Ability of a urine gene expression classifier to reduce the number of follow-up cystoscopies in bladder cancer patients.

This study aimed to improve our previous urine gene expression classifiers focusing on the detection of non-high-risk non-muscle-invasive bladder cancer (NMIBC), and develop a new classifier able to decrease the frequency of cystoscopies during bladder cancer (BC) patients' surveillance. A total of 597 urines from BC patients, controls and patients in follow-up for BC (PFBC) were included. The study has 3 phases. In the urinary biomarker discovery phase, 84 urines from BC and control patients were retrospectively included and analyzed by Ribonucleic Acid (RNA) sequencing. In the classifier development phase, a total of 132 selected genes from previous phase were evaluated by nCounter in 214 prospectively collected urines from PFBC (98 with tumor). A diagnostic classifier was generated by logistic regression. Finally, in the classifier validation phase, a multicentric and international cohort of 248 urines (134 BC and 114 nonrecurrent PFBC) was used to validate classifier performance. A total of 521 genes were found differentially expressed between non-high-risk NMIBC samples and all other groups (P < 0.05). An 8-gene diagnostic classifier with an area under curve (AUC) of 0.893 was developed. Validation of this classifier in a cohort of PFBC achieved an overall sensitivity (SN) and a negative predictive value (NPV) of 96% and 97%, respectively (AUC = 0.823). Notably, this accuracy was maintained in non-high-risk NMIBC group (SN = 94%; NPV = 98%). In conclusion, this 8-gene expression classifier has high SN and NPV in a real clinical scenario. The use of this classifier can reduce the number of follow-up cystoscopies in PFBC, although assessing its final place in clinical setting is necessary.

Gene expression test for the non-invasive diagnosis of bladder cancer: A prospective, blinded, international and multicenter validation study.

OBJECTIVE: This study aimed to validate, in a prospective, blinded, international and multicenter cohort, our previously reported four non-invasive tests for bladder cancer (BC) diagnosis based on the gene expression patterns of urine. METHODS: Consecutive voided urine samples from BC patients and controls were prospectively collected in five European centres (n=789). Finally, 525 samples were successfully analysed. Gene expression values were quantified using TaqMan Arrays and previously reported diagnostic algorithms were applied to gene expression data. Results from the most accurate gene signature for BC diagnosis were associated with clinical parameters using analysis of variance test. RESULTS: High diagnostic accuracy for the four gene signatures was found in the independent validation set (area under curve [AUC]=0.903-0.918), with the signature composed of two genes (GS_D2) having the best performance (sensitivity: 81.48%; specificity: 91.26%; AUC: 0.918). The diagnostic accuracy of GS_D2 was not affected by the number of tumours (p=0.58) but was statistically associated with tumour size (p=0.008). Also, GS_D2 diagnostic accuracy increases with increasing BC tumour risk. We found no differences in the performance of the GS_D2 test among the populations and centres in detecting tumours (p=0.7) and controls (p=0.2). CONCLUSIONS: Our GS_D2 test is non-invasive, non-observer dependent and non-labour-intensive, and has demonstrated diagnostic accuracy in an independent, international and multicenter study, equal or superior to the current gold standard (cystoscopy combined with cytology). Additionally, it has higher sensitivity than cytology while maintaining its specificity. Consequently, it meets the requirements for consideration as a molecular test applicable to clinical practice in the management of BC.

Technical solutions to improve the management of non-muscle-invasive transitional cell carcinoma: summary of a European Association of Urology Section for Uro-Technology (ESUT) and Section for Uro-Oncology (ESOU) expert meeting and current and future perspectives.

The aim of the present review was to compare state-of-the-art care and future perspectives for the detection and treatment of non-muscle-invasive transitional cell carcinoma (TCC) of the bladder. We provide a summary of the third expert meeting on 'Optimising the management of non-muscle-invasive bladder cancer, organized by the European Association of Urology Section for Uro-Technology (ESUT) in collaboration with the Section for Uro-Oncology (ESOU), including a systematic literature review. The article includes a detailed discussion on the current and future perspectives for TCC, including photodynamic diagnosis, optical coherence tomography, narrow band imaging, the Storz Professional Image Enhancement system, magnification and high definition techniques. We also provide a detailed discussion of future surgical treatment options, including en bloc resection and tumour enucleation. Intensive research has been conducted to improve tumour detection and there are promising future perspectives, that require proven clinical efficacy. En bloc resection of bladder tumours may be advantageous, but is currently considered to be experimental.

Intraoperative imprint cytology for real-time assessment of surgical margins during partial nephrectomy: A comparison with frozen section.

