Risk Of Urothelial Carcinoma Research Articles

Evaluation of Sienna Cancer Diagnostics hTERT Antibody on 500 Consecutive Urinary Tract Specimens

Objectives: Telomerase activity can be detected in up to 90% of urothelial carcinomas (UC). Telomerase activity can also be detected in urinary tract cytology (UTC) specimens and indicate an increased risk of UC. We evaluated the performance of a commercially available antibody that putatively binds the telomerase reverse transcriptase (hTERT) subunit on 500 UTC specimens. Study Design: Unstained Cytospin^TM preparations were created from residual urine specimens and were stained using the anti-hTERT antibody (SCD-A7). Two algorithms were developed for concatenating the hTERT result and cytologic diagnosis: a “no indeterminates algorithm,” in which a negative cytology and positive hTERT result are considered positive, and a “high-specificity algorithm,” in which a negative cytology and positive hTERT result are considered indeterminate (and thus negative for comparison to the gold standard). Results: The “no indeterminates algorithm” and “high-specificity algorithm” yielded a sensitivity of 60.6 and 52.1%, a specificity of 70.4 and 90.7%, a positive predictive value of 39.1 and 63.8%, and a negative predictive value of 85.0 and 85.8%, respectively. Conclusions: A positive hTERT result may identify a subset of patients with an increased risk of high-grade UC (HGUC) who may otherwise not be closely followed, while a negative hTERT immunocytochemistry result is associated with a reduction in risk for HGUC.

Clinical Utility of Cxbladder Monitor for Patients with a History of Urothelial Carcinoma: A Physician-Patient Real-World Clinical Data Analysis.

IntroductionInternational guidelines advocate regular surveillance of patients following urothelial carcinoma (UC). A validated molecular diagnostic non-invasive urine test, Cxbladder Monitor, correctly identifies patients with a UC history who have low-probability of recurrence. The present study assesses the clinical utility of Cxbladder Monitor in reducing the number and frequency of urologic procedures ordered without missing detection of recurrent UC.MethodsData from 828 physician–patient assessments were generated from 18 participant physicians who each evaluated the same real-world clinical case data for 30 patients undergoing surveillance for recurrent UC. Each physician ordered tests and procedures and their timing, following review of the patient’s demographic data, pre-existing conditions, risk factors and clinical history before and after disclosure of Cxbladder Monitor results. Changes in the number, type and timing of procedures ordered were assessed.ResultsThe addition of Cxbladder Monitor significantly reduced the overall number of tests ordered by 38.7%, including flexible cystoscopy by 43%, for patients whose Cxbladder Monitor result was low-probability. When the result was elevated-probability, the number of procedures ordered, including cystoscopy, was increased consistent with the increased risk of recurrent UC. Importantly, based on the tests ordered by each physician for each of the patients, all cases of recurrent UC would have been detected.ConclusionThe increase in clinical utility of Cxbladder Monitor for the management of patients undergoing surveillance for recurrent UC was shown to be driven by the reduction in procedures ordered for low-probability patients and for the more invasive procedures ordered for elevated-probability patients. In this study, the total number of procedures ordered, including the number of cystoscopies, was reduced especially in patients with low-probability of UC. The invasive procedures were ordered in a more targeted fashion for elevated-probability patients, without compromising the detection of recurrent UC.Clinicaltrials.gov IdentifierNCT02700659.FundingPacific Edge Limited.Electronic supplementary materialThe online version of this article (10.1007/s40487-018-0059-5) contains supplementary material, which is available to authorized users.

Clinical utility of a non-invasive urine test for risk assessing patients with no obvious benign cause of hematuria: a physician-patient real world data analysis

