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THE ROLE OF BLADDER EPICHECK TEST ™ IN FOLLOW-UP OF PATIENTS WITH NON MUSCLE INVASIVE BLADDER CANCER.
Abstract
Introduction
EpiCheck is a new urinary test that analyses DNA methylation biomarkers in order to identify high-risk urothelial cancer
Materials and methods
A prospective single centre study was performed. We analysed Epicheck results in a population of 231 patients in follow-up for non-muscle invasive bladder cancer. The primary endpoint was to evaluate sensitivity and specificity of Epicheck in detecting any type of bladder cancer recurrence. The secondary endpoint was to evaluate specificity and sensitivity of Epicheck in patients with high-risk recurrence and in patients recently treated with endovesical therapy (< 3 months).
Results
Negative predictive value (NPV) for cytology was 83 % while for bladder Epicheck it was 89 %, while positive predictive value (PPV) was 67 % and 73 % for cytology and Epicheck respectively. Considering only high grade non muscle invasive bladder cancer the sensitivity of Epicheck was 91 % and for cytology was 81 %, specificity was 85 % and 83 % and negative predictive value of Epicheck outreached 96 % compared to 92 % of cytology. Among patients with an ongoing or recent endovesical treatment it appears that sensitivity of Epicheck was 88% % compared to 73 % of cytology, specificity was 97 % and 85 % and NPV was 92 % compared to 82 % for cytology.
Conclusion
The EpiCheck (test showed very high diagnostic values, higher than the currently, gold standard. The test might clinically improve the BCa management in terms of, reduced number of inconclusive/suspicious reports of cytology and endoscopy, reduced number of further examinations, reduced associated patient and economic
... respectively and achieved a great improvement in sensitivity, specificity and NPV in the detection of high grade-BLCA (HG-BLCA) recurrence. [77][78][79][80][81][82][83] In addition to DNA methylation, DNA mutations could also provide new urine-based biomarkers for the surveillance of BLCA. 84 Mutations in TERT promoter occur in over 60% of BLCA. ...
Bladder cancer (BLCA) is a most common urological tumours with high rate of recurrence, which needs long‐term of follow‐up. To date, diagnosis and surveillance of BLCA still rely on cystoscopy, an invasive and expensive method that increases the difficulty for routine follow‐up. Therefore, exploring new biomarkers or tests is an effective way to improve the current clinical management of BLCA. Recent years, liquid biopsy has received increasing attention, especially for its great potential for clinical application in the non‐invasive detection of tumours. In addition, liquid biopsy involves a wide range of biomarkers, including DNA, RNA, proteins, extracellular vesicles and metabolites in blood, urine or other body fluids. For BLCA, urine is a most ideal body fluid to achieve non‐invasive diagnosis and surveillance. Here, we address recent developments of urine‐based biomarkers or tests for clinical diagnostic challenges in BLCA, such as early detection, minimal residual, recurrence monitoring and therapeutic response. Meanwhile, the many challenges of urine biomarkers that need to be overcome are also discussed. (1)Development of liquid biopsy has great potential of clinical application in non‐invasive detection of tumours. (2)Urine‐based biomarkers or tests for clinical management in bladder cancer can be widely used for early detection, minimal residual, recurrence monitoring and therapeutic response. (3)Many challenges need to be overcomed in the discovery and validation studies of urine biomarkers for bladder cancer.
... In addition, since it is a PCR analysis, there is no interobserver variation. Two recent prospective trials have confirmed the high diagnostic value of the BE in the followup of NMIBC patients treated with intravesical therapy and state that it may replace cytology [12,13]. Considering the test characteristics, BE might even be used to diminish the amount of follow-up cystoscopies [14,15]. ...
PurposeIn the Netherlands yearly more than 5000 patients are diagnosed with non-muscle invasive bladder cancer (NMIBC). With a specificity of 88.0% and a negative predictive value (NPV) for high grade NMIBC of 99.3%, the Bladder EpiCheck (BE) urine test may be used in NMIBC to reduce the burden of follow-up cystoscopies.Methods
In this study a cost analysis of the BE follow-up strategy in the Dutch healthcare system was performed. In half of the follow-up appointments, BE was used as a rule-in for cystoscopy. In addition, the possible delay in recurrence detection was estimated. A cost calculation tool was developed using Microsoft Excel.ResultsThe BE strategy results in an estimated cost reduction of 8%, 4% and 9% in low, intermediate and high risk patients, respectively. In the Netherlands this may result in a cost reduction of approximately 1.6 million euro per year. The estimated delay in the detection of recurrent disease would be 3.9, 1.7 and 1.3 months in low, intermediate and high risk NMIBC patients respectively.Conclusion
To conclude, the BE can be used to reduce the costs of NMIBC follow-up, with a small delay in diagnosis of recurrent disease.
