Timothy Y. Tseng

Oxidative Stress Regulates Expression of VEGFR1 in Myeloid Cells: Link to Tumor-Induced Immune Suppression in Renal Cell Carcinoma

Metastatic renal cell carcinoma (RCC) associates with overproduction of vascular endothelial growth factor (VEGF) due to the mutation/inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene. Herein we demonstrate that implantation of human RCC tumor cells into athymic nude mice promotes the appearance of VEGF receptor 1 (VEGFR1)/CD11b double-positive myeloid cells in peripheral blood. Avastin-mediated VEGF neutralization was capable of significantly reducing the numbers of circulating VEGFR1+ myeloid cells. Conversely, up-regulation of VEGFR1 by myeloid cells could also be achieved in vitro by coculturing bone marrow cells with RCC-conditioned medium or by short-term exposure of naive myeloid cells to oxidative stress. Treatment of myeloid cells with H2O2, lipid peroxidation product 4-hydroxy-2(E)-nonenal, or an inhibitor of thioredoxin reductase all resulted in increased expression of VEGFR1. Furthermore, after exposure to oxidative stress, myeloid cells acquire immunosuppressive features and become capable of inhibiting T cell proliferation. Data suggest that tumor-induced oxidative stress may promote both VEGFR1 up-regulation and immunosuppressive function in bone marrow-derived myeloid cells. Analysis of tumor tissue and peripheral blood from patients with metastatic RCC revealed that VEGFR1+ cells can be also found in cancer patients. Restoration of immunocompetence in metastatic RCC patients by pharmacological elimination of VEGFR1+ cells may have a significant impact on the therapeutic efficacy of cancer vaccines or other immune-based therapies.

Impact of nutritional factors on incident kidney stone formation: A report from the WHI OS

PURPOSE Increased fluid intake, and decreased dietary sodium and animal protein intake are thought to reduce the risk of kidney stones but the role of calcium intake is controversial. We evaluated the relationship between dietary factors and incident kidney stone formation. MATERIALS AND METHODS Secondary analysis was done of 78,293 women from the prospective WHI OS (Womens Health Initiative Observational Study) with no history of nephrolithiasis who completed the validated food frequency questionnaire. Multivariate logistic regression was used to determine demographic and dietary factors, and supplement use independently associated with incident kidney stones. RESULTS Overall 1,952 women (2.5%) reported an incident kidney stone in 573,575 person-years of followup. The risk of incident kidney stones was decreased by 5% to 28% (p = 0.01) with higher dietary calcium intake and by 13% to 31% (p = 0.002) with higher water intake after adjusting for nephrolithiasis risk factors. Conversely higher dietary sodium intake increased the risk of nephrolithiasis by 11% to 61% (p <0.001) after adjustment with the most pronounced effect in women with the highest intake. Higher body mass index independently increased the risk of incident nephrolithiasis (adjusted OR 1.19-2.01, p <0.001). Animal protein intake was not associated with nephrolithiasis on multivariate analysis. CONCLUSIONS This study adds to the growing evidence underscoring the importance of maintaining adequate fluid and dietary calcium intake. Greater dietary calcium intake significantly decreased the risk of incident kidney stones. In contrast, excess sodium intake increased the risk of incident nephrolithiasis, especially in women with the highest intake. Animal protein intake was not independently associated with nephrolithiasis.

How to Use a Systematic Literature Review and Meta-Analysis

PURPOSE This article introduces practicing urologists to the critical appraisal of systematic reviews and meta-analyses to guide their evidence-based clinical practice. MATERIALS AND METHODS Using a urological clinical case scenario we introduce a 3-step process in evaluating systematic reviews and meta-analyses by considering 1) the validity of the review results, 2) what the results are, and 3) the extent to which the results can and should be applied to patient care. RESULTS A systematic review seeks to synthesize the medical literature about a specific clinical question using explicit methods to perform a comprehensive literature search, identify and select eligible studies, critically appraise their methods, and judiciously summarize the results considering how they vary with study characteristics. When this summary involves statistical methods, ie a meta-analysis, reviewers can offer a pooled estimate that will have greater precision and will apply more broadly than the individual studies. The quality of the underlying studies, the consistency of results across studies and the precision of the pooled estimate can considerably affect the strength of inference from systematic reviews. CONCLUSIONS Valid systematic reviews of high quality studies can increase the confidence with which urologists and patients make evidence-based decisions. Thus, urologists need to recognize the inherent limitations, understand the results and apply them judiciously to patient care.

Evaluating the evidence : the methodological and reporting quality of comparative observational studies of surgical interventions in urological publications

To develop and apply a standardized evaluation form for assessing the methodological and reporting quality of observational studies of surgical interventions in urology.

Prostatic carcinosarcoma 15 years after combined external beam radiation and brachytherapy for prostatic adenocarcinoma: A case report

A 65-year-old man with a history of combined pelvic external beam radiation therapy (EBRT) and brachytherapy for prostatic adenocarcinoma 15 years prior underwent total pelvic exenteration for presumed rectal sarcoma with prostatic invasion. Pathology revealed carcinosarcoma of prostatic origin. This patient exhibited the longest reported interval between initial presentation with prostatic adenocarcinoma and development of carcinosarcoma. This case is also the first reported case of prostatic carcinosarcoma occurring after combined EBRT and brachytherapy. The increasing use of such combination high-dose radiation therapy may potentially lead to an increased incidence of secondary malignancies such as prostatic carcinosarcoma in the future.