BackgroundThe non-invasive Cxbladder urine test system has demonstrated clinical utility in ruling out urothelial carcinoma (UC) in patients with asymptomatic microscopic hematuria (AMH), suggesting that the number of invasive diagnostic tests, including cystoscopy, used in this patient population may be reduced by Cxbladder testing prior to conducting a full urological work-up. The aim of this study was to demonstrate the enhanced clinical utility of communicating objective information on diagnostic decisions made by individual physicians on individual patients with AMH.MethodsThree hundred ninety-six physician-patient decisions were generated from twelve participant physicians evaluating real world case notes from the same 33 patients presenting with AMH. Each physician reviewed and recommended diagnostic tests and procedures based on each patient’s referral data and then re-evaluated their clinical recommendation following disclosure of the non-invasive Cxbladder urine test result. Changes assessed were the total number of requested diagnostic procedures and the number of invasive procedures, including cystoscopy, following addition of information from Cxbladder in the Triage and Triage and Detect modalities.ResultsPhysicians made significant changes to their diagnostic behavior for patients with AMH when presented with Cxbladder test results, including a reduction in the number of total and invasive procedures including cystoscopy for individuals identified as having a low probability of UC. The intensity of investigation was targeted and increased, including use of total procedures and cystoscopy, for patients identified by Cxbladder tests as having a high probability of UC: urologists increased the level of investigation for both total procedures and invasive procedures. The outcome resulted in patients with a high risk of UC receiving appropriate guideline-recommended invasive diagnostic tests. Patients who tested negative were offered fewer and significantly less invasive procedures. This change in physician behavior results in an increased clinical and patient utility, lower risk of missed UC and invasive test-related harm incidents.ConclusionsThis study demonstrated the potential for increased clinical resolution and significantly enhanced patient management, when physicians consider Cxbladder test results in their clinical evaluation. The change in physician behavior led to more appropriate diagnostic procedure selection and resource allocation to the benefit of both patients and healthcare systems.

Dietary intake of nutrients involved in one-carbon metabolism and risk of urothelial cell carcinoma: A prospective cohort study.

Nutrients involved in one-carbon metabolism may play a role in carcinogenesis through DNA replication, repair and methylation mechanisms. Most studies on urothelial cell carcinoma (UCC) have focused on folate. We sought to examine the association between B-group vitamins and methionine intake and UCC risk, overall and by subtype, and to test whether these associations are different for population subgroups whose nutritional status may be compromised. We followed participants in the Melbourne Collaborative Cohort Study (N = 41,513) for over 20 years and observed 500 UCC cases (89% originating in the bladder; superficial: 279, invasive: 221). Energy-adjusted dietary intakes of B vitamins (B1, B2, B3, B5, B6, B8, B9 and B12) and methionine were estimated from a 121-item food frequency questionnaire administered at baseline (1990-1994), using the residuals method. We used Cox regression models to compute hazard ratios (HRs) of UCC risk per standard deviation (SD) of log-transformed nutrient intakes and 95% confidence intervals, adjusted for potential confounders. We investigated associations by tumor subtype, and tested interactions with sex, country of birth, smoking and alcohol drinking. The risk of UCC appeared not to be associated with intake of B-group vitamins or methionine, and findings were consistent across tumor subtypes and across demographic and lifestyle characteristics of the participants. A potential interaction between vitamin B1 and alcohol drinking was observed (all participants: HR per 1 SD = 0.99 (0.91-1.09), never drinkers: HR = 0.81 (0.69-0.97), p-interaction = 0.02), which needs to be confirmed by other studies. Our findings do not indicate that dietary intake of nutrients involved in one-carbon metabolism are associated with UCC risk.

265 BK-Virus Positive Invasive High-Grade Urothelial Carcinoma in an 8-Year-Old Renal Transplant Recipient With BK Virus Nephropathy