Context:
This overview presents the updated European Association of Urology (EAU) guidelines for non-muscle-invasive bladder cancer (NMIBC), TaT1, and carcinoma in situ (CIS).
Objective:
To provide practical recommendations on the clinical management of NMIBC with a focus on clinical presentation and recommendations.
Evidence acquisition:
A broad and comprehensive scoping exercise covering all areas of the NMIBC guidelines has been performed annually since the last published version in 2017. Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries. Previous guidelines were updated, and the level of evidence and grade of recommendation were assigned.
Evidence synthesis:
Tumours staged as Ta, T1, and/or CIS are grouped under the heading of NMIBC. Diagnosis depends on cystoscopy and histological evaluation of the tissue obtained by transurethral resection (TURB) in papillary tumours or by multiple bladder biopsies in CIS. In papillary lesions, a complete TURB is essential for the patient's prognosis and correct diagnosis. Where the initial resection is incomplete, where there is no muscle in the specimen, or where a T1 tumour is detected, a second TURB should be performed within 2-6 wk. The risks of both recurrence and progression may be estimated for individual patients using the European Organisation for Research and Treatment of Cancer (EORTC) scoring system. Stratification of patients into low-, intermediate-, and high-risk groups is pivotal to the recommendation of adjuvant treatment. In patients with tumours presumed to be at a low risk and in those presumed to be at an intermediate risk with a low previous recurrence rate and an expected EORTC recurrence score of <5, one immediate chemotherapy instillation is recommended. Patients with intermediate-risk tumours should receive 1 yr of full-dose bacillus Calmette-Guérin (BCG) intravesical immunotherapy or instillations of chemotherapy for a maximum of 1 yr. In patients with high-risk tumours, full-dose intravesical BCG for 1-3 yr is indicated. In patients at the highest risk of tumour progression, immediate radical cystectomy should be considered. Cystectomy is recommended in BCG-unresponsive tumours. The extended version of the guidelines is available at the EAU website: https://uroweb.org/guideline/non-muscle-invasive-bladder-cancer/.
Conclusions:
These abridged EAU guidelines present updated information on the diagnosis and treatment of NMIBC for incorporation into clinical practice.
Patient summary:
The European Association of Urology Non-muscle-invasive Bladder Cancer (NMIBC) Panel has released an updated version of their guidelines, which contains information on classification, risk factors, diagnosis, prognostic factors, and treatment of NMIBC. The recommendations are based on the current literature (until the end of 2018), with emphasis on high-level data from randomised clinical trials and meta-analyses. Stratification of patients into low-, intermediate-, and high-risk groups is essential for deciding appropriate use of adjuvant intravesical chemotherapy or bacillus Calmette-Guérin (BCG) instillations. Surgical removal of the bladder should be considered in case of BCG-unresponsive tumours or in NMIBCs with the highest risk of progression.
Objectives
To prospectively investigate the clinical utility and influence on decision making of Bladder EpiCheckTM, a non‐invasive urine test, in the surveillance of non‐muscle‐invasive bladder cancer (NMIBC).
Materials and methods
Urine samples from 440 patients undergoing surveillance for NMIBC were prospectively collected at five centers and evaluated using the Bladder EpiCheckTM test (NCT02647112). Multivariable nomogram and decision curve analysis (DCA) were used to evaluate the impact of Bladder EpiCheck TM on decision making when used in clinical routine. The test was designed to rule out recurrent disease.
Results
Data from 357 patients was available for analysis. The test had a specificity of 88% (95% CI 84 ‐ 91) and a negative predictive value (NPV) of 94.4% (95% CI 91 ‐ 97) for the detection of any cancer and a NPV of 99.3% for the detection of high grade cancer. In multivariable analysis, positive Bladder EpiCheck TM results were independently associated with any and high‐grade disease recurrence (OR 18.1; 95%CI 8.7 ‐ 40.2; p < 0.001 and OR 78.3; 95%CI 19.2 ‐ 547; p < 0.001). Addition of Bladder EpiCheck TM to standard variables improved its prediction for any and high‐grade disease recurrence by a difference of 16% and 22%, respectively (area under the curve 85.9% and 96.1% for any and high‐grade cancer). DCA showed an improvement in the net benefit relative to cystoscopy over a large threshold of probability, resulting in a significant reduction of unnecessary investigations. These results were similar in subgroups assessing the impact of specific clinical features.
Conclusions
Bladder EpiCheckTM is a robust high performing diagnostic test in patients with NMIBC undergoing surveillance, potentially reducing the number of unnecessary investigations.
