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

Analiza proteinskih adukata kao biomarkera kratkotrajne izloženosti etilen oksidu i rezultati biomonitoringa

An accidental exposure of six workers to ethylene oxide (EO) provided the rationale for a biomonitoring and follow-up study, whose aim was to analyse protein adduct kinetics and examine the differentiation between accidental and environmental exposure, e.g., from tobacco smoke. For this purpose, the decrease in the concentration of the haemoglobin adduct N-2-hydroxyethylvaline (HEV) was followed during a fi ve-month period after the accident, together with N-2-cyanoethylvaline (CEV) and urinary cotinine, two well-established biomarkers for smoking. The follow-up study showed that EO adduct concentrations significantly increased after a short but presumably high exposure. Initial biomonitoring revealed HEV levels above 500 pmol g-1 globin in all cases, with a maximum of about 2,400 pmol g-1 globin. This compares to a German EKA value (exposure equivalent for carcinogenic substances) for a daily 8-h-exposure to 1 ppm EO of 90 μg L-1 blood (~3,900 pmol g-1 globin). The adduct levels dropped in accordance with the expected zero-order kinetics for a single exposure. After the five-month observation interval, the HEV concentrations in blood refl ected the individual background from tobacco smoking. The results of this study show that even a short exposure to ethylene oxide may result in a signifi cant rise in haemoglobin adduct levels. Although protein adducts and their occupational-medical assessment values are considered for long-term exposure surveillance, they can also be used for monitoring accidental exposures. In these cases, the calculation of daily ‘ppm-equivalents’ may provide a means for a comparison with the existing assessment values.U radu su prikazani rezultati biomonitoringa provedenog neposredno nakon akcidentalnog izlaganja šestorice radnika etilen oksidu i studije praćenja (follow up) provedene u cilju procjene kinetike razgradnje proteinskih adukata i utvrđivanja razlika nakon kratkotrajne izloženosti i izlaganja čimbenicima iz okoliša kao što je duhanski dim. U tu smo svrhu tijekom petomjesečnoga razdoblja nakon nezgode pratili smanjenje koncentracije hemoglobinskog adukta N-2-hidroksietilvalina usporedo s mjerenjem razina N-2-cijanoetilvalina i kotinina u mokraći, koji su pouzdani biomarkeri za dokazivanje pušenja duhana. Studija praćenja je pokazala da su koncentracije adukata etilen oksida značajno porasle nakon kratkotrajnoga izlaganja visokoj razini etilen oksida. U početnom biomonitoringu svih radnika izmjerene su razine N-2-hidroksietilvalina iznad 500 pmol g-1 globina, s maksimalnom vrijednošću od oko 2400 pmol g-1 globina. Ti su podaci usporedivi s vrijednostima njemačkih normi ekvivalenata izlaganja kancerogenim tvarima (EKA) od 90 μg L-1 krvi (~3900 pmol g-1 globina) kroz osmosatno dnevno izlaganje koncentraciji od 1 ppm etilen oksida. Razine adukata smanjile su se u skladu s očekivanom kinetikom nultoga reda za jednokratno izlaganje. Koncentracije N-2-hidroksietilvalina izmjerene u krvi radnika nakon petomjesečnoga praćenja mogu se povezati s njihovim osobnim pušačkim navikama. Rezultati toga istraživanja pokazuju da čak i kratkotrajna izloženost etilen oksidu može znatno povisiti razine adukata hemoglobina. Premda se u zdravstvenom nadzoru u okviru medicine rada proteinski adukti i njihove vrijednosti razmatraju u procjeni dugotrajnoga izlaganja, oni se mogu koristiti i za praćenje akcidentalnih izlaganja. U tim slučajevima izračun dnevnih vrijednosti (tzv. ppm-ekvivalenata) može poslužiti za usporedbu s postojećim procijenjenim vrijednostima