Urothelial carcinoma is extremely rare in children and may be fundamentally different than in adults. Fewer than 30 cases have been reported in patients under 10 years old. BK polyomavirus infection is a major problem in transplantation, especially in renal transplant recipients. According to literature, 1%-10% of renal transplant recipients develop polyomavirus-associated nephropathy. The possibility that BK polyomavirus may be carcinogenic in humans is controversial, but SV40 large T antigen is known to inhibit tumor suppressors pRB and p53, and to transform some cell lines in culture. Adult renal transplant recipients have a 3-5x increased risk of urothelial carcinoma. The cystoprostatectomy specimen from an 8-year-old boy with a history of renal transplantation was processed according to standard procedure, and evaluated using H&E and immunohistochemical stains (IHC). Additional ancillary testing included molecular studies for BK virus using PCR for VP1 and identity testing using HLA typing. The patient was an 8-year-old ex 32-week gestation twin boy with a history of chronic kidney disease and developmental delay. He had end-stage renal disease of unclear etiology and underwent kidney transplantation five years earlier from a living non-related donor who was a smoker. He had been immunosuppressed since transplantation, and his course was complicated by uncontrolled BK viremia and BK nephropathy despite prolonged treatment. Five years after his renal transplant, he was noted to have gross painless hematuria. Biopsy of a bladder lesion showed high-grade urothelial carcinoma, and ureteroscopy of native and transplant ureters showed no gross malignancy. He underwent cystoprostatectomy and bilateral native nephroureterectomies with cutaneous ureterostomy from the transplant kidney. Histological examination of the bladder revealed invasive high-grade urothelial carcinoma with micropapillary features with invasion into muscularis propria. Lymphovascular invasion was also noted. The bilateral native kidneys were atrophic with simple cysts and chronic inflammation. The prostate, bilateral seminal vesicles, vas deferens, and distal transplant ureter cuff were negative for tumor. Immunohistochemical staining of the tumor for SV40 antigen showed strong and diffuse staining. In contrast, immunohistochemistry for viral protein VP1 was negative. Molecular testing for BK virus by PCR for VP1 was positive. Immunohistochemistry for mismatch repair proteins showed normal, preserved expression. Identity testing confirmed that the tumor cells belonged to the patient and not to the donor. BK virus positivity has been reported in rare cases of urothelial carcinomas, mainly in adult transplant patients. To our knowledge, this is the first reported incidence of BK virus-associated urothelial carcinoma in a pediatric patient. Absence of late VP1 expression by IHC in conjunction with positive SV40 staining and positive BK virus PCR is consistent with a non-productive BK virus infection. Pathologists should be aware that identity testing should be considered in transplant patients with urothelial carcinoma to confirm the genetic origin of the tumor. Micropapillary differentiation may be a feature of BK virus-associated carcinoma.

Polymorphisms of TNF-α -308 G/A and IL-8 -251 T/A Genes Associated with Urothelial Carcinoma: A Case-Control Study.

Cigarette smoking and exposure to environmental tobacco smoke are well-known risk factors for urothelial carcinoma (UC). We conducted a hospital-based case-control study involving 287 UC cases and 574 cancer-free controls to investigate the joint effects of cigarette smoking and polymorphisms of inflammatory genes on UC risk. Tumor necrosis factor alpha (TNF-α) -308 G/A and interleukin-8 (IL-8) -251 T/A polymorphisms were determined using a polymerase chain reaction-restriction fragment length polymorphism method. People who had ever smoked and those who were exposed to environmental tobacco smoke had significantly increased UC odds ratios (ORs) of 1.65 and 1.68, respectively. Participants who had smoked more than 18 pack-years had a significantly increased UC OR of 2.64. People who had ever smoked and who carried the A/A genotype of the TNF-α -308 G/A polymorphism had a significantly higher UC OR (10.25) compared to people who had never smoked and who carried the G/G or G/A genotype. In addition, people who had ever smoked and who carried the IL-8 -251 T/T genotype had a significantly increased UC OR (3.08) compared to people who had never smoked and who carried the T/A or A/A genotype. In a combined analysis of three major risk factors (cumulative cigarette smoking, the TNF-α -308 A/A genotype, and the IL-8 -251 T/T genotype), subjects with any one, any two, and all three risk factors experienced significantly increased UC ORs of 1.55, 2.89, and 3.77, respectively, compared to individuals with none of the risk factors. Conclusions. Our results indicate that the combined effects of cumulative cigarette exposure and the TNF-α -308 A/A genotype and/or the IL-8 -251 T/T genotype on UC OR showed a significant dose-response relationship.

Dopamine receptor D2 genetic variations is associated with the risk and clinicopathological variables of urothelial cell carcinoma in a Taiwanese population.

Dopamine receptor D2 (DRD2) is overexpressed in several kinds of cancers and was correlated with the prognosis of these cancers. Polymorphisms within the DRD2 gene were shown to be associated with lung and colon cancers. The purpose of this study was to explore effects of DRD2 gene polymorphisms on the susceptibility to and clinicopathological characteristics of urothelial cell carcinoma (UCC). In total, 369 patients diagnosed with UCC and 738 healthy controls were enrolled to analyze DRD2 genotypes at four loci (rs1799732, -141C>del; rs1079597, TaqIB; rs6277, 957C>T; and rs1800497, TaqIA) using a TaqMan-based real-time polymerase chain reaction (PCR). We found a significantly lower risk for UCC in individuals with the DRD2 rs6277 CT genotype compared to those with the wild-type CC genotype (adjusted odds ratio (AOR)=0.405, 95% confidence interval (CI): 0.196~0.837, p=0.015). In 124 younger patients (aged < 65 years) of the recruited UCC cohort, patients who carried at least one T allele of DRD2 rs1800497 were at higher risk (AOR=2.270, 95% CI: 1.060~4.860, p=0.033) of developing an invasive stage (pT2~pT4). In 128 female patients of the recruited UCC cohort, patients who carried at least one deletion allele of DRD2 rs1799732 showed a higher incidence of having an invasive stage (AOR=2.585, 95% CI: 1.066~6.264, p=0.032) and a large tumor (AOR=2.778, 95% CI: 1.146~6.735, p=0.021). Further analyses of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets revealed correlations of the expression of DRD2 with an invasive tumor, tumor metastasis, and the lower survival rate in patients with UCC. Our findings suggest that DRD2 levels might affect the progression of UCC, and the polymorphisms rs6277, rs1800497, and rs1799732 of DRD2 are probably associated with the susceptibility and clinicopathologic development of UCC in a Taiwanese population.