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Abstract Background In case of high grade non-muscle invasive bladder cancer (HG-NMIBC), intravesical BCG represents the first-line treatment; despite the “gold” standard therapy, up to 50% of patients relapse, needing radical cystectomy. Hence, alternative therapeutic strategies have been developed. The aim of the study was to evaluate a first-line salvage treatment with EMDA®-MMC in patients with HGNMIBC unresponsive to BCG. Methods We carried out a prospective, single-center, single-arm Phase II study in order to evaluate the efficacy (in terms of recurrence and progression) and the safety of the EMDA®-MMC treatment in 26 (21 male, 5 female) consecutive patients with “BCG refractory” HGNMIBC on a 3 years follow-up. EMDA®-MMC treatment consisted of 40 mg of MMC diluted in 100 ml of sterile water retained in the bladder for 30 min with 20 mA pulsed electric current. EMDA®-MMC regimen consisted of an induction course of 6 weekly instillations followed by a maintenance course of 6 monthly instillations. Follow-up was performed with systematic mapping biopsies of the bladder (with sampling in the prostatic urethra for men), voiding and washing urinary cytology, radiological study of the upper urinary tract. We performed Survival Kaplan-Meier curves and Log-rank test in order to analyze high grade disease-free survival. Results At the end of follow-up, 16 patients (61.5%) preserved their native bladder; 10 patients (38.4%) underwent radical cystectomy, in 6 patients (23.1%) for recurrent HGNMIBC and in 4 patients (15.4%) for progression to muscle-invasive disease. At the end of follow-up, stratifying patients based on TNM classification (TaG3, T1G3, Cis, TaT1G3 + Cis), disease-free rates were 75, 71.4, 50 and 25%, respectively; survival curves showed statistically significant differences (p value
Background:
The highly frequent strategy of surveillance for non-muscle-invasive bladder cancer (NMIBC) involves cystoscopy and cytology. Urine assays currently available have not shown performance sufficient to replace the current gold standard for follow-up, which would require a very high negative predictive value (NPV), especially for high-grade tumors. Bladder EpiCheck (BE) is a novel urine assay that uses 15 proprietary DNA methylation biomarkers to assess the presence of bladder cancer.
Objective:
To assess the performance of BE for NMIBC recurrence.
Design, setting, and participants:
This was a blinded, single-arm, prospective multicenter study. The inclusion criteria were age ≥22 yr, urothelial carcinoma (UC) being monitored cystoscopically at 3-mo intervals, all UC resected within 12 mo, able to produce 10ml of urine, and able to consent.
Outcome measurements and statistical analysis:
The BE test characteristics were calculated and compared to cytology and cystoscopy results confirmed by pathology.
Results and limitations:
Out of 440 patients recruited, 353 were eligible for the performance analysis. Overall sensitivity, specificity, NPV, and positive predictive value were 68.2%, 88.0%, 95.1%, and 44.8%, respectively. Excluding low-grade (LG) Ta recurrences, the sensitivity was 91.7% and NPV was 99.3%. The area under receiver operating characteristic (ROC) curves with and without LG Ta lesions was 0.82 and 0.94, respectively.
Conclusions:
In follow-up of NMIBC patients, the BE test showed an overall high NPV of 95.1%, and 99.3% when excluding LG Ta recurrences. With high specificity of 88.0%, the test could be incorporated in NMIBC follow-up since high-grade recurrences would be instantly detected with high confidence. Thus, the current burden of repeat cystoscopies and cytology tests could be reduced.
Patient summary:
The Bladder EpiCheck urine test has a clinically relevant and high negative predictive value. Its use in clinical routine could reduce the number of follow-up cystoscopies, and thus associated patient and financial burdens.
Objectives:
With the advent of novel genomic and transcriptomic technologies, new urinary biomarkers have been identified and tested for bladder cancer (BCa) surveillance. To summarize the current status of urinary biomarkers for the detection of recurrence and/or progression in the follow-up of non-muscle invasive BCa patients, and to assess the value of urinary biomarkers in predicting response to intravesical Bacillus Calmette-Guerin (BCG) therapy.
Methods and materials:
A medline/pubmed© literature search was performed. The performance of commercially available and investigational biomarkers has been reviewed. End points were cancer detection (recurrence), cancer progression, and response to BCG therapy.
Results:
The performance requirements for biomarkers are variable according to the clinical scenario. The clinical role of urinary biomarkers in the follow-up of non-muscle invasive BCa patients remains undefined. The FDA-approved tests provide unsatisfactory sensitivity and specificity levels and their use is limited. Fluorescence in situ hybridization (FISH) has been shown to be useful in specific scenarios, mostly as a reflex test and in the setting of equivocal urinary cytology. FISH and immunocytology could conceivably be used to assess BCG response. Recently developed biomarkers have shown promising results; upcoming large trials will test their utility in specific clinical scenarios in a manner similar to a phased drug development strategy.
Conclusions:
Current commercially available urinary biomarker-based tests are not sufficiently validated to be widely used in clinical practice. Several novel biomarkers are currently under investigation. Prospective multicenter analyses will be needed to establish their clinical relevance and value.
