David R. Yates

Promoter hypermethylation identifies progression risk in bladder cancer.

Purpose: New methods to accurately predict an individual tumor behavior are urgently required to improve the treatment of cancer. We previously found that promoter hypermethylation can be an accurate predictor of bladder cancer progression, but it is not cancer specific. Here, we investigate a panel of methylated loci in a prospectively collected cohort of bladder tumors to determine whether hypermethylation has a useful role in the management of patients with bladder cancer. Experimental Design: Quantitative methylation-specific PCR was done at 17 gene promoters, suspected to be associated with tumor progression, in 96 malignant and 30 normal urothelial samples. Statistical analysis and artificial intelligence techniques were used to interrogate the results. Results: Using log-rank analysis, five loci were associated with progression to more advanced disease (RASSF1a, E-cadherin, TNFSR25, EDNRB, and APC; P < 0.05). Multivariate analysis revealed that the overall degree of methylation was more significantly associated with subsequent progression and death (Cox, P = 0.002) than tumor stage (Cox, P = 0.008). Neuro-fuzzy modeling confirmed that these five loci were those most associated with tumor progression. Epigenetic predictive models developed using artificial intelligence techniques identified the presence and timing of tumor progression with 97% specificity and 75% sensitivity. Conclusion: Promoter hypermethylation seems a reliable predictor of tumor progression in bladder cancer. It is associated with aggressive tumors and could be used to identify patients with either superficial disease requiring radical treatment or a low progression risk suitable for less intensive surveillance. Multicenter studies are warranted to validate this marker.

Molecular Detection of Localized Prostate Cancer Using Quantitative Methylation-Specific PCR on Urinary Cells Obtained Following Prostate Massage

Purpose: The diagnosis of localized prostate cancer is difficult due to a lack of cancer-specific biomarkers. Many patients require repeat prostate biopsies to diagnose the disease. We investigated whether aberrant promoter hypermethylation in prostatic fluid could reliably detect prostate cancer. Experimental Design: Urine samples were collected after prostate massage from 95 patients with localized prostate cancer undergoing radical prostatectomy (63 pT1, 31 pT2, and 1 pT3) and from 38 control patients. Ten genes (GSTP1, RASSF1a, ECDH1, APC, DAPK, MGMT, p14, p16, RARβ2, and TIMP3) were investigated using quantitative real-time methylation-specific PCR. Receiver operator curves were generated. Results: The frequency of gene methylation ranged from 6.3% (p14) to 83.2% (GSTP1) in prostate cancer patients. At least one gene was hypermethylated in 93% of cancer patients. The specificity of methylation was 0.74. Methylation was significantly more frequent (P < 0.05) in cancer than control patients for all genes except p14 and p16. According to receiver operator curve analysis, the four-gene combination of GSTP1 (0.86), RASSF1a (0.85), RARβ2 (0.80), and APC (0.74) best discriminated malignant from nonmalignant cases. The sensitivity and accuracy of this four-gene set were 86% and 89%, respectively. Conclusions: The presence of aberrant methylation in urinary cells obtained after prostate massage is significantly associated with prostate cancer. A panel of four genes could stratify patients into low and high risk of having prostate cancer and optimize the need for repeat prostatic biopsies.

Upper Urinary Tract Urothelial Cell Carcinomas and Other Urological Malignancies Involved in the Hereditary Nonpolyposis Colorectal Cancer (Lynch Syndrome) Tumor Spectrum

CONTEXT The data describing the urologic extracolonic cancers associated with hereditary nonpolyposis colorectal cancer (HNPCC) are variable. OBJECTIVE Provide an update about the current urologic tumor spectrum in HNPCC. EVIDENCE ACQUISITION Data on HNPCC extracolonic tumor spectrum published in the literature were analysed using MEDLINE with emphasis on urological malignancies, upper tract tumors, clinical criteria, genetic diagnosis and counselling. EVIDENCE SYNTHESIS HNPCC is a form of colorectal cancer with a dominant autosomal mode of inheritance. HNPCC is caused by germ-line mutations affecting one or several mismatch repair genes. Cancers other than colorectal cancer are sometimes associated with HNPCC. These include specific urological malignancies, most notably tumors of the upper urinary tract, which have been reported to occur at a rate x22 higher than the general population. Upper urinary tract tumors rank third (5%) after colon (63%) and endometrial (9%) cancer within the group of HNPCC related tumors. Prostate cancer and testicular germ cell tumors are rarely associated. Due to lack of appreciation of such hereditary associations, some inherited cancers are still misclassified as sporadic and their incidence is underestimated. The biological tests requested in suspected cases of HNPCC are: microsatellite instability (MSI) analysis, immunohistochemistry and DNA sequencing. When gene mutations are detected, the patient and their family will benefit from a multidisciplinary management approach. The presence of other HNPCC-associated cancers is sought and close monitoring of patients is undertaken. Genetic counselling is provided to the patients family. CONCLUSIONS The recognized urologic tumor spectrum in HNPCC includes upper tract tumors. However, in order not to overlook a hereditary cancer, urologists should be aware of the possible urological malignancies associated with HNPCC (i.e., prostate and testicular carcinomas) and evaluate appropriately anyone they feel are at high risk of underlying HNPCC based on set clinical criteria.