Urologic malignancies in kidney transplantation.

With advances in immunosuppression, graft and patient outcomes after kidney transplantation have improved considerably. As a result, long-term complications of transplantation, such as urologic malignancies, have become increasingly important. Kidney transplant recipients, for example, have a 7-fold risk of renal cell carcinoma (RCC) and 3-fold risk of urothelial carcinoma (UC) compared with the general population. While extrapolation of data from the general population suggest that routine cancer screening in transplant recipients would allow for earlier diagnosis and management of these potentially lethal malignancies, currently there is no consensus for posttransplantation RCC or UC screening as supporting data are limited. Further understanding of risk factors, presentation, optimal management of, and screening for urologic malignancies in kidney transplant patients is warranted, and as such, this review will focus on the incidence, surveillance, and treatment of urologic malignancies in kidney transplant recipients.

Strong associations between chromosomal aberrations in blood lymphocytes and the risk of urothelial and squamous cell carcinoma of the bladder

Chromosomal aberrations (CAs) in blood lymphocytes have been shown to be associated with overall cancer risk and aging. However, their relationship to bladder cancer risk remains to be elucidated. In a case-control study of bladder cancer in Egypt, we examined the relationship between the increased frequency of CAs in blood lymphocytes and bladder cancer risk. High frequency of CAs was significantly associated with an increased risk of bladder cancer [adjusted odds ratios (OR) = 3.90, 95% confidence interval (CI) = 2.65–5.73]. The associations were somewhat stronger in squamous cell carcinomas (SCC, OR = 4.90) than in urothelial carcinomas (UC, OR = 3.62). We also identified chromosome specific CAs for chromosomes 3, 4, 5, 8, 9, 10, 11, 12, 17, 19 that were significantly associated with an increased risk of bladder cancer. We observed particularly strong associations between aberrations of chromosomes 12, 13, 17 and risk of SCC (OR = 7.06, 6.91 and 6.23, respectively). Conclusion: increased frequency of chromosomal aberrations in blood lymphocytes was significantly associated with bladder cancer risk. Overall and chromosome specific aberrations in blood lymphocytes may be a unique set of biomarkers for risk assessments of SCC and UC.

Urothelial cell carcinoma after BK polyomavirus infection in kidney transplant recipients: A cohort study of veterans.

BK polyomavirus (BKPyV) reactivation is a common clinical occurrence in kidney transplant recipients (KTR). Several other polyomaviruses have been implicated as pathogens with a direct role in the development of malignancies, raising the question of whether BKPyV might also be oncogenic. This study is the first retrospective, multicenter cohort study evaluating the relative risk for urothelial cell carcinoma (UCC) associated with BKPyV infection among KTR, and was conducted among veterans who underwent transplantation between 2000 and 2009. BKPyV cases were defined as those veterans with any clinical evidence of BKPyV infection, including positive polymerase chain reaction testing of urine and/or serum for BKPyV or kidney biopsy showing BKPyV-associated nephropathy. Among the 646 veterans who met inclusion criteria for the study, 103 had clinical evidence of BKPyV infection (16%). The overall relative risk for developing any malignancy after BKPyV infection was 1.13 (95% confidence interval [CI] 0.89-1.44). The adjusted relative risk for malignancy after BKPyV infection was greatest with UCC (8.21, 95% CI 0.75-89.7) and with metastatic disease of unknown etiology (8.21, 95% CI 0.75-89.7). The screening prevalence for BKPyV infection increased from 18% for those veterans who underwent transplantation in 2000 to 86% for those veterans who underwent transplantation in 2009, during which time the measured prevalence of BKPyV infection increased from 7% to 24%. In this cohort of KTR veterans, no overall increased or decreased relative risk for malignancy was associated with evidence of prior BKPyV infection. A >8-fold increased risk of developing UCC after BKPyV infection was seen, although this risk was not found to be statistically significant.