INTRODUCTION: Partial nephrectomy (PN) is the standard therapy for small renal masses. Resection margin assessment continues to be a key issue during PN. Biopsy of the residual kidney and intraoperative gross pathological consultations are the most common methods today. Intraoperative imprint cytology (IC) examinations have been successfully used in other tumor entities to assess surgical margins. We aim to evaluate the diagnostic value of intraoperative IC for surgical margin assessment during PN. MATERIALS AND METHODS: In addition to routinely performed frozen-section (FS) analysis, intraoperative IC examinations were performed on 114 tumors, which were resected with PN in our department between 2005 and 2010. These 2 were then matched with final histopathological examination findings. Before FS, roll-off IC slides were obtained, air dried, and stained by Hemacolor quick staining. Both the pathologist and the cytologist were blinded to the findings. RESULTS: Our study included 29 women and 76 men. Of 331 IC slides, 317 (96%) contained sufficient diagnostic cells. IC revealed 21 tumors with positive resection margins. Of the 21 positive resection margins, 2 were false positives. IC showed a specificity of 98%, sensitivity of 100%, a positive predictive value of 90%, and negative predictive value of 100%. FS examinations revealed positive resection margins in 20 tumors. One of these 20 margins was false positive. Furthermore FS examination failed to diagnose a positive resection margin in 1 tumor. FS examination showed a specificity of 99% and sensitivity of 98% in assessing surgical margins with a positive predictive value of 95% and negative predictive value 98%. CONCLUSION: IC examinations exhibit equivalent diagnostic value compared with FS analysis. IC is an inexpensive method with an ability to give rapid and highly accurate information. Like any cytological examination, there is interobserver variability. IC could be considered as an alternative to FS especially when the nature of resection margins is suspected but further investigations are necessary.

Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data.

BACKGROUND: Studies on hexaminolevulinate (HAL) cystoscopy report improved detection of bladder tumours. However, recent meta-analyses report conflicting effects on recurrence. OBJECTIVE: To assess available clinical data for blue light (BL) HAL cystoscopy on the detection of Ta/T1 and carcinoma in situ (CIS) tumours, and on tumour recurrence. DESIGN, SETTING, AND PARTICIPANTS: This meta-analysis reviewed raw data from prospective studies on 1345 patients with known or suspected non-muscle-invasive bladder cancer (NMIBC). INTERVENTION: A single application of HAL cystoscopy was used as an adjunct to white light (WL) cystoscopy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We studied the detection of NMIBC (intention to treat [ITT]: n=831; six studies) and recurrence (per protocol: n=634; three studies) up to 1 yr. DerSimonian and Laird's random-effects model was used to obtain pooled relative risks (RRs) and associated 95% confidence intervals (CIs) for outcomes for detection. RESULTS AND LIMITATIONS: BL cystoscopy detected significantly more Ta tumours (14.7%; p<0.001; odds ratio [OR]: 4.898; 95% CI, 1.937-12.390) and CIS lesions (40.8%; p<0.001; OR: 12.372; 95% CI, 6.343-24.133) than WL. There were 24.9% patients with at least one additional Ta/T1 tumour seen with BL (p<0.001), significant also in patients with primary (20.7%; p<0.001) and recurrent cancer (27.7%; p<0.001), and in patients at high risk (27.0%; p<0.001) and intermediate risk (35.7%; p=0.004). In 26.7% of patients, CIS was detected only by BL (p<0.001) and was also significant in patients with primary (28.0%; p<0.001) and recurrent cancer (25.0%; p<0.001). Recurrence rates up to 12 mo were significantly lower overall with BL, 34.5% versus 45.4% (p=0.006; RR: 0.761 [0.627-0.924]), and lower in patients with T1 or CIS (p=0.052; RR: 0.696 [0.482-1.003]), Ta (p=0.040; RR: 0.804 [0.653-0.991]), and in high-risk (p=0.050) and low-risk (p=0.029) subgroups. Some subgroups had too few patients to allow statistically meaningful analysis. Heterogeneity was minimised by the statistical analysis method used. CONCLUSIONS: This meta-analysis confirms that HAL BL cystoscopy significantly improves the detection of bladder tumours leading to a reduction of recurrence at 9-12 mo. The benefit is independent of the level of risk and is evident in patients with Ta, T1, CIS, primary, and recurrent cancer.

Hybrid renal cell carcinomas containing histopathologic features of chromophobe renal cell carcinomas and oncocytomas have excellent oncologic outcomes.