Methylational urinalysis: a prospective study of bladder cancer patients and age stratified benign controls.

Tumour suppressor gene (TSG) methylation has been proposed as a diagnostic marker for urothelial cancer (UC). Here, we compare the frequency of urinary TSG methylation in young and elderly patients, with and without UC. Urine samples were obtained prospectively from 35 UC patients, 35 benign controls over the age of 70 years and 34 healthy volunteers under the age of 40 years. Methylation analysis was performed for eight gene promoters using quantitative methylation-specific PCR. Methylation was detected in urine DNA from all three patient groups. The highest frequencies were seen in UC patients. Significantly less methylation was present in control samples than UC cases for RASSF1a and APC (P<0.034). The ‘methylation index’ and level of methylation was highest in the UC group and lowest in the young control group. A marker panel of RASSF1a, E-cad and APC generated a sensitivity of 69%, a specificity of 60% and a diagnostic accuracy of 86%. TSG methylation is detectable in urine DNA from patients with and without bladder cancer. The frequency and extent of methylation appears to increase with age and malignancy. The lack of tumour specificity suggests that further investigation is required before this test is introduced into clinical practice.

Prediction of Cancer Specific Survival After Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: Development of an Optimized Postoperative Nomogram Using Decision Curve Analysis

PURPOSE We conceived and proposed a unique and optimized nomogram to predict cancer specific survival after radical nephroureterectomy in patients with upper tract urothelial carcinoma by merging the 2 largest multicenter data sets reported in this population. MATERIALS AND METHODS The international and the French national collaborative groups on upper tract urothelial carcinoma pooled data on 3,387 patients treated with radical nephroureterectomy for whom full data for nomogram development were available. The merged study population was randomly split into the development cohort (2,371) and the external validation cohort (1,016). Cox regressions were used for univariable and multivariable analyses, and to build different models. The ultimate reduced nomogram was assessed using Harrells concordance index (c-index) and decision curve analysis. RESULTS Of the 2,371 patients in the nomogram development cohort 510 (21.5%) died of upper tract urothelial carcinoma during followup. The actuarial cancer specific survival probability at 5 years was 73.7% (95% CI 71.9-75.6). Decision curve analysis revealed that the use of the best model was associated with benefit gains relative to the prediction of cancer specific survival. The optimized nomogram included only 5 variables associated with cancer specific survival on multivariable analysis, those of age (p = 0.001), T stage (p <0.001), N stage (p = 0.001), architecture (p = 0.02) and lymphovascular invasion (p = 0.001). The discriminative accuracy of the nomogram was 0.8 (95% CI 0.77-0.86). CONCLUSIONS Using standard pathological features obtained from the largest data set of upper tract urothelial carcinomas worldwide, we devised and validated an accurate and ultimate nomogram, superior to any single clinical variable, for predicting cancer specific survival after radical nephroureterectomy.

The role of chemotherapy in the treatment of urothelial cell carcinoma of the upper urinary tract (UUT-UCC).

OBJECTIVE Urothelial cell carcinoma of the upper urinary tract (UUT-UCC) is a rare, aggressive urologic cancer with a propensity for multifocality, local recurrence, and metastasis. This review highlights the main chemotherapy regimens available for UUT-UCCs based on the recent literature. MATERIALS AND METHODS Data on urothelial malignancies and UUT-UCCs management in the literature were searched using MEDLINE and by matching the following key words: urinary tract cancer; urothelial carcinomas; upper urinary tract; carcinoma; transitional cell; renal pelvis; ureter; bladder cancer; chemotherapy; nephroureterectomy; adjuvant treatment; neoadjuvant treatment; recurrence; risk factors; and survival. RESULTS No evidence level 1 information from prospective randomized trials was available. Because of its many similarities with bladder urothelial carcinomas, chemotherapy with a cisplatin-containing regimen is often proposed in patients with metastatic or locally advanced disease. Most teams have proposed a neoadjuvant or an adjuvant treatment based either on the combination of methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) or on gemcitabine/cisplatin (GC). These regimens have been shown to prolong survival moderately. All recent studies have included limited numbers of patients and have reported poor patient outcomes after both neoadjuvant and adjuvant chemotherapy. Regarding metastatic UUT-UCCs, vinflunine has demonstrated moderate activity in these patients with a manageable toxicity. Interestingly, specific molecular markers [microsatellite instability (MSI), E-cadherin, HIF-1α, and RNA levels of the telomerase gene] can provide useful information that can help diagnose and determine patient prognosis in patients with UUT-UCC. CONCLUSION Chemotherapy with a cisplatin-containing regimen is often proposed in patients with metastatic or locally advanced disease. However, there is no strong evidence that chemotherapy is effective due to the rarity of the disease and the lack of data in the current literature. Thus, physicians must take into account the specific clinical characteristics of each individual patient with regard to renal function, medical comorbidities, tumor location, grade, and stage, and molecular marker status when determining the optimal treatment regimen for their patients. The ongoing identification of the oncologic mechanisms of this type of cancer might pave the way for the development of specific treatments that are targeted to the characteristics of each patients tumor in the future.