Universal Point of Care Testing for Lynch Syndrome in Patients with Upper Tract Urothelial Carcinoma.

Patients with Lynch syndrome are at risk for upper tract urothelial carcinoma. We sought to identify the incidence and most reliable means of point of care screening for Lynch syndrome in patients with upper tract urothelial carcinoma. A total of 115 consecutive patients with upper tract urothelial carcinoma without a history of Lynch syndrome were universally screened during followup from January 2013 through July 2016. We evaluated patient and family history using AMS (Amsterdam criteria) I and II, and tumor immunohistochemistry for mismatch repair proteins and microsatellite instability. Patients who were positive for AMS I/II, microsatellite instability or immunohistochemistry were classified as potentially having Lynch syndrome and referred for clinical genetic analysis and counseling. Patients with known Lynch syndrome served as positive controls. Of the 115 patients 16 (13.9%) screened positive for potential Lynch syndrome. Of these patients 7.0% met AMS II criteria, 11.3% had loss of at least 1 mismatch repair protein and 6.0% had high microsatellite instability. All 16 patients were referred for germline testing, 9 completed genetic analysis and counseling, and 6 were confirmed to have Lynch syndrome. All 7 patients with upper tract urothelial carcinoma who had a known history of Lynch syndrome were positive for AMS II criteria and at least a single mismatch repair protein loss while 5 of 6 had high microsatellite instability. We identified 13.9% of upper tract urothelial carcinoma cases as potential Lynch syndrome and 5.2% as confirmed Lynch syndrome at the point of care. These findings have important implications for universal screening of upper tract urothelial carcinoma, representing one of the highest rates of undiagnosed genetic disease in a urological cancer.

AB047. Fluid intake-to-bed time, nocturia frequency and the risk of urothelial carcinoma of the bladder: a case-control study

BackgroundTo clarify the potential role of fluid intake-to-bed time and nocturia frequency on bladder cancer (BCa) risk in a hospital-based case-control study with Chinese people.Methods407 patients with histologically diagnosed BCa and 400 matched controls were enrolled in this study. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression model.ResultsThe fluid intake-to-bed time was associated with a decreased risk of BCa, with an OR of 0.586 (95% CI: 0.375–0.916, ≤1 h) and 0.257 (95% CI: 0.162–0.407, >1 h). The adjusted ORs of BCa for subjects with more nocturia frequency were 2.268 (95% CI: 1.481–3.474), compared to those with no nocturia.ConclusionsWe suggested strong protective effect of long fluid intake-to-bed time on BCa risk, especially in ones with ≥2 times nocturia frequency. These results provide evidence for identifying high-risk individuals and modifying their behavior and lifestyle.

Urinary tract washing specimens containing atypical urothelial tissue fragments are significantly associated with urothelial neoplasia.

We previously found that the presence of atypical urothelial tissue fragments (AUTF) was associated with an increased risk of high-grade urothelial carcinoma (HGUC) but not low-grade urothelial neoplasia (LGUN) in voided urine (VU) specimens. However, we subsequently found that patients with LGUN were more likely to have cytologic atypia in urinary washing (UW) specimens, suggesting that cytologic atypia found in UW specimens might be associated with both LGUN and HGUC. In this study, we retrospectively examined UW specimens containing AUTF to determine whether they were associated with HGUC, LGUN, or both HGUC and LGUN. 1173 UW specimens and any follow up biopsies were identified over a 10-year period and the presence of AUTF was recorded based on the original clinical diagnosis. The presence of AUTF in UW specimens was significantly associated with high-risk indeterminate diagnosis or definitive diagnosis of HGUC (P < .001). In addition, AUTF specimens were significantly associated with a neoplastic diagnosis of low-grade urothelial carcinoma (LGUC) or HGUC on subsequent biopsies when compared to specimens lacking AUTF (P = .047). The overall rate of CIS/HGUC in specimens with AUTF was 33.0 vs. 13.5% for specimens without AUTF (P = .051). Urothelial tissue fragments (UTF) found in UW specimens should be examined for the presence of cytomorphological atypia, as the presence of AUTF almost triples the risk of HGUC. As opposed to what has been found in VU specimens, AUTF in UW specimens is also associated with an increased risk of LGUN.

