Vladimir Yutkin

Extracorporeal shock wave lithotripsy in prepubertal children: 22-year experience at a single institution with a single lithotriptor.

PURPOSE The sophistication of percutaneous nephrolithotomy and ureteroscopy challenges the efficacy of ESWL for urolithiasis in prepubertal patients. We evaluated our long-term experience with ESWL in these patients and determined its efficiency. MATERIALS AND METHODS We retrospectively reviewed the charts of all prepubertal patients who underwent ESWL. We evaluated the need for tubing, the 3-month stone-free rate, the need for additional ESWL, and the effect of stone size and location, and cystinuria on the 3-month stone-free rate. RESULTS Between 1986 and 2008, 119 males and 97 females with a mean age of 6.6 years who had urolithiasis underwent ESWL using the Dornier HM3 lithotriptor. We treated 157 children with renal calculi with an average +/- SD diameter of 14.9 +/- 8.9 mm, of whom 66 (42%) required a tube in the urinary system. The 3-month stone-free rate was 80% and 31 patients (19.7%) needed an additional procedure. Stone location did not affect the stone-free rate but stone size did. We treated 59 patients for ureteral stones with an average stone length of 9.5 +/- 4.8 mm, of whom 41 (69%) required tube insertion. The 3-month stone-free rate was 78% and 13 patients (22%) needed an additional procedure. The 3-month stone-free rate did not depend on stone location or size. The rate was 37.5% in patients with cystinuria and 82.5% in all others (p <0.0001). Six patients (2.8%) had complications. CONCLUSIONS The 3-month stone-free rate after ESWL in prepubertal patients is 80% and 20% of patients require additional procedures. ESWL is most effective for kidney stones less than 11 mm. ESWL has inferior results for cystine stones compared to other calculi. Complications are rare.

β-TrCP Inhibition Reduces Prostate Cancer Cell Growth via Upregulation of the Aryl Hydrocarbon Receptor

Background Prostate cancer is a common and heterogeneous disease, where androgen receptor (AR) signaling plays a pivotal role in development and progression. The initial treatment for advanced prostate cancer is suppression of androgen signaling. Later on, essentially all patients develop an androgen independent stage which does not respond to anti hormonal treatment. Thus, alternative strategies targeting novel molecular mechanisms are required. β-TrCP is an E3 ligase that targets various substrates essential for many aspects of tumorigenesis. Methodology/Principal Findings Here we show that β-TrCP depletion suppresses prostate cancer and identify a relevant growth control mechanism. shRNA targeted against β-TrCP reduced prostate cancer cell growth and cooperated with androgen ablation in vitro and in vivo. We found that β-TrCP inhibition leads to upregulation of the aryl hydrocarbon receptor (AhR) mediating the therapeutic effect. This phenomenon could be ligand independent, as the AhR ligand 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) did not alter prostate cancer cell growth. We detected high AhR expression and activation in basal cells and atrophic epithelial cells of human cancer bearing prostates. AhR expression and activation is also significantly higher in tumor cells compared to benign glandular epithelium. Conclusions/Significance Together these observations suggest that AhR activation may be a cancer counteracting mechanism in the prostate. We maintain that combining β-TrCP inhibition with androgen ablation could benefit advanced prostate cancer patients.

Is radical cystectomy mandatory in every patient with variant histology of bladder cancer.