Promoter hypermethylation in circulating blood cells identifies prostate cancer progression.

Promoter hypermethylation of circulating cell DNA has been advocated as a diagnostic marker for prostate cancer, but its prognostic use is currently unclear. To assess this role, we compared hypermethylation of circulating cell DNA from prostate cancer patients with (Group 1, n = 20) and without (Group 2, n = 22) disease progression and age‐matched controls (benign prostatic hyperplasia, Group 3, n = 22). We measured hypermethylation of 10 gene promoters in 2 sequential venous samples, obtained at diagnosis and during disease progression (median time, 15 months later). Matched time samples were obtained in the nonprogressing patients. We found that more hypermethylation was detected in the diagnostic sample from the patients with cancer than in controls for GSTP1, RASSF1a, APC and RARβ (p < 0.0001). Patients undergoing disease progression had a significant increase in methylation levels of these 4 genes when compared to the other patients (p < 0.001). Patients at risk of disease progression have higher detectable concentrations of circulating cell hypermethylation, than those without progression. The extent of this hypermethylation increases during disease progression and can be used to identify the extent and duration of treatment response in prostate cancer.

Treatment Options Available for Bacillus Calmette-Guérin Failure in Non–muscle-invasive Bladder Cancer

CONTEXT Intravesical bacillus Calmette-Guérin (BCG) is a standard conservative treatment for patients with high-risk non-muscle-invasive bladder cancer (NMIBC). Many patients will experience recurrence or progression following BCG and are termed BCG failures. OBJECTIVE To summarise the current treatment options available for patients with high-risk NMIBC who experience BCG failure. EVIDENCE ACQUISITION We searched the Medline, Embase, and Cochrane Trials databases for studies of BCG failure using predetermined relevant Medical Subject Heading terms and free text terms. EVIDENCE SYNTHESIS Radical cystectomy (RC) should be strongly recommended when a patient has been deemed to fail BCG, if the patient is fit and fully informed of the risks, benefits, and quality-of-life issues. RC achieves long-term survival in excess of 90% with ongoing improvements in morbidity. While other salvage intravesical therapies have to be considered oncologically inferior to RC, several options are now available if bladder preservation is the objective. The options can be categorised as immunotherapy, chemotherapy, device-assisted therapy, and sequential combinations of these newer modalities with conventional therapy. Some agents have shown specific promise in BCG-failure patients (eg, gemcitabine, thermochemotherapy, taxane chemotherapy), and some modalities have been shown to be effective only in non-BCG-failure cohorts (eg, electromotive mitomycin). CONCLUSIONS The definition, prediction, and treatment of BCG failure remain unclear secondary to inconsistent studies and the heterogeneous entity of patients with NMIBC. RC should be the default position upon failing BCG, but if bladder preservation is sought, then several promising intravesical salvage options are available. It will be necessary to individually tailor the management of such patients based on tumour risk and medical profiles. Currently data are still inadequate to formulate definitive recommendations, and larger studies of salvage intravesical agents are urgently required.

From Leonardo to da Vinci: the history of robot‐assisted surgery in urology

Whats known on the subject? and What does the study add?

A comparison of the performance of microsatellite and methylation urine analysis for predicting the recurrence of urothelial cell carcinoma, and definition of a set of markers by Bayesian network analysis

To compare the potential of two diagnostic methods for detecting recurrence of urothelial cell carcinoma (UCC) of the bladder, by (i) detecting alterations in microsatellite DNA markers and loss of heterozygosity (LOH), and (ii) detecting aberrant gene hypermethylation, as UCC has a high recurrence rate in the urinary tract and the disease can invade muscle if new tumours are overlooked.