Epidemiology of urothelial carcinoma.

The epithelium lining is defined as the mucosal surfaces of the renal collecting tubules, calyces and pelvis, as well as the ureter, bladder and urethra. The term "urothelium" is used to refer to these surfaces. Upper tract urothelial carcinoma is a rare subset of urothelial cancers with a poor prognosis. Urinary bladder cancer is the most common malignancy involving the urinary system. Upper tract urothelial carcinoma is more common in men than in women, with a male-to-female ratio of 2:1. The incidence of urinary bladder cancer is also higher in men. Cigarette smoking and occupational exposure are the main upper tract urothelial carcinoma and urinary bladder cancer risk factors, while other factors are more specific to the carcinogenesis of upper tract urothelial carcinoma (i.e. Balkan endemic nephropathy, Chinese herb nephropathy). In Egypt until recent years, urinary bladder cancer was the most frequently diagnosed cancer due to Schistosoma haematobium. Substantial knowledge exists regarding the causes of upper tract urothelial carcinoma and urinary bladder cancer, and epidemiological studies have identified various chemical carcinogens that are believed to be responsible for most cases of urothelial carcinoma. In the era of precision medicine, genetic effects might play a direct role in the initiation and progression of urothelial carcinoma.

MP10-20 PROSPECTIVE EVALUATION OF A CLINICAL TOOL FOR SEGREGATION OF HEMATURIA PATIENTS AT RISK FOR HIGH-GRADE UROTHELIAL CARCINOMA

You have accessJournal of UrologyBladder Cancer: Epidemiology & Evaluation II1 Apr 2017MP10-20 PROSPECTIVE EVALUATION OF A CLINICAL TOOL FOR SEGREGATION OF HEMATURIA PATIENTS AT RISK FOR HIGH-GRADE UROTHELIAL CARCINOMA Jay D. Raman, Laimonis Kavaliers, Paul O'Sullivan, David Darling, Parry Guilford, and Jimmie Suttie Jay D. RamanJay D. Raman More articles by this author , Laimonis KavaliersLaimonis Kavaliers More articles by this author , Paul O'SullivanPaul O'Sullivan More articles by this author , David DarlingDavid Darling More articles by this author , Parry GuilfordParry Guilford More articles by this author , and Jimmie SuttieJimmie Suttie More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.348AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES To-date there are no urine-based tests that provide clinical resolution of the severity or grade of urothelial carcinoma (UC) in patients presenting with primary hematuria. Such information permits timely diagnosis and specific management of hematuria patients identified with high grade and/or advanced UC disease. The objective of this study was, therefore, to develop and investigate the performance of Cxbladder Resolve, a new urine-based test offering identification and accurate segregation of patients with high-grade (HG) and/or late-stage disease at the time of initial urological investigation. METHODS Participants in the study (N=863) were recruited from patients presenting with micro-(n=66) or macrohematuria (n=797) across centers in the U.S., New Zealand and Australia. An index incorporating 2 clinical variables and 5 gene expression biomarkers measured in urine was developed to segregate patients into 3 groups: 1. Low risk of UC; 2. Elevated risk of low grade (LG) UC; and 3. High risk of high grade (HG) UC. RESULTS Of the 863 recruited patients, 89 (10.3%) primary cases of UC were observed including 40 LG and 49 HG. Cxbladder Resolve segregated the 863 participants into: low risk of UC (n=479; 55%), elevated risk of LG UC (n=288; 33%) and high risk of HG UC disease (n=96; 11%). (Table) Of the 40 patients with LG bladder tumors, 27 were correctly categorized as Elevated risk of low grade UC, with the remainder; 9 as High risk of HG UC, and 4 as Low risk of UC. Of the 49 patients with HG UC, 47 (96%) were correctly identified as having High risk of HG UC and the remaining 2 patients were classified as elevated risk of LG UC. No patients with HG UC were classified as low risk of UC. Overall a negative predictive value [NPV] of =99% was observed. CONCLUSIONS Cxbladder Resolve accurately identifies over 95% of HG UC patients with a reciprocal high NPV (99%) for low risk patients. The index has a low probability of incorrectly classifying pathologic HG UC patients as low risk. Clinical utility is demonstrated for stratifying hematuria patients into risk groups allowing for prioritization of high risk patients with aggressive disease requiring early investigative procedures. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e116 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Jay D. Raman More articles by this author Laimonis Kavaliers More articles by this author Paul O'Sullivan More articles by this author David Darling More articles by this author Parry Guilford More articles by this author Jimmie Suttie More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Lynch syndrome-associated upper tract urothelial cancer: Assessment of clinical screening criteria and tissue-based point of care testing.