Urothelial carcinomas have an established propensity for divergent differentiation. Most of these variant tumors are muscle invasive but not all. The response of non muscle invasive variant tumors to intravesical immunotherapy with BCG is not established in the literature, and is reported here. Between June 1995 and December 2007, 760 patients (mean age of 67.5 years) underwent transurethral resection of first time bladder tumors in our institution. Histologically variant tumors were found in 79 patients (10.4%). Of these 57 patients (72%) of them had muscle-invasive disease or extensive non-muscle invasive tumors and remaining 22 patients (28%) were treated with BCG immunotherapy. These included 7 patients with squamous differentiation, 4 with glandular, 6 with nested, 4 with micropapillary and 1 patient with sarcomatoid variant. The response of these patients to immunotherapy was compared with that of 144 patients having high-grade conventional urothelial carcinomas. Median follow-up was 46 months. The 2 and 5-year progression (muscle-invasion) free survival rates were 92% and 84.24% for patients with conventional carcinoma compared to 81.06% and 63.16% for patients with variant disease (P=0.02). The 2 and 5-year disease specific survival rates were 97% and 91.43% for patients with conventional carcinoma compared to 94.74 % and 82% for patients with variant disease (P=0.33). 5 patients (22.7%) of variant group and 13 patients (9.03%) of conventional group underwent cystectomy during follow-up (P=0.068). Patients with non-muscle invasive variants of bladder cancers can be managed with intravesical immunotherapy if tumor is not bulky (>4 cm). Although progression to muscle invasive disease is more common than in conventional group and occurs in about 40% of the patients, life expectancy is similar to patients with conventional high-grade urothelial carcinomas provided that follow-up is meticulous.

Radical cystectomy vs. chemoradiation in T2-4aN0M0 bladder cancer: A case-control study

BACKGROUND Muscle-invasive bladder cancer is most commonly treated by radical cystectomy. Patients who are too sick to go through this surgery or who are unwilling to accept the mutilation associated with it are referred to chemoradiation. We compared the results of these 2 modalities using age-matched populations. PARTICIPANTS AND METHODS Between 1998 and 2008, 33 patients were treated with chemoradiation for biopsy-proven T2-4aN0M0 urothelial bladder cancer. For every patient treated with chemoradiation, an age-matched patient who underwent radical cystectomy on the same year was selected for comparison. Mean radiotherapy dose was 62 Gy (standard deviation = 8.4) and median follow-up of both groups was approximately 36 months. RESULTS The groups were similar in age, proportion of men, and length of follow-up. However, the Charlson comorbidity index was significantly lower for operated patients (3.45 vs. 4.36, P = 0.01). Furthermore, 2 patients (6%) in the chemoradiation group had salvage cystectomy (one for disease recurrence and another for bladder shrinkage). The 2- and 5-year overall survival rates after surgery were 74.4% and 54.8%, respectively, and after chemoradiation were 70.2% and 56.6% (P = 0.8), respectively. The 2- and 5-year disease-free survival rates after surgery were 67.8% and 63.2%, respectively, and after chemoradiation were 63% and 54.3% (P = 0.89), respectively. Side effects were mild in both groups, with grade 3+toxicity seen in only 2 operated and 4 irradiated patients. CONCLUSIONS Despite having a significantly higher comorbidity index, patients treated with chemoradiation had similar overall and disease-free survival rates with low toxicity. Treatment with chemoradiation should be considered in patients with T2-4aN0M0 bladder cancer.

External Validation of CROES Nephrolithometry as a Preoperative Predictive System for Percutaneous Nephrolithotomy Outcomes.

PURPOSE We externally validated CROES (Clinical Research Office of the Endourological Society) nephrolithometry and evaluated the predictive accuracy of the nomogram. MATERIALS AND METHODS Data were collected on patients who underwent percutaneous nephrolithotomy between January 2012 and February 2015. The CROES nomogram was applied to all patients and externally validated. The AUC and calibration plot were used for discrimination and clinical validity assessment. RESULTS A total of 176 patients were included in study. Mean ± SD patient age was 55.2 ± 13.9 years and the mean stone burden was 640.0 ± 911.4 mm(2). The CROES nomogram was significantly associated with stone number, location and burden, and the number of implicated calyces, punctures and tracts. The postoperative treatment success rate was 85.8%. The number of stones, number of implicated calyces and CROES score were independent predictors of treatment success. The estimated AUC was 0.715 and the model provided good calibration. CONCLUSIONS The CROES nomogram is an accurate tool to estimate renal stone complexity. CROES nephrolithometry provides great accuracy to predict postoperative efficacy.

