Michael Nasterlack

Nuclear matrix protein-22: a prospective evaluation in a population at risk for bladder cancer. Results from the UroScreen study

Study Type – Diagnostic (non‐consecutive cohort without consistently applied reference standard)

Performance of Survivin mRNA as a Biomarker for Bladder Cancer in the Prospective Study UroScreen

Background Urinary biomarkers have the potential to improve the early detection of bladder cancer. Most of the various known markers, however, have only been evaluated in studies with cross-sectional design. For proper validation a longitudinal design would be preferable. We used the prospective study UroScreen to evaluate survivin, a potential biomarker that has multiple functions in carcinogenesis. Methods/Results Survivin was analyzed in 5,716 urine samples from 1,540 chemical workers previously exposed to aromatic amines. The workers participated in a surveillance program with yearly examinations between 2003 and 2010. RNA was extracted from urinary cells and survivin was determined by Real-Time PCR. During the study, 19 bladder tumors were detected. Multivariate generalized estimation equation (GEE) models showed that β-actin, representing RNA yield and quality, had the strongest influence on survivin positivity. Inflammation, hematuria and smoking did not confound the results. Survivin had a sensitivity of 21.1% for all and 36.4% for high-grade tumors. Specificity was 97.5%, the positive predictive value (PPV) 9.5%, and the negative predictive value (NPV) 99.0%. Conclusions In this prospective and so far largest study on survivin, the marker showed a good NPV and specificity but a low PPV and sensitivity. This was partly due to the low number of cases, which limits the validity of the results. Compliance, urine quality, problems with the assay, and mRNA stability influenced the performance of survivin. However, most issues could be addressed with a more reliable assay in the future. One important finding is that survivin was not influenced by confounders like inflammation and exhibited a relatively low number of false-positives. Therefore, despite the low sensitivity, survivin may still be considered as a component of a multimarker panel.

Chromosomal instability and bladder cancer: the UroVysion (TM) test in the UroScreen study

UroVysion™ is a multicolour fluorescence in situ hybridisation assay that detects DNA gain at chromosomes 3, 7 and 17 and loss at the 9p21 locus in exfoliated urothelial cells. This cell‐based test is time‐consuming and costly compared with voided urine cytology or other molecular markers for the early detection of bladder cancer. We determined copy number changes at chromosomes 3, 7 and 17 and at the 9p21 locus with UroVysion in a prospective screening study among chemical workers. Strong correlations between DNA gains yield a similar performance in detecting bladder cancer with just one of the probes for chromosomes 3, 7 or 17 instead of all, supporting the development of a simpler and cheaper assay.

Health and safety protection for chemical industry employees in a rotating shift system: program design and acute injury and illness experience at work.

Objectives: To describe a comprehensive health protection program for rotating shift employees and evaluate the program effectiveness in injury and illness prevention. Methods: For 14,128 shift and 17,218 day wage employees, occupational medical records were linked to job assignment records and studied over an 11-year period. Results: Between 1995 and 2005, initiatives directed to shift employees contributed to their 59% and 100% greater participation in medical examinations and health seminar days, respectively, compared to day wage employees. Injury rates declined over time and with increasing employee age and were not elevated among rotating shift compared to day wage employees. Clinic visit rates for acute illnesses were generally higher for day than shift work employees. Conclusion: Coupling of active medical monitoring with additional health and safety initiatives appears to mitigate the expected adverse physiological and psychosocial stresses of shift work.

Occupational stress perception and its potential impact on work ability

OBJECTIVE To examine perceived stress across employees with different occupational status, to investigate the impact of stress on work ability and to derive conclusions regarding health promotion activities. PARTICIPANTS AND METHODS A comprehensive survey combining questionnaire and medical examination was offered in one division in BASF Ludwigshafen. Among 867 voluntary participants, 653 returned complete questionnaires. The questions were directed at perception of safety at the workplace, self-rated health status, frequency of stress symptoms, unrealistic job demands, time pressure and maladjustment of work life balance. The outcome of interest was self-estimated health measured by the Work Ability Index (WAI). RESULTS Occupational stressors were perceived differently across occupational status groups. Frontline operators had more health concerns due to workplace conditions, while professional and managerial staff reported higher frequencies of perceived tension, time pressure, and maladjustment of work life balance. After adjustment for occupational status, demographic and lifestyle factors, perceived stress was associated with a modest to strong decline in WAI scores. CONCLUSION While perceived occupational stress had an apparent impact on WAI, and WAI has been demonstrated to be predictive of early retirement, more intensive and employee group-specific stress management interventions are being implemented beyond traditional strategies of routine occupational medical surveillance.