371 Background: Lynch syndrome (LS) is an inherited syndrome that places patients at risk for upper tract urothelial carcinoma (UTUC). Our goal was to identify the most reliable means of screening for LS in patients with UTUC at the point of care (POC). Methods: Patient information was retrospectively collected in an IRB-approved protocol on UTUC patients. LS screening was universally performed on all patients presenting from 1/2013-7/2016. We evaluated patient and family history (Amsterdam I and II criteria; AMS1 and AMS2, respectively), tumor immunohistochemistry (IHC) for 4 mismatch repair proteins (MMRP), tumor and normal tissue polymerase-chain reaction for microsatellite instability (MSI), and clinical genetic analysis and counseling (GAC), in those with undiagnosed LS. Patients who were AMS 2 positive, MSI positive, or IHC positive were considered as presumed Lynch syndrome (PLS) and were referred for GAC. Results: 101 UTUC patients without a history of LS were universally screened during clinical follow-up. A total of 15/101 (15%) patients were PLS. 7/101 (7%) patients met AMS2 criteria. 4 patients meeting AMS2 criteria had intact expression of MMRP and no MSI instability. 11 (11%) patients had either loss of one or more MMRP. There were two cases of MSI high instability, both in patients with MMRP loss. There were no cases of MSI-high instability and negative IHC. Insufficient tissue was found in 1/101 (1%) of IHC and 8/88 (9%) of MSI tests (p=0.0164). All patients with any positive screen were referred for GAC, 5 followed-up and all 5 patients had a confirmed germline mutation. The remaining did not follow through with GAC because of financial/insurance barriers. Conclusions: We identified 15% of universally screened UTUC as PLS at the POC using IHC and AMS2 criteria. IHC and AMS2 criteria appear to provide the most reliable screening. MSI is limited by requirement for normal tissue, a greater amount of tumor tissue, and can miss cases of MMRP loss. There are significant barriers to GAC. Our findings of a 15% rate of LS-related UTUC is consistent with prior laboratory tissue studies and has significant implications for universal POC testing of UTUC patients.

Combined Genetic Biomarkers Confer Susceptibility to Risk of Urothelial Bladder Carcinoma in a Saudi Population.

We evaluated the associations between seven single nucleotide polymorphisms and susceptibility to urothelial bladder carcinoma (UBC) in a Saudi population. Genomic DNA was taken from buccal cells of 52 patients with UBC and 104 controls for genotyping of GSTT1, GSTM1, rs4646903, rs1048943, TP53 rs1042522, rs1801133, and rs1801394 using PCR and TaqMan® assays. The rs1801133 and rs1801394 variants showed strong associations with UBC (OR = 2.3, P = 0.0002; OR = 2.6, P = 0.0001, resp.). Homozygosity of Pro72 conferred a significant double risk in cases compared with controls (30.8% versus 15.4%), but the homozygote Arg/Arg had no effect on risk. Genotypic combinations of GSTM1/GSTT1, rs4646903/rs1048943, and rs1801133/rs1801394 exhibited significant linkage with the disease (χ2 = 10.3, P = 0.006; χ2 = 13.9, P = 0.003; and χ2 = 20.4, P = 0.0004, resp.). The GSTM1 and rs1042522Arg and rs1801394G variant alleles were more frequent in current smokers with UBC (52.4%, 52.5%, and 64.3%, resp.) than were the corresponding wild-types. Despite some variants having only a slight effect on UBC risk, the interaction effect of combined genetic biomarkers—or even the presence of one copy of a variant allele—is potentially much greater. Perhaps more studies regarding next-generation genetic sequencing and its utility can add to the risk of UBC.