Can urinary biomarkers replace cystoscopic examination in bladder cancer surveillance

Non-muscle-invasive bladder tumors comprise more than 80% of newly diagnosed cases of bladder cancer and are often cured by transurethral surgery, with or without intravesical chemotherapy or immunotherapy. However, more than 50% of patients develop recurrent tumors [1] and in 10–15% of them, progression to a higher grade or a higher stage occurs [2]. After endoscopic removal of the tumors, lifelong surveillance is recommended, which makes bladder cancer one of the most expensive cancers to manage from diagnosis to death [3]. The American Urological Association and the European Association of Urology have published similar guidelines for follow-up, which include periodic cystoscopy and urine cytology [4,5]. Although cystoscopy with a flexible endoscope is less painful than rigid cystoscopy, it is still an invasive and unpleasant procedure. It may also miss flat tumors, such as carcinoma in situ . [6]. Urine cytology is highly sensitive for detecting high-grade tumors (79%) but is limited by low sensitivity (26%) in detecting low-grade tumors, which constitute the majority of recurrent bladder tumors. These limitations have led to an extensive effort to find alternative, noninvasive techniques for the detection of recurrent bladder tumors. Investigators have examined various techniques to detect exfoliated malignant cells in urine samples: flow cytometry, computerized image cytometry, immunostaining of the Lewis X antigen, cytokeratin 20 and other markers. Flow cytometry requires bladder washings, which are as invasive as cystoscopy, to obtain a sufficient number of exfoliated cells. Immunocytology of cells from voided urine using various monoclonal anti bodies has resulted in better sensitivity than that obtained by cytology. The evaluation of immunocytology slides is much simpler than that of cytopathology since the only criterion for a positive result is the presence of a significant number of cells with a typical red–brown color. However, these assays can be quite laborious. The results of immunocytology depend not only on the antibodies used but also on the technique of slide preparation. Poor preservation of cells, pyuria and an insufficient number of cells has prevented the evaluation of many samples. Only one immunocytochemical test has become commercially available: Immunocyt/uCyt+TM. It uses fluorescentlabeled antibodies to three antigens that are commonly found on malignant urothelial cells. This test has demonstrated high sensitivity for low-grade tumors but a relatively high rate of false-positive results, especially after intravesical treatment with bacillus Calmette–Guérin (BCG) (Table 1). Other investigators have used molecular techniques such as real-time PCR for survivin and cytokeratin 20, microsatellite ana lysis, gene-expression microarrays and FISH in order to detect genetic alterations that occur during malignant transformation of the urothelium. The UroVysion assay is a commercially available, US FDAapproved assay designed to detect aneuploidy for chromosomes 3, 7 and 17 and loss of the 9p21 locus using FISH in cells from urine specimens. Vladimir Yutkin

The Response of Variant Histology Bladder Cancer to Intravesical Immunotherapy Compared to Conventional Cancer

Background High-grade urothelial carcinomas (UCs) often show foci of variant differentiation. There is limited information in the literature about the response of these variant urothelial tumors to immunotherapy with bacillus Calmette–Guerin (BCG). We compared the response, to treatment with BCG, of UC containing glandular, squamous, nested, and micropapillary types of differentiation to response of conventional non-muscle invasive high-grade UC. Methods A total of 100 patients were diagnosed with variant histology urothelial cancer between June 1995 and December 2013. Forty-one patients with Ta or T1, confirmed by second look biopsies, received immunotherapy with BCG. Fourteen patients in this group were diagnosed with micropapillary differentiation, 13 patients with squamous differentiation, 9 patients with glandular differentiation, and 7 patients with nested variants. The control group included 140 patients with conventional high-grade UC. Both groups have been treated and followed similarly. Findings Patients with variant tumors had similar clinical features to patients with conventional disease, including age, male to female ratio, stage, the presence of Tis, and median follow-up. Patients with variant tumors had a significantly worse prognosis compared to patients with conventional high-grade UC, including 5-year recurrence-free survival (63.5 Vs. 71.5%, p = 0.05), 5-year progression (≥T2)-free survival (60 Vs. 82.5%, p = 0.002), 5-year disease-specific survival (73 Vs. 92.5%, p = 0.0004), and overall survival (66 Vs. 89.5%, 0.05). Interpretation A patient with variant bladder cancer treated with intravesical immunotherapy has a 27% chance of dying from this disease within 5 years compared to 7.5% chance for a patient with conventional high-grade UC.