BACKGROUND: Modern histopathology is able to differentiate chromophobe renal cell carcinomas (cRCCs), oncocytomas, and chromophobe-oncocytic hybrid RCCs; however, the true frequency and clinical courses of these tumors remain unclear. OBJECTIVE: To determine the clinical course of hybrid RCC. DESIGN, SETTING, AND PARTICIPANTS: Ninety-one surgically treated tumors, originally classified as oncocytoma or cRCC, were slide reviewed and reclassified by an experienced uropathologist. Immunohistochemical cytokeratin-7 (CK7) staining was used to distinguish oncocytoma (CK7 positive in <10% of the cells) and hybrid RCCs (CK7 positive in >10% of the cells). INTERVENTIONS: Radical tumor nephrectomy or nephron-sparing surgery. MEASUREMENTS: Recurrence-free and tumor-specific survival. RESULTS AND LIMITATIONS: Overall, 16 tumors (17.6%) were hybrid RCCs, 32 tumors were cRCCs, and 43 tumors were pure oncocytomas. Perinephric tissue invasion (pT3a) was found in one pure oncocytoma and in two hybrid RCCs. The pathologic stage for cRCC was pT1 in 50% of tumors (n=17), pT2 in 23.5% of tumors (n=8), and pT3a in 26.5% of tumors (n=9). Low-grade RCC was found in 76.5% of tumors (n=26), and vascular invasion was found in 11.8% of tumors (n=4). After a mean follow-up of 50 mo, no oncocytomas or hybrid RCCs were found, but two cRCCs had recurred. The 3-yr tumor-specific survival rates for patients with oncocytoma, hybrid RCCs, and cRCC were 100%, 100%, and 97%, respectively. CONCLUSIONS: Hybrid RCCs are more common than expected. The survival rate is 100% for both hybrid RCCs and oncocytomas. Hybrid RCCs may be candidates for active surveillance, and surgery may be unnecessary. CRCCs should be treated because a small proportion of these tumors exhibit aggressive clinical courses.

Fluorescence cystoscopy with high-resolution optical coherence tomography imaging as an adjunct reduces false-positive findings in the diagnosis of urothelial carcinoma of the bladder.

BACKGROUND: The advantage of photodynamic diagnosis in detecting urothelial cell carcinoma (UCC) of the bladder has been demonstrated clearly, but it comes at the price of a higher false-positive rate. Optical coherence tomography (OCT) is a noninvasive, real-time, microstructural imaging modality that uses near-infrared light for a point analysis of the bladder-wall microstructure. OBJECTIVE: To evaluate whether adding targeted OCT analysis of lesions that are suspicious at white-light (WL) and hexaminolevulinate (HAL) fluorescence cystoscopy improves diagnostic accuracy in the detection of UCC. DESIGN, SETTING, AND PARTICIPANTS: In this prospective single-center study with same-patient comparison, patients with suspected UCC first received an intravesical instillation of HAL. Cystoscopy was performed in WL, followed by blue-light inspection and OCT scanning. INTERVENTION: Suspicious lesions identified by WL or HAL were evaluated by OCT and were subsequently resected or biopsied. MEASUREMENTS: We measured changes in sensitivity and specificity in detecting UCC using WL, HAL, and targeted OCT. RESULTS AND LIMITATIONS: In 66 patients studied, 232 lesions were detected, were scanned by OCT, and were subsequently resected or biopsied. Additionally, 132 areas of normal-appearing urothelium were investigated by all three methods and biopsied. On a per-lesion basis, sensitivity and specificity were respectively 69.3% and 83.7% for WL, 97.5% and 78.6% for HAL, and 97.5% and 97.9% for HAL combined with OCT. Overall, UCC was diagnosed in 58 patients (87.9%), with a per-patient sensitivity of 89.7% for WL and 100% for both HAL alone and HAL with targeted OCT. Per-patient specificity for HAL alone and targeted HAL was 62.5% and 87.5%, respectively. The limitation of OCT results from poor visualization of flat lesions in WL, making scanning a time-consuming procedure. CONCLUSIONS: Combining fluorescence cystoscopy with targeted OCT increases the specificity of fluorescence cystoscopy significantly, with no added morbidity, and reduces the need for unnecessary (false-positive) biopsies.

Follow-up of nonmuscle invasive transitional cell carcinoma of the bladder: how and how often?

PURPOSE OF REVIEW: Nonmuscle invasive bladder cancer represents a heterogeneous disease due to different natural history of its various appearances. The purpose of this article is to review recent literature regarding follow-up strategies. RECENT FINDINGS: Management of nonmuscle invasive bladder cancer has become more complex in respect to diagnosis, treatment and follow-up. Follow-up should therefore be based on individual patient-risk assessment. In addition to improved diagnosis by fluorescence-guided cystoscopy and other new diagnostic tools like optical-coherence tomography management has concentrated on optimizing different concepts of intravesical therapy. SUMMARY: The intent of nonmuscle invasive bladder cancer management is to control recurrence and progression and to identify invasive tumours at the earliest possible stage. To obtain exact staging, besides a proper transurethral resection of bladder, a restaging transurethral resection of bladder should be performed in T1 patients. Data from the literature supports the immediate postoperative intravesical instillation of different chemotherapeutic agents in low-risk patients. Multifocal papillary lesions might necessitate a more intensive adjuvant regimen, whereas intravesical immunotherapy using bacillus Calmette-Guerin is recommended in patients who are at a high-risk of progression. Early cystectomy should be considered in patients with recurrent T1 tumours or refractory carcinoma in situ to avoid unfavourable tumour progression.