Prospective evaluation of fluorescence-in situ-hybridization to detect bladder cancer: Results from the UroScreen-Study

BACKGROUND UroScreen is a prospective study for early diagnosis of bladder cancer (BC) in chemical workers formerly exposed to aromatic amines, aimed to assess the performance of molecular tumor markers in comparison with urinary cytology. Here we evaluate the cancer-predictive values and potential effect modifiers of fluorescence-in-situ-hybridization (FISH). SUBJECTS AND METHODS A FISH test was performed in 7,091 urine samples from 1,609 subjects between 2007 and 2010. Cystoscopy was recommended in case of positive or suspicious findings. Logistic regression models were applied to estimate the influence of potential test confounders like urinary creatinine and hematuria on detecting BC. Receiver operating characteristic (ROC) curves for FISH were adjusted for test confounders. Cancer-predictive values were calculated from test results in the last sample before diagnosis. RESULTS Histopathology revealed 16 incidental BCs and 5 recurrent tumors in 20 study participants. FISH was positive in 9 BC cases of which 7 were high grade. Cytology detected 8 tumors. FISH overlapped with cytology in 7 cases. Sensitivity was 45.0% and PPV (positive predictive value) was 16.4% in all and 53.85% and 13.21% in high-grade tumors. Specificity and negative predictive value (NPV) were 96.97% and 99.26% in all bladder tumors. BC detected during UroScreen was associated with an odds ratio (OR) of 6.88 (95% CI 1.72-27.44) for positive FISH and with an OR of 8.81 (95% CI 1.41-54.96) for gross hematuria. The adjusted area under the curve was 0.77 (95% CI 0.62-0.92) for all and for high-grade lesions (0.85; 95% CI 0.69-1.00). CONCLUSIONS FISH showed a performance in detecting bladder cancer comparable to cytology but a larger number or false-positive results. It remains to be investigated if chromosomal instability can be detected earlier than morphologic changes of exfoliated bladder cancer cells.

Chromosomal alterations in exfoliated urothelial cells from bladder cancer cases and healthy men: a prospective screening study

BackgroundChromosomal instability in exfoliated urothelial cells has been associated with the development of bladder cancer. Here, we analyzed the accumulation of copy number variations (CNVs) using fluorescence in situ hybridization in cancer cases and explored factors associated with the detection of CNVs in tumor-free men.MethodsThe prospective UroScreen study was designed to investigate the performance of UroVysion™ and other tumor tests for the early detection of bladder cancer in chemical workers from 2003–2010. We analyzed a database compiling CNVs of chromosomes 3, 7, and 17 and at 9p21 that were detected in 191,434 exfoliated urothelial cells from 1,595 men. We assessed the accumulation of CNVs in 1,400 cells isolated from serial samples that were collected from 18 cancer cases up to the time of diagnosis. A generalized estimating equation model was applied to evaluate the influence of age, smoking, and urine status on CNVs in cells from tumor-free men.ResultsTetrasomy of chromosomes 3, 7 and 17, and DNA loss at 9p21 were the most frequently observed forms of CNV. In bladder cancer cases, we observed an accumulation of CNVs that started approximately three years before diagnosis. During the year prior to diagnosis, cells from men with high-grade bladder cancer accumulated more CNVs than those obtained from cases with low-grade cancer (CNV < 2: 7.5% vs. 1.1%, CNV > 2: 16-17% vs. 9-11%). About 1% of cells from tumor-free men showed polysomy of chromosomes 3, 7, or 17 or DNA loss at 9p21. Men aged ≥50 years had 1.3-fold more cells with CNVs than younger men; however, we observed no further age-related accumulation of CNVs in tumor-free men. Significantly more cells with CNVs were detected in samples with low creatinine concentrations.ConclusionsWe found an accumulation of CNVs during the development of bladder cancer starting three years before diagnosis, with more altered cells identified in high-grade tumors. Also, a small fraction of cells with CNVs were exfoliated into urine of tumor-free men, mainly exhibiting tetraploidy or DNA loss at 9p21. Whether these cells are preferentially cleared from the urothelium or are artifacts needs further exploration.

