or progression to chronic kidney disease (P = .594) at 9 months were identified. CONCLUSION: Compared with MAC, clamping of the renal vein in addition to the main renal artery does not appear to adversely affect postoperative renal function. Future studies comparing MAC with MVAC partial nephrectomy in patients with baseline chronic kidney disease, a solitary kidney and complex tumors with prolonged warm ischemia time are necessary.

Risk factors for infectious readmissions following radical cystectomy: results from a prospective multicenter dataset.

INTRODUCTION: Radical cystectomy (RC) is the gold standard treatment for muscle-invasive bladder cancer. This procedure has a high rate of perioperative complications, many of which are infectious in nature. The objective of our study was to evaluate demographic, intrinsic and extrinsic patient variables associated with developing readmission within 30 days due to infectious complications following RC. METHODS: We acquired data available from the American College of Surgeons National Surgical Quality Improvement Program. We queried this dataset to identify all patients who underwent RC for muscle-invasive malignant disease (CPT 188.x) in 2012 based on CPT coding. Logistic regression analysis was used to investigate the relationship between preoperative variables and readmissions for infectious complications. RESULTS: Of the 961 patients undergoing cystectomy for malignancy, 159 (17%) required readmission for any indications at a median of 16 days (interquartile range 13-22 days) postoperatively. We identified 71 of a total of 159 (45%) readmissions, which were due to infectious complications. Smoking was more prevalent in the patient population readmitted for an infectious complication compared with the patient population readmitted for a non-infectious complication (37% versus 25%; p = 0.03). Using logistic regression analysis smoking was associated with a significant risk for readmission due to an infectious cause (odds ratio 2.28, 95% confidence interval 1.82-2.97, p = 0.02). Readmission due to an infectious etiology was not associated with other perioperative factors including type of urinary diversion, sex, duration of operation, hypertension, or recent weight loss. CONCLUSION: Readmission following RC is a common occurrence and infectious complications drive readmission in almost half of the cases. Current smoking was the only independent risk factor for an infectious readmission. Counseling patients in smoking cessation prior to the procedure may provide an avenue for quality improvement to limit readmissions.

Association of Urine Dipstick Proteinuria and Postoperative Renal Function Following Robotic Partial Nephrectomy.

INTRODUCTION: In patients with normal estimated renal function before robot-assisted partial nephrectomy (RPN), there is still a risk for de Novo chronic kidney disease (CKD). We assessed the role of dipstick spot proteinuria in risk stratifying patients for CKD progression. MATERIALS AND METHODS: From our prospectively maintained, institutional review board-approved database of patients undergoing RPN, we queried those with estimated glomerular filtration rate (eGFR) >60 and bilateral functional units. We assessed proteinuria through dipstick (trace or above) on voided urine in preoperative urologic appointment <3 weeks before RPN. Proteinuric patients were compared with the remainder of the cohort with parametric comparisons for continuous and chi-squared analysis for categoric variables. Multivariate logistic regression analyses were performed assessing the risk of de Novo CKD stage III development, estimated by the CKD-EPI equation. RESULTS: We found 269 patients with eGFR >60 preoperatively, of whom 57 (21%) had proteinuria preoperatively. In univariate analysis, these patients were more likely to be diabetic (p = 0.023) and to be on an angiotensin converting enzyme inhibitor or angiotensin receptor blocker (p = 0.001) but had similar age (p = 0.13), body mass index (p = 0.09), and tumor size (p = 0.56) with similar rates of hypertension (p = 0.07). At a median 16 months, controlling for confounding variables, preoperative proteinuria on urinary dipstick was associated with a 2.3× (95% confidence interval 1.03-4.95) increased risk of de Novo CKD stage III progression. CONCLUSIONS: Patients with proteinuria preoperatively, despite a normal eGFR, likely have intrinsic medicorenal disease. These patients should be counseled preoperatively that they have a higher risk of CKD progression following RPN.

Pheochromocytoma diagnosed pathologically with previous negative serum markers.

BACKGROUND AND OBJECTIVES: Patients presenting with adrenal masses require workup with catecholamine or metabolite measurements to rule out pheochromocytoma. There is a select portion of patients with marker negative pheochromocytoma. The aim of this study is to compare patient characteristics and presentations between marker positive and marker negative tumors. METHODS: We performed an IRB-approved retrospective chart review of 88 cases of pheochromocytoma excised at our institution from 1995 to 2013. We considered any abnormal elevation in diagnostic test to be marker-positive. RESULTS: Seventy-eight cases had laboratory results available. Among these, seven had no elevations in laboratory testing. There was no difference in age or tumor size, but marker-negative patients had higher BMI than marker-positive patients. Marker negative patients were more likely to present with vertigo/dizziness (P = 0.003). Neither was more likely to have a genetic syndrome associated with risk of pheochromocytoma. CONCLUSIONS: Marker-negative pheochromocytoma is uncommon, representing 9% of cases in our series. Of patients with adrenal masses or presentation suggesting catecholamine excess with normal labs, those with vertigo/dizziness may warrant a metaiodobenzylguanidine scan or repeat testing to avoid missing pheochromocytoma. Clinicians may need a high degree of suspicion for pheochromocytoma in patients with negative testing and elevated BMI.