Objective:
Patients with urothelial carcinoma (UC) undergo rigorous surveillance for recurrence. Noninvasive urine tests are not currently recommended by guideline panels owing to insufficient clinical benefit. The objective of this study was to prospectively compare the performance of the Cxbladder Monitor test to other commonly available urine markers and cytology for surveillance of patients with UC.
Methods and materials:
A total of 1,036 urine samples were collected from 803 patients undergoing surveillance for UC. Of these, 1,016 samples were directly assessed using cytology, NMP22 Bladderchek and NMP22 enzyme-linked immunosorbent assay (ELISA), and the clinically validated Cxbladder Monitor test. An exploratory analysis was also performed comparing data from 157 samples where UroVysion fluorescence in situ hybridization analysis was performed locally.
Results:
The sensitivity of Cxbladder Monitor (0.91) significantly outperformed cytology (0.22), NMP22 ELISA (0.26), and NMP22 BladderChek (0.11). The negative predictive value of Cxbladder Monitor was also superior at 0.96 compared with cytology (0.87), NMP22 ELISA (0.87), and NMP22 BladderChek (0.86). All false-negative results (n = 14) observed using Cxbladder Monitor were also negative for cytology, NMP22 ELISA, and NMP22 BladderChek. In the more limited set, UroVysion fluorescence in situ hybridization also had inferior sensitivity (0.33) and negative predictive value (0.92).
Conclusions:
The Cxbladder Monitor test significantly outperforms current Food and Drug Administration-approved urine-based monitoring tests, as well as cytology, in a large representative population undergoing surveillance for recurrent UC. This supports using Cxbladder Monitor as a confirmatory negative adjunct to cystoscopy or to justify postponing cystoscopic investigations in patients with a low risk of recurrence.
Background
Spectrum effects refer to the phenomenon that test performance varies across subgroups of a population. When spectrum effects occur during diagnostic testing for cancer, difficult patient misdiagnoses can occur. Our objective was to evaluate the effect of test indication, age, gender, race, and smoking status on the performance characteristics of two commonly used diagnostic tests for bladder cancer, urine cytology and fluorescence in situ hybridization (FISH).
Methods
We assessed all subjects who underwent cystoscopy, cytology, and FISH at our institution from 2003 to 2012. The standard diagnostic test performance metrics were calculated using marginal models to account for clustered/repeated measures within subjects. We calculated test performance for the overall cohort by test indication as well as by key patient variables: age, gender, race, and smoking status.
Results
A total of 4023 cystoscopy-cytology pairs and 1696 FISH-cystoscopy pairs were included in the analysis. In both FISH and cytology, increasing age, male gender, and history of smoking were associated with increased sensitivity and decreased specificity. FISH performance was most impacted by age, with an increase in sensitivity from 17 % at age 40 to 49 % at age 80. The same was true of cytology, with an increase in sensitivity from 50 % at age 40 to 67 % at age 80. Sensitivity of FISH was higher for a previous diagnosis of bladder cancer (46 %) than for hematuria (26 %). Test indication had no impact on the performance of cytology and race had no significant impact on the performance of either test.
Conclusions
The diagnostic performance of urine cytology and FISH vary significantly according to the patient demographic in which they were tested. Hence, the reporting of spectrum effects in diagnostic tests should become part of standard practice. Patient-related factors must contextualize the clinicians’ interpretation of test results and their decision-making.
The potential risk of recurrence and progression in patients with non-muscle-invasive bladder cancer necessitates followup by cystoscopy. The risk of progression to muscle-invasive bladder cancer is estimated based on the European Organisation of Research and Treatment of Cancer score, a combination of several clinicopathological variables. However, pathological assessment is not objective and reproducibility is insufficient. The use of molecular markers could contribute to the estimation of tumor aggressiveness. We recently demonstrated that methylation of GATA2, TBX2, TBX3, and ZIC4 genes could predict progression in Ta tumors. In this study, we aimed to validate the markers in a large patient set using DNA from formalin-fixed and paraffin-embedded tissue.
● To assess the ability of reflex UroVysion fluorescence in situ hybridization (FISH) testing to predict recurrence and progression in non-muscle invasive bladder cancer (NMIBC) patients with suspicious cytology but negative cystoscopy.
● Patients on NMIBC surveillance were followed with office cystoscopy and urinary cytology every three-to-six months. ● Between March 2007 and February 2012, 500 consecutive patients with suspicious cytology underwent reflexive FISH analysis. ● Clinical and pathologic data were reviewed retrospectively. ● Predictors for recurrence, progression, and findings on subsequent cystoscopy (within two-to-six months after FISH) were evaluated using univariate and multivariate Cox regression.