Predicting the Risk of High-Grade Bladder Cancer Using Noninvasive Data

Aim: To examine the hypothesis that the risk of high-grade bladder cancer can be predicted using noninvasively obtained data. Patients and Methods: We retrospectively analyzed the database of 431 patients that had transurethral resection of first-time bladder tumors between June 1998 and December 2009. Pre-operative parameters evaluated were: patients’ age; gender; sonographic tumor diameter, number and location of tumor inside the bladder; presence of hydronephrosis, and results of urinary cytology. Parameters that showed significance in multivariate analysis were incorporated into the nomogram. Results: Multivariate analysis of the data showed that patient’s age, the presence of hydronephrosis, sonographic tumor diameter (risk of a high-grade tumor: 14, 29, 43.3, 55.7 and 69.4% at diameters: 0.5–1.5, 1.6–2, 2.1–2.5, 2.6–3 and >3 cm, respectively), location of tumor in the bladder (risk of high-grade tumor: 28.8, 47, 67.5 and 90.5% in the lateral walls, posterior/base, anterior and dome, respectively), and urinary cytology were all highly significant and independent predictors of high-grade tumors. A nomogram constructed using these variables scored an area of 0.853 in the ROC curve. Conclusions: The risk of high-grade bladder tumor can be accurately predicted using non-invasively obtained information. This prediction can help to triage patients with newly detected bladder cancer for biopsy.

Prevention of renal stone disease recurrence. A systematic review of contemporary pharmaceutical options

Introduction: Renal stone disease has a high recurrence rate. Prompt metabolic evaluation followed by appropriate medical management is of paramount importance for preventing disease recurrence. Areas covered: A PubMed/Medline search was performed to identify randomized controlled studies evaluating medical treatments against renal stone recurrence. Due to the limited number of published randomized studies, non-randomized studies of significant importance were included and reported. Expert opinion: Thiazides are widely used for lowering calcium levels in urine and thus preventing calcium stone formation. Citrate supplements may increase the urine citrate level and increase pH. Allopurinol has shown significant efficacy for preventing formation of calcium stones in hyperuricosuric patients. Prevention of recurrence of infection stones and cystine stones has not been widely studied. Several agents that are used today have shown efficacy outside randomized controlled studies. However, they may produce severe adverse events, which are minimizing their use.

History of Ureteral Stenting Negatively Affects the Outcomes of Extracorporeal Shockwave Lithotripsy. Results of a Matched-pair Analysis

To evaluate the impact of ureteral stenting history to the outcomes of extracorporeal shockwave lithotripsy, we retrospectively analysed patients who underwent shockwave lithotripsy with Dornier Gemini lithotripter between September 2010 and August 2012. Forty seven patients (group A) who had a double J stent which was removed just before the procedure were matched-paired with another 47 patients (group B) who underwent shockwave lithotripsy having no stent history. The correlation between ureteral stenting history and stone-free rates was assessed. Stone-free rates were 68.1% and 87.2% for patients of group A and B, respectively (p=0.026). Postoperative complications were not different between groups. Multivariate analysis revealed that stone size (p=0.007), stone location (p=0.044) and history of ureteral stenting (p=0.046) were independent predictors for stone clearance after shockwave lithotripsy. Ureteral stents adversely affect shockwave lithotripsy outcome, even if they are removed before the procedure. Stenting history should divert treatment plan towards intracorporeal lithotripsy.