Rad u smjenama i rak - znanstvene spoznaje i praktične posljedice

In 2007, an expert Working Group convened by the IARC Monographs Programme concluded that shift work that involves circadian disruption is probably carcinogenic to humans (Group 2A). We scrutinised the epidemiological basis for this conclusion, with a focus on, but not limited to, breast and prostate cancers. We further considered practical consequences for shift workers in our industry against the background of new findings. We carried out a literature search including the epidemiological studies cited by IARC and newer available literature on shift work and cancer. Since the IARC assessment, eleven new studies have emerged, ten of which have already been published, with inconclusive results. Heterogeneity of exposure metrics and study outcomes and emphasis on positive but non-signifi cant results make it diffi cult to draw general conclusions. Also, several reviews and commentaries, which have been published meanwhile, came to equivocal results. Published evidence is widely seen as suggestive but inconclusive for an adverse association between night work and breast cancer, and limited and inconsistent for cancers at other sites and all cancers combined. At this point in time it can not be ruled out that shift work including night work may increase the risk for some cancers in those who perform it. However, shift schedules can be organised in ways that minimise the associated health risks, and the risks may be further reduced through the implementation of structured and sustained health promotion programs specifi cally tailored to the needs of shift workers.Stručna radna skupina, koju je okupio Program monografija Međunarodne agencije za istraživanje raka (eng. International Agency for Research on Cancer, krat. IARC), 2007. godine zaključila je da je rad u smjenama, koji uključuje prekid cirkadijurnoga ritma, najvjerojatnije kancerogen za ljude (skupina 2A). Procijenili smo epidemiološku osnovu takvoga zaključka i usredotočili se na rak dojke i rak prostate između ostalih malignih bolesti. Nadalje, razmatrali smo praktične posljedice koje rad u smjenama ima na radnike u kemijskoj kompaniji BASF u okvirima novih spoznaja na tom području. Istražili smo literaturu, uključujući i epidemiološka istraživanja studije koje citira IARC kao i noviju literaturu o povezanosti rada u smjenama i raku. Od zaključka IARC-a nastalo je jedanaest novih istraživanja, a deset ih je već objavljeno. Njihovi rezultati ipak ne dovode do konačnoga i jednoznačnoga zaključka. Heterogenost mjerenja izloženosti i ishoda istraživanja i naglasak na pozitivne, ali ne uvijek i značajne rezultate, otežavaju postavljanje općih zaključaka. Jednako tako u nekoliko nedavno objavljenih recenzija i komentara ne iznose se jednoznačni rezultati. Objavljeni znanstveno utemeljeni dokazi samo upućuju, ali ne dovode u očiglednu vezu noćni rad i rak dojke. Nadalje, ograničeni su i nedosljedni za malignome na drugim lokacijama u tijelu, kao i za sve malignome zajedno. U ovom trenutku nije moguće odbaciti hipotezu da smjenski rad (uključujući noćni rad) može povećati rizik nastanka određenih malignih bolesti. Međutim, raspored smjena se može organizirati na način da se opasnosti za zdravlje svedu na najmanju moguću mjeru. Rizici se također mogu dodatno smanjiti provedbom strukturiranih programa promicanja održivoga zdravlja koji bi bili posebno osmišljeni prema potrebama radnika

Considerations on Occupational Medical Surveillance in Employees Handling Nanoparticles

The use of engineered nanoparticles not only offers new technical perspectives but also raises questions regarding possible health aspects for producers and users. Nanoparticles may, just by virtue of their size, exert biological effects unrelated to the chemicals they are composed of. These considerations, and results from experimental animal studies suggesting that engineered nanomaterials may pose a health hazard to employees, all underscore the need for preventive measures. In this context, the need for, the feasibility, and the appropriateness of targeted occupational medical surveillance are currently subject to debate. Methods We compared established concepts for the development of occupational medical surveillance programs to existing knowledge on exposures in workplaces and on health effects of nanomaterials. Results A variety of potential effect parameters have been proposed for medical surveillance of exposed personnel, such as heart rate variability, blood-clotting parameters, pro-inflammatory cytokines, etc. None of these parameters are specific, most are not validated as individual health risk indicators, and some require sophisticated equipment not routinely available. Against this background, BASF currently puts specific weight on risk assessment and exposure control in workplaces. Particle emissions are primarily avoided by manufacturing in closed systems or using effective extraction systems. Appropriate personal protective equipment has been defined for such operations where an exposure potential cannot be excluded. Conclusions While there is presently no evidence-based foundation for “nano-specific” occupational medical screening, one can perform general medical screening with methods targeted at some of the health outcomes under discussion. The results of such examinations can provide a basis for future epidemiologic studies. Therefore, the establishment of exposure registries to enable the conduct of large-scale multi-centric prospective epidemiologic studies is recommended