● 243 patients with suspicious cytology also had negative surveillance cystoscopy. ● Positive FISH was a significant predictor for recurrence (hazard ratio 2.35, 95% confidence interval [CI] 1.42, 3.90, p=0.001) in multivariate analysis and for progression (hazard ratio 3.01, 95% CI 1.10, 8.21, p=0.03) in univariate analysis, compared to negative FISH. ● However, positive FISH was not significantly associated with evidence of tumor on subsequent surveillance cystoscopy compared to negative FISH (odds ratio 0.8, 95% CI 0.26, 2.74, p=1).
● Positive FISH predicts for recurrence and progression in NMIBC surveillance patients with suspicious cytology but negative cystoscopy. ● However, an association was not found between FISH result and tumor recurrence in the immediate follow-up period. ● Reflex FISH testing for suspicious cytology may have limited ability to modify surveillance strategies in NMIBC.
Voided urine samples continue to play an important role in the surveillance of urothelial malignancy and also as a screening mode for high risk patients. In some cases, it is difficult to reliably distinguish changes induced by inflammation, stone or other reactive condition from neoplasm, and these cases are categorized as atypical. The aim of our study is to evaluate the prevalence and the significance of atypical diagnosis in the voided urine samples and also to identify the cytomorphologic features that are seen more frequently in the atypical malignant urine samples.
All voided urine cytology samples with a diagnosis of atypical urothelial cells, between the period of 2000 and 2009, were obtained from the cytology database. Only those cases with histologic follow-up were included in the study. The cytology and the histology slides were retrieved and reviewed. The following parameters were evaluated: cellularity, cell clusters, nuclear membrane irregularities, hyperchromasia and India-ink type nuclei, the presence of spindle cells and the cytoplasmic characteristics.
Out of 72 voided urine samples included in the study, 49 cases (68%) had a positive histologic diagnosis of urothelial malignancy in the follow-up histology; of these (55%) were high-grade urothelial carcinoma. Increased cellularity, papillary cell clusters, nuclear membrane irregularity, hyperchromasia and India-ink type nuclei were observed more frequently in the atypical malignant urine samples, while cytoplasmic vacuolization were seen more in the negative reactive urine samples.
The atypical category diagnosis is associated with a significant proportion of urothelial carcinoma. It should be used by the pathologist to convey concern to the clinician in difficult cases that may require close follow-up.
Aging is a multifaceted process characterized by genetic and epigenetic changes in the genome. The genetic component of aging received initially all of the attention. Telomere attrition and accumulation of mutations due to a progressive deficiency in the repair of DNA damage with age remain leading causes of genomic instability. However, epigenetic mechanisms have now emerged as key contributors to the alterations of genome structure and function that accompany aging. The three pillars of epigenetic regulation are DNA methylation, histone modifications, and noncoding RNA species. Alterations of these epigenetic mechanisms affect the vast majority of nuclear processes, including gene transcription and silencing, DNA replication and repair, cell cycle progression, and telomere and centromere structure and function. Here, we summarize the lines of evidence indicating that these epigenetic defects might represent a major factor in the pathophysiology of aging and aging-related diseases, especially cancer.
The aim of this study was to find out the characteristic morphology of malignant atypical cells which were missed on routine cytology of urine.
In this retrospective study, we examined detailed cytomorphology of 18 cases of atypical urinary cytology which were missed on routine examination and were further proved on histopathology as transitional cell carcinoma (TCC) of bladder. The cytological features of these cases were compared with 10 cases of benign urine samples.
There were 11 cases of high grade TCC and 7 cases of low grade TCC on histopathology of the atypical urine samples. Necrosis in the background and necrosed papillae were mostly seen in malignant atypical cells. The comet cells and cells with India ink nuclei (single cells with deep black structure-less nuclei) were only observed in malignant atypical cells. The most consistent features in malignant atypical cells were: i) high nuclear and cytoplasmic (N/C) ratio ii) nuclear pleomorphism iii) nuclear margin irregularity iv) hyperchromasia and v) chromatin abnormalities
The present study emphasizes that nuclear features such as high N/C ratio, hyperchromasia and chromatin abnormalities are particularly useful for assessing the malignant atypical cells. Other cytological features such as comet cells and cells with India ink nuclei are also helpful for diagnosis but have limited value because they are less frequently seen.
Background:
The objective of the current study was to compare the diagnostic accuracy of 2 new real-time polymerase chain reaction-based urinary markers with each other and with urinary cytology, cystoscopy, and/or histology in patients being followed for non-muscle-invasive bladder cancer.
Methods:
A total of 487 patients were enrolled in the study. Patients were evaluated using voided urine cytology, the Xpert Bladder Cancer Monitor, the Bladder EpiCheck test, and white light cystoscopy.