Near-infrared fluorescence imaging to facilitate super-selective arterial clamping during zero-ischaemia robotic partial nephrectomy.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: There is concern that warm ischaemia time during partial nephrectomy may have an adverse impact on postoperative renal function. As a result, there is increased interest in developing a safe and effective method for performing non-ischaemic partial nephrectomy. Several novel approaches have recently been described. We present our initial experience performing zero-ischaemia partial nephrectomy using near-infrared fluorescence imaging to facilitate super-selective arterial clamping. We report the operative and early postoperative outcomes from such cases as compared with a matched cohort of patients undergoing traditional partial nephrectomy with clamping of the main renal artery. We show that this technique is both safe and effective and may lead to improved renal preservation at short-term follow-up. OBJECTIVE: To describe a novel technique of eliminating renal ischaemia during robotic partial nephrectomy (RPN) using near-infrared fluorescence (NIRF) imaging. PATIENTS AND METHODS: Over an 8-month period (March 2011 to November 2011), 34 patients were considered for zero-ischaemia RPN using the da Vinci NIRF system. Targeted tertiary/higher-order tumour-specific branches were controlled with robotic bulldog(s) or neurosurgical aneurysm micro-bulldog(s). Indocyanine green dye was given, and NIRF imaging used to confirm super-selective ischaemia, defined as darkened tumour/peri-tumour area with green fluorescence of remaining kidney. Matched pair analysis was performed by matching each patient undergoing zero-ischaemia RPN (n = 27) to a previous conventional RPN (n = 27) performed by the same surgeon. RESULTS: Of 34 patients, 27 (79.4%) underwent successful zero-ischaemia RPN; seven (20.6%) required conversion to main renal artery clamping (ischaemia time <30 min) for the following reasons: persistent tumour fluorescence after clamping indicating inadequate tumoral devascularization (n = 5), and parenchymal bleeding during RPN (n = 2). Matched-pair analysis showed comparable outcomes between cohorts, except for longer operating time (256 vs 212 min, P = 0.02) and superior kidney function (reduction of estimated glomerular filtration rate (-1.8% vs -14.9%, P = 0.03) in the zero-ischaemia cohort. All surgical margins were negative. CONCLUSIONS: In this pilot study, we show that zero-ischaemia RPN with NIRF is a safe alternative to conventional RPN with main renal artery clamping. Eliminating global ischaemia may improve functional outcomes at short-term follow-up.

Cell therapy with human renal cell cultures containing erythropoietin-positive cells improves chronic kidney injury.

New therapeutic strategies for chronic kidney disease (CKD) are necessary to offset the rising incidence of CKD and donor shortage. Erythropoietin (EPO), a cytokine produced by fibroblast-like cells in the kidney, has recently emerged as a renoprotective factor with anti-inflammatory, antioxidant properties. This study (a) determined whether human renal cultures (human primary kidney cells [hPKC]) can be enriched in EPO-positive cells (hPKC(F+)) by using magnetic-bead sorting; (b) characterized hPKC(F+) following cell separation; and (c) established that intrarenal delivery of enriched hPKC(F+) cells would be more beneficial in treatment of renal injury, inflammation, and oxidative stress than unsorted hPKC cultures in a chronic kidney injury model. Fluorescence-activated cell sorting analysis revealed higher expression of EPO (36%) and CD73 (27%) in hPKC(F+) as compared with hPKC. After induction of renal injury, intrarenal delivery of hPKC(F+) or hPKC significantly reduced serum creatinine, interstitial fibrosis in the medulla, and abundance of CD68-positive cells in the cortex and medulla (p < .05). However, only hPKC(F+) attenuated interstitial fibrosis in the renal cortex and decreased urinary albumin (3.5-fold) and urinary tubular injury marker kidney injury molecule 1 (16-fold). hPKC(F+) also significantly reduced levels of renal cortical monocyte chemotactic protein 1 (1.8-fold) and oxidative DNA marker 8-hydroxy-deoxyguanosine (8-OHdG) (2.4-fold). After 12 weeks, we detected few injected cells, which were localized mostly to the cortical interstitium. Although cell therapy with either hPKC(F+) or hPKC improved renal function, the hPKC(F+) subpopulation provides greater renoprotection, perhaps through attenuation of inflammation and oxidative stress. We conclude that hPKC(F+) may be used as components of cell-based therapies for degenerative kidney diseases.