Sequential Intravesical Mitomycin plus Bacillus Calmette–Guérin for Non–Muscle-Invasive Urothelial Bladder Carcinoma: Translational and Phase I Clinical Trial

Purpose: To determine the safety and toxicities of sequential MMC (mitomycin C) + BCG (bacillus Calmette–Guérin) in patients with non–muscle-invasive bladder cancer (NMIBC) and explore evidence for potentiation of BCG activity by MMC. Experimental Design: A 3 + 3 phase I dose-escalation trial of six weekly treatments was conducted in patients with NMIBC. MMC (10, 20, or 40 mg) was instilled intravesically for 30 minutes, followed by a 10-minute washout with gentle saline irrigation and then instillation of BCG (half or full strength) for 2 hours. Urine cytokines were monitored and compared with levels in a control cohort receiving BCG only. Murine experiments were carried out as described previously. Results: Twelve patients completed therapy, including 3 patients receiving full doses. The regimen was well tolerated with no treatment-related dose-limiting toxicities. Urinary frequency and urgency, and fatigue were common. Eleven (91.7%) patients were free of disease at a mean (range) follow-up of 21.4 (8.4–27.0) months. Median posttreatment urine concentrations of IL2, IL8, IL10, and TNFα increased over the 6-week treatment period. A greater increase in posttreatment urinary IL8 during the 6-week period was observed in patients receiving MMC + BCG compared with patients receiving BCG monotherapy. In mice, intravesical MMC + BCG skewed tumor-associated macrophages (TAM) toward a beneficial M1 phenotype. Conclusions: Instillation of sequential MMC + BCG is safe tolerable up to 40-mg MMC plus full-strength BCG. This approach could provide improved antitumor activity over BCG monotherapy by augmenting beneficial M1 TAMs. Clin Cancer Res; 21(2); 303–11. ©2014 AACR.

Laterality of nephrocalcinosis in kidney stone formers with severe hypocitraturia

Study Type – Aetiology (case series)
Level of Evidence 4

Medical and Medical/ Urologic Approaches in Acute and Chronic Urologic Stone Disease

Urinary stone disease is a condition with far-reaching implications. Patients with their initial instance of acute renal colic enter the health care system through 2 routes. Severe cases are generally seen in the emergency room, whereas more tolerable cases may be seen by primary care physicians. Patients with urinary stone disease are then managed in the long-term by a urologist. Timely and appropriate treatment of patients with urinary stone disease is essential to prevent the development of sepsis and progressive renal insufficiency. This article reviews the epidemiology, pathogenesis, presentation, and short- and long-term management of acute and chronic urinary stone disease.

Apical soft tissue biopsies predict biochemical failure in radical perineal prostatectomy patients with apical cancer involvement

The aim of the study was to prospectively assess the role of apical soft tissue biopsies in radical perineal prostatectomy (RPP) patients with documented apical prostate cancer (PCA) involvement. Between June 1998 and May 1999, 77 consecutive men with localized PCA and documented invasion of the prostatic apex underwent RPP by a single surgeon. Soft tissue biopsies were systematically obtained from the prostatic fossa overlying the apex at the time of surgery. Time to biochemical failure was calculated using the Kaplan–Meier method. The rates of positive apical margins and positive apical soft tissue biopsies were 23.4% (18/77) and 15.6% (12/77). The sensitivity, specificity and positive predictive value of positive apical margins for residual apical disease as determined by apical soft tissue biopsy were 41.7, 80, and 28%, respectively. The overall biochemical failure rate was 28.6% (22/77) with a median follow-up of 51 months (range 3–73 months). The 36-month biochemical recurrence-free survival rate was 55.9±14.9% for patients with positive apical biopsies and 78.7±5.3% for those with negative biopsies (P=0.023). In conclusion, positive apical soft tissue biopsy is an independent predictor of biochemical failure in patients with apical PCA who undergo RPP. Positive apical surgical margins poorly predict residual apical disease that is frequently identifiable by apical soft tissue biopsy. Apical soft tissue biopsies should therefore be obtained in patients with known extensive apical cancer involvement at the time of RPP.

Understanding results: P-values, confidence intervals, and number need to treat.

Objectives: With the increasing emphasis on evidence-based medicine, the urology literature has seen a rapid growth in the number of high-quality randomized controlled trials along with increased statistical rigor in the reporting of study results. P-values, CI, and number needed to treat (NNT) are becoming increasingly common in the literature. This paper seeks to familiarize the reader with statistical measures commonly used in the evidence-based literature. Materials and Methods: The meaning and appropriate interpretation of these statistical measures is reviewed through the use of a clinical scenario. Results: The reader will be better able to understand such statistical measures and apply them to the critical appraisal of the literature. Conclusions: P-values, CI, and NNT each provide a slightly different estimate of statistical truth. Together, they provide a more complete picture of the true effect observed in a study. An understanding of these measures is essential to the critical appraisal of study results in evidence-based medicine.