Results:
The overall sensitivity was 27.17% for cytology, 64.13% for the Bladder EpiCheck test, and 66.3% for the Xpert Bladder Cancer Monitor. The overall specificity was 98.82% for cytology, 82.06% for the Bladder EpiCheck test, and 76.47% for the Xpert Bladder Cancer Monitor. The negative predictive value was very similar for the 3 tests at 83.56% for cytology, 89.42% for the Bladder EpiCheck test, and 89.35% for the Xpert Bladder Cancer Monitor. When combined, the Bladder EpiCheck test and Xpert Bladder Cancer Monitor detected overall 79.35% of the tumors: 70.37% in low-grade and 92.11% in high-grade tumors.
Conclusions:
The Xpert Bladder Cancer Monitor and Bladder EpiCheck test were found to perform very well in terms of sensitivity. Together, the 2 tests detected approximately 92.11% of high-grade tumors. Their specificity was high but could not reach the excellent value of cytology. The negative predictive value was the same for both tests and was higher than that for cytology, especially when the tests were used together (92.24%). These 2 new tests hold promise as urinary biomarkers. They may be used in combination to maximize sensitivity in a less invasive way, thereby reducing invasiveness in the follow-up of patients with non-muscle-invasive bladder cancer and decreasing discomfort for the patients as well as complications and costs.
Background
The objective of this study was to evaluate the diagnostic accuracy of the Bladder EpiCheck test in the follow‐up of patients with non–muscle‐invasive bladder cancer (NMIBC) and to compare it with the accuracy of urinary cytology, cystoscopy, and/or histology.
Methods
In total, 243 patients were enrolled in the current study. Patients were evaluated by voided urine cytology, by the Bladder EpiCheck test, and by white‐light cystoscopy.
Results
Overall sensitivity was 33.3% for cytology, 62.3% for Bladder EpiCheck, and 66.7% for the 2 tests combined. The sensitivity of cytology increased from 7.7% in low‐grade (LG) tumors to 66.6% in high‐grade (HG) tumors; whereas, for the Bladder EpiCheck test, the sensitivity was 46.1% in LG tumors and 83.3% in HG tumors. Combined cytology and Bladder EpiCheck testing yielded an overall sensitivity of 56.4% for LG tumors and 90% for HG tumors. Overall specificity was 98.6% for cytology, 86.3% for Bladder EpiCheck, and 85.6% for the 2 tests combined. The positive predictive value was 92% for cytology and 68.2% for Bladder EpiCheck. For the 2 tests combined, it was 68.6%. The negative predictive value was similar for the 2 tests: 75.8% for cytology, 82.9% for Bladder EpiCheck, and 84.5% for the 2 tests combined.
Conclusions
The sensitivity of the Bladder EpiCheck test was significantly higher than that of cytology. The test performed very well in terms of specificity but could not reach the high value of cytology. The positive predictive value was higher for Bladder EpiCheck, whereas the negative predictive value was approximately the same for both tests.
Purpose:
To compare blue light flexible cystoscopy (BLFC) with white light flexible cystoscopy (WLFC) in the detection of bladder cancer during surveillance.
Materials and methods:
Patients at high risk of recurrence received intravesical HAL before WLFC and randomization to BLFC. All suspicious lesions were documented. Patients with suspicious lesions were referred to the operating room (OR) for repeat WLC (white light) and BLC (blue light) cystoscopy. All suspected lesions underwent biopsy or resection and specimens were examined by an independent pathology consensus panel. PRIMARY ENDPOINT: the proportion of patients with histologically confirmed malignancy detected only with BLFC. Additional endpoints: false positive rate, detection of CIS, additional tumors detected only with BLC.
Results:
Following surveillance, 103/304 patients were referred: 63/103 had malignancy confirmed, including 26 with CIS. In 13/63 patients (20.6% (95% CI: 11.5%, 32.7%)) recurrence was seen only with BLFC (p<0.0001); five of these were confirmed as CIS. From the OR examination, 26/63 patients (41%) were confirmed as CIS: 9/26 (34.6% (95% CI: 17.2%, 55.7%)) were detected only with BLC (p<0.0001). BLC identified additional malignant lesions in 29/63 patients (46%). False positive rates were the same for WLC and BLC (9.1%). There were 12 AEs during surveillance, none of which were serious.
Conclusions:
Office-based blue light flexible cystoscopy significantly improves detection of patients with recurrent bladder cancer, and is safe when used for surveillance. Blue light cystoscopy in the OR significantly improves detection of CIS, and detects lesions that are missed with WLC.
Purpose:
To investigate the predictive factors of failure and to provide a resource consumption analysis in patients who underwent active surveillance (AS) for Non-Muscle Invasive Bladder Cancer (NMIBC).