Upper tract urothelial carcinomas: frequency of association with mismatch repair protein loss and lynch syndrome

Increased risk for upper tract urothelial carcinoma is described in patients with Lynch syndrome, caused by germline mutations in mismatch repair genes. We aimed to identify the frequency of mismatch repair protein loss in upper tract urothelial carcinoma and its potential for identifying an association with Lynch syndrome. We queried our database to identify upper tract urothelial carcinomas. Patients were cross-referenced for history of colorectal carcinoma or other common Lynch syndrome-associated neoplasms to enrich for potential Lynch syndrome cases. Tumor histopathologic characteristics were reviewed and each case was analyzed for loss of mismatch repair proteins, MLH1, MSH2, MSH6, and PMS2, by immunohistochemistry. Of 444 patients with upper tract urothelial carcinoma, a subset of 215 (encompassing 30 with upper tract urothelial carcinoma and another common Lynch syndrome-associated neoplasm) was analyzed for loss of mismatch repair protein expression. Of 30 patients with Lynch syndrome-associated neoplasms, six had documented Lynch syndrome, including two with Muir–Torre syndrome. Mismatch repair protein loss was identified in 7% of total upper tract urothelial carcinomas and 30% of patients with Lynch syndrome-associated neoplasms (including all patients with Lynch syndrome/Muir–Torre syndrome). Of patients without history of Lynch syndrome-associated neoplasms, 5 of 184 (2.7%) had loss of mismatch repair protein expression. Twelve cases with mismatch repair protein loss demonstrated loss of MSH2 and MSH6, and 2 had isolated loss of MSH6. MLH1 and PMS2 expression were consistently retained. Although increased intratumoral lymphocytes, inverted growth, pushing tumor-stromal interface, and lack of nuclear pleomorphism were more commonly seen in cases with mismatch repair protein loss, only intratumoral lymphocytes and presence of pushing borders were statistically significant. MLH1 and PMS2 testing appear to have little utility in upper tract urothelial carcinoma; however, mismatch repair protein loss of MSH2 and/or MSH6 by immunohistochemistry seems relatively sensitive and specific for identifying patients with potential Lynch syndrome.

Fluid intake-to-bed time, nocturia frequency and the risk of urothelial carcinoma of the bladder: a case-control study.

Objectives: To clarify the potential role of fluid intake-to-bed time and nocturia frequency on bladder cancer risk in a hospital-based case-control study with Chinese people.Materials and Methods: Four hundred and seven patients with histologically diagnosed bladder cancer and 400 matched controls were enrolled in this study. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression model.Results: After adjustment for potential confounders, the fluid intake-to-bed time was associated with a decreased risk of BCa, with an OR of 0.586 (95% CI= 0.375-0.916, ≤1h) and 0.257 (95% CI= 0.162-0.407, >1h). The adjusted OR of BCa for subjects with more nocturia frequency (≥2 times) was 2.268 (95 % CI= 1.481-3474), compared to those with no nocturia.Conclusion: We suggested strong protective effect of long fluid intake-to-bed time on BCa risk, especially in ones with ≥2 times nocturia frequency. These results provide evidence for identifying high-risk individuals and modifying their behaviors and lifestyle.

Relationships among DNA hypomethylation, Cd, and Pb exposure and risk of cigarette smoking-related urothelial carcinoma

Cigarette smoking and environmental exposure to heavy metals are important global health issues, especially for urothelial carcinoma (UC). However, the effects of cadmium and lead exposure, as well as the levels of DNA hypomethylation, on UC risk are limited. We evaluated the possible exposure sources of Cd and Pb and the relationship among DNA hypomethylation, urinary Cd and Pb levels, and UC risk. We recruited 209 patients with UC and 417 control patients for a hospital-based case–control study between June 2011 and August 2014. We collected environmental exposure-related information with questionnaires. Blood and urine samples were analyzed to measure the Cd and Pb exposure and 5-methyl-2′-deoxycytidine levels as a proxy for DNA methylation. Multivariate logistic regression and 95% confidence intervals were applied to estimate the risk for UC. Study participants with high Cd and Pb exposure in blood or urine had significantly increased risk of UC, especially among the smokers. After adjusting for age and gender, the possible connections of individual cumulative cigarette smoking or herb medicine exposure with the increased levels of Cd and Pb were observed in the controls. Participants with 8.66%–12.39% of DNA hypomethylation had significantly increased risk of UC compared with those with ≥12.39% of DNA hypomethylation. Environmental factors including cigarette smoking and herb medicine may contribute to the internal dose of heavy metals levels. Repeat measurements of heavy metals with different study design, detailed dietary information, and types of herb medicine should be recommended for exploring UC carcinogenesis in future studies.