Role of medical surveillance in risk management.

Objective: Occupational physicians face increasing pressure by health authorities, employers, and employees to provide practical, targeted, and meaningful medical surveillance to workers handling nanoparticles. Methods: On the basis of experience and literature review, examples were identified for successful medical surveillance activities. Consideration was given to the respective context in which they provide benefit, and whether these examples may be extrapolated to the present situation with nanoparticles. Results: Occupational medical surveillance based on existing knowledge of hazards and potentially associated health effects is both feasible and useful. In the absence of sufficient knowledge, results from surveillance programs may still provide new insights into exposure–response relationships or help to identify new hazards. In some situations, however, medical surveillance may also produce harm. Conclusions: Medical surveillance provides benefits on the individual, company, and societal level, provided that it is planned and performed with its limitations in mind.

IS HEALTH, MEASURED BY WORK ABILITY INDEX, AFFECTED BY 12-HOUR ROTATING SHIFT SCHEDULES?

Two forms of continuously forward rotating 12-h shift schedules exist at BASFs Ludwigshafen site. These shift schedules were compared with a daytime working system to investigate potential differential effects on employees health status assessed with the Work Ability Index (WAI). In the 3 × 12 system, a 12-h day shift is followed 24 h later by a 12-h night shift, and after a day off the employee returns to the day shift. The 4 × 12 schedule follows the same pattern except that there are 2 days off between the night and next day shift. A total of 924 participants (278 3 × 12 and 321 4 × 12 shiftworkers and 325 day workers) were recruited. A self-administered questionnaire was used to obtain information about shiftwork schedule, demographic characteristics, and lifestyle and social factors, and the WAI was applied. The outcomes of interest were the WAI sum score and its seven dimensions. In examining the relationship with the WAI categories, a Proportional Odds Model (POM) was used to identify the potential determinants. Logistic regression models were used to estimate the impact of age on single dimensions of WAI after adjustment for potential confounding factors. Increasing age and obesity (BMI ≥ 30) were the only significant determinants of poorer WAI. Although a positive association was found linking the second WAI dimension (work ability in relation to job demands) with age, an inverse association was demonstrated consistently between age and the third and fourth WAI dimensions, i.e., number of diagnosed diseases and estimated work impairment due to disease, after adjustment for potential confounders. The age-dependency was moderate overall, but seemed to be stronger among shift- than day workers, although this difference did not reach statistical significance. There was no significant differential impact of the working time systems on the WAI sum score or on the individual WAI dimensions. Thus, there is no indication of an excessive adverse health impact of these shift schedules compared to day work, to the extent that health can be measured by the WAI. (Author correspondence: mei.yong@basf.com)

Hepatotoxic effects of solvent exposure around permissible limits and alcohol consumption in printers over a 4-year period

Two field studies were carried out in 1987 and 1991 in order to evaluate the effect of chronic exposure to solvent mixture on liver enzyme patterns. The results in 33 workers who participated in both studies and had complete sets of data are presented. The magnitude of chemical workload was assessed by means of ambient air monitoring and biomonitoring of solvent concentrations. Alanine aminotransferase, aspartate aminotransferase and γ-glutamyl transpeptidase were used as markers for possible biological effects. No dose-response relationship was found between exposure to complex solvent mixtures in ambient air, reaching and sometimes even exceeding the threshold limit values for mixtures, and liver enzyme activities. Self-reported alcohol intake was the only factor identified as statistically related to increased liver enzyme activity.