Material & methods:
This is a prospective observational study, which monitored patients with a history of pathologically confirmed stage pTa (G1-G2) or pT1a (G2) NMIBC and recurrent small size and number tumors without haematuria and positive urine cytology. The primary end-point was the failure rate of AS. The assessment of failure-predictive variables and per-year "direct-hospital" resource consumption analysis were secondary outcomes. Descriptive statistical analysis and Cox regression test with univariable and multivariable analysis complemented data.
Results:
Out of 625 patients with NMIBC, 122 patients (overall 146 AS events) were included in the protocol. Fifty-nine (40.4%) events were deemed to require treatment after entering in AS. The median time on AS was 11 months (IQI 5-26). Currently, 76 patients (62.3%) are still under observation. In univariable analysis only time from first TUR to active surveillance start seems to be inversely associated with recurrence free survival (HR 0.99, 95% CI 0.98-1.00, p=0.027), while multivariable analysis showed association also with age at AS start (HR 0.97, 95% CI 0.94 - 1.00, p=0.031) and the size of the lesion at first TUR (HR 1.55, 95% CI 1.06 - 2.27, p=0.025). Specific annual resource consumption savings for each avoided TURBT was on average 1.378€ for each intervention avoided.
Conclusion:
AS might be a reasonable clinical and cost-effective strategy in patients presenting with small low-grade pTa/pT1a recurrent papillary bladder tumors.
The treatment of non muscle-invasive bladder cancer (NMIBC) encompasses a range of different procedures. Electromotive drug administration (EMDA) and chemo-hyperthermia (C-HT; Synergo) represent a minimally-invasive methods of intravesical instillation of therapeutic agents as mitomycin C (MMC). We selected patients with high grade NMIBC, BCG non responder, treated with EMDA/MMC and C-HT/MMC and we also examined the morphological changes in urine cytology samples.
During the period from 2012 to 2014, 110 patients with high grade NMIBC, BCG refractory were selected. All cases examined were classified according to The Paris System Classification as negative for high urothelial carcinoma (NHGUC) or atypical urothelial cells (AUC) with a mean of follow-up of 15 months and the cytological diagnosis were confirmed by histological biopsies.
In particular 50 patients were treated with EMDA/MMC and 60 patients underwent to C-HT/MMC. The morphological changes were evaluated in urine samples processed by Thin Prep method.
In the 50 patients treated with EMDA/MMC, 35 samples were classified as NHGUC and 15 cases were classified as AUC, while in the 60 patients treated with C-HT/MMC, 43 samples were NHGUC and 17 cases were classified AUC.
The increase of cellularity and nuclear size with the alteration of nuclear/cytoplasmatic ratio (N/C) were common in patients treated with EMDA/MMC and C-HT/MMC without clinical and histological evidence of recurrence of neoplasia. The hyperchromasia and irregular nuclear chromatin were rarely observed. The irregular nuclear membrane rarely identified in urine cytology after EMDA/MMC treatment, is a feature present in patients C-HT/MMC treated.
A handful of therapeutic procedures are used to treat malignancies of the urinary tract, most frequently intravesical immunotherapy or chemotherapy, but also neoadjuvant systemic chemotherapy. These treatment modalities produce morphological changes in the urothelium that can be mistaken for carcinoma; in particular, these therapies frequently mimic urothelial carcinoma in situ (CIS) urothelial dysplasia or true invasive neoplasia. Drugs such as mitomycin C used after transurethral resection of bladder tumour to reduce recurrences, bacillus Calmette–Guérin (BCG) intravesical immunotherapy to treat high-risk non-muscle-invasive bladder cancer and urothelial CIS and platin-based systemic chemotherapy to improve postcystectomy disease-specific survival are examples of therapy-related atypia seen in the urinary tract. To complicate the pathologist's life, a number of systemic drugs in use to treat other diseases, such cyclophosphamide, used to treat some autoimmune disorders or certain haematological malignancies or, in the case of anaesthetics, ketamine, used increasingly as an illegal recreational drug, may produce similarly relevant atypical changes in the urothelium, and therefore need to be differentiated from intraepithelial neoplasia. Other less frequent procedures, such as photodynamic and laser therapy or the newer gene therapy to treat urothelial neoplasia, remain experimental. An immunohistochemical approach to reactive urothelium versus carcinoma in situ using p53, cytokeratin 20 and CD44 is also valid in the post-therapy setting. The pathologist should be aware of these novelties, as he or she plays a crucial role in evaluating treatment efficacy, but at the same time needs to avoid misdiagnosing secondary atypia as intraepithelial neoplasia.
Rationale:
Numerous molecular urine markers for the diagnosis of bladder cancer have been developed and evaluated mostly in case-control settings through the past decades. However, despite all efforts none of them has been included into clinical decision-making and guideline recommendations until today. The aim of this retrospective longitudinal analysis was to investigate if a molecular marker might be able to replace cystoscopy as a primary examination in diagnosis and follow-up of patients with pTa grade 1-2 bladder cancer.