Diagnostic accuracy of computed tomography-guided percutaneous biopsy of renal masses.

OBJECTIVE: Modern imaging modalities increase the detection of small (

Are small renal tumors harmless? Analysis of histopathological features according to tumors 4 cm or less in diameter.

PURPOSE: Small renal tumors detected incidentally are considered to have less aggressive potential. This assumption is mainly based on the low tendency to increase in size on serial imaging studies, but histopathological parameters of progression in larger patient series are scant. MATERIALS AND METHODS: We reviewed data of 287 tumor bearing kidneys in which solid tumors 4 cm or less in diameter were detected by cross-sectional imaging and subsequently removed surgically. Tumor size as documented by preoperative computerized tomography was correlated to histological diagnosis, and in cases of malignancy correlated to tumor type, pathological TNM stage and nuclear (Fuhrman) grade. With multifocal lesions the largest single tumor was considered the reference lesion but multifocality was also considered a separate parameter. RESULTS: At a mean tumor diameter of 2.94 +/- 0.87 cm 65 (22.6%) tumors were 2 cm or less, 103 (35.9%) were 2.1 to 3.0 cm and 119 (41.5%) were 3.1 to 4 cm in diameter. A total of 56 (19.5%) tumors were benign with no correlation to tumor size (Pearson test p = 0.660). Renal cell cancer was found in 227 (79.1%) patients with 159 (70.0%) clear cell, 47 (20.7%) papillary, 11 (4.8%) chromophobe and 10 others with no correlation to tumor diameter. Of the kidneys 31 (13.6%) had multifocal renal cell carcinoma, with a significant correlation to larger tumor diameter (linear regression p = 0.048) and papillary renal cell carcinoma subtype (linear regression p = 0.018). Two (4.2%), 4 (5%) and 25 (25.5%) cases of renal cell carcinoma 2 cm or less, 2.1 to 3 cm and 3.1 to 4 cm in diameter had Fuhrman grade G3/4, respectively (Pearson p = 0.0007). Advanced stage (pT3a or greater) was documented in 2 (4.2%), 12 (14.9%) and 35 (35.7%) cases for the same categories, respectively (p = 0.0023). Whereas distant metastases were diagnosed in only 4 patients with renal cell carcinoma with tumors 3 cm or less, distant metastases were in 10 (8.4%) patients with tumors 3.1 to 4 cm (p = 0.045). CONCLUSIONS: The aggressive potential of small renal cell carcinoma increases dramatically beyond a tumor diameter of 3 cm. Given the difficulty in measuring tumor diameters reliably with sequential imaging studies, the threshold for selecting patients for a surveillance strategy should be set well under this parameter.

Nephrovesical subcutaneous ureteric bypass: long-term results in patients with advanced metastatic disease-improvement of renal function and quality of life.

OBJECTIVE: Placing a percutaneous nephrostomy often is the only and final solution for patients with metastatic disease, where internal ureteral stenting proved to be impossible. METHODS: Between August 1999 and June 2005, 31 nephrovesical ureteric bypasses were implanted in 28 patients with advanced metastatic disease. The ureteric bypass consists of two subcutaneously connected 12F polyurethane tubes, placed as a nephrostomy and cystostomy. Urinary culture, serum creatinine, quality of life score, and renal ultrasonography were evaluated at follow-up. RESULTS: Mean follow-up was 11.9 mo (range, 2-54 mo). Preoperative hydronephrosis was eliminated in 27 cases (87.1%) and reduced in the remaining four kidneys (12.9%). Preoperative serum creatinine levels (5.9+/-3.2 mg%) decreased significantly postoperatively (1.4+/-0.9 mg%). Mean quality of life score was 3.4+/-1.4 preoperatively and 7.6+/-1.0 postoperatively. In five patients (17.9%) the system had to be replaced due to occlusion at a mean follow-up of 10.2 mo. CONCLUSION: This nephrovesical ureteric bypass is a simple, minimally invasive, and highly effective treatment for patients with hydronephrosis resulting from advanced oncologic disease. Patients gain a better quality of life due to increased independence and mobility during their final stages of life.