Materials and methods:
Totally 36 patients (32 men) with pTa grade 1-2 bladder cancer underwent 232 follow-up examinations including urine analysis, cytology, immunocytology (uCyt+), and urethrocystoscopy (UC). Mean age at study entry was 63 years. Patients were observed through a median follow-up interval of 3.8 years.
Results:
In summary, 47 Transurethral Resection of Bladder Tumors (TURB) procedures were indicated based upon a positive UC (44) or as re-TURB (3) and 33 tumors (plus 1 case of pTa G0) were histopathologically confirmed. Although uCyt+was positive in 12/13 primary tumors (92.3%), sensitivity dropped to 13/20 (65%) in tumor recurrence presumably because of their smaller size. Urine cytology had a sensitivity and a specificity of 30.3% and 94.9%, respectively, but did not improve the sensitivity of uCyt+alone. If UC was based upon a positive uCyt+test, 8/33 tumors (24.2%) would have been overlooked or diagnosed late. In contrast, 173 UCs (74%) would have been saved and 5 presumably unnecessary TURB procedures would not have been indicated.
Conclusions:
This longitudinal study suggests a potential of molecular urine tests in replacing cystoscopy in the follow-up of patients with pTa G1-2 bladder cancer. The use of additional markers might further improve sensitivity of urine testing. A prospective randomized study has been initiated to prospectively investigate the performance of a marker panel against UC.
Background:
More than 120000 people are diagnosed annually with bladder cancer in the 28 countries of the European Union (EU). With >40000 people dying of it each year, it is the sixth leading cause of cancer. However, to date, no systematic cost-of-illness study has assessed the economic impact of bladder cancer in the EU.
Objective:
To estimate the annual economic costs of bladder cancer in the EU for 2012.
Design, setting, and participants:
Country-specific cancer cost data were estimated using aggregate data on morbidity, mortality, and health care resource use, obtained from numerous international and national sources.
Outcome measurements and statistical analysis:
Health care costs were estimated from expenditures on primary, outpatient, emergency, and inpatient care, as well as medications. Costs of unpaid care and lost earnings due to morbidity and early death were estimated.
Results and limitations:
Bladder cancer cost the EU €4.9 billion in 2012, with health care accounting for €2.9 billion (59%) and representing 5% of total health care cancer costs. Bladder cancer accounted for 3% of all cancer costs in the EU (€143 billion) in 2012 and represented an annual health care cost of €57 per 10 EU citizens, with costs varying >10 times between the country with the lowest cost, Bulgaria (€8 for every 10 citizens), and highest cost, Luxembourg (€93). Productivity losses and informal care represented 23% and 18% of bladder cancer costs, respectively. The quality and availability of comparable cancer-related data across the EU need further improvement.
Conclusions:
Our results add to essential public health and policy intelligence for delivering affordable bladder cancer care systems and prioritising the allocation of public research funds.
Patient summary:
We looked at the economic costs of bladder cancer across the European Union (EU). We found bladder cancer to cost €4.9 billion in 2012, with health care accounting for €2.9 billion. Our study provides data that can be used to inform affordable cancer care in the EU.
Objective
We studied whether atypical, non-superficial urothelial cells (AUC) could be separated into new subcategories including AUC of undetermined significance' (AUC-US) and cannot exclude high grade'' (AUC-H) in order to help to standardize urine cytopathology reports, as it is widely accepted in the Bethesda system for gynaecological cytopathology. Methods
We investigated whether AUC-US and AUC-H, defined by distinctive cytological criteria, might be separated with statistical significance according to actual diagnosis and follow-up data. A series of 534 cyto-histological comparisons taken in 139 patients, including 221 AUC at various steps of their clinical history was studied. There were 513 (96.1%) postcystoscopy and 469 (87.8%) ThinPrep (R) liquid-based specimens (95.9% and 89.1% of AUC cases, respectively). Patients viewed between 1999 and 2011 had histological control in a 0- to 6-months delay and were followed-up during an additional 5.99.2 (0- to 56-) months period. ResultsThe 221 AUC represented 0.8-2% of the specimens viewed during the study period. Among AUC-H cases, 70 out of 185 (37.8%) matched with high-grade lesions, compared with 3 of 38 (8.3%) of AUC-US cases (P=0.0003). Conservatively treated patients with AUC-H more frequently developed high-grade lesions than those with AUC-US (54.1% versus 16.7%, P=0.0007) with a 17.6-months mean delay. Nuclear hyperchromasia, a nuclear to cytoplasm (N/C) ratio>0.7 and the combination of both were the more informative diagnostic criteria, all with P<0.01. Conclusion
We conclude that the new subcategories could help to standardize urine cytopathology reports and contribute to the patient's management, provided it is validated